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Sample records for acute cerebellar ataxia

  1. Acute cerebellar ataxia

    MedlinePlus

    Cerebellar ataxia; Ataxia - acute cerebellar; Cerebellitis; Post-varicella acute cerebellar ataxia; PVACA ... Acute cerebellar ataxia in children, especially younger than age 3, may occur several weeks after an illness caused by a virus. ...

  2. [Residual cerebellar ataxia following acute phenytoin intoxication].

    PubMed

    Awada, A; Amene, P; al Jumah, M; al Beladi, K

    1999-04-01

    A 30-year-old man was given high doses of phenytoin together with 4 antituberculous drugs for a seizure associated with a probable brain tuberculoma. He developed hepatic toxicity and his serum phenytoin reached the high level of 298 mumol/l (therapeutic range 40-79 mumol/l). All drugs were stopped and the biological parameters returned progressively to normal over the next 15 days. However, he remained with a cerebellar axial syndrome and was still severely ataxic 2 months later. Brain CT and MRI showed mild cerebellar atrophy. This case and the few other published ones, together with some recent experimental data, show that high doses of phenytoin can be toxic to the cerebellar cortical cells. The rarity of similar cases, while millions of epileptics are under phenytoin treatment, would however suggest that individual susceptibility may play a role in this toxicity. PMID:10367328

  3. Walking unsteadily: a case of acute cerebellar ataxia.

    PubMed

    Simonetta, Federico; Christou, Fotini; Vandoni, Riccardo E; Nierle, Thomas

    2013-01-01

    Acute cerebellar ataxia is an infrequent neurological syndrome in adults especially if complicated by additional neurological deficits. We report the case of a 69-year-old woman who presented with sudden onset of left facial droop, dizziness, slurred speech and impaired balance. Her medical history included paroxysmal atrial fibrillation and a sigmoid diverticular abscess treated with ciprofloxacin and metronidazole. Cranial computed tomographic angiography and MRI showed no signs of acute ischaemia or haemorrhage but demonstrated symmetrically distributed lesions in the cerebellar dentate nuclei. A diagnosis of metronidazole-induced encephalopathy was suspected. Metronidazole was stopped and the patient completely recovered. Metronidazole is a commonly prescribed medication. Clinicians should be aware of the clinical and radiological presentation of metronidazole-induced encephalopathy so that this serious but completely reversible condition can be promptly diagnosed. PMID:23283615

  4. Post-Plasmodium vivax malaria cerebellar ataxia and optic neuritis: A new form of delayed cerebellar ataxia or cerebellar variant of acute disseminated encephalomyelitis?

    PubMed Central

    Kasundra, Gaurav M.; Bhargava, Amita Narendra; Bhushan, Bharat; Shubhakaran, Khichar; Sood, Isha

    2015-01-01

    Acute disseminated encephalomyelitis (ADEM) is commonly seen after viral and bacterial infections, immunization, and Plasmodium falciparum (PF) malaria. Plasmodium vivax (PV) rarely causes ADEM. We report a 14-year-old female patient who presented with acute onset bilateral cerebellar ataxia and optic neuritis, 2 weeks after recovery from PV. Magnetic resonance imaging showed bilateral cerebellar hyperintensities suggestive of ADEM. No specific viral etiology was found on cerebrospinal fluid examination. Patient responded well to treatment without any sequelae. Thus, PV too is an important cause of ADEM along with PF. Two of the previously reported cases had co-infection with falciparum malaria. The only other two reported cases, as also this patient, are from Asia. A geographical or racial predisposition needs to be evaluated. Also, a possibility of post-PV delayed cerebellar ataxia, which is classically described post-PF infection, may be considered as it may be clinically, radiologically, and prognostically indistinguishable from a milder presentation of ADEM. PMID:25878748

  5. A case of midbrain infarction with acute bilateral cerebellar ataxia visualized by diffusion tensor imaging.

    PubMed

    Maya, Yuka; Kawabori, Masahito; Oura, Daisuke; Niiya, Yoshimasa; Iwasaki, Motoyuki; Mabuchi, Shoji

    2016-08-31

    An 85-year-old woman with hypertension was admitted with a sudden onset of gait disturbance and dysarthria. On admission, the patient showed severe bilateral cerebellar ataxia with moderate right medial longitudinal fasciculus (MLF) syndrome. Magnetic resonance (MR) imaging showed an acute infarction in the lower and medial part of midbrain. Diffusion tensor imaging (DTI) started from both cerebellar peduncles revealed that the lesion of the acute infarction matched the decussation of superior cerebellar peduncle where crossing of tract was seen and a part of its tract was interrupted at the site. Interruption of the cerebellum red nuclear path at the medial part of midbrain was considered to be the reason for bilateral cerebellar ataxia and visualization of cerebellum red nuclear path by DTI can give better understanding of the neurological symptom. PMID:27477572

  6. Autosomal recessive cerebellar ataxias

    PubMed Central

    Palau, Francesc; Espinós, Carmen

    2006-01-01

    Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2–4/100,000), ataxia-telangiectasia (1–2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2). Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning), electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia. PMID:17112370

  7. Barr humbug: acute cerebellar ataxia due to Epstein-Barr virus.

    PubMed

    Davies, Benjamin; Machin, Nicholas; Lavin, Timothy; Ul Haq, Mian Ayaz

    2016-01-01

    Epstein-Barr virus (EBV) infection is associated with neurological sequellae, but rarely there is acute cerebellar ataxia (ACA) in an adult. We present a novel case of a 26-year-old man, who presented with ACA. He had normal MRI and CSF analysis. Serum testing confirmed active EBV. A course of oral prednisolone 1 mg/kg for 4 weeks, with a subsequent taper was started. He made a full recovery within 3 weeks of presentation. PMID:27558189

  8. Metronidazole induced cerebellar ataxia

    PubMed Central

    Hari, Aditya; Srikanth, B. Akshaya; Lakshmi, G. Sriranga

    2013-01-01

    Metronidazole is a widely used antimicrobial usually prescribed by many specialist doctors for a short duration of 10-15 days. Prolonged use of metronidazole is rare. The present case is of a patient who used the drug for 4 months and developed peripheral neuropathy, convulsions, and cerebellar ataxia. He was treated with diazepam and levetiracetam. The patient recovered completely following discontinuation of metronidazole. PMID:23833378

  9. Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias.

    PubMed

    Mitoma, Hiroshi; Adhikari, Keya; Aeschlimann, Daniel; Chattopadhyay, Partha; Hadjivassiliou, Marios; Hampe, Christiane S; Honnorat, Jérôme; Joubert, Bastien; Kakei, Shinji; Lee, Jongho; Manto, Mario; Matsunaga, Akiko; Mizusawa, Hidehiro; Nanri, Kazunori; Shanmugarajah, Priya; Yoneda, Makoto; Yuki, Nobuhiro

    2016-04-01

    In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto's encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Miller Fisher syndrome, ataxia associated with systemic lupus erythematosus, and paraneoplastic cerebellar degeneration. Humoral mechanisms, cell-mediated immunity, inflammation, and vascular injuries contribute to the cerebellar deficits in immune-mediated cerebellar ataxias. PMID:25823827

  10. Cerebellar ataxia as presenting feature of hypothyroidism.

    PubMed

    Kotwal, Suman Kumar; Kotwal, Shalija; Gupta, Rohan; Singh, Jang Bhadur; Mahajan, Annil

    2016-04-01

    Symptoms and signs of the hypothyroidism vary in relation to the magnitude and acuteness of the thyroid hormone deficiency. The usual clinical features are constipation, fatigue, cold intolerance and weight gain. Rarely it can present with neurologic problems like reversible cerebellar ataxia, dementia, peripheral neuropathy, psychosis and coma. Hypothyroidism should be suspected in all cases of ataxia, as it is easily treatable. A 40 year-old male presented with the history facial puffiness, hoarseness of voice and gait-ataxia. Investigations revealed frank primary hypothyroidism. Anti-TPO antibody was positive. Thyroxine was started and patient improved completely within eight weeks. Hypothyroidism can present with ataxia as presenting feature. Hypothyroidism should be considered in all cases of cerebellar ataxia as it is a reversible cause of ataxia. PMID:26886095

  11. Ataxias and Cerebellar or Spinocerebellar Degeneration

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Ataxias and Cerebellar or Spinocerebellar Degeneration Information Page Synonym(s): ... Publications and Information Publicaciones en Español What are Ataxias and Cerebellar or Spinocerebellar Degeneration? Ataxia often occurs ...

  12. [Clinical manifestations of cerebellar ataxias].

    PubMed

    Abdulkerimov, Kh T

    2003-01-01

    The analysis of clinical manifestations and focal symptoms in 18 patients with cerebellar ataxia (CA) has shown that these markers are not sufficient for making an accurate diagnosis in all CA cases. It is recommended to verify an ataxia form with objective methods, computed stabilography, in particular. PMID:12958853

  13. Speech Prosody in Cerebellar Ataxia

    ERIC Educational Resources Information Center

    Casper, Maureen A.; Raphael, Lawrence J.; Harris, Katherine S.; Geibel, Jennifer M.

    2007-01-01

    Persons with cerebellar ataxia exhibit changes in physical coordination and speech and voice production. Previously, these alterations of speech and voice production were described primarily via perceptual coordinates. In this study, the spatial-temporal properties of syllable production were examined in 12 speakers, six of whom were healthy…

  14. Speech prosody in cerebellar ataxia.

    PubMed

    Casper, Maureen A; Raphael, Lawrence J; Harris, Katherine S; Geibel, Jennifer M

    2007-01-01

    Persons with cerebellar ataxia exhibit changes in physical coordination and speech and voice production. Previously, these alterations of speech and voice production were described primarily via perceptual coordinates. In this study, the spatial-temporal properties of syllable production were examined in 12 speakers, six of whom were healthy speakers and six with ataxia. The speaking task was designed to elicit six different prosodic conditions and four contrastive prosodic events. Distinct prosodic patterns were elicited by the examiner for cerebellar patients and healthy speakers. These utterances were digitally recorded and analysed acoustically and statistically. The healthy speakers showed statistically significant differences among all four prosodic contrasts. The normal model described by the prosodic contrasts provided a sensitive index of cerebellar pathology with quantitative acoustic analyses. A significant interaction between subject groups and prosodic conditions revealed a compromised prosody in cerebellar patients. Significant differences were found for durational parameters, F0 and formant frequencies. The cerebellar speakers demonstrated different patterns of syllable lengthening and syllable reduction from that of the healthy speakers. PMID:17613097

  15. Hereditary Cerebellar Ataxias: A Korean Perspective

    PubMed Central

    Kim, Ji Sun; Cho, Jin Whan

    2015-01-01

    Hereditary ataxia is a heterogeneous disorder characterized by progressive ataxia combined with/without peripheral neuropathy, extrapyramidal symptoms, pyramidal symptoms, seizure, and multiple systematic involvements. More than 35 autosomal dominant cerebellar ataxias have been designated as spinocerebellar ataxia, and there are 55 recessive ataxias that have not been named systematically. Conducting genetic sequencing to confirm a diagnosis is difficult due to the large amount of subtypes with phenotypic overlap. The prevalence of hereditary ataxia can vary among countries, and estimations of prevalence and subtype frequencies are necessary for planning a diagnostic strategy in a specific population. This review covers the various hereditary ataxias reported in the Korean population with a focus on the prevalence and subtype frequencies as the clinical characteristics of the various subtypes. PMID:26090078

  16. An update on Spino-cerebellar ataxias

    PubMed Central

    Mondal, Banashree; Paul, Pritikanta; Paul, Madhuparna; Kumar, Hrishikesh

    2013-01-01

    The dominantly inherited ataxias, also known as Spino-cerebellar ataxias (SCAs), are rapidly expanding entities. New mutations are being identified at remarkable regularity. Recent awareness of molecular abnormalities in SCAs has addressed some of the long sought questions, but gaps in knowledge still exist. Three major categories of SCAs, according to molecular mechanisms, have evolved over recent few years: Polyglutamate expansion ataxia, non-coding zone repeat ataxia, and ataxia due to conventional mutation. Using the fulcrum of these mechanisms, the article provides an update of SCAs. Shared and specific clinical features, genetic abnormalities, and possible links between molecular abnormalities and cerebellar degeneration have been discussed. Emphasis has been placed on the mechanisms of polyglutamate toxicity. PMID:24101804

  17. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    MedlinePlus

    ... Health Conditions ARCA1 autosomal recessive cerebellar ataxia type 1 Enable Javascript to view the expand/collapse boxes. ... Close All Description Autosomal recessive cerebellar ataxia type 1 ( ARCA1 ) is a condition characterized by progressive problems ...

  18. Speech prosody in cerebellar ataxia

    NASA Astrophysics Data System (ADS)

    Casper, Maureen

    The present study sought an acoustic signature for the speech disturbance recognized in cerebellar degeneration. Magnetic resonance imaging was used for a radiological rating of cerebellar involvement in six cerebellar ataxic dysarthric speakers. Acoustic measures of the [pap] syllables in contrastive prosodic conditions and of normal vs. brain-damaged patients were used to further our understanding both of the speech degeneration that accompanies cerebellar pathology and of speech motor control and movement in general. Pair-wise comparisons of the prosodic conditions within the normal group showed statistically significant differences for four prosodic contrasts. For three of the four contrasts analyzed, the normal speakers showed both longer durations and higher formant and fundamental frequency values in the more prominent first condition of the contrast. The acoustic measures of the normal prosodic contrast values were then used as a model to measure the degree of speech deterioration for individual cerebellar subjects. This estimate of speech deterioration as determined by individual differences between cerebellar and normal subjects' acoustic values of the four prosodic contrasts was used in correlation analyses with MRI ratings. Moderate correlations between speech deterioration and cerebellar atrophy were found in the measures of syllable duration and f0. A strong negative correlation was found for F1. Moreover, the normal model presented by these acoustic data allows for a description of the flexibility of task- oriented behavior in normal speech motor control. These data challenge spatio-temporal theory which explains movement as an artifact of time wherein longer durations predict more extreme movements and give further evidence for gestural internal dynamics of movement in which time emerges from articulatory events rather than dictating those events. This model provides a sensitive index of cerebellar pathology with quantitative acoustic

  19. Cerebellar ataxia as a possible complication of babesiosis in two dogs.

    PubMed

    Jacobson, L S

    1994-09-01

    A 6-month-old Miniature Doberman Pinscher was presented with inappetance and cerebellar signs. Babesia canis organisms were found on a capillary bloodsmear. The cerebellar signs resolved rapidly following treatment with diminazene aceturate. A 7-month-old Siberian Husky developed cerebellar signs, blindness and quadriparesis 9 d after presentation with clinical signs typical of uncomplicated canine babesiosis. The dog responded favourably to treatment with prednisolone. Both acute and delayed cerebellar ataxia have been associated with malaria in humans. The clinical signs shown by these dogs were similar to those reported for malaria in humans. Cerebellar ataxia should be considered a possible complication of canine babesiosis. PMID:7595921

  20. Ethanol-Induced Cerebellar Ataxia: Cellular and Molecular Mechanisms.

    PubMed

    Dar, M Saeed

    2015-08-01

    The cerebellum is an important target of ethanol toxicity given that cerebellar ataxia is the most consistent physical manifestation of acute ethanol consumption. Despite the significance of the cerebellum in ethanol-induced cerebellar ataxia (EICA), the cellular and molecular mechanisms underlying EICA are incompletely understood. However, two important findings have shed greater light on this phenomenon. First, ethanol-induced blockade of cerebellar adenosine uptake in rodent models points to a role for adenosinergic A1 modulation of EICA. Second, the consistent observation that intracerebellar administration of nicotine in mice leads to antagonism of EICA provides evidence for a critical role of cerebellar nitric oxide (NO) in EICA reversal. Based on these two important findings, this review discusses the potential molecular events at two key synaptic sites (mossy fiber-granule cell-Golgi cell (MGG synaptic site) and granule cell parallel fiber-Purkinje cell (GPP synaptic site) that lead to EICA. Specifically, ethanol-induced neuronal NOS inhibition at the MGG synaptic site acts as a critical trigger for Golgi cell activation which leads to granule cell deafferentation. Concurrently, ethanol-induced inhibition of adenosine uptake at the GPP synaptic site produces adenosine accumulation which decreases glutamate release and leads to the profound activation of Purkinje cells (PCs). These molecular events at the MGG and GPP synaptic sites are mutually reinforcing and lead to cerebellar dysfunction, decreased excitatory output of deep cerebellar nuclei, and EICA. The critical importance of PCs as the sole output of the cerebellar cortex suggests normalization of PC function could have important therapeutic implications. PMID:25578036

  1. Acute Ataxia in Childhood: 11-Year Experience at a Major Pediatric Neurology Referral Center.

    PubMed

    Thakkar, Kavita; Maricich, Stephen M; Alper, Gulay

    2016-08-01

    We categorized the causes of acute ataxia in the pediatric population-referred to the Division of Neurology-at a large, urban pediatric medical center. Of the 120 cases identified over the past 11 years, post-infectious cerebellar ataxia was the most commonly diagnosed (59%), followed by drug intoxication, opsoclonus-myoclonus ataxia syndrome, episodic ataxia, acute cerebellitis, cerebellar stroke, ADEM, meningitis, cerebral vein thrombosis, Leigh's disease, Miller-Fisher syndrome, and concussion. Among the patients with post-infectious cerebellar ataxia, 85% were 1-6 years old and all had a history of antecedent viral illness. CSF pleocytosis was present in 40% of patients; all had normal brain MRIs. The majority (91%) recovered within 30 days. We conclude that post-infectious cerebellar ataxia remains the most common cause of acute ataxia in childhood and that it carries a good prognosis. We also differentiate acute post-infectious cerebellar ataxia from other causes with similar presentations. PMID:27071467

  2. The physiological basis of therapies for cerebellar ataxias.

    PubMed

    Mitoma, Hiroshi; Manto, Mario

    2016-09-01

    Cerebellar ataxias represent a group of heterogeneous disorders impacting on activities of daily living and quality of life. Various therapies have been proposed to improve symptoms in cerebellar ataxias. This review examines the physiological background of the various treatments currently administered worldwide. We analyze the mechanisms of action of drugs with a focus on aminopyridines and other antiataxic medications, of noninvasive cerebellar stimulation, and of motor rehabilitation. Considering the cerebellum as a controller, we propose the novel concept of 'restorable stage'. Because of its unique anatomical architecture and its diffuse connectivity in particular with the cerebral cortex, keeping in mind the anatomophysiology of the cerebellar circuitry is a necessary step to understand the rationale of therapies of cerebellar ataxias and develop novel therapeutic tools. PMID:27582895

  3. The physiological basis of therapies for cerebellar ataxias

    PubMed Central

    Mitoma, Hiroshi; Manto, Mario

    2016-01-01

    Cerebellar ataxias represent a group of heterogeneous disorders impacting on activities of daily living and quality of life. Various therapies have been proposed to improve symptoms in cerebellar ataxias. This review examines the physiological background of the various treatments currently administered worldwide. We analyze the mechanisms of action of drugs with a focus on aminopyridines and other antiataxic medications, of noninvasive cerebellar stimulation, and of motor rehabilitation. Considering the cerebellum as a controller, we propose the novel concept of ‘restorable stage’. Because of its unique anatomical architecture and its diffuse connectivity in particular with the cerebral cortex, keeping in mind the anatomophysiology of the cerebellar circuitry is a necessary step to understand the rationale of therapies of cerebellar ataxias and develop novel therapeutic tools. PMID:27582895

  4. [Familial cerebellar ataxia: clinical, radiological and electrophysiological findings].

    PubMed

    Gajkowski, K; Rysz, A; Walecki, J; Bojakowski, J

    1988-01-01

    A family with cerebellar ataxia of late onset occurring in four generations was observed. Neurological abnormalities included signs of cerebellar ataxia, pyramidal tract damage and damage to the peripheral motor neuron. Computerized tomography demonstrated in five out of six studied patients an image suggesting olivo-ponto-cerebellar atrophy. In the cerebellar structures, brainstem and cerebral hemispheres evidence of atrophy was detected. No correlation was demonstrated between the intensity of the clinical signs and the progression of changes in CT image. Electrophysiological investigations demonstrated changes compatible with damage to the motor and sensory fibres in the peripheral nerves and signs suggesting damage to the spinal motor neurons and pyramidal tract. These observations confirm the multilevel development of the process. The use of similar diagnostic methods will permit a more accurate classification of cerebellar ataxia and obtaining of better information for prognostication of individual cases. PMID:3164096

  5. Asymptomatic cerebellar atrophy after acute enteroviral encephalitis.

    PubMed

    Vitaszil, Edina; Kamondi, Anita; Csillik, Anita; Velkey, Imre; Szirmai, Imre

    2005-07-01

    We report on a 13-year-old male who had acute enteroviral encephalitis causing cerebellar symptoms at the age of 10 years. Magnetic resonance imaging (MRI) showed no abnormalities. Clinically he appeared to be recovered completely after 6 months. Twenty-three months after the recovery, MRI was performed because he presented with slight lower-limb and truncal ataxia experienced as lack of foot coordination while playing football or riding a bicycle. MRI demonstrated severe cerebellar atrophy. Clinically he recovered completely in 10 days. Only sophisticated electrophysiological methods revealed cerebellar dysfunction. The case provides evidence for the plasticity of cerebellar regulatory structures involved in the coordination of fine movements. It seems that in childhood the slow, isolated disintegration of cerebellar systems can be compensated for by upper thalamic or telencephalic connections, in a similar way to a congenital deficit of the cerebellum. PMID:15991870

  6. Landmark Based Shape Analysis for Cerebellar Ataxia Classification and Cerebellar Atrophy Pattern Visualization

    PubMed Central

    Yang, Zhen; Abulnaga, S. Mazdak; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi; Ying, Sarah H.; Prince, Jerry L.

    2016-01-01

    Cerebellar dysfunction can lead to a wide range of movement disorders. Studying the cerebellar atrophy pattern associated with different cerebellar disease types can potentially help in diagnosis, prognosis, and treatment planning. In this paper, we present a landmark based shape analysis pipeline to classify healthy control and different ataxia types and to visualize the characteristic cerebellar atrophy patterns associated with different types. A highly informative feature representation of the cerebellar structure is constructed by extracting dense homologous landmarks on the boundary surfaces of cerebellar sub-structures. A diagnosis group classifier based on this representation is built using partial least square dimension reduction and regularized linear discriminant analysis. The characteristic atrophy pattern for an ataxia type is visualized by sampling along the discriminant direction between healthy controls and the ataxia type. Experimental results show that the proposed method can successfully classify healthy controls and different ataxia types. The visualized cerebellar atrophy patterns were consistent with the regional volume decreases observed in previous studies, but the proposed method provides intuitive and detailed understanding about changes of overall size and shape of the cerebellum, as well as that of individual lobules. PMID:27303111

  7. Landmark based shape analysis for cerebellar ataxia classification and cerebellar atrophy pattern visualization

    NASA Astrophysics Data System (ADS)

    Yang, Zhen; Abulnaga, S. Mazdak; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi; Ying, Sarah H.; Prince, Jerry L.

    2016-03-01

    Cerebellar dysfunction can lead to a wide range of movement disorders. Studying the cerebellar atrophy pattern associated with different cerebellar disease types can potentially help in diagnosis, prognosis, and treatment planning. In this paper, we present a landmark based shape analysis pipeline to classify healthy control and different ataxia types and to visualize the characteristic cerebellar atrophy patterns associated with different types. A highly informative feature representation of the cerebellar structure is constructed by extracting dense homologous landmarks on the boundary surfaces of cerebellar sub-structures. A diagnosis group classifier based on this representation is built using partial least square dimension reduction and regularized linear discriminant analysis. The characteristic atrophy pattern for an ataxia type is visualized by sampling along the discriminant direction between healthy controls and the ataxia type. Experimental results show that the proposed method can successfully classify healthy controls and different ataxia types. The visualized cerebellar atrophy patterns were consistent with the regional volume decreases observed in previous studies, but the proposed method provides intuitive and detailed understanding about changes of overall size and shape of the cerebellum, as well as that of individual lobules.

  8. [A woman with cerebellar ataxia and hypergonadotropic hypogonadism].

    PubMed

    Wada, Sayoko; Takaoka, Toshio; Kasama, Shuhei; Kimura, Takashi; Kajiyama, Koji; Takeda, Masanaka; Yoshikawa, Hiroo

    2010-01-01

    A 26-year-old woman with primary amenorrhea in association with hypergonadotropinism, and lacking a vagina and uterus, suffered from a gradually progressive gait disturbance in her adolescence. The patient has no family history of ataxia and a chromosome study showed a normal karyotype (46,XX). Using the revised Hasegawa Dementia Scale, her cognitive function was measured as that of a normal adult, however, neurological examination revealed symptoms of scanning speech, horizontal gaze-evoked nystagmus, and ataxia. Bulging eyes, high-arched palate, scoliosis and ventricular septal defect were also observed. A brain MRI showed atrophy of the cerebellum. A 123I-IMP brain SPECT study showed hypoperfusion in the cerebellum. Previous studies show that among patients with cerebellar ataxia and hypergonadotropic hypogonadism, some show an autosomal recessive inheritance, while others have no family history. As a cause, a chromosomal abnormality is unlikely because all reported karyotypes were normal. This case is different from other reported cases in that she is not mentally impaired or deaf. The present case indicates that there is a close relationship between cerebellar ataxia and hypogonadism, and that other symptoms such as deafness and mental impairment could be an additional variable in patients with cerebellar ataxia arid hypergonadotropic hypogonadism. PMID:20120350

  9. Deep Learning for Cerebellar Ataxia Classification and Functional Score Regression

    PubMed Central

    Yang, Zhen; Zhong, Shenghua; Carass, Aaron; Ying, Sarah H.; Prince, Jerry L.

    2014-01-01

    Cerebellar ataxia is a progressive neuro-degenerative disease that has multiple genetic versions, each with a characteristic pattern of anatomical degeneration that yields distinctive motor and cognitive problems. Studying this pattern of degeneration can help with the diagnosis of disease subtypes, evaluation of disease stage, and treatment planning. In this work, we propose a learning framework using MR image data for discriminating a set of cerebellar ataxia types and predicting a disease related functional score. We address the difficulty in analyzing high-dimensional image data with limited training subjects by: 1) training weak classifiers/regressors on a set of image subdomains separately, and combining the weak classifier/regressor outputs to make the decision; 2) perturbing the image subdomain to increase the training samples; 3) using a deep learning technique called the stacked auto-encoder to develop highly representative feature vectors of the input data. Experiments show that our approach can reliably classify between one of four categories (healthy control and three types of ataxia), and predict the functional staging score for ataxia. PMID:25553339

  10. Predicting and correcting ataxia using a model of cerebellar function

    PubMed Central

    Bhanpuri, Nasir H.; Okamura, Allison M.

    2014-01-01

    Cerebellar damage results in uncoordinated, variable and dysmetric movements known as ataxia. Here we show that we can reliably model single-joint reaching trajectories of patients (n = 10), reproduce patient-like deficits in the behaviour of controls (n = 11), and apply patient-specific compensations that improve reaching accuracy (P < 0.02). Our approach was motivated by the theory that the cerebellum is essential for updating and/or storing an internal dynamic model that relates motor commands to changes in body state (e.g. arm position and velocity). We hypothesized that cerebellar damage causes a mismatch between the brain’s modelled dynamics and the actual body dynamics, resulting in ataxia. We used both behavioural and computational approaches to demonstrate that specific cerebellar patient deficits result from biased internal models. Our results strongly support the idea that an intact cerebellum is critical for maintaining accurate internal models of dynamics. Importantly, we demonstrate how subject-specific compensation can improve movement in cerebellar patients, who are notoriously unresponsive to treatment. PMID:24812203

  11. Early Cerebellar Network Shifting in Spinocerebellar Ataxia Type 6.

    PubMed

    Falcon, M I; Gomez, C M; Chen, E E; Shereen, A; Solodkin, A

    2016-07-01

    Spinocerebellar ataxia 6 (SCA6), an autosomal dominant degenerative disease, is characterized by diplopia, gait ataxia, and incoordination due to severe progressive degeneration of Purkinje cells in the vestibulo- and spinocerebellum. Ocular motor deficits are common, including difficulty fixating on moving objects, nystagmus and disruption of smooth pursuit movements. In presymptomatic SCA6, there are alterations in saccades and smooth-pursuit movements. We sought to assess functional and structural changes in cerebellar connectivity associated with a visual task, hypothesizing that gradual changes would parallel disease progression. We acquired functional magnetic resonance imaging and diffusion tensor imaging data during a passive smooth-pursuit task in 14 SCA6 patients, representing a range of disease duration and severity, and performed a cross-sectional comparison of cerebellar networks compared with healthy controls. We identified a shift in activation from vermis in presymptomatic individuals to lateral cerebellum in moderate-to-severe cases. Concomitantly, effective connectivity between regions of cerebral cortex and cerebellum was at its highest in moderate cases, and disappeared in severe cases. Finally, we noted structural differences in the cerebral and cerebellar peduncles. These unique results, spanning both functional and structural domains, highlight widespread changes in SCA6 and compensatory mechanisms associated with cerebellar physiology that could be utilized in developing new therapies. PMID:26209844

  12. 4-aminopyridine reverses ataxia and cerebellar firing deficiency in a mouse model of spinocerebellar ataxia type 6

    PubMed Central

    Jayabal, Sriram; Chang, Hui Ho Vanessa; Cullen, Kathleen E.; Watt, Alanna J.

    2016-01-01

    Spinocerebellar ataxia type 6 (SCA6) is a devastating midlife-onset autosomal dominant motor control disease with no known treatment. Using a hyper-expanded polyglutamine (84Q) knock-in mouse, we found that cerebellar Purkinje cell firing precision was degraded in heterozygous (SCA684Q/+) mice at 19 months when motor deficits are observed. Similar alterations in firing precision and motor control were observed at disease onset at 7 months in homozygous (SCA684Q/84Q) mice, as well as a reduction in firing rate. We further found that chronic administration of the FDA-approved drug 4-aminopyridine (4-AP), which targets potassium channels, alleviated motor coordination deficits and restored cerebellar Purkinje cell firing precision to wildtype (WT) levels in SCA684Q/84Q mice both in acute slices and in vivo. These results provide a novel therapeutic approach for treating ataxic symptoms associated with SCA6. PMID:27381005

  13. 4-aminopyridine reverses ataxia and cerebellar firing deficiency in a mouse model of spinocerebellar ataxia type 6.

    PubMed

    Jayabal, Sriram; Chang, Hui Ho Vanessa; Cullen, Kathleen E; Watt, Alanna J

    2016-01-01

    Spinocerebellar ataxia type 6 (SCA6) is a devastating midlife-onset autosomal dominant motor control disease with no known treatment. Using a hyper-expanded polyglutamine (84Q) knock-in mouse, we found that cerebellar Purkinje cell firing precision was degraded in heterozygous (SCA6(84Q/+)) mice at 19 months when motor deficits are observed. Similar alterations in firing precision and motor control were observed at disease onset at 7 months in homozygous (SCA6(84Q/84Q)) mice, as well as a reduction in firing rate. We further found that chronic administration of the FDA-approved drug 4-aminopyridine (4-AP), which targets potassium channels, alleviated motor coordination deficits and restored cerebellar Purkinje cell firing precision to wildtype (WT) levels in SCA6(84Q/84Q) mice both in acute slices and in vivo. These results provide a novel therapeutic approach for treating ataxic symptoms associated with SCA6. PMID:27381005

  14. Sun1 deficiency leads to cerebellar ataxia in mice

    PubMed Central

    Wang, Jing-Ya; Yu, I.-Shing; Huang, Chien-Chi; Chen, Chia-Yen; Wang, Wan-Ping; Lin, Shu-Wha; Jeang, Kuan-Teh; Chi, Ya-Hui

    2015-01-01

    ABSTRACT Migration and organization of the nucleus are essential for the proliferation and differentiation of cells, including neurons. However, the relationship between the positioning of the nucleus and cellular morphogenesis remains poorly understood. Inherited recessive cerebellar ataxia has been attributed to mutations in SYNE1, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex. Regardless, Syne1-mutant mice present with normal cerebellar development. The Sad1-Unc-84 homology (SUN)-domain proteins are located at the inner nuclear membrane and recruit Syne proteins through the KASH domain to the outer nuclear membrane. Here, we report an unrecognized contribution of Sun1 and Sun2 to the postnatal development of murine cerebellum. Mice depleted of Sun1 showed a marked reduction in the cerebellar volume, and this phenotype is exacerbated with additional loss of a Sun2 allele. Consistent with these histological changes, Sun1−/− and Sun1−/−Sun2+/− mice exhibited defective motor coordination. Results of immunohistochemical analyses suggested that Sun1 is highly expressed in Purkinje cells and recruits Syne2 to the periphery of the nucleus. Approximately 33% of Purkinje cells in Sun1−/− mice and 66% of Purkinje cells in Sun1−/−Sun2+/− mice were absent from the surface of the internal granule layer (IGL), whereas the proliferation and migration of granule neurons were unaffected. Furthermore, the Sun1−/−Sun2+/− Purkinje cells exhibited retarded primary dendrite specification, reduced dendritic complexity and aberrant patterning of synapses. Our findings reveal a cell-type-specific role for Sun1 and Sun2 in nucleokinesis during cerebellar development, and we propose the use of Sun-deficient mice as a model for studying cerebellar ataxia that is associated with mutation of human SYNE genes or loss of Purkinje cells. PMID:26035387

  15. The cerebellar component of Friedreich’s ataxia

    PubMed Central

    Davis, Ashley N.; Morral, Jennifer A.

    2016-01-01

    Lack of frataxin in Friedreich’s ataxia (FRDA) causes a complex neurological and pathological phenotype. Progressive atrophy of the dentate nucleus (DN) is a major intrinsic central nervous system lesion. Antibodies to neuron-specific enolase (NSE), calbindin, glutamic acid decarboxylase (GAD), and vesicular glutamate transporters 1 and 2 (VGluT1, VGluT2) allowed insight into the disturbed synaptic circuitry of the DN. The available case material included autopsy specimens of 24 patients with genetically defined FRDA and 14 normal controls. In FRDA, the cerebellar cortex revealed intact Purkinje cell somata and dendrites as assessed by calbindin immunore-activity. The DN, however, displayed severe loss of large NSE-reactive neurons. Small neurons remained intact. Labeling of Purkinje cells, basket fibers, Golgi neurons, and Golgi axonal plexuses with antibodies to GAD indicated normal intrinsic circuitry of the cerebellar cortex involving γ-aminobutyric acid (GABA). In contrast, the DN displayed severe loss of GABA-ergic terminals and formation of GAD- and calbindin-reactive grumose degeneration. The surviving small GAD-positive DN neurons provided normal GABA-ergic terminals to intact inferior olivary nuclei. The olives also received normal glutamatergic terminals as shown by VGluT2-reactivity. VGluT1-immunocytochemistry of the cerebellar cortex confirmed normal glutamatergic input to the molecular layer by parallel fibers and the granular layer by mossy fibers. VGluT2-immunoreactivity visualized normal climbing fibers and mossy fiber terminals. The DN, however, showed depletion of VGluT1- and VGluT2-reactive terminals arising from climbing and mossy fiber collaterals. The main functional deficit underlying cerebellar ataxia in FRDA is defective processing of inhibitory and excitatory impulses that converge on the large neurons of the DN. The reason for the selective vulnerability of these nerve cells remains elusive. PMID:21638087

  16. Insights From Cerebellar Transcriptomic Analysis Into the Pathogenesis of Ataxia

    PubMed Central

    Bettencourt, Conceição; Ryten, Mina; Forabosco, Paola; Schorge, Stephanie; Hersheson, Joshua; Hardy, John; Houlden, Henry

    2015-01-01

    IMPORTANCE The core clinical and neuropathological feature of the autosomal dominant spinocerebellar ataxias (SCAs) is cerebellar degeneration. Mutations in the known genes explain only 50% to 60% of SCA cases. To date, no effective treatments exist, and the knowledge of drug-treatable molecular pathways is limited. The examination of overlapping mechanisms and the interpretation of how ataxia genes interact will be important in the discovery of potential disease-modifying agents. OBJECTIVES To address the possible relationships among known SCA genes, predict their functions, identify overlapping pathways, and provide a framework for candidate gene discovery using whole-transcriptome expression data. DESIGN, SETTING, AND PARTICIPANTS We have used a systems biology approach based on whole-transcriptome gene expression analysis. As part of the United Kingdom Brain Expression Consortium, we analyzed the expression profile of 788 brain samples obtained from 101 neuropathologically healthy individuals (10 distinct brain regions each). Weighted gene coexpression network analysis was used to cluster 24 SCA genes into gene coexpression modules in an unsupervised manner. The overrepresentation of SCA transcripts in modules identified in the cerebellum was assessed. Enrichment analysis was performed to infer the functions and molecular pathways of genes in biologically relevant modules. MAIN OUTCOMES AND MEASURES Molecular functions and mechanisms implicating SCA genes, as well as lists of relevant coexpressed genes as potential candidates for novel SCA causative or modifier genes. RESULTS Two cerebellar gene coexpression modules were statistically enriched in SCA transcripts (P = .021 for the tan module and P = 2.87 × 10−5 for the light yellow module) and contained established granule and Purkinje cell markers, respectively. One module includes genes involved in the ubiquitin-proteasome system and contains SCA genes usually associated with a complex phenotype, while the

  17. A case of cystinuria presenting with cerebellar ataxia and dementia.

    PubMed

    Tohge, Rie; Sakamoto, Shinichi; Takahashi, Makio

    2016-08-01

    Cystinuria normally manifests as recurrent urinary stones and renal dysfunction, but can present to neurologists with ataxia, posterior column impairment, intellectual deficiency and pyramidal and extrapyramidal signs; the neuroradiological features include cerebellar, brainstem and cerebral atrophy. It is an autosomal recessive disease caused by a transport disorder of cystine and dibasic amino acids in renal proximal tubules. Most cases have an SLC3A1 and/or SLC7A9 gene mutation but some recent Japanese patients have had distinct heterozygous gene mutations. We report a patient with cystinuria with a heterozygous P482L mutation in the SLC7A9 gene, presenting with atrophy in the cerebellum, brainstem and cerebrum and with no urinary stones. Cystine, an amino acid comprising two cysteine molecules, is transported into cells via a cystine transporter. It is essential for producing hydrogen sulfate and the cellular antioxidant glutathione: these exert neuroprotection in astrocytes and cerebellar Purkinje cells. Although cystinuria is a metabolic disorder associated with renal dysfunction, we suspect that a trafficking defect of transporter rBAT-BAT1 in brain might cause neuronal degeneration, leading to cerebellar and cerebral atrophy. PMID:26929440

  18. Cerebrospinal fluid as a reflector of central cholinergic and amino acid neurotransmitter activity in cerebellar ataxia.

    PubMed

    Manyam, B V; Giacobini, E; Ferraro, T N; Hare, T A

    1990-11-01

    Cerebrospinal fluid (CSF) amino acid neurotransmitters, related compounds, and their precursors, choline levels, and acetylcholinesterase activity were measured in the CSF of patients with cerebellar ataxia during a randomized, double-blind, crossover, placebo-controlled clinical trial of physostigmine salicylate. The CSF gamma-aminobutyric acid, methionine, and choline levels, adjusted for age, were significantly lower in patients with cerebellar ataxia compared with controls. Physostigmine selectively reduced the level of CSF isoleucine and elevated the levels of phosphoethanolamine. No change occurred in CSF acetylcholinesterase activity and in the levels of plasma amino compounds in patients with cerebellar ataxia when compared with controls. Median ataxia scores did not statistically differ between placebo and physostigmine nor did functional improvement occur in any of the patients. PMID:1978660

  19. SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.

    PubMed

    Synofzik, Matthis; Smets, Katrien; Mallaret, Martial; Di Bella, Daniela; Gallenmüller, Constanze; Baets, Jonathan; Schulze, Martin; Magri, Stefania; Sarto, Elisa; Mustafa, Mona; Deconinck, Tine; Haack, Tobias; Züchner, Stephan; Gonzalez, Michael; Timmann, Dagmar; Stendel, Claudia; Klopstock, Thomas; Durr, Alexandra; Tranchant, Christine; Sturm, Marc; Hamza, Wahiba; Nanetti, Lorenzo; Mariotti, Caterina; Koenig, Michel; Schöls, Ludger; Schüle, Rebecca; de Jonghe, Peter; Anheim, Mathieu; Taroni, Franco; Bauer, Peter

    2016-05-01

    Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause a relatively pure, slowly progressive cerebellar recessive ataxia mostly identified in Quebec, Canada. Combining next-generation sequencing techniques and deep-phenotyping (clinics, magnetic resonance imaging, positron emission tomography, muscle histology), we here established the frequency, phenotypic spectrum and genetic spectrum of SYNE1 in a screening of 434 non-Canadian index patients from seven centres across Europe. Patients were screened by whole-exome sequencing or targeted panel sequencing, yielding 23 unrelated families with recessive truncating SYNE1 mutations (23/434 = 5.3%). In these families, 35 different mutations were identified, 34 of them not previously linked to human disease. While only 5/26 patients (19%) showed the classical SYNE1 phenotype of mildly progressive pure cerebellar ataxia, 21/26 (81%) exhibited additional complicating features, including motor neuron features in 15/26 (58%). In three patients, respiratory dysfunction was part of an early-onset multisystemic neuromuscular phenotype with mental retardation, leading to premature death at age 36 years in one of them. Positron emission tomography imaging confirmed hypometabolism in extra-cerebellar regions such as the brainstem. Muscle biopsy reliably showed severely reduced or absent SYNE1 staining, indicating its potential use as a non-genetic indicator for underlying SYNE1 mutations. Our findings, which present the largest systematic series of SYNE1 patients and mutations outside Canada, revise the view that SYNE1 ataxia causes mainly a relatively pure cerebellar recessive ataxia and that it is largely limited to Quebec. Instead, complex phenotypes with a wide range of extra-cerebellar neurological and non-neurological dysfunctions are frequent, including in particular motor neuron and brainstem dysfunction. The disease course in this multisystemic neurodegenerative disease can be fatal

  20. Contribution of Somatic and Dendritic SK Channels in the Firing Rate of Deep Cerebellar Nuclei: Implication in Cerebellar Ataxia

    PubMed Central

    Abbasi, Samira; Abbasi, Ataollah; Sarbaz, Yashar; Shahabi, Parviz

    2016-01-01

    Introduction: Loss of inhibitory output from Purkinje cells leads to hyperexcitability of the Deep Cerebellar Nuclei (DCN), which results in cerebellar ataxia. Also, inhibition of small-conductance calcium-activated potassium (SK) channel increases firing rate of DCN, which could cause cerebellar ataxia. Therefore, SK channel activators can be effective in reducing the symptoms of this disease, and used for the treatment of cerebellar ataxia. In this regard, we hypothesized that blockade of SK channels in different compartments of DCN would increase firing rate with different value. The location of these channels has different effects on increasing firing rate. Methods: In this study, multi-compartment computational model of DCN was used. This computational stimulation allowed us to study the changes in the firing activity of DCN neuron without concerns about interfering parameters in the experiment. Results: The simulation results demonstrated that blockade of somatic and dendritic SK channel increased the firing rate of DCN. In addition, after hyperpolarization (AHP) amplitude increased with blocking SK channel, and its regularity and resting potential changed. However, action potentials amplitude and duration had no significant changes. The simulation results illustrated a more significant contribution of SK channels on the dendritic tree to the DCN firing rate. SK channels in the proximal dendrites have more impact on firing rate compared to distal dendrites. Discussion: Therefore, inhibition of SK channel in DCN can cause cerebellar ataxia, and SK channel openers can have a therapeutic effect on cerebellar ataxia. In addition, the location of SK channels could be important in therapeutic goals. Dendritic SK channels can be a more effective target compared to somatic SK channels. PMID:27303600

  1. Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans.

    PubMed

    Wang, Yubin; Hersheson, Joshua; Lopez, Dulce; Hammer, Monia; Liu, Yan; Lee, Ka-Hung; Pinto, Vanessa; Seinfeld, Jeff; Wiethoff, Sarah; Sun, Jiandong; Amouri, Rim; Hentati, Faycal; Baudry, Neema; Tran, Jennifer; Singleton, Andrew B; Coutelier, Marie; Brice, Alexis; Stevanin, Giovanni; Durr, Alexandra; Bi, Xiaoning; Houlden, Henry; Baudry, Michel

    2016-06-28

    A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans. PMID:27320912

  2. Defects in the CAPN1 gene result in alterations in cerebellar development and in cerebellar ataxia in mice and humans

    PubMed Central

    Wang, Yubin; Hersheson, Joshua; Lopez, Dulce; Hamad, Monia Ben; Liu, Yan; Lee, Ka-Hung; Pinto, Vanessa; Seinfeld, Jeff; Wiethoff, Sarah; Sun, Jiandong; Amouri, Rim; Hentati, Faycal; Baudry, Neema; Tran, Jennifer; Singleton, Andrew B; Coutelier, Marie; Brice, Alexis; Stevanin, Giovanni; Durr, Alexandra; Bi, Xiaoning; Houlden, Henry; Baudry, Michel

    2016-01-01

    SUMMARY A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous CAPN1 null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knock-out (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1 mediated cleavage of PH domain and Leucine rich repeat Protein Phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis, and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans. PMID:27320912

  3. Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia

    PubMed Central

    Schmidt, Wolfgang M.; Rutledge, S. Lane; Schüle, Rebecca; Mayerhofer, Benjamin; Züchner, Stephan; Boltshauser, Eugen; Bittner, Reginald E.

    2015-01-01

    Hereditary ataxias comprise a group of genetically heterogeneous disorders characterized by clinically variable cerebellar dysfunction and accompanied by involvement of other organ systems. The molecular underpinnings for many of these diseases are widely unknown. Previously, we discovered the disruption of Scyl1 as the molecular basis of the mouse mutant mdf, which is affected by neurogenic muscular atrophy, progressive gait ataxia with tremor, cerebellar vermis atrophy, and optic-nerve thinning. Here, we report on three human individuals, from two unrelated families, who presented with recurrent episodes of acute liver failure in early infancy and are affected by cerebellar vermis atrophy, ataxia, and peripheral neuropathy. By whole-exome sequencing, compound-heterozygous mutations within SCYL1 were identified in all affected individuals. We further show that in SCYL1-deficient human fibroblasts, the Golgi apparatus is massively enlarged, which is in line with the concept that SCYL1 regulates Golgi integrity. Thus, our findings define SCYL1 mutations as the genetic cause of a human hepatocerebellar neuropathy syndrome. PMID:26581903

  4. Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia.

    PubMed

    Schmidt, Wolfgang M; Rutledge, S Lane; Schüle, Rebecca; Mayerhofer, Benjamin; Züchner, Stephan; Boltshauser, Eugen; Bittner, Reginald E

    2015-12-01

    Hereditary ataxias comprise a group of genetically heterogeneous disorders characterized by clinically variable cerebellar dysfunction and accompanied by involvement of other organ systems. The molecular underpinnings for many of these diseases are widely unknown. Previously, we discovered the disruption of Scyl1 as the molecular basis of the mouse mutant mdf, which is affected by neurogenic muscular atrophy, progressive gait ataxia with tremor, cerebellar vermis atrophy, and optic-nerve thinning. Here, we report on three human individuals, from two unrelated families, who presented with recurrent episodes of acute liver failure in early infancy and are affected by cerebellar vermis atrophy, ataxia, and peripheral neuropathy. By whole-exome sequencing, compound-heterozygous mutations within SCYL1 were identified in all affected individuals. We further show that in SCYL1-deficient human fibroblasts, the Golgi apparatus is massively enlarged, which is in line with the concept that SCYL1 regulates Golgi integrity. Thus, our findings define SCYL1 mutations as the genetic cause of a human hepatocerebellar neuropathy syndrome. PMID:26581903

  5. Exome Sequencing in the Clinical Diagnosis of Sporadic or Familial Cerebellar Ataxia

    PubMed Central

    Fogel, Brent L.; Lee, Hane; Deignan, Joshua L.; Strom, Samuel P.; Kantarci, Sibel; Wang, Xizhe; Quintero-Rivera, Fabiola; Vilain, Eric; Grody, Wayne W.; Perlman, Susan; Geschwind, Daniel H.; Nelson, Stanley F.

    2015-01-01

    IMPORTANCE Cerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established. OBJECTIVE To investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia. DESIGN, SETTING, AND PARTICIPANTS We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia. MAIN OUTCOMES AND MEASURES Next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation. RESULTS We identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias. CONCLUSIONS AND RELEVANCE This study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia

  6. Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation.

    PubMed

    Dard, Rodolphe; Mignot, Cyril; Durr, Alexandra; Lesca, Gaetan; Sanlaville, Damien; Roze, Emmanuel; Mochel, Fanny

    2015-12-01

    ATP1A3, the gene encoding the α3-subunit of the Na(+) /K(+) -ATPase pump, has been involved in four clinical neurological entities: (1) alternating hemiplegia of childhood (AHC); (2) rapid-onset dystonia parkinsonism (RDP); (3) CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss) syndrome; and (4) early infantile epileptic encephalopathy. Here, we report on a 34-year-old female presenting with a new ATP1A3-related entity involving a relapsing encephalopathy characterized by recurrent episodes of cerebellar ataxia and altered consciousness during febrile illnesses. The term RECA is suggested - relapsing encephalopathy with cerebellar ataxia. The phenotype of this patient, resembling mitochondrial oxidative phosphorylation defects, emphasizes the possible role of brain energy deficiency in patients with ATP1A3 mutations. Rather than multiple overlapping syndromes, ATP1A3-related disorders might be seen as a phenotypic continuum. PMID:26400718

  7. PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia.

    PubMed

    Jobling, Rebekah K; Assoum, Mirna; Gakh, Oleksandr; Blaser, Susan; Raiman, Julian A; Mignot, Cyril; Roze, Emmanuel; Dürr, Alexandra; Brice, Alexis; Lévy, Nicolas; Prasad, Chitra; Paton, Tara; Paterson, Andrew D; Roslin, Nicole M; Marshall, Christian R; Desvignes, Jean-Pierre; Roëckel-Trevisiol, Nathalie; Scherer, Stephen W; Rouleau, Guy A; Mégarbané, André; Isaya, Grazia; Delague, Valérie; Yoon, Grace

    2015-06-01

    Non-progressive cerebellar ataxias are a rare group of disorders that comprise approximately 10% of static infantile encephalopathies. We report the identification of mutations in PMPCA in 17 patients from four families affected with cerebellar ataxia, including the large Lebanese family previously described with autosomal recessive cerebellar ataxia and short stature of Norman type and localized to chromosome 9q34 (OMIM #213200). All patients present with non-progressive cerebellar ataxia, and the majority have intellectual disability of variable severity. PMPCA encodes α-MPP, the alpha subunit of mitochondrial processing peptidase, the primary enzyme responsible for the maturation of the vast majority of nuclear-encoded mitochondrial proteins, which is necessary for life at the cellular level. Analysis of lymphoblastoid cells and fibroblasts from patients homozygous for the PMPCA p.Ala377Thr mutation and carriers demonstrate that the mutation impacts both the level of the alpha subunit encoded by PMPCA and the function of mitochondrial processing peptidase. In particular, this mutation impacts the maturation process of frataxin, the protein which is depleted in Friedreich ataxia. This study represents the first time that defects in PMPCA and mitochondrial processing peptidase have been described in association with a disease phenotype in humans. PMID:25808372

  8. PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia

    PubMed Central

    Jobling, Rebekah K.; Assoum, Mirna; Gakh, Oleksandr; Blaser, Susan; Raiman, Julian A.; Mignot, Cyril; Roze, Emmanuel; Dürr, Alexandra; Brice, Alexis; Lévy, Nicolas; Prasad, Chitra; Paton, Tara; Paterson, Andrew D.; Roslin, Nicole M.; Marshall, Christian R.; Desvignes, Jean-Pierre; Roëckel-Trevisiol, Nathalie; Scherer, Stephen W.; Rouleau, Guy A.; Mégarbané, André; Isaya, Grazia

    2015-01-01

    Non-progressive cerebellar ataxias are a rare group of disorders that comprise approximately 10% of static infantile encephalopathies. We report the identification of mutations in PMPCA in 17 patients from four families affected with cerebellar ataxia, including the large Lebanese family previously described with autosomal recessive cerebellar ataxia and short stature of Norman type and localized to chromosome 9q34 (OMIM #213200). All patients present with non-progressive cerebellar ataxia, and the majority have intellectual disability of variable severity. PMPCA encodes α-MPP, the alpha subunit of mitochondrial processing peptidase, the primary enzyme responsible for the maturation of the vast majority of nuclear-encoded mitochondrial proteins, which is necessary for life at the cellular level. Analysis of lymphoblastoid cells and fibroblasts from patients homozygous for the PMPCA p.Ala377Thr mutation and carriers demonstrate that the mutation impacts both the level of the alpha subunit encoded by PMPCA and the function of mitochondrial processing peptidase. In particular, this mutation impacts the maturation process of frataxin, the protein which is depleted in Friedreich ataxia. This study represents the first time that defects in PMPCA and mitochondrial processing peptidase have been described in association with a disease phenotype in humans. PMID:25808372

  9. Does modulation of the endocannabinoid system have potential therapeutic utility in cerebellar ataxia?

    PubMed

    Stephens, G J

    2016-08-15

    Cerebellar ataxias represent a spectrum of disorders which are, however, linked by common symptoms of motor incoordination and typically associated with deficiency in Purkinje cell firing activity and, often, degeneration. Cerebellar ataxias currently lack a curative agent. The endocannabinoid (eCB) system includes eCB compounds and their associated metabolic enzymes, together with cannabinoid receptors, predominantly the cannabinoid CB1 receptor (CB1 R) in the cerebellum; activation of this system in the cerebellar cortex is associated with deficits in motor coordination characteristic of ataxia, effects which can be prevented by CB1 R antagonists. Of further interest are various findings that CB1 R deficits may also induce a progressive ataxic phenotype. Together these studies suggest that motor coordination is reliant on maintaining the correct balance in eCB system signalling. Recent work also demonstrates deficient cannabinoid signalling in the mouse 'ducky(2J) ' model of ataxia. In light of these points, the potential mechanisms whereby cannabinoids may modulate the eCB system to ameliorate dysfunction associated with cerebellar ataxias are considered. PMID:26970080

  10. Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome: a slowly progressive disorder with stereotypical presentation.

    PubMed

    Cazzato, Daniele; Bella, Eleonora Dalla; Dacci, Patrizia; Mariotti, Caterina; Lauria, Giuseppe

    2016-02-01

    Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a newly described condition with onset in adulthood, characterized by progressive balance impairment and sensory disturbances in the lower limbs, which can severely affect patients' quality of life. Its pathogenesis remains obscure and the diagnosis challenging. We described four patients complaining of slowly progressive gait unbalance and sensory disturbances at the feet followed, after a period ranging 2-6 years, by cerebellar dysfunction. All patients showed gait and limb ataxia, positive Romberg sign, cerebellar dysarthria, gaze-evoked nystagmus, absent deep tendon reflexes, and impaired vibratory sensation. Nerve conduction studies revealed axonal sensory neuropathy, brain magnetic resonance imaging showed cerebellar atrophy, and otoneurological investigation demonstrated bilateral vestibular areflexia with impaired vestibulo-ocular reflexes. The diagnosis of CANVAS should be suspected on clinical ground based on homogeneous course of symptoms and signs, and addressed by video-oculography eye movement recording. PMID:26566912

  11. Familial cerebellar ataxia and hypogonadotropic hypogonadism: evidence for hypothalamic LHRH deficiency.

    PubMed Central

    Berciano, J; Amado, J A; Freijanes, J; Rebollo, M; Vaquero, A

    1982-01-01

    A family with familial cerebellar ataxia and hypogonadotropic hypogonadism is described. The condition was inherited as an autosomal recessive defect. CT scan in one case revealed cerebellar and brain stem atrophy. Endocrinological tests showed abnormalities only in two patients who were clinically affected. In both cases raised gonadotropic levels were found after repetitive stimulation with luteining hormone-releasing hormone which suggests that the hypogonadism was due to a primary hypothalamic disturbance. Images PMID:6813427

  12. Cerebellar Ataxia with Bilateral Vestibulopathy: Description of a Syndrome and Its Characteristic Clinical Sign

    ERIC Educational Resources Information Center

    Migliaccio, Americo A.; Halmagyi, G. Michael; McGarvie, Leigh A.; Cremer, Phillip D.

    2004-01-01

    We report four patients with the syndrome of cerebellar ataxia with bilateral vestibulopathy (CABV) and, using search coil oculography, we validate its characteristic clinical sign, namely impairment of the visually enhanced vestibulo-ocular reflex (VVOR) or doll's head reflex. In our four patients, CABV began in the sixth decade of life; they are…

  13. The Diagnostic Accuracy of Truncal Ataxia and HINTS as Cardinal Signs for Acute Vestibular Syndrome

    PubMed Central

    Carmona, Sergio; Martínez, Carlos; Zalazar, Guillermo; Moro, Marcela; Batuecas-Caletrio, Angel; Luis, Leonel; Gordon, Carlos

    2016-01-01

    The head impulse, nystagmus type, test of skew (HINTS) protocol set a new paradigm to differentiate peripheral vestibular disease from stroke in patients with acute vestibular syndrome (AVS). The relationship between degree of truncal ataxia and stroke has not been systematically studied in patients with AVS. We studied a group of 114 patients who were admitted to a General Hospital due to AVS, 72 of them with vestibular neuritis (based on positive head impulse, abnormal caloric tests, and negative MRI) and the rest with stroke: 32 in the posterior inferior cerebellar artery (PICA) territory (positive HINTS findings, positive MRI) and 10 in the anterior inferior cerebellar artery (AICA) territory (variable findings and grade 3 ataxia, positive MRI). Truncal ataxia was measured by independent observers as grade 1, mild to moderate imbalance with walking independently; grade 2, severe imbalance with standing, but cannot walk without support; and grade 3, falling at upright posture. When we applied the HINTS protocol to our sample, we obtained 100% sensitivity and 94.4% specificity, similar to previously published findings. Only those patients with stroke presented with grade 3 ataxia. Of those with grade 2 ataxia (n = 38), 11 had cerebellar stroke and 28 had vestibular neuritis, not related to the patient’s age. Grade 2–3 ataxia was 92.9% sensitive and 61.1% specific to detect AICA/PICA stroke in patients with AVS, with 100% sensitivity to detect AICA stroke. In turn, two signs (nystagmus of central origin and grade 2–3 Ataxia) had 100% sensitivity and 61.1% specificity. Ataxia is less sensitive than HINTS but much easier to evaluate. PMID:27551274

  14. The Diagnostic Accuracy of Truncal Ataxia and HINTS as Cardinal Signs for Acute Vestibular Syndrome.

    PubMed

    Carmona, Sergio; Martínez, Carlos; Zalazar, Guillermo; Moro, Marcela; Batuecas-Caletrio, Angel; Luis, Leonel; Gordon, Carlos

    2016-01-01

    The head impulse, nystagmus type, test of skew (HINTS) protocol set a new paradigm to differentiate peripheral vestibular disease from stroke in patients with acute vestibular syndrome (AVS). The relationship between degree of truncal ataxia and stroke has not been systematically studied in patients with AVS. We studied a group of 114 patients who were admitted to a General Hospital due to AVS, 72 of them with vestibular neuritis (based on positive head impulse, abnormal caloric tests, and negative MRI) and the rest with stroke: 32 in the posterior inferior cerebellar artery (PICA) territory (positive HINTS findings, positive MRI) and 10 in the anterior inferior cerebellar artery (AICA) territory (variable findings and grade 3 ataxia, positive MRI). Truncal ataxia was measured by independent observers as grade 1, mild to moderate imbalance with walking independently; grade 2, severe imbalance with standing, but cannot walk without support; and grade 3, falling at upright posture. When we applied the HINTS protocol to our sample, we obtained 100% sensitivity and 94.4% specificity, similar to previously published findings. Only those patients with stroke presented with grade 3 ataxia. Of those with grade 2 ataxia (n = 38), 11 had cerebellar stroke and 28 had vestibular neuritis, not related to the patient's age. Grade 2-3 ataxia was 92.9% sensitive and 61.1% specific to detect AICA/PICA stroke in patients with AVS, with 100% sensitivity to detect AICA stroke. In turn, two signs (nystagmus of central origin and grade 2-3 Ataxia) had 100% sensitivity and 61.1% specificity. Ataxia is less sensitive than HINTS but much easier to evaluate. PMID:27551274

  15. Cerebellar Dysfunction and Ataxia in Patients with Epilepsy: Coincidence, Consequence, or Cause?

    PubMed Central

    Marcián, Václav; Filip, Pavel; Bareš, Martin; Brázdil, Milan

    2016-01-01

    Basic epilepsy teachings assert that seizures arise from the cerebral cortex, glossing over infratentorial structures such as the cerebellum that are believed to modulate rather than generate seizures. Nonetheless, ataxia and other clinical findings in epileptic patients are slowly but inevitably drawing attention to this neural node. Tracing the evolution of this line of inquiry from the observed coincidence of cerebellar atrophy and cerebellar dysfunction (most apparently manifested as ataxia) in epilepsy to their close association, this review considers converging clinical, physiological, histological, and neuroimaging evidence that support incorporating the cerebellum into epilepsy pathology. We examine reports of still controversial cerebellar epilepsy, studies of cerebellar stimulation alleviating paroxysmal epileptic activity, studies and case reports of cerebellar lesions directly associated with seizures, and conditions in which ataxia is accompanied by epileptic seizures. Finally, the review substantiates the role of this complex brain structure in epilepsy whether by coincidence, as a consequence of deleterious cortical epileptic activity or antiepileptic drugs, or the very cause of the disease. PMID:27375960

  16. Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics.

    PubMed

    Fujioka, Shinsuke; Sundal, Christina; Wszolek, Zbigniew K

    2013-01-01

    Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments. PMID:23331413

  17. Paraneoplastic cerebellar ataxia associated with anti-Hu antibodies and benign ganglioneuroma.

    PubMed

    Fancellu, Roberto; Corsini, Elena; Bernardi, Giorgio; Buzzo, Paolo; Ferrari, Maria Luisa; Lamantea, Eleonora; Garaventa, Alberto; Truini, Mauro; Salvarani, Sandro

    2014-01-01

    We describe a case of cerebellar ataxia associated with anti-Hu antibodies and benign ganglioneuroma. A 28-year-old woman developed progressive ataxia with hyporeflexia at the age of 19. Brain MRI showed progressive cerebellar atrophy. Neurophysiological studies, screening of immune-mediated ataxias, oncological markers, vitamin E and genetic tests for spinocerebellar ataxia types 1,2,3, Friedreich ataxia and POLG1 were negative. Anti-Hu antibodies were positive in Western blot and indirect immunofluorescence (1:640). Total-body computed tomography revealed a mediastinum mass; the histological diagnosis was maturing ganglioneuroma. Immunohistochemistry showed a mild reaction between the tumor and the patient's serum, and no reaction between the tumor and control serum. After surgery, serum anti-Hu titer decreased, while ataxic symptoms initially worsened and then stabilized. Ganglioneuroma is a benign tumor, usually derived from the maturation of a neuroblastoma. The benign histology and the presence of anti-Hu antibodies could be related to the positive oncological prognosis and to the slow clinical course mimicking a degenerative ataxia. PMID:25764259

  18. Gluten Sensitivity – A Potentially Reversible Cause of Progressive Cerebellar Ataxia and Myoclonus - A Case Report

    PubMed Central

    Bohra, Vikram; Duggal, Ashish; Ghuge, Vijay V; Chaudhary, Neera

    2015-01-01

    Gluten sensitivity is an umbrella term used for diverse clinical manifestations occurring as a result of abnormal immunological reactivity to dietary gluten in genetically susceptible individuals. Celiac disease is the most well-known but not the only manifestation of gluten sensitivity. Myoclonus with Ataxia is a rare manifestation of gluten sensitivity and should be considered in the differential diagnosis of all patients with idiopathic sporadic ataxia. The presence of gluten-related immune markers in normal population however complicates the reliable diagnosis of gluten related neurological disorders and clinical improvement on gluten free diet can serve as a diagnostic tool for this disease. We report a case of sporadic progressive cerebellar ataxia with myoclonus with positive antigliadin antibodies, which improved with a trial of gluten free diet. This case highlights an important diagnostic and therapeutic principle in management of late onset idiopathic ataxia. PMID:26673942

  19. Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.

    PubMed

    Shi, Yuting; Wang, Junling; Li, Jia-Da; Ren, Haigang; Guan, Wenjuan; He, Miao; Yan, Weiqian; Zhou, Ying; Hu, Zhengmao; Zhang, Jianguo; Xiao, Jingjing; Su, Zheng; Dai, Meizhi; Wang, Jun; Jiang, Hong; Guo, Jifeng; Zhou, Yafang; Zhang, Fufeng; Li, Nan; Du, Juan; Xu, Qian; Hu, Yacen; Pan, Qian; Shen, Lu; Wang, Guanghui; Xia, Kun; Zhang, Zhuohua; Tang, Beisha

    2013-01-01

    Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia. PMID:24312598

  20. Identification of CHIP as a Novel Causative Gene for Autosomal Recessive Cerebellar Ataxia

    PubMed Central

    Shi, Yuting; Wang, Junling; Li, Jia-Da; Ren, Haigang; Guan, Wenjuan; He, Miao; Yan, Weiqian; Zhou, Ying; Hu, Zhengmao; Zhang, Jianguo; Xiao, Jingjing; Su, Zheng; Dai, Meizhi; Wang, Jun; Jiang, Hong; Guo, Jifeng; Zhou, Yafang; Zhang, Fufeng; Li, Nan; Du, Juan; Xu, Qian; Hu, Yacen; Pan, Qian; Shen, Lu; Wang, Guanghui; Xia, Kun; Zhang, Zhuohua; Tang, Beisha

    2013-01-01

    Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia. PMID:24312598

  1. The interrelationship between disease severity, dynamic stability, and falls in cerebellar ataxia.

    PubMed

    Schniepp, Roman; Schlick, Cornelia; Pradhan, Cauchy; Dieterich, Marianne; Brandt, Thomas; Jahn, Klaus; Wuehr, Max

    2016-07-01

    Cerebellar ataxia (CA) results in discoordination of body movements (ataxia), a gait disorder, and falls. All three aspects appear to be obviously interrelated; however, experimental evidence is sparse. This study systematically correlated the clinical rating of the severity of ataxia with dynamic stability measures and the fall frequency in patients with CA. Clinical severity of CA in patients with sporadic (n = 34) and hereditary (n = 24) forms was assessed with the Scale for the Assessment and Rating of Ataxia (SARA). Gait performance was examined during slow, preferred, and maximally fast walking speeds. Spatiotemporal variability parameters in the fore-aft and medio-lateral directions were analyzed. The fall frequency was assessed using a standardized interview about fall events within the last 6 months. Fore-aft gait variability showed significant speed-dependent characteristics with highest magnitudes during slow and fast walking. The SARA score correlated positively with fore-aft gait variability, most prominently during fast walking. The fall frequency was significantly associated to fore-aft gait variability during slow walking. Severity of ataxia, dynamic stability, and the occurrence of falls were interrelated in a speed-dependent manner: (a) Severity of ataxia symptoms was closely related to instability during fast walking. (b) Fall frequency was associated with instability during slow walking. These findings suggest the presence of a speed-dependent, twofold cerebellar locomotor control. Assessment of gait performance during non-preferred, slow and fast walking speeds provides novel insights into the pathophysiology of cerebellar locomotor control and may become a useful approach in the clinical evaluation of patients with CA. PMID:27159995

  2. Cerebellar ataxia with recovery related to central pontine myelinolysis.

    PubMed

    Steller, U; Koschorek, F; Strenge, H

    1988-07-01

    Development of severe ataxia and mild pyramidal signs without mental deterioration, tetraparesis or pseudobulbar palsy during recovery from withdrawal delirium and initial hyponatraemia are unusual clinical features consistent with central pontine myelinolysis. This diagnosis was confirmed by magnetic resonance imaging (MRI) in an alcoholic man. Clinical and electrodiagnostic improvement occurred, whereas the MRI findings remained unchanged in a follow-up study. PMID:3171622

  3. Family exhibiting cerebellar-like ataxia, photosensitivity and shortness of stature - a new inborn error of tryptophan metabolism.

    PubMed Central

    Fenton, D A; Wilkinson, J D; Toseland, P A

    1983-01-01

    Two cases in a brother and sister of a previously undescribed hereditary syndrome are reported. The features, which include shortness of stature, photosensitivity and cerebellar-like ataxia, are attributed to a new inborn error of tryptophan metabolism. PMID:6620277

  4. Autosomal dominant cerebellar ataxia type I: A review of the phenotypic and genotypic characteristics

    PubMed Central

    2011-01-01

    Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular

  5. Ataxia.

    PubMed

    Winchester, Sara; Singh, Piyush K; Mikati, Mohamad A

    2013-01-01

    The approach to the child with ataxia requires a detailed history and careful general and neurological examination as well as selected blood work and brain imaging and increasingly available genetic testing for inherited ataxias that usually have an episodic or progressive presentation. The differential of acute and recurring ataxia covered in this chapter includes intoxication (e.g., antiepileptics, lead, alcohol), postinfectious cerebellitis, hemorrhage, ischemic stroke, tumor (posterior fossa or cerebellum), brainstem encephalitis, occult neuroblastoma, Miller Fisher syndrome, conversion reaction, multiple sclerosis, epileptic pseudoataxia, vasculitis (e.g., Kawasaki), metabolic etiologies (e.g., maple syrup urine disease, pyruvate dehydrogenase deficiency, ornithine transcarbamylase deficiency, biotinidase deficiency, Hartnup disease, and argininosuccinic aciduria), migraine, migraine equivalents (benign paroxysmal positional vertigo), autosomal dominant episodic ataxias (with seven types currently identified), and hypothyroidism. Cooperation with therapists and providers from other specialties including ophthalmology and genetics and metabolism is essential to caring for these children and their families. PMID:23622331

  6. Familial cosegregation of manic-depressive illness and a form of hereditary cerebellar ataxia

    SciTech Connect

    Piqueras, J.F.; Santos, J.; Puertollano, R.

    1995-06-19

    We report on a Spanish family with co-occurrence of manic-depression and a form of hereditary cerebellar ataxia. All affected individuals in the second generation showed cerebellar ataxia and manic-depression simultaneously. Since anticipation has been described in both disorders and the pattern of segregation may be autosomal as well as X-linked, we have searched for a possible involvement of two candidate genes which are located either on an autosome (SCA1) or on the X-chromosome (GABRA3). We concluded that expansion of trinucleotide repeats at SCA1 gene cannot be considered as a disease-causing mutation, and this gene should be initially discarded. 19 refs., 3 figs.

  7. Two sibs with chorioretinal dystrophy, hypogonadotrophic hypogonadism, and cerebellar ataxia: Boucher-Neuhäuser syndrome.

    PubMed Central

    Rump, R; Hamel, B C; Pinckers, A J; van Dop, P A

    1997-01-01

    We describe two sibs with chorioretinal dystrophy, hypogonadotrophic hypogonadism, and cerebellar ataxia, Boucher-Neuhäuser syndrome, a rare but distinct pleiotropic single gene disorder with an autosomal recessive pattern of inheritance. The cases presented illustrate that this syndrome is still poorly recognised. We provide a review and analysis of previously reported cases and the differential diagnosis, which might aid in the identification of additional cases. Images PMID:9321767

  8. Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) - a case report and review of literature.

    PubMed

    Figura, Monika; Gaweł, Małgorzata; Kolasa, Anna; Janik, Piotr

    2014-01-01

    CANVAS (cerebellar ataxia with neuropathy and vestibular areflexia syndrome) is a rare neurological syndrome of unknown etiology. The main clinical features include bilateral vestibulopathy, cerebellar ataxia and sensory neuropathy. An abnormal visually enhanced vestibulo-ocular reflex is the hallmark of the disease. We present a case of 58-year-old male patient who has demonstrated gait disturbance, imbalance and paresthesia of feet for 2 years. On examination ataxia of gait, diminished knee and ankle reflexes, absence of plantar reflexes, fasciculations of thigh muscles, gaze-evoked downbeat nystagmus and abnormal visually enhanced vestibulo-ocular reflex were found. Brain magnetic resonance imaging revealed cerebellar atrophy. Vestibular function testing showed severely reduced horizontal nystagmus in response to bithermal caloric stimulation. Nerve conduction study revealed loss of upper and lower limb sensory nerve action potentials. The course of illness was progressive with ataxic gait and unsteadiness as the most disabling symptoms. We report 4-year follow-up of the patient since the beginning of the disease. PMID:25440017

  9. Hereditary cerebellar ataxia progressively impairs force adaptation during goal-directed arm movements.

    PubMed

    Maschke, Matthias; Gomez, Christopher M; Ebner, Timothy J; Konczak, Jürgen

    2004-01-01

    We investigated how humans with hereditary cerebellar degeneration [spinocerebellar ataxia (SCA) type 6 and 8, n = 9] and age- and sex-matched healthy controls (n = 9) adapted goal-directed arm movements to an unknown external force field. We tested whether learning could be generalized to untrained regions in the workspace, an aspect central to the idea of an internal model, and if any learning could be retained. After removal of the force field, SCA patients showed little or no learning-related aftereffects indicating that repeated force-field exposure never led to successful force compensation. In contrast, healthy control subjects quickly adapted their movements to the new force field. The difference in force adaptation was significant for movements to targets that required both the shoulder and elbow joint (P < 0.001). Moreover, the generalization of learned movements to targets outside the learned workspace was prevented by the cerebellar degeneration (P < 0.01). Retention of force adaptation was significantly lower in SCA patients (P = 0.003). The severity of ataxia in SCA patients correlated negatively with the extent of learning (r = -0.84, P = 0.004). Our findings imply that progressive loss of cerebellar function gradually impairs force adaptation. The failure to generalize learning suggests that cerebellar degeneration prevents the formation of an internal representation of the limb dynamics. PMID:13679403

  10. A case of human immunodeficiency virus infection with cerebellar ataxia that suggested by an association with autoimmunity.

    PubMed

    Nagao, Shigeto; Kondo, Takayuki; Nakamura, Takashi; Nakagawa, Tomokazu; Matsumoto, Sadayuki

    2016-04-28

    We report a case of human immunodeficiency virus (HIV) infection that showed subacute progressive cerebellar ataxia without HIV encephalopathy or other encephalopathies, including progressive multifocal leukoencephalopathy or encephalitis of other human herpes virus (HHV) infections. A 43-year-old man exhibited unsteady gait. Neurological examination disclosed ataxia of the trunk and lower extremities. Personality change and dementia were absent. Magnetic resonance imaging did not reveal any abnormal finding, including of the cerebellum. The serum HIV-1-RNA was 1.2 × 10(5) copies/ml, and the absolute CD4 lymphocyte count was 141 cells/ml. Remarkably, the serum anti-Yo antibody, as an anti-cerebellar antibody of paraneoplastic syndrome, and anti-gliadin antibody, associated with celiac disease or gluten ataxia, were positive. The cerebrospinal fluid (CSF) immunoglobulin G index was 1.2 (< 0.8), and oligoclonal bands were present. PCR of the CSF was negative for HIV, JC virus, other HHVs, and mycosis. Previous reports presented HIV-infected patients with concurrent autoimmune diseases such as systemic lupus erythematosus, anti-phospholipid syndrome, autoimmune thrombocytopenia, vasculitis, polymyositis and dermatomyositis, sarcoidosis, Graves' disease, and hepatic diseases. These might have been present in patients with a CD4 T lymphocyte count of more than 200 cells/ml. On the other hand, paraneoplastic syndrome, gluten ataxia, cerebellar ataxia associated with anti-glutamic acid decarboxylase antibody, and Hashimoto's encephalopathy might manifest as autoimmune cerebellar ataxia. As regards the association of HIV infection and autoimmune cerebellar ataxia, a previous report suggested that anti-gliadin antibody was detected in about 30% of HIV-infected children, though there is no reference to an association with cerebellar ataxia. Moreover, to our knowledge, detection of anti-Yo antibody in an HIV-infected patient with cerebellar ataxia has not been reported

  11. Speech changes after coordinative training in patients with cerebellar ataxia: a pilot study.

    PubMed

    Tykalova, Tereza; Pospisilova, Mariana; Cmejla, Roman; Jerabek, Jaroslav; Mares, Pavel; Rusz, Jan

    2016-02-01

    Although rehabilitative training is a necessary adjunct in the management of gait ataxia, it remains unknown whether the possible beneficial effect of intensive coordinative training may translate to activities of daily living, which are closely connected with postural alignment. The aim of the present study was to examine the effectiveness of a 2-week intensive coordinative motor training on speech production. Speech and motor performances in a cohort of ten individuals with cerebellar degeneration were examined three times; before the introduction of training, directly and 4 weeks after the last training session. Each patient was instructed to perform a speaking task of fast syllable repetition and monologue. Objective acoustic analyses were used to investigate six key aspects of speech production disturbed in ataxic dysarthria including accuracy of consonant articulation, accuracy of vowel articulation, irregular alternating motion rates, prolonged phonemes, slow alternating motion rates and inappropriate segmentation. We found that coordinative training had a mild beneficial effect on speech in cerebellar patients. Immediately after the last training session, slight speech improvements were evident in all ten patients. Furthermore, follow-up assessment performed 4 weeks later revealed that 90 % of the patients showed better speech performance than before initiation of the therapy. The present study supports evidence that the intensive rehabilitative training may positively affect fine-motor movements such as speech in patients with cerebellar ataxia. PMID:26377098

  12. Orthostatic hypotension in acute cerebellar infarction.

    PubMed

    Kim, Hyun-Ah; Lee, Hyung

    2016-01-01

    To investigate the frequency and pattern of orthostatic hypotension (OH) associated with acute isolated cerebellar infarction, and to identify the cerebellar structure(s) potentially responsible for OH, 29 patients (mean age 60.0) with acute isolated cerebellar infarction performed a standard battery of autonomic function tests including the head up tilt test using Finapres for recording of the beat-to-beat BP response during the acute period. Cerebellar infarction related OH was defined as fall in BP (>20 mmHg systolic BP) on tilting in patients without any disease(s) that could potentially cause autonomic dysfunction, or in patients who had a potential cause of autonomic dysfunction, but showed the absence of OH during a follow-up test. The severity and distribution of autonomic dysfunction were measured by the composite autonomic severity score (CASS). Nine patients (31 %) had OH (range 24-53 mmHg) on tilting during the acute period. Most patients (7/9) had a remarkable decrement in systolic BP immediately upon tilting, but OH rapidly normalized. Mean of maximal decrease in systolic BP during head up tilt test was 37.0 mmHg. The OH group showed mild autonomic dysfunctions (CASS, 3.7) with adrenergic sympathetic dysfunction appearing as the most common abnormality. Lesion subtraction analyses revealed that damage to the medial part of the superior semilunar lobule (Crus I) and tonsil was more frequent in OH group compared to non-OH group. Cerebellar infarction may cause a brief episode of OH. The medial part of the superior semilunar lobule and tonsil may participate in regulating the early BP response during orthostasis. PMID:26530504

  13. Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia

    PubMed Central

    2011-01-01

    Background To investigate whether Stiff-person syndrome (SPS) and cerebellar ataxia (CA) are associated with distinct GAD65-Ab epitope specificities and neuronal effects. Methods Purified GAD65-Ab from neurological patients and monoclonal GAD65-Ab with distinct epitope specificities (b78 and b96.11) were administered in vivo to rat cerebellum. Effects of intra-cerebellar administration of GAD65-Ab were determined using neurophysiological and neurochemical methods. Results Intra-cerebellar administration of GAD65-Ab from a SPS patient (Ab SPS) impaired the NMDA-mediated turnover of glutamate, but had no effect on NMDA-mediated turnover of glycerol. By contrast, GAD65-Ab from a patient with cerebellar ataxia (Ab CA) markedly decreased the NMDA-mediated turnover of glycerol. Both GAD65-Ab increased the excitability of the spinal cord, as assessed by the F wave/M wave ratios. The administration of BFA, an inhibitor of the recycling of vesicles, followed by high-frequency stimulation of the cerebellum, severely impaired the cerebello-cortical inhibition only when Ab CA was used. Moreover, administration of transcranial direct current stimulation (tDCS) of the motor cortex revealed a strong disinhibition of the motor cortex with Ab CA. Monoclonal antibodies b78 and b96.11 showed distinct effects, with greater effects of b78 in terms of increase of glutamate concentrations, impairment of the adaptation of the motor cortex to repetitive peripheral stimulation, disinhibition of the motor cortex following tDCS, and increase of the F/M ratios. Ab SPS shared antibody characteristics with b78, both in epitope recognition and ability to inhibit enzyme activity, while Ab CA had no effect on GAD65 enzyme activity. Conclusions These results suggest that, in vivo, neurological impairments caused by GAD65-Ab could vary according to epitope specificities. These results could explain the different neurological syndromes observed in patients with GAD65-Ab. PMID:21294897

  14. A case report of HTLV-I associated myelopathy presenting with cerebellar ataxia and nystagmus.

    PubMed

    Taki, Masakatsu; Nin, Fumiaki; Hasegawa, Tatsuhisa; Sakaguchi, Hirofumi; Suzuki, Toshihiro; Hisa, Yasuo; Azuma, Yumiko; Nakagawa, Masanori

    2011-06-01

    HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) is characterized by spastic paraparesis in the lower extremities, and urinary disturbance. HAM/TSP has also been less frequently associated with cerebellar syndromes and nystagmus. We report a case of HAM/TSP presenting with cerebellar ataxia and nystagmus. The patient was a 73-year-old woman who was born in southern Japan. At age 41, she developed pain and spasticity in the bilateral lower limbs and gradually progressive gait disturbance. At age 57, she was diagnosed with HAM/TSP based on spastic paraparesis in the lower limbs, urinary disturbance and positive anti HTLV-I antibody in serum and cerebrospinal fluid. In June 2008, she was referred to our university and hospitalized for rehabilitation. Twenty days later, she experienced rotatory vertigo sensation. Magnetic resonance imaging revealed pontocerebellar atrophy. The patient presented with cerebellar signs in the upper limbs, gaze-evoked nystagmus in the sitting position and right-beating horizontal nystagmus in the supine and head-hanging positions. Electronystagmography (ENG) showed horizontal saccadic overshoot dysmetria and horizontal saccadic pursuit. Nystagmus is rare among the literature on HAM/TSP. ENG is helpful to evaluate and confirm the cerebellar syndromes of HAM/TSP. PMID:21035292

  15. Transplantation of human induced cerebellar granular-like cells improves motor functions in a novel mouse model of cerebellar ataxia

    PubMed Central

    Zhu, Tongming; Tang, Hailiang; Shen, Yiwen; Tang, Qisheng; Chen, Luping; Wang, Zhifu; Zhou, Ping; Xu, Feng; Zhu, Jianhong

    2016-01-01

    Stem cell-based reparative approaches have been applied to cerebellum-related disorders during the last two decades. Direct lineage reprogramming of human fibroblasts into functional granular neurons holds great promise for biomedical applications such as cerebellum regeneration and cellbased disease modeling. In the present study, we showed that a combination of Ascl1, Sox2 and OCT4, in a culture subsequently treated with secreted factors (BMP4, Wnt3a and FGF8b), was capable of converting human fibroblasts from the scalp tissue of patients with traumatic brain injury (TBI) into functional human induced cerebellar granular-like cells (hiCGCs). Morphological analysis, immunocytochemistry, gene expression and electrophysiological analysis were performed to identify the similarity of induced neuronal cells to human cerebellum granular cells. Our strategy improved the efficiency for hiCGCs induction, which gave the highest conversion efficiency 12.30±0.88%, and Ath1+/Tuj1+ double positive cells to 5.56±0.80%. We transplanted hiCGCs into the cerebellum of NmycTRE/TRE: tTS mice, a novel mouse model of cerebellar ataxia, and demonstrated that the hiCGCs were able to survive, migrate, proliferate and promote mild functional recovery after been grafted into cerebellum. PMID:27158363

  16. Induced pluripotent stem cell technology for modelling and therapy of cerebellar ataxia

    PubMed Central

    Watson, Lauren M.; Wong, Maggie M. K.; Becker, Esther B. E.

    2015-01-01

    Induced pluripotent stem cell (iPSC) technology has emerged as an important tool in understanding, and potentially reversing, disease pathology. This is particularly true in the case of neurodegenerative diseases, in which the affected cell types are not readily accessible for study. Since the first descriptions of iPSC-based disease modelling, considerable advances have been made in understanding the aetiology and progression of a diverse array of neurodegenerative conditions, including Parkinson's disease and Alzheimer's disease. To date, however, relatively few studies have succeeded in using iPSCs to model the neurodegeneration observed in cerebellar ataxia. Given the distinct neurodevelopmental phenotypes associated with certain types of ataxia, iPSC-based models are likely to provide significant insights, not only into disease progression, but also to the development of early-intervention therapies. In this review, we describe the existing iPSC-based disease models of this heterogeneous group of conditions and explore the challenges associated with generating cerebellar neurons from iPSCs, which have thus far hindered the expansion of this research. PMID:26136256

  17. Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome

    PubMed Central

    Thomas, Anna C.; Williams, Hywel; Setó-Salvia, Núria; Bacchelli, Chiara; Jenkins, Dagan; O’Sullivan, Mary; Mengrelis, Konstantinos; Ishida, Miho; Ocaka, Louise; Chanudet, Estelle; James, Chela; Lescai, Francesco; Anderson, Glenn; Morrogh, Deborah; Ryten, Mina; Duncan, Andrew J.; Pai, Yun Jin; Saraiva, Jorge M.; Ramos, Fabiana; Farren, Bernadette; Saunders, Dawn; Vernay, Bertrand; Gissen, Paul; Straatmaan-Iwanowska, Anna; Baas, Frank; Wood, Nicholas W.; Hersheson, Joshua; Houlden, Henry; Hurst, Jane; Scott, Richard; Bitner-Glindzicz, Maria; Moore, Gudrun E.; Sousa, Sérgio B.; Stanier, Philip

    2014-01-01

    Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum. PMID:25439728

  18. Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome.

    PubMed

    Thomas, Anna C; Williams, Hywel; Setó-Salvia, Núria; Bacchelli, Chiara; Jenkins, Dagan; O'Sullivan, Mary; Mengrelis, Konstantinos; Ishida, Miho; Ocaka, Louise; Chanudet, Estelle; James, Chela; Lescai, Francesco; Anderson, Glenn; Morrogh, Deborah; Ryten, Mina; Duncan, Andrew J; Pai, Yun Jin; Saraiva, Jorge M; Ramos, Fabiana; Farren, Bernadette; Saunders, Dawn; Vernay, Bertrand; Gissen, Paul; Straatmaan-Iwanowska, Anna; Baas, Frank; Wood, Nicholas W; Hersheson, Joshua; Houlden, Henry; Hurst, Jane; Scott, Richard; Bitner-Glindzicz, Maria; Moore, Gudrun E; Sousa, Sérgio B; Stanier, Philip

    2014-11-01

    Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum. PMID:25439728

  19. Inferior cerebellar hypoplasia resembling a Dandy-Walker-like malformation in purebred Eurasier dogs with familial non-progressive ataxia: a retrospective and prospective clinical cohort study.

    PubMed

    Bernardino, Filipa; Rentmeister, Kai; Schmidt, Martin J; Bruehschwein, Andreas; Matiasek, Kaspar; Matiasek, Lara A; Lauda, Alexander; Schoon, Heinz A; Fischer, Andrea

    2015-01-01

    Cerebellar malformations can be inherited or caused by insults during cerebellar development. To date, only sporadic cases of cerebellar malformations have been reported in dogs, and the genetic background has remained obscure. Therefore, this study`s objective was to describe the clinical characteristics, imaging features and pedigree data of a familial cerebellar hypoplasia in purebred Eurasier dogs. A uniform cerebellar malformation characterized by consistent absence of the caudal portions of the cerebellar vermis and, to a lesser degree, the caudal portions of the cerebellar hemispheres in association with large retrocerebellar fluid accumulations was recognized in 14 closely related Eurasier dogs. Hydrocephalus was an additional feature in some dogs. All dogs displayed non-progressive ataxia, which had already been noted when the dogs were 5-6 weeks old. The severity of the ataxia varied between dogs, from mild truncal sway, subtle dysmetric gait, dysequilibrium and pelvic limb ataxia to severe cerebellar ataxia in puppies and episodic falling or rolling. Follow-up examinations in adult dogs showed improvement of the cerebellar ataxia and a still absent menace response. Epileptic seizures occurred in some dogs. The association of partial vermis agenesis with an enlarged fourth ventricle and an enlarged caudal (posterior) fossa resembled a Dandy-Walker-like malformation in some dogs. Pedigree analyses were consistent with autosomal recessive inheritance. PMID:25668516

  20. UBA5 Mutations Cause a New Form of Autosomal Recessive Cerebellar Ataxia.

    PubMed

    Duan, Ranhui; Shi, Yuting; Yu, Li; Zhang, Gehan; Li, Jia; Lin, Yunting; Guo, Jifeng; Wang, Junling; Shen, Lu; Jiang, Hong; Wang, Guanghui; Tang, Beisha

    2016-01-01

    Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. For many affected patients, the genetic cause remains undetermined. Through whole-exome sequencing, we identified compound heterozygous mutations in ubiquitin-like modifier activating enzyme 5 gene (UBA5) in two Chinese siblings presenting with ARCA. Moreover, copy number variations in UBA5 or ubiquitin-fold modifier 1 gene (UFM1) were documented with the phenotypes of global developmental delays and gait disturbances in the ClinVar database. UBA5 encodes UBA5, the ubiquitin-activating enzyme of UFM1. However, a crucial role for UBA5 in human neurological disease remains to be reported. Our molecular study of UBA5-R246X revealed a dramatically decreased half-life and loss of UFM1 activation due to the absence of the catalytic cysteine Cys250. UBA5-K310E maintained its interaction with UFM1, although with less stability, which may affect the ability of this UBA5 mutant to activate UFM1. Drosophila modeling revealed that UBA5 knockdown induced locomotive defects and a shortened lifespan accompanied by aberrant neuromuscular junctions (NMJs). Strikingly, we found that UFM1 and E2 cofactor knockdown induced markedly similar phenotypes. Wild-type UBA5, but not mutant UBA5, significantly restored neural lesions caused by the absence of UBA5. The finding of a UBA5 mutation in cerebellar ataxia suggests that impairment of the UFM1 pathway may contribute to the neurological phenotypes of ARCA. PMID:26872069

  1. UBA5 Mutations Cause a New Form of Autosomal Recessive Cerebellar Ataxia

    PubMed Central

    Yu, Li; Zhang, Gehan; Li, Jia; Lin, Yunting; Guo, Jifeng; Wang, Junling; Shen, Lu; Jiang, Hong; Wang, Guanghui; Tang, Beisha

    2016-01-01

    Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. For many affected patients, the genetic cause remains undetermined. Through whole-exome sequencing, we identified compound heterozygous mutations in ubiquitin-like modifier activating enzyme 5 gene (UBA5) in two Chinese siblings presenting with ARCA. Moreover, copy number variations in UBA5 or ubiquitin-fold modifier 1 gene (UFM1) were documented with the phenotypes of global developmental delays and gait disturbances in the ClinVar database. UBA5 encodes UBA5, the ubiquitin-activating enzyme of UFM1. However, a crucial role for UBA5 in human neurological disease remains to be reported. Our molecular study of UBA5-R246X revealed a dramatically decreased half-life and loss of UFM1 activation due to the absence of the catalytic cysteine Cys250. UBA5-K310E maintained its interaction with UFM1, although with less stability, which may affect the ability of this UBA5 mutant to activate UFM1. Drosophila modeling revealed that UBA5 knockdown induced locomotive defects and a shortened lifespan accompanied by aberrant neuromuscular junctions (NMJs). Strikingly, we found that UFM1 and E2 cofactor knockdown induced markedly similar phenotypes. Wild-type UBA5, but not mutant UBA5, significantly restored neural lesions caused by the absence of UBA5. The finding of a UBA5 mutation in cerebellar ataxia suggests that impairment of the UFM1 pathway may contribute to the neurological phenotypes of ARCA. PMID:26872069

  2. Emerging evidence of coding mutations in the ubiquitin-proteasome system associated with cerebellar ataxias.

    PubMed

    Ronnebaum, Sarah M; Patterson, Cam; Schisler, Jonathan C

    2014-01-01

    Cerebellar ataxia (CA) is a disorder associated with impairments in balance, coordination, and gait caused by degeneration of the cerebellum. The mutations associated with CA affect functionally diverse genes; furthermore, the underlying genetic basis of a given CA is unknown in many patients. Exome sequencing has emerged as a cost-effective technology to discover novel genetic mutations, including autosomal recessive CA (ARCA). Five recent studies that describe how exome sequencing performed on a diverse pool of ARCA patients revealed 14 unique mutations in STUB1, a gene that encodes carboxy terminus of Hsp70-interacting protein (CHIP). CHIP mediates protein quality control through chaperone and ubiquitin ligase activities and is implicated in alleviating proteotoxicity in several neurodegenerative diseases. However, these recent studies linking STUB1 mutations to various forms of ataxia are the first indications that CHIP is directly involved in the progression of a human disease. Similar exome-sequencing studies have revealed novel mutations in ubiquitin-related proteins associated with CA and other neurological disorders. This review provides an overview of CA, describes the benefits and limitations of exome sequencing, outlines newly discovered STUB1 mutations, and theorizes on how CHIP and other ubiquitin-related proteins function to prevent neurological deterioration. PMID:27081508

  3. Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity.

    PubMed

    Stefely, Jonathan A; Licitra, Floriana; Laredj, Leila; Reidenbach, Andrew G; Kemmerer, Zachary A; Grangeray, Anais; Jaeg-Ehret, Tiphaine; Minogue, Catherine E; Ulbrich, Arne; Hutchins, Paul D; Wilkerson, Emily M; Ruan, Zheng; Aydin, Deniz; Hebert, Alexander S; Guo, Xiao; Freiberger, Elyse C; Reutenauer, Laurence; Jochem, Adam; Chergova, Maya; Johnson, Isabel E; Lohman, Danielle C; Rush, Matthew J P; Kwiecien, Nicholas W; Singh, Pankaj K; Schlagowski, Anna I; Floyd, Brendan J; Forsman, Ulrika; Sindelar, Pavel J; Westphall, Michael S; Pierrel, Fabien; Zoll, Joffrey; Dal Peraro, Matteo; Kannan, Natarajan; Bingman, Craig A; Coon, Joshua J; Isope, Philippe; Puccio, Hélène; Pagliarini, David J

    2016-08-18

    The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease. PMID:27499294

  4. Cerebellar Expression of the Neurotrophin Receptor p75 in Naked-Ataxia Mutant Mouse

    PubMed Central

    Rahimi Balaei, Maryam; Jiao, Xiaodan; Ashtari, Niloufar; Afsharinezhad, Pegah; Ghavami, Saeid; Marzban, Hassan

    2016-01-01

    Spontaneous mutation in the lysosomal acid phosphatase 2 (Acp2) mouse (nax—naked-ataxia mutant mouse) correlates with severe cerebellar defects including ataxia, reduced size and abnormal lobulation as well as Purkinje cell (Pc) degeneration. Loss of Pcs in the nax cerebellum is compartmentalized and harmonized to the classic pattern of gene expression of the cerebellum in the wild type mouse. Usually, degeneration starts in the anterior and posterior zones and continues to the central and nodular zones of cerebellum. Studies have suggested that the p75 neurotrophin receptor (NTR) plays a role in Pc degeneration; thus, in this study, we investigated the p75NTR pattern and protein expression in the cerebellum of the nax mutant mouse. Despite massive Pc degeneration that was observed in the nax mouse cerebellum, p75NTR pattern expression was similar to the HSP25 pattern in nax mice and comparable with wild type sibling cerebellum. In addition, immunoblot analysis of p75NTR protein expression did not show any significant difference between nax and wild type sibling (p > 0.5). In comparison with wild type counterparts, p75NTR pattern expression is aligned with the fundamental cytoarchitecture organization of the cerebellum and is unchanged in the nax mouse cerebellum despite the severe neurodevelopmental disorder accompanied with Pc degeneration. PMID:26784182

  5. Cerebellar ataxia and severe muscle CoQ10 deficiency in a patient with a novel mutation in ADCK3.

    PubMed

    Barca, E; Musumeci, O; Montagnese, F; Marino, S; Granata, F; Nunnari, D; Peverelli, L; DiMauro, S; Quinzii, C M; Toscano, A

    2016-08-01

    Inherited ataxias are a group of heterogeneous disorders in children or adults but their genetic definition remains still undetermined in almost half of the patients. However, CoQ10 deficiency is a rare cause of cerebellar ataxia and ADCK3 is the most frequent gene associated with this defect. We herein report a 48 year old man, who presented with dysarthria and walking difficulties. Brain magnetic resonance imaging showed a marked cerebellar atrophy. Serum lactate was elevated. Tissues obtained by muscle and skin biopsies were studied for biochemical and genetic characterization. Skeletal muscle biochemistry revealed decreased activities of complexes I+III and II+III and a severe reduction of CoQ10 , while skin fibroblasts showed normal CoQ10 levels. A mild loss of maximal respiration capacity was also found by high-resolution respirometry. Molecular studies identified a novel homozygous deletion (c.504del_CT) in ADCK3, causing a premature stop codon. Western blot analysis revealed marked reduction of ADCK3 protein levels. Treatment with CoQ10 was started and, after 1 year follow-up, patient neurological condition slightly improved. This report suggests the importance of investigating mitochondrial function and, in particular, muscle CoQ10 levels, in patients with adult-onset cerebellar ataxia. Moreover, clinical stabilization by CoQ10 supplementation emphasizes the importance of an early diagnosis. PMID:26818466

  6. Ataxia

    PubMed Central

    Akbar, Umar; Ashizawa, Tetsuo

    2014-01-01

    Balance and coordination are products of complex circuitry involving the basal ganglia, cerebellum and cerebral cortex, as well as peripheral motor and sensory pathways. Malfunction of any part of this intricate circuitry can lead to imbalance and incoordination, or ataxia, of gait, the limbs or eyes, or a combination thereof. Ataxia can be a symptom of a multisystemic disorder, or it can manifest as the major component of a disease process. Ongoing discoveries of genetic abnormalities suggest the role ofmitochondrial dysfunction, oxidative stress, abnormal mechanisms of DNA repair, possible protein misfolding, and abnormalities in cytoskeletal proteins. Few ataxias are fully treatable, and most are symptomatically managed. A discussion of the ataxias is presented here with brief mention of acquired ataxias, and a greater focus on inherited ataxias. PMID:25432731

  7. Cerebellar Soluble Mutant Ataxin-3 Level Decreases during Disease Progression in Spinocerebellar Ataxia Type 3 Mice

    PubMed Central

    Weber, Jonasz Jeremiasz; Grueninger, Stephan; Riess, Olaf; Weiss, Andreas

    2013-01-01

    Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominantly inherited neurodegenerative disease caused by an expanded polyglutamine stretch in the ataxin-3 protein. A pathological hallmark of the disease is cerebellar and brainstem atrophy, which correlates with the formation of intranuclear aggregates in a specific subset of neurons. Several studies have demonstrated that the formation of aggregates depends on the generation of aggregation-prone and toxic intracellular ataxin-3 fragments after proteolytic cleavage of the full-length protein. Despite this observed increase in aggregated mutant ataxin-3, information on soluble mutant ataxin-3 levels in brain tissue is lacking. A quantitative method to analyze soluble levels will be a useful tool to characterize disease progression or to screen and identify therapeutic compounds modulating the level of toxic soluble ataxin-3. In the present study we describe the development and application of a quantitative and easily applicable immunoassay for quantification of soluble mutant ataxin-3 in human cell lines and brain samples of transgenic SCA3 mice. Consistent with observations in Huntington disease, transgenic SCA3 mice reveal a tendency for decrease of soluble mutant ataxin-3 during disease progression in fractions of the cerebellum, which is inversely correlated with aggregate formation and phenotypic aggravation. Our analyses demonstrate that the time-resolved Förster resonance energy transfer immunoassay is a highly sensitive and easy method to measure the level of soluble mutant ataxin-3 in biological samples. Of interest, we observed a tendency for decrease of soluble mutant ataxin-3 only in the cerebellum of transgenic SCA3 mice, one of the most affected brain regions in Spinocerebellar Ataxia Type 3 but not in whole brain tissue, indicative of a brain region selective change in mutant ataxin-3 protein homeostasis. PMID:23626768

  8. Cerebellar soluble mutant ataxin-3 level decreases during disease progression in Spinocerebellar Ataxia Type 3 mice.

    PubMed

    Nguyen, Huu Phuc; Hübener, Jeannette; Weber, Jonasz Jeremiasz; Grueninger, Stephan; Riess, Olaf; Weiss, Andreas

    2013-01-01

    Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominantly inherited neurodegenerative disease caused by an expanded polyglutamine stretch in the ataxin-3 protein. A pathological hallmark of the disease is cerebellar and brainstem atrophy, which correlates with the formation of intranuclear aggregates in a specific subset of neurons. Several studies have demonstrated that the formation of aggregates depends on the generation of aggregation-prone and toxic intracellular ataxin-3 fragments after proteolytic cleavage of the full-length protein. Despite this observed increase in aggregated mutant ataxin-3, information on soluble mutant ataxin-3 levels in brain tissue is lacking. A quantitative method to analyze soluble levels will be a useful tool to characterize disease progression or to screen and identify therapeutic compounds modulating the level of toxic soluble ataxin-3. In the present study we describe the development and application of a quantitative and easily applicable immunoassay for quantification of soluble mutant ataxin-3 in human cell lines and brain samples of transgenic SCA3 mice. Consistent with observations in Huntington disease, transgenic SCA3 mice reveal a tendency for decrease of soluble mutant ataxin-3 during disease progression in fractions of the cerebellum, which is inversely correlated with aggregate formation and phenotypic aggravation. Our analyses demonstrate that the time-resolved Förster resonance energy transfer immunoassay is a highly sensitive and easy method to measure the level of soluble mutant ataxin-3 in biological samples. Of interest, we observed a tendency for decrease of soluble mutant ataxin-3 only in the cerebellum of transgenic SCA3 mice, one of the most affected brain regions in Spinocerebellar Ataxia Type 3 but not in whole brain tissue, indicative of a brain region selective change in mutant ataxin-3 protein homeostasis. PMID:23626768

  9. Rapid Onset of Motor Deficits in a Mouse Model of Spinocerebellar Ataxia Type 6 Precedes Late Cerebellar Degeneration123

    PubMed Central

    Ljungberg, Lovisa; Cormier, Alexander; Quilez, Sabrina

    2015-01-01

    Abstract Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant cerebellar ataxia that has been associated with loss of cerebellar Purkinje cells. Disease onset is typically at midlife, although it can vary widely from late teens to old age in SCA6 patients. Our study focused on an SCA6 knock-in mouse model with a hyper-expanded (84X) CAG repeat expansion that displays midlife-onset motor deficits at ∼7 months old, reminiscent of midlife-onset symptoms in SCA6 patients, although a detailed phenotypic analysis of these mice has not yet been reported. Here, we characterize the onset of motor deficits in SCA684Q mice using a battery of behavioral assays to test for impairments in motor coordination, balance, and gait. We found that these mice performed normally on these assays up to and including at 6 months, but motor impairment was detected at 7 months with all motor coordination assays used, suggesting that motor deficits emerge rapidly during a narrow age window in SCA684Q mice. In contrast to what is seen in SCA6 patients, the decrease in motor coordination was observed without alterations in gait. No loss of cerebellar Purkinje cells or striatal neurons were observed at 7 months, the age at which motor deficits were first detected, but significant Purkinje cell loss was observed in 2-year-old SCA684Q mice, arguing that Purkinje cell death does not significantly contribute to the early stages of SCA6. PMID:26730403

  10. Abnormal cerebellar volume in acute and remitted major depression.

    PubMed

    Depping, Malte S; Wolf, Nadine D; Vasic, Nenad; Sambataro, Fabio; Hirjak, Dusan; Thomann, Philipp A; Wolf, Robert C

    2016-11-01

    Abnormal cortical volume is well-documented in patients with major depressive disorder (MDD), but cerebellar findings have been heterogeneous. It is unclear whether abnormal cerebellar structure relates to disease state or medication. In this study, using structural MRI, we investigated cerebellar volume in clinically acute (with and without psychotropic treatment) and remitted MDD patients. High-resolution structural MRI data at 3T were obtained from acute medicated (n=29), acute unmedicated (n=14) and remitted patients (n=16). Data from 29 healthy controls were used for comparison purposes. Cerebellar volume was investigated using cerebellum-optimized voxel-based analysis methods. Patients with an acute MDD episode showed increased volume of left cerebellar area IX, and this was true for both medicated and unmedicated individuals (p<0.05 cluster-corrected). Remitted patients exhibited bilaterally increased area IX volume. In remitted, but not in acutely ill patients, area IX volume was significantly associated with measures of depression severity, as assessed by the Hamilton Depression Rating Scale (HAMD). In addition, area IX volume in remitted patients was significantly related to the duration of antidepressant treatment. In acutely ill patients, no significant relationships were established using clinical variables, such as HAMD, illness or treatment duration and number of depressive episodes. The data suggest that cerebellar area IX, a non-motor region that belongs to a large-scale brain functional network with known relevance to core depressive symptom expression, exhibits abnormal volume in patients independent of clinical severity or medication. Thus, the data imply a possible trait marker of the disorder. However, given bilaterality and an association with clinical scores at least in remitted patients, the current findings raise the possibility that cerebellar volume may be reflective of successful treatment as well. PMID:27321187

  11. The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation

    PubMed Central

    Mallaret, Martial; Synofzik, Matthis; Lee, Jaeho; Sagum, Cari A.; Mahajnah, Muhammad; Sharkia, Rajech; Drouot, Nathalie; Renaud, Mathilde; Klein, Fabrice A. C.; Anheim, Mathieu; Tranchant, Christine; Mignot, Cyril; Mandel, Jean-Louis; Bedford, Mark; Bauer, Peter; Salih, Mustafa A.; Schüle, Rebecca; Schöls, Ludger; Aldaz, C. Marcelo

    2014-01-01

    We previously localized a new form of recessive ataxia with generalized tonic-clonic epilepsy and mental retardation to a 19 Mb interval in 16q21-q23 by homozygosity mapping of a large consanguineous Saudi Arabian family. We now report the identification by whole exome sequencing of the missense mutation changing proline 47 into threonine in the first WW domain of the WW domain containing oxidoreductase gene, WWOX, located in the linkage interval. Proline 47 is a highly conserved residue that is part of the WW motif consensus sequence and is part of the hydrophobic core that stabilizes the WW fold. We demonstrate that proline 47 is a key amino acid essential for maintaining the WWOX protein fully functional, with its mutation into a threonine resulting in a loss of peptide interaction for the first WW domain. We also identified another highly conserved homozygous WWOX mutation changing glycine 372 to arginine in a second consanguineous family. The phenotype closely resembled the index family, presenting with generalized tonic-clonic epilepsy, mental retardation and ataxia, but also included prominent upper motor neuron disease. Moreover, we observed that the short-lived Wwox knock-out mouse display spontaneous and audiogenic seizures, a phenotype previously observed in the spontaneous Wwox mutant rat presenting with ataxia and epilepsy, indicating that homozygous WWOX mutations in different species causes cerebellar ataxia associated with epilepsy. PMID:24369382

  12. Vermectomy enhances parvalbumin expression and improves motor performance in weaver mutant mice: an animal model for cerebellar ataxia.

    PubMed

    Grüsser-Cornehls, U; Grüsser, C; Bäurle, J

    1999-01-01

    In the Weaver mutant mouse (wv/wv), an animal model for hereditary cerebellar ataxia, electrophysiological experiments have revealed a disorganized output of cerebellar Purkinje cells (the latter using GABA as an inhibitory transmitter) which, by a cascade of mechanisms, was thought to be the cause of the poor motor abilities. In Purkinje cell degeneration mice (pcd/pcd) lacking nearly all Purkinje cells and displaying milder motor deficiencies than wv, in comparison to wild-type mice, a strong increase in parvalbumin- and (co-localized with parvalbumin) glycine-immunopositive somata in the deep cerebellar and vestibular nuclei has recently been found. It was therefore intriguing to investigate whether motor performance in weaver mutants could be ameliorated by applying cerebellar lesions to eliminate the faulty output and to look for a change in transmitter weighting, indicated by a strong increase in parvalbumin-positive somata in areas (the respective target areas) which were formerly devoid of it. Ten Weaver mutants were subjected to cerebellar lesions. After removal of the vermis a total abolition of tremor, a definite improvement in the balance of affected body parts, an increase in locomotor activity when tested in an open-field matrix, and a strong increase in parvalbumin expression in Weaver mutant deep cerebellar and vestibular nuclei in comparison to wild-types have indeed been found. Increase in motor activity (or explorative behaviour) has been placed in relation to learning mechanisms. The increase in parvalbumin expression and the observed improvement in motor abilities and mechanisms probably related to learning underline the hypothesis that any change in the physiological equilibrium of the brain function by removal of input or output related to an assembly of nerve cells leads to a cascade of changes at the transmitter and neuronal level in near or distant connected brain structures. PMID:10336081

  13. Lgr4 protein deficiency induces ataxia-like phenotype in mice and impairs long term depression at cerebellar parallel fiber-Purkinje cell synapses.

    PubMed

    Guan, Xin; Duan, Yanhong; Zeng, Qingwen; Pan, Hongjie; Qian, Yu; Li, Dali; Cao, Xiaohua; Liu, Mingyao

    2014-09-19

    Cerebellar dysfunction causes ataxia characterized by loss of balance and coordination. Until now, the molecular and neuronal mechanisms of several types of inherited cerebellar ataxia have not been completely clarified. Here, we report that leucine-rich G protein-coupled receptor 4 (Lgr4/Gpr48) is highly expressed in Purkinje cells (PCs) in the cerebellum. Deficiency of Lgr4 leads to an ataxia-like phenotype in mice. Histologically, no obvious morphological changes were observed in the cerebellum of Lgr4 mutant mice. However, the number of PCs was slightly but significantly reduced in Lgr4(-/-) mice. In addition, in vitro electrophysiological analysis showed an impaired long term depression (LTD) at parallel fiber-PC (PF-PC) synapses in Lgr4(-/-) mice. Consistently, immunostaining experiments showed that the level of phosphorylated cAMP-responsive element-binding protein (Creb) was significantly decreased in Lgr4(-/-) PCs. Furthermore, treatment with forskolin, an adenylyl cyclase agonist, rescued phospho-Creb in PCs and reversed the impairment in PF-PC LTD in Lgr4(-/-) cerebellar slices, indicating that Lgr4 is an upstream regulator of Creb signaling, which is underlying PF-PC LTD. Together, our findings demonstrate for first time an important role for Lgr4 in motor coordination and cerebellar synaptic plasticity and provide a potential therapeutic target for certain types of inherited cerebellar ataxia. PMID:25063812

  14. [An acute severe heat stroke patient showing abnormal diffuse high intensity of the cerebellar cortex in diffusion weighted image: a case report].

    PubMed

    Fujioka, Yusuke; Yasui, Keizo; Hasegawa, Yasuhiro; Takahashi, Akira; Sobue, Gen

    2009-10-01

    A 47-year-old man was admitted to the hospital because of general convulsion, loss of consciousness and hyperthermia. A diagnosis of acute heat stroke was made clinically and neuroradiologically. As the consciousness level ameliorated, he developed severe abulia and mutism, then cerebellar ataxic syndrome (viz. truncal ataxia, hypermetria, ataxic speech and nystagmus). An MRI (diffusion weighted image; DWI) disclosed abnormal diffuse high signal intensity of the cerebellar cortex with reduced apparent diffusion coefficient (ADC). Two months later after the onset, truncal ataxia and dysarthria significantly improved, while dysmetria of the extremities rather worsened. At that time, the abnormal signal intensity of the cerebellar cortex disappeared, and the cerebellum became atrophic. The cerebellar blood flow was significantly decreased on brain SPECT (99mTc-ECD). The abnormal DWI signal intensity of the cerebellar cortex in the present patient may represent the cytotoxic edema of Purkinje cells resulting from heat stroke-related hyperthermia It is essential to repeat MRI examination for cerebellar pathology and to obtain better insight into sequelae in patients with acute heat stroke. Protirelin tartrate seemed to be valid for improvement of abulia in the present patient. Further study is indicated. PMID:19999144

  15. Accuracy and repeatability of two methods of gait analysis - GaitRite™ und Mobility Lab™ - in subjects with cerebellar ataxia.

    PubMed

    Schmitz-Hübsch, Tanja; Brandt, Alexander U; Pfueller, Caspar; Zange, Leonora; Seidel, Adrian; Kühn, Andrea A; Paul, Friedemann; Minnerop, Martina; Doss, Sarah

    2016-07-01

    Instrumental gait analysis is increasingly recognized as a useful tool for the evaluation of movement disorders. The various assessment devices available to date have mostly been evaluated in healthy populations only. We aimed to explore whether reliability and validity seen in healthy subjects can also be assumed in subjects with cerebellar ataxic gait. Gait was recorded simultaneously with two devices - a sensor-embedded walkway and an inertial sensor based system - to explore test accuracy in two groups of subjects: one with mild to moderate cerebellar ataxia due to a subtype of autosomal-dominantly inherited neurodegenerative disorder (SCA14), the other were healthy subjects matched for age and height (CTR). Test precision was assessed by retest within session for each device. In conclusion, accuracy and repeatability of gait measurements were not compromised by ataxic gait disorder. The accuracy of spatial measures was speed-dependent and a direct comparison of stride length from both devices will be most reliably made at comfortable speed. Measures of stride variability had low agreement between methods in CTR and at retest in both groups. However, the marked increase of stride variability in ataxia outweighs the observed amount of imprecision. PMID:27289221

  16. Verb Generation in Children and Adolescents with Acute Cerebellar Lesions

    ERIC Educational Resources Information Center

    Frank, B.; Schoch, B.; Hein-Kropp, C.; Dimitrova, A.; Hovel, M.; Ziegler, W.; Gizewski, E. R.; Timmann, D.

    2007-01-01

    The aim of the present study was to examine verb generation in a larger group of children and adolescents with acute focal lesions of the cerebellum. Nine children and adolescents with cerebellar tumours participated. Subjects were tested a few days after tumour surgery. For comparison, a subgroup was tested also 1 or 2 days before surgery. None…

  17. A SEL1L Mutation Links a Canine Progressive Early-Onset Cerebellar Ataxia to the Endoplasmic Reticulum–Associated Protein Degradation (ERAD) Machinery

    PubMed Central

    Kyöstilä, Kaisa; Cizinauskas, Sigitas; Seppälä, Eija H.; Suhonen, Esko; Jeserevics, Janis; Sukura, Antti; Syrjä, Pernilla; Lohi, Hannes

    2012-01-01

    Inherited ataxias are characterized by degeneration of the cerebellar structures, which results in progressive motor incoordination. Hereditary ataxias occur in many species, including humans and dogs. Several mutations have been found in humans, but the genetic background has remained elusive in dogs. The Finnish Hound suffers from an early-onset progressive cerebellar ataxia. We have performed clinical, pathological, and genetic studies to describe the disease phenotype and to identify its genetic cause. Neurological examinations on ten affected dogs revealed rapidly progressing generalized cerebellar ataxia, tremors, and failure to thrive. Clinical signs were present by the age of 3 months, and cerebellar shrinkage was detectable through MRI. Pathological and histological examinations indicated cerebellum-restricted neurodegeneration. Marked loss of Purkinje cells was detected in the cerebellar cortex with secondary changes in other cortical layers. A genome-wide association study in a cohort of 31 dogs mapped the ataxia gene to a 1.5 Mb locus on canine chromosome 8 (praw = 1.1×10−7, pgenome = 7.5×10−4). Sequencing of a functional candidate gene, sel-1 suppressor of lin-12-like (SEL1L), revealed a homozygous missense mutation, c.1972T>C; p.Ser658Pro, in a highly conserved protein domain. The mutation segregated fully in the recessive pedigree, and a 10% carrier frequency was indicated in a population cohort. SEL1L is a component of the endoplasmic reticulum (ER)–associated protein degradation (ERAD) machinery and has not been previously associated to inherited ataxias. Dysfunctional protein degradation is known to cause ER stress, and we found a significant increase in expression of nine ER stress responsive genes in the cerebellar cortex of affected dogs, supporting the pathogenicity of the mutation. Our study describes the first early-onset neurodegenerative ataxia mutation in dogs, establishes an ERAD–mediated neurodegenerative disease model

  18. Into the depths of ataxia

    PubMed Central

    Orr, Harry T.

    2004-01-01

    Ataxia is a lethal neurological disease characterized by incoordination, postural abnormalities, difficulties with gait, and problems with clarity of speech. The etiology of ataxia is divided equally between hereditary and sporadic forms. Regardless of cause, the cerebellar cortex is often a target in ataxia. Thus, how a disruption in cerebellar cortex might lead to ataxia is of considerable interest. A report in this issue of the JCI links ataxia to enhanced hyperexcitability of neurons in the deep cerebellar nuclei. PMID:14966557

  19. Vitamin B12 deficiency presenting as acute ataxia.

    PubMed

    Crawford, John Ross; Say, Daphne

    2013-01-01

    A previously healthy 7-year-old Caucasian boy was hospitalised for evaluation of acute ataxia and failure to thrive, initially suspicious for an intracranial mass. Weight and body mass index were below the third percentile and he demonstrated loss of joint position and vibratory sense on examination. Laboratory studies revealed megaloblastic anaemia while an initial MRI of the brain showed no evidence of mass lesions or other abnormalities. A dietary history revealed the child subscribed to a restrictive vegan diet with little to no intake of animal products or other fortified foods. The child was diagnosed with presumed vitamin B12 deficiency and was treated with intramuscular B12 injections. Neurological symptoms resolved promptly within several days after starting therapy. This case underlines the importance of assessing nutritional status in the evaluation of neurological dysfunction in the pediatric patient. PMID:23536622

  20. Vitamin B12 deficiency presenting as acute ataxia

    PubMed Central

    Crawford, John Ross; Say, Daphne

    2013-01-01

    A previously healthy 7-year-old Caucasian boy was hospitalised for evaluation of acute ataxia and failure to thrive, initially suspicious for an intracranial mass. Weight and body mass index were below the third percentile and he demonstrated loss of joint position and vibratory sense on examination. Laboratory studies revealed megaloblastic anaemia while an initial MRI of the brain showed no evidence of mass lesions or other abnormalities. A dietary history revealed the child subscribed to a restrictive vegan diet with little to no intake of animal products or other fortified foods. The child was diagnosed with presumed vitamin B12 deficiency and was treated with intramuscular B12 injections. Neurological symptoms resolved promptly within several days after starting therapy. This case underlines the importance of assessing nutritional status in the evaluation of neurological dysfunction in the pediatric patient. PMID:23536622

  1. Loss of Intrinsic Organization of Cerebellar Networks in Spinocerebellar Ataxia Type 1: Correlates with Disease Severity and Duration

    PubMed Central

    Peri, Eitan; Chen, E. Elinor; Ben-Jacob, Eshel; Gomez, Christopher M.

    2011-01-01

    The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of cerebellar degenerative disorders, characterized by progressive gait unsteadiness, hand incoordination, and dysarthria. The mutational mechanism in SCA1, a dominantly inherited form of SCA, consists of an expanded trinucleotide CAG repeat. In SCA1, there is loss of Purkinje cells, neuronal loss in dentate nucleus, olives, and pontine nuclei. In the present study, we sought to apply intrinsic functional connectivity analysis combined with diffusion tensor imaging to define the state of cerebellar connectivity in SCA1. Our results on the intrinsic functional connectivity in lateral cerebellum and thalamus showed progressive organizational changes in SCA1 noted as a progressive increase in the absolute value of the correlation coefficients. In the lateral cerebellum, the anatomical organization of functional clusters seen as parasagittal bands in controls is lost, changing to a patchy appearance in SCA1. Lastly, only fractional anisotropy in the superior peduncle and changes in functional organization in thalamus showed a linear dependence to duration and severity of disease. The present pilot work represents an initial effort describing connectivity biomarkers of disease progression in SCA1. The functional changes detected with intrinsic functional analysis and diffusion tensor imaging suggest that disease progression can be analyzed as a disconnection syndrome. PMID:20886327

  2. Targeted Next-Generation Sequencing of a 12.5 Mb Homozygous Region Reveals ANO10 Mutations in Patients with Autosomal-Recessive Cerebellar Ataxia

    PubMed Central

    Vermeer, Sascha; Hoischen, Alexander; Meijer, Rowdy P.P.; Gilissen, Christian; Neveling, Kornelia; Wieskamp, Nienke; de Brouwer, Arjan; Koenig, Michel; Anheim, Mathieu; Assoum, Mirna; Drouot, Nathalie; Todorovic, Slobodanka; Milic-Rasic, Vedrana; Lochmüller, Hanns; Stevanin, Giovanni; Goizet, Cyril; David, Albert; Durr, Alexandra; Brice, Alexis; Kremer, Berry; van de Warrenburg, Bart P.C.; Schijvenaars, Mascha M.V.A.P.; Heister, Angelien; Kwint, Michael; Arts, Peer; van der Wijst, Jenny; Veltman, Joris; Kamsteeg, Erik-Jan; Scheffer, Hans; Knoers, Nine

    2010-01-01

    Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations provide incomplete coverage for genotyping of patients. By combining SNP array-based linkage analysis and targeted resequencing of relevant sequences in the linkage interval with the use of next-generation sequencing technology, we identified a mutation in a gene and have shown its association with autosomal-recessive cerebellar ataxia. In a Dutch consanguineous family with three affected siblings a homozygous 12.5 Mb region on chromosome 3 was targeted by array-based sequence capture. Prioritization of all detected sequence variants led to four candidate genes, one of which contained a variant with a high base pair conservation score (phyloP score: 5.26). This variant was a leucine-to-arginine substitution in the DUF 590 domain of a 16K transmembrane protein, a putative calcium-activated chloride channel encoded by anoctamin 10 (ANO10). The analysis of ANO10 by Sanger sequencing revealed three additional mutations: a homozygous mutation (c.1150_1151del [p.Leu384fs]) in a Serbian family and a compound-heterozygous splice-site mutation (c.1476+1G>T) and a frameshift mutation (c.1604del [p.Leu535X]) in a French family. This illustrates the power of using initial homozygosity mapping with next-generation sequencing technology to identify genes involved in autosomal-recessive diseases. Moreover, identifying a putative calcium-dependent chloride channel involved in cerebellar ataxia adds another pathway to the list of pathophysiological mechanisms that may cause cerebellar ataxia. PMID:21092923

  3. Acute cerebellar dysfunction with neuromuscular manifestations after scorpionism presumably caused by Tityus obscurus in Santarém, Pará / Brazil.

    PubMed

    Torrez, Pasesa P Q; Quiroga, Mariana M M; Abati, Paulo A M; Mascheretti, Melissa; Costa, Walter Silva; Campos, Luciana P; França, Francisco O S

    2015-03-01

    Scorpionism is a public health problem in many tropical countries, especially in North Africa, South India, Latin America and the Middle East. In Brazil, patients with severe scorpion envenoming have mainly cardiovascular events, including acute heart failure, acute respiratory distress syndrome and shock, death is rare. We described 58 accidents presumably caused by Tityus obscurus in Brazilian Amazonia. Patients reported a sensation of "electric shocks" which could last hours. The vast majority of patients presented a clinical picture compatible with acute cerebellar dysfunction, beginning minutes and lasting up to 2 days after the accident. They presented cerebellar ataxia, dysdiadochokinesia, dysmetry, dysarthria, dyslalia, nausea and vomiting. Besides, some patients presented myoclonus and fasciculation which can also be attributed to cerebellar dysfunction or maybe the result of direct action on skeletal muscle. Two patients had evidence of intense rhabdomyolysis and acute kidney injury. The clinical picture in this scorpion envenoming is mainly characterized by an acute dysfunction of cerebellar activities and abnormal neuromuscular manifestations and in some cases muscle injury which are not described in any other region of the world. This work presents clinical, epidemiologic, laboratory and treatment aspects of this unmatched scorpion envenoming in the state of Pará, northern Brazil. PMID:25549940

  4. Cerebellar Hypoplasia

    MedlinePlus

    ... disorders that begin in early childhood, such as ataxia telangiectasia. In an infant or young child, symptoms of a disorder that features cerebellar hypoplasia might include floppy muscle tone, developmental or ...

  5. More falls in cerebellar ataxia when standing on a slow up-moving tilt of the support surface

    PubMed Central

    PAQUETTE, Caroline; FRANZÉN, Erika; HORAK, Fay B

    2016-01-01

    We investigated how subjects with cerebellar ataxia (CA) adapt their postural stability and alignment to a slow and small tilt of the support surface allowing for online postural corrections. Eight subjects with CA and eight age- and gender-matched healthy control subjects participated in the study. Subjects stood eyes closed for 1 minute after which the support surface was tilted 5° toes-up at a ramp velocity of 1°/s. The toes-up position was held for 2.5 minutes after which the surface rotated back down to level with identical tilt characteristics. As reflected by the large number of falls, subjects with CA had marked difficulty adapting their posture to the up-moving incline in contrast to control subjects. Subjects with CA who lost their balance had faster trunk velocity and excessive backward trunk reorientation beginning within the first second after onset of the tilting surface. In contrast, the down-moving tilt to level did not result in instability in CA subjects. These results suggest that instability and falls associated with CA derives from an inability to maintain trunk orientation to vertical while standing on a slow-moving or unstable surface. This study underscores the importance of the cerebellum in the online sensory control of the upper body orientation during small amplitude and slow velocity movements of the support surface. PMID:26202671

  6. More Falls in Cerebellar Ataxia When Standing on a Slow Up-Moving Tilt of the Support Surface.

    PubMed

    Paquette, Caroline; Franzén, Erika; Horak, Fay B

    2016-06-01

    We investigated how subjects with cerebellar ataxia (CA) adapt their postural stability and alignment to a slow and small tilt of the support surface allowing for online postural corrections. Eight subjects with CA and eight age- and gender-matched healthy control subjects participated in the study. Subjects stood eyes closed for 1 min after which the support surface was tilted 5° toes-up at a ramp velocity of 1°/s. The toes-up position was held for 2.5 min after which the surface rotated back down to level with identical tilt characteristics. As reflected by the large number of falls, subjects with CA had marked difficulty adapting their posture to the up-moving incline in contrast to control subjects. Subjects with CA who lost their balance had faster trunk velocity and excessive backward trunk reorientation beginning within the first second after onset of the tilting surface. In contrast, the down-moving tilt to level did not result in instability in CA subjects. These results suggest that instability and falls associated with CA derive from an inability to maintain trunk orientation to vertical while standing on a slow-moving or unstable surface. This study underscores the importance of the cerebellum in the online sensory control of the upper body orientation during small amplitude and slow velocity movements of the support surface. PMID:26202671

  7. SETX mutations are a frequent genetic cause of juvenile and adult onset cerebellar ataxia with neuropathy and elevated serum alpha-fetoprotein

    PubMed Central

    2013-01-01

    Objectives/background Ataxia with oculomotor apraxia defines a group of genetically distinct recessive ataxias including ataxia-telangectasia (A-T, ATM gene), ataxia with oculomotor apraxia type 1 (AOA1, APTX gene) and type 2 (AOA2, SETX gene). Although, a few unique clinical features differentiate each of these forms, the patients also share common clinical signs, such as the presence of cerebellar atrophy, sensorimotor axonal neuropathy, and elevated alpha-fetoprotein (AFP) serum level. Materials and methods We selected 22 Italian patients from 21 families, presenting progressive cerebellar ataxia, axonal neuropathy, and elevated serum AFP. We screened the coding regions of ATM, APTX and SETX genes for point mutations by direct sequencing or DHPLC, and searched genomic rearrangements in SETX by MLPA analysis. In selected cases, quantification of ATM and senataxin proteins was performed by Western blot. Clinical, neurophysiological, and neuroimaging data were collected. Results Thirteen patients (12 families) carried SETX mutations (AOA2, 57%), two were mutated in ATM (A-T), and three in APTX (AOA1). In three remaining patients, we could not find pathogenic mutations, and in one case we found, in homozygosis, the SETX p.K992R polymorphism (population frequency 1-2%). In AOA2 cases, we identified 14 novel and three reported SETX mutations. Signs at onset were gait ataxia and facial dyskinesia, and the age ranged between 11 and 18 years. None had obvious oculomotor apraxia at the latest examination (age 14–45 years). The patient carrying the p.K992R SETX polymorphism had a phenotype similar to that of the diagnosed AOA2 patients, while the other three undiagnosed subjects had a very late onset and a few distinguishing clinical features. Discussion and conclusions We describe a large series of 13 AOA2 Italian patients. The phenotype was consistent with previous descriptions of AOA2, except for a higher frequency of strabism, and for the absence of oculomotor

  8. Segmentation of the Cerebellar Peduncles Using a Random Forest Classifier and a Multi-object Geometric Deformable Model: Application to Spinocerebellar Ataxia Type 6

    PubMed Central

    Ye, Chuyang; Yang, Zhen; Ying, Sarah H.; Prince, Jerry L.

    2016-01-01

    The cerebellar peduncles, comprising the superior cerebellar peduncles (SCPs), the middle cerebellar peduncle (MCP), and the inferior cerebellar peduncles (ICPs), are white matter tracts that connect the cerebellum to other parts of the central nervous system. Methods for automatic segmentation and quantification of the cerebellar peduncles are needed for objectively and efficiently studying their structure and function. Diffusion tensor imaging (DTI) provides key information to support this goal, but it remains challenging because the tensors change dramatically in the decussation of the SCPs (dSCP), the region where the SCPs cross. This paper presents an automatic method for segmenting the cerebellar peduncles, including the dSCP. The method uses volumetric segmentation concepts based on extracted DTI features. The dSCP and noncrossing portions of the peduncles are modeled as separate objects, and are initially classified using a random forest classifier together with the DTI features. To obtain geometrically correct results, a multi-object geometric deformable model is used to refine the random forest classification. The method was evaluated using a leave-one-out cross-validation on five control subjects and four patients with spinocerebellar ataxia type 6 (SCA6). It was then used to evaluate group differences in the peduncles in a population of 32 controls and 11 SCA6 patients. In the SCA6 group, we have observed significant decreases in the volumes of the dSCP and the ICPs and significant increases in the mean diffusivity in the noncrossing SCPs, the MCP, and the ICPs. These results are consistent with a degeneration of the cerebellar peduncles in SCA6 patients. PMID:25749985

  9. Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency.

    PubMed

    De Munter, Stephanie; Verheijden, Simon; Vanderstuyft, Esther; Malheiro, Ana Rita; Brites, Pedro; Gall, David; Schiffmann, Serge N; Baes, Myriam

    2016-10-01

    The cerebellar pathologies in peroxisomal diseases underscore that these organelles are required for the normal development and maintenance of the cerebellum, but the mechanisms have not been resolved. Here we investigated the origins of the early-onset coordination impairment in a mouse model with neural selective deficiency of multifunctional protein-2, the central enzyme of peroxisomal β-oxidation. At the age of 4weeks, Nestin-Mfp2(-/-) mice showed impaired motor learning on the accelerating rotarod and underperformed on the balance beam test. The gross morphology of the cerebellum and Purkinje cell arborization were normal. However, electrophysiology revealed a reduced Purkinje cell firing rate, a decreased excitability and an increased membrane capacitance. The distribution of climbing and parallel fiber synapses on Purkinje cells was immature and was accompanied by an increased spine length. Despite normal myelination, Purkinje cell axon degeneration was evident from the occurrence of axonal swellings containing accumulated organelles. In conclusion, the electrical activity, axonal integrity and wiring of Purkinje cells are exquisitely dependent on intact peroxisomal β-oxidation in neural cells. PMID:27353294

  10. Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46).

    PubMed

    Sultana, Saki; Reichbauer, Jennifer; Schüle, Rebecca; Mochel, Fanny; Synofzik, Matthis; van der Spoel, Aarnoud C

    2015-09-11

    Glucosylceramide is a membrane glycolipid made up of the sphingolipid ceramide and glucose, and has a wide intracellular distribution. Glucosylceramide is degraded to ceramide and glucose by distinct, non-homologous enzymes, including glucocerebrosidase (GBA), localized in the endolysosomal pathway, and β-glucosidase 2 (GBA2), which is associated with the plasma membrane and/or the endoplasmic reticulum. It is well established that mutations in the GBA gene result in endolysosomal glucosylceramide accumulation, which triggers Gaucher disease. In contrast, the biological significance of GBA2 is less well understood. GBA2-deficient mice present with male infertility, but humans carrying mutations in the GBA2 gene are affected with a combination of cerebellar ataxia and spastic paraplegia, as well as with thin corpus callosum and cognitive impairment (SPastic Gait locus #46, SPG46). To improve our understanding of the biochemical consequences of the GBA2 mutations, we have evaluated five nonsense and five missense GBA2 mutants for their enzyme activity. In transfected cells, the mutant forms of GBA2 were present in widely different amounts, ranging from overabundant to very minor, compared to the wild type enzyme. Nevertheless, none of the GBA2 mutant cDNAs raised the enzyme activity in transfected cells, in contrast to the wild-type enzyme. These results suggest that SPG46 patients have a severe deficit in GBA2 activity, because the GBA2 mutants are intrinsically inactive and/or reduced in amount. This assessment of the expression levels and enzyme activities of mutant forms of GBA2 offers a first insight in the biochemical basis of the complex pathologies seen in SPG46. PMID:26220345

  11. Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry.

    PubMed

    Protasova, Maria S; Grigorenko, Anastasia P; Tyazhelova, Tatiana V; Andreeva, Tatiana V; Reshetov, Denis A; Gusev, Fedor E; Laptenko, Alexander E; Kuznetsova, Irina L; Goltsov, Andrey Y; Klyushnikov, Sergey A; Illarioshkin, Sergey N; Rogaev, Evgeny I

    2016-04-01

    X-linked congenital cerebellar ataxia is a heterogeneous nonprogressive neurodevelopmental disorder with onset in early childhood. We searched for a genetic cause of this condition, previously reported in a Buryat pedigree of Mongolian ancestry from southeastern Russia. Using whole-genome sequencing on Illumina HiSeq 2000 platform, we found a missense mutation in the ABCB7 (ABC-binding cassette transporter B7) gene, encoding a mitochondrial transporter, involved in heme synthesis and previously associated with sideroblastic anemia and ataxia. The mutation resulting in a substitution of a highly conserved glycine to serine in position 682 is apparently a major causative factor of the cerebellar hypoplasia/atrophy found in affected individuals of a Buryat family who had no evidence of sideroblastic anemia. Moreover, in these affected men we also found the genetic defects in two other genes closely linked to ABCB7 on chromosome X: a deletion of a genomic region harboring the second exon of copper-transporter gene (ATP7A) and a complete deletion of PGAM4 (phosphoglycerate mutase family member 4) retrogene located in the intronic region of the ATP7A gene. Despite the deletion, eliminating the first of six metal-binding domains in ATP7A, no signs for Menkes disease or occipital horn syndrome associated with ATP7A mutations were found in male carriers. The role of the PGAM4 gene has been previously implicated in human reproduction, but our data indicate that its complete loss does not disrupt male fertility. Our finding links cerebellar pathology to the genetic defect in ABCB7 and ATP7A structural variant inherited as X-linked trait, and further reveals the genetic heterogeneity of X-linked cerebellar disorders. PMID:26242992

  12. A VARIANT OF NESPRIN1 GIANT DEVOID OF KASH DOMAIN UNDERLIES THE MOLECULAR ETIOLOGY OF AUTOSOMAL RECESSIVE CEREBELLAR ATAXIA TYPE I

    PubMed Central

    Razafsky, David; Hodzic, Didier

    2015-01-01

    Nonsense mutations across the whole coding sequence of Syne1/ Nesprin1 have been linked to Autosomal Recessive Cerebellar Ataxia Type I (ARCA1). However, nothing is known about the molecular etiology of this late-onset debilitating pathology. In this work, we report that Nesprin1 giant is specifically expressed in CNS tissues. We also identified a CNS-specific splicing event that leads to the abundant expression of a KASH-LESS variant of Nesprin1giant (KLNes1g) in the cerebellum. KLNes1g displayed a noncanonical localization at glomeruli of cerebellar mossy fibers whereas Nesprin2 exclusively decorated the nuclear envelope of all cerebellar neurons. In immunogold electron microscopy, KLNes1g colocalized both with synaptic vesicles within mossy fibers and with dendritic membranes of cerebellar granule neurons. We further identified vesicle- and membrane-associated proteins in KLNes1g immunoprecipitates. Together, our results suggest that the loss of function of KLNes1g resulting from Nesprin1 nonsense mutations underlie the molecular etiology of ARCA1. PMID:25843669

  13. Persistent cerebellar dysfunction following acute lithium toxicity: A report of two cases

    PubMed Central

    Banwari, Girish; Chaudhary, Pradhyuman; Panchmatia, Ankit; Patel, Nisheet

    2016-01-01

    Neurological disturbances caused by lithium range from simple side effects such as benign tremor to acute reversible neurotoxicity. Rarely, lithium is reported to cause irreversible, permanent neurological sequelae most commonly manifested as cerebellar dysfunction, although other presentations have also been described. We report two cases of persistent cerebellar syndrome following acute lithium toxicity and discuss them in the light of existing literature on the subject. PMID:27298510

  14. Presence of an autoantibody against a Golgi cisternal membrane protein in the serum and cerebrospinal fluid from a patient with idiopathic late onset cerebellar ataxia.

    PubMed

    Gaspar, M L; Marcos, M A; Gutierrez, C; Martín, M J; Bonifacino, J S; Sandoval, I V

    1988-03-01

    Tissue and cultured cells of different species and embryological origins incubated with serum (diluted up to 10,000-fold) or cerebrospinal fluid (CSF) (6-fold dilution) from a 48-year-old female patient with idiopathic late-onset cerebellar ataxia, exhibited a bright specific perinuclear staining when studied by indirect immunofluorescence microscopy. The pattern of the staining was that characteristic of the Golgi apparatus, consisting of a crescent-shaped juxtanuclear reticulum located in the vicinity of the microtubule organizing center. Changes in location and organization of the organelle stained by the patient's serum during mitosis or after incubation of the cells with Colcemid, taxol or monensin, resulted in a disruption of the reticulum that followed the expected patterns for Golgi apparatus. The staining was specifically absorbed with Golgi cisternae-enriched membrane fractions. Finally, dot-immunoblotting studies of membrane and soluble fractions of Golgi cisternae and vesicles showed that the anti-Golgi antibody (AGA) reacted with the cytoplasmic domain of an integral membrane protein contained in the Golgi cisternae. The presence of this unusual autoantibody in an idiopathic late-onset cerebellar ataxia-bearing patient can afford some insights into the pathogenesis of these neurological diseases. PMID:3339121

  15. Hereditary Coproporphyria Associated with the Q306X Mutation in the Coproporphyrin Oxidase Gene Presenting with Acute Ataxia

    PubMed Central

    Jiménez-Jiménez, Félix Javier; Agúndez, José A. G.; Martínez, Carmen; Navacerrada, Francisco; Plaza-Nieto, José Francisco; Pilo-de-la-Fuente, Belén; Alonso-Navarro, Hortensia; García-Martín, Elena

    2013-01-01

    Background Hereditary coproporphyria (HCPO) is a low-penetrance, autosomal dominant, acute hepatic porphyria characterized by the overproduction and excretion of coproporphyrin. The most common neurological manifestations of this entity include peripheral, predominantly motor dysfunction, and central nervous system dysfunction. Ataxia associated with HCPO has not been reported previously. The aim of this article is to report a patient with HCPO presenting with acute ataxia. Case Report We describe a 44-year-old patient presenting clinically with acute ataxia who was diagnosed with HCPO; mutations were analyzed in the coproporphyrin-oxidase III (CPOX) gene in the patient and in six asymptomatic first-degree relatives. Discussion The patient was heterozygous for a mutation causing the amino acid exchange Q306X in the CPOX gene. No relatives carried the same or another mutation in the CPOX gene. HCPO should be considered in the differential diagnosis for patients presenting with ataxia. PMID:24156084

  16. Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation

    PubMed Central

    Liu, Yo-Tsen; Hersheson, Joshua; Plagnol, Vincent; Fawcett, Katherine; Duberley, Kate E C; Preza, Elisavet; Hargreaves, Iain P; Chalasani, Annapurna; Laurá, Matilde; Wood, Nick W; Reilly, Mary M; Houlden, Henry

    2014-01-01

    Background The autosomal-recessive cerebellar ataxias (ARCA) are a clinically and genetically heterogeneous group of neurodegenerative disorders. The large number of ARCA genes leads to delay and difficulties obtaining an exact diagnosis in many patients and families. Ubiquinone (CoQ10) deficiency is one of the potentially treatable causes of ARCAs as some patients respond to CoQ10 supplementation. The AarF domain containing kinase 3 gene (ADCK3) is one of several genes associated with CoQ10 deficiency. ADCK3 encodes a mitochondrial protein which functions as an electron-transfer membrane protein complex in the mitochondrial respiratory chain (MRC). Methods We report two siblings from a consanguineous Pakistani family who presented with cerebellar ataxia and severe myoclonus from adolescence. Whole exome sequencing and biochemical assessment of fibroblasts were performed in the index patient. Results A novel homozygous frameshift mutation in ADCK3 (p.Ser616Leufs*114), was identified in both siblings. This frameshift mutation results in the loss of the stop codon, extending the coding protein by 81 amino acids. Significant CoQ10 deficiency and reduced MRC enzyme activities in the index patient's fibroblasts suggested that the mutant protein may reduce the efficiency of mitochondrial electron transfer. CoQ10 supplementation was initiated following these genetic and biochemical analyses. She gained substantial improvement in myoclonic movements, ataxic gait and dysarthric speech after treatment. Conclusion This study highlights the importance of diagnosing ADCK3 mutations and the potential benefit of treatment for patients. The identification of this new mutation broadens the phenotypic spectrum associated with ADCK3 mutations and provides further understanding of their pathogenic mechanism. PMID:24218524

  17. Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases.

    PubMed

    Mallaret, Martial; Renaud, Mathilde; Redin, Claire; Drouot, Nathalie; Muller, Jean; Severac, Francois; Mandel, Jean Louis; Hamza, Wahiba; Benhassine, Traki; Ali-Pacha, Lamia; Tazir, Meriem; Durr, Alexandra; Monin, Marie-Lorraine; Mignot, Cyril; Charles, Perrine; Van Maldergem, Lionel; Chamard, Ludivine; Thauvin-Robinet, Christel; Laugel, Vincent; Burglen, Lydie; Calvas, Patrick; Fleury, Marie-Céline; Tranchant, Christine; Anheim, Mathieu; Koenig, Michel

    2016-07-01

    Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series. The correct gene was predicted in 61 and 78 % of the cases by the two assessors, respectively. There was a high inter-rater agreement [K = 0.85 (0.55-0.98) p < 0.001] confirming the algorithm's reproducibility. Phenotyping patients with proper clinical examination, imaging, biochemical investigations and nerve conduction studies remain crucial for the guidance of molecular analysis and to interpret next generation sequencing results. The proposed algorithm should be helpful for diagnosing ARCA in clinical practice. PMID:27142713

  18. A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia.

    PubMed

    Coutelier, Marie; Blesneac, Iulia; Monteil, Arnaud; Monin, Marie-Lorraine; Ando, Kunie; Mundwiller, Emeline; Brusco, Alfredo; Le Ber, Isabelle; Anheim, Mathieu; Castrioto, Anna; Duyckaerts, Charles; Brice, Alexis; Durr, Alexandra; Lory, Philippe; Stevanin, Giovanni

    2015-11-01

    Hereditary cerebellar ataxias (CAs) are neurodegenerative disorders clinically characterized by a cerebellar syndrome, often accompanied by other neurological or non-neurological signs. All transmission modes have been described. In autosomal-dominant CA (ADCA), mutations in more than 30 genes are implicated, but the molecular diagnosis remains unknown in about 40% of cases. Implication of ion channels has long been an ongoing topic in the genetics of CA, and mutations in several channel genes have been recently connected to ADCA. In a large family affected by ADCA and mild pyramidal signs, we searched for the causative variant by combining linkage analysis and whole-exome sequencing. In CACNA1G, we identified a c.5144G>A mutation, causing an arginine-to-histidine (p.Arg1715His) change in the voltage sensor S4 segment of the T-type channel protein Cav3.1. Two out of 479 index subjects screened subsequently harbored the same mutation. We performed electrophysiological experiments in HEK293T cells to compare the properties of the p.Arg1715His and wild-type Cav3.1 channels. The current-voltage and the steady-state activation curves of the p.Arg1715His channel were shifted positively, whereas the inactivation curve had a higher slope factor. Computer modeling in deep cerebellar nuclei (DCN) neurons suggested that the mutation results in decreased neuronal excitability. Taken together, these data establish CACNA1G, which is highly expressed in the cerebellum, as a gene whose mutations can cause ADCA. This is consistent with the neuropathological examination, which showed severe Purkinje cell loss. Our study further extends our knowledge of the link between calcium channelopathies and CAs. PMID:26456284

  19. A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia

    PubMed Central

    Coutelier, Marie; Blesneac, Iulia; Monteil, Arnaud; Monin, Marie-Lorraine; Ando, Kunie; Mundwiller, Emeline; Brusco, Alfredo; Le Ber, Isabelle; Anheim, Mathieu; Castrioto, Anna; Duyckaerts, Charles; Brice, Alexis; Durr, Alexandra; Lory, Philippe; Stevanin, Giovanni

    2015-01-01

    Hereditary cerebellar ataxias (CAs) are neurodegenerative disorders clinically characterized by a cerebellar syndrome, often accompanied by other neurological or non-neurological signs. All transmission modes have been described. In autosomal-dominant CA (ADCA), mutations in more than 30 genes are implicated, but the molecular diagnosis remains unknown in about 40% of cases. Implication of ion channels has long been an ongoing topic in the genetics of CA, and mutations in several channel genes have been recently connected to ADCA. In a large family affected by ADCA and mild pyramidal signs, we searched for the causative variant by combining linkage analysis and whole-exome sequencing. In CACNA1G, we identified a c.5144G>A mutation, causing an arginine-to-histidine (p.Arg1715His) change in the voltage sensor S4 segment of the T-type channel protein Cav3.1. Two out of 479 index subjects screened subsequently harbored the same mutation. We performed electrophysiological experiments in HEK293T cells to compare the properties of the p.Arg1715His and wild-type Cav3.1 channels. The current-voltage and the steady-state activation curves of the p.Arg1715His channel were shifted positively, whereas the inactivation curve had a higher slope factor. Computer modeling in deep cerebellar nuclei (DCN) neurons suggested that the mutation results in decreased neuronal excitability. Taken together, these data establish CACNA1G, which is highly expressed in the cerebellum, as a gene whose mutations can cause ADCA. This is consistent with the neuropathological examination, which showed severe Purkinje cell loss. Our study further extends our knowledge of the link between calcium channelopathies and CAs. PMID:26456284

  20. Cerebellar abiotrophy.

    PubMed

    DeBowes, R M; Leipold, H W; Turner-Beatty, M

    1987-08-01

    Cerebellar abiotrophy is a degenerative condition of Arabian horses that produces signs of head tremors and ataxia. Affected foals demonstrate clinical signs between the time of birth and 6 months of age. The condition is untreatable, although some animals have reportedly improved to varying degrees. The disease is believed to be inherited; however, definitive evidence is lacking at this time. PMID:3497695

  1. Humor, laughter, and the cerebellum: insights from patients with acute cerebellar stroke.

    PubMed

    Frank, B; Andrzejewski, K; Göricke, S; Wondzinski, E; Siebler, M; Wild, B; Timmann, D

    2013-12-01

    Extent of cerebellar involvement in cognition and emotion is still a topic of ongoing research. In particular, the cerebellar role in humor processing and control of laughter is not well known. A hypermetric dysregulation of affective behavior has been assumed in cerebellar damage. Thus, we aimed at investigating humor comprehension and appreciation as well as the expression of laughter in 21 patients in the acute or subacute state after stroke restricted to the cerebellum, and in the same number of matched healthy control subjects. Patients with acute and subacute cerebellar damage showed preserved comprehension and appreciation of humor using a validated humor test evaluating comprehension, funniness and aversiveness of cartoons ("3WD Humor Test"). Additionally, there was no difference when compared to healthy controls in the number and intensity of facial reactions and laughter while observing jokes, humorous cartoons, or video sketches measured by the Facial Action Coding System. However, as depression scores were significantly increased in patients with cerebellar stroke, a concealing effect of accompanying depression cannot be excluded. Current findings add to descriptions in the literature that cognitive or affective disorders in patients with lesions restricted to the cerebellum, even in the acute state after damage, are frequently mild and might only be present in more sensitive or specific tests. PMID:23661243

  2. Altered Cerebellar White Matter Integrity in Patients with Mild Traumatic Brain Injury in the Acute Stage

    PubMed Central

    Wang, Zhongqiu; Wu, Wenzhong; Liu, Yongkang; Wang, Tianyao; Chen, Xiao; Zhang, Jianhua; Zhou, Guoxing; Chen, Rong

    2016-01-01

    Background and Purpose Imaging studies of traumatic brain injury demonstrate that the cerebellum is often affected. We aim to examine fractional anisotropy alteration in acute-phase mild traumatic brain injury patients in cerebellum-related white matter tracts. Materials and Methods This prospective study included 47 mild traumatic brain injury patients in the acute stage and 37 controls. MR imaging and neurocognitive tests were performed in patients within 7 days of injury. White matter integrity was examined by using diffusion tensor imaging. We used three approaches, tract-based spatial statistics, graphical-model-based multivariate analysis, and region-of-interest analysis, to detect altered cerebellar white matter integrity in mild traumatic brain injury patients. Results Results from three analysis methods were in accordance with each other, and suggested fractional anisotropy in the middle cerebellar peduncle and the pontine crossing tract was changed in the acute-phase mild traumatic brain injury patients, relative to controls (adjusted p-value < 0.05). Higher fractional anisotropy in the middle cerebellar peduncle was associated with worse performance in the fluid cognition composite (r = -0.289, p-value = 0.037). Conclusion Altered cerebellar fractional anisotropy in acute-phase mild traumatic brain injury patients is localized in specific regions and statistically associated with cognitive deficits detectable on neurocognitive testing. PMID:26967320

  3. Promoting Motor Cortical Plasticity with Acute Aerobic Exercise: A Role for Cerebellar Circuits

    PubMed Central

    Mang, Cameron S.; Brown, Katlyn E.; Neva, Jason L.; Snow, Nicholas J.; Campbell, Kristin L.; Boyd, Lara A.

    2016-01-01

    Acute aerobic exercise facilitated long-term potentiation-like plasticity in the human primary motor cortex (M1). Here, we investigated the effect of acute aerobic exercise on cerebellar circuits, and their potential contribution to altered M1 plasticity in healthy individuals (age: 24.8 ± 4.1 years). In Experiment   1, acute aerobic exercise reduced cerebellar inhibition (CBI) (n = 10, p = 0.01), elicited by dual-coil paired-pulse transcranial magnetic stimulation. In Experiment   2, we evaluated the facilitatory effects of aerobic exercise on responses to paired associative stimulation, delivered with a 25 ms (PAS25) or 21 ms (PAS21) interstimulus interval (n = 16 per group). Increased M1 excitability evoked by PAS25, but not PAS21, relies on trans-cerebellar sensory pathways. The magnitude of the aerobic exercise effect on PAS response was not significantly different between PAS protocols (interaction effect: p = 0.30); however, planned comparisons indicated that, relative to a period of rest, acute aerobic exercise enhanced the excitatory response to PAS25 (p = 0.02), but not PAS21 (p = 0.30). Thus, the results of these planned comparisons indirectly provide modest evidence that modulation of cerebellar circuits may contribute to exercise-induced increases in M1 plasticity. The findings have implications for developing aerobic exercise strategies to “prime” M1 plasticity for enhanced motor skill learning in applied settings. PMID:27127659

  4. Smad2 protein disruption in the central nervous system leads to aberrant cerebellar development and early postnatal ataxia in mice.

    PubMed

    Wang, Lixiang; Nomura, Masatoshi; Goto, Yutaka; Tanaka, Kimitaka; Sakamoto, Ryuichi; Abe, Ichiro; Sakamoto, Shohei; Shibata, Atsushi; Enciso, Patricio L M; Adachi, Masahiro; Ohnaka, Keizo; Kawate, Hisaya; Takayanagi, Ryoichi

    2011-05-27

    Smad2 is a critical mediator of TGF-β signals that are known to play an important role in a wide range of biological processes in various cell types. Its role in the development of the CNS, however, is largely unknown. Mice lacking Smad2 in the CNS (Smad2-CNS-KO) were generated by a Cre-loxP approach. These mice exhibited behavioral abnormalities in motor coordination from an early postnatal stage and mortality at approximately 3 weeks of age, suggestive of severe cerebellar dysfunction. Gross observation of Smad2-CNS-KO cerebella demonstrated aberrant foliations in lobule IX and X. Further analyses revealed increased apoptotic cell death, delayed migration and maturation of granule cells, and retardation of dendritic arborization of Purkinje cells. These findings indicate that Smad2 plays a key role in cerebellar development and motor function control. PMID:21464123

  5. A hitherto undescribed case of cerebellar ataxia as the sole presentation of thyrotoxicosis in a young man: a plausible association.

    PubMed

    Elhadd, Tarik Abdelkareim; Linton, Kathryn; McCoy, Caoihme; Saha, Subrata; Holden, Roger

    2014-01-01

    A 16-year-old male presented to hospital following an episode of unusual behavior on the football pitch, where he was witnessed as grossly ataxic by his teammates. The assessment demonstrated marked cerebellar signs on examination but no other neurological deficit. The investigation showed the evidence of biochemical thyrotoxicosis with free T4 at 37 pmol/L (normal reference range: 11-27) and thyrotropin (TSH) < 0.003 mU/L. Following admission, full investigations including computed tomographic brain scan with contrast, lumbar puncture with cerebrospinal fluid examination, magnetic resonance imaging, and magnetic resonance angiography did not reveal abnormalities. He was initiated on carbimazole 40 mg every day. Thyroid ultrasonography revealed a goiter with increased blood flow, and his thyroid antibodies showed positive thyroid peroxidase antibodies but negative TSH receptor antibodies. Electroencephalogram did not reveal any abnormalities. His neurological disability resolved completely after his thyroid function normalized. The association of cerebellar syndromes is well described with hypothyroidism; however, it is hitherto undescribed with thyrotoxicosis. The causal relationship is plausible because alternative etiologies were excluded, and the normalization of thyroid function with treatment was coupled with complete resolution of the neurological syndrome. Cerebellar syndromes may well be one of the presenting features of thyrotoxicosis, and this should be in the list of its differential diagnosis. PMID:25827703

  6. CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene.

    PubMed

    Heimer, Gali; Sadaka, Yair; Israelian, Lori; Feiglin, Ariel; Ruggieri, Alessandra; Marshall, Christian R; Scherer, Stephen W; Ganelin-Cohen, Esther; Marek-Yagel, Dina; Tzadok, Michal; Nissenkorn, Andreea; Anikster, Yair; Minassian, Berge A; Zeev, Bruria Ben

    2015-11-01

    We describe the molecular basis of a distinctive syndrome characterized by infantile stress-induced episodic weakness, ataxia, and sensorineural hearing loss, with permanent areflexia and optic nerve pallor. Whole exome sequencing identified a deleterious heterozygous c.2452 G>A, p.(E818K) variant in the ATP1A3 gene and structural analysis predicted its protein-destabilizing effect. This variant has not been reported in context with rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood, the 2 main diseases associated with ATP1A3. The clinical presentation in the family described here differs categorically from these diseases in age of onset, clinical course, cerebellar over extrapyramidal movement disorder predominance, and peripheral nervous system involvement. While this paper was in review, a highly resembling phenotype was reported in additional patients carrying the same c.2452 G>A variant. Our findings substantiate this variant as the cause of a unique inherited autosomal dominant neurologic syndrome that constitutes a third allelic disease of the ATP1A3 gene. PMID:25895915

  7. The Spinocerebellar Ataxias

    PubMed Central

    Paulson, Henry L.

    2009-01-01

    Slowly progressive ataxia accompanied by cerebellar degeneration is often genetic in origin. The past fifteen years have witnessed a revolution in our understanding of the causes of dominantly inherited ataxias, now known as the spinocerebellar ataxias (SCAs). Nearly 30 distinct genetic causes of SCA are known, numbered chronologically in order of discovery. All SCAs display classic cerebellar signs and many display disabling noncerebellar features, most commonly brainstem dysfunction. Eye movement abnormalities are common, reflecting cerebellar and brainstem degeneration. Visual loss from retinal degeneration is rare in SCA, occurring most commonly and profoundly in SCA7. Although the SCAs are relentlessly progressive and currently untreatable, recent scientific advances have begun to shed light on various disease mechanisms that may lead to preventive therapies. PMID:19726947

  8. Top-Down but Not Bottom-Up Visual Scanning is Affected in Hereditary Pure Cerebellar Ataxia

    PubMed Central

    Matsuda, Shunichi; Matsumoto, Hideyuki; Furubayashi, Toshiaki; Fukuda, Hideki; Emoto, Masaki; Hanajima, Ritsuko; Tsuji, Shoji; Ugawa, Yoshikazu; Terao, Yasuo

    2014-01-01

    The aim of this study was to clarify the nature of visual processing deficits caused by cerebellar disorders. We studied the performance of two types of visual search (top-down visual scanning and bottom-up visual scanning) in 18 patients with pure cerebellar types of spinocerebellar degeneration (SCA6: 11; SCA31: 7). The gaze fixation position was recorded with an eye-tracking device while the subjects performed two visual search tasks in which they looked for a target Landolt figure among distractors. In the serial search task, the target was similar to the distractors and the subject had to search for the target by processing each item with top-down visual scanning. In the pop-out search task, the target and distractor were clearly discernible and the visual salience of the target allowed the subjects to detect it by bottom-up visual scanning. The saliency maps clearly showed that the serial search task required top-down visual attention and the pop-out search task required bottom-up visual attention. In the serial search task, the search time to detect the target was significantly longer in SCA patients than in normal subjects, whereas the search time in the pop-out search task was comparable between the two groups. These findings suggested that SCA patients cannot efficiently scan a target using a top-down attentional process, whereas scanning with a bottom-up attentional process is not affected. In the serial search task, the amplitude of saccades was significantly smaller in SCA patients than in normal subjects. The variability of saccade amplitude (saccadic dysmetria), number of re-fixations, and unstable fixation (nystagmus) were larger in SCA patients than in normal subjects, accounting for a substantial proportion of scattered fixations around the items. Saccadic dysmetria, re-fixation, and nystagmus may play important roles in the impaired top-down visual scanning in SCA, hampering precise visual processing of individual items. PMID:25545148

  9. Rare case of phenytoin induced acute generalized exanthematous pustulosis with cerebellar syndrome

    PubMed Central

    Shingade, Pravin U; Wankhede, Vaishali; Kataria, Pritam S; Sonone, Nitin

    2014-01-01

    Acute generalized exanthematous pustulosis (AGEP) is a rare drug induced cutaneous hypersensitivity reaction characterized by sudden onset of fever with sterile pustules overlying an erythematous skin occurring all over the body. The offending drugs are usually B-lactams and macrolides. Among anticonvulsants carbamazepine and Phenobarbital are commonly associated with AGEP. Only one case of phenytoin induced AGEP has been reported in literature. We present a rare case of AGEP with cerebellar syndrome occurring after receiving loading dose of phenytoin. PMID:24700960

  10. Clinical and radiologic features and their relationships with neurofunctional scores in patients with acute cerebellar infarct

    PubMed Central

    Kozak, Hasan Hüseyin; Uca, Ali Ulvi; Poyraz, Necdet; Anliaçık, Süleyman Ömer; Tokgöz, Osman Serhat

    2016-01-01

    Background: Cerebellar infarct is a rare condition with very nonspecific clinical features. The aim of this study was to assess the full spectrum of the clinical characteristics, neuroimaging findings and neurofunctional analyses of cerebellar infarction, and the relationship between them. Materials and Methods: Data were collected from 59 patients admitted to our department during an 8-year period. We retrospectively analyzed the relationship between demographic characteristics, clinical symptomatology, etiological factors, functional condition, vascular distribution, frequency of subcortical white matter lesions (WMLs), and concomitant lesion outside the cerebellum in patients with acute cerebellar infarct (ACI) at time of admission. Results: The mean age in our series was 65.2 years, with most being male (57.6%). The posterior inferior cerebellar (PICA) artery was the most commonly affected territory at 62.7%. There was concomitant lesion outside the cerebellum in 45.7%. The main etiology in PICA was cardioembolism. While mean National Institutes of Health Stroke Scale on admission was 2.08 ± 1.67 in study group, modified Rankin Scale (mRS) on admission was detected to be mRS1 (n: 44, 74.5%) and mRS2 (n: 12, 20.3%) most frequently. Fourteen (35%) patients were detected to be in Fazekas stage 0; 11 (27.5%) patients in Fazekas stage 1; 6 (15%) patients in Fazekas stage 2; and 9 (22.5%) patients in Fazekas stage 3. Conclusion: Cerebellar infarct is very heterogeneous. The other cerebral area infarcts which accompany ACI negatively affect neurologic functional scores. Although it is difficult to detect the relationship between WMLs and neurologic functional severity, timely detection of risk factors and their modulation may be associated with prevention and treatability of WMLs, and this may be one of the important points for prevention of stroke-related disability. PMID:27293332

  11. Friedreich's Ataxia

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Friedreich's Ataxia Information Page Condensed from Friedreich's Ataxia Fact Sheet ... Español Additional resources from MedlinePlus What is Friedreich's Ataxia? Friedreich's ataxia is a rare inherited disease that ...

  12. [Adult GM2 gangliosidosis: improvement of ataxia with GABAergic drugs].

    PubMed

    Gazulla Abío, J; Benavente Aguilar, I

    2002-03-01

    The authors present a case of adult GM2 gangliosidosis, B1 enzymatic type. The main clinical features found were cerebellar ataxia, proximal lower limb weakness and myokymia. The neurological examination, and the biochemical, electrophysiologic and imaging studies are all described. Decreased activity of the enzyme beta-hexosaminidase A in the metabolism of the sulfate substrate 4-MU-NAGS was found in serum. Global cerebellar atrophy was observed in a cranial nuclear magnetic resonance. The electrophysiologic study showed continuous spontaneous activity integrated by myokymia and neuromyotonic discharges in addition to signs of acute and chronic denervation. Disappearance of the myokymia and improvement in the ataxia were attained with the use of the GABAergic drugs gabapentin and tiagabine. The authors try to explain the clinical improvement obtained with the drugs by relating their mechanisms of action to the central nervous system neurotransmitter alterations proposed for this disease. PMID:11927106

  13. Childhood Ataxia with Cerebral Hypomyelination Syndrome: a Variant of Patient with Early Childhood Onset Related to EIF2B3 Mutation. A Case Report.

    PubMed

    Perfetto, F; Stoppino, L P; Calì, A; Milillo, P; Grilli, G; Vinci, R; Macarini, L

    2012-03-01

    Childhood ataxia with central nervous system hypomyelination (CACH) syndrome is an autosomal recessive transmitted leukodystrophy characterised by early childhood onset and acute deterioration following febrile illnesses or head trauma. We describe the case of a child with early onset of CACH syndrome. He presented with cerebellar ataxia beginning around two years of age with mild mental retardation. MRI showed diffuse white matter signal changes with thinning of the corpus callosum. PMID:24028880

  14. The Usefulness of the TOAST Classification and Prognostic Significance of Pyramidal Symptoms During the Acute Phase of Cerebellar Ischemic Stroke.

    PubMed

    Dziadkowiak, Edyta; Chojdak-Łukasiewicz, Justyna; Guziński, Maciej; Noga, Leszek; Paradowski, Bogusław

    2016-04-01

    Cerebellar stroke is a rare condition with very nonspecific clinical features. The symptoms in the acute phase could imitate acute peripheral vestibular disorders or a brainstem lesion. The aim of this study was to assess the usefulness of the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification in cerebellar stroke and the impact of clinical features on the prognosis. We retrospectively analyzed 107 patients with diagnosed ischemic cerebellar infarction. We studied the clinical features and compared them based on the location of the ischemic lesion and its distribution in the posterior interior cerebellar artery (PICA), superior cerebellar artery (SCA), and anterior inferior cerebellar artery (AICA) territories. According to the TOAST classification, stroke was more prevalent in atrial fibrillation (26/107) and when the lesion was in the PICA territory (39/107). Pyramidal signs occurred in 29/107 of patients and were more prevalent when the lesion was distributed in more than two vascular regions (p = 0.00640). Mortality was higher among patients with ischemic lesion caused by cardiac sources (p = 0.00094) and with pyramidal signs (p = 0.00640). The TOAST classification is less useful in assessing supratentorial ischemic infarcts. Cardioembolic etiology, location of the ischemic lesion, and pyramidal signs support a negative prognosis. PMID:26041073

  15. Consensus Paper: Management of Degenerative Cerebellar Disorders

    PubMed Central

    Ilg, W.; Bastian, A. J.; Boesch, S.; Burciu, R. G.; Celnik, P.; Claaßen, J.; Feil, K.; Kalla, R.; Miyai, I.; Nachbauer, W.; Schöls, L.; Strupp, M.; Synofzik, M.; Teufel, J.

    2015-01-01

    Treatment of motor symptoms of degenerative cerebellar ataxia remains difficult. Yet there are recent developments that are likely to lead to significant improvements in the future. Most desirable would be a causative treatment of the underlying cerebellar disease. This is currently available only for a very small subset of cerebellar ataxias with known metabolic dysfunction. However, increasing knowledge of the pathophysiology of hereditary ataxia should lead to an increasing number of medically sensible drug trials. In this paper, data from recent drug trials in patients with recessive and dominant cerebellar ataxias will be summarized. There is consensus that up to date, no medication has been proven effective. Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy. For many years, well-controlled rehabilitation studies in patients with cerebellar ataxia were lacking. Data of recently published studies show that coordinative training improves motor function in both adult and juvenile patients with cerebellar degeneration. Given the well-known contribution of the cerebellum to motor learning, possible mechanisms underlying improvement will be outlined. There is consensus that evidence-based guidelines for the physiotherapy of degenerative cerebellar ataxia need to be developed. Future developments in physiotherapeutical interventions will be discussed including application of non-invasive brain stimulation. PMID:24222635

  16. [Pharmacotherapy of Vestibular Disorders, Nystagmus and Cerebellar Disorders].

    PubMed

    Feil, K; Böttcher, N; Kremmyda, O; Muth, C; Teufel, J; Zwergal, A; Brandt, T; Strupp, M

    2015-09-01

    There are currently different groups of drugs for the pharmacotherapy of vertigo, nystagmus and cerebellar disorders: antiemetics; anti-inflammatories, antimenieres, and antimigraineous medications and antidepressants, anticonvulsants, aminopyridines as well as acetyl-DL-leucine. In acute unilateral vestibulopathy, corticosteroids improve the recovery of peripheral vestibular function, but currently there is not sufficient evidence for a general recommendation. There is insufficient evidence to support the view that 16 mg t. i. d. or 48 mg t. i. d. betahistine has an effect in Menière's disease. Therefore, higher dosages are recommended. In animal studies, it was shown that betahistine increases cochlear blood flow. In vestibular paroxysmia, oxcarbazepine was effective (one randomized controlled trial (RCT)). Aminopyridines are recommended for the treatment of downbeat nystagmus (two RCTs) and episodic ataxia type 2 (EA2, one RCT). There has been no RCT on the efficacy of beta-blockers or topiramate but one RCT on flunarizine in vestibular migraine. Based on clinical experience, a treatment analogous to that for migraine without aura can be recommended. Acetyl-DL-leucine improved cerebellar ataxia (two observational studies); it also accelerated central compensation in an animal model of acute unilateral lesion, but RCTs were negative. There are ongoing RCTs on treatment of vestibular paroxysmia with carbamazepine (VESPA), acute unilateral vestibulopathy with betahistine (BETAVEST), vestibular migraine with metoprolol (PROVEMIG), benign paroxysmal positional vertigo with vitamin D (VitD@BPPV), EA2 with 4-aminopyridine versus acetazolamide (EAT-2-TREAT), and cerebellar ataxias with acetyl-DL-leucine (ALCAT). PMID:26421856

  17. Synaptic action of ethanol on cerebellar auditory granule cells reveals acute tolerance

    SciTech Connect

    Huang, C.M.; Liu, G.; Huang, R.H. )

    1991-03-11

    The cerebellum is very sensitive to acute intoxication by ethanol. The authors have recorded electrophysiological responses of granule cells to auditory stimulation from the posterior cerebellar vermis of cats before and after a relatively low dose of ethanol. Auditory responses of granule cells were severely inhibited by ethanol at a transient, peak ethanol concentration of 15-18 mM in the cerebrospinal fluid (CSF). Thereafter, the clearance of ethanol from CSF followed an exponential time course, with 50% of the CSF ethanol being cleared with every passing hour. Auditory responses of granule cells returned to control levels within 60-90 minutes, despite the presence of a DSF ethanol concentration at 8-10mM, indicating acute tolerance. Moreover, a second, identical dose of ethanol, delivered two hours after the first dose produced an attenuated inhibition in the auditory response of cerebellar granule cells. The inhibition took a longer time to be evident but a shorter time to recover than that followed by the first dose of ethanol.

  18. Solitary C1 spinal osteochondroma causing vertebral artery compression and acute cerebellar infarct.

    PubMed

    Zhang, Yaxia; Ilaslan, Hakan; Hussain, Muhammad S; Bain, Mark; Bauer, Thomas W

    2015-02-01

    Osteochondroma is a common benign bone lesion, usually involving the long bones. Spinal involvement is rare. The clinical presentation of spinal osteochondroma varies according to the site of the lesion. The most common reported clinical presentation is secondary to encroachment of the lesion on the spinal canal or nerve roots. Less common presentations such as a palpable neck mass, dysphagia, sleep apnea, paralysis of left vocal cord or acute respiratory distress have been reported when the lesions compress the anatomic structures anteriorly. We describe a rare case of a young patient who presented with an emergent critical condition of acute cerebellar infarct as a result of vertebral artery compression caused by a solitary C1 spinal osteochondroma. PMID:25109381

  19. Clinical manifestations of cerebellar disease.

    PubMed

    Javalkar, Vijayakumar; Khan, Misbba; Davis, Debra E

    2014-11-01

    Clinical manifestations of cerebellar disease include ataxia and tremor, as well as nystagmus, dysarthria, and cognitive dysfunction. Recognition of the cerebellar pattern of disease can aid in the prompt and correct diagnosis and lead to appropriate treatment and rehabilitation to minimize disability. PMID:25439285

  20. Spinocerebellar Ataxia Type 5 (SCA5)

    MedlinePlus

    ... areas of the brain. It is considered a “pure cerebellar ataxia.” What is the prognosis for SCA5? ... SCA5 have, on rare occasions, been reported in individuals under age 20. Those individuals with early onset ...

  1. A Novel Mutation in Isoform 3 of the Plasma Membrane Ca2+ Pump Impairs Cellular Ca2+ Homeostasis in a Patient with Cerebellar Ataxia and Laminin Subunit 1α Mutations.

    PubMed

    Calì, Tito; Lopreiato, Raffaele; Shimony, Joshua; Vineyard, Marisa; Frizzarin, Martina; Zanni, Ginevra; Zanotti, Giuseppe; Brini, Marisa; Shinawi, Marwan; Carafoli, Ernesto

    2015-06-26

    The particular importance of Ca(2+) signaling to neurons demands its precise regulation within their cytoplasm. Isoform 3 of the plasma membrane Ca(2+) ATPase (the PMCA3 pump), which is highly expressed in brain and cerebellum, plays an important role in the regulation of neuronal Ca(2+). A genetic defect of the PMCA3 pump has been described in one family with X-linked congenital cerebellar ataxia. Here we describe a novel mutation in the ATP2B3 gene in a patient with global developmental delay, generalized hypotonia and cerebellar ataxia. The mutation (a R482H replacement) impairs the Ca(2+) ejection function of the pump. It reduces the ability of the pump expressed in model cells to control Ca(2+) transients generated by cell stimulation and impairs its Ca(2+) extrusion function under conditions of low resting cytosolic Ca(2+) as well. In silico analysis of the structural effect of the mutation suggests a reduced stabilization of the portion of the pump surrounding the mutated residue in the Ca(2+)-bound state. The patient also carries two missense mutations in LAMA1, encoding laminin subunit 1α. On the basis of the family pedigree of the patient, the presence of both PMCA3 and laminin subunit 1α mutations appears to be necessary for the development of the disease. Considering the observed defect in cellular Ca(2+) homeostasis and the previous finding that PMCAs act as digenic modulators in Ca(2+)-linked pathologies, the PMCA3 dysfunction along with LAMA1 mutations could act synergistically to cause the neurological phenotype. PMID:25953895

  2. Clinical and MRI findings in spinocerebellar ataxia type 5.

    PubMed

    Stevanin, G; Herman, A; Brice, A; Dürr, A

    1999-10-12

    Spinocerebellar ataxia type 5 (SCA5), one of the genetically heterogeneous autosomal dominant cerebellar ataxias, was assigned to chromosome 11 in a single family descending from the grandparents of President Abraham Lincoln. We report a second, apparently unrelated, SCA5 family of French origin. The overall clinical picture was a slowly progressive cerebellar syndrome beginning mostly in the third decade (27+/-10 years, range 14 to 40). MRI showed a marked global cerebellar atrophy similar to SCA6. PMID:10522902

  3. Friedreich's Ataxia

    MedlinePlus

    ... diabetes. The disorder does not affect thinking and reasoning abilities (cognitive functions). Friedreich’s ataxia is caused by ... A diagnosis of Friedreich's ataxia requires a careful clinical examination, which includes a medical history and a ...

  4. Friedreich's Ataxia

    MedlinePlus

    Friedreich's ataxia is an inherited disease that damages your nervous system. The damage affects your spinal cord and the ... of 5 and 15. The main symptom is ataxia, which means trouble coordinating movements. Specific symptoms include ...

  5. Pharmacotherapy of vestibular and cerebellar disorders and downbeat nystagmus: translational and back-translational research.

    PubMed

    Strupp, Michael; Zwergal, Andreas; Feil, Katharina; Bremova, Tatiana; Brandt, Thomas

    2015-04-01

    There are currently eight groups of drugs for the pharmacotherapy of vertigo, nystagmus, and cerebellar disorders: antiemetics; anti-inflammatories, antimenieres, and antimigraineous medications; antidepressants, anticonvulsants, aminopyridines, and acetyl-DL-leucine ("the eight A's"). In acute unilateral vestibulopathy, corticosteroids improve the recovery of peripheral vestibular function, but there is not sufficient current evidence for a general recommendation. There is also insufficient evidence that 48 or 144 mg/day betahistine has an effect in Ménière's disease. Therefore, higher dosages are currently recommended; in animal studies, it was shown that betahistine increases cochlear blood flow. In vestibular paroxysmia, oxcarbazepine was effective (one yet not randomized controlled trial (RCT)). Aminopyridines are recommended for the treatment of downbeat nystagmus (two RCTs) and episodic ataxia type 2 (EA2, one RCT). There are so far no RCTs on vestibular migraine, so currently no treatment can be recommended. Acetyl-dl-leucine improves cerebellar ataxia (three observational studies); it also accelerates central compensation in an animal model of acute unilateral lesion, but RCTs were negative. There are ongoing RCTs on vestibular paroxysmia with carbamazepine (VESPA), acute unilateral vestibulopathy with betahistine (BETAVEST), vestibular migraine with metoprolol (PROVEMIG), benign paroxysmal positional vertigo with vitamin D (VitD@BPPV), EA2 with 4-aminopyridine versus acetazolamide (EAT-2-TREAT), and cerebellar ataxias with acetyl-DL-leucine (ALCAT). PMID:25903394

  6. Intermittent ataxia and immunodeficiency with multiple carboxylase deficiencies: a biotin-responsive disorder.

    PubMed

    Sander, J E; Malamud, N; Cowan, M J; Packman, S; Amman, A J; Wara, D W

    1980-11-01

    A small group of inborn errors of metabolism are manifested by intermittent cerebellar ataxia. We have previously reported a family with an inherited metabolic defect resulting in multiple carboxylase deficiencies which were responsive to pharmacological doses of biotin. Affected children presented with a skin rash, infections, acute intermittent ataxia, and lactic acidosis. Two affected siblings died prior to diagnosis and therapy, and a detailed postmortem examination was performed on one of them. The brain was characterized by atrophy restricted to the superior vermis of the cerebellum, a finding strikingly similar to that found in chronic alcoholism. Intermittent ataxia would suggest a potentially treatable metabolic disease, and clinical evaluation should include studies of intermediary metabolism and immune function. PMID:7436398

  7. Spinocerebellar ataxia type 15.

    PubMed

    Storey, Elsdon; Gardner, R J McKinlay

    2012-01-01

    Spinocerebellar ataxia type 15 (SCA15), first described in 2001, is a slowly progressive, relatively pure dominantly inherited ataxia. Six pedigrees have been reported to date, in Anglo-Celtic and Japanese populations. Other than notably slow progression, its main distinguishing characteristic is tremor, often affecting the head, which is seen in about half of affecteds and which may be the presenting feature. Neuroradiology shows cerebellar atrophy, particularly affecting the anterior and dorsal vermis. SCA15 is due to various deletions of the inositol 1,4,5-triphosphate receptor 1 gene (ITPR1) on the distal short arm of chromosome 3. The potential of point mutations in ITPR1 to cause SCA15 is not yet confirmed. "SCA16" has now been shown to be due to an ITPR1 mutation, and has now been subsumed into SCA15. PMID:21827915

  8. Causes of Ataxia

    MedlinePlus

    ... Donate to the National Ataxia Foundation Causes of Ataxia The hereditary ataxias are genetic, which means they ... the disease is inherited as a recessive gene. Ataxia Gene Identified in 1993 The first ataxia gene ...

  9. Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

    PubMed Central

    Baldarçara, Leonardo; Currie, Stuart; Hadjivassiliou, M.; Hoggard, Nigel; Jack, Allison; Jackowski, Andrea P.; Mascalchi, Mario; Parazzini, Cecilia; Reetz, Kathrin; Righini, Andrea; Schulz, Jörg B.; Vella, Alessandra; Webb, Sara Jane; Habas, Christophe

    2016-01-01

    Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine. PMID:25382714

  10. Isolated Hemiataxia and Cerebellar Diaschisis after a Small Dorsolateral Medullary Infarct

    PubMed Central

    Kishi, Masahiko; Sakakibara, Ryuji; Nagao, Takeki; Terada, Hitoshi; Ogawa, Emina

    2009-01-01

    Isolated hemiataxia after a medullary infarct is rare. We describe a case of isolated hemiataxia after a small infarct localized at the ipsilateral dorsolateral medulla. An 83-year-old man developed acute onset of ataxia in the left arm and in both legs. Speech and extraocular movement were normal, and he did not have any other neurological manifestations. Brain MRI showed a small infarct localized at the left dorsolateral medulla, which involved the inferior cerebellar peduncle. 123ECD-SPECT showed hypoperfusion in the left cerebellar hemisphere without clear vascular territory. Neuroimaging findings for our patient suggested the involvement of the inferior cerebellar peduncle that projects to the cerebellum in our patient. PMID:20847835

  11. A Case of Ataxia with Isolated Vitamin E Deficiency Initially Diagnosed as Friedreich's Ataxia

    PubMed Central

    Bonello, Michael; Ray, Partha

    2016-01-01

    Ataxia with isolated vitamin E deficiency (AVED) is a rare autosomal recessive condition that is caused by a mutation in the alpha tocopherol transfer protein gene. It is almost indistinguishable clinically from Friedreich's ataxia but with appropriate treatment its devastating neurological features can be prevented. Patients can present with a progressive cerebellar ataxia, pyramidal spasticity, and evidence of a neuropathy with absent deep tendon reflexes. It is important to screen for this condition on initial evaluation of a young patient presenting with progressive ataxia and it should be considered in patients with a long standing ataxia without any diagnosis in view of the potential therapeutics and genetic counselling. In this case report we present a patient who was initially diagnosed with Friedreich's ataxia but was later found to have AVED. PMID:26989534

  12. Cell biology of spinocerebellar ataxia

    PubMed Central

    2012-01-01

    Ataxia is a neurological disorder characterized by loss of control of body movements. Spinocerebellar ataxia (SCA), previously known as autosomal dominant cerebellar ataxia, is a biologically robust group of close to 30 progressive neurodegenerative diseases. Six SCAs, including the more prevalent SCA1, SCA2, SCA3, and SCA6 along with SCA7 and SCA17 are caused by expansion of a CAG repeat that encodes a polyglutamine tract in the affected protein. How the mutated proteins in these polyglutamine SCAs cause disease is highly debated. Recent work suggests that the mutated protein contributes to pathogenesis within the context of its “normal” cellular function. Thus, understanding the cellular function of these proteins could aid in the development of therapeutics. PMID:22508507

  13. Ornidazole-induced ataxia in an Indian woman: A case report

    PubMed Central

    Gopinath, Kango Gopal; Wilson, Benny Paul; Viggeswarpu, Surekha; Mathews, Prasad K; Mani, Sunithi

    2015-01-01

    The nitroimidazole group of antibiotics like metronidazole have been reported to cause cerebellar ataxia as a rare side effect. Ornidazole, the newest derivative of this class, has a long half life and is very rarely known to cause cerebellar ataxia. Here, we report a 61-year-old patient who developed ataxia due to ornidazole to highlight an unusual adverse event that improved rapidly after discontinuation of the offending drug.

  14. Friedreich ataxia

    MedlinePlus

    ... for Friedreich ataxia includes: Counseling Speech therapy Physical therapy Walking aids or wheelchairs Orthopedic devices (braces) may be needed for scoliosis and foot problems. Treating heart disease and diabetes help people live longer and improve their quality ...

  15. Ataxia - telangiectasia

    MedlinePlus

    ... results from defects in the ataxia telangiectasia mutated (ATM) gene. Defects in this gene can lead to ... Genetic testing to look for mutations in the ATM gene Glucose tolerance test Serum immunoglobulin levels (IgE, ...

  16. Ataxia Telangiectasia

    MedlinePlus

    ... Funding Information Research Programs Training & Career Awards Enhancing Diversity Find People About NINDS NINDS Ataxia Telangiectasia Information ... News From NINDS | Find People | Training | Research | Enhancing Diversity Careers@NINDS | FOIA | Accessibility Policy | Contact Us | Privacy ...

  17. Genes and Genetic Testing in Hereditary Ataxias

    PubMed Central

    Sandford, Erin; Burmeister, Margit

    2014-01-01

    Ataxia is a neurological cerebellar disorder characterized by loss of coordination during muscle movements affecting walking, vision, and speech. Genetic ataxias are very heterogeneous, with causative variants reported in over 50 genes, which can be inherited in classical dominant, recessive, X-linked, or mitochondrial fashion. A common mechanism of dominant ataxias is repeat expansions, where increasing lengths of repeated DNA sequences result in non-functional proteins that accumulate in the body causing disease. Greater understanding of all ataxia genes has helped identify several different pathways, such as DNA repair, ubiquitination, and ion transport, which can be used to help further identify new genes and potential treatments. Testing for the most common mutations in these genes is now clinically routine to help with prognosis and treatment decisions, but next generation sequencing will revolutionize how genetic testing will be done. Despite the large number of known ataxia causing genes, however, many individuals with ataxia are unable to obtain a genetic diagnosis, suggesting that more genes need to be discovered. Utilization of next generation sequencing technologies, expression studies, and increased knowledge of ataxia pathways will aid in the identification of new ataxia genes. PMID:25055202

  18. Acute hemicerebellitis in a young adult: a case report and literature review.

    PubMed

    Suzuki, Keisuke; Nakamura, Toshiki; Numao, Ayaka; Fujita, Hiroaki; Komagamine, Tomoko; Nagashima, Takahide; Asakawa, Yohei; Watanabe, Yuji; Takekawa, Hidehiro; Hirata, Koichi

    2014-12-15

    Acute hemicerebellitis, marked by headache with or without cerebellar signs, is a rare clinical entity involving a unilateral cerebellar hemisphere. The pathogenesis of acute hemicerebellitis remains unclear, and the disease rarely occurs in adults. Here, we report an 18-year-old woman who presented with a lack of coordination of the right hand and leg lasting longer than one week, following a pulsatile headache. A neurological examination disclosed ocular dysmetria, right-sided limb ataxia and slight truncal ataxia. Cerebrospinal fluid analysis showed mononuclear pleocytosis. The serology and autoimmune studies were unremarkable. Brain magnetic resonance imaging (MRI) revealed a focal signal change in the right cerebellar hemisphere and vermis. Acute hemicerebellitis was diagnosed, and the patient was treated with intravenous methylprednisolone sodium succinate and acyclovir. Subsequently, the headache resolved, and the cerebellar signs were markedly improved. Twenty days after admission, she became asymptomatic and brain MRI showed resolution of cerebellar hyperintensity on the right side. In conclusion, we identified only 6 additional patients with adult-onset acute hemicerebellitis from previous reports, highlighting the importance of recognizing this rare clinical entity. Its clinical outcome is usually favorable, but in the acute phase, attention should be directed toward clinical symptoms that are suggestive of increased intracranial pressure. PMID:25454647

  19. Automated cerebellar lobule segmentation with application to cerebellar structural analysis in cerebellar disease.

    PubMed

    Yang, Zhen; Ye, Chuyang; Bogovic, John A; Carass, Aaron; Jedynak, Bruno M; Ying, Sarah H; Prince, Jerry L

    2016-02-15

    The cerebellum plays an important role in both motor control and cognitive function. Cerebellar function is topographically organized and diseases that affect specific parts of the cerebellum are associated with specific patterns of symptoms. Accordingly, delineation and quantification of cerebellar sub-regions from magnetic resonance images are important in the study of cerebellar atrophy and associated functional losses. This paper describes an automated cerebellar lobule segmentation method based on a graph cut segmentation framework. Results from multi-atlas labeling and tissue classification contribute to the region terms in the graph cut energy function and boundary classification contributes to the boundary term in the energy function. A cerebellar parcellation is achieved by minimizing the energy function using the α-expansion technique. The proposed method was evaluated using a leave-one-out cross-validation on 15 subjects including both healthy controls and patients with cerebellar diseases. Based on reported Dice coefficients, the proposed method outperforms two state-of-the-art methods. The proposed method was then applied to 77 subjects to study the region-specific cerebellar structural differences in three spinocerebellar ataxia (SCA) genetic subtypes. Quantitative analysis of the lobule volumes shows distinct patterns of volume changes associated with different SCA subtypes consistent with known patterns of atrophy in these genetic subtypes. PMID:26408861

  20. Cavernous angioma with olivary hypertrophy and contralateral cerebellar diaschisis.

    PubMed

    Komaba, Y; Nomoto, T; Kitamura, S; Terashi, A

    1997-07-01

    We describe a 66-year-old man with a 20-year history of ataxic gait who suddenly developed diplopia on rightward gaze. Neurologic examination revealed right hemi-ataxia and hemi-hypesthesia, and left internuclear ophthalmoplegia. MRI showed a cavernous angioma in the left tectum, mild right cerebellar atrophy, and left interior olivary hypertrophy. Single photon emission computed tomography (SPECT) imaging demonstrated contralateral cerebellar diaschisis. We discuss the findings and review the literature concerning contralateral cerebellar diaschisis. PMID:9240502

  1. The Cerebellar Mutism Syndrome and Its Relation to Cerebellar Cognitive Function and the Cerebellar Cognitive Affective Disorder

    ERIC Educational Resources Information Center

    Wells, Elizabeth M.; Walsh, Karin S.; Khademian, Zarir P.; Keating, Robert F.; Packer, Roger J.

    2008-01-01

    The postoperative cerebellar mutism syndrome (CMS), consisting of diminished speech output, hypotonia, ataxia, and emotional lability, occurs after surgery in up to 25% of patients with medulloblastoma and occasionally after removal of other posterior fossa tumors. Although the mutism is transient, speech rarely normalizes and the syndrome is…

  2. X-linked disorders with cerebellar dysgenesis

    PubMed Central

    2011-01-01

    X-linked disorders with cerebellar dysgenesis (XLCD) are a genetically heterogeneous and clinically variable group of disorders in which the hallmark is a cerebellar defect (hypoplasia, atrophy or dysplasia) visible on brain imaging, caused by gene mutations or genomic imbalances on the X-chromosome. The neurological features of XLCD include hypotonia, developmental delay, intellectual disability, ataxia and/or other cerebellar signs. Normal cognitive development has also been reported. Cerebellar dysgenesis may be isolated or associated with other brain malformations or multiorgan involvement. There are at least 15 genes on the X-chromosome that have been constantly or occasionally associated with a pathological cerebellar phenotype. 8 XLCD loci have been mapped and several families with X-linked inheritance have been reported. Recently, two recurrent duplication syndromes in Xq28 have been associated with cerebellar hypoplasia. Given the report of several forms of XLCD and the excess of males with ataxia, this group of conditions is probably underestimated and families of patients with neuroradiological and clinical evidence of a cerebellar disorder should be counseled for high risk of X-linked inheritance. PMID:21569638

  3. Myocarditis along with acute ischaemic cerebellar, pontine and lacunar infarction following viper bite.

    PubMed

    Bhatt, Alok; Menon, Aravind Ajakumar; Bhat, Rama; Ramamoorthi, Kusugodlu

    2013-01-01

    Cerebrovascular complications are rare following viper bites. A 65-year-old man presented with loss of consciousness and developed haemiparesis following a viper bite. Coagulation parameters were severely deranged. MRI showed acute ischaemic infarction on the left side in the precentral and postcentral gyrus, hemipons and cerebellum. Troponin T was elevated and transient left bundle branch block was seen. The patient had a good outcome following treatment with Anti Snake Venom and supportive therapy. Possible mechanisms of infarction are discussed. PMID:24014571

  4. Myocarditis along with acute ischaemic cerebellar, pontine and lacunar infarction following viper bite

    PubMed Central

    Bhatt, Alok; Menon, Aravind Ajakumar; Bhat, Rama; Ramamoorthi, Kusugodlu

    2013-01-01

    Cerebrovascular complications are rare following viper bites. A 65-year-old man presented with loss of consciousness and developed haemiparesis following a viper bite. Coagulation parameters were severely deranged. MRI showed acute ischaemic infarction on the left side in the precentral and postcentral gyrus, hemipons and cerebellum. Troponin T was elevated and transient left bundle branch block was seen. The patient had a good outcome following treatment with Anti Snake Venom and supportive therapy. Possible mechanisms of infarction are discussed. PMID:24014571

  5. Update on the pharmacotherapy of cerebellar and central vestibular disorders.

    PubMed

    Kalla, Roger; Teufel, Julian; Feil, Katharina; Muth, Caroline; Strupp, Michael

    2016-04-01

    An overview of the current pharmacotherapy of central vestibular syndromes and the most common forms of central nystagmus as well as cerebellar disorders is given. 4-aminopyridine (4-AP) is recommended for the treatment of downbeat nystagmus, a frequent form of acquired persisting fixation nystagmus, and upbeat nystagmus. Animal studies showed that this non-selective blocker of voltage-gated potassium channels increases Purkinje cell excitability and normalizes the irregular firing rate, so that the inhibitory influence of the cerebellar cortex on vestibular and deep cerebellar nuclei is restored. The efficacy of 4-AP in episodic ataxia type 2, which is most often caused by mutations of the PQ-calcium channel, was demonstrated in a randomized controlled trial. It was also shown in an animal model (the tottering mouse) of episodic ataxia type 2. In a case series, chlorzoxazone, a non-selective activator of small-conductance calcium-activated potassium channels, was shown to reduce the DBN. The efficacy of acetyl-DL-leucine as a potential new symptomatic treatment for cerebellar diseases has been demonstrated in three case series. The ongoing randomized controlled trials on episodic ataxia type 2 (sustained-release form of 4-aminopyridine vs. acetazolamide vs. placebo; EAT2TREAT), vestibular migraine with metoprolol (PROVEMIG-trial), cerebellar gait disorders (sustained-release form of 4-aminopyridine vs. placebo; FACEG) and cerebellar ataxia (acetyl-DL-leucine vs. placebo; ALCAT) will provide new insights into the pharmacotherapy of cerebellar and central vestibular disorders. PMID:27083881

  6. Cerebellar Stroke-manifesting as Mania.

    PubMed

    Jagadesan, Venkatesan; Thiruvengadam, Kannapiran R; Muralidharan, Rengarajalu

    2014-07-01

    Secondary mania resulting from cerebral Cortex are described commonly. But secondary mania produced by cerebellar lesions are relatively uncommon. This case report describes a patient who developed cerebellar stoke and manic features simultaneously. 28 years old male developed giddiness and projectile vomiting. Then he would lie down for about an hour only to find that he could not walk. He became quarrelsome. His Psycho motor activities and speech were increased. He was euphoric and was expressing grandiose ideas. Bender Gestalt Test showed signs of organicity. Score in Young mania relating scale was 32; productivity was low in Rorschach. Neurological examination revealed left cerebellar signs like ataxia and slurring of speech. Computed tomography of brain showed left cerebellar infarct. Relationship between Psychiatric manifestations and cerebellar lesion are discussed. PMID:25035567

  7. Cerebellar Stroke-manifesting as Mania

    PubMed Central

    Jagadesan, Venkatesan; Thiruvengadam, Kannapiran R.; Muralidharan, Rengarajalu

    2014-01-01

    Secondary mania resulting from cerebral Cortex are described commonly. But secondary mania produced by cerebellar lesions are relatively uncommon. This case report describes a patient who developed cerebellar stoke and manic features simultaneously. 28 years old male developed giddiness and projectile vomiting. Then he would lie down for about an hour only to find that he could not walk. He became quarrelsome. His Psycho motor activities and speech were increased. He was euphoric and was expressing grandiose ideas. Bender Gestalt Test showed signs of organicity. Score in Young mania relating scale was 32; productivity was low in Rorschach. Neurological examination revealed left cerebellar signs like ataxia and slurring of speech. Computed tomography of brain showed left cerebellar infarct. Relationship between Psychiatric manifestations and cerebellar lesion are discussed. PMID:25035567

  8. Ataxias with autosomal, X-chromosomal or maternal inheritance.

    PubMed

    Finsterer, Josef

    2009-07-01

    Heredoataxias are a group of genetic disorders with a cerebellar syndrome as the leading clinical manifestation. The current classification distinguishes heredoataxias according to the trait of inheritance into autosomal dominant, autosomal recessive, X-linked, and maternally inherited heredoataxias. The autosomal dominant heredoataxias are separated into spinocerebellar ataxias (SCA1-8, 10-15, 17-23, 25-30, and dentato-rubro-pallido-luysian atrophy), episodic ataxias (EA1-7), and autosomal dominant mitochondrial heredoataxias (Leigh syndrome, MIRAS, ADOAD, and AD-CPEO). The autosomal recessive ataxias are separated into Friedreich ataxia, ataxia due to vitamin E deficiency, ataxia due to Abeta-lipoproteinemia, Refsum disease, late-onset Tay-Sachs disease, cerebrotendineous xanthomatosis, spinocerebellar ataxia with axonal neuropathy, ataxia telangiectasia, ataxia telangiectasia-like disorder, ataxia with oculomotor apraxia 1 and 2, spastic ataxia of Charlevoix-Saguenay, Cayman ataxia, Marinesco-Sjögren syndrome, and autosomal recessive mitochondrial ataxias (AR-CPEO, SANDO, SCAE, AHS, IOSCA, MEMSA, LBSL CoQ-deficiency, PDC-deficiency). Only two of the heredoataxias, fragile X/tremor/ataxia syndrome, and XLSA/A are transmitted via an X-linked trait. Maternally inherited heredoataxias are due to point mutations in genes encoding for tRNAs, rRNAs, respiratory chain subunits or single large scale deletions/duplications of the mitochondrial DNA and include MELAS, MERRF, KSS, PS, MILS, NARP, and non-syndromic mitochondrial disorders. Treatment of heredoataxias is symptomatic and supportive and may have a beneficial effect in single patients. **Please see page 424 for abbreviation list. PMID:19650351

  9. Dystonia and Cerebellar Degeneration in the Leaner Mouse Mutant

    PubMed Central

    Raike, Robert S.; Hess, Ellen J.; Jinnah, H.A.

    2015-01-01

    Cerebellar degeneration is traditionally associated with ataxia. Yet, there are examples of both ataxia and dystonia occurring in individuals with cerebellar degeneration. There is also substantial evidence suggesting that cerebellar dysfunction alone may cause dystonia. The types of cerebellar defects that may cause ataxia, dystonia, or both have not been delineated. In the current study, we explored the relationship between cerebellar degeneration and dystonia using the leaner mouse mutant. Leaner mice have severe dystonia that is associated with dysfunctional and degenerating cerebellar Purkinje cells. Whereas the density of Purkinje cells was not significantly reduced in 4 week-old leaner mice, approximately 50% of the neurons were lost by 34 weeks of age. On the other hand, the dystonia and associated functional disability became significantly less severe during this same interval. In other words, dystonia improved as Purkinje cells were lost, suggesting that dysfunctional Purkinje cells, rather than Purkinje cell loss, contribute to the dystonia. These results provide evidence that distorted cerebellar function may cause dystonia and support the concept that different types of cerebellar defects can have different functional consequences. PMID:25791619

  10. Cellular and circuit mechanisms underlying spinocerebellar ataxias.

    PubMed

    Meera, Pratap; Pulst, Stefan M; Otis, Thomas S

    2016-08-15

    Degenerative ataxias are a common form of neurodegenerative disease that affect about 20 individuals per 100,000. The autosomal dominant spinocerebellar ataxias (SCAs) are caused by a variety of protein coding mutations (single nucleotide changes, deletions and expansions) in single genes. Affected genes encode plasma membrane and intracellular ion channels, membrane receptors, protein kinases, protein phosphatases and proteins of unknown function. Although SCA-linked genes are quite diverse they share two key features: first, they are highly, although not exclusively, expressed in cerebellar Purkinje neurons (PNs), and second, when mutated they lead ultimately to the degeneration of PNs. In this review we summarize ataxia-related changes in PN neurophysiology that have been observed in various mouse knockout lines and in transgenic models of human SCA. We also highlight emerging evidence that altered metabotropic glutamate receptor signalling and disrupted calcium homeostasis in PNs form a common, early pathophysiological mechanism in SCAs. Together these findings indicate that aberrant calcium signalling and profound changes in PN neurophysiology precede PN cell loss and are likely to lead to cerebellar circuit dysfunction that explains behavioural signs of ataxia characteristic of the disease. PMID:27198167

  11. Ataxia Telangiectasia–Mutated Gene Polymorphisms and Acute Normal Tissue Injuries in Cancer Patients After Radiation Therapy: A Systematic Review and Meta-analysis

    SciTech Connect

    Dong, Lihua; Cui, Jingkun; Tang, Fengjiao; Cong, Xiaofeng; Han, Fujun

    2015-04-01

    Purpose: Studies of the association between ataxia telangiectasia–mutated (ATM) gene polymorphisms and acute radiation injuries are often small in sample size, and the results are inconsistent. We conducted the first meta-analysis to provide a systematic review of published findings. Methods and Materials: Publications were identified by searching PubMed up to April 25, 2014. Primary meta-analysis was performed for all acute radiation injuries, and subgroup meta-analyses were based on clinical endpoint. The influence of sample size and radiation injury incidence on genetic effects was estimated in sensitivity analyses. Power calculations were also conducted. Results: The meta-analysis was conducted on the ATM polymorphism rs1801516, including 5 studies with 1588 participants. For all studies, the cut-off for differentiating cases from controls was grade 2 acute radiation injuries. The primary meta-analysis showed a significant association with overall acute radiation injuries (allelic model: odds ratio = 1.33, 95% confidence interval: 1.04-1.71). Subgroup analyses detected an association between the rs1801516 polymorphism and a significant increase in urinary and lower gastrointestinal injuries and an increase in skin injury that was not statistically significant. There was no between-study heterogeneity in any meta-analyses. In the sensitivity analyses, small studies did not show larger effects than large studies. In addition, studies with high incidence of acute radiation injuries showed larger effects than studies with low incidence. Power calculations revealed that the statistical power of the primary meta-analysis was borderline, whereas there was adequate power for the subgroup analysis of studies with high incidence of acute radiation injuries. Conclusions: Our meta-analysis showed a consistency of the results from the overall and subgroup analyses. We also showed that the genetic effect of the rs1801516 polymorphism on acute radiation injuries was

  12. Time-resolved functional analysis of acute impairment of frataxin expression in an inducible cell model of Friedreich ataxia.

    PubMed

    Poburski, Dörte; Boerner, Josefine Barbara; Koenig, Michel; Ristow, Michael; Thierbach, René

    2016-01-01

    Friedreich ataxia is a neurodegenerative disease caused by a GAA triplet repeat expansion in the first intron of the frataxin gene, which results in reduced expression levels of the corresponding protein. Despite numerous animal and cellular models, therapeutic options that mechanistically address impaired frataxin expression are lacking. Here, we have developed a new mammalian cell model employing the Cre/loxP recombination system to induce a homozygous or heterozygous frataxin knockout in mouse embryonic fibroblasts. Induction of Cre-mediated disruption by tamoxifen was successfully tested on RNA and protein levels. After loss of frataxin protein, cell division, aconitase activity and oxygen consumption rates were found to be decreased, while ROS production was increased in the homozygous state. By contrast, in the heterozygous state no such changes were observed. A time-resolved analysis revealed the loss of aconitase activity as an initial event after induction of complete frataxin deficiency, followed by secondarily elevated ROS production and a late increase in iron content. Initial impairments of oxygen consumption and ATP production were found to be compensated in the late state and seemed to play a minor role in Friedreich ataxia pathophysiology. In conclusion and as predicted from its proposed role in iron sulfur cluster (ISC) biosynthesis, disruption of frataxin primarily causes impaired function of ISC-containing enzymes, whereas other consequences, including elevated ROS production and iron accumulation, appear secondary. These parameters and the robustness of the newly established system may additionally be used for a time-resolved study of pharmacological candidates in a HTS manner. PMID:27106929

  13. Time-resolved functional analysis of acute impairment of frataxin expression in an inducible cell model of Friedreich ataxia

    PubMed Central

    Poburski, Dörte; Boerner, Josefine Barbara; Koenig, Michel; Ristow, Michael

    2016-01-01

    ABSTRACT Friedreich ataxia is a neurodegenerative disease caused by a GAA triplet repeat expansion in the first intron of the frataxin gene, which results in reduced expression levels of the corresponding protein. Despite numerous animal and cellular models, therapeutic options that mechanistically address impaired frataxin expression are lacking. Here, we have developed a new mammalian cell model employing the Cre/loxP recombination system to induce a homozygous or heterozygous frataxin knockout in mouse embryonic fibroblasts. Induction of Cre-mediated disruption by tamoxifen was successfully tested on RNA and protein levels. After loss of frataxin protein, cell division, aconitase activity and oxygen consumption rates were found to be decreased, while ROS production was increased in the homozygous state. By contrast, in the heterozygous state no such changes were observed. A time-resolved analysis revealed the loss of aconitase activity as an initial event after induction of complete frataxin deficiency, followed by secondarily elevated ROS production and a late increase in iron content. Initial impairments of oxygen consumption and ATP production were found to be compensated in the late state and seemed to play a minor role in Friedreich ataxia pathophysiology. In conclusion and as predicted from its proposed role in iron sulfur cluster (ISC) biosynthesis, disruption of frataxin primarily causes impaired function of ISC-containing enzymes, whereas other consequences, including elevated ROS production and iron accumulation, appear secondary. These parameters and the robustness of the newly established system may additionally be used for a time-resolved study of pharmacological candidates in a HTS manner. PMID:27106929

  14. Cerebellar Disorders

    MedlinePlus

    ... Problems with the cerebellum include Cancer Genetic disorders Ataxias - failure of muscle control in the arms and legs that result in movement disorders Degeneration - disorders caused by brain cells decreasing in ...

  15. Ethanol modulates facial stimulation-evoked outward currents in cerebellar Purkinje cells in vivo in mice.

    PubMed

    Wu, Mao-Cheng; Bing, Yan-Hua; Chu, Chun-Ping; Qiu, De-Lai

    2016-01-01

    Acute ethanol overdose can induce dysfunction of cerebellar motor regulation and cerebellar ataxia. In this study, we investigated the effect of ethanol on facial stimulation-evoked inhibitory synaptic responses in cerebellar Purkinje cells (PCs) in urethane-anesthetized mice, using in vivo patch-clamp recordings. Under voltage-clamp conditions, ethanol (300 mM) decreased the amplitude, half-width, rise time and decay time of facial stimulation-evoked outward currents in PCs. The ethanol-induced inhibition of facial stimulation-evoked outward currents was dose-dependent, with an IC50 of 148.5 mM. Notably, the ethanol-induced inhibition of facial stimulation-evoked outward currents were significantly abrogated by cannabinoid receptor 1 (CB1) antagonists, AM251 and O-2050, as well as by the CB1 agonist WIN55212-2. Moreover, the ethanol-induced inhibition of facial stimulation-evoked outward currents was prevented by cerebellar surface perfusion of the PKA inhibitors H-89 and Rp-cAMP, but not by intracellular administration of the PKA inhibitor PKI. Our present results indicate that ethanol inhibits the facial stimulation-evoked outward currents by activating presynaptic CB1 receptors via the PKA signaling pathway. These findings suggest that ethanol overdose impairs sensory information processing, at least in part, by inhibiting GABA release from molecular layer interneurons onto PCs. PMID:27489024

  16. Ethanol modulates facial stimulation-evoked outward currents in cerebellar Purkinje cells in vivo in mice

    PubMed Central

    Wu, Mao-Cheng; Bing, Yan-Hua; Chu, Chun-Ping; Qiu, De-Lai

    2016-01-01

    Acute ethanol overdose can induce dysfunction of cerebellar motor regulation and cerebellar ataxia. In this study, we investigated the effect of ethanol on facial stimulation-evoked inhibitory synaptic responses in cerebellar Purkinje cells (PCs) in urethane-anesthetized mice, using in vivo patch-clamp recordings. Under voltage-clamp conditions, ethanol (300 mM) decreased the amplitude, half-width, rise time and decay time of facial stimulation-evoked outward currents in PCs. The ethanol-induced inhibition of facial stimulation-evoked outward currents was dose-dependent, with an IC50 of 148.5 mM. Notably, the ethanol-induced inhibition of facial stimulation-evoked outward currents were significantly abrogated by cannabinoid receptor 1 (CB1) antagonists, AM251 and O-2050, as well as by the CB1 agonist WIN55212-2. Moreover, the ethanol-induced inhibition of facial stimulation-evoked outward currents was prevented by cerebellar surface perfusion of the PKA inhibitors H-89 and Rp-cAMP, but not by intracellular administration of the PKA inhibitor PKI. Our present results indicate that ethanol inhibits the facial stimulation-evoked outward currents by activating presynaptic CB1 receptors via the PKA signaling pathway. These findings suggest that ethanol overdose impairs sensory information processing, at least in part, by inhibiting GABA release from molecular layer interneurons onto PCs. PMID:27489024

  17. 'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization.

    PubMed

    García-Murias, María; Quintáns, Beatriz; Arias, Manuel; Seixas, Ana I; Cacheiro, Pilar; Tarrío, Rosa; Pardo, Julio; Millán, María J; Arias-Rivas, Susana; Blanco-Arias, Patricia; Dapena, Dolores; Moreira, Ramón; Rodríguez-Trelles, Francisco; Sequeiros, Jorge; Carracedo, Angel; Silveira, Isabel; Sobrido, María J

    2012-05-01

    Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56. Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century. We found the presence of the spinocerebellar ataxia 36 mutation co-segregating with disease in these families in whom we had previously identified an ~0.8 Mb linkage region to chromosome 20 p. Subsequent screening revealed the NOP56 expansion in eight additional Galician ataxia kindreds. While normal alleles contain 5-14 hexanucleotide repeats, expanded alleles range from ~650 to 2500 repeats, within a shared haplotype. Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions. We found a total of 63 individuals carrying the mutation, 44 of whom were confirmed to be clinically affected; over 400 people are at risk. We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss. There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis. Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy. We estimated the origin of the founder mutation in Galicia to have occurred ~1275 years ago. Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36, while 15 (9.4%) showed other of the routinely tested dominant spinocerebellar ataxia types. Spinocerebellar ataxia 36 is

  18. Retinal and pontine striations: neurodiagnostic signs of autosomal recessive spastic ataxia of Charlevoix-Saguenay.

    PubMed

    Leavitt, Jacqueline A; Singer, Wolfgang; Brown, William L; Pulido, Jose S; Brodsky, Michael C

    2014-12-01

    A 39-year-old man with long-standing ataxia, spasticity, dysarthria, and peripheral neuropathy was found to have diffuse thickening of the retinal nerve fiber layer in both eyes, as manifested by prominent retinal striations and confirmed by optical coherence tomography. Magnetic resonance imaging showed severe atrophy of the superior cerebellar vermis with linear "footprint" hypointensities in the pons with irregular striations. Genetic testing confirmed the diagnosis of spastic ataxia of Charlevoix-Saguenay (ARSACS). The clinical evaluation of progressive cerebellar ataxia should include a dedicated search for retinal nerve fiber layer thickening, which establishes the diagnosis of ARSACS. PMID:25237835

  19. Speech Characteristics Associated with Three Genotypes of Ataxia

    ERIC Educational Resources Information Center

    Sidtis, John J.; Ahn, Ji Sook; Gomez, Christopher; Sidtis, Diana

    2011-01-01

    Purpose: Advances in neurobiology are providing new opportunities to investigate the neurological systems underlying motor speech control. This study explores the perceptual characteristics of the speech of three genotypes of spino-cerebellar ataxia (SCA) as manifest in four different speech tasks. Methods: Speech samples from 26 speakers with SCA…

  20. Progressive Ataxia and Palatal Tremor: Think about POLG Mutations

    PubMed Central

    Mongin, Marie; Delorme, Cécile; Lenglet, Timothée; Jardel, Claude; Vignal, Catherine; Roze, Emmanuel

    2016-01-01

    Background Progressive ataxia and palatal tremor (PAPT) can be observed in both acquired brainstem or cerebellar lesions and genetic disorders. Phenomenology shown PAPT due to mutation in POLG, the gene encoding the mitochondrial DNA polymerase. Educational value POLG mutation should be considered in patients with PAPT, particularly when additional clues such as a sensory neuronopathy or an ophthalmoplegia are present.

  1. Cerebellar Degeneration

    MedlinePlus

    ... Degeneration? Cerebellar degeneration is a process in which neurons in the cerebellum - the area of the brain ... proteins that are necessary for the survival of neurons. Associated diseases: Diseases that are specific to the ...

  2. Cerebellar liponeurocytoma.

    PubMed

    Owler, Brian K; Makeham, John M; Shingde, Meena; Besser, Michael

    2005-04-01

    A case of cerebellar liponeurocytoma in a 34-year-old man is reported. There are only 19 other cases reporting this entity in the medical literature. The diagnostic, radiological and clinical features associated with this tumour are reviewed and discussed in relation to our case. The differences in behaviour and prognosis between medulloblastoma and cerebellar liponeurocytoma are presented with the corresponding implications for management. PMID:15851097

  3. SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases.

    PubMed

    Choquet, Karine; Tétreault, Martine; Yang, Sharon; La Piana, Roberta; Dicaire, Marie-Josée; Vanstone, Megan R; Mathieu, Jean; Bouchard, Jean-Pierre; Rioux, Marie-France; Rouleau, Guy A; Boycott, Kym M; Majewski, Jacek; Brais, Bernard

    2016-07-01

    Hereditary cerebellar ataxias and hereditary spastic paraplegias are clinically and genetically heterogeneous and often overlapping neurological disorders. Mutations in SPG7 cause the autosomal recessive spastic paraplegia type 7 (SPG7), but recent studies indicate that they are also one of the most common causes of recessive cerebellar ataxia. In Quebec, a significant number of patients affected with cerebellar ataxia and spasticity remain without a molecular diagnosis. We performed whole-exome sequencing in three French Canadian (FC) patients affected with spastic ataxia and uncovered compound heterozygous variants in SPG7 in all three. Sanger sequencing of SPG7 exons and exon/intron boundaries was used to screen additional patients. In total, we identified recessive variants in SPG7 in 22 FC patients belonging to 12 families (38.7% of the families screened), including two novel variants. The p.(Ala510Val) variant was the most common in our cohort. Cerebellar features, including ataxia, were more pronounced than spasticity in this cohort. These results strongly suggest that variants affecting the function of SPG7 are the fourth most common form of recessive ataxia in FC patients. Thus, we propose that SPG7 mutations explain a significant proportion of FC spastic ataxia cases and that this gene should be considered in unresolved patients. PMID:26626314

  4. Neuronal Atrophy Early in Degenerative Ataxia Is a Compensatory Mechanism to Regulate Membrane Excitability

    PubMed Central

    Dell'Orco, James M.; Wasserman, Aaron H.; Chopra, Ravi; Ingram, Melissa A. C.; Hu, Yuan-Shih; Singh, Vikrant; Wulff, Heike; Opal, Puneet; Orr, Harry T.

    2015-01-01

    Neuronal atrophy in neurodegenerative diseases is commonly viewed as an early event in a continuum that ultimately results in neuronal loss. In a mouse model of the polyglutamine disorder spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that cerebellar Purkinje neuron atrophy serves an adaptive role rather than being simply a nonspecific response to injury. In acute cerebellar slices from SCA1 mice, we find that Purkinje neuron pacemaker firing is initially normal but, with the onset of motor dysfunction, becomes disrupted, accompanied by abnormal depolarization. Remarkably, subsequent Purkinje cell atrophy is associated with a restoration of pacemaker firing. The early inability of Purkinje neurons to support repetitive spiking is due to unopposed calcium currents resulting from a reduction in large-conductance calcium-activated potassium (BK) and subthreshold-activated potassium channels. The subsequent restoration of SCA1 Purkinje neuron firing correlates with the recovery of the density of these potassium channels that accompanies cell atrophy. Supporting a critical role for BK channels, viral-mediated increases in BK channel expression in SCA1 Purkinje neurons improves motor dysfunction and partially restores Purkinje neuron morphology. Cerebellar perfusion of flufenamic acid, an agent that restores the depolarized membrane potential of SCA1 Purkinje neurons by activating potassium channels, prevents Purkinje neuron dendritic atrophy. These results suggest that Purkinje neuron dendritic remodeling in ataxia is an adaptive response to increases in intrinsic membrane excitability. Similar adaptive remodeling could apply to other vulnerable neuronal populations in neurodegenerative disease. SIGNIFICANCE STATEMENT In neurodegenerative disease, neuronal atrophy has long been assumed to be an early nonspecific event preceding neuronal loss. However, in a mouse model of spinocerebellar ataxia type 1 (SCA1), we identify a previously unappreciated

  5. Diagnostic Approach to Childhood-onset Cerebellar Atrophy: A 10-Year Retrospective Study of 300 Patients

    PubMed Central

    Al-Maawali, Almundher; Blaser, Susan; Yoon, Grace

    2013-01-01

    Hereditary ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. Selection of appropriate clinical and genetic tests for patients with cerebellar atrophy poses a diagnostic challenge. Neuroimaging is a crucial initial investigation in the diagnostic evaluation of ataxia in childhood, and the presence of cerebellar atrophy helps guide further investigations. We performed a detailed review of 300 patients with confirmed cerebellar atrophy on magnetic resonance imaging over a 10-year period. A diagnosis was established in 47% of patients: Mitochondrial disorders were most common, followed by the neuronal ceroid lipofuscinoses, ataxia telangectasia, and late GM2-gangliosidosis. We review the common causes of cerebellar atrophy in childhood and propose a diagnostic approach based on correlating specific neuroimaging patterns with clinical and genetic diagnoses. PMID:22764178

  6. Hereditary ataxias and paraplegias in Cantabria, Spain. An epidemiological and clinical study.

    PubMed

    Polo, J M; Calleja, J; Combarros, O; Berciano, J

    1991-04-01

    A clinical, genetic and epidemiological study of hereditary ataxias and paraplegias was conducted within a defined area (Cantabria) in Northern Spain from 1974 to 1986. The series comprised 48 index cases and 65 affected relatives. On prevalence day, 103 patients were alive, giving a prevalence of 20.2 cases per 100,000. There were 24 patients (18 families) with Friedreich's ataxia (FA), 12 (6 families) with early onset cerebellar ataxia (EOCA) differing from FA, 6 (3 families) with dominantly transmitted late onset cerebellar ataxia (LOCA), 11 with 'idiopathic' LOCA, 49 (9 families) with 'pure' hereditary spastic paraplegia (HSP), and 1 patient with congenital cerebellar ataxia. The prevalence found here is comparable with the highest figures described in previous surveys. This may in part be due to the great number of secondary cases in our series. A high frequency of parental consanguinity occurred in FA patients, 'pseudodominant' inheritance being observed in 1 family. The clinical features were those of classical FA except for later onset and slower course in 1 family, and retained tendon reflexes in the lower limbs in 2 cases. Such data indicate the need for modification of the essential criteria for the disease. EOCA included 4 patients with normoreflexic ataxia and 1 patient with ataxia and luteinizing hormone-releasing hormone deficiency. In addition, there were 7 patients from 2 unrelated families with a homogeneous syndrome characterized by autosomal recessive inheritance, cerebellar ataxia, retinitis pigmentosa and sensory neuropathy. This syndrome is therefore a well defined nosological entity to be added to the list of autosomal recessive mendelian phenotypes. The clinical picture of patients with LOCA was either a 'pure' cerebellar or a 'cerebellar-plus' syndrome. Genetic subgroups of 'pure' HSP were autosomal dominant type I in 5 families and type II in 2, and autosomal recessive in 2 families. PMID:2043954

  7. Diagnosis of Ataxia

    MedlinePlus

    ... the fingers, hands, arms, legs, body, speech, and eye movements. The word ataxia is often used to describe ... motor control such as writing and eating. Slow eye movements can be seen in some form of ataxia. ...

  8. National Ataxia Foundation

    MedlinePlus

    ... naf@ataxia.org . Charity Navigator Awards NAF Four-Star Rating Charity Navigator, America’s premier charity evaluator, has ... Ataxia Foundation received a four out of four star rating. This is the fourth consecutive year NAF ...

  9. Spinocerebellar ataxia type 12 identified in two Italian families may mimic sporadic ataxia.

    PubMed

    Brussino, Alessandro; Graziano, Claudio; Giobbe, Dario; Ferrone, Marina; Dragone, Elisa; Arduino, Carlo; Lodi, Raffaele; Tonon, Caterina; Gabellini, Anna; Rinaldi, Rita; Miccoli, Sara; Grosso, Enrico; Bellati, Maria Cristina; Orsi, Laura; Migone, Nicola; Brusco, Alfredo

    2010-07-15

    SCA12 is an autosomal dominant cerebellar ataxia characterized by onset in the fourth decade of life with action tremor of arms and head, mild ataxia, dysmetria, and hyperreflexia. The disease is caused by an expansion of >or=51 CAGs in the 5' region of the brain- specific phosphatase 2 regulatory subunit B-beta isoform (PPP2R2B) gene. SCA12 is very rare, except for a single ethnic group in India. We screened 159 Italian ataxic patients for SCA12 and identified two families that segregated an expanded allele of 57 to 58 CAGs, sharing a common haplotype. The age at onset, phenotype, and variability of symptoms were compatible with known cases. In one family, the disease was apparently sporadic due to possible incomplete penetrance and/or late age at onset. Our data indicate that SCA12 is also present in Italian patients, and its genetic testing should be applied to both sporadic and familial ataxias. PMID:20629122

  10. Cerebellar Motor Function in Spina Bifida Meningomyelocele

    PubMed Central

    Dennis, Maureen; Salman, Michael S.; Juranek, Jenifer; Fletcher, Jack M.

    2010-01-01

    Spina bifida meningomyelocele (SBM), a congenital neurodevelopmental disorder, involves dysmorphology of the cerebellum, and its most obvious manifestations are motor deficits. This paper reviews cerebellar neuropathology and motor function across several motor systems well studied in SBM in relation to current models of cerebellar motor and timing function. Children and adults with SBM have widespread motor deficits in trunk, upper limbs, eyes, and speech articulators that are broadly congruent with those observed in adults with cerebellar lesions. The structure and function of the cerebellum are correlated with a range of motor functions. While motor learning is generally preserved in SBM, those motor functions requiring predictive signals and precise calibration of the temporal features of movement are impaired, resulting in deficits in smooth movement coordination as well as in the classical cerebellar triad of dysmetria, ataxia, and dysarthria. That motor function in individuals with SBM is disordered in a manner phenotypically similar to that in adult cerebellar lesions, and appears to involve similar deficits in predictive cerebellar motor control, suggests that age-based cerebellar motor plasticity is limited in individuals with this neurodevelopmental disorder. PMID:20652468

  11. [Cerebellar stroke].

    PubMed

    Paradowski, Michał; Zimny, Anna; Paradowski, Bogusław

    2015-01-01

    Cerebellar stroke belongs to a group of rare diseases of vascular origin. Cerebellum, supplied by three pairs of arteries (AICA, PICA, SCA) with many anastomoses between them is less susceptible for a stroke, especially ischemic one. Diagnosis of the stroke in this region is harder due to lower sensibility of commonly used CT of the head in case of stroke suspicion. The authors highlight clinical symptoms distinguishing between vascular territories or topographical locations of the stroke, diagnostic procedures, classical and surgical treatment, the most common misdiagnoses are also mentioned. The authors suggest a diagnostic and therapeutic algorithm development, including rtPA treatment criteria for ischemic cerebellar stroke. PMID:26181157

  12. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy.

    PubMed

    Valenzano, Kenneth J; Tafesse, Laykea; Lee, Gary; Harrison, James E; Boulet, Jamie M; Gottshall, Susan L; Mark, Lilly; Pearson, Michelle S; Miller, Wendy; Shan, Shen; Rabadi, Leyana; Rotshteyn, Yakov; Chaffer, Suzanne M; Turchin, Paul I; Elsemore, David A; Toth, Mathew; Koetzner, Lee; Whiteside, Garth T

    2005-04-01

    To date, two cannabinoid receptors have been identified, CB1 and CB2. Activation of these receptors with non-selective cannabinoid receptor agonists reduces pain sensitivity in animals and humans. However, activation of CB1 receptors is also associated with central side effects, including ataxia and catalepsy. More recently, a role for selective CB2 agonists in pain modification has been demonstrated. GW405833, a selective CB2 agonist, was recently reported to partially reverse the inflammation and hyperalgesia in a rat model of acute inflammation. In the current report, we extend the characterization and therapeutic potential of this compound. For the first time, we show that GW405833 selectively binds both rat and human CB2 receptors with high affinity, where it acts as a partial agonist (approximately 50% reduction of forskolin-mediated cAMP production compared to the full cannabinoid agonist, CP55,940). We also report for the first time that intraperitoneal administration of GW405833 (0.3-100 mg/kg) to rats shows linear, dose-dependent increases in plasma levels and substantial penetration into the central nervous system. In addition, GW405833 (up to 30 mg/kg) elicits potent and efficacious antihyperalgesic effects in rodent models of neuropathic, incisional and chronic inflammatory pain, the first description of this compound in these models. In contrast, analgesia, sedation and catalepsy were not observed in this dose range, but were apparent at 100 mg/kg. Additionally, GW405833 was not antihyperalgesic against chronic inflammatory pain in CB2 knockout mice. These data support the tenet that selective CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists, and highlight the utility of GW405833 for the investigation of CB2 physiology. PMID:15814101

  13. Milestones in ataxia

    PubMed Central

    Klockgether, Thomas; Paulson, Henry

    2010-01-01

    The past 25 years have seen enormous progress in the deciphering of the genetic and molecular basis of ataxias resulting in an improved understanding of their pathogenesis. The most significant milestones during this period were the cloning of the genes associated with the common spinocerebellar ataxias (SCAs), ataxia telangiectasia (AT) and Friedreich ataxia (FRDA). To date, the causative mutations of more than 30 SCAs and 20 recessive ataxias have been identified. In addition, there are numerous acquired ataxias with defined molecular causes so that the entire number of distinct ataxia disorders exceeds 50 and possibly approaches 100. Despite this enormous heterogeneity, a few recurrent pathopyhsiological themes stand out. These include protein aggregation, failure of protein homoestasis, perturbations in ion channel function, defects in DNA repair and mitochondrial dysfunction. The clinical phenotypes of the most common ataxia disorders have been firmly established, and their natural history is being studied in ongoing large observational trials. Effective therapies for ataxias are still lacking. However, novel drug targets are under investigation, and it is expected that there will be an increasing number of therapeutic trials in ataxia. PMID:21626557

  14. Cell Signaling and Neurotoxicity: 3H-Arachidonic acid release (Phospholipase A2) in cerebellar granule neurons

    EPA Science Inventory

    Cell signaling is a complex process which controls basic cellular activities and coordinates actions to maintain normal cellular homeostasis. Alterations in signaling processes have been associated with neurological diseases such as Alzheimer's and cerebellar ataxia, as well as, ...

  15. Speech and Language Findings Associated with Paraneoplastic Cerebellar Degeneration

    ERIC Educational Resources Information Center

    Paslawski, Teresa; Duffy, Joseph R.; Vernino, Steven

    2005-01-01

    Paraneoplastic cerebellar degeneration (PCD) is an autoimmune disease that can be associated with cancer of the breast, lung, and ovary. The clinical presentation of PCD commonly includes ataxia, visual disturbances, and dysarthria. The speech disturbances associated with PCD have not been well characterized, despite general acceptance that…

  16. Gene Testing for Hereditary Ataxia

    MedlinePlus

    ... have a family history of ataxia, but diagnostic tests for known ataxia genes cannot explain the ataxia in their family. In recent years, scientists have developed technologies to sequence thousands of genes at the same ...

  17. SNP Analysis and Whole Exome Sequencing: Their Application in the Analysis of a Consanguineous Pedigree Segregating Ataxia

    PubMed Central

    Nickerson, Sarah L.; Marquis-Nicholson, Renate; Claxton, Karen; Ashton, Fern; Leong, Ivone U. S.; Prosser, Debra O.; Love, Jennifer M.; George, Alice M.; Taylor, Graham; Wilson, Callum; McKinlay Gardner, R. J.; Love, Donald R.

    2015-01-01

    Autosomal recessive cerebellar ataxia encompasses a large and heterogeneous group of neurodegenerative disorders. We employed single nucleotide polymorphism (SNP) analysis and whole exome sequencing to investigate a consanguineous Maori pedigree segregating ataxia. We identified a novel mutation in exon 10 of the SACS gene: c.7962T>G p.(Tyr2654*), establishing the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Our findings expand both the genetic and phenotypic spectrum of this rare disorder, and highlight the value of high-density SNP analysis and whole exome sequencing as powerful and cost-effective tools in the diagnosis of genetically heterogeneous disorders such as the hereditary ataxias.

  18. [Late onset Friedreich ataxia: clinical description of a family in Argentina].

    PubMed

    Pérez Akly, Manuel; Alvarez, Fernando

    2013-01-01

    Friedreich Ataxia (FA) is the most common hereditary ataxia, caused by abnormal expansion of the GAA triplet of the first intron of the X25 gene on chromosome 9. Clinically it occurs in patients under the age of 25 and it is frequently associated with musculoskeletal, endocrine and myocardial disorders. Among their phenotypic variants there are patients starting their symptoms after the age of 25. The latter group is defined as late onset Freidreich ataxia (LOFA). The objective of this work is to present three siblings affected by late onset Friedreich ataxia. Their symptoms began between the ages of 32 and 34, with gait disturbance and dysarthria of cerebellar type, which worsened, thus becoming more evident in the course of 6-12 months. None had musculoskeletal or myocardial involvement. There was no family history of ataxia or other neurological disorders. Two of these patients underwent genetic study that showed abnormal expansion of GAA triplet confirming the diagnosis of FA. A magnetic resonance imaging (MRI) of the brain was performed. Proximal spinal cord atrophy, sparing cerebellar structures, was found in two of the cases and vermian atrophy associated with proximal spinal cord atrophy was observed in the third one. Molecular testing GAA expansions in the FA gene should be considered in cerebellar ataxia with dysarthria and loss of proprioception. PMID:24152405

  19. [Case of cerebellar and spinal cord infarction presenting with acute brachial diplegia due to right vertebral artery occlusion].

    PubMed

    Fujii, Takayuki; Santa, Yo; Akutagawa, Noriko; Nagano, Sukehisa; Yoshimura, Takeo

    2012-01-01

    A 73-year-old man was admitted for evaluation of sudden onset of dizziness, bilateral shoulder pain, and brachial diplegia. Neurological examination revealed severe bilateral weakness of the triceps brachii, wrist flexor, and wrist extensor muscles. There was no paresis of the lower limbs. His gait was ataxic. Pinprick and temperature sensations were diminished at the bilateral C6-C8 dermatomes. Vibration and position senses were intact. An MRI of the head revealed a right cerebellar infarction and occlusion of the right vertebral artery. An MRI of the cervical spine on T₂ weighted imaging (T₂WI) showed cord compression at the C3/4-C5/6 level secondary to spondylotic degeneration without any intramedullary signal changes of the cord. On the following day, however, high-signal lesions on T₂WI appeared in the C5-C6 spinal cord, suggesting cord infarction. Unilateral vertebral artery occlusion does not usually result in cervical cord infarction because of anastomosis of arteries. Because of the long-term mechanical compression in our case, it was likely that cervical cord ischemia was present before the onset of symptoms. On the basis of chronic cord compression, our case suggests that occlusion of a unilateral vertebral artery could cause cervical cord infarction. PMID:22790805

  20. Metabolic anatomy of paraneoplastic cerebellar degeneration

    SciTech Connect

    Anderson, N.E.; Posner, J.B.; Sidtis, J.J.; Moeller, J.R.; Strother, S.C.; Dhawan, V.; Rottenberg, D.A.

    1988-06-01

    Eleven patients with acquired cerebellar degeneration (10 of whom had paraneoplastic cerebellar degeneration (PCD)) were evaluated using neuropsychological tests and /sup 18/F-fluorodeoxyglucose/positron emission tomography to (1) quantify motor, cognitive, and metabolic abnormalities; (2) determine if characteristic alterations in the regional cerebral metabolic rate for glucose (rCMRGlc) are associated with PCD; and (3) correlate behavioral and metabolic measures of disease severity. Eighteen volunteer subjects served as normal controls. Although some PCD neuropsychological test scores were abnormal, these results could not, in general, be dissociated from the effects of dysarthria and ataxia. rCMRGlc was reduced in patients with PCD (versus normal control subjects) in all regions except the brainstem. Analysis of patient and control rCMRGlc data using a mathematical model of regional metabolic interactions revealed two metabolic pattern descriptors, SSF1 and SSF2, which distinguished patients with PCD from normal control subjects; SSF2, which described a metabolic coupling between cerebellum, cuneus, and posterior temporal, lateral frontal, and paracentral cortex, correlated with quantitative indices of cerebellar dysfunction. Our inability to document substantial intellectual impairment in 7 of 10 patients with PCD contrasts with the 50% incidence of dementia in PCD reported by previous investigators. Widespread reductions in PCD rCMRGlc may result from the loss of cerebellar efferents to thalamus and forebrain structures, a reverse cerebellar diaschisis.

  1. Spinocerebellar ataxia type 20.

    PubMed

    Storey, Elsdon; Gardner, R J McKinlay

    2012-01-01

    Spinocerebellar ataxia type 20 (SCA20), first reported in 2004, is a slowly progressive dominantly inherited disorder so far reported in a single Anglo-Celtic family from Australia. It is characterized by dentate calcification from an early stage of the illness. Dysarthria without ataxia is the first symptom in the majority - an unusual feature amongst the SCAs. In addition to ataxia, examination often reveals spasmodic dysphonia and palatal tremor, but the syndrome is otherwise fairly pure. The responsible genetic abnormality has been tentatively identified as a 260-kb duplication in the pericentric region of chromosome 11, but confirmation will necessarily await description of further families. PMID:21827916

  2. Ocular motor characteristics of different subtypes of spinocerebellar ataxia: distinguishing features.

    PubMed

    Kim, Ji Sun; Kim, Ji Soo; Youn, Jinyoung; Seo, Dae-Won; Jeong, Yuri; Kang, Ji-Hoon; Park, Jeong Ho; Cho, Jin Whan

    2013-08-01

    Because of frequent involvement of the cerebellum and brainstem, ocular motor abnormalities are key features of spinocerebellar ataxias and may aid in differential diagnosis. Our objective for this study was to distinguish the subtypes by ophthalmologic features after head-shaking and positional maneuvers, which are not yet recognized as differential diagnostic tools in most common forms of spinocerebellar ataxias. Of the 302 patients with a diagnosis of cerebellar ataxia in 3 Korean University Hospitals from June 2011 to June 2012, 48 patients with spinocerebellar ataxia types 1, 2, 3, 6, 7, or 8 or with undetermined spinocerebellar ataxias were enrolled. All patients underwent a video-oculographic recording of fixation abnormalities, gaze-evoked nystagmus, positional and head-shaking nystagmus, and dysmetric saccades. Logistic regression analysis controlling for disease duration revealed that spontaneous and positional downbeat nystagmus and perverted head-shaking nystagmus were strong predictors for spinocerebellar ataxia 6, whereas saccadic intrusions and oscillations were identified as positive indicators of spinocerebellar ataxia 3. In contrast, the presence of gaze-evoked nystagmus and dysmetric saccades was a negative predictor of spinocerebellar ataxia 2. Positional maneuvers and horizontal head shaking occasionally induced or augmented saccadic intrusions/oscillations in patients with spinocerebellar ataxia types 1, 2, and 3 and undetermined spinocerebellar ataxia. The results indicated that perverted head-shaking nystagmus may be the most sensitive parameter for SCA6, whereas saccadic intrusions/oscillations are the most sensitive for spinocerebellar ataxia 3. In contrast, a paucity of gaze-evoked nystagmus and dysmetric saccades is more indicative of spinocerebellar ataxia 2. Head-shaking and positional maneuvers aid in defining ocular motor characteristics in spinocerebellar ataxias. © 2013 Movement Disorder Society. PMID:23609488

  3. Neuropsychological picture of 33 spinocerebellar ataxia cases.

    PubMed

    Orsi, Laura; D'Agata, Federico; Caroppo, Paola; Franco, Alessandra; Caglio, Marcella Maria; Avidano, Federica; Manzone, Cristina; Mortara, Paolo

    2011-03-01

    We administered a large battery of neuropsychological tests to an heterogeneous cohort of genetically defined spinocerebellar ataxia (SCA) patients in order to assess their cognitive profile and to compare cognitive impairment among different SCA genotypes, particularly between SCA with the classical pattern of olivo-ponto-cerebellar atrophy (SCA1 and SCA2) and those with a relatively "pure" olivo-cerebellar atrophy (SCA6 and SCA8). Our data revealed a neuropsychological picture characterized by fronto-parietal involvement with mnestic, linguistic, visuospatial, attentional, executive, and mood changes, in agreement with the cerebellar cognitive affective syndrome definition. We found a homogeneous neuropsychological profile among SCA subgroups with a prominent role of frontal dysfunction--particularly, attention, memory, and executive functions. We analyzed the possible interactions between neuropsychological pattern and clinical, demographical, and genetic variables. We found the presence of a cognitive impairment at the early stages of the disease, without visuospatial alterations, which appeared later. Age and education represented the most important demographic factors to predict the neuropsychological performance in SCA and in controls, but their effect in patients had definitely more impact. In our sample education could represent a protective factor and a marker of an enriched environment or a better developmental cognitive differentiation. We demonstrated that in our patients there was a distinct subgroup of high functional subjects and that triplet repeats modulated the effect of aging on cognition and progression of motor disability. PMID:21302172

  4. Diet for Ataxia

    MedlinePlus

    ... discuss these guidelines with a physical therapist and nutritionist familiar with movement disorders. Ataxia is a complex ... fiber to your diet with your physician or nutritionist, ask them if you might also benefit by ...

  5. Friedreich's Ataxia Research Alliance

    MedlinePlus

    ... Cookies ? Yes Wait Leave Provided by OpenGlobal E-commerce Please wait while your page loads ... FARA Cure ... Help Ways to Donate rideATAXIA Team FARA FARA Energy Ball Grassroots Fundraising Fundraising Tools Raising Awareness Advocacy ...

  6. Neuropsychological test performance of patients with Friedreich's ataxia.

    PubMed

    Wollmann, Tone; Barroso, Jose; Monton, Fernando; Nieto, Antonieta

    2002-08-01

    Although recognized as one of the most common hereditary diseases of the nervous system, the neuropsychological deficits in Friedreich's ataxia (FA) have rarely been studied. A protocol was constructed to assess the major cognitive areas in patients with FA and pair-matched normal controls. Motor difficulties, dysarthria and fatigability were taken into account. Neuropsychological assessment showed decreased motor and mental reaction times, reduced verbal span, deficits in letter fluency, impaired acquisition and consolidation of verbal information, proactive interference effect, and alterations in complex visuoperceptual and visuoconstructive abilities, in comparison with the control group. Magnetic resonance images showing cerebellar atrophy in the majority of patients suggest that cerebellar degeneration and the interruption of afferent and efferent cerebellar connections could be related to the cognitive deficits shown by our patients. PMID:12187450

  7. Nutritional cerebellar degeneration, with comments on its relationship to Wernicke disease and alcoholism.

    PubMed

    Laureno, Robert

    2012-01-01

    Nutritional cerebellar degeneration occurs in alcoholism and other states that predispose to malnutrition, such as gastric bypass surgery. Gait ataxia is the principal clinical manifestation. Ataxia of the lower limbs is not uncommon, but upper extremity ataxia and nystagmus are rare. Atrophy of the anterior superior vermis is the primary pathological manifestation in established disease. Typically, the onset is subacute. This cerebellar disease is part of the spectrum of the Wernicke-Korsakoff syndrome, i.e. the cerebellar manifestation of Wernicke disease. It may occur with other lesions of Wernicke disease or in isolation. Rarely, with florid disease, lesions may be hemorrhagic. Active disease should be treated with thiamine in the same way that one treats Wernicke disease. Clinicopathologic correlation in this disease has provided the best evidence that the anterior superior vermis is important in coordinating bipedal locomotion. PMID:21827888

  8. Cerebellar transcranial direct current stimulation in neurological disease.

    PubMed

    Ferrucci, Roberta; Bocci, Tommaso; Cortese, Francesca; Ruggiero, Fabiana; Priori, Alberto

    2016-01-01

    Several studies have highlighted the therapeutic potential of transcranial direct current stimulation (tDCS) in patients with neurological diseases, including dementia, epilepsy, post-stroke dysfunctions, movement disorders, and other pathological conditions. Because of this technique's ability to modify cerebellar excitability without significant side effects, cerebellar tDCS is a new, interesting, and powerful tool to induce plastic modifications in the cerebellum. In this report, we review a number of interesting studies on the application of cerebellar tDCS for various neurological conditions (ataxia, Parkinson's disease, dystonia, essential tremor) and the possible mechanism by which the stimulation acts on the cerebellum. Study findings indicate that cerebellar tDCS is a promising therapeutic tool in treating several neurological disorders; however, this method's efficacy appears to be limited, given the current data. PMID:27595007

  9. Episodic ataxia type 1: clinical characterization, quality of life and genotype–phenotype correlation

    PubMed Central

    Graves, Tracey D.; Cha, Yoon-Hee; Hahn, Angelika F.; Barohn, Richard; Salajegheh, Mohammed K.; Griggs, Robert C.; Bundy, Brian N.; Jen, Joanna C.; Baloh, Robert W.

    2014-01-01

    Episodic ataxia type 1 is considered a rare neuronal ion channel disorder characterized by brief attacks of unsteadiness and dizziness with persistent myokymia. To characterize the natural history, develop outcome measures for future clinical trials, and correlate genotype with phenotype, we undertook an international, prospective, cross-sectional study. Thirty-nine individuals (51% male) were enrolled: median age 37 years (range 15–65 years). We identified 10 different pathogenic point mutations in KCNA1 that accounted for the genetic basis of 85% of the cohort. Participants with KCNA1 mutations were more likely to have a positive family history. Analysis of the total cohort showed that the first episode of ataxia occurred before age 20 in all but one patient, with an average age of onset of 7.9 years. Physical exertion, emotional stress and environmental temperature were the most common triggers for attacks. Attack frequency ranged from daily to monthly, even with the same KCNA1 genotype. Average attack duration was in the order of minutes. Ten participants (26%) developed permanent cerebellar signs, which were related to disease duration. The average Scale for the Assessment and Rating of Ataxia score (SARA, a standardized measure of cerebellar dysfunction on clinical examination, scores range from 0–40) was an average of 3.15 for all participants (range 0–14), but was only 2 in those with isolated episodic ataxia compared with 7.7 in those with progressive cerebellar ataxia in addition to episodic ataxia. Thirty-seven participants completed the SF-36, a quality of life survey; all eight domain norm-based average scores (mean = 50) were below normal with mental health being the lowest (41.3) in those with mutation positive episodic ataxia type 1. Scores on SF-36 correlated negatively with attack frequency. Of the 39 participants in the study, 33 harboured mutations in KCNA1 whereas the remaining six had no mutation identified. Episodic ataxia type 1

  10. The spinocerebellar ataxia 2 locus is located within a 3-cm interval on chromosome 12q23-24.1

    SciTech Connect

    Allotey, R.; Twells, R.; Cemal, C.

    1995-07-01

    The autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of neurodegenerative disorders characterized by a predominantly cerebellar syndrome of onset with gait ataxia, dysarthria, dysmetria, and dysdiadochokinesia. Pathologically, the disorders are characterized by premature neuronal loss in the cerebellar cortex and the inferior olivary and pontine nuclei, with degeneration of the spinal cord. We have previously assigned the spinocerebellar ataxia 2 locus to chromosome 12q23-24.1, within a 31-cM interval flanked by the loci D12S58 and PLA2. Linkage to SCA2 has been demonstrated in pedigrees from Europe, Japan, and North America, the latter serving to refine the candidate region to a 16-cM interval. We report here genetic analysis undertaken between SCA2 and nine microsatellite loci known to span 8 cM within this interval. 12 refs., 2 figs., 1 tab.

  11. Bilateral cerebellar dysfunctions in a unilateral meso-diencephalic lesion.

    PubMed Central

    von Cramon, D

    1981-01-01

    The clinical syndrome of a 65-year-old patient with a slit-shaped right-sided meso-diencephalic lesion was analysed. A cerebellar syndrome with limb-kinetic ataxia, intention tremor and hypotonicity in all extremities as well as ataxic dysarthria was found. The disruption of the two cerebello-(rubro)-thalamic pathways probably explained the signs of bilateral cerebellar dysfunction. The uncrossed ascending limb of the right, and the crossed one of the left brachium conjunctivum may have been damaged by the unilateral lesion extending between caudal midbrain and dorsal thalamus. Images PMID:7241166

  12. A case considered gluten ataxia with anti-TG6 IgA antibodies.

    PubMed

    Sato, Kenji; Kobayashi, Makiko; Ueta, Yuki; Tanaka, Nobuyuki; Nanri, Kazunori

    2016-06-22

    An 81-year-old woman presented with a chief complaint of gait disturbance. Brain magnetic resonance imaging (MRI) showed mild cerebellar atrophy and cerebral blood flow scintigraphy revealed reduced blood flow in the cerebellum. The patient was diagnosed with cortical cerebellar atrophy, and was given taltirelin hydrate, but symptoms slowly progressed. Thirteen years after onset, a positive result for anti-transglutaminase 6 (TG6) IgA antibodies was identified, and gluten ataxia was diagnosed. Despite steroid therapy and gluten-free diet therapy, no improvements were seen, and independent walking became difficult for the patient. High-dose intravenous immunoglobulin therapy resulted in improvements in the Posture and Gait subscore of the International Cooperative Ataxia Rating Scale (ICARS) from 15 to 11 points, and the patient regained the ability to walk independently. Gluten ataxia are rarely reported in Japan and anti-TG6 antibodies were considered useful for its diagnosis. PMID:27212675

  13. An elderly man with progressive ataxia and palatal tremor presenting with dizziness and oculopalatal tremor.

    PubMed

    Tsukahara, Yuka; Suzuki, Keisuke; Kokubun, Norito; Nakamura, Toshiki; Takekawa, Hidehiro; Hirata, Koichi

    2016-08-31

    A 74-year-old man was referred to our department for dizziness and progressive unsteady gait over 6 years. His family history was unremarkable. Neurological examination showed dysarthria, saccadic eye movement, palatal tremor (1.7 Hz)-synchronous with rotational ocular movement, and truncal ataxia. T2-weighted magnetic resonance imaging (MRI) of the brain revealed hyperintense and hypertrophic bilateral inferior olivary nuclei at the medulla and mild cerebellar atrophy. On the basis of neurological findings of oculopalatal tremor and cerebellar ataxia with brain MRI findings, the diagnosis of progressive ataxia and palatal tremor (PAPT) was made. PAPT should be included in differential diagnosis of dizziness observed in elderly individuals. PMID:27477579

  14. Genetics Home Reference: episodic ataxia

    MedlinePlus

    ... Ebers GC. A genome-wide screen and linkage mapping for a large pedigree with episodic ataxia. Neurology. ... investigators. Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain. 2007 Oct;130(Pt 10):2484-93. Epub ...

  15. What Is Ataxia-Telangiectasia?

    MedlinePlus

    ... what led to naming this disease "ataxia-telangiectasia." Immune System Problems... For most (about 70 percent) of children ... A-T patients, the combination of a weakened immune system and the progressive ataxia can ultimately lead to ...

  16. The first knockin mouse model of episodic ataxia type 2.

    PubMed

    Rose, Samuel J; Kriener, Lisa H; Heinzer, Ann K; Fan, Xueliang; Raike, Robert S; van den Maagdenberg, Arn M J M; Hess, Ellen J

    2014-11-01

    Episodic ataxia type 2 (EA2) is an autosomal dominant disorder associated with attacks of ataxia that are typically precipitated by stress, ethanol, caffeine or exercise. EA2 is caused by loss-of-function mutations in the CACNA1A gene, which encodes the α1A subunit of the CaV2.1 voltage-gated Ca(2+) channel. To better understand the pathomechanisms of this disorder in vivo, we created the first genetic animal model of EA2 by engineering a mouse line carrying the EA2-causing c.4486T>G (p.F1406C) missense mutation in the orthologous mouse Cacna1a gene. Mice homozygous for the mutated allele exhibit a ~70% reduction in CaV2.1 current density in Purkinje cells, though surprisingly do not exhibit an overt motor phenotype. Mice hemizygous for the knockin allele (EA2/- mice) did exhibit motor dysfunction measurable by rotarod and pole test. Studies using Cre-flox conditional genetics explored the role of cerebellar Purkinje cells or cerebellar granule cells in the poor motor performance of EA2/- mice and demonstrate that manipulation of either cell type alone did not cause poor motor performance. Thus, it is possible that subtle dysfunction arising from multiple cell types is necessary for the expression of certain ataxia syndromes. PMID:25109669

  17. MME mutation in dominant spinocerebellar ataxia with neuropathy (SCA43)

    PubMed Central

    Depondt, Chantal; Donatello, Simona; Rai, Myriam; Wang, François Charles; Manto, Mario; Simonis, Nicolas

    2016-01-01

    Objective: To identify the causative gene mutation in a 5-generation Belgian family with dominantly inherited spinocerebellar ataxia and polyneuropathy, in which known genetic etiologies had been excluded. Methods: We collected DNA samples of 28 family members, including 7 living affected individuals, whose clinical records were reviewed by a neurologist experienced in ataxia. We combined linkage data of 21 family members with whole exome sequencing in 2 affected individuals to identify shared heterozygous variants mapping to potentially linked regions. Variants were screened for rarity and for predicted damaging effect. A candidate mutation was confirmed by Sanger sequencing and tested for cosegregation with the disease. Results: Affected individuals presented with late-onset sensorimotor axonal polyneuropathy; all but one also had cerebellar ataxia. We identified a variant in the MME gene, p.C143Y, that was absent from control databases, cosegregated with the phenotype, and was predicted to have a strong damaging effect on the encoded protein by all algorithms we used. Conclusions: MME encodes neprilysin (NEP), a zinc-dependent metalloprotease expressed in most tissues, including the central and peripheral nervous systems. The mutated cysteine 143 forms a disulfide bridge, which is 100% conserved in NEP and in similar enzymes. The recent identification of recessive MME mutations in 10 unrelated individuals from Japan with axonal polyneuropathy further supports the causality of the mutation, despite the dominant mode of inheritance and the presence of cerebellar involvement in our study family. Functional studies are needed to identify the mechanisms underlying these differences. PMID:27583304

  18. Friedreich's Ataxia (FA)

    MedlinePlus

    ... About Friedreich’s Ataxia Updated December 2009 Michelle Moffitt Smith Michelle and James Smith at their wedding Dear Friends: W hen I ... for a doctorate. I met my husband, James Smith, through MDA’s magazine, Quest. He also has a ...

  19. Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11.

    PubMed

    Ranum, L P; Schut, L J; Lundgren, J K; Orr, H T; Livingston, D M

    1994-11-01

    Autosomal dominant ataxias are a genetically heterogeneous group of disorders for which spinocerebellar ataxia (SCA) loci on chromosomes 6p, 12q, 14q and 16q have been reported. We have examined 170 individuals (56 of whom were affected) from a previously unreported ten-generation kindred with a dominant ataxia that is clinically and genetically distinct from those previously mapped. The family has two major branches which both descend from the paternal grandparents of President Abraham Lincoln. Among those examined, 56 individuals have a generally non-life threatening cerebellar ataxia. Disease onset varies from 10-68 years and anticipation is evident. We have mapped this gene, spinocerebellar ataxia type 5 (SCA5), to the centromeric region of chromosome 11. PMID:7874171

  20. Principal component analysis of cerebellar shape on MRI separates SCA types 2 and 6 into two archetypal modes of degeneration.

    PubMed

    Jung, Brian C; Choi, Soo I; Du, Annie X; Cuzzocreo, Jennifer L; Geng, Zhuo Z; Ying, Howard S; Perlman, Susan L; Toga, Arthur W; Prince, Jerry L; Ying, Sarah H

    2012-12-01

    Although "cerebellar ataxia" is often used in reference to a disease process, presumably there are different underlying pathogenetic mechanisms for different subtypes. Indeed, spinocerebellar ataxia (SCA) types 2 and 6 demonstrate complementary phenotypes, thus predicting a different anatomic pattern of degeneration. Here, we show that an unsupervised classification method, based on principal component analysis (PCA) of cerebellar shape characteristics, can be used to separate SCA2 and SCA6 into two classes, which may represent disease-specific archetypes. Patients with SCA2 (n=11) and SCA6 (n=7) were compared against controls (n=15) using PCA to classify cerebellar anatomic shape characteristics. Within the first three principal components, SCA2 and SCA6 differed from controls and from each other. In a secondary analysis, we studied five additional subjects and found that these patients were consistent with the previously defined archetypal clusters of clinical and anatomical characteristics. Secondary analysis of five subjects with related diagnoses showed that disease groups that were clinically and pathophysiologically similar also shared similar anatomic characteristics. Specifically, Archetype #1 consisted of SCA3 (n=1) and SCA2, suggesting that cerebellar syndromes accompanied by atrophy of the pons may be associated with a characteristic pattern of cerebellar neurodegeneration. In comparison, Archetype #2 was comprised of disease groups with pure cerebellar atrophy (episodic ataxia type 2 (n=1), idiopathic late-onset cerebellar ataxias (n=3), and SCA6). This suggests that cerebellar shape analysis could aid in discriminating between different pathologies. Our findings further suggest that magnetic resonance imaging is a promising imaging biomarker that could aid in the diagnosis and therapeutic management in patients with cerebellar syndromes. PMID:22258915

  1. Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction

    PubMed Central

    Akizu, Naiara; Cantagrel, Vincent; Zaki, Maha S.; Al-Gazali, Lihadh; Wang, Xin; Rosti, Rasim Ozgur; Dikoglu, Esra; Gelot, Antoinette Bernabe; Rosti, Basak; Vaux, Keith K.; Scott, Eric M.; Silhavy, Jennifer L.; Schroth, Jana; Copeland, Brett; Schaffer, Ashleigh E.; Gordts, Philip; Esko, Jeffrey D.; Buschman, Matthew D.; Fields, Seth J.; Napolitano, Gennaro; Ozgul, R. Koksal; Sagiroglu, Mahmut Samil; Azam, Matloob; Ismail, Samira; Aglan, Mona; Selim, Laila; Gamal, Iman; Hadi, Sawsan Abdel; El Badawy, Amera; Sadek, Abdelrahim A.; Mojahedi, Faezeh; Kayserili, Hulya; Masri, Amira; Bastaki, Laila; Temtamy, Samia; Müller, Ulrich; Desguerre, Isabelle; Casanova, Jean-Laurent; Dursun, Ali; Gunel, Murat; Gabriel, Stacey B.; de Lonlay, Pascale; Gleeson, Joseph G.

    2015-01-01

    Pediatric-onset ataxias often present clinically with developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a novel clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in sorting nexin 14 (SNX14), encoding a ubiquitously expressed modular PX-domain-containing sorting factor. We found SNX14 localized to lysosomes, and associated with phosphatidyl-inositol (3,5)P2, a key component of late endosomes/lysosomes. Patient cells showed engorged lysosomes and slower autophagosome clearance rate upon starvation induction. Zebrafish morphants showed dramatic loss of cerebellar parenchyma, accumulated autophagosomes, and activation of apoptosis. Our results suggest a unique ataxia syndrome due to biallelic SNX14 mutations, leading to lysosome-autophagosome dysfunction. PMID:25848753

  2. Transplantation and Stem Cell Therapy for Cerebellar Degenerations.

    PubMed

    Cendelin, Jan

    2016-02-01

    Stem cell-based and regenerative therapy may become a hopeful treatment for neurodegenerative diseases including hereditary cerebellar degenerations. Neurotransplantation therapy mainly aims to substitute lost cells, but potential effects might include various mechanisms including nonspecific trophic effects and stimulation of endogenous regenerative processes and neural plasticity. Nevertheless, currently, there remain serious limitations. There is a wide spectrum of human hereditary cerebellar degenerations as well as numerous cerebellar mutant mouse strains that serve as models for the development of effective therapy. By now, transplantation has been shown to ameliorate cerebellar function, e.g. in Purkinje cell degeneration mice, Lurcher mutant mice and mouse models of spinocerebellar ataxia type 1 and type 2 and Niemann-Pick disease type C. Despite the lack of direct comparative studies, it appears that there might be differences in graft development and functioning between various types of cerebellar degeneration. Investigation of the relation of graft development to specific morphological, microvascular or biochemical features of the diseased host tissue in various cerebellar degenerations may help to identify factors determining the fate of grafted cells and potential of their functional integration. PMID:26155762

  3. Differential cerebellar GABAA receptor expression in mice with mutations in CaV2.1 (P/Q-type) calcium channels.

    PubMed

    Kaja, S; Payne, A J; Nielsen, E Ø; Thompson, C L; van den Maagdenberg, A M J M; Koulen, P; Snutch, T P

    2015-09-24

    Ataxia is the predominant clinical manifestation of cerebellar dysfunction. Mutations in the human CACNA1A gene, encoding the pore-forming α1 subunit of CaV2.1 (P/Q-type) calcium channels, underlie several neurological disorders, including Episodic Ataxia type 2 and Familial Hemiplegic Migraine type 1 (FHM1). Several mouse mutants exist that harbor mutations in the orthologous Cacna1a gene. The spontaneous Cacna1a mutants Rolling Nagoya (tg(rol)), Tottering (tg) and Leaner (tg(ln)) mice exhibit behavioral motor phenotypes, including ataxia. Transgenic knock-in (KI) mouse strains with the human FHM1 R192Q and S218L missense mutations have been generated. R192Q KI mice are non-ataxic, whereas S218L KI mice display a complex behavioral phenotype that includes cerebellar ataxia. Given the dependence of γ-aminobutyric acid type A (GABAA) receptor subunit functioning on localized calcium currents, and the functional link between GABAergic inhibition and ataxia, we hypothesized that cerebellar GABAA receptor expression is differentially affected in Cacna1a mutants and contributes to the ataxic phenotype. Herein we quantified functional GABAA receptors and pharmacologically dissociated cerebellar GABAA receptors in several Cacna1a mutants. We did not identify differences in the expression of GABAA receptor subunits or in the number of functional GABAA receptors in the non-ataxic R192Q KI strain. In contrast, tg(rol) mice had a ∼15% decrease in the number of functional GABAA receptors, whereas S218L KI mice showed a ∼29% increase. Our data suggest that differential changes in cerebellar GABAA receptor expression profile may contribute to the neurological phenotype of cerebellar ataxia and that targeting GABAA receptors might represent a feasible complementary strategy to treat cerebellar ataxia. PMID:26208839

  4. Cerebellar cortical degeneration in three English bulldogs: clinical and neuropathological findings.

    PubMed

    Gandini, G; Botteron, C; Brini, E; Fatzer, R; Diana, A; Jaggy, A

    2005-06-01

    This case report describes the clinical and neuropathological findings in three young English bulldogs affected by cerebellar cortical degeneration. The dogs, born from the same parents, were presented with clinical signs indicating progressive cerebellar dysfunction: a wide-based stance, severe cerebellar ataxia characterised by marked hypermetria, spasticity, and intention tremors of the head and trunk with loss of balance. On histopathological examination, lesions were confined to the cerebellum and consisted of diffuse degenerative cortical lesions, and there was a loss of Purkinje and granule cells. The history, clinical signs and neuropathological findings confirmed the diagnosis of cerebellar cortical degeneration. To the authors' knowledge, this is the first report of cerebellar cortical degeneration in the English bulldog. PMID:15971900

  5. Parallel fiber to Purkinje cell synaptic impairment in a mouse model of spinocerebellar ataxia type 27

    PubMed Central

    Tempia, Filippo; Hoxha, Eriola; Negro, Giulia; Alshammari, Musaad A.; Alshammari, Tahani K.; Panova-Elektronova, Neli; Laezza, Fernanda

    2015-01-01

    Genetically inherited mutations in the fibroblast growth factor 14 (FGF14) gene lead to spinocerebellar ataxia type 27 (SCA27), an autosomal dominant disorder characterized by heterogeneous motor and cognitive impairments. Consistently, genetic deletion of Fgf14 in Fgf14−/− mice recapitulates salient features of the SCA27 human disease. In vitro molecular studies in cultured neurons indicate that the FGF14F145S SCA27 allele acts as a dominant negative mutant suppressing the FGF14 wild type function and resulting in inhibition of voltage-gated Na+ and Ca2+ channels. To gain insights in the cerebellar deficits in the animal model of the human disease, we applied whole-cell voltage-clamp in the acute cerebellar slice preparation to examine the properties of parallel fibers (PF) to Purkinje neuron synapses in Fgf14−/− mice and wild type littermates. We found that the AMPA receptor-mediated excitatory postsynaptic currents evoked by PF stimulation (PF-EPSCs) were significantly reduced in Fgf14−/− animals, while short-term plasticity, measured as paired-pulse facilitation (PPF), was enhanced. Measuring Sr2+-induced release of quanta from stimulated synapses, we found that the size of the PF-EPSCs was unchanged, ruling out a postsynaptic deficit. This phenotype was corroborated by decreased expression of VGLUT1, a specific presynaptic marker at PF-Purkinje neuron synapses. We next examined the mGluR1 receptor-induced response (mGluR1-EPSC) that under normal conditions requires a gradual build-up of glutamate concentration in the synaptic cleft, and found no changes in these responses in Fgf14−/− mice. These results provide evidence of a critical role of FGF14 in maintaining presynaptic function at PF-Purkinje neuron synapses highlighting critical target mechanisms to recapitulate the complexity of the SCA27 disease. PMID:26089778

  6. Sensorimotor processing for balance in spinocerebellar ataxia type 6

    PubMed Central

    Bunn, Lisa M.; Marsden, Jonathan F.; Voyce, Daniel C.; Giunti, Paola

    2015-01-01

    Abstract Background We investigated whether balance impairments caused by cerebellar disease are associated with specific sensorimotor processing deficits that generalize across all sensory modalities. Experiments focused on the putative cerebellar functions of scaling and coordinate transformation of balance responses evoked by stimulation of single sensory channels. Methods Vestibular, visual, and proprioceptive sensory channels were stimulated in isolation using galvanic vestibular stimulation, moving visual scenery, and muscle vibration, respectively, in 16 subjects with spinocerebellar ataxia type 6 (SCA6) and 16 matched healthy controls. Two polarities of each stimulus type evoked postural responses of similar form in the forward and backward directions. Disease severity was assessed using the Scale for Assessment and Rating of Ataxia. Results Impaired balance of SCA6 subjects during unperturbed stance was reflected in faster than normal body sway (P = 0.009), which correlated with disease severity (r = 0.705, P < 0.001). Sensory perturbations revealed a sensorimotor processing abnormality that was specific to response scaling for the visual channel. This manifested as visually evoked postural responses that were approximately three times larger than normal (backward, P < 0.001; forward P = 0.005) and correlated with disease severity (r = 0.543, P = 0.03). Response direction and habituation properties were no different from controls for all three sensory modalities. Conclusion Cerebellar degeneration disturbs the scaling of postural responses evoked by visual motion, possibly through disinhibition of extracerebellar visuomotor centers. The excessively high gain of the visuomotor channel without compensatory decreases in gains of other sensorimotor channels provides a potential mechanism for instability of the balance control system in cerebellar disease. © 2015 The Authors. Movement Disorders published by Wiley Periodicals, Inc

  7. Genetics Home Reference: ataxia neuropathy spectrum

    MedlinePlus

    ... Genetics Home Health Conditions ataxia neuropathy spectrum ataxia neuropathy spectrum Enable Javascript to view the expand/collapse ... Download PDF Open All Close All Description Ataxia neuropathy spectrum is part of a group of conditions ...

  8. Esophoria or esotropia in adulthood: a sign of cerebellar dysfunction?

    PubMed

    Hüfner, Katharina; Frenzel, Claudia; Kremmyda, Olympia; Adrion, Christine; Bardins, Stanislavs; Glasauer, Stefan; Brandt, Thomas; Strupp, Michael

    2015-03-01

    Convergent strabismus is a common diagnosis in early childhood, when it is mostly considered benign. If it develops later in life, strabismus can, however, be a sign of neurological disease. In these cases the underlying pathophysiological mechanisms are largely unknown. In this retrospective case-control study we analyzed the neuro-ophthalmological examination reports of 400 adult patients who presented at the German Center for Vertigo and Balance Disorders to determine an association between ocular misalignment and cerebellar dysfunction. Patients with cerebellar signs (i.e., cerebellar ataxia and/or cerebellar ocular motor signs) had a 4.49 (95 % CI [1.60; 13.78]) times higher frequency of ocular misalignment and specifically a 13.3 (95 % CI [3.80; 55.73]) times increased frequency of esophoria/esotropia (ESO) during distant gaze than patients without cerebellar dysfunction. ESO when looking into the distance was associated with saccadic smooth pursuit, dysmetria of saccades, and downbeat nystagmus (DBN) (χ (2) test, p < 0.0001 for all associations). Patients with cerebellar dysfunction also showed mildly impaired eye abduction (χ (2) test, left eye and right eye: p < 0.0001), associated with horizontal gaze-evoked nystagmus (χ (2) test, p < 0.0001). The association of ESO and DBN implicates a pathophysiological involvement of the cerebellar flocculus, while the association with dysmetric saccades suggests involvement of the oculomotor vermis. This is compatible with animal studies showing that the pathways of the flocculus/posterior interposed nucleus and vermis/nucleus fastigii are both involved in vergence movements and static binocular alignment. From a clinical point of view, a newly diagnosed esophoria/esotropia only during distant gaze may be a sign of a cerebellar disease. PMID:25522697

  9. Broad distribution of ataxin 1 silencing in rhesus cerebella for spinocerebellar ataxia type 1 therapy.

    PubMed

    Keiser, Megan S; Kordower, Jeffrey H; Gonzalez-Alegre, Pedro; Davidson, Beverly L

    2015-12-01

    Spinocerebellar ataxia type 1 is one of nine polyglutamine expansion diseases and is characterized by cerebellar ataxia and neuronal degeneration in the cerebellum and brainstem. Currently, there are no effective therapies for this disease. Previously, we have shown that RNA interference mediated silencing of ATXN1 mRNA provides therapeutic benefit in mouse models of the disease. Adeno-associated viral delivery of an engineered microRNA targeting ATXN1 to the cerebella of well-established mouse models improved motor phenotypes, neuropathy, and transcriptional changes. Here, we test the translatability of this approach in adult rhesus cerebella. Nine adult male and three adult female rhesus macaque were unilaterally injected with our therapeutic vector, a recombinant adeno-associated virus type 1 (rAAV1) expressing our RNAi trigger (miS1) and co-expressing enhanced green fluorescent protein (rAAV1.miS1eGFP) into the deep cerebellar nuclei using magnetic resonance imaging guided techniques combined with a Stealth Navigation system (Medtronics Inc.). Transduction was evident in the deep cerebellar nuclei, cerebellar Purkinje cells, the brainstem and the ventral lateral thalamus. Reduction of endogenous ATXN1 messenger RNA levels were ≥30% in the deep cerebellar nuclei, the cerebellar cortex, inferior olive, and thalamus relative to the uninjected hemisphere. There were no clinical complications, and quantitative and qualitative analyses suggest that this therapeutic intervention strategy and subsequent reduction of ATXN1 is well tolerated. Collectively the data illustrate the biodistribution and tolerability of rAAV1.miS1eGFP administration to the adult rhesus cerebellum and are supportive of clinical application for spinocerebellar ataxia type 1. PMID:26490326

  10. Consensus Paper: Revisiting the Symptoms and Signs of Cerebellar Syndrome.

    PubMed

    Bodranghien, Florian; Bastian, Amy; Casali, Carlo; Hallett, Mark; Louis, Elan D; Manto, Mario; Mariën, Peter; Nowak, Dennis A; Schmahmann, Jeremy D; Serrao, Mariano; Steiner, Katharina Marie; Strupp, Michael; Tilikete, Caroline; Timmann, Dagmar; van Dun, Kim

    2016-06-01

    The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of recent advances in our understanding of cerebellar operations. The key symptoms and signs of cerebellar dysfunction, often grouped under the generic term of ataxia, are discussed. Vertigo, dizziness, and imbalance are associated with lesions of the vestibulo-cerebellar, vestibulo-spinal, or cerebellar ocular motor systems. The cerebellum plays a major role in the online to long-term control of eye movements (control of calibration, reduction of eye instability, maintenance of ocular alignment). Ocular instability, nystagmus, saccadic intrusions, impaired smooth pursuit, impaired vestibulo-ocular reflex (VOR), and ocular misalignment are at the core of oculomotor cerebellar deficits. As a motor speech disorder, ataxic dysarthria is highly suggestive of cerebellar pathology. Regarding motor control of limbs, hypotonia, a- or dysdiadochokinesia, dysmetria, grasping deficits and various tremor phenomenologies are observed in cerebellar disorders to varying degrees. There is clear evidence that the cerebellum participates in force perception and proprioceptive sense during active movements. Gait is staggering with a wide base, and tandem gait is very often impaired in cerebellar disorders. In terms of cognitive and affective operations, impairments are found in executive functions, visual-spatial processing, linguistic function, and affective regulation (Schmahmann's syndrome). Nonmotor linguistic deficits including disruption of articulatory and graphomotor planning, language dynamics, verbal fluency, phonological, and semantic word retrieval, expressive and receptive syntax, and various aspects of reading and writing may be impaired after cerebellar damage. The cerebellum is organized into (a) a primary sensorimotor region in the anterior lobe and adjacent part of lobule VI, (b) a second sensorimotor

  11. A gene for nystagmus-associated episodic ataxia maps to chromosome 19p

    SciTech Connect

    Kramer, P.L.; Root, D.; Gancher, S.

    1994-09-01

    Episodic ataxia (EA) is a rare, autosomal dominant disorder, characterized by attacks of generalized ataxia and relatively normal neurological function between attacks. Onset occurs in childhood or adolescence and persists through adulthood. Penetrance is nearly complete. EA is clinically heterogeneous, including at least two distinct entities: (1) episodes of ataxia and dysarthria lasting hours to days, generally with interictal nystagmus (MIM 108500); (2) episodes of ataxia and dysarthria lasting only minutes, with interictal myokymia (MMM 160120). The EA/nystagmus patients sometimes develop persistent ataxia and cerebellar atrophy. Previously we reported linkage in four EA/myokymia families to a K{sup +} channel gene on chromosome 12p. We excluded this region in a large family with EA/nystagmus. We now report evidence for linkage to chromosome 19p in this and in one other EA/nystagmus family, based on eight microsatellite markers which span approximately 30 cM. The region is flanked distally by D19S209 and proximally by D19S226. All six markers within this region gave positive evidence for linkage; the highest total two-point lod scores occurred wtih D19S221 (3.98 at theta = 0.10) and D19S413 (3.37 at theta = 0.05). Interestingly, Joutel et al. (1993) mapped a gene for familial hemiplegic migraine (FHM) to the region around D19S221. Some individuals in these families have ataxia, cerebellar atrophy and interictal nystagmus, but no episodic ataxia. These results demonstrate that the clinical heterogeneity in EA reflects underlying genetic hetreogeneity. In addition, they suggest that EA/nystagmus and some FHM may represent different mutations in the same gene locus on chromosome 19p.

  12. Parahippocampal gray matter alterations in Spinocerebellar Ataxia Type 2 identified by voxel based morphometry.

    PubMed

    Mercadillo, Roberto E; Galvez, Víctor; Díaz, Rosalinda; Hernández-Castillo, Carlos Roberto; Campos-Romo, Aurelio; Boll, Marie-Catherine; Pasaye, Erick H; Fernandez-Ruiz, Juan

    2014-12-15

    Spinocerebellar Ataxia Type 2 (SCA2) is a genetic disorder causing cerebellar degeneration that result in motor and cognitive alterations. Voxel-based morphometry (VBM) analyses have found neurodegenerative patterns associated to SCA2, but they show some discrepancies. Moreover, behavioral deficits related to non-cerebellar functions are scarcely discussed in those reports. In this work we use behavioral and cognitive tests and VBM to identify and confirm cognitive and gray matter alterations in SCA2 patients compared with control subjects. Also, we discuss the cerebellar and non-cerebellar functions affected by this disease. Our results confirmed gray matter reduction in the cerebellar vermis, pons, and insular, frontal, parietal and temporal cortices. However, our analysis also found unreported loss of gray matter in the parahippocampal gyrus bilaterally. Motor performance test ratings correlated with total gray and white matter reductions, but executive performance and clinical features such as CAG repetitions and disease progression did not show any correlation. This pattern of cerebellar and non-cerebellar morphological alterations associated with SCA2 has to be considered to fully understand the motor and non-motor deficits that include language production and comprehension and some social skill changes that occur in these patients. PMID:25263602

  13. Atrophy of the Cerebellar Vermis in Essential Tremor: Segmental Volumetric MRI Analysis.

    PubMed

    Shin, Hyeeun; Lee, Dong-Kyun; Lee, Jong-Min; Huh, Young-Eun; Youn, Jinyoung; Louis, Elan D; Cho, Jin Whan

    2016-04-01

    Postmortem studies of essential tremor (ET) have demonstrated the presence of degenerative changes in the cerebellum, and imaging studies have examined related structural changes in the brain. However, their results have not been completely consistent and the number of imaging studies has been limited. We aimed to study cerebellar involvement in ET using MRI segmental volumetric analysis. In addition, a unique feature of this study was that we stratified ET patients into subtypes based on the clinical presence of cerebellar signs and compared their MRI findings. Thirty-nine ET patients and 36 normal healthy controls, matched for age and sex, were enrolled. Cerebellar signs in ET patients were assessed using the clinical tremor rating scale and International Cooperative Ataxia Rating Scale. ET patients were divided into two groups: patients with cerebellar signs (cerebellar-ET) and those without (classic-ET). MRI volumetry was performed using CIVET pipeline software. Data on whole and segmented cerebellar volumes were analyzed using SPSS. While there was a trend for whole cerebellar volume to decrease from controls to classic-ET to cerebellar-ET, this trend was not significant. The volume of several contiguous segments of the cerebellar vermis was reduced in ET patients versus controls. Furthermore, these vermis volumes were reduced in the cerebellar-ET group versus the classic-ET group. The volume of several adjacent segments of the cerebellar vermis was reduced in ET. This effect was more evident in ET patients with clinical signs of cerebellar dysfunction. The presence of tissue atrophy suggests that ET might be a neurodegenerative disease. PMID:26062905

  14. Speech prosody in Friedreich's and olivo-ponto cerebellar atrophy

    NASA Astrophysics Data System (ADS)

    Casper, Maureen

    2001-05-01

    A critical issue in the study of speech motor control is the identification of the mechanisms that generate the temporal flow of serially ordered articulatory events. Two staged models of serial ordered events (Lashley, 1951; Lindblom, 1963) claim that time controls events whereas dynamic models predict a relative relation between time and space. Each of these models predicts a different relation between the acoustic measures of formant frequency and segmental duration. The most recent method described herein provides a sensitive index of speech deterioration which is both acoustically robust and phonetically systematic. Both acoustic and magnetic resonance imaging measures were used to describe the speech disturbance in two neurologically distinct groups of cerebellar ataxia: Friedreich's ataxia and olivo-ponto cerebellar ataxia. The speaking task was designed to elicit six different prosodic conditions and four prosodic contrasts. All subjects read the same syllable embedded in a sentence, under six different prosodic conditions. Pair-wise comparisons derived from the six conditions were used to describe (1) final lengthening, (2) phrasal accent, (3) nuclear accent and (4) syllable reduction. An estimate of speech deterioration as determined by individual and normal subects' acoustic values of syllable duration, formant and fundamental frequencies was used in correlation analyses with magnetic resonance imaging ratings.

  15. Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy.

    PubMed

    Levite, Mia

    2014-08-01

    .g., chronic progressive limbic Encephalitis, Paraneoplastic Encephalitis or Herpes Simplex Virus Encephalitis), Schizophrenia, Mania, Stroke, or Sjorgen syndrome. In some patients, the anti-NMDA-NR2A/B antibodies are present in both the serum and the CSF. Some of the anti-NMDA-NR2A/B antibodies cross-react with dsDNA, while others do not. Some of the anti-NMDA-NR2A/B antibodies associate with neuropsychiatric/cognitive/behavior/mood impairments in SLE patients, while others do not. The anti-NMDA-NR2A/B antibodies can undoubtedly be very pathogenic, since they can kill neurons by activating NMDA receptors and inducing 'Excitotoxicity', damage the brain, cause dramatic decrease of membranal NMDA receptors expressed in hippocampal neurons, and also induce behavioral cognitive impairments in animal models. Yet, the concentration of the anti-NMDA-NR2A/B antibodies seems to determine if they have positive or negative effects on the activity of glutamate receptors and on the survival of neurons. Thus, at low concentration, the anti-NMDA-NR2A/B antibodies were found to be positive modulators of receptor function and increase the size of NMDA receptor-mediated excitatory postsynaptic potentials, whereas at high concentration they are pathogenic as they promote 'Excitotoxcity' through enhanced mitochondrial permeability transition. (4) Anti-mGluR1 antibodies were found thus far in very few patients with Paraneoplastic Cerebellar Ataxia, and in these patients they are produced intrathecally and therefore present in much higher levels in the CSF than in the serum. The anti-mGluR1 antibodies can be very pathogenic in the brain since they can reduce the basal neuronal activity, block the induction of long-term depression of Purkinje cells, and altogether cause cerebellar motor coordination deficits by a combination of rapid effects on both the acute and the plastic responses of Purkinje cells, and by chronic degenerative effects. Strikingly, within 30 min after injection of anti-mGluR1

  16. Ataxia-Telangiectasia Presenting as Cerebral Palsy and Recurrent Wheezing: A Case Report

    PubMed Central

    Navratil, Marta; Đuranović, Vlasta; Nogalo, Boro; Švigir, Alen; Dubravčić, Iva Dumbović; Turkalj, Mirjana

    2015-01-01

    Patient: Male, 8 Final Diagnosis: Ataxia-telangiectasia Symptoms: Ataxia • sinopulmonary infection • telangiectasiae • wheezing Medication: — Clinical Procedure: IVIG supstitution Specialty: Pediatrics and Neonatology Objective: Rare disease Background: Ataxia-telangiectasia (A-T) is an autosomal recessive disease that consists of progressive cerebellar ataxia, variable immunodeficiency, sinopulmonary infections, oculocutaneous telangiectasia, radiosensitivity, early aging, and increased incidence of cancer. Case Report: We report the case of an 8-year-old boy affected by A-T. At 12 months of age, he had a waddling gait, with his upper body leaning forward. Dystonic/dyskinetic cerebral palsy was diagnosed at the age of 3 years. At age 6 he was diagnosed with asthma based on recurrent wheezing episodes. A-T was confirmed at the age 8 years on the basis of clinical signs and laboratory findings (increased alpha fetoprotein - AFP, immunodeficiency, undetectable ataxia-telangiectasia mutated (ATM) protein on immunoblotting, and identification A-T mutation, 5932G>T). Conclusions: The clinical and immunological presentation of ataxia-telangiectasia (A-T) is very heterogeneous and diagnostically challenging, especially at an early age, leading to frequent misdiagnosis. PMID:26380989

  17. Principal Component Analysis of Cerebellar Shape on MRI Separates SCA Types 2 and 6 into Two Archetypal Modes of Degeneration

    PubMed Central

    Jung, Brian C.; Choi, Soo I.; Du, Annie X.; Cuzzocreo, Jennifer L.; Geng, Zhuo Z.; Ying, Howard S.; Perlman, Susan L.; Toga, Arthur W.; Prince, Jerry L.

    2014-01-01

    Although “cerebellar ataxia” is often used in reference to a disease process, presumably there are different underlying pathogenetic mechanisms for different subtypes. Indeed, spinocerebellar ataxia (SCA) types 2 and 6 demonstrate complementary phenotypes, thus predicting a different anatomic pattern of degeneration. Here, we show that an unsupervised classification method, based on principal component analysis (PCA) of cerebellar shape characteristics, can be used to separate SCA2 and SCA6 into two classes, which may represent disease-specific archetypes. Patients with SCA2 (n=11) and SCA6 (n=7) were compared against controls (n=15) using PCA to classify cerebellar anatomic shape characteristics. Within the first three principal components, SCA2 and SCA6 differed from controls and from each other. In a secondary analysis, we studied five additional subjects and found that these patients were consistent with the previously defined archetypal clusters of clinical and anatomical characteristics. Secondary analysis of five subjects with related diagnoses showed that disease groups that were clinically and pathophysiologically similar also shared similar anatomic characteristics. Specifically, Archetype #1 consisted of SCA3 (n=1) and SCA2, suggesting that cerebellar syndromes accompanied by atrophy of the pons may be associated with a characteristic pattern of cerebellar neurodegeneration. In comparison, Archetype #2 was comprised of disease groups with pure cerebellar atrophy (episodic ataxia type 2 (n=1), idiopathic late-onset cerebellar ataxias (n=3), and SCA6). This suggests that cerebellar shape analysis could aid in discriminating between different pathologies. Our findings further suggest that magnetic resonance imaging is a promising imaging biomarker that could aid in the diagnosis and therapeutic management in patients with cerebellar syndromes. PMID:22258915

  18. Cerebellar and Brainstem Malformations.

    PubMed

    Poretti, Andrea; Boltshauser, Eugen; Huisman, Thierry A G M

    2016-08-01

    The frequency and importance of the evaluation of the posterior fossa have increased significantly over the past 20 years owing to advances in neuroimaging. Conventional and advanced neuroimaging techniques allow detailed evaluation of the complex anatomic structures within the posterior fossa. A wide spectrum of cerebellar and brainstem malformations has been shown. Familiarity with the spectrum of cerebellar and brainstem malformations and their well-defined diagnostic criteria is crucial for optimal therapy, an accurate prognosis, and correct genetic counseling. This article discusses cerebellar and brainstem malformations, with emphasis on neuroimaging findings (including diagnostic criteria), neurologic presentation, systemic involvement, prognosis, and recurrence. PMID:27423798

  19. Humor and laughter in patients with cerebellar degeneration.

    PubMed

    Frank, B; Propson, B; Göricke, S; Jacobi, H; Wild, B; Timmann, D

    2012-06-01

    Humor is a complex behavior which includes cognitive, affective and motor responses. Based on observations of affective changes in patients with cerebellar lesions, the cerebellum may support cerebral and brainstem areas involved in understanding and appreciation of humorous stimuli and expression of laughter. The aim of the present study was to examine if humor appreciation, perception of humorous stimuli, and the succeeding facial reaction differ between patients with cerebellar degeneration and healthy controls. Twenty-three adults with pure cerebellar degeneration were compared with 23 age-, gender-, and education-matched healthy control subjects. No significant difference in humor appreciation and perception of humorous stimuli could be found between groups using the 3 Witz-Dimensionen Test, a validated test asking for funniness and aversiveness of jokes and cartoons. Furthermore, while observing jokes, humorous cartoons, and video sketches, facial expressions of subjects were videotaped and afterwards analysed using the Facial Action Coding System. Using depression as a covariate, the number, and to a lesser degree, the duration of facial expressions during laughter were reduced in cerebellar patients compared to healthy controls. In sum, appreciation of humor appears to be largely preserved in patients with chronic cerebellar degeneration. Cerebellar circuits may contribute to the expression of laughter. Findings add to the literature that non-motor disorders in patients with chronic cerebellar disease are generally mild, but do not exclude that more marked disorders may show up in acute cerebellar disease and/or in more specific tests of humor appreciation. PMID:22012411

  20. Deep brain stimulation or thalamotomy in fragile X-associated tremor/ataxia syndrome? Case report.

    PubMed

    Tamás, Gertrúd; Kovács, Norbert; Varga, Noémi Ágnes; Barsi, Péter; Erőss, Loránd; Molnár, Mária Judit; Balás, István

    2016-01-01

    We present the case of a 66-year-old man who has been treated for essential tremor since the age of 58. He developed mild cerebellar gait ataxia seven years after tremor onset. Moderate, global brain atrophy was identified on MRI scans. At the age of 68, only temporary tremor relief could be achieved by bilateral deep brain stimulation of the ventral intermedius nucleus of the thalamus. Bilateral stimulation of the subthalamic nucleus also resulted only in transient improvement. In the meantime, progressive gait ataxia and tetraataxia developed accompanied by other cerebellar symptoms, such as nystagmus and scanning speech. These correlated with progressive development of bilateral symmetric hyperintensity of the middle cerebellar peduncles on T2 weighted MRI scans. Genetic testing revealed premutation of the FMR1 gene, establishing the diagnosis of fragile X-associated tremor/ataxia syndrome. Although this is a rare disorder, it should be taken into consideration during preoperative evaluation of essential tremor. Postural tremor ceased two years later after thalamotomy on the left side, while kinetic tremor of the right hand also improved. PMID:27375149

  1. Progression of Brain Atrophy in Spinocerebellar Ataxia Type 2: A Longitudinal Tensor-Based Morphometry Study

    PubMed Central

    Mascalchi, Mario; Diciotti, Stefano; Giannelli, Marco; Ginestroni, Andrea; Soricelli, Andrea; Nicolai, Emanuele; Aiello, Marco; Tessa, Carlo; Galli, Lucia; Dotti, Maria Teresa; Piacentini, Silvia; Salvatore, Elena; Toschi, Nicola

    2014-01-01

    Spinocerebellar ataxia type 2 (SCA2) is the second most frequent autosomal dominant inherited ataxia worldwide. We investigated the capability of magnetic resonance imaging (MRI) to track in vivo progression of brain atrophy in SCA2 by examining twice 10 SCA2 patients (mean interval 3.6 years) and 16 age- and gender-matched healthy controls (mean interval 3.3 years) on the same 1.5 T MRI scanner. We used T1-weighted images and tensor-based morphometry (TBM) to investigate volume changes and the Inherited Ataxia Clinical Rating Scale to assess the clinical deficit. With respect to controls, SCA2 patients showed significant higher atrophy rates in the midbrain, including substantia nigra, basis pontis, middle cerebellar peduncles and posterior medulla corresponding to the gracilis and cuneatus tracts and nuclei, cerebellar white matter (WM) and cortical gray matter (GM) in the inferior portions of the cerebellar hemisphers. No differences in WM or GM volume loss were observed in the supratentorial compartment. TBM findings did not correlate with modifications of the neurological deficit. In conclusion, MRI volumetry using TBM is capable of demonstrating the progression of pontocerebellar atrophy in SCA2, supporting a possible role of MRI as biomarker in future trials. PMID:24586758

  2. Exome sequencing reveals a novel CWF19L1 mutation associated with intellectual disability and cerebellar atrophy.

    PubMed

    Evers, Christina; Kaufmann, Lilian; Seitz, Angelika; Paramasivam, Nagarajan; Granzow, Martin; Karch, Stephanie; Fischer, Christine; Hinderhofer, Katrin; Gdynia, Georg; Elsässer, Michael; Pinkert, Stefan; Schlesner, Matthias; Bartram, Claus R; Moog, Ute

    2016-06-01

    Intellectual disability (ID) with cerebellar ataxia comprises a genetically heterogeneous group of neurodevelopmental disorders. We identified a homozygous frameshift mutation in CWF19L1 (c.467delC; p.(P156Hfs*33)) by a combination of linkage analysis and Whole Exome Sequencing in a consanguineous Turkish family with a 9-year-old boy affected by early onset cerebellar ataxia and mild ID. Serial MRI showed mildly progressive cerebellar atrophy. Absent C19L1 protein expression in lymphoblastoid cell lines strongly suggested that c.467delC is a disease-causing alteration. One further pregnancy of the mother had been terminated at 22 weeks of gestation because of a small cerebellum and agenesis of corpus callosum. The homozygous CWF19L1 variant was also present in the fetus. Postmortem examination of the fetus in addition showed unilateral hexadactyly and vertebral malformations. These features have not been reported and may represent an expansion of the CWF19L1-related phenotypic spectrum, but could also be due to another, possibly autosomal recessive disorder. The exact function of the evolutionarily highly conserved C19L1 protein is unknown. So far, homozygous or compound heterozygous mutations in CWF19L1 have been identified in two Turkish siblings and a Dutch girl, respectively, affected by cerebellar ataxia and ID. A zebrafish model showed that CWF19L1 loss-of-function mutations result in abnormal cerebellar morphology and movement disorders. Our report corroborates that loss-of-function mutations in CWF19Ll lead to early onset cerebellar ataxia and (progressive) cerebellar atrophy. © 2016 Wiley Periodicals, Inc. PMID:27016154

  3. Brain glucose metabolism in adults with ataxia-telangiectasia and their asymptomatic relatives.

    PubMed

    Volkow, Nora D; Tomasi, Dardo; Wang, Gene-Jack; Studentsova, Yana; Margus, Brad; Crawford, Thomas O

    2014-06-01

    Ataxia-telangiectasia is a recessive genetic disorder (ATM is the mutated gene) of childhood with severe motor impairments and whereas homozygotes manifest the disorder, heterozygotes are asymptomatic. Structural brain imaging and post-mortem studies in individuals with ataxia-telangiectasia have reported cerebellar atrophy; but abnormalities of motor control characteristic of extrapyramidal dysfunction suggest impairment of broader motor networks. Here, we investigated possible dysfunction in other brain areas in individuals with ataxia-telangiectasia and tested for brain changes in asymptomatic relatives to assess if heterozygocity affects brain function. We used positron emission tomography and (18)F-fluorodeoxyglucose to measure brain glucose metabolism (quantified as µmol/100 g/min), which serves as a marker of brain function, in 10 adults with ataxia-telangiectasia, 19 non-affected adult relatives (12 siblings, seven parents) and 29 age-matched healthy controls. Statistical parametric mapping and region of interest analyses were used to compare individuals with ataxia-telangiectasia, asymptomatic relatives, and unrelated controls. We found that participants with ataxia-telangiectasia had lower metabolism in cerebellar hemispheres (14%, P < 0.001), anterior vermis (40%, P < 0.001) and fusiform gyrus (20%, P < 0.001) compared with controls or siblings, and lower metabolism in hippocampus (12%, P = 0.05) compared with controls, and showed significant intersubject variability (decreases in vermis ranged from 18% to 60%). Participants with ataxia-telangiectasia also had higher metabolism in globus pallidus (16%, P = 0.05), which correlated negatively with motor performance. Asymptomatic relatives had lower metabolism in anterior vermis (12%; P = 0.01) and hippocampus (19%; P = 0.002) than controls. Our results indicate that, in addition to the expected decrease in cerebellar metabolism, participants with ataxia-telangiectasia had widespread changes in metabolic

  4. HIV-related opsoclonus-myoclonus-ataxia syndrome: report on two cases.

    PubMed

    Kanjanasut, Natlada; Phanthumchinda, Kammant; Bhidayasiri, Roongroj

    2010-09-01

    Opsoclonus-myoclonus-ataxia (OMA) syndrome is a rare neurological disorder, characterized by a rapid onset of generalized myoclonus in association with chaotic multi-directional eye movements and, less frequently, cerebellar ataxia. OMA is commonly related to a paraneoplastic process, specifically neuroblastoma in children and lung or breast cancer in adults. Nevertheless, OMA may occur in association with various infectious agents, such as Coxsackie virus B3, Epstein-Barr virus, mumps, enterovirus, and streptococcus. We recently encountered two cases of HIV-related OMA syndrome. The first patient developed a sudden onset of OMA at the time of HIV seroconversion. The second patient experienced severe ataxia with a mild degree of myoclonus and opsoclonus, associated with an elevated CD4 count following the initiation of highly active antiretroviral therapy (HAART). We suggest that OMA syndrome may be another rare manifestation of HIV infection at the time of seroconversion or during an immune restoration period. PMID:20427123

  5. A case of cerebellar dysarthria as the presenting symptom of HIV infection.

    PubMed

    Siddiqi, Zeba; Karoli, Ritu; Fatima, Jalees; Dey, Rahul; Kazmi, Khursheed

    2014-08-01

    A 37 year old man presented with progressive dysarthria for 2 weeks. A week later he developed ataxia and bilateral cerebellar signs including intention tremors, dysmetria and dysdiadokokinesia. During evaluation for aetiology of cerebellar dysarthria, MRI brain revealed asymmetric altered signal intensities in bilateral cerebellar hemispheres and right side of pons suggesting demyelinating lesions. ELISA for Human Immune Deficiency virus-1 was positive. We kept a presumptive diagnosis of Progressive Multifocal Leukoencephalopathy (PML) on the basis of clinico-radiological picture. PML is an under investigated and under diagnosed CNS infection seen in HIV patients with advanced disease. We present an unusual case report where isolated cerebellar involvement occurred as the first AIDS defining event in the absence of appreciable immunodeficiency in a patient with previously undiagnosed HIV infection. PMID:25856948

  6. Spinocerebellar Ataxia Type 7: Clinical Course, Phenotype-Genotype Correlations, and Neuropathology

    PubMed Central

    Horton, Laura C.; Frosch, Matthew P.; Vangel, Mark G.; Weigel-DiFranco, Carol; Berson, Eliot L.; Schmahmann, Jeremy D.

    2012-01-01

    INTRODUCTION Spinocerebellar ataxia type 7 is a neurodegenerative polyglutamine disease characterized by ataxia and retinal degeneration. The longitudinal course is unknown, and relationships between repeat expansion, clinical manifestations, and neuropathology remain uncertain. METHODS We followed 16 affected individuals of a 61-member kindred over 27 years with electroretinograms, neurological examinations including the Brief Ataxia Rating Scale, neuroimaging in 5, and autopsy in 4 cases. RESULTS We identified 4 stages of the illness. Stage 0; gene positive but phenotypically silent. Stage 1; no symptoms, but hyperreflexia and/or abnormal electroretinograms. Stage 2; symptoms and signs progress modestly. Stage 3; rapid clinical progression. CAG repeat length correlated inversely with age of onset of visual or motor signs (r=-0.74, p=0.002). Stage 3 rate of progression did not differ between cases (p=0.18). Electroretinograms correlated with Brief Ataxia Rating Scale score and were a biomarker of disease onset and progression. All symptomatic patients developed gait ataxia, extremity dysmetria, dysarthria, dysrhythmia, and oculomotor abnormalities. Funduscopy revealed pale optic discs and pigmentary disturbances. Visual acuity declined to blindness in those with longer CAG expansions. Hyperreflexia was present from Stage 1 onwards. Restless legs syndrome and sensory impairment were common. Neuropathological hallmarks were neuronal loss in cerebellar cortex, deep cerebellar nuclei, inferior olive, and anterior horns of the spinal cord, and axonal loss in spinocerebellar tracts, dorsal nerve roots and posterior columns. Retinal pathology included photoreceptor degeneration and disruption of retinal pigment epithelium. DISCUSSION Spinocerebellar ataxia type 7 evolves through 4 clinical stages; neuropathological findings underlie the clinical presentation; electroretinograms are a potential biomarker of disease progression. PMID:22915085

  7. Heterogeneity in clinical features and disease severity in ataxia-associated SYNE1 mutations.

    PubMed

    Wiethoff, Sarah; Hersheson, Joshua; Bettencourt, Conceicao; Wood, Nicholas W; Houlden, Henry

    2016-08-01

    The autosomal recessive spinocerebellar ataxias are an exciting field of study, with a growing number of causal genes and an expanding phenotypic spectrum. SYNE1 was originally discovered in 2007 as the causal gene underlying autosomal recessive spinocerebellar ataxia 1, a disease clinically thought to manifest with mainly pure cerebellar ataxia. Since the original report SYNE1 mutations have also been identified in families with motor neuronopathy and arthrogryposis but few families have been screened as the gene is very large at 146 exons in length. We screened 196 recessive and sporadic ataxia patients for mutations in SYNE1 using next generation sequencing in order to assess its frequency and extend the clinicogenetic spectrum. We identified four novel truncating mutations spread throughout the SYNE1 gene from three families living in London that originated from England, Turkey and Sri Lanka. The phenotype was mainly pure cerebellar ataxia in two families, cognitive decline was present in all three families, axonal neuropathy in one family and marked spasticity in the Turkish family, with a range of disease severities. Searching for genotype-phenotype correlations in the SYNE1 gene, defects located near the 3' prime end of the gene are more frequently associated with motor neuron or neuromuscular involvement so far. Our data indicate SYNE1 mutations are not an uncommon cause of recessive ataxia with or without additional clinical features in patients from various ethnicities. The use of next generation sequencing allows the rapid analysis of large genes and will likely reveal more SYNE1 associated cases and further expand genotype-phenotype correlations. PMID:27178001

  8. [Heart involvement in Friedreich's ataxia].

    PubMed

    Weidemann, F; Scholz, F; Florescu, C; Liu, D; Hu, K; Herrmann, S; Ertl, G; Störk, S

    2015-03-01

    Friedreich's ataxia is a rare hereditary disease and although the gene defect has already been identified as a deficiency of the mitochondrial protein frataxin, the pathophysiology is still unknown. Although a multisystem disorder organ involvement is predominantly neurological. Besides the characteristic features of spinocerebellar ataxia the heart is frequently also affected. Cardiac involvement typically manifests as hypertrophic cardiomyopathy, which can progress to heart failure and death. So far most research has focused on the neurological aspects and cardiac involvement in Friedreich's ataxia has not been systematically investigated. Thus, a better understanding of the progression of the cardiomyopathy, cardiac complications and long-term cardiac outcome is warranted. Although no specific treatment is available general cardiac therapeutic options for cardiomyopathy should be considered. The current review focuses on clinical and diagnostic features of cardiomyopathy and discusses potential therapeutic developments for Friedreich's ataxia. PMID:24848865

  9. Fragile X-Associated Tremor Ataxia Syndrome: The Expanding Clinical Picture, Pathophysiology, Epidemiology, and Update on Treatment

    PubMed Central

    Hall, Deborah A.; O'keefe, Joan A.

    2012-01-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive degenerative movement disorder characterized by kinetic tremor, cerebellar gait ataxia, parkinsonism, and cognitive decline. This disorder occurs in both males and females, frequently in families with children who have fragile X syndrome. The clinical features of this disorder, both classic and newly described, are summarized in this paper. In screening studies, fragile X mental retardation 1 (FMR1) gene premutation (55–200 CGG) expansions are most frequently seen in men with ataxia who have tested negative for spinocerebellar ataxias. Since the original description, the classic FXTAS phenotype has now been reported in females and in carriers of smaller (45–54 CGG) and larger (>200 CGG) expansions in FMR1. Premutation carriers may present with a Parkinson disease phenotype or hypotension, rather than with tremor and/or ataxia. Parkinsonism and gait ataxia may also be seen in individuals with gray zone (41–54 CGG) expansions. Studies regarding medication to treat the symptoms in FXTAS are few in number and suggest that medications targeted to specific symptoms, such as kinetic tremor or gait ataxia, may be most beneficial. Great progress has been made in regards to FXTAS research, likely given the readily available gene test and the screening of multiple family members, including parents and grandparents, of fragile X syndrome children. Expansion of genotypes and phenotypes in the disorder may suggest that a broader disease definition might be necessary in the future. PMID:23439567

  10. Importance of genetics in fetal alcohol effects: null mutation of the nNOS gene worsens alcohol-induced cerebellar neuronal losses and behavioral deficits

    PubMed Central

    Bonthius, Daniel J.; Winters, Zachary; Karacay, Bahri; Bousquet, Samantha Larimer; Bonthius, Daniel J.

    2014-01-01

    The cerebellum is a major target of alcohol-induced damage in the developing brain. However, the cerebella of some children are much more seriously affected than others by prenatal alcohol exposure. As a consequence of in utero alcohol exposure, some children have substantial reductions in cerebellar volume and corresponding neurodevelopmental problems, including microencephaly, ataxia, and balance deficits, while other children who were exposed to similar alcohol quantities are spared. One factor that likely plays a key role in determining the impact of alcohol on the fetal cerebellum is genetics. However, no specific gene variant has yet been identified that worsens cerebellar function as a consequence of developmental alcohol exposure. Previous studies have revealed that mice carrying a homozygous mutation of the gene for neuronal nitric oxide synthase (nNOS−/− mice) have more severe acute alcohol-induced neuronal losses from the cerebellum than wild type mice. Therefore, the goals of this study were to determine whether alcohol induces more severe cerebellum-based behavioral deficits in nNOS−/− mice than in wild type mice and to determine whether these worsened behavior deficits are associated with worsened cerebellar neuronal losses. nNOS−/− mice and their wild type controls received alcohol (0.0, 2.2, or 4.4 mg/g) daily over postnatal days 4–9. In adulthood, the mice underwent behavioral testing, followed by neuronal quantification. Alcohol caused dose-related deficits in rotarod and balance beam performance in both nNOS−/− and wild type mice. However, the alcohol-induced behavioral deficits were substantially worse in the nNOS−/− mice than in wild type. Likewise, alcohol exposure led to losses of Purkinje cells and cerebellar granule cells in mice of both genotypes, but the cell losses were more severe in the nNOS−/− mice than in wild type. Behavioral performances were correlated with neuronal number in the nNOS−/− mice, but not

  11. Acute Cerebellitis in Children: A Many-Faceted Disease.

    PubMed

    Kornreich, Liora; Shkalim-Zemer, Vered; Levinsky, Yoel; Abdallah, Wafa; Ganelin-Cohen, Esther; Straussberg, Rachel

    2016-07-01

    Acute cerebellitis is a rare inflammatory condition. It may have a benign, self-limiting course or present as a fulminant disease resulting in severe cerebellar damage or even sudden death. We present the clinical, laboratory, and radiologic data in 9 children diagnosed with acute cerebellitis, who were identified by database search in our pediatric medical center from January 2000 to November 2014. The main presenting symptom was headache, and the main presenting sign was ataxia. Bilateral diffuse hemispheric involvement was the most common imaging finding at presentation. Mycoplasma pneumoniae was the most common infectious pathogen found. Treatment included steroids in all cases, antibiotics in 4, and intravenous immunoglobulins in 6. Six patients had a full recovery, and 3 had residual neurologic complications. Magnetic resonance imaging (MRI) is the modality of choice for diagnosis. The course of acute cerebellitis varies from a commonly benign and self-limiting disease to an occasionally fulminant disease, resulting in severe cerebellar damage or sudden death. PMID:26961264

  12. Purkinje cell apoptosis in arabian horses with cerebellar abiotrophy.

    PubMed

    Blanco, A; Moyano, R; Vivo, J; Flores-Acuña, R; Molina, A; Blanco, C; Monterde, J G

    2006-08-01

    Purkinje cerebellar cells were studied in three Arabian horses aged between 6 and 8 months with clinical disorders in their movements, tremors and ataxia; the occurrence of apoptosis in this cell population was investigated by the (terminal deoxynucleotidyl transferase biotin-dUTP nick-end labelling (TUNEL) method. Both optical and electron microscopical images showed a scant number of Purkinje cells, most of them with morphological features of apoptosis such as condensation of the nucleus and cytoplasm as well as segregation and fragmentation of the nucleus into apoptotic bodies. The TUNEL technique revealed a substantial number (65%) of positive immunoreactive Purkinje cells. PMID:16901270

  13. SCA15 due to large ITPR1 deletions in a cohort of 333 Caucasian families with dominant ataxia

    PubMed Central

    Marelli, Cecilia; van de Leemput, Joyce; Johnson, Janel O; Tison, Francois; Thauvin-Robinet, Christel; Picard, Fabienne; Tranchant, Christine; Hernandez, Dena G; Huttin, Bernard; Boulliat, Jacques; Sangla, Iban; Marescaux, Christian; Brique, Serge; Dollfus, Hélène; Arepalli, Sampath; Benatru, Isabelle; Ollagnon, Elisabeth; Forlani, Sylvie; Hardy, John; Stevanin, Giovanni; Dürr, Alexandra; Singleton, Andrew; Brice, Alexis

    2011-01-01

    Objectives to determine the frequency and the phenotypical spectrum of SCA15 patients. Methods in the index cases of 333 families with autosomal dominant cerebellar ataxia (ADCA) negative for CAG repeat expansions in coding exons (SCA1,2,3,6,7,17 and dentatorubropallidoluysian atrophy), we searched for heterozygous rearrangements in ITPR1. Taqman PCR (258 index cases) or SNP genome-wide genotyping (75 index cases) were used. Results a deletion of ITPR1 was found in 6/333 (1.8%) families, corresponding to 13 SCA15 patients. Age at onset ranged from 18 to 66 years with a mean of 35±16 years. The symptom at onset was mainly cerebellar gait ataxia, except for one patient presenting with isolated upper limb tremor. Although we tested a large cohort of families irrespective of their phenotype, the main clinical features of SCA15 patients were homogeneous and characterized by a very slowly progressive gait and limb cerebellar ataxia with dysarthria. However, pyramidal signs (two patients), and mild cognitive problems (two patients) were occasionally present. Ocular alterations consisted of nystagmus, mainly horizontal and gaze-evoked (ten patients), and saccadic pursuit (seven patients). Radiological findings showed global or predominant vermian cerebellar atrophy in all patients. Conclusions In this series ITPR1 deletions are rare and account for ~1% of all ADCA. The SCA15 phenotype mostly consists of a slowly progressive isolated cerebellar ataxia with variable age at onset; an additional pyramidal syndrome and problems in executive functions may be present in a minority of patients. PMID:21555639

  14. Cerebellar Zonal Patterning Relies on Purkinje Cell Neurotransmission

    PubMed Central

    White, Joshua J.; Arancillo, Marife; Stay, Trace L.; George-Jones, Nicholas A.; Levy, Sabrina L.; Heck, Detlef H.

    2014-01-01

    Cerebellar circuits are patterned into an array of topographic parasagittal domains called zones. The proper connectivity of zones is critical for motor coordination and motor learning, and in several neurological diseases cerebellar circuits degenerate in zonal patterns. Despite recent advances in understanding zone function, we still have a limited understanding of how zones are formed. Here, we focused our attention on Purkinje cells to gain a better understanding of their specific role in establishing zonal circuits. We used conditional mouse genetics to test the hypothesis that Purkinje cell neurotransmission is essential for refining prefunctional developmental zones into sharp functional zones. Our results show that inhibitory synaptic transmission in Purkinje cells is necessary for the precise patterning of Purkinje cell zones and the topographic targeting of mossy fiber afferents. As expected, blocking Purkinje cell neurotransmission caused ataxia. Using in vivo electrophysiology, we demonstrate that loss of Purkinje cell communication altered the firing rate and pattern of their target cerebellar nuclear neurons. Analysis of Purkinje cell complex spike firing revealed that feedback in the cerebellar nuclei to inferior olive to Purkinje cell loop is obstructed. Loss of Purkinje neurotransmission also caused ectopic zonal expression of tyrosine hydroxylase, which is only expressed in adult Purkinje cells when calcium is dysregulated and if excitability is altered. Our results suggest that Purkinje cell inhibitory neurotransmission establishes the functional circuitry of the cerebellum by patterning the molecular zones, fine-tuning afferent circuitry, and shaping neuronal activity. PMID:24920627

  15. Cerebellar Symptoms Are Associated With Omission Errors and Variability of Response Time in Children With ADHD.

    PubMed

    Goetz, Michal; Schwabova, Jaroslava; Hlavka, Zdenek; Ptacek, Radek; Zumrova, Alena; Hort, Vladimír; Doyle, Robert

    2014-01-10

    Objective: We examined the presence of cerebellar symptoms in ADHD and their association with behavioral markers of this disorder. Method: Sixty-two children with ADHD and 62 typically developing (TD) children were examined for cerebellar symptoms using the ataxia rating scale and tested using Conners' Continuous Performance Test. Results: Children with ADHD had significantly more cerebellar symptoms compared with the TD children. Cerebellar symptom scores decreased with age in the ADHD group; in the TD group remained stable. In both groups, cerebellar symptoms were associated with parent-rated hyperactive/impulsive symptoms, variability of response time standard error (RT-SE) and increase of RT-SE as the test progresses. More variables were associated with cerebellar symptoms in the ADHD group including omission errors, overall RT-SE and its increase for prolonged interstimulus intervals. Conclusion: Our results highlight the importance of research into motor functions in children with ADHD and indicate a role for cerebellar impairment in this disorder. (J. of Att. Dis. XXXX; XX(X) 1-XX). PMID:24412970

  16. ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency.

    PubMed

    Balreira, Andrea; Boczonadi, Veronika; Barca, Emanuele; Pyle, Angela; Bansagi, Boglarka; Appleton, Marie; Graham, Claire; Hargreaves, Iain P; Rasic, Vedrana Milic; Lochmüller, Hanns; Griffin, Helen; Taylor, Robert W; Naini, Ali; Chinnery, Patrick F; Hirano, Michio; Quinzii, Catarina M; Horvath, Rita

    2014-11-01

    Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation. PMID:25182700

  17. Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann-Pick disease type C patients treated with miglustat.

    PubMed

    Bowman, Elizabeth A; Walterfang, Mark; Abel, Larry; Desmond, Patricia; Fahey, Michael; Velakoulis, Dennis

    2015-09-01

    Niemann-Pick disease type C (NPC) is a rare neurovisceral disorder resulting in impaired intracellular lipid trafficking. The only disease-modifying treatment available to date is miglustat, an iminosugar inhibiting the accumulation of lipid by-products in neurons. This study explored how changes in cerebellar grey and white matter volumes, and in subcortical volumes, related to patient treatment status and disability and ataxia ratings. Nine adult-onset NPC patients and 17 matched controls underwent T1-weighted MRI. One patient was not receiving miglustat, and pre-treatment data were available for a further patient. Semi-automated cerebellar and subcortical segmentation was undertaken, and the rates of change in putamen, hippocampal, thalamic and caudal volumes, and grey and white matter cerebellar volumes, were compared to rates of change in Iturriaga disability score, Brief Ataxia Rating Scale (BARS), and horizontal saccadic gain. Untreated NPC patients appeared to lose cerebellar grey and white matter, bilateral thalamic volume, and right caudate volume faster than treated patients. Cerebellar grey matter volume loss and volume loss in the left thalamus were significantly correlated with Iturriaga disability scale changes. Change in both cerebellar grey and white matter was correlated with decrease in horizontal saccadic gain, but not with change in BARS. This is the first study to examine longitudinal treatment effects of miglustat on cerebellar and subcortical volumes in patients with adult-onset NPC, and is evidence that miglustat may have a protective effect on cerebellar and subcortical structure and function. PMID:26092521

  18. Unilateral cerebellar aplasia.

    PubMed

    Boltshauser, E; Steinlin, M; Martin, E; Deonna, T

    1996-02-01

    We describe three children with unilateral cerebellar aplasia (UCA). Deliveries at term and neonatal periods were uneventful. Pregnancy was normal in one and complicated by mild bleeding (in second and fourth month respectively) in two instances. Presenting signs were delayed motor development with marked contralateral torticollis (n = 1), hemiplegia (n = 1) and unusual head nodding (n = 1). Neuroradiological investigations revealed complete aplasia (n = 1) and subtotal aplasia (n = 2) of one cerebellar hemisphere with only a residual wing-like structure below the tentorium. There was contralateral underdevelopment of the brainstem. The infant with hemiplegic cerebral palsy had an additional supratentorial periventricular parenchymal defect, contralateral to the cerebellar hypoplasia. In view of literature reports, describing similar neuroradiological or neuropathological findings in asymptomatic individuals, it is doubtful whether UCA is responsible for our patient's problems. In our cases UCA has presumably resulted from a prenatal destructive lesion, possibly an infarct, but the timing and exact nature are unknown. PMID:8677027

  19. Localization of the candidate gene d-amino acid oxidase outside the refined 1-cM region of spinocerebellar ataxia 2

    SciTech Connect

    Auburger, G.; Gispert, S.; Lunkes, A.

    1995-10-01

    Spinocerebellar ataxia 2 (SCA2) is one form of the neurodegenerative autosomal dominant cerebellar ataxias and has been linked to chromosome 12q in 25 previously described and 13 new families from a founder collective of {ge}500 patients in Holguin, Cuba. Although SCA2 in most patients cannot be distinguished from other spinocerebellar ataxias by clinical criteria, in some patients it exhibits a particular phenotype with early neuropathy/late slow saccades and late myoclonus. Autopsy in 11 patients demonstrated olivo-ponto-cerebellar atrophy with a selective sparing of the dentate nucleus. Complete allelic association within the Holguin population was established with the microsatellite D12S105, and the candidate region was determined to be within a 6-cM region distal to the marker D12S84, contrasting previous reports by Pulst and Lopes-Cendes and according to preliminary data between D12S84 and D12S1329. 17 refs., 1 fig., 1 tab.

  20. Friedreich Ataxia in Classical Galactosaemia.

    PubMed

    Neville, Siobhán; O'Sullivan, Siobhan; Sweeney, Bronagh; Lynch, Bryan; Hanrahan, Donncha; Knerr, Ina; Lynch, Sally Ann; Crushell, Ellen

    2016-01-01

    Movement disorders such as ataxia are a recognized complication of classical galactosaemia, even in diet-compliant patients. Here, we report the coexistence of classical galactosaemia and Friedreich ataxia (FRDA) in nine children from seven Irish Traveller families. These two autosomal recessive disorders, the loci for which are located on either side of the centromere of chromosome 9, appear to be in linkage disequilibrium in this subgroup. Both conditions are known to occur with increased frequency amongst the Irish Traveller population.Each member of our cohort had been diagnosed with galactosaemia in the neonatal period, and all are homozygous for the common Q188R mutation in the GALT gene. Eight of the nine patients later presented with progressive ataxia, between the ages of 5-13 years. Another child presented in cardiac failure secondary to dilated cardiomyopathy at 7 years of age. He was not ataxic at presentation and, one year from diagnosis, his neurological examination remains normal. The diagnosis of FRDA was confirmed by detecting the common pathogenic GAA expansion in both alleles of the frataxin gene (FXN) in each patient.Neurological symptoms are easily attributed to an underlying diagnosis of galactosaemia. It is important to consider a diagnosis of Friedreich ataxia in a child from the Irish Traveller population with galactosaemia who presents with ataxia or cardiomyopathy. PMID:26219880

  1. Pharmacotherapy for Friedreich ataxia.

    PubMed

    Tsou, Amy Y; Friedman, Lisa S; Wilson, Robert B; Lynch, David R

    2009-01-01

    Friedreich ataxia (FA) is a progressive genetic neurological disorder associated with degeneration of the dorsal columns, spinocerebellar tracts and other regions of the nervous system. The disorder results from mutations in the gene referred to as FXN. Almost all mutations are expansions of an intronic GAA repeat in this gene, which gives rise to decreased transcription of the gene product (called frataxin). Following these discoveries, drug discovery has moved at a rapid pace. Therapeutic trials in the next 5 years are expected to address amelioration of the effects of frataxin deficiency and methods for increasing frataxin expression. These therapies are directed at all levels of biochemical dysfunction in FA. Agents such as idebenone potentially improve mitochondrial function and decrease production of reactive oxygen species. Idebenone is presently in a phase III trial in the US and in Europe, with the primary outcome measure being neurological function. Deferiprone, an atypical iron chelator, may decrease build-up of toxic iron in the mitochondria in patients. It has entered a phase II trial in Europe, Australia and Canada directed toward improvement of neurological abilities. Finally, targeted histone deacetylase (HDAC) inhibitors and erythropoietin increase levels of frataxin when used in vitro, suggesting that they may provide methods for increasing frataxin levels in patients. Erythropoietin has been tested in a small phase II trial in Austria, while HDAC inhibitors are still at a preclinical stage. Symptomatic therapies are also in use for specific symptoms such as spasticity (baclofen). Thus, there is substantial optimism for development of new therapies for FA in the near future, and we suggest that one or several may be available over the next few years. However, continued development of new therapies will require creation of new, more sensitive measures for neurological dysfunction in FA, and clinically relevant measures of cardiac dysfunction. PMID

  2. Cerebellar cortex development in the weaver condition presents regional and age-dependent abnormalities without differences in Purkinje cells neurogenesis.

    PubMed

    Martí, Joaquín; Santa-Cruz, María C; Hervás, José P; Bayer, Shirley A; Villegas, Sandra

    2016-01-01

    Ataxias are neurological disorders associated with the degeneration of Purkinje cells (PCs). Homozygous weaver mice (wv/wv) have been proposed as a model for hereditary cerebellar ataxia because they present motor abnormalities and PC loss. To ascertain the physiopathology of the weaver condition, the development of the cerebellar cortex lobes was examined at postnatal day (P): P8, P20 and P90. Three approaches were used: 1) quantitative determination of several cerebellar features; 2) qualitative evaluation of the developmental changes occurring in the cortical lobes; and 3) autoradiographic analyses of PC generation and placement. Our results revealed a reduction in the size of the wv/wv cerebellum as a whole, confirming previous results. However, as distinguished from these reports, we observed that quantified parameters contribute differently to the abnormal growth of the wv/wv cerebellar lobes. Qualitative analysis showed anomalies in wv/wv cerebellar cytoarchitecture, depending on the age and lobe analyzed. Such abnormalities included the presence of the external granular layer after P20 and, at P90, ectopic cells located in the molecular layer following several placement patterns. Finally, we obtained autoradiographic evidence that wild-type and wv/wv PCs presented similar neurogenetic timetables, as reported. However, the innovative character of this current work lies in the fact that the neurogenetic gradients of wv/wv PCs were not modified from P8 to P90. A tendency for the accumulation of late-formed PCs in the anterior and posterior lobes was found, whereas early-generated PCs were concentrated in the central and inferior lobes. These data suggested that wv/wv PCs may migrate properly to their final destinations. The extrapolation of our results to patients affected with cerebellar ataxias suggests that all cerebellar cortex lobes are affected with several age-dependent alterations in cytoarchitectonics. We also propose that PC loss may be regionally

  3. Ataxia telangiectasia: learning from previous mistakes

    PubMed Central

    Kumar, Naveen; Aggarwal, Puneet; Dev, Nishanth; kumar, Gunjan

    2012-01-01

    Ataxia telangiectasia is an early onset neurodegenerative disorder. We report a case of childhood onset ataxia and ocular telangiectasia, presenting with pulmonary infection. The patient was diagnosed as ataxia telangiectasia. The patient succumbed to death owing to late diagnosis and sepsis. PMID:23242084

  4. Ataxia telangiectasia in Chinese children. A clinical and electrophysiological study.

    PubMed

    Wong, V; Yu, Y L; Chan-Lui, W Y; Woo, E; Yeung, C Y

    1987-01-01

    The clinical manifestations, immunological, chromosomal, and multimodal electrophysiological studies of five Chinese patients with ataxia telangiectasia are described. One died of hepatocellular carcinoma not associated with Hepatitis B-antigenaemia. Another died of respiratory failure. Two siblings are free of sinopulmonary infections although they are wheelchair bound. Computed tomography of the brain showed cerebellar atrophy in four cases. Nerve conduction studies showed evidence of axonal neuropathy in all cases with the earliest detection at six years. Electromyography showed mild denervation changes in two cases. Two patients had abnormal somatosensory evoked potentials and one had abnormal visual and brain stem auditory evoked potentials. The level of alpha foetal protein was elevated whereas the serum carcino-embryonic antigen was normal in all patients. PMID:3665286

  5. Diphtheria toxin mutant selectively kills cerebellar Purkinje neurons.

    PubMed Central

    Riedel, C J; Muraszko, K M; Youle, R J

    1990-01-01

    CRM107 (crossreacting material 107), a double point mutant of diphtheria toxin that lacks receptor-binding activity, specifically kills cerebellar Purkinje cells in vivo. After injection into guinea pig cerebrospinal fluid, CRM107 (0.9 micrograms) and CRM107-monoclonal antibody conjugates (10 micrograms) kill up to 90% of the total Purkinje cell population with no detectable toxicity to other neurons. Animals exhibit ataxia, tremor, and abnormalities of posture and tone. Native diphtheria toxin, ricin, and ricin A chain do not cause ataxia and do not reduce the Purkinje cell population after intrathecal injection into guinea pigs at toxic or maximally tolerated doses. However, in rats, which will tolerate higher doses of diphtheria toxin than guinea pigs, Purkinje cells can be killed by both CRM107 and diphtheria toxin. A truncated mutant of diphtheria toxin, called CRM45, can also cause Purkinje cell killing but has additional toxicity not seen with CRM107. Animals treated with intrathecal CRM107 or CRM107 linked to antibodies may serve as models for Purkinje cell loss in a broad spectrum of human diseases and may be used to further study cerebellar physiology. Understanding the basis for the Purkinje cell sensitivity to CRM107 may illuminate other causes of Purkinje cell loss. Images PMID:2367523

  6. HSF1-deficiency affects gait coordination and cerebellar calbindin levels.

    PubMed

    Ingenwerth, Marc; Estrada, Veronica; Stahr, Anna; Müller, Hans Werner; von Gall, Charlotte

    2016-09-01

    Heat shock proteins (HSPs) play an important role in cell homeostasis and protect against cell damage. They were previously identified as key players in different ataxia models. HSF1 is the main transcription factor for HSP activation. HSF1-deficient mice (HSF1-/-) are known to have deficiencies in motor control test. However, little is known about effects of HSF1-deficiency on locomotor, especially gait, coordination. Therefore, we compared HSF-deficient (HSF1-/-) mice and wildtype littermates using an automated gait analysis system for objective assessment of gait coordination. We found significant changes in gait parameters of HSF1-/- mice reminiscent of cerebellar ataxia. Immunohistochemical analyses of a cerebellum revealed co-localization of HSF1 and calbindin in Purkinje cells. Therefore, we tested the hypothesis of a potential interconnection between HSF1 and calbindin in Purkinje cells. Calbindin levels were analyzed qualitatively and quantitatively by immunohistochemistry and immunoblotting, respectively. While quantitative PCR revealed no differences in calbindin mRNA levels between HSF1+/+ and HSF1-/- mice, calbindin protein levels, however, were significantly decreased in a cerebellum of HSF1-/- mice. A pathway analysis supports the hypothesis of an interconnection between HSF1 and calbindin. In summary, the targeted deletion of HSF1 results in changes of locomotor function associated with changes in cerebellar calbindin protein levels. These findings suggest a role of HSF1 in regular Purkinje cell calcium homeostasis. PMID:27173427

  7. Impaired Spatio-Temporal Predictive Motor Timing Associated with Spinocerebellar Ataxia Type 6.

    PubMed

    Broersen, Robin; Onuki, Yoshiyuki; Abdelgabar, Abdel R; Owens, Cullen B; Picard, Samuel; Willems, Jessica; Boele, Henk-Jan; Gazzola, Valeria; Van der Werf, Ysbrand D; De Zeeuw, Chris I

    2016-01-01

    Many daily life activities demand precise integration of spatial and temporal information of sensory inputs followed by appropriate motor actions. This type of integration is carried out in part by the cerebellum, which has been postulated to play a central role in learning and timing of movements. Cerebellar damage due to atrophy or lesions may compromise forward-model processing, in which both spatial and temporal cues are used to achieve prediction for future motor states. In the present study we sought to further investigate the cerebellar contribution to predictive and reactive motor timing, as well as to learning of sequential order and temporal intervals in these tasks. We tested patients with spinocerebellar ataxia type 6 (SCA6) and healthy controls for two related motor tasks; one requiring spatio-temporal prediction of dynamic visual stimuli and another one requiring reactive timing only. We found that healthy controls established spatio-temporal prediction in their responses with high temporal precision, which was absent in the cerebellar patients. SCA6 patients showed lower predictive motor timing, coinciding with a reduced number of correct responses during the 'anticipatory' period on the task. Moreover, on the task utilizing reactive motor timing functions, control participants showed both sequence order and temporal interval learning, whereas patients only showed sequence order learning. These results suggest that SCA6 affects predictive motor timing and temporal interval learning. Our results support and highlight cerebellar contribution to timing and argue for cerebellar engagement during spatio-temporal prediction of upcoming events. PMID:27571363

  8. Impaired Spatio-Temporal Predictive Motor Timing Associated with Spinocerebellar Ataxia Type 6

    PubMed Central

    Onuki, Yoshiyuki; Abdelgabar, Abdel R.; Owens, Cullen B.; Picard, Samuel; Willems, Jessica; Boele, Henk-Jan; Gazzola, Valeria; Van der Werf, Ysbrand D.; De Zeeuw, Chris I.

    2016-01-01

    Many daily life activities demand precise integration of spatial and temporal information of sensory inputs followed by appropriate motor actions. This type of integration is carried out in part by the cerebellum, which has been postulated to play a central role in learning and timing of movements. Cerebellar damage due to atrophy or lesions may compromise forward-model processing, in which both spatial and temporal cues are used to achieve prediction for future motor states. In the present study we sought to further investigate the cerebellar contribution to predictive and reactive motor timing, as well as to learning of sequential order and temporal intervals in these tasks. We tested patients with spinocerebellar ataxia type 6 (SCA6) and healthy controls for two related motor tasks; one requiring spatio-temporal prediction of dynamic visual stimuli and another one requiring reactive timing only. We found that healthy controls established spatio-temporal prediction in their responses with high temporal precision, which was absent in the cerebellar patients. SCA6 patients showed lower predictive motor timing, coinciding with a reduced number of correct responses during the ‘anticipatory’ period on the task. Moreover, on the task utilizing reactive motor timing functions, control participants showed both sequence order and temporal interval learning, whereas patients only showed sequence order learning. These results suggest that SCA6 affects predictive motor timing and temporal interval learning. Our results support and highlight cerebellar contribution to timing and argue for cerebellar engagement during spatio-temporal prediction of upcoming events. PMID:27571363

  9. 5-hydroxytryptamine and Lyme disease. Opportunity for a novel therapy to reduce the cerebellar tremor?

    PubMed

    Maximov, G K; Maximov, K G; Chokoeva, A A; Lotti, T; Wollina, U; Patterson, J W; Guarneri, C; Tana, C; Fioranelli, M; Roccia, M G; Kanazawa, N; Tchernev, G

    2016-01-01

    Lyme boreliosis is caused by the spirochete Borrelia burdorferi, which is transmitted by ticks. A 59 year-old woman developed pyrexia, strong headaches, ataxia, dysarthria and tremor of the limbs after a tick bite. She was unable to work and eat on her own. She was hospitalized three times and diagnosed with cerebellar intention tremor, cerebellar ataxia, dysarthria, bilateral horizontal gaze paralysis and a central lesion of the left facial nerve. There were no pyramidal, sensory or psychiatric disturbances. The brain MRI showed multifocal leucoencephalopathy with many hyperintense areas in both hemispheres, as well as in the left superior pedunculus cerebellaris. Diagnosis was confirmed by serologic examination. Treatment with cephtriaxone, doxycycline, methylprednisolone, cephixime and ciprofloxacine was administered without effect on the tremor, ataxia and horizontal gaze paralysis. Treatment was then administered with 5-hydroxytriptamine (5-HT) in increased doses. The result of the three-month treatment with 5-HT was a gradual diminution of the tremor and the ataxia and an increase in the ability to eat, walk and work independently. PMID:27373127

  10. Origin of the spinocerebellar ataxia type 7 gene mutation in Mexican population.

    PubMed

    Magaña, J J; Gómez, R; Maldonado-Rodríguez, M; Velázquez-Pérez, L; Tapia-Guerrero, Y S; Cortés, H; Leyva-García, N; Hernández-Hernández, O; Cisneros, B

    2013-12-01

    Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by progressive cerebellar ataxia associated with macular degeneration that leads, in the majority of patients, to loss of autonomy and blindness. The cause of the disease has been identified as (CAG) n repeat expansion in the coding sequence of the ATXN7 gene on chromosome 3p21.1. SCA7 is one of the least common genetically verified autosomal dominant cerebellar ataxias found worldwide; however, we previously identified the Mexican population showing high prevalence of SCA7, suggesting the occurrence of a common founder effect. In this study, haplotype analysis using four SCA7 gene-linked markers revealed that all 72 SCA7 carriers studied share a common haplotype, A-254-82-98, for the intragenic marker 3145G/A and centromeric markers D3S1287, D3S1228, and D3S3635, respectively. This multiloci combination is uncommon in healthy relatives and Mexican general population, suggesting that a single ancestral mutation is responsible for all SCA7 cases in this population. Furthermore, genotyping using 17 short tandem repeat markers from the non-recombining region of the Y chromosome and further phylogenetic relationship analysis revealed that Mexican patients possess the Western European ancestry, which might trace the SCA7 ancestral mutation to that world region. PMID:23828024

  11. Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum

    PubMed Central

    2013-01-01

    Background Mutations in SACS, leading to autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), have been identified as a frequent cause of recessive early-onset ataxia around the world. Here we aimed to enlarge the spectrum of SACS mutations outside Quebec, to establish the pathogenicity of novel variants, and to expand the clinical and imaging phenotype. Methods Sequencing of SACS in 22 patients with unexplained early-onset ataxia, assessment of novel SACS variants in 3.500 European control chromosomes and extensive phenotypic investigations of all SACS carriers. Results We identified 11 index patients harbouring 17 novel SACS variants. 9/11 patients harboured two variants of at least probable pathogenicity which were not observed in controls and, in case of missense mutations, were located in highly conserved domains. These 9 patients accounted for at least 11% (9/83) in our series of unexplained early onset ataxia subjects. While most patients (7/9) showed the classical ARSACS triad, the presenting phenotype reached from pure neuropathy (leading to the initial diagnosis of Charcot-Marie-Tooth disease) in one subject to the absence of any signs of neuropathy in another. In contrast to its name “spastic ataxia”, neither spasticity (absent in 2/9=22%) nor extensor plantar response (absent in 3/9=33%) nor cerebellar ataxia (absent in 1/9=11%) were obligate features. Autonomic features included urine urge incontinence and erectile dysfunction. Apart from the well-established MRI finding of pontine hypointensities, all patients (100%) showed hyperintensities of the lateral pons merging into the (thickened) middle cerebellar peduncles. In addition, 63% exhibited bilateral parietal cerebral atrophy, and 63% a short circumscribed thinning of the posterior midbody of the corpus callosum. In 2 further patients with differences in important clinical features, VUS class 3 variants (c.1373C>T [p.Thr458Ile] and c.2983 G>T [p.Val995Phe]) were identified

  12. Fragile X Premutation Tremor/Ataxia Syndrome: Molecular, Clinical, and Neuroimaging Correlates

    PubMed Central

    Jacquemont, Sébastien; Hagerman, Randi J.; Leehey, Maureen; Grigsby, Jim; Zhang, Lin; Brunberg, James A.; Greco, Claudia; Des Portes, Vincent; Jardini, Tristan; Levine, Richard; Berry-Kravis, Elizabeth; Brown, W. Ted; Schaeffer, Stephane; Kissel, John; Tassone, Flora; Hagerman, Paul J.

    2003-01-01

    We present a series of 26 patients, all >50 years of age, who are carriers of the fragile X premutation and are affected by a multisystem, progressive neurological disorder. The two main clinical features of this new syndrome are cerebellar ataxia and/or intention tremor, which were chosen as clinical inclusion criteria for this series. Other documented symptoms were short-term memory loss, executive function deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction. Symmetrical regions of increased T2 signal intensity in the middle cerebellar peduncles and adjacent cerebellar white matter are thought to be highly sensitive for this neurologic condition, and their presence is the radiological inclusion criterion for this series. Molecular findings include elevated mRNA and low-normal or mildly decreased levels of fragile X mental retardation 1 protein. The clinical presentation of these patients, coupled with a specific lesion visible on magnetic resonance imaging and with neuropathological findings, affords a more complete delineation of this fragile X premutation–associated tremor/ataxia syndrome and distinguishes it from other movement disorders. PMID:12638084

  13. Fragile X-associated tremor/ataxia syndrome

    PubMed Central

    Hagerman, Paul J; Hagerman, Randi J

    2014-01-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects some but not all carriers of small, non-coding CGG-repeat expansions (55–200 repeats; premutation) within the fragile X gene (FMR1). Principal features of FXTAS include intention tremor, cerebellar ataxia, Parkinsonism, memory and executive function deficits, autonomic dysfunction, brain atrophy with white matter disease, and cognitive decline. Although FXTAS was originally considered to be confined to the premutation range, rare individuals with a gray zone (45 to 54 repeats) or an unmethylated full mutation (>200 repeats) allele have now been described; the constant feature of the disorder remaining the requirement for FMR1 expression, in contradistinction to the gene silencing mechanism of fragile X syndrome. Although transcriptional activity is required for FXTAS pathogenesis, the specific trigger(s) for FXTAS pathogenesis remains elusive, highlighting the need for more research in this area. This need is underscored by recent neuroimaging findings of changes in the central nervous system that consistently appear well before the onset of clinical symptoms, thus creating an opportunity to delay or prevent the appearance of FXTAS. PMID:25622649

  14. Childhood colon cancer in a patient with ataxia telangiectasia

    PubMed Central

    Jo, Kyeong Min; Park, Jong Ha; Kim, Tae Oh; Jeong, Heui Jeong; Heo, Chang Min; Jang, Ji Hoon; Hur, So Chong; Jeong, Na Ri; Jeong, Su Jin; Seol, Sang Hoon; Nam, Kyung Han

    2016-01-01

    Background Ataxia-telangiectasia (AT) is a rare autosomal recessive disease characterized by progressive neurologic impairment and cerebellar ataxia. In addition, patients with this disease are known to have an inherent increased susceptibility to the development of cancer, predominantly hematologic malignancies. Methods We report the case of a young boy with AT from Russia, who had abdominal pain. Laboratory tests and radiologic examinations were performed to him. Results After abdominal computed tomography (CT), colonoscopy and surgical interventions, the young boy was diagnosed with colon cancer that had signet ring cell features. Conclusions It is known that the patient with AT appeared to be predisposed to various tumors, including leukemia or lymphoma, which are more common in childhood. Even if the patient with AT could have solid tumor such as stomach cancer or breast cancer, it is less likely to have colon cancer, especially signet ring cell type. Actually, no case of colon cancer has ever been reported, especially in young patient and hence, we have focused on this point and are hereby reporting this unique case. PMID:26855947

  15. Cerebrospinal Fluid Biomarkers in Spinocerebellar Ataxia: A Pilot Study.

    PubMed

    Brouillette, Ashley M; Öz, Gülin; Gomez, Christopher M

    2015-01-01

    Neurodegenerative diseases, including the spinocerebellar ataxias (SCA), would benefit from the identification of reliable biomarkers that could serve as disease subtype-specific and stage-specific indicators for the development and monitoring of treatments. We analyzed the cerebrospinal fluid (CSF) level of tau, α-synuclein, DJ-1, and glial fibrillary acidic protein (GFAP), proteins previously associated with neurodegenerative processes, in patients with the autosomal dominant SCA1, SCA2, and SCA6, and the sporadic disease multiple system atrophy, cerebellar type (MSA-C), compared with age-matched controls. We estimated disease severity using the Scale for the Assessment and Rating of Ataxia (SARA). Most proteins measured trended higher in disease versus control group yet did not reach statistical significance. We found the levels of tau in both SCA2 and MSA-C patients were significantly higher than control. We found that α-synuclein levels were lower with higher SARA scores in SCA1 and tau levels were higher with greater SARA in MSA-C, although this final correlation did not reach statistical significance after post hoc correction. Additional studies with larger sample sizes are needed to improve the power of these studies and validate the use of CSF biomarkers in SCA and MSA-C. PMID:26265793

  16. Cerebrospinal Fluid Biomarkers in Spinocerebellar Ataxia: A Pilot Study

    PubMed Central

    Brouillette, Ashley M.; Öz, Gülin; Gomez, Christopher M.

    2015-01-01

    Neurodegenerative diseases, including the spinocerebellar ataxias (SCA), would benefit from the identification of reliable biomarkers that could serve as disease subtype-specific and stage-specific indicators for the development and monitoring of treatments. We analyzed the cerebrospinal fluid (CSF) level of tau, α-synuclein, DJ-1, and glial fibrillary acidic protein (GFAP), proteins previously associated with neurodegenerative processes, in patients with the autosomal dominant SCA1, SCA2, and SCA6, and the sporadic disease multiple system atrophy, cerebellar type (MSA-C), compared with age-matched controls. We estimated disease severity using the Scale for the Assessment and Rating of Ataxia (SARA). Most proteins measured trended higher in disease versus control group yet did not reach statistical significance. We found the levels of tau in both SCA2 and MSA-C patients were significantly higher than control. We found that α-synuclein levels were lower with higher SARA scores in SCA1 and tau levels were higher with greater SARA in MSA-C, although this final correlation did not reach statistical significance after post hoc correction. Additional studies with larger sample sizes are needed to improve the power of these studies and validate the use of CSF biomarkers in SCA and MSA-C. PMID:26265793

  17. Huntington’s disease masquerading as spinocerebellar ataxia

    PubMed Central

    Rodríguez-Quiroga, Sergio Alejandro; Gonzalez-Morón, Dolores; Garretto, Nelida; Kauffman, Marcelo Andres

    2013-01-01

    Huntington’s disease (HD) is a neurodegenerative disorder of the central nervous system characterised by the presence of choreic abnormal movements, behavioural or psychiatric disturbances and dementia. Noteworthy, despite atypical motor symptoms other than chorea have been reported as initial presentation in some patients, a very few number of HD patients, presenting at onset mostly cerebellar dysfunction masquerading dominant spinocerebellar ataxias (SCA), were occasionally reported. We report the case of a 42-year-old man with a 5-year history of gait disturbance, dysarthria and cognitive impairment and familial antecedents of dementia and movement disorders. Initially the clinical picture suggested the diagnosis of a dominant SCA, but finally a diagnosis of HD was made based on the molecular evidence of abnormal 39 Cytosine-Adenine-Guanine (CAG) repeats in exon 1 of Huntingtin gene. The authors highlight the importance of suspecting HD in the aetiology of spinocerebellar ataxias when dementia is a prominent feature in the proband or their family. PMID:23853009

  18. [Static disorders in hereditary ataxias].

    PubMed

    Badalian, L O; Lebedeva, N N; Sidorova, O P

    1987-01-01

    Static disorders elicited by the adequate methods of the assessment of equilibrium (stabilography) and gait (plantography) in hereditary ataxias have been analyzed. These techniques of examination make it possible to quantitatively estimate motor disorders, supplement clinical findings and provide an opportunity for objective evaluation of the efficacy of the conducted therapy. PMID:3115017

  19. Clinical, neuroradiological and molecular characterization of cerebellar dysplasia with cysts (Poretti-Boltshauser syndrome).

    PubMed

    Micalizzi, Alessia; Poretti, Andrea; Romani, Marta; Ginevrino, Monia; Mazza, Tommaso; Aiello, Chiara; Zanni, Ginevra; Baumgartner, Bastian; Borgatti, Renato; Brockmann, Knut; Camacho, Ana; Cantalupo, Gaetano; Haeusler, Martin; Hikel, Christiane; Klein, Andrea; Mandrile, Giorgia; Mercuri, Eugenio; Rating, Dietz; Romaniello, Romina; Santorelli, Filippo Maria; Schimmel, Mareike; Spaccini, Luigina; Teber, Serap; von Moers, Arpad; Wente, Sarah; Ziegler, Andreas; Zonta, Andrea; Bertini, Enrico; Boltshauser, Eugen; Valente, Enza Maria

    2016-08-01

    Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti-Boltshauser syndrome (PBS). Clinical features comprise non-progressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS. Here we report the detailed clinical, neuroimaging and genetic characterization of 18 PBS patients from 15 unrelated families. Biallelic LAMA1 variants were identified in 14 families (93%). The only non-mutated proband presented atypical clinical and neuroimaging features, challenging the diagnosis of PBS. Sixteen distinct variants were identified, which were all novel. In particular, the frameshift variant c.[2935delA] recurred in six unrelated families on a shared haplotype, suggesting a founder effect. No LAMA1 variants could be detected in 27 probands with different cerebellar dysplasias or non-progressive cerebellar ataxia, confirming the strong correlate between LAMA1 variants and PBS. PMID:26932191

  20. The Use of a Trained Dog as a Gait Aid for Clients with Ataxia: A Case Report

    PubMed Central

    Janelle, Caroline; Vocos, Maria

    2014-01-01

    ABSTRACT Purpose: To illustrate the use of a trained dog as a therapeutic tool to optimize physical and psychosocial adaptation of clients with ataxia. Method: The gait pattern and gait speed of two people with cerebellar ataxia using different gait aids, including a trained intervention dog and an assistance dog, were compared. Participants' experience of working with the dogs was documented via semi-structured interviews. Results: The use of an intervention dog as part of rehabilitation allowed clients to explore the benefits of an assistance dog and to optimize their physical functioning. The assistance dog had a less destabilizing effect than other walking aids on the clients' self-image. Conclusion: Trained dogs may represent an innovative and positive alternative for mobility for people with ataxia, improving both physical and psychosocial parameters. Assistance dogs seem to be a suitable gait aid, since they facilitate ambulation, promoting independent mobility. PMID:24719506

  1. More Than Ataxia: Hyperkinetic Movement Disorders in Childhood Autosomal Recessive Ataxia Syndromes

    PubMed Central

    Pearson, Toni S.

    2016-01-01

    Background The autosomal recessive ataxias are a heterogeneous group of disorders that are characterized by complex neurological features in addition to progressive ataxia. Hyperkinetic movement disorders occur in a significant proportion of patients, and may sometimes be the presenting motor symptom. Presentations with involuntary movements rather than ataxia are diagnostically challenging, and are likely under-recognized. Methods A PubMed literature search was performed in October 2015 utilizing pairwise combinations of disease-related terms (autosomal recessive ataxia, ataxia–telangiectasia, ataxia with oculomotor apraxia type 1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2), Friedreich ataxia, ataxia with vitamin E deficiency), and symptom-related terms (movement disorder, dystonia, chorea, choreoathetosis, myoclonus). Results Involuntary movements occur in the majority of patients with ataxia–telangiectasia and AOA1, and less frequently in patients with AOA2, Friedreich ataxia, and ataxia with vitamin E deficiency. Clinical presentations with an isolated hyperkinetic movement disorder in the absence of ataxia include dystonia or dystonia with myoclonus with predominant upper limb and cervical involvement (ataxia–telangiectasia, ataxia with vitamin E deficiency), and generalized chorea (ataxia with oculomotor apraxia type 1, ataxia-telangiectasia). Discussion An awareness of atypical presentations facilitates early and accurate diagnosis in these challenging cases. Recognition of involuntary movements is important not only for diagnosis, but also because of the potential for effective targeted symptomatic treatment. PMID:27536460

  2. Kv3.3 potassium channels and spinocerebellar ataxia.

    PubMed

    Zhang, Yalan; Kaczmarek, Leonard K

    2016-08-15

    The voltage-dependent potassium channel subunit Kv3.3 is expressed at high levels in cerebellar Purkinje cells, in auditory brainstem nuclei and in many other neurons capable of firing at high rates. In the cerebellum, it helps to shape the very characteristic complex spike of Purkinje cells. Kv3.3 differs from other closely related channels in that human mutations in the gene encoding Kv3.3 (KCNC3) result in a unique neurodegenerative disease termed spinocerebellar ataxia type 13 (SCA13). This primarily affects the cerebellum, but also results in extracerebellar symptoms. Different mutations produce either early onset SCA13, associated with delayed motor and impaired cognitive skill acquisition, or late onset SCA13, which typically produces cerebellar degeneration in middle age. This review covers the localization and physiological function of Kv3.3 in the central nervous system and how the normal function of the channel is altered by the disease-causing mutations. It also describes experimental approaches that are being used to understand how Kv3.3 mutations are linked to neuronal survival, and to develop strategies for treatment. PMID:26442672

  3. Ataxia and Hypogonadotropic Hypogonadism with Intrafamilial Variability Caused by RNF216 Mutation

    PubMed Central

    Alqwaifly, Mohammed; Bohlega, Saeed

    2016-01-01

    Gordon Holmes syndrome (GHS) is a distinct phenotype of autosomal recessive cerebellar ataxia, characterized by ataxia, dementia, reproductive defects and hypogonadism; it has been recently found to be associated with RNF216 mutation. We performed whole-exome sequencing and filtered the resulting novel variants by the coordinates of the shared autozygome. We identified a novel splicing variant in RNF216 that is likely to abolish the canonical splice site at the junction of exon/intron 13 (NM_207111.3:c.2061G>A). We herein report two patients with GHS caused by a novel RNF216 mutation as the first follow up report on RNF216-related GHS, and show interfamilial variability of phenotype supporting the previously reported RNF216-related cases. PMID:27441066

  4. Ataxia and Hypogonadotropic Hypogonadism with Intrafamilial Variability Caused by RNF216 Mutation.

    PubMed

    Alqwaifly, Mohammed; Bohlega, Saeed

    2016-06-15

    Gordon Holmes syndrome (GHS) is a distinct phenotype of autosomal recessive cerebellar ataxia, characterized by ataxia, dementia, reproductive defects and hypogonadism; it has been recently found to be associated with RNF216 mutation. We performed whole-exome sequencing and filtered the resulting novel variants by the coordinates of the shared autozygome. We identified a novel splicing variant in RNF216 that is likely to abolish the canonical splice site at the junction of exon/intron 13 (NM_207111.3:c.2061G>A). We herein report two patients with GHS caused by a novel RNF216 mutation as the first follow up report on RNF216-related GHS, and show interfamilial variability of phenotype supporting the previously reported RNF216-related cases. PMID:27441066

  5. Balance control in sitting and standing in children and young adults with benign cerebellar tumors.

    PubMed

    Schoch, Beate; Hogan, Aidan; Gizewski, Elke R; Timmann, Dagmar; Konczak, Juergen

    2010-09-01

    Children and young adolescents with chronic surgical cerebellar lesions show persistent balance control problems during standing when lesions affect the deep cerebellar fastigial and adjacent interposed nuclei. The purpose of this study is to confirm that the same lesion sites are also associated with permanent signs of trunkal ataxia during sitting. A second aim is to demonstrate that examining the postural control of patients while sitting or standing on a foam cushion may constitute a simple clinical exam yielding results commensurate to a more involved dynamic posturography exam. Balance control was assessed in 16 patients after surgery of a benign cerebellar tumor in chronic state and healthy age- and gender-matched control subjects. Using an ultrasound-based kinematic recording system, trunkal and shoulder sway was measured during sitting and standing in different conditions. High-resolution MRI scans were acquired in the cerebellar patients. Voxel-wise statistical lesion symptom mapping was performed to compare lesioned areas between affected and unaffected patients in a given condition using χ² tests. During sitting, 56% of cerebellar patients exhibited trunkal sway outside the range of healthy controls, and 87.5% of cerebellar patients revealed abnormal sway patterns during standing. Abnormalities were most pronounced when visual information was absent, and somatosensory information became unreliable and/or when the base of support along the medio-lateral axis was minimized during tandem stance. Lesion symptom mapping revealed that pathological values in the behavior data were more likely in patients with surgical lesions involving the fastigial nuclei (NF) and adjacent interposed nuclei (NI). In patients with surgery <1-year lesions of the inferior cerebellar vermis also had an impact on balance function. Our results corroborate previous evidence that the extent of permanent damage to the deep cerebellar nuclei greatly impacts on the recovery on balance

  6. Supratentorial and infratentorial damage in spinocerebellar ataxia 2: a diffusion-weighted MRI study.

    PubMed

    Salvatore, Elena; Tedeschi, Enrico; Mollica, Carmine; Vicidomini, Caterina; Varrone, Andrea; Coda, Anna Rita Daniela; Brunetti, Arturo; Salvatore, Marco; De Michele, Giuseppe; Filla, Alessandro; Pappatà, Sabina

    2014-05-01

    Spinocerebellar ataxia type 2 (SCA2) is an autosomal-dominant degenerative disorder that is neuropathologically characterized primarily by infratentorial damage, although less severe supratentorial involvement may contribute to the clinical manifestation. Diffusion-weighted imaging (DWI)-Magnetic Resonance Imaging (MRI) studies of SCA2 have enabled in vivo quantification of neurodegeneration in infratentorial regions, whereas supratentorial regions have been explored less thoroughly. We measured microstructural changes in both infratentorial and supratentorial regions in 13 SCA2 patients (9 men, 4 women; mean age, 50 ± 12 years) and 15 controls (10 men, 5 women; mean age, 49 ± 14 years) using DWI-MRI and correlated the DWI changes with disease severity and duration. Disease severity was evaluated using the International Cooperative Ataxia Rating Scale and the Inherited Ataxia Clinical Rating Scale. Cerebral diffusion trace ( D¯) values were generated, and regions of interest (ROIs) and voxel-based analysis with Statistical Parametric Mapping (SPM) were used for data analysis. In SCA2 patients, ROI analysis and SPM confirmed significant increases in D¯ values in the pons, cerebellar white matter (CWM) and middle cerebellar peduncles. Moreover, SPM analysis revealed increased D¯ values in the right thalamus, bilateral temporal cortex/white matter, and motor cortex/pyramidal tract regions. Increased diffusivity in the frontal white matter (FWM) and the CWM was significantly correlated with ataxia severity. DWI-MRI revealed that both infratentorial and supratentorial microstructural changes may characterize SCA2 patients in the course of the disease and might contribute to the severity of the symptoms. PMID:24375449

  7. Gait and Functional Mobility Deficits in Fragile X-Associated Tremor/Ataxia Syndrome.

    PubMed

    O'Keefe, Joan A; Robertson-Dick, Erin E; Hall, Deborah A; Berry-Kravis, Elizabeth

    2016-08-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) results from a "premutation" (PM) size CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Cerebellar gait ataxia is the primary feature in some FXTAS patients causing progressive disability. However, no studies have quantitatively characterized gait and mobility deficits in FXTAS. We performed quantitative gait and mobility analysis in seven FMR1 PM carriers with FXTAS and ataxia, six PM carriers without FXTAS, and 18 age-matched controls. We studied four independent gait domains, trunk range of motion (ROM), and movement transitions using an instrumented Timed Up and Go (i-TUG). We correlated these outcome measures with FMR1 molecular variables and clinical severity scales. PM carriers with FXTAS were globally impaired in every gait performance domain except trunk ROM compared to controls. These included total i-TUG duration, stride velocity, gait cycle time, cadence, double-limb support and swing phase times, turn duration, step time before turn, and turn-to-sit duration, and increased gait variability on several measures. Carriers without FXTAS did not differ from controls on any parameters, but double-limb support time was close to significance. Balance and disability scales correlated with multiple gait and movement transition parameters, while the FXTAS Rating Scale did not. This is the first study to quantitatively examine gait and movement transitions in FXTAS patients. Gait characteristics were consistent with those from previous cohorts with cerebellar ataxia. Sensitive measures like the i-TUG may help determine efficacy of interventions, characterize disease progression, and provide early markers of disease in FXTAS. PMID:26298472

  8. [Cerebellar cognitive affective syndrome secondary to a cerebellar tumour].

    PubMed

    Domínguez-Carral, J; Carreras-Sáez, I; García-Peñas, J J; Fournier-Del Castillo, C; Villalobos-Reales, J

    2015-01-01

    Cerebellar cognitive affective syndrome is characterized by disturbances of executive function, impaired spatial cognition, linguistic difficulties, and personality change. The case of an 11 year old boy is presented, with behavior problems, learning difficulties and social interaction problems. In the physical examination he had poor visual contact, immature behavior, reduced expressive language and global motor disability with gait dyspraxia, with no defined cerebellar motor signs. In the neuropsychological evaluation he has a full scale overall intellectual quotient of 84, with signs of cerebellar cognitive affective syndrome. A tumour affecting inferior cerebellar vermis was observed in the magnetic resonance imaging, which had not significantly grown during 5 years of follow up. The cerebellum participates in controlling cognitive and affective functions. Cerebellar pathology must be considered in the differential diagnosis of children with cognitive or learning disorder with associated behavioral and emotional components. PMID:24954915

  9. Cerebellar hypoplasia of genetic origin in calves.

    PubMed

    O'Sullivan, B M; McPhee, C P

    1975-10-01

    Within 2 years, following the introduction of 2 Shorthorn bulls from the same stud into an Australian Illawarra Shorthorn (AIS) herd, 16 calves were born with cerebellar hypoplasia. All affected calves were the progeny of one bull mated to the daughters of the other. All other progeny of these bulls, most of which were from AIS dams, were normal. Affected calves exhibited severe ataxia, consistent head movement and abduction of the forelimbs. Microscopic changes in the cerebellum included sparsity of cells of the granular layer, loss of Purkinje cells and narrowing of the molecular layer. Observations on the frequencies of normal and abnormal calves are consistent with the hypothesis that the condition is caused by an autosomal recessive gene for which affected calves were homozygous and which was introduced into the herd in heterozygous condition by both of the Shorthorn bulls. Evidence is given for an unusually high frequency of the gene in the stud of origin of the Shorthorn bulls and a procedure for reducing its frequency is outlined. The possibility of a viral or toxic aetiology is discussed but is considered to be an unlikely explanation for the condition in this herd. PMID:1200928

  10. Effects of 4-aminopyridine on nystagmus and vestibulo-ocular reflex in ataxia-telangiectasia.

    PubMed

    Shaikh, Aasef G; Marti, Sarah; Tarnutzer, Alexander A; Palla, Antonella; Crawford, Thomas O; Zee, David S; Straumann, Dominik

    2013-11-01

    Ataxia-telangiectasia (A-T) is a progressive neurodegenerative disorder with prominent eye movement deficits localizing to the cerebellum. We sought to determine if 4-aminopyridine (4-AP), which putatively enhances the precision of Purkinje neurons, could improve the disorders of eye movements and vestibular function in A-T. The influence of 4-AP on disorders of eye movements and vestibular function was studied in four A-T patients. The effects on the cerebellar control of vestibulo-ocular reflex (VOR) was quantitatively assessed by the decay time constant of per- and post-rotational nystagmus during constant velocity en bloc rotations. The length of the VOR time constant determines the fidelity of the vestibular velocity storage, a neural mechanism that increases the bandwidth of VOR under cerebellar control. The VOR time constant was not increased in A-T patients. The latter is explained by the extent of cerebellar lesion as previously described in A-T and other cerebellar disorders. Nevertheless, 4-AP shortened the VOR time constant during horizontal rotations. Severe disinhibition of velocity storage in subjects with putatively profound cerebellar degeneration manifest periodic alternating nystagmus (PAN). Among two A-T subjects who manifested PAN, 4-AP reduced the peak slow phase velocity of the more severely affected individual and abrogated the PAN in the other. Two A-T subjects manifested horizontal and vertical spontaneous nystagmus (SN) in primary gaze, 4-AP reduced its slow phase velocity. We conclude that in subjects with A-T 4-AP has a prominent effect on the ocular motor and vestibular deficits that are ascribed to the loss of cerebellar Purkinje neurons. PMID:23884713

  11. Extensive White Matter Alterations and Its Correlations with Ataxia Severity in SCA 2 Patients

    PubMed Central

    Hernandez-Castillo, Carlos R.; Galvez, Victor; Mercadillo, Roberto; Diaz, Rosalinda; Campos-Romo, Aurelio; Fernandez-Ruiz, Juan

    2015-01-01

    Background Previous studies of SCA2 have revealed significant degeneration of white matter tracts in cerebellar and cerebral regions. The motor deficit in these patients may be attributable to the degradation of projection fibers associated with the underlying neurodegenerative process. However, this relationship remains unclear. Statistical analysis of diffusion tensor imaging enables an unbiased whole-brain quantitative comparison of the diffusion proprieties of white matter tracts in vivo. Methods Fourteen genetically confirmed SCA2 patients and aged-matched healthy controls participated in the study. Tract-based spatial statistics were performed to analyze structural white matter damage using two different measurements: fractional anisotropy (FA) and mean diffusivity (MD). Significant diffusion differences were correlated with the patient's ataxia impairment. Results Our analysis revealed decreased FA mainly in the inferior/middle/superior cerebellar peduncles, the bilateral posterior limb of the internal capsule and the bilateral superior corona radiata. Increases in MD were found mainly in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Clinical impairment measured with the SARA score correlated with FA in superior parietal white matter and bilateral anterior corona radiata. Correlations with MD were found in cerebellar white matter and the middle cerebellar peduncle. Conclusion Our findings show significant correlations between diffusion measurements in key areas affected in SCA2 and measures of motor impairment, suggesting a disruption of information flow between motor and sensory-integration areas. These findings result in a more comprehensive view of the clinical impact of the white matter degeneration in SCA2. PMID:26263162

  12. Genetics Home Reference: X-linked sideroblastic anemia and ataxia

    MedlinePlus

    ... linked sideroblastic anemia and ataxia X-linked sideroblastic anemia and ataxia Enable Javascript to view the expand/ ... Open All Close All Description X-linked sideroblastic anemia and ataxia is a rare condition characterized by ...

  13. Genetics Home Reference: dilated cardiomyopathy with ataxia syndrome

    MedlinePlus

    ... dilated cardiomyopathy with ataxia syndrome dilated cardiomyopathy with ataxia syndrome Enable Javascript to view the expand/collapse ... Open All Close All Description Dilated cardiomyopathy with ataxia (DCMA) syndrome is an inherited condition characterized by ...

  14. Direct transcranial puncture for Onyx embolization of a cerebellar hemangioblastoma.

    PubMed

    Ding, Dale; Starke, Robert M; Evans, Avery J; Liu, Kenneth C

    2014-06-01

    Intracranial hemangioblastomas are benign but hypervascular tumors, most commonly located in the cerebellum, which are difficult to resect without significant operative blood loss. While preoperative embolization may decrease the amount of operative bleeding, the vascular supply of cerebellar hemangioblastomas frequently precludes safe embolization by an endovascular route due to the risk of thromboembolic vertebrobasilar infarction. Direct puncture embolization overcomes many of the limitations of endovascular embolization but its safety and feasibility for intracranial tumors is unknown. We report a 48-year-old man who was diagnosed with a large cerebellar mass after presenting with headaches and gait ataxia. Based on diagnostic angiography, which demonstrated a highly vascular tumor supplied by the posterior inferior cerebellar and posterior meningeal arteries, we decided to embolize the tumor by a direct transcranial puncture approach. After trephinating the skull in a standard fashion, a catheter-needle construct, composed of an Echelon 10 microcatheter (ev3 Endovascular, Plymouth, MN, USA) placed into a 21-gauge spinal needle, was inserted into the tumor under biplanar angiographic guidance. Using continuous angiographic monitoring, 9cc of Onyx 34 (ev3 Endovascular) was injected through the catheter, resulting in 75% tumor devascularization without evidence of complications. The patient was taken directly to surgery where a gross total resection of the hemangioblastoma was achieved with an acceptable operative blood loss. At his 2 year follow-up, the patient was neurologically intact without neuroimaging evidence of residual tumor. We describe, to our knowledge, the first case of direct transcranial puncture for preoperative embolization of a cerebellar hemangioblastoma. PMID:24370504

  15. Episodic ataxia type 2 manifests as epileptiform electroencephalographic activity with no epileptic attacks in two family members.

    PubMed

    Kaido, Misako; Furuta, Mitsuru; Nakamori, Masayuki; Yuasa, Yoshihito; Takahashi, Masanori P

    2016-04-28

    Here, we report two cases of episodic ataxia type 2 (EA2) in a 63-year-old woman and her 36-year-old daughter. The mother experienced recurrent attacks of cerebellar dysfunction lasting 4 to 5 hours since the age of 41 years. On several occasions, she was admitted to the emergency room, where she was diagnosed with epilepsy or stroke. Based on these diagnoses, she was treated with antiepileptic or anticoagulant drugs, but both treatments were eventually discontinued. The frequency of the attacks increased after the patient reached the age of 62. Interictal neurological examination demonstrated signs of slight cerebellar ataxia, i.e. saccadic eye movements, gaze-directed nystagmus, and mild truncal ataxia. Brain magnetic resonance imaging (MRI) showed cerebellar vermis atrophy. Electroencephalography (EEG) revealed various spike and wave patterns: solitary spikes, spike-and-slow wave complexes, and slow wave bursts. Photoparoxysmal response (PPR) type 3 was also observed. Treatment with acetazolamide abolished the patient's attacks almost completely. The daughter started experiencing 5- to 10-minute ataxic episodes at the age of 16 years. Based on her epileptiform EEG activities with PPR (type 2), antiepileptic drugs (valproate and zonisamide) were prescribed. Despite pharmacological treatment, the attacks recurred; however, their frequency gradually decreased with time, until they almost entirely disappeared when the patient was 33. Unfortunately, migraine-like headaches arose instead. Subtle truncal ataxia was observed during interictal periods. Sanger sequencing of the exons of the CACNA1A gene revealed a novel single base deletion (c.3575delA) in both patients. Despite the difference in age of onset and clinical course, both patients showed clearly epileptiform EEG activities without experiencing the concurrent epileptic episodes. Thus, EA2 is a disease that may be misdiagnosed as epilepsy or stroke in the field of emergency medicine. PMID:27025991

  16. Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways.

    PubMed

    Ingram, Melissa; Wozniak, Emily A L; Duvick, Lisa; Yang, Rendong; Bergmann, Paul; Carson, Robert; O'Callaghan, Brennon; Zoghbi, Huda Y; Henzler, Christine; Orr, Harry T

    2016-03-16

    SCA1, a fatal neurodegenerative disorder, is caused by a CAG expansion encoding a polyglutamine stretch in the protein ATXN1. We used RNA sequencing to profile cerebellar gene expression in Pcp2-ATXN1[82Q] mice with ataxia and progressive pathology and Pcp2-ATXN1[30Q]D776 animals having ataxia in absence of Purkinje cell progressive pathology. Weighted Gene Coexpression Network Analysis of the cerebellar expression data revealed two gene networks that significantly correlated with disease and have an expression profile correlating with disease progression in ATXN1[82Q] Purkinje cells. The Magenta Module provides a signature of suppressed transcriptional programs reflecting disease progression in Purkinje cells, while the Lt Yellow Module reflects transcriptional programs activated in response to disease in Purkinje cells as well as other cerebellar cell types. Furthermore, we found that upregulation of cholecystokinin (Cck) and subsequent interaction with the Cck1 receptor likely underlies the lack of progressive Purkinje cell pathology in Pcp2-ATXN1[30Q]D776 mice. PMID:26948890

  17. A rare saccade velocity profile in Stiff-Person Syndrome with cerebellar degeneration.

    PubMed

    Zivotofsky, Ari Z; Siman-Tov, Tali; Gadoth, Natan; Gordon, Carlos R

    2006-06-01

    Stiff-Person Syndrome (SPS) is an immune-mediated disorder of the central nervous system characterized by muscle rigidity, episodic muscle spasms, and high titers of antibodies against glutamic acid decarboxylase (GAD). The presence of cerebellar ataxia in SPS is extremely rare, but occurs. Clinical observations of ocular motor abnormalities have been noted in a few SPS patients. The purpose of this study is to provide a detailed quantitative documentation of ocular motor abnormalities in a patient with SPS and progressive cerebellar signs. Detailed clinical assessment of a woman with SPS and precise eye movement recordings using the magnetic search coil technique was performed. In addition to other ocular motor abnormalities that included longer latencies for saccades, downbeat nystagmus, and loss of downward smooth pursuit, a rare saccade velocity profile consisting of multi-component saccades was observed. We postulate that these ocular motor findings are related to impairment of GABAergic neurotransmission because antibodies to glutamic acid decarboxylase (GAD-Abs) have been implicated in the pathogenesis of both SPS and some cases of cerebellar ataxia. In addition, this unusual saccadic velocity profile may have important implications for modeling the saccadic system and furthering a complete understanding of saccade generation. PMID:16725126

  18. BK Channels Control Cerebellar Purkinje and Golgi Cell Rhythmicity In Vivo

    PubMed Central

    Cheron, Guy; Sausbier, Matthias; Sausbier, Ulrike; Neuhuber, Winfried; Ruth, Peter; Dan, Bernard; Servais, Laurent

    2009-01-01

    Calcium signaling plays a central role in normal CNS functioning and dysfunction. As cerebellar Purkinje cells express the major regulatory elements of calcium control and represent the sole integrative output of the cerebellar cortex, changes in neural activity- and calcium-mediated membrane properties of these cells are expected to provide important insights into both intrinsic and network physiology of the cerebellum. We studied the electrophysiological behavior of Purkinje cells in genetically engineered alert mice that do not express BK calcium-activated potassium channels and in wild-type mice with pharmacological BK inactivation. We confirmed BK expression in Purkinje cells and also demonstrated it in Golgi cells. We demonstrated that either genetic or pharmacological BK inactivation leads to ataxia and to the emergence of a beta oscillatory field potential in the cerebellar cortex. This oscillation is correlated with enhanced rhythmicity and synchronicity of both Purkinje and Golgi cells. We hypothesize that the temporal coding modification of the spike firing of both Purkinje and Golgi cells leads to the pharmacologically or genetically induced ataxia. PMID:19956720

  19. Modulation of error-sensitivity during a prism adaptation task in people with cerebellar degeneration.

    PubMed

    Hanajima, Ritsuko; Shadmehr, Reza; Ohminami, Shinya; Tsutsumi, Ryosuke; Shirota, Yuichiro; Shimizu, Takahiro; Tanaka, Nobuyuki; Terao, Yasuo; Tsuji, Shoji; Ugawa, Yoshikazu; Uchimura, Motoaki; Inoue, Masato; Kitazawa, Shigeru

    2015-10-01

    Cerebellar damage can profoundly impair human motor adaptation. For example, if reaching movements are perturbed abruptly, cerebellar damage impairs the ability to learn from the perturbation-induced errors. Interestingly, if the perturbation is imposed gradually over many trials, people with cerebellar damage may exhibit improved adaptation. However, this result is controversial, since the differential effects of gradual vs. abrupt protocols have not been observed in all studies. To examine this question, we recruited patients with pure cerebellar ataxia due to cerebellar cortical atrophy (n = 13) and asked them to reach to a target while viewing the scene through wedge prisms. The prisms were computer controlled, making it possible to impose the full perturbation abruptly in one trial, or build up the perturbation gradually over many trials. To control visual feedback, we employed shutter glasses that removed visual feedback during the reach, allowing us to measure trial-by-trial learning from error (termed error-sensitivity), and trial-by-trial decay of motor memory (termed forgetting). We found that the patients benefited significantly from the gradual protocol, improving their performance with respect to the abrupt protocol by exhibiting smaller errors during the exposure block, and producing larger aftereffects during the postexposure block. Trial-by-trial analysis suggested that this improvement was due to increased error-sensitivity in the gradual protocol. Therefore, cerebellar patients exhibited an improved ability to learn from error if they experienced those errors gradually. This improvement coincided with increased error-sensitivity and was present in both groups of subjects, suggesting that control of error-sensitivity may be spared despite cerebellar damage. PMID:26311179

  20. Middle cerebellar peduncles: Magnetic resonance imaging and pathophysiologic correlate

    PubMed Central

    Morales, Humberto; Tomsick, Thomas

    2015-01-01

    We describe common and less common diseases that can cause magnetic resonance signal abnormalities of middle cerebellar peduncles (MCP), offering a systematic approach correlating imaging findings with clinical clues and pathologic mechanisms. Myelin abnormalities, different types of edema or neurodegenerative processes, can cause areas of abnormal T2 signal, variable enhancement, and patterns of diffusivity of MCP. Pathologies such as demyelinating disorders or certain neurodegenerative entities (e.g., multiple system atrophy or fragile X-associated tremor-ataxia syndrome) appear to have predilection for MCP. Careful evaluation of concomitant imaging findings in the brain or brainstem; and focused correlation with key clinical findings such as immunosuppression for progressive multifocal leukoencephalopahty; hypertension, post-transplant status or high dose chemotherapy for posterior reversible encephalopathy; electrolyte disorders for myelinolysis or suspected toxic-drug related encephalopathy; would yield an appropriate and accurate differential diagnosis in the majority of cases. PMID:26751508

  1. Lipids and lipoproteins in Friedreich's ataxia.

    PubMed Central

    Walker, J L; Chamberlain, S; Robinson, N

    1980-01-01

    Friedreich's ataxia is an autosomal recessively inherited disease affecting the nervous system with a high incidence of heart involvement. Abnormalities of lipid metabolism are known to be associated with several progressive ataxic conditions. In this study of 46 Friedreich's ataxia patients, serum lipids, fatty acids and lipoproteins were assayed and compared with some earlier findings on Friedreich's ataxia and related disorders. Abnormalities of low and high density lipoproteins suggestive of a major defect have been reported; in the present study the level and chemical composition of high density lipoprotein has been assessed in 20 Friedreich's ataxia patients but previous abnormalities could not be substantiated. Lipid compositional analysis of Friedreich's ataxia central nervous tissue and heart, which has not been previously reported, did not markedly differ from control tissue. PMID:7359148

  2. Fragile X-associated tremor/ataxia syndrome - features, mechanisms and management.

    PubMed

    Hagerman, Randi J; Hagerman, Paul

    2016-07-01

    Many physicians are unaware of the many phenotypes associated with the fragile X premutation, an expansion in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene that consists of 55-200 CGG repeats. The most severe of these phenotypes is fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in the majority of ageing male premutation carriers but in fewer than 20% of ageing women with the premutation. The prevalence of the premutation is 1 in 150-300 females, and 1 in 400-850 males, so physicians are likely to see people affected by FXTAS. Fragile X DNA testing is broadly available in the Western world. The clinical phenotype of FXTAS at presentation can vary and includes intention tremor, cerebellar ataxia, neuropathic pain, memory and/or executive function deficits, parkinsonian features, and psychological disorders, such as depression, anxiety and/or apathy. FXTAS causes brain atrophy and white matter disease, usually in the middle cerebellar peduncles, the periventricular area, and the splenium and/or genu of the corpus callosum. Here, we review the complexities involved in the clinical management of FXTAS and consider how targeted treatment for these clinical features of FXTAS will result from advances in our understanding of the molecular mechanisms that underlie this neurodegenerative disorder. Such targeted approaches should also be more broadly applicable to earlier forms of clinical involvement among premutation carriers. PMID:27340021

  3. Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia.

    PubMed

    Renaud, Mathilde; Guissart, Claire; Mallaret, Martial; Ferdinandusse, Sacha; Cheillan, David; Drouot, Nathalie; Muller, Jean; Claustres, Mireille; Tranchant, Christine; Anheim, Mathieu; Koenig, Michel

    2016-08-01

    Peroxisomal biogenesis disorders (PBDs) consist of a heterogeneous group of autosomal recessive diseases, in which peroxisome assembly and proliferation are impaired leading to severe multisystem disease and early death. PBDs include Zellweger spectrum disorders (ZSDs) with a relatively mild clinical phenotype caused by PEX1, (MIM# 602136), PEX2 (MIM# 170993), PEX6 (MIM# 601498), PEX10 (MIM# 602859), PEX12 (MIM# 601758), and PEX16 (MIM# 603360) mutations. Three adult patients are reported belonging to a non-consanguineous French family affected with slowly progressive cerebellar ataxia, axonal neuropathy, and pyramidal signs. Mental retardation and diabetes mellitus were optional. The age at onset was in childhood or in adolescence (3-15 years). Brain MRI showed marked cerebellar atrophy. Biochemical blood analyses suggested a mild peroxisomal defect. With whole exome sequencing, two mutations in PEX10 were found in the three patients: c.827G>T (novel) causing the missense change p.Cys276Phe and c.932G>A causing the missense change p.Arg311Gln. The phenotypic spectrum related to PEX10 mutations includes slowly progressive, syndromic recessive ataxia. PMID:27230853

  4. Change in the Cortical Complexity of Spinocerebellar Ataxia Type 3 Appears Earlier than Clinical Symptoms

    PubMed Central

    Soong, Bing-Wen; Wu, Hsiu-Mei; Shyu, Kuo-Kai; Wang, Po-Shan; Wu, Yu-Te

    2015-01-01

    Patients with spinocerebellar ataxia type 3 (SCA3) have exhibited cerebral cortical involvement and various mental deficits in previous studies. Clinically, conventional measurements, such as the Mini-Mental State Examination (MMSE) and electroencephalography (EEG), are insensitive to cerebral cortical involvement and mental deficits associated with SCA3, particularly at the early stage of the disease. We applied a three-dimensional fractal dimension (3D-FD) method, which can be used to quantify the shape complexity of cortical folding, in assessing cortical degeneration. We evaluated 48 genetically confirmed SCA3 patients by employing clinical scales and magnetic resonance imaging and using 50 healthy participants as a control group. According to the Scale for the Assessment and Rating of Ataxia (SARA), the SCA3 patients were diagnosed with cortical dysfunction in the cerebellar cortex; however, no significant difference in the cerebral cortex was observed according to the patients’ MMSE ratings. Using the 3D-FD method, we determined that cortical involvement was more extensive than involvement of traditional olivopontocerebellar regions and the corticocerebellar system. Moreover, the significant correlation between decreased 3D-FD values and disease duration may indicate atrophy of the cerebellar cortex and cerebral cortex in SCA3 patients. The change of the cerebral complexity in the SCA3 patients can be detected throughout the disease duration, especially it becomes substantial at the late stage of the disease. Furthermore, we determined that atrophy of the cerebral cortex may occur earlier than changes in MMSE scores and EEG signals. PMID:25897782

  5. Intracellular FGF14 (iFGF14) Is Required for Spontaneous and Evoked Firing in Cerebellar Purkinje Neurons and for Motor Coordination and Balance.

    PubMed

    Bosch, Marie K; Carrasquillo, Yarimar; Ransdell, Joseph L; Kanakamedala, Ajay; Ornitz, David M; Nerbonne, Jeanne M

    2015-04-29

    Mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia (SCA27). In addition, mice lacking Fgf14 (Fgf14(-/-)) exhibit an ataxia phenotype resembling SCA27, accompanied by marked changes in the excitability of cerebellar granule and Purkinje neurons. It is not known, however, whether these phenotypes result from defects in neuronal development or if they reflect a physiological requirement for iFGF14 in the adult cerebellum. Here, we demonstrate that the acute and selective Fgf14-targeted short hairpin RNA (shRNA)-mediated in vivo "knock-down" of iFGF14 in adult Purkinje neurons attenuates spontaneous and evoked action potential firing without measurably affecting the expression or localization of voltage-gated Na(+) (Nav) channels at Purkinje neuron axon initial segments. The selective shRNA-mediated in vivo "knock-down" of iFGF14 in adult Purkinje neurons also impairs motor coordination and balance. Repetitive firing can be restored in Fgf14-targeted shRNA-expressing Purkinje neurons, as well as in Fgf14(-/-) Purkinje neurons, by prior membrane hyperpolarization, suggesting that the iFGF14-mediated regulation of the excitability of mature Purkinje neurons depends on membrane potential. Further experiments revealed that the loss of iFGF14 results in a marked hyperpolarizing shift in the voltage dependence of steady-state inactivation of the Nav currents in adult Purkinje neurons. We also show here that expressing iFGF14 selectively in adult Fgf14(-/-) Purkinje neurons rescues spontaneous firing and improves motor performance. Together, these results demonstrate that iFGF14 is required for spontaneous and evoked action potential firing in adult Purkinje neurons, thereby controlling the output of these cells and the regulation of motor coordination and balance. PMID:25926453

  6. CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.

    PubMed

    Damaj, Lena; Lupien-Meilleur, Alexis; Lortie, Anne; Riou, Émilie; Ospina, Luis H; Gagnon, Louise; Vanasse, Catherine; Rossignol, Elsa

    2015-11-01

    CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks. PMID:25735478

  7. Clinical analysis of adult-onset spinocerebellar ataxias in Thailand

    PubMed Central

    2014-01-01

    Background Non-ataxic symptoms of spinocerebellar ataxias (SCAs) vary widely and often overlap with various types of SCAs. Duration and severity of the disease and genetic background may play a role in such phenotypic diversity. We conducted the study in order to study clinical characteristics of common SCAs in Thailand and the factors that may influence their phenotypes. Methods 131 (49.43%) out of 265 Thai ataxia families with cerebellar degeneration had positive tests for SCA1, SCA2, Machado-Joseph disease (MJD) or SCA6. The study evaluated 83 available families including SCA1 (21 patients), SCA2 (15), MJD (39) and SCA6 (8). Comparisons of frequency of each non-ataxic sign among different SCA subtypes were analysed. Multivariate logistic regression analyses were undertaken to analyze parameters in association with disease severity and size of CAG repeat. Results Mean ages at onset were not different among patients with different SCAs (40.31 ± 11.33 years, mean ± SD). Surprisingly, SCA6 patients often had age at onset and phenotypes indistinguishable from SCA1, SCA2 and MJD. Frequencies of ophthalmoparesis, nystagmus, hyperreflexia and areflexia were significantly different among the common SCAs, whilst frequency of slow saccade was not. In contrast to Caucasian patients, parkinsonism, dystonia, dementia, and facial fasciculation were uncommon in Thai patients. Multivariate logistic regression analysis demonstrated that ophthalmoparesis (p < 0.001) and sensory impairment (p = 0.025) were associated with the severity of the disease. Conclusions We described clinical characteristics of the 4 most common SCAs in Thailand accounting for almost 90% of familial spinocerebellar ataxias. There were some different observations compared to Caucasian patients including earlier age at onset of SCA6 and the paucity of extrapyramidal features, cognitive impairment and facial fasciculation. Severity of the disease, size of the pathological CAG repeat allele

  8. Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4.

    PubMed

    Bras, Jose; Alonso, Isabel; Barbot, Clara; Costa, Maria Manuela; Darwent, Lee; Orme, Tatiana; Sequeiros, Jorge; Hardy, John; Coutinho, Paula; Guerreiro, Rita

    2015-03-01

    Hereditary autosomal-recessive cerebellar ataxias are a genetically and clinically heterogeneous group of disorders. We used homozygosity mapping and exome sequencing to study a cohort of nine Portuguese families who were identified during a nationwide, population-based, systematic survey as displaying a consistent phenotype of recessive ataxia with oculomotor apraxia (AOA). The integration of data from these analyses led to the identification of the same homozygous PNKP (polynucleotide kinase 3'-phosphatase) mutation, c.1123G>T (p.Gly375Trp), in three of the studied families. When analyzing this particular gene in the exome sequencing data from the remaining cohort, we identified homozygous or compound-heterozygous mutations in five other families. PNKP is a dual-function enzyme with a key role in different pathways of DNA-damage repair. Mutations in this gene have previously been associated with an autosomal-recessive syndrome characterized by microcephaly; early-onset, intractable seizures; and developmental delay (MCSZ). The finding of PNKP mutations associated with recessive AOA extends the phenotype associated with this gene and identifies a fourth locus that causes AOA. These data confirm that MCSZ and some forms of ataxia share etiological features, most likely reflecting the role of PNKP in DNA-repair mechanisms. PMID:25728773

  9. Spinocerebellar ataxias in Venezuela: genetic epidemiology and their most likely ethnic descent.

    PubMed

    Paradisi, Irene; Ikonomu, Vassiliki; Arias, Sergio

    2016-03-01

    Dominantly inherited ataxias (spinocerebellar ataxias, SCAs) are a genetically heterogeneous group of neurologic diseases characterized by progressive cerebellar and spinal tract degeneration with ataxia and other signs, common to all known subtypes. Several types are relatively frequent worldwide, but in several countries, one specific SCA may show a higher prevalence owing to founder phenomena. In Venezuela, genetic epidemiological features of SCAs have been assessed during the last 30 years; mutations in ATXN1 (SCA1), ATXN2 (SCA2), ATXN3 (SCA3), CACNA1A (SCA6), ATXN7 (SCA7), ATXN8 (SCA8), ATXN10 (SCA10), TBP (SCA17) and ATN1 (dentatorubral pallidoluysian atrophy, DRPLA) loci were searched among 115 independent families. SCA7 was the most frequent subtype (26.6%), followed by SCA3 (25.0%), SCA2 (21.9%), SCA1 (17.2%), SCA10 (4.7%) and DRPLA (3.1%); in 43% of the families, the subtype remained unidentified. SCA7 mutations displayed strong geographic aggregation in two independent founder foci, and SCA1 showed a very remote founder effect for a subset of families. SCA10 families were scattered across the country, but all had an identical in-phase haplotype carried also by Mexican, Brazilian and Sioux patients, supporting a very old common Amerindian origin. Prevalence for dominant SCAs in Venezuela was estimated as 1:25 000 nuclear families, provenances of which are either Caucasoid, African or Amerindian. PMID:26538302

  10. Targeted disruption of Ataxia-telangiectasia mutated gene in miniature pigs by somatic cell nuclear transfer

    SciTech Connect

    Kim, Young June; Ahn, Kwang Sung; Kim, Minjeong; Kim, Min Ju; Park, Sang-Min; Ryu, Junghyun; Ahn, Jin Seop; Heo, Soon Young; Kang, Jee Hyun; Choi, You Jung; Choi, Seong-Jun; Shim, Hosup

    2014-10-03

    Highlights: • ATM gene-targeted pigs were produced by somatic cell nuclear transfer. • A novel large animal model for ataxia telangiectasia was developed. • The new model may provide an alternative to the mouse model. - Abstract: Ataxia telangiectasia (A-T) is a recessive autosomal disorder associated with pleiotropic phenotypes, including progressive cerebellar degeneration, gonad atrophy, and growth retardation. Even though A-T is known to be caused by the mutations in the Ataxia telangiectasia mutated (ATM) gene, the correlation between abnormal cellular physiology caused by ATM mutations and the multiple symptoms of A-T disease has not been clearly determined. None of the existing ATM mouse models properly reflects the extent to which neurological degeneration occurs in human. In an attempt to provide a large animal model for A-T, we produced gene-targeted pigs with mutations in the ATM gene by somatic cell nuclear transfer. The disrupted allele in the ATM gene of cloned piglets was confirmed via PCR and Southern blot analysis. The ATM gene-targeted pigs generated in the present study may provide an alternative to the current mouse model for the study of mechanisms underlying A-T disorder and for the development of new therapies.

  11. Abnormal N400 word repetition effects in fragile X-associated tremor/ataxia syndrome

    PubMed Central

    Chan, Shiaohui; Wong, Ling M.; Schneider, Andrea; Seritan, Andreea; Niese, Adam; Yang, Jin-Chen; Laird, Kelsey; Teichholtz, Sara; Khan, Sara; Tassone, Flora; Hagerman, Randi

    2010-01-01

    Fragile X-associated tremor/ataxia syndrome, a neurodegenerative disorder associated with premutation alleles (55–200 CGG repeats) of the FMR1 gene, affects many carriers in late-life. Patients with fragile X-associated tremor/ataxia syndrome typically have cerebellar ataxia, intranuclear inclusions in neurons and astrocytes, as well as cognitive impairment. Dementia can also be present with cognitive deficits that are as severe as in Alzheimer’s disease, however frontosubcortical type impairment is more pronounced in fragile X-associated tremor/ataxia syndrome. We sought to characterize the P600 and N400 word repetition effects in patients with fragile X-associated tremor/ataxia syndrome, using an event-related potential word repetition paradigm with demonstrated sensitivity to very early Alzheimer’s disease. We hypothesized that the fragile X-associated tremor/ataxia syndrome-affected participants with poor declarative verbal memory would have pronounced abnormalities in the P600 repetition effect. In the event-related potential experiment, subjects performed a category decision task whilst an electroencephalogram was recorded. Auditory category statements were each followed by an associated visual target word (50% ‘congruous’ category exemplars, 50% ‘incongruous’ nouns). Two-thirds of the stimuli (category statement–target word pairs) were repeated, either at short-lag (∼10–40 s) or long-lag (∼100–140 s). The N400 and P600 amplitude data were submitted to split-plot analyses of variance. These analyses of variance showed a highly significant reduction of the N400 repetition effect (F = 22.5, P < 0.001), but not of the P600 repetition effect, in mild fragile X-associated tremor/ataxia syndrome (n = 32, mean age = 68.7, mean Mini-Mental State Examination score = 26.8). Patients with fragile X-associated tremor/ataxia syndrome had significantly smaller late positive amplitude (550–800 ms post-stimulus onset) to congruous words (P = 0

  12. Cerebellar allocentric and action-intentional spatial neglect.

    PubMed

    Milano, Nicholas J; Heilman, Kenneth M

    2014-09-01

    Contralesional hemispatial neglect most often results from lesions in the right posterior temporoparietal cortex. Less commonly, contralesional and ipsilesional neglect are caused by lesions in the frontal lobe. Although unilateral left cerebellar lesions have been reported to cause body-centered (egocentric) ipsilesional neglect, they have not been reported to cause left-side object-centered (allocentric) neglect together with a leftward action-intentional bias. We describe a patient who had these signs of neglect 7 months after a left cerebellar hemorrhage. This 61-year-old right-handed woman reported emotional lability and difficulty walking, frequently bumping into things on her left side. Neurologic examination revealed ocular dysmetria and left-side limb ataxia. Neuropsychological tests showed evidence of neglect. On a clock-drawing test, the patient accurately drew a circle but her number placement deviated to the left side. She showed the same leftward deviation when she tried to draw a circle composed of small triangles. Although her line bisection was normal, on an allocentric task of open-triangle cancellation she was most likely to neglect triangles with a left-side opening. Her performance on this task indicated left allocentric neglect. Her leftward deviation on the clock and figure drawing tasks seems to be a form of an action-intentional grasp, which may have been induced by right frontal dysfunction superimposed on a deficit of global attention. PMID:25237748

  13. Motor pathway degeneration in young ataxia telangiectasia patients: A diffusion tractography study

    PubMed Central

    Sahama, Ishani; Sinclair, Kate; Fiori, Simona; Doecke, James; Pannek, Kerstin; Reid, Lee; Lavin, Martin; Rose, Stephen

    2015-01-01

    Background Our understanding of the effect of ataxia–telangiectasia mutated gene mutations on brain structure and function is limited. In this study, white matter motor pathway integrity was investigated in ataxia telangiectasia patients using diffusion MRI and probabilistic tractography. Methods Diffusion MRI were obtained from 12 patients (age range: 7–22 years, mean: 12 years) and 12 typically developing age matched participants (age range 8–23 years, mean: 13 years). White matter fiber tracking and whole tract statistical analyses were used to assess quantitative fractional anisotropy and mean diffusivity differences along the cortico-ponto-cerebellar, cerebellar-thalamo-cortical, somatosensory and lateral corticospinal tract length in patients using a linear mixed effects model. White matter tract streamline number and apparent fiber density in patient and control tracts were also assessed. Results Reduced fractional anisotropy along all analyzed patient tracts were observed (p < 0.001). Mean diffusivity was significantly elevated in anterior tract locations but was reduced within cerebellar peduncle regions of all patient tracts (p < 0.001). Reduced tract streamline number and tract volume in the left and right corticospinal and somatosensory tracts were observed in patients (p < 0.006). In addition, reduced apparent fiber density in the left and right corticospinal and right somatosensory tracts (p < 0.006) occurred in patients. Conclusions Whole tract analysis of the corticomotor, corticospinal and somatosensory pathways in ataxia telangiectasia showed significant white matter degeneration along the entire length of motor circuits, highlighting that ataxia–telangiectasia gene mutation impacts the cerebellum and multiple other motor circuits in young patients. PMID:26413479

  14. Paraneoplastic downbeat nystagmus associated with cerebellar hypermetabolism especially in the nodulus.

    PubMed

    Choi, Seo Young; Park, Seong-Ho; Kim, Hyo-Jung; Kim, Ji-Soo

    2014-08-15

    A 52-year-old man with vertigo and imbalance for two weeks showed spontaneous downbeat (DBN), horizontal gaze-evoked, and positional apogeotropic nystagmus along with severe limb and truncal ataxia. Gadolinium-enhanced brain MRI was normal, but whole body and brain 2-deoxy-2-[F18]fluoro-d-glucose-positron emission tomography revealed hypermetabolism in the right lower lobe of the lung and the cerebellum, especially in the nodulus. The lesion in the lung was confirmed as mixed cell carcinoma. Paraneoplastic DBN may be associated with cerebellar hypermetabolism, especially in the nodulus. PMID:24928076

  15. Ataxia-telangiectasia: future prospects

    PubMed Central

    Chaudhary, Mohammed Wajid; Al-Baradie, Raidah Saleem

    2014-01-01

    Ataxia-telangiectasia (A-T) is an autosomal recessive multi-system disorder caused by mutation in the ataxia-telangiectasia mutated gene (ATM). ATM is a large serine/threonine protein kinase, a member of the phosphoinositide 3-kinase-related protein kinase (PIKK) family whose best-studied function is as master controller of signal transduction for the DNA damage response (DDR) in the event of double strand breaks (DSBs). The DDR rapidly recognizes DNA lesions and initiates the appropriate cellular programs to maintain genome integrity. This includes the coordination of cell-cycle checkpoints, transcription, translation, DNA repair, metabolism, and cell fate decisions, such as apoptosis or senescence. DSBs can be generated by exposure to ionizing radiation (IR) or various chemical compounds, such as topoisomerase inhibitors, or can be part of programmed generation and repair of DSBs via cellular enzymes needed for the generation of the antibody repertoire as well as the maturation of germ cells. AT patients have immunodeficiency, and are sterile with gonadal dysgenesis as a result of defect in meiotic recombination. In the cells of nervous system ATM has additional role in vesicle dynamics as well as in the maintenance of the epigenetic code of histone modifications. Moderate levels of ATM are associated with prolonged lifespan through resistance to oxidative stress. ATM inhibitors are being viewed as potential radiosensitizers as part of cancer radiotherapy. Though there is no cure for the disease at present, glucocorticoids have been shown to induce alternate splicing site in the gene for ATM partly restoring its activity, but their most effective timing in the disease natural history is not yet known. Gene therapy is promising but large size of the gene makes it technically difficult to be delivered across the blood–brain barrier at present. As of now, apart from glucocorticoids, use of histone deacetylase inhibitors/EZH2 to minimize effect of the absence of

  16. Clinical and MRI findings of cerebellar agenesis in two living adult patients

    PubMed Central

    Gelal, Fazıl Mustafa; Kalaycı, Tuğçe Özlem; Çelebisoy, Mehmet; Karakaş, Levent; Akkurt, Hülya Erdoğan; Koç, Feray

    2016-01-01

    Cerebellar agenesis (CA) is an extremely rare entity. We present two adult patients with CA. The 61-year-old man had ataxia, dysarthria, abnormalities in cerebellar tests, severe cognitive impairment, and moderate mental retardation. The 26-year-old woman had dysmetria, dysdiadochokinesia, and dysarthria as well as mild cognitive impairment and mild mental retardation. Magnetic resonance imaging (MRI) showed complete absence of the cerebellum with small residual vermis. Brainstem was hypoplastic and structures above tentorium were normal. Supratentorial white matter bundles were unaffected in diffusion tensor tractography. Only few adult patients with CA have so far been published. These cases show that patients with CA present with a variety of developmental, clinical, and mental abnormalities; and emphasize the role of the cerebellum in normal motor, language, and mental development. PMID:27293341

  17. Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis.

    PubMed

    Sepulveda-Falla, Diego; Barrera-Ocampo, Alvaro; Hagel, Christian; Korwitz, Anne; Vinueza-Veloz, Maria Fernanda; Zhou, Kuikui; Schonewille, Martijn; Zhou, Haibo; Velazquez-Perez, Luis; Rodriguez-Labrada, Roberto; Villegas, Andres; Ferrer, Isidro; Lopera, Francisco; Langer, Thomas; De Zeeuw, Chris I; Glatzel, Markus

    2014-04-01

    Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A-associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca2+ channels IP3Rs and CACNA1A were downregulated, and Ca2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration. PMID:24569455

  18. Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

    PubMed Central

    Sepulveda-Falla, Diego; Barrera-Ocampo, Alvaro; Hagel, Christian; Korwitz, Anne; Vinueza-Veloz, Maria Fernanda; Zhou, Kuikui; Schonewille, Martijn; Zhou, Haibo; Velazquez-Perez, Luis; Rodriguez-Labrada, Roberto; Villegas, Andres; Ferrer, Isidro; Lopera, Francisco; Langer, Thomas; De Zeeuw, Chris I.; Glatzel, Markus

    2014-01-01

    Familial Alzheimer’s disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A–associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca2+ channels IP3Rs and CACNA1A were downregulated, and Ca2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration. PMID:24569455

  19. Speech characteristics associated with three genotypes of ataxia

    PubMed Central

    Sidtis, John J.; Ahn, Ji Sook; Gomez, Christopher; Sidtis, Diana

    2011-01-01

    Purpose Advances in neurobiology are providing new opportunities to investigate the neurological systems underlying motor speech control. This study explores the perceptual characteristics of the speech of three genotypes of spino-cerebellar ataxia (SCA) as manifest in four different speech tasks. Methods Speech samples from 26 speakers with SCA were perceptually rated by experienced listeners. The genotypes were: SCA1, SCA5, or SCA6. The speech tasks were: diadochokinesis, word repetition, sentence reading, and picture description. The speech samples were rated using two sets of dimensions characterized as primary (e.g., articulation, rate, and rhythm) or secondary (e.g., imprecise consonants, excess and equal stress, and harsh voice). Results On primary dimensions, SCA6 was the most impaired generally. Articulation was the most severely affected dimension and the diadochokinesis task was most effective in revealing speech impairments. On secondary dimensions, picture description was the task most likely to produce abnormal speech. The SCA groups shared articulatory problems but differed with respect to abnormal voice features. Conclusions These results support previous characterizations of ataxic dysarthria, and provide further information about the speech characteristics of genetic subtypes. Task demands affect perceptual ratings. Voice characteristics may be key to differentiating ataxic subtypes. As the genetic disorders that affect speech become better understood, more detailed characterizations of motor control systems should emerge. PMID:21592489

  20. Morphometric magnetic resonance imaging and genetic testing in cerebellar abiotrophy in Arabian horses

    PubMed Central

    2013-01-01

    Background Cerebellar abiotrophy (CA) is a rare but significant disease in Arabian horses caused by progressive death of the Purkinje cells resulting in cerebellar ataxia characterized by a typical head tremor, jerky head movements and lack of menace response. The specific role of magnetic resonance imaging (MRI) to support clinical diagnosis has been discussed. However, as yet MR imaging has only been described in one equine CA case. The role of MR morphometry in this regard is currently unknown. Due to the hereditary nature of the disease, genetic testing can support the diagnosis of CA. Therefore, the objective of this study was to perform MR morphometric analysis and genetic testing in four CA-affected Arabian horses and one German Riding Pony with purebred Arabian bloodlines in the third generation. Results CA was diagnosed pathohistologically in the five affected horses (2 months - 3 years) supported by clinical signs, necropsy, and genetic testing which confirmed the TOE1:g.2171G>A SNP genotype A/A in all CA-affected horses. On MR images morphometric analysis of the relative cerebellar size and relative cerebellar cerebrospinal fluid (CSF) space were compared to control images of 15 unaffected horses. It was demonstrated that in MR morphometric analyses, CA affected horses displayed a relatively smaller cerebellum compared to the entire brain mass than control animals (P = 0.0088). The relative cerebellar CSF space was larger in affected horses (P = 0.0017). Using a cut off value of 11.0% for relative cerebellar CSF space, the parameter differentiated between CA-affected horses and controls with a sensitivity of 100% and a specificity of 93.3%. Conclusions In conclusion, morphometric MRI and genetic analysis could be helpful to support the diagnosis of CA in vivo. PMID:23702154

  1. Primary Diffuse Large B-cell Lymphoma Arising in the Tongue Accompanied by Ataxia-telangiectasia: A Case Report

    PubMed Central

    Kaneoya, Ayano; Mochizuki, Yumi; Harada, Hiroyuki

    2015-01-01

    Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder that is characterized by progressive cerebellar ataxia, telangiectasia, immunodeficiency, and a predisposition to leukemia/lymphoma. Here we report a rare case of lymphoma of the tongue accompanied by AT. Tumour extirpation was performed and diffuse large B-cell lymphoma was diagnosed following pathologic examination. A whole-body survey showed no other enlarged lymph nodes or tumour. The female patient then received a modified dosage of COPAD (cyclophosphamide, vinblastine, pirarubicin, and prednisolone) plus rituximab to avoid severe complications. As of follow-up after 3 years and 5 months, she remains in complete remission. Patients showing AT need careful surveillance and long-term continuous follow-up. PMID:26266230

  2. Sporadic Ataxia and Multiple System Atrophy (MSA)

    MedlinePlus

    ... sporadic ataxia and MSA. The disorders include rapid eye movement (REM) sleep behavior disorder, a condition in which ... sleep disorders and provide specific treatment for rapid eye movement sleep behavior disorder as well as obstructive sleep ...

  3. Vestibular ataxia and its measurement in man

    NASA Technical Reports Server (NTRS)

    Fregly, A. R.

    1974-01-01

    Methods involved in and results obtained with a new comprehensive ataxia test battery are described, and definitions of spontaneous and induced vestibular ataxia in man are given in terms of these findings. In addition, the topic of alcohol-induced ataxia in relation to labyrinth function is investigated. Items in the test battery comprise a sharpened Romberg test, in which the subject stands on the floor with eyes closed and arms folded against his chest, feet heel-to-toe, for 60 seconds; an eyes-open walking test; an eyes-open standing test; an eyes-closed standing test; an eyes-closed on-leg standing test; an eyes-closed walk a line test; an eyes-closed heel-to-toe walking test; and supplementary ataxia tests such as the classical Romberg test.

  4. Nav2 hypomorphic mutant mice are ataxic and exhibit abnormalities in cerebellar development

    PubMed Central

    McNeill, Elizabeth M.; Klöckner-Bormann, Mariana; Roesler, Elizabeth C.; Talton, Lynn E.; Moechars, Dieder; Clagett-Dame, Margaret

    2011-01-01

    Development of the cerebellum involves a coordinated program of neuronal process outgrowth and migration resulting in a foliated structure that plays a key role in motor function. Neuron navigator 2 (Nav2) is a cytoskeletal-interacting protein that functions in neurite outgrowth and axonal elongation. Herein we show that hypomorphic mutant mice lacking the full-length Nav2 transcript exhibit ataxia and defects in cerebellar development. At embryonic day (E)17.5, the mutant cerebellum is reduced in size and exhibits defects in vermal foliation. Reduction in cell proliferation at early times (E12.5 and E14.5) may contribute to this size reduction. The full-length Nav2 transcript is expressed in the premigratory zone of the external granule layer (EGL). Granule cells in the germinal zone of the EGL appear to proliferate normally, however, due to the reduction in cerebellar circumference there are fewer total BrdU-labeled granule cells in the mutants, and these fail to migrate normally toward the interior of the cerebellum. In Nav2 hypomorphs, fewer granule cells migrate out of cerebellar EGL explants and neurite outgrowth from both explants and isolated external granule cell cultures is reduced. This suggests the formation of parallel axon fibers and neuronal migration is disrupted in Nav2 mutants. This work supports an essential role for full-length Nav2 in cerebellar development, including axonal elongation and migration of the EGL neurons. PMID:21419114

  5. Adaptation and aftereffects of split-belt walking in cerebellar lesion patients.

    PubMed

    Hoogkamer, Wouter; Bruijn, Sjoerd M; Sunaert, Stefan; Swinnen, Stephan P; Van Calenbergh, Frank; Duysens, Jacques

    2015-09-01

    To walk efficiently and stably on different surfaces under various constrained conditions, humans need to adapt their gait pattern substantially. Although the mechanisms behind locomotor adaptation are still not fully understood, the cerebellum is thought to play an important role. In this study we aimed to address the specific localization of cerebellar involvement in split-belt adaptation by comparing performance in patients with stable focal lesions after cerebellar tumor resection and in healthy controls. We observed that changes in symmetry of those parameters that were most closely related to interlimb coordination (such as step length and relative double stance time) were similar between healthy controls and cerebellar patients during and after split-belt walking. In contrast, relative stance times (proportions of stance in the gait cycle) were more asymmetric for the patient group than for the control group during the early phase of the post-split-belt condition. Patients who walked with more asymmetric relative stance times were more likely to demonstrate lesions in vermal lobules VI and Crus II. These results confirm that deficits in gait adaptation vary with ataxia severity and between patients with different types of cerebellar damage. PMID:26203113

  6. Nav2 hypomorphic mutant mice are ataxic and exhibit abnormalities in cerebellar development.

    PubMed

    McNeill, Elizabeth M; Klöckner-Bormann, Mariana; Roesler, Elizabeth C; Talton, Lynn E; Moechars, Dieder; Clagett-Dame, Margaret

    2011-05-15

    Development of the cerebellum involves a coordinated program of neuronal process outgrowth and migration resulting in a foliated structure that plays a key role in motor function. Neuron navigator 2 (Nav2) is a cytoskeletal-interacting protein that functions in neurite outgrowth and axonal elongation. Herein we show that hypomorphic mutant mice lacking the full-length Nav2 transcript exhibit ataxia and defects in cerebellar development. At embryonic day (E)17.5, the mutant cerebellum is reduced in size and exhibits defects in vermal foliation. Reduction in cell proliferation at early times (E12.5 and E14.5) may contribute to this size reduction. The full-length Nav2 transcript is expressed in the premigratory zone of the external granule layer (EGL). Granule cells in the germinal zone of the EGL appear to proliferate normally, however, due to the reduction in cerebellar circumference there are fewer total BrdU-labeled granule cells in the mutants, and these fail to migrate normally toward the interior of the cerebellum. In Nav2 hypomorphs, fewer granule cells migrate out of cerebellar EGL explants and neurite outgrowth from both explants and isolated external granule cell cultures is reduced. This suggests that the formation of parallel axon fibers and neuronal migration is disrupted in Nav2 mutants. This work supports an essential role for full-length Nav2 in cerebellar development, including axonal elongation and migration of the EGL neurons. PMID:21419114

  7. Primary cerebellar endodermal sinus tumor: A case report.

    PubMed

    Kuang, Hongmei; Zhang, Chun; Gong, Honghan; Guo, Linghong; Yu, Chen; Zeng, Xianjun

    2014-10-01

    Endodermal sinus tumors are rare malignant germ cell tumors that usually originate from the gonads and are rarely observed extragonadally. Pure primary endodermal sinus tumors of the cerebellar hemisphere are extremely rare and patients diagnosed with the disease often have a poor prognosis. The symptoms of YSTs are unspecific and associated with the location of tumors. Intracranial YSTs (such as cerebellar hemispheres) always present with symptoms including headache and poor vision. The present study reports the case of a three-year-old male who presented to The First Affiliated Hospital of Nanchang University (Nanchang, China) with a headache that had persisted for one month, and then worsened for the last 10 days. This was accompanied by vomiting and gait disturbance. An abnormal signal mass was identified in the left cerebellar hemisphere on brain magnetic resonance imaging. The case initially presented as a medulloblastoma and the patient was followed up for six months. The final pathology report revealed an endodermal sinus tumor, also known as a yolk sac tumor. Six months following resection of the left cerebellar tumor, the patient succumbed to recurrence of the disease, due to acute vomiting and severe headache. PMID:25202397

  8. Biallelic CACNA1A mutations cause early onset epileptic encephalopathy with progressive cerebral, cerebellar, and optic nerve atrophy.

    PubMed

    Reinson, Karit; Õiglane-Shlik, Eve; Talvik, Inga; Vaher, Ulvi; Õunapuu, Anne; Ennok, Margus; Teek, Rita; Pajusalu, Sander; Murumets, Ülle; Tomberg, Tiiu; Puusepp, Sanna; Piirsoo, Andres; Reimand, Tiia; Õunap, Katrin

    2016-08-01

    The CACNA1A gene encodes the transmembrane pore-forming alpha-1A subunit of the Cav 2.1 P/Q-type voltage-gated calcium channel. Several heterozygous mutations within this gene, including nonsense mutations, missense mutations, and expansion of cytosine-adenine-guanine repeats, are known to cause three allelic autosomal dominant conditions-episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6. An association with epilepsy and CACNA1A mutations has also been described. However, the link with epileptic encephalopathies has emerged only recently. Here we describe two patients, sister and brother, with compound heterozygous mutations in CACNA1A. Exome sequencing detected biallelic mutations in CACNA1A: A missense mutation c.4315T>A (p.Trp1439Arg) in exon 27, and a seven base pair deletion c.472_478delGCCTTCC (p.Ala158Thrfs*6) in exon 3. Both patients were normal at birth, but developed daily recurrent seizures in early infancy with concomitant extreme muscular hypotonia, hypokinesia, and global developmental delay. The brain MRI images showed progressive cerebral, cerebellar, and optic nerve atrophy. At the age of 5, both patients were blind and bedridden with a profound developmental delay. The elder sister died at that age. Their parents and two siblings were heterozygotes for one of those pathogenic mutations and expressed a milder phenotype. Both of them have intellectual disability and in addition the mother has adult onset cerebellar ataxia with a slowly progressive cerebellar atrophy. Compound heterozygous mutations in the CACNA1A gene presumably cause early onset epileptic encephalopathy, and progressive cerebral, cerebellar and optic nerve atrophy with reduced lifespan. © 2016 Wiley Periodicals, Inc. PMID:27250579

  9. Modeling Suggests TRPC3 Hydrogen Bonding and Not Phosphorylation Contributes to the Ataxia Phenotype of the Moonwalker Mouse

    PubMed Central

    2015-01-01

    A gain-of-function mutation (T635A) in the transient receptor potential (TRP) channel TRPC3 results in abnormal channel gating and causes cerebellar ataxia in the dominant Moonwalker (Mwk) mouse mutant. However, the underlying molecular and structural mechanisms are unclear. Here, we used a combined approach of computational modeling and functional characterization of proposed TRPC3 mutants. Our findings support a mechanism by which the hydrogen bonding capability of threonine 635 plays a significant role in maintaining a stable, closed state channel. This capability is lost in the Mwk mutant, suggesting a structural basis for the disease-causing phenotype in the Mwk mouse. PMID:26112884

  10. Congenital cataract, ataxia, external ophthalmoplegia and dysphagia in two siblings. A Marinesco-Sjögren-like syndrome.

    PubMed

    Schulz, S; Vielhaber, S; Muschke, P; Mohnike, K; Gooding, R; Wieacker, P

    2007-04-01

    Marinesco-Sjögren syndrome (MSS) is an autosomal recessive multiorgan disorder with clinical and genetic heterogeneity. The key features of MSS include cerebellar ataxia, early bilateral cataracts, delayed motor development, and to a varying degree mental retardation. The syndrome was recently mapped to chromosome 5q31, and loss-of-function mutations in the SIL1 gene have been identified as the primary pathology. Here, we describe two German siblings with clinical characteristics resembling those seen in many cases of MSS except that a marked cerebellar atrophy was not detectable in our patients. In addition, both patients presented with external ophthalmoplegia and paralytic dysphagia. Sequencing of all 10 exons of the SIL1 gene did not detect any SIL1 mutation in our patients. PMID:17712737

  11. Alcohol Withdrawal and Cerebellar Mitochondria.

    PubMed

    Jung, Marianna E

    2015-08-01

    Cerebellar disorders trigger the symptoms of movement problems, imbalance, incoordination, and frequent fall. Cerebellar disorders are shown in various CNS illnesses including a drinking disorder called alcoholism. Alcoholism is manifested as an inability to control drinking in spite of adverse consequences. Human and animal studies have shown that cerebellar symptoms persist even after complete abstinence from drinking. In particular, the abrupt termination (ethanol withdrawal) of long-term excessive ethanol consumption has shown to provoke a variety of neuronal and mitochondrial damage to the cerebellum. Upon ethanol withdrawal, excitatory neurotransmitter molecules such as glutamate are overly released in brain areas including cerebellum. This is particularly relevant to the cerebellar neuronal network as glutamate signals are projected to Purkinje neurons through granular cells that are the most populated neuronal type in CNS. This excitatory neuronal signal may be elevated by ethanol withdrawal stress, which promotes an increase in intracellular Ca(2+) level and a decrease in a Ca(2+)-binding protein, both of which result in the excessive entry of Ca(2+) to the mitochondria. Subsequently, mitochondria undergo a prolonged opening of mitochondrial permeability transition pore and the overproduction of harmful free radicals, impeding adenosine triphosphate (ATP)-generating function. This in turn provokes the leakage of mitochondrial molecule cytochrome c to the cytosol, which triggers a cascade of adverse cytosol reactions. Upstream to this pathway, cerebellum under the condition of ethanol withdrawal has shown aberrant gene modifications through altered DNA methylation, histone acetylation, or microRNA expression. Interplay between these events and molecules may result in functional damage to cerebellar mitochondria and consequent neuronal degeneration, thereby contributing to motoric deficit. Mitochondria-targeting research may help develop a powerful new

  12. Failure of Fixation Suppression of Spontaneous Nystagmus in Cerebellar Infarction: Frequency, Pattern, and a Possible Structure.

    PubMed

    Kim, Hyun-Ah; Yi, Hyon-Ah; Lee, Hyung

    2016-04-01

    To investigate the frequency and pattern of failure of the fixation suppression (FFS) of spontaneous nystagmus (SN) in unilateral cerebellar infarction, and to identify the structure responsible for FFS, 29 patients with acute, mainly unilateral, isolated cerebellar infarction who had SN with a predominantly horizontal component were enrolled in this study. The ocular fixation index (OFI) was defined as the mean slow phase velocity (SPV) of the horizontal component of SN with fixation divided by the mean SPV of the horizontal component of SN without fixation. The OFI from age- and sex-matched patients with vestibular neuritis was calculated and used as the control data. The FFS of SN was only found in less than half (41 %, 12/29) of the patients. Approximately 65 % (n = 7) of the patients with isolated anterior inferior cerebellar artery territory cerebellar infarction showed FFS, whereas only a quarter (n = 3) of the patients with isolated posterior inferior cerebellar artery (PICA) territory cerebellar infarction showed FFS. The proportion of gaze-evoked nystagmus (6/12 [50 %] vs. 2/17 [12 %], p = 0.04) and deficient gain of ipsilesional pursuit (10/12 [83 %] vs. 6/17 [35 %], p = 0.05) was more frequent in the FFS group than in the group without FFS. Lesion subtraction analysis in isolated PICA territory cerebellar infarction revealed that the nodulus was commonly damaged in patients with FFS, compared to that of patients without FFS. Our study shows that FFS of SN due to acute cerebellar infarction is less common than previously thought and the nodulus may be an important structure for the suppression of SN in humans. PMID:26082303

  13. GDNF-induced cerebellar toxicity: A brief review.

    PubMed

    Luz, Matthias; Mohr, Erich; Fibiger, H Christian

    2016-01-01

    Recombinant-methionyl human glial cell line-derived neurotrophic factor (GDNF) is known for its neurorestorative and neuroprotective effects in rodent and primate models of Parkinson's disease (PD). When administered locally into the putamen of Parkinsonian subjects, early clinical studies showed its potential promise as a disease-modifying agent. However, the development of GDNF for the treatment of PD has been significantly clouded by findings of cerebellar toxicity after continuous intraputamenal high-dose administration in a 6-month treatment/3-month recovery toxicology study in rhesus monkeys. Specifically, multifocal cerebellar Purkinje cell loss affecting 1-21% of the cerebellar cortex was observed in 4 of 15 (26.7%; 95% confidence interval [CI]: 10.5-52.4%) animals treated at the highest dose level tested (3000μg/month). No cerebellar toxicity was observed at lower doses (450 and 900μg/month) in the same study, or at similar or higher doses (up to 10,000μg/month) in subchronic or chronic toxicology studies testing intermittent intracerebroventricular administration. While seemingly associated with the use of GDNF, the pathogenesis of the cerebellar lesions has not been fully understood to date. This review integrates available information to evaluate potential pathogenic mechanisms and provide a consolidated assessment of the findings. While other explanations are considered, the existing evidence is most consistent with the hypothesis that leakage of GDNF into cerebrospinal fluid during chronic infusions into the putamen down-regulates GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF generates the observed lesions. The implications of these findings for clinical studies with GDNF are discussed. PMID:26535469

  14. Orthostatic tremor: a cerebellar pathology?

    PubMed Central

    Popa, Traian; García-Lorenzo, Daniel; Valabregue, Romain; Legrand, André-Pierre; Apartis, Emmanuelle; Marais, Lea; Degos, Bertrand; Hubsch, Cecile; Fernández-Vidal, Sara; Bardinet, Eric; Roze, Emmanuel; Lehéricy, Stéphane; Meunier, Sabine; Vidailhet, Marie

    2016-01-01

    See Muthuraman et al. (doi:10.1093/aww164) for a scientific commentary on this article. Primary orthostatic tremor is characterized by high frequency tremor affecting the legs and trunk during the standing position. Cerebellar defects were suggested in orthostatic tremor without direct evidence. We aimed to characterize the anatomo-functional defects of the cerebellar motor pathways in orthostatic tremor. We used multimodal neuroimaging to compare 17 patients with orthostatic tremor and 17 age- and gender-matched healthy volunteers. Nine of the patients with orthostatic tremor underwent repetitive transcranial stimulation applied over the cerebellum during five consecutive days. We quantified the duration of standing position and tremor severity through electromyographic recordings. Compared to healthy volunteers, grey matter volume in patients with orthostatic tremor was (i) increased in the cerebellar vermis and correlated positively with the duration of the standing position; and (ii) increased in the supplementary motor area and decreased in the lateral cerebellum, which both correlated with the disease duration. Functional connectivity between the lateral cerebellum and the supplementary motor area was abnormally increased in patients with orthostatic tremor, and correlated positively with tremor severity. After repetitive transcranial stimulation, tremor severity and functional connectivity between the lateral cerebellum and the supplementary motor area were reduced. We provide an explanation for orthostatic tremor pathophysiology, and demonstrate the functional relevance of cerebello-thalamo-cortical connections in tremor related to cerebellar defects. PMID:27329770

  15. The compartmental restriction of cerebellar interneurons

    PubMed Central

    Consalez, G. Giacomo; Hawkes, Richard

    2013-01-01

    The Purkinje cells (PC's) of the cerebellar cortex are subdivided into multiple different molecular phenotypes that form an elaborate array of parasagittal stripes. This array serves as a scaffold around which afferent topography is organized. The ways in which cerebellar interneurons may be restricted by this scaffolding are less well-understood. This review begins with a brief survey of cerebellar topography. Next, it reviews the development of stripes in the cerebellum with a particular emphasis on the embryological origins of cerebellar interneurons. These data serve as a foundation to discuss the hypothesis that cerebellar compartment boundaries also restrict cerebellar interneurons, both excitatory [granule cells, unipolar brush cells (UBCs)] and inhibitory (e.g., Golgi cells, basket cells). Finally, it is proposed that the same PC scaffold that restricts afferent terminal fields to stripes may also act to organize cerebellar interneurons. PMID:23346049

  16. Ataxia and Encephalitis in a Young Adult with EBV Mononucleosis: A Case Report.

    PubMed

    Hussain, Rashid S; Hussain, Naaz A

    2013-01-01

    Neurological manifestations of mononucleosis are extremely rare, occurring in about 1% of all cases. However, when they occur, appropriate treatment must be undertaken to ensure appropriate symptomatic management and reduce morbidity. We present the case of a 25-year-old graduate student with weeklong complaints of fever, sore throat, fatigue, nausea, and "dizziness." She later developed increased sleep requirements, ataxia, vertigo, and nystagmus with a positive EBV IgM titer confirming acute infectious mononucleosis. The patient was clinically diagnosed with EBV-associated cerebellitis and encephalitis, displaying neurological and psychiatric impairment commonly seen in postconcussion syndrome. MRI showed no acute changes. She was started on valacyclovir and a prednisone taper, recovering by the end of twelve weeks. Though corticosteroids and acyclovir are not recommended therapy in patients presenting with EBV-associated ataxia, clinicians may want to keep a low threshold to start these medications in case more serious neurological sequelae develop. PMID:23781357

  17. Genetics Home Reference: myoclonic epilepsy myopathy sensory ataxia

    MedlinePlus

    ... Me Understand Genetics Home Health Conditions MEMSA myoclonic epilepsy myopathy sensory ataxia Enable Javascript to view the ... Download PDF Open All Close All Description Myoclonic epilepsy myopathy sensory ataxia , commonly called MEMSA , is part ...

  18. Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS)

    MedlinePlus

    ... Resources and Publications Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS): Overview Skip sharing on social media ... this: Page Content Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset condition (occurs ...

  19. Cytokines in Machado Joseph Disease/Spinocerebellar Ataxia 3.

    PubMed

    da Silva Carvalho, Gerson; Saute, Jonas Alex Morales; Haas, Clarissa Branco; Torrez, Vitor Rocco; Brochier, Andressa Wigner; Souza, Gabriele Nunes; Furtado, Gabriel Vasata; Gheno, Tailise; Russo, Aline; Monte, Thais Lampert; Schumacher-Schuh, Artur; D'Avila, Rui; Donis, Karina Carvalho; Castilhos, Raphael Machado; Souza, Diogo Onofre; Saraiva-Pereira, Maria Luiza; Torman, Vanessa Leotti; Camey, Suzi; Portela, Luis Valmor; Jardim, Laura Bannach

    2016-08-01

    The aim of the present study is to describe the serum concentrations of a broad spectrum of cytokines in symptomatic and asymptomatic carriers of Machado Joseph disease (SCA3/MJD) CAG expansions. Molecularly confirmed carriers and controls were studied. Age at onset, disease duration, and clinical scales Scale for the Assessment and Rating of Ataxia (SARA), Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), SCA Functional Index (SCAFI), and Composite Cerebellar Functional Score (CCFS) were obtained from the symptomatic carriers. Serum was obtained from all individuals and a cytokine panel "consisted of" eotaxin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-α, IFN-γ, interleukin (IL)-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-a, MIP-b, regulated on activation, normal T cell expressed and secreted (RANTES) and tumor necrosis factor (TNF)-α was analyzed. In a subgroup of symptomatic carriers, the cytokine panel was repeated after 360 days. Cytokine distribution among groups was studied by discriminant analysis; changes in serum levels after 360 days were studied by generalized estimation equation. Sixty-six symptomatic carriers, 13 asymptomatic carriers, and 43 controls were studied. No differences in cytokine patterns were found between controls and carriers of the CAG expansions or between controls and symptomatic carriers only. In contrast, eotaxin concentrations were significantly higher in asymptomatic than in symptomatic carriers or in controls (p = 0.001, ANCOVA). Eotaxin did not correlate with age, disease duration, CAG expansion, NESSCA score, and SARA score. Among symptomatic carriers, eotaxin dropped after 360 days (p = 0.039, GEE). SCA3/MJD patients presented a benign pattern of

  20. Ataxia with Parkinsonism and dystonia after intentional inhalation of liquefied petroleum gas

    PubMed Central

    Godani, Massimiliano; Canavese, Francesca; Migliorini, Sonia; Sette, Massimo Del

    2015-01-01

    The practice of inhaling liquefied petroleum gas (LPG) to commit suicide is uncommon and almost exclusively a prerogative of the prison population. Numerous cases of sudden deaths caused by intentional propane and/or butane inhalation have been described, but these cases survived and a description of the consequences is very rare. We describe a prisoner who survived after voluntary inhalation of LPG, and who developed ataxia, Parkinsonism, and dystonia. Brain MRI showed bilateral hyperintensity in the basal ganglia and in the cerebellar hemispheres. The clinical evolution and the MRI abnormalities are similar to those described in cases of poisoning by CO where the mechanism of brain injury is related to histotoxic hypoxia. We believe that LPG, considered until now a mixture of gas with low neurotoxic power, may have caused direct toxic damage to the brain, mediated by a mechanism of hypoxia, such as in CO intoxication. PMID:26005350

  1. Ataxia with Parkinsonism and dystonia after intentional inhalation of liquefied petroleum gas.

    PubMed

    Godani, Massimiliano; Canavese, Francesca; Migliorini, Sonia; Sette, Massimo Del

    2015-01-01

    The practice of inhaling liquefied petroleum gas (LPG) to commit suicide is uncommon and almost exclusively a prerogative of the prison population. Numerous cases of sudden deaths caused by intentional propane and/or butane inhalation have been described, but these cases survived and a description of the consequences is very rare. We describe a prisoner who survived after voluntary inhalation of LPG, and who developed ataxia, Parkinsonism, and dystonia. Brain MRI showed bilateral hyperintensity in the basal ganglia and in the cerebellar hemispheres. The clinical evolution and the MRI abnormalities are similar to those described in cases of poisoning by CO where the mechanism of brain injury is related to histotoxic hypoxia. We believe that LPG, considered until now a mixture of gas with low neurotoxic power, may have caused direct toxic damage to the brain, mediated by a mechanism of hypoxia, such as in CO intoxication. PMID:26005350

  2. Ataxia and Purkinje cell degeneration in mice lacking the CAMTA1 transcription factor.

    PubMed

    Long, Chengzu; Grueter, Chad E; Song, Kunhua; Qin, Song; Qi, Xiaoxia; Kong, Y Megan; Shelton, John M; Richardson, James A; Zhang, Chun-Li; Bassel-Duby, Rhonda; Olson, Eric N

    2014-08-01

    Members of the calmodulin-binding transcription activator (CAMTA) family of proteins function as calcium-sensitive regulators of gene expression in multicellular organisms ranging from plants to humans. Here, we show that global or nervous system deletion of CAMTA1 in mice causes severe ataxia with Purkinje cell degeneration and cerebellar atrophy, partially resembling the consequences of haploinsufficiency of the human CAMTA1 locus. Gene-expression analysis identified a large collection of neuronal genes that were dysregulated in the brains of CAMTA1-mutant mice, and elucidation of a consensus sequence for binding of CAMTA proteins to DNA revealed the association of CAMTA-binding sites with many of these genes. We conclude that CAMTA1 plays an essential role in the control of Purkinje cell function and survival. CAMTA1-mutant mice provide a model to study the molecular mechanisms of neurodegenerative diseases and for screening potential therapeutic interventions for such disorders. PMID:25049392

  3. Vitamin E deficiency ataxia associated with adenoma.

    PubMed

    Benomar, A; Yahyaoui, M; Marzouki, N; Birouk, N; Bouslam, N; Belaidi, H; Amarti, A; Ouazzani, R; Chkili, T

    1999-01-01

    Vitamin E is one of the most important lipid-soluble antioxidant nutrient. Severe vitamin E deficiency (VED) can have a profound effect on the central nervous system. VED causes ataxia and peripheral neuropathy that resembles Friedreich's ataxia. We report here a patient presenting this syndrome, but also a prolactin and FSH adenoma. Both the neurological syndromes and the adenoma regressed after treatment with alpha-tocopherol. Although, the presence of the prolactinoma in this patient may not be related to his vitamin E deficiency, alpha-tocopherol treatment seems to be beneficial and might usefully be tested in patients with hypophyseal secreting other forms of adenoma. PMID:10064178

  4. Progressive multifocal leukoencephalopathy with bilateral middle cerebellar peduncle lesions confirmed by repeated CSF-JC virus tests and coexistence of JC virus granule cell neuronopathy. Report of a case.

    PubMed

    Ito, Daisuke; Yasui, Keizo; Hasegawa, Yasuhiro; Nakamichi, Kazuo; Katsuno, Masahisa; Takahashi, Akira

    2016-07-28

    A 65 year-old woman with small lymphocytic leukemia presented with subacute cerebellar ataxia. Six months after rituximab chemotherapy, a cranial MRI revealed lesions in the bilateral middle cerebellar peduncles. Both cerebrospinal fluid (CSF) JC virus (JCV)-DNA PCR test on three occasions and brain biopsy were negative. CSF tests were repeated. The fourth test performed 6 months after the onset showed positive JCV-DNA, and a definite diagnosis of progressive multifocal leukoencephalopathy (PML) was made. Neuroimaging of cerebellar atrophy was considered to be coexistence of granule cell neuronopathy. Medication with mirtazapine and mefloquine was temporarily effective for several months. Little are known solitary bilateral MRI lesions of the middle cerebellar peduncle in PML. JCV-PCR test of CSF may be negative at an earlier stage of PML. Repeated CSF tests should be essential to confirming the diagnosis in such cases. PMID:27356732

  5. Expansion of the Spinocerebellar ataxia type 10 (SCA10) repeat in a patient with Sioux Native American ancestry.

    PubMed

    Bushara, Khalaf; Bower, Matthew; Liu, Jilin; McFarland, Karen N; Landrian, Ivette; Hutter, Diane; Teive, Hélio A G; Rasmussen, Astrid; Mulligan, Connie J; Ashizawa, Tetsuo

    2013-01-01

    Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant cerebellar ataxia, is caused by the expansion of the non-coding ATTCT pentanucleotide repeat in the ATAXIN 10 gene. To date, all cases of SCA10 are restricted to patients with ancestral ties to Latin American countries. Here, we report on a SCA10 patient with Sioux Native American ancestry and no reported Hispanic or Latino heritage. Neurological exam findings revealed impaired gait with mild, age-consistent cerebellar atrophy and no evidence of epileptic seizures. The age at onset for this patient, at 83 years of age, is the latest documented for SCA10 patients and is suggestive of a reduced penetrance allele in his family. Southern blot analysis showed an SCA10 expanded allele of 1400 repeats. Established SNPs surrounding the SCA10 locus showed a disease haplotype consistent with the previously described "SCA10 haplotype". This case suggests that the SCA10 expansion represents an early mutation event that possibly occurred during the initial peopling of the Americas. PMID:24278426

  6. Widespread neuronal damage and cognitive dysfunction in spinocerebellar ataxia type 3.

    PubMed

    Lopes, Tátila Martins; D'Abreu, Anelyssa; França, Marcondes Cavalcante; Yasuda, Clarissa Lin; Betting, Luiz Eduardo; Samara, Adriana Bastos; Castellano, Gabriela; Somazz, Júlio César; Balthazar, Marcio Luiz Figueredo; Lopes-Cendes, Iscia; Cendes, Fernando

    2013-09-01

    Previous studies demonstrated cognitive impairments in spinocerebellar ataxia type 3 (SCA3/MJD); however, there is no consensus about the cognitive domains affected and the correlation with structural brain abnormalities. We investigated the neuropsychological profile and 3T-MRI findings, including high-resolution T1-images, diffusion tensor imaging and magnetic resonance spectroscopy of 32 patients with SCA3/MJD and 32 age-, gender- and educational level-matched healthy controls. We reviewed patients' clinical history and CAG repeat length, and performed assessment and rating of ataxia (SARA)-Brazilian version and the neuropsychiatric inventory. Patients presented worse performance in episodic and working memory and Beck inventories (depression and anxiety). SCA3/MJD patients had a reduction of gray matter volume (GM) in the cerebellum, putamen, cingulum, precentral and parietal lobe. A positive correlation was identified between the cognitive findings and GM of temporal, frontal, parietal, culmen and insula. We observed positive correlation between the brainstem's fractional anisotropy and digit span-forward. The following cerebellar metabolite groups (measured relative to creatine) were reduced in patients: N-acetyl-aspartate (NAA), NAA + N-acetyl-aspartate-glutamate and glutamate + glutamine (Glx). We found a positive correlation between Corsi's block-tapping task forward with Glx; semantic verbal fluency with phosphorylcholine and glycerophosphorylcholine; digits span-forward with NAA. The cognitive impairments in SCA3/MJD are associated not only with cerebellar and brainstem abnormalities, but also with neuroimaging evidence of diffuse neuronal and axonal dysfunction, particularly in temporal, frontal, parietal and insular areas. PMID:23775343

  7. ATP1A3 Mutation in Adult Rapid-Onset Ataxia

    PubMed Central

    Sweadner, Kathleen J.; Toro, Camilo; Whitlow, Christopher T.; Snively, Beverly M.; Cook, Jared F.; Ozelius, Laurie J.; Markello, Thomas C.; Brashear, Allison

    2016-01-01

    A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient’s ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative. PMID:26990090

  8. Cerebellar mature teratoma in adulthood.

    PubMed

    Zavanone, M; Alimehmeti, R; Campanella, R; Ram-Pini, P; Locatelli, M; Egidi, M; Righini, A; Bauer, D

    2002-03-01

    Mature teratoma of the posterior cranial fossa in adults is extremely rare. We report a particularly rare case of medio-lateral cerebellar mature teratoma that became symptomatic in a middle-aged man. The CT revealed the lesion of heterogeneous density with calcifications in the solid medial portion. Only the MRI could reliably define the borders of the cystic component extending into the left cerebellar lobe. Histologically the presence of fully matured representative tissues of the 3 germ layers ensured the diagnosis of mature teratoma. We suggest that the cyst formation from progressive latent hemorrhage and/or secretion from the gland cells of the tumor, may be responsible for the clinical decompensation even in adulthood. PMID:12118223

  9. Cerebellar neurocognition and Korsakoff's syndrome: an hypothesis.

    PubMed

    Wijnia, Jan W; Goossensen, Anne

    2010-08-01

    In literature, the cerebellum is given a substantial role in cognitive processes, in addition to traditional views on cerebellar function of regulating motor behaviour. The phenomenon of cerebellar damage causing impairments in memory and executive functioning was observed in various cerebellar disorders. Cerebellar cognitive dysfunction can be interpreted as a disturbance of cerebello-cerebral connections to areas of the cerebral cortex involved in cognitive processing, but the exact nature of the cognitive dysregulation is not known. Memory and executive dysfunction are important clinical features of Korsakoff's syndrome. We hypothesize that the Korsakoff syndrome might be an example of cerebellar neurocognitive dysfunctioning, caused by cerebello-cerebral pathways being disconnected in brain areas that are classically affected in Wernicke's encephalopathy. Further research is needed to support the possibility of cerebellar neurocognitive disturbances in Korsakoff's syndrome. If correct, this hypothesis may contribute to a better understanding of the clinical and neuropsychological profile of Korsakoff's syndrome. PMID:20303220

  10. A Deletion in the VLDLR Gene in Eurasier Dogs with Cerebellar Hypoplasia Resembling a Dandy-Walker-Like Malformation (DWLM)

    PubMed Central

    Gerber, Martina; Fischer, Andrea; Jagannathan, Vidhya; Drögemüller, Michaela; Drögemüller, Cord; Schmidt, Martin J.; Bernardino, Filipa; Manz, Eberhard; Matiasek, Kaspar; Rentmeister, Kai; Leeb, Tosso

    2015-01-01

    Dandy-Walker-like malformation (DWLM) is the result of aberrant brain development and mainly characterized by cerebellar hypoplasia. DWLM affected dogs display a non-progressive cerebellar ataxia. Several DWLM cases were recently observed in the Eurasier dog breed, which strongly suggested a monogenic autosomal recessive inheritance in this breed. We performed a genome-wide association study (GWAS) with 9 cases and 11 controls and found the best association of DWLM with markers on chromosome 1. Subsequent homozygosity mapping confirmed that all 9 cases were homozygous for a shared haplotype in this region, which delineated a critical interval of 3.35 Mb. We sequenced the genome of an affected Eurasier and compared it with the Boxer reference genome and 47 control genomes of dogs from other breeds. This analysis revealed 4 private non-synonymous variants in the critical interval of the affected Eurasier. We genotyped these variants in additional dogs and found perfect association for only one of these variants, a single base deletion in the VLDLR gene encoding the very low density lipoprotein receptor. This variant, VLDLR:c.1713delC is predicted to cause a frameshift and premature stop codon (p.W572Gfs*10). Variants in the VLDLR gene have been shown to cause congenital cerebellar ataxia and mental retardation in human patients and Vldlr knockout mice also display an ataxia phenotype. Our combined genetic data together with the functional knowledge on the VLDLR gene from other species thus strongly suggest that VLDLR:c.1713delC is indeed causing DWLM in Eurasier dogs. PMID:25668033

  11. Oculopalatal tremor, facial myokymia and truncal ataxia in a patient with neurosarcoidosis.

    PubMed

    Sidiropoulos, Christos; Sripathi, Naganand; Nasrallah, Khalil; Mitsias, Panayiotis

    2014-12-01

    Symptomatic palatal tremor (SPT) is the result of a structural lesion, in the form of stroke, trauma or demyelinating disease. SPT is due to contractions of the levator veli palatini and can be accompanied by simultaneous movements of the facial and ocular muscles. Facial myokymia (FM) is a persistent quivering of the facial muscles. FM is usually encountered with conditions involving the pontine tegmentum. We report, to our knowledge, the first patient with neurosarcoidosis with simultaneous SPT and FM. A 49-year-old African American woman, with non-caseating granulomas in a paratracheal lymph node biopsy, presented with progressive gait disturbances for the last 3 years. Neurological examination revealed ataxic speech, bilateral rotatory nystagmus, myokymia of the chin and perioral muscles, palatal tremor without ear click and marked truncal ataxia. MRI demonstrated a lesion involving the facial nucleus and the right middle cerebellar peduncle. Based on exclusion of alternative etiologies, a diagnosis of neurosarcoidosis was made and the patient was started on methotrexate for 9 months, with minimal improvement. She was then switched to intravenous infliximab without major adverse events. The patient's speech and gait ataxia improved and follow up MRI demonstrated resolution of the enhancing lesions. To our knowledge, this is the first reported case of the combination of palatal tremor and FM due to neurosarcoidosis. Methotrexate may fail to produce clinical or radiographic response in up to 39% of patients. Tumor necrosis factor-α inhibitors, such as infliximab, should be considered in refractory cases. PMID:25103854

  12. Motor training in degenerative spinocerebellar disease: ataxia-specific improvements by intensive physiotherapy and exergames.

    PubMed

    Synofzik, Matthis; Ilg, Winfried

    2014-01-01

    The cerebellum is essentially involved in movement control and plays a critical role in motor learning. It has remained controversial whether patients with degenerative cerebellar disease benefit from high-intensity coordinative training. Moreover, it remains unclear by which training methods and mechanisms these patients might improve their motor performance. Here, we review evidence from different high-intensity training studies in patients with degenerative spinocerebellar disease. These studies demonstrate that high-intensity coordinative training might lead to a significant benefit in patients with degenerative ataxia. This training might be based either on physiotherapy or on whole-body controlled videogames ("exergames"). The benefit shown in these studies is equal to regaining one or more years of natural disease progression. In addition, first case studies indicate that even subjects with advanced neurodegeneration might benefit from such training programs. For both types of training, the observed clinical improvements are paralleled by recoveries in ataxia-specific dysfunctions (e.g., multijoint coordination and dynamic stability). Importantly, for both types of training, the retention of the effects seems to depend on the frequency and continuity of training. Based on these studies, we here present preliminary recommendations for clinical practice, and articulate open questions that might guide future studies on neurorehabilitation in degenerative spinocerebellar disease. PMID:24877117

  13. A high frequency of distinct ATM gene mutations in ataxia-telangiectasia

    SciTech Connect

    Wright, J.; Teraoka, S.; Concannon, P.

    1996-10-01

    The clinical features of the autosomal recessive disorder ataxia-telangiectasia (AT) include a progressive cerebellar ataxia, hypersensitivity to ionizing radiation, and an increased susceptibility to malignancies. Epidemiological studies have suggested that AT heterozygotes may also be at increased risk for malignancy, possibly as a consequence of radiation exposure. A gene mutated in AT patients (ATM) has recently been isolated, making mutation screening in both patients and the general population possible. Because of the relatively large size of the ATM gene, the design of screening programs will depend on the types and distribution of mutations in the general population. In this report, we describe 30 mutations identified in a panel of unrelated AT patients and controls. Twenty-five of the 30 were distinct, and most patients were compound heterozygotes. The most frequently detected mutation was found in three different families and had previously been reported in five others. This corresponds to a frequency of 8% of all reported ATM mutations. Twenty-two of the alterations observed would be predicted to lead to protein truncation at sites scattered throughout the molecule. Two fibroblast cell lines, which displayed normal responses to ionizing radiation, also proved to be heterozygous for truncation mutations of ATM. These observations suggest that the carrier frequency of ATM mutations may be sufficiently high to make population screening practical. However, such screening may need to be done prospectively, that is, by searching for new mutations rather than by screening for just those already identified in AT families. 33 refs., 1 fig., 1 tab.

  14. Motor Training in Degenerative Spinocerebellar Disease: Ataxia-Specific Improvements by Intensive Physiotherapy and Exergames

    PubMed Central

    2014-01-01

    The cerebellum is essentially involved in movement control and plays a critical role in motor learning. It has remained controversial whether patients with degenerative cerebellar disease benefit from high-intensity coordinative training. Moreover, it remains unclear by which training methods and mechanisms these patients might improve their motor performance. Here, we review evidence from different high-intensity training studies in patients with degenerative spinocerebellar disease. These studies demonstrate that high-intensity coordinative training might lead to a significant benefit in patients with degenerative ataxia. This training might be based either on physiotherapy or on whole-body controlled videogames (“exergames”). The benefit shown in these studies is equal to regaining one or more years of natural disease progression. In addition, first case studies indicate that even subjects with advanced neurodegeneration might benefit from such training programs. For both types of training, the observed clinical improvements are paralleled by recoveries in ataxia-specific dysfunctions (e.g., multijoint coordination and dynamic stability). Importantly, for both types of training, the retention of the effects seems to depend on the frequency and continuity of training. Based on these studies, we here present preliminary recommendations for clinical practice, and articulate open questions that might guide future studies on neurorehabilitation in degenerative spinocerebellar disease. PMID:24877117

  15. Anti Transglutaminase Antibodies Cause Ataxia in Mice

    PubMed Central

    Boscolo, Sabrina; Lorenzon, Andrea; Sblattero, Daniele; Florian, Fiorella; Stebel, Marco; Marzari, Roberto; Not, Tarcisio; Aeschlimann, Daniel; Ventura, Alessandro; Hadjivassiliou, Marios; Tongiorgi, Enrico

    2010-01-01

    Background Celiac disease (CD) is an autoimmune gastrointestinal disorder characterized by the presence of anti-transglutaminase 2 (TG2) and anti-gliadin antibodies. Amongst the neurological dysfunctions associated with CD, ataxia represents the most common one. Methods We analyzed by immunohistochemistry, the anti-neural reactivity of the serum from 20 CD patients. To determine the role of anti-TG2 antibodies in ataxia, two anti-TG2 single chain variable fragments (scFv), isolated from a phage-display IgA antibody library, were characterized by immunohistochemistry and ELISA, and injected in mice to study their effects on motor coordination. We found that 75% of the CD patient population without evidence of neurological involvement, has circulating anti-neural IgA and/or IgG antibodies. Two anti-TG2 scFvs, cloned from one CD patient, stained blood vessels but only one reacted with neurons. This anti-TG2 antibody showed cross reactivity with the transglutaminase isozymes TG3 and TG6. Intraventricular injection of the anti-TG2 or the anti-TG2/3/6 cross-reactive scFv provoked transient, equally intensive ataxia in mice. Conclusion The serum from CD patients contains anti-TG2, TG3 and TG6 antibodies that may potentially cause ataxia. PMID:20300628

  16. Neurological and cerebellar soft signs do not discriminate schizophrenia from bipolar disorder patients.

    PubMed

    Chrobak, Adrian Andrzej; Siwek, Grzegorz Przemysław; Siuda-Krzywicka, Katarzyna; Arciszewska, Aleksandra; Starowicz-Filip, Anna; Siwek, Marcin; Dudek, Dominika

    2016-01-01

    Patients with schizophrenia (SZ) and bipolar disorder (BD) share subtle motor abnormalities called the neurological soft signs (NSS). Since in both diseases there is evidence for alterations in cerebellar functions, structure and connectivity, we expected that the cerebellar soft signs (CSS), analogue of NSS focusing strictly on cerebellar symptoms, would be also a common trait in SZ and BD. We examined 30 patients with BD, 30 patients with SZ and 28 control subjects using the Neurological Evaluation Scale (NES, for NSS) and International Cooperative Ataxia Rating Scale (ICARS, for CSS). SZ and BD did not differ in total and subscales' scores in both NES and ICARS. Subscale analysis revealed that SZ performed significantly worse than controls in all the subscales of both NES and ICARS. BD patients scored significantly worse than controls in all NES subscales and in oculomotor and kinetic subscales of the ICARS, while other ICARS subscales did not differentiate those two groups. To our knowledge this is the first study to show that CSS constitute common symptoms in BD and SZ. We recommend a special focus on those diseases in further research regarding structural and functional changes of cerebellum and their clinical outcome. PMID:26241859

  17. Characterization of the Brain Injury, Neurobehavioral Profiles and Histopathology in a Rat Model of Cerebellar Hemorrhage

    PubMed Central

    Lekic, Tim; Rolland, William; Hartman, Richard; Kamper, Joel; Suzuki, Hidenori; Tang, Jiping; Zhang, John H.

    2010-01-01

    Spontaneous cerebellar hemorrhage (SCH) represents approximately 10% of all intracerebral hemorrhage (ICH), and is an important clinical problem of which little is known. This study stereotaxically infused collagenase (type VII) into the deep cerebellar paramedian white matter, which corresponds to the most common clinical injury region. Measures of hemostasis (brain water, hemoglobin assay, Evans blue, collagen-IV, ZO-1, and MMP-2 and MMP-9) and neurodeficit were quantified twenty-four hours later (Experiment 1). Long-term functional outcomes were measured over thirty days using the ataxia scale (modified Luciani), open field, wire suspension, beam balance and inclined plane (Experiment 2). Neurocognitive ability was assessed on the third week using the rotarod (motor learning), T-maze (working memory) and water-maze (spatial learning and memory) (Experiment 3), followed by a histopathological analysis one week later (Experiment 4). Stereotaxic collagenase infusion caused dose-dependent elevations in brain edema, neurodeficit, hematoma volume and blood-brain barrier rupture, while physiological variables remained stable. Most functional outcomes normalized by third week, while neurocognitive testing showed deficits parallel to the cystic-cavitary lesion at thirty days. All animals survived until sacrifice, and obstructive hydrocephalus did not develop. These results suggest that the model can generate important translational information about this subtype of ICH, and could be used for future investigations of therapeutic mechanisms after cerebellar hemorrhage. PMID:20887722

  18. Infantile intracranial aneurysm of the superior cerebellar artery.

    PubMed

    Del Santo, Molly Ann; Cordina, Steve Mario

    2016-01-01

    Intracranial aneurysms in the pediatric population are rare. We report a case of a 3-month-old infant who presented with inconsolable crying, vomiting, and sunset eye sign. CT revealed a subarachnoid hemorrhage, with CT angiogram revealing a superior cerebellar artery aneurysm. An external ventricular drain was placed for acute management of hydrocephalus, with definitive treatment by endovascular technique with a total of six microcoils to embolize the aneurysm. Serial transcranial Dopplers revealed no subsequent vasospasm. Although aneurysms in the pediatric population are rare, once the diagnosis is established, early treatment results in better outcomes. PMID:26929222

  19. The contribution of the cerebellum to cognition in Spinocerebellar Ataxia Type 6.

    PubMed

    Cooper, Freya E; Grube, Manon; Elsegood, Kelly J; Welch, John L; Kelly, Thomas P; Chinnery, Patrick F; Griffiths, Timothy D

    2010-01-01

    This study sought evidence for a specific cerebellar contribution to cognition by characterising the cognitive phenotype of Spinocerebellar Ataxia Type 6 (SCA-6); an autosomal dominant genetic disease which causes a highly specific late-onset cerebellar degeneration. A comprehensive neuropsychological assessment was administered to 27 patients with genetically confirmed SCA-6. General intellectual ability, memory and executive function were examined using internationally standardised tests (Wechsler Adult Intelligence Scale-III, Wechsler Memory Scale-III, Delis and Kaplan Executive Function System, Brixton Spatial Anticipation test). The patient group showed no evidence of intellectual or memory decline. However, tests of executive function involving skills of cognitive flexibility, inhibition of response and verbal reasoning and abstraction demonstrated significant impairment at the group level with large effect sizes. The results demonstrate an executive deficit due to SCA-6 that can be conceptualised as parallel to the motor difficulties suffered by these patients: the data support a role for the cerebellum in the regulation and coordination of cognitive, as well as motor processes that is relevant to individual performance. PMID:20714057

  20. Parametric fMRI of paced motor responses uncovers novel whole-brain imaging biomarkers in spinocerebellar ataxia type 3.

    PubMed

    Duarte, João Valente; Faustino, Ricardo; Lobo, Mercês; Cunha, Gil; Nunes, César; Ferreira, Carlos; Januário, Cristina; Castelo-Branco, Miguel

    2016-10-01

    Machado-Joseph Disease, inherited type 3 spinocerebellar ataxia (SCA3), is the most common form worldwide. Neuroimaging and neuropathology have consistently demonstrated cerebellar alterations. Here we aimed to discover whole-brain functional biomarkers, based on parametric performance-level-dependent signals. We assessed 13 patients with early SCA3 and 14 healthy participants. We used a combined parametric behavioral/functional neuroimaging design to investigate disease fingerprints, as a function of performance levels, coupled with structural MRI and voxel-based morphometry. Functional magnetic resonance imaging (fMRI) was designed to parametrically analyze behavior and neural responses to audio-paced bilateral thumb movements at temporal frequencies of 1, 3, and 5 Hz. Our performance-level-based design probing neuronal correlates of motor coordination enabled the discovery that neural activation and behavior show critical loss of parametric modulation specifically in SCA3, associated with frequency-dependent cortico/subcortical activation/deactivation patterns. Cerebellar/cortical rate-dependent dissociation patterns could clearly differentiate between groups irrespective of grey matter loss. Our findings suggest functional reorganization of the motor network and indicate a possible role of fMRI as a tool to monitor disease progression in SCA3. Accordingly, fMRI patterns proved to be potential biomarkers in early SCA3, as tested by receiver operating characteristic analysis of both behavior and neural activation at different frequencies. Discrimination analysis based on BOLD signal in response to the applied parametric finger-tapping task significantly often reached >80% sensitivity and specificity in single regions-of-interest.Functional fingerprints based on cerebellar and cortical BOLD performance dependent signal modulation can thus be combined as diagnostic and/or therapeutic targets in hereditary ataxia. Hum Brain Mapp 37:3656-3668, 2016. © 2016 Wiley

  1. The Immp2l mutation causes age-dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment.

    PubMed

    Liu, Chunlian; Li, Xue; Lu, Baisong

    2016-02-01

    Reactive oxygen species are implicated in age-associated neurodegeneration, although direct in vivo evidence is lacking. We recently showed that mice with a mutation in the Inner Mitochondrial Membrane Peptidase 2-like (Immp2l) gene had elevated levels of mitochondrial superoxide, impaired fertility and age-associated phenotypes, including kyphosis and ataxia. Here we show that ataxia and cerebellar hypoplasia occur in old mutant mice (> 16 months). Cerebellar granule neurons (CGNs) are significantly underrepresented; Purkinje cells and cells in the molecular layer are not affected. Treating mutant mice with the mitochondria-targeted antioxidant SkQ1 from 6 weeks to 21 months protected cerebellar granule neurons. Apoptotic granule neurons were observed in mutant mice but not in age-matched normal control mice or SkQ1-treated mice. Old mutant mice showed increased serum protein carbonyl content, cerebellar 4-hydroxynonenal (HNE), and nitrotyrosine modification compared to old normal control mice. SOD2 expression was increased in Purkinje cells but decreased in granule neurons of old mutant mice. Mitochondrial marker protein VDAC1 also was decreased in CGNs of old mutant mice, suggesting decreased mitochondrial number. SkQ1 treatment decreased HNE and nitrotyrosine modification, and restored SOD2 and VDAC1 expression in CGNs of old mutant mice. Neuronal expression of nitric oxide synthase was increased in cerebella of young mutant mice but decreased in old mutant mice. Our work provides evidence for a causal role of oxidative stress in neurodegeneration of Immp2l mutant mice. The Immp2l mutant mouse model could be valuable in elucidating the role of oxidative stress in age-associated neurodegeneration. PMID:26616244

  2. A case of slowly progressive anti-Yo-associated paraneoplastic cerebellar degeneration successfully treated with antitumor and immunotherapy.

    PubMed

    Tsuboguchi, Shintaro; Yajima, Ryuji; Higuchi, You; Ishikawa, Masanori; Kawachi, Izumi; Koyama, Yu; Nishizawa, Masatoyo

    2016-07-28

    We report a case of slowly progressive anti-Yo-associated paraneoplastic cerebellar degeneration (PCD) with breast cancer in a 54-year-old woman. The symptoms of limb and truncal ataxia, and dysarthria gradually progressed during the course of 1 year, and the modified Rankin scale (mRS) score was 2. A mastectomy with sentinel lymph node resection was performed for the breast cancer. No malignant cells were found on histopathological examination of the lymph node. Combination chemotherapy with adriamycin and cyclophosphamide (AC) prevented neurologic deterioration. However, subsequent treatment with trastuzumab and paclitaxel did not prevent progression of the symptoms (mRS score 3). Brain magnetic resonance imaging showed atrophy of the cerebellar hemispheres without brain stem atrophy. Anti-Yo antibody was detected in the serum, which led to a diagnosis of anti-Yo-associated PCD. We resected an enlarged axillary lymph node, which was found on computed tomography. The histopathological analysis of the lymph node revealed foreign body granuloma, which suggested an association with necrotic malignant tissue. Following additional tegafur-uracil therapy and two courses of intravenous immunoglobulin (IVIg), the cerebellar signs and symptoms gradually improved (mRS score 2). The clinical course shows that PCD can present as a slowly progressive cerebellar symptom. We propose an active treatment for anti-Yo-associated PCD consisting of tumor resection, combined chemotherapy, and IVIg. PMID:27356731

  3. Cerebellar neurodegeneration in the absence of microRNAs

    PubMed Central

    Schaefer, Anne; O'Carroll, Dónal; Tan, Chan Lek; Hillman, Dean; Sugimori, Mutsuyuki; Llinas, Rodolfo; Greengard, Paul

    2007-01-01

    Genome-encoded microRNAs (miRNAs) are potent regulators of gene expression. The significance of miRNAs in various biological processes has been suggested by studies showing an important role of these small RNAs in regulation of cell differentiation. However, the role of miRNAs in regulation of differentiated cell physiology is not well established. Mature neurons express a large number of distinct miRNAs, but the role of miRNAs in postmitotic neurons has not been examined. Here, we provide evidence for an essential role of miRNAs in survival of differentiated neurons. We show that conditional Purkinje cell–specific ablation of the key miRNA-generating enzyme Dicer leads to Purkinje cell death. Deficiency in Dicer is associated with progressive loss of miRNAs, followed by cerebellar degeneration and development of ataxia. The progressive neurodegeneration in the absence of Dicer raises the possibility of an involvement of miRNAs in neurodegenerative disorders. PMID:17606634

  4. Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A.

    PubMed

    García Segarra, Nuria; Gautschi, Ivan; Mittaz-Crettol, Laureane; Kallay Zetchi, Christine; Al-Qusairi, Lama; Van Bemmelen, Miguel Xavier; Maeder, Philippe; Bonafé, Luisa; Schild, Laurent; Roulet-Perez, Eliane

    2014-07-15

    Mutations in the CACNA1A gene, encoding the α1 subunit of the voltage-gated calcium channel Ca(V)2.1 (P/Q-type), have been associated with three neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6). We report a child with congenital ataxia, abnormal eye movements and developmental delay who presented severe attacks of hemiplegic migraine triggered by minor head traumas and associated with hemispheric swelling and seizures. Progressive cerebellar atrophy was also observed. Remission of the attacks was obtained with acetazolamide. A de novo 3 bp deletion was found in heterozygosity causing loss of a phenylalanine residue at position 1502, in one of the critical transmembrane domains of the protein contributing to the inner part of the pore. We characterized the electrophysiology of this mutant in a Xenopus oocyte in vitro system and showed that it causes gain of function of the channel. The mutant Ca(V)2.1 activates at lower voltage threshold than the wild type. These findings provide further evidence of this molecular mechanism as causative of FHM1 and expand the phenotypic spectrum of CACNA1A mutations with a child exhibiting severe SHM1 and non-episodic ataxia of congenital onset. PMID:24836863

  5. A novel missense mutation in CACNA1A evaluated by in silico protein modeling is associated with non-episodic spinocerebellar ataxia with slow progression.

    PubMed

    Bürk, Katrin; Kaiser, Frank J; Tennstedt, Stephanie; Schöls, Ludger; Kreuz, Friedmar R; Wieland, Thomas; Strom, Tim M; Büttner, Thomas; Hollstein, Ronja; Braunholz, Diana; Plaschke, Jens; Gillessen-Kaesbach, Gabriele; Zühlke, Christine

    2014-04-01

    Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are allelic disorders of the gene CACNA1A encoding the P/Q subunit of a voltage gated calcium channel. While SCA6 is related to repeat expansions affecting the C-terminal part of the protein, EA2 and FHM phenotypes are usually associated with nonsense and missense mutations leading to impaired channel properties. In three unrelated families with dominant cerebellar ataxia, symptoms cosegregated with CACNA1A missense mutations of evolutionary highly conserved amino acids (exchanges p.E668K, p.R583Q and p.D302N). To evaluate pathogenic effects, in silico, protein modeling analyses were performed which indicate structural alterations of the novel mutation p.E668K within the homologous domain 2 affecting CACNA1A protein function. The phenotype is characterised by a very slowly progressive ataxia, while ataxic episodes or migraine are uncommon. These findings enlarge the phenotypic spectrum of CACNA1A mutations. PMID:24486772

  6. Learning of Sensory Sequences in Cerebellar Patients

    ERIC Educational Resources Information Center

    Frings, Markus; Boenisch, Raoul; Gerwig, Marcus; Diener, Hans-Christoph; Timmann, Dagmar

    2004-01-01

    A possible role of the cerebellum in detecting and recognizing event sequences has been proposed. The present study sought to determine whether patients with cerebellar lesions are impaired in the acquisition and discrimination of sequences of sensory stimuli of different modalities. A group of 26 cerebellar patients and 26 controls matched for…

  7. Metronidazole-Induced Cerebellar Toxicity

    PubMed Central

    Agarwal, Amit; Kanekar, Sangam; Sabat, Shyam; Thamburaj, Krishnamurthy

    2016-01-01

    Metronidazole is a very common antibacterial and antiprotozoal with wide usage across the globe, including the least developed countries. It is generally well-tolerated with a low incidence of serious side-effects. Neurological toxicity is fairly common with this drug, however majority of these are peripheral neuropathy with very few cases of central nervous toxicity reported. We report the imaging findings in two patients with cerebellar dysfunction after Metronidazole usage. Signal changes in the dentate and red nucleus were seen on magnetic resonance imaging in these patients. Most of the cases reported in literature reported similar findings, suggesting high predilection for the dentate nucleus in metronidazole induced encephalopathy. PMID:27127600

  8. Cellular and molecular basis of cerebellar development

    PubMed Central

    Martinez, Salvador; Andreu, Abraham; Mecklenburg, Nora; Echevarria, Diego

    2013-01-01

    Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering, and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification, and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function. PMID:23805080

  9. Dual Transgene Expression in Murine Cerebellar Purkinje Neurons by Viral Transduction In Vivo

    PubMed Central

    Bosch, Marie K.; Nerbonne, Jeanne M.; Ornitz, David M.

    2014-01-01

    Viral-vector mediated gene transfer to cerebellar Purkinje neurons in vivo is a promising avenue for gene therapy of cerebellar ataxias and for genetic manipulation in functional studies of animal models of cerebellar disease. Here, we report the results of experiments designed to identify efficient methods for viral transduction of adult murine Purkinje neurons in vivo. For these analyses, several lentiviral and an adeno-associated virus (AAV), serotype 1, vector with various promoter combinations were generated and compared for in situ transduction efficiency, assayed by fluorescent reporter protein expression in Purkinje neurons. Additional experiments were also conducted to identify the optimal experimental strategy for co-expression of two proteins in individual Purkinje neurons. Of the viruses tested, AAV1 with a CAG promoter exhibited the highest specificity for Purkinje neurons. To deliver two proteins to the same Purkinje neuron, several methods were tested, including: an internal ribosome entry site (IRES), a 2A sequence, a dual promoter vector, and co-injection of two viruses. Efficient expression of both proteins in the same Purkinje neuron was only achieved by co-injecting two AAV1-CAG viruses. We found that use of an AAV1-CAG virus outperformed similar lentivirus vectors and that co-injection of two AAV1-CAG viruses could be used to efficiently deliver two proteins to the same Purkinje neuron in adult mice. AAV1 with a CAG promoter is highly efficient and selective at transducing adult cerebellar Purkinje neurons and two AAV-CAG viruses can be used to efficiently express two proteins in the same neuron in vivo. PMID:25093726

  10. Thiamine and spinocerebellar ataxia type 2

    PubMed Central

    Costantini, Antonio; Pala, Maria Immacolata; Colangeli, Marco; Savelli, Serena

    2013-01-01

    Spinocerebellar ataxia type 2 is a genetic disorder characterised by the degeneration of the cerebellum, its connections and degeneration in brainstem areas. Some observations indicate that high doses of thiamine may lead to the partial regression of the symptoms. One patient was under rehabilitative treatment from June 2011 to July 2012. We assessed the level of fatigue using the Fatigue Severity Scale. We performed the Scale for Assessment and Rating of Ataxia and Robertson Profile for Dysarthria (Italian version). Thiamine and thiamine pyrophosphate levels in the blood were within the healthy reference range. We started a parenteral therapy with 100 mg intramuscular every 7 days. The therapy led to a partial regression of fatigue within a few days. After about 3 months, a discreet improvement of motor symptoms especially in speech was observed. The symptoms could derive from a focal thiamine deficiency that could determine a selective neuronal loss. PMID:23314445

  11. Ataxia-ocular motor apraxia syndrome: an investigation of cellular radiosensitivity of patients and their families.

    PubMed Central

    Hannan, M A; Sigut, D; Waghray, M; Gascon, G G

    1994-01-01

    Although ataxia-ocular motor apraxia (AOA) has been described as a disease entity mimicking ataxia telangiectasia (AT), no radiobiological studies have been carried out on cells from patients with AOA to find their possible relationship to AT. In the present study, cultured fibroblasts from three patients with AOA and their asymptomatic relatives (parents and sibs) were, therefore, compared with those from a classical AT homozygote, an AT heterozygote, and four healthy subjects for cell survival after acute and chronic irradiation. While a moderately increased cellular sensitivity (compared to normal) was observed in two AOA patients and most of their relatives, the degree of their radiosensitivity was quite different from that of the AT homozygote after both acute and chronic irradiation. One AOA patient exhibited increased cellular sensitivity similar to that of a classical AT homozygote up to 4% survival level after chronic irradiation but not after acute irradiation. A comparison of peripheral blood lymphocytes from two AOA patients, an AT homozygote, and two normal controls for spontaneous and (acute) radiation induced chromosomal breaks also failed to show any similarity between AOA and AT. These data support the notion that AOA is different from classical AT, and may represent a distinct disease entity controlled by specific gene(s), or compound heterozygotes involving different AT genes promoting the manifestation of AOA characteristics. PMID:7891378

  12. Developmental Cerebellar Cognitive Affective Syndrome in Ex-preterm Survivors Following Cerebellar Injury

    PubMed Central

    Brossard-Racine, Marie; du Plessis, Adre J.; Limperopoulos, Catherine

    2015-01-01

    Cerebellar injury is increasingly recognized as an important complication of very preterm birth. However, the neurodevelopmental consequences of early life cerebellar injury in prematurely born infants have not been well elucidated. We performed a literature search of studies published between 1997 and 2014 describing neurodevelopmental outcomes of preterm infants following direct cerebellar injury or indirect cerebellar injury/underdevelopment. Available data suggests that both direct and indirect mechanisms of cerebellar injury appear to stunt cerebellar growth and adversely affect neurodevelopment. This review also provides important insights into the highly integrated cerebral-cerebellar structural and functional correlates. Finally, this review highlights that early life impairment of cerebellar growth extends far beyond motor impairments and plays a critical, previously underrecognized role in the long-term cognitive, behavioral, and social deficits associated with brain injury among premature infants. These data point to a developmental form of the cerebellar cognitive affective syndrome previously described in adults. Longitudinal prospective studies using serial advanced magnetic resonance imaging techniques are needed to better delineate the full extent of the role of prematurity-related cerebellar injury and topography in the genesis of cognitive, social-behavioral dysfunction. PMID:25241880

  13. LXR agonist rescued the deficit in the proliferation of the cerebellar granule cells induced by dexamethasone.

    PubMed

    Bian, Xuting; Zhong, Hongyu; Li, Fen; Cai, Yulong; Li, Xin; Wang, Lian; Fan, Xiaotang

    2016-09-01

    Dexamethasone (DEX) exposure during early postnatal life produces permanent neuromotor and intellectual deficits and stunts cerebellar growth. The liver X receptor (LXR) plays important roles in CNS development. However, the effects of LXR on the DEX-mediated impairment of cerebellar development remain undetermined. Thus, mice were pretreated with LXR agonist TO901317 (TO) and were later exposed to DEX to evaluate its protective effects on DEX-mediated deficit during cerebellar development. The results showed that an acute exposure of DEX on postnatal day 7 resulted in a significant impairment in cerebellar development and decreased the proliferation of granule neuron precursors in the external granule layer of cerebellum. This effect was attenuated by pretreatment with TO. We further found that the decrease in the proliferation caused by DEX occurred via up-regulation of glucocorticoid receptor and p27kip1, which could be partially prevented by LXR agonist pretreatment. Overall, our results suggest that LXR agonist pretreatment could protect against DEX-induced deficits in cerebellar development in postnatal mice and may thus be perspective recruited to counteract such GC side effects. PMID:27369072

  14. Genome-wide mRNA sequencing of a single canine cerebellar cortical degeneration case leads to the identification of a disease associated SPTBN2 mutation

    PubMed Central

    2012-01-01

    Background Neonatal cerebellar cortical degeneration is a neurodegenerative disease described in several canine breeds including the Beagle. Affected Beagles are unable to ambulate normally from the onset of walking and the main pathological findings include Purkinje cell loss with swollen dendritic processes. Previous reports suggest an autosomal recessive mode of inheritance. The development of massively parallel sequencing techniques has presented the opportunity to investigate individual clinical cases using genome-wide sequencing approaches. We used genome-wide mRNA sequencing (mRNA-seq) of cerebellum tissue from a single Beagle with neonatal cerebellar cortical degeneration as a method of candidate gene sequencing, with the aim of identifying the causal mutation. Results A four-week old Beagle dog presented with progressive signs of cerebellar ataxia and the owner elected euthanasia. Histopathology revealed findings consistent with cerebellar cortical degeneration. Genome-wide mRNA sequencing (mRNA-seq) of RNA from cerebellum tissue was used as a method of candidate gene sequencing. After analysis of the canine orthologues of human spinocerebellar ataxia associated genes, we identified a homozygous 8 bp deletion in the β-III spectrin gene, SPTBN2, associated with spinocerebellar type 5 in humans. Genotype analysis of the sire, dam, ten clinically unaffected siblings, and an affected sibling from a previous litter, showed the mutation to fully segregate with the disorder. Previous studies have shown that β-III spectrin is critical for Purkinje cell development, and the absence of this protein can lead to cell damage through excitotoxicity, consistent with the observed Purkinje cell loss, degeneration of dendritic processes and associated neurological dysfunction in this Beagle. Conclusions An 8 bp deletion in the SPTBN2 gene encoding β-III spectrin is associated with neonatal cerebellar cortical degeneration in Beagle dogs. This study shows that m

  15. Ataxia with Vitamin E Deficiency May Present with Cervical Dystonia

    PubMed Central

    Becker, Andrew E.; Vargas, Wendy; Pearson, Toni S.

    2016-01-01

    Background Ataxia with vitamin E deficiency (AVED) is an autosomal recessive disorder that usually presents with ataxia, areflexia, and proprioceptive and vibratory sensory loss. Dystonia has been reported rarely. Case Report An 11-year-old female presented with dystonic head tremor and cervical and bilateral arm dystonia. Her 14-year-old older brother had dystonic head tremor and generalized dystonia. One year later, the brother developed dysarthria, limb dysmetria, and gait ataxia. Compound heterozygous mutations in TTPA were detected, confirming the diagnosis of AVED. Discussion AVED may present with dystonia rather than ataxia, and should be considered in the differential diagnosis of progressive dystonia. PMID:27274910

  16. Genetics Home Reference: PRICKLE1-related progressive myoclonus epilepsy with ataxia

    MedlinePlus

    ... myoclonus epilepsy with ataxia PRICKLE1-related progressive myoclonus epilepsy with ataxia Enable Javascript to view the expand/ ... All Close All Description PRICKLE1 -related progressive myoclonus epilepsy with ataxia is a rare inherited condition characterized ...

  17. Comparison of an expanded ataxia interactome with patient medical records reveals a relationship between macular degeneration and ataxia

    PubMed Central

    Kahle, Juliette J.; Gulbahce, Natali; Shaw, Chad A.; Lim, Janghoo; Hill, David E.; Barabási, Albert-László; Zoghbi, Huda Y.

    2011-01-01

    Spinocerebellar ataxias 6 and 7 (SCA6 and SCA7) are neurodegenerative disorders caused by expansion of CAG repeats encoding polyglutamine (polyQ) tracts in CACNA1A, the alpha1A subunit of the P/Q-type calcium channel, and ataxin-7 (ATXN7), a component of a chromatin-remodeling complex, respectively. We hypothesized that finding new protein partners for ATXN7 and CACNA1A would provide insight into the biology of their respective diseases and their relationship to other ataxia-causing proteins. We identified 118 protein interactions for CACNA1A and ATXN7 linking them to other ataxia-causing proteins and the ataxia network. To begin to understand the biological relevance of these protein interactions within the ataxia network, we used OMIM to identify diseases associated with the expanded ataxia network. We then used Medicare patient records to determine if any of these diseases co-occur with hereditary ataxia. We found that patients with ataxia are at 3.03-fold greater risk of these diseases than Medicare patients overall. One of the diseases comorbid with ataxia is macular degeneration (MD). The ataxia network is significantly (P= 7.37 × 10−5) enriched for proteins that interact with known MD-causing proteins, forming a MD subnetwork. We found that at least two of the proteins in the MD subnetwork have altered expression in the retina of Ataxin-7266Q/+ mice suggesting an in vivo functional relationship with ATXN7. Together these data reveal novel protein interactions and suggest potential pathways that can contribute to the pathophysiology of ataxia, MD, and diseases comorbid with ataxia. PMID:21078624

  18. Urgent decisions and a tight spot: embolic infarction of a herniated cerebellar tonsil.

    PubMed

    Mc Donagh, Ruth; Bradley, David; Harbison, Joseph Augustine

    2016-01-01

    A previously well 30-year-old woman presented at 17:30 with a sudden onset of dizziness, ataxia and headache. She was initially investigated with a CT scan of the brain and lumbar puncture, which yielded no diagnosis. Subsequent MR scan revealed multiple posterior circulation infarcts, along with a previously undiagnosed Arnold-Chiari 2 malformation with an associated syrinx of her cervical and thoracic spine. The infarct involved one of the herniated cerebellar tonsils. Oedema of an infarct in the herniated tonsils caused compression of the medulla at the foramen magnum, with associated neurological symptoms including Lhermitte's phenomenon and headache on valsalva manoeuvre. Owing to these symptoms a surgical decompression was performed. The most likely aetiology of her stroke was determined to be a paradoxical embolus via patent foramen ovale. PMID:27489065

  19. Multilobular tumour of the caudal cranium causing severe cerebral and cerebellar compression in a dog

    PubMed Central

    Psychas, Vassilios; Polizopoulou, Zoe S.; Sofianidis, Georgios

    2009-01-01

    Multilobular tumour of bone (MTB) is an uncommon tumour and is usually located in the skull. A 13-year-old mixed breed dog was presented with a two-week history of progressively worsening vestibular dysfunction and cognitive abnormalities; it appeared demented and showed asymmetric ataxia and hypermetria of all limbs. The owner opted to have the animal euthanised. Necropsy revealed a large mass occupying the right occipital, parietal and temporal bones, severely compressing the cerebellum and the right occipital lobe. Histologically, it was characterised by the presence of multiple lobules containing osteoid or cartilage and separated by fibrous septae, features typical of MTB. Lung metastases were evident. To our knowledge, this is the first report of an MTB causing both severe cerebral and cerebellar compression and the second detailed report of an MTB of the occipital bone. MTB should be included in the differential diagnosis of bone tumours as well as in cases with central vestibular disease. PMID:19255529

  20. Pediatric Neurocutaneous Syndromes with Cerebellar Involvement.

    PubMed

    Bosemani, Thangamadhan; Huisman, Thierry A G M; Poretti, Andrea

    2016-08-01

    Neurocutaneous syndromes encompasses a broad group of genetic disorders with different clinical, genetic, and pathologic features that share developmental lesions of the skin as well as central and peripheral nervous system. Cerebellar involvement has been shown in numerous types of neurocutaneous syndrome. It may help or be needed for the diagnosis and to explain the cognitive and behavioral phenotype of affected children. This article describes various types of neurocutaneous syndrome with cerebellar involvement. For each neurocutaneous disease or syndrome, clinical features, genetic, neuroimaging findings, and the potential role of the cerebellar involvement is discussed. PMID:27423801

  1. Sonic hedgehog patterning during cerebellar development.

    PubMed

    De Luca, Annarita; Cerrato, Valentina; Fucà, Elisa; Parmigiani, Elena; Buffo, Annalisa; Leto, Ketty

    2016-01-01

    The morphogenic factor sonic hedgehog (Shh) actively orchestrates many aspects of cerebellar development and maturation. During embryogenesis, Shh signaling is active in the ventricular germinal zone (VZ) and represents an essential signal for proliferation of VZ-derived progenitors. Later, Shh secreted by Purkinje cells sustains the amplification of postnatal neurogenic niches: the external granular layer and the prospective white matter, where excitatory granule cells and inhibitory interneurons are produced, respectively. Moreover, Shh signaling affects Bergmann glial differentiation and promotes cerebellar foliation during development. Here we review the most relevant functions of Shh during cerebellar ontogenesis, underlying its role in physiological and pathological conditions. PMID:26499980

  2. Alcohol enhances GABAergic transmission to cerebellar granule cells via an increase in Golgi cell excitability.

    PubMed

    Carta, Mario; Mameli, Manuel; Valenzuela, C Fernando

    2004-04-14

    Alcohol intoxication alters coordination and motor skills, and this is responsible for a significant number of traffic accident-related deaths around the world. Although the precise mechanism of action of ethanol (EtOH) is presently unknown, studies suggest that it acts, in part, by interfering with normal cerebellar functioning. An important component of cerebellar circuits is the granule cell. The excitability of these abundantly expressed neurons is controlled by the Golgi cell, a subtype of GABAergic interneuron. Granule cells receive GABAergic input in the form of phasic and tonic currents that are mediated by synaptic and extrasynaptic receptors, respectively. Using the acute cerebellar slice preparation and patch-clamp electrophysiological techniques, we found that ethanol induces a parallel increase in both the frequency of spontaneous IPSCs and the magnitude of the tonic current. EtOH (50 mm) did not produce this effect when spontaneous action potentials were blocked with tetrodotoxin. Recordings in the loose-patch cell-attached configuration demonstrated that ethanol increases the frequency of spontaneous action potentials in Golgi cells. Taken together, these findings indicate that ethanol enhances GABAergic inhibition of granule cells via a presynaptic mechanism that involves an increase in action potential-dependent GABA release from Golgi cells. This effect is likely to have an impact on the flow of information through the cerebellar cortex and may contribute to the mechanism by which acute ingestion of alcoholic beverages induces motor impairment. PMID:15084654

  3. Genetics Home Reference: VLDLR-associated cerebellar hypoplasia

    MedlinePlus

    ... malformation leads to problems with balance and coordination (ataxia) that become apparent in infancy and remain stable ... The resulting problems with brain development lead to ataxia and the other major features of this condition. ...

  4. Electrophysiologic characterization in spinocerebellar ataxia 17.

    PubMed

    Manganelli, F; Perretti, A; Nolano, M; Lanzillo, B; Bruni, A C; De Michele, G; Filla, A; Santoro, L

    2006-03-28

    The authors performed a multimodal electrophysiologic evaluation in nine patients belonging to four SCA17 (spinocerebellar ataxia type 17) families. Peripheral nerve and visual system were not involved. Brainstem auditory evoked potentials were constantly abnormal with central type lesions. Magnetic motor evoked potentials were abnormal only in the lower limbs, suggesting a length-dependent involvement of the pyramidal tract. Somatosensory evoked potentials were abnormal in almost all our patients, and abnormalities were consistent with a somatosensory pathway involvement along the brainstem. PMID:16567717

  5. Longitudinal Cerebral Blood Flow Changes during Speech in Hereditary Ataxia

    ERIC Educational Resources Information Center

    Sidtis, John J.; Strother, Stephen C.; Naoum, Ansam; Rottenberg, David A.; Gomez, Christopher

    2010-01-01

    The hereditary ataxias constitute a group of degenerative diseases that progress over years or decades. With principal pathology involving the cerebellum, dysarthria is an early feature of many of the ataxias. Positron emission tomography was used to study regional cerebral blood flow changes during speech production over a 21 month period in a…

  6. Dysarthria and Friedreich's Ataxia: What Can Intelligibility Assessment Tell Us?

    ERIC Educational Resources Information Center

    Blaney, Bronagh; Hewlett, Nigel

    2007-01-01

    Background: Friedreich's ataxia is one of the most common hereditary disorders of the nervous system. Dysarthria is a pervasive symptom of Friedreich's ataxia, yet the clinical presentation of speech symptoms remains poorly understood, leaving clinicians without the evidence required to develop therapy interventions. Aims: The research reported…

  7. Individuals with cerebellar degeneration show similar adaptation deficits with large and small visuomotor errors

    PubMed Central

    Xu, Jing; Klemfuss, Nola M.; Griffiths, Thomas L.; Ivry, Richard B.

    2013-01-01

    The cerebellum has long been recognized to play an important role in motor adaptation. Individuals with cerebellar ataxia exhibit impaired learning in visuomotor adaptation tasks such as prism adaptation and force field learning. Both types of tasks involve the adjustment of an internal model to compensate for an external perturbation. This updating process is error driven, with the error signal based on the difference between anticipated and actual sensory information. This process may entail a credit assignment problem, with a distinction made between error arising from faulty representation of the environment and error arising from noise in the controller. We hypothesized that people with ataxia may perform poorly at visuomotor adaptation because they attribute a greater proportion of their error to their motor control difficulties. We tested this hypothesis using a computational model based on a Kalman filter. We imposed a 20-deg visuomotor rotation in either a single large step or in a series of smaller 5-deg steps. The ataxic group exhibited a comparable deficit in both conditions. The computational analyses indicate that the patients' deficit cannot be accounted for simply by their increased motor variability. Rather, the patients' deficit in learning may be related to difficulty in estimating the instability in the environment or variability in their motor system. PMID:23197450

  8. Ataxia with oculomotor apraxia type1 (AOA1): novel and recurrent aprataxin mutations, coenzyme Q10 analyses, and clinical findings in Italian patients.

    PubMed

    Castellotti, Barbara; Mariotti, Caterina; Rimoldi, Marco; Fancellu, Roberto; Plumari, Massimo; Caimi, Sara; Uziel, Graziella; Nardocci, Nardo; Moroni, Isabella; Zorzi, Giovanna; Pareyson, Davide; Di Bella, Daniela; Di Donato, Stefano; Taroni, Franco; Gellera, Cinzia

    2011-08-01

    Ataxia with oculomotor apraxia type1 (AOA1, MIM 208920) is a rare autosomal recessive disease caused by mutations in the APTX gene. We screened a cohort of 204 patients with cerebellar ataxia and 52 patients with early-onset isolated chorea. APTX gene mutations were found in 13 ataxic patients (6%). Eleven patients were homozygous for the known p.W279X, p.W279R, and p.P206L mutations. Three novel APTX mutations were identified: c.477delC (p.I159fsX171), c.C541T (p.Q181X), and c.C916T (p.R306X). Expression of mutated proteins in lymphocytes from these patients was greatly decreased. No mutations were identified in subjects with isolated chorea. Two heterozygous APTX sequence variants (p.L248M and p.D185E) were found in six families with ataxic phenotype. Analyses of coenzyme Q10 in muscle, fibroblasts, and plasma demonstrated normal levels of coenzyme in five of six mutated subjects. The clinical phenotype was homogeneous, irrespectively of the type and location of the APTX mutation, and it was mainly characterized by early-onset cerebellar signs, sensory neuropathy, cognitive decline, and oculomotor deficits. Three cases had slightly raised alpha-fetoprotein. Our survey describes one of the largest series of AOA1 patients and contributes in defining clinical, molecular, and biochemical characteristics of this rare hereditary neurological condition. PMID:21465257

  9. Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.

    PubMed

    Chen, Dong-Hui; Below, Jennifer E; Shimamura, Akiko; Keel, Sioban B; Matsushita, Mark; Wolff, John; Sul, Youngmee; Bonkowski, Emily; Castella, Maria; Taniguchi, Toshiyasu; Nickerson, Deborah; Papayannopoulou, Thalia; Bird, Thomas D; Raskind, Wendy H

    2016-06-01

    Ataxia-pancytopenia (AP) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure and myeloid leukemia, sometimes associated with monosomy 7. Here, in the four-generation family UW-AP, linkage analysis revealed four regions that provided the maximal LOD scores possible, one of which was in a commonly microdeleted chromosome 7q region. Exome sequencing identified a missense mutation (c.2640C>A, p.His880Gln) in the sterile alpha motif domain containing 9-like gene (SAMD9L) that completely cosegregated with disease. By targeted sequencing of SAMD9L, we subsequently identified a different missense mutation (c.3587G>C, p.Cys1196Ser) in affected members of the first described family with AP syndrome, Li-AP. Neither variant is reported in the public databases, both affect highly conserved amino acid residues, and both are predicted to be damaging. With time in culture, lymphoblastic cell lines (LCLs) from two affected individuals in family UW-AP exhibited copy-neutral loss of heterozygosity for large portions of the long arm of chromosome 7, resulting in retention of only the wild-type SAMD9L allele. Newly established LCLs from both individuals demonstrated the same phenomenon. In addition, targeted capture and sequencing of SAMD9L in uncultured blood DNA from both individuals showed bias toward the wild-type allele. These observations indicate in vivo hematopoietic mosaicism. The hematopoietic cytopenias that characterize AP syndrome and the selective advantage for clones that have lost the mutant allele support the postulated role of SAMD9L in the regulation of cell proliferation. Furthermore, we show that AP syndrome is distinct from the dyskeratoses congenita telomeropathies, with which it shares some clinical characteristics. PMID:27259050

  10. In vivo neurometabolic profiling in patients with spinocerebellar ataxia types 1, 2, 3, and 7.

    PubMed

    Adanyeguh, Isaac M; Henry, Pierre-Gilles; Nguyen, Tra M; Rinaldi, Daisy; Jauffret, Celine; Valabregue, Romain; Emir, Uzay E; Deelchand, Dinesh K; Brice, Alexis; Eberly, Lynn E; Öz, Gülin; Durr, Alexandra; Mochel, Fanny

    2015-04-15

    Spinocerebellar ataxias (SCAs) belong to polyglutamine repeat disorders and are characterized by a predominant atrophy of the cerebellum and the pons. Proton magnetic resonance spectroscopy ((1) H MRS) using an optimized semiadiabatic localization by adiabatic selective refocusing (semi-LASER) protocol was performed at 3 T to determine metabolite concentrations in the cerebellar vermis and pons of a cohort of patients with SCA1 (n=16), SCA2 (n=12), SCA3 (n=21), and SCA7 (n=12) and healthy controls (n=33). Compared with controls, patients displayed lower total N-acetylaspartate and, to a lesser extent, lower glutamate, reflecting neuronal loss/dysfunction, whereas the glial marker, myoinositol (myo-Ins), was elevated. Patients also showed higher total creatine as reported in Huntington's disease, another polyglutamine repeat disorder. A strong correlation was found between the Scale for the Assessment and Rating of Ataxia and the neurometabolites in both affected regions of patients. Principal component analyses confirmed that neuronal metabolites (total N-acetylaspartate and glutamate) were inversely correlated in the vermis and the pons to glial (myo-Ins) and energetic (total creatine) metabolites, as well as to disease severity (motor scales). Neurochemical plots with selected metabolites also allowed the separation of SCA2 and SCA3 from controls. The neurometabolic profiles detected in patients underlie cell-specific changes in neuronal and astrocytic compartments that cannot be assessed by other neuroimaging modalities. The inverse correlation between metabolites from these two compartments suggests a metabolic attempt to compensate for neuronal damage in SCAs. Because these biomarkers reflect dynamic aspects of cellular metabolism, they are good candidates for proof-of-concept therapeutic trials. © 2015 International Parkinson and Movement Disorder Society. PMID:25773989

  11. In vivo neurometabolic profiling in patients with spinocerebellar ataxia type 1, 2, 3 and 7

    PubMed Central

    Adanyeguh, Isaac M.; Henry, Pierre-Gilles; Nguyen, Tra M.; Rinaldi, Daisy; Jauffret, Celine; Valabregue, Romain; Emir, Uzay E.; Deelchand, Dinesh K.; Brice, Alexis; Eberly, Lynn E.; Öz, Gülin; Durr, Alexandra; Mochel, Fanny

    2015-01-01

    Background Spinocerebellar Ataxias (SCAs) belong to polyglutamine repeat disorders and are characterized by a predominant atrophy of the cerebellum and the pons. Methods Proton magnetic resonance spectroscopy (1H MRS) using an optimised semiadiabatic localization by adiabatic selective refocusing (semi-LASER) protocol was performed at 3 T to determine metabolite concentrations in the cerebellar vermis and pons of a cohort of patients with SCA1 (n = 16), SCA2 (n = 12), SCA3 (n = 21), SCA7 (n = 12) and healthy controls (n = 33). Results Compared to controls, patients displayed lower total N-acetylaspartate and, to a lesser extent, lower glutamate, reflecting neuronal loss/dysfunction, while the glial marker, myo-inositol, was elevated. Patients also showed higher total creatine as reported in Huntington disease, another polyglutamine repeat disorder. There was a strong correlation between the Scale for the Assessment and Rating of Ataxia and the neurometabolites in both affected regions of patients. Principal component analyses confirmed that neuronal metabolites (total N-acetylaspartate and glutamate) were inversely correlated in the vermis and the pons to glial (myo-inositol) and energetic (total creatine) metabolites, as well as to disease severity (motor scales). Neurochemical plots with selected metabolites also allowed the separation of SCA2 and SCA3 from controls. Conclusion The neurometabolic profiles detected in patients underlie cell-specific changes in neuronal and astrocytic compartments that cannot be assessed by other neuroimaging modalities. The inverse correlation between metabolites from these two compartments suggests a metabolic attempt to compensate for neuronal damage in SCAs. Because these biomarkers reflect dynamic aspects of cellular metabolism, they are good candidates for proof-of-concept therapeutic trials. PMID:25773989

  12. Expression of Caytaxin Protein in Cayman Ataxia Mouse Models Correlates with Phenotype Severity

    PubMed Central

    Sikora, Kristine M.; Nosavanh, LaGina M.; Kantheti, Prameela; Burmeister, Margit; Hortsch, Michael

    2012-01-01

    Caytaxin is a highly-conserved protein, which is encoded by the Atcay/ATCAY gene. Mutations in Atcay/ATCAY have been identified as causative of cerebellar disorders such as the rare hereditary disease Cayman ataxia in humans, generalized dystonia in the dystonic (dt) rat, and marked motor defects in three ataxic mouse lines. While several lines of evidence suggest that Caytaxin plays a critical role in maintaining nervous system processes, the physiological function of Caytaxin has not been fully characterized. In the study presented here, we generated novel specific monoclonal antibodies against full-length Caytaxin to examine endogenous Caytaxin expression in wild type and Atcay mutant mouse lines. Caytaxin protein is absent from brain tissues in the two severely ataxic Atcayjit (jittery) and Atcayswd (sidewinder) mutant lines, and markedly decreased in the mildly ataxic/dystonic Atcayji-hes (hesitant) line, indicating a correlation between Caytaxin expression and disease severity. As the expression of wild type human Caytaxin in mutant sidewinder and jittery mice rescues the ataxic phenotype, Caytaxin’s physiological function appears to be conserved between the human and mouse orthologs. Across multiple species and in several neuronal cell lines Caytaxin is expressed as several protein isoforms, the two largest of which are caused by the usage of conserved methionine translation start sites. The work described in this manuscript presents an initial characterization of the Caytaxin protein and its expression in wild type and several mutant mouse models. Utilizing these animal models of human Cayman Ataxia will now allow an in-depth analysis to elucidate Caytaxin’s role in maintaining normal neuronal function. PMID:23226316

  13. Friedreich`s ataxia in American families

    SciTech Connect

    D`Costa, A.; Maguire, B.A.; Sylvester, J.E.

    1994-09-01

    Freidreich`s ataxia (FRDA) is a progressive neurodegenerative disorder presenting with dysarthia, loss of tendon reflexes, and ataxic gait. Both diabetes mellitus and cardiomyopathy are frequently found associated with the disease. The gene, FRDA, has been localized to 9q13-21. Recent reports of recombination events in individuals homozygous by descent have positioned the gene to a 450 KB region in the FRDA locus centromeric to the original markers. Candidate cDNA`s have been isolated from part of this region, and characterized, but not shown to be responsible for the disease. We have performed linkage analysis on 46 American families with markers in the FRDA region. A recombination has been detected in a family which has the phenotypic criteria for Friedreich`s; none of the three affected exhibit signs of cardiomyopathy which is a required diagnostic criteria. Since this recombination lies within the now excluded D9S5/D9S15 region, it is being tested for linkage to the {open_quotes}ataxia with selective vitamin E deficiency{close_quotes} (AVED) locus on chromosome 8q. Our lab has work in progress to subclone appropriate regions from YACs in order to identify expressed sequences and nucleotide variations (by SSCP) in the FRDA locus.

  14. Mitochondrial dysfunction in ataxia-telangiectasia.

    PubMed

    Valentin-Vega, Yasmine A; Maclean, Kirsteen H; Tait-Mulder, Jacqueline; Milasta, Sandra; Steeves, Meredith; Dorsey, Frank C; Cleveland, John L; Green, Douglas R; Kastan, Michael B

    2012-02-01

    Ataxia-telangiectasia mutated (ATM) plays a central role in DNA damage responses, and its loss leads to development of T-cell malignancies. Here, we show that ATM loss also leads to intrinsic mitochondrial abnormalities in thymocytes, including elevated reactive oxygen species, increased aberrant mitochondria, high cellular respiratory capacity, and decreased mitophagy. A fraction of ATM protein is localized in mitochondria, and it is rapidly activated by mitochondrial dysfunction. Unexpectedly, allelic loss of the autophagy regulator Beclin-1 significantly delayed tumor development in ATM-null mice. This effect was not associated with rescue of DNA damage signaling but rather with a significant reversal of the mitochondrial abnormalities. These data support a model in which ATM plays direct roles in modulating mitochondrial homeostasis and suggest that mitochondrial dysfunction and associated increases in mitochondrial reactive oxygen species contribute to the cancer-prone phenotype observed in organisms lacking ATM. Thus, ataxia-telangiectasia should be considered, at least in part, as a mitochondrial disease. PMID:22144182

  15. Cerebellar White Matter Abnormalities following Primary Blast Injury in US Military Personnel

    PubMed Central

    Mac Donald, Christine; Johnson, Ann; Cooper, Dana; Malone, Thomas; Sorrell, James; Shimony, Joshua; Parsons, Matthew; Snyder, Abraham; Raichle, Marcus; Fang, Raymond; Flaherty, Stephen; Russell, Michael; Brody, David L.

    2013-01-01

    Little is known about the effects of blast exposure on the human brain in the absence of head impact. Clinical reports, experimental animal studies, and computational modeling of blast exposure have suggested effects on the cerebellum and brainstem. In US military personnel with isolated, primary blast-related ‘mild’ traumatic brain injury and no other known insult, we found diffusion tensor MRI abnormalities consistent with cerebellar white matter injury in 3 of 4 subjects. No abnormalities in other brain regions were detected. These findings add to the evidence supporting the hypothesis that primary blast exposure contributes to brain injury in the absence of head impact and that the cerebellum may be particularly vulnerable. However, the clinical effects of these abnormalities cannot be determined with certainty; none of the subjects had ataxia or other detected evidence of cerebellar dysfunction. The details of the blast events themselves cannot be disclosed at this time, thus additional animal and computational modeling will be required to dissect the mechanisms underlying primary blast-related traumatic brain injury. Furthermore, the effects of possible subconcussive impacts and other military-related exposures cannot be determined from the data presented. Thus many aspects of topic will require further investigation. PMID:23409052

  16. Primary cerebellar extramedullary myeloid cell tumor mimicking oligodendroglioma.

    PubMed

    Ho, D M; Wong, T T; Guo, W Y; Chang, K P; Yen, S H

    1997-10-01

    Extramedullary myeloid cell tumors (EMCTs) are tumors consisting of immature cells of the myeloid series that occur outside the bone marrow. Most of them are associated with acute myelogenous leukemia or other myeloproliferative disorders, and a small number occur as primary lesions, i.e., are not associated with hematological disorders. Occurrence inside the cranium is rare, and there has been only one case of primary EMCT involving the cerebellum reported in the literature. The case we report here is a blastic EMCT occurring in the cerebellum of a 3-year-old boy who had no signs of leukemia or any hematological disorder throughout the entire course. The cerebellar tumor was at first misdiagnosed as an "oligodendroglioma" because of the uniformity and "fried egg" artifact of the tumor cells. The tumor disappeared during chemotherapy consisting of 12 treatments. However, it recurred and metastasized to the cerebrospinal fluid (CSF) shortly after the therapy was completed. A diagnosis of EMCT was suspected because of the presence of immature myeloid cells in the CSF, and was confirmed by anti-myeloperoxidase and anti-lysozyme immunoreactivity of the cerebellar tumor. The patient succumbed 1 year and 3 months after the first presentation of the disease. PMID:9341943

  17. Social and Cultural Elements Associated with Neurocognitive Dysfunctions in Spinocerebellar Ataxia Type 2 Patients

    PubMed Central

    Mercadillo, Roberto Emmanuele; Galvez, Víctor; Díaz, Rosalinda; Paredes, Lorena; Velázquez-Moctezuma, Javier; Hernandez-Castillo, Carlos R.; Fernandez-Ruiz, Juan

    2015-01-01

    Spinocerebellar Ataxia Type 2 (SCA2) is a rare genetic disorder producing cerebellar degeneration and affecting motor abilities. Neuroimaging studies also show neurodegeneration in subcortical and cortical regions related to emotional and social processes. From social neuroscience, it is suggested that motor and social abilities can be influenced by particular cultural dynamics so, culture is fundamental to understand the effect of brain-related alterations. Here, we present the first analysis about the cultural elements related to the SCA2 disorder in 15 patients previously evaluated with neuroimaging and psychometric instruments, and their nuclear relationships distributed in six geographical and cultural regions in Mexico. Ethnographic records and photographic and video archives about the quotidian participant’s routine were obtained from the patients, their relatives and their caregivers. The information was categorized and interpreted taking into consideration cultural issues and patients’ medical files. Our analyses suggest that most of the participants do not understand the nature of the disease and this misunderstanding favors magic and non-medical explanations. Patients’ testimonies suggest a decrease in pain perception as well as motor alterations that may be related to interoceptive dysfunctions. Relatives’ testimonies indicate patients’ lack of social and emotional interests that may be related to frontal, temporal, and cerebellar degeneration. In general, participants use their religious beliefs to deal with the disease and only a few of them trust the health system. Patients and their families are either openly rejected and ignored, tolerated or even helped by their community accordingly to different regional traits. We propose that ethnography can provide social representations to understand the patients’ alterations, to formulate neurobiological hypotheses, to develop neurocognitive interventions, and to improve the medical approach to

  18. Social and Cultural Elements Associated with Neurocognitive Dysfunctions in Spinocerebellar Ataxia Type 2 Patients.

    PubMed

    Mercadillo, Roberto Emmanuele; Galvez, Víctor; Díaz, Rosalinda; Paredes, Lorena; Velázquez-Moctezuma, Javier; Hernandez-Castillo, Carlos R; Fernandez-Ruiz, Juan

    2015-01-01

    Spinocerebellar Ataxia Type 2 (SCA2) is a rare genetic disorder producing cerebellar degeneration and affecting motor abilities. Neuroimaging studies also show neurodegeneration in subcortical and cortical regions related to emotional and social processes. From social neuroscience, it is suggested that motor and social abilities can be influenced by particular cultural dynamics so, culture is fundamental to understand the effect of brain-related alterations. Here, we present the first analysis about the cultural elements related to the SCA2 disorder in 15 patients previously evaluated with neuroimaging and psychometric instruments, and their nuclear relationships distributed in six geographical and cultural regions in Mexico. Ethnographic records and photographic and video archives about the quotidian participant's routine were obtained from the patients, their relatives and their caregivers. The information was categorized and interpreted taking into consideration cultural issues and patients' medical files. Our analyses suggest that most of the participants do not understand the nature of the disease and this misunderstanding favors magic and non-medical explanations. Patients' testimonies suggest a decrease in pain perception as well as motor alterations that may be related to interoceptive dysfunctions. Relatives' testimonies indicate patients' lack of social and emotional interests that may be related to frontal, temporal, and cerebellar degeneration. In general, participants use their religious beliefs to deal with the disease and only a few of them trust the health system. Patients and their families are either openly rejected and ignored, tolerated or even helped by their community accordingly to different regional traits. We propose that ethnography can provide social representations to understand the patients' alterations, to formulate neurobiological hypotheses, to develop neurocognitive interventions, and to improve the medical approach to the disease

  19. Seeking a unified framework for cerebellar function and dysfunction: from circuit operations to cognition

    PubMed Central

    D'Angelo, Egidio; Casali, Stefano

    2013-01-01

    Following the fundamental recognition of its involvement in sensory-motor coordination and learning, the cerebellum is now also believed to take part in the processing of cognition and emotion. This hypothesis is recurrent in numerous papers reporting anatomical and functional observations, and it requires an explanation. We argue that a similar circuit structure in all cerebellar areas may carry out various operations using a common computational scheme. On the basis of a broad review of anatomical data, it is conceivable that the different roles of the cerebellum lie in the specific connectivity of the cerebellar modules, with motor, cognitive, and emotional functions (at least partially) segregated into different cerebro-cerebellar loops. We here develop a conceptual and operational framework based on multiple interconnected levels (a meta-levels hypothesis): from cellular/molecular to network mechanisms leading to generation of computational primitives, thence to high-level cognitive/emotional processing, and finally to the sphere of mental function and dysfunction. The main concept explored is that of intimate interplay between timing and learning (reminiscent of the “timing and learning machine” capabilities long attributed to the cerebellum), which reverberates from cellular to circuit mechanisms. Subsequently, integration within large-scale brain loops could generate the disparate cognitive/emotional and mental functions in which the cerebellum has been implicated. We propose, therefore, that the cerebellum operates as a general-purpose co-processor, whose effects depend on the specific brain centers to which individual modules are connected. Abnormal functioning in these loops could eventually contribute to the pathogenesis of major brain pathologies including not just ataxia but also dyslexia, autism, schizophrenia, and depression. PMID:23335884

  20. Implications on cerebellar function from information coding.

    PubMed

    Huang, Chiming

    2008-01-01

    One function of the cerebellar cortex is to process information. There are at least two types of information. Temporal information is encoded in the timing pattern of action and synaptic potentials, whereas structural information is encoded in the spatial pattern of the cerebellar synaptic circuitry. Intuitively, analysis of highly complex information in the time domain would require a cerebellar cortex with structural complexity to match. Information theory offers a way to estimate quantitatively both types of information and thereby helps to test hypotheses or advance theories of cerebellar neurobiology. These estimates suggest: (i) That the mossy-fiber-granule-cell system carries far more (temporal) information than the climbing fiber system, (ii) that Purkinje cells extract only a fraction of the (temporal) information from their afferents, and (iii) that the cerebellar cortex has a large (spatial) information coding capacity. Concerning information, one can argue that the cerebellar cortex analyzes temporal information in its afferents as a search engine, in search of coincidental mossy fiber events based on timing cues provided by climbing fiber events. Results of successive searches are continuously being converted into structural information encoded in the spatial distribution pattern of granule-cell-Purkinje-cell synapses along granule cell axons, thereby providing an adaptive and indeed self-correcting dimension to the structural information code. The search engine operation involves cellular mechanisms acting on temporal events and is part of an associative learning process. The conversion and generation of structural information involves neuroplasticity mechanisms acting at the synaptic level, with electrophysiological as well as structural consequences, and may be part of the short- and long-term memory process. These and other attributes qualify the cerebellar cortex as a dynamic information processing center, contributing to memory and learning while

  1. Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease.

    PubMed

    Pierce, Sarah B; Gulsuner, Suleyman; Stapleton, Gail A; Walsh, Tom; Lee, Ming K; Mandell, Jessica B; Morales, Augusto; Klevit, Rachel E; King, Mary-Claire; Rogers, R Curtis

    2016-07-01

    Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism. Whole-exome sequencing revealed that the patient is compound heterozygous for previously unreported variants in the C10orf2 gene: a paternally inherited frameshift variant (c.333delT; p.L112Sfs*3) and a maternally inherited missense variant (c.904C>T; p.R302W). The identification of novel C10orf2 mutations extends the spectrum of mutations in the Twinkle helicase causing recessive disease, in particular the intermediate IOSCA phenotype. Structural modeling suggests that the p.R302W mutation and many other recessively inherited Twinkle mutations impact the position or interactions of the linker region, which is critical for the oligomeric ring structure and activity of the helicase. This study emphasizes the utility of whole-exome sequencing for the genetic diagnosis of a complex multisystemic disorder. PMID:27551684

  2. Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature.

    PubMed

    Nachbauer, Wolfgang; Nocker, Michael; Karner, Elfriede; Stankovic, Iva; Unterberger, Iris; Eigentler, Andreas; Schneider, Rainer; Poewe, Werner; Delazer, Margarete; Boesch, Sylvia

    2014-05-01

    Episodic ataxia type 2 (EA2) is an autosomal dominant inherited neurological disorder that is characterized by paroxysmal episodes of ataxia. The causative gene for EA2 is CACNA1A which codes for the alpha 1A subunit of the voltage-gated P/Q-type calcium channel (Cav2.1). We detected a novel point mutation in the CACNA1A gene in a large Austrian family. All ten affected family members harbored a heterozygous c.3089+2T>C nucleotide exchange in intron 19. In silico modeling demonstrated a loss of the splice site of exon 19 by the mutation, which most likely results in exon skipping without frameshifting or use of an alternative splice site.Clinically, the family exhibited frequent ataxic episodes accompanied by headache in some individuals, which showed a good treatment response to acetazolamide or aminopyridine. Interictal phenotype variability was high ranging from an unremarkable clinical examination to a progressive cerebellar syndrome. Detailed cognitive testing with standardized neuropsychological tests revealed specific deficits in various domains including memory,executive functions and visual abilities. Moreover, a striking coincidence of socio-phobic behavior and anxiety disorders was detected within this family, which interfered with activities of daily living and has to be taken in consideration in EA2 patient management. We here characterize the phenotype of this novel CACNA1A mutation,review the respective literature and discuss implications on diagnosis and patient management. PMID:24658662

  3. Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1.

    PubMed

    Platonov, Fedor A; Tyryshkin, Kathrin; Tikhonov, Dmitriy G; Neustroyeva, Tatyana S; Sivtseva, Tatyana M; Yakovleva, Natalya V; Nikolaev, Valerian P; Sidorova, Oksana G; Kononova, Sardana K; Goldfarb, Lev G; Renwick, Neil M

    2016-07-01

    Spinocerebellar ataxia type 1 (SCA1) is the major and likely the only type of autosomal dominant cerebellar ataxia in the Sakha (Yakut) people of Eastern Siberia. The prevalence rate of SCA1 has doubled over the past 21 years peaking at 46 cases per 100,000 rural population. The age at death correlates closely with the number of CAG triplet repeats in the mutant ATXN1 gene (r = -0.81); most patients with low-medium (39-55) repeat numbers survived until the end of reproductive age. The number of CAG repeats expands in meiosis, particularly in paternal transmissions; the average total increase in intergenerational transmissions in our cohort was estimated at 1.6 CAG repeats. The fertility rates of heterozygous carriers of 39-55 CAG repeats in women were no different from those of the general Sakha population. Overall, the survival of mutation carriers through reproductive age, unaltered fertility rates, low childhood mortality in SCA1-affected families, and intergenerational transmission of increasing numbers of CAG repeats in the ATXN1 gene indicate that SCA1 in the Sakha population will be maintained at high prevalence levels. The low (0.19) Crow's index of total selection intensity in our SCA1 cohort implies that this mutation is unlikely to be eliminated through natural selection alone. PMID:27106293

  4. Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease

    PubMed Central

    Gulsuner, Suleyman; Stapleton, Gail A.; Walsh, Tom; Lee, Ming K.; Mandell, Jessica B.; Morales, Augusto; Klevit, Rachel E.; King, Mary-Claire; Rogers, R. Curtis

    2016-01-01

    Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism. Whole-exome sequencing revealed that the patient is compound heterozygous for previously unreported variants in the C10orf2 gene: a paternally inherited frameshift variant (c.333delT; p.L112Sfs*3) and a maternally inherited missense variant (c.904C>T; p.R302W). The identification of novel C10orf2 mutations extends the spectrum of mutations in the Twinkle helicase causing recessive disease, in particular the intermediate IOSCA phenotype. Structural modeling suggests that the p.R302W mutation and many other recessively inherited Twinkle mutations impact the position or interactions of the linker region, which is critical for the oligomeric ring structure and activity of the helicase. This study emphasizes the utility of whole-exome sequencing for the genetic diagnosis of a complex multisystemic disorder. PMID:27551684

  5. Impaired vestibulo-ocular reflex (VOR) in spinocerebellar ataxia type 3 (SCA3): bedside and search coil evaluation.

    PubMed

    Gordon, Carlos R; Zivotofsky, Ari Z; Caspi, Avi

    2014-01-01

    Vestibulo-Ocular Reflex (VOR) abnormalities in cerebellar ataxias are a matter of renewed interest. We have previously reported vestibular areflexia in a group of Yemenite-Jews with Spinocerebellar Ataxia Type 3 (SCA3) who had clear bilateral pathological horizontal Head Impulse Test (HIT). The objective of this study was to evaluate the VOR of ten SCA3 patients who have variable bedside HIT responses by recording their eye movements using magnetic search coils and to correlate these results with their clinical and genetic data. Eight out of the ten patients have abnormal horizontal HIT detected by both clinical bedside examination and laboratory tests. Results of bedside HIT testing were significantly correlated with the VOR gain recorded using magnetic search coils. No significant correlations were found between VOR gain and other clinical or genetic data. Our study confirms the presence of defective VOR in SCA3 patients and corroborates the useful of the HIT as a reliable bedside test for diagnosis of VOR deficits. PMID:25564077

  6. RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2.

    PubMed

    Salvi, Julie; Bertaso, Federica; Mausset-Bonnefont, Anne-Laure; Metz, Alexandra; Lemmers, Céline; Ango, Fabrice; Fagni, Laurent; Lory, Philippe; Mezghrani, Alexandre

    2014-08-01

    Episodic ataxia type-2 (EA2) is a dominantly inherited human neurological disorder caused by loss of function mutations in the CACNA1A gene, which encodes the CaV2.1 subunit of P/Q-type voltage-gated calcium channels. It remains however unknown whether the deficit of cerebellar CaV2.1 in adult is in direct link with the disease. To address this issue, we have used lentiviral based-vector RNA interference (RNAi) to knock-down CaV2.1 expression in the cerebellum of adult mice. We show that suppression of the P/Q-type channels in Purkinje neurons induced motor abnormalities, such as imbalance and ataxic gait. Interestingly, moderate channel suppression caused no basal ataxia, while β-adrenergic activation and exercise mimicked stress induced motor disorders. Moreover, stress-induced ataxia was stable, non-progressive and totally abolished by acetazolamide, a carbonic anhydrase inhibitor used to treat EA2. Altogether, these data reveal that P/Q-type channel suppression in adult mice supports the episodic status of EA2 disease. PMID:24768804

  7. Molecular mechanism of Spinocerebellar Ataxia type 6: glutamine repeat disorder, channelopathy and transcriptional dysregulation. The multifaceted aspects of a single mutation.

    PubMed

    Giunti, Paola; Mantuano, Elide; Frontali, Marina; Veneziano, Liana

    2015-01-01

    Spinocerebellar Ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease characterized by late onset, slowly progressive, mostly pure cerebellar ataxia. It is one of three allelic disorders associated to CACNA1A gene, coding for the Alpha1 A subunit of P/Q type calcium channel Cav2.1 expressed in the brain, particularly in the cerebellum. The other two disorders are Episodic Ataxia type 2 (EA2), and Familial Hemiplegic Migraine type 1 (FHM1). These disorders show distinct phenotypes that often overlap but have different pathogenic mechanisms. EA2 and FHM1 are due to mutations causing, respectively, a loss and a gain of channel function. SCA6, instead, is associated with short expansions of a polyglutamine stretch located in the cytoplasmic C-terminal tail of the protein. This domain has a relevant role in channel regulation, as well as in transcription regulation of other neuronal genes; thus the SCA6 CAG repeat expansion results in complex pathogenic molecular mechanisms reflecting the complex Cav2.1 C-terminus activity. We will provide a short review for an update on the SCA6 molecular mechanism. PMID:25762895

  8. Molecular mechanism of Spinocerebellar Ataxia type 6: glutamine repeat disorder, channelopathy and transcriptional dysregulation. The multifaceted aspects of a single mutation

    PubMed Central

    Giunti, Paola; Mantuano, Elide; Frontali, Marina; Veneziano, Liana

    2015-01-01

    Spinocerebellar Ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease characterized by late onset, slowly progressive, mostly pure cerebellar ataxia. It is one of three allelic disorders associated to CACNA1A gene, coding for the Alpha1 A subunit of P/Q type calcium channel Cav2.1 expressed in the brain, particularly in the cerebellum. The other two disorders are Episodic Ataxia type 2 (EA2), and Familial Hemiplegic Migraine type 1 (FHM1). These disorders show distinct phenotypes that often overlap but have different pathogenic mechanisms. EA2 and FHM1 are due to mutations causing, respectively, a loss and a gain of channel function. SCA6, instead, is associated with short expansions of a polyglutamine stretch located in the cytoplasmic C-terminal tail of the protein. This domain has a relevant role in channel regulation, as well as in transcription regulation of other neuronal genes; thus the SCA6 CAG repeat expansion results in complex pathogenic molecular mechanisms reflecting the complex Cav2.1 C-terminus activity. We will provide a short review for an update on the SCA6 molecular mechanism. PMID:25762895

  9. The role of the cerebellum in dynamic changes of the sense of body ownership: a study in patients with cerebellar degeneration.

    PubMed

    Fiorio, Mirta; Mariotti, Caterina; Panzeri, Marta; Antonello, Emanuele; Classen, Joseph; Tinazzi, Michele

    2014-04-01

    The sense of the body is deeply rooted in humans, and it can be experimentally manipulated by inducing illusions in at least two aspects: a subjective feeling of ownership and a proprioceptive sense of limb position. Previous studies mapped these different aspects onto anatomically distinct neuronal regions, with the ventral premotor cortex processing subjective experience of ownership and the inferior parietal lobule processing proprioceptive calibration. Lines of evidence suggest an involvement also of the cerebellum, but its precise role is not clear yet. To investigate the contribution of the cerebellum in the sense of body ownership, we applied the rubber-hand illusion paradigm in 28 patients affected by neurodegenerative cerebellar ataxia, selectively involving the cerebellum, and in 26 age-matched control participants. The rubber hand illusion is established by synchronous stroking of the participants' real unseen hand and a visible fake hand. Short asynchronous stroking does not bring about the illusion. We tested the subjective experience of the illusion, evaluated through a questionnaire and the proprioceptive drift of the real unseen hand toward the viewed rubber hand. In patients with cerebellar ataxia, we observed reduced sense of the subjective illusory experience specifically after synchronous stroking. In contrast, the proprioceptive drift was enhanced after synchronous and after asynchronous stimulation. These findings support the contention that the mechanisms underlying the presence of the illusion and the proprioceptive drift may be differently affected in different conditions. Impairment of the subjective sense of the illusion in cerebellar patients might hint at an involvement of cerebellar-premotor networks, whereas the proprioceptive drift typically associated with synchronous stroking appears to rely on other circuits, likely involving the cerebellum and the parietal regions. PMID:24236765

  10. Oculomotor studies of cerebellar function in autism.

    PubMed

    Nowinski, Caralynn V; Minshew, Nancy J; Luna, Beatriz; Takarae, Yukari; Sweeney, John A

    2005-11-15

    Histopathological, neuroimaging and genetic findings indicate cerebellar abnormalities in autism, but the extent of neurophysiological dysfunction associated with those findings has not been systematically examined. Suppression of intrusive saccades (square wave jerks) and the ability to sustain eccentric gaze, two phenomena requiring intact cerebellar function, were examined in 52 high-functioning individuals with autism and 52 age- and IQ-matched healthy subjects during visual fixation of static central and peripheral targets. Rates of intrusive saccades were not increased in autism during visual fixation, and foveopetal ocular drift was also not increased when subjects held an eccentric gaze. The absence of gross disturbances of visual fixation associated with cerebellar disease in individuals with autism, such as increased square wave jerk rates and foveopetal drift when holding eccentric gaze, indicates that the functional integrity of cerebellar--brainstem networks devoted to oculomotor control is preserved in autism despite reported anatomic variations. However, increased amplitude of intrusive saccades and reduced latency of target refixation after intrusive saccades were observed in individuals with autism, especially when subjects maintained fixation of remembered target locations without sensory guidance. The atypical metrics of intrusive saccades that were observed may be attributable to faulty functional connectivity in cortico-cerebellar networks. PMID:16214219

  11. Cerebellar modules operate at different frequencies

    PubMed Central

    Zhou, Haibo; Lin, Zhanmin; Voges, Kai; Ju, Chiheng; Gao, Zhenyu; Bosman, Laurens WJ; Ruigrok, Tom JH; Hoebeek, Freek E

    2014-01-01

    Due to the uniform cyto-architecture of the cerebellar cortex, its overall physiological characteristics have traditionally been considered to be homogeneous. In this study, we show in awake mice at rest that spiking activity of Purkinje cells, the sole output cells of the cerebellar cortex, differs between cerebellar modules and correlates with their expression of the glycolytic enzyme aldolase C or zebrin. Simple spike and complex spike frequencies were significantly higher in Purkinje cells located in zebrin-negative than zebrin-positive modules. The difference in simple spike frequency persisted when the synaptic input to, but not intrinsic activity of, Purkinje cells was manipulated. Blocking TRPC3, the effector channel of a cascade of proteins that have zebrin-like distribution patterns, attenuated the simple spike frequency difference. Our results indicate that zebrin-discriminated cerebellar modules operate at different frequencies, which depend on activation of TRPC3, and that this property is relevant for all cerebellar functions. DOI: http://dx.doi.org/10.7554/eLife.02536.001 PMID:24843004

  12. Neurodevelopmental malformations of the cerebellar vermis in genetically engineered rats

    EPA Science Inventory

    The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformati...

  13. Restricted diffusion in Wallerian degeneration of the middle cerebellar peduncles following pontine infarction

    PubMed Central

    Musson, Rachel; Romanowski, Charles

    2010-01-01

    Summary Background: Acute Wallerian degeneration following infarction has been show to result in areas of restricted diffusion within the brain. Very few reports describe this appearance in middle cerebellar peduncles. Case Report: A 37 year old woman was admitted to hospital following sudden collapse and was subsequently found to have a pontine infarct. The complex clinical course resulted in MR imaging including DWI at day 4, 9 and 23 after the initial presentation. The cerebellar peduncles were normal when imaged on day 4 and 9. At day 23, symmetrical high T2 signal was seen in both cerebellar peduncles. The DWI illustrated high signal with corresponding low signal on the ADC map consistent with restricted diffusion. We discuss why this appearance is in keeping with Wallerian degeneration and also describe the fibre pathways involved. Conclusions: Symmetrical high signal with restricted diffusion in the middle cerebellar peduncles following a pontine lesion is almost certainly attributable to Wallerian degeneration and should not be mistaken for a new ischaemia. PMID:22802803

  14. Animal and cellular models of Friedreich ataxia.

    PubMed

    Perdomini, Morgane; Hick, Aurore; Puccio, Hélène; Pook, Mark A

    2013-08-01

    The development and use of animal and cellular models of Friedreich ataxia (FRDA) are essential requirements for the understanding of FRDA disease mechanisms and the investigation of potential FRDA therapeutic strategies. Although animal and cellular models of lower organisms have provided valuable information on certain aspects of FRDA disease and therapy, it is intuitive that the most useful models are those of mammals and mammalian cells, which are the closest in physiological terms to FRDA patients. To date, there have been considerable efforts put into the development of several different FRDA mouse models and relevant FRDA mouse and human cell line systems. We summarize the principal mammalian FRDA models, discuss the pros and cons of each system, and describe the ways in which such models have been used to address two of the fundamental, as yet unanswered, questions regarding FRDA. Namely, what is the exact pathophysiology of FRDA and what is the detailed genetic and epigenetic basis of FRDA? PMID:23859342

  15. Swayback (Enzootic Ataxia) in Alberta Lambs

    PubMed Central

    Chalmers, G. A.

    1974-01-01

    Swayback (enzootic ataxia), a disease not previously described in Canada, occurred in newborn lambs in Alberta in 1972. Of 100 lambs born in one flock, over 60 succumbed in the enzootic. The diagnosis was based on the presence of a) gross cavitations and gelatinous lesions of the cerebral white matter in 16 of 24 (66.67%) lambs examined, b) central chromatolysis and hyalinization of neurons of the red and vestibular nuclei and reticular formation and of the lateral and ventral horns of the spinal cord, c) myelin deficiencies of the dorsolateral and sulcomarginal funiculi of the spinal cord and d) low hepatic and serum copper levels in affected lambs and low serum copper levels in the ewes. The feeding of sugar beet-(beta saccharifera) top silage to the ewes during pregnancy, lambing and lactation, and its relationship to the enzootic is discussed. ImagesFig. 1.Fig. 2.Fig. 3.Fig. 4. PMID:4274817

  16. Subarachnoid hemorrhage then thrombosis of posterior inferior cerebellar artery dissection: is early surgical exploration warranted?

    PubMed

    Alexiades, Nikita G; Ellis, Jason A; Meyers, Philip M; Connolly, E Sander

    2016-06-01

    The natural history of spontaneous cerebral artery dissection and thrombosis remains uncertain. Concurrent subarachnoid hemorrhage further complicates the therapeutic approach. Thus the best strategy for managing patients with acute vessel thrombosis in the setting of subarachnoid hemorrhage is unclear. Here we present a case of spontaneous posterior inferior cerebellar artery dissection presenting with subarachnoid hemorrhage and acute thrombosis. Although the patient was initially managed conservatively, angiographic follow-up demonstrated recanalization of the diseased vessel, necessitating definitive treatment. Thus we propose that angiographic follow-up is necessary in the management of patients with subarachnoid hemorrhage in association with apparent vessel thrombosis. PMID:25987592

  17. Simultaneous occurrence of internal capsule infarct and cerebellar haemorrhage in a patient with hemiplegia.

    PubMed

    Pande, Nikhil; Vivek, Ganapathiraman; Hande, Manjunath; Acharya, Vasudeva

    2014-01-01

    A 68-year-old woman with hypertension with no history of cerebrovascular events presented with a left-sided hemiplegia which had developed acutely 2 days ago. She was not on maintenance therapy with antiplatelets or anticoagulants. A CT scan showed acute ischaemic infarction of the right internal capsule and cerebellar haemorrhage. Cardiac evaluation was normal. Doppler ultrasonography of the extracranial carotid and vertebral arteries showed diffuse arteriosclerotic changes, but did not reveal any haemodynamic occlusion. The simultaneous development of dual strokes was considered to be an extension of the same arteriosclerotic process to the intracranial carotid and basilar arteries. PMID:24408941

  18. Cerebellar contribution to feedforward control of locomotion

    PubMed Central

    Pisotta, Iolanda; Molinari, Marco

    2014-01-01

    The cerebellum is an important contributor to feedforward control mechanisms of the central nervous system, and sequencing—the process that allows spatial and temporal relationships between events to be recognized—has been implicated as the fundamental cerebellar mode of operation. By adopting such a mode and because cerebellar activity patterns are sensitive to a variety of sensorimotor-related tasks, the cerebellum is believed to support motor and cognitive functions that are encoded in the frontal and parietal lobes of the cerebral cortex. In this model, the cerebellum is hypothesized to make predictions about the consequences of a motor or cognitive command that originates from the cortex to prepare the entire system to cope with ongoing changes. In this framework, cerebellar predictive mechanisms for locomotion are addressed, focusing on sensorial and motoric sequencing. The hypothesis that sequence recognition is the mechanism by which the cerebellum functions in gait control is presented and discussed. PMID:25009490

  19. Cerebellar Glioblastoma Multiforme in an Adult

    PubMed Central

    Hur, Hyuk; Jung, Tae-Young; Kim, In-Young

    2008-01-01

    Primary cerebellar glioblastoma multiforme (GBM) is a rare tumor in adults that accounts for just 1% of all cases of GBM. Due to their rarity, cerebellar GBMs are not yet completely understood about the pathogenesis and the prognosis. Here, we present a case of GBM in a 69-year-old man. Neurologic examination revealed the presence of cerebellar signs. Magnetic resonance imaging (MRI) showed a 4.5 × 3.6 cm-sized, ill-defined, heterogeneously enhancing mass in the left cerebellum and two patchy hyperintense lesions in the right cerebellum with minimal enhancement. After operation, glioblastoma was histologically confirmed. Postoperative radiotherapy with concomitant and adjuvant temozolomide chemotherapy was subsequently followed. Here, a case of unusual GBM in the cerebellum is reported with review of literature regarding the pathogenesis, the differential diagnosis and prognosis. There was no evidence of recurrence during postoperative one year. This patient showed a good prognosis in spite of the multiple lesions. PMID:19096643

  20. Cerebellar contribution to feedforward control of locomotion.

    PubMed

    Pisotta, Iolanda; Molinari, Marco

    2014-01-01

    The cerebellum is an important contributor to feedforward control mechanisms of the central nervous system, and sequencing-the process that allows spatial and temporal relationships between events to be recognized-has been implicated as the fundamental cerebellar mode of operation. By adopting such a mode and because cerebellar activity patterns are sensitive to a variety of sensorimotor-related tasks, the cerebellum is believed to support motor and cognitive functions that are encoded in the frontal and parietal lobes of the cerebral cortex. In this model, the cerebellum is hypothesized to make predictions about the consequences of a motor or cognitive command that originates from the cortex to prepare the entire system to cope with ongoing changes. In this framework, cerebellar predictive mechanisms for locomotion are addressed, focusing on sensorial and motoric sequencing. The hypothesis that sequence recognition is the mechanism by which the cerebellum functions in gait control is presented and discussed. PMID:25009490

  1. 21 CFR 882.5820 - Implanted cerebellar stimulator.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Implanted cerebellar stimulator. 882.5820 Section... (CONTINUED) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Therapeutic Devices § 882.5820 Implanted cerebellar stimulator. (a) Identification. An implanted cerebellar stimulator is a device used to...

  2. 21 CFR 882.5820 - Implanted cerebellar stimulator.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Implanted cerebellar stimulator. 882.5820 Section... (CONTINUED) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Therapeutic Devices § 882.5820 Implanted cerebellar stimulator. (a) Identification. An implanted cerebellar stimulator is a device used to...

  3. 21 CFR 882.5820 - Implanted cerebellar stimulator.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Implanted cerebellar stimulator. 882.5820 Section... (CONTINUED) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Therapeutic Devices § 882.5820 Implanted cerebellar stimulator. (a) Identification. An implanted cerebellar stimulator is a device used to...

  4. Postirradiation cerebellar glioma. Case report

    SciTech Connect

    Raffel, C.; Edwards, M.S.; Davis, R.L.; Ablin, A.R.

    1985-02-01

    A 13-year-old girl developed an anaplastic astrocytoma of the cerebellum 7 years after irradiation of the central nervous system and prophylactic chemotherapy for acute lymphocytic leukemia. The fact that the astrocytoma was anaplastic and infiltrative was unusual for astroglial tumors at this site. It is proposed that this is a radiation-induced glioma.

  5. Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation

    PubMed Central

    Dias, Cristina; McDonald, Allison; Sincan, Murat; Rupps, Rosemarie; Markello, Thomas; Salvarinova, Ramona; Santos, Rui F; Menghrajani, Kamal; Ahaghotu, Chidi; Sutherland, Darren P; Fortuno, Edgardo S; Kollmann, Tobias R; Demos, Michelle; Friedman, Jan M; Speert, David P; Gahl, William A; Boerkoel, Cornelius F

    2013-01-01

    Inflammation is an important contributor to pediatric and adult neurodegeneration. Understanding the genetic determinants of neuroinflammation provides valuable insight into disease mechanism. We characterize a disorder of recurrent immune-mediated neurodegeneration. We report two sisters who presented with neurodegeneration triggered by infections. The proband, a previously healthy girl, presented at 22.5 months with ataxia and dysarthria following mild gastroenteritis. MRI at onset showed a symmetric signal abnormality of the cerebellar and peritrigonal white matter. Following a progressive course of partial remissions and relapses, she died at 5 years of age. Her older sister had a similar course following varicella infection, she died within 13 months. Both sisters had unremarkable routine laboratory testing, with exception of a transient mild cytopenia in the proband 19 months after presentation. Exome sequencing identified a biallelic perforin1 mutation (PRF1; p.R225W) previously associated with familial hemophagocytic lymphohistiocytosis (FHL). In contrast to FHL, these girls did not have hematopathology or cytokine overproduction. However, 3 years after disease onset, the proband had markedly deficient interleukin-1 beta (IL-1β) production. These observations extend the spectrum of disease associated with perforin mutations to immune-mediated neurodegeneration triggered by infection and possibly due to primary immunodeficiency. PMID:23443029

  6. Molecular Pathogenesis and Cellular Pathology of Spinocerebellar Ataxia Type 7 Neurodegeneration

    PubMed Central

    Garden, Gwenn A.; La Spada, Albert R.

    2013-01-01

    Spinocerebellar ataxia type 7 (SCA7) is unique among CAG / polyglutamine (polyQ) repeat diseases due to dramatic intergenerational instability in repeat length and an associated cone-rod dystrophy retinal degeneration phenotype. SCA7 is caused by a polyQ expansion in the protein ataxin-7. Like other neurodegenerative diseases caused by polyQ expansion mutations, the spectrum of clinical severity and disease progression worsens with increasing polyQ length. Several potential mechanisms for the molecular pathogenesis of polyQ-expanded ataxin-7 have been suggested. These include, but are not limited to, alteration of endogenous ataxin-7 function, abnormal processing and stability of polyQ ataxin-7, and alteration of transcriptional regulation via interaction of polyQ-expanded ataxin-7 with other transcriptional regulators. Ataxin-7's normal function as a transcription factor may contribute to the selective vulnerability of specific cellular populations in SCA7, and the resolution of the mechanistic basis of this pathogenic cascade is a major focus of SCA7 disease research. PolyQ-expanded ataxin-7 can cause non-cell autonomous neurodegeneration in cerebellar Purkinje cells. Advances in understanding SCA7's molecular basis have led to important insights into cell-type specific neurodegeneration. We expect that further study of ataxin-7 normal function, insights into the molecular basis of SCA7 neurodegeneration, and the development of therapeutic interventions for SCA7 will greatly influence related endeavors directed at other CAG / polyQ repeat diseases. PMID:18418675

  7. High-dose thiamine improves the symptoms of Friedreich's ataxia

    PubMed Central

    Costantini, Antonio; Giorgi, Rafaela; D'Agostino, Sonia; Pala, Maria Immacolata

    2013-01-01

    Friedreich's ataxia (FRDA) is an autosomal recessive inherited disorder characterised by progressive gait and limb ataxia, dysarthria, areflexia, loss of position sense and a progressive motor weakness of central origin. Some observations indicate that all symptoms of FRDA ataxia could be the manifestation of a thiamine deficiency because of enzymatic abnormalities. Two patients with FRDA were under rehabilitative treatment from February 2012 to February 2013. The scale for assessment and rating of ataxia was performed. The patient began an intramuscular therapy with 100 mg of thiamine every 3–5  days. Injection of high-dose thiamine was effective in reversing the motor failure. From this clinical observation, it is reasonable to infer that a thiamine deficiency due to enzymatic abnormalities could cause a selective neuronal damage in the centres that are typically affected by this disease. PMID:23704441

  8. Antiphospholipid antibodies bind to rat cerebellar granule cells: the role of N-methyl-D-aspartate receptors.

    PubMed

    Riccio, A; Andreassi, C; Eboli, M L

    1998-11-27

    IgGs from sera containing antiphospholipid antibodies (aPL), detected as antibodies to cardiolipin, or control sera were incubated with rat cerebellar granule cells in primary culture. Using a mitochondrial dehydrogenase activity assay (MTT test), aPL IgGs were shown to decrease MTT metabolism after 24 h incubation with the cells, and to cause non-toxic amounts of glutamate to become neurotoxic when added to the cells for 45 min. Acute and chronic aPL toxicity were prevented by MK-801. Sera containing aPL bound to intact cerebellar neurons, as revealed by an immunofluorescent technique. These results suggest that antiphospholipid antibodies interfere with excitatory pathways in glutamatergic cerebellar granule cells by a mechanism involving overactivation of the NMDA glutamate receptor. PMID:9865941

  9. Alcohol Excites Cerebellar Golgi Cells by Inhibiting the Na+/K+ ATPase

    PubMed Central

    Botta, Paolo; de Souza, Fabio M Simões; Sangrey, Thomas; De Schutter, Erik; Valenzuela, C Fernando

    2010-01-01

    Alcohol-induced alterations of cerebellar function cause motor coordination impairments that are responsible for millions of injuries and deaths worldwide. Cognitive deficits associated with alcoholism are also a consequence of cerebellar dysfunction. The mechanisms responsible for these effects of ethanol are poorly understood. Recent studies have identified neurons in the input layer of the cerebellar cortex as important ethanol targets. In this layer, granule cells (GrCs) receive the majority of sensory inputs to the cerebellum through the mossy fibers. Information flow at these neurons is gated by a specialized pacemaker interneuron known as the Golgi cell, which provides divergent GABAergic input to thousands of GrCs. In vivo electrophysiological experiments have previously shown that acute ethanol exposure abolishes GrC responsiveness to sensory inputs carried by mossy fibers. Slice electrophysiological studies suggest that ethanol causes this effect by potentiating GABAergic transmission at Golgi cell-to-GrC synapses through an increase in Golgi cell excitability. Using patch-clamp electrophysiological techniques in cerebellar slices and computer modeling, we show here that ethanol excites Golgi cells by inhibiting the Na+/K+ ATPase. Voltage-clamp recordings of Na+/K+ ATPase currents indicated that ethanol partially inhibits this pump and this effect could be mimicked by low concentrations of ouabain. Partial inhibition of Na+/K+ ATPase function in a computer model of the Golgi cell reproduced these experimental findings. These results establish a novel mechanism of action of ethanol on neuronal excitability, which likely has a role in ethanol-induced cerebellar dysfunction and may also contribute to neuronal functional alterations in other brain regions. PMID:20520600

  10. Mitigation of cerebellar neuropathy in globoid cell leukodystrophy mice by AAV-mediated gene therapy.

    PubMed

    Lin, Dar-Shong; Hsiao, Chung-Der; Lee, Allan Yueh-Luen; Ho, Che-Sheng; Liu, Hsuan-Liang; Wang, Tuen-Jen; Jian, Yuan-Ren; Hsu, Jui-Cheng; Huang, Zon-Darr; Lee, Tsung-Han; Chiang, Ming-Fu

    2015-10-15

    Globoid cell leukodystrophy (GLD) is an autosomal recessive, lysosomal storage disease caused by deficiency of the enzyme galactocerebrosidase (GALC). The absence of GALC activity leads to the accumulation of the toxic substance psychosine and the preferential loss of myelinating cells in the central and peripheral nervous systems. Profound demyelination, astrogliosis and axonopathy are the hallmarks of the pathogenesis of GLD, and cerebellar ataxia is one of the dominant manifestations in adolescents and adults affected with GLD. To date, studies regarding cerebellar degeneration in GLD are limited. In this study, the efficacy of cerebellum-targeted gene therapy on the cerebellar neuropathology in twitcher mice (a murine model of GLD) has been validated. We observed degeneration of Purkinje cells, Bergmann glia, and granule cells in addition to astrocytosis and demyelination in the cerebellum of the twitcher mice. Ultrastructural analysis revealed dark cell degeneration and disintegration of the cellular composition of Purkinje cells in untreated twitcher mice. In addition, the expressions of neurotrophic factors CNTF, GDNF and IGF-I were up-regulated and the expression of BDNF was down-regulated. Intracerebellar-mediated gene therapy efficiently corrected enzymatic deficiency by direct transduction to Purkinje cells and cross-correction in other cell types in the cerebellum, leading to the amelioration of both neuroinflammation and demyelination. The population, dendritic territory, and axonal processes of Purkinje cells remained normal in the cerebellum of treated twitcher mice, where radial fibers of Bergmann glia spanned the molecular layer and collateral branches ensheathed the dendritic processes of Purkinje cells. Moreover, the aberrant expressions of neurotrophic factors were mitigated in the cerebellum of treated twitcher mice, indicating the preservation of cellular function in addition to maintaining the neuronal architecture. The life span of the

  11. Radiation-induced cerebellar chondrosarcoma. Case report

    SciTech Connect

    Bernstein, M.; Perrin, R.G.; Platts, M.E.; Simpson, W.J.

    1984-07-01

    The authors report a case of chondrosarcoma arising in the cerebellum 16 years after treatment of a cerebellar malignant astrocytoma by subtotal resection and irradiation. It is thought that the chondrosarcoma arising within the intracranial cavity was a probable consequence of previous ionizing radiation.

  12. Improving cerebellar segmentation with statistical fusion

    NASA Astrophysics Data System (ADS)

    Plassard, Andrew J.; Yang, Zhen; Prince, Jerry L.; Claassen, Daniel O.; Landman, Bennett A.

    2016-03-01

    The cerebellum is a somatotopically organized central component of the central nervous system well known to be involved with motor coordination and increasingly recognized roles in cognition and planning. Recent work in multiatlas labeling has created methods that offer the potential for fully automated 3-D parcellation of the cerebellar lobules and vermis (which are organizationally equivalent to cortical gray matter areas). This work explores the trade offs of using different statistical fusion techniques and post hoc optimizations in two datasets with distinct imaging protocols. We offer a novel fusion technique by extending the ideas of the Selective and Iterative Method for Performance Level Estimation (SIMPLE) to a patch-based performance model. We demonstrate the effectiveness of our algorithm, Non- Local SIMPLE, for segmentation of a mixed population of healthy subjects and patients with severe cerebellar anatomy. Under the first imaging protocol, we show that Non-Local SIMPLE outperforms previous gold-standard segmentation techniques. In the second imaging protocol, we show that Non-Local SIMPLE outperforms previous gold standard techniques but is outperformed by a non-locally weighted vote with the deeper population of atlases available. This work advances the state of the art in open source cerebellar segmentation algorithms and offers the opportunity for routinely including cerebellar segmentation in magnetic resonance imaging studies that acquire whole brain T1-weighted volumes with approximately 1 mm isotropic resolution.

  13. Improving Cerebellar Segmentation with Statistical Fusion

    PubMed Central

    Plassard, Andrew J.; Yang, Zhen; Prince, Jerry L.; Claassen, Daniel O.; Landman, Bennett A.

    2016-01-01

    The cerebellum is a somatotopically organized central component of the central nervous system well known to be involved with motor coordination and increasingly recognized roles in cognition and planning. Recent work in multi-atlas labeling has created methods that offer the potential for fully automated 3-D parcellation of the cerebellar lobules and vermis (which are organizationally equivalent to cortical gray matter areas). This work explores the trade offs of using different statistical fusion techniques and post hoc optimizations in two datasets with distinct imaging protocols. We offer a novel fusion technique by extending the ideas of the Selective and Iterative Method for Performance Level Estimation (SIMPLE) to a patch-based performance model. We demonstrate the effectiveness of our algorithm, Non-Local SIMPLE, for segmentation of a mixed population of healthy subjects and patients with severe cerebellar anatomy. Under the first imaging protocol, we show that Non-Local SIMPLE outperforms previous gold-standard segmentation techniques. In the second imaging protocol, we show that Non-Local SIMPLE outperforms previous gold standard techniques but is outperformed by a non-locally weighted vote with the deeper population of atlases available. This work advances the state of the art in open source cerebellar segmentation algorithms and offers the opportunity for routinely including cerebellar segmentation in magnetic resonance imaging studies that acquire whole brain T1-weighted volumes with approximately 1 mm isotropic resolution. PMID:27127334

  14. Vergence Deficits in Patients with Cerebellar Lesions

    ERIC Educational Resources Information Center

    Sander, T.; Sprenger, A.; Neumann, G.; Machner, B.; Gottschalk, S.; Rambold, H.; Helmchen, C.

    2009-01-01

    The cerebellum is part of the cortico-ponto-cerebellar circuit for conjugate eye movements. Recent animal data suggest an additional role of the cerebellum for the control of binocular alignment and disconjugate, i.e. vergence eye movements. The latter is separated into two different components: fast vergence (to step targets) and slow vergence…

  15. Inverse Stochastic Resonance in Cerebellar Purkinje Cells

    PubMed Central

    Häusser, Michael; Gutkin, Boris S.; Roth, Arnd

    2016-01-01

    Purkinje neurons play an important role in cerebellar computation since their axons are the only projection from the cerebellar cortex to deeper cerebellar structures. They have complex internal dynamics, which allow them to fire spontaneously, display bistability, and also to be involved in network phenomena such as high frequency oscillations and travelling waves. Purkinje cells exhibit type II excitability, which can be revealed by a discontinuity in their f-I curves. We show that this excitability mechanism allows Purkinje cells to be efficiently inhibited by noise of a particular variance, a phenomenon known as inverse stochastic resonance (ISR). While ISR has been described in theoretical models of single neurons, here we provide the first experimental evidence for this effect. We find that an adaptive exponential integrate-and-fire model fitted to the basic Purkinje cell characteristics using a modified dynamic IV method displays ISR and bistability between the resting state and a repetitive activity limit cycle. ISR allows the Purkinje cell to operate in different functional regimes: the all-or-none toggle or the linear filter mode, depending on the variance of the synaptic input. We propose that synaptic noise allows Purkinje cells to quickly switch between these functional regimes. Using mutual information analysis, we demonstrate that ISR can lead to a locally optimal information transfer between the input and output spike train of the Purkinje cell. These results provide the first experimental evidence for ISR and suggest a functional role for ISR in cerebellar information processing. PMID:27541958

  16. Cerebellar Disease in an Adult Cow

    PubMed Central

    Oz, H. H.; Nicholson, S. S.; Al-Bagdadi, F. K.; Zeman, D. H.

    1986-01-01

    This is the report of clinical signs and lesions of a cerebellar disorder in an adult four year old Limousin cow grazing perennial ryegrass (Lolium perenne). The most striking histopathological lesion was a marked paucity of Purkinje cells throughout the cerebellum. ImagesFigure 1.Figure 2. PMID:17422607

  17. Inverse Stochastic Resonance in Cerebellar Purkinje Cells.

    PubMed

    Buchin, Anatoly; Rieubland, Sarah; Häusser, Michael; Gutkin, Boris S; Roth, Arnd

    2016-08-01

    Purkinje neurons play an important role in cerebellar computation since their axons are the only projection from the cerebellar cortex to deeper cerebellar structures. They have complex internal dynamics, which allow them to fire spontaneously, display bistability, and also to be involved in network phenomena such as high frequency oscillations and travelling waves. Purkinje cells exhibit type II excitability, which can be revealed by a discontinuity in their f-I curves. We show that this excitability mechanism allows Purkinje cells to be efficiently inhibited by noise of a particular variance, a phenomenon known as inverse stochastic resonance (ISR). While ISR has been described in theoretical models of single neurons, here we provide the first experimental evidence for this effect. We find that an adaptive exponential integrate-and-fire model fitted to the basic Purkinje cell characteristics using a modified dynamic IV method displays ISR and bistability between the resting state and a repetitive activity limit cycle. ISR allows the Purkinje cell to operate in different functional regimes: the all-or-none toggle or the linear filter mode, depending on the variance of the synaptic input. We propose that synaptic noise allows Purkinje cells to quickly switch between these functional regimes. Using mutual information analysis, we demonstrate that ISR can lead to a locally optimal information transfer between the input and output spike train of the Purkinje cell. These results provide the first experimental evidence for ISR and suggest a functional role for ISR in cerebellar information processing. PMID:27541958

  18. Neurogenic stunned myocardium as a manifestation of encephalitis involving cerebellar tonsils.

    PubMed

    Lin, Wen-Sou; Sung, Yueh-Feng

    2012-11-01

    Neurogenic stunned myocardium is defined as a myocardial injury or dysfunction after neurological insults. It is most commonly reported in patients with subarachnoid hemorrhage, and the presenting symptoms may mimic an acute myocardial infarction or myocarditis. In severe cases, cardiogenic shock and acute pulmonary edema may occur and lead to a devastating event. Therefore, it requires prompt recognition and proper intervention. We herein report the case of a 25-year-old woman who presented to our hospital with the symptoms of acute pulmonary edema, shock, and consciousness disturbance. The diagnosis of encephalitis of cerebellar tonsils complicated with acute hydrocephalus and neurogenic stunned myocardium was made. Detailed neurologic examinations, neuroimaging studies, and characteristic echocardiographic changes expedite the correct diagnosis and treatment. PMID:22205010

  19. Improved segmentation of cerebellar structures in children

    PubMed Central

    Narayanan, Priya Lakshmi; Boonazier, Natalie; Warton, Christopher; Molteno, Christopher D; Joseph, Jesuchristopher; Jacobson, Joseph L; Jacobson, Sandra W; Zöllei, Lilla; Meintjes, Ernesta M

    2016-01-01

    Background Consistent localization of cerebellar cortex in a standard coordinate system is important for functional studies and detection of anatomical alterations in studies of morphometry. To date, no pediatric cerebellar atlas is available. New method The probabilistic Cape Town Pediatric Cerebellar Atlas (CAPCA18) was constructed in the age-appropriate National Institute of Health Pediatric Database asymmetric template space using manual tracings of 16 cerebellar compartments in 18 healthy children (9–13 years) from Cape Town, South Africa. The individual atlases of the training subjects were also used to implement multi atlas label fusion using multi atlas majority voting (MAMV) and multi atlas generative model (MAGM) approaches. Segmentation accuracy in 14 test subjects was compared for each method to ‘gold standard’ manual tracings. Results Spatial overlap between manual tracings and CAPCA18 automated segmentation was 73% or higher for all lobules in both hemispheres, except VIIb and X. Automated segmentation using MAGM yielded the best segmentation accuracy over all lobules (mean Dice Similarity Coefficient 0.76; range 0.55–0.91). Comparison with existing methods In all lobules, spatial overlap of CAPCA18 segmentations with manual tracings was similar or higher than those obtained with SUIT (spatially unbiased infra-tentorial template), providing additional evidence of the benefits of an age appropriate atlas. MAGM segmentation accuracy was comparable to values reported recently by Park et al. (2014) in adults (across all lobules mean DSC = 0.73, range 0.40–0.89). Conclusions CAPCA18 and the associated multi atlases of the training subjects yield improved segmentation of cerebellar structures in children. PMID:26743973

  20. Anatomy and approaches along the cerebellar-brainstem fissures.

    PubMed

    Matsushima, Ken; Yagmurlu, Kaan; Kohno, Michihiro; Rhoton, Albert L

    2016-01-01

    OBJECT Fissure dissection is routinely used in the supratentorial region to access deeply situated pathology while minimizing division of neural tissue. Use of fissure dissection is also practical in the posterior fossa. In this study, the microsurgical anatomy of the 3 cerebellar-brainstem fissures (cerebellomesencephalic, cerebellopontine, and cerebellomedullary) and the various procedures exposing these fissures in brainstem surgery were examined. METHODS Seven cadaveric heads were examined with a microsurgical technique and 3 with fiber dissection to clarify the anatomy of the cerebellar-brainstem and adjacent cerebellar fissures, in which the major vessels and neural structures are located. Several approaches directed along the cerebellar surfaces and fissures, including the supracerebellar infratentorial, occipital transtentorial, retrosigmoid, and midline suboccipital approaches, were examined. The 3 heads examined using fiber dissection defined the anatomy of the cerebellar peduncles coursing in the depths of these fissures. RESULTS Dissections directed along the cerebellar-brainstem and cerebellar fissures provided access to the posterior and posterolateral midbrain and upper pons, lateral pons, floor and lateral wall of the fourth ventricle, and dorsal and lateral medulla. CONCLUSIONS Opening the cerebellar-brainstem and adjacent cerebellar fissures provided access to the brainstem surface hidden by the cerebellum, while minimizing division of neural tissue. Most of the major cerebellar arteries, veins, and vital neural structures are located in or near these fissures and can be accessed through them. PMID:26274986

  1. Harry Lee Parker and paroxysmal dysarthria and ataxia

    PubMed Central

    Klaas, James P.; Burkholder, David B.; Singer, Wolfgang

    2013-01-01

    Objective: To review descriptions of paroxysmal dysarthria and ataxia in multiple sclerosis (MS), with special attention given to Parker and his 1946 case series. Methods: Evaluation of original publications describing paroxysmal dysarthria and ataxia, bibliographic information, writings, and unpublished letters from the Mayo Clinic Historical Unit. Results: In 1940, Störring described a patient with MS with paroxysmal symptoms that included dizziness and trouble speaking, but also unilateral extremity weakness. In 1946, Parker published a series of 11 patients with paroxysmal dysarthria and ataxia. Six of these patients had MS, and he recognized this phenomenon as a manifestation of the disease. The term “paroxysmal dysarthria and ataxia” was first used in 1959 by Andermann and colleagues. Since that time, paroxysmal dysarthria and ataxia has become a well-recognized phenomenon in MS. More recent reports have suggested that the responsible lesion is located in the midbrain, near or involving the red nucleus. Conclusions: Parker was the first to accurately describe paroxysmal dysarthria and ataxia in patients with MS. PMID:23319475

  2. Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain

    PubMed Central

    Preston, Chet; Wang, Louis; Yi, Jae Kyo; Lin, Chih-Li; Sun, Wei; Spyropoulos, Demetri D.; Rhee, Soyoung; Li, Mingsong; Zhou, Jie; Ge, Shaoyu; Zhang, Guofeng; Snider, Ashley J.; Hannun, Yusuf A.; Obeid, Lina M.; Mao, Cungui

    2015-01-01

    Dyshomeostasis of both ceramides and sphingosine-1-phosphate (S1P) in the brain has been implicated in aging-associated neurodegenerative disorders in humans. However, mechanisms that maintain the homeostasis of these bioactive sphingolipids in the brain remain unclear. Mouse alkaline ceramidase 3 (Acer3), which preferentially catalyzes the hydrolysis of C18:1-ceramide, a major unsaturated long-chain ceramide species in the brain, is upregulated with age in the mouse brain. Acer3 knockout causes an age-dependent accumulation of various ceramides and C18:1-monohexosylceramide and abolishes the age-related increase in the levels of sphingosine and S1P in the brain; thereby resulting in Purkinje cell degeneration in the cerebellum and deficits in motor coordination and balance. Our results indicate that Acer3 plays critically protective roles in controlling the homeostasis of various sphingolipids, including ceramides, sphingosine, S1P, and certain complex sphingolipids in the brain and protects Purkinje cells from premature degeneration. PMID:26474409

  3. Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain.

    PubMed

    Wang, Kai; Xu, Ruijuan; Schrandt, Jennifer; Shah, Prithvi; Gong, Yong Z; Preston, Chet; Wang, Louis; Yi, Jae Kyo; Lin, Chih-Li; Sun, Wei; Spyropoulos, Demetri D; Rhee, Soyoung; Li, Mingsong; Zhou, Jie; Ge, Shaoyu; Zhang, Guofeng; Snider, Ashley J; Hannun, Yusuf A; Obeid, Lina M; Mao, Cungui

    2015-10-01

    Dyshomeostasis of both ceramides and sphingosine-1-phosphate (S1P) in the brain has been implicated in aging-associated neurodegenerative disorders in humans. However, mechanisms that maintain the homeostasis of these bioactive sphingolipids in the brain remain unclear. Mouse alkaline ceramidase 3 (Acer3), which preferentially catalyzes the hydrolysis of C18:1-ceramide, a major unsaturated long-chain ceramide species in the brain, is upregulated with age in the mouse brain. Acer3 knockout causes an age-dependent accumulation of various ceramides and C18:1-monohexosylceramide and abolishes the age-related increase in the levels of sphingosine and S1P in the brain; thereby resulting in Purkinje cell degeneration in the cerebellum and deficits in motor coordination and balance. Our results indicate that Acer3 plays critically protective roles in controlling the homeostasis of various sphingolipids, including ceramides, sphingosine, S1P, and certain complex sphingolipids in the brain and protects Purkinje cells from premature degeneration. PMID:26474409

  4. SCA7 cerebellar disease requires the coordinated action of mutant ataxin-7 in neurons and glia, and displays non-cell autonomous Bergmann glia degeneration

    PubMed Central

    Furrer, Stephanie A.; Mohanachandran, Mathini S.; Waldherr, Sarah M.; Chang, Christopher; Damian, Vincent A.; Sopher, Bryce L.; Garden, Gwenn A.; La Spada, Albert R.

    2011-01-01

    Spinocerebellar ataxia type 7 (SCA7) is a dominantly inherited disorder characterized by cerebellum and brainstem neurodegeneration. SCA7 is caused by a CAG/polyglutamine (polyQ) repeat expansion in the ataxin-7 gene. We previously reported that directed expression of polyQ-ataxin-7 in Bergmann glia (BG) in transgenic mice leads to ataxia and non-cell autonomous Purkinje cell (PC) degeneration. To further define the cellular basis of SCA7, we derived a conditional inactivation mouse model by inserting a loxP-flanked ataxin-7 cDNA with 92 repeats into the translational start site of the murine prion protein (PrP) gene in a bacterial artificial chromosome (BAC). The PrP-floxed-SCA7-92Q BAC mice developed neurological disease, and exhibited cerebellar degeneration and BG process loss. To inactivate polyQ-ataxin-7 expression in specific cerebellar cell types, we crossed PrP-floxed-SCA7-92Q BAC mice with Gfa2-Cre transgenic mice (to direct Cre to BG) or Pcp2-Cre transgenic mice (which yields Cre in PCs and inferior olive). Excision of ataxin-7 from BG partially rescued the behavioral phenotype, but did not prevent BG process loss or molecular layer thinning, while excision of ataxin-7 from PCs and inferior olive provided significantly greater rescue and prevented both pathological changes, revealing a non-cell autonomous basis for BG pathology. When we prevented expression of mutant ataxin-7 in BG, PCs, and inferior olive by deriving Gfa2-Cre;Pcp2-Cre;PrP-floxed-SCA7-92Q BAC triple transgenic mice, we noted a dramatic improvement in SCA7 disease phenotypes. These findings indicate that SCA7 disease pathogenesis involves a convergence of alterations in a variety of different cell types to fully recapitulate the cerebellar degeneration. PMID:22072678

  5. Comorbid Medical Conditions in Friedreich Ataxia: Association With Inflammatory Bowel Disease and Growth Hormone Deficiency.

    PubMed

    Shinnick, Julianna E; Schadt, Kimberly; Strawser, Cassandra; Wilcox, Nicholas; Perlman, Susan L; Wilmot, George R; Gomez, Christopher M; Mathews, Katherine D; Yoon, Grace; Zesiewicz, Theresa; Hoyle, Chad; Subramony, S H; Yiu, Eppie M; Delatycki, Martin B; Brocht, Alicia F; Farmer, Jennifer M; Lynch, David R

    2016-08-01

    Friedreich ataxia is a progressive degenerative disease with neurologic and cardiac involvement. This study characterizes comorbid medical conditions in a large cohort of patients with Friedreich ataxia. Patient diagnoses were collected in a large natural history study of 641 subjects. Prevalence of diagnoses in the cohort with Friedreich ataxia was compared with prevalence in the population without Friedreich ataxia. Ten patients (1.6%) had inflammatory bowel disease, 3.5 times more common in this cohort of individuals with Friedreich ataxia than in the general population. Four subjects were growth hormone deficient, reflecting a prevalence in Friedreich ataxia that is 28 times greater than the general population. The present study identifies specific diagnoses not traditionally associated with Friedreich ataxia that are found at higher frequency in this disease. These associations could represent coincidence, shared genetic background, or potentially interactive disease mechanisms with Friedreich ataxia. PMID:27071470

  6. Studying Cerebellar Circuits by Remote Control of Selected Neuronal Types with GABAA Receptors

    PubMed Central

    Wisden, William; Murray, Andrew J.; McClure, Christina; Wulff, Peer

    2009-01-01

    Although GABAA receptor-mediated inhibition of cerebellar Purkinje cells by molecular layer interneurons (MLIs) has been studied intensely at the cellular level, it has remained unclear how this inhibition regulates cerebellum-dependent behaviour. We have implemented two complementary approaches to investigate the function of the MLI-Purkinje cell synapse on the behavioural level. In the first approach we permanently disrupted inhibitory fast synaptic transmission at the synapse by genetically removing the postsynaptic GABAA receptors from Purkinje cells (PC-Δγ2 mice). We found that chronic disruption of the MLI-Purkinje cell synapse strongly impaired cerebellar learning of the vestibular occular reflex (VOR), presumably by disrupting the temporal patterns of Purkinje cell activity. However, in PC-Δγ2 mice the baseline VOR reflex was only mildly affected; indeed PC-Δγ2 mice show no ataxia or gait abnormalities, suggesting that MLI control of Purkinje cell activity is either not involved in ongoing motor tasks or that the system compensates for its loss. To investigate the latter possibility we developed an alternative genetic technique; we made the MLI-Purkinje cell synapse selectively sensitive to rapid manipulation with the GABAA receptor modulator zolpidem (PC-γ2-swap mice). Minutes after intraperitoneal zolpidem injection, these PC-γ2-swap mice developed severe motor abnormalities, revealing a substantial contribution of the MLI-Purkinje cell synapses to real time motor control. The cell-type selective permanent knockout of synaptic GABAergic input and the fast reversible modulation of GABAergic input at the same synapse illustrate how pursuing both strategies gives a fuller view. PMID:20076763

  7. Optic ataxia: from Balint's syndrome to the parietal reach region.

    PubMed

    Andersen, Richard A; Andersen, Kristen N; Hwang, Eun Jung; Hauschild, Markus

    2014-03-01

    Optic ataxia is a high-order deficit in reaching to visual goals that occurs with posterior parietal cortex (PPC) lesions. It is a component of Balint's syndrome that also includes attentional and gaze disorders. Aspects of optic ataxia are misreaching in the contralesional visual field, difficulty preshaping the hand for grasping, and an inability to correct reaches online. Recent research in nonhuman primates (NHPs) suggests that many aspects of Balint's syndrome and optic ataxia are a result of damage to specific functional modules for reaching, saccades, grasp, attention, and state estimation. The deficits from large lesions in humans are probably composite effects from damage to combinations of these functional modules. Interactions between these modules, either within posterior parietal cortex or downstream within frontal cortex, may account for more complex behaviors such as hand-eye coordination and reach-to-grasp. PMID:24607223

  8. Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion

    PubMed Central

    Emre Onat, Onur; Gulsuner, Suleyman; Bilguvar, Kaya; Nazli Basak, Ayse; Topaloglu, Haluk; Tan, Meliha; Tan, Uner; Gunel, Murat; Ozcelik, Tayfun

    2013-01-01

    Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebro-cerebellar structures required for posture and gait in humans. PMID:22892528

  9. Restoration of Central Programmed Movement Pattern by Temporal Electrical Stimulation-Assisted Training in Patients with Spinal Cerebellar Atrophy

    PubMed Central

    Huang, Ying-Zu; Chang, Yao-Shun; Hsu, Miao-Ju; Wong, Alice M. K.; Chang, Ya-Ju

    2015-01-01

    Disrupted triphasic electromyography (EMG) patterns of agonist and antagonist muscle pairs during fast goal-directed movements have been found in patients with hypermetria. Since peripheral electrical stimulation (ES) and motor training may modulate motor cortical excitability through plasticity mechanisms, we aimed to investigate whether temporal ES-assisted movement training could influence premovement cortical excitability and alleviate hypermetria in patients with spinal cerebellar ataxia (SCA). The EMG of the agonist extensor carpi radialis muscle and antagonist flexor carpi radialis muscle, premovement motor evoked potentials (MEPs) of the flexor carpi radialis muscle, and the constant and variable errors of movements were assessed before and after 4 weeks of ES-assisted fast goal-directed wrist extension training in the training group and of general health education in the control group. After training, the premovement MEPs of the antagonist muscle were facilitated at 50 ms before the onset of movement. In addition, the EMG onset latency of the antagonist muscle shifted earlier and the constant error decreased significantly. In summary, temporal ES-assisted training alleviated hypermetria by restoring antagonist premovement and temporal triphasic EMG patterns in SCA patients. This technique may be applied to treat hypermetria in cerebellar disorders. (This trial is registered with NCT01983670.) PMID:26417459

  10. A special type of head stereotypies in children with developmental (?cerebellar) disorder: description of 8 cases and literature review.

    PubMed

    Hottinger-Blanc, Pauline M Z; Ziegler, Anne-Lise; Deonna, Thierry

    2002-01-01

    The authors report eight children, who presented in the first year of life with isolated head stereotypies, that corresponded neither to the usual normal 'rhythmic habit patterns of infancy', nor to various types of abnormal repetitive head movements described in young children. Their head stereotypies closely resembled those described in bobble-head doll syndrome. The neurological status evidenced axial hypotonia, ataxia, oculomotor abnormalities, motor and language delay. The patients were followed for several years clinically and with video recordings. No single aetiology was found. Computed tomography (CT) or magnetic resonance imaging (MRI) show a congenital cerebellar abnormality in two children but no hydrocephalus. The outcome of these children showed in all but one patient a normal cognitive and psychosocial development, even though the head stereotypies are still present in six of eight patients and all remain significantly clumsy. The association of head stereotypies and motor delay should prompt a search for cerebellar congenital malformation. The outcome of those patients was much better than originally anticipated and these head stereotypies are not related either to mental retardation, or to psychopathology. The possible mechanisms involved are also discussed. PMID:12363101

  11. Restoration of Central Programmed Movement Pattern by Temporal Electrical Stimulation-Assisted Training in Patients with Spinal Cerebellar Atrophy.

    PubMed

    Huang, Ying-Zu; Chang, Yao-Shun; Hsu, Miao-Ju; Wong, Alice M K; Chang, Ya-Ju

    2015-01-01

    Disrupted triphasic electromyography (EMG) patterns of agonist and antagonist muscle pairs during fast goal-directed movements have been found in patients with hypermetria. Since peripheral electrical stimulation (ES) and motor training may modulate motor cortical excitability through plasticity mechanisms, we aimed to investigate whether temporal ES-assisted movement training could influence premovement cortical excitability and alleviate hypermetria in patients with spinal cerebellar ataxia (SCA). The EMG of the agonist extensor carpi radialis muscle and antagonist flexor carpi radialis muscle, premovement motor evoked potentials (MEPs) of the flexor carpi radialis muscle, and the constant and variable errors of movements were assessed before and after 4 weeks of ES-assisted fast goal-directed wrist extension training in the training group and of general health education in the control group. After training, the premovement MEPs of the antagonist muscle were facilitated at 50 ms before the onset of movement. In addition, the EMG onset latency of the antagonist muscle shifted earlier and the constant error decreased significantly. In summary, temporal ES-assisted training alleviated hypermetria by restoring antagonist premovement and temporal triphasic EMG patterns in SCA patients. This technique may be applied to treat hypermetria in cerebellar disorders. (This trial is registered with NCT01983670.). PMID:26417459

  12. [Diagnostic and treatment of hypertensive cerebellar hematomas].

    PubMed

    Krylov, V V; Dash'ian, V G; Murashko, A A; Burov, S A

    2009-01-01

    Authors analyzed the results of treatment of 56 patients with hypertensive cerebellar hemorrhages (volume 0,5-41 cm3). Brain stem symptoms were found in 45 (80%) of patients. The dislocation of brain stem was observed in 38 (68%) cases, occlusive hydrocephaly - in 22 (39%), intraventricular hemorrhage - in 26 (46%). Severity of state depended on character of disease course, presence of stem symptoms, awakening level, volume and localization of cerebellar hematoma, development of intraventricular hemorrhage, occlusive hydrocephaly and dislocation of brain stem. Thirty-six patients were operated. After the neurosurgical intervention, 22 (61%) patients were discharged without or with the minimal neurological deficit, 1 (3%) with marked disability and 13 (36%) patients died. In conclusion, the removal of hematoma is recommended in dislocation of brain stem and disturbance of consiousnes: the ventricular drainage - in occlusive hydrocephaly developed as a consequence of hemotamponade of IV ventricular. The surgical treatment is not recommended to patients with cerebellar hematomas with the volume less than 7 cm3. PMID:19491806

  13. Learning of Sensory Sequences in Cerebellar Patients

    PubMed Central

    Frings, Markus; Boenisch, Raoul; Gerwig, Marcus; Diener, Hans-Christoph; Timmann, Dagmar

    2004-01-01

    A possible role of the cerebellum in detecting and recognizing event sequences has been proposed. The present study sought to determine whether patients with cerebellar lesions are impaired in the acquisition and discrimination of sequences of sensory stimuli of different modalities. A group of 26 cerebellar patients and 26 controls matched for age, sex, handedness, musicality, and level of education were tested. Auditory and visual sensory sequences were presented out of different sensory pattern categories (tones with different acoustic frequencies and durations, visual stimuli with different spatial locations and colors, sequential vision of irregular shapes) and different ranges of inter-cue time intervals (fast and slow). Motor requirements were small, with vocal responses and no time restrictions. Perception of visual and acoustic stimuli was generally preserved in patients and controls. The number of errors was significantly higher in the faster tempo of sequence presentation in learning of sequences of tones of different frequencies and in learning of sequences of visual stimuli of different spatial locations and different colors. No difference in tempo between the groups was shown. The total number of errors between the two groups was identical in the sequence conditions. No major disturbances in acquisition or discrimination of various sensory sequences were observed in the group of cerebellar patients. Sequence learning may be impaired only in tasks with significant motor demands. PMID:15169865

  14. From cerebellar texture to movement optimization.

    PubMed

    Sultan, Fahad

    2014-10-01

    The cerebellum is a major site for supervised procedural learning and appears to be crucial for optimizing sensorimotor performance. However, the site and origin of the supervising signal are still elusive. Furthermore, its relationship with the prominent neuronal circuitry remains puzzling. In this paper, I will review the relevant information and seek to synthesize a working hypothesis that explains the unique cerebellar structure. The aim of this review was to link the distinctive functions of the cerebellum, as derived from cerebellar lesion studies, with potential elementary computations, as observed by a bottom-up approach from the cerebellar microcircuitry. The parallel fiber geometry is ideal for performing millisecond computations that extract instructive signals. In this scenario, the higher time derivatives of kinematics such as acceleration and/or jerk that occur during motor performance are detected via a tidal wave mechanism and are used (with appropriate gating) as the instructive signal to guide motor smoothing. The advantage of such a mechanism is that movements are optimized by reducing "jerkiness" which, in turn, lowers their energy requirements. PMID:25037239

  15. Spinocerebellar ataxia type 36 in the Han Chinese

    PubMed Central

    Lee, Yi-Chung; Tsai, Pei-Chien; Guo, Yuh-Cherng; Hsiao, Cheng-Tsung; Liu, Guan-Ting

    2016-01-01

    Objective: To ascertain the genetic and clinical characteristics of the GGCCTG hexanucleotide repeat expansion in the nucleolar protein 56 gene (NOP56) in patients with spinocerebellar ataxia (SCA), sporadic ataxia, or amyotrophic lateral sclerosis (ALS) in Taiwan. Methods: We conducted clinical and molecular genetic studies of 109 probands with molecularly unassigned SCA from 512 SCA pedigrees, 323 healthy controls, 502 patients with sporadic ataxia syndromes, and 144 patients with ALS. Repeat-primed PCR assays and PCR-fragment analysis for the number of short hexanucleotide repeats (<40 units) were performed to ascertain NOP56 hexanucleotide repeat expansion. Genotyping included 8 microsatellite markers and 17 single nucleotide polymorphisms flanking NOP56 and covering a region of 1.8 Mb to assess a possible founder effect. Results: Eleven individuals from 3 SCA pedigrees have the NOP56 repeat expansions. The 3 pedigrees share a common haplotype spanning 5.3 kb flanking the NOP56 repeat expansions, suggesting a founder effect of spinocerebellar ataxia type 36 (SCA36) in the Han Chinese. The average age at symptom onset was 44.8 ± 3.8 years with truncal ataxia as the initial manifestation. Common features included slowly progressive truncal/limb ataxia, dysarthria, generalized hyperreflexia, and hearing impairment. Evidence of lower motor neuron involvement, including atrophy and fasciculation in the limb muscles and tongue, was mostly found in patients with prolonged disease duration. NOP56 repeat expansion was not detected in controls or patients with sporadic ataxic syndromes or ALS. Conclusions: SCA36 is an uncommon subtype, which accounted for 0.6% (3/512) of SCA cases in the Han Chinese population. PMID:27123487

  16. Cerebro-cerebellar circuits in autism spectrum disorder

    PubMed Central

    D'Mello, Anila M.; Stoodley, Catherine J.

    2015-01-01

    The cerebellum is one of the most consistent sites of abnormality in autism spectrum disorder (ASD) and cerebellar damage is associated with an increased risk of ASD symptoms, suggesting that cerebellar dysfunction may play a crucial role in the etiology of ASD. The cerebellum forms multiple closed-loop circuits with cerebral cortical regions that underpin movement, language, and social processing. Through these circuits, cerebellar dysfunction could impact the core ASD symptoms of social and communication deficits and repetitive and stereotyped behaviors. The emerging topography of sensorimotor, cognitive, and affective subregions in the cerebellum provides a new framework for interpreting the significance of regional cerebellar findings in ASD and their relationship to broader cerebro-cerebellar circuits. Further, recent research supports the idea that the integrity of cerebro-cerebellar loops might be important for early cortical development; disruptions in specific cerebro-cerebellar loops in ASD might impede the specialization of cortical regions involved in motor control, language, and social interaction, leading to impairments in these domains. Consistent with this concept, structural, and functional differences in sensorimotor regions of the cerebellum and sensorimotor cerebro-cerebellar circuits are associated with deficits in motor control and increased repetitive and stereotyped behaviors in ASD. Further, communication and social impairments are associated with atypical activation and structure in cerebro-cerebellar loops underpinning language and social cognition. Finally, there is converging evidence from structural, functional, and connectivity neuroimaging studies that cerebellar right Crus I/II abnormalities are related to more severe ASD impairments in all domains. We propose that cerebellar abnormalities may disrupt optimization of both structure and function in specific cerebro-cerebellar circuits in ASD. PMID:26594140

  17. Spontaneous Intracranial Hypotension Associated with Kinetic Tremor and Ataxia

    PubMed Central

    Salazar, Richard

    2016-01-01

    Background Spontaneous intracranial hypotension (SIH) is a clinically variable syndrome caused by low cerebrospinal fluid (CSF) pressure due to a non-traumatic CSF leak. Phenomenology Shown This case describes a 68-year-old gentleman who presents with chronic and slightly progressive kinetic tremor of bilateral hands associated with gait ataxia and gait start hesitation. Educational Value This case underscores the importance of having a high index of suspicion for the diagnosis of SIH when encountering a patient presenting with late-onset progressive kinetic tremor and gait ataxia syndrome. PMID:27351232

  18. Bilateral maculopathy in a patient with ataxia telangiectasia.

    PubMed

    Gioia, Lauren V; Bonsall, Dean; Moffett, Kathryn; Leys, Monique

    2016-02-01

    We report a case of toxoplasmosis with bilateral maculopathy in a 7-year-old boy diagnosed with ataxia telangiectasia (AT) at age 6. AT manifests as ataxia, apraxia, telangiectasia, and dysarthria. Common ophthalmologic findings in AT include fine conjunctival telangiectasia. Patients also suffer from recurrent sinopulmonary infections; however, serious opportunistic infection is rarely diagnosed. At 8 years of age he developed disseminated Toxoplasma gondii (toxoplasmosis) infection and meningoencephalitis. This ophthalmologic finding and the subsequent toxoplasmosis meningoencephalitis have not been previously reported in AT. PMID:26917084

  19. Cerebellar liponeurocytoma in two siblings suggests a possible familial predisposition.

    PubMed

    Pikis, Stylianos; Fellig, Yakov; Margolin, Emil

    2016-10-01

    There is limited data on the genetic origin and natural history of cerebellar liponeurocytoma. To the best of our knowledge there has been only one report of a familial presentation of this rare entity. We report a 72-year-old female with a posterior fossa tumor presenting with progressive cerebellar signs and symptoms. The patient underwent total tumor resection via an uncomplicated sub-occipital craniotomy. Histopathologic examination was diagnostic for cerebellar liponeurocytoma. Her sister was previously treated for a similar tumor. Our report provides further evidence for the possible existence of a hereditary abnormality predisposing afflicted families to cerebellar liponeurocytoma development. PMID:27349466

  20. Ex vivo imaging of postnatal cerebellar granule cell migration using confocal macroscopy.

    PubMed

    Bénard, Magalie; Lebon, Alexis; Komuro, Hitoshi; Vaudry, David; Galas, Ludovic

    2015-01-01

    During postnatal development, immature granule cells (excitatory interneurons) exhibit tangential migration in the external granular layer, and then radial migration in the molecular layer and the Purkinje cell layer to reach the internal granular layer of the cerebellar cortex. Default in migratory processes induces either cell death or misplacement of the neurons, leading to deficits in diverse cerebellar functions. Centripetal granule cell migration involves several mechanisms, such as chemotaxis and extracellular matrix degradation, to guide the cells towards their final position, but the factors that regulate cell migration in each cortical layer are only partially known. In our method, acute cerebellar slices are prepared from P10 rats, granule cells are labeled with a fluorescent cytoplasmic marker and tissues are cultured on membrane inserts from 4 to 10 hr before starting real-time monitoring of cell migration by confocal macroscopy at 37 °C in the presence of CO2. During their migration in the different cortical layers of the cerebellum, granule cells can be exposed to neuropeptide agonists or antagonists, protease inhibitors, blockers of intracellular effectors or even toxic substances such as alcohol or methylmercury to investigate their possible role in the regulation of neuronal migration. PMID:25992599

  1. Ex Vivo Imaging of Postnatal Cerebellar Granule Cell Migration Using Confocal Macroscopy

    PubMed Central

    Bénard, Magalie; Lebon, Alexis; Komuro, Hitoshi; Vaudry, David; Galas, Ludovic

    2015-01-01

    During postnatal development, immature granule cells (excitatory interneurons) exhibit tangential migration in the external granular layer, and then radial migration in the molecular layer and the Purkinje cell layer to reach the internal granular layer of the cerebellar cortex. Default in migratory processes induces either cell death or misplacement of the neurons, leading to deficits in diverse cerebellar functions. Centripetal granule cell migration involves several mechanisms, such as chemotaxis and extracellular matrix degradation, to guide the cells towards their final position, but the factors that regulate cell migration in each cortical layer are only partially known. In our method, acute cerebellar slices are prepared from P10 rats, granule cells are labeled with a fluorescent cytoplasmic marker and tissues are cultured on membrane inserts from 4 to 10 hr before starting real-time monitoring of cell migration by confocal macroscopy at 37 °C in the presence of CO2. During their migration in the different cortical layers of the cerebellum, granule cells can be exposed to neuropeptide agonists or antagonists, protease inhibitors, blockers of intracellular effectors or even toxic substances such as alcohol or methylmercury to investigate their possible role in the regulation of neuronal migration. PMID:25992599

  2. Characterization and Early Detection of Balance Deficits in Fragile X Premutation Carriers With and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).

    PubMed

    O'Keefe, Joan A; Robertson-Dick, Erin; Dunn, Emily J; Li, Yan; Deng, Youping; Fiutko, Amber N; Berry-Kravis, Elizabeth; Hall, Deborah A

    2015-12-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) results from a "premutation" size 55-200 CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Core motor features include cerebellar gait ataxia and kinetic tremor, resulting in progressive mobility disability. There are no published studies characterizing balance deficits in FMR1 premutation carriers with and without FXTAS using a battery of quantitative measures to test the sensory integration underlying postural control, automatic postural reflexes, and dynamic postural stability limits. Computerized dynamic posturography (CDP) and two performance-based balance measures were administered in 44 premutation carriers, 21 with FXTAS and 23 without FXTAS, and 42 healthy controls to compare balance and functional mobility between these groups. Relationships between FMR1 molecular variables, age, and sex and CDP scores were explored. FXTAS subjects demonstrated significantly lower scores on the sensory organization test (with greatest reductions in the vestibular control of balance), longer response latencies to balance perturbations, and reduced stability limits compared to controls. Premutation carriers without FXTAS also demonstrated significantly delayed response latencies and disrupted sensory weighting for balance control. Advancing age, male sex, increased CGG repeat size, and reduced X activation of the normal allele in premutation carrier women predicted balance dysfunction. These postural control deficits in carriers with and without FXTAS implicate dysfunctional cerebellar neural networks and may provide valuable outcome markers for tailored rehabilitative interventions. Our findings suggest that CDP may provide sensitive measures for early detection of postural control impairments in at-risk carriers and better characterize balance dysfunction and progression in FXTAS. PMID:25763861

  3. Motor dysfunction in the tottering mouse is linked to cerebellar spontaneous low frequency oscillations revealed by flavoprotein autofluorescence optical imaging

    NASA Astrophysics Data System (ADS)

    Chen, Gang; Popa, Laurentiu S.; Wang, Xinming; Gao, Wangcai; Barnes, Justin; Hendrix, Claudia M.; Hess, Ellen J.; Ebner, Timothy J.

    2009-02-01

    Flavoprotein autofluorescence optical imaging is developing into a powerful research tool to study neural activity, particularly in vivo. In this study we used this imaging technique to investigate the neuronal mechanism underlying the episodic movement disorder that is characteristic of the tottering (tg) mouse, a model of episodic ataxia type 2. Both EA2 and the tg mouse are caused by mutations in the gene encoding Cav2.1 (P/Q-type) voltage-gated Ca2+ channels. These mutations result in a reduction in P/Q Ca2+ channel function. Both EA2 patients and tg mice have a characteristic phenotype consisting of transient motor attacks triggered by stress, caffeine or ethanol. The neural events underlying these episodes of dystonia are unknown. Flavoprotein autofluorescence optical imaging revealed spontaneous, transient, low frequency oscillations in the cerebellar cortex of the tg mouse. Lasting from 30 - 120 minutes, the oscillations originate in one area then spread to surrounding regions over 30 - 60 minutes. The oscillations are reduced by removing extracellular Ca2+ and blocking Cav 1.2/1.3 (L-type) Ca2+ channels. The oscillations are not affected by blocking AMPA receptors or by electrical stimulation of the parallel fiber - Purkinje cell circuit, suggesting the oscillations are generated intrinsically in the cerebellar cortex. Conversely, L-type Ca2+ agonists generate oscillations with similar properties. In the awake tg mouse, transcranial flavoprotein imaging revealed low frequency oscillations that are accentuated during caffeine induced attacks of dystonia. The oscillations increase during the attacks of dystonia and are coupled to oscillations in face and hindlimb EMG activity. These transient oscillations and the associated cerebellar dysfunction provide a novel mechanism by which an ion channel disorder results in episodic motor dysfunction.

  4. Cerebellar hemorrhage provoked by combined use of nattokinase and aspirin in a patient with cerebral microbleeds.

    PubMed

    Chang, Yung-Yee; Liu, Jia-Shou; Lai, Shung-Lon; Wu, Hsiu-Shan; Lan, Min-Yu

    2008-01-01

    Nattokinase is used as a health-promoting medicine for preventing thrombosis due to its fibrinolytic activity. Cerebral microbleed is remnant of blood extravasations from the damaged vessels related to cerebral microangiopathies. We report a patient, having used aspirin for secondary stroke prevention, who had an acute cerebellar hemorrhage after taking nattokinase 400 mg daily for 7 consecutive days. In addition to the hemorrhagic lesion, multiple microbleeds were demonstrated on brain MR images. We suggest that nattokinase may increase risk of intracerebral hemorrhage in patients who have bleeding-prone cerebral microangiopathy and are receiving other antithrombotic agent at the same time. PMID:18310985

  5. Reconstructive endovascular treatment of ruptured vertebral artery dissection involving the posterior inferior cerebellar artery.

    PubMed

    Ota, Takahiro; Sato, Masayuki; Amano, Tatsuo; Saito, Akira; Matsumaru, Yuji

    2016-06-01

    Two cases with ruptured vertebral artery (VA) dissection involving the origin of the posterior inferior cerebellar artery (PICA) are presented. Endovascular proximal occlusion of the dissected segment proximal to the PICA origin was performed, leaving the PICA patent in the acute stage. Stent placement from the PICA to the VA through the contralateral VA and coil embolization were added to the residual dissection in the chronic stage. Rebleedings were not observed. This is the first report of a staged, combined strategy for the treatment of a ruptured PICA involving VA dissection, which enabled preservation of the PICA without bypass surgery. PMID:27038168

  6. Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability

    PubMed Central

    Selcen, Duygu; Brengman, Joan

    2014-01-01

    Objective: To identify and characterize the molecular basis of a syndrome associated with myasthenia, cortical hyperexcitability, cerebellar ataxia, and intellectual disability. Methods: We performed in vitro microelectrode studies of neuromuscular transmission, performed exome and Sanger sequencing, and analyzed functional consequences of the identified mutation in expression studies. Results: Neuromuscular transmission at patient endplates was compromised by reduced evoked quantal release. Exome sequencing identified a dominant de novo variant, p.Ile67Asn, in SNAP25B, a SNARE protein essential for exocytosis of synaptic vesicles from nerve terminals and of dense-core vesicles from endocrine cells. Ca2+-triggered exocytosis is initiated when synaptobrevin attached to synaptic vesicles (v-SNARE) assembles with SNAP25B and syntaxin anchored in the presynaptic membrane (t-SNAREs) into an α-helical coiled-coil held together by hydrophobic interactions. Pathogenicity of the Ile67Asn mutation was confirmed by 2 measures. First, the Ca2+ triggered fusion of liposomes incorporating v-SNARE with liposomes containing t-SNAREs was hindered when t-SNAREs harbored the mutant SNAP25B moiety. Second, depolarization of bovine chromaffin cells transfected with mutant SNAP25B or with mutant plus wild-type SNAP25B markedly reduced depolarization-evoked exocytosis compared with wild-type transfected cells. Conclusion: Ile67Asn variant in SNAP25B is pathogenic because it inhibits synaptic vesicle exocytosis. We attribute the deleterious effects of the mutation to disruption of the hydrophobic α-helical coiled-coil structure of the SNARE complex by replacement of a highly hydrophobic isoleucine by a strongly hydrophilic asparagine. PMID:25381298

  7. 'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'.

    PubMed

    Abeti, R; Parkinson, M H; Hargreaves, I P; Angelova, P R; Sandi, C; Pook, M A; Giunti, P; Abramov, A Y

    2016-01-01

    Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (▵Ψm) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure. PMID:27228352

  8. 'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'

    PubMed Central

    Abeti, R; Parkinson, M H; Hargreaves, I P; Angelova, P R; Sandi, C; Pook, M A; Giunti, P; Abramov, A Y

    2016-01-01

    Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (▵Ψm) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure. PMID:27228352

  9. Analysis of spinocerebellar ataxia types 1, 2, 3, and 6, dentatorubral-pallidoluysian atrophy, and Friedreich's ataxia genes in spinocerebellar ataxia patients in the UK.

    PubMed Central

    Leggo, J; Dalton, A; Morrison, P J; Dodge, A; Connarty, M; Kotze, M J; Rubinsztein, D C

    1997-01-01

    Accurate clinical diagnosis of the spinocerebellar ataxias (SCAs) can be difficult because of overlap in phenotype with other disorders and variation in clinical manifestations. Six SCA loci have been mapped and four disease causing genes identified, in addition to the causative gene for Friedreich's ataxia (FA). All of the identified mutations are expansions of trinucleotide repeat tracts. The SCA2 and SCA6 genes were published recently. The extent of the normal CAG size ranges at these loci and the relative frequencies of the known causes of SCA in the UK are not known. This study first investigated the normal size ranges of the SCA2 and SCA6 loci by genotyping control populations of West African and South African subjects, since African populations generally show the greatest allelic diversity. We found one allele larger than the previously determined normal range for SCA2, and our results at the SCA6 locus agreed with the previously reported normal range. The second component of the study assessed the relative frequencies of the SCA1, 2, 3, and 6, DRPLA, and FA trinucleotide repeat mutations in 146 patients presenting with SCA-like symptoms referred to genetic diagnostic laboratories in the UK. We detected mutations in 14% of patients referred with a diagnosis of autosomal dominant SCA, and in 15% of patients referred with spinocerebellar ataxia where we did not have sufficient family history data available to allow categorisation as familial or sporadic cases. Friedreich's ataxia accounted for 3% of the latter category of cases in our sample, but the most common causes of SCA were SCA2 and SCA6. PMID:9429138

  10. Targeting the prodromal stage of spinocerebellar ataxia type 17 mice: G-CSF in the prevention of motor deficits via upregulating chaperone and autophagy levels.

    PubMed

    Chang, Ya-Chin; Lin, Chia-Wei; Hsu, Chen-Ming; Lee-Chen, Guey-Jen; Su, Ming-Tsan; Ro, Long-Sun; Chen, Chiung-Mei; Huang, Hei-Jen; Hsieh-Li, Hsiu Mei

    2016-05-15

    Spinocerebellar ataxia type 17 (SCA17), an autosomal dominant cerebellar ataxia, is a devastating, incurable disease caused by the polyglutamine (polyQ) expansion of transcription factor TATA binding protein (TBP). The polyQ expansion causes misfolding and aggregation of the mutant TBP, further leading to cytotoxicity and cell death. The well-recognized prodromal phase in many forms of neurodegeneration suggests a prolonged period of partial neuronal dysfunction prior to cell loss that may be amenable to therapeutic intervention. The objective of this study was to assess the effects and molecular mechanisms of granulocyte-colony stimulating factor (G-CSF) therapy during the pre-symptomatic stage in SCA17 mice. Treatment with G-CSF at the pre-symptomatic stage improved the motor coordination of SCA17 mice and reduced the cell loss, insoluble mutant TBP protein, and vacuole formation in the Purkinje neurons of these mice. The neuroprotective effects of G-CSF may be produced by increases in Hsp70, Beclin-1, LC3-II and the p-ERK survival pathway. Upregulation of chaperone and autophagy levels further enhances the clearance of mutant protein aggregation, slowing the progression of pathology in SCA17 mice. Therefore, we showed that the early intervention of G-CSF has a neuroprotective effect, delaying the progression of SCA17 in mutant mice via increases in the levels of chaperone expression and autophagy. PMID:26972528

  11. Voicing Status of Word Final Plosives in Friedreich's Ataxia Dysarthria

    ERIC Educational Resources Information Center

    Blaney, B. E.; Hewlett, N.

    2007-01-01

    In a previous study, the authors identified final plosive voicing contrast as the highest single error source in dysarthria associated with Friedreich's Ataxia in a group of Irish English-speaking participants. This study aimed to determine the acoustic features underlying misperceptions of voicing status and implications for clinical management.…

  12. Genetics Home Reference: ataxia with vitamin E deficiency

    MedlinePlus

    ... this condition have developed an eye disorder called retinitis pigmentosa that causes vision loss. Most people who have ... Registry: Ataxia with vitamin E deficiency MedlinePlus Encyclopedia: Retinitis pigmentosa MedlinePlus Encyclopedia: Vitamin E These resources from MedlinePlus ...

  13. Speech Perception Ability in Individuals with Friedreich Ataxia

    ERIC Educational Resources Information Center

    Rance, Gary; Fava, Rosanne; Baldock, Heath; Chong, April; Barker, Elizabeth; Corben, Louise; Delatycki

    2008-01-01

    The aim of this study was to investigate auditory pathway function and speech perception ability in individuals with Friedreich ataxia (FRDA). Ten subjects confirmed by genetic testing as being homozygous for a GAA expansion in intron 1 of the FXN gene were included. While each of the subjects demonstrated normal, or near normal sound detection, 3…

  14. Visual System Involvement in Patients with Friedreich's Ataxia

    ERIC Educational Resources Information Center

    Fortuna, Filippo; Barboni, Piero; Liguori, Rocco; Valentino, Maria Lucia; Savini, Giacomo; Gellera, Cinzia; Mariotti, Caterina; Rizzo, Giovanni; Tonon, Caterina; Manners, David; Lodi, Raffaele; Sadun, Alfredo A.; Carelli, Valerio

    2009-01-01

    Optic neuropathy is common in mitochondrial disorders, but poorly characterized in Friedreich's ataxia (FRDA), a recessive condition caused by lack of the mitochondrial protein frataxin. We investigated 26 molecularly confirmed FRDA patients by studying both anterior and posterior sections of the visual pathway using a new, integrated approach.…

  15. Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration.

    PubMed

    Chung, Chan; Puthanveetil, Prasanth; Ory, Daniel S; Lieberman, Andrew P

    2016-04-01

    Niemann-Pick C1 (NPC) disease, an autosomal recessive lipid trafficking disorder caused by loss-of-function mutations in the NPC1 gene, is characterized by progressive neurodegeneration resulting in cognitive impairment, ataxia and early death. Little is known about the cellular pathways leading to neuron loss. Here, we studied the effects of diminishing expression of cystatin B, an endogenous inhibitor of cathepsins B, H and L, on the development of NPC neuropathology. We show that decreased expression of cystatin B in patient fibroblasts enhances cathepsin activity. Deletion of the encoding Cstb gene in Npc1-deficient mice resulted in striking deleterious effects, particularly within the cerebellum where diffuse loss of Purkinje cells was observed in young mice. This severe pathology occurred through cell autonomous mechanisms that triggered Purkinje cell death. Moreover, our analyses demonstrated the mislocalization of lysosomal cathepsins within the cytosol of Npc1-deficient Purkinje cells. We provide evidence that this may be a consequence of damage to lysosomal membranes by reactive oxygen species (ROS), leading to the leakage of lysosomal contents that culminates in apoptotic cell death. Consistent with this notion, toxicity from ROS was attenuated in an NPC cell model by cystatin B over-expression or pharmacological inhibition of cathepsin B. The observation that Npc1 and Cstb deletion genetically interact to potently enhance the degenerative phenotype of the NPC cerebellum provides strong support for the notion that lysosomal membrane permeabilization contributes to cerebellar degeneration in NPC disease. PMID:26908626

  16. [Cerebellar Control of Ocular Movements: Application to the Topographical Diagnosis of Cerebellar Lesions].

    PubMed

    Hirose, Genjiro

    2016-03-01

    Over the last decade, substantial information on cerebellar oculomotor control has been provided by the use of sophisticated neuroanatomical, neurophysiological, and imaging techniques. We now know that an intact cerebellum is a prerequisite for normal oculomotor performance. This review clarifies the current knowledge on structure-function correlations of the cerebellum in relation to ocular movements and allows them to be applied to topographical diagnosis of cerebellar lesions. The cerebellar regions most closely related to oculomotor function are: (1) the flocculus/paraflocculus for VOR suppression, cancellation, smooth pursuit eye movement and gaze-holding, (2) the nodulus/ventral uvula for velocity storage and low frequency prolonged vestibular response, and (3) the dorsal oculomotor vermis (declive VI, folium VII) and the posterior portion of the fastigial nucleus (fastigial oculomotor region) for saccades and smooth pursuit initiation. Symptomatically, defects in the flocculus/parflocculus cause saccadic pursuit, downbeat nystagmus, and impairments to visual suppression of the VOR. Lesions of the nodulus/uvula reveal as periodic alternating nystagmus. Lesions of the oculomotor vermis and the fastigial nucleus can induce saccadic dysmetria, while fastigial nucleus lesions may also cause ocular flutter/opsoclonus. A detailed knowledge of cerebellar anatomy and the physiology of eye movements enables localization of lesions to specific areas of the cerebellum. PMID:27001776

  17. Brain activation during immediate and delayed reaching in optic ataxia.

    PubMed

    Himmelbach, Marc; Nau, Marion; Zündorf, Ida; Erb, Michael; Perenin, Marie-Therese; Karnath, Hans-Otto

    2009-05-01

    Patients with optic ataxia after lesions of the occipito-parietal cortex demonstrate gross deviations of movements to visual targets in their peripheral visual field. When the same patients point to remembered target locations their accuracy improves considerably. Taking into account opposite findings in a single patient suffering from visual form agnosia due to bilateral occipito-temporal lesions (D.F.), this paradoxical improvement was attributed to brain structures outside the dorsal stream, and supposed to be specifically associated with delayed movement execution. This conclusion was based on the still unverified assumption that the dorsal system is almost completely lacking any localization function in patients with optic ataxia who demonstrate the paradoxical delay effect. We thus investigated brain activity associated with immediately executed and delayed movements in a patient with optic ataxia due to extensive bilateral lesions (I.G.) and in 16 healthy subjects using functional magnetic resonance imaging. Our analysis revealed robust and indistinguishable activation of intact dorsal occipital and parietal areas adjacent to the patient's lesions for both types of movements. In healthy subjects, we found the same visuomotor network activated during immediate and delayed movements as well as additionally higher signal increases for movements to visible targets than for delayed movements in bilateral occipito-parietal and occipito-temporal areas. Our results suggest that in healthy subjects as well as in the optic ataxia patient I.G. dorsal areas are not only involved in immediate but also in delayed reaching. This observation questions the hypothesis that residual visuospatial abilities in patients with optic ataxia could only be mediated by a system outside of the dorsal stream. PMID:19428407

  18. Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth

    PubMed Central

    Haldipur, Parthiv; Gillies, Gwendolyn S; Janson, Olivia K; Chizhikov, Victor V; Mithal, Divakar S; Miller, Richard J; Millen, Kathleen J

    2014-01-01

    Loss of Foxc1 is associated with Dandy-Walker malformation, the most common human cerebellar malformation characterized by cerebellar hypoplasia and an enlarged posterior fossa and fourth ventricle. Although expressed in the mouse posterior fossa mesenchyme, loss of Foxc1 non-autonomously induces a rapid and devastating decrease in embryonic cerebellar ventricular zone radial glial proliferation and concurrent increase in cerebellar neuronal differentiation. Subsequent migration of cerebellar neurons is disrupted, associated with disordered radial glial morphology. In vitro, SDF1α, a direct Foxc1 target also expressed in the head mesenchyme, acts as a cerebellar radial glial mitogen and a chemoattractant for nascent Purkinje cells. Its receptor, Cxcr4, is expressed in cerebellar radial glial cells and conditional Cxcr4 ablation with Nes-Cre mimics the Foxc1−/− cerebellar phenotype. SDF1α also rescues the Foxc1−/− phenotype. Our data emphasizes that the head mesenchyme exerts a considerable influence on early embryonic brain development and its disruption contributes to neurodevelopmental disorders in humans. DOI: http://dx.doi.org/10.7554/eLife.03962.001 PMID:25513817

  19. Cerebellar atrophy and prognosis after temporal lobe resection.

    PubMed Central

    Specht, U; May, T; Schulz, R; Rohde, M; Ebner, A; Schmidt, R C; Schütz, M; Wolf, P

    1997-01-01

    OBJECTIVE: Experimental data indicate inhibitory effects of the cerebellum on seizure activity. Structural damage such as cerebellar atrophy, which is a common finding in patients with chronic epilepsy, may reduce these effects. METHODS: Outcome after temporal lobectomy was studied in 78 consecutive patients, with or without cerebellar atrophy diagnosed by MRI. RESULTS: Thirty five patients (45%) showed cerebellar atrophy. At a mean follow up of 14.6 (range, 6-40) months, 50 patients (64%) had no postoperative seizures. In these patients, the frequency of cerebellar atrophy was significantly lower (34%) than in patients who relapsed (64%, p < 0.01). Occurrence of generalised tonic-clonic seizures (GTCS) within two years before surgery, occurrence of GTCS at any time preoperatively, long duration of epilepsy, and older age at surgery were also associated with recurrence of seizures. Multiple logistic regression analysis suggested occurrence of GTCS within two years before surgery and cerebellar atrophy as the main predictive indicators. When both factors were present, the percentage of patients remaining seizure free since surgery fell to 30%, compared with 60% when only GTCS were present, 78.6% when only cerebellar atrophy was present, and 87.5% when both factors were absent. CONCLUSIONS: Cerebellar atrophy shown by MRI was a frequent finding in surgically treated patients with temporal lobe epilepsy. The presence of cerebellar atrophy seems to worsen the prognosis after temporal lobe resection. Images PMID:9153610

  20. Pre- and Postnatal Neuroimaging of Congenital Cerebellar Abnormalities.

    PubMed

    Poretti, Andrea; Boltshauser, Eugen; Huisman, Thierry A G M

    2016-02-01

    The human cerebellum has a protracted development that makes it vulnerable to a broad spectrum of developmental disorders including malformations and disruptions. Starting from 19 to 20 weeks of gestation, prenatal magnetic resonance imaging (MRI) can reliably study the developing cerebellum. Pre- and postnatal neuroimaging plays a key role in the diagnostic work-up of congenital cerebellar abnormalities. Diagnostic criteria for cerebellar malformations and disruptions are based mostly on neuroimaging findings. The diagnosis of a Dandy-Walker malformation is based on the presence of hypoplasia, elevation, and counterclockwise upward rotation of the cerebellar vermis and cystic dilatation of the fourth ventricle, which extends posteriorly filling out the posterior fossa. For the diagnosis of Joubert syndrome, the presence of the molar tooth sign (thickened, elongated, and horizontally orientated superior cerebellar peduncles and an abnormally deep interpeduncular fossa) is needed. The diagnostic criteria of rhombencephalosynapsis include a complete or partial absence of the cerebellar vermis and continuity of the cerebellar hemispheres across the midline. Unilateral cerebellar hypoplasia is defined by the complete aplasia or hypoplasia of one cerebellar hemisphere. Familiarity with these diagnostic criteria as well as the broad spectrum of additional neuroimaging findings is important for a correct pre- and postnatal diagnosis. A correct diagnosis is essential for management, prognosis, and counseling of the affected children and their family. PMID:26166429

  1. De novo cerebellar malignant glioma: A case report

    PubMed Central

    Matsumoto, Hiroaki; Yoshida, Yasuhisa

    2016-01-01

    Introduction Gliomas of the cerebellum are rare in adults, and their natural history and clinical behavior are not well known. Because cerebellar glioma is not usually diagnosed until clinical symptoms have appeared, no reports have described the developmental process of new cerebellar gliomas. We describe a case of de novo cerebellar anaplastic astrocytoma in which the developmental process was detected on magnetic resonance imaging (MRI). Presentation of case A 78-year-old man with a history of cerebral infarction was undergoing follow-up MRI every 6 months. This follow-up revealed a small abnormality in the left cerebellar hemisphere without clinical symptoms. Subsequent MRI showed lesion growth accompanying clinical symptoms. As cerebellar tumor was suspected, the lesion was extirpated. The histological diagnosis was anaplastic astrocytoma. Local recurrence developed and the patient died 20 months postoperatively. Discussion Cerebellar gliomas sometimes do not exhibit the common MRI findings of supratentorial gliomas, leading to difficulty with preoperative diagnosis. In this case, we initially diagnosed asymptomatic cerebellar infarction because the lesion was small and asymptomatic. The abnormal lesion gradually grew and clinical symptoms appeared. Cerebellar glioma may show few signs characteristic of tumor on MRI in the initial stages. Conclusion When MRI detects a new, faint abnormality in the cerebellum, close follow-up of clinical symptoms and MRI on suspicion of glioma is warranted PMID:27017277

  2. Increased cerebellar volume and BDNF level following quadrato motor training.

    PubMed

    Ben-Soussan, Tal Dotan; Piervincenzi, Claudia; Venditti, Sabrina; Verdone, Loredana; Caserta, Micaela; Carducci, Filippo

    2015-01-01

    Using whole-brain structural measures coupled to analysis of salivary brain-derived neurotrophic factor (BDNF), we demonstrate sensory motor training-induced plasticity, including cerebellar gray matter volume increment and increased BDNF level. The increase of cerebellar volume was positively correlated with the increase of BDNF level. PMID:25311848

  3. Distinct Critical Cerebellar Subregions for Components of Verbal Working Memory

    ERIC Educational Resources Information Center

    Cooper, Freya E.; Grube, Manon; Von Kriegstein, Katharina; Kumar, Sukhbinder; English, Philip; Kelly, Thomas P.; Chinnery, Patrick F.; Griffiths, Timothy D.

    2012-01-01

    A role for the cerebellum in cognition has been proposed based on studies suggesting a profile of cognitive deficits due to cerebellar stroke. Such studies are limited in the determination of the detailed organisation of cerebellar subregions that are critical for different aspects of cognition. In this study we examined the correlation between…

  4. Cerebellar control of gait and interlimb coordination.

    PubMed

    Vinueza Veloz, María Fernanda; Zhou, Kuikui; Bosman, Laurens W J; Potters, Jan-Willem; Negrello, Mario; Seepers, Robert M; Strydis, Christos; Koekkoek, Sebastiaan K E; De Zeeuw, Chris I

    2015-11-01

    Synaptic and intrinsic processing in Purkinje cells, interneurons and granule cells of the cerebellar cortex have been shown to underlie various relatively simple, single-joint, reflex types of motor learning, including eyeblink conditioning and adaptation of the vestibulo-ocular reflex. However, to what extent these processes contribute to more complex, multi-joint motor behaviors, such as locomotion performance and adaptation during obstacle crossing, is not well understood. Here, we investigated these functions using the Erasmus Ladder in cell-specific mouse mutant lines that suffer from impaired Purkinje cell output (Pcd), Purkinje cell potentiation (L7-Pp2b), molecular layer interneuron output (L7-Δγ2), and granule cell output (α6-Cacna1a). We found that locomotion performance was severely impaired with small steps and long step times in Pcd and L7-Pp2b mice, whereas it was mildly altered in L7-Δγ2 and not significantly affected in α6-Cacna1a mice. Locomotion adaptation triggered by pairing obstacle appearances with preceding tones at fixed time intervals was impaired in all four mouse lines, in that they all showed inaccurate and inconsistent adaptive walking patterns. Furthermore, all mutants exhibited altered front-hind and left-right interlimb coordination during both performance and adaptation, and inconsistent walking stepping patterns while crossing obstacles. Instead, motivation and avoidance behavior were not compromised in any of the mutants during the Erasmus Ladder task. Our findings indicate that cell type-specific abnormalities in cerebellar microcircuitry can translate into pronounced impairments in locomotion performance and adaptation as well as interlimb coordination, highlighting the general role of the cerebellar cortex in spatiotemporal control of complex multi-joint movements. PMID:25139623

  5. Mutant β-III Spectrin Causes mGluR1α Mislocalization and Functional Deficits in a Mouse Model of Spinocerebellar Ataxia Type 5

    PubMed Central

    Armbrust, Karen R.; Wang, Xinming; Hathorn, Tyisha J.; Cramer, Samuel W.; Chen, Gang; Zu, Tao; Kangas, Takashi; Zink, Anastasia N.; Öz, Gülin; Ebner, Timothy J.

    2014-01-01

    Spinocerebellar ataxia type 5 (SCA5), a dominant neurodegenerative disease characterized by profound Purkinje cell loss, is caused by mutations in SPTBN2, a gene that encodes β-III spectrin. SCA5 is the first neurodegenerative disorder reported to be caused by mutations in a cytoskeletal spectrin gene. We have developed a mouse model to understand the mechanistic basis for this disease and show that expression of mutant but not wild-type β-III spectrin causes progressive motor deficits and cerebellar degeneration. We show that endogenous β-III spectrin interacts with the metabotropic glutamate receptor 1α (mGluR1α) and that mice expressing mutant β-III spectrin have cerebellar dysfunction with altered mGluR1α localization at Purkinje cell dendritic spines, decreased mGluR1-mediated responses, and deficient mGluR1-mediated long-term potentiation. These results indicate that mutant β-III spectrin causes mislocalization and dysfunction of mGluR1α at dendritic spines and connects SCA5 with other disorders involving glutamatergic dysfunction and synaptic plasticity abnormalities. PMID:25057192

  6. Otogenic cerebellar abscess: a case report.

    PubMed

    Richter, Gresham T; Smith, Jason A; Dornhoffer, John L

    2009-04-01

    This case report describes the gradual deterioration of a healthy, highly functioning man who initially presented with a draining right ear. The patient's indolent neurologic decline and referral to an otologist ultimately led to the diagnosis and treatment of an otogenic cerebellar abscess, an increasingly rare intracranial complication of otitis media. We report this case to illustrate that severe complications of chronic otitis media still occur in the United States, to stress the importance of clinical suspicion in the postantibiotic era, and to review the literature regarding the most appropriate time to perform the otologic portion of the surgery. PMID:19358116

  7. Marked reduction of cerebellar deficits in upper limbs following transcranial cerebello-cerebral DC stimulation: tremor reduction and re-programming of the timing of antagonist commands

    PubMed Central

    Grimaldi, Giuliana; Oulad Ben Taib, Nordeyn; Manto, Mario; Bodranghien, Florian

    2014-01-01

    Cerebellar ataxias represent a very heterogeneous group of disabling disorders for which we lack effective symptomatic therapies in most cases. There is currently an intense interest in the use of non-invasive transcranial DC stimulation (tDCS) to modulate the activity of the cerebellum in ataxic disorders. We performed a detailed laboratory assessment of the effects of transcranial cerebello-cerebral DC stimulation (tCCDCS, including a sham procedure) on upper limb tremor and dysmetria in 2 patients presenting a dominant spinocerebellar ataxia (SCA) type 2, one of the most common SCAs encountered during practice. Both patients had a very similar triplet expansion size in the ATXN2 gene (respectively, 39 and 40 triplets). tCCDCS reduced both postural tremor and action tremor, as confirmed by spectral analysis. Quadratical PSD (power spectral density) of postural tremor dropped to 38.63 and 41.42% of baseline values in patient 1 and 2, respectively. The integral of the subband 4–20 Hz dropped to 46.9 and 62.3% of baseline values, respectively. Remarkably, tCCDCS canceled hypermetria and reduced dramatically the onset latency of the antagonist EMG activity associated with fast goal-directed movements toward 3 aimed targets (0.2, 0.3, and 0.4 rad). Following tCCDCS, the latency dropped from 108–98 to 63–57 ms in patient 1, and from 74–87 to 41–46 ms in patient 2 (mean control values ± SD: 36 ± 8 to 45 ± 11 ms), corresponding to a major drop of z scores for the 2 patients from 7.12 ± 0.69 to 1.28 ± 1.27 (sham procedure: 6.79 ± 0.71). This is the first demonstration that tCCDCS improves upper limb tremor and hypermetria in SCA type 2. In particular, this is the first report of a favorable effect on the onset latency of the antagonist EMG activity, a neurophysiological marker of the defect in programming of timing of motor commands. Our results indicate that tCCDCS should be considered in the symptomatic management of upper limb motor deficits in

  8. New evidence for the cerebellar involvement in personality traits

    PubMed Central

    Picerni, Eleonora; Petrosini, Laura; Piras, Fabrizio; Laricchiuta, Daniela; Cutuli, Debora; Chiapponi, Chiara; Fagioli, Sabrina; Girardi, Paolo; Caltagirone, Carlo; Spalletta, Gianfranco

    2013-01-01

    Following the recognition of its role in sensory-motor coordination and learning, the cerebellum has been involved in cognitive, emotional, and even personality domains. This study investigated the relationships between cerebellar macro- and micro-structural variations and temperamental traits measured by Temperament and Character Inventory (TCI). High resolution T1-weighted, and Diffusion Tensor Images of 100 healthy subjects aged 18–59 years were acquired by 3 Tesla Magnetic Resonance scanner. In multiple regression analyses, cerebellar Gray Matter (GM) or White Matter (WM) volumes, GM Mean Diffusivity (MD), and WM Fractional Anisotropy (FA) were used as dependent variables, TCI scores as regressors, gender, age, and education years as covariates. Novelty Seeking scores were associated positively with the cerebellar GM volumes and FA, and negatively with MD. No significant association between Harm Avoidance, Reward Dependence or Persistence scores and cerebellar structural measures was found. The present data put toward a cerebellar involvement in the management of novelty. PMID:24106465

  9. Insights into cerebellar development and medulloblastoma.

    PubMed

    Bihannic, Laure; Ayrault, Olivier

    2016-01-01

    Cerebellar development is an extensive process that begins during early embryonic stages and persists more than one year after birth in human. Therefore, the cerebellum is susceptible to acquire various developmental abnormalities leading to numerous diseases such as medulloblastoma, the most common pediatric malignant brain tumor. One third of the patients with medulloblastoma are incurable and survivors have a poor quality of life due to the aggressiveness of the broad-spectrum treatments. Within the past few years, it has been highlighted that medulloblastoma is a heterogeneous disease that is divided in four molecular subgroups. This recent advance in the field, combined with the development of associated preclinical models for each subgroup, should enable, in the future, the discovery and use of targeted therapy in clinical treatments for each subtype of medulloblastoma. In this review, we first aim to show how deregulation of cerebellar development can lead to medulloblastoma formation and then to present the advances in the molecular subgrouping of medulloblastoma and the associated preclinical models. PMID:26688373

  10. Profound ataxia in complexin I knockout mice masks a complex phenotype that includes exploratory and habituation deficits.

    PubMed

    Glynn, Dervila; Drew, Cheney J; Reim, Kerstin; Brose, Nils; Morton, A Jennifer

    2005-08-15

    Complexins are presynaptic proteins that bind to the SNARE complex where they modulate neurotransmitter release. A number of studies report changes in complexins in psychiatric (schizophrenia and depression) and neurodegenerative disorders (Huntington's disease, Wernicke's encephalopathy and Parkinson's disease). Here, we characterize the behavioural phenotype of Cplx1 knockout (Cplx1-/-) mice. Cplx1-/- mice develop a strong ataxia in the absence of cerebellar degeneration. Although originally reported to die within 2-4 months after birth, when reared using an enhanced feeding regime, these mice survive normally (i.e. >2 years). Cplx1-/- mice show pronounced deficits in motor coordination and locomotion including abnormal gait, inability to run or swim, impaired rotarod performance, reduced neuromuscular strength, dystonia and resting tremor. Although the abnormal motor phenotype dominates their overt symptoms, Cplx1-/- mice also show other behavioural deficits, particularly in complex behaviours. They have deficits in grooming and rearing behaviour and show reduced exploration in several different paradigms. They also show deficits in tasks reflecting emotional reactivity. They fail to habituate to confinement and show a 'panic' response when exposed to water. The abnormalities seen in the behaviour of Cplx1-/- mice reflect those predicted from the distribution of complexin I in the brain. Our data show that complexin I is essential not only for normal motor function in mice, but also for normal performance of other complex behaviours. These results support the idea that altered expression of complexins in disease states may contribute to the symptomatology of disorders in which they are dysregulated. PMID:16000319

  11. Prenatal Cerebellar Disruptions: Neuroimaging Spectrum of Findings in Correlation with Likely Mechanisms and Etiologies of Injury.

    PubMed

    Poretti, Andrea; Boltshauser, Eugen; Huisman, Thierry A G M

    2016-08-01

    There is increasing evidence that the cerebellum is susceptible to prenatal infections and hemorrhages and that congenital morphologic anomalies of the cerebellum may be caused by disruptive (acquired) causes. Starting from the neuroimaging pattern, this report describes a spectrum of prenatal cerebellar disruptions including cerebellar agenesis, unilateral cerebellar hypoplasia, cerebellar cleft, global cerebellar hypoplasia, and vanishing cerebellum in Chiari type II malformation. The neuroimaging findings, possible causative disruptive events, and clinical features of each disruption are discussed. Recognition of cerebellar disruptions and their differentiation from cerebellar malformations is important in terms of diagnosis, prognosis, and genetic counselling. PMID:27423799

  12. Contribution of Cerebellar Sensorimotor Adaptation to Hippocampal Spatial Memory

    PubMed Central

    Passot, Jean-Baptiste; Sheynikhovich, Denis; Duvelle, Éléonore; Arleo, Angelo

    2012-01-01

    Complementing its primary role in motor control, cerebellar learning has also a bottom-up influence on cognitive functions, where high-level representations build up from elementary sensorimotor memories. In this paper we examine the cerebellar contribution to both procedural and declarative components of spatial cognition. To do so, we model a functional interplay between the cerebellum and the hippocampal formation during goal-oriented navigation. We reinterpret and complete existing genetic behavioural observations by means of quantitative accounts that cross-link synaptic plasticity mechanisms, single cell and population coding properties, and behavioural responses. In contrast to earlier hypotheses positing only a purely procedural impact of cerebellar adaptation deficits, our results suggest a cerebellar involvement in high-level aspects of behaviour. In particular, we propose that cerebellar learning mechanisms may influence hippocampal place fields, by contributing to the path integration process. Our simulations predict differences in place-cell discharge properties between normal mice and L7-PKCI mutant mice lacking long-term depression at cerebellar parallel fibre-Purkinje cell synapses. On the behavioural level, these results suggest that, by influencing the accuracy of hippocampal spatial codes, cerebellar deficits may impact the exploration-exploitation balance during spatial navigation. PMID:22485133

  13. Neural correlates of impaired emotional face recognition in cerebellar lesions.

    PubMed

    Adamaszek, Michael; Kirkby, Kenneth C; D'Agata, Fedrico; Olbrich, Sebastian; Langner, Sönke; Steele, Christopher; Sehm, Bernhard; Busse, Stefan; Kessler, Christof; Hamm, Alfons

    2015-07-10

    Clinical and neuroimaging data indicate a cerebellar contribution to emotional processing, which may account for affective-behavioral disturbances in patients with cerebellar lesions. We studied the neurophysiology of cerebellar involvement in recognition of emotional facial expression. Participants comprised eight patients with discrete ischemic cerebellar lesions and eight control patients without any cerebrovascular stroke. Event-related potentials (ERP) were used to measure responses to faces from the Karolinska Directed Emotional Faces Database (KDEF), interspersed in a stream of images with salient contents. Images of faces augmented N170 in both groups, but increased late positive potential (LPP) only in control patients without brain lesions. Dipole analysis revealed altered activation patterns for negative emotions in patients with cerebellar lesions, including activation of the left inferior prefrontal area to images of faces showing fear, contralateral to controls. Correlation analysis indicated that lesions of cerebellar area Crus I contribute to ERP deviations. Overall, our results implicate the cerebellum in integrating emotional information at different higher order stages, suggesting distinct cerebellar contributions to the proposed large-scale cerebral network of emotional face recognition. PMID:25912431

  14. Cerebellar Processing of Sensory Inputs Primes Motor Cortex Plasticity

    PubMed Central

    Velayudhan, B.; Hubsch, C.; Pradeep, S.; Roze, E.; Vidailhet, M.; Meunier, S.; Kishore, A.

    2013-01-01

    Plasticity of the human primary motor cortex (M1) has a critical role in motor control and learning. The cerebellum facilitates these functions using sensory feedback. We investigated whether cerebellar processing of sensory afferent information influences the plasticity of the primary motor cortex (M1). Theta-burst stimulation protocols (TBS), both excitatory and inhibitory, were used to modulate the excitability of the posterior cerebellar cortex and to condition an ongoing M1 plasticity. M1 plasticity was subsequently induced in 2 different ways: by paired associative stimulation (PAS) involving sensory processing and TBS that exclusively involves intracortical circuits of M1. Cerebellar excitation attenuated the PAS-induced M1 plasticity, whereas cerebellar inhibition enhanced and prolonged it. Furthermore, cerebellar inhibition abolished the topography-specific response of PAS-induced M1 plasticity, with the effects spreading to adjacent motor maps. Conversely, cerebellar excitation had no effect on the TBS-induced M1 plasticity. This demonstrates the key role of the cerebellum in priming M1 plasticity, and we propose that it is likely to occur at the thalamic or olivo-dentate nuclear level by influencing the sensory processing. We suggest that such a cerebellar priming of M1 plasticity could shape the impending motor command by favoring or inhibiting the recruitment of several muscle representations. PMID:22351647

  15. Developmental dyslexia and widespread activation across the cerebellar hemispheres.

    PubMed

    Baillieux, Hanne; Vandervliet, Everhard J M; Manto, Mario; Parizel, Paul M; De Deyn, Peter P; Mariën, Peter

    2009-02-01

    Developmental dyslexia is the most common learning disability in school-aged children with an estimated incidence of five to ten percent. The cause and pathophysiological substrate of this developmental disorder is unclear. Recently, a possible involvement of the cerebellum in the pathogenesis of dyslexia has been postulated. In this study, 15 dyslexic children and 7 age-matched control subjects were investigated by means of functional neuroimaging (fMRI) using a noun-verb association paradigm. Comparison of activation patterns between dyslexic and control subjects revealed distinct and significant differences in cerebral and cerebellar activation. Control subjects showed bilaterally well-defined and focal activation patterns in the frontal and parietal lobes and the posterior regions of the cerebellar hemispheres. The dyslexic children, however, presented widespread and diffuse activations on the cerebral and cerebellar level. Cerebral activations were found in frontal, parietal, temporal and occipital regions. Activations in the cerebellum were found predominantly in the cerebellar cortex, including Crus I, Crus II, hemispheric lobule VI, VII and vermal lobules I, II, III, IV and VII. This preliminary study is the first to reveal a significant difference in cerebellar functioning between dyslexic children and controls during a semantic association task. As a result, we propose a new hypothesis regarding the pathophysiological mechanisms of developmental dyslexia. Given the sites of activation in the cerebellum in the dyslexic group, a defect of the intra-cerebellar distribution of activity is suspected, suggesting a disorder of the processing or transfer of information within the cerebellar cortex. PMID:18986695

  16. Using human pluripotent stem cells to study Friedreich ataxia cardiomyopathy.

    PubMed

    Crombie, Duncan E; Pera, Martin F; Delatycki, Martin B; Pébay, Alice

    2016-06-01

    Friedreich ataxia (FRDA) is the most common of the inherited ataxias. It is an autosomal recessive disease characterised by degeneration of peripheral sensory neurons, regions of the central nervous system and cardiomyopathy. FRDA is usually due to homozygosity for trinucleotide GAA repeat expansions found within first intron of the FRATAXIN (FXN) gene, which results in reduced levels of the mitochondrial protein FXN. Reduced FXN protein results in mitochondrial dysfunction and iron accumulation leading to increased oxidative stress and cell death in the nervous system and heart. Yet the precise functions of FXN and the underlying mechanisms leading to disease pathology remain elusive. This is particularly true of the cardiac aspect of FRDA, which remains largely uncharacterized at the cellular level. Here, we summarise current knowledge on experimental models in which to study FRDA cardiomyopathy, with a particular focus on the use of human pluripotent stem cells as a disease model. PMID:27019046

  17. Variant PTA Terminating in Cerebellar Artery, Associated with Multiple Aneurysms

    PubMed Central

    Hwang, Yeong Uk

    2016-01-01

    Persistent trigeminal artery (PTA) is one of the remnant fetal anastomoses between the carotid artery and basilar artery. PTAs are classified according to angiographic appearance and various connection. Among them, those directly terminating in the cerebellar arteries are rare subtype. In addition, aneurysms of the PTA are unusual in the literature and have not previously accompanied this subtype of PTA connecting cerebellar artery. We present the first case of an aneurysm of the PTA which is directly terminating in the cerebellar arteries and combined with multiple aneurysms. PMID:27446623

  18. Variant PTA Terminating in Cerebellar Artery, Associated with Multiple Aneurysms.

    PubMed

    Hwang, Yeong Uk; Kim, Jin Woo

    2016-01-01

    Persistent trigeminal artery (PTA) is one of the remnant fetal anastomoses between the carotid artery and basilar artery. PTAs are classified according to angiographic appearance and various connection. Among them, those directly terminating in the cerebellar arteries are rare subtype. In addition, aneurysms of the PTA are unusual in the literature and have not previously accompanied this subtype of PTA connecting cerebellar artery. We present the first case of an aneurysm of the PTA which is directly terminating in the cerebellar arteries and combined with multiple aneurysms. PMID:27446623

  19. Friedreich Ataxia: From the Eye of a Molecular Biologist.

    PubMed

    Muthuswamy, Srinivasan; Agarwal, Sarita

    2015-09-01

    Friedreich ataxia (FRDA) is caused by the expansion of a GAA triplet repeat in the first intron of the FXN gene. This disease was named after Nicholaus Friedreich, Germany, who depicted the essential finding. Among ataxias, FRDA is the most common hereditary ataxia. It has the autosomal recessive pattern of inheritance. The expansion of the GAA triplet repeat hinders the transcription, thereby reducing the level of the FXN transcript and consequently reducing the level of frataxin, a 210-amino acid protein. The disease pathogenesis is fundamentally due to a lack of frataxin, which is claimed to play a role in iron-sulfur cluster synthesis. Oxidative stress builds up as a result of Fe accumulation in the mitochondria, causing degeneration of the cells, which primarily occurs in the neurons and later in the cardiac tissues, and to some extent in the pancreas. The therapeutic interventions are at infancy; however, current treatments are targeted toward the reduction of iron overload and its effects. PMID:26375377

  20. Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities

    PubMed Central

    Lefevre, Sophie; Sliwa, Dominika; Seguin, Alexandra; Camadro, Jean-Michel; Lesuisse, Emmanuel

    20