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Sample records for episodic ataxia type

  1. Spinocerebellar ataxia type 6 with positional vertigo and acetazolamide responsive episodic ataxia

    PubMed Central

    Jen, J.; Yue, Q.; Karrim, J.; Nelson, S.; Baloh, R.

    1998-01-01

    The SCA6 mutation, a small expansion of a CAG repeat in a calcium channel gene CACNA1A, was identified in three pedigrees. Point mutations in other parts of the gene CACNA1A were excluded and new clinical features of SCA6 reported—namely, central positional nystagmus and episodic ataxia responsive to acetazolamide. The three allelic disorders, episodic ataxia type 2, familial hemiplegic migraine, and SCA6, have overlapping clinical features.

 PMID:9771787

  2. 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.

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

    PubMed

    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; Hanna, Michael G

    2014-04-01

    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 phenocopies

  4. 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

  5. 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 ...

  6. The dynamic regulation of cortical excitability is altered in episodic ataxia type 2.

    PubMed

    Helmich, Rick C; Siebner, Hartwig R; Giffin, Nicola; Bestmann, Sven; Rothwell, John C; Bloem, Bastiaan R

    2010-12-01

    Episodic ataxia type 2 and familial hemiplegic migraine are two rare hereditary disorders that are linked to dysfunctional ion channels and are characterized clinically by paroxysmal neurological symptoms. Impaired regulation of cerebral excitability is thought to play a role in the occurrence of these paroxysms, but the underlying mechanisms are poorly understood. Normal ion channels are crucial for coordinating neuronal firing in response to facilitatory input. Thus, we hypothesized that channel dysfunction in episodic ataxia type 2 and familial hemiplegic migraine may impair the ability to adjust cerebral excitability after facilitatory events. We tested this hypothesis in patients with episodic ataxia type 2 (n = 6), patients with familial hemiplegic migraine (n = 7) and healthy controls (n = 13). All subjects received a high-frequency burst (10 pulses at 20 Hz) of transcranial magnetic stimulation to transiently increase the excitability of the motor cortex. Acute burst-induced excitability changes were probed at 50, 250, 500 and 1000 ms after the end of the burst. This was done using single-pulse transcranial magnetic stimulation to assess corticospinal excitability, and paired-pulse transcranial magnetic stimulation at an interstimulus interval of 2 and 10 ms to assess intracortical inhibition and facilitation, respectively. The time course of burst-induced excitability changes differed between groups. Healthy controls showed a short-lived increase in excitability that was only present 50 ms after the burst. In contrast, patients with episodic ataxia type 2 showed an abnormally prolonged increase in corticospinal excitability that was still present 250 ms after the transcranial magnetic stimulation burst. Furthermore, while controls showed a decrease in intracortical facilitation during the 1 s period following the transcranial magnetic stimulation burst, patients with episodic ataxia type 2 had increased intracortical facilitation 1000 ms after the burst

  7. In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2

    PubMed Central

    Tan, S. Veronica; Burke, David; Labrum, Robyn W.; Haworth, Andrea; Gibbons, Vaneesha S.; Sweeney, Mary G.; Griggs, Robert C.; Kullmann, Dimitri M.; Bostock, Hugh; Hanna, Michael G.

    2016-01-01

    Ion channel dysfunction causes a range of neurological disorders by altering transmembrane ion fluxes, neuronal or muscle excitability, and neurotransmitter release. Genetic neuronal channelopathies affecting peripheral axons provide a unique opportunity to examine the impact of dysfunction of a single channel subtype in detail in vivo. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the neuronal voltage-gated calcium channel Cav2.1. In peripheral motor axons, this channel is highly expressed at the presynaptic neuromuscular junction where it contributes to action potential-evoked neurotransmitter release, but it is not expressed mid-axon or thought to contribute to action potential generation. Eight patients from five families with genetically confirmed episodic ataxia type 2 underwent neurophysiological assessment to determine whether axonal excitability was normal and, if not, whether changes could be explained by Cav2.1 dysfunction. New mutations in the CACNA1A gene were identified in two families. Nerve conduction studies were normal, but increased jitter in single-fibre EMG studies indicated unstable neuromuscular transmission in two patients. Excitability properties of median motor axons were compared with those in 30 age-matched healthy control subjects. All patients had similar excitability abnormalities, including a high electrical threshold and increased responses to hyperpolarizing (P < 0.00007) and depolarizing currents (P < 0.001) in threshold electrotonus. In the recovery cycle, refractoriness (P < 0.0002) and superexcitability (P < 0.006) were increased. Cav2.1 dysfunction in episodic ataxia type 2 thus has unexpected effects on axon excitability, which may reflect an indirect effect of abnormal calcium current fluxes during development. PMID:26912519

  8. In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2.

    PubMed

    Tomlinson, Susan E; Tan, S Veronica; Burke, David; Labrum, Robyn W; Haworth, Andrea; Gibbons, Vaneesha S; Sweeney, Mary G; Griggs, Robert C; Kullmann, Dimitri M; Bostock, Hugh; Hanna, Michael G

    2016-02-01

    Ion channel dysfunction causes a range of neurological disorders by altering transmembrane ion fluxes, neuronal or muscle excitability, and neurotransmitter release. Genetic neuronal channelopathies affecting peripheral axons provide a unique opportunity to examine the impact of dysfunction of a single channel subtype in detail in vivo. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the neuronal voltage-gated calcium channel Cav2.1. In peripheral motor axons, this channel is highly expressed at the presynaptic neuromuscular junction where it contributes to action potential-evoked neurotransmitter release, but it is not expressed mid-axon or thought to contribute to action potential generation. Eight patients from five families with genetically confirmed episodic ataxia type 2 underwent neurophysiological assessment to determine whether axonal excitability was normal and, if not, whether changes could be explained by Cav2.1 dysfunction. New mutations in the CACNA1A gene were identified in two families. Nerve conduction studies were normal, but increased jitter in single-fibre EMG studies indicated unstable neuromuscular transmission in two patients. Excitability properties of median motor axons were compared with those in 30 age-matched healthy control subjects. All patients had similar excitability abnormalities, including a high electrical threshold and increased responses to hyperpolarizing (P < 0.00007) and depolarizing currents (P < 0.001) in threshold electrotonus. In the recovery cycle, refractoriness (P < 0.0002) and superexcitability (P < 0.006) were increased. Cav2.1 dysfunction in episodic ataxia type 2 thus has unexpected effects on axon excitability, which may reflect an indirect effect of abnormal calcium current fluxes during development.

  9. Mutations underlying Episodic Ataxia type-1 antagonize Kv1.1 RNA editing.

    PubMed

    Ferrick-Kiddie, Elizabeth A; Rosenthal, Joshua J C; Ayers, Gregory D; Emeson, Ronald B

    2017-02-20

    Adenosine-to-inosine RNA editing in transcripts encoding the voltage-gated potassium channel Kv1.1 converts an isoleucine to valine codon for amino acid 400, speeding channel recovery from inactivation. Numerous Kv1.1 mutations have been associated with the human disorder Episodic Ataxia Type-1 (EA1), characterized by stress-induced ataxia, myokymia, and increased prevalence of seizures. Three EA1 mutations, V404I, I407M, and V408A, are located within the RNA duplex structure required for RNA editing. Each mutation decreased RNA editing both in vitro and using an in vivo mouse model bearing the V408A allele. Editing of transcripts encoding mutant channels affects numerous biophysical properties including channel opening, closing, and inactivation. Thus EA1 symptoms could be influenced not only by the direct effects of the mutations on channel properties, but also by their influence on RNA editing. These studies provide the first evidence that mutations associated with human genetic disorders can affect cis-regulatory elements to alter RNA editing.

  10. Mutations underlying Episodic Ataxia type-1 antagonize Kv1.1 RNA editing

    PubMed Central

    Ferrick-Kiddie, Elizabeth A.; Rosenthal, Joshua J. C.; Ayers, Gregory D.; Emeson, Ronald B.

    2017-01-01

    Adenosine-to-inosine RNA editing in transcripts encoding the voltage-gated potassium channel Kv1.1 converts an isoleucine to valine codon for amino acid 400, speeding channel recovery from inactivation. Numerous Kv1.1 mutations have been associated with the human disorder Episodic Ataxia Type-1 (EA1), characterized by stress-induced ataxia, myokymia, and increased prevalence of seizures. Three EA1 mutations, V404I, I407M, and V408A, are located within the RNA duplex structure required for RNA editing. Each mutation decreased RNA editing both in vitro and using an in vivo mouse model bearing the V408A allele. Editing of transcripts encoding mutant channels affects numerous biophysical properties including channel opening, closing, and inactivation. Thus EA1 symptoms could be influenced not only by the direct effects of the mutations on channel properties, but also by their influence on RNA editing. These studies provide the first evidence that mutations associated with human genetic disorders can affect cis-regulatory elements to alter RNA editing. PMID:28216637

  11. New insights into the pathogenesis and therapeutics of episodic ataxia type 1

    PubMed Central

    D’Adamo, Maria Cristina; Hasan, Sonia; Guglielmi, Luca; Servettini, Ilenio; Cenciarini, Marta; Catacuzzeno, Luigi; Franciolini, Fabio

    2015-01-01

    Episodic ataxia type 1 (EA1) is a K+ channelopathy characterized by a broad spectrum of symptoms. Generally, patients may experience constant myokymia and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance. During attacks additional symptoms may be reported such as vertigo, blurred vision, diplopia, nausea, headache, diaphoresis, clumsiness, stiffening of the body, dysarthric speech, and difficulty in breathing. These episodes may be precipitated by anxiety, emotional stress, fatigue, startle response or sudden postural changes. Epilepsy is overrepresented in EA1. The disease is inherited in an autosomal dominant manner, and genetic analysis of several families has led to the discovery of a number of point mutations in the voltage-dependent K+ channel gene KCNA1 (Kv1.1), on chromosome 12p13. To date KCNA1 is the only gene known to be associated with EA1. Functional studies have shown that these mutations impair Kv1.1 channel function with variable effects on channel assembly, trafficking and biophysics. Despite the solid evidence obtained on the molecular mechanisms underlying EA1, how these cause dysfunctions within the central and peripheral nervous systems circuitries remains elusive. This review summarizes the main breakthrough findings in EA1, discusses the neurophysiological mechanisms underlying the disease, current therapies, future challenges and opens a window onto the role of Kv1.1 channels in central nervous system (CNS) and peripheral nervous system (PNS) functions. PMID:26347608

  12. Whole-exome sequencing as a diagnostic tool in a family with episodic ataxia type 1

    PubMed Central

    Tacik, Pawel; Guthrie, Kimberly J.; Strongosky, Audrey J.; Broderick, Daniel F.; Riegert-Johnson, Douglas L.; Tang, Sha; El-Khechen, Dima; Parker, Alexander S.; Ross, Owen A.; Wszolek, Zbigniew K.

    2015-01-01

    Complex neurological phenotypes are inherently difficult to diagnose. Whole-exome sequencing (WES) is a new tool in the neurologist's diagnostic armamentarium. WES can be applied to investigate the “diagnostic odyssey” cases. These cases involve patients with rare diseases of likely genetic etiology who have failed to obtain a diagnosis by clinical evaluation and targeted gene testing. The 22-year-old adopted proband presented with episodes of jerking ataxic movements that affected his whole body and mild intellectual developmental disability. He underwent numerous multidisciplinary and multicentric evaluations throughout his life that failed to establish a clear diagnosis. Following his visit to the Mayo Clinic, WES was applied for genetic determination of the unknown disorder in the proband, his biological parents and sister. Besides, four other paternal relatives were reported to have similar complaints. Additional clinical evaluation, and magnetic resonance neuroimaging (MRI), electromyography (EMG) and electroencephalography (EEG) of the proband were performed to verify the phenotype after the WES results were available. Eleven months after the proband's initial visit, WES identified the c.1210G>A (p.V404I) mutation in the potassium voltage-gated channel, shaker-related subfamily, member 1 gene in the proband, his father, and his sister, and thus the diagnosis of episodic ataxia type 1 was established. The proband's MRI demonstrated mild vermian hypoplasia, EMG myokymic discharges, and EEG generalized background slowing. Acetazolamide therapy was beneficial for him at the daily dose of 500 mg. PMID:25659636

  13. Mechanisms of vestibulo-ocular reflex (VOR) cancellation in spinocerebellar ataxia type 3 (SCA-3) and episodic ataxia type 2 (EA-2).

    PubMed

    Gordon, Carlos R; Caspi, Avi; Levite, Ronen; Zivotofsky, Ari Z

    2008-01-01

    The vestibulo-ocular reflex (VOR) mechanism triggers eye movements as a result of head motion in order to keep gaze stationary relative to the world. However, in order to shift the direction of the gaze along with head motion, the VOR mechanism must be overridden ("cancelled"). Two mechanisms have been proposed to explain this cancellation: a reduction of the VOR gain or activation of smooth pursuit (SP) eye movements in the opposite direction. We studied VOR cancellation using the magnetic search coil in six spinocerebellar ataxia type 3 (SCA-3) and four episodic ataxia type 2 (EA-2) patients, conditions that are known to have degraded SP but different degrees of VOR impairment. Abnormal VOR was found in two of the four EA-2 patients and all of the SCA-3 patients. All subjects possessed residual VOR, although when tested using head thrusts it was almost negligible in the SCA-3 patients. The EA-2 patients showed essentially no SP and the SCA-3 patients had poor SP. However, for all patients, the gain during VOR cancellation was comparable to normals. These results provide additional evidence that SP cancellation of the VOR cannot be the sole mechanism utilized in overriding the VOR in these patients.

  14. 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.

  15. 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.

  16. Episodic Ataxias: Clinical and Genetic Features

    PubMed Central

    Choi, Kwang-Dong; Choi, Jae-Hwan

    2016-01-01

    Episodic ataxia (EA) is a clinically heterogeneous group of disorders that are characterized by recurrent spells of truncal ataxia and incoordination lasting minutes to hours. Most have an autosomal dominant inheritance pattern. To date, 8 subtypes have been defined according to clinical and genetic characteristics, and five genes are known to be linked to EAs. Both EA1 and EA2, which are caused by mutations in KCNA1 and CACNA1A, account for the majority of EA, but many patients with no identified mutations still exhibit EA-like clinical features. Furthermore, genetically confirmed EAs have mostly been identified in Caucasian families. In this article, we review the current knowledge on the clinical and genetic characteristics of EAs. Additionally, we summarize the phenotypic features of the genetically confirmed EA2 families in Korea. PMID:27667184

  17. Episodic ataxia type-1 mutations in the hKv1.1 cytoplasmic pore region alter the gating properties of the channel.

    PubMed Central

    D'Adamo, M C; Liu, Z; Adelman, J P; Maylie, J; Pessia, M

    1998-01-01

    Episodic ataxia type-1 is a rare human neurological syndrome which occurs during childhood and persists through the whole life of affected patients. Several heterozygous point mutations have been found in the coding sequence of the voltage-gated potassium channel gene hKv1.1 of different affected families. V408A and E325D mutations are located in the cytoplasmic putative pore region of hKv1.1 channels and profoundly alter their gating properties. V408A channels showed increased kinetic rates of activation, deactivation and C-type inactivation. Expression of E325D channels in Xenopus oocytes led to an approximately 13-fold current amplitude reduction and to a 52.4 mV positive shift in the voltage dependence of activation. Moreover, the E325D mutation altered the kinetics of activation, deactivation, C-type inactivation and channel open probability. Heteromeric channels composed of two wild-type and two mutated subunits, linked as dimers, showed gating properties intermediate between channels formed from four normal or four mutated subunits. The results demonstrate that the highly conserved residues Val408 and Glu325 play a pivotal role in several gating processes of a human potassium channel, and suggest a pathogenetic mechanism by which the impairment of the delayed-rectifier function of affected neurons is related to the type and number of mutated subunits which make up the hKv1.1 channels. PMID:9482717

  18. The episodic ataxia type 1 mutation I262T alters voltage-dependent gating and disrupts protein biosynthesis of human Kv1.1 potassium channels

    PubMed Central

    Chen, Szu-Han; Fu, Ssu-Ju; Huang, Jing-Jia; Tang, Chih-Yung

    2016-01-01

    Voltage-gated potassium (Kv) channels are essential for setting neuronal membrane excitability. Mutations in human Kv1.1 channels are linked to episodic ataxia type 1 (EA1). The EA1-associated mutation I262T was identified from a patient with atypical phenotypes. Although a previous report has characterized its suppression effect, several key questions regarding the impact of the I262T mutation on Kv1.1 as well as other members of the Kv1 subfamily remain unanswered. Herein we show that the dominant-negative effect of I262T on Kv1.1 current expression is not reversed by co-expression with Kvβ1.1 or Kvβ2 subunits. Biochemical examinations indicate that I262T displays enhanced protein degradation and impedes membrane trafficking of Kv1.1 wild-type subunits. I262T appears to be the first EA1 mutation directly associated with impaired protein stability. Further functional analyses demonstrate that I262T changes the voltage-dependent activation and Kvβ1.1-mediated inactivation, uncouples inactivation from activation gating, and decelerates the kinetics of cumulative inactivation of Kv1.1 channels. I262T also exerts similar dominant effects on the gating of Kv1.2 and Kv1.4 channels. Together our data suggest that I262T confers altered channel gating and reduced functional expression of Kv1 channels, which may account for some of the phenotypes of the EA1 patient. PMID:26778656

  19. The episodic ataxia type 1 mutation I262T alters voltage-dependent gating and disrupts protein biosynthesis of human Kv1.1 potassium channels.

    PubMed

    Chen, Szu-Han; Fu, Ssu-Ju; Huang, Jing-Jia; Tang, Chih-Yung

    2016-01-18

    Voltage-gated potassium (Kv) channels are essential for setting neuronal membrane excitability. Mutations in human Kv1.1 channels are linked to episodic ataxia type 1 (EA1). The EA1-associated mutation I262T was identified from a patient with atypical phenotypes. Although a previous report has characterized its suppression effect, several key questions regarding the impact of the I262T mutation on Kv1.1 as well as other members of the Kv1 subfamily remain unanswered. Herein we show that the dominant-negative effect of I262T on Kv1.1 current expression is not reversed by co-expression with Kvβ1.1 or Kvβ2 subunits. Biochemical examinations indicate that I262T displays enhanced protein degradation and impedes membrane trafficking of Kv1.1 wild-type subunits. I262T appears to be the first EA1 mutation directly associated with impaired protein stability. Further functional analyses demonstrate that I262T changes the voltage-dependent activation and Kvβ1.1-mediated inactivation, uncouples inactivation from activation gating, and decelerates the kinetics of cumulative inactivation of Kv1.1 channels. I262T also exerts similar dominant effects on the gating of Kv1.2 and Kv1.4 channels. Together our data suggest that I262T confers altered channel gating and reduced functional expression of Kv1 channels, which may account for some of the phenotypes of the EA1 patient.

  20. A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias

    PubMed Central

    Kalla, R.; Claassen, J.; Adrion, C.; Mansmann, U.; Klopstock, T.; Freilinger, T.; Neugebauer, H.; Spiegel, R.; Dichgans, M.; Lehmann-Horn, F.; Jurkat-Rott, K.; Brandt, T.; Jen, J.C.; Jahn, K.

    2011-01-01

    Objective: The therapeutic effects of 4-aminopyridine (4AP) were investigated in a randomized, double-blind, crossover trial in 10 subjects with familial episodic ataxia with nystagmus. Methods: After randomization, placebo or 4AP (5 mg 3 times daily) was administered for 2 3-month-long treatment periods separated by a 1-month-long washout period. The primary outcome measure was the number of ataxia attacks per month; the secondary outcome measures were the attack duration and patient-reported quality of life (Vestibular Disorders Activities of Daily Living Scale [VDADL]). Nonparametric tests and a random-effects model were used for statistical analysis. Results: The diagnosis of episodic ataxia type 2 (EA2) was genetically confirmed in 7 subjects. Patients receiving placebo had a median monthly attack frequency of 6.50, whereas patients taking 4AP had a frequency of 1.65 (p = 0.03). Median monthly attack duration decreased from 13.65 hours with placebo to 4.45 hours with 4AP (p = 0.08). The VDADL score decreased from 6.00 to 1.50 (p = 0.02). 4AP was well-tolerated. Conclusions: This controlled trial on EA2 and familial episodic ataxia with nystagmus demonstrated that 4AP decreases attack frequency and improves quality of life. Level of evidence: This crossover study provides Class II evidence that 4AP decreases attack frequency and improves the patient-reported quality of life in patients with episodic ataxia and related familial ataxias. PMID:21734179

  1. Spinocerebellar ataxia type 10 - A review.

    PubMed

    Teive, Hélio A G; Munhoz, Renato P; Arruda, Walter O; Raskin, Salmo; Werneck, Lineu César; Ashizawa, Tetsuo

    2011-11-01

    Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant inherited ataxia caused by an expanded ATTCT pentanucleotide repeat in intron 9 of the ATXN10 gene, on chromosome 22q13.3. SCA10 represents a rare form of SCA, until now only described in Latin America, particularly in Mexico, Brazil, Argentina and Venezuela. In Mexico and Brazil SCA10 represents the second most common type of autosomal dominant cerebellar ataxia. The phenotype described in Mexico, is characterized by the association of cerebellar ataxia with epilepsy, while in Brazil the SCA10 phenotype is that of a pure cerebellar ataxia. As yet unidentified genotypic variables may account for this phenotypic difference.

  2. Spinocerebellar ataxia--type 6.

    PubMed

    Gangopadhyay, P K; Ghosh, B; Roy, T; Basu, N; Basu, N; Bhattacharya, N P

    2001-06-01

    Fifty six years lady presented with pure cerebellar ataxia with positive family history from paternal side presented to our clinic. DNA screening found to be SCA6. This is the first case report of SCA6 from India.

  3. Writer's cramp in spinocerebellar ataxia Type 1

    PubMed Central

    Khwaja, Geeta Anjum; Srivastava, Abhilekh; Ghuge, Vijay Vishwanath; Chaudhry, Neera

    2016-01-01

    Dystonia can be encountered in a small subset of patients with spinocerebellar ataxia (SCA), but task specific dystonia is extremely rare. We report a case of a 48-year-old male with confirmed SCA Type 1 (SCA1) with mild progressive cerebellar ataxia and a prominent and disabling Writer's cramp. This case highlights the ever-expanding phenotypic heterogeneity of the SCA's in general and SCA1 in particular. PMID:27695243

  4. Prism adaptation in spinocerebellar ataxia type 2.

    PubMed

    Fernandez-Ruiz, Juan; Velásquez-Perez, Luis; Díaz, Rosalinda; Drucker-Colín, René; Pérez-González, Ruth; Canales, Nalia; Sánchez-Cruz, Gilberto; Martínez-Góngora, Edilberto; Medrano, Yaquelín; Almaguer-Mederos, Luis; Seifried, Carola; Auburger, Georg

    2007-09-20

    Patients with spinocerebellar ataxia type 2 (SCA2), develop severe pontine nuclei, inferior olives, and Purkinje cell degeneration. This form of autosomal dominant cerebellar ataxia is accompanied by progressive ataxia and dysarthria. Although the motor dysfunction is well characterized in these patients, nothing is known about their motor learning capabilities. Here we tested 43 SCA2 patients and their matched controls in prism adaptation, a kind of visuomotor learning task. Our results show that their pattern of brain damage does not entirely disrupt motor learning. Rather, patients had impaired adaptation decrement, but surprisingly a normal aftereffect. Moreover, the mutation degree could discriminate the degree of adaptation. This pattern could reflect the net contribution of two adaptive mechanisms: strategic control and spatial realignment. Accordingly, SCA2 patients show an impaired strategic control that affects the adaptation rate, but a normal spatial realignment measured through the aftereffect. Our results suggest that the neural areas subserving spatial realignment are spared in this form of spinocerebellar ataxia.

  5. 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.

  6. Genetics Home Reference: spinocerebellar ataxia type 1

    MedlinePlus

    ... and Stroke: Ataxias and Cerebellar or Spinocerebellar Degeneration Information Page Educational Resources (7 links) Boston Children's Hospital: Dysphagia Disease InfoSearch: Spinocerebellar ataxia 1 ...

  7. Spinocerebellar ataxia type 2 presenting with cognitive regression in childhood.

    PubMed

    Ramocki, Melissa B; Chapieski, Lynn; McDonald, Ryan O; Fernandez, Fabio; Malphrus, Amy D

    2008-09-01

    Spinocerebellar ataxia type 2 typically presents in adulthood with progressive ataxia, dysarthria, tremor, and slow saccadic eye movements. Childhood-onset spinocerebellar ataxia type 2 is rare, and only the infantile-onset form has been well characterized clinically. This article describes a girl who met all developmental milestones until age 3(1/2) years, when she experienced cognitive regression that preceded motor regression by 6 months. A diagnosis of spinocerebellar ataxia type 2 was delayed until she presented to the emergency department at age 7 years. This report documents the results of her neuropsychologic evaluation at both time points. This case broadens the spectrum of spinocerebellar ataxia type 2 presentation in childhood, highlights the importance of considering a spinocerebellar ataxia in a child who presents with cognitive regression only, and extends currently available clinical information to help clinicians discuss the prognosis in childhood spinocerebellar ataxia type 2.

  8. Ataxia.

    PubMed

    Akbar, Umar; Ashizawa, Tetsuo

    2015-02-01

    Ataxia is a disorder of balance and coordination resulted from dysfunctions involving cerebellum and its afferent and efferent connections. While a variety of disorders can cause secondary ataxias, the list of genetic causes of ataxias is growing longer. Genetic abnormalities may involve mitochondrial dysfunction, oxidative stress, abnormal mechanisms of DNA repair, possible protein misfolding, and abnormalities in cytoskeletal proteins. Few ataxias are fully treatable while hope for efficacious gene therapy and pharmacotherapy is emerging. A discussion of the ataxias is presented here with brief mention of acquired ataxias, and a greater focus on inherited ataxias.

  9. Thiamine and spinocerebellar ataxia type 2.

    PubMed

    Costantini, Antonio; Pala, Maria Immacolata; Colangeli, Marco; Savelli, Serena

    2013-01-10

    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.

  10. Trial in Adult Subjects With Spinocerebellar Ataxia

    ClinicalTrials.gov

    2017-03-08

    Spinocerebellar Ataxias; Spinocerebellar Ataxia Type 1; Spinocerebellar Ataxia Type 2; Spinocerebellar Ataxia Type 3; Spinocerebellar Ataxia Type 6; Spinocerebellar Ataxia Type 7; Spinocerebellar Ataxia Type 8; Spinocerebellar Ataxia Type 10

  11. 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

  12. Three spinocerebellar ataxia type 2 siblings with ataxia, parkinsonism, and motor neuronopathy.

    PubMed

    Nishikawa, Noriko; Nagai, Masahiro; Tsujii, Tomoaki; Tanabe, Nachi; Takashima, Hiroshi; Nomoto, Masahiro

    2011-01-01

    Spinocerebellar ataxia type 2 (SCA2) represents a family of dominant neurodegenerative disorders that results from CAG expansion repeat mutations. The phenotype consists of some common features, most notably progressive ataxia. We describe three siblings with SCA2, manifesting parkinsonism and ataxia in the first sibling, juvenile parkinsonism in the second and motor neuronopathy in the third. Genetic examination revealed expansion to 42, 43, and 42 CAG repeats. There was no relationship between the number of repeats and phenotype. The SCA2 gene should be studied in families with heterogeneous neurodegenerative disorders, including motor neuron disease.

  13. Episodic Ataxia

    MedlinePlus

    ... changes in posture or, in some cases, high- carbohydrate meals. The attacks of EAl are usually associated ... genes does not work properly. (Genes are microscopic structures within the cells of our bodies that contain ...

  14. Acetazolamide-responsive ataxia.

    PubMed

    Kotagal, Vikas

    2012-11-01

    Acetazolamide-responsive ataxia represents a unique collection of genetically distinct episodic ataxia (EA) disorders associated with paroxysmal cerebellar symptoms many of which are responsive to medical treatment with acetazolamide, a carbonic anhydrase inhibitor. Among all of the subtypes of episodic ataxia, types 2 (EA2), 3 (EA3), and 5 (EA5) are thought be the most medication responsive. Some patients with episodic ataxia type 1 (EA1) will also describe improvement with acetazolamide. Each of these individual genetic syndromes is characterized by its own unique mechanism and clinical presentation. In this review, the author provides an overview of the pathophysiology of acetazolamide-responsive ataxia, its natural history, and its clinical management.

  15. 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.

  16. Spinocerebellar ataxia type 2 in a Turkish family.

    PubMed

    Dirik, Eray; Yiş, Uluç; Başak, Nazli; Soydan, Esra; Hüdaoğlu, Orkide; Ozgönül, Figen

    2007-07-01

    Autosomal dominant spinocerebellar ataxias are neurodegenerative disorders that generally present in adulthood. Due to extreme expansion of the repeat size during spermatogenesis, they can also be observed in childhood. The diagnosis in childhood is very difficult in the absence of family history. Here we describe an 8-year-old girl with spinocerebellar ataxia type 2 who presented with progressive ataxia, cognitive deficits, and dysarthria. A detailed family history exhibited similarly affected cases on the paternal side. Molecular testing for spinocerebellar ataxia type 2 revealed abnormal "cytosineadenine-guanosine" expansion in all affected family members. The number of cytosine-adenine-guanosine repeats in the index case was 70. The mean size of expansion in the relatives of the patient was 42 (39-46). This finding explains the early onset of symptoms in the index case.

  17. Spinocerebellar ataxia type 7 without retinal degeneration: a case report.

    PubMed Central

    Kim, Byeong-Chae; Kim, Myeong-Kyu; Cho, Ki-Hyun; Jeon, Beom S.

    2002-01-01

    A 60-yr-old man developed progressive gait disturbance and limb ataxia at the age of 52. Family history was absent for neurological disorders. Examinations showed pure cerebellar syndrome. There was no retinal degeneration for 7 yr. A brain MRI done at the age of 56 showed atrophy of the cerebellar hemispheres and vermis. Genetic test confirmed the spinocerebellar ataxia type 7 with CAG repeat number of 42. PMID:12172062

  18. Cognitive Functions in Ataxia with Oculomotor Apraxia Type 2

    PubMed Central

    Klivényi, Peter; Nemeth, Dezso; Sefcsik, Tamas; Janacsek, Karolina; Hoffmann, Ildiko; Haden, Gabor Peter; Londe, Zsuzsa; Vecsei, Laszlo

    2012-01-01

    Background: Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by cerebellar atrophy, peripheral neuropathy, oculomotor apraxia, and elevated serum alpha-fetoprotein (AFP) levels. The disease is caused by a recessive mutation in the senataxin gene. Since it is a very rare cerebellar disorder, no detailed examination of cognitive functions in AOA2 has been published to date. The aim of the present study was to investigate the neuropsychological profile of a 54-year-old patient with AOA2. Methods: A broad range of neuropsychological examination protocol was administered including the following domains: short-term, working- and episodic-memories, executive functions, implicit sequence learning, and the temporal parameters of speech. Results: The performance on the Listening Span, Letter Fluency, Serial Reaction Time Task, and pause ratio in speech was 2 or more standard deviations (SD) lower compared to controls, and 1 SD lower on Backward Digit Span, Semantic Fluency, articulation rate, and speech tempo. Conclusion: These findings indicate that the pathogenesis of the cerebrocerebellar circuit in AOA2 is responsible for the weaker coordination of complex cognitive functions such as working memory, executive functions, speech, and sequence learning. PMID:23015802

  19. Infantile childhood onset of spinocerebellar ataxia type 2.

    PubMed

    Di Fabio, Roberto; Santorelli, Filippo; Bertini, Enrico; Balestri, Martina; Cursi, Laura; Tessa, Alessandra; Pierelli, Francesco; Casali, Carlo

    2012-06-01

    Spinocerebellar ataxia type 2 (SCA2) is a late-onset autosomal dominant cerebellar ataxia caused by triplet CAG/CTG expansion in the ATX2 gene. The initial symptoms usually appear when subjects are in their 30s.Pediatric onset is less common and usually associated with larger triplet expansions. We here report the case of a 1-year-old girl who presented with facial dysmorphism,dystonic features, developmental delay, and retinitis pigmentosa.She was diagnosed as carrying an expanded CAG/CTG tract (92 repeats) before a molecular diagnosis of SCA2 was made in her father. Facial dysmorphism associated with developmental delay and retinitis pigmentosa in early childhood should prompt a careful family investigation for ataxia and study of ATX2.

  20. Spinocerebellar ataxia type 7: report of a new Italian family.

    PubMed

    Italiano, Domenico; Tarantino, Patrizia; De Marco, Elvira Valeria; Calabrò, Rocco Salvatore; Bramanti, Placido; Quattrone, Aldo; Annesi, Grazia

    2012-01-01

    Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by degeneration of the cerebellum, brainstem and retina. We herein describe a family from southern Italy whose proband was a 49-year-old man presenting with ataxia with progressive gait disturbances, clumsiness and visual impairment. A molecular analysis identified 38 cytosine-adenine-guanine (CAG) repeat expansions within the SCA7 gene. Our study confirms the marked anticipation previously observed in SCA7 and extends the small number of patients studied thus far. In this family, the disease is most likely caused by a de novo expansion of a premutated intermediate allele carried by one parent.

  1. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene-KCNA1 (Kv1.1)

    SciTech Connect

    Browne, D.L.; Gancher, S.T.; Nutt, J.G.

    1994-09-01

    Episodic ataxia (EA) is a rare, familial disorder producing attacks of generalized ataxia, with normal or near-normal neurological function between attacks. One type of EA (MIM No.160120) displays autosomal dominant inheritance and is characterized by episodes of ataxia lasting seconds to minutes with myokymia (rippling of small muscles) evident between attacks. Genetic linkage studies in 4 families suggested localization of an EA/myokymia gene near the K{sup +} channel gene KCNA1 (Kv1.1) on chromosome 12p. Chemical cleavage mismatch and DNA sequence analysis of the KCNA1 coding region in these families identified 4 different missense point mutations present in the heterozygous state. The mutations found were Val174Phe, Arg239Ser, Phe249Ile and Val408Ala; the residue numbers correspond to those in the published amino acid sequence of KCNA1 (Genbank Accession No. L02750). Each of these mutations affects an amino acid residue that is invariant among Drosophila melanogaster, mouse, rat and human, The mutations were present in the affected members of the family and absent in all of the unaffected members and in at least 70 unrelated control individuals. These data strongly suggest that EA/myokymia can result from mutations in the KCNA1 gene.

  2. Oxidative stress as a cofactor in spinocerebellar ataxia type 2.

    PubMed

    Guevara-García, Mariela; Gil-del Valle, Lizette; Velásquez-Pérez, Luis; García-Rodríguez, Julio César

    2012-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a redox-sensitive neurodegenerative disease affecting the cerebellum, fibre connections in the cerebellum, the peripheral nervous system, and extracerebellar central pathways. Currently, Cuba has the highest reported global rate for this disease. The aim of this review article is to summarize and discuss the current knowledge about evidence of oxidative stress during SCA2. Recent reports have suggested that ataxin 2 and other related factors contribute to the redox imbalance in this disease. It is important to recognize and clarify the molecular mechanisms associated with the redox imbalance to consider ataxias innovative approaches to counteract oxidative stress-induced tissue damage, through alternative therapeutic or nutritional intervention in SCA2 and related diseases.

  3. A comprehensive review of spinocerebellar ataxia type 2 in Cuba.

    PubMed

    Velázquez-Pérez, Luis; Rodríguez-Labrada, Roberto; García-Rodríguez, Julio Cesar; Almaguer-Mederos, Luis Enrique; Cruz-Mariño, Tania; Laffita-Mesa, José Miguel

    2011-06-01

    Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia characterized by a progressive cerebellar syndrome associated to saccadic slowing, peripheral neuropathy, cognitive disorders, and other multisystem features. SCA2 is caused by the abnormal expansion of cytosine-adenine-guanine triplet repeats in the encoding region of the ATXN2 gene and therefore the expression of toxic polyglutamine expansions in the ataxin 2 protein, which cause progressive neuronal death of Purkinje cells in the cerebellum and several pontine, mesencephalic, and thalamic neurons among other cells. Worldwide, SCA2 is the second most frequent type of spinocerebellar ataxia, only surpassed by SCA3. Nevertheless, in Holguin, Cuba, the disease reaches the highest prevalence, resulting from a putative foundational effect. This review discusses the most important advances in the genotypical and phenotypical studies of SCA2, highlighting the comprehensive characterization reached in Cuba through clinical, neuroepidemiological, neurochemical, and neurophysiological evaluation of SCA2 patients and pre-symptomatic subjects, which has allowed the identification of new disease biomarkers and therapeutical opportunities. These findings provide guidelines, from a Cuban viewpoint, for the clinical management of the disease, its diagnosis, genetic counseling, and therapeutical options through rehabilitative therapy and/or pharmacological options.

  4. Aerosol characteristics of different types of episode.

    PubMed

    Kuo, Chung-Yih; Lin, Yan-Ruei; Chang, Shih-Yu; Lin, Chuan-Yao; Chou, Chun-Hung

    2013-12-01

    Daily and hourly average data from nine air-quality monitoring stations distributed across central Taiwan, which include ten items (i.e., PM₁₀, PM₂.₅, wind direction, wind speed, temperature, relative humidity, SO₂, NO₂, NO, and CO), were collected from 2005 to 2009. Four episode types: long-range transport with dust storms (DS), long-range transport with frontal pollution (FP), river dust (RD), and stagnant weather (SW), and one mixed type of episode were identified. Of these four episode types, the SW was the dominant type, averaging about 70%. The mean ratio of PM₂.₅/PM₁₀ was the lowest during the RD episodes (0.42), while the mean ratio of PM₂.₅/PM₁₀ was the highest during the SW episodes (0.64). Fine aerosol (PM₂.₅) and coarse aerosol (PM₁₀-₂.₅) samples were collected by high-volume samplers for chemical composition analysis, from only three stations (Douliou, Lunbei, and Siansi) during the days of SW, RD, DS, and FP. The concentrations of PM₂.₅ and three ionic species (NH₄⁺, NO₃⁻, and SO₄²⁻) all showed significant differences among the four episode types. The highest levels of NO₃⁻ (12.1 μg/m(3)) and SO₄²⁻ (20.5 μg/m(3)) were found during the SW and FP episodes, respectively. A comparison on the spatial similarity of aerosol compositions among the episodes and/or non-episodes (control) was characterized by the coefficient of divergence (CD). The results showed higher CD values in PM₁₀-₂.₅ than in PM₂.₅, and the CD values between RD episodes and the other three episodes were higher than those between two types of episode for the other three episodes. The ratios of SOR (sulfur oxidation ratio), SO₄²⁻/EC (elemental carbon), NOR (nitrogen oxidation ratio), and NO₃⁻/EC showed that sulfate formation was most rapid during the FP, while nitrate formation was most rapid during the SW.

  5. Genetics Home Reference: spinocerebellar ataxia type 3

    MedlinePlus

    ... along with ubiquitin and ataxin-3, cluster together to form clumps (aggregates) within the nucleus of the cells. It is unclear how these aggregates affect cell function, because they are found in healthy cells as well as those that die. Nerve cells ( neurons ) and other types of brain ...

  6. Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia.

    PubMed

    Schwarz, N; Hahn, A; Bast, T; Müller, S; Löffler, H; Maljevic, S; Gaily, E; Prehl, I; Biskup, S; Joensuu, T; Lehesjoki, A-E; Neubauer, B A; Lerche, H; Hedrich, U B S

    2016-02-01

    Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by -4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na(+) current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain-of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia.

  7. 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

  8. 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

  9. Itajaí, Santa Catarina - Azorean ancestry and spinocerebellar ataxia type 3.

    PubMed

    Teive, Hélio A G; Moro, Adriana; Arruda, Walter O; Raskin, Salmo; Teive, Gladys M G; Dalabrida, Norberto; Munhoz, Renato P

    2016-10-01

    The authors present a historical review of spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), the most common form of spinocerebellar ataxia in Brazil, and consider the high frequency of cases in families from Itajaí, a city on the coast of the state of Santa Catarina with a large population of Portuguese/Azorean descent.

  10. Progress in pathogenesis studies of spinocerebellar ataxia type 1.

    PubMed

    Cummings, C J; Orr, H T; Zoghbi, H Y

    1999-06-29

    Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited disorder characterized by progressive loss of coordination, motor impairment and the degeneration of cerebellar Purkinje cells, spinocerebellar tracts and brainstem nuclei. Many dominantly inherited neurodegenerative diseases share the mutational basis of SCA1: the expansion of a translated CAG repeat coding for glutamine. Mice lacking ataxin-1 display learning deficits and altered hippocampal synaptic plasticity but none of the abnormalities seen in human SCA1; mice expressing ataxin-1 with an expanded CAG tract (82 glutamine residues), however, develop Purkinje cell pathology and ataxia. These results suggest that mutant ataxin-1 gains a novel function that leads to neuronal degeneration. This novel function might involve aberrant interaction(s) with cell-specific protein(s), which in turn might explain the selective neuronal pathology. Mutant ataxin-1 interacts preferentially with a leucine-rich acidic nuclear protein that is abundantly expressed in cerebellar Purkinje cells and other brain regions affected in SCA1. Immunolocalization studies in affected neurons of patients and SCA1 transgenic mice showed that mutant ataxin-1 localizes to a single, ubiquitin-positive nuclear inclusion (NI) that alters the distribution of the proteasome and certain chaperones. Further analysis of NIs in transfected HeLa cells established that the proteasome and chaperone proteins co-localize with ataxin-1 aggregates. Moreover, overexpression of the chaperone HDJ-2/HSDJ in HeLa cells decreased ataxin-1 aggregation, suggesting that protein misfolding might underlie NI formation. To assess the importance of the nuclear localization of ataxin-1 and its role in SCA1 pathogenesis, two lines of transgenic mice were generated. In the first line, the nuclear localization signal was mutated so that full-length mutant ataxin-1 would remain in the cytoplasm; mice from this line did not develop any ataxia or pathology. This

  11. A comprehensive clinical and genetic study of a large Mexican population with spinocerebellar ataxia type 7.

    PubMed

    Velázquez-Pérez, L; Cerecedo-Zapata, C M; Hernández-Hernández, O; Martínez-Cruz, E; Tapia-Guerrero, Y S; González-Piña, R; Salas-Vargas, J; Rodríguez-Labrada, R; Gurrola-Betancourth, R; Leyva-García, N; Cisneros, B; Magaña, J J

    2015-01-01

    Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder characterized by progressive cerebellar ataxia associated with macular degeneration. We recently described one of the largest series of patients with SCA7 that originated from a founder effect in a Mexican population, which allowed us to perform herein the first comprehensive clinical, neurophysiological, and genetic characterization of Mexican patients with SCA7. In this study, 50 patients, categorized into adult or early phenotype, were clinically assessed using standard neurological exams and genotyped using fluorescent PCR and capillary electrophoresis. Patients with SCA7 exhibited the classical phenotype of the disease characterized by cerebellar ataxia and visual loss; however, we reported, for the first time, frontal-executive disorders and altered sensory-motor peripheral neuropathy in these patients. Semiquantitative analysis of ataxia-associated symptoms was performed using Scale for the Assessment and Rating of Ataxia (SARA) and the Brief Ataxia Rating Scale (BARS) scores, while extracerebellar features were measured employing the Inventory of Non-ataxia Symptoms (INAS) scale. Ataxia rating scales confirmed the critical role size of cytosine-adenine-guanine (CAG) repeat size on age at onset and disease severity, while analysis of CAG repeat instability showed that paternal rather than maternal transmission led to greater instability.

  12. Spinocerebellar ataxia type 6 in eastern India: Some new observations

    PubMed Central

    Bhattacharyya, Kalyan B; Pulai, Debabrata; Guin, Deb Shankar; Ganguly, Goutam; Joardar, Anindita; Roy, Sarnava; Rai, Saurabh; Biswas, Atanu; Pandit, Alok; Roy, Arijit; Senapati, Asit Kumar

    2016-01-01

    Introduction: Spinocerebellar ataxias (SCAs) are hereditary, autosomal dominant progressive neurodegenerative disorders showing clinical and genetic heterogeneity. They are usually manifested clinically in the third to fifth decade of life although there is a wide variability in the age of onset. More than 36 different types of SCAs have been reported so far and about half of them are caused by pathological expansion of the trinucleotide, Cytosine Alanine Guanine (CAG) repeat. The global prevalence of SCA is 0.3-2 per 100,000 population, SCA3 being the commonest variety worldwide, accounting for 20-50 per cent of all cases, though SCA 2 is generally considered as the commonest one in India. However, SCA6 has not been addressed adequately from India though it is common in the eastern Asian countries like, Japan, Korea and Thailand. Objective: The present study was undertaken to identify the prevalence of SCA6 in the city of Kolkata and the eastern part of India. Materials and Methods: 83 consecutive patients were recruited for the study of possible SCAs and their clinical features and genotype were investigated. Results: 6 of the 83 subjects turned out positive for SCA6, constituting therefore, 13.33% of the patient pool. Discussion: SCA6 is prevalent in the eastern part of India, though not as frequent as the other common varieties. Conclusions: Further community based studies are required in order to understand the magnitude of SCA6 in the eastern part, as well as in other regions of India. PMID:27570389

  13. Comparative multiplex dosage analysis in spinocerebellar ataxia type 2 patients.

    PubMed

    Calì, F; Chiavetta, V; Ragalmuto, A; Vinci, M; Ruggeri, G; Schinocca, P; Romano, V

    2013-04-12

    We developed a new application of comparative multiplex dosage analysis (CMDA) for evaluation of the ataxin 2 gene. Expansions of the triplet CAG can cause spinocerebellar ataxia type 2 (SCA2), a neurodegenerative disease with an autosomal-dominant mode of inheritance. Molecular diagnosis of SCA2 is routinely based on the use of conventional PCR to detect the CAG expansion. However, PCR does not amplify an allele with an expansion of many triplets (>80), which is typically found in infantile and juvenile forms of SCA2, thus leading to false negatives. We propose the analysis of the ATXN2 gene by CMDA to complement existing methods currently used for the detection of large expansions of the CAG repeat. Using CMDA, the presence of any longer mutated allele in a heterozygous patient or fetus would be inferred due to dosage variation of the very frequent normal allele #22. CMDA can be completed in 1 day, at very low cost, and would be a useful tool for prenatal diagnosis and for diagnosis of presymptomatic forms of early-onset SCA2.

  14. Masseter reflex in the study of spinocerebellar ataxia type 2 and type 3.

    PubMed

    García, Antonio; Alvarez, Silvia; Infante, Jon; Berciano, José

    2009-10-01

    In this investigation we assess the utility of the masseter reflex for diagnostic purposes in autosomal dominant cerebellar ataxias. We studied the masseter reflex electrophysiologically in spinocerebellar ataxia type 2 (SCA2, 10 patients) and type 3 (SCA3/MJD, 13 patients). In SCA2, the masseter reflex was abnormal in 9 (90%) patients. In SCA3/MJD, the masseter reflex was normal in all 13 patients. Our findings suggest that the masseter reflex is a reliable test that provides additional data prior to molecular study in the differentiation between SCA2 and SCA3/MJD. Masseter reflex abnormalities in SCA2 patients could be better explained by dysfunction of the mesencephalic trigeminal nucleus/tract.

  15. Determination of Genotypic and Phenotypic Characteristics of Friedreich’s Ataxia and Autosomal Dominant Spinocerebellar Ataxia Types 1, 2, 3, and 6

    PubMed Central

    BOZ, Pınar Bengi; KOÇ, Filiz; KOCATÜRK SEL, Sabriye; GÜZEL, Ali İrfan; KASAP, Halil

    2016-01-01

    Introduction This study aimed to analyze the genotypic characteristics of Friedreich’s ataxia (FA) and autosomal dominant ataxias [such as spinocerebellar ataxia (SCA) types 1, 2, 3, and 6] using molecular and biological methods in hereditary cerebellar ataxia considering both clinical and electrophysiological findings. Methods The study included 129 indexed cases, who applied to the neurology department and were diagnosed with hereditary cerebellar ataxia through clinical, laboratory, and electrophysiological findings, and 15 sibling patients who were diagnosed through family scanning (144 cases in total); their genetic analyses were also performed. Detailed physical and neurological examinations, pedigree analyses, electroneurography, evoked potentials, cerebral–spinal magnetic resonance imaging, and echocardiographic analyses were performed for all cases. Blood samples were collected from patients, and the genotypic characteristics of autosomal dominant SCA types 1, 2, 3, and 6 were investigated. Statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS Inc; Chicago, IL, USA) 17.0. Results Almost 50% of patients were defined as FA. Moreover, two SCA1 cases and one SCA6 case were detected. Conclusion In our study, 47.2% of patients with FA had developed hereditary cerebellar ataxia. Ground and autosomal dominant-linked SCA1 and SCA6 were each detected in one family. These data suggest that patients with cerebellar ataxia of hereditary origin should be primarily examined for FA. PMID:28360782

  16. A locus for the nystagmus-associated form of episodic ataxia maps to an 11-cM region on chromosome 19p

    SciTech Connect

    Kramer, P.L.; Gancher, S.T.; Nutt, J.G.

    1995-07-01

    Episodic ataxia (EA) is a rare neurological disorder characterized by attacks of generalized ataxia and near-normal neurological function between attacks. Most inherited cases are the result of an autosomal dominant condition with unknown neuropathology. It is heterogeneous and includes at least two distinct forms. In EA-1, attacks last minutes and interictal myokymia may be present. In EA-2, attacks may last hours and interictal nystagmus may occur. We reported linkage in four EA-1 families to chromosome 12p13 and identified mutations in these families in a potassium channel gene, KCNA1. Recently, we reported linkage in two EA-2 families to a 30-cM region on chromosome 19p. This report is based on members of the same two families and one additional kindred. 18 refs., 1 fig., 1 tab.

  17. 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

  18. 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.

  19. Genetic and clinical analysis of spinocerebellar ataxia type 8 repeat expansion in Yugoslavia.

    PubMed

    Topisirovic, I; Dragasevic, N; Savic, D; Ristic, A; Keckarevic, M; Keckarevic, D; Culjkovic, B; Petrovic, I; Romac, S; Kostic, V S

    2002-10-01

    Spinocerebellar ataxia type 8 (SCA8) is a slowly progressive ataxia causally associated with untranslated CTG repeat expansion on chromosome 13q21. However, the role of the CTG repeat in SCA8 pathology is not yet well understood. Therefore, we studied the length of the SCA8 CTA/CTG expansions (combined repeats, CRs) in 115 patients with ataxia, 64 unrelated individuals with non-triplet neuromuscular diseases, 70 unrelated patients with schizophrenia, and 125 healthy controls. Only one patient with apparently sporadic ataxia was identified with an expansion of 100 CRs. He had inherited the expansion from his asymptomatic father (140 CRs) and transmitted the mutation to his son (92 CRs). Paternal transmission in this family produced contractions of 40 and 8 CRs, respectively. None of the subjects from other studied groups had an expansion at the SCA8 locus. In the control group the number of CRs at the SCA8 locus ranged from 14 to 34. Our findings support the notion that allelic variants of the expansion mutation at the SCA8 locus can predispose to ataxia.

  20. Pathoanatomy of cerebellar degeneration in spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3).

    PubMed

    Scherzed, W; Brunt, E R; Heinsen, H; de Vos, R A; Seidel, K; Bürk, K; Schöls, L; Auburger, G; Del Turco, D; Deller, T; Korf, H W; den Dunnen, W F; Rüb, U

    2012-09-01

    The cerebellum is one of the well-known targets of the pathological processes underlying spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Despite its pivotal role for the clinical pictures of these polyglutamine ataxias, no pathoanatomical studies of serial tissue sections through the cerebellum have been performed in SCA2 and SCA3 so far. Detailed pathoanatomical data are an important prerequisite for the identification of the initial events of the underlying disease processes of SCA2 and SCA3 and the reconstruction of its spread through the brain. In the present study, we performed a pathoanatomical investigation of serial thick tissue sections through the cerebellum of clinically diagnosed and genetically confirmed SCA2 and SCA3 patients. This study demonstrates that the cerebellar Purkinje cell layer and all four deep cerebellar nuclei consistently undergo considerable neuronal loss in SCA2 and SCA3. These cerebellar findings contribute substantially to the pathogenesis of clinical symptoms (i.e., dysarthria, intention tremor, oculomotor dysfunctions) of SCA2 and SCA3 patients and may facilitate the identification of the initial pathological alterations of the pathological processes of SCA2 and SCA3 and reconstruction of its spread through the brain.

  1. Corticomuscular Coherence: a Novel Tool to Assess the Pyramidal Tract Dysfunction in Spinocerebellar Ataxia Type 2.

    PubMed

    Velázquez-Pérez, Luis; Tünnerhoff, Johannes; Rodríguez-Labrada, Roberto; Torres-Vega, Reidenis; Belardinelli, Paolo; Medrano-Montero, Jacqueline; Peña-Acosta, Arnoy; Canales-Ochoa, Nalia; Vázquez-Mojena, Yaimeé; González-Zaldivar, Yanetza; Auburger, Georg; Ziemann, Ulf

    2016-10-11

    Clinical signs of corticospinal tract dysfunction are a common feature of spinocerebellar ataxia type 2 (SCA2) patients. The objective of this study is to assess dysfunction of the corticospinal tract in SCA2 using corticomuscular coherence. Testing corticomuscular coherence and rating of ataxia severity and non-ataxia symptoms were performed in 19 SCA2 patients and 24 age-matched controls. Central motor conduction times (CMCT) to upper and lower right limbs were obtained for the SCA2 group using Transcraneal magnetic stimulation (TMS). SCA2 patients exhibited a significant reduction of corticomuscular coherence for lower limbs, but not for upper limbs. This difference remained significant, even when excluding those individuals with clinical signs of corticospinal tract dysfunction. Corticomuscular coherence for lower limbs correlated inversely with CMCT to tibialis anterior muscle. Corticomuscular coherence could be a valuable electrophysiological tool to assess the corticospinal tract involvement in SCA2, even in the absence of clinical signs of corticospinal tract dysfunction.

  2. Bolivian Kindred with Combined Spinocerebellar Ataxia Type 2 and 10

    PubMed Central

    Baizabal-Carvallo, José Fidel; Xia, Guangbin; Botros, Peter; Laguna, Janeth; Ashizawa, Tetsuo; Jankovic, Joseph

    2015-01-01

    Spinocerebellar ataxias (SCA) are a group of rare hereditary neurodegenerative disorders. Rare cases of two SCA mutations in the same individual have been reported in the literature, however, family descriptions are lacking. Here we present the clinical features and genetic findings of a Bolivian family expressing both SCA2 and SCA10 mutations. The index case and his mother had both SCA2 and SCA10 mutations with a combined clinical phenotype of both disorders, including slow saccades (SCA2) and seizures (SCA10). The uncle of the index case had only a SCA10 mutation. Although the presence of two SCA mutations in the same individuals may be coincidental, the low probability of having both mutations suggests that these mutations might be particularly prevalent in Bolivian population. This is the first description of a family with two SCA mutations with affected subjects having a combined SCA2 and SCA10 phenotype. PMID:25630585

  3. 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

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

    PubMed Central

    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

  5. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia.

    PubMed Central

    Escayg, A; De Waard, M; Lee, D D; Bichet, D; Wolf, P; Mayer, T; Johnston, J; Baloh, R; Sander, T; Meisler, M H

    2000-01-01

    Inactivation of the beta4 subunit of the calcium channel in the mouse neurological mutant lethargic results in a complex neurological disorder that includes absence epilepsy and ataxia. To determine the role of the calcium-channel beta4-subunit gene CACNB4 on chromosome 2q22-23 in related human disorders, we screened for mutations in small pedigrees with familial epilepsy and ataxia. The premature-termination mutation R482X was identified in a patient with juvenile myoclonic epilepsy. The R482X protein lacks the 38 C-terminal amino acids containing part of an interaction domain for the alpha1 subunit. The missense mutation C104F was identified both in a German family with generalized epilepsy and praxis-induced seizures and in a French Canadian family with episodic ataxia. These coding mutations were not detected in 255 unaffected control individuals (510 chromosomes), and they may be considered candidate disease mutations. The results of functional tests of the truncated protein R482X in Xenopus laevis oocytes demonstrated a small decrease in the fast time constant for inactivation of the cotransfected alpha1 subunit. Further studies will be required to evaluate the in vivo consequences of these mutations. We also describe eight noncoding single-nucleotide substitutions, two of which are present at polymorphic frequency, and a previously unrecognized first intron of CACNB4 that interrupts exon 1 at codon 21. PMID:10762541

  6. 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

  7. Natural History of Spinocerebellar Ataxia Type 31: a 4-Year Prospective Study.

    PubMed

    Nakamura, Katsuya; Yoshida, Kunihiro; Matsushima, Akira; Shimizu, Yusaku; Sato, Shunichi; Yahikozawa, Hiroyuki; Ohara, Shinji; Yazawa, Masanobu; Ushiyama, Masao; Sato, Mitsuto; Morita, Hiroshi; Inoue, Atsushi; Ikeda, Shu-Ichi

    2017-04-01

    Spinocerebellar ataxia type 31 (SCA31) is known as a late-onset, relatively pure cerebellar form of ataxia, but a longitudinal prospective study on the natural history of SCA31 has not been done yet. In this prospective cohort study, we enrolled 44 patients (mean ± standard deviation 73.6 ± 8.5 years) with genetically confirmed SCA31 from 10 ataxia referral centers in the Nagano area, Japan. Patients were evaluated every year for 4 years using the Scale for the Assessment and Rating of Ataxia (SARA) and the Barthel Index (BI). Of the 176 follow-up visits (91.5%), 161 were completed in this study. Five patients (11.4%) died during the follow-up period, and two patients (4.5%) were lost to follow-up. The annual progression of the SARA score was 0.8 ± 0.1 points/year and that of the BI was -2.3 ± 0.4 points/year (mean ± standard error). Shorter disease duration at baseline was associated with faster progression of the SARA score. Our study indicated the averaged clinical course of SCA31 as follows: the patients develop ataxic symptoms at 58.5 ± 10.3 years, become wheelchair bound at 79.4 ± 1.7 years, and died at 88.5 ± 0.7 years. Our prospective dataset provides important information for clinical trials of forthcoming disease-modifying therapies for cerebellar ataxia. It also represents a useful resource for SCA31 patients and their family members in genetic counseling sessions.

  8. Two young sisters with spinocerebellar ataxia type 2 showing different clinical progression of disease.

    PubMed

    Yiş, Uluç; Dirik, Eray; Kurul, Semra Hiz; Eken, Asli Gündoğdu; Başak, A Nazli

    2009-06-01

    Spinocerebellar ataxia type 2 is a neurodegenerative disease caused by a CAG repeat expansion in the ataxin-2 gene. Gain-of-toxic effects caused by expanded polyglutamine tracts are important for the disease pathogenesis and there is an inverse relationship between the number of CAG repeats and the age of onset and clinical severity. Previously, we reported an extended Turkish family with spinocerebellar ataxia type 2 with several affected members in three generations. Two sisters in this generation showed an earlier age of onset (5 and 7 years, respectively) than their father (30 years). In this paper, we present a further interesting finding regarding the disease onset and manifestation in the two sisters. Interestingly, the age of onset was delayed and the clinical severity of the disease was milder in the child who had more CAG repeats (84 vs. 70). This finding suggests that there are other factors contributing to the age of onset and clinical severity in spinocerebellar ataxia type 2 other than the increased CAG repeat.

  9. Spinocerebellar ataxia type 2 (SCA2): clinical features and genetic analysis.

    PubMed

    Mutesa, Léon; Pierquin, Geneviève; Segers, Karin; Vanbellinghen, Jean François; Gahimbare, Laetitia; Bours, Vincent

    2008-10-01

    Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease that results from the expansion of an unstable trinucleotide CAG repeat encoding for a polyglutamine tract. In normal individuals, alleles contain between 14 and 31 CAG repeats, whereas the pathological alleles have more than 35 CAG repeats. The clinical phenotype of SCA2 includes a progressive cerebellar ataxia with additional features such as ophthalmoplegia, extra-pyramidal or pyramidal signs and peripheral neuropathy. We report a SCA2 large African family with several affected individuals. A major pathological allele carrying 43 CAG repeats was identified in the proband. To our knowledge, this is a first report of a SCA disorder described in Central African patients, thus indicating the need to consider this diagnosis in young African ataxic patients.

  10. Spinocerebellar ataxia type 10 in Peru: the missing link in the Amerindian origin of the disease.

    PubMed

    Leonardi, Luca; Marcotulli, Christian; McFarland, Karen N; Tessa, Alessandra; DiFabio, Roberto; Santorelli, Filippo M; Pierelli, Francesco; Ashizawa, Tetsuo; Casali, Carlo

    2014-09-01

    Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder manifested by ataxia with a variable presentation of epileptic seizures, which is caused by a large expansion of an intronic ATTCT pentanucleotide repeat in ATXN10 on 22q13.3. Herein, we report the first description of SCA10 in a Peruvian family, supporting the Amerindian origin of SCA10 and the Panamerican geographical distribution of the disease in North, Central and South America. Moreover, the presence of an interruption motif in the SCA10 expansion along with epileptic seizures in this family supports the correlation between the two, as seen in other families. Finally, this is the first SCA10 patient ever observed outside of America, specifically in Italy. Since this patient is a Peruvian immigrant of Amerindian ancestry, our case report highlights the growing need for awareness amongst clinicians of seemingly geographically restricted rare diseases.

  11. [A case of spinocerebellar ataxia type 2 presenting with a clinical course similar to spastic paraparesis].

    PubMed

    Miyaji, Yosuke; Doi, Hiroshi; Koyano, Shigeru; Baba, Yasuhisa; Suzuki, Yume; Kuroiwa, Yoshiyuki

    2010-09-01

    We report a 50-year-old woman with an unremarkable birth and developmental history, and with no family history of neurological disorders. The patient had a 6-year history of progressive cervical dystonia, oral dyskinesia, and hyperreflexia. She was initially considered to have spastic paraparesis of unknown cause. Because brain MRI showed mild atrophy of the cerebellar vermis, genetic analysis for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 12, and 17, and dentatorubral-pallidoluysian atrophy was performed. The results revealed an abnormal expansion of CAG repeats (38 repeats) in one allele of ATXN2, and the patient was diagnosed with spinocerebellar ataxia type 2 (SCA2). She had no major clinical features of SCA2 such as cerebellar ataxia, slow saccade, or hyporeflexia. Recent reports have shown the CAG repeat expansion in ATXN2 to be detected in patients with familial L-dopa-responsive parkinsonism. The present case suggests that CAG repeat expansion in ATXN2 may be detected in some patients with spastic paraparesis, and that wide variations of clinical manifestations exist in SCA2.

  12. A new model to study neurodegeneration in ataxia oculomotor apraxia type 2

    PubMed Central

    Becherel, Olivier J.; Sun, Jane; Yeo, Abrey J.; Nayler, Sam; Fogel, Brent L.; Gao, Fuying; Coppola, Giovanni; Criscuolo, Chiara; De Michele, Giuseppe; Wolvetang, Ernst; Lavin, Martin F.

    2015-01-01

    Ataxia oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia. Recent evidence suggests that the protein defective in this syndrome, senataxin (SETX), functions in RNA processing to protect the integrity of the genome. To date, only patient-derived lymphoblastoid cells, fibroblasts and SETX knockdown cells were available to investigate AOA2. Recent disruption of the Setx gene in mice did not lead to neurobehavioral defects or neurodegeneration, making it difficult to study the etiology of AOA2. To develop a more relevant neuronal model to study neurodegeneration in AOA2, we derived neural progenitors from a patient with AOA2 and a control by induced pluripotent stem cell (iPSC) reprogramming of fibroblasts. AOA2 iPSC and neural progenitors exhibit increased levels of oxidative damage, DNA double-strand breaks, increased DNA damage-induced cell death and R-loop accumulation. Genome-wide expression and weighted gene co-expression network analysis in these neural progenitors identified both previously reported and novel affected genes and cellular pathways associated with senataxin dysfunction and the pathophysiology of AOA2, providing further insight into the role of senataxin in regulating gene expression on a genome-wide scale. These data show that iPSCs can be generated from patients with the autosomal recessive ataxia, AOA2, differentiated into neurons, and that both cell types recapitulate the AOA2 cellular phenotype. This represents a novel and appropriate model system to investigate neurodegeneration in this syndrome. PMID:26231220

  13. Progression of brain atrophy in spinocerebellar ataxia type 2: a longitudinal tensor-based morphometry study.

    PubMed

    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.

  14. Lisuride reduces involuntary periodic leg movements in spinocerebellar ataxia type 2 patients.

    PubMed

    Velázquez-Pérez, Luis; Rodríguez-Labrada, Roberto; Álvarez-González, Lázaro; Aguilera-Rodríguez, Raúl; Álvarez Sánchez, Mario; Canales-Ochoa, Nalia; Galicia Polo, Lourdes; Haro-Valencia, Reyes; Medrano-Montero, Jacqueline; Vázquez-Mojena, Yaimeé; Peña-Acosta, Arnoy; Estupiñán-Rodríguez, Annelié; Rodríguez Pupo, Noemí

    2012-12-01

    Periodic leg movements (PLMs) are a common sleep disorder in spinocerebellar ataxia type 2 (SCA2) being associated to higher disease severity and altered sleep patterns. To assess the efficacy and safety of lisuride for the treatment of PLMs in SCA2 patients, an open-label clinical trial was conducted in 12 SCA2 patients suffering from PLMs associated to other subjective sleep complaints. All subjects received 0.1 mg of oral lisuride daily for 4 weeks. Primary outcome measure was the change of PLMs index. Changes in the subjective sleep quality, other polysomnographical sleep parameters, Scale for the Assessment and Rating of Ataxia score, and saccadic velocity were assessed as secondary outcome parameters. Safety assessments included hemoglobin, hematocrit, cholesterol, creatinine, and TGP. A significant decrease in both the PLMs index and R stage latency were observed during the treatment, associated to subjective improvement of frequent awakenings, early insomnia, restless leg syndrome, and nocturnal limb paresthesias in most cases. Ataxia score and saccadic pathology were unchanged. No significantly adverse events were observed. Our study suggests the efficacy of dopamine agonist therapy in the treatment of PLMs in SCA2, improving various subjective sleep complaints. These findings serve to promote the adequate management of sleep-related disorders in SCA2, which could improve the life quality of the patients.

  15. 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

  16. 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.

  17. Generation of spinocerebellar ataxia type 2 patient-derived iPSC line H266.

    PubMed

    Marthaler, Adele G; Schmid, Benjamin; Tubsuwan, Alisa; Poulsen, Ulla B; Hyttel, Poul; Nielsen, Troels T; Nielsen, Jørgen E; Holst, Bjørn

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. Here, we demonstrate the generation of an induced pluripotent stem cell (iPSC) line of a SCA2 patient. The selected clone has been proven to be a bona fide iPSC line, which retains a normal karyotype. Due to its differentiation potential into neurons, this iPSC line will be a valuable tool in studying a disease-specific phenotype of SCA2.

  18. Generation of spinocerebellar ataxia type 2 patient-derived iPSC line H271.

    PubMed

    Marthaler, Adele G; Tubsuwan, Alisa; Schmid, Benjamin; Poulsen, Ulla B; Hyttel, Poul; Nielsen, Jørgen E; Nielsen, Troels T; Holst, Bjørn

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. Here, we demonstrate the generation of an induced pluripotent stem cell (iPSC) line of a SCA2 patient. The selected clone has been proven to be a bona fide iPSC line, which retains a normal karyotype. Due to its differentiation potential into neurons, this iPSC line will be a valuable tool in studying a disease-specific phenotype of SCA2.

  19. Generation of spinocerebellar ataxia type 2 patient-derived iPSC line H196.

    PubMed

    Marthaler, Adele G; Schmid, Benjamin; Tubsuwan, Alisa; Poulsen, Ulla B; Hyttel, Poul; Nielsen, Troels T; Nielsen, Jørgen E; Holst, Bjørn

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. Here, we demonstrate the generation of an induced pluripotent stem cell (iPSC) line of a SCA2 patient. The selected clone has been proven to be a bona fide iPSC line, which retains a normal karyotype. Due to its differentiation potential into neurons, this iPSC line will be a valuable tool in studying a disease-specific phenotype of SCA2.

  20. Assessing the efficacy of specific cerebellomodulatory drugs for use as therapy for spinocerebellar ataxia type 1.

    PubMed

    Nag, Nupur; Tarlac, Volga; Storey, Elsdon

    2013-02-01

    Spinocerebellar ataxias are autosomal dominant diseases, associated in some types with a CAG repeat expansion, and characterised by a progressive loss of motor function. Currently, as there is no cure for most ataxias, treatment predominantly involves physical therapy. Various symptomatic drug treatments have been tried; however, published clinical studies have provided inconsistent results, likely due to small sample sizes, mixed patient populations and insensitive or subjective assessment scales. SCA1(154Q) transgenic mice display motor function impairments and ultimately a reduced number of cerebellar Purkinje neurons-characteristics comparable to most forms of sporadic and hereditary ataxias. We monitored motor function in SCA1(154Q) mice from 5 to 20 weeks of age and assessed the efficacy of four potential cerebellar modulatory drugs in attenuating deficits in rotor-rod performance. The drugs riluzole, amantadine, zolpidem and buspirone were selected based on their different mechanisms of action and their Food and Drug Administration (FDA)/Australian Therapeutic Goods Administration approval for other indications. SCA1(154Q) and C57/Bl6 wild-type mice were administered with four ascending acute doses of each drug, over 2 days. Following each dose, mice were assesed for motor function on the accelerating rotor-rod. None of the four drugs attenuated motor deficts in SCA1(154Q) mice at any dose; at FDA equivalent and higher dose administration of zolpidem and buspirone led to sedation in both strains. Our results suggest that the aforementioned drugs are likely to be ineffective for symptomatic treatment of SCA1 and most other ataxic patients and emphasise the need for comphrehensive drug studies prior to clinical use.

  1. Motor Dysfunctions and Neuropathology in Mouse Models of Spinocerebellar Ataxia Type 2: A Comprehensive Review

    PubMed Central

    Alves-Cruzeiro, João M. Da Conceição; Mendonça, Liliana; Pereira de Almeida, Luís; Nóbrega, Clévio

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant ataxia caused by an expansion of CAG repeats in the exon 1 of the gene ATXN2, conferring a gain of toxic function that triggers the appearance of the disease phenotype. SCA2 is characterized by several symptoms including progressive gait ataxia and dysarthria, slow saccadic eye movements, sleep disturbances, cognitive impairments, and psychological dysfunctions such as insomnia and depression, among others. The available treatments rely on palliative care, which mitigate some of the major symptoms but ultimately fail to block the disease progression. This persistent lack of effective therapies led to the development of several models in yeast, C. elegans, D. melanogaster, and mice to serve as platforms for testing new therapeutic strategies and to accelerate the research on the complex disease mechanisms. In this work, we review 4 transgenic and 1 knock-in mouse that exhibit a SCA2-related phenotype and discuss their usefulness in addressing different scientific problems. The knock-in mice are extremely faithful to the human disease, with late onset of symptoms and physiological levels of mutant ataxin-2, while the other transgenic possess robust and well-characterized motor impairments and neuropathological features. Furthermore, a new BAC model of SCA2 shows promise to study the recently explored role of non-coding RNAs as a major pathogenic mechanism in this devastating disorder. Focusing on specific aspects of the behavior and neuropathology, as well as technical aspects, we provide a highly practical description and comparison of all the models with the purpose of creating a useful resource for SCA2 researchers worldwide. PMID:28018166

  2. Peripheral Neuropathy in Spinocerebellar Ataxia Type 1, 2, 3, and 6.

    PubMed

    Linnemann, Christoph; Tezenas du Montcel, Sophie; Rakowicz, Maryla; Schmitz-Hübsch, Tanja; Szymanski, Sandra; Berciano, Jose; van de Warrenburg, Bart P; Pedersen, Karine; Depondt, Chantal; Rola, Rafal; Klockgether, Thomas; García, Antonio; Mutlu, Gurkan; Schöls, Ludger

    2016-04-01

    Spinocerebellar ataxias (SCAs) are characterized by autosomal dominantly inherited progressive ataxia but are clinically heterogeneous due to variable involvement of non-cerebellar parts of the nervous system. Non-cerebellar symptoms contribute significantly to the burden of SCAs, may guide the clinician to the underlying genetic subtype, and might be useful markers to monitor disease. Peripheral neuropathy is frequently observed in SCA, but subtype-specific features and subclinical manifestations have rarely been evaluated. We performed a multicenter nerve conduction study with 162 patients with genetically confirmed SCA1, SCA2, SCA3, and SCA6. The study proved peripheral nerves to be involved in the neurodegenerative process in 82 % of SCA1, 63 % of SCA2, 55 % of SCA3, and 22 % of SCA6 patients. Most patients of all subtypes revealed affection of both sensory and motor fibers. Neuropathy was most frequently of mixed type with axonal and demyelinating characteristics in all SCA subtypes. However, nerve conduction velocities of SCA1 patients were slower compared to other genotypes. SCA6 patients revealed less axonal damage than patients with other subtypes. No influence of CAG repeat length or biometric determinants on peripheral neuropathy could be identified in SCA1, SCA3, and SCA6. In SCA2, earlier onset and more severe ataxia were associated with peripheral neuropathy. We proved peripheral neuropathy to be a frequent site of the neurodegenerative process in all common SCA subtypes. Since damage to peripheral nerves is readily assessable by electrophysiological means, nerve conduction studies should be performed in a longitudinal approach to assess these parameters as potential progression markers.

  3. Motor Dysfunctions and Neuropathology in Mouse Models of Spinocerebellar Ataxia Type 2: A Comprehensive Review.

    PubMed

    Alves-Cruzeiro, João M Da Conceição; Mendonça, Liliana; Pereira de Almeida, Luís; Nóbrega, Clévio

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant ataxia caused by an expansion of CAG repeats in the exon 1 of the gene ATXN2, conferring a gain of toxic function that triggers the appearance of the disease phenotype. SCA2 is characterized by several symptoms including progressive gait ataxia and dysarthria, slow saccadic eye movements, sleep disturbances, cognitive impairments, and psychological dysfunctions such as insomnia and depression, among others. The available treatments rely on palliative care, which mitigate some of the major symptoms but ultimately fail to block the disease progression. This persistent lack of effective therapies led to the development of several models in yeast, C. elegans, D. melanogaster, and mice to serve as platforms for testing new therapeutic strategies and to accelerate the research on the complex disease mechanisms. In this work, we review 4 transgenic and 1 knock-in mouse that exhibit a SCA2-related phenotype and discuss their usefulness in addressing different scientific problems. The knock-in mice are extremely faithful to the human disease, with late onset of symptoms and physiological levels of mutant ataxin-2, while the other transgenic possess robust and well-characterized motor impairments and neuropathological features. Furthermore, a new BAC model of SCA2 shows promise to study the recently explored role of non-coding RNAs as a major pathogenic mechanism in this devastating disorder. Focusing on specific aspects of the behavior and neuropathology, as well as technical aspects, we provide a highly practical description and comparison of all the models with the purpose of creating a useful resource for SCA2 researchers worldwide.

  4. Strategy use, planning, and rule acquisition deficits in spinocerebellar ataxia type 2 patients.

    PubMed

    Vaca-Palomares, Israel; Díaz, Rosalinda; Rodríguez-Labrada, Roberto; Medrano-Montero, Jacqueline; Aguilera-Rodríguez, Raúl; Vázquez-Mojena, Yaimeé; Fernandez-Ruiz, Juan; Velázquez-Pérez, Luis

    2015-03-01

    Our goal was to improve spinocerebellar ataxia type 2 (SCA2) cognitive profile characterization by testing the hypothesis that strategy, planning and rule acquisition capacities are affected in SCA2. Forty one patients with SCA2 were evaluated with the Spatial Working Memory (SWM), the Stockings of Cambridge (SOC), and the Intra-Extra Dimensional Shift (IED) tests of the Executive module of the Cambridge Neuropsychological Testing Automated Battery (CANTAB). Paired Associates Learning (PAL) and Delayed Matching to Sample (DMS) from the CANTAB memory module were also assessed to corroborate previous findings. Motor deterioration was measured using the Scale for the Assessment and Rating of Ataxia (SARA). We found significant SCA2 related deficits in strategy, planning, and rule acquisition. Our results also corroborated significant memory deficits in these patients with SCA2. Further analysis also showed that patients with large motor deterioration had poorer associative learning and spatial planning scores. Patients with SCA2 show strategy, planning, and rule acquisition deficits as revealed with the CANTAB battery. These deficits should be noted when planning an effective therapy for these patients.

  5. Common origin of pure and interrupted repeat expansions in spinocerebellar ataxia type 2 (SCA2).

    PubMed

    Ramos, Eliana Marisa; Martins, Sandra; Alonso, Isabel; Emmel, Vanessa E; Saraiva-Pereira, Maria Luiza; Jardim, Laura Bannach; Coutinho, Paula; Sequeiros, Jorge; Silveira, Isabel

    2010-03-05

    The spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by gait and limb ataxia. This disease is caused by the expansion of a (CAG)(n) located in the ATXN2, that encodes a polyglutamine tract of more than 34 repeats. Lately, alleles with 32-33 CAGs have been associated to late-onset disease cases. Repeat interruptions by CAA triplets are common in normal alleles, while expanded alleles usually contain a pure repeat tract. To investigate the mutational origin and the instability associated to the ATXN2 repeat, we performed an extensive haplotype study and sequencing of the CAG/CAA repeat, in a cohort of families of different geographic origins and phenotypes. Our results showed (1) CAA interruptions also in expanded ATXN2 alleles; (2) that pathological CAA interrupted alleles shared an ancestral haplotype with pure expanded alleles; and (3) higher genetic diversity in European SCA2 families, suggesting an older European ancestry of SCA2. In conclusion, we found instability towards expansion in interrupted ATXN2 alleles and a shared ancestral ATXN2 haplotype for pure and interrupted expanded alleles; this finding has strong implications in mutation diagnosis and counseling. Our results indicate that interrupted alleles, below the pathological threshold, may be a reservoir of mutable alleles, prone to expansion in subsequent generations, leading to full disease mutation.

  6. Genetic and clinical analysis in a Chinese parkinsonism-predominant spinocerebellar ataxia type 2 family.

    PubMed

    Sun, Hao; Satake, Wataru; Zhang, Changjun; Nagai, Yoshitaka; Tian, Youyong; Fu, Shouzhi; Yu, Jiankun; Qian, Yaping; Qian, Yuan; Chu, Jiayou; Toda, Tatsushi

    2011-04-01

    Parkinson's disease is a degenerative central nervous system disorder that often impairs motor skills, speech and other functions. We discovered a large Chinese family showing primarily parkinsonism symptoms with autosomal dominant inheritance. Six affected individuals in the family showed typical parkinsonism symptoms, including pill-rolling tremor. Two other affected individuals showed cerebellar ataxia symptoms. A whole-genome scan using the 50K single nucleotide polymorphism array with three different linkage methods detected two positive regions on chromosome 12q24.1 and 5q13.3. The ATXN2 gene, responsible for spinocerebellar ataxia type 2 (SCA2) was located precisely in the center of the positive region on chromosome 12. Further analysis of SCA2 revealed heterozygous pathological CAG expansions in the family. The affected individuals' symptoms were typical of parkinsonism, but complex. Inverse correlation between CAG repeat size and age of onset is not obvious in this pedigree. This parkinsonism-predominant SCA2 family shared the same disease gene locus with other 'standard' SCA2 families, but it is possible that variations in one or more modifier genes might account for the parkinsonism-predominant SCA2 predisposition observed in this pedigree.

  7. Change in the cortical complexity of spinocerebellar ataxia type 3 appears earlier than clinical symptoms.

    PubMed

    Wang, Tzu-Yun; Jao, Chii-Wen; 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.

  8. Repeat interruptions in spinocerebellar ataxia type 10 expansions are strongly associated with epileptic seizures.

    PubMed

    McFarland, Karen N; Liu, Jilin; Landrian, Ivette; Zeng, Desmond; Raskin, Salmo; Moscovich, Mariana; Gatto, Emilia M; Ochoa, Adriana; Teive, Hélio A G; Rasmussen, Astrid; Ashizawa, Tetsuo

    2014-03-01

    Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant neurodegenerative disorder, is the result of a non-coding, pentanucleotide repeat expansion within intron 9 of the Ataxin 10 gene. SCA10 patients present with pure cerebellar ataxia; yet, some families also have a high incidence of epilepsy. SCA10 expansions containing penta- and heptanucleotide interruption motifs, termed "ATCCT interruptions," experience large contractions during germline transmission, particularly in paternal lineages. At the same time, these alleles confer an earlier age at onset which contradicts traditional rules of genetic anticipation in repeat expansions. Previously, ATCCT interruptions have been associated with a higher prevalence of epileptic seizures in one Mexican-American SCA10 family. In a large cohort of SCA10 families, we analyzed whether ATCCT interruptions confer a greater risk for developing seizures in these families. Notably, we find that the presence of repeat interruptions within the SCA10 expansion confers a 6.3-fold increase in the risk of an SCA10 patient developing epilepsy (6.2-fold when considering patients of Mexican ancestry only) and a 13.7-fold increase in having a positive family history of epilepsy (10.5-fold when considering patients of Mexican ancestry only). We conclude that the presence of repeat interruptions in SCA10 repeat expansion indicates a significant risk for the epilepsy phenotype and should be considered during genetic counseling.

  9. 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

  10. Spinocerebellar ataxia type 6 protein aggregates cause deficits in motor learning and cerebellar plasticity.

    PubMed

    Mark, Melanie D; Krause, Martin; Boele, Henk-Jan; Kruse, Wolfgang; Pollok, Stefan; Kuner, Thomas; Dalkara, Deniz; Koekkoek, Sebastiaan; De Zeeuw, Chris I; Herlitze, Stefan

    2015-06-10

    Spinocerebellar ataxia type 6 (SCA6) is linked to poly-glutamine (polyQ) within the C terminus (CT) of the pore-forming subunits of P/Q-type Ca(2+) channels (Cav2.1) and is characterized by CT protein aggregates found in cerebellar Purkinje cells (PCs). One hypothesis regarding SCA6 disease is that a CT fragment of the Cav2.1 channel, which is detected specifically in cytosolic and nuclear fractions in SCA6 patients, is associated with the SCA6 pathogenesis. To test this hypothesis, we expressed P/Q-type channel protein fragments from two different human CT splice variants, as predicted from SCA6 patients, in PCs of mice using viral and transgenic approaches. These splice variants represent a short (CT-short without polyQs) and a long (CT-long with 27 polyQs) CT fragment. Our results show that the different splice variants of the CTs differentially distribute within PCs, i.e., the short CTs reveal predominantly nuclear inclusions, whereas the long CTs prominently reveal both nuclear and cytoplasmic aggregates. Postnatal expression of CTs in PCs in mice reveals that only CT-long causes SCA6-like symptoms, i.e., deficits in eyeblink conditioning (EBC), ataxia, and PC degeneration. The physiological phenotypes associated specifically with the long CT fragment can be explained by an impairment of LTD and LTP at the parallel fiber-to-PC synapse and alteration in spontaneous PC activity. Thus, our results suggest that the polyQ carrying the CT fragment of the P/Q-type channel is sufficient to cause SCA6 pathogenesis in mice and identifies EBC as a new diagnostic strategy to evaluate Ca(2+) channel-mediated human diseases.

  11. RNA-binding disturbances as a continuum from spinocerebellar ataxia type 2 to Parkinson disease.

    PubMed

    Nkiliza, Aurore; Mutez, Eugénie; Simonin, Clémence; Leprêtre, Frédéric; Duflot, Aurélie; Figeac, Martin; Villenet, Céline; Semaille, Pierre; Comptdaer, Thomas; Genet, Alexandre; Sablonnière, Bernard; Devos, David; Defebvre, Luc; Destée, Alain; Chartier-Harlin, Marie-Christine

    2016-12-01

    CAG triplet expansions in Ataxin-2 gene (ATXN2) cause spinocerebellar ataxia type 2 and have a role that remains to be clarified in Parkinson's disease (PD). To study the molecular events associated with these expansions, we sequenced them and analyzed the transcriptome from blood cells of controls and three patient groups diagnosed with spinocerebellar ataxia type 2 (herein referred to as SCA2c) or PD with or without ATXN2 triplet expansions (named SCA2p). The transcriptome profiles of these 40 patients revealed three main observations: i) a specific pattern of pathways related to cellular contacts, proliferation and differentiation associated with SCA2p group, ii) similarities between the SCA2p and sporadic PD groups in genes and pathways known to be altered in PD such as Wnt, Ephrin and Leukocyte extravasation signaling iii) RNA metabolism disturbances with "RNA-binding" and "poly(A) RNA-binding" as a common feature in all groups. Remarkably, disturbances of ALS signaling were shared between SCA2p and sporadic PD suggesting common molecular dysfunctions in PD and ALS including CACNA1, hnRNP, DDX and PABPC gene family perturbations. Interestingly, the transcriptome profiles of patients with parkinsonian phenotypes were prevalently associated with alterations of translation while SCA2c and PD patients presented perturbations of splicing. While ATXN2 RNA expression was not perturbed, its protein expression in immortalized lymphoblastoid cells was significantly decreased in SCA2c and SCA2p versus control groups assuming post-transcriptional biological perturbations. In conclusion, the transcriptome data do not exclude the role of ATXN2 mutated alleles in PD but its decrease protein expression in both SCA2c and SCA2p patients suggest a potential involvement of this gene in PD. The perturbations of "RNA-binding" and "poly(A) RNA-binding" molecular functions in the three patient groups as well as gene deregulations of factors not yet described in PD but known to be

  12. Spinocerebellar ataxia type 2: clinical presentation, molecular mechanisms, and therapeutic perspectives.

    PubMed

    Magaña, J J; Velázquez-Pérez, L; Cisneros, B

    2013-02-01

    Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant genetic disease characterized by cerebellar dysfunction associated with slow saccades, early hyporeflexia, severe tremor of postural or action type, peripheral neuropathy, cognitive disorders, and other multisystemic features. SCA2, one of the most common ataxias worldwide, is caused by the expansion of a CAG triplet repeat located in the N-terminal coding region of the ATXN2 gene, which results in the incorporation of a segment of polyglutamines in the mutant protein, being longer expansions associated with earlier onset and more sever disease in subsequent generations. In this review, we offer a detailed description of the clinical manifestations of SCA2 and compile the experimental evidence showing the participation of ataxin-2 in crucial cellular processes, including messenger RNA maturation and translation, and endocytosis. In addition, we discuss in the light of present data the potential molecular mechanisms underlying SCA2 pathogenesis. The mutant protein exhibits a toxic gain of function that is mainly attributed to the generation of neuronal inclusions of phosphorylated and/or proteolytic cleaved mutant ataxin-2, which might alter normal ataxin-2 function, leading to cell dysfunction and death of target cells. In the final part of this review, we discuss the perspectives of development of therapeutic strategies for SCA2. Based on previous experience with other polyglutamine disorders and considering the molecular basis of SCA2 pathogenesis, a nuclei-acid-based strategy focused on the specific silencing of the dominant disease allele that preserves the expression of the wild-type allele is highly desirable and might prevent toxic neurodegenerative sequelae.

  13. Psychotic-affective symptoms and multiple system atrophy expand phenotypes of spinocerebellar ataxia type 2.

    PubMed

    Chen, Kai-Hsiang; Lin, Chin-Hsien; Wu, Ruey-Meei

    2012-03-20

    Spinocerebellar ataxia type 2 (SCA2) is a progressive neurodegenerative disorder, characterised by ataxic gait, slow saccades and peripheral neuropathy. Levodopa-responsive parkinsonism could be a clinical phenotype of SCA2, especially those of Chinese origin. In addition to these motor symptoms, SCA2 has been associated with depression and cognitive dysfunction, with only rare reports of psychosis. The authors report the presence of severe psychosis, major depression and multiple system atrophy in affected subjects of a Taiwanese family with intermediate CAG repeats within the ATXN2 gene. The identification of this rare and distinctive SCA2 phenotype expands the current knowledge of the phenotypic variability of SCA2 and suggests that modifier genes could influence the clinical phenotype of SCA2.

  14. Comparative studies of the CAG repeats in the spinocerebellar ataxia type 1 (SCA1) gene.

    PubMed

    Limprasert, P; Nouri, N; Nopparatana, C; Deininger, P L; Keats, B J

    1997-09-19

    The CAG repeat tract at the autosomal dominant spinocerebellar ataxia type 1 (SCA1) locus was analyzed in SCA1 families and French-Acadian, African-American, Caucasian, Greenland Inuit, and Thai populations. The normal alleles had 9-37 repeats, whereas disease alleles contained 44-64 repeats. The CAG repeat tract contained one or two CAT interruptions in 44 of 47 normal human chromosomes and in all five chimpanzees examined. In contrast, no CAT interruptions were found in Old World monkeys or expanded human alleles. The number and positions of CAT interruptions may be important in stabilizing CAG repeat tracts in normal chromosomes. At least five codons occupy the region corresponding to the polyglutamine tract at the SCA1 locus in mice, rats, and other rodents. They comprise three or four CCN (coding for proline) in addition to one or two CAG repeats.

  15. An electrophysiological study of visual processing in spinocerebellar ataxia type 2 (SCA2).

    PubMed

    Kremlacek, Jan; Valis, Martin; Masopust, Jiri; Urban, Ales; Zumrova, Alena; Talab, Radomir; Kuba, Miroslav; Kubova, Zuzana; Langrova, Jana

    2011-03-01

    Reports of visual functional impairment in spinocerebellar ataxia type 2 (SCA2) have been studied previously using pattern reversal visually evoked potentials (VEPs) with contradictory results. To provide additional evidence to this area, visual functions were studied using VEPs and event-related potentials (ERPs) in a group of ten patients with genetically verified SCA2. The electrophysiological examination included pattern reversal and motion-onset VEPs as well as visually driven oddball ERPs with an evaluation of a target and a pre-attentive response. In six patients, we found abnormal visual/cognitive processing that differed from normal values in latency, but not in the amplitude of the dominant VEP/ERP peaks. Among the VEPs/ERPs used, the motion-onset VEPs exhibited the highest sensitivity and showed a strong Spearman correlation to SCA2 duration (from r = 0.82 to r = 0.90, p < 0.001) and clinical state assessed by Brief Ataxia Rating Scale (from r = 0.71 (p = 0.022) to r = 0.80 (p < 0.001)). None of the VEP/ERP latencies showed a correlation to the triplet repeats of the SCA2 gene. In three patients, we did not find any visual/cognitive pathology, and one subject showed only a single subtle prolongation of the VEP peak. The observed visual/cognitive deficit was related to the subjects' clinical state and the illness duration, but no relationship to the genetic marker of SCA2 was found. From the VEP/ERP types used, the motion-onset VEPs seems to be the most promising candidate for clinical state monitoring rather than a tool for early diagnostic use.

  16. Spinocerebellar ataxia type 4 (SCA4): Initial pathoanatomical study reveals widespread cerebellar and brainstem degeneration.

    PubMed

    Hellenbroich, Y; Gierga, K; Reusche, E; Schwinger, E; Deller, T; de Vos, R A I; Zühlke, C; Rüb, U

    2006-07-01

    Spinocerebellar ataxia type 4 (SCA4), also known as 'hereditary ataxia with sensory neuropathy', represents a very rare, progressive and untreatable form of an autosomal dominant inherited cerebellar ataxia (ADCA). Due to a lack of autopsy cases, no neuropathological or clinicopathological studies had yet been performed in SCA4. In the present study, the first available cerebellar and brainstem tissue of a clinically diagnosed and genetically-confirmed German SCA4 patient was pathoanatomically studied using serial thick sections. During this systematic postmortem investigation, along with an obvious demyelinization of cerebellar and brainstem fiber tracts we observed widespread cerebellar and brainstem neurodegeneration with marked neuronal loss in the substantia nigra and ventral tegmental area, central raphe and pontine nuclei, all auditory brainstem nuclei, in the abducens, principal trigeminal, spinal trigeminal, facial, superior vestibular, medial vestibular, interstitial vestibular, dorsal motor vagal, hypoglossal, and prepositus hypoglossal nuclei, as well as in the nucleus raphe interpositus, all dorsal column nuclei, and in the principal and medial subnuclei of the inferior olive. Severe neuronal loss was seen in the Purkinje cell layer of the cerebellum, in the cerebellar fastigial nucleus, in the red, trochlear, lateral vestibular, and lateral reticular nuclei, the reticulotegmental nucleus of the pons, and the nucleus of Roller. In addition, immunocytochemical analysis using the anti-polyglutamine antibody 1C2 failed to detect any polyglutamine-related immunoreactivity in the central nervous regions of this SCA4 patient studied. In view of the known functional role of affected nuclei and related fiber tracts, the present findings not only offer explanations for the well-known disease symptoms of SCA4 patients (i.e. ataxic symptoms, dysarthria and somatosensory deficits), but for the first time help to explain why diplopia, gaze-evoked nystagmus

  17. Disruption of visual and motor connectivity in spinocerebellar ataxia type 7.

    PubMed

    Hernandez-Castillo, Carlos R; Alcauter, Sarael; Galvez, Victor; Barrios, Fernando A; Yescas, Petra; Ochoa, Adriana; Garcia, Lizbeth; Diaz, Rosalinda; Gao, Wei; Fernandez-Ruiz, Juan

    2013-10-01

    Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder characterized by progressive ataxia and retinal dystrophy. It is caused by a CAG trinucleotide expansion in the ataxin7 gene. Anatomical studies have shown severe cerebellar degeneration and region-specific neocortical atrophy in SCA7 patients. However, the impact of the neurodegeneration on the functional integration of the remaining tissue is still unknown. The aim of this study was to examine functional connectivity abnormalities in areas with significant gray matter atrophy in SCA7 patients and their relationship with number of CAG repeats. Using a combination of voxel-based morphometry and resting-state fMRI, we studied 26 genetically confirmed SCA7 patients and aged-matched healthy controls. In SCA7 patients we found reduced functional interaction between the cerebellum and the middle and superior frontal gyri, disrupted functional connectivity between the visual and motor cortices, and increased functional coordination between atrophied areas of the cerebellum and a range of visual cortical areas compared with healthy controls. The degree of mutation expansion showed a negative effect on both the functional interaction between the right anterior cerebellum and the left superior frontal gyrus and the connectivity between the right anterior cerebellum and left parahippocampal gyrus. We found abnormal functional connectivity patterns, including both hypo- and hyperconnectivity, compared with controls. These abnormal patterns show reasonable association with the severity of gene mutation. Our findings suggest that aberrant changes are prevalent in both motor and visual systems, adding significantly to our understanding of the pathophysiology of SCA7.

  18. Causes of Ataxia

    MedlinePlus

    ... and Type 2 (AOA1 and AOA2). Affects the Nervous System The various abnormal genes that cause ataxia have ... cord. The details of which parts of the nervous system are most affected vary with the different types ...

  19. 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 ...

  20. 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 ...

  1. Ataxia - telangiectasia

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001394.htm Ataxia - telangiectasia To use the sharing features on this page, please enable JavaScript. Ataxia-telangiectasia is a rare childhood disease. It affects ...

  2. Ataxia Telangiectasia

    MedlinePlus

    Ataxia-telangiectasia (A-T) is a rare, inherited disease. It affects the nervous system, immune system, and ... young children, usually before age 5. They include Ataxia - trouble coordinating movements Poor balance Slurred speech Tiny, ...

  3. [THE ANALYSIS OF LIFE SPAN AND MORTALITY OF PATIENTS WITH SPINOCEREBELLAR ATAXIA TYPE I].

    PubMed

    Tikhonov, D G; Goldfarb, L G; Neustroeva, T S; Yakovleva, N V; Timofeev, L F; Luckan, I P; Platonov, F A

    2015-01-01

    The article presents results of investigation of certain unclear aspects of mortality of patients with spinocerebellar ataxia type I including patients with the same number of CAG-repetitions. The analysis of mortality of patients observed from 1993 to nowadays was implemented. Sampling included 112 patients during that period 53 patients died. The comparative analysis was implemented concerning received data and results of analysis of mortality of patients died prior to 1980. According received data, average value of CAG-repetitions of normal allele was equal to 30.2, and ofpathologic allele--48.7. The average life span made up to 52.8 years, average age of disease onset--38 years and natural duration of disease--14.8 years. The analysis of life span of patients with equal length of repetitions demonstrated that range of life span of patients makes up to from 8 to 23 years. It is established that life of patients becomes shorter because of accidents, cancer and concomitant diseases of cardiovascular system. The presence of such concomitant disease as tuberculosis of lungs results in no shortening of life of patients. The comparative analysis of mortality during the period over 34 years demonstrated that age of disease onset turned out to be more conservative and stable indicator of morbidity. Despite of lacking of effective methods of treatment of disease, the natural duration of disease increased statistically reliable up to 1.8 times during period of observation. The analysis of life span ofpatients with spinocerebellar ataxia type I demonstrated that their life span except length of CAG-expansion depends on a number of factors accelerating and retarding development of disease. At that, life span of patients with the same number of CAG-repetitions can significantly differ The malignant neoplasms, diseases of cardiovascular system and external causes are to be referred to factors accelerating and retarding development of main disease. The addition oftuberculosis

  4. Vulnerability of Purkinje Cells Generated from Spinocerebellar Ataxia Type 6 Patient-Derived iPSCs.

    PubMed

    Ishida, Yoshihito; Kawakami, Hideshi; Kitajima, Hiroyuki; Nishiyama, Ayaka; Sasai, Yoshiki; Inoue, Haruhisa; Muguruma, Keiko

    2016-11-01

    Spinocerebellar ataxia type 6 (SCA6) is a dominantly inherited neurodegenerative disease characterized by loss of Purkinje cells in the cerebellum. SCA6 is caused by CAG trinucleotide repeat expansion in CACNA1A, which encodes Cav2.1, α1A subunit of P/Q-type calcium channel. However, the pathogenic mechanism and effective therapeutic treatments are still unknown. Here, we have succeeded in generating differentiated Purkinje cells that carry patient genes by combining disease-specific iPSCs and self-organizing culture technologies. Patient-derived Purkinje cells exhibit increased levels of full-length Cav2.1 protein but decreased levels of its C-terminal fragment and downregulation of the transcriptional targets TAF1 and BTG1. We further demonstrate that SCA6 Purkinje cells exhibit thyroid hormone depletion-dependent degeneration, which can be suppressed by two compounds, thyroid releasing hormone and Riluzole. Thus, we have constructed an in vitro disease model recapitulating both ontogenesis and pathogenesis. This model may be useful for pathogenic investigation and drug screening.

  5. 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

  6. Ataxia Oculomotor Apraxia Type 1 in the Siblings of a Family: A Novel Mutation

    PubMed Central

    KARIMZADEH, Parvaneh; KHAYATZADEH KAKHKI, Simin; ESMAIL NEJAD, Shaghayegh Sadat; HOUSHMAND, Masood; GHOFRANI, Mohammad

    2017-01-01

    Although AOA1 (ataxia oculomotor apraxia1) is one of the most common causes of autosomal recessive cerebellar ataxias in Japanese population, it is reported from all over the world. The clinical manifestations are similar to ataxia telangiectasia in which non-neurological manifestations are absent and include almost 10% of autosomal recessive cerebellar ataxias. Dysarthria and gait disorder are the most two common and typical manifestations. Oculomotor apraxia is usually seen a few years after the manifestations start. APTX gene on 9p13.3 chromosome is expressed in the cells of all human body tissues and different mutations had been discovered. Here we report two siblings (a girl and a boy) of consanguineous parents visited at Mofid Pediatrics Hospital in 2015, with history of gait ataxia, titubation, tremor, and oculomotor apraxia around five yr old and after that. The brother showed symptoms of disease earlier and more severe than his sister did. After ruling out the common etiologies of progressive ataxia, we did genetic study for AOA1 that showed a homozygous frameshift mutation as c.418_418 del was found. This mutation was not reported before so this was a new mutation in APTX gene. PMID:28277561

  7. Neuropathological staging of spinocerebellar ataxia type 2 by semiquantitative 1C2-positive neuron typing. Nuclear translocation of cytoplasmic 1C2 underlies disease progression of spinocerebellar ataxia type 2.

    PubMed

    Koyano, Shigeru; Yagishita, Saburo; Kuroiwa, Yoshiyuki; Tanaka, Fumiaki; Uchihara, Toshiki

    2014-11-01

    Spinocerebellar ataxia type 2 (SCA2) is a hereditary neurodegenerative disorder caused by the expansion of the trinucleotide CAG repeats encoding elongated polyglutamine tract in ataxin-2, the SCA2 gene product. Polyglutamine diseases comprise nine genetic entities, including seven different forms of spinocerebellar ataxias, Huntington's disease, and spinal and bulbar muscular atrophy. These are pathologically characterized by neuronal loss and intranuclear aggregates or inclusions of mutant proteins including expanded polyglutamine in selected neuronal groups. Previously, we examined immunolocalization of ubiquitin, expanded polyglutamine (probed by 1C2 antibody), and ataxin-2 in genetically confirmed SCA2 patients. In the present study, we expanded this approach by distinguishing different patterns of subcellular 1C2 immunoreactivity ("granular cytoplasmic," "cytoplasmic and nuclear" and "nuclear with inclusions.") and by quantifying their regional frequencies in three autopsied SCA2 brains at different stage of the disease. Comparison with neuronal loss and gliosis revealed that overall 1C2 immunoreactivity was paralleled with their severity. Furthermore, appearance of granular cytoplasmic pattern corresponded to early stage, cytoplasmic and nuclear pattern to active stage, and nuclear with inclusions pattern to final stage. We conclude that this 1C2-immunoreactive typing may be useful for evaluating the overall severity and extent of affected regions and estimating the neuropathological stage of SCA2.

  8. Crystallographic and Computational Analyses of AUUCU Repeating RNA That Causes Spinocerebellar Ataxia Type 10 (SCA10)

    PubMed Central

    Park, HaJeung; González, Àlex L.; Yildirim, Ilyas; Tran, Tuan; Lohman, Jeremy R.; Fang, Pengfei; Guo, Min; Disney, Matthew D.

    2016-01-01

    Spinocerebellar ataxia type 10 (SCA10) is caused by a pentanucleotide repeat expansion of r(AUUCU) within intron 9 of the ATXN10 pre-mRNA. The RNA causes disease by a gain-of-function mechanism in which it inactivates proteins involved in RNA biogenesis. Spectroscopic studies showed that r(AUUCU) repeats form a hairpin structure; however, there were no high-resolution structural models prior to this work. Herein, we report the first crystal structure of model r(AUUCU) repeats refined to 2.8 Å and analysis of the structure via molecular dynamics simulations. The r(AUUCU) tracts adopt an overall A-form geometry in which 3 × 3 nucleotide 5′UCU3′/3′UCU5′ internal loops are closed by AU pairs. Helical parameters of the refined structure as well as the corresponding electron density map on the crystallographic model reflect dynamic features of the internal loop. The computational analyses captured dynamic motion of the loop closing pairs, which can form single-stranded conformations with relatively low energies. Overall, the results presented here suggest the possibility for r(AUUCU) repeats to form metastable A-from structures, which can rearrange into single-stranded conformations and attract proteins such as heterogeneous nuclear ribonucleoprotein K (hnRNP K). The information presented here may aid in the rational design of therapeutics targeting this RNA. PMID:26039897

  9. Subtle rapid eye movement sleep abnormalities in presymptomatic spinocerebellar ataxia type 2 gene carriers.

    PubMed

    Rodríguez-Labrada, Roberto; Velázquez-Perez, Luis; Ochoa, Nalia Canales; Polo, Lourdes Galicia; Valencia, Reyes Haro; Cruz, Gilberto Sánchez; Montero, Jacqueline Medrano; Laffita-Mesa, José M; Mederos, Luis E Almaguer; Zaldívar, Yanetza González; Parra, Cira Torres; Acosta, Arnoy Peña; Mariño, Tania Cruz

    2011-02-01

    Rapid eye movement (REM) sleep disorders are commonly associated to patients with spinocerebellar ataxia type 2 (SCA2); however, these abnormalities have not been studied in presymptomatic gene carriers. To determine whether the REM sleep pathology is detectable before clinical manifestation of SCA2 and evaluate it as a preclinical biomarker, we studied 36 presymptomatic SCA2 individuals and 36 controls by video-polysomnography (VPSG) and sleep questionnaires. Presymptomatic subjects showed significant decrease of REM sleep percentage, REMs density, total sleep time, and sleep efficiency. Aging effect on REM sleep percentage was significant in both groups. There was no correlation between cytosine-adenine-guanine (CAG) repeat length and REM sleep. Our findings identified the REM sleep pathology as a prominent herald sign of SCA2, conferring a special importance to VPSG as a sensitive neurophysiological tool to detect early changes associated with SCA2, which contributes to the understanding of disease pathophysiology and the development of therapeutic trials focused on the preclinical disease stage.

  10. A randomized controlled pilot trial of lithium in spinocerebellar ataxia type 2.

    PubMed

    Saccà, Francesco; Puorro, Giorgia; Brunetti, Arturo; Capasso, Giovambattista; Cervo, Amedeo; Cocozza, Sirio; de Leva, Mariafulvia; Marsili, Angela; Pane, Chiara; Quarantelli, Mario; Russo, Cinzia Valeria; Trepiccione, Francesco; De Michele, Giuseppe; Filla, Alessandro; Morra, Vincenzo Brescia

    2015-01-01

    Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant disorder. Lithium is able to stimulate autophagy, and to reduce Ca(2+) efflux from the inositol-1,4,5-triphosphate receptor. We designed a phase II, randomized, placebo-controlled, double-blind, 48-week trial with lithium carbonate in 20 patients with SCA2. The primary objective was to determine safety and tolerability of lithium. The secondary objectives were to determine disease progression, quality of life, mood, and brain volume change. Sixteen patients completed the trial, 8 randomized to lithium, 8 to placebo. Forty adverse events (AEs) were reported during the trial, twenty-eight in the lithium and 12 in the placebo group (p = 0.11). Mean AE duration was 57.4 ± 60.8 and 77.4 ± 68.5 days (p = 0.37). Non-significant differences were observed for the SARA and for brain volume change, whereas a significant reduction in the BDI-II was observed for lithium group (p < 0.05). Lithium was well tolerated and reported AEs were similar to those previously described for bipolar disorder patients. A correctly powered phase III trial is needed to assess if lithium may slow disease progression in SCA2.

  11. 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.

  12. Spinocerebellar ataxia type 2 neurodegeneration differentially affects error-based and strategic-based visuomotor learning.

    PubMed

    Vaca-Palomares, Israel; Díaz, Rosalinda; Rodríguez-Labrada, Roberto; Medrano-Montero, Jacqeline; Vázquez-Mojena, Yaimé; Velázquez-Pérez, Luis; Fernandez-Ruiz, Juan

    2013-12-01

    There are different types of visuomotor learning. Among the most studied is motor error-based learning where the sign and magnitude of the error are used to update motor commands. However, there are other instances where individuals show visuomotor learning even if the sign or magnitude of the error is precluded. Studies with patients suggest that the former learning is impaired after cerebellar lesions, while basal ganglia lesions disrupt the latter. Nevertheless, the cerebellar role is not restricted only to error-based learning, but it also contributes to several cognitive processes. Therefore, here, we tested if cerebellar ataxia patients are affected in two tasks, one that depends on error-based learning and the other that prevents the use of error-based learning. Our results showed that cerebellar patients have deficits in both visuomotor tasks; however, while error-based learning tasks deficits correlated with the motor impairments, the motor error-dependent task did not correlate with any motor measure.

  13. Role of glutathione S-transferases in the spinocerebellar ataxia type 2 clinical phenotype.

    PubMed

    Almaguer-Gotay, D; Almaguer-Mederos, L E; Aguilera-Rodríguez, R; Estupiñán-Rodríguez, A; González-Zaldivar, Y; Cuello-Almarales, D; Laffita-Mesa, J M; Vázquez-Mojena, Y

    2014-06-15

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative and incurable hereditary disorder caused by a CAG repeat expansion mutation on ATXN2 gene. The identification of reliable biochemical markers of disease severity is of paramount significance for the development and assessment of clinical trials. In order to evaluate the potential use of glutathione-S-transferase (GST) activity as a biomarker for SCA2, a case-control study in 38 affected, presymptomatic individuals or healthy controls was conducted. An enlarged sample of 121 affected individuals was set to assess the impact of GST activity on SCA2 clinical expression. There was a significant increase in GST activity in affected individuals relative to controls, although sensibility and specificity were not high. GST activity was not significantly influenced by sex, age, disease duration or CAG repeat size and did not significantly influence disease severity markers. These findings show a disruption of in vivo GST activity in SCA2, suggesting a role for oxidative stress in the neurodegenerative process.

  14. Estimation of the age at onset in spinocerebellar ataxia type 2 Cuban patients by survival analysis.

    PubMed

    Almaguer-Mederos, L E; Falcón, N S; Almira, Y R; Zaldivar, Y G; Almarales, D C; Góngora, E M; Herrera, M P; Batallán, K E; Armiñán, R R; Manresa, M V; Cruz, G S; Laffita-Mesa, J; Cyuz, T M; Chang, V; Auburger, G; Gispert, S; Pérez, L V

    2010-08-01

    Previous studies have investigated the close association that exists between CAG repeat number and the age at onset in SCA2 = spinocerebellar ataxia type 2. These studies have focused on affected individuals. To further characterize this association and estimate the risk of a carrier developing SCA2 at a particular age as a function of a specific CAG repeat size, we have analyzed a large group of 924 individuals, including 394 presymptomatic and 530 affected individuals with a CAG repeat length of 32-79 units. Using a Kaplan-Meier survival analysis, we obtained cumulative probability curves for disease manifestation at a particular age for each CAG repeat length in the 34-45 range. These curves were significantly different (p < 0.001) and showed small overlap. All these information may be very valuable in predictive-testing programs, in the planning of studies for the identification of other genetic and environmental factors as modifiers of age at onset, and in the design of clinical trials for people at enlarged risk for SCA2.

  15. Pattern of Peripheral Nerve Involvement in Spinocerebellar Ataxia Type 2: a Neurophysiological Assessment.

    PubMed

    Bezerra, Marcio Luiz Escorcio; Pedroso, José Luiz; Braga-Neto, Pedro; Abrahao, Agessandro; de Albuquerque, Marcus Vinicius Cristino; Borges, Franklin Roberto Pereira; Saraiva-Pereira, Maria Luiza; Jardim, Laura Bannach; de Oliveira Braga, Nadia Iandoli; Manzano, Gilberto Mastrocola; Barsottini, Orlando G P

    2016-12-01

    Peripheral neuropathy is frequent in spinocerebellar ataxia type 2 (SCA2), but the pattern and characteristics of nerve involvement are still an unsettled issue. This study aimed to evaluate the prevalence, extent, and distribution of nerve involvement in SCA2 patients through neurophysiological studies. Thirty-one SCA2 patients and 20 control subjects were enrolled in this study. All subjects were prospectively evaluated through electromyography, including nerve conduction, needle electromyography in proximal and distal muscles of the upper and lower limbs, and sural radial amplitude ratio (SRAR). We aimed to differentiate distal axonopathy from diffuse nerve commitment, characterizing neuronopathy. Nerve involvement was observed in 83.6 % (26 individuals) of SCA2 patients. Among these, 19 had diffuse sensory abnormalities on nerve conduction predominantly on the upper limbs, with diffuse chronic denervation on needle electromyography and elevated SRAR values. Four individuals had only diffuse sensory involvement, and 2 had only motor involvement on needle evaluation and normal nerve conduction. These were interpreted as neuronopathy due to the diffuse distribution of the involvement. One individual had distal sensory axonopathy, with lower limb predominance. In this study, we found neuronopathy as the main pattern of nerve involvement in SCA2 patients and that motor involvement is a frequent feature. This information brings new insights into the understanding of the pathophysiology of nerve involvement in SCA2 and sets some key points about the phenotype, which is relevant to guide the genetic/molecular diagnosis.

  16. The contribution of the cerebellum to cognition in Spinocerebellar Ataxia Type 6

    PubMed Central

    Cooper, Freya E.; Grube, Manon; Elsegood, Kelly J.; Welch, John L.; Kelly, Thomas P.; Chinnery, Patrick F.; Griffiths, Timothy D.

    2014-01-01

    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

  17. Spinocerebellar ataxia type 13 mutant potassium channel alters neuronal excitability and causes locomotor deficits in zebrafish.

    PubMed

    Issa, Fadi A; Mazzochi, Christopher; Mock, Allan F; Papazian, Diane M

    2011-05-04

    Whether changes in neuronal excitability can cause neurodegenerative disease in the absence of other factors such as protein aggregation is unknown. Mutations in the Kv3.3 voltage-gated K(+) channel cause spinocerebellar ataxia type 13 (SCA13), a human autosomal-dominant disease characterized by locomotor impairment and the death of cerebellar neurons. Kv3.3 channels facilitate repetitive, high-frequency firing of action potentials, suggesting that pathogenesis in SCA13 is triggered by changes in electrical activity in neurons. To investigate whether SCA13 mutations alter excitability in vivo, we expressed the human dominant-negative R420H mutant subunit in zebrafish. The disease-causing mutation specifically suppressed the excitability of Kv3.3-expressing, fast-spiking motor neurons during evoked firing and fictive swimming and, in parallel, decreased the precision and amplitude of the startle response. The dominant-negative effect of the mutant subunit on K(+) current amplitude was directly responsible for the reduced excitability and locomotor phenotype. Our data provide strong evidence that changes in excitability initiate pathogenesis in SCA13 and establish zebrafish as an excellent model system for investigating how changes in neuronal activity impair locomotor control and cause cell death.

  18. Ataxin-3 phosphorylation decreases neuronal defects in spinocerebellar ataxia type 3 models

    PubMed Central

    Matos, Carlos A.; Nóbrega, Clévio; Louros, Susana R.; Almeida, Bruno; Ferreiro, Elisabete; Valero, Jorge; Pereira de Almeida, Luís; Macedo-Ribeiro, Sandra

    2016-01-01

    Different neurodegenerative diseases are caused by aberrant elongation of repeated glutamine sequences normally found in particular human proteins. Although the proteins involved are ubiquitously distributed in human tissues, toxicity targets only defined neuronal populations. Changes caused by an expanded polyglutamine protein are possibly influenced by endogenous cellular mechanisms, which may be harnessed to produce neuroprotection. Here, we show that ataxin-3, the protein involved in spinocerebellar ataxia type 3, also known as Machado-Joseph disease, causes dendritic and synapse loss in cultured neurons when expanded. We report that S12 of ataxin-3 is phosphorylated in neurons and that mutating this residue so as to mimic a constitutive phosphorylated state counters the neuromorphologic defects observed. In rats stereotaxically injected with expanded ataxin-3–encoding lentiviral vectors, mutation of serine 12 reduces aggregation, neuronal loss, and synapse loss. Our results suggest that S12 plays a role in the pathogenic pathways mediated by polyglutamine-expanded ataxin-3 and that phosphorylation of this residue protects against toxicity. PMID:26880203

  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.

  20. Autonomic nervous system abnormalities in spinocerebellar ataxia type 2: a cardiovascular neurophysiologic study.

    PubMed

    De Joanna, G; De Rosa, A; Salvatore, E; Castaldo, I; De Luca, N; Izzo, R; Manzo, V; Filla, A; De Michele, G

    2008-12-15

    Autonomic nervous system dysfunction is part of the spinocerebellar ataxia (SCA) clinical picture, but few data are available on this topic. The present study is aimed to report a detailed investigation of autonomic nervous system in patients with molecular diagnosis of SCA type 2, one of the most frequent forms and the commonest in Italy. Nine patients with a mild to moderate form of SCA2 underwent a questionnaire about dysautonomic symptoms and a complete cardiovascular neurophysiologic evaluation of both sympathetic and parasympathetic system, comprising head-up tilt, standing, isometric hand grip, cold pressure, mental arithmetic, Valsalva manoeuvre, deep breathing, and hyperventilation tests. An echocardiographic study and Holter-ECG recording were also performed. All patients complained dysautonomic problems regarding urinary tract, cardiovascular system, or gastrointestinal dysfunction. The neurophysiologic study showed both sympathetic and parasympathetic involvement, with highly variable degree and pattern of dysautonomia. The present study results show that the autonomic dysfunction is common in SCA2 representing a significant component of the complex picture of the disease. We found a wide spectrum of cardiovascular autonomic abnormalities, without a typical pattern of dysfunction and without correlation with clinical variables.

  1. Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

    PubMed Central

    Snijder, Pauline M; Baratashvili, Madina; Grzeschik, Nicola A; Leuvenink, Henri G D; Kuijpers, Lucas; Huitema, Sippie; Schaap, Onno; Giepmans, Ben N G; Kuipers, Jeroen; Miljkovic, Jan Lj; Mitrovic, Aleksandra; Bos, Eelke M; Szabó, Csaba; Kampinga, Harm H; Dijkers, Pascale F; den Dunnen, Wilfred F A; Filipovic, Milos R; van Goor, Harry; Sibon, Ody C M

    2015-01-01

    Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder caused by a CAG repeat expansion in the ataxin-3 (ATXN3) gene resulting in toxic protein aggregation. Inflammation and oxidative stress are considered secondary factors contributing to the progression of this neurodegenerative disease. There is no cure that halts or reverses the progressive neurodegeneration of SCA3. Here we show that overexpression of cystathionine γ-lyase, a central enzyme in cysteine metabolism, is protective in a Drosophila model for SCA3. SCA3 flies show eye degeneration, increased oxidative stress, insoluble protein aggregates, reduced levels of protein persulfidation and increased activation of the innate immune response. Overexpression of Drosophila cystathionine γ-lyase restores protein persulfidation, decreases oxidative stress, dampens the immune response and improves SCA3-associated tissue degeneration. Levels of insoluble protein aggregates are not altered; therefore, the data implicate a modifying role of cystathionine γ-lyase in ameliorating the downstream consequence of protein aggregation leading to protection against SCA3-induced tissue degeneration. The cystathionine γ-lyase expression is decreased in affected brain tissue of SCA3 patients, suggesting that enhancers of cystathionine γ-lyase expression or activity are attractive candidates for future therapies. PMID:26467707

  2. Crystallographic and Computational Analyses of AUUCU Repeating RNA That Causes Spinocerebellar Ataxia Type 10 (SCA10).

    PubMed

    Park, HaJeung; González, Àlex L; Yildirim, Ilyas; Tran, Tuan; Lohman, Jeremy R; Fang, Pengfei; Guo, Min; Disney, Matthew D

    2015-06-23

    Spinocerebellar ataxia type 10 (SCA10) is caused by a pentanucleotide repeat expansion of r(AUUCU) within intron 9 of the ATXN10 pre-mRNA. The RNA causes disease by a gain-of-function mechanism in which it inactivates proteins involved in RNA biogenesis. Spectroscopic studies showed that r(AUUCU) repeats form a hairpin structure; however, there were no high-resolution structural models prior to this work. Herein, we report the first crystal structure of model r(AUUCU) repeats refined to 2.8 Å and analysis of the structure via molecular dynamics simulations. The r(AUUCU) tracts adopt an overall A-form geometry in which 3 × 3 nucleotide (5')UCU(3')/(3')UCU(5') internal loops are closed by AU pairs. Helical parameters of the refined structure as well as the corresponding electron density map on the crystallographic model reflect dynamic features of the internal loop. The computational analyses captured dynamic motion of the loop closing pairs, which can form single-stranded conformations with relatively low energies. Overall, the results presented here suggest the possibility for r(AUUCU) repeats to form metastable A-from structures, which can rearrange into single-stranded conformations and attract proteins such as heterogeneous nuclear ribonucleoprotein K (hnRNP K). The information presented here may aid in the rational design of therapeutics targeting this RNA.

  3. 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

  4. Altered Kv3.3 channel gating in early-onset spinocerebellar ataxia type 13.

    PubMed

    Minassian, Natali A; Lin, Meng-Chin A; Papazian, Diane M

    2012-04-01

    Mutations in Kv3.3 cause spinocerebellar ataxia type 13 (SCA13). Depending on the causative mutation, SCA13 is either a neurodevelopmental disorder that is evident in infancy or a progressive neurodegenerative disease that emerges during adulthood. Previous studies did not clarify the relationship between these distinct clinical phenotypes and the effects of SCA13 mutations on Kv3.3 function. The F448L mutation alters channel gating and causes early-onset SCA13. R420H and R423H suppress Kv3 current amplitude by a dominant negative mechanism. However, R420H results in the adult form of the disease whereas R423H produces the early-onset, neurodevelopmental form with significant clinical overlap with F448L. Since individuals with SCA13 have one wild type and one mutant allele of the Kv3.3 gene, we analysed the properties of tetrameric channels formed by mixtures of wild type and mutant subunits. We report that one R420H subunit and at least one R423H subunit can co-assemble with the wild type protein to form active channels. The functional properties of channels containing R420H and wild type subunits strongly resemble those of wild type alone. In contrast, channels containing R423H and wild type subunits show significantly altered gating, including a hyperpolarized shift in the voltage dependence of activation, slower activation, and modestly slower deactivation. Notably, these effects resemble the modified gating seen in channels containing a mixture of F448L and wild type subunits, although the F448L subunit slows deactivation more dramatically than the R423H subunit. Our results suggest that the clinical severity of R423H reflects its dual dominant negative and dominant gain of function effects. However, as shown by R420H, reducing current amplitude without altering gating does not result in infant onset disease. Therefore, our data strongly suggest that changes in Kv3.3 gating contribute significantly to an early age of onset in SCA13.

  5. Molecular and Clinical Correlations in Spinocerebellar Ataxia Type I: Evidence for Familial Effects on the Age at Onset

    PubMed Central

    Ranum, Laura P. W.; Chung, Ming-Yi; Banfi, Sandro; Bryer, Alan; Schut, Lawrence J.; Ramesar, Raj; Duvick, Lisa A.; McCall, Alanna; Subramony, S. H.; Goldfarb, Lev; Gomez, Christopher; Sandkuijl, Lodewijk A.; Orr, Harry T.; Zoghbi, Huda Y.

    1994-01-01

    The spinocerebellar ataxias are a group of debilitating neurodegenerative diseases for which a clinical classification system has proved unreliable. We have recently isolated the gene for spinocerebellar ataxia type 1 (SCA1) and have shown that the disease is caused by an expanded, unstable, CAG trinucleotide repeat within an expressed gene. Normal alleles have a size range of 19–36 repeats, while SCA1 alleles have 42-81 repeats. In this study, we examined the frequency and variability of the SCA1 repeat expansion in 87 kindreds with diverse ethnic backgrounds and dominantly inherited ataxia. All nine families for which linkage to the SCA1 region of 6p had previously been established showed repeat expansion, while 3 of the remaining 78 showed a similar abnormality. For 113 patients from the families with repeat expansion, inverse correlations between CAG repeat size and both age at onset and disease duration were observed. Repeat size accounted for 66% of the variation in age at onset in these patients. After correction for repeat size, interfamilial differences in age at onset remained significant, suggesting that additional genetic factors affect the expression of the SCA1 gene product. PMID:8037204

  6. Mutation analysis of spinocerebellar ataxia type 1 (SCA1) in a large Iakut kinship of Eastern Siberia

    SciTech Connect

    Goldfarb, L.G.; Lunkes, A.; Vaconcelos, O.

    1994-09-01

    We have studied 131 patients with autosomal dominant cerebellar ataxia clinically and pathologically expressed as olivopontocerebellar atrophy. The disease in this Siberian kinship has been genetically linked to the SCA1 gene on chromosome 6p, and the pedigree was screened for the recently described CAG repeat expansion in this gene using the GeneScan program (ABI). The normal allele in the affected individuals had 26 to 32 repeats, and among 424 analyzed normal alleles of the unaffected members of the kinship, unrelated controls and patients with other neurological disorders, the range of repeat numbers was 26 to 37, with 92% within 28 to 30 repeats. All 65 normal alleles in which the repeat area has been sequenced show a CAT or CATCAGCAT interruption between the first and the second stretches of 10 to 17 CAG repeats. The SCA1 allele was extended to 39 to 60 uninterrupted repeats in all fifty-nine analyzed ataxia patients. Repeat numbers of 40 to 55 were also found in thirty-nine of 105 tested unaffected first and second degree relatives. Two patients and an unaffected child were homozygous for the elongated allele. In seven of 10 paternal transmissions an increase of 2 to 11 repeats have occurred; in nine maternal transmissions the repeat numbers remained the same or grew for just one repeat. Mutation analysis provides new opportunities in diagnosis and risk assessment of spinocerebellar ataxia type 1.

  7. Non-motor and Extracerebellar Features in Spinocerebellar Ataxia Type 2.

    PubMed

    Pedroso, José Luiz; Braga-Neto, Pedro; Escorcio-Bezerra, Marcio Luiz; Abrahão, Agessandro; de Albuquerque, Marcus Vinicius Cristino; Filho, Flavio Moura Rezende; de Souza, Paulo Victor Sgobbi; de Rezende Pinto, Wladimir Bocca Vieira; Borges, Franklin Roberto Pereira; Saraiva-Pereira, Maria Luiza; Jardim, Laura Bannach; Barsottini, Orlando G P

    2017-02-01

    Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant degenerative disease. Pathological studies have demonstrated not only cerebellar and brainstem atrophy, but substantia nigra, motoneurons, basal ganglia, thalamus, and peripheral nerves involvement. These findings may explain non-motor and extra-cerebellar features in SCA2. We accessed the non-motor symptoms and extra-cerebellar signs in SCA2 patients in order to provide a better understanding on pathophysiological mechanisms and natural history of brain degeneration in the disease. Thirty-three SCA2 patients were evaluated and compared with 26 healthy subjects. We investigated the following variables: sleep disorders, cognitive deficit, olfactory impairment, urinary dysfunction, psychiatric symptoms, cramps, pain, movement disorders, and weight loss. SCA2 had a high frequency of REM sleep behavior disorder (48.48 %, N = 16) as well as excessive daytime sleepiness (42.42 %, N = 14). Chorea was present in 15.15 % (N = 5), dystonia in 27.27 % (N = 9), and parkinsonism in 27.27 % (N = 9). Slow saccadic pursuit was present in 87.87 % (N = 29) and ophtalmoparesis in 78.78 % (N = 26) of patients. Regarding sleep disorders, 18.18 % (N = 6) of patients had restless leg syndrome. Dysphagia was present in 39.39 % (N = 13), weight loss 24.24 % (N = 8), and urinary dysfunction 27.27 % (N = 9). Cramps was present in only 6 % of patients (N = 2). This study highlighted the high frequency of non-motor symptoms and extra-cerebellar signs in SCA2. Our findings demonstrate the widespread of nervous system involvement in SCA2 patients and contribute to better understand the natural history of brain degeneration in this genetic condition.

  8. An autopsy case of an aged patient with spinocerebellar ataxia type 2.

    PubMed

    Ishida, Chiho; Komai, Kiyonobu; Yonezawa, Kohei; Sakajiri, Ken-Ichi; Nitta, Eishun; Kawashima, Atsuhiro; Yamada, Masahito

    2011-10-01

    We report the case of a woman who developed limb clumsiness in her fifties and gait disturbance in her sixties. She was bedridden after bone fractures at age 75 and showed disorientation, slow eye movement, gaze palsy, ataxic speech, muscle atrophy and weakness, and areflexia with pathological reflex. She died of respiratory failure at age 85. This patient was diagnosed genetically as having spinocerebellar ataxia type 2 (SCA2), and the number of expanded CAG repeats was 41. At autopsy, the brain weighed 965 g, and the brainstem, cerebellum, frontal convexity and spinal cord were atrophic. Neuronal loss and gliosis were severe in the pontine nucleus, inferior olivary nucleus, cerebellar cortex, gracile and cuneate nuclei and moderate in the substantia nigra, cerebellar dentate nucleus, anterior horns of the spinal cord and dorsal root ganglia. Axonal loss was observed in the middle and inferior cerebellar peduncles, pyramidal tract and posterior column of the spinal cord. Senile plaques and neurofibrillary tangles (NFTs) were diffusely found in the cerebrum (plaque stage C; NFT stage IV). Expanded polyglutamine-immunoreactive inclusions in the neuronal cytoplasm were widely distributed in the CNS, and neuronal intranuclear inclusions were observed in the pontine nucleus and cerebral cortex. This patient in this autopsy case is a late-onset and aged patient with SCA2, and this is the first report of SCA2 combined with Alzheimer's disease (AD) pathology. Neuropathological findings in this patient, except for AD pathology, were consistent with those of reported SCA2 cases. However, the olivo-ponto-cerebellar system of this patient was relatively preserved and the cerebellar dentate nucleus was more involved as compared with previously reported cases. These results suggest that age at onset or the number of CAG repeat expansions could correlate with the distribution pattern of SCA2 neurodegeneration.

  9. MRI shows a region-specific pattern of atrophy in spinocerebellar ataxia type 2.

    PubMed

    Jung, Brian C; Choi, Soo I; Du, Annie X; Cuzzocreo, Jennifer L; Ying, Howard S; Landman, Bennett A; Perlman, Susan L; Baloh, Robert W; Zee, David S; Toga, Arthur W; Prince, Jerry L; Ying, Sarah H

    2012-03-01

    In this study, we used manual delineation of high-resolution magnetic resonance imaging (MRI) to determine the spatial and temporal characteristics of the cerebellar atrophy in spinocerebellar ataxia type 2 (SCA2). Ten subjects with SCA2 were compared to ten controls. The volume of the pons, the total cerebellum, and the individual cerebellar lobules were calculated via manual delineation of structural MRI. SCA2 showed substantial global atrophy of the cerebellum. Furthermore, the degeneration was lobule specific, selectively affecting the anterior lobe, VI, Crus I, Crus II, VIII, uvula, corpus medullare, and pons, while sparing VIIB, tonsil/paraflocculus, flocculus, declive, tuber/folium, pyramis, and nodulus. The temporal characteristics differed in each cerebellar subregion: (1) duration of disease: Crus I, VIIB, VIII, uvula, corpus medullare, pons, and the total cerebellar volume correlated with the duration of disease; (2) age: VI, Crus II, and flocculus correlated with age in control subjects; and (3) clinical scores: VI, Crus I, VIIB, VIII, corpus medullare, pons, and the total cerebellar volume correlated with clinical scores in SCA2. No correlations were found with the age of onset. Our extrapolated volumes at the onset of symptoms suggest that neurodegeneration may be present even during the presymptomatic stages of disease. The spatial and temporal characteristics of the cerebellar degeneration in SCA2 are region specific. Furthermore, our findings suggest the presence of presymptomatic atrophy and a possible developmental component to the mechanisms of pathogenesis underlying SCA2. Our findings further suggest that volumetric analysis may aid in the development of a non-invasive, quantitative biomarker.

  10. Generation of human-induced pluripotent stem cells to model spinocerebellar ataxia type 2 in vitro.

    PubMed

    Xia, Guangbin; Santostefano, Katherine; Hamazaki, Takashi; Liu, Jilin; Subramony, S H; Terada, Naohiro; Ashizawa, Tetsuo

    2013-10-01

    Spinocerebellar ataxia type 2 (SCA2) is caused by triple nucleotide repeat (CAG) expansion in the coding region of the ATAXN2 gene on chromosome 12, which produces an elongated, toxic polyglutamine tract, leading to Purkinje cell loss. There is currently no effective therapy. One of the main obstacles that hampers therapeutic development is lack of an ideal disease model. In this study, we have generated and characterized SCA2-induced pluripotent stem (iPS) cell lines as an in vitro cell model. Dermal fibroblasts (FBs) were harvested from primary cultures of skin explants obtained from a SCA2 subject and a healthy subject. For reprogramming, hOct4, hSox2, hKlf4, and hc-Myc were transduced to passage-3 FBs by retroviral infection. Both SCA2 iPS and control iPS cells were successfully generated and showed typical stem cell growth patterns with normal karyotype. All iPS cell lines expressed stem cell markers and differentiated in vitro into cells from three embryonic germ layers. Upon in vitro neural differentiation, SCA2 iPS cells showed abnormality in neural rosette formation but successfully differentiated into neural stem cells (NSCs) and subsequent neural cells. SCA2 and normal FBs showed a comparable level of ataxin-2 expression; whereas SCA2 NSCs showed less ataxin-2 expression than normal NSCs and SCA2 FBs. Within the neural lineage, neurons had the most abundant expression of ataxin-2. Time-lapsed neural growth assay indicated terminally differentiated SCA2 neural cells were short-lived compared with control neural cells. The expanded CAG repeats of SCA2 were stable throughout reprogramming and neural differentiation. In conclusion, we have established the first disease-specific human SCA2 iPS cell line. These mutant iPS cells have the potential for neural differentiation. These differentiated neural cells harboring mutations are invaluable for the study of SCA2 pathogenesis and therapeutic drug development.

  11. 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

  12. Validity of a wearable accelerometer to quantify gait in spinocerebellar ataxia type 6.

    PubMed

    Hickey, Aodhán; Gunn, Eleanor; Alcock, Lisa; Del Din, Silvia; Godfrey, Alan; Rochester, Lynn; Galna, Brook

    2016-11-01

    Biomarkers are required to track disease progression and measure the effectiveness of interventions for people with spinocerebellar ataxia type-6 (SCA6). Gait is a potential biomarker that is sensitive to SCA6 which can be measured using wearable technology, reducing the need for expensive specialist facilities. However, algorithms used to calculate gait using data from wearables have not been validated in SCA6. This study sought to examine the validity of a single wearable for deriving 14 spatio-temporal gait characteristics in SCA6 and control cohorts. Participants performed eight intermittent walks along a 7 m instrumented walkway at their preferred walking pace while also wearing a single accelerometer-based wearable on L5. Gait algorithms previously validated in neurological populations and controls were used to derive gait characteristics. We assessed the bias, agreement and sensitivity of gait characteristics derived using the instrumented walkway and the wearable. Mean gait characteristics showed good to excellent agreement for both groups, although gait variability and asymmetry showed poor agreement between the two systems. Agreement improved considerably in the SCA6 group when people who used walking sticks were excluded from the analysis, suggesting poorer agreement in people with more severe gait impairment. Despite poor agreement for some characteristics, gait measured using the wearable was generally more sensitive to group differences than the instrumented walkway. Our findings indicate mean gait characteristics can be accurately measured using an accelerometer-based wearable in people SCA6 with mild-to-moderately severe gait impairment yet further development of algorithms are required for people with more severe symptoms.

  13. 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.

  14. Inhibition of Ataxia Telangiectasia Mutated (ATM) Kinase Suppresses Herpes Simplex Virus Type 1 (HSV-1) Keratitis

    PubMed Central

    Alekseev, Oleg; Donovan, Kelly; Azizkhan-Clifford, Jane

    2014-01-01

    Purpose. Herpes keratitis (HK) remains the leading cause of cornea-derived blindness in the developed world, despite the availability of effective antiviral drugs. Treatment toxicity and the emergence of drug resistance highlight the need for additional therapeutic approaches. This study examined ataxia telangiectasia mutated (ATM), an apical kinase in the host DNA damage response, as a potential new target for the treatment of HK. Methods. Small molecule inhibitor of ATM (KU-55933) was used to treat herpes simplex virus type 1 (HSV-1) infection in three experimental models: (1) in vitro—cultured human corneal epithelial cells, hTCEpi, (2) ex vivo—organotypically explanted human and rabbit corneas, and (3) in vivo—corneal infection in young C57BL/6J mice. Infection productivity was assayed by plaque assay, real-time PCR, Western blot, and disease scoring. Results. Robust ATM activation was detected in HSV-1-infected human corneal epithelial cells. Inhibition of ATM greatly suppressed viral replication in cultured cells and in explanted human and rabbit corneas, and reduced the severity of stromal keratitis in mice. The antiviral effect of KU-55933 in combination with acyclovir was additive, and KU-55933 suppressed replication of a drug-resistant HSV-1 strain. KU-55933 caused minimal toxicity, as monitored by clonogenic survival assay and fluorescein staining. Conclusions. This study identifies ATM as a potential target for the treatment of HK. ATM inhibition by KU-55933 reduces epithelial infection and stromal disease severity without producing appreciable toxicity. These findings warrant further investigations into the DNA damage response as an area for therapeutic intervention in herpetic ocular diseases. PMID:24370835

  15. Expansion, mosaicism and interruption: mechanisms of the CAG repeat mutation in spinocerebellar ataxia type 1.

    PubMed

    Kraus-Perrotta, Cara; Lagalwar, Sarita

    2016-01-01

    Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that primarily affects the cerebellum and brainstem. The genetic mutation is an expansion of CAG trinucleotide repeats within the coding region of the ataxin-1 gene, characterizing SCA1 as a polyglutamine expansion disease like Huntington's. As with most polyglutamine expansion diseases, SCA1 follows the rules of genetic anticipation: the larger the expansion, the earlier and more rapid the symptoms. Unlike the majority of polyglutamine expansion diseases, the presence of histidine interruptions within the polyglutamine tract of ataxin-1 protein can prevent or mitigate disease. The present review aims to synthesize three decades of research on the ataxin-1 polyglutamine expansion mutation that causes SCA1. Data from genetic population studies and case studies is gathered along with data from manipulation studies in animal models. Specifically, we examine the molecular mechanisms that cause tract expansions and contractions, the molecular pathways that confer instability of tract length in gametic and somatic cells resulting in gametic and somatic mosaicism, the influence of maternal or paternal factors in inheritance of the expanded allele, and the effects of CAT/histidine interruptions to the ataxin-1 allele and protein product. Our review of existing data supports the following conclusions. First, polyCAG expansion of gametic alleles occur due to the failure of gap repair mechanisms for single or double strand breaks during the transition from an immature haploid spermatid to a mature haploid sperm cell. Equivalent failures were not detected in female gametic cells. Second, polyCAG expansion of somatic alleles occur due to hairpins formed on Okazaki fragments and slipped strand structures due to failures in mismatch repair and transcription-coupled nucleotide excision repair mechanisms. Third, CAT trinucleotide interruptions, which code for histidines in the translated

  16. Identifying Niemann-Pick type C in early-onset ataxia: two quick clinical screening tools.

    PubMed

    Synofzik, Matthis; Fleszar, Zofia; Schöls, Ludger; Just, Jennifer; Bauer, Peter; Torres Martin, Juan V; Kolb, Stefan

    2016-10-01

    Niemann-Pick disease type C (NP-C) is a rare multisystemic lysosomal disorder which, albeit treatable, is still starkly underdiagnosed. As NP-C features early onset ataxia (EOA) in 85-90 % of cases, EOA presents a promising target group for undiagnosed NP-C patients. Here, we assessed the ability of the previously established NP-C suspicion index (SI) and a novel abbreviated '2/3 SI' tool for rapid appraisal of suspected NP-C in unexplained EOA. This was a retrospective observational study comparing 'NP-C EOA' cases (EOA patients with confirmed NP-C) with non-NP-C EOA controls (EOA patients negative for NP-C gene mutations). NP-C risk prediction scores (RPS) from both the original and 2/3 SIs were calculated and their discriminatory performance evaluated. Among 133 patients (47 NP-C EOA cases; 86 non-NP-C EOA controls), moderate (40-69 points) and high (≥70 points) RPS were common based on original SI assessments in non-NP-C EOA controls [16 (19 %) and 8 (9 %), respectively], but scores ≥70 points were far more frequent [46 (98 %)] among NP-C EOA cases. RPS cut-off values provided 98 % sensitivity and 91 % specificity for NP-C at 70-point cut-off, and ROC analysis revealed an AUC of 0.982. Using the 2/3 SI, 90 % of NP-C EOA cases had scores of 2 or 3, and RPS analysis showed an AUC of 0.961. In conclusion, the NP-C SI and the new, quick-to-apply 2/3 SI distinguished well between NP-C and non-NP-C patients, even in EOA populations with high background levels of broadly NPC-compatible multisystemic disease features. While the original SI showed the greatest sensitivity, both tools reliably aided identification of patients with unexplained EOA who warranted further investigation for NP-C.

  17. Spinocerebellar ataxia type 2 is associated with Parkinsonism and Lewy body pathology.

    PubMed

    Takao, Masaki; Aoyama, Masahiro; Ishikawa, Kinya; Sakiyama, Yoshio; Yomono, Harumi; Saito, Yuko; Kurisaki, Hiroshi; Mihara, Ban; Murayama, Shigeo

    2011-04-01

    Clinical phenotype of individuals with spinocerebellar ataxia 2 (SCA2) is characterised by cerebellar ataxia and cognitive impairment. Although L-dopa-responsive Parkinsonism is considered as a rare clinical presentation in SCA2, it has been brought to the attention of many neurologists in several studies. The authors report an autopsy case of SCA2 with Parkinsonism from a Japanese family using archival materials of our Brain Bank to describe unique neuropathologic findings. The individual clinically showed Parkinsonism as a predominant phenotype instead of cerebellar ataxia. Besides the classic SCA2 neuropathologic alterations, Lewy bodies and Lewy neurites were present in the brainstem nuclei. Genetic analysis revealed shorter abnormal expansion of CAG repeats (less than 39). In contrast, the authors could not find α-synuclein pathology in two SCA2 cases without Parkinsonism. The present case will provide a neuropathologic evidence of correlation between α-synucleinopathy and Parkinsonism of SCA2 as well as shed light on understanding the pathomechanism of Parkinsonism in SCA2.

  18. 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

    2015-03-05

    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.

  19. Using wearable cameras to categorise type and context of accelerometer-identified episodes of physical activity

    PubMed Central

    2013-01-01

    Background Accelerometers can identify certain physical activity behaviours, but not the context in which they take place. This study investigates the feasibility of wearable cameras to objectively categorise the behaviour type and context of participants’ accelerometer-identified episodes of activity. Methods Adults were given an Actical hip-mounted accelerometer and a SenseCam wearable camera (worn via lanyard). The onboard clocks on both devices were time-synchronised. Participants engaged in free-living activities for 3 days. Actical data were cleaned and episodes of sedentary, lifestyle-light, lifestyle-moderate, and moderate-to-vigorous physical activity (MVPA) were identified. Actical episodes were categorised according to their social and environmental context and Physical Activity (PA) compendium category as identified from time-matched SenseCam images. Results There were 212 days considered from 49 participants from whom SenseCam images and associated Actical data were captured. Using SenseCam images, behaviour type and context attributes were annotated for 386 (out of 3017) randomly selected episodes (such as walking/transportation, social/not-social, domestic/leisure). Across the episodes, 12 categories that aligned with the PA Compendium were identified, and 114 subcategory types were identified. Nineteen percent of episodes could not have their behaviour type and context categorized; 59% were outdoors versus 39% indoors; 33% of episodes were recorded as leisure time activities, with 33% transport, 18% domestic, and 15% occupational. 33% of the randomly selected episodes contained direct social interaction and 22% were in social situations where the participant wasn’t involved in direct engagement. Conclusion Wearable camera images offer an objective method to capture a spectrum of activity behaviour types and context across 81% of accelerometer-identified episodes of activity. Wearable cameras represent the best objective method currently

  20. LADA type diabetes, celiac diasease, cerebellar ataxia and stiff person syndrome. A rare association of autoimmune disorders.

    PubMed

    Soós, Zsuzsanna; Salamon, Mónika; Erdei, Katalin; Kaszás, Nóra; Folyovich, András; Szücs, Anna; Barcs, Gábor; Arányi, Zsuzsanna; Skaliczkis, József; Vadasdi, Károly; Winkler, Gábor

    2014-05-30

    Celiac disease--in its typical form--is a chronic immune-mediated enteropathy with typical clinical symptoms that develops against gliadin content of cereal grains, and is often associated with other autoimmune diseases. In cases of atypical manifestation classic symptoms may be absent or mild, and extra-intestinal symptoms or associated syndromes dominate clinical picture. The authors present a longitudinal follow-up of such a case. A 63-years old woman was diagnosed with epilepsy at the age of 19, and with progressive limb ataxia at the age of 36, which was initially thought to be caused by cerebellar atrophy, later probably by stiff person syndrome. At the age 59, her diabetes mellitus manifested with type 2 diabetic phenotype, but based on GAD positivity later was reclassified as type 1 diabetes. Only the last check-up discovered the celiac disease, retrospectively explaining the entire disease course and neurological symptoms. By presenting this case, the authors would like to draw attention to the fact that one should think of the possibility of celiac disease when cerebellar ataxia, progressive neurological symptoms and diabetes are present at the same time. An early diagnosis may help to delay the progression of disease and help better treatment.

  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. Spinocerebellar ataxia type 2 (SCA2): identification of early brain degeneration in one monozygous twin in the initial disease stage.

    PubMed

    Hoche, Franziska; Balikó, Laszlo; den Dunnen, Wilfred; Steinecker, Katalin; Bartos, Laszlo; Sáfrány, Eniko; Auburger, Georg; Deller, Thomas; Korf, Horst-Werner; Klockgether, Thomas; Rüb, Udo; Melegh, Bela

    2011-06-01

    Spinocerebellar ataxia type 2 (SCA2) is a progressive autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG repeat or polyglutamine diseases. Recent morphological studies characterized the pathoanatomical features in heterozygous SCA2 patients and revealed severe neuronal loss in a large variety of cerebellar and extra-cerebellar brain sites. In the present study, we examined the brain pathoanatomy of a monozygous twin of a large Hungarian SCA2 family with pathologically extended CAG repeats in both SCA2 alleles. This unique patient was in the initial clinical stage of SCA2 and died almost 3 years after SCA2 onset. Upon pathoanatomical investigation, we observed loss of giant Betz pyramidal cells in the primary motor cortex, degeneration of sensory thalamic nuclei, the Purkinje cell layer, and deep cerebellar nuclei, as well as select brainstem nuclei (i.e., substantia nigra, oculomotor nucleus, reticulotegmental nucleus of the pons, facial, lateral vestibular, and raphe interpositus nuclei, inferior olive). All of these degenerated brain gray matter structures are known as consistent targets of the underlying pathological process in heterozygous SCA2 patients. Since they were already involved in our patient within 3 years after disease onset, we think that we were for the first time able to identify the early brain targets of the pathological process of SCA2.

  3. Executive deficit in spinocerebellar ataxia type 2 is related to expanded CAG repeats: evidence from antisaccadic eye movements.

    PubMed

    Rodríguez-Labrada, Roberto; Velázquez-Pérez, Luis; Aguilera-Rodríguez, Raúl; Seifried-Oberschmidt, Carola; Peña-Acosta, Arnoy; Canales-Ochoa, Nalia; Medrano-Montero, Jacqueline; Estupiñan-Rodríguez, Annelié; Vázquez-Mojena, Yaimeé; González-Zaldivar, Yanetza; Laffita Mesa, Jose M

    2014-11-01

    Although antisaccadic task is a sensitive research tool in psychopathology, it has not been systematically studied in patients with spinocerebellar ataxia type 2 (SCA2). To identify putative biomarkers of executive dysfunction in SCA2 we assessed the antisaccade performance in 41 SCA2 patients and their sex-and-age matched controls using an electronystagmography device. We studied the relationship between findings in the antisaccade task and CAG repeat length and motor function as assessed using the Scale for the Assessment and Rating of Ataxia (SARA), Nine-Hole Pegboard Test and a validated battery for executive dysfunctions. SCA2 patients showed a significant increase of inhibition and omission antisaccadic error rates, decrease of corrected antisaccadic errors and prolongation of antisaccadic latency and antisaccadic correction latency. Multiple regression predictions identified the expanded CAG repeat as a significant contributing factor on inhibition antisaccadic error rate and percentage of corrected antisaccadic errors. Impaired antisaccadic performance was associated to higher Stroop interference task and verbal fluency test deficits. In conclusion, antisaccadic eye movement abnormalities are a newly recognized association with the genetic abnormality in SCA2 and correlate with executive dysfunction in SCA2. Antisaccade parameters are a promising source of cognitive biomarkers for exploring the disease pathophysiology, and assessing the efficacy of therapeutic options.

  4. Sleep paralysis episode frequency and number, types, and structure of associated hallucinations.

    PubMed

    Cheyne, J A

    2005-09-01

    Sleep paralysis (SP) episodes are often accompanied by vivid hallucinoid experiences that have been found to fall into three major categories thought to be organized according to intrinsic rapid eye movement (REM) processes. Prior research has, however, combined data for individuals with varying degrees of experience with SP episodes, rendering interpretations of the source of this structure ambiguous. The present study of 5799 current SP experients compares the nature and structure of the hallucinations of novice SP experients with those reporting varying numbers of episodes. Both qualitative and quantitative differences were found in reported hallucinations as a function of episode frequency, although the underlying three-factor structure of the hallucinoid experiences was highly similar for all groups. Novice experients' reports were, however, characterized by clearer differentiation of factors, likely because of a tendency of experienced SP experients to conflate experiences across episodes. Age and age of onset of SP episodes were associated with differences in the variety and types of hallucinations but not their underlying structure. Earlier onset of SP episodes was also associated with more frequent episodes. The results are consistent with the hypothesis that the basic form and patterning of hallucinatory experiences is a result of intrinsic processes, independent of prior experience, likely associated with underlying REM neurophysiology.

  5. Phenotype variability in spinocerebellar ataxia type 2: a longitudinal family survey and a case featuring an unusual benign course of disease.

    PubMed

    Hering, Sascha; Achmüller, Clemens; Köhler, Andrea; Poewe, Werner; Schneider, Raine; Boesch, Sylvia M

    2009-04-15

    We report a 67 years old female patient out of a multigenerational family with spinocerebellar ataxia type 2 (SCA2) with an unusually benign course of disease. Although all SCA2 gene carriers have by now developed the predominant gait ataxia and brainstem oculomotor dysfunction, the index patient presented with a very mild course of disease, scoring only six points on the Scale for the Assessment and Rating of Ataxia after a disease duration of 13 years. Otherwise, intragenerational variability within family members such as the age at onset of disease and the course of disease was low. Reinvestigation of the genetic background variables in the SCA2 gene carrier reported here showed 27 repeats in the normal allele and 37 noninterrupted repeats in the abnormal allele. Interestingly, this patient has been taking lithium-carbonate over more than 30 years because of psychotic depression. Although anecdotic, this SCA2 case may provide promising insights into possible disease modifying mechanisms in SCA2.

  6. Spinocerebellar ataxia type 13 mutation that is associated with disease onset in infancy disrupts axonal pathfinding during neuronal development.

    PubMed

    Issa, Fadi A; Mock, Allan F; Sagasti, Alvaro; Papazian, Diane M

    2012-11-01

    Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominant disease caused by mutations in the Kv3.3 voltage-gated potassium (K(+)) channel. SCA13 exists in two forms: infant onset is characterized by severe cerebellar atrophy, persistent motor deficits and intellectual disability, whereas adult onset is characterized by progressive ataxia and progressive cerebellar degeneration. To test the hypothesis that infant- and adult-onset mutations have differential effects on neuronal development that contribute to the age at which SCA13 emerges, we expressed wild-type Kv3.3 or infant- or adult-onset mutant proteins in motor neurons in the zebrafish spinal cord. We characterized the development of CaP (caudal primary) motor neurons at ∼36 and ∼48 hours post-fertilization using confocal microscopy and 3D digital reconstruction. Exogenous expression of wild-type Kv3.3 had no significant effect on CaP development. In contrast, CaP neurons expressing the infant-onset mutation made frequent pathfinding errors, sending long, abnormal axon collaterals into muscle territories that are normally innervated exclusively by RoP (rostral primary) or MiP (middle primary) motor neurons. This phenotype might be directly relevant to infant-onset SCA13 because interaction with inappropriate synaptic partners might trigger cell death during brain development. Importantly, pathfinding errors were not detected in CaP neurons expressing the adult-onset mutation. However, the adult-onset mutation tended to increase the complexity of the distal axonal arbor. From these results, we speculate that infant-onset SCA13 is associated with marked changes in the development of Kv3.3-expressing cerebellar neurons, reducing their health and viability early in life and resulting in the withered cerebellum seen in affected children.

  7. Postnatal Loss of P/Q-type Channels Confined to Rhombic Lip Derived Neurons Alters Synaptic Transmission at the Parallel Fiber to Purkinje Cell Synapse and Replicates Genomic Cacna1a Mutation Phenotype of Ataxia and Seizures in Mice

    PubMed Central

    Maejima, Takashi; Wollenweber, Patric; Teusner, Lena U. C.; Noebels, Jeffrey L.; Herlitze, Stefan; Mark, Melanie D.

    2013-01-01

    Ataxia, episodic dyskinesia and thalamocortical seizures are associated with an inherited loss of P/Q-type voltage-gated Ca2+ channel function. P/Q-type channels are widely expressed throughout the neuraxis, obscuring identification of the critical networks underlying these complex neurological disorders. We recently showed that the conditional postnatal loss of P/Q-type channels in cerebellar Purkinje cells (PCs) in mice (purky) leads to these aberrant phenotypes, suggesting that intrinsic alteration in PC output is a sufficient pathogenic factor for disease initiation. The question arises whether P/Q-type channel deletion confined to a single upstream cerebellar synapse might induce the pathophysiological abnormality of genomically inherited P/Q-type channel disorders. PCs integrate two excitatory inputs, climbing fibers from inferior olive and parallel fibers (PFs) from granule cells (GCs) that receive mossy fiber (MF) input derived from precerebellar nuclei. In this paper, we introduce a new mouse model with a selective knock-out of P/Q-type channels in rhombic lip derived neurons including PF- and MF-pathways (quirky). We found that in quirky mice, PF-PC synaptic transmission is reduced during low-frequency stimulation. Using focal light stimulation of GCs that express optogenetic light-sensitive channels, channelrhodopsin-2, we found that modulation of PC firing via GC input is reduced in quirky mice. Phenotypic analysis revealed that quirky mice display ataxia, dyskinesia and absence epilepsy. These results suggest that developmental alteration of patterned input confined to only one of the main afferent cerebellar excitatory synaptic pathways has a significant role in generating the neurological phenotype associated with the global genomic loss of P/Q-type channel function. PMID:23516282

  8. Gray and white matter alterations in spinocerebellar ataxia type 7: an in vivo DTI and VBM study.

    PubMed

    Alcauter, Sarael; Barrios, Fernando A; Díaz, Rosalinda; Fernández-Ruiz, Juan

    2011-03-01

    Spinocerebellar ataxia type 7 (SCA7) is a progressive neurodegenerative disorder characterized by cerebellar ataxia and visual loss. It is caused by a CAG repeat expansion in the gene encoding the ataxin 7 protein. Visual loss is due to a progressive atrophy of photoreceptor cells that results in macular degeneration in more advanced stages. Initial semiautomatic measures in magnetic resonance imaging (MRI) studies on the brain stem have shown a diminished volume mainly in the cerebellum and pons, while T2 images have shown hyperintensities in transverse fibers at the pons. Neuropathological research, however, has shown more widespread brain damage including loss of myelinated fibers. In this study we decided to take advantage of recent MRI methodological advances to further explore the gray and white matter changes that occur in SCA7 patients. We studied nine genetically confirmed SCA7 patients and their matched controls using voxel based morphometry and tract-based spatial statistics. As expected, we found significant bilateral gray matter volume reductions (p<0.05, corrected for multiple comparisons) in patients' cerebellar cortex. However, we also found significant bilateral gray matter reductions in pre and postcentral gyrus, inferior and medial frontal, parietal inferior, parahippocampal and occipital cortices. The analysis also showed a decrement in fractional anisotropy (p<0.05, corrected) of SCA7 patients in the cerebellum's white matter, brainstem, cerebellar and cerebral peduncles, midbrain, anterior and posterior internal capsule, external/extreme capsule, corpus callosum, corona radiata, optical radiations, and the occipital, temporal and frontal lobe's white matter. These results confirm previous evidence of widespread damage beyond the cerebellum and the pons in SCA7 patients. They also confirmed previous results that had been only detectable through neuropathological analyses and, more importantly, identified new regions affected by the disease that

  9. Cerebellar Ataxia.

    PubMed

    Perlman

    2000-05-01

    There is nothing more discouraging than for a patient to be given a specific diagnosis, then to be told that there is nothing that can be done. Physicians are equally disheartened to see exponential progress being made in the understanding of the pathophysiology of a complex disorder but few direct benefits resulting for their patients. Over the past 5 years, molecular genetic research has completely revolutionized the way in which the progressive cerebellar ataxias are classified and diagnosed, but it has yet to produce effective gene-based, neuroprotective, or neurorestorative therapies. The treatment of cerebellar ataxia remains primarily a neurorehabilitation challenge, employing physical, occupational, speech, and swallowing therapy; adaptive equipment; driver safety training; and nutritional counseling. Modest additional gains are seen with the use of medications that can improve imbalance, incoordination, or dysarthria (amantadine, buspirone, acetazolamide); cerebellar tremor (clonazepam, propranolol); and cerebellar or central vestibular nystagmus (gabapentin, baclofen, clonazepam). Many of the progressive cerebellar syndromes have associated features involving other neurologic systems (eg, spasticity, dystonia or rigidity, resting or rubral tremor, chorea, motor unit weakness or fatigue, autonomic dysfunction, peripheral or posterior column sensory loss, neuropathic pain or cramping, double vision, vision and hearing loss, dementia, and bowel, bladder, and sexual dysfunction), which can impede the treatment of the ataxic symptoms or can worsen with the use of certain drugs. Treatment of the associated features themselves may in turn worsen the ataxia either directly (as side effects of medication) or indirectly (eg, relaxation of lower limb spasticity that was acting as a stabilizer for an ataxic gait). Secondary complications of progressive ataxia can include deconditioning or immobility, weight loss or gain, skin breakdown, recurrent pulmonary and

  10. Episodic Memories

    ERIC Educational Resources Information Center

    Conway, Martin A.

    2009-01-01

    An account of episodic memories is developed that focuses on the types of knowledge they represent, their properties, and the functions they might serve. It is proposed that episodic memories consist of "episodic elements," summary records of experience often in the form of visual images, associated to a "conceptual frame" that provides a…

  11. Transcriptional response of wild-type and ataxia telangiectasia lymphoblasts following exposure to equitoxic doses of ionizing radiation.

    PubMed

    Klising-Sireul, Eve; Rigaud, Odile; Ory, Katherine; Ugolin, Nicolas; Lebeau, Jérome; Levalois, Céline; Lectard, Bruno; Chevillard, Sylvie

    2006-11-01

    Experiments were designed to compare the transcriptional response to ionizing radiation (IR) of wild-type (WT) and ataxia telangiectasia (AT) cells. mRNA levels were assessed 2, 4 and 24 h after exposure to equitoxic doses using cDNA microarrays. Data reveal distinct patterns of gene expression between AT and WT cells since IR-responsive genes were mostly cell-type specific, this group representing 87 and 94% of the responding genes in WT and AT cells, respectively. In both cell lines, transcriptional alterations of genes associated with proliferation correlated with the observed cell cycle and growth data. Deregulated genes involved in apoptosis suggest that wild-type cells were more prone to cell death by apoptosis than AT cells. Furthermore, genes associated with the response to oxidative stress were particularly deregulated in wild-type cells whereas alterations of genes related to unexpected pathways including RNA processing, protein synthesis and lipid metabolism were specifically found in irradiated AT cells. These data suggest that under radiation conditions leading to a similar survival of WT and AT cells, the mechanisms triggered after radiation were mainly dependent on ATM status and thus on the intrinsic radiosensitivity.

  12. Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2.

    PubMed

    Kasumu, Adebimpe W; Hougaard, Charlotte; Rode, Frederik; Jacobsen, Thomas A; Sabatier, Jean Marc; Eriksen, Birgitte L; Strøbæk, Dorte; Liang, Xia; Egorova, Polina; Vorontsova, Dasha; Christophersen, Palle; Rønn, Lars Christian B; Bezprozvanny, Ilya

    2012-10-26

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by a polyglutamine expansion within the Ataxin-2 (Atxn2) protein. Purkinje cells (PC) of the cerebellum fire irregularly and eventually die in SCA2. We show here that the type 2 small conductance calcium-activated potassium channel (SK2) play a key role in control of normal PC activity. Using cerebellar slices from transgenic SCA2 mice we demonstrate that SK channel modulators restore regular pacemaker activity of SCA2 PCs. Furthermore, we also show that oral delivery of a more selective positive modulator of SK2/3 channels (NS13001) alleviates behavioral and neuropathological phenotypes of aging SCA2 transgenic mice. We conclude that SK2 channels constitute a therapeutic target for SCA2 treatment and that the developed selective SK2/3 modulator NS13001 holds promise as a potential therapeutic agent for treatment of SCA2 and possibly other cerebellar ataxias.

  13. On the Distribution of Intranuclear and Cytoplasmic Aggregates in the Brainstem of Patients with Spinocerebellar Ataxia Type 2 and 3.

    PubMed

    Seidel, Kay; Siswanto, Sonny; Fredrich, Michaela; Bouzrou, Mohamed; den Dunnen, Wilfred F A; Özerden, Inci; Korf, Horst-Werner; Melegh, Bela; de Vries, Jeroen J; Brunt, Ewout R; Auburger, Georg; Rüb, Udo

    2016-07-05

    The polyglutamine (polyQ) diseases are a group of genetically and clinically heterogeneous neurodegenerative diseases, characterized by the expansion of polyQ sequences in unrelated disease proteins, which form different types of neuronal aggregates. The aim of this study was to characterize the aggregation pathology in the brainstem of spinocerebellar ataxia type 2 (SCA2) and 3 (SCA3) patients. For good recognition of neurodegeneration and rare aggregates, we employed 100 µm PEG embedded brainstem sections, which were immunostained with the 1C2 antibody, targeted at polyQ expansions, or with an antibody against p62, a reliable marker of protein aggregates. Brainstem areas were scored semiquantitatively for neurodegeneration, severity of granular cytoplasmic staining (GCS) and frequency of neuronal nuclear inclusions (NNI). SCA2 and SCA3 tissue exhibited the same aggregate types and similar staining patterns. Several brainstem areas showed statistically significant differences between disease groups, whereby SCA2 showed more severe GCS and SCA3 showed more numerous NNI. We observed a positive correlation between GCS severity and neurodegeneration in SCA2 and SCA3 and an inverse correlation between the frequency of NNI and neurodegeneration in SCA3. Although their respective disease proteins are unrelated, SCA2 and SCA3 showed the same aggregate types. Apparently, the polyQ sequence alone is sufficient as a driver of protein aggregation. This is then modified by protein context and intrinsic properties of neuronal populations. The severity of GCS was the best predictor of neurodegeneration in both disorders, while the inverse correlation of neurodegeneration and NNI in SCA3 tissue implies a protective role of these aggregates.

  14. Spinocerebellar ataxia type 3/Machado-Joseph disease: segregation patterns and factors influencing instability of expanded CAG transmissions.

    PubMed

    Souza, G N; Kersting, N; Krum-Santos, A C; Santos, A S P; Furtado, G V; Pacheco, D; Gonçalves, T A; Saute, J A; Schuler-Faccini, L; Mattos, E P; Saraiva-Pereira, M L; Jardim, L B

    2016-08-01

    Controversies about Mendelian segregation and CAG expansion (CAGexp) instabilities during meiosis in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) need clarification. Additional evidence about these issues was obtained from the cohort of all SCA3/MJD individuals living in South Brazil. A survey was carried out to update information registered since 2001. Deaths were checked with the Public Information System, and data was made anonymous. Anticipation and delta-CAGexp from parent-offspring pairs, and delta-CAGexp between siblings were obtained. One hundred and fifty-nine families (94% of the entire registry) were retrieved, comprising 3725 living individuals as of 2015, 625 of these being symptomatic. Minimal prevalence was 6:100,000. Carriers of a CAGexp represented 65.6% of sibs in the genotyped offspring (p < 0.001). Median instability was larger among paternal than maternal transmissions, and instabilities correlated with anticipation (r = 0.38; p = 0.001). Age of the parent correlated to delta-CAGexp among 115 direct parent-offspring CAGexp transmissions (ρ = 0.23, p = 0.014). In 98 additional kindreds, the delta-CAGexp between 269 siblings correlated with their delta-of-age (ρ = 0.27, p < 0.0001). SCA3/MJD was associated with a segregation distortion favoring the expanded allele in our cohort. Instability of expansion during meiosis was weakly influenced by the age of the transmitting parent at the time of conception.

  15. Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3.

    PubMed

    Rodríguez-Cueto, Carmen; Hernández-Gálvez, Mariluz; Hillard, Cecilia J; Maciel, Patricia; García-García, Luis; Valdeolivas, Sara; Pozo, Miguel A; Ramos, José A; Gómez-Ruiz, María; Fernández-Ruiz, Javier

    2016-12-17

    Spinocerebellar ataxia type-3 (SCA-3) is a rare disease but it is the most frequent type within the autosomal dominant inherited ataxias. The disease lacks an effective treatment to alleviate major symptoms and to modify disease progression. Our recent findings that endocannabinoid receptors and enzymes are significantly altered in the post-mortem cerebellum of patients affected by autosomal-dominant hereditary ataxias suggest that targeting the endocannabinoid signaling system may be a promising therapeutic option. Our goal was to investigate the status of the endocannabinoid signaling system in a transgenic mouse model of SCA-3, in the two CNS structures most affected in this disease - cerebellum and brainstem. These animals exhibited progressive motor incoordination, imbalance, abnormal gait, muscle weakness, and dystonia, in parallel to reduced in vivo brain glucose metabolism, deterioration of specific neuron subsets located in the dentate nucleus and pontine nuclei, small changes in microglial morphology, and reduction in glial glutamate transporters. Concerning the endocannabinoid signaling, our data indicated no changes in CB2 receptors. By contrast, CB1 receptors increased in the Purkinje cell layer, in particular in terminals of basket cells, but they were reduced in the dentate nucleus. We also measured the levels of endocannabinoid lipids and found reductions in anandamide and oleoylethanolamide in the brainstem. These changes correlated with an increase in the FAAH enzyme in the brainstem, which also occurred in some cerebellar areas, whereas other endocannabinoid-related enzymes were not altered. Collectively, our results in SCA-3 mutant mice confirm a possible dysregulation in the endocannabinoid system in the most important brain structures affected in this type of ataxia, suggesting that a pharmacological manipulation addressed to correct these changes could be a promising option in SCA-3.

  16. Fusion of Human Fetal Mesenchymal Stem Cells with “Degenerating” Cerebellar Neurons in Spinocerebellar Ataxia Type 1 Model Mice

    PubMed Central

    Fan, Yiping; Suzuki, Mamiko; Konno, Ayumu; Matsuzaki, Yasunori; Takahashi, Nobutaka; Chan, Jerry K. Y.; Hirai, Hirokazu

    2016-01-01

    Mesenchymal stem cells (MSCs) migrate to damaged tissues, where they participate in tissue repair. Human fetal MSCs (hfMSCs), compared with adult MSCs, have higher proliferation rates, a greater differentiation capacity and longer telomeres with reduced senescence. Therefore, transplantation of quality controlled hfMSCs is a promising therapeutic intervention. Previous studies have shown that intravenous or intracortical injections of MSCs result in the emergence of binucleated cerebellar Purkinje cells (PCs) containing an MSC-derived marker protein in mice, thus suggesting a fusion event. However, transdifferentiation of MSCs into PCs or transfer of a marker protein from an MSC to a PC cannot be ruled out. In this study, we unequivocally demonstrated the fusion of hfMSCs with murine PCs through a tetracycline-regulated (Tet-off) system with or without a Cre-dependent genetic inversion switch (flip-excision; FLEx). In the FLEx-Tet system, we performed intra-cerebellar injection of viral vectors expressing tetracycline transactivator (tTA) and Cre recombinase into either non-symptomatic (4-week-old) or clearly symptomatic (6–8-month-old) spinocerebellar ataxia type 1 (SCA1) mice. Then, the mice received an injection of 50,000 genetically engineered hfMSCs that expressed GFP only in the presence of Cre recombinase and tTA. We observed a significant emergence of GFP-expressing PCs and interneurons in symptomatic, but not non-symptomatic, SCA1 mice 2 weeks after the MSC injection. These results, together with the results obtained using age-matched wild-type mice, led us to conclude that hfMSCs have the potential to preferentially fuse with degenerating PCs and interneurons but not with healthy neurons. PMID:27802273

  17. Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2.

    PubMed

    Fogel, Brent L; Cho, Ellen; Wahnich, Amanda; Gao, Fuying; Becherel, Olivier J; Wang, Xizhe; Fike, Francesca; Chen, Leslie; Criscuolo, Chiara; De Michele, Giuseppe; Filla, Alessandro; Collins, Abigail; Hahn, Angelika F; Gatti, Richard A; Konopka, Genevieve; Perlman, Susan; Lavin, Martin F; Geschwind, Daniel H; Coppola, Giovanni

    2014-09-15

    Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4.

  18. A human β-III-spectrin spinocerebellar ataxia type 5 mutation causes high-affinity F-actin binding

    PubMed Central

    Avery, Adam W.; Crain, Jonathan; Thomas, David D.; Hays, Thomas S.

    2016-01-01

    Spinocerebellar ataxia type 5 (SCA5) is a human neurodegenerative disease that stems from mutations in the SPTBN2 gene encoding the protein β-III-spectrin. Here we investigated the molecular consequence of a SCA5 missense mutation that results in a L253P substitution in the actin-binding domain (ABD) of β-III-spectrin. We report that the L253P substitution in the isolated β-III-spectrin ABD causes strikingly high F-actin binding affinity (Kd = 75.5 nM) compared to the weak F-actin binding affinity of the wild-type ABD (Kd = 75.8 μM). The mutation also causes decreased thermal stability (Tm = 44.6 °C vs 59.5 °C). Structural analyses indicate that leucine 253 is in a loop at the interface of the tandem calponin homology (CH) domains comprising the ABD. Leucine 253 is predicted to form hydrophobic contacts that bridge the CH domains. The decreased stability of the mutant indicates that these bridging interactions are probably disrupted, suggesting that the high F-actin binding affinity of the mutant is due to opening of the CH domain interface. These results support a fundamental role for leucine 253 in regulating opening of the CH domain interface and binding of the ABD to F-actin. This study indicates that high-affinity actin binding of L253P β-III-spectrin is a likely driver of neurodegeneration. PMID:26883385

  19. Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2.

    PubMed

    Vinther-Jensen, Tua; Ek, Jakob; Duno, Morten; Skovby, Flemming; Hjermind, Lena E; Nielsen, Jørgen E; Nielsen, Troels Tolstrup

    2013-06-01

    The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms. A subgroup of the ataxias is caused by unstable CAG-repeat expansions in their respective genes leading to pathogenic expansions of polyglutamine stretches in the encoded proteins. In general, unstable CAG repeats have an uninterrupted CAG repeat, whereas stable CAG repeats are either short or interrupted by CAA codons, which - like CAG codons - code for glutamine. Here we report on an infantile SCA2 patient who, due to germ-line CAG repeat instability in her father, inherited an extremely expanded CAG repeat in the SCA2 locus. Surprisingly, the expanded allele of the father was an interrupted CAG repeat sequence. Furthermore, analyses of single spermatozoa showed a high frequency of paternal germ-line repeat sequence instability of the expanded SCA2 locus.

  20. Epigallocatechin-3-gallate and tetracycline differently affect ataxin-3 fibrillogenesis and reduce toxicity in spinocerebellar ataxia type 3 model.

    PubMed

    Bonanomi, Marcella; Natalello, Antonino; Visentin, Cristina; Pastori, Valentina; Penco, Amanda; Cornelli, Giuseppina; Colombo, Giorgio; Malabarba, Maria G; Doglia, Silvia M; Relini, Annalisa; Regonesi, Maria E; Tortora, Paolo

    2014-12-15

    The polyglutamine (polyQ)-containing protein ataxin-3 (AT3) triggers the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3) when its polyQ tract is expanded beyond a critical length. This results in protein aggregation and generation of toxic oligomers and fibrils. Currently, no effective treatment is available for such and other polyQ diseases. Therefore, plenty of investigations are being carried on to assess the mechanism of action and the therapeutic potential of anti-amyloid agents. The polyphenol compound epigallocatechin-3-gallate (EGCG) and tetracycline have been shown to exert some effect in preventing fibrillogenesis of amyloidogenic proteins. Here, we have incubated an expanded AT3 variant with either compound to assess their effects on the aggregation pattern. The process was monitored by atomic force microscopy and Fourier transform infrared spectroscopy. Whereas in the absence of any treatment, AT3 gives rise to amyloid β-rich fibrils, whose hallmark is the typical glutamine side-chain hydrogen bonding, when incubated in the presence of EGCG it generated soluble, SDS-resistant aggregates, much poorer in β-sheets and devoid of any ordered side-chain hydrogen bonding. These are off-pathway species that persist until the latest incubation time and are virtually absent in the control sample. In contrast, tetracycline did not produce major alterations in the structural features of the aggregated species compared with the control, but substantially increased their solubility. Both compounds significantly reduced toxicity, as shown by the MTT assay in COS-7 cell line and in a transgenic Caenorhabditis elegans strain expressing in the nervous system an AT3 expanded variant in fusion with GFP.

  1. Polyglutamine length-dependent toxicity from α1ACT in Drosophila models of spinocerebellar ataxia type 6

    PubMed Central

    Tsou, Wei-Ling; Qiblawi, Sultan H.; Hosking, Ryan R.; Gomez, Christopher M.

    2016-01-01

    ABSTRACT Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that results from abnormal expansion of a polyglutamine (polyQ) repeat. SCA6 is caused by CAG triplet repeat expansion in the gene CACNA1A, resulting in a polyQ tract of 19-33 in patients. CACNA1A, a bicistronic gene, encodes the α1A calcium channel subunit and the transcription factor, α1ACT. PolyQ expansion in α1ACT causes degeneration in mice. We recently described the first Drosophila models of SCA6 that express α1ACT with a normal (11Q) or hyper-expanded (70Q) polyQ. Here, we report additional α1ACT transgenic flies, which express full-length α1ACT with a 33Q repeat. We show that α1ACT33Q is toxic in Drosophila, but less so than the 70Q version. When expressed everywhere, α1ACT33Q-expressing adults die earlier than flies expressing the normal allele. α1ACT33Q causes retinal degeneration and leads to aggregated species in an age-dependent manner, but at a slower pace than the 70Q counterpart. According to western blots, α1ACT33Q localizes less readily in the nucleus than α1ACT70Q, providing clues into the importance of polyQ tract length on α1ACT localization and its site of toxicity. We expect that these new lines will be highly valuable for future work on SCA6. PMID:27979829

  2. Prevention of repeated episodes of type 2 reaction of leprosy with the use of thalidomide 100 mg/day*

    PubMed Central

    Putinatti, Maria Stella de Mello Ayres; Lastória, Joel Carlos; Padovani, Carlos Roberto

    2014-01-01

    BACKGROUND Leprosy can have its course interrupted by type 1 and 2 reactional episodes, the last named of erythema nodosum leprosum (ENL). Thalidomide has been the medication of choice for the control of ENL episodes since 1965. OBJECTIVES These episodes can repeat and cause damages to the patient. In order to prevent these episodes, an extra dose of 100 mg/day thalidomide was used during six months, followed by a follow-up period of six more months after thalidomide discontinuation. METHODS We included 42 patients with multibacillary (MB) leprosy who had episodes of ENL. They were male and female patients aged between 18 and 84 years. RESULTS Of the 42 patients, 39 (92.85%) had the lepromatous form and three (7.15%) had the borderline form. We found that 100% of patients had no reactional episode during the use of the drug. During the follow-up period after thalidomide discontinuation, 33 (78.57%) patients had no reactional episode and nine (21.43%), all of them with the lepromatous form, had mild episodes, which were controlled using non-steroidal anti-inflammatory. There were no thalidomide-related side effects. CONCLUSION A maintenance dose of 100 mg/day of thalidomide showed to be effective to prevent repeated type 2 reactional episodes of ENL. PMID:24770503

  3. [Autosomal recessive cerebellar ataxias].

    PubMed

    Tranchant, Christine; Anheim, Mathieu

    2009-12-01

    Friedreich ataxia is the most frequent recessive cerebral ataxia d should always be researched first. Ataxia with isolated vitamin E deficiency and abetalipoproteinemia have a specific treatment. Associated neurological signs such polyneuroapthy, ophtalmologic or oculomotor signs, pyramidal signs, and cerebellar MRI can lead to the etiological diagnosis. Biological tests should be: vitamin E, cholesterol, alpha-fetoprotein levels, acanthocytes, than phytanic acid, cholestanol, lysosomal enzymes. Numerous autosomal recessive cerebellar ataxia remain without etiology.

  4. n-Butilydenephthalide exhibits protection against neurotoxicity through regulation of tryptophan 2, 3 dioxygenase in spinocerebellar ataxia type 3.

    PubMed

    Rajamani, Karthyayani; Liu, Jen-Wei; Wu, Cheng-Han; Chiang, I-Tsang; You, Deng-Huwei; Lin, Si-Yin; Hsieh, Dean-Kuo; Lin, Shinn-Zong; Harn, Horng-Jyh; Chiou, Tzyy-Wen

    2017-02-18

    Spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3/MJD) is characterized by the repetition of a CAG codon in the ataxin-3 gene (ATXN3), which leads to the formation of an elongated mutant ATXN3 protein that can neither be denatured nor undergo proteolysis in the normal manner. This abnormal proteolysis leads to the accumulation of cleaved fragments, which have been identified as toxic and further they act as a seed for more aggregate formation, thereby increasing toxicity in neuronal cells. To date, there have been few studies or treatment strategies that have focused on controlling toxic fragment formation. The aim of this study is to develop a potential treatment strategy for addressing the complications of toxic fragment formation and to provide an alternative treatment strategy for SCA3. Our preliminary data on anti-aggregation and toxic fragment formation using an HEK (human embryonic kidney cells) 293T-84Q-eGFP (green fluorescent protein) cell model identified n-butilydenephthalide (n-BP) as a potential drug treatment for SCA3. n-BP decreased toxic fragment formation in both SCA3 cell and animal models. Moreover, results showed that n-BP can improve gait, motor coordination, and activity in SCA3 mice. To comprehend the molecular basis behind the control of toxic fragment formation, we used microarray analysis to identify tryptophan metabolism as a major player in controlling the fate of mutant ATXN3 aggregates. We also demonstrated that n-BP functions by regulating the early part of the kynurenine pathway through the downregulation of tryptophan 2, 3-dioxygenase (TDO2), which decreases the downstream neurotoxic product, quinolinic acid (QA). In addition, through the control of TDO2, n-BP also decreases active calpain levels, an important enzyme involved in the proteolysis of mutant ATXN3, thereby decreasing toxic fragment formation and associated neurotoxicity. Collectively, these findings indicate a correlation between n-BP, TDO2, QA, calpain, and

  5. Poorly controlled type 2 diabetes complicated by an episode of severe hypertriglyceridaemia-induced pancreatitis.

    PubMed

    Denecker, Nathalie; Decochez, Katelijn

    2013-04-29

    A 23-year-old woman with a history of type 2 diabetes and non-compliance presented to the emergency department with abdominal epigastric pain and nausea. Laboratory examination revealed a mild ketoacidosis while an abdominal CT scan performed the following day demonstrated a severe acute pancreatitis of the body and tail (Balthazar grade E) despite normal amylase serum levels on admission. The presence of a lactescent serum was the clue to an extremely high triglyceride level (>10 000 mg/dl) causing the pancreatitis. The hypertriglyceridaemia itself was attributed mainly to the diabetic ketoacidosis. There was no family history of hypertriglyceridaemia. The triad consisting of diabetic ketoacidosis, hypertriglyceridaemia and acute pancreatitis is an unusual presentation of poorly controlled diabetes which can occur in type 1 as well as type 2 diabetic adults and children. Treatment with intravenous insulin and hydration successfully resolved the ketoacidosis and hypertriglyceridaemia and reversed the episode of acute pancreatitis.

  6. Early onset, non fluctuating spinocerebellar ataxia and a novel missense mutation in CACNA1A gene.

    PubMed

    Tonelli, Alessandra; D'Angelo, Maria Grazia; Salati, Roberto; Villa, Laura; Germinasi, Chiara; Frattini, Tiziano; Meola, Giovanni; Turconi, Anna Carla; Bresolin, Nereo; Bassi, Maria Teresa

    2006-02-15

    Mutations in the brain-specific P/Q type Ca2+ channel alpha1 subunit gene, CACNA1A, have been identified in three clinically distinct disorders, spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2), and familial hemiplegic migraine type 1 (FHM1). SCA6 is associated with small expansions of a CAG repeat at the 3' end of the gene, while point mutations are mostly responsible for its two allelic disorders, FHMI and EA2. From the electrophysiological point of view, while FHMI mutations lead to a gain of function [Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, et al. Familial hemiplegic migraine mutations increase Ca2+ influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. Proc Natl Acad Sci 99 (20) (2002) 13284-13289.], EA2 mutations usually generate a loss of channel function [Guida S, Trettel F, Pagnutti S, Mantuano E, Tottene A, Veneziano L, et al. Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2. Am J Hum Genet 68 (3) (2001) 759-764, Wappl E, Koschak A, Poteser M, Sinnegger MJ, Walter D, Eberhart A, et al. Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia. J Biol Chem 277 (9) (2002) 6960-6966.]. In the present study, we describe a child affected by permanent non-fluctuating limb and trunk ataxia with a quite early age of onset. Interestingly, the size of the CACNA1A triplet repeat region in the patient is within the normal range while he carries a novel de novo missense mutation in this gene, p.R1664Q. Although functional data are not available, based on the literature data indicating that severe reductions in P/Q-type channel activity favour episodic and/or progressive ataxic symptoms [Wappl E, Koschak A, Poteser M, Sinnegger MJ, Walter D, Eberhart A, et al. Functional consequences of P/Q-type Ca2+ channel Cav2

  7. The patient with ataxia.

    PubMed

    Maggs, F G

    2014-01-01

    In this article we look at the causes of ataxia, and how the patient presenting with ataxia should be managed. One of the difficulties in managing the patient with ataxia is that acute ataxia has many causes, but usually these can be teased out by means of a careful history and examination. Investigations can then be targeted at confirming or disproving the differential diagnosis. Some patients with ataxia need to be managed in hospital, but many can be investigated, and receive therapy, as an outpatient.

  8. Clinical and molecular effect on offspring of a marriage of consanguineous spinocerebellar ataxia type 7 mutation carriers: a family case report

    PubMed Central

    Magaña, Jonathan J; Tapia-Guerrero, Yessica S; Velázquez-Pérez, Luis; Cruz-Mariño, Tania; Cerecedo-Zapata, Cesar M; Gómez, Rocío; Murillo-Melo, Nadia M; González-Piña, Rigoberto; Hernández-Hernández, Oscar; Cisneros, Bulmaro

    2014-01-01

    Spinocerebellar ataxia type 7 (SCA7) is a genetic disorder characterized by degeneration of the cerebellum, brainstem, and retina that is caused by abnormal expansion of a CAG repeat located in the ATXN7 gene encoding sequence on chromosome 3p21.1. Although SCA7 is an uncommon autosomal dominant ataxia, we previously found increased prevalence of the disease in a Southeastern Mexican population. In this study, we described to our knowledge for the first time a marriage of consanguineous SCA7 mutation carriers and their offspring effect. We characterized a severely affected infantile-onset female patient whose parents and two siblings exhibited no symptoms of the disease at time of diagnosis. A comprehensive clinical analysis of the proband showed a progressive cerebellar syndrome, including gait ataxia, movement disorders, and saccadic movements, as well as hyperreflexia, visual deterioration, urinary and cardiovascular dysfunction, and impaired nerve conduction. The SCA7 mutation was detected in the proband patient. Subsequently, genetic examination using four ATXN7 gene-linked markers (three centromeric microsatellite markers [D3S1228, D3S1287, and D3S3635] and an intragenic Single Nucleotide Polymorphism [SNP-3145G/A]) revealed that the proband descends from a couple of consanguineous SCA7 mutation carriers. Genotyping analysis demonstrated that all offspring inherited only one mutant allele, and that the severe infantile-onset phenotype is caused by germinal expansion (from 37 to 72 CAG repeats) of the paternal mutant allele. Interestingly, the couple also referred a miscarriage. Finally, we found no CAA interruptions in the ATXN7 gene CAG repeats tract in this family, which might explain, at least in part, the triplet instability in the proband. PMID:25664129

  9. Clinical and molecular studies of 73 Italian families with autosomal dominant cerebellar ataxia type I: SCA1 and SCA2 are the most common genotypes.

    PubMed

    Pareyson, D; Gellera, C; Castellotti, B; Antonelli, A; Riggio, M C; Mazzucchelli, F; Girotti, F; Pietrini, V; Mariotti, C; Di Donato, S

    1999-05-01

    We clinically and genetically evaluated 73 Italian families with autosomal dominant cerebellar ataxia (ADCA) type I. Spinocerebellar ataxia (SCA) type 1 was the most common genotype (SCA1), accounting for 41% of cases (30 families), SCA2 was slightly less frequent (29%, 21 families), and the remaining families were negative for the SCA1, SCA2, and SCA3 mutations. Among the positively genotyped families, SCA1 was found most frequently in families from northern Italy (50%), while SCA2 was the most common mutation in families from the southern part of the country (56%). Slow saccades and decreased deep tendon reflexes were observed significantly more frequently in SCA2 patients, while increased deep tendon reflexes and nystagmus were more common in SCA1. In SCA1 and SCA2 families there was a significant inverse correlation between expansion size and age at onset. Analysis of triplet repeat numbers in parent-offspring pairs showed greater meiotic instability, which was associated with an earlier onset of the disease in SCA2 families than in SCA1 families.

  10. Aspirin in episodic tension-type headache: placebo-controlled dose-ranging comparison with paracetamol.

    PubMed

    Steiner, T J; Lange, R; Voelker, M

    2003-02-01

    Most people with episodic tension-type headache (TTH) treat themselves with over-the-counter analgesics. In the absence of clear evidence of dose-related efficacy of the two most commonly used analgesics, aspirin (acetylsalicylic acid) and paracetamol (acetaminophen), this study compared two doses of each with placebo. In a double-blind, double-dummy, randomized parallel-groups comparative trial, 638 consenting subjects aged 16-65 years with episodic TTH (but not migraine) by IHS criteria were recruited from the UK general population by advertisement. They treated one episode of moderate or severe TTH with a single dose of 500 or 1000 mg aspirin, 500 or 1000 mg paracetamol or placebo. The primary objective was to compare aspirin 1000 mg with placebo, and the primary end-point was subjective pain relief (total or worthwhile) 2 h after treatment ('response'). Additionally, pain intensity on a 100-mm visual analogue scale and functional impairment were monitored regularly for 4 h and at 24 h, although rescue medication was allowed after 2 h. The analysis was of the intention-to-treat population of 542 who took treatment (all providing outcome data). Treatment groups were matched at baseline. Aspirin 1000 mg (75.7% response rate; P = 0.0009) and to a lesser extent aspirin 500 mg (70.3%; P = 0.011) and paracetamol 1000 mg (71.2%; P = 0.007), but not paracetamol 500 mg (63.8%; P = 0.104), were statistically more effective than placebo despite a high placebo-response rate (54.5%). Outcome was not affected by headache intensity at baseline. Secondary end-points including functional recovery (by median times of 4.0-13.5 h) were consistent with these findings, although a minority of subjects recorded long-duration functional impairment (37-54 h). Adverse events reported by 13.4-18.9% of subjects were mild or moderate, and transient. No safety concerns arose.

  11. Spinocerebellar ataxias type 27 derived from a disruption of the fibroblast growth factor 14 gene with mimicking phenotype of paroxysmal non-kinesigenic dyskinesia.

    PubMed

    Shimojima, Keiko; Okumura, Akihisa; Natsume, Jun; Aiba, Kaori; Kurahashi, Hirokazu; Kubota, Tetsuo; Yokochi, Kenji; Yamamoto, Toshiyuki

    2012-03-01

    Many types of spinocerebellar ataxias (SCAs) manifest as progressive disorders with cerebellar involvement. SCA type 27 (SCA27) is a rare type of SCA caused by mutations in the fibroblast growth factor 14 gene (FGF14). FGF14 disruption caused by a de novo reciprocal chromosomal translocation between chromosomes 13 and 21 was identified in a patient with the phenotype of paroxysmal non-kinesigenic dyskinesia (PNKD). This indicated genetic heterogeneity of PNKD, since 60% of the patients with PNKD exhibit mutations in another gene responsible for PNKD, the myofibrillogenesis regulator 1 gene (MR-1). We hypothesized that the remaining 40% of patients with PNKD may have FGF14 mutations; therefore, the nucleotide sequences of MR-1 and FGF14 were analyzed in another six patients with PNKD, but no nucleotide alterations were observed in these genes for these patients. Further studies should be conducted on the phenotypic heterogeneity of FGF14 mutations and/or haploinsufficiency in SCA27 and PNKD.

  12. Prevalence and type of functional somatic complaints in patients with first-episode depression.

    PubMed

    Grover, S; Kumar, V; Chakrabarti, S; Hollikatti, P; Singh, P; Tyagi, S; Kulhara, P; Avasthi, A

    2012-12-01

    OBJECTIVE. To study the prevalence and type of functional somatic complaints in patients with first-episode depression. METHODS. A total of 164 patients attending the outpatient department of a general hospital psychiatric unit were evaluated using the Patient Health Questionnaire-15 (PHQ-15) and Hamilton Depression Rating Scale (HDRS). RESULTS. More than half of the sample were male (n = 85; 52%) and most of the subjects were married (n = 128; 78%). The mean (standard deviation) HDRS score was 19.9 (5.4). All patients had at least 1 functional somatic complaint, and that the mean (range) number of functional somatic complaints per patient on the PHQ-15 was 8 (1-15). The most common functional somatic complaints included feeling tired or having little energy (93%); trouble sleeping (80%); nausea, gas and indigestion (68%); headache (68%); pain in arms, legs, or joints (66%); and feeling the heart racing (65%). Total PHQ-15 scores indicated the presence of moderate-to-severe severity of functional somatic complaints. Back pain, as well as pain in arms, legs, or joints, were found to be more common in females. The number and severity of functional somatic complaints did not differ significantly in relation to other socio-demographics (locality, marital status, age, education, income) and clinical variables (duration, physical co-morbidity, and atypical features). CONCLUSIONS. Functional somatic complaints are quite prevalent in subjects with first-episode depression. Hence, clinicians should routinely evaluate patients with depression for these symptoms.

  13. Differences in saccade dynamics between spinocerebellar ataxia 2 and late-onset cerebellar ataxias.

    PubMed

    Federighi, Pamela; Cevenini, Gabriele; Dotti, Maria T; Rosini, Francesca; Pretegiani, Elena; Federico, Antonio; Rufa, Alessandra

    2011-03-01

    The cerebellum is implicated in maintaining the saccadic subsystem efficient for vision by minimizing movement inaccuracy and by learning from endpoint errors. This ability is often disrupted in degenerative cerebellar diseases, as demonstrated by saccade kinetic abnormalities. The study of saccades in these patients may therefore provide insights into the neural substrate underlying saccadic motor control. We investigated the different extent of saccade dynamic abnormalities in spinocerebellar ataxia type 2 and late-onset cerebellar ataxias, genetically undefined and with prevalent cerebellar atrophy. Reflexive and voluntary saccades of different amplitude (10°-18°) were studied in seven patients with spinocerebellar ataxia 2, eight patients with late-onset cerebellar ataxia and 25 healthy controls. Quantitative analysis of saccade parameters and measures of saccade accuracy were performed. Detailed neurological, neurophysiological and magnetic resonance imaging assessment was obtained for each patient. Genetic and laboratory screening for spinocerebellar ataxias and other forms of late-onset cerebellar ataxias were also performed. A lower peak saccade velocity and longer duration was observed in patients with spinocerebellar ataxia 2 with respect to those with late-onset cerebellar ataxia and controls. Unlike subjects with spinocerebellar ataxia 2, patients with late-onset cerebellar ataxia showed main sequence relationships to similar saccades made by normal subjects. Saccades were significantly more inaccurate, namely hypometric, in late-onset cerebellar ataxia than in spinocerebellar ataxia 2 and inaccuracy increased with saccade amplitude. The percentage of hypometric primary saccades and of larger secondary corrective saccades were consistently higher in late-onset cerebellar ataxia than in spinocerebellar ataxia 2 and controls. No other significant differences were found between groups. Two different mechanisms were adopted to redirect the fovea as fast

  14. Identification and localization of ataxin-7 in brain and retina of a patient with cerebellar ataxia type II using anti-peptide antibody.

    PubMed

    Mauger, C; Del-Favero, J; Ceuterick, C; Lübke, U; van Broeckhoven, C; Martin, J

    1999-12-10

    Autosomal dominant cerebellar ataxias (ADCAs) are a complex group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. The spinocerebellar ataxia type 7 (SCA7) is associated with pigmentary macular dystrophy and retinal degeneration leading to blindness caused by a CAG/polyglutamine (polyGln) expansion in the coding region of the SCA7 gene/protein. The SCA7 gene codes for ataxin-7, a protein of unknown function. To investigate its cellular and subcellular localization, we have developed a sequence-specific polyclonal antibody against the N-terminal part of the protein. Immunohistochemical analysis indicated that ataxin-7 accumulates as single nuclear inclusion (NI) in the cells of the brain and retina of a SCA7 patient but not of controls. The 1C2 antibody, directed against expanded polyGln, confirmed the aggregation of mutant ataxin-7 in these NIs. Furthermore, ubiquitin was found in these aggregates, suggesting that mutant ataxin-7 is a target for ubiquitin-dependent proteolysis, but resistant to removal. Electron microscopic studies using immunogold labeling showed that ataxin-7 immunoreactive NIs appear as dense aggregates containing a mixture of granular and filamentary structures. Together, these data confirm the presence of NIs in brain and retina of a SCA7 patient, a common characteristic of disorders caused by expanded CAG/polyGln repeats.

  15. Ataxia is the major neuropathological finding in arylsulfatase G-deficient mice: similarities and dissimilarities to Sanfilippo disease (mucopolysaccharidosis type III).

    PubMed

    Kowalewski, Björn; Heimann, Peter; Ortkras, Theresa; Lüllmann-Rauch, Renate; Sawada, Tomo; Walkley, Steven U; Dierks, Thomas; Damme, Markus

    2015-04-01

    Deficiency of arylsulfatase G (ARSG) leads to a lysosomal storage disease in mice resembling biochemical and pathological features of the mucopolysaccharidoses and particularly features of mucopolysaccharidosis type III (Sanfilippo syndrome). Here we show that Arsg KO mice share common neuropathological findings with other Sanfilippo syndrome models and patients, but they can be clearly distinguished by the limitation of most phenotypic alterations to the cerebellum, presenting with ataxia as the major neurological finding. We determined in detail the expression of ARSG in the central nervous system and observed highest expression in perivascular macrophages (which are characterized by abundant vacuolization in Arsg KO mice) and oligodendrocytes. To gain insight into possible mechanisms leading to ataxia, the pathology in older adult mice (>12 months) was investigated in detail. This study revealed massive loss of Purkinje cells and gliosis in the cerebellum, and secondary accumulation of glycolipids like GM2 and GM3 gangliosides and unesterified cholesterol in surviving Purkinje cells, as well as neurons of some other brain regions. The abundant presence of ubiquitin and p62-positive aggregates in degenerating Purkinje cells coupled with the absence of significant defects in macroautophagy is consistent with lysosomal membrane permeabilization playing a role in the pathogenesis of Arsg-deficient mice and presumably Sanfilippo disease in general. Our data delineating the phenotype of mucopolysaccharidosis IIIE in a mouse KO model should help in the identification of possible human cases of this disease.

  16. Disentangling different types of El Niño episodes by evolving climate network analysis.

    PubMed

    Radebach, Alexander; Radebach, A; Donner, Reik V; Donner, R V; Runge, Jakob; Runge, J; Donges, Jonathan F; Donges, J F; Kurths, Jürgen; Kurths, J

    2013-11-01

    Complex network theory provides a powerful toolbox for studying the structure of statistical interrelationships between multiple time series in various scientific disciplines. In this work, we apply the recently proposed climate network approach for characterizing the evolving correlation structure of the Earth's climate system based on reanalysis data for surface air temperatures. We provide a detailed study of the temporal variability of several global climate network characteristics. Based on a simple conceptual view of red climate networks (i.e., networks with a comparably low number of edges), we give a thorough interpretation of our evolving climate network characteristics, which allows a functional discrimination between recently recognized different types of El Niño episodes. Our analysis provides deep insights into the Earth's climate system, particularly its global response to strong volcanic eruptions and large-scale impacts of different phases of the El Niño Southern Oscillation.

  17. [Comprehensive assessment of ischemic episodes and vasomotor function of vascular endothelium in patients with type II diabetes mellitus].

    PubMed

    Tatarchenko, I P; Posdniakova, N V; Dudukina, E A; Morozova, O I

    2007-01-01

    Value of functional state of endothelium in assessment of episodes of ischemia was studied in 93 patients (52 men and 41 women, mean age 58.3 +/- 4.8 years) divided into 2 groups. Group 1 comprised 47 patients with ischemic heart disease (IHD) and type II diabetes, group 2 comprised 46 patients with IHD without disturbances of carbohydrate metabolism. Patients of these groups had similar sex, age, and main risk factors. Examination included Holter ECG monitoring, stress test, echocardiography, test with reactive hyperemia (ultrasound measurement of endothelium dependent vasodilation of brachial artery). Number of painless ischemic episodes (PIE), total duration of episodes of ischemia, maximal depth of ST-segment lowering were greater in patients of group I compared with group 2. Correlation analysis revealed significant negative relationship between endothelial dysfunction and number and duration of episodes of ischemia, time interval between appearances of pain and ischemic ST depression.

  18. 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 ...

  19. Medications for Ataxia Symptoms

    MedlinePlus

    ... Namenda) NATIONAL ATAXIA FOUNDATION Muscle cramps or spasms : Baclofen, Tizanidine (Zanaflex) Muscle strength : Creatine Myofascial pain : Cymbalta, Lyrica, Gabapentin Neuropathy : Cymbalta, Lyrica; as well ...

  20. [Chronic ataxia in childhood].

    PubMed

    Erazo Torricelli, Ricardo

    2013-01-01

    Chronic ataxias are an heterogeneous group of disorders that affect the child at different ages. Thus, the congenital forms, generally non progressive are observed from first months of life and are expressed by hypotonia and motor delay long before the ataxia became evident. The cerebral magnetic resonance images (MRI) may be diagnostic in some pictures like Joubert syndrome. The group of progressive hereditary ataxias, usually begin after the infant period. The clinical signs are gait instability and ocular apraxia that can be associated with oculocutaneous telangiectasias (ataxia-telangiesctasia) or with sensory neuropathy (Friedreich ataxia). In this review are briefly described congenital ataxias and in more detailed form the progressive hereditary ataxias autosomal recessive, autosomal dominants and mitochondrials. The importance of genetic study is emphasized, because it is the key to obtain the diagnosis in the majority of these diseases. Although now there are no treatments for the majority of progressive hereditary ataxias, some they have like Refsum disease, vitamine E deficiency, Coenzyme Q10 deficiency and others, thus the diagnosis in these cases is even more important. At present the diagnosis of childhood hereditary ataxia not yet treatable is fundamental to obtain suitable handling, determine a precise outcome and to give to the family an opportune genetic counseling.

  1. Modulation of age at onset in Huntington's disease and spinocerebellar ataxia type 2 patients originated from eastern India.

    PubMed

    Chattopadhyay, Biswanath; Ghosh, Subho; Gangopadhyay, Prasanta K; Das, Shaymal K; Roy, T; Sinha, Krishna K; Jha, Dilip K; Mukherjee, Subhash C; Chakraborty, Ambar; Singhal, Bhim S; Bhattacharya, Anup K; Bhattacharyya, Nitai P

    2003-07-17

    To identify the genetic modifier(s) that might alter the age at onset in Huntington's disease (HD) we have analyzed variations in GluR6 kainate receptor (GluR6), CA150 gene, Delta2642 and polymorphic CCG repeat variation in huntingtin (htt) gene in 77 HD patients and normal individuals. In addition, variation in the RAI1 gene was analyzed in 30 spinocerebellar ataxia (SCA2) patients and normal individuals to show the possible influence on the age at onset. Multiple regression analysis indicated that variation in GluR6 and CCG repeat genotype might explain 6.2% and 3.1%, respectively, of the variability in the age at onset in HD. Similar analysis with SCA2 patients indicated that RAI1 might explain about 13% of the variability in the age at onset. Specific alleles in GluR6 and CA150 locus were only observed in HD patients.

  2. Kv3.3 channels harbouring a mutation of spinocerebellar ataxia type 13 alter excitability and induce cell death in cultured cerebellar Purkinje cells.

    PubMed

    Irie, Tomohiko; Matsuzaki, Yasunori; Sekino, Yuko; Hirai, Hirokazu

    2014-01-01

    The cerebellum plays crucial roles in controlling sensorimotor functions. The neural output from the cerebellar cortex is transmitted solely by Purkinje cells (PCs), whose impairment causes cerebellar ataxia. Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominant disease, and SCA13 patients exhibit cerebellar atrophy and cerebellar symptoms. Recent studies have shown that missense mutations in the voltage-gated K(+) channel Kv3.3 are responsible for SCA13. In the rodent brain, Kv3.3 mRNAs are expressed most strongly in PCs, suggesting that the mutations severely affect PCs in SCA13 patients. Nevertheless, how these mutations affect the function of Kv3.3 in PCs and, consequently, the morphology and neuronal excitability of PCs remains unclear. To address these questions, we used lentiviral vectors to express mutant mouse Kv3.3 (mKv3.3) channels harbouring an R424H missense mutation, which corresponds to the R423H mutation in the Kv3.3 channels of SCA13 patients, in mouse cerebellar cultures. The R424H mutant-expressing PCs showed decreased outward current density, broadened action potentials and elevated basal [Ca(2+)]i compared with PCs expressing wild-type mKv3.3 subunits or those expressing green fluorescent protein alone. Moreover, expression of R424H mutant subunits induced impaired dendrite development and cell death selectively in PCs, both of which were rescued by blocking P/Q-type Ca(2+) channels in the culture conditions. We therefore concluded that expression of R424H mutant subunits in PCs markedly affects the function of endogenous Kv3 channels, neuronal excitability and, eventually, basal [Ca(2+)]i, leading to cell death. These results suggest that PCs in SCA13 patients also exhibit similar defects in PC excitability and induced cell death, which may explain the pathology of SCA13.

  3. 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.

  4. Rational design of ligands targeting triplet repeating transcripts that cause RNA dominant disease: application to myotonic muscular dystrophy type 1 and spinocerebellar ataxia type 3.

    PubMed

    Pushechnikov, Alexei; Lee, Melissa M; Childs-Disney, Jessica L; Sobczak, Krzysztof; French, Jonathan M; Thornton, Charles A; Disney, Matthew D

    2009-07-22

    Herein, we describe the design of high affinity ligands that bind expanded rCUG and rCAG repeat RNAs expressed in myotonic dystrophy type 1 (DM1) and spinocerebellar ataxia type 3. These ligands also inhibit, with nanomolar IC(50) values, the formation of RNA-protein complexes that are implicated in both disorders. The expanded rCUG and rCAG repeats form stable RNA hairpins with regularly repeating internal loops in the stem and have deleterious effects on cell function. The ligands that bind the repeats display a derivative of the bisbenzimidazole Hoechst 33258, which was identified by searching known RNA-ligand interactions for ligands that bind the internal loop displayed in these hairpins. A series of 13 modularly assembled ligands with defined valencies and distances between ligand modules was synthesized to target multiple motifs in these RNAs simultaneously. The most avid binder, a pentamer, binds the rCUG repeat hairpin with a K(d) of 13 nM. When compared to a series of related RNAs, the pentamer binds to rCUG repeats with 4.4- to >200-fold specificity. Furthermore, the affinity of binding to rCUG repeats shows incremental gains with increasing valency, while the background binding to genomic DNA is correspondingly reduced. Then, it was determined whether the modularly assembled ligands inhibit the recognition of RNA repeats by Muscleblind-like 1 (MBNL1) protein, the expanded-rCUG binding protein whose sequestration leads to splicing defects in DM1. Among several compounds with nanomolar IC(50) values, the most potent inhibitor is the pentamer, which also inhibits the formation of rCAG repeat-MBNL1 complexes. Comparison of the binding data for the designed synthetic ligands and MBNL1 to repeating RNAs shows that the synthetic ligand is 23-fold higher affinity and more specific to DM1 RNAs than MBNL1. Further studies show that the designed ligands are cell permeable to mouse myoblasts. Thus, cell permeable ligands that bind repetitive RNAs have been designed

  5. Generation of an isogenic, gene-corrected control cell line of the spinocerebellar ataxia type 2 patient-derived iPSC line H266.

    PubMed

    Marthaler, Adele G; Tubsuwan, Alisa; Schmid, Benjamin; Poulsen, Ulla B; Engelbrecht, Alexander F; Mau-Holzmann, Ulrike A; Hyttel, Poul; Nielsen, Troels T; Nielsen, Jørgen E; Holst, Bjørn

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. We have successfully generated bona fide induced pluripotent stem cell (iPSC) lines of SCA2 patients in order to study a disease-specific phenotype. Here, we demonstrate the gene correction of the iPSC line H266 clone 10 where we have exchanged the expanded CAG repeat of the ATXN2 gene with the normal length found in healthy alleles. This gene corrected cell line will provide the ideal control to model SCA2 by iPSC technology.

  6. Generation of an isogenic, gene-corrected control cell line of the spinocerebellar ataxia type 2 patient-derived iPSC line H271.

    PubMed

    Marthaler, Adele G; Schmid, Benjamin; Tubsuwan, Alisa; Poulsen, Ulla B; Engelbrecht, Alexander F; Mau-Holzmann, Ulrike A; Hyttel, Poul; Nielsen, Jørgen E; Nielsen, Troels T; Holst, Bjørn

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. We have successfully generated bona fide induced pluripotent stem cell (iPSC) lines of SCA2 patients in order to study a disease-specific phenotype. Here, we demonstrate the gene correction of the iPSC line H271 clone 1 where we have exchanged the expanded CAG repeat of the ATXN2 gene with the normal length found in healthy alleles. This gene corrected cell line will provide the ideal control to model SCA2 by iPSC technology.

  7. Generation of an isogenic, gene-corrected control cell line of the spinocerebellar ataxia type 2 patient-derived iPSC line H196.

    PubMed

    Marthaler, Adele G; Schmid, Benjamin; Tubsuwan, Alisa; Poulsen, Ulla B; Engelbrecht, Alexander F; Mau-Holzmann, Ulrike A; Hyttel, Poul; Nielsen, Jørgen E; Nielsen, Troels T; Holst, Bjørn

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. We have successfully generated bona fide induced pluripotent stem cell (iPSC) lines of SCA2 patients in order to study a disease-specific phenotype. Here, we demonstrate the gene correction of the iPSC line H196 clone 7 where we have exchanged the expanded CAG repeat of the ATXN2 gene with the normal length found in healthy alleles. This gene corrected cell line will provide the ideal control to model SCA2 by iPSC technology.

  8. Myofascial trigger points in the suboccipital muscles in episodic tension-type headache.

    PubMed

    Fernández-de-Las-Peñas, César; Alonso-Blanco, Cristina; Cuadrado, Maria Luz; Pareja, Juan A

    2006-08-01

    Referred pain evoked by suboccipital muscle trigger points (TrPs) spreads to the side of the head over the occipital and temporal bones and is usually perceived as bilateral headache. This paper describes the presence of referred pain from suboccipital muscle TrPs in subjects with episodic tension-type headache (ETTH) and in healthy controls. Ten patients presenting with ETTH and 10 matched controls without headache were examined by a blinded assessor for the presence of suboccipital muscle TrPs. Diagnostic criteria described by Simons and Gerwin were adapted to diagnose TrPs, i.e. presence of tenderness in the suboccipital region, referred pain evoked by maintained pressure for 10 s, and increased referred pain on muscle contraction. Six ETTH patients (60%) had active TrPs and 4 had latent TrPs (40%). On the other hand, 2 control subjects also had latent TrPs. Differences in the presence of suboccipital muscle TrPs between both groups were significant for active TrPs (P<0.001), but not for latent TrPs. Active TrPs were only present in ETTH patients, although TrP activity was not related to any clinical variable concerning the intensity and the temporal profile of headache. Myofascial TrPs in the suboccipital muscles might contribute to the origin and/or maintenance of headache, but a comprehensive knowledge of the role of these muscles in tension-type headache awaits further research.

  9. Spinocerebellar ataxias types 2 and 3: degeneration of the pre-cerebellar nuclei isolates the three phylogenetically defined regions of the cerebellum.

    PubMed

    Rüb, U; Gierga, K; Brunt, E R; de Vos, R A I; Bauer, M; Schöls, L; Bürk, K; Auburger, G; Bohl, J; Schultz, C; Vuksic, M; Burbach, G J; Braak, H; Deller, T

    2005-11-01

    The pre-cerebellar nuclei act as a gate for the entire neocortical, brainstem and spinal cord afferent input destined for the cerebellum. Since no pathoanatomical studies of these nuclei had yet been performed in spinocerebellar ataxia type 2 (SCA2) or type 3 (SCA3), we carried out a detailed postmortem study of the pre-cerebellar nuclei in six SCA2 and seven SCA3 patients in order to further characterize the extent of brainstem degeneration in these ataxic disorders. By means of unconventionally thick serial sections through the brainstem stained for lipofuscin pigment and Nissl material, we could show that all of the pre-cerebellar nuclei (red, pontine, arcuate, prepositus hypoglossal, superior vestibular, lateral vestibular, medial vestibular, interstitial vestibular, spinal vestibular, vermiform, lateral reticular, external cuneate, subventricular, paramedian reticular, intercalate, interfascicular hypoglossal, and conterminal nuclei, pontobulbar body, reticulotegmental nucleus of the pons, inferior olive, and nucleus of Roller) are among the targets of both of the degenerative processes underlying SCA2 and SCA3. These novel findings are in contrast to the current neuropathological literature, which assumes that only a subset of pre-cerebellar nuclei in SCA2 and SCA3 may undergo neurodegeneration. Widespread damage to the pre-cerebellar nuclei separates all three phylogenetically and functionally defined regions of the cerebellum, impairs their physiological functions and thus explains the occurrence of gait, stance, limb and truncal ataxia, dysarthria, truncal and postural instability with disequilibrium, impairments of the vestibulo-ocular reaction and optokinetic nystagmus, slowed and saccadic smooth pursuits, dysmetrical horizontal saccades, and gaze-evoked nystagmus during SCA2 and SCA3.

  10. Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach

    PubMed Central

    Sinha, Siddharth; Goyal, Sukriti; Somvanshi, Pallavi; Grover, Abhinav

    2017-01-01

    Spinocerebellar ataxia (SCA-2) type-2 is a rare neurological disorder among the nine polyglutamine disorders, mainly caused by polyQ (CAG) trinucleotide repeats expansion within gene coding ataxin-2 protein. The expanded trinucleotide repeats within the ataxin-2 protein sequesters transcriptional cofactors i.e., CREB-binding protein (CBP), Ataxin-2 binding protein 1 (A2BP1) leading to a state of hypo-acetylation and transcriptional repression. Histone de-acetylases inhibitors (HDACi) have been reported to restore transcriptional balance through inhibition of class IIa HDAC's, that leads to an increased acetylation and transcription as demonstrated through in-vivo studies on mouse models of Huntington's. In this study, 61 di-aryl cyclo-propanehydroxamic acid derivatives were used for developing three dimensional (3D) QSAR and pharmacophore models. These models were then employed for screening and selection of anti-ataxia compounds. The chosen QSAR model was observed to be statistically robust with correlation coefficient (r2) value of 0.6774, cross-validated correlation coefficient (q2) of 0.6157 and co-relation coefficient for external test set (pred_r2) of 0.7570. A high F-test value of 77.7093 signified the robustness of the model. Two potential drug leads ZINC 00608101 (SEI) and ZINC 00329110 (ACI) were selected after a coalesce procedure of pharmacophore based screening using the pharmacophore model ADDRR.20 and structural analysis using molecular docking and dynamics simulations. The pharmacophore and the 3D-QSAR model generated were further validated for their screening and prediction ability using the enrichment factor (EF), goodness of hit (GH), and receiver operating characteristics (ROC) curve analysis. The compounds SEI and ACI exhibited a docking score of −10.097 and −9.182 kcal/mol, respectively. An evaluation of binding conformation of ligand-bound protein complexes was performed with MD simulations for a time period of 30 ns along with free

  11. Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach.

    PubMed

    Sinha, Siddharth; Goyal, Sukriti; Somvanshi, Pallavi; Grover, Abhinav

    2016-01-01

    Spinocerebellar ataxia (SCA-2) type-2 is a rare neurological disorder among the nine polyglutamine disorders, mainly caused by polyQ (CAG) trinucleotide repeats expansion within gene coding ataxin-2 protein. The expanded trinucleotide repeats within the ataxin-2 protein sequesters transcriptional cofactors i.e., CREB-binding protein (CBP), Ataxin-2 binding protein 1 (A2BP1) leading to a state of hypo-acetylation and transcriptional repression. Histone de-acetylases inhibitors (HDACi) have been reported to restore transcriptional balance through inhibition of class IIa HDAC's, that leads to an increased acetylation and transcription as demonstrated through in-vivo studies on mouse models of Huntington's. In this study, 61 di-aryl cyclo-propanehydroxamic acid derivatives were used for developing three dimensional (3D) QSAR and pharmacophore models. These models were then employed for screening and selection of anti-ataxia compounds. The chosen QSAR model was observed to be statistically robust with correlation coefficient (r(2)) value of 0.6774, cross-validated correlation coefficient (q(2)) of 0.6157 and co-relation coefficient for external test set (pred_r(2)) of 0.7570. A high F-test value of 77.7093 signified the robustness of the model. Two potential drug leads ZINC 00608101 (SEI) and ZINC 00329110 (ACI) were selected after a coalesce procedure of pharmacophore based screening using the pharmacophore model ADDRR.20 and structural analysis using molecular docking and dynamics simulations. The pharmacophore and the 3D-QSAR model generated were further validated for their screening and prediction ability using the enrichment factor (EF), goodness of hit (GH), and receiver operating characteristics (ROC) curve analysis. The compounds SEI and ACI exhibited a docking score of -10.097 and -9.182 kcal/mol, respectively. An evaluation of binding conformation of ligand-bound protein complexes was performed with MD simulations for a time period of 30 ns along with free

  12. Diagnosis of Ataxia

    MedlinePlus

    ... by postal mail: National Ataxia Foundation 2600 Fernbrook Lane Suite 119 Minneapolis, MN 55447-4752 Phone: (763) ... 2006-2017 NAF • National Ataxia Foundation • 2600 Fernbrook Lane Suite 119 • Minneapolis, MN 55447 • 763.553.0020 ...

  13. Friedreich ataxia: an overview

    PubMed Central

    Delatycki, M.; Williamson, R.; Forrest, S.

    2000-01-01

    Friedreich ataxia, an autosomal recessive neurodegenerative disease, is the most common of the inherited ataxias. The recent discovery of the gene that is mutated in this condition, FRDA, has led to rapid advances in the understanding of the pathogenesis of Friedreich ataxia. About 98% of mutant alleles have an expansion of a GAA trinucleotide repeat in intron 1 of the gene. This leads to reduced levels of the protein, frataxin. There is mounting evidence to suggest that Friedreich ataxia is the result of accumulation of iron in mitochondria leading to excess production of free radicals, which then results in cellular damage and death. Currently there is no known treatment that alters the natural course of the disease. The discovery of the FRDA gene and its possible function has raised hope that rational therapeutic strategies will be developed.


Keywords: Friedreich ataxia; FRDA gene PMID:10633128

  14. Saccadic latency is prolonged in Spinocerebellar Ataxia type 2 and correlates with the frontal-executive dysfunctions.

    PubMed

    Rodríguez-Labrada, Roberto; Velázquez-Pérez, Luis; Seigfried, Carola; Canales-Ochoa, Nalia; Auburger, Georg; Medrano-Montero, Jacqueline; Sánchez-Cruz, Gilberto; Aguilera-Rodríguez, Raúl; Laffita-Mesa, José; Vázquez-Mojena, Yaimeé; Verdecia-Ramirez, Marisleydis; Motta, Maribel; Quevedo-Batista, Yudith

    2011-07-15

    Data on saccadic latency in patients with Spinocerebellar Ataxia 2 (SCA2) are sparse and contradictory. In order to determine whether saccadic latency is definitely prolonged, identify its possible determinants and evaluate it as disease biomarker we assessed the saccadic latency by electronystagmography in 110 SCA2 patients and their paired controls. Mean saccadic latencies were significantly longer in patients when compared to controls for all tested target displacements. Forty-six percent of SCA2 patients had saccadic latencies above the normal range. Reciprobit plots of saccadic latency demonstrated a skewed distribution in the direction of longer latencies for the patients compared to controls. As saccadic latency increased, the velocity and amplitude of saccades significantly decreased in SCA2 subjects but not in controls. Saccadic latency was not influenced by any demographical, clinical or molecular SCA2 variables, but it showed a significant correlation with the performance of the Stroop test, the verbal fluency test and the Wisconsin Card Sorting Test in SCA2 patients. This paper demonstrated that saccadic latency is prolonged in SCA2 patients and it significantly correlates with the performance of frontal-executive functions, thus this parameter could be a useful biomarker to evaluate the efficiency of future therapeutical options on these dysfunctions.

  15. Ataxin-3 protein and RNA toxicity in spinocerebellar ataxia type 3: current insights and emerging therapeutic strategies.

    PubMed

    Evers, Melvin M; Toonen, Lodewijk J A; van Roon-Mom, Willeke M C

    2014-06-01

    Ataxin-3 is a ubiquitously expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription. The C-terminus of the ataxin-3 protein contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the neurodegenerative disease spinocerebellar ataxia 3 (SCA3). In spite of extensive research, the molecular mechanisms underlying the cellular toxicity resulting from mutant ataxin-3 remain elusive and no preventive treatment is currently available. It has become clear over the last decade that the hallmark intracellular ataxin-3 aggregates are likely not the main toxic entity in SCA3. Instead, the soluble PolyQ containing fragments arising from proteolytic cleavage of ataxin-3 by caspases and calpains are now regarded to be of greater influence in pathogenesis. In addition, recent evidence suggests potential involvement of a RNA toxicity component in SCA3 and other PolyQ expansion disorders, increasing the pathogenic complexity. Herein, we review the functioning of ataxin-3 and the involvement of known protein and RNA toxicity mechanisms of mutant ataxin-3 that have been discovered, as well as future opportunities for therapeutic intervention.

  16. Recovering and Preventing Loss of Detailed Memory: Differential Rates of Forgetting for Detail Types in Episodic Memory

    ERIC Educational Resources Information Center

    Sekeres, Melanie J.; Bonasia, Kyra; St-Laurent, Marie; Pishdadian, Sara; Winocur, Gordon; Grady, Cheryl; Moscovitch, Morris

    2016-01-01

    Episodic memories undergo qualitative changes with time, but little is known about how different aspects of memory are affected. Different types of information in a memory, such as perceptual detail, and central themes, may be lost at different rates. In patients with medial temporal lobe damage, memory for perceptual details is severely impaired,…

  17. The Prevalence, Types and Perceived Outcomes of Crisis Episodes in Early Adulthood and Midlife: A Structured Retrospective-Autobiographical Study

    ERIC Educational Resources Information Center

    Robinson, Oliver C.; Wright, Gordon R. T.

    2013-01-01

    The objective of the study was to gain data on the prevalence, types and perceived outcomes of crisis episodes in three age decades of adult life: 20-29, 30-39 and 40-49. A further aim was to explore the relationship between crisis occurrence and empathy. A retrospective-autobiographical survey instrument and an empathy questionnaire were…

  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. 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 ...

  20. National Ataxia Foundation

    MedlinePlus

    ... in San Antonio! 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 ...

  1. Acute cerebellar ataxia

    MedlinePlus

    ... Alcohol, medications, and insecticides Bleeding into the cerebellum Multiple sclerosis Strokes of the cerebellum Vaccination ... swelling (inflammation) of the cerebellum (such as from multiple sclerosis) Cerebellar ataxia caused by a recent viral infection ...

  2. Structural and functional MRI abnormalities of cerebellar cortex and nuclei in SCA3, SCA6 and Friedreich's ataxia.

    PubMed

    Stefanescu, Maria R; Dohnalek, Moritz; Maderwald, Stefan; Thürling, Markus; Minnerop, Martina; Beck, Andreas; Schlamann, Marc; Diedrichsen, Joern; Ladd, Mark E; Timmann, Dagmar

    2015-05-01

    Spinocerebellar ataxia type 3, spinocerebellar ataxia type 6 and Friedreich's ataxia are common hereditary ataxias. Different patterns of atrophy of the cerebellar cortex are well known. Data on cerebellar nuclei are sparse. Whereas cerebellar nuclei have long been thought to be preserved in spinocerebellar ataxia type 6, histology shows marked atrophy of the nuclei in Friedreich's ataxia and spinocerebellar ataxia type 3. In the present study susceptibility weighted imaging was used to assess atrophy of the cerebellar nuclei in patients with spinocerebellar ataxia type 6 (n = 12, age range 41-76 years, five female), Friedreich's ataxia (n = 12, age range 21-55 years, seven female), spinocerebellar ataxia type 3 (n = 10, age range 34-67 years, three female), and age- and gender-matched controls (total n = 23, age range 22-75 years, 10 female). T1-weighted magnetic resonance images were used to calculate the volume of the cerebellum. In addition, ultra-high field functional magnetic resonance imaging was performed with optimized normalization methods to assess function of the cerebellar cortex and nuclei during simple hand movements. As expected, the volume of the cerebellum was markedly reduced in spinocerebellar ataxia type 6, preserved in Friedreich's ataxia, and mildy reduced in spinocerebellar ataxia type 3. The volume of the cerebellar nuclei was reduced in the three patient groups compared to matched controls (P-values < 0.05; two-sample t-tests). Atrophy of the cerebellar nuclei was most pronounced in spinocerebellar ataxia type 6. On a functional level, hand-movement-related cerebellar activation was altered in all three disorders. Within the cerebellar cortex, functional magnetic resonance imaging signal was significantly reduced in spinocerebellar ataxia type 6 and Friedreich's ataxia compared to matched controls (P-values < 0.001, bootstrap-corrected cluster-size threshold; two-sample t-tests). The difference missed significance in spinocerebellar ataxia

  3. Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1

    PubMed Central

    2013-01-01

    Background Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1. Results Symptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells. Conclusions These data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA

  4. 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

  5. The therapeutic mode of action of 4-aminopyridine in cerebellar ataxia

    PubMed Central

    Alviña, Karina; Khodakhah, Kamran

    2010-01-01

    Episodic ataxia type-2 (EA2) is a hereditary cerebellar ataxia associated with mutations in the P/Q-type voltage-gated calcium channels. Therapeutic approaches for treatment of EA2 are very limited. Presently, the potassium channel blocker 4-aminopyridine (4-AP) constitutes the most promising treatment although its mechanism of action is not understood. Here we show that, in contrast to that commonly believed, therapeutic concentrations of 4-AP do not increase the inhibitory drive of cerebellar Purkinje cells. Instead, 4-AP restores the severely diminished precision of pacemaking in Purkinje cells of EA2 mutant mice by prolonging the action potential, and increasing the action potential afterhyperpolarization. Consistent with this mode of action, the therapeutic efficacy of 4-AP was comparable, and not additive, to chlorzoxazone, an activator of calcium-dependent potassium channels that also restores the precision of Purkinje cell pacemaking. The likely target of 4-AP at the concentrations used are the Kv1 family of potassium channels, possibly the Kv1.5 subtype. Because at higher concentrations 4-AP blocks a large array of potassium channels and is a pro-convulsant, use of selective Kv1 channel blockers is likely to be a safer substitute for treatment of cerebellar ataxia. PMID:20505092

  6. Promoter Variation and Expression Levels of Inflammatory Genes IL1A, IL1B, IL6 and TNF in Blood of Spinocerebellar Ataxia Type 3 (SCA3) Patients.

    PubMed

    Raposo, Mafalda; Bettencourt, Conceição; Ramos, Amanda; Kazachkova, Nadiya; Vasconcelos, João; Kay, Teresa; Bruges-Armas, Jácome; Lima, Manuela

    2017-03-01

    Age at onset in spinocerebellar ataxia type 3 (SCA3/MJD) is incompletely explained by the size of the CAG tract at the ATXN3 gene, implying the existence of genetic modifiers. A role of inflammation in SCA3 has been postulated, involving altered cytokines levels; promoter variants leading to alterations in cytokines expression could influence onset. Using blood from 86 SCA3 patients and 106 controls, this work aimed to analyse promoter variation of four cytokines (IL1A, IL1B, IL6 and TNF) and to investigate the association between variants detected and their transcript levels, evaluated by quantitative PCR. Moreover, the effect of APOE isoforms, known to modulate cytokines, was investigated. Correlations between cytokine variants and onset were tested; the cumulative modifier effects of cytokines and APOE were analysed. Patients carrying the IL6*C allele had a significant earlier onset (4 years in average) than patients carrying the G allele, in agreement with lower mRNA levels produced by IL6*C carriers. The presence of APOE*ɛ2 allele seems to anticipate onset in average 10 years in patients carrying the IL6*C allele; a larger number of patients will be needed to confirm this result. These results highlight the pertinence of conducting further research on the role of cytokines as SCA3 modulators, pointing to the presence of shared mechanisms involving IL6 and APOE.

  7. Effect of trehalose on the properties of mutant {gamma}PKC, which causes spinocerebellar ataxia type 14, in neuronal cell lines and cultured Purkinje cells.

    PubMed

    Seki, Takahiro; Abe-Seki, Nana; Kikawada, Takahiro; Takahashi, Hideyuki; Yamamoto, Kazuhiro; Adachi, Naoko; Tanaka, Shigeru; Hide, Izumi; Saito, Naoaki; Sakai, Norio

    2010-10-22

    Several missense mutations in the protein kinase Cγ (γPKC) gene have been found to cause spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that the mutant γPKC found in SCA14 is susceptible to aggregation, which induces apoptotic cell death. The disaccharide trehalose has been reported to inhibit aggregate formation and to alleviate symptoms in cellular and animal models of Huntington disease, Alzheimer disease, and prion disease. Here, we show that trehalose can be incorporated into SH-SY5Y cells and reduces the aggregation of mutant γPKC-GFP, thereby inhibiting apoptotic cell death in SH-SY5Y cells and primary cultured Purkinje cells (PCs). Trehalose acts by directly stabilizing the conformation of mutant γPKC without affecting protein turnover. Trehalose was also found to alleviate the improper development of dendrites in PCs expressing mutant γPKC-GFP without aggregates but not in PCs with aggregates. In PCs without aggregates, trehalose improves the mobility and translocation of mutant γPKC-GFP, probably by inhibiting oligomerization and thereby alleviating the improper development of dendrites. These results suggest that trehalose counteracts various cellular dysfunctions that are triggered by mutant γPKC in both neuronal cell lines and primary cultured PCs by inhibiting oligomerization and aggregation of mutant γPKC.

  8. 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

  9. Gluten-related disorders: gluten ataxia.

    PubMed

    Hadjivassiliou, Marios; Sanders, David D; Aeschlimann, Daniel P

    2015-01-01

    The term gluten-related disorders (GRD) refers to a spectrum of diverse clinical manifestations triggered by the ingestion of gluten in genetically susceptible individuals. They include both intestinal and extraintestinal manifestations. Gluten ataxia (GA) is one of the commonest neurological manifestations of GRD. It was originally defined as otherwise idiopathic sporadic ataxia in the presence of circulating antigliadin antibodies of IgA and/or IgG type. Newer more specific serological markers have been identified but are not as yet readily available. GA has a prevalence of 15% amongst all ataxias and 40% of all idiopathic sporadic ataxias. It usually presents with gait and lower limb ataxia. It is of insidious onset with a mean age at onset of 53 years. Up to 40% of patients have evidence of enteropathy on duodenal biopsy. Gastrointestinal symptoms are seldom prominent and are not a reliable indicator for the presence of enteropathy. Furthermore, the presence of enteropathy does not influence the response to a gluten-free diet. Most patients will stabilise or improve with strict adherence to gluten-free diet depending on the duration of the ataxia prior to the treatment. Up to 60% of patients with GA have evidence of cerebellar atrophy on MR imaging, but all patients have spectroscopic abnormalities primarily affecting the vermis. Recent evidence suggests that patients with newly diagnosed coeliac disease presenting to the gastroenterologists have abnormal MR spectroscopy at presentation associated with clinical evidence of subtle cerebellar dysfunction. The advantage of early diagnosis and treatment (mean age 42 years in patients presenting with gastrointestinal symptoms vs. 53 years in patients presenting with ataxia) may protect the first group from the development and/or progression of neurological dysfunction.

  10. Recovering and preventing loss of detailed memory: differential rates of forgetting for detail types in episodic memory

    PubMed Central

    Bonasia, Kyra; St-Laurent, Marie; Pishdadian, Sara; Winocur, Gordon; Grady, Cheryl; Moscovitch, Morris

    2016-01-01

    Episodic memories undergo qualitative changes with time, but little is known about how different aspects of memory are affected. Different types of information in a memory, such as perceptual detail, and central themes, may be lost at different rates. In patients with medial temporal lobe damage, memory for perceptual details is severely impaired, while memory for central details is relatively spared. Given the sensitivity of memory to loss of details, the present study sought to investigate factors that mediate the forgetting of different types of information from naturalistic episodic memories in young healthy adults. The study investigated (1) time-dependent loss of “central” and “peripheral” details from episodic memories, (2) the effectiveness of cuing with reminders to reinstate memory details, and (3) the role of retrieval in preventing forgetting. Over the course of 7 d, memory for naturalistic events (film clips) underwent a time-dependent loss of peripheral details, while memory for central details (the core or gist of events) showed significantly less loss. Giving brief reminders of the clips just before retrieval reinstated memory for peripheral details, suggesting that loss of details is not always permanent, and may reflect both a storage and retrieval deficit. Furthermore, retrieving a memory shortly after it was encoded prevented loss of both central and peripheral details, thereby promoting retention over time. We consider the implications of these results for behavioral and neurobiological models of retention and forgetting. PMID:26773100

  11. 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 ...

  12. Genetics Home Reference: Friedreich ataxia

    MedlinePlus

    ... Facebook Share on Twitter Your Guide to Understanding Genetic Conditions Search MENU Toggle navigation Home Page Search ... Conditions Genes Chromosomes & mtDNA Resources Help Me Understand Genetics Home Health Conditions Friedreich ataxia Friedreich ataxia Enable ...

  13. Childhood Cerebellar Ataxia

    PubMed Central

    Fogel, Brent L.

    2012-01-01

    Childhood presentations of ataxia, an impairment of balance and coordination caused by damage to or dysfunction of the cerebellum, can often be challenging to diagnose. Presentations tend to be clinically heterogeneous but key considerations may vary based on the child's age at onset, the course of illness, and subtle differences in phenotype. Systematic investigation is recommended for efficient diagnosis. In this review, we outline common etiologies and describe a comprehensive approach to the evaluation of both acquired and genetic cerebellar ataxia in children. PMID:22764177

  14. Reduced brain-derived neurotrophic factor (BDNF) mRNA expression and presence of BDNF-immunoreactive granules in the spinocerebellar ataxia type 6 (SCA6) cerebellum.

    PubMed

    Takahashi, Makoto; Ishikawa, Kinya; Sato, Nozomu; Obayashi, Masato; Niimi, Yusuke; Ishiguro, Taro; Yamada, Mitsunori; Toyoshima, Yasuko; Takahashi, Hitoshi; Kato, Takeo; Takao, Masaki; Murayama, Shigeo; Mori, Osamu; Eishi, Yoshinobu; Mizusawa, Hidehiro

    2012-12-01

    Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant neurodegenerative disorder caused by a small expansion of tri-nucleotide (CAG) repeat encoding polyglutamine (polyQ) in the gene for α(1A) voltage-dependent calcium channel (Ca(v) 2.1). Thus, this disease is one of the nine neurodegenerative disorders called polyQ diseases. The Purkinje cell predominant neuronal loss is the characteristic neuropathology of SCA6, and a 75-kDa carboxy-terminal fragment (CTF) of Ca(v) 2.1 containing polyQ, which remains soluble in normal brains, becomes insoluble in the cytoplasm of SCA6 Purkinje cells. Because the suppression of the brain-derived neurotrophic factor (BDNF) expression is a potentially momentous phenomenon in many other polyQ diseases, we implemented BDNF expression analysis in SCA6 human cerebellum using quantitative RT-PCR for the BDNF mRNA, and by immunohistochemistry for the BDNF protein. We observed significantly reduced BDNF mRNA levels in SCA6 cerebellum (n = 3) compared to controls (n = 6) (Mann-Whitney U-test, P = 0.0201). On immunohistochemistry, BDNF protein was only weakly stained in control cerebellum. On the other hand, we found numerous BDNF-immunoreactive granules in dendrites of SCA6 Purkinje cells. We did not observe similar BDNF-immunoreactive granules in other polyQ diseases, such as Huntington's disease or SCA2. As we often observed that the 1C2-positive Ca(v) 2.1 aggregates existed more proximally than the BDNF-positive granules in the dendrites, we speculated that the BDNF protein trafficking in dendrites may be disturbed by Ca(v) 2.1 aggregates in SCA6 Purkinje cells. We conclude that the SCA6 pathogenic mechanism associates with the BDNF mRNA expression reduction and abnormal localization of BDNF protein.

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

    PubMed

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

    2015-07-01

    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.

  16. 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 ...

  17. Relationship between frequency of hypoglycemic episodes and changes in carotid atherosclerosis in insulin-treated patients with type 2 diabetes mellitus

    PubMed Central

    Mita, Tomoya; Katakami, Naoto; Shiraiwa, Toshihiko; Yoshii, Hidenori; Kuribayashi, Nobuichi; Osonoi, Takeshi; Kaneto, Hideaki; Kosugi, Keisuke; Umayahara, Yutaka; Gosho, Masahiko; Shimomura, Iichiro; Watada, Hirotaka

    2017-01-01

    The effect of hypoglycemia on the progression of atherosclerosis in patients with type 2 diabetes mellitus (T2DM) remains largely unknown. This is a post hoc analysis of a randomized trial to investigate the relationship between hypoglycemic episodes and changes in carotid intima-media thickness (IMT). Among 274 study subjects, 104 patients experienced hypoglycemic episodes. Increases in the mean IMT and left maximum IMT of the common carotid arteries (CCA) were significantly greater in patients with hypoglycemia compared to those without hypoglycemia. Classification of the patients into three groups according to the frequency of hypoglycemic episodes showed that high frequency of hypoglycemic events was associated with increases in mean IMT-CCA, and left max-IMT-CCA and right max-IMT-CCA. In addition, repetitive episodes of hypoglycemia were associated with a reduction in the beneficial effects of sitagliptin on carotid IMT. Our data suggest that frequency of hypoglycemic episodes was associated with changes in carotid atherosclerosis. PMID:28067320

  18. Congenital ataxia, mental retardation, and dyskinesia associated with a novel CACNA1A mutation.

    PubMed

    Blumkin, Lubov; Michelson, Marina; Leshinsky-Silver, Esther; Kivity, Sara; Lev, Dorit; Lerman-Sagie, Tally

    2010-07-01

    The CACNA1A gene encodes the pore forming alpha-1A subunit of neuronal voltage-dependent P/Q-type Ca( 2+) channels. Mutations in this gene result in clinical heterogeneity, and present with either chronic progressive symptoms, paroxysmal events, or both, with clinical overlap among the different phenotypes. The authors describe a seven year-old boy with mental retardation and congenital cerebellar ataxia that developed dyskinesia at the age of a few months, and recurrent episodes of coma following mild head trauma associated with motor and autonomic signs, from the second year of life. An extensive metabolic evaluation, interictal electroencephalography (EEG), and muscle biopsy were normal. Brain magnetic resonance imaging (MRI) during one of these episodes revealed edema of the right hemisphere and cerebellar atrophy. Genetic testing revealed a R1350Q mutation in the CACNA1A gene. This is a novel de novo mutation.Congenital cerebellar ataxia can be a result of CACNA1A mutations, especially when associated with recurrent unexplained coma.

  19. ‘Costa da Morte’ ataxia is spinocerebellar ataxia 36: clinical and genetic characterization

    PubMed Central

    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, Ángel; Silveira, Isabel

    2012-01-01

    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

  20. Frontal lobe ataxia.

    PubMed

    Thompson, Philip D

    2012-01-01

    The precise anatomy and physiology of human walking remains poorly understood. The frontal lobes appear crucial, and, on the basis of clinical observation, contribute to the control of truncal motion, postural responses, and the maintenance of equilibrium and locomotion. The rich repertoire of frontal gait disorders gives some indication of this complexity. Variable combinations of disequilibrium with a wide stance base, increased body sway and falls, loss of control of truncal motion, locomotor disability with gait ignition failure, start hesitation, shuffling, and freezing are encountered in diseases of the frontal lobes. Furthermore, the pattern of gait may change as the frontal disease progresses. The slowness of walking, lack of heel-shin or upper limb ataxia, dysarthria or nystagmus distinguishes the wide stance base from cerebellar gait ataxia. A lively facial expression, normal voluntary movements of the upper limbs, upper motor neuron signs, and the absence of a rest tremor distinguish the hypokinetic elements from Parkinson's disease. Poor truncal mobility, impaired postural responses, and falls after the slightest perturbation eventually make walking impossible even though simple leg movements may still be possible while seated or lying. One or more of these features usually predominates in the initial presentation of a frontal gait syndrome. Accordingly, there is considerable variation in the manner of presentation and evolution of frontal gait disorders. The gait syndrome is accompanied by frontal motor and cognitive changes, which may be subtle or overshadowed by the gait disorder. This complexity of clinical presentation accounts for the plethora of descriptions from "frontal ataxia" to "gait apraxia". As suggested in the original descriptions of frontal ataxia, the spectrum of gait disturbance is likely to be due to damage to frontal cortex and its connections with subcortical structures including the basal ganglia, cerebellum, and the brainstem.

  1. [Therapeutic developments in chronic ataxias].

    PubMed

    Buompadre, María Celeste

    2013-01-01

    Autosomal recessive cerebellar ataxias belong to a broader group of disorders known as inherited ataxias. In most cases onset occurs before the age of 20. These neurological disorders are characterized by degeneration or abnormal development of the cerebellum and spinal cord. Currently, specific treatment is only available for some of the chronic ataxias, more specifically those related to a known metabolic defect, such as abetalipoproteinemia, ataxia with vitamin E deficiency, and cerebrotendinous xanthomatosis. Treatment based on a diet with reduced intake of fat, supplementation of oral vitamins E and A, and the administration of chenodeoxycholic acid could modify the course of the disease. Although for most of autosomal recessive ataxias there is no definitive treatment, iron chelators and antioxidants have been proposed to reduce the mitochondrial iron overload in Friederich's ataxia patients. Corticosteroids have been used to reduce ataxia symptoms in ataxia telangiectasia. Coenzyme Q10 deficiency associated with ataxia may be responsive to Co Q10 or ubidecarenone supplementations. Early treatment of these disorders may be associated with a better drug response.

  2. Talking about Teaching Episodes

    ERIC Educational Resources Information Center

    Nemirovsky, Ricardo; DiMattia, Cara; Ribeiro, Branca; Lara-Meloy, Teresa

    2005-01-01

    This paper examines two types of discourse in which teachers engage when discussing case studies based on classroom episodes, and the ways in which the availability of video data of these episodes may motivate a shift in the mode of discourse used. We interviewed two pairs of secondary school mathematics teachers after they had read a case study…

  3. A 70-year-old male with peripheral neuropathy, ataxia and antigliadin antibodies shows improvement in neuropathy, but not ataxia, after intravenous immunoglobulin and gluten-free diet

    PubMed Central

    Anandacoomaraswamy, Dharshan; Ullal, Jagdeesh; Vinik, Aaron I

    2008-01-01

    This is a case of a 70-year-old man with severe peripheral neuropathy, type 2 diabetes and progressively worsening cerebellar ataxia. He was found to have circulating antigliadin and antireticulin antibodies compatible with celiac disease in the absence of intestinal pathology. The peripheral neuropathy improved with a gluten-free diet, antioxidants and intravenous immunoglobulin, whereas the ataxia did not. This case illustrates the need to test for celiac disease in patients with idiopathic ataxia and peripheral neuropathy and the need for alternative therapies for ataxia. PMID:21197340

  4. A 70-year-old male with peripheral neuropathy, ataxia and antigliadin antibodies shows improvement in neuropathy, but not ataxia, after intravenous immunoglobulin and gluten-free diet.

    PubMed

    Anandacoomaraswamy, Dharshan; Ullal, Jagdeesh; Vinik, Aaron I

    2008-10-01

    This is a case of a 70-year-old man with severe peripheral neuropathy, type 2 diabetes and progressively worsening cerebellar ataxia. He was found to have circulating antigliadin and antireticulin antibodies compatible with celiac disease in the absence of intestinal pathology. The peripheral neuropathy improved with a gluten-free diet, antioxidants and intravenous immunoglobulin, whereas the ataxia did not. This case illustrates the need to test for celiac disease in patients with idiopathic ataxia and peripheral neuropathy and the need for alternative therapies for ataxia.

  5. Hypertrophic cardiomyopathy in Friedreich's ataxia.

    PubMed

    Fayssoil, A; Nardi, O; Orlikowski, D; Annane, D

    2008-07-21

    Friedreich's ataxia is an autosomal recessive disorder characterized by spinocerebellar degeneration. It is caused by a mutation that consists of an unstable expansion of GAA repeats in the first intron of the gene encoding frataxin on chromosome 9 (9q13). We reported a case of hypertrophic cardiomyopathy associated with Friedreich's ataxia in a twenty year old patient.

  6. Leprosy type-I reaction episode mimicking facial cellulitis-the importance of early diagnosis*

    PubMed Central

    Fernandes, Tania Rita Moreno de Oliveira; Brandão, Graziele Áquila de Souza; Souza, Bruno de Castro e

    2015-01-01

    Leprosy is aneasily recognizable disease due to its dermato-neurological manifestations. It must be present in the physician’s diagnostic repertoire, especially for those working in endemic areas. However, leprosy reaction is not always easily recognized by non-dermatologists, becoming one of the major problems in the management of patients with leprosy, as it presents clinical complications characterized by inflammatory process, accompanied by pain, malaise and sometimes the establishment or worsening of the patient’s disabilities. We report the case of a patient with type-1 periorbital reaction admitted to the hospital, diagnosed and treated as facial cellulitis, whose late diagnosis may have contributed to the appearance or worsening of facial neuritis. PMID:26312679

  7. Mutations in the Cacnl1a4 calcium channel gene are associated with seizures, cerebellar degeneration, and ataxia in tottering and leaner mutant mice.

    PubMed

    Doyle, J; Ren, X; Lennon, G; Stubbs, L

    1997-02-01

    Tottering and leaner, two mutations of the mouse tottering locus, have been studied extensively as models for human epilepsy. Here we describe the isolation, mapping, and expression analysis of Cacnl1a4, a gene encoding the alpha subunit of a proposed P-type calcium channel, and also report the physical mapping and expression patterns of the orthologous human gene. DNA sequencing and gene expression data demonstrate that Cacnl1a4 mutations are the primary cause of seizures and ataxia in tottering and leaner mutant mice, and suggest that tottering locus mutations and human diseases, episodic ataxia 2 and familial hemiplegic migraine, represent mutations in mouse and human versions of the same channel-encoding gene.

  8. Chiropractic management of episodic tension-type headache: a survey of clinical specialists

    PubMed Central

    Vernon, Howard; McDermaid, Cameron

    1998-01-01

    Tension-type headache (TTH) is a highly prevalent condition experienced annually by 30-70% of the population. As a chief complaint, it occupies 5-8% of chiropractors’ caseloads, but is probably more prevalent in multiple complaint cases. While numerous clinical descriptions exist in the literature of the management of TTH by chiropractors, and while there is a small body of clinical trials of the treatment of non-migrainous headache by spinal manipulation, there is no systematic survey of the approaches to its treatment by chiropractors. The goals of this study were to determine the test-retest reliability of a questionnaire designed to identify the most commonly used treatments for TTH and to report on any consistent findings as a potential profile of typical practice approach. The respondents consisted of a group of Canadian chiropractic clinical specialists. Respondents were asked to complete a survey which consisted of a comprehensive list of chiropractic treatment procedures including standard manual manipulations and mobilisations, soft tissue therapies, modalities, exercises, behavioral therapies, acupuncture, nutrition and four “systems” techniques. The respondents were asked to rate their frequency of use of these procedures on a 4-point scale ranging from “always” to “never”. The surveys were completed twice within a two day interval. The response rate was 18/25 (72%). Eighty-seven percent (87%) of the items were rated identically on both surveys. All but one of the items achieved a statistically significant reliability coefficient. The highest rated items were “upper cervical manipulations”, “upper cervical soft tissue therapy” and “neck stretching exercises”. The items which received the lowest endorsement were: chiropractic procedures to the dorso-lumbo-pelvic spine, most therapy modalities and the “systems” techniques which were included in the survey. Years in practice appeared to have very little effect on the use of

  9. Attentional Episodes in Visual Perception

    ERIC Educational Resources Information Center

    Wyble, Brad; Potter, Mary C.; Bowman, Howard; Nieuwenstein, Mark

    2011-01-01

    Is one's temporal perception of the world truly as seamless as it appears? This article presents a computationally motivated theory suggesting that visual attention samples information from temporal episodes (episodic simultaneous type/serial token model; Wyble, Bowman, & Nieuwenstein, 2009). Breaks between these episodes are punctuated by periods…

  10. Comparison of three clinical rating scales in Friedreich ataxia (FRDA).

    PubMed

    Bürk, Katrin; Mälzig, Ulrike; Wolf, Stefanie; Heck, Suzette; Dimitriadis, Konstantinos; Schmitz-Hübsch, Tanja; Hering, Sascha; Lindig, Tobias M; Haug, Verena; Timmann, Dagmar; Degen, Ingrid; Kruse, Bernd; Dörr, Jan-Markus; Ratzka, Susanne; Ivo, Anja; Schöls, Ludger; Boesch, Sylvia; Klockgether, Thomas; Klopstock, Thomas; Schulz, Jörg B

    2009-09-15

    To test the validity and reliability of the scale for the assessment and rating of ataxia (SARA) in Friedreich ataxia (FRDA). SARA is limited to eight items and can be performed rapidly. Ninety-six patients with a molecular genetic diagnosis of FRDA were rated using three different clinical scales, the FRDA Rating Scale (FARS), the International Cooperative Ataxia Rating Scale (ICARS), and SARA. Despite considerable discrepancies in scale size and subscale structure, SARA total scores were significantly correlated with ICARS (r = 0.953, P < 0.0001) and FARS (r = 0.938, P < 0.0001) total scores. SARA total scores also correlated with the activities of daily living (ADL, r = 0.929, P < 0.0001). Although originally developed for the use in dominantly inherited ataxias, which are primarily ataxias of the cerebellar type, SARA can also be used successfully to assess afferent ataxia, which is the predominant form in FRDA. Because SARA is characterized by high interrater reliability and practicability, SARA is applicable and well suited forclinical trials of FRDA.

  11. Characteristics of an environmentally monitored prolonged type 2 vaccine derived poliovirus shedding episode that stopped without intervention.

    PubMed

    Hovi, Tapani; Paananen, Anja; Blomqvist, Soile; Savolainen-Kopra, Carita; Al-Hello, Haider; Smura, Teemu; Shimizu, Hiroyuki; Nadova, Katarina; Sobotova, Zdenka; Gavrilin, Eugene; Roivainen, Merja

    2013-01-01

    Vaccine derived poliovirus (VDPV) type 2 strains strongly divergent from the corresponding vaccine strain, Sabin 2, were repeatedly isolated from sewage in Slovakia over a period of 22 months in 2003-2005. Cell cultures of stool specimens from known immune deficient patients and from an identified putative source population of 500 people failed to identify the potential excretor(s) of the virus. The occurrence of VDPV in sewage stopped without any intervention. No paralytic cases were reported in Slovakia during the episode. According to a GenBank search and similarity plotting-analysis, the closest known relative of the first isolate PV2/03/SVK/E783 through all main sections of the genome was the type 2 poliovirus Sabin strain, with nucleotide identities in 5'UTR, P1, P2, P3, and 3'UTR parts of the genome of 88.6, 85.9, 87.3, 88.5, and 94.0 percent, respectively. Phenotypic properties of selected Slovakian aVDPV strains resembled those of VDPV strains isolated from immune deficient individuals with prolonged PV infection (iVDPV), including antigenic changes and moderate neurovirulence in the transgenic mouse model. One hundred and two unique VP1 coding sequences were determined from VDPV strains isolated from 34 sewage specimens. Nucleotide differences from Sabin 2 in the VP1 coding region ranged from 12.5 to 15.6 percent, and reached a maximum of 9.6 percent between the VDPV strains under study. Most of the nucleotide substitutions were synonymous but as many as 93 amino acid positions out of 301 in VP1 showed substitutions. We conclude that (1) individuals with prolonged poliovirus infection are not as rare as suggested by the studies on immune deficient patients known to the health care systems and (2) genetic divergence of VDPV strains may remain extensive during years long replication in humans.

  12. Deep Brain Stimulation for Tremor Associated with Underlying Ataxia Syndromes: A Case Series and Discussion of Issues

    PubMed Central

    Oyama, Genko; Thompson, Amanda; Foote, Kelly D.; Limotai, Natlada; Abd-El-Barr, Muhammad; Maling, Nicholas; Malaty, Irene A.; Rodriguez, Ramon L.; Subramony, Sankarasubramoney H.; Ashizawa, Tetsuo; Okun, Michael S.

    2014-01-01

    Background Deep brain stimulation (DBS) has been utilized to treat various symptoms in patients suffering from movement disorders such as Parkinson's disease, dystonia, and essential tremor. Though ataxia syndromes have not been formally or frequently addressed with DBS, there are patients with ataxia and associated medication refractory tremor or dystonia who may potentially benefit from therapy. Methods A retrospective database review was performed, searching for cases of ataxia where tremor and/or dystonia were addressed by utilizing DBS at the University of Florida Center for Movement Disorders and Neurorestoration between 2008 and 2011. Five patients were found who had DBS implantation to address either medication refractory tremor or dystonia. The patient's underlying diagnoses included spinocerebellar ataxia type 2 (SCA2), fragile X associated tremor ataxia syndrome (FXTAS), a case of idiopathic ataxia (ataxia not otherwise specified [NOS]), spinocerebellar ataxia type 17 (SCA17), and a senataxin mutation (SETX). Results DBS improved medication refractory tremor in the SCA2 and the ataxia NOS patients. The outcome for the FXTAS patient was poor. DBS improved dystonia in the SCA17 and SETX patients, although dystonia did not improve in the lower extremities of the SCA17 patient. All patients reported a transient gait dysfunction postoperatively, and there were no reports of improvement in ataxia-related symptoms. Discussion DBS may be an option to treat tremor, inclusive of dystonic tremor in patients with underlying ataxia; however, gait and other symptoms may possibly be worsened. PMID:25120941

  13. Ataxia-Telangiectasia Children's Project

    MedlinePlus

    ... find a cure Our RESEARCH Focusing innovative scientific strategies Ataxia-telangiectasia a RARE disease striving for BIG results via the A-T Clinical Center at Johns Hopkins and global research initiatives Upcoming Events Swingin' for Emily Golf ...

  14. Autosomal dominant cerebellar ataxia deafness and narcolepsy.

    PubMed

    Melberg, A; Hetta, J; Dahl, N; Nennesmo, I; Bengtsson, M; Wibom, R; Grant, C; Gustavson, K H; Lundberg, P O

    1995-12-01

    A new autosomal dominant syndrome in a Swedish pedigree is described. Five patients were affected with cerebellar ataxia and sensorineural deafness. Four of these patients had symptoms of narcolepsy. Optic atrophy, other neurological abnormalities and psychiatric symptoms developed with increasing disease duration. Three patients had non-neurological disease in addition, including diabetes mellitus in two and hypertrophic cardiomyopathy in one. Autopsy with neuropathological examination was performed in one case. Molecular studies focused on the short arm of chromosome 6, including the HLA DR2 locus associated with narcolepsy and the (CAG)n repeat at the spinocerebellar ataxia type 1 (SCA1) locus. Biochemical investigation of muscle biopsy of one case indicated mitochondrial dysfunction with selective decrease in ATP production for substrates that normally give the highest rates. The activity of glutamate dehydrogenase was reduced, indicating a low mitochondrial density. We postulate an autosomal dominant genetic factor responsible for this syndrome. Linkage was excluded to HLA DR2, and a normal sized SCA1 repeat was observed. We conclude that a locus predisposing to ataxia, deafness and narcolepsy exists outside this region of chromosome 6.

  15. Cardiac transplantation in Friedreich ataxia.

    PubMed

    Yoon, Grace; Soman, Teesta; Wilson, Judith; George, Kristen; Mital, Seema; Dipchand, Anne I; McCabe, Jane; Logan, William; Kantor, Paul

    2012-09-01

    In this article, we describe a 14-year-old boy with a confirmed diagnosis of Friedreich ataxia who underwent cardiac transplantation for left ventricular failure secondary to dilated cardiomyopathy with restrictive physiology. His neurological status prior to transplantation reflected early signs of neurological disease, with evidence of dysarthria, weakness, mild gait impairment, and limb ataxia. We review the ethical issues considered during the process leading to the decision to offer cardiac transplantation.

  16. Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes.

    PubMed

    Tezenas du Montcel, Sophie; Durr, Alexandra; Bauer, Peter; Figueroa, Karla P; Ichikawa, Yaeko; Brussino, Alessandro; Forlani, Sylvie; Rakowicz, Maria; Schöls, Ludger; Mariotti, Caterina; van de Warrenburg, Bart P C; Orsi, Laura; Giunti, Paola; Filla, Alessandro; Szymanski, Sandra; Klockgether, Thomas; Berciano, José; Pandolfo, Massimo; Boesch, Sylvia; Melegh, Bela; Timmann, Dagmar; Mandich, Paola; Camuzat, Agnès; Goto, Jun; Ashizawa, Tetsuo; Cazeneuve, Cécile; Tsuji, Shoji; Pulst, Stefan-M; Brusco, Alfredo; Riess, Olaf; Brice, Alexis; Stevanin, Giovanni

    2014-09-01

    Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.

  17. Infantile onset spinocerebellar ataxia 2 (SCA2): a clinical report with review of previous cases.

    PubMed

    Singh, Ankur; Faruq, Mohammed; Mukerji, Mitali; Dwivedi, Manish Kumar; Pruthi, Sumit; Kapoor, Seema

    2014-01-01

    Autosomal dominant cerebellar ataxia type I is a heterogeneous group of spinocerebellar ataxias with variable neurologic presentations, with age of onset varying from infancy to adulthood. Autosomal dominant cerebellar ataxia type I is composed mainly of 3 prevalent spinocerebellar ataxia types with different pathogenic loci, specifically spinocerebellar ataxia 1 (6p24-p23), spinocerebellar ataxia 2 (12q24.1), and spinocerebellar ataxia 3 (14q32.1). The shared pathogenic mutational event is the expansion of the CAG repeat that results in polyglutamine extended stretches in the encoded proteins. CAG repeat disorders generally show the phenomenon of anticipation, which is more often associated with paternal transmission. In this report, we describe a patient with infantile-onset spinocerebellar ataxia type 2 (~320 CAG repeat) who inherited the disease from his father (47 CAG repeats). We have summarized the clinical, neuroimaging, electroencephalographic (EEG), and molecular data of previous cases and attempt to highlight the most consistent findings. Our intent is to help treating clinicians to suspect this disorder and to offer timely genetic counseling for a currently potentially untreatable disorder.

  18. 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.

  19. Lidocaine injection of pericranial myofascial trigger points in the treatment of frequent episodic tension-type headache

    PubMed Central

    2013-01-01

    Background The present study aimed to evaluate the efficacy of local lidocaine injections into the myofascial trigger points (TPs) located at the pericranial muscles in patients with episodic tension-type headache (ETTH). Methods The study included 108 patients with frequent ETTH that were randomized into 4 groups. One injection of saline (NaCl 0.9%) was administered to group 1 (n = 27), 1 injection of lidocaine (0.5%) was administered to group 2 (n = 27), group 3 (n = 27) received 5 injections of saline (NaCl 0.9%), and group 4 (n = 27) received 5 injections of lidocaine (0.5%); on alternate days 2 mL for each muscle was injected into the frontal, temporal, masseter, sternocleidomastoid, semispinalis capitis, trapezius and splenius capitis muscles bilaterally. The frequency of painful days per month (FPD) and the patients’ visual analogue scales (VAS) were evaluated before treatment, and 2, 4 and 6 months after treatment. Results Mean age of the patients was 36.28 ± 9.41 years (range: 18–54 years). FPD scores improved significantly in group 2, 3 and 4 at 2 months posttreatment compared to pre- treatment (all P < 0.05), and also VAS scores improved significantly in group 2 and 4 at 2 months posttreatment (P < 0.05) but this improvement insisted at the 6 month only in group 4. Group 2 had better VAS and FPD than group 1 only at 2. and 4. months after treatment (for VAS P < 0.0121, P = 0.0232; for FPD P = 0.0003, P = 0.0004, respectively). Group 4 had better scores than group 3 at the 2., 4. and 6. months after treatment in both parameters (all P < 0.05). Group 2 had better scores than group 1 in FPD at the 2. and 4. months posttreatment (P = 0.0003, P = 0.0004, respectively), but not at the 6. month. Conclusion Local lidocaine injections into the myofascial TPs located in the pericranial muscles could be considered as an effective alternative treatment for ETTH. PMID:23698019

  20. A Gain-of-Function Mutation in NALCN in a Child with Intellectual Disability, Ataxia, and Arthrogryposis.

    PubMed

    Aoyagi, Kyota; Rossignol, Elsa; Hamdan, Fadi F; Mulcahy, Ben; Xie, Lin; Nagamatsu, Shinya; Rouleau, Guy A; Zhen, Mei; Michaud, Jacques L

    2015-08-01

    NALCN and its homologues code for the ion channel responsible for half of background Na(+) -leak conductance in vertebrate and invertebrate neurons. Recessive mutations in human NALCN cause intellectual disability (ID) with hypotonia. Here, we report a de novo heterozygous mutation in NALCN affecting a conserved residue (p.R1181Q) in a girl with ID, episodic and persistent ataxia, and arthrogryposis. Interestingly, her episodes of ataxia were abolished by the administration of acetazolamide, similar to the response observed in episodic ataxia associated with other ion channels. Introducing the analogous mutation in the Caenorhabditis elegans homologue nca-1 induced a coiling locomotion phenotype, identical to that obtained with previously characterized C. elegans gain-of-function nca alleles, suggesting that p.R1181Q confers the same property to NALCN. This observation thus suggests that dominant mutations in NALCN can cause a neurodevelopmental phenotype that overlaps with, while being mostly distinct from that associated with recessive mutations in the same gene.

  1. Reduced DNA topoisomerase II activity in ataxia-telangiectasia cells.

    PubMed Central

    Singh, S P; Mohamed, R; Salmond, C; Lavin, M F

    1988-01-01

    Considerable evidence supports a defect at the level of chromatin structure or recognition of that structure in cells from patients with the human genetic disorder ataxia-telangiectasia. Accordingly, we have investigated the activities of enzymes that alter the topology of DNA in Epstein Barr Virus-transformed lymphoblastoid cells from patients with this syndrome. Reduced activity of DNA topoisomerase II, determined by unknotting of P4 phage DNA, was observed in partially purified extracts from 5 ataxia-telangiectasia cell lines. The levels of enzyme activity was reduced substantially in 4 of these cell lines and to a lesser extent in the other cell line compared to controls. DNA topoisomerase I, assayed by relaxation of supercoiled DNA, was found to be present at comparable levels in both cell types. Reduced activity of topoisomerase II in ataxia-telangiectasia is compatible with the molecular, cellular and clinical changes described in this syndrome. Images PMID:2836804

  2. 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…

  3. Migration of objects and inferences across episodes.

    PubMed

    Hannigan, Sharon L; Reinitz, Mark Tippens

    2003-04-01

    Participants viewed episodes in the form of a series of photographs portraying ordinary routines (e.g., eating at a restaurant) and later received a recognition test. In Experiment 1, it was shown that objects (e.g., a vase of flowers, a pewter lantern) that appeared in a single episode during the study phase migrated between memories of episodes described by the same abstract schema (e.g., from Restaurant Episode A at study to Restaurant Episode B at test), and not between episodes anchored by different schemas. In Experiment 2, it was demonstrated that backward causal inferences from one study episode influenced memories of other episodes described by the same schema, and that high-schema-relevant items viewed in one episode were sometimes remembered as having occurred in another episode of the same schematic type.

  4. Paroxysmal ataxia and dysarthria in multiple sclerosis.

    PubMed

    Iorio, R; Capone, F; Plantone, D; Batocchi, A P

    2014-01-01

    Paroxysmal ataxia and dysarthria are part of the spectrum of transient neurological disturbances that can be frequently encountered in multiple sclerosis (MS). Prompt recognition of these symptoms is important because they can be the only manifestation of a MS relapse and symptomatic therapy is often beneficial. We report a patient who developed paroxysmal ataxia and dysarthria, documented by video imaging, while he was recovering from a MS relapse. Treatment with carbamazepine resulted in the complete reversal of the paroxysmal ataxia and dysarthria.

  5. Mirror agnosia and mirror ataxia constitute different parietal lobe disorders.

    PubMed

    Binkofski, F; Buccino, G; Dohle, C; Seitz, R J; Freund, H J

    1999-07-01

    We describe two new clinical syndromes, mirror agnosia and mirror ataxia, both characterized by the deficit of reaching for an object through a mirror in association with a lesion of either parietal lobe. Clinical investigation of 13 patients demonstrated that the impairments affected both sides of the body. In mirror agnosia, the patients always reached toward the virtual object in the mirror and they were not capable of changing their behavior even after presentation of the position of the object in real visual space. In mirror ataxia (resembling optic ataxia) although some patients initially tended to reach for the virtual object in the mirror, they soon learned to guide their arms toward the real object, all of them producing many directional errors. Both patient groups performed poorly on mental rotation, but only the patients with mirror agnosia were impaired in line orientation. Only 1 of the patients suffered from neglect and 3 from apraxia. Magnetic resonance imaging showed that in mirror agnosia the common zone of lesion overlap was scattered around the posterior angular gyrus/superior temporal gyrus and in mirror ataxia around the postcentral sulcus. We propose that both these clinical syndromes may represent different types of dissociation of retinotopic space and body scheme, or likewise, of allocentric and egocentric space normally adjusted in the parietal lobe.

  6. Genetics Home Reference: ataxia with vitamin E deficiency

    MedlinePlus

    ... Conditions ataxia with vitamin E deficiency ataxia with vitamin E deficiency Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Ataxia with vitamin E deficiency is a disorder that impairs the body's ability ...

  7. The inherited ataxias: genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics.

    PubMed

    Hersheson, Joshua; Haworth, Andrea; Houlden, Henry

    2012-09-01

    The inherited cerebellar ataxias are a diverse group of clinically and genetically heterogeneous neurodegenerative disorders. Inheritance patterns of these disorders can be complex with autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance demonstrated by one or more ataxic syndromes. The broad range of mutation types found in inherited ataxia contributes to the complex genetic etiology of these disorders. The majority of inherited ataxias are caused by repeat expansions; however, conventional mutations are important causes of the rarer dominant and recessive ataxias. Advances in sequencing technology have allowed for much broader testing of these rare ataxia genes. This is relevant to the aims of the Human Variome Project, which aims to collate and store gene variation data through mutation databases. Variant data is currently located in a range of public and commercial resources. Few locus-specific databases have been created to catalogue variation in the dominant ataxia genes although there are several databases for some recessive genes. Developing these resources will facilitate a better understanding of the complex genotype-phenotype relationships in these disorders and assist interpretation of gene variants as testing for rarer ataxia genes becomes commonplace.

  8. The scale for the assessment and rating of ataxia correlates with dysarthria assessment in Friedreich's ataxia.

    PubMed

    Eigentler, Andreas; Rhomberg, Johanna; Nachbauer, Wolfgang; Ritzer, Irmgard; Poewe, Werner; Boesch, Sylvia

    2012-03-01

    Dysarthria is an acquired neurogenic sensorimotor speech symptom and an integral part within the clinical spectrum of ataxia syndromes. Ataxia measurements and disability scores generally focus on the assessment of motor functions. Since comprehensive investigations of dysarthria in ataxias are sparse, we assessed dysarthria in ataxia patients using the Frenchay Dysarthria Assessment. The Frenchay Dysarthria Assessment is a ten-item validated test in which eight items focus on the observation of oral structures and speech functions. Fifteen Friedreich's ataxia patients and 15 healthy control individuals were analyzed using clinical and logopedic methodology. All patients underwent neurological assessment applying the Scale for the Assessment and Rating of Ataxia. In Friedreich's ataxia patients, the Frenchay sub-item voice showed to be most affected compared to healthy individuals followed by items such as reflexes, palate, tongue, and intelligibility. Scoring of lips, jaw, and respiration appeared to be mildly affected. Ataxia severity in Friedreich's ataxia patients revealed a significant correlation with the Frenchay dysarthria sum score. The introduction of a binary Adapted Dysarthria Score additionally allowed allocation to distinct dysarthria pattern in ataxias. The Frenchay Dysarthria Assessment proved to be a valid dysarthria measure in Friedreich's ataxia. Its availability in several languages provides a major advantage regarding the applicability in international clinical studies. Shortcomings of the Frenchay test are the multiplicity of items tested and its alphabetic coding. Numerical scoring and condensation of assessments in a modified version may, however, provide an excellent clinical tool for the measurement and scoring of dysarthria in ataxic speech disorders.

  9. Imagining the personal past: Episodic counterfactuals compared to episodic memories and episodic future projections.

    PubMed

    Özbek, Müge; Bohn, Annette; Berntsen, Dorthe

    2017-04-01

    Episodic counterfactuals are imagined events that could have happened, but did not happen, in a person's past. Such imagined past events are important aspects of mental life, affecting emotions, decisions, and behaviors. However, studies examining their phenomenological characteristics and content have been few. Here we introduced a new method to systematically compare self-generated episodic counterfactuals to self-generated episodic memories and future projections with regard to their phenomenological characteristics (e.g., imagery, emotional valence, and rehearsal) and content (e.g., reference to a cultural life script), and how these were affected by temporal distance (1 month, 1 year, 5+ years). The findings showed that the three types of events differed phenomenologically. First, episodic memories were remembered more easily, with more sensory details, and from a dominantly field perspective, as compared to both future projections and episodic counterfactuals. Second, episodic future projections were more positive, more voluntarily rehearsed, and more central to life story and identity than were both episodic memories and episodic counterfactuals. Third, episodic counterfactuals differed from both episodic memories and future projections by neither having the positivity bias of the future events nor the enhanced sensory details of the past events. Across all three event types, sensory details decreased, whereas importance, reference to a cultural life script, and centrality increased with increasing temporal distance. The findings show that imagined events are phenomenologically different from memories of experienced events, consistent with reality-monitoring theory, and that imagined future events are different from both actual and imagined past events, consistent with some theories of motivation.

  10. 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

  11. Genes and genetic testing in hereditary ataxias.

    PubMed

    Sandford, Erin; Burmeister, Margit

    2014-07-22

    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.

  12. A novel mutant mouse, joggle, with inherited ataxia.

    PubMed

    Chen, Ziyan; Hayasaka, Shizu; Takagishi, Yoshiko; Murata, Yoshiharu; Oda, Sen-ichi

    2006-07-01

    While establishing a new mouse strain, we discovered a novel mutant mouse that exhibited ataxia. Mating experiments showed that the mutant phenotype was due to a single autosomal recessive gene, which we have termed joggle (gene symbol: jog). The ataxia becomes apparent around postnatal day 12, when the mice first attempt to walk, and worsens thereafter. The life span of the mutant mouse is comparable to that of the wild-type mouse. After 21 days of age, the cerebellum weights of the jog/jog mice are significantly lower than those of the wild-type mice. These observations indicate that jog/jog mutant mice could be useful models for biomedical research.

  13. 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

  14. The effects of cervical traction, cranial rhythmic impulse, and Mckenzie exercise on headache and cervical muscle stiffness in episodic tension-type headache patients

    PubMed Central

    Choi, Sung-Yong; Choi, Jung-Hyun

    2016-01-01

    [Purpose] The purpose of this study was to examine the effects of cervical traction treatment, cranial rhythmic impulse treatment, a manual therapy, and McKenzie exercise, a dynamic strengthening exercise, on patients who have the neck muscle stiffness of the infrequent episodic tension-type (IETTH) headache and frequent episodic tension-type headache(FETTH), as well as to provide the basic materials for clinical interventions. [Subjects] Twenty-seven subjects (males: 15, females: 12) who were diagnosed with IETTH and FETTH after treatment by a neurologist were divided into three groups: (a cervical traction group (CTG, n=9), a cranial rhythmic contractiongroup (CRIG, n=9), and a McKenzie exercise group (MEG, n=9). An intervention was conducted for each group and the differences in their degrees of neck pain and changes in muscle tone were observed. [Results] In the within-group comparison of each group, headache significantly decreased in CTG. According to the results of the analysis of the muscle tone of the upper trapezius, there was a statistically significant difference in MEG on the right side and in CRIG on the left side. According to the results of the analysis of the muscle tone of the sternocleidomastoid muscle, there was a statistically significant difference in MEG on the right side and in CRIG on the left side. [Conclusion] In the comparison of the splenius capitis muscle between the groups, there was a statistically significant difference on the right side. Hence, compared to the other methods, cervical traction is concluded to be more effective at reducing headaches in IETTH and FETTH patients. PMID:27134368

  15. The effects of cervical traction, cranial rhythmic impulse, and Mckenzie exercise on headache and cervical muscle stiffness in episodic tension-type headache patients.

    PubMed

    Choi, Sung-Yong; Choi, Jung-Hyun

    2016-03-01

    [Purpose] The purpose of this study was to examine the effects of cervical traction treatment, cranial rhythmic impulse treatment, a manual therapy, and McKenzie exercise, a dynamic strengthening exercise, on patients who have the neck muscle stiffness of the infrequent episodic tension-type (IETTH) headache and frequent episodic tension-type headache(FETTH), as well as to provide the basic materials for clinical interventions. [Subjects] Twenty-seven subjects (males: 15, females: 12) who were diagnosed with IETTH and FETTH after treatment by a neurologist were divided into three groups: (a cervical traction group (CTG, n=9), a cranial rhythmic contractiongroup (CRIG, n=9), and a McKenzie exercise group (MEG, n=9). An intervention was conducted for each group and the differences in their degrees of neck pain and changes in muscle tone were observed. [Results] In the within-group comparison of each group, headache significantly decreased in CTG. According to the results of the analysis of the muscle tone of the upper trapezius, there was a statistically significant difference in MEG on the right side and in CRIG on the left side. According to the results of the analysis of the muscle tone of the sternocleidomastoid muscle, there was a statistically significant difference in MEG on the right side and in CRIG on the left side. [Conclusion] In the comparison of the splenius capitis muscle between the groups, there was a statistically significant difference on the right side. Hence, compared to the other methods, cervical traction is concluded to be more effective at reducing headaches in IETTH and FETTH patients.

  16. The Cellular Ataxia Telangiectasia-Mutated Kinase Promotes Epstein-Barr Virus Lytic Reactivation in Response to Multiple Different Types of Lytic Reactivation-Inducing Stimuli

    PubMed Central

    Hagemeier, Stacy R.; Barlow, Elizabeth A.; Meng, Qiao

    2012-01-01

    The Epstein-Barr virus (EBV) latent-to-lytic switch is mediated by the viral proteins BZLF1 (Z), BRLF1 (R), and BRRF1 (Na). Since we previously showed that DNA-damaging agents (including chemotherapy and irradiation) can induce EBV lytic reactivation and recently demonstrated that wild-type p53 contributes to lytic reactivation, we investigated the role of the ATM kinase during EBV reactivation. ATM phosphorylates and activates p53, as well as numerous other substrates involved in the cellular DNA damage response. Using an ATM inhibitor (KU55933), we found that ATM activity is required for efficient induction of EBV lytic gene expression by a variety of different stimuli, including a histone deacetylase (HDAC) inhibitor, the transforming growth factor β (TGF-β) cytokine, a demethylating agent (5-azacytidine), B cell receptor engagement with anti-IgG antibody, hydrogen peroxide, and the proteosome inhibitor bortezomib. In EBV-infected AGS (gastric) cells, knockdown of ATM, or p53, expression inhibits EBV reactivation. Conversely, treatment of these cells with nutlin-3 (which activates p53 and ATM) robustly induces lytic reactivation in a p53- and ATM-dependent manner. The ability of the EBV R and Na proteins to induce lytic reactivation in EBV-infected AGS cells is ATM dependent. However, overexpression of Z induces lytic gene expression in the presence or absence of ATM activity. Our results suggest that ATM enhances Z promoter activity in the context of the intact EBV genome and that p53 contributes to the ATM effect. Nevertheless, since we found that ATM inhibitors also reduce lytic reactivation in Burkitt lymphoma cells that have no p53, additional ATM substrates must also contribute to the ATM effect. PMID:23015717

  17. Clinical and Molecular Characterization of Ataxia with Oculomotor Apraxia Patients In Saudi Arabia

    PubMed Central

    2011-01-01

    Background Autosomal recessive ataxias represent a group of clinically overlapping disorders. These include ataxia with oculomotor apraxia type1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2) and ataxia-telangiectasia-like disease (ATLD). Patients are mainly characterized by cerebellar ataxia and oculomotor apraxia. Although these forms are not quite distinctive phenotypically, different genes have been linked to these disorders. Mutations in the APTX gene were reported in AOA1 patients, mutations in SETX gene were reported in patients with AOA2 and mutations in MRE11 were identified in ATLD patients. In the present study we describe in detail the clinical features and results of genetic analysis of 9 patients from 4 Saudi families with ataxia and oculomotor apraxia. Methods This study was conducted in the period between 2005-2010 to clinically and molecularly characterize patients with AOA phenotype. Comprehensive sequencing of all coding exons of previously reported genes related to this disorder (APTX, SETX and MRE11). Results A novel nonsense truncating mutation c.6859 C > T, R2287X in SETX gene was identified in patients from one family with AOA2. The previously reported missense mutation W210C in MRE11 gene was identified in two families with autosomal recessive ataxia and oculomotor apraxia. Conclusion Mutations in APTX , SETX and MRE11 are common in patients with autosomal recessive ataxia and oculomotor apraxia. The results of the comprehensive screening of these genes in 4 Saudi families identified mutations in SETX and MRE11 genes but failed to identify mutations in APTX gene. PMID:21324166

  18. [Prolonged states of virtual recovery after atypical pubertal schizophrenic episodes with over-valuation disorders of the "metaphysical intoxication" type].

    PubMed

    Bil'zho, A G

    1986-01-01

    Using clinical and follow-up methods of investigation the authors studied a number of patients with juvenile slowly progressive schizophrenia in whom the disease picture in youth was characterized by over-worship disturbances of the "metaphysical intoxication" type which were attended by marked social and occupational disadaptation. A group of patients (n = 25) was identified with a state of practical cure after youth. Three most characteristic patterns of personality changes in these patients were described. The dominant role in their structure was played by manifestations of delay of mental maturation and the syndrome of psychic juvenilism of a dissociated nature. A certain relationship was found between the level and nature of the patients' occupational adaptation and the type of their personality changes. The question is discussed about the determination of the disease stage in such cases. The authors consider them as recovery states with some personality changes which can be ascribed to residual schizophrenia.

  19. Friedreich's ataxia 1979: an overview.

    PubMed

    Barbeau, A

    1979-05-01

    This overview summarizes the investigations carried out during the second part of Phase Two of the Quebec Cooperative Study of Friedreich's Ataxia. These investigations outline in more details the fundamental role played by an abnormality in the fatty acid composition (deficient linoleic acid, 18:2) of the cholesterol esters of high density lipoproteins (HDL) in the phenotypic expression of the disease. They postulate a defective incorporation of linoleic acid to surface phosphatidylcholine of chylomicrons and consequent relative and absolute decreases in lipoprotein protein components because of overpacking with defective cholesteryl esters. Secondarily to these changes, the postulated lack of activation of the lipoamide dehydrogenase (LAD) of the pyruvate dehydrogenase (PDH) complex could result in slow pyruvate oxidation, glucose intolerance, deficient synthesis of acetylcholine, and depletion of glutamic and aspartic acid pools. In parallel, abnormal phosphatidyl-choline molecules could be incorporated to membranes, resulting in specific defects in some functions of these membranes, including transport of calcium and/or taurine and myelinization. The framework of an understanding of Friedreich's ataxia is now available, but much fundamental and clinical work remains to be done to fill in and prove each one of these postulated steps.

  20. Genetics Home Reference: spinocerebellar ataxia type 2

    MedlinePlus

    ... that ataxin-2 may be involved in processing RNA, a chemical cousin of DNA. Ataxin-2 is ... a role in the production of proteins from RNA (translation of DNA's genetic information). The ATXN2 gene ...

  1. Genetics Home Reference: spinocerebellar ataxia type 6

    MedlinePlus

    ... CaV2.1 channels play an essential role in communication between neurons in the brain. The CACNA1A gene ... calcium channels in the cell membrane impairs cell communication between neurons in the brain. Diminished cell communication ...

  2. Spinocerebellar Ataxia Type 10 (SCA10)

    MedlinePlus

    ... responsible for this disease is passed along from generation to generation by family members who carry it. Genetic diseases ... disease, and the gene passes directly from one generation to the next without skipping generations. Each child ...

  3. Spinocerebellar Ataxia Type 5 (SCA5)

    MedlinePlus

    ... is sometimes called “Lincoln’s ataxia” because a 10-generation family with the condition has ancestries that trace ... disease, and the gene passes directly from one generation to the next with out ski ppi ng ...

  4. 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

  5. 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.

  6. Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

    ClinicalTrials.gov

    2016-09-01

    ; Non Progressive Epilepsy and/or Ataxia With Myoclonus as a Major Feature; Spectrin-associated Autosomal Recessive Cerebellar Ataxia; Spasticity-ataxia-gait Anomalies Syndrome; Spastic Ataxia With Congenital Miosis; Spastic Ataxia - Corneal Dystrophy; Spastic Ataxia; Rare Hereditary Ataxia; Rare Ataxia; Recessive Mitochondrial Ataxia Syndrome; Progressive Epilepsy and/or Ataxia With Myoclonus as a Major Feature; Posterior Column Ataxia - Retinitis Pigmentosa; Post-Stroke Ataxia; Post-Head Injury Ataxia; Post Vaccination Ataxia; Polyneuropathy - Hearing Loss - Ataxia - Retinitis Pigmentosa - Cataract; Muscular Atrophy - Ataxia - Retinitis Pigmentosa - Diabetes Mellitus; Non-progressive Cerebellar Ataxia With Intellectual Disability; Non-hereditary Degenerative Ataxia; Paroxysmal Dystonic Choreathetosis With Episodic Ataxia and Spasticity; Olivopontocerebellar Atrophy - Deafness; NARP Syndrome; Myoclonus - Cerebellar Ataxia - Deafness; Multiple System Atrophy, Parkinsonian Type; Multiple System Atrophy, Cerebellar Type; Multiple System Atrophy; Maternally-inherited Leigh Syndrome; Machado-Joseph Disease Type 3; Machado-Joseph Disease Type 2; Machado-Joseph Disease Type 1; Lethal Ataxia With Deafness and Optic Atrophy; Leigh Syndrome; Leukoencephalopathy With Mild Cerebellar Ataxia and White Matter Edema; Leukoencephalopathy - Ataxia - Hypodontia - Hypomyelination; Leigh Syndrome With Nephrotic Syndrome; Leigh Syndrome With Leukodystrophy; Leigh Syndrome With Cardiomyopathy; Late-onset Ataxia With Dementia; Intellectual Disability-hyperkinetic Movement-truncal Ataxia Syndrome; Infection or Post Infection Ataxia; Infantile-onset Autosomal Recessive Nonprogressive Cerebellar Ataxia; Infantile Onset Spinocerebellar Ataxia; GAD Ataxia; Hereditary Episodic Ataxia; Gliadin/Gluten Ataxia; Friedreich Ataxia; Fragile X-associated Tremor/Ataxia Syndrome; Familial Paroxysmal Ataxia; Exposure to Medications Ataxia; Episodic Ataxia With Slurred Speech; Episodic Ataxia Unknown Type

  7. 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

  8. Identification of a novel candidate gene in the iron-sulfur pathway implicated in ataxia-susceptibility: human gene encoding HscB, a J-type co-chaperone.

    PubMed

    Sun, Guifeng; Gargus, J Jay; Ta, Dennis T; Vickery, Larry E

    2003-01-01

    Iron-sulfur proteins participate in a wide range of biochemical processes, including many that are central to mitochondrial electron transfer and energy metabolism. Mutations in two such proteins, frataxin and ABCB7, cause Friedreich ataxia and X-linked sideroblastic anemia with ataxia, respectively, rendering other participants in this pathway functional candidates for hereditary ataxia syndromes. Recently frataxin was shown to have an identical phylogenetic distribution with two genes and was most likely specifically involved in the same sub-process in iron-sulfur cluster assembly as one gene, designated hscB, in bacteria. To set the stage for an analysis of the potential role of this candidate gene in human disease, we defined the human HscB cDNA, its genomic locus, and its pattern of expression in normal human tissues. The isolated human HscB cDNA spans 785 bp and encodes a conserved 235-amino-acid protein, including a putative mitochondrial import leader. The HscB gene is found at chromosome 22q11-12 and is composed of six exons and five introns. Northern blot analyses of RNA from adult and fetal tissues defined a pattern of expression in mitochondria-rich tissues similar to that of frataxin, an expression pattern compatible with its implied role in mitochondrial energetics and related disease phenotypes.

  9. 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.

  10. [Pathophysiology of Ataxia in Fisher Syndrome].

    PubMed

    Kuwabara, Satoshi

    2016-12-01

    Fisher syndrome is regarded as a peculiar inflammatory neuropathy associated with ophthalmoplegia, ataxia, and areflexia. The disorder is associated with preceding infection, cerebrospinal fluid albumino-cytological dissociation, and spontaneous recovery, and regarded as a variant of Guillain-Barré syndrome. The discovery of anti-GQ1b IgG antibodies led to dramatic advances in understanding the pathophysiology of Fisher syndrome. The lesions in Fisher syndrome are determined by expression of ganglioside GQ1b in the human nervous system. This review article focuses on the pathophysiology of ataxia in Fisher syndrome. Current evidence suggests that antibody attack on Group Ia neurons in the dorsal root ganglia is mainly responsible for the sensory ataxia. Involvement of the muscle spindles might also contribute to the development of ataxia.

  11. Genetics Home Reference: ataxia with oculomotor apraxia

    MedlinePlus

    ... high amounts of a protein called alpha-fetoprotein (AFP) in their blood. (An increase in the level ... tissue. The effect of abnormally high levels of AFP or CPK in people with ataxia with oculomotor ...

  12. Neoproterozoic A-type granitoids of the central and southern Appalachians: Intraplate magmatism associated with episodic rifting of the Rodinian supercontinent

    USGS Publications Warehouse

    Tollo, R.P.; Aleinikoff, J.N.; Bartholomew, M.J.; Rankin, D.W.

    2004-01-01

    Emplacement of compositionally distinctive granitic plutons accompanied two pulses (765-680 and 620-550Ma) of crustal extension that affected the Rodinian craton at the present location of the central Appalachians during the Neoproterozoic. The dominantly metaluminous plutons display mineralogical and geochemical characteristics of A-type granites including high FeO t/MgO ratios, high abundances of Nb, Zr, Y, Ta, and REE (except Eu), and low concentrations of Sc, Ba, Sr, and Eu. These dike-like, sheet complexes occur throughout the Blue Ridge province of Virginia and North Carolina, and were emplaced at shallow levels in continental crust during active extension, forming locally multiple-intrusive plutons elongated perpendicular to the axis of extension. New U-Pb zircon ages obtained from the Polly Wright Cove (706??4Ma) and Suck Mountain (680??4Ma) plutons indicate that metaluminous magmas continued to be replenished near the end of the first pulse of rifting. The Suck Mountain body is presently the youngest known igneous body associated with earlier rifting. U-Pb zircon ages for the Pound Ridge Granite Gneiss (562??5Ma) and Yonkers Gneiss (563??2Ma) in the Manhattan prong of southeastern New York constitute the first evidence of plutonic felsic activity associated with the later period of rifting in the U.S. Appalachians, and suggest that similar melt-generation processes were operative during both intervals of crustal extension. Fractionation processes involving primary minerals were responsible for much of the compositional variation within individual plutons. Compositions of mapped lithologic units in a subset of plutons studied in detail define overlapping data arrays, indicating that, throughout the province, similar petrologic processes operated locally on magmas that became successively more chemically evolved. Limited variation in source-sensitive Y/Nb and Yb/Ta ratios is consistent with results of melting experiments and indicates that metaluminous

  13. Progressive decrease in N-acetylaspartate/Creatine ratio in a teenager with type 1 diabetes and repeated episodes of ketoacidosis without clinically apparent cerebral edema: Evidence for permanent brain injury.

    PubMed

    Wootton-Gorges, S L; Buonocore, M H; Caltagirone, R A; Kuppermann, N; Glaser, N S

    2010-04-01

    Recent data suggest that DKA may contribute to cognitive impairment in children with type 1 DM. We measured the NAA/Cr ratio in a teenager during and following 2 separate episodes of DKA without clinically apparent cerebral edema. The NAA/Cr ratio decreased during DKA and improved following recovery. However, the NAA/Cr value was lower after the second episode of DKA (1.76) than after the first (1.97). These findings provide support for the hypothesis that neuronal injury may result from DKA.

  14. Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia

    PubMed Central

    Reilly, James L.; Harris, Margret S. H.; Patel, Shitalben R.; Kittles, Rick; Badner, Judith A.; Prasad, Konasale M.; Nimgaonkar, Vishwajit L.; Keshavan, Matcheri S.; Sweeney, John A.

    2014-01-01

    Rationale Type-3 metabotropic glutamate receptor gene (GRM3) single nucleotide polymorphisms (SNPs) have been associated with cognitive performance and prefrontal cortex brain activity in chronically treated schizophrenia patients. Whether these SNPs are associated with cognitive and symptom response to antipsychotic therapy has not been extensively evaluated. Objectives The aim of the study was to examine pharmacogenetic relationships between GRM3 and selected variants in relevant dopamine genes with changes in spatial working memory and clinical symptoms after treatment. Methods Sixty-one untreated first-episode schizophrenia patients were assessed before and after 6 weeks of antipsychotic pharmacotherapy, primarily consisting of risperidone. Patients’ level of cognitive performance on a spatial working memory task was assessed with a translational oculomotor paradigm. Changes after treatment in cognitive and clinical measures were examined in relationship to genetic polymorphisms in the GRM3, COMT, and DRD2/ANKK1 gene regions. Results Spatial working memory performance worsened after antipsychotic treatment. This worsening was associated with GRM3 rs1468412, with the genetic subgroup of patients known to have altered glutamate activity having greater adverse changes in working memory performance after antipsychotic treatment. Negative symptom improvement was associated with GRM3 rs6465084. There were no pharmacogenetic associations between DRD2/ANKK1 and COMT with working memory changes or symptom response to treatment. Conclusions These findings suggest important pharmacogenetic relationships between GRM3 variants and changes in cognition and symptom response with exposure to antipsychotics. This information may be useful in identifying patients susceptible to adverse cognitive outcomes associated with antipsychotic treatment and suggest that glutamatergic mechanisms contribute to such effects. PMID:25096017

  15. A Single Amino Acid Deletion (ΔF1502) in the S6 Segment of CaV2.1 Domain III Associated with Congenital Ataxia Increases Channel Activity and Promotes Ca2+ Influx

    PubMed Central

    Drechsel, Oliver; Rahman, Rubayte; Marcé-Grau, Anna; Prieto, Marta; Ossowski, Stephan; Macaya, Alfons; Fernández-Fernández, José M.

    2015-01-01

    Mutations in the CACNA1A gene, encoding the pore-forming CaV2.1 (P/Q-type) channel α1A subunit, result in heterogeneous human neurological disorders, including familial and sporadic hemiplegic migraine along with episodic and progressive forms of ataxia. Hemiplegic Migraine (HM) mutations induce gain-of-channel function, mainly by shifting channel activation to lower voltages, whereas ataxia mutations mostly produce loss-of-channel function. However, some HM-linked gain-of-function mutations are also associated to congenital ataxia and/or cerebellar atrophy, including the deletion of a highly conserved phenylalanine located at the S6 pore region of α1A domain III (ΔF1502). Functional studies of ΔF1502 CaV2.1 channels, expressed in Xenopus oocytes, using the non-physiological Ba2+ as the charge carrier have only revealed discrete alterations in channel function of unclear pathophysiological relevance. Here, we report a second case of congenital ataxia linked to the ΔF1502 α1A mutation, detected by whole-exome sequencing, and analyze its functional consequences on CaV2.1 human channels heterologously expressed in mammalian tsA-201 HEK cells, using the physiological permeant ion Ca2+. ΔF1502 strongly decreases the voltage threshold for channel activation (by ~ 21 mV), allowing significantly higher Ca2+ current densities in a range of depolarized voltages with physiological relevance in neurons, even though maximal Ca2+ current density through ΔF1502 CaV2.1 channels is 60% lower than through wild-type channels. ΔF1502 accelerates activation kinetics and slows deactivation kinetics of CaV2.1 within a wide range of voltage depolarization. ΔF1502 also slowed CaV2.1 inactivation kinetic and shifted the inactivation curve to hyperpolarized potentials (by ~ 28 mV). ΔF1502 effects on CaV2.1 activation and deactivation properties seem to be of high physiological relevance. Thus, ΔF1502 strongly promotes Ca2+ influx in response to either single or trains of action

  16. A Single Amino Acid Deletion (ΔF1502) in the S6 Segment of CaV2.1 Domain III Associated with Congenital Ataxia Increases Channel Activity and Promotes Ca2+ Influx.

    PubMed

    Bahamonde, Maria Isabel; Serra, Selma Angèlica; Drechsel, Oliver; Rahman, Rubayte; Marcé-Grau, Anna; Prieto, Marta; Ossowski, Stephan; Macaya, Alfons; Fernández-Fernández, José M

    2015-01-01

    Mutations in the CACNA1A gene, encoding the pore-forming CaV2.1 (P/Q-type) channel α1A subunit, result in heterogeneous human neurological disorders, including familial and sporadic hemiplegic migraine along with episodic and progressive forms of ataxia. Hemiplegic Migraine (HM) mutations induce gain-of-channel function, mainly by shifting channel activation to lower voltages, whereas ataxia mutations mostly produce loss-of-channel function. However, some HM-linked gain-of-function mutations are also associated to congenital ataxia and/or cerebellar atrophy, including the deletion of a highly conserved phenylalanine located at the S6 pore region of α1A domain III (ΔF1502). Functional studies of ΔF1502 CaV2.1 channels, expressed in Xenopus oocytes, using the non-physiological Ba2+ as the charge carrier have only revealed discrete alterations in channel function of unclear pathophysiological relevance. Here, we report a second case of congenital ataxia linked to the ΔF1502 α1A mutation, detected by whole-exome sequencing, and analyze its functional consequences on CaV2.1 human channels heterologously expressed in mammalian tsA-201 HEK cells, using the physiological permeant ion Ca2+. ΔF1502 strongly decreases the voltage threshold for channel activation (by ~ 21 mV), allowing significantly higher Ca2+ current densities in a range of depolarized voltages with physiological relevance in neurons, even though maximal Ca2+ current density through ΔF1502 CaV2.1 channels is 60% lower than through wild-type channels. ΔF1502 accelerates activation kinetics and slows deactivation kinetics of CaV2.1 within a wide range of voltage depolarization. ΔF1502 also slowed CaV2.1 inactivation kinetic and shifted the inactivation curve to hyperpolarized potentials (by ~ 28 mV). ΔF1502 effects on CaV2.1 activation and deactivation properties seem to be of high physiological relevance. Thus, ΔF1502 strongly promotes Ca2+ influx in response to either single or trains of action

  17. Genetics Home Reference: neuropathy, ataxia, and retinitis pigmentosa

    MedlinePlus

    ... Genetics Home Health Conditions NARP neuropathy, ataxia, and retinitis pigmentosa Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Neuropathy, ataxia, and retinitis pigmentosa ( NARP ) is a condition that causes a variety ...

  18. 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.

  19. 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

  20. A case of opsoclonus-myoclonus-ataxia with neuroblastoma.

    PubMed

    Mukherjee, Asha; Mukherjee, Arabinda; Chakrabarty, Suparna

    2004-11-01

    A 2 year old boy presented with features of opsoclonus, myoclonus and ataxia. Routine investigations of blood, urine, x-ray chest, bone scan, EEG and MRI of brain, were normal. Urine for VMA was negative. A right suprarenal mass was detected at MRI of abdomen. The mass was resected completely and was found histologically to be of differentiating type of neuroblastoma. The child was treated initially with prednisolone for 6 weeks along with sodium valproate. He is still on sodium valproate for his neurological symptoms. His symptoms still persist though they have decreased in intensity.

  1. Truncal ataxia from infarction involving the inferior olivary nucleus.

    PubMed

    Park, Jae Hyun; Ryoo, Sookyung; Moon, So Young; Seo, Sand Won; Na, Duk L

    2012-08-01

    Truncal ataxia in medullary infarction may be caused by involvement of the lateral part of the medulla; however, truncal ataxia in infarction involving the inferior olivary nucleus (ION) has received comparatively little attention. We report a patient with truncal ataxia due to medial medullary infarction located in the ION. A lesion in the ION could produce a contralateral truncal ataxia due to increased inhibitory input to the contralesional vestibular nucleus from the contralesional flocculus.

  2. 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

  3. Structural and Functional Magnetic Resonance Imaging of the Cerebellum: Considerations for Assessing Cerebellar Ataxias.

    PubMed

    Deistung, Andreas; Stefanescu, Maria R; Ernst, Thomas M; Schlamann, Marc; Ladd, Mark E; Reichenbach, Jürgen R; Timmann, Dagmar

    2016-02-01

    Magnetic resonance imaging (MRI) of the brain is of high interest for diagnosing and understanding degenerative ataxias. Here, we present state-of-the-art MRI methods to characterize structural alterations of the cerebellum and introduce initial experiments to show abnormalities in the cerebellar nuclei. Clinically, T1-weighted MR images are used to assess atrophy of the cerebellar cortex, the brainstem, and the spinal cord, whereas T2-weighted and PD-weighted images are typically employed to depict potential white matter lesions that may be associated with certain types of ataxias. More recently, attention has also focused on the characterization of the cerebellar nuclei, which are discernible on spatially highly resolved iron-sensitive MR images due to their relatively high iron content, including T2 (*)-weighted images, susceptibility-weighted images (SWI), effective transverse relaxation rate (R2 (*)) maps, and quantitative susceptibility maps (QSM). Among these iron-sensitive techniques, QSM reveals the best contrast between cerebellar nuclei and their surroundings. In particular, the gyrification of the dentate nuclei is prominently depicted, even at the clinically widely available field strength of 3 T. The linear relationship between magnetic susceptibility and local iron content allows for determination of iron deposition in cerebellar nuclei non-invasively. The increased signal-to-noise ratio of ultrahigh-field MRI (B0 ≥ 7 T) and advances in spatial normalization methods enable functional MRI (fMRI) at the level of the cerebellar cortex and cerebellar nuclei. Data from initial fMRI studies are presented in three common forms of hereditary ataxias (Friedreich's ataxia, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6). Characteristic changes in the fMRI signal are discussed in the light of histopathological data and current knowledge of the underlying physiology of the fMRI signal in the cerebellum.

  4. Ataxia with Vitamin E Deficiency in Norway

    PubMed Central

    Elkamil, Areej; Johansen, Krisztina K.; Aasly, Jan

    2015-01-01

    Objective Ataxia with vitamin E deficiency (AVED) is a rare autosomal recessive neurological disorder which usually starts in childhood. The clinical presentation is very similar to Friedreich ataxia, most patients have progressive truncal and extremity ataxia, areflexia, positive Babinski sign, dysarthria and sensory neuropathy. Methods We made an inquiry to our colleagues in Norway, we included information from a prevalence study published southern Norway and added data from our own known case. Results A newly published prevalence study of hereditary ataxias (total of 171 subjects) found only one subject with AVED in Southeast Norway. We describe two more patients, one from the Central part and one from the Northern part of Norway. All 3 cases had age of onset in early childhood (age of 4–5 years) and all experienced gait ataxia and dysarthria. The genetic testing confirmed that they had pathogenic mutations in the α-tocopherol transfer protein gene (TTPA). All were carriers of the non-sense c.400C > T mutation, one was homozygous for that mutation and the others were compound heterozygous, either with c.358G > A or c.513_514insTT. The homozygous carrier was by far the most severely affected case. Conclusions We estimate the occurrence of AVED in Norway to be at least 0.6 per million inhabitants. We emphasize that all patients who develop ataxia in childhood should be routinely tested for AVED to make an early diagnosis for initiating treatment with high dose vitamin E to avoid severe neurological deficits. PMID:25614784

  5. Grenvillian magmatism in the northern Virginia Blue Ridge: Petrologic implications of episodic granitic magma production and the significance of postorogenic A-type charnockite

    USGS Publications Warehouse

    Tollo, R.P.; Aleinikoff, J.N.; Borduas, E.A.; Dickin, A.P.; McNutt, R.H.; Fanning, C.M.

    2006-01-01

    Grenvillian (1.2 to 1.0 Ga) plutonic rocks in northern Virginia preserve evidence of episodic, mostly granitic magmatism that spanned more than 150 million years (m.y.) of crustal reworking. Crystallization ages determined by sensitive high resolution ion microprobe (SHRIMP) U-Pb isotopic analyses of zircon and monazite, combined with results from previous studies, define three periods of magmatic activity at 1183-1144 Ma (Magmatic Interval I), 1120-1111 Ma (Magmatic Interval II), and 1078-1028 Ma (Magmatic Interval III). Magmatic activity produced dominantly tholeiitic plutons composed of (1) low-silica charnockite, (2) leucogranite, (3) non-leucocratic granitoid (with or without orthopyroxene (opx)), and (4) intermediate biotite-rich granitoid. Field, petrologic, geochemical, and geochronologic data indicate that charnockite and non-charnockitic granitoids were closely associated in both space and time, indicating that presence of opx is related to magmatic conditions, not metamorphic grade. Geochemical and Nd isotopic data, combined with results from experimental studies, indicate that leucogranites (Magmatic Intervals I and III) and non-leucocratic granitoids (Magmatic Intervals I and II) were derived from parental magmas produced by either a high degree of partial melting of isotopically evolved tonalitic sources or less advanced partial melting of dominantly tonalitic sources that also included a more mafic component. Post-orogenic, circa 1050 Ma low-silica charnockite is characterized by A-type compositional affinity including high FeOt/(FeOt + MgO), Ga/Al, Zr, Nb, Y, and Zn, and was derived from parental magmas produced by partial melting of potassic mafic sources in the lower crust. Linear geochemical trends defined by leucogranites, low-silica charnockite, and biotite-rich monzogranite emplaced during Magmatic Interval III reflect differences in source-related characteristics; these features do not represent an igneous fractionation sequence. A

  6. ELOVL5 Mutations Cause Spinocerebellar Ataxia 38

    PubMed Central

    Di Gregorio, Eleonora; Borroni, Barbara; Giorgio, Elisa; Lacerenza, Daniela; Ferrero, Marta; Lo Buono, Nicola; Ragusa, Neftj; Mancini, Cecilia; Gaussen, Marion; Calcia, Alessandro; Mitro, Nico; Hoxha, Eriola; Mura, Isabella; Coviello, Domenico A.; Moon, Young-Ah; Tesson, Christelle; Vaula, Giovanna; Couarch, Philippe; Orsi, Laura; Duregon, Eleonora; Papotti, Mauro Giulio; Deleuze, Jean-François; Imbert, Jean; Costanzi, Chiara; Padovani, Alessandro; Giunti, Paola; Maillet-Vioud, Marcel; Durr, Alexandra; Brice, Alexis; Tempia, Filippo; Funaro, Ada; Boccone, Loredana; Caruso, Donatella; Stevanin, Giovanni; Brusco, Alfredo

    2014-01-01

    Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases. PMID:25065913

  7. ELOVL5 mutations cause spinocerebellar ataxia 38.

    PubMed

    Di Gregorio, Eleonora; Borroni, Barbara; Giorgio, Elisa; Lacerenza, Daniela; Ferrero, Marta; Lo Buono, Nicola; Ragusa, Neftj; Mancini, Cecilia; Gaussen, Marion; Calcia, Alessandro; Mitro, Nico; Hoxha, Eriola; Mura, Isabella; Coviello, Domenico A; Moon, Young-Ah; Tesson, Christelle; Vaula, Giovanna; Couarch, Philippe; Orsi, Laura; Duregon, Eleonora; Papotti, Mauro Giulio; Deleuze, Jean-François; Imbert, Jean; Costanzi, Chiara; Padovani, Alessandro; Giunti, Paola; Maillet-Vioud, Marcel; Durr, Alexandra; Brice, Alexis; Tempia, Filippo; Funaro, Ada; Boccone, Loredana; Caruso, Donatella; Stevanin, Giovanni; Brusco, Alfredo

    2014-08-07

    Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases.

  8. Frequently Asked Questions about Friedreich's Ataxia (FRDA)

    MedlinePlus

    ... has partnered with the Coordination of 2600 Fernbrook Lane Suite 119 Rare Diseases at Sanford (CoRDS) national ... CoRDS/CoRD- SRegistryForm/ National Ataxia Foundation 2600 Fernbrook Lane, Suite 119 • Minneapolis, MN 55447-4752 Phone: (763) ...

  9. Acute cerebellar ataxia and infectious mononucleosis.

    PubMed Central

    Wadhwa, N. K.; Ghose, R. R.

    1983-01-01

    A 28-year-old man, who presented with acute cerebellar ataxia, was found to have haematological features of infectious mononucleosis. There was serological evidence of recent infection with Epstein-Barr virus. It is speculated that cerebellar dysfunction results from virus-induced inflammatory changes within the central nervous system. PMID:6312442

  10. Friedreich ataxia: dysarthria profile and clinical data.

    PubMed

    Brendel, Bettina; Ackermann, Hermann; Berg, Daniela; Lindig, Tobias; Schölderle, Theresa; Schöls, Ludger; Synofzik, Matthis; Ziegler, Wolfram

    2013-08-01

    Friedreich ataxia (FRDA) is the most frequent recessive ataxia in the Western world. Dysarthria is a cardinal feature of FRDA, often leading to severe impairments in daily functioning, but its exact characteristics are only poorly understood so far. We performed a comprehensive evaluation of dysarthria severity and the profile of speech motor deficits in 20 patients with a genetic diagnosis of FRDA based on a carefully selected battery of speaking tasks and two widely used paraspeech tasks, i.e., oral diadochokinesis and sustained vowel productions. Perceptual ratings of the speech samples identified respiration, voice quality, voice instability, articulation, and tempo as the most affected speech dimensions. Whereas vocal instability predicted ataxia severity, tempo turned out as a significant correlate of disease duration. Furthermore, articulation predicted the overall intelligibility score as determined by a systematic speech pathology assessment tool. In contrast, neurologists' ratings of intelligibility--a component of the "Scale for the Assessment and Rating of Ataxia"--were found to be related to perceived speech tempo. Obviously, clinicians are more sensitive to slowness of speech than to any other feature of spoken language during dysarthria evaluation. Our results suggest that different components of speech production and trunk/limb motor functions are differentially susceptible to FRDA pathology. Furthermore, evidence emerged that paraspeech tasks do not allow for an adequate scaling of speech deficits in FRDA.

  11. An investigation of objective and subjective types of binge eating episodes in a clinical sample of people with co-morbid obesity

    PubMed Central

    2013-01-01

    Background Objective binge eating episodes (OBEs) refer to binge eating on an unusually large amount of food and are the core symptom in current definitions of bulimia nervosa (BN) and binge eating disorder (BED). Subjective binge eating episodes (SBEs) refer to eating on a small or moderate amount of food (that is perceived as large) and like OBEs are associated with loss of control (LOC). Reaching consensus on what is considered a large amount of food can however be problematic and it remains unclear if the size of a binge is an essential component for defining a binge eating episode. The aim of this study was to compare the eating disorder features and general psychopathology of subjects reporting OBEs with those reporting only SBEs. Methods This is a retrospective secondary analysis of data from 70 obese participants at the recruitment phase of a multicentre trial for BED. Individuals who answered positively to the presence of binge eating and LOC over eating had their binge eating episodes further explored by interview and self-report. Two groups, those who reported current OBEs (with or without SBEs) and those who reported current SBEs only were compared for age, gender, marital status, body mass index (BMI), indicators of LOC over eating, severity of binge-eating and associated psychopathology. Results The majority of participants in both the OBE and SBE groups endorsed the experience of at least four indicators of LOC. There were no significant differences between the groups. Both groups had high levels of binge-eating severity, moderate severity of associated depressive symptoms and frequent psychiatric co-morbidity. Conclusion Treatment seeking participants with obesity who reported SBEs alone were similar to those who reported OBEs in terms of eating disorder features and general psychopathology. These findings suggest that classificatory systems of mental illnesses should consider introducing SBEs as a feature of the diagnostic criteria for binge eating

  12. Immunodeficiency in ataxia telangiectasia is correlated strongly with the presence of two null mutations in the ataxia telangiectasia mutated gene

    PubMed Central

    Staples, E R; McDermott, E M; Reiman, A; Byrd, P J; Ritchie, S; Taylor, A M R; Davies, E G

    2008-01-01

    Immunodeficiency affects over half of all patients with ataxia telangiectasia (A-T) and when present can contribute significantly to morbidity and mortality. A retrospective review of clinical history, immunological findings, ataxia telangiectasia mutated (ATM) enzyme activity and ATM mutation type was conducted on 80 consecutive patients attending the National Clinic for Ataxia Telangiectasia, Nottingham, UK between 1994 and 2006. The aim was to characterize the immunodeficiency in A-T and determine its relationship to the ATM mutations present. Sixty-one patients had mutations resulting in complete loss of ATM kinase activity (group A) and 19 patients had leaky splice or missense mutations resulting in residual kinase activity (group B). There was a significantly higher proportion of patients with recurrent sinopulmonary infections in group A compared with group B (31 of 61 versus four of 19 P = 0·03) and a greater need for prophylactic antibiotics (30 of 61 versus one of 19 P = 0·001). Comparing group A with group B patients, 25 of 46 had undetectable/low immunoglobulin A (IgA) levels compared with none of 19; T cell lymphopenia was found in 28 of 56 compared with one of 18 and B cell lymphopenia in 35 of 55 compared with four of 18 patients (P = 0·00004, 0·001 and 0·003 respectively). Low IgG2 subclass levels and low levels of antibodies to pneumococcal polysaccharide were more common in group A than group B (16 of 27 versus one of 11 P = 0·01; 34/43 versus six of 17 P = 0·002) patients. Ig replacement therapy was required in 10 (12·5%) of the whole cohort, all in group A. In conclusion, A-T patients with no ATM kinase activity had a markedly more severe immunological phenotype than those expressing low levels of ATM activity. PMID:18505428

  13. Nano-Mechanical Characterization of Ataxia Telangiectasia Cells Treated with Dexamethasone.

    PubMed

    Menotta, Michele; Biagiotti, Sara; Bartolini, Giulia; Marzia, Bianchi; Orazi, Sara; Germani, Aldo; Chessa, Luciana; Magnani, Mauro

    2017-03-01

    Ataxia telangiectasia is a rare genetic disease and no therapy is currently available. Glucocorticoid analogues have been shown to improve the neurological symptoms of treated patients. In the present study ataxia telangiectasia and wild type cells were used as a cellular model and treated with dexamethasone. The cells were subsequently investigated for membrane and whole cell mechanical properties by atomic force microscopy. In addition, cytoskeleton protein dynamics and nuclear shapes were assayed by fluorescence microscopy, while western blots were used to assess actin and tubulin content. At the macro level, dexamethasone directly modified the cell shape, Young's modulus and cytoskeleton protein dynamics. At the nano level, the roughness of the cell surface and the local nano-mechanical proprieties were found to be affected by Dexa. Our results show that ataxia telangiectasia and wild type cells are affected by Dexa, although there are dissimilarities in some macro-level and nano-level features between the tested cell lines. The Young's modulus of the cells appears to depend mainly on nuclear shape, with a slight contribution from the tested cytoskeleton proteins. The current study proposes that dexamethasone influences ataxia telangiectasia cell membranes contents, cell components and cell shape.

  14. First Episode Psychosis

    MedlinePlus

    ... About Psychosis Treatment Share Fact Sheet: First Episode Psychosis Download PDF Download ePub Order a free hardcopy En Español Facts About Psychosis The word psychosis is used to describe conditions ...

  15. From Mild Ataxia to Huntington Disease Phenocopy: The Multiple Faces of Spinocerebellar Ataxia 17

    PubMed Central

    Panas, Marios; Paraskevas, George P.; Bougea, Anastasia M.; Karadima, Georgia; Kapaki, Elisabeth

    2014-01-01

    Introduction. Spinocerebellar ataxia 17 (SCA 17) is a rare autosomal dominant cerebellar ataxia (ADCA) caused by a CAG/CAA expansion in the TBP gene, reported from a limited number of countries. It is a very heterogeneous ADCA characterized by ataxia, cognitive decline, psychiatric symptoms, and involuntary movements, with some patients presenting with Huntington disease (HD) phenocopies. The SCA 17 expansion is stable during parent-child transmission and intrafamilial phenotypic homogeneity has been reported. However, significant phenotypic variability within families has also been observed. Report of the Family. We presently report a Greek family with a pathological expansion of 54 repeats at the SCA 17 locus that displayed remarkable phenotypic variability. Among 3 affected members, one presented with HD phenocopy; one with progressive ataxia, dementia, chorea, dystonia, and seizures, and one with mild slowly progressive ataxia with minor cognitive and affective symptoms. Conclusions. This is the first family with SCA 17 identified in Greece and highlights the multiple faces of this rare disorder, even within the same family. PMID:25349749

  16. Acute cerebellar ataxia, acute cerebellitis, and opsoclonus-myoclonus syndrome.

    PubMed

    Desai, Jay; Mitchell, Wendy G

    2012-11-01

    Acute cerebellar ataxia and acute cerebellitis represent a process characterized by parainfectious, postinfectious, or postvaccination cerebellar inflammation. There is considerable overlap between these entities. The mildest cases of acute cerebellar ataxia represent a benign condition that is characterized by acute truncal and gait ataxia, variably with appendicular ataxia, nystagmus, dysarthria, and hypotonia. It occurs mostly in young children, presents abruptly, and recovers over weeks. Neuroimaging is normal. Severe cases of cerebellitis represent the other end of the spectrum, presenting with acute cerebellar signs often overshadowed by alteration of consciousness, focal neurological deficits, raised intracranial pressure, hydrocephalus, and even herniation. Neuroimaging is abnormal and the prognosis is less favorable than in acute cerebellar ataxia. Acute disseminated encephalomyelitis may be confused with acute cerebellitis when the clinical findings are predominantly cerebellar, but lesions on neuroimaging are usually widespread. Paraneoplastic opsoclonus-myoclonus syndrome is often initially misdiagnosed as acute cerebellar ataxia, but has very specific features, course, and etiopathogensis.

  17. Ataxia induced by small amounts of alcohol

    PubMed Central

    Setta, F; Jacquy, J; Hildebrand, J; Manto, M

    1998-01-01

    A patient is described who exhibited cerebellar ataxia after drinking small amounts of alcohol. Intake of 5 g alcohol induced a gaze evoked nystagmus, a scanning speech, a body sway after eye closure, and bilateral postural leg tremor. Kinematic and EMG analysis of fast wrist movements showed normal movements before and marked hypermetria after alcohol intake. Dysmetria was due to abnormal programming of antagonist muscle activity.

 PMID:9728953

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

    PubMed

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

    2010-05-01

    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 (approximately 10-40 s) or long-lag (approximately 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

  19. Clinical variability in ataxia-telangiectasia.

    PubMed

    Lohmann, Ebba; Krüger, Stefanie; Hauser, Ann-Kathrin; Hanagasi, Hasmet; Guven, Gamze; Erginel-Unaltuna, Nihan; Biskup, Saskia; Gasser, Thomas

    2015-07-01

    Ataxia-telangiectasia (A-T) is an autosomal recessive inherited disease characterized by progressive childhood-onset cerebellar ataxia, oculomotor apraxia, choreoathetosis and telangiectasias of the conjunctivae. Further symptoms may be immunodeficiency and frequent infections, and an increased risk of malignancy. As well as this classic manifestation, several other non-classic forms exist, including milder or incomplete A-T phenotypes caused by homozygous or compound heterozygous mutations in the ATM gene. Recently, ATM mutations have been found in 13 Canadian Mennonites with early-onset, isolated, predominantly cervical dystonia, in a French family with generalized dystonia and in an Indian family with dopa-responsive cervical dystonia. In this article, we will describe a Turkish family with three affected sibs. Their phenotypes range from pure cervical dystonia associated with hand tremor to truncal and more generalized dystonic postures. Exome sequencing has revealed the potentially pathogenic compound heterozygous variants p.V2716A and p.G301VfsX19 in the ATM gene. The variants segregated perfectly with the phenotypes within the family. Both mutations detected in ATM have been shown to be pathogenic, and the α-fetoprotein, a marker of ataxia telangiectasia, was found to be increased. This report supports recent literature showing that ATM mutations are not exclusively associated with A-T but may also cause a more, even intra-familial variable phenotype in particular in association with dystonia.

  20. Early onset autosomal dominant spinocerebellar ataxia with miosis: four cases.

    PubMed

    Timby, Niklas; Stattin, Eva-Lena; Kristiansen, Ingela; Eriksson, Urban; Erikson, Anders

    2008-01-01

    Previously, at least 29 different forms of autosomal dominant spinocerebellar ataxias (SCAs) have been described. We describe a family with four members through three generations with autosomal dominant ataxia in combination with miosis and hyperreflexia. This family's ataxia does not match any of the previously described SCAs and is probably a novel form of SCA. To continue with the search for the genetic background of this disease, more cases are needed.

  1. Response of sensitive human ataxia and resistant T-1 cell lines to accelerated heavy ions

    SciTech Connect

    Tobias, C.A.; Blakely, E.A.; Chang, P.Y.; Lommel, L.; Roots, R.

    1983-07-01

    The radiation dose responses of fibroblast from a patient with Ataxia telangiectasis (AT-2SF) and an established line of human T-1 cells were studied. Nearly monoenergetic accelerated neon and argon ions were used at the Berkeley Bevalac with various residual range values. The LET of the particles varied from 30 keV/..mu..m to over 1000 keV/..mu..m. All Ataxia survival curves were exponential functions of the dose. Their radiosensitivity reached peak values at 100 to 200 keV/..mu..m. Human T-1 cells have effective sublethal damage repair as has been evidenced by split dose experiments, and they are much more resistant to low LET than to high LET radiation. The repair-misrepair model has been used to interpret these results. We have obtained mathematical expressions that describe the cross sections and inactivation coefficients for both human cell lines as a function of the LET and the type of particle used. The results suggest either that high-LET particles induce a greater number of radiolesions per track or that heavy-ions at high LET induce lesions that kill cells more effectively and that are different from those produced at low LET. We assume that the lesions induced in T-1 and Ataxia cells are qualitatively similar and that each cell line attempts to repair these lesions. The result in most irradiated Ataxia cells, however, is either lethal misrepair or incomplete repair leading to cell death. 63 references, 10 figures, 1 table.

  2. Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation

    PubMed Central

    Doi, Hiroshi; Ushiyama, Masao; Baba, Takashi; Tani, Katsuko; Shiina, Masaaki; Ogata, Kazuhiro; Miyatake, Satoko; Fukuda-Yuzawa, Yoko; Tsuji, Shoji; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Miyake, Noriko; Saitsu, Hirotomo; Ikeda, Shu-ichi; Tanaka, Fumiaki; Matsumoto, Naomichi; Yoshida, Kunihiro

    2014-01-01

    Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias (ARHSPs) are clinically and genetically heterogeneous neurological disorders. Herein we describe Japanese siblings with a midlife-onset, slowly progressive type of cerebellar ataxia and spastic paraplegia, without intellectual disability. Using whole exome sequencing, we identified a homozygous missense mutation in DDHD2, whose mutations were recently identified as the cause of early-onset ARHSP with intellectual disability. Brain MRI of the patient showed a thin corpus callosum. Cerebral proton magnetic resonance spectroscopy revealed an abnormal lipid peak in the basal ganglia, which has been reported as the hallmark of DDHD2-related ARHSP (SPG 54). The mutation caused a marked reduction of phospholipase A1 activity, supporting that this mutation is the cause of SPG54. Our cases indicate that the possibility of SPG54 should also be considered when patients show a combination of adult-onset spastic ataxia and a thin corpus callosum. Magnetic resonance spectroscopy may be helpful in the differential diagnosis of patients with spastic ataxia phenotype. PMID:25417924

  3. 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

  4. 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 ...

  5. [Episodic paroxysmal hemicrania with seasonal waxing and waning pattern].

    PubMed

    Selekler, Hamit Macit; Temel, Ozden; Kutlu, Ayşe

    2010-01-01

    The chronic form of paroxysmal hemicrania was defined first. Although the episodic form was thought to be inevitably chronic, in time, episodic forms that never reach the chronic phase were identified. The supposed incidence of paroxysmal hemicrania is 1/50.000, and the ratio of the episodic to chronic form is 1:4. A seasonal type of episodic form, which is limited to three cases in the literature, has also been reported. In this article, a case who remained episodic for 40 years with seasonal waxing and waning attack variations is reported.

  6. The neural substrate of predictive motor timing in spinocerebellar ataxia.

    PubMed

    Bares, Martin; Lungu, Ovidiu V; Liu, Tao; Waechter, Tobias; Gomez, Christopher M; Ashe, James

    2011-06-01

    The neural mechanisms involved in motor timing are subcortical, involving mainly cerebellum and basal ganglia. However, the role played by these structures in predictive motor timing is not well understood. Unlike motor timing, which is often tested using rhythm production tasks, predictive motor timing requires visuo-motor coordination in anticipation of a future event, and it is evident in behaviors such as catching a ball or shooting a moving target. We examined the role of the cerebellum and striatum in predictive motor timing in a target interception task in healthy (n = 12) individuals and in subjects (n = 9) with spinocerebellar ataxia types 6 and 8. The performance of the healthy subjects was better than that of the spinocerebellar ataxia. Successful performance in both groups was associated with increased activity in the cerebellum (right dentate nucleus, left uvula (lobule V), and lobule VI), thalamus, and in several cortical areas. The superior performance in the controls was related to activation in thalamus, putamen (lentiform nucleus) and cerebellum (right dentate nucleus and culmen-lobule IV), which were not activated either in the spinocerebellar subjects or within a subgroup of controls who performed poorly. Both the cerebellum and the basal ganglia are necessary for the predictive motor timing. The degeneration of the cerebellum associated with spinocerebellar types 6 and 8 appears to lead to quantitative rather than qualitative deficits in temporal processing. The lack of any areas with greater activity in the spinocerebellar group than in controls suggests that limited functional reorganization occurs in this condition.

  7. Friedreich's ataxia--a case of aberrant transcription termination?

    PubMed

    Butler, Jill Sergesketter; Napierala, Marek

    2015-01-01

    Reduced expression of the mitochondrial protein Frataxin (FXN) is the underlying cause of Friedreich's ataxia. We propose a model of premature termination of FXN transcription induced by pathogenic expanded GAA repeats that links R-loop structures, antisense transcription, and heterochromatin formation as a novel mechanism of transcriptional repression in Friedreich's ataxia.

  8. Acute cerebellar ataxia with human parvovirus B19 infection

    PubMed Central

    Shimizu, Y.; Ueno, T.; Komatsu, H.; Takada, H.; Nunoue, T.

    1999-01-01

    A 2 year old boy developed acute cerebellar ataxia in association with erythema infectiosum. During the disease, genomic DNA and antibodies against human parvovirus B19 were detected in serum but not in cerebrospinal fluid. Parvovirus B19 associated acute cerebellar ataxia might occur due to transient vascular reaction in the cerebellum during infection.

 PMID:10325764

  9. 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…

  10. 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…

  11. Survival and severity in dominant cerebellar ataxias

    PubMed Central

    Monin, Marie-Lorraine; Tezenas du Montcel, Sophie; Marelli, Cecilia; Cazeneuve, Cecile; Charles, Perrine; Tallaksen, Chantal; Forlani, Sylvie; Stevanin, Giovanni; Brice, Alexis; Durr, Alexandra

    2015-01-01

    Inherited spinocerebellar ataxias (SCAs) are known to be genetically and clinically heterogeneous. Whether severity and survival are variable, however, is not known. We, therefore, studied survival and severity in 446 cases and 509 relatives with known mutations. Survival was 68 years [95% CI: 65–70] in 223 patients with polyglutamine expansions versus 80 years [73–84] in 23 with other mutations (P < 0.0001). Disability was also more severe in the former: at age 60, 30% were wheelchair users versus 3% with other SCAs (P < 0.001). This has implications for genetic counseling and the design of therapeutic trials. PMID:25750924

  12. Approach to acute ataxia in childhood: diagnosis and evaluation.

    PubMed

    Sivaswamy, Lalitha

    2014-04-01

    Ataxia refers to motor incoordination that is usually most prominent during movement or when a child is attempting to maintain a sitting posture. The first part of the review focuses on the anatomic localization of ataxia--both within the nervous system and without--using a combination of historical features and physical findings. The remainder of the review discusses etiological considerations that vary depending on the age group under consideration. In infancy, certain specific diseases, such as opsoclonus myoclonus ataxia syndrome, must receive special mention because the underlying disease process may be amenable to surgical intervention. In the toddler- and school-age groups, certain conditions (such as stroke and acute cerebellitis) require immediate recognition and imaging, whereas others (such as post-infectious ataxia and concussion) require close follow-up. Finally, mention must be made of diseases outside of the central nervous system that can present with ataxia, such as Guillain-Barré syndrome.

  13. A missense mutation in PIK3R5 gene in a family with ataxia and oculomotor apraxia.

    PubMed

    Al Tassan, Nada; Khalil, Dania; Shinwari, Jameela; Al Sharif, Latifa; Bavi, Prashant; Abduljaleel, Zainularifeen; Abu Dhaim, Nada; Magrashi, Amna; Bobis, Steve; Ahmed, Hala; Alahmed, Samaher; Bohlega, Saeed

    2012-02-01

    Autosomal recessive ataxias are heterogeneous group of disorders characterized by cerebellar atrophy and peripheral sensorimotor neuropathy. Molecular characterization of this group of disorders identified a number of genes contributing to these overlapping phenotypes. Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive form of ataxia caused by mutations in the SETX gene. We report on a consanguineous family with autosomal recessive inheritance and clinical characteristics of AOA2, and no mutations in the SETX gene. We mapped the AOA locus in this family to chromosome 17p12-p13. Sequencing of all genes in the refined region identified a homozygous missense mutation in PIK3R5 that was absent in 477 normal controls. Our characterization of the PIK3R5 protein and findings suggest that it may play a role in the development of the cerebellum and vermis.

  14. Acute post-infectious cerebellar ataxia due to co-infection of human herpesvirus-6 and adenovirus mimicking myositis.

    PubMed

    Naselli, Aldo; Pala, Giovanna; Cresta, Federico; Finetti, Martina; Biancheri, Roberta; Renna, Salvatore

    2014-11-26

    Acute cerebellar ataxia (ACA) is a relatively common neurological disease in children. Most common types of ACA are acute post-infectious (APCA) and acute disseminated encephalomyelitis (ADEM). Less common but important causes include opsoclonus-myoclonus syndrome (OMS) and acute cerebellitis. Cerebellar neoplasms and acute hydrocephalus are additional causes of paediatric ataxia. APCA is the most common cause of ACA in children, comprising about 30-50% of total cases. This is a report about an immunocompetent 4-yrs-old male affected by APCA, due to co-infection by human herpesvirus-6 (HHV-6) and adenovirus, with symptoms mimicking myositis.

  15. Hemicrania continua evolving from episodic paroxysmal hemicrania.

    PubMed

    Castellanos-Pinedo, F; Zurdo, M; Martínez-Acebes, E

    2006-09-01

    A 45-year-old woman, who had been diagnosed in our unit with episodic paroxysmal hemicrania, was seen 2 years later for ipsilateral hemicrania continua in remitting form. Both types of headache had a complete response to indomethacin and did not occur simultaneously. The patient had a previous history of episodic moderate headaches that met criteria for probable migraine without aura and also had a family history of headache. The clinical course in this case suggests a pathogenic relationship between both types of primary headache.

  16. 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.

  17. Otoneurological Abnormalities in Patients with Friedreich's Ataxia

    PubMed Central

    Zeigelboim, Bianca Simone; Mesti, Juliana Cristina; Fonseca, Vinicius Ribas; Faryniuk, João Henrique; Marques, Jair Mendes; Cardoso, Rafaella Cardosa; Teive, Hélio Afonso Ghizoni

    2016-01-01

    Introduction Friedreich's ataxia is a neurodegenerative disease and progressive by nature. It has autosomal recessive inheritance and early onset in most cases. Nystagmus and hearing loss (in some cases) make up some of the common symptoms seen in this disorder. Objective The objective of this study is to examine vestibular disorders in patients with Friedreich ataxia. Methods We conducted a retrospective cross-sectional study. We evaluated 30 patients with ages ranging from six to 72 years (mean age of 38.6 ( ±  14.7). The patients underwent the following procedures: anamnesis, ENT, and vestibular evaluations. Results Clinically, the patients commonly had symptoms of incoordination of movement (66.7%), gait disturbances (56.7%), and dizziness (50%). In vestibular testing, alterations were predominantly evident under caloric testing (73.4%), gaze nystagmus testing (50.1%), rotational chair testing (36.7%), and optokinetic nystagmus testing (33.4%). The presence of alterations occurred under examination in 90% of subjects, with the majority occurring in those with central vestibular dysfunction (70% of the examinations). Conclusion The most evident neurotological symptoms were incoordination of movement, gait disturbances, and dizziness. Alterations in vestibular examinations occurred in 90% of patients, mostly in the caloric test, with a predominance of deficient central vestibular system dysfunction. PMID:28050212

  18. Episodes, events, and models

    PubMed Central

    Khemlani, Sangeet S.; Harrison, Anthony M.; Trafton, J. Gregory

    2015-01-01

    We describe a novel computational theory of how individuals segment perceptual information into representations of events. The theory is inspired by recent findings in the cognitive science and cognitive neuroscience of event segmentation. In line with recent theories, it holds that online event segmentation is automatic, and that event segmentation yields mental simulations of events. But it posits two novel principles as well: first, discrete episodic markers track perceptual and conceptual changes, and can be retrieved to construct event models. Second, the process of retrieving and reconstructing those episodic markers is constrained and prioritized. We describe a computational implementation of the theory, as well as a robotic extension of the theory that demonstrates the processes of online event segmentation and event model construction. The theory is the first unified computational account of event segmentation and temporal inference. We conclude by demonstrating now neuroimaging data can constrain and inspire the construction of process-level theories of human reasoning. PMID:26578934

  19. Perspectives on Episodic-Like and Episodic Memory

    PubMed Central

    Pause, Bettina M.; Zlomuzica, Armin; Kinugawa, Kiyoka; Mariani, Jean; Pietrowsky, Reinhard; Dere, Ekrem

    2013-01-01

    Episodic memory refers to the conscious recollection of a personal experience that contains information on what has happened and also where and when it happened. Recollection from episodic memory also implies a kind of first-person subjectivity that has been termed autonoetic consciousness. Episodic memory is extremely sensitive to cerebral aging and neurodegenerative diseases. In Alzheimer’s disease deficits in episodic memory function are among the first cognitive symptoms observed. Furthermore, impaired episodic memory function is also observed in a variety of other neuropsychiatric diseases including dissociative disorders, schizophrenia, and Parkinson disease. Unfortunately, it is quite difficult to induce and measure episodic memories in the laboratory and it is even more difficult to measure it in clinical populations. Presently, the tests used to assess episodic memory function do not comply with even down-sized definitions of episodic-like memory as a memory for what happened, where, and when. They also require sophisticated verbal competences and are difficult to apply to patient populations. In this review, we will summarize the progress made in defining behavioral criteria of episodic-like memory in animals (and humans) as well as the perspectives in developing novel tests of human episodic memory which can also account for phenomenological aspects of episodic memory such as autonoetic awareness. We will also define basic behavioral, procedural, and phenomenological criteria which might be helpful for the development of a valid and reliable clinical test of human episodic memory. PMID:23616754

  20. The Role of Episodic and Semantic Memory in Episodic Foresight

    ERIC Educational Resources Information Center

    Martin-Ordas, Gema; Atance, Cristina M.; Louw, Alyssa

    2012-01-01

    In this paper we describe a special form of future thinking, termed "episodic foresight" and its relation with episodic and semantic memory. We outline the methodologies that have largely been developed in the last five years to assess this capacity in young children and non-human animals. Drawing on Tulving's definition of episodic and semantic…

  1. Concealed semantic and episodic autobiographical memory electrified

    PubMed Central

    Ganis, Giorgio; Schendan, Haline E.

    2013-01-01

    Electrophysiology-based concealed information tests (CIT) try to determine whether somebody possesses concealed information about a crime-related item (probe) by comparing event-related potentials (ERPs) between this item and comparison items (irrelevants). Although the broader field is sometimes referred to as “memory detection,” little attention has been paid to the precise type of underlying memory involved. This study begins addressing this issue by examining the key distinction between semantic and episodic memory in the autobiographical domain within a CIT paradigm. This study also addresses the issue of whether multiple repetitions of the items over the course of the session habituate the brain responses. Participants were tested in a 3-stimulus CIT with semantic autobiographical probes (their own date of birth) and episodic autobiographical probes (a secret date learned just before the study). Results dissociated these two memory conditions on several ERP components. Semantic probes elicited a smaller frontal N2 than episodic probes, consistent with the idea that the frontal N2 decreases with greater pre-existing knowledge about the item. Likewise, semantic probes elicited a smaller central N400 than episodic probes. Semantic probes also elicited a larger P3b than episodic probes because of their richer meaning. In contrast, episodic probes elicited a larger late positive complex (LPC) than semantic probes, because of the recent episodic memory associated with them. All these ERPs showed a difference between probes and irrelevants in both memory conditions, except for the N400, which showed a difference only in the semantic condition. Finally, although repetition affected the ERPs, it did not reduce the difference between probes and irrelevants. These findings show that the type of memory associated with a probe has both theoretical and practical importance for CIT research. PMID:23355816

  2. Evaluation of the child with acute ataxia: a systematic review.

    PubMed

    Whelan, Harry T; Verma, Sumit; Guo, Yan; Thabet, Farouq; Bozarth, Xiuhua; Nwosu, Michelle; Katyayan, Akshat; Parachuri, Venu; Spangler, Katie; Ruggeri, Barbara E; Srivatsal, Sindhu; Zhang, Guojun; Ashwal, Stephen

    2013-07-01

    Evaluation of acute ataxia in a child poses a dilemma for the clinician in determining the extent and timing of initial screening tests. This article reviews the evidence concerning the diagnostic yield of commonly ordered tests in evaluating the child with acute ataxia. The literature revealed the following frequencies of laboratory screening abnormalities in children with acute ataxia: CT (∼2.5%), MRI (∼5%), lumbar puncture (43%), EEG (42%), and toxicology (49%). In most studies, abnormalities detected by these screening tests were nondiagnostic. There are insufficient data to assess yields of testing for autoimmune disorders or inborn errors of metabolism. A toxicology screen should be considered in all children presenting with acute ataxia. Neuroimaging should be considered in all children with new onset ataxia. Cerebrospinal fluid analysis has limited diagnostic specificity unless clinically indicated. Studies to examine neurophysiology testing did have sufficient evidence to support their use. There is insufficient evidence to establish a role for autoantibody testing or for routine screening for inborn error of metabolism in children presenting with acute ataxia. Finally, in a child presenting with ataxia and opsoclonus myoclonus, urine catecholamine testing for occult neuroblastoma is recommended. Nuclear scan may be considered, however, there is insufficient evidence for additional body imaging.

  3. Opsoclonus-myoclonus-ataxia syndrome in an AIDS patient.

    PubMed

    Vale, Thiago Cardoso; Silva, Rodrigo Alencar E; Cunningham, Mauro César Quintão E Silva; Maia, Débora Palma; Camargos, Sarah Teixeira; Cardoso, Francisco

    2013-12-01

    We report the case of a 38-year-old woman with AIDS who developed opsoclonus-myoclonus-ataxia syndrome during a period different from other cases reported in literature. Opsoclonus-myoclonus-ataxia syndrome had already been reported as the initial neurological presentation of AIDS, as well as at the time of HIV-seroconversion and immune reconstitution syndrome. Our case is unique since the patient had an elevated CD4 count and negative viral load in the period when the opsoclonus-myoclonus-ataxia syndrome occurred.

  4. Ataxia with vitamin E deficiency associated with deafness.

    PubMed

    Kara, Bülent; Uzümcü, Abdullah; Uyguner, Oya; Rosti, Rasim Ozgür; Koçbaş, Ayça; Ozmen, Meral; Kayserili, Hülya

    2008-01-01

    Ataxia with vitamin E deficiency (AVED) is a rare autosomal recessive disorder, usually with a phenotype resembling Friedreich ataxia, caused by selective impairment of gastrointestinal vitamin E absorption. Vitamin E supplementation improves symptoms and prevents disease progress. In North Africa and Southern Europe, AVED is as common as Friedreich ataxia. There are no reported cases from Turkey. We herein report a 16-year-old Turkish girl with AVED, who was found to have total deletion of the TTPA gene as well as sensorineural deafness, and we present her follow-up data after vitamin E therapy.

  5. 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?

  6. Recurrent Episodes of Dissociative Fugue

    PubMed Central

    Angothu, Hareesh; Pabbathi, Lokeswar Reddy

    2016-01-01

    Dissociative fugue is rare entity to encounter with possible differentials of epilepsy and malingering. It is one of the dissociative disorders rarely seen in clinical practice more often because of the short lasting nature of this condition. This might also be because of organized travel of the individuals during the episodes and return to their families after the recovery from episodes. This is a case description of a patient who has experienced total three episodes of dissociative fugue. The patient has presented during the third episode and two prior episodes were diagnosed as fugue episodes retrospectively based on the history. Planned travel in this case by the patient to a distant location was prevented because of early diagnosis and constant vigilance till the recovery. As in this case, it may be more likely that persons with Dissociative fugue may develop similar episodes if they encounter exceptional perceived stress. However, such conclusions may require follow-up studies. PMID:27114633

  7. An Episodic Reddening of Triton

    NASA Astrophysics Data System (ADS)

    Pascu, D.; Rohde, J. R.; Seidelmann, P. K.; Wells, E. N.; Hershey, J. L.; Zellner, B. H.; Storrs, A. D.; Currie, D. G.; Bosh, A. S.

    1999-09-01

    In July of 1997 we obtained 39 HST images of Neptune and satellites in the BVI filters for photometric, as well as astrometric and dynamical studies. Our preliminary photometric reductions (Pascu et al. BAAS 30 1101, 1998) indicated leading/trailing brightness asymmetries for both Triton and Proteus, as well as a large color difference between the two moons. The color difference, in (B-V) and (V-I), implied an unusually blue color for Proteus, or a red color for Triton. However, HST/NICMOS observations indicate that Proteus is a red object (B.A. Smith 1998, Pers. Comm.), and Buratti et al. (BAAS 30 1107, 1998) report a reddening in Triton's spectrum in observations made in October, 1997. We have reanalyzed our observations, with results in substantial agreement with our earlier determinations. We are now left with the conclusion that we have observed an "episodic" reddening of Triton, of the type described by Buratti et al. (Icarus 110, 1994).

  8. [Progression from episodic migraine to chronic migraine].

    PubMed

    Yamane, Kiyomi

    2014-01-01

    Migraine is, essentially, an episodic disease. However, characteristics of headache of some episodic migraine change like as tension-type headache and number of headache days also increased, as a result, develop into chronic migraine.However, it is difficult to distinguish chronic migraine and medication oversuse headache. For this reason, and because of the general rule, The international Classification of Headache Disorders, 3rd edition, beta version (ICHD- 3beta) defined the patients meeting criteria for chronic migraine and for medication overuse headache should be given both diagnoses. The pathophysiology of transformation from episodic to chronic migraine is still unknown. Epidemiological study revealed several risk factors such as medication overusue, frequency of headache, obesity, low education, low income, snoring, depression, neck/head trauma and so on. It is important to control these risk factors for migraine chronification.

  9. Neurobehavioral deficits in the KIKO mouse model of Friedreich's ataxia.

    PubMed

    McMackin, Marissa Z; Henderson, Chelsea K; Cortopassi, Gino A

    2017-01-01

    Friedreich's Ataxia (FA) is a pediatric neurodegenerative disease whose clinical presentation includes ataxia, muscle weakness, and peripheral sensory neuropathy. The KIKO mouse is an animal model of FA with frataxin deficiency first described in 2002, but neurobehavioral deficits have never been described in this model. The identification of robust neurobehavioral deficits in KIKO mice could support the testing of drugs for FA, which currently has no approved therapy. We tested 13 neurobehavioral tasks to identify a robust KIKO phenotype: Open Field, Grip Strength Test(s), Cylinder, Skilled Forelimb Grasp Task(s), Treadmill Endurance, Locotronic Motor Coordination, Inverted Screen, Treadscan, and Von Frey. Of these, Inverted Screen, Treadscan and Von Frey produced significant neurobehavioral deficits at >8 months of age, and relate to the clinically relevant endpoints of muscle strength and endurance, gait ataxia, and peripheral insensitivity. Thus we identify robust phenotypic measures related to Friedreich's ataxia clinical endpoints which could be used to test effectiveness of potential drug therapy.

  10. Past, Present and Future Therapeutics for Cerebellar Ataxias

    PubMed Central

    Marmolino, D; Manto, M

    2010-01-01

    Cerebellar ataxias are a group of disabling neurological disorders. Patients exhibit a cerebellar syndrome and can also present with extra-cerebellar deficits, namely pigmentary retinopathy, extrapyramidal movement disorders, pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms), and peripheral neuropathy. Recently, deficits in cognitive operations have been unraveled. Cerebellar ataxias are heterogeneous both at the phenotypic and genotypic point of view. Therapeutical trials performed during these last 4 decades have failed in most cases, in particular because drugs were not targeting a deleterious pathway, but were given to counteract putative defects in neurotransmission. The identification of the causative mutations of many hereditary ataxias, the development of relevant animal models and the recent identifications of the molecular mechanisms underlying ataxias are impacting on the development of new drugs. We provide an overview of the pharmacological treatments currently used in the clinical practice and we discuss the drugs under development. PMID:20808545

  11. High-dose thiamine improves the symptoms of Friedreich's ataxia.

    PubMed

    Costantini, Antonio; Giorgi, Rafaela; D'Agostino, Sonia; Pala, Maria Immacolata

    2013-05-22

    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.

  12. Comprehensive study of early features in spinocerebellar ataxia 2: delineating the prodromal stage of the disease.

    PubMed

    Velázquez-Pérez, Luis; Rodríguez-Labrada, Roberto; Cruz-Rivas, Edilia M; Fernández-Ruiz, Juan; Vaca-Palomares, Israel; Lilia-Campins, Jandy; Cisneros, Bulmaro; Peña-Acosta, Arnoy; Vázquez-Mojena, Yaimeé; Diaz, Rosalinda; Magaña-Aguirre, Jonathan J; Cruz-Mariño, Tania; Estupiñán-Rodríguez, Annelié; Laffita-Mesa, José M; González-Piña, Rigoberto; Canales-Ochoa, Nalia; González-Zaldivar, Yanetza

    2014-10-01

    The prodromal phase of spinocerebellar ataxias (SCAs) has not been systematically studied. Main findings come from a homogeneous SCA type 2 (SCA2) population living in Cuba. The aim of this study was to characterize extensively the prodromal phase of SCA2 by several approaches. Thirty-seven non-ataxic SCA2 mutation carriers and its age- and sex-matched controls underwent clinical assessments, including standardized neurological exam, structured interviews and clinical scales, and looking for somatic and autonomic features, as well as a neuropsychological battery, antisaccadic recordings, and MRI scans. Main clinical somatic features of non-ataxic mutation carriers were cramps, sensory symptoms, sleep disorders, and hyperreflexia, whereas predominating autonomic symptoms were pollakiuria/nocturia, constipation, and frequent throat clearing. Cognitive impairments included early deficits of executive functions and visual memory, suggesting the involvement of cerebro-cerebellar-cerebral loops and/or reduced cholinergic basal forebrain input to the cortex. Antisaccadic task revealed impaired oculomotor inhibitory control but preserved ability for error correction. Cognitive and antisaccadic deficits were higher as carriers were closer to the estimated onset of ataxia, whereas higher Scale for the Assessment and Rating of Ataxia (SARA) scores were associated most notably to vermis atrophy. The recognition of early features of SCA2 offers novel insights into the prodromal phase and physiopathological base of the disease, allowing the assessment of its progression and the efficacy of treatments, in particular at early phases when therapeutical options should be most effective.

  13. Quantitative evaluation protocol for upper limb motor coordination analysis in patients with ataxia.

    PubMed

    Marini, F; Chwastek, C; Romei, M; Cavalleri, M; Bonato, S; Reni, G

    2010-01-01

    Objective and quantitative measurement is crucial in the definition of functional impairment and in the tracking of disease progress over time of patients affected by progressive pathologies, such as ataxia. A new experimental procedure for the quantitative description of upper limb movement and coordination analysis was developed by the integration of an optoelectronic system and dedicated electronic board with four visual and pressure stimuli. 20 passive retroreflective markers were placed on the subject's body and two types pointing tests were defined: in the first one, the subjects were asked to reach with the index finger five consecutive times each of the three targets ("repetitive test"), and in the second one, the subjects were asked to randomly reach the targets with the index finger ("random test"). The preliminary results showed that patients affected by ataxia took more time with a less smooth finger tip movement to perform the reaching tests when compared to healthy subjects. The velocity was lower and its profile was more irregular in ataxic subjects. The new developed experimental procedure seems to be very promising in the quantitative description of upper limb movements of pathological and healthy subjects and it seems to be able to distinguish the impairments due to different levels of ataxia.

  14. 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.

  15. 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.

  16. Lower Blood Glucose and Variability Are Associated with Earlier Recovery from Renal Injury Caused by Episodic Urinary Tract Infection in Advanced Type 2 Diabetic Chronic Kidney Disease

    PubMed Central

    Chiu, Ping-Fang; Wu, Chia-Lin; Huang, Ching-Hui; Liou, Hung-Hsiang; Chang, Chirn-Bin

    2014-01-01

    Purpose In our previous study, type 2 diabetic chronic kidney disease (CKD) patients with glomerular filtration rates of <30 mL/min upon hospitalization for urinary tract infection (UTI) were at a risk for acute kidney injury. This study aimed to clarify the effect of glucose and its variability on renal outcomes during admission for the treatment of UTI. Materials and Methods Based on the date of renal recovery (RIFLE criteria: acute kidney injury occurred within 1–7 days and was sustained over 1 day), we divided these patients into early- (≤9 days, Group A) and late-recovery (>9 days, Group B) groups. The differences in the continuous and categorical variables of the two groups were assessed separately. The mean glucose levels and their variability (using the standard deviation and the coefficient of standard deviation) were compared at the fasting, midday pre-meal, evening pre-meal, and evening post-meal time points during hospitalization. We have organized the manuscript in a manner compliant with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement. Results Acute kidney injury occurred within the two groups (p = 0.007 and p = 0.001, respectively). The early-morning blood glucose levels (149.7±44.0 mg/dL) and average blood glucose levels (185.6±52.0 mg/dL) were better in Group A (p = 0.01, p = 0.02). Group A patients also had lower glucose variability than Group B at the different time points (p<0.05). Group A also had earlier renal recovery. More relevant pathogens were identified from blood in Group B (p = 0.038). Conclusions Early-morning fasting and mean blood glucose levels and their variability can be good indicators of severe infection and predictors of renal outcome in type 2 diabetic patients with CKD and UTI. PMID:25259806

  17. Ataxia in patients with brain infarcts and hemorrhages.

    PubMed

    Caplan, Louis R

    2012-01-01

    Gait and limb incoordination and ataxia are most often found in patients with brainstem and cerebellar infarcts and hemorrhages. Lesions involving the thalamus and the deep portions of the cerebral hemispheres also may cause ataxia accompanied by weakness and sensory symptoms. Patients who have lesions in the lateral medulla and inferior cerebellum often topple, lean, or veer when attempting to sit, stand, or walk. They list to the side or abruptly veer when walking. The affected limbs are often hypotonic. In pontine lesions, ataxia is accompanied by weakness and pyramidal tract signs as part of an ataxic hemiparesis syndrome. In lesions affecting the superior cerebellum and the brachium conjunctivum, limb dysmetria and overshoot and dysarthria predominate and gait ataxia is absent or slight and transient. Infarcts affecting the thalamus can cause gait instability and astasia with ataxia. Lateral thalamic lesions are characterized by hemisensory symptoms, extrapyramidal limb postures and dysfunction, and gait ataxia. Lesions that affect the posterior limb of the internal capsule and its afferent and efferent projections may also cause an ataxic hemiparesis syndrome, often with accompanying hemisensory abnormalities.

  18. The Episodic Nature of Episodic-Like Memories

    ERIC Educational Resources Information Center

    Easton, Alexander; Webster, Lisa A. D.; Eacott, Madeline J.

    2012-01-01

    Studying episodic memory in nonhuman animals has proved difficult because definitions in humans require conscious recollection. Here, we assessed humans' experience of episodic-like recognition memory tasks that have been used with animals. It was found that tasks using contextual information to discriminate events could only be accurately…

  19. 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.

  20. Chromosome aberrations in ataxia telangiectasia cells exposed to heavy ions

    NASA Astrophysics Data System (ADS)

    Kawata, T.; Cucinotta, F.; George, K.; Wu, H.; Shigematsu, N.; Furusawa, Y.; Uno, T.; Isobe, K.; Ito, H.

    Understanding of biological effects of heavy ions is important to assess healt h risk in space. One of the most important issues may be to take into account individual susceptibility. Ataxia telangiectasia (A-T) cells are known to exhibit abnormal responses to radiations but the mechanism of hyper radiosensitivity of A-T still remains unknown. We report chromosome aberrations in normal human fibroblasts and AT fibroblasts exposed to low- and high-LET radiations. A chemical-induced premature chromosome condensation (PCC) technique combined with chromosome- painting technique was applied to score chromosome aberrations in G2/M-phase cells. Following gamma irradiation, GM02052 cells were approximately 5 times more sensitive to g-rays than AG1522 cells. GM02052 cells had a much higher frequency of deletions and misrejoining than AG1522 cells. When the frequency of complex type aberrations was compared, GM02052 cells showed more than 10 times higher frequency than AG1522 cells. The results will be compared with those obtained from high-LET irradiations.

  1. 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.

  2. Dysarthria in Friedreich's ataxia: a perceptual analysis.

    PubMed

    Folker, Joanne; Murdoch, Bruce; Cahill, Louise; Delatycki, Martin; Corben, Louise; Vogel, Adam

    2010-01-01

    The aims of this study were to: (1) evaluate the perceptual speech dimensions, speech intelligibility and dysarthria severity of a group of individuals diagnosed with Friedreich's ataxia (FRDA); (2) determine the presence of subgroups within FRDA dysarthria; (3) investigate the relationship between the speech outcome and the clinical factors of disease progression. The study included 38 individuals (21 female, 17 male) with a confirmed diagnosis of FRDA. A group of 20 non-neurologically impaired individuals served as controls. Perceptual analysis, investigating 30 different dimensions of speech, was conducted on a speech sample obtained from each participant. In addition, the Assessment of Intelligibility of Dysarthria Speech was administered. All FRDA participants presented with dysarthria with severities ranging from mild to moderate. Cluster analysis revealed 3 subgroups, the first presenting with mild dysarthric symptoms, the second with increased velopharyngeal involvement and the third characterized by increased laryngeal dysfunction. Dysarthria severity showed a significant correlation to disease duration but to no other clinical measure. The findings support the notion of subgroups in FRDA dysarthria, representing distinct impairments of the speech mechanism and perhaps reflective of differing evolutions beyond the cerebellum.

  3. 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

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

    PubMed

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

    2016-01-15

    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.

  5. Presentation and progression of Friedreich ataxia and implications for physical therapist examination.

    PubMed

    Maring, Joyce R; Croarkin, Earllaine

    2007-12-01

    Friedreich ataxia, although rare, is the most prevalent inherited ataxia. Recent insight into the disease pathogenesis is creating new hope for effective therapies. The purposes of this update are: (1) to review the etiology, presentation, and progression of Friedreich ataxia and (2) to describe a comprehensive physical therapist examination emphasizing valid and reliable performance measurements associated with disease progression. Early identification of individuals with Friedreich ataxia and precise characterization of impairments and functional limitations gain importance as new drug therapies are considered.

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

    MedlinePlus

    ... Page Dupré N, Gros-Louis F, Chrestian N, Verreault S, Brunet D, de Verteuil D, Brais B, Bouchard ... F, Dupré N, Dion P, Fox MA, Laurent S, Verreault S, Sanes JR, Bouchard JP, Rouleau GA. Mutations in ...

  7. 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.

  8. Optic ataxia: from Balint's syndrome to the parietal reach region.

    PubMed

    Andersen, Richard A; Andersen, Kristen N; Hwang, Eun Jung; Hauschild, Markus

    2014-03-05

    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.

  9. The Salih ataxia mutation impairs Rubicon endosomal localization.

    PubMed

    Assoum, M; Salih, M A; Drouot, N; Hnia, K; Martelli, A; Koenig, M

    2013-12-01

    We previously described a new form of recessive ataxia, Salih ataxia, in a large consanguineous Saudi Arabian family with three affected children carrying a new identified mutation in the KIAA0226 gene (c.2624delC; p.Ala875ValfsX146) coding for Rubicon. The pathogenicity of such mutation remains to be identified. Hence, we address the cellular impact of Rubicon p.Ala875ValfsX146 on endosomal/lysosomal machinery on cultured cells. We confirm that Rubicon colocalizes with the late endosome marker Rab7 and demonstrate that it also colocalizes with LampI at lysosomes. The Salih ataxia mutation leads to a diffuse cytosolic distribution and mislocalized protein from the late endosomes, indicating that deletion of the diacylglycerol binding-like motif in the mutant protein interferes with normal Rubicon subcellular localization and confirming the pathogenicity of the mutation.

  10. 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

  11. Episodic future thinking in children compared to adolescents.

    PubMed

    Gott, Chloe; Lah, Suncica

    2014-01-01

    Episodic thinking involves the ability to re-create past and to construct future personal events, which contain event-specific (episodic) and general (semantic) details. The richness of episodic thought for past events improves as children move into adolescence. The current study aims to examine changes in episodic future thinking and to establish the cognitive underpinning of these changes. Typically developing children (n = 14) and adolescents (n = 15) were tested using an adapted version of the Child Autobiographical Interview (CAI) that required generation of past and future personally relevant events. Relational memory and executive skills were also examined. Significant developmental gains were found in richness of events recall across temporal directions (past and future) and across different types of details (episodic and semantic). Developmental gains in richness of past events were also shown to correspond to developmental gains in generation of future events. Moreover, developmental changes in relational memory and (to a lesser extent) executive functions were found to relate to increases in the amount of episodic (but not semantic) details provided. Our study highlighted the similarities between past and future episodic thinking in typically developing children and adolescents. It also raises a possibility that children with developmental and neurological disorders with impaired relational memory and/or executive skills may be at risk of difficulties with episodic thinking.

  12. 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

  13. Behind the Webb Episode 27

    NASA Video Gallery

    This episode of "Behind the Webb" explores the multi-tasking capabilities of one of the cameras on the Webb Space Telescope, the Near-Infrared Spectrograph. Newly designed technology known as "micr...

  14. Hypoxic Episodes in Bronchopulmonary Dysplasia

    PubMed Central

    Martin, Richard J.; Di Fiore, Juliann M.; Walsh, Michele C.

    2015-01-01

    Hypoxic episodes are troublesome components of bronchopulmonary dysplasia in preterm infants. Immature respiratory control appears to be the major contributor, typically superimposed upon abnormal respiratory function. As a result, relatively short respiratory pauses may precipitate desaturation and accompanying bradycardia. As this population is predisposed to pulmonary hypertension, it is likely that pulmonary vasoconstriction may also play a role in hypoxic episodes. The natural history of intermittent hypoxic episodes has been well characterized in the preterm population at risk for BPD. However, the consequences of these episodes are less clear. Proposed associations of intermittent hypoxia include retinopathy of prematurity, sleep disordered breathing, and neurodevelopmental delay. Future study should address whether these associations are causal relationships. PMID:26593081

  15. Ecological momentary assessment of eating episodes in obese adults

    PubMed Central

    Goldschmidt, Andrea B.; Crosby, Ross D.; Cao, Li; Engel, Scott G.; Durkin, Nora; Beach, Heather M.; Berg, Kelly C.; Wonderlich, Stephen A.; Crow, Scott J.; Peterson, Carol B.

    2015-01-01

    Objective The context of eating episodes in obesity is poorly understood. This study examined emotional, physiological, and environmental correlates of pathological and non-pathological eating episodes in a heterogeneous sample of obese adults. Methods Community-based participants [n=50; 84% female (n=42); M body mass index=40.3±8.5; M age=43.0±11.9] with (n=5; 10%) and without binge eating disorder (BED; n=45; 90%) recorded all eating episodes and their associated emotional, physiological, and environmental factors via ecological momentary assessment for two weeks. Generalized estimating equations examined relations between these variables and eating episodes characterized by both self-identified loss of control while eating and overeating (binge eating; BE), loss of control only (LOC), overeating only (OE), and neither loss of control nor overeating (non-pathological eating; NE). Results Episodes involving loss of control (BE and LOC) were associated with the highest levels of pre- and post-episode negative affect (Wald chi-square range=15.67–24.39; ps≤.001), while those involving overeating (BE and OE) were associated with the lowest levels of pre- and post-episode hunger (Wald chi-square range=18.14–39.75; ps<.001). LOC episodes were followed by the highest level of post-episode cravings (Wald chi-square=25.87; p<.001) and were most likely to occur when participants were alone (Wald chi-square=13.20; p=.004). Conclusion Binge and loss of control eating were more consistently associated with emotional and physiological cues than overeating and non-pathological eating, while most environmental variables did not differ among eating episode types. Results support distinctions among the different objective and subjective constructs characterizing aberrant eating, and should be used to inform interventions for obesity and related eating pathology. PMID:25373891

  16. Neuronal nicotinic receptor agonists improve gait and balance in olivocerebellar ataxia.

    PubMed

    Wecker, L; Engberg, M E; Philpot, R M; Lambert, C S; Kang, C W; Antilla, J C; Bickford, P C; Hudson, C E; Zesiewicz, T A; Rowell, Peter P

    2013-10-01

    Clinical studies have reported that the nicotinic receptor agonist varenicline improves balance and coordination in patients with several types of ataxia, but confirmation in an animal model has not been demonstrated. This study investigated whether varenicline and nicotine could attenuate the ataxia induced in rats following destruction of the olivocerebellar pathway by the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP (70 mg/kg followed by 300 mg niacinamide/kg; i.p.) led to an 85% loss of inferior olivary neurons within one week without evidence of recovery, and was accompanied by a 72% decrease in rotorod activity, a 3-fold increase in the time to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) for one week improved rotorod performance by 50% and normalized the increased hindpaw stride width, effects that were prevented by the daily preadministration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg). Varenicline (1 and 3 mg free base/kg daily) also improved rotorod performance by approximately 50% following one week of administration, and although it did not alter the time to traverse the beam, it did improve the ability to maintain balance on the beam. Neither varenicline nor nicotine, at doses that improved balance, affected impaired locomotor activity in the open field. Results provide evidence that nicotinic agonists are of benefit for alleviating some of the behavioral deficits in olivocerebellar ataxia and warrant further studies to elucidate the specific mechanism(s) involved.

  17. 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.…

  18. 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…

  19. 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…

  20. Arachnodactyly, aminoaciduria, congenital cataracts, cerebellar ataxia, and delayed developmental milestones

    PubMed Central

    Bhaskar, P. A.; Jagannathan, K.; Valmikinathan, K.

    1974-01-01

    Two male cousins are reported with arachnodactyly, selective aminoaciduria, congenital cataracts, cerebellar ataxia, and delayed developmental milestones, and a distant female relative with similar abnormalities. The syndrome is thought to be previously undescribed, though it has resemblances to Marinesco-Sjögren and Marfan's syndromes. Images PMID:4448994

  1. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

    MedlinePlus

    ... but almost always with less severity. Most affected women have some degree of tremor and/or ataxia. While the psychiatric and mood disorders are also less frequent in females, they are at higher risk for anxiety and depression in general. Additional symptoms affecting some ...

  2. 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.…

  3. Paraneoplastic opsoclonus-myoclonus-ataxia syndrome revealing dual malignancy.

    PubMed

    Nasri, A; Kacem, I; Jerdak, F; Djebara, M Ben; Mejri, N; Sidhom, Y; Gargouri, A; Gouider, Riadh

    2016-10-01

    Dual malignancy has been rarely associated to paraneoplastic syndromes. We describe an unusual case of metachronous small cell lung carcinoma revealed by opsoclonus-myoclonus ataxia syndrome in a 69-year-old patient with known prostate adenocarcinoma, with positive anti-Hu and anti-Yo antibodies and good responsiveness to corticosteroids and chemotherapy.

  4. Protein-protein interaction networks in the spinocerebellar ataxias

    PubMed Central

    Rubinsztein, David C

    2006-01-01

    A large yeast two-hybrid study investigating whether the proteins mutated in different forms of spinocerebellar ataxia have interacting protein partners in common suggests that some forms do share common pathways, and will provide a valuable resource for future work on these diseases. PMID:16904001

  5. 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. PMID:27351300

  6. Longitudinal cerebral blood flow changes during speech in hereditary ataxia

    PubMed Central

    Sidtis, John J.; Strother, Stephen C.; Groshung, 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 group of seven right-handed subjects with hereditary ataxia (6 females and 1 male, 3 SCA1 and 4 SCA5, aged 38.3 +/− 18.9 years). The decline in blood flow was greatest in cerebellar regions. In contrast, blood flow actually increased during speech production in the classic speech area (Broca’s area) but not in its right hemisphere homologue at the second evaluation. This increase in cortical flow may have been compensatory for cerebellar degeneration as speech intelligibility did not decline significantly during this period. Compensation was not complete, though, as syllable timing shifted in the direction of equal syllable duration, one of the characteristics of ataxic dysarthria. These results are consistent with previous functional imaging studies of ataxia demonstrating a pattern of brain activity that reflects both loss of function and relative compensation when clinical signs and symptoms are still mild. The combination of disease-relevant tasks, behavioral measurement, and functional imaging may provide insight into the early changes associated with neurodegenerative disease. PMID:20417959

  7. 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

  8. 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

  9. A role for vascular deficiency in retinal pathology in a mouse model of ataxia-telangiectasia.

    PubMed

    Raz-Prag, Dorit; Galron, Ronit; Segev-Amzaleg, Niva; Solomon, Arieh S; Shiloh, Yosef; Barzilai, Ari; Frenkel, Dan

    2011-09-01

    Ataxia-telangiectasia is a multifaceted syndrome caused by null mutations in the ATM gene, which encodes the protein kinase ATM, a key participant in the DNA damage response. Retinal neurons are highly susceptible to DNA damage because they are terminally differentiated and have the highest metabolic activity in the central nervous system. In this study, we characterized the retina in young and aged Atm-deficient mice (Atm(-/-)). At 2 months of age, angiography revealed faint retinal vasculature in Atm(-/-) animals relative to wild-type controls. This finding was accompanied by increased expression of vascular endothelial growth factor protein and mRNA. Fibrinogen, generally absent from wild-type retinal tissue, was evident in Atm(-/-) retinas, whereas mRNA of the tight junction protein occludin was significantly decreased. Immunohistochemistry labeling for occludin in 6-month-old mice showed that this decrease persists in advanced stages of the disease. Concurrently, we noticed vascular leakage in Atm(-/-) retinas. Labeling for glial fibrillary acidic protein demonstrated morphological alterations in glial cells in Atm(-/-) retinas. Electroretinographic examination revealed amplitude aberrations in 2-month-old Atm(-/-) mice, which progressed to significant functional deficits in the older mice. These results suggest that impaired vascularization and astrocyte-endothelial cell interactions in the central nervous system play an important role in the etiology of ataxia-telangiectasia and that vascular abnormalities may underlie or aggravate neurodegeneration.

  10. Friedreich's ataxia 1980. An overview of the physiopathology.

    PubMed

    Barbeau, A

    1980-11-01

    Phase three of the Quebec Cooperative Study of Friedreich's Ataxia was devoted to an understanding of the physiopathology of individual symptoms on the basis of previously discovered biochemical leads. The present paper attempts to pull these results together by presenting, as a hypothesis, a unifying scheme of possible interactions and relationships. The central core of this hypothesis is the demonstration in Friedreich's ataxia of a state of mitochondrial energy deprivation. This is indirectly responsible for such associated and important symptoms as muscle weakness, dying-back neuropathy, scoliosis and hypertrophic cardiomyopathy. Secondarily, and possibly as an independent but linked-event, the entry of glucose into cells and pyruvate oxidation, are slowed down, favoring the development of diabetes. As a consequence, tissue concentrations of glutamic acid and aspartic acid are decreased, particularly in more vulnerable areas such as the cerebellum, brain stem and dorsal root ganglia. This tissue deficiency in putative excitatory neurotransmitters is directly responsible for the symptom of ataxia. This conclusion is reinforced by the correction of the ataxia in experimental animals, by the intraventricular injection of the same amino acids, and not by the injection of other stimulants of motricity. The observed mitochondrial energy deprivation could be the metabolic consequence of major changes in the linoleic acid (18.2) composition of inner mitochondrial membrane phospholipids, such as cardiolipin. Such decreases in membrane 18:2 could be the result of interference with the normal incorporation of this fatty acid to lipoproteins and/or cell membranes. It is at this level that the search for the specific enzyme defect in Friedreich's ataxia is continuing.

  11. Factitious psychogenic nonepileptic paroxysmal episodes.

    PubMed

    Romano, Alissa; Alqahtani, Saeed; Griffith, James; Koubeissi, Mohamad Z

    2014-01-01

    Mistaking psychogenic nonepileptic paroxysmal episodes (PNEPEs) for epileptic seizures (ES) is potentially dangerous, and certain features should alert physicians to a possible PNEPE diagnosis. Psychogenic nonepileptic paroxysmal episodes due to factitious seizures carry particularly high risks of morbidity or mortality from nonindicated emergency treatment and, often, high costs in wasted medical treatment expenditures. We report a case of a 28-year-old man with PNEPEs that were misdiagnosed as ES. The patient had been on four antiseizure medications (ASMs) with therapeutic serum levels and had had multiple intubations in the past for uncontrolled episodes. He had no episodes for two days of continuous video-EEG monitoring. He then disconnected his EEG cables and had an episode of generalized stiffening and cyanosis, followed by jerking and profuse bleeding from the mouth. The manifestations were unusually similar to those of ES, except that he was clearly startled by spraying water on his face, while he was stiff in all extremities and unresponsive. There were indications that he had sucked blood from his central venous catheter to expel through his mouth during his PNEPEs while consciously holding his breath. Normal video-EEG monitoring; the patient's volitional and deceptive acts to fabricate the appearance of illness, despite pain and personal endangerment; and the absence of reward other than remaining in a sick role were all consistent with a diagnosis of factitious disorder.

  12. Episodic Memory: A Comparative Approach

    PubMed Central

    Martin-Ordas, Gema; Call, Josep

    2013-01-01

    Historically, episodic memory has been described as autonoetic, personally relevant, complex, context-rich, and allowing mental time travel. In contrast, semantic memory, which is theorized to be free of context and personal relevance, is noetic and consists of general knowledge of facts about the world. The field of comparative psychology has adopted this distinction in order to study episodic memory in non-human animals. Our aim in this article is not only to reflect on the concept of episodic memory and the experimental approaches used in comparative psychology to study this phenomenon, but also to provide a critical analysis of these paradigms. We conclude the article by providing new avenues for future research. PMID:23781179

  13. 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

  14. Clinical manifestation, imaging, and genotype analysis of two pedigrees with spinocerebellar ataxia.

    PubMed

    Peipei, Liu; Yang, Liu; Weihong, Gu; Xiaonan, Song

    2011-12-01

    The objective of this study was to analyze the clinical manifestation, imaging characteristics, genotype, and the relationship between the three aforementioned parameters in two pedigrees suffering from spinocerebellar ataxia. To evaluate the clinical manifestation of the two pedigrees and to compare the characteristics, we performed the MRI analysis of some patients from both pedigrees, while 2 ml of the peripheral blood sample was collected for gene analysis. The gene analysis data showed that pedigree 1 was certified spinocerebellar ataxia type-2 (SCA2); the CAG repeats in the proband, proband's mother, and proband's brother were 44, 36, and 38, respectively. The MRI revealed brainstem cerebellar atrophy and "cross sign" and "ordinate sign" of pons. Pedigree 2 was certified SCA1; the CAG repeats of the proband, proband's aunt, and proband's asymptomatic cousin were 60, 51, and 52, respectively. The MRI revealed cerebellar atrophy in these individuals. We, therefore, concluded that it was difficult to diagnose the SCA subset solely through the clinical manifestation. The imaging characteristics analysis and final diagnosis depended basically on gene analysis data.

  15. p53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotes

    PubMed Central

    Prodosmo, Andrea; De Amicis, Andrea; Nisticò, Cecilia; Gabriele, Mario; Di Rocco, Giuliana; Monteonofrio, Laura; Piane, Maria; Cundari, Enrico; Chessa, Luciana; Soddu, Silvia

    2013-01-01

    Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder characterized by radiosensitivity, genomic instability, and predisposition to cancer. A-T is caused by biallelic mutations in the ataxia-telangiectasia mutated (ATM) gene, but heterozygous carriers, though apparently healthy, are believed to be at increased risk for cancer and more sensitive to ionizing radiation than the general population. Despite progress in functional and sequencing-based assays, no straightforward, rapid, and inexpensive test is available for the identification of A-T homozygotes and heterozygotes, which is essential for diagnosis, genetic counseling, and carrier prediction. The oncosuppressor p53 prevents genomic instability and centrosomal amplification. During mitosis, p53 localizes at the centrosome in an ATM-dependent manner. We capitalized on the latter finding and established a simple, fast, minimally invasive, reliable, and inexpensive test to determine mutant ATM zygosity. The percentage of mitotic lymphoblasts or PBMCs bearing p53 centrosomal localization clearly discriminated among healthy donors (>75%), A-T heterozygotes (40%–56%), and A-T homozygotes (<30%). The test is specific for A-T, independent of the type of ATM mutations, and recognized tumor-associated ATM polymorphisms. In a preliminary study, our test confirmed that ATM is a breast cancer susceptibility gene. These data open the possibility of cost-effective, early diagnosis of A-T homozygotes and large-scale screenings for heterozygotes. PMID:23454770

  16. Neuroprotective Role of Liver Growth Factor “LGF” in an Experimental Model of Cerebellar Ataxia

    PubMed Central

    Calatrava-Ferreras, Lucía; Gonzalo-Gobernado, Rafael; Reimers, Diana; Herranz, Antonio S.; Jiménez-Escrig, Adriano; Díaz-Gil, Juan José; Casarejos, María José; Montero-Vega, María Teresa; Bazán, Eulalia

    2014-01-01

    Cerebellar ataxias (CA) comprise a heterogeneous group of neurodegenerative diseases characterized by a lack of motor coordination. They are caused by disturbances in the cerebellum and its associated circuitries, so the major therapeutic goal is to correct cerebellar dysfunction. Neurotrophic factors enhance the survival and differentiation of selected types of neurons. Liver growth factor (LGF) is a hepatic mitogen that shows biological activity in neuroregenerative therapies. We investigate the potential therapeutic activity of LGF in the 3-acetylpiridine (3-AP) rat model of CA. This model of CA consists in the lesion of the inferior olive-induced by 3-AP (40 mg/kg). Ataxic rats were treated with 5 µg/rat LGF or vehicle during 3 weeks, analyzing: (a) motor coordination by using the rota-rod test; and (b) the immunohistochemical and biochemical evolution of several parameters related with the olivo-cerebellar function. Motor coordination improved in 3-AP-lesioned rats that received LGF treatment. LGF up-regulated NeuN and Bcl-2 protein levels in the brainstem, and increased calbindin expression and the number of neurons receiving calbindin-positive projections in the cerebellum. LGF also reduced extracellular glutamate and GABA concentrations and microglia activation in the cerebellum. In view of these results, we propose LGF as a potential therapeutic agent in cerebellar ataxias. PMID:25338046

  17. Ataxia rating scales--psychometric profiles, natural history and their application in clinical trials.

    PubMed

    Saute, Jonas Alex Morales; Donis, Karina Carvalho; Serrano-Munuera, Carmen; Genis, David; Ramirez, Luís Torres; Mazzetti, Pilar; Pérez, Luis Velázquez; Latorre, Pilar; Sequeiros, Jorge; Matilla-Dueñas, Antoni; Jardim, Laura Bannach

    2012-06-01

    We aimed to perform a comprehensive systematic review of the existing ataxia scales. We described the disorders for which the instruments have been validated and used, the time spent in its application, its validated psychometric properties, and their use in studies of natural history and clinical trials. A search from 1997 onwards was performed in the MEDLINE, LILACS, and Cochrane databases. The web sites ClinicalTrials.gov and Orpha.net were also used to identify the endpoints used in ongoing randomized clinical trials. We identified and described the semiquantitative ataxia scales (ICARS, SARA, MICARS, BARS); semiquantitative ataxia and non-ataxia scales (UMSARS, FARS, NESSCA); a semiquantitative non-ataxia scale (INAS); quantitative ataxia scales (CATSYS 2000, AFCS, CCFS and CCFSw, and SCAFI); and the self-performed ataxia scale (FAIS). SARA and ICARS were the best studied and validated so far, and their reliability sustain their use. Ataxia and non-ataxia scores will probably provide a better view of the overall disability in long-term trials and studies of natural history. Up to now, no clear advantage has been disclosed for any of them; however, we recommend the use of specific measurements of gait since gait ataxia is the first significant manifestation in the majority of ataxia disorders and comment on the best scales to be used in specific ataxia forms. Quantitative ataxia scales will be needed to speed up evidence from phase II clinical trials, from trials focused on the early phase of diseases, and for secondary endpoints in phase III trials. Finally, it is worth remembering that estimation of the actual minimal clinically relevant difference is still lacking; this, together with changes in quality of life, will probably be the main endpoints to measure in future therapeutic studies.

  18. Postmortem study of ataxia with retinitis pigmentosa by mutation of the α-tocopherol transfer protein gene

    PubMed Central

    Yokota, T; Uchihara, T; Kumagai, J; Shiojiri, T; Pang, J; Arita, M; Arai, H; Hayashi, M; Kiyosawa, M; Okeda, R; Mizusawa, H

    2000-01-01

    A new syndrome of ataxia and retinitis pigmentosa with vitamin E deficiency caused by the missense mutation of α-tocopherol transfer protein (α-TTP) gene was recently proposed. After studying the first postmortem case with this mutation pathologically and biochemically, whether the symptoms can be treated by supplementation of vitamin E or not is discussed. The major pathological findings were retinal atrophy; severe dying back-type degeneration of the posterior column; and massive accumulation of lipofuscin in neurons including dorsal root ganglion (DRG) cells, which were almost identical to those in vitamin E deficient animals and patients with fat malabsorption. Also, mild loss of Purkinje cells was noted. Because robust expression of α-TTP was detected in the cerebellum as well as in the liver and the tissue concentration of vitamin E in the cerebellum was still low even after oral supplementation, the mild Purkinje cell loss might be related to the mutant α-TTP in the cerebellum. By contrast, in the DRG, thought to be mainly responsible for ataxia, no expression of α-TTP was detected, and the tissue concentration of vitamin E increased to normal after supplementation. It is therefore considered that oral supplementation of vitamin E should effectively counteract the progression of ataxia.

 PMID:10727494

  19. Episodic Response Pproject research plan

    SciTech Connect

    Thornton, K.; Baker, J.P.; Marmorek, D.; Bernard, D.; Eshleman, K.N.

    1988-02-01

    In some geographic locations, acidic deposition is known to be affecting surface water chemistry on both long-term and short-term time scales. Considerable research in the past decade has greatly improved our understanding of the biological effects of acidification, particularly the relationship between chronic chemical conditions and biological responses. In comparison, relatively little is known about the role that short-term acidification is having on the composition or functioning of aquatic biological communities. Despite this scientific uncertainty, it is generally presumed that short-term acidification ('episodes') can result in significant adverse effects on aquatic resources of interest, particularly fish communities. Recognizing episodes as a potentially important source of uncertainty in index-based estimates of acidic deposition effects on populations of lakes and streams, the EPA has initiated the Episodic Response Project (ERP). From an acidification perspective, the ERP is designed primarily to quantify this component of uncertainty in regional population estimates, and to determine the degree to which acidic episodes adversely affect fish populations.

  20. RAGG - R EPISODIC AGGREGATION PACKAGE

    EPA Science Inventory

    The RAGG package is an R implementation of the CMAQ episodic model aggregation method developed by Constella Group and the Environmental Protection Agency. RAGG is a tool to provide climatological seasonal and annual deposition of sulphur and nitrogen for multimedia management. ...

  1. Gender differences in episodic memory.

    PubMed

    Herlitz, A; Nilsson, L G; Bäckman, L

    1997-11-01

    The relationship between gender and memory has been largely neglected by research, despite occasional studies reporting gender differences in episodic memory performance. The present study examined potential gender differences in episodic memory, semantic memory, primary memory, and priming. Five hundred thirty women and 470 men, randomly sampled from the city of Umeå, Sweden, 35-80 years of age, participated in the study. There were no differences between men and women with regard to age or education, or on a measure of global intellectual functioning. As has been demonstrated previously, men out performed women on a visuospatial task and women outperformed men on tests of verbal fluency. In addition, the results demonstrated that women consistently performed at a higher level than did men on the episodic memory tasks, although there were no differences between men and women on the tasks assessing semantic memory, primary memory, or priming. The women's higher level of performance on the episodic memory tasks could not be fully explained by their higher verbal ability.

  2. Quantitative Phosphoproteomics of the Ataxia Telangiectasia-Mutated (ATM) and Ataxia Telangiectasia-Mutated and Rad3-related (ATR) Dependent DNA Damage Response in Arabidopsis thaliana*

    PubMed Central

    Roitinger, Elisabeth; Hofer, Manuel; Köcher, Thomas; Pichler, Peter; Novatchkova, Maria; Yang, Jianhua; Schlögelhofer, Peter; Mechtler, Karl

    2015-01-01

    The reversible phosphorylation of proteins on serine, threonine, and tyrosine residues is an important biological regulatory mechanism. In the context of genome integrity, signaling cascades driven by phosphorylation are crucial for the coordination and regulation of DNA repair. The two serine/threonine protein kinases ataxia telangiectasia-mutated (ATM) and Ataxia telangiectasia-mutated and Rad3-related (ATR) are key factors in this process, each specific for different kinds of DNA lesions. They are conserved across eukaryotes, mediating the activation of cell-cycle checkpoints, chromatin modifications, and regulation of DNA repair proteins. We designed a novel mass spectrometry-based phosphoproteomics approach to study DNA damage repair in Arabidopsis thaliana. The protocol combines filter aided sample preparation, immobilized metal affinity chromatography, metal oxide affinity chromatography, and strong cation exchange chromatography for phosphopeptide generation, enrichment, and separation. Isobaric labeling employing iTRAQ (isobaric tags for relative and absolute quantitation) was used for profiling the phosphoproteome of atm atr double mutants and wild type plants under either regular growth conditions or challenged by irradiation. A total of 10,831 proteins were identified and 15,445 unique phosphopeptides were quantified, containing 134 up- and 38 down-regulated ATM/ATR dependent phosphopeptides. We identified known and novel ATM/ATR targets such as LIG4 and MRE11 (needed for resistance against ionizing radiation), PIE1 and SDG26 (implicated in chromatin remodeling), PCNA1, WAPL, and PDS5 (implicated in DNA replication), and ASK1 and HTA10 (involved in meiosis). PMID:25561503

  3. Typhoid fever presenting as acute cerebellar ataxia and severe thrombocytopenia.

    PubMed

    Cheong, B M K

    2008-03-01

    Typhoid fever being a systemic infection can present in a multitude of ways, involving various systems. Here we describe a case of typhoid fever presenting with acute cerebellar ataxia and marked thrombocytopenia. This atypical presentation is not common in typhoid fever and can lead to misdiagnosis as well as a delay in the initiation of appropriate therapy. Prompt clinical improvement and the return of platelet counts to normal were noted after the patient was started on IV Ceftriaxone.

  4. Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities

    PubMed Central

    Lefevre, Sophie; Sliwa, Dominika; Seguin, Alexandra; Camadro, Jean-Michel; Lesuisse, Emmanuel

    2010-01-01

    Abstract Mitochondrial dysfunction and oxidative damage are at the origin of numerous neurodegenerative diseases like Friedreich ataxia and Alzheimer and Parkinson diseases. Friedreich ataxia (FRDA) is the most common hereditary ataxia, with one individual affected in 50,000. This disease is characterized by progressive degeneration of the central and peripheral nervous systems, cardiomyopathy, and increased incidence of diabetes mellitus. FRDA is caused by a dynamic mutation, a GAA trinucleotide repeat expansion, in the first intron of the FXN gene. Fewer than 5% of the patients are heterozygous and carry point mutations in the other allele. The molecular consequences of the GAA triplet expansion is transcription silencing and reduced expression of the encoded mitochondrial protein, frataxin. The precise cellular role of frataxin is not known; however, it is clear now that several mitochondrial functions are not performed correctly in patient cells. The affected functions include respiration, iron–sulfur cluster assembly, iron homeostasis, and maintenance of the redox status. This review highlights the molecular mechanisms that underlie the disease phenotypes and the different hypothesis about the function of frataxin. In addition, we present an overview of the most recent therapeutic approaches for this severe disease that actually has no efficient treatment. Antioxid. Redox Signal. 13, 0000–0000. PMID:20156111

  5. 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

  6. Chinese patients with Huntington's disease initially presenting with spinocerebellar ataxia.

    PubMed

    Dong, Y; Sun, Y-M; Liu, Z-J; Ni, W; Shi, S-S; Wu, Z-Y

    2013-04-01

    Recent studies have described Huntington's disease (HD) patients with atypical onset of ataxia. Symptoms in these patients can overlap with those of spinocerebellar ataxia (SCA). We retrospectively examined clinical data for 82 HD probands and found 7 had initially been clinically diagnosed as SCA cases. Clinical features in these patients were further investigated and the number of CAG repeats in the huntingtin (HTT) gene was determined by direct sequencing. Genetic screenings for SCAs in the 7 patients were all negative. By contrast, HTT was heterozygous in each patient. The distribution of CAG number in the 7 patients was statistically the same as that in the other 75 patients. Each of 7 HD patients had presented with atypical onset of ataxia. The mean time from onset to HTT genetic testing was 5.6 ± 5.52 years. Three of the patients developed chorea, but the others did not. Our observations confirm the clinical heterogeneity of HD in Han Chinese. Based on these findings, testing for HTT expansions should be considered for clinically diagnosed SCA patients who test negatively in genetic screening of SCA genes.

  7. Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia

    PubMed Central

    Koht, Jeanette; Pihlstrøm, Lasse; Rengmark, Aina H.; Henriksen, Sandra P.; Tallaksen, Chantal M. E.; Toft, Mathias

    2017-01-01

    Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease. Pathogenic and likely-pathogenic variants were identified in 20 probands (19%) and variants of uncertain significance in ten probands (10%). Together these accounted for 30 probands (29%) and involved 18 different genes. Among several interesting findings, dominantly inherited KIF1A variants, p.(Val8Met) and p.(Ile27Thr) segregated in two independent families, both presenting with a pure spastic paraplegia phenotype. Two homozygous missense variants, p.(Gly4230Ser) and p.(Leu4221Val) were found in SACS in one consanguineous family, presenting with spastic ataxia and isolated cerebellar atrophy. The average disease duration in probands with pathogenic and likely-pathogenic variants was 31 years, ranging from 4 to 51 years. In conclusion, this study confirmed and expanded the clinical phenotypes associated with known disease genes. The results demonstrate that gene panel sequencing and similar sequencing approaches can serve as efficient diagnostic tools for different heterogeneous disorders. Early use of such strategies may help to reduce both costs and time of the diagnostic process. PMID:28362824

  8. Decreased cerebellar blood flow in postinfectious acute cerebellar ataxia

    PubMed Central

    Nagamitsu, S.; Matsuishi, T.; Ishibashi, M.; Yamashita, Y.; Nishimi, T.; Ichikawa, K.; Yamanishi, K.; Kato, H.

    1999-01-01

    OBJECTIVE—The aim of the present study was to evaluate the regional cerebral blood flow (rCBF) in patients with postinfectious acute cerebellar ataxia using single photon emission computed tomography (SPECT).
METHODS—Five children with postinfectious acute cerebellar ataxia and five control subjects were examined. The distribution of rCBF was measured by SPECT imaging after intravenous administration of 123I-IMP (111 MBq). The rCBF ratio—defined as the ratio of rCBF in the region of interest (ROI) to that in the occipital cortex—was calculated for each cortical and subcortical ROI. The mean rCBF ratio of each region was then compared between the ataxic and control subjects. These patients and all control subjects were also evaluated using MRI.
RESULTS—The rCBF ratio was significantly lower in the cerebellum of the ataxic patients than in the cerebellum of the control subjects (p<0.05). No abnormal cerebellar morphology and no abnormal signal intensities were found on MRI.
CONCLUSION—123I-IMP SPECT clearly demonstrated the decreased rCBF in the cerebellum of all patients with postinfectious acute cerebellar ataxia.

 PMID:10369834

  9. Antecedents of Manic versus Other First-Psychotic Episodes in 263 Bipolar-I Disorder Patients

    PubMed Central

    Salvatore, Paola; Baldessarini, Ross J.; Khalsa, Hari-Mandir K.; Vázquez, Gustavo; Perez, Jesus; Faedda, Gianni L.; Amore, Mario; Maggini, Carlo; Tohen, Mauricio

    2013-01-01

    Objective Since initial episode-type can predict later morbidity in bipolar disorder, we tested the hypothesis that clinical antecedents might predict initial episode-types. Method We studied 263 first-episode, adult, DSM-IV-TR type-I bipolar disorder (BD-I) subjects within the McLean-Harvard-International First-Episode Project. Based on blinded assessments of antecedents from SCID examinations and clinical records, we compared first-lifetime Manic vs. Other (mixed, depressive, or nonaffective) major psychotic-episodes. Results We identified 32 antecedents arising at early, intermediate or later times, starting 12.3±10.7 years prior to first-lifetime major psychotic-episodes. Based on multivariate modeling, antecedents associated significantly and independently with Other (n=113) more than Manic (n=150) first-lifetime major psychotic-episodes ranked by Odds Ratio: more early attentional disturbances, more late depression, more early perplexity, more detoxification, more early unstable-mixed affects, more antidepressants, more early dysphoria, more intermediate depression, more early impulsivity, more late anhedonia, longer early-to-intermediate intervals, more intermediate substance abuse, more family history of major depression, and younger at earliest antecedents. Antecedents selectively preceding Manic more than Other first-psychotic episodes included more late behavioral problems and more risk of familial BD-I. Conclusion Clinical antecedents in adult, BD-I patients, beginning a decade before first major-episodes and progressing through sequential stages were dissimilar in Manic versus Other first-psychotic-episodes. PMID:23837831

  10. Classification of ischaemic episodes with ST/HR diagrams.

    PubMed

    Faganeli Pucer, Jana; Demšar, Janez; Kukar, Matjaž

    2012-01-01

    Coronary artery disease is the developed world's premier cause of mortality and the most probable cause of myocardial ischaemia. More advanced diagnostic tests aside, in electrocardiogram (ECG) analysis it manifests itself as a ST segment deviation, targeted by both exercise ECG and ambulatory ECG. In ambulatory ECG, besides ischaemic ST segment deviation episodes there are also non-ischaemic heart rate related episodes which aggravate real ischaemia detection. We present methods to transform the features developed for the heart rate adjustment of ST segment depression in exercise ECG for use in ambulatory ECG. We use annotations provided by the Long-Term ST Database to plot the ST/HR diagrams and then estimate the overall and maximal slopes of the diagrams in the exercise and recovery phase for each ST segment deviation episode. We also estimate the angle at the extrema of the ST/HR diagrams. Statistical analysis shows that ischaemic ST segment deviation episodes have significantly steeper overall and maximal slopes than heart rate related episodes, which indicates the explored features' utility for distinguishing between the two types of episodes. This makes the proposed features very useful in automated ECG analysis.

  11. Fragile X-associated tremor/ataxia syndrome: An under-recognised cause of tremor and ataxia.

    PubMed

    Kalus, Sarah; King, John; Lui, Elaine; Gaillard, Frank

    2016-01-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive degenerative movement disorder resulting from a fragile X "premutation", defined as 55-200 CGG repeats in the 5'-untranslated region of the FMR1 gene. The FMR1 premutation occurs in 1/800 males and 1/250 females, with FXTAS affecting 40-45% of male and 8-16% of female premutation carriers over the age of 50. FXTAS typically presents with kinetic tremor and cerebellar ataxia. FXTAS has a classical imaging profile which, in concert with clinical manifestations and genetic testing, participates vitally in its diagnosis. The revised FXTAS diagnostic criteria include two major radiological features. The "MCP sign", referring to T2 hyperintensity in the middle cerebellar peduncle, has long been considered the radiological hallmark of FXTAS. Recently included as a major radiological criterion in the diagnosis of FXTAS is T2 hyperintensity in the splenium of the corpus callosum. Other imaging features of FXTAS include T2 hyperintensities in the pons, insula and periventricular white matter as well as generalised brain and cerebellar atrophy. FXTAS is an under-recognised and misdiagnosed entity. In patients with unexplained tremor, ataxia and cognitive decline, the presence of middle cerebellar peduncle and/or corpus callosum splenium hyperintensity should raise suspicion of FXTAS. Diagnosis of FXTAS has important implications not only for the patient but also, through genetic counselling and testing, for future generations.

  12. A new model for quantifying climate episodes

    NASA Astrophysics Data System (ADS)

    Biondi, Franco; Kozubowski, Tomasz J.; Panorska, Anna K.

    2005-07-01

    When long records of climate (precipitation, temperature, stream runoff, etc.) are available, either from instrumental observations or from proxy records, the objective evaluation and comparison of climatic episodes becomes necessary. Such episodes can be quantified in terms of duration (the number of time intervals, e.g. years, the process remains continuously above or below a reference level) and magnitude (the sum of all series values for a given duration). The joint distribution of duration and magnitude is represented here by a stochastic model called BEG, for bivariate distribution with exponential and geometric marginals. The model is based on the theory of random sums, and its mathematical derivation confirms and extends previous empirical findings. Probability statements that can be obtained from the model are illustrated by applying it to a 2300-year dendroclimatic reconstruction of water-year precipitation for the eastern Sierra Nevada-western Great Basin. Using the Dust Bowl drought period as an example, the chance of a longer or greater drought is 8%. Conditional probabilities are much higher, i.e. a drought of that magnitude has a 62% chance of lasting for 11 years or longer, and a drought that lasts 11 years has a 46% chance of having an equal or greater magnitude. In addition, because of the bivariate model, we can estimate a 6% chance of witnessing a drought that is both longer and greater. Additional examples of model application are also provided. This type of information provides a way to place any climatic episode in a temporal perspective, and such numerical statements help with reaching science-based management and policy decisions.

  13. Planning Physical Education Lessons as Teaching "Episodes"

    ERIC Educational Resources Information Center

    Chatoupis, Constantine

    2016-01-01

    An "episode" is a unit of time within which teachers and students are working on the same objective and are engaged in the same teaching/learning style. The duration of each episode, as well as the number of them in a single lesson, may vary. Additionally, the multiple episodes of a lesson may have similar objectives, offer similar…

  14. Cell and Molecular Biology of Ataxia Telangiectasia Heterozygous Human Mammary Epithelial Cells Irradiated in Culture

    NASA Technical Reports Server (NTRS)

    Richmond, Robert C.

    2001-01-01

    Autologous isolates of cell types from obligate heterozygotes with the autosomal disorder ataxia-telangiectasia (A-T)were used to begin a tissue culture model for assessing pathways of radiation-induced cancer formation in this target tissue. This was done by establishing cultures of stromal fibroblasts and long-term growth human mammary epithelial cells (HMEC) in standard 2-dimensional tissue culture in order to establish expression of markers detailing early steps of carcinogenesis. The presumptive breast cancer susceptibility of A-T heterozygotes as a sequel to damage caused by ionizing radiation provided reason to study expression of markers in irradiated HMEC. Findings from our study with HMEC have included determination of differences in specific protein expression amongst growth phase (e.g., log vs stationary) and growth progression (e.g., pass 7 vs pass 9), as well as differences in morphologic markers within populations of irradiated HMEC (e.g., development of multinucleated cells).

  15. Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay.

    PubMed

    Kim, Myungjin; Sandford, Erin; Gatica, Damian; Qiu, Yu; Liu, Xu; Zheng, Yumei; Schulman, Brenda A; Xu, Jishu; Semple, Ian; Ro, Seung-Hyun; Kim, Boyoung; Mavioglu, R Nehir; Tolun, Aslıhan; Jipa, Andras; Takats, Szabolcs; Karpati, Manuela; Li, Jun Z; Yapici, Zuhal; Juhasz, Gabor; Lee, Jun Hee; Klionsky, Daniel J; Burmeister, Margit

    2016-01-26

    Autophagy is required for the homeostasis of cellular material and is proposed to be involved in many aspects of health. Defects in the autophagy pathway have been observed in neurodegenerative disorders; however, no genetically-inherited pathogenic mutations in any of the core autophagy-related (ATG) genes have been reported in human patients to date. We identified a homozygous missense mutation, changing a conserved amino acid, in ATG5 in two siblings with congenital ataxia, mental retardation, and developmental delay. The subjects' cells display a decrease in autophagy flux and defects in conjugation of ATG12 to ATG5. The homologous mutation in yeast demonstrates a 30-50% reduction of induced autophagy. Flies in which Atg5 is substituted with the mutant human ATG5 exhibit severe movement disorder, in contrast to flies expressing the wild-type human protein. Our results demonstrate the critical role of autophagy in preventing neurological diseases and maintaining neuronal health.

  16. Characterization of aerosol episodes in the greater Mediterranean Sea area from satellite observations (2000-2007)

    NASA Astrophysics Data System (ADS)

    Gkikas, A.; Hatzianastassiou, N.; Mihalopoulos, N.; Torres, O.

    2016-03-01

    An algorithm able to identify and characterize episodes of different aerosol types above sea surfaces of the greater Mediterranean basin (GMB), including the Black Sea and the Atlantic Ocean off the coasts of Iberia and northwest Africa, is presented in this study. Based on this algorithm, five types of intense (strong and extreme) aerosol episodes in the GMB are identified and characterized using daily aerosol optical properties from satellite measurements, namely MODIS-Terra, Earth Probe (EP)-TOMS and OMI-Aura. These aerosol episodes are: (i) biomass-burning/urban-industrial (BU), (ii) desert dust (DD), (iii) dust/sea-salt (DSS), (iv) mixed (MX) and (v) undetermined (UN). The identification and characterization is made with our algorithm using a variety of aerosol properties, namely aerosol optical depth (AOD), Ångström exponent (α), fine fraction (FF), effective radius (reff) and Aerosol Index (AI). During the study period (2000-2007), the most frequent aerosol episodes are DD, observed primarily in the western and central Mediterranean Sea, and off the northern African coasts, 7 times/year for strong episodes and 4 times/year for extreme ones, on average. The DD episodes yield 40% of all types of strong aerosol episodes in the study region, while they account for 71.5% of all extreme episodes. The frequency of occurrence of strong episodes exhibits specific geographical patterns, for example the BU are mostly observed along the coasts of southern Europe and off the Atlantic coasts of Portugal, the MX episodes off the Spanish Mediterranean coast and over the Adriatic and northern Aegean Sea, while the DSS ones over the western and central Mediterranean Sea. On the other hand, the extreme episodes for all but DD aerosol display more patchy spatial patterns. The strong episodes exhibit AOD at 550 nm as high as 1.6 in the southernmost parts of central and eastern Mediterranean Sea, which rise up to 5 for the extreme, mainly DD and DSS, episodes. Although more

  17. Episodic Memories in Anxiety Disorders: Clinical Implications

    PubMed Central

    Zlomuzica, Armin; Dere, Dorothea; Machulska, Alla; Adolph, Dirk; Dere, Ekrem; Margraf, Jürgen

    2014-01-01

    The aim of this review is to summarize research on the emerging role of episodic memories in the context of anxiety disorders (AD). The available literature on explicit, autobiographical, and episodic memory function in AD including neuroimaging studies is critically discussed. We describe the methodological diversity of episodic memory research in AD and discuss the need for novel tests to measure episodic memory in a clinical setting. We argue that alterations in episodic memory functions might contribute to the etiology of AD. We further explain why future research on the interplay between episodic memory function and emotional disorders as well as its neuroanatomical foundations offers the promise to increase the effectiveness of modern psychological treatments. We conclude that one major task is to develop methods and training programs that might help patients suffering from AD to better understand, interpret, and possibly actively use their episodic memories in a way that would support therapeutic interventions and counteract the occurrence of symptoms. PMID:24795583

  18. There May Be More to Reaching than Meets the Eye: Re-Thinking Optic Ataxia

    ERIC Educational Resources Information Center

    Jackson, Stephen R.; Newport, Roger; Husain, Masud; Fowlie, Jane E.; O'Donoghue, Michael; Bajaj, Nin

    2009-01-01

    Optic ataxia (OA) is generally thought of as a disorder of visually guided reaching movements that cannot be explained by any simple deficit in visual or motor processing. In this paper we offer a new perspective on optic ataxia; we argue that the popular characterisation of this disorder is misleading and is unrepresentative of the pattern of…

  19. Hereditary ataxias and paediatric neurology: new movers and shakers enter the field.

    PubMed

    Morrison, Patrick J

    2003-01-01

    Over 25 autosomal dominant and autosomal recessive spinocerebellar ataxias have been isolated over the last decade. The recognition of paediatric ataxia phenotypes and, in addition, other movement disorders including hereditary choreiform and parkinsonian syndromes, has improved our knowledge of these diseases. Advances in molecular genetics has allowed fuller delineation and better recognition of these diseases.

  20. Impaired Inhibition of Prepotent Motor Tendencies in Friedreich Ataxia Demonstrated by the Simon Interference Task

    ERIC Educational Resources Information Center

    Corben, L. A.; Akhlaghi, H.; Georgiou-Karistianis, N.; Bradshaw, J. L.; Egan, G. F.; Storey, E.; Churchyard, A. J.; Delatycki, M. B.

    2011-01-01

    Friedreich ataxia (FRDA) is the most common of the genetically inherited ataxias. We recently demonstrated that people with FRDA have impairment in motor planning--most likely because of pathology affecting the cerebral cortex and/or cerebello-cortical projections. We used the Simon interference task to examine how effective 13 individuals with…

  1. The use of muscle biopsy in the diagnosis of undefined ataxia with cerebellar atrophy in children

    PubMed Central

    Terracciano, Alessandra; Renaldo, Florence; Zanni, Ginevra; D’Amico, Adele; Pastore, Anna; Barresi, Sabina; Valente, Enza Maria; Piemonte, Fiorella; Tozzi, Giulia; Carrozzo, Rosalba; Valeriani, Massimiliano; Boldrini, Renata; Mercuri, Eugenio; Santorelli, Filippo Maria; Bertini, Enrico

    2012-01-01

    Childhood cerebellar ataxias, and particularly congenital ataxias, are heterogeneous disorders and several remain undefined. We performed a muscle biopsy in patients with congenital ataxia and children with later onset undefined ataxia having neuroimaging evidence of cerebellar atrophy. Significant reduced levels of Coenzyme Q10 (COQ10) were found in the skeletal muscle of 9 out of 34 patients that were consecutively screened. A mutation in the ADCK3/Coq8 gene (R347X) was identified in a female patient with ataxia, seizures and markedly reduced COQ10 levels. In a 2.5-years-old male patient with non syndromic congenital ataxia and autophagic vacuoles in the muscle biopsy we identified a homozygous nonsense mutation R111X mutation in SIL1 gene, leading to early diagnosis of Marinesco-Sjogren syndrome. We think that muscle biopsy is a valuable procedure to improve diagnostic assesement in children with congenital ataxia or other undefined forms of later onset childhood ataxia associated to cerebellar atrophy at MRI. PMID:21873089

  2. Autosomal recessive cerebellar ataxia of adult onset due to STUB1 mutations.

    PubMed

    Depondt, Chantal; Donatello, Simona; Simonis, Nicolas; Rai, Myriam; van Heurck, Roxane; Abramowicz, Marc; D'Hooghe, Marc; Pandolfo, Massimo

    2014-05-13

    Autosomal recessive ataxias affect about 1 person in 20,000. Friedreich ataxia accounts for one-third of the cases in Caucasians; the others are due to a growing list of very rare molecular defects, including mild forms of metabolic diseases. In nearly 50%, the genetic cause remains undetermined.

  3. Cerebral venous thrombosis presenting with cerebellar ataxia and cortical blindness.

    PubMed

    Ben Sassi, Samia; Mizouni, Habiba; Nabli, Fatma; Kallel, Lamia; Kefi, Mounir; Hentati, Fayçal

    2010-01-01

    Venous infarction in the cerebellum has been reported only rarely, probably because of the abundant venous collateral drainage in this region. Bilateral occipital infarction is a rare cause of visual loss in cerebral venous thrombosis. We describe a 50-year-old woman with a history of ulcerative colitis who developed acute cerebellar ataxia and cortical blindness. She had bilateral cerebellar and occipital lesions related to sigmoid venous thrombosis and achieved complete recovery with anticoagulation therapy. Cerebral venous thrombosis should be considered in cases of simultaneous cerebellar and occipital vascular lesions.

  4. [Ataxia telangiectasia. Diagnosis and follow-up in 4 cases].

    PubMed

    Monterrubio Ledezma, César Eduardo; Corona Rivera, Alfredo; Corona Rivera, Jorge Román; Rodríguez Casillas, Lourdes Jocelyn; Hernández Rocha, Juan; Barros Nuñez, Patricio; Bobadilla Morales, Lucina

    2013-01-01

    Ataxia telangiectasia (AT) is a chromosomal instability syndrome with autosomal recessive inheritance, it is caused by more than 500 mutations of the ATM gene, which is involved in the cellular response to DNA damage. The diagnosis becomes difficult due to the evolution of the disease, their poor knowledge, and limited access to diagnostic tests. Chromosomal damage induced by ionizing radiation (IR) assay is still a sensitive method for early diagnosis, and it is essential for better management and genetic counseling. This paper shows diagnosis and follow-up in four cases with AT.

  5. Bluetongue in Belgium: episode II.

    PubMed

    Méroc, E; Herr, C; Verheyden, B; Hooyberghs, J; Houdart, P; Raemaekers, M; Vandenbussche, F; De Clercq, K; Mintiens, K

    2009-03-01

    Bluetongue (BT) is an arthropod-borne viral disease of ruminants. In August 2006, domestic ruminant populations in Northern Europe became infected with BT virus serotype 8 (BTV-8). The first BTV-8-case of the year 2007 in Belgium was notified in July. This case was the starting point of a second wave of BT outbreaks. The main objective of this study was to describe the evolution and the clinical impact of the second episode of BT in Belgium. In addition, the main differences with the previous episode (August-December 2006) are reported. Both outbreak and rendering plant data were analysed. Overall cumulative incidence at herd level was estimated at 11.5 (11.2-11.8) and 7.5 (7.3-7.8) per cent in cattle and sheep populations respectively. The findings went in favour of a negative association between within-herd prevalence in 2006 and the risk of showing clinical signs of BT in 2007 (via protective immunity). A high level of correlation was demonstrated between BT incidence and small ruminant mortality data when shifting the latter of 1-week backwards. This result supports the hypothesis that the high increase in small ruminant mortality observed in 2007 was the consequence of the presence of BT. For cattle, the correlation was not as high. An increase in cattle foetal mortality was also observed during the year 2007 and a fair correlation was found between BT incidence and foetal mortality.

  6. Episodic future thinking and episodic counterfactual thinking: intersections between memory and decisions.

    PubMed

    Schacter, Daniel L; Benoit, Roland G; De Brigard, Felipe; Szpunar, Karl K

    2015-01-01

    This article considers two recent lines of research concerned with the construction of imagined or simulated events that can provide insight into the relationship between memory and decision making. One line of research concerns episodic future thinking, which involves simulating episodes that might occur in one's personal future, and the other concerns episodic counterfactual thinking, which involves simulating episodes that could have happened in one's personal past. We first review neuroimaging studies that have examined the neural underpinnings of episodic future thinking and episodic counterfactual thinking. We argue that these studies have revealed that the two forms of episodic simulation engage a common core network including medial parietal, prefrontal, and temporal regions that also supports episodic memory. We also note that neuroimaging studies have documented neural differences between episodic future thinking and episodic counterfactual thinking, including differences in hippocampal responses. We next consider behavioral studies that have delineated both similarities and differences between the two kinds of episodic simulation. The evidence indicates that episodic future and counterfactual thinking are characterized by similarly reduced levels of specific detail compared with episodic memory, but that the effects of repeatedly imagining a possible experience have sharply contrasting effects on the perceived plausibility of those events during episodic future thinking versus episodic counterfactual thinking. Finally, we conclude by discussing the functional consequences of future and counterfactual simulations for decisions.

  7. Significance of autobiographical episodes and spacing effects in incidental memory.

    PubMed

    Toyota, Hiroshi

    2013-10-01

    Participants were presented with target words on two occasions, and were asked each time to generate a memory of a past episode associated with the targets. Participants were also instructed to rate the importance (significance elaboration) or pleasantness of the pisode (pleasantness elaboration) in an orienting task, followed by an unexpect d recall test. Significance elaboration led to better recall than pleasantness elaboration, but only in the spaced presentation. The spaced presentation led to better tree recall than massed presentation with significance elaboration, but the difference between the two types of presentation was not observed with pleasantness elaboration. These results suggest that the significance of an episode is more critical than the pleasantness of an episode in determining the effectiveness of autobiographical elaboration in facilitating recall.

  8. Effects on incidental memory of affective tone in associated past and future episodes: influence of emotional intelligence.

    PubMed

    Toyota, Hiroshi

    2011-02-01

    The present study examined the effects of emotion elicited by episodes (past events or expected future events) and the relationship between individual differences in emotional intelligence and memory. Participants' emotional intelligence was assessed on the Japanese version of Emotional Skills and Competence Questionnaire. They rated the pleasantness of episodes they associated with targets, and then performed unexpected free recall tests. When the targets were associated with episodes that were past events, all participants recalled more of the targets associated with pleasant and unpleasant episodes than those associated with neutral episodes. However, when the targets were associated with episodes expected to occur in the future, only participants with higher emotional intelligence scores recalled more of the targets associated with pleasant and unpleasant episodes. The participants with lower emotional intelligence scores recalled the three target types with similar accuracy. These results were interpreted as showing that emotional intelligence is associated with the processing of targets associated with future episodes as retrieval cues.

  9. 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

  10. Functional Analysis Helps to Define KCNC3 Mutational Spectrum in Dutch Ataxia Cases

    PubMed Central

    Fokkens, Michiel R.; Meijer, Michel; Boerrigter, Melissa; Verschuuren-Bemelmans, Corien C.; Kremer, Berry P. H.; van de Warrenburg, Bart P.; Dooijes, Dennis; Boddeke, Erik; Sinke, Richard J.; Verbeek, Dineke S.

    2015-01-01

    Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominantly inherited neurodegenerative disorder of the cerebellum caused by mutations in the voltage gated potassium channel KCNC3. To identify novel pathogenic SCA13 mutations in KCNC3 and to gain insights into the disease prevalence in the Netherlands, we sequenced the entire coding region of KCNC3 in 848 Dutch cerebellar ataxia patients with familial or sporadic origin. We evaluated the pathogenicity of the identified variants by co-segregation analysis and in silico prediction followed by biochemical and electrophysiological studies. We identified 19 variants in KCNC3 including 2 non-coding, 11 missense and 6 synonymous variants. Two missense variants did not co-segregate with the disease and were excluded as potentially disease-causing mutations. We also identified the previously reported p.R420H and p.R423H mutations in our cohort. Of the remaining 7 missense variants, functional analysis revealed that 2 missense variants shifted Kv3.3 channel activation to more negative voltages. These variations were associated with early disease onset and mild intellectual disability. Additionally, one other missense variant shifted channel activation to more positive voltages and was associated with spastic ataxic gait. Whereas, the remaining missense variants did not change any of the channel characteristics. Of these three functional variants, only one variant was in silico predicted to be damaging and segregated with disease. The other two variants were in silico predicted to be benign and co-segregation analysis was not optimal or could only be partially confirmed. Therefore, we conclude that we have identified at least one novel pathogenic mutation in KCNC3 that cause SCA13 and two additionally potential SCA13 mutations. This leads to an estimate of SCA13 prevalence in the Netherlands to be between 0.6% and 1.3%. PMID:25756792

  11. NPC1 is enriched in unexplained early onset ataxia: a targeted high-throughput screening.

    PubMed

    Synofzik, Matthis; Harmuth, Florian; Stampfer, Miriam; Müller Vom Hagen, Jennifer; Schöls, Ludger; Bauer, Peter

    2015-11-01

    Niemann-Pick disease type C (NP-C) is a rare autosomal-recessive neurodegenerative disease featuring pleiotropic neurological, psychiatric and visceral manifestations. Since many of the adult manifestations can be non-specific or missed, NP-C often goes undetected in adult-onset patients. Here we hypothesized that targeted high-throughput sequencing allows identifying NP-C patients among subjects with unexplained early-onset ataxia (EOA) and, moreover, that this population is enriched for NPC1 mutations. From 204 consecutive EOA patients, all 108 subjects with an established diagnosis were removed (including 4 NPC1 patients), yielding a target cohort of 96 subjects with unexplained EOA, but without primary suspicion of NP-C. This cohort was investigated for NPC1/NPC2 mutations using a high-coverage HaloPlex gene panel including 122 ataxia genes. Among 96 samples, we identified 4 known NPC1 mutations, 3 novel NPC1 missense variants of uncertain significance (VUS) and 1 novel NPC2 missense VUS. The total mutant allele frequency (8/192 = 4.17 %) was significantly enriched compared with control population data (1.57 %; p = 0.011). Two NPC1-positive patients were identified (both with non-specific incipient clinical features), giving a NPC1 patient frequency of 2/96 = 2.1 % in unexplained EOA and of 6/204 = 2.9 % in the total EOA series. NPC1 mutations are substantially enriched in unexplained EOA, demonstrating EOA as a risk-group for NP-C disease. Targeted high-throughput sequencing allows to identify also those NP-C patients with non-specific conditions where the diagnosis has initially been missed. This method does not require having considered NP-C during differential diagnosis, but allows identification of NP-C as part of the default analysis.

  12. Spontaneous shaker rat mutant – a new model for X-linked tremor/ataxia

    PubMed Central

    Figueroa, Karla P.; Paul, Sharan; Calì, Tito; Lopreiato, Raffaele; Karan, Sukanya; Frizzarin, Martina; Ames, Darren; Zanni, Ginevra; Brini, Marisa; Dansithong, Warunee; Milash, Brett; Scoles, Daniel R.; Carafoli, Ernesto; Pulst, Stefan M.

    2016-01-01

    ABSTRACT The shaker rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC) degeneration exhibiting a shaking ataxia and wide stance. Generation of Wistar Furth (WF)/Brown Norwegian (BN) F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm). In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R) to cysteine (C) change at codon 35 of the ATPase, Ca2+ transporting, plasma membrane 3 (Atp2b3) gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT) replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3R35C function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker rat presents a good candidate for the shaker rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes. PMID:27013529

  13. Virtual Reality as an Ecologically Valid Tool for Assessing Multifaceted Episodic Memory in Children and Adolescents

    ERIC Educational Resources Information Center

    Picard, Laurence; Abram, Maria; Orriols, Eric; Piolino, Pascale

    2017-01-01

    The majority of episodic memory (EM) tests are far removed from what we experience in daily life and from the definition of this type of memory. This study examines the developmental trajectory of the main aspects of episodic memory--what, where, and when--and of feature binding in a naturalistic virtual environment. A population of 125…

  14. [Therapeutic strategies in the first psychotic episode].

    PubMed

    Douki, S; Taktak, M J; Ben Zineb, S; Cheour, M

    1999-11-01

    principles for first-episode psychosis are to maximise benefit and minimise side effects because the first experience of medication may influence a patient's future attitudes of therapy of all types. Effective strategies which may reduce long-term morbidity and improve recovery are currently available but their implementation is too often delayed. The time lag between the onset of symptoms and the start of treatment can be many months or years and this delay can have serious consequences. The critical period of the first 2-5 years after the first psychotic episode is a time of maximum vulnerability and of maximum opportunity. Consequently, actions should be undertaken to promote early recognition and assistance in psychotic disorders: understanding of the factors that may cause delay in treatment can help minimise this problem and lead to the initiation of appropriate treatment at the earliest opportunity. Training the general practitioners who have an important part to play in the early recognition is also of crucial importance.

  15. Gastrocnemius and soleus spasticity and muscle length in Friedreich's ataxia.

    PubMed

    Milne, Sarah C; Corben, Louise A; Yiu, Eppie; Delatycki, Martin B; Georgiou-Karistianis, Nellie

    2016-07-01

    Lower limb spasticity compromises the independence of people with Friedreich's ataxia (FRDA). This study sought to examine lower limb spasticity in FRDA in order to offer new insight as to the best approach and timing of spasticity management. Gastrocnemius and soleus spasticity and muscle length were measured by the Modified Tardieu Scale (MTS) in 31 participants with typical and late-onset FRDA. Relationships between the MTS and the Friedreich Ataxia Rating Scale (FARS), Functional Independence Measure (FIM), and disease duration were analysed. Differences between ambulant (n=18) and non-ambulant (n=13) participants were also examined. All participants had spasticity in at least one muscle, and 38.9% of ambulant and 69.2% of non-ambulant participants had contracture in one or both of their gastrocnemius muscles. Significant negative correlations were found between both gastrocnemius and soleus angle of catch and the FARS score. The FIM score also demonstrated significant correlations with gastrocnemius muscle length and angle of catch. Gastrocnemius and soleus spasticity and contracture is apparent in people with FRDA. Spasticity is evident early in the disease and in ambulant participants. Management of spasticity and reduced muscle length should be considered in people with FRDA at disease onset to optimise function.

  16. Fragile X-associated tremor/ataxia syndrome.

    PubMed

    Hagerman, Paul J; Hagerman, Randi J

    2015-03-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects some but not all carriers of small, noncoding 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 (45-54 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.

  17. 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

  18. Common data elements for clinical research in Friedreich's ataxia.

    PubMed

    Lynch, David R; Pandolfo, Massimo; Schulz, Jorg B; Perlman, Susan; Delatycki, Martin B; Payne, R Mark; Shaddy, Robert; Fischbeck, Kenneth H; Farmer, Jennifer; Kantor, Paul; Raman, Subha V; Hunegs, Lisa; Odenkirchen, Joanne; Miller, Kristy; Kaufmann, Petra

    2013-02-01

    To reduce study start-up time, increase data sharing, and assist investigators conducting clinical studies, the National Institute of Neurological Disorders and Stroke embarked on an initiative to create common data elements for neuroscience clinical research. The Common Data Element Team developed general common data elements, which are commonly collected in clinical studies regardless of therapeutic area, such as demographics. In the present project, we applied such approaches to data collection in Friedreich's ataxia (FRDA), a neurological disorder that involves multiple organ systems. To develop FRDA common data elements, FRDA experts formed a working group and subgroups to define elements in the following: ataxia and performance measures; biomarkers; cardiac and other clinical outcomes; and demographics, laboratory tests, and medical history. The basic development process included identification of international experts in FRDA clinical research, meeting by teleconference to develop a draft of standardized common data elements recommendations, vetting of recommendations across the subgroups, and dissemination of recommendations to the research community for public comment. The full recommendations were published online in September 2011 at http://www.commondataelements.ninds.nih.gov/FA.aspx. The subgroups' recommendations are classified as core, supplemental, or exploratory. Template case report forms were created for many of the core tests. The present set of data elements should ideally lead to decreased initiation time for clinical research studies and greater ability to compare and analyze data across studies. Their incorporation into new, ongoing studies will be assessed in an ongoing fashion to define their utility in FRDA.

  19. Measuring Inhibition and Cognitive Flexibility in Friedreich Ataxia.

    PubMed

    Corben, Louise A; Klopper, Felicity; Stagnitti, Monique; Georgiou-Karistianis, Nellie; Bradshaw, John L; Rance, Gary; Delatycki, Martin B

    2017-02-22

    Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with subtle impact on cognition. Inhibitory processes and cognitive flexibility were examined in FRDA by assessing the ability to suppress a predictable verbal response. We administered the Hayling Sentence Completion Test (HSCT), the Trail Making Test, and the Stroop Test to 43 individuals with FRDA and 42 gender- and age-matched control participants. There were no significant group differences in performance on the Stroop or Trail Making Test whereas significant impairment in cognitive flexibility including the ability to predict and inhibit a pre-potent response as measured in the HSCT was evident in individuals with FRDA. These deficits did not correlate with clinical characteristics of FRDA (age of disease onset, disease duration, number of guanine-adenine-adenine repeats on the shorter or larger FXN allele, or Friedreich Ataxia Rating Scale score), suggesting that such impairment may not be related to the disease process in a straightforward way. The observed specific impairment of inhibition and predictive capacity in individuals with FRDA on the HSCT task, in the absence of impairment in associated executive functions, supports cerebellar dysfunction in conjunction with disturbance to cortico-thalamo-cerebellar connectivity, perhaps via inability to access frontal areas necessary for successful task completion.

  20. Consensus Paper: Pathological Mechanisms Underlying Neurodegeneration in Spinocerebellar Ataxias

    PubMed Central

    Matilla-Dueñas, A.; Ashizawa, T.; Brice, A.; Magri, S.; McFarland, K. N.; Pandolfo, M.; Pulst, S. M.; Riess, O.; Rubinsztein, D. C.; Schmidt, J.; Schmidt, T.; Scoles, D. R.; Stevanin, G.; Taroni, F.; Underwood, B. R.; Sánchez, I.

    2014-01-01

    Intensive scientific research devoted in the recent years to understand the molecular mechanisms or neurodegeneration in spinocerebellar ataxias (SCAs) are identifying new pathways and targets providing new insights and a better understanding of the molecular pathogenesis in these diseases. In this consensus manuscript, the authors discuss their current views on the identified molecular processes causing or modulating the neurodegenerative phenotype in spinocerebellar ataxias with the common opinion of translating the new knowledge acquired into candidate targets for therapy. The following topics are discussed: transcription dysregulation, protein aggregation, autophagy, ion channels, the role of mitochondria, RNA toxicity, modulators of neurodegeneration and current therapeutic approaches. Overall point of consensus includes the common vision of neurodegeneration in SCAs as a multifactorial, progressive and reversible process, at least in early stages. Specific points of consensus include the role of the dysregulation of protein folding, transcription, bioenergetics, calcium handling and eventual cell death with apoptotic features of neurons during SCA disease progression. Unresolved questions include how the dysregulation of these pathways triggers the onset of symptoms and mediates disease progression since this understanding may allow effective treatments of SCAs within the window of reversibility to prevent early neuronal damage. Common opinions also include the need for clinical detection of early neuronal dysfunction, for more basic research to decipher the early neurodegenerative process in SCAs in order to give rise to new concepts for treatment strategies and for the translation of the results to preclinical studies and, thereafter, in clinical practice. PMID:24307138

  1. Episodic Accretion in Young Stars

    NASA Astrophysics Data System (ADS)

    Audard, M.; Ábrahám, P.; Dunham, M. M.; Green, J. D.; Grosso, N.; Hamaguchi, K.; Kastner, J. H.; Kóspál, Á.; Lodato, G.; Romanova, M. M.; Skinner, S. L.; Vorobyov, E. I.; Zhu, Z.

    In the last 20 years, the topic of episodic accretion has gained significant interest in the star-formation community. It is now viewed as a common, although still poorly understood, phenomenon in low-mass star formation. The FU Orionis objects (FUors) are long-studied examples of this phenomenon. FU Orionis objects are believed to undergo accretion outbursts during which the accretion rate rapidly increases from typically 10-7 to a few 10-4 M⊙ yr-1, and remains elevated over several decades or more. EXors, a loosely defined class of pre-main-sequence stars, exhibit shorter and repetitive outbursts, associated with lower accretion rates. The relationship between the two classes, and their connection to the standard pre-main-sequence evolutionary sequence, is an open question: Do they represent two distinct classes, are they triggered by the same physical mechanism, and do they occur in the same evolutionary phases? Over the past couple of decades, many theoretical and numerical models have been developed to explain the origin of FUor and EXor outbursts. In parallel, such accretion bursts have been detected at an increasing rate, and as observing techniques improve, each individual outburst is studied in increasing detail. We summarize key observations of pre-main-sequence star outbursts, and review the latest thinking on outburst triggering mechanisms, the propagation of outbursts from star/disk to disk/jet systems, the relation between classical EXors and FUors, and newly discovered outbursting sources — all of which shed new light on episodic accretion. We finally highlight some of the most promising directions for this field in the near- and long-term.

  2. Fragment based G-QSAR and molecular dynamics based mechanistic simulations into hydroxamic-based HDAC inhibitors against spinocerebellar ataxia.

    PubMed

    Sinha, Siddharth; Tyagi, Chetna; Goyal, Sukriti; Jamal, Salma; Somvanshi, Pallavi; Grover, Abhinav

    2016-10-01

    Expansion of polyglutamine (CAG) triplets within the coding gene ataxin 2 results in transcriptional repression, forming the molecular basis of the neurodegenerative disorder named spinocerebellar ataxia type-2 (SCA2). HDAC inhibitors (HDACi) have been elements of great interest in polyglutamine disorders such as Huntington's and Ataxia's. In this study, we have selected hydroxamic acid derivatives as HDACi and performed fragment-based G-QSAR, molecular docking studies and molecular dynamics simulations for elucidating the dynamic mode of action of HDACi with His-Asp catalytic dyad of HDAC4. The model was statistically validated to establish its predictive robustness. The model was statistically significant with r(2) value of .6297, cross-validated co-relation coefficient q(2) value of .5905 and pred_r(2) (predicted square co-relation coefficient) value of .85. An F-test value of 56.11 confirms absolute robustness of the model. Two combinatorial libraries comprising of 3180 compounds were created with hydroxamate moiety as the template and their pIC50 activities were predicted based on the G-QSAR model. The combinatorial library created was screened on the basis of predicted activity (pIC50), with two resultant top scoring compounds, HIC and DHC. The interaction of the compounds with His-Asp dyad in terms of H-bond interactions with His802, Asp840, Pro942, and Gly975 residues of HDAC4 was evaluated by docking and 20 ns long molecular dynamics simulations. This study provides valuable leads for structural substitutions required for hydroxamate moiety to exhibit enhanced inhibitory activity against HDAC4. The reported compounds demonstrated good binding and thus can be considered as potent therapeutic leads against ataxia.

  3. Impact of episodic thinking on altruism.

    PubMed

    Yi, Richard; Pickover, Alison; Stuppy-Sullivan, Allison M; Baker, Sydney; Landes, Reid D

    2016-07-01

    Episodic future thinking, which refers to the use of prospective imagery to concretely imagine oneself in future scenarios, has been shown to reduce delay discounting (enhance self-control). A parallel approach, in which prospective imagery is used to concretely imagine other's scenarios, may similarly reduce social discounting (i.e., enhance altruism). In study 1, participants engaged in episodic thinking about the self or others, in a repeated-measures design, while completing a social discounting task. Reductions in social discounting were observed as a function of episodic thinking about others, though an interaction with order was also observed. Using an independent-measures design in study 2, the effect of episodic thinking about others was replicated. Study 3 addressed a limitation of studies 1 and 2, the possibility that simply thinking about others decreased social discounting. Capitalizing on Construal Level Theory, which specifies that social distance and time in the future are both dimensions of a common psychological distance, we hypothesized that episodic future thinking should also decrease social discounting. Participants engaged in episodic future thinking or episodic present thinking, in a repeated-measures design, while completing a social discounting task. The pattern of results was similar to study 1, providing support for the notion that episodic thinking about psychologically distant outcomes (for others or in the future) reduces social discounting. Application of similar episodic thinking approaches may enhance altruism.

  4. Variable Protostellar Accretion with Episodic Bursts

    NASA Astrophysics Data System (ADS)

    Vorobyov, Eduard I.; Basu, Shantanu

    2015-06-01

    We present the latest development of the disk gravitational instability and fragmentation model, originally introduced by us to explain episodic accretion bursts in the early stages of star formation. Using our numerical hydrodynamics model with improved disk thermal balance and star-disk interaction, we computed the evolution of protostellar disks formed from the gravitational collapse of prestellar cores. In agreement with our previous studies, we find that cores of higher initial mass and angular momentum produce disks that are more favorable to gravitational instability and fragmentation, while a higher background irradiation and magnetic fields moderate the disk tendency to fragment. The protostellar accretion in our models is time-variable, thanks to the nonlinear interaction between different spiral modes in the gravitationally unstable disk, and can undergo episodic bursts when fragments migrate onto the star owing to the gravitational interaction with other fragments or spiral arms. Most bursts occur in the partly embedded Class I phase, with a smaller fraction taking place in the deeply embedded Class 0 phase and a few possible bursts in the optically visible Class II phase. The average burst duration and mean luminosity are found to be in good agreement with those inferred from observations of FUors. The model predicts the existence of two types of bursts: the isolated ones, showing well-defined luminosity peaks separated with prolonged periods (˜ {{10}4} yr) of quiescent accretion, and clustered ones, demonstrating several bursts occurring one after another during just a few hundred years. Finally, we estimate that 40%-70% of the star-forming cores can display bursts after forming a star-disk system.

  5. Different subregional metabolism patterns in patients with cerebellar ataxia by 18F-fluorodeoxyglucose positron emission tomography.

    PubMed

    Oh, Minyoung; Kim, Jae Seung; Oh, Jungsu S; Lee, Chong Sik; Chung, Sun Ju

    2017-01-01

    We evaluated cerebellar subregional metabolic alterations in patients with cerebellar ataxia, a representative disease involving the spinocerebellum. We retrospectively analyzed 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) images in 44 patients with multiple system atrophy of the cerebellar type (MSA-C), 9 patients with spinocerebellar ataxia (SCA) type 2, and 14 patients with SCA type 6 and compared with 15 patients with crossed cerebellar diaschisis (CCD) and 89 normal controls. Cerebellar subregional metabolism was assessed using 13 cerebellar subregions (bilateral anterior lobes [ANT], superior/mid/inferior posterior lobes [SUPP/MIDP/INFP], dentate nucleus [DN], anterior vermis [ANTV], and superior/inferior posterior vermis [SUPV/INFV]) to determine FDG uptake ratios. MSA-C and SCA type 2 showed severely decreased metabolic ratios in all cerebellar subregions compared to normal controls (ANT, 0.58 ± 0.08 and 0.50 ± 0.06 vs. 0.82 ± 0.07, respectively, p < 0.001). SCA type 6 showed lower metabolic ratios in almost all cerebellar subregions (ANT, 0.57 ± 0.06, p < 0.001) except INFV. Anterior-posterior lobe ratio measurements revealed that SCA type 2 (Right, 0.81 ± 0.05 vs. 0.88 ± 0.04, p < 0.001; Left, 0.83 ± 0.05 vs. 0.88 ± 0.04, p = 0.003) and SCA type 6 (Right, 0.72 ± 0.05 vs. 0.88 ± 0.04, p < 0.001; Left, 0.72 ± 0.05 vs. 0.88 ± 0.04, p < 0.001) showed preferential hypometabolism in the anterior lobe compared to normal controls, which was not observed in CCD and MSA-C. Asymmetric indices were higher in CCD and MSA-C than in normal controls (p < 0.001), whereas such differences were not found in SCA types 2 and 6. In summary, quantitative analysis of cerebellar subregional metabolism ratios revealed preferential involvement of the anterior lobe, corresponding to the spinocerebellum, in patients with cerebellar ataxia, whereas patients with CCD and MSA-C exhibited more asymmetric hypometabolism in the posterior lobe.

  6. Different subregional metabolism patterns in patients with cerebellar ataxia by 18F-fluorodeoxyglucose positron emission tomography

    PubMed Central

    Kim, Jae Seung; Oh, Jungsu S.; Lee, Chong Sik; Chung, Sun Ju

    2017-01-01

    We evaluated cerebellar subregional metabolic alterations in patients with cerebellar ataxia, a representative disease involving the spinocerebellum. We retrospectively analyzed 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) images in 44 patients with multiple system atrophy of the cerebellar type (MSA-C), 9 patients with spinocerebellar ataxia (SCA) type 2, and 14 patients with SCA type 6 and compared with 15 patients with crossed cerebellar diaschisis (CCD) and 89 normal controls. Cerebellar subregional metabolism was assessed using 13 cerebellar subregions (bilateral anterior lobes [ANT], superior/mid/inferior posterior lobes [SUPP/MIDP/INFP], dentate nucleus [DN], anterior vermis [ANTV], and superior/inferior posterior vermis [SUPV/INFV]) to determine FDG uptake ratios. MSA-C and SCA type 2 showed severely decreased metabolic ratios in all cerebellar subregions compared to normal controls (ANT, 0.58 ± 0.08 and 0.50 ± 0.06 vs. 0.82 ± 0.07, respectively, p < 0.001). SCA type 6 showed lower metabolic ratios in almost all cerebellar subregions (ANT, 0.57 ± 0.06, p < 0.001) except INFV. Anterior-posterior lobe ratio measurements revealed that SCA type 2 (Right, 0.81 ± 0.05 vs. 0.88 ± 0.04, p < 0.001; Left, 0.83 ± 0.05 vs. 0.88 ± 0.04, p = 0.003) and SCA type 6 (Right, 0.72 ± 0.05 vs. 0.88 ± 0.04, p < 0.001; Left, 0.72 ± 0.05 vs. 0.88 ± 0.04, p < 0.001) showed preferential hypometabolism in the anterior lobe compared to normal controls, which was not observed in CCD and MSA-C. Asymmetric indices were higher in CCD and MSA-C than in normal controls (p < 0.001), whereas such differences were not found in SCA types 2 and 6. In summary, quantitative analysis of cerebellar subregional metabolism ratios revealed preferential involvement of the anterior lobe, corresponding to the spinocerebellum, in patients with cerebellar ataxia, whereas patients with CCD and MSA-C exhibited more asymmetric hypometabolism in the posterior lobe. PMID:28319124

  7. Depression as the Primary Cause of Insomnia and Excessive Daytime Sleepiness in a Family with Multiple Cases of Spinocerebellar Ataxia

    PubMed Central

    Hsu, Chun-Hsien; Chen, Yen-Lin; Pei, Dee; Yu, Shu-Man; Liu, I-Chao

    2016-01-01

    Spinocerebellar ataxia (SCA) is a hereditary disease characterized by central nervous system-related motor dysfunctions. Sleep disorders and frequent non-motor manifestations are commonly comorbid with SCA. To elucidate this relationship, we present three cases in a family that included multiple SCA type 2 patients with various sleep disorders. Complete physical examination, and genetic and imaging studies were performed. Anti-parkinsonism medications were prescribed after neurological examination. Clonazepam and/or quetiapine were administered for sleep disorders but failed to resolve insomnia and excessive daytime sleepiness (EDS). Based on DSM-5 criteria, all cases were diagnosed with depression. After treatment with serotonin-norepinephrine reuptake inhibitors and noradrenergic and specific serotonergic antidepressants, symptoms of insomnia and EDS, which are strongly associated with depression in SCA type 2 patients, improved significantly. It is crucial to recognize insomnia and EDS in neurodegenerative diseases, not only for earlier diagnosis, but also to improve quality of life. Citation: Hsu CH, Chen YL, Pei D, Yu SM, Liu IC. Depression as the primary cause of insomnia and excessive daytime sleepiness in a family with multiple cases of spinocerebellar ataxia. J Clin Sleep Med 2016;12(7):1059–1061. PMID:27166302

  8. Childhood Ataxia: Clinical Features, Pathogenesis, Key Unanswered Questions, and Future Directions

    PubMed Central

    Ashley, Claire N.; Hoang, Kelly D.; Lynch, David R.; Perlman, Susan L.; Maria, Bernard L.

    2013-01-01

    Childhood ataxia is characterized by impaired balance and coordination primarily due to cerebellar dysfunction. Friedreich ataxia, a form of childhood ataxia, is the most common multisystem autosomal recessive disease. Most of these patients are homozygous for the GAA repeat expansion located on the first intron of the frataxin gene on chromosome 9. Mutations in the frataxin gene impair mitochondrial function, increase reactive oxygen species, and trigger redistribution of iron in the mitochondria and cytosol. Targeted therapies for Friedreich ataxia are undergoing testing. In addition, a centralized database, patient registry, and natural history study have been launched to support clinical trials in Friedreich ataxia. The 2011 Neurobiology of Disease in Children symposium, held in conjunction with the 40th annual Child Neurology Society meeting, aimed to (1) describe clinical features surrounding Friedreich ataxia, including cardiomyopathy and genetics; (2) discuss recent advances in the understanding of the pathogenesis of Friedreich ataxia and developments of clinical trials; (3) review new investigations of characteristic symptoms; (4) establish clinical and biochemical overlaps in neurodegenerative diseases and possible directions for future basic, translational, and clinical studies. PMID:22859693

  9. The effectiveness of allied health care in patients with ataxia: a systematic review.

    PubMed

    Fonteyn, Ella M R; Keus, Samyra H J; Verstappen, Carla C P; Schöls, Ludger; de Groot, Imelda J M; van de Warrenburg, Bart P C

    2014-02-01

    Many patients with cerebellar ataxia have serious disabilities in daily life, while pharmacological treatment options are absent. Therefore, allied health care is considered to be important in the management of these patients. The goal of this review is to evaluate scientific evidence for allied health care in cerebellar ataxia, to identify effective treatment strategies, and to give recommendations for clinical practice and further research. A systematic search for clinical trials concerning allied health care in cerebellar ataxias was conducted using the electronic databases of PubMed, Medline, Embase, Cinahl and Pedro, and references lists of articles, in the time period from 1980 up to and including December 2011 in English and Dutch. We identified 14 trials, of which the four best studies were formally of moderate methodological quality. There was a wide variation in disease entities and interventions. The combined data indicate that physical therapy may lead to an improvement of ataxia symptoms and daily life functions in patients with degenerative cerebellar ataxia (level 2), and in other diseases causing cerebellar ataxia (level 3). When added to physical therapy, occupational therapy might improve global functional status, and occupational therapy alone may diminish symptoms of depression (level 3). There are insufficient data for speech and language therapy. Despite the widespread use of allied health care interventions in cerebellar ataxia, there is a lack of good quality studies that have evaluated such interventions. We found some support for the implementation of physical therapy and occupational therapy, but more research is needed to develop recommendations for clinical practice.

  10. Episodic plate tectonics on Venus

    NASA Technical Reports Server (NTRS)

    Turcotte, Donald

    1992-01-01

    Studies of impact craters on Venus from the Magellan images have placed important constraints on surface volcanism. Some 840 impact craters have been identified with diameters ranging from 2 to 280 km. Correlations of this impact flux with craters on the Moon, Earth, and Mars indicate a mean surface age of 0.5 +/- 0.3 Ga. Another important observation is that 52 percent of the craters are slightly fractured and only 4.5 percent are embayed by lava flows. These observations led researchers to hypothesize that a pervasive resurfacing event occurred about 500 m.y. ago and that relatively little surface volcanism has occurred since. Other researchers have pointed out that a global resurfacing event that ceased about 500 MYBP is consistent with the results given by a recent study. These authors carried out a series of numerical calculations of mantle convection in Venus yielding thermal evolution results. Their model considered crustal recycling and gave rapid planetary cooling. They, in fact, suggested that prior to 500 MYBP plate tectonics was active in Venus and since 500 MYBP the lithosphere has stabilized and only hot-spot volcanism has reached the surface. We propose an alternative hypothesis for the inferred cessation of surface volcanism on Venus. We hypothesize that plate tectonics on Venus is episodic. Periods of rapid plate tectonics result in high rates of subduction that cool the interior resulting in more sluggish mantle convection.

  11. Psychiatric disorders and muscle tenderness in episodic and chronic migraine.

    PubMed

    Mongini, Franco; Deregibus, Andrea; Rota, Eugenia

    2005-09-01

    This review first reports on the data concerning the relationship between migraine and personality traits and psychiatric disorders. The relationship between migraine and tenderness of the pericranial and cervical muscles is then discussed. In one study, a psychologic assessment was performed in 56 women with migraine, and the Minnesota Multiphase Personality Inventory (MMPI) and State Trait Anxiety Inventory were administered at baseline (T0) and after 6-7 years (T2). Frequency, severity and duration of migraine were recorded at T0, after treatment (T1) and at T2, and their relationship to the prevalence of depression, MMPI and State Trait Anxiety Inventory data were examined. Pain parameters improved in all patients in T0-1, but were higher at T2 in patients with depression at T0. The patients whose migraine improved at T2 had significantly lower MMPI and State Trait Anxiety Inventory scores at T0 and T2. Moreover, the prevalence of depression of the patients whose migraine improved at T2 was 37.5% at T0 and decreased to 12.5% at T2. The authors subsequently studied the function of the frontal lobe in 23 female patients previously treated for chronic migraine and 23 controls by applying three neuropsychologic tests (gambling task, tower of hanoi-3 and object alternation test). The patient group performed significantly worse on the tower of hanoi-3 and the object alternation test. In order to assess the extent to which muscle tenderness may relate to psychiatric disorders in patients with migraine and tension-type headache, diagnosed according International Headache Society criteria [2004], a psychologic assessment was performed and palpation tenderness scores calculated for the pericranial and cervical muscles in 459 patients. In total, 125 patients had frequent episodic migraine, 97 had chronic migraine, 82 had frequent episodic tension-type headache and chronic tension-type headache was present in 83. In a further 72 patients, both episodic migraine and

  12. Training Lessons Learned from Peak Performance Episodes.

    ERIC Educational Resources Information Center

    Fobes, James L.

    A major challenge confronting the United States Army is to obtain optimal performance from both its human and machine resources. This study examines episodes of peak performance in soldiers and athletes. Three cognitive components were found to enable episodes of peak performance: psychological readiness (activating optimal arousal and emotion…

  13. Police Response to Family Abduction Episodes.

    ERIC Educational Resources Information Center

    Plass, Peggy S.; And Others

    1995-01-01

    Examines role of police in responding to family abduction episodes using data from a national survey. Addresses questions concerning frequency of police involvement, how abductions to which police respond differ from those to which they don't, actions taken by police, and the effects of their actions on episode outcomes. (LKS)

  14. A Transactional Approach to Transfer Episodes

    ERIC Educational Resources Information Center

    Jornet, Alfredo; Roth, Wolff-Michael; Krange, Ingeborg

    2016-01-01

    In this article we present an analytical framework for approaching transfer episodes--episodes in which participants declare or can be declared to bring prior experience to bear on the current task organization. We build on Dewey's writings about the continuity of experience, Vygotsky's ideas of unit analysis, as well as more recent developments…

  15. Vitamin B12 deficiency presenting as acute ataxia.

    PubMed

    Crawford, John Ross; Say, Daphne

    2013-03-26

    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.

  16. Neuropathology in classical and variant ataxia-telangiectasia.

    PubMed

    Verhagen, Mijke M M; Martin, Jean-Jacques; van Deuren, Marcel; Ceuterick-de Groote, Chantal; Weemaes, Corry M R; Kremer, Berry H P H; Taylor, Malcolm A R; Willemsen, Michèl A A P; Lammens, Martin

    2012-06-01

    Ataxia-telangiectasia (A-T) is classically characterized by progressive neurodegeneration, oculocutaneous telangiectasia, immunodeficiency and elevated α-fetoprotein levels. Some patients, classified as variant A-T, exhibit a milder clinical course. In the latter patients extrapyramidal symptoms, instead of cerebellar ataxia, tend to be the dominating feature and other classical disease hallmarks, like telangiectasia, appear later or even may be absent. Some patients with variant disease have clinically pronounced anterior horn cell degeneration. Neuropathological studies of genetically proven A-T patients are lacking. The aims of our study were to describe the neuropathology of three A-T patients; in two of them the diagnosis was genetically confirmed. The neuropathological findings were compared with those of all known published autopsy findings in A-T patients up to now. Two classical A-T patients aged 19 and 22 and a 33-year-old patient with variant disease were autopsied. In line with previous reports, our patients had severe cerebellar atrophy, less pronounced degeneration of the dentate nucleus and inferior olive, degeneration of the posterior columns and neurogenic muscular atrophy. In addition, all three had anterior horn cell degeneration, which was most prominent at the lumbar level. Compared to the literature, the degenerative changes in the brain stem of the variant A-T patient were somewhat less than anticipated for his age. Degenerative changes in the cerebellum and spinal cord were comparable with those in the literature. Progeric changes were lacking. In conclusion, compared to classical A-T, the variant A-T patient showed essentially the same, only slightly milder neuropathological abnormalities, except for anterior horn degeneration.

  17. Ayurvedic approach in the management of spinocerebellar ataxia-2

    PubMed Central

    Singh, Sarvesh Kumar; Rajoria, Kshipra

    2016-01-01

    Spinocerebellar ataxia -2 is a progressive, degenerative genetic disease caused by an expanded (CAG) trinucleotide repetition on the chromosome 12 resulting in production of an abnormal protein called ataxin-2. There is no known effective management or cure in biomedicine for this genetic disease. In the present study a case of SCA2 that was treated with Ayurvedic intervention is reported. Ayurvedic treatments in this case were directed towards alleviating symptoms and to reduce severe disability due to progressive nature of disease. A 42 year old male patient was diagnosed for Vāta vyādhi (group of various neurological disorders) and was- treated with Śālisastika pinda svedana (sudation with bolus of medicated cooked rice) for 30 days-, Śirobasti (sudation of head with the help of a cap on head) with Aśvagandhā taila for 45 days and Balādi ksīra basti (enema with medicated milk) with Aśvagandhā taila anuvāsana (enema with oil) for 30 days in Karma basti krama (30 days regime of purification and oleation enema) along with a combination of Ayurvedic oral drugs which consisted of Brahadvātacintāmanirasa – 125 mg, Vasantāmaltī rasa- 125 mg, Daśamūla kvātha- 40 ml, Aśvagandhā cūrṇa (powder of Withania somnifera DUNAL)- 3g, Amrtā cūrṇa (powder of Tinospora cordifolia Willd.)- 500 mg, Muktāśukti pisti – 500 mg, Yogarāja Guggulu – 500 mg twice a day for 2 months. Patient's condition was assessed on the Scale for Assessment and Rating of Ataxia (SARA). Before treatment, mean SARA score was 35. This reduced to 15 after treatment. Good relief in dysarthria, fasciculation, heaviness in eye, blurred vision, axial tremor; constipation and quality of life were observed in this case. PMID:27143801

  18. Divergent thinking and constructing episodic simulations.

    PubMed

    Addis, Donna Rose; Pan, Ling; Musicaro, Regina; Schacter, Daniel L

    2016-01-01

    Divergent thinking likely plays an important role in simulating autobiographical events. We investigated whether divergent thinking is differentially associated with the ability to construct detailed imagined future and imagined past events as opposed to recalling past events. We also examined whether age differences in divergent thinking might underlie the reduced episodic detail generated by older adults. The richness of episodic detail comprising autobiographical events in young and older adults was assessed using the Autobiographical Interview. Divergent thinking abilities were measured using the Alternative Uses Task. Divergent thinking was significantly associated with the amount of episodic detail for imagined future events. Moreover, while age was significantly associated with imagined episodic detail, this effect was strongly related to age-related changes in episodic retrieval rather than divergent thinking.

  19. The effect of bleomycin on DNA synthesis in ataxia telangiectasia lymphoid cells

    SciTech Connect

    Cohen, M.M.; Simpson, S.J.

    1982-01-01

    Bleomycin, a radiomimetic glycopeptide, inhibits de novo DNA synthesis in ataxia telangiectasia lymphoblastoid B cells to a markedly lesser extent than in normal and xeroderma pigmentosum lymphoid cells. This observation is similar to that following ionizing radiation; however, the effect is slower following the chemical treatment. Recovery of the normal cells occurs 15-18 hours after treatment, whereas the ataxia telangiectasia lines do not attain normal levels of DNA synthesis during the entire 24-hour observation period. Similar differences were not observed following treatment with mitomycin C, a bifunctional alkylating agent, indicating a specific effect of bleomycin on DNA synthesis in ataxia telangiectasia cells. Following bleomycin treatment and preincubation with hydroxyurea, residual DNA synthesis in ataxia telangiectasia cells was similar to that in both normal and xeroderma pigmentosum lymphoid lines, suggesting that the capacity to repair the induced DNA lesion is present.

  20. Memory loss and ataxia after hyperemesis gravidarum: a case of Wernicke-Korsakoff syndrome.

    PubMed

    Accetta, Solange G; Abeche, Alberto M; Buchabqui, Jorge A; Hammes, Luciano; Pratti, Raquel; Afler, Taciana; Capp, Edison

    2002-04-10

    Hyperemesis gravidarum can induce Wernicke-Korsakoff syndrome (WKS), a thiamin deficiency disorder characterized by ocular abnormalities, ataxia and disturbance of consciousness. This should be considered in the differential diagnosis of pregnant patients with persisting vomiting and neurological alterations.

  1. How do episodic and semantic memory contribute to episodic foresight in young children?

    PubMed Central

    Martin-Ordas, Gema; Atance, Cristina M.; Caza, Julian S.

    2014-01-01

    Humans are able to transcend the present and mentally travel to another time, place, or perspective. Mentally projecting ourselves backwards (i.e., episodic memory) or forwards (i.e., episodic foresight) in time are crucial characteristics of the human memory system. Indeed, over the past few years, episodic memory has been argued to be involved both in our capacity to retrieve our personal past experiences and in our ability to imagine and foresee future scenarios. However, recent theory and findings suggest that semantic memory also plays a significant role in imagining future scenarios. We draw on Tulving’s definition of episodic and semantic memory to provide a critical analysis of their role in episodic foresight tasks described in the developmental literature. We conclude by suggesting future directions of research that could further our understanding of how both episodic memory and semantic memory are intimately connected to episodic foresight. PMID:25071690

  2. Paroxysmal dysarthria-ataxia in remitting-relapsing Bickerstaff's-like encephalitis.

    PubMed

    Piffer, Silvio; Turri, Giulia; Acler, Michele; Richelli, Silvia; Cerini, Roberto; Fiaschi, Antonio; Monaco, Salvatore; Bonetti, Bruno

    2014-06-15

    Paroxysmal dysarthria-ataxia is a rare neurological condition due to ephaptic transmission, generally appearing in multiple sclerosis patients characterized by stereotyped attacks of slurred speech usually accompanied by ataxia, appearing many times a day. Here we describe a patient with an unusual remitting-relapsing form of Bickerstaff's-like brainstem encephalitis who manifested PDA after a relapse with the involvement of a peculiar region below the red nuclei and benefited from lamotrigine.

  3. [Anaesthesia for correction of scoliosis in pediatric patient with Friedreich's ataxia].

    PubMed

    Agámez Medina, G L; Pantin, E J; Lorthé, J; Therrien, P J

    2015-01-01

    Friedreich ataxia (FA) is an inherited autosomal recessive disease characterized by a neurological degenerative process of the cerebellum, spinal cord, and peripheral nerves. FA is associated with ataxia, dysarthria, motor and sensory impairment, scoliosis, cardiomyopathy, and diabetes. There is a significant risk of perioperative major complications during the anesthetic management of these patients. We present the case of a fourteen-year-old patient with FA, who had a posterior spinal fusion and instrumentation underwent to total intravenous anesthesia.

  4. Muscle coenzyme Q10 deficiencies in ataxia with oculomotor apraxia 1.

    PubMed

    Le Ber, I; Dubourg, O; Benoist, J-F; Jardel, C; Mochel, F; Koenig, M; Brice, A; Lombès, A; Dürr, A

    2007-01-23

    APTX gene mutations responsible for ataxia-oculomotor apraxia 1 (AOA1) were identified in a family previously reported with ataxia and coenzyme Q10 (CoQ10) deficiency. We measured muscle CoQ10 levels in six patients with AOA1 and found decreased levels in five. Patients homozygous for the W279X mutation had lower values (p = 0.003). A therapeutic trial of CoQ10 may be warranted in patients with AOA1.

  5. Rating disease progression of Friedreich’s ataxia by the International Cooperative Ataxia Rating Scale: analysis of a 603-patient database

    PubMed Central

    Coppard, Nicholas; Cooper, Jonathon M.; Delatycki, Martin B.; Dürr, Alexandra; Di Prospero, Nicholas A.; Giunti, Paola; Lynch, David R.; Schulz, J. B.; Rummey, Christian; Meier, Thomas

    2013-01-01

    The aim of this cross-sectional study was to analyse disease progression in Friedreich’s ataxia as measured by the International Cooperative Ataxia Rating Scale. Single ratings from 603 patients with Friedreich’s ataxia were analysed as a function of disease duration, age of onset and GAA repeat lengths. The relative contribution of items and subscales to the total score was studied as a function of disease progression. In addition, the scaling properties were assessed using standard statistical measures. Average total scale progression per year depends on the age of disease onset, the time since diagnosis and the GAA repeat length. The age of onset inversely correlates with increased GAA repeat length. For patients with an age of onset ≤14 years associated with a longer repeat length, the average yearly rate of decline was 2.5 ± 0.18 points in the total International Cooperative Ataxia Rating Scale for the first 20 years of disease duration, whereas patients with a later onset progress more slowly (1.8 ± 0.27 points/year). Ceiling effects in posture, gait and lower limb scale items lead to a reduced sensitivity of the scale in the severely affected population with a total score of >60 points. Psychometric scaling analysis shows generally favourable properties for the total scale, but the subscale grouping could be improved. This cross-sectional study provides a detailed characterization of the International Cooperative Ataxia Rating Scale. The analysis further provides rates of change separated for patients with early and late disease onset, which is driven by the GAA repeat length. Differences in the subscale dynamics merit consideration in the design of future clinical trials applying this scale as a neurological assessment instrument in Friedreich’s ataxia. PMID:23365101

  6. [Bipolar disorder: inter-episode symptoms].

    PubMed

    Azorin, J-M

    2012-12-01

    The importance of inter-episode symptoms in bipolar disorder can be traced back to the middle of the 19th century, at a time when the two fathers of the concept in France, Falret and Baillarger were opposed on the issue as to whether the presence of free intervals between the episodes had to be part or not of the disease's definition. Modern studies have reported rates between 50 and 68% for those symptoms which refer to subsyndromal manifestations present between affective episodes but that do not meet the required criteria for episodes definition. These manifestations comprise residual symptoms, prodromes, axis I comorbid psychiatric disorders, side effects of treatment, temperamental features, and comorbidity with personality disorders. Inter- episodes symptoms represent a risk factor for the occurrence of relapses and recurrences and are usually associated with impairments in functioning in almost all domains of psychosocial and family life. As they are easy to miss, it is important in clinical practice, to draw the attention of clinicians, patients and relatives to the role they have in the course of the illness. As far as their management, it may be crucial to achieve a full remission of the episodes, using adequate dosages of psychotropic drugs. Residual symptoms, prodromes as well as other inter-episode symptoms may respond to strategies based on cognitive-behaviour therapy, and/or psychoeducation.

  7. Episodic acidification of small streams in the northeastern united states: ionic controls of episodes

    USGS Publications Warehouse

    Wigington, P.J.; DeWalle, David R.; Murdoch, Peter S.; Kretser, W.A.; Simonin, H.A.; Van Sickle, J.; Baker, J.P.

    1996-01-01

    As part of the Episodic Response Project (ERP), we intensively monitored discharge and stream chemistry of 13 streams located in the Northern Appalachian region of Pennsylvania and in the Catskill and Adirondack Mountains of New York from fall 1988 to spring 1990. The ERP clearly documented the occurrence of acidic episodes with minimum episodic pH ??? 5 and inorganic monomeric Al (Alim) concentrations >150 ??g/L in at least two study streams in each region. Several streams consistently experienced episodes with maximum Alim concentrations >350 ??g/L. Acid neutralizing capacity (ANC) depressions resulted from complex interactions of multiple ions. Base cation decreases often made the most important contributions to ANC depressions during episodes. Organic acid pulses were also important contributors to ANC depressions in the Adirondack streams, and to a lesser extent, in the Catskill and Pennsylvania streams. Nitrate concentrations were low in the Pennsylvania streams, whereas the Catskill and Adirondack study streams had high NO3- concentrations and large episodic pulses (???54 ??eq/L). Most of the Pennsylvania study streams also frequently experienced episodic pulses of SO42- (???78 ??eq/L), whereas the Adirondack and Catskill streams did not. High baseline concentrations of SO42- (all three study areas) and NO3- (Adirondacks and Catskills) reduced episodic minimum ANC, even when these ions did not change during episodes. The ion changes that controlled the most severe episodes (lowest minimum episodic ANC) differed from the ion changes most important to smaller, more frequent episodes. Pulses of NO3- (Catskills and Adirondacks), SO42- (Pennsylvania), or organic acids became more important during major episodes. Overall, the behavior of streamwater SO42- and NO4- is an indicator that acidic deposition has contributed to the severity of episodes in the study streams.

  8. Monitoring progression in Friedreich ataxia (FRDA): the use of clinical scales.

    PubMed

    Bürk, Katrin; Schulz, Stefanie R; Schulz, Jörg B

    2013-08-01

    Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder associated with ataxia, dysarthria, pyramidal tract signs, sensory loss, cardiomyopathy and diabetes. There is no cure for FRDA so far. Studies of the natural history of the disease and future therapeutic trials require development of appropriate outcome markers. Since any therapeutic benefit is expected to modulate deterioration over time rather than to reverse disability, potential outcome measures must be sensitive instruments carefully analysed for their significance. Clinical scales may represent an appropriate measuring tool. Over the last few years the construction, evaluation and validation of sensitive clinical scales for the assessment of disease severity and progression in ataxia have had considerable impact on our understanding of the disease. Currently, there are three different scales that are most frequently applied: The International Cooperative Ataxia Rating Scale (ICARS), the Friedreich Ataxia Rating Scale (FARS) and the Scale for the Assessment and Rating of Ataxia (SARA). All scales have been validated and compared with regard to their testing properties.

  9. Magnetic resonance imaging biomarkers in patients with progressive ataxia: current status and future direction.

    PubMed

    Currie, Stuart; Hadjivassiliou, Marios; Craven, Ian J; Wilkinson, Iain D; Griffiths, Paul D; Hoggard, Nigel

    2013-04-01

    A diagnostic challenge commonly encountered in neurology is that of an adult patient presenting with ataxia. The differential is vast and clinical assessment alone may not be sufficient due to considerable overlap between different causes of ataxia. Magnetic resonance (MR)-based biomarkers such as voxel-based morphometry, MR spectroscopy, diffusion-weighted and diffusion-tensor imaging and functional MR imaging are gaining great attention for their potential as indicators of disease. A number of studies have reported correlation with clinical severity and underlying pathophysiology, and in some cases, MR imaging has been shown to allow differentiation of conditions causing ataxia. However, despite recent advances, their sensitivity and specificity vary. In addition, questions remain over their validity and reproducibility, especially when applied in routine clinical practice. This article extensively reviews the current literature regarding MR-based biomarkers for the patient with predominantly adult-onset ataxia. Imaging features characteristic of a particular ataxia are provided and features differentiating ataxia groups and subgroups are discussed. Finally, discussion will turn to the feasibility of applying these biomarkers in routine clinical practice.

  10. The case for episodic memory in animals.

    PubMed

    Dere, E; Kart-Teke, E; Huston, J P; De Souza Silva, M A

    2006-01-01

    The conscious recollection of unique personal experiences in terms of their details (what), their locale (where) and temporal occurrence (when) is known as episodic memory and is thought to require a 'self-concept', autonoetic awareness/conciousness, and the ability to subjectively sense time. It has long been held that episodic memory is unique to humans, because it was accepted that animals lack a 'self-concept', 'autonoetic awareness', and the ability to 'subjectively sense time'. These assumptions are now being questioned by behavioral evidence showing that various animal species indeed show behavioral manifestations of different features of episodic memory such as, e.g. 'metacognition', 'conscious recollection' of past events, 'temporal order memory', 'mental time travel' and have the capacity to remember personal experiences in terms of what happened, where and when. The aim of this review is to provide a comprehensive overview on the current progress in attempts to model different prerequisites and features of human episodic memory in animals and to identify possible neural substrates of animal episodic memory. The literature covered includes behavioral and physiological studies performed with different animal species, such as non-human primates, rodents, dolphins and birds. The search for episodic memory in animals has forced researchers to define objective behavioral criteria by which different features of episodic memory can be operationalized experimentally and assessed in both animals and humans. This is especially important because the current definition of episodic memory in terms of mentalistic constructs such as 'self', 'autonoetic awareness/consciousness', and 'subjectively sensed time', not only hinders animal research on the neurobiology of episodic memory but also research with healthy human subjects as well as neuropsychiatric patients with impaired language or in children with less-developed verbal abilities.

  11. The Spinocerebellar Ataxia-associated Gene Tau Tubulin Kinase 2 (TTBK2) Controls the Initiation of Ciliogenesis

    PubMed Central

    Goetz, Sarah C.; Liem, Karel F.; Anderson, Kathryn V.

    2012-01-01

    The primary cilium has critical roles in human development and disease, but the mechanisms that regulate ciliogenesis are not understood. Here we show that Tau tubulin kinase 2 (TTBK2) is a dedicated regulator of the initiation of ciliogenesis in vivo. We identified a null allele of mouse Ttbk2 based on loss of Sonic hedgehog activity, a signaling pathway that requires the primary cilium. Despite a normal basal body template, Ttbk2 mutants lack cilia. TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. Dominant truncating mutations in human TTBK2 cause Spinocerebellar Ataxia type 11 (SCA11); these mutant proteins do not promote ciliogenesis and inhibit ciliogenesis in wild-type cells. We propose that cell cycle regulators target TTBK2 to the basal body, where it modifies specific targets to initiate ciliogenesis. PMID:23141541

  12. Modelisation of northerly snow episodes over Andorra (Pyrenees) using WRF

    NASA Astrophysics Data System (ADS)

    Trapero, L.; Esteban, P.

    2010-09-01

    North episodes over the Pyrenees represent a challenge in terms of forecasting associated effects, especially during the winter season. Andorra, a small country located in the Pyrenees, between France and Spain, is highly sensitive to these episodes. Usually these episodes generate heavy snowfalls and intense windstorms which can substantially increase hazards and accident occurrence in this mountainous region. Slight variations of the forecasted snowfall distribution and accumulation can cause a severe impact to the population: avalanche hazard, incidents on the communication systems and transports and other derivates social impacts. With north episodes, precipitation mainly affects the North Slope of the Pyrenees and nearby areas. However, in some cases, certain factors allow the precipitation to cross over to the leeward mountain slope and intense snowfalls can affect an extended area and low elevations. The challenge comes down to the difficulty that the models have in forecasting the regional effects of these events and how far over the southern side of the Pyrenees range will precipitation extend. The episode that took place on the 10-11th February 2009 is a recent example. Previous research done by Esteban et al. (2005) over this area, examined the relationship between circulation types and heavy snowfall days in Andorra. Additionally, this study has provided a first climatology of N-NW episodes with at least 30 cm of snow in a 24h period during the winter seasons from 1986 to 2001 and has pointed out differences between similar atmospheric fluxes in the snow precipitation amount and distribution. The specific objective of this study is to determine common features of these events and evaluate the ability of the high-resolution Weather Research and Forecast model (WRF) over complex terrain to predict them, especially the spatial precipitation distribution. Preliminary experiments for 10-11 February 2009 case have tested the performance of two different land

  13. Characterization of intense aerosol episodes in the Mediterranean basin from satellite observations

    NASA Astrophysics Data System (ADS)

    Gkikas, Antonis; Hatzianastassiou, Nikos; Mihalopoulos, Nikolaos

    2014-05-01

    The properties and distribution of aerosols over the broader Mediterranean region are complex since particles of different nature are either produced within its boundaries or transported from other regions. Thus, coarse dust aerosols are transported primarily from Sahara and secondarily from Middle East, while fine polluted aerosols are either produced locally from anthropogenic activities or they are transported from neighbouring or remote European areas. Also during summer biomass aerosols are transported towards the Mediterranean, originating from massive and extended fires occurring in northern Balkans and Eastern Europe and favoured by the prevailing synoptic conditions. In addition, sea-salt aerosols originate from the Mediterranean Sea or the Atlantic Ocean. Occasionally, aerosols are encountered at very high concentrations (aerosol episodes or events) significantly affecting atmospheric dynamics and climate as well as human health. Given the coexistence of different aerosols as internal and external mixtures characterizing and discriminating between the different types of aerosol episodes is a big challenge. A characterization and classification of intense aerosol episodes in the Mediterranean basin (March 2000 - February 2007) is attempted in the present study. This is achieved by implementing an objective and dynamic algorithm which uses daily aerosol optical properties derived from satellite measurements, namely MODIS-Terra, Earth Probe (EP)-TOMS and OMI-Aura. The aerosol episodes are first classified into strong and extreme ones, according to their intensity, by means of aerosol optical depth at 550nm (AOD550nm). Subsequently, they are discriminated into the following aerosol types: (i) biomass/urban-industrial (BU), (ii) desert dust (DD), (iii) sea-salt like (SS), (iv) mixed (MX) and (v) undetermined (UN). The classification is based on aerosol optical properties accounting for the particles' size (Ångström exponent, Effective radius), the

  14. Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects

    PubMed Central

    Wikoff, William R.; Gatchel, Jennifer R.; Wang, Lu; Barupal, Dinesh K.; Crespo-Barreto, Juan; Fiehn, Oliver

    2013-01-01

    We have shown that lithium treatment improves motor coordination in a spinocerebellar ataxia type 1 (SCA1) disease mouse model (Sca1154Q/+). To learn more about disease pathogenesis and molecular contributions to the neuroprotective effects of lithium, we investigated metabolomic profiles of cerebellar tissue and plasma from SCA1-model treated and untreated mice. Metabolomic analyses of wild-type and Sca1154Q/+ mice, with and without lithium treatment, were performed using gas chromatography time-of-flight mass spectrometry and BinBase mass spectral annotations. We detected 416 metabolites, of which 130 were identified. We observed specific metabolic perturbations in Sca1154Q/+ mice and major effects of lithium on metabolism, centrally and peripherally. Compared to wild-type, Sca1154Q/+ cerebella metabolic profile revealed changes in glucose, lipids, and metabolites of the tricarboxylic acid cycle and purines. Fewer metabolic differences were noted in Sca1154Q/+ mouse plasma versus wild-type. In both genotypes, the major lithium responses in cerebellum involved energy metabolism, purines, unsaturated free fatty acids, and aromatic and sulphur-containing amino acids. The largest metabolic difference with lithium was a 10-fold increase in ascorbate levels in wild-type cerebella (p<0.002), with lower threonate levels, a major ascorbate catabolite. In contrast, Sca1154Q/+ mice that received lithium showed no elevated cerebellar ascorbate levels. Our data emphasize that lithium regulates a variety of metabolic pathways, including purine, oxidative stress and energy production pathways. The purine metabolite level, reduced in the Sca1154Q/+ mice and restored upon lithium treatment, might relate to lithium neuroprotective properties. PMID:23936457

  15. Hippocampal place cells, context, and episodic memory.

    PubMed

    Smith, David M; Mizumori, Sheri J Y

    2006-01-01

    Although most observers agree that the hippocampus has a critical role in learning and memory, there remains considerable debate about the precise functional contribution of the hippocampus to these processes. Two of the most influential accounts hold that the primary function of the hippocampus is to generate cognitive maps and to mediate episodic memory processes. The well-documented spatial firing patterns (place fields) of hippocampal neurons in rodents, along with the spatial learning impairments observed with hippocampal damage support the cognitive mapping hypothesis. The amnesia for personally experienced events seen in humans with hippocampal damage and the data of animal models, which show severe memory deficits associated with hippocampal lesions, support the episodic memory account. Although an extensive literature supports each of these hypotheses, a specific contribution of place cells to episodic memory has not been clearly demonstrated. Recent data from our laboratory, together with previous findings, indicate that hippocampal place fields and neuronal responses to task-relevant stimuli are highly sensitive to the context, even when the contexts are defined by abstract task demands rather than the spatial geometry of the environment. On the basis of these findings, it is proposed that place fields reflect a more general context processing function of the hippocampus. Hippocampal context representations could serve to differentiate contexts and prime the relevant memories and behaviors. Since episodic memories, by definition, include information about the time and place where the episode occurred, contextual information is a necessary prerequisite for any episodic memory. Thus, place fields contribute importantly to episodic memory as part of the needed context representations. Additionally, recent findings indicate that hippocampal neurons differentiate contexts at progressively finer levels of detail, suggesting a hierarchical coding scheme which

  16. Timing of spontaneous sleep-paralysis episodes.

    PubMed

    Girard, Todd A; Cheyne, J Allan

    2006-06-01

    The objective of this prospective naturalistic field study was to determine the distribution of naturally occurring sleep-paralysis (SP) episodes over the course of nocturnal sleep and their relation to bedtimes. Regular SP experiencers (N = 348) who had previously filled out a screening assessment for SP as well as a general sleep survey were recruited. Participants reported, online over the World Wide Web, using a standard reporting form, bedtimes and subsequent latencies of spontaneous episodes of SP occurring in their homes shortly after their occurrence. The distribution of SP episodes over nights was skewed to the first 2 h following bedtime. Just over one quarter of SP episodes occurred within 1 h of bedtime, although episodes were reported throughout the night with a minor mode around the time of normal waking. SP latencies following bedtimes were moderately consistent across episodes and independent of bedtimes. Additionally, profiles of SP latencies validated self-reported hypnagogic, hypnomesic, and hypnopompic SP categories, as occurring near the beginning, middle, and end of the night/sleep period respectively. Results are consistent with the hypothesis that SP timing is controlled by mechanisms initiated at or following sleep onset. These results also suggest that SP, rather than uniquely reflecting anomalous sleep-onset rapid eye movement (REM) periods, may result from failure to maintain sleep during REM periods at any point during the sleep period. On this view, SP may sometimes reflect the maintenance of REM consciousness when waking and SP hallucinations the continuation of dream experiences into waking life.

  17. Spontaneous downbeat nystagmus as a clue for the diagnosis of ataxia associated with anti-GAD antibodies.

    PubMed

    Vale, Thiago Cardoso; Pedroso, José Luiz; Alquéres, Rafaela Almeida; Dutra, Lívia Almeida; Barsottini, Orlando Graziani Povoas

    2015-12-15

    Glutamic acid decarboxylase (GAD) is the enzyme that catalyzes the conversion of glutamic acid to the neurotransmitter gamma-amino butyric acid. Antibodies against GAD (anti-GAD-Ab) are associated with an array of autoimmune-related neurological conditions, such as stiff-person syndrome, cerebellar ataxia, epilepsy and limbic encephalitis. The clinical spectrum of ataxia associated with anti-GAD-Ab comprises slowly progressive cerebellar ataxia syndrome evolving in months or years, associated with cerebellar atrophy on brain MRI. There are few reports of patients with ataxia associated with anti-GAD-Ab presenting with abnormal ocular movements, such as downbeat nystagmus (DBN).We present two patients with ataxia associated with anti-GAD-Ab from a large series of ataxic subjects who presented with cerebellar ataxia combined with spontaneous DBN. All patients underwent a thorough neurological evaluation with the use of ataxia scales, brain MRI scans, cerebrospinal fluid examination, 18FDG-PET/CT scans, laboratory work-up with on coneural and immune encephalitis antibodies, serum and cerebrospinal fluid levels of anti-GAD-Ab, and the antibody specificity index to measure the intrathecal synthesis of anti-GAD-Ab. All patients were treated with cycles of intravenous immunoglobulin and had mild/partial ataxia improvement and no improvement of DBN. The finding of DBN may work as a diagnostic clue in the context of adult-onset non-hereditary ataxias.

  18. Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay

    PubMed Central

    Kim, Myungjin; Sandford, Erin; Gatica, Damian; Qiu, Yu; Liu, Xu; Zheng, Yumei; Schulman, Brenda A; Xu, Jishu; Semple, Ian; Ro, Seung-Hyun; Kim, Boyoung; Mavioglu, R Nehir; Tolun, Aslıhan; Jipa, Andras; Takats, Szabolcs; Karpati, Manuela; Li, Jun Z; Yapici, Zuhal; Juhasz, Gabor; Lee, Jun Hee; Klionsky, Daniel J; Burmeister, Margit

    2016-01-01

    Autophagy is required for the homeostasis of cellular material and is proposed to be involved in many aspects of health. Defects in the autophagy pathway have been observed in neurodegenerative disorders; however, no genetically-inherited pathogenic mutations in any of the core autophagy-related (ATG) genes have been reported in human patients to date. We identified a homozygous missense mutation, changing a conserved amino acid, in ATG5 in two siblings with congenital ataxia, mental retardation, and developmental delay. The subjects' cells display a decrease in autophagy flux and defects in conjugation of ATG12 to ATG5. The homologous mutation in yeast demonstrates a 30-50% reduction of induced autophagy. Flies in which Atg5 is substituted with the mutant human ATG5 exhibit severe movement disorder, in contrast to flies expressing the wild-type human protein. Our results demonstrate the critical role of autophagy in preventing neurological diseases and maintaining neuronal health. DOI: http://dx.doi.org/10.7554/eLife.12245.001 PMID:26812546

  19. Iron chelators increase the resistance of Ataxia telangeictasia cells to oxidative stress.

    PubMed

    Shackelford, Rodney E; Manuszak, Ryan P; Johnson, Cybele D; Hellrung, Daniel J; Link, Charles J; Wang, Suming

    2004-10-05

    Ataxia telangeictasia (A-T) is an autosomal recessive disorder characterized by immune dysfunction, genomic instability, chronic oxidative damage, and increased cancer incidence. Previously, desferal was found to increase the resistance of A-T, but not normal cells to exogenous oxidative stress in the colony forming-efficiency assay, suggesting that iron metabolism is dysregulated in A-T. Since desferal both chelates iron and modulates gene expression, we tested the effects of apoferritin and the iron chelating flavonoid quercetin on A-T cell colony-forming ability. We demonstrate that apoferritin and quercetin increase the ability of A-T cells to form colonies. We also show that labile iron levels are significantly elevated in Atm-deficient mouse sera compared to syngeniec wild type mice. Our findings support a role for labile iron acting as a Fenton catalyst in A-T, contributing to the chronic oxidative stress seen in this disease. Our findings further suggest that iron chelators might promote the survival of A-T cells and hence, individuals with A-T.

  20. Assessment of ataxia phenotype in a new mouse model of galactose-1 phosphate uridylyltransferase (GALT) deficiency.

    PubMed

    Chen, Wyman; Caston, Rose; Balakrishnan, Bijina; Siddiqi, Anwer; Parmar, Kamalpreet; Tang, Manshu; Feng, Merry; Lai, Kent

    2017-01-01

    Despite adequate dietary management, patients with classic galactosemia continue to have increased risks of cognitive deficits, speech dyspraxia, primary ovarian insufficiency, and abnormal motor development. A recent evaluation of a new galactose-1 phosphate uridylyltransferase (GALT)-deficient mouse model revealed reduced fertility and growth restriction. These phenotypes resemble those seen in human patients. In this study, we further assess the fidelity of this new mouse model by examining the animals for the manifestation of a common neurological sequela in human patients: cerebellar ataxia. The balance, grip strength, and motor coordination of GALT-deficient and wild-type mice were tested using a modified rotarod. The results were compared to composite phenotype scoring tests, typically used to evaluate neurological and motor impairment. The data demonstrated abnormalities with varying severity in the GALT-deficient mice. Mice of different ages were used to reveal the progressive nature of motor impairment. The varying severity and age-dependent impairments seen in the animal model agree with reports on human patients. Finally, measurements of the cerebellar granular and molecular layers suggested that mutant mice experience cerebellar hypoplasia, which could have resulted from the down-regulation of the PI3K/Akt signaling pathway.

  1. Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10

    PubMed Central

    Yang, Wang-Yong; Gao, Rui; Southern, Mark; Sarkar, Partha S.; Disney, Matthew D.

    2016-01-01

    RNA is an important target for chemical probes of function and lead therapeutics; however, it is difficult to target with small molecules. One approach to tackle this problem is to identify compounds that target RNA structures and utilize them to multivalently target RNA. Here we show that small molecules can be identified to selectively bind RNA base pairs by probing a library of RNA-focused small molecules. A small molecule that selectively binds AU base pairs informed design of a dimeric compound (2AU-2) that targets the pathogenic RNA, expanded r(AUUCU) repeats, that causes spinocerebellar ataxia type 10 (SCA10) in patient-derived cells. Indeed, 2AU-2 (50 nM) ameliorates various aspects of SCA10 pathology including improvement of mitochondrial dysfunction, reduced activation of caspase 3, and reduction of nuclear foci. These studies provide a first-in-class chemical probe to study SCA10 RNA toxicity and potentially define broadly applicable compounds targeting RNA AU base pairs in cells. PMID:27248057

  2. Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10.

    PubMed

    Yang, Wang-Yong; Gao, Rui; Southern, Mark; Sarkar, Partha S; Disney, Matthew D

    2016-06-01

    RNA is an important target for chemical probes of function and lead therapeutics; however, it is difficult to target with small molecules. One approach to tackle this problem is to identify compounds that target RNA structures and utilize them to multivalently target RNA. Here we show that small molecules can be identified to selectively bind RNA base pairs by probing a library of RNA-focused small molecules. A small molecule that selectively binds AU base pairs informed design of a dimeric compound (2AU-2) that targets the pathogenic RNA, expanded r(AUUCU) repeats, that causes spinocerebellar ataxia type 10 (SCA10) in patient-derived cells. Indeed, 2AU-2 (50 nM) ameliorates various aspects of SCA10 pathology including improvement of mitochondrial dysfunction, reduced activation of caspase 3, and reduction of nuclear foci. These studies provide a first-in-class chemical probe to study SCA10 RNA toxicity and potentially define broadly applicable compounds targeting RNA AU base pairs in cells.

  3. Linear and angular control of circular walking in healthy older adults and subjects with cerebellar ataxia.

    PubMed

    Goodworth, Adam D; Paquette, Caroline; Jones, Geoffrey Melvill; Block, Edward W; Fletcher, William A; Hu, Bin; Horak, Fay B

    2012-05-01

    Linear and angular control of trunk and leg motion during curvilinear navigation was investigated in subjects with cerebellar ataxia and age-matched control subjects. Subjects walked with eyes open around a 1.2-m circle. The relationship of linear to angular motion was quantified by determining the ratios of trunk linear velocity to trunk angular velocity and foot linear position to foot angular position. Errors in walking radius (the ratio of linear to angular motion) also were quantified continuously during the circular walk. Relative variability of linear and angular measures was compared using coefficients of variation (CoV). Patterns of variability were compared using power spectral analysis for the trunk and auto-covariance analysis for the feet. Errors in radius were significantly increased in patients with cerebellar damage as compared to controls. Cerebellar subjects had significantly larger CoV of feet and trunk in angular, but not linear, motion. Control subjects also showed larger CoV in angular compared to linear motion of the feet and trunk. Angular and linear components of stepping differed in that angular, but not linear, foot placement had a negative correlation from one stride to the next. Thus, walking in a circle was associated with more, and a different type of, variability in angular compared to linear motion. Results are consistent with increased difficulty of, and role of the cerebellum in, control of angular trunk and foot motion for curvilinear locomotion.

  4. The genetics of ataxia: through the labyrinth of the Minotaur, looking for Ariadne's thread.

    PubMed

    Mancuso, M; Orsucci, D; Siciliano, G; Bonuccelli, U

    2014-09-01

    Among the hereditary cerebellar ataxias (CAs), there are at least 36 different forms of autosomal dominant cerebellar ataxia (ADCAs), 20 autosomal recessive cerebellar ataxias (ARCAs), two X-linked ataxias, and several forms of ataxia associated with mitochondrial defects. Despite the steady increase in the number of newly discovered CA genes, patients, especially those with putative ARCAs, cannot yet be genotyped. Moreover, in daily clinical practice, ataxia may present as an isolated cerebellar syndrome or, more often, it is associated with a broad spectrum of neurological manifestations including pyramidal, extrapyramidal, sensory, and cognitive dysfunction. Furthermore, non-neurological symptoms may also coexist. A close integration between clinical records, neurophysiological, neuroradiological and, in some instances, biochemical findings will help physicians in the diagnostic work-up (including selection of the correct genetic tests) and may lead to timely therapy. Some inherited CAs are in fact potentially treatable, and the efficacy of the therapy is directly related to the severity of the cerebellar atrophy and to the time of onset of the disease. Most cases of CA are sporadic, and the diagnostic work-up remains a challenge. Detailed anamnesis and deep investigation of the family pedigree are usually enough to discriminate between acquired and genetic conditions. In the case of ADCA, molecular testing should be guided by taking into account the main associated symptoms. In sporadic cases, a multi-disciplinary approach is needed and should consider the following points: (1) onset and clinical course; (2) associated features; (3) neurophysiological parameters, with special attention to the occurrence of peripheral neuropathy; (4) neuroimaging results; and (5) laboratory findings. A late-onset sporadic ataxia, in which other possible causes have been excluded by following the proposed steps, might be attributable to metabolic disorders, which in some

  5. Physiotherapy in degenerative cerebellar ataxias: utilisation, patient satisfaction, and professional expertise.

    PubMed

    Fonteyn, Ella M R; Keus, Samyra H J; Verstappen, Carla C P; van de Warrenburg, Bart P C

    2013-12-01

    Physiotherapy plays an important role in the management of patients with degenerative cerebellar ataxias. However, our insight in the quantity and quality of physiotherapy prescription in this group of patients is incomplete. The purposes of this study were to investigate the utilization of physiotherapy and patient satisfaction in patients with degenerative ataxias in The Netherlands and to examine the level of expertise and needs of physiotherapists treating ataxia patients. Questionnaires were sent to members of the Dutch association for patients with degenerative cerebellar ataxias (n = 532). In addition, 181 questionnaires were sent to the physiotherapists who had recently treated the patients who responded. Eventually, 317 questionnaires from patients (60 %) and 114 questionnaires from physiotherapists (63 %) could be used for further analysis. Sixty-four percent of the patients were currently treated by a physiotherapist. Their median treatment duration was 5 years. Nineteen percent of the patients had never been referred, often despite the presence of limitations in daily activities. On the other hand, some participants without reported limitations had received physiotherapy. In general, participants were satisfied with their physiotherapist. The most reported treatment goals were improvement or maintenance of balance, general physical condition, and mobility. Physiotherapists reported lack of ataxia-specific expertise and expressed the need for education and evidence-based guidelines. Referral to and use of physiotherapy in patients with degenerative cerebellar ataxia in The Netherlands are currently inconsistent and not in agreement with the little scientific evidence available. Referral rates are high, but referrals and actual necessity are discrepant; treatment duration is long; and ataxia-specific expertise among physiotherapists is insufficient. Evidence-based recommendations and specific training of physiotherapists are needed.

  6. Evaluation and Management of Pulmonary Disease in Ataxia-Telangiectasia

    PubMed Central

    McGrath-Morrow, Sharon A.; Gower, W. Adam; Rothblum-Oviatt, Cynthia; Brody, Alan S.; Langston, Claire; Fan, Leland L.; Lefton-Greif, Maureen A.; Crawford, Thomas O.; Troche, Michelle; Sandlund, John T; Auwaerter, Paul G.; Easley, Blaine; Loughlin, Gerald M.; Carroll, John L.; Lederman, Howard M.

    2014-01-01

    Summary Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ATM gene, resulting in faulty repair of breakages in double-stranded DNA. The clinical phenotype is complex, and is characterized by neurologic abnormalities, immunodeficiencies, susceptibility to malignancies, recurrent sinopulmonary infections, and cutaneous abnormalities. Lung disease is common in patients with A-T and often progresses with age and neurological decline. Diseases of the respiratory system cause significant morbidity and are a frequent cause of death in the A-T population. Lung disease in this population is thought to exhibit features of one or more of the following phenotypes: recurrent sinopulmonary infections with bronchiectasis, interstitial lung disease, and lung disease associated with neurological abnormalities. Here, we review available evidence and present expert opinion on the diagnosis, evaluation, and management of lung disease in A-T, as discussed in a recent multidisciplinary workshop. Although more data are emerging on this unique population, many recommendations are made based on similarities to other more well-studied diseases. Gaps in current knowledge and areas for future research in the field of pulmonary disease in A-T are also outlined. PMID:20583220

  7. Ralstonia pickettii-Induced Ataxia in Immunodeficient Mice

    PubMed Central

    Berard, Marion; Medaille, Christine; Simon, Meredith; Serre, Stéphanie; Pritchett-Corning, Kathleen; Dangles-Marie, Virginie

    2009-01-01

    We report here the characterization of an asymmetric ataxia syndrome (head tilt and circling, with death in the most severe cases) demonstrated by profoundly immunodeficient mice housed at the Institut Curie SPF facility. The immune system of the affected mice had been genetically modified so that they were deficient in both B and T cells. Extensive bacteriologic, parasitic, serologic, and histopathologic analysis of the affected animals and their healthy controls led us to identify Ralstonia pickettii as the causative agent of the ataxic syndrome. The outbreak was managed through a test-and-cull process. Even though they also carried Ralstonia pickettii, immunocompetent mice that were kept in the same facility, did not show any of the signs that were expressed by their immunodeficient counterparts. This case highlights the difficulty of maintaining immunocompetent and immunodeficient mice in the same microbiologic unit and the importance of enlarging the spectrum of health monitoring to opportunistic agents when investigating clinical cases in populations of immunocompromised rodents. PMID:19389312

  8. The Chemical Form of Mitochondrial Iron in Friedreich's Ataxia

    SciTech Connect

    Popescu, B.F.Gh.; Pickering, I.J.; George, G.N.; Nichol, H.; /Saskatchewan U.

    2007-07-12

    Friedreich's ataxia (FRDA) results from cellular damage caused by a deficiency in the mitochondrial matrix protein frataxin. To address the effect of frataxin deficiency on mitochondrial iron chemistry, the heavy mitochondrial fraction (HMF) was isolated from primary fibroblasts from FRDA affected and unaffected individuals. X-ray absorption spectroscopy was used to characterize the chemical form of iron. Near K-edge spectra were fitted with a series of model iron compounds to determine the proportion of each iron species. Most of the iron in both affected and unaffected fibroblasts was ferrihydrite. The iron K-edge from unaffected HMFs were best fitted with poorly organized ferrihydrite modeled by frataxin whereas HMFs from affected cells were best fitted with highly organized ferrihydrite modeled by ferritin. Both had several minor iron species but these did not differ consistently with disease. Since the iron K-edge spectra of ferritin and frataxin are very similar, we present additional evidence for the presence of ferritin-bound iron in HMF. The predominant ferritin subunit in HMFs from affected cells resembled mitochondrial ferritin (MtFt) in size and antigenicity. Western blotting of native gels showed that HMF from affected cells had 3-fold more holoferritin containing stainable iron. We conclude that most of the iron in fibroblast HMF from both affected and unaffected cells is ferrihydrite but only FRDA affected cells mineralize significant iron in mitochondrial ferritin.

  9. Neurodegeneration in ataxia-telangiectasia is caused by horror autotoxicus.

    PubMed

    Kuljis, R O; Aguila, M C

    1999-05-01

    Ataxia-telangiectasia (A-T) is a pleiotropic, multi-system disorder with manifestations that include immune deficiency, sensitivity to ionizing radiation and neoplasms. Many of these manifestations are understood in principle since the identification in A-T patients of mutations in a gene encoding a protein kinase that plays a key role in signaling and repair of DNA damage. However, the cause of the neurodegeneration that afflicts patients with A-T for at least a decade before they succumb to overwhelming infections or malignancy remains mysterious. Based on our work in a mouse model of A-T and previous evidence of extra-neural autoimmune disorders in A-T, we postulate that the neurodegenerative process in A-T is not due to a function for A-T mutated (ATM) essential for the postnatal brain, but to an autoimmune process (hence 'horror autotoxicus', Paul Ehrlich's term for autoimmune disorder). This hypothetical mechanism may be analogous to that in the so-called 'paraneoplastic' neurodegenerative syndromes in patients with various malignancies. Thus, alterations in the balance between cellular and humoral immunity in A-T probably result in autoantibodies to cerebral epitopes shared with cells of the immune system. This hypothesis has important implications for the understanding and development of effective palliative and even preventative strategies for A-T, and probably for other so far relentlessly progressive neurodegenerative disorders.

  10. Uncloned expanded CAG/CTG repeat sequences in autosomal dominant cerebellar ataxia (ADCA) detected by the repeat expansion detection (RED) method.

    PubMed Central

    Pujana, M A; Volpini, V; Gratacós, M; Corral, J; Banchs, I; Sánchez, A; Genís, D; Cervera, C; Estivill, X

    1998-01-01

    In some neurodegenerative diseases, genetic anticipation correlates with expansions of the CAG/CTG repeat sequence above the normal range through the generations of a pedigree. Among these neurodegenerative diseases are late onset autosomal dominant cerebellar ataxias (ADCA). ADCA are genetically heterogeneous disorders with different cloned genes for spinocerebellar ataxia type 1 (SCA1), type 2 (SCA2), type 3 or Machado-Joseph disease (SCA3/MJD), and type 6 (SCA6). Another related dominant ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), also shows CAG/CTG repeat expansions. Genetic anticipation has been reported for all of them except for the recently cloned SCA6 gene. Other, as yet undetected SCA genes may show the same features. We have used the repeat expansion detection (RED) method to detect repeat expansions directly in DNA samples from ADCA patients not resulting from known genes. Our sample consists of 19 affected index cases, corresponding to 52.8% of our ADCA families without CAG/CTG repeat expansions in the SCA1, SCA2, SCA3/MJD, SCA6, or DRPLA genes. Eighty-nine percent of the index cases had expansions of a CAG/CTG sequence greater than 40 repeats by RED, while these were observed in only 26.9% of 78 healthy subjects from the general population (p < 0.0001). The distribution of RED fragments in controls and ADCA patients also shows significant differences with the Mann-Whitney U test (U = 376.5, p = 0.0007). Moreover, there was a significant inverse correlation between the size of expansion and the age of onset (r = -0.54, p = 0.018). These results show CAG/CTG repeat expansions of over 40 repeats in our sample of ADCA families not resulting from known SCA genes. Images PMID:9507387

  11. Episodic and Semantic Memory Contribute to Familiar and Novel Episodic Future Thinking

    PubMed Central

    Wang, Tong; Yue, Tong; Huang, Xi Ting

    2016-01-01

    Increasing evidence indicates that episodic future thinking (EFT) relies on both episodic and semantic memory; however, event familiarity may importantly affect the extent to which episodic and semantic memory contribute to EFT. To test this possibility, two behavioral experiments were conducted. In Experiment 1, we directly compared the proportion of episodic and semantic memory used in an EFT task. The results indicated that more episodic memory was used when imagining familiar future events compared with novel future events. Conversely, significantly more semantic memory was used when imagining novel events compared with familiar events. Experiment 2 aimed to verify the results of Experiment 1. In Experiment 2, we found that familiarity moderated the effect of priming the episodic memory system on EFT; particularly, it increased the time required to construct a standard familiar episodic future event, but did not significantly affect novel episodic event reaction time. Collectively, these findings support the hypothesis that event familiarity importantly moderates episodic and semantic memory's contribution to EFT. PMID:27891106

  12. Molecular-genetic characterization and rescue of a TSFM mutation causing childhood-onset ataxia and nonobstructive cardiomyopathy.

    PubMed

    Emperador, Sonia; Bayona-Bafaluy, M Pilar; Fernández-Marmiesse, Ana; Pineda, Mercedes; Felgueroso, Blanca; López-Gallardo, Ester; Artuch, Rafael; Roca, Iria; Ruiz-Pesini, Eduardo; Couce, María Luz; Montoya, Julio

    2016-01-01

    Oxidative phosphorylation dysfunction has been found in many different disorders. This biochemical pathway depends on mitochondrial protein synthesis. Thus, mutations in components of the mitochondrial translation system can be responsible for some of these pathologies. We identified a new homozygous missense mutation in the mitochondrial translation elongation factor Ts gene in a patient suffering from slowly progressive childhood ataxia and hypertrophic cardiomyopathy. Using cell, biochemical and molecular-genetic protocols, we confirm it as the etiologic factor of this phenotype. Moreover, as an important functional confirmation, we rescued the normal molecular phenotype by expression of the wild-type TSFM cDNA in patient's fibroblasts. Different TSFM mutations can produce the same or very different clinical phenotypes, going from abortions to moderately severe presentations. On the other hand, the same TSFM mutation can also produce same or different phenotypes within the same range of presentations, therefore suggesting the involvement of unknown factors.

  13. Host cell reactivation of sunlamp-exposed adenovirus in fibroblasts from patients with Bloom's syndrome, ataxia telangiectasia, and Huntington's disease

    SciTech Connect

    Rainbow, A.J. )

    1991-01-01

    In this study, a sensitive host cell reactivation (HCR) technique was used to examine the repair capacity for DNA damaged by sunlamp exposure in fibroblast strains derived from 5 normal individuals and 8 patients representing three different diseases associated with DNA repair deficiencies. Adenovirus type 2 (Ad 2) was exposed to radiation from a GE 275 W sunlamp and subsequently used to infect fibroblast monolayers. At 48 hr after infection, cells were scored for the presence of viral structural antigens (Vag) using indirect immunofluorescent staining. Previous reports using this technique showed a substantial reduction in the HCR of sunlamp-exposed Ad 2 for infection of excision repair deficient fibroblasts from patients with xeroderma pigmentosum. In contrast, the HCR of Vag synthesis for sunlamp-exposed Ad 2 was in the normal range for the three ataxia telangiectasia, three Bloom's syndrome, and two Huntington's disease fibroblasts strains.

  14. Progressive gait ataxia following deep brain stimulation for essential tremor: adverse effect or lack of efficacy?

    PubMed

    Reich, Martin M; Brumberg, Joachim; Pozzi, Nicolò G; Marotta, Giorgio; Roothans, Jonas; Åström, Mattias; Musacchio, Thomas; Lopiano, Leonardo; Lanotte, Michele; Lehrke, Ralph; Buck, Andreas K; Volkmann, Jens; Isaias, Ioannis U

    2016-09-21

    Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple (18)F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar

  15. 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.

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

    PubMed Central

    2016-01-01

    Abstract 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 (CB1R) 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 CB1R antagonists. Of further interest are various findings that CB1R 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 ‘ducky2J’ 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

  17. Episodic memories predict adaptive value-based decision-making.

    PubMed

    Murty, Vishnu P; FeldmanHall, Oriel; Hunter, Lindsay E; Phelps, Elizabeth A; Davachi, Lila

    2016-05-01

    Prior research illustrates that memory can guide value-based decision-making. For example, previous work has implicated both working memory and procedural memory (i.e., reinforcement learning) in guiding choice. However, other types of memories, such as episodic memory, may also influence decision-making. Here we test the role for episodic memory-specifically item versus associative memory-in supporting value-based choice. Participants completed a task where they first learned the value associated with trial unique lotteries. After a short delay, they completed a decision-making task where they could choose to reengage with previously encountered lotteries, or new never before seen lotteries. Finally, participants completed a surprise memory test for the lotteries and their associated values. Results indicate that participants chose to reengage more often with lotteries that resulted in high versus low rewards. Critically, participants not only formed detailed, associative memories for the reward values coupled with individual lotteries, but also exhibited adaptive decision-making only when they had intact associative memory. We further found that the relationship between adaptive choice and associative memory generalized to more complex, ecologically valid choice behavior, such as social decision-making. However, individuals more strongly encode experiences of social violations-such as being treated unfairly, suggesting a bias for how individuals form associative memories within social contexts. Together, these findings provide an important integration of episodic memory and decision-making literatures to better understand key mechanisms supporting adaptive behavior.

  18. Episodic Memory and Episodic Foresight in 3- and 5-Year-Old Children

    ERIC Educational Resources Information Center

    Hayne, Harlene; Gross, Julien; McNamee, Stephanie; Fitzgibbon, Olivia; Tustin, Karen

    2011-01-01

    In the present study, we examined the development of episodic memory and episodic foresight. Three- and 5-year-olds were interviewed individually using a personalised timeline that included photographs of them at different points in their life. After constructing the timeline with the experimenter, each child was asked to discuss a number of…

  19. [Glucose transporter type 1 (GLUT-1) deficiency].

    PubMed

    Cano, A; Ticus, I; Chabrol, B

    2008-11-01

    Impaired glucose transport across the blood brain barrier results in glucose transporter type 1 (GLUT-1) deficiency syndrome, first described in 1991. It is characterized by infantile seizures refractory to anticonvulsive treatments, microcephaly, delays in mental and motor development, spasticity, ataxia, dysarthria and other paroxysmal neurologic phenomena, often occurring prior to meals. Affected infants are normal at birth following an uneventful pregnancy and delivery. Seizures usually begin between the age of one and four months and can be preceded by apneic episodes or abnormal eyes movements. Patients with atypical presentations such as mental retardation and intermittent ataxia without seizures, or movement disorders characterized by choreoathetosis and dystonia, have also been described. Glucose is the principal fuel source for the brain and GLUT-1 is the only vehicle by which glucose enters the brain. In case of GLUT-1 deficiency, the risk of clinical manifestations is increased in infancy and childhood, when the brain glucose demand is maximal. The hallmark of the disease is a low glucose concentration in the cerebrospinal fluid in a presence of normoglycemia (cerebrospinal fluid/blood glucose ratio less than 0.4). The GLUT-1 defect can be confirmed by molecular analysis of the SCL2A1 gene or in erythrocytes by glucose uptake studies and GLUT-1 immunoreactivity. Several heterozygous mutations, with a majority of de novo mutations, resulting in GLUT-1 haploinsufficiency, have been described. Cases with an autosomal dominant transmission have been established and adults can exhibit symptoms of this deficiency. Ketogenic diet is an effective treatment of epileptic manifestations as ketone bodies serve as an alternative fuel for the developing brain. However, this diet is not effective on cognitive impairment and other treatments are being evaluated. The physiopathology of this disorder is partially unclear and its understanding could explain the clinical

  20. Episodic confusional state: Due to insulinoma

    PubMed Central

    Jagadheesan, Venkatesan; Suresh, Stelina Sophie Dina

    2008-01-01

    This case report deals with 45-year-old male who came for consultation in the psychiatry department for the persisting symptoms, after consulting various departments with no relief. He had episodes of confusion with disorganized behavior, restlessness, and symptoms like talking irrelevantly once a week lasting up to 10-30 min in the preceding six months. Investigations like computerized tomography scan, electroencephalogram were not contributory. While under observation in our ward for evaluation and diagnosis, one such episode with intense sweating and clouding of consciousness was witnessed and helped in clinching the diagnosis of insulinoma. The case is reported for its rarity and as one of the causes of episodic confusional state. PMID:19742181

  1. Novel aberrant genetic and epigenetic events in Friedreich's ataxia.

    PubMed

    Quesada, Mari Paz; Jones, Jonathan; Rodríguez-Lozano, F J; Moraleda, Jose M; Martinez, Salvador

    2015-07-01

    It is generally accepted that Friedreich's ataxia (FRDA) is caused by a deficiency in frataxin expression, a mitochondrial protein involved in iron homeostasis, which mainly affects the brain, dorsal root ganglia of the spinal cord, heart and in certain cases the pancreas. However, there is little knowledge as to other possible genes that may be affected in this disorder, and which can contribute to its complexity. In the current study we compared human periodontal ligament cells gene expression of healthy individuals and FRDA patients. The expression of active-caspase 3, as well as other apoptosis-related genes, was increased in the FRDA cells. Furthermore, iron-sulphur cluster genes, as well as oxidative stress-related genes were overexpressed in FRDA. Moreover, brain-derived neurotrophic factor, neuregulin 1 and miR-132 were all upregulated. These three genes are capable of regulating the expression of each other. Interestingly, when the cells from FRDA patients were co-cultured in the presence of idebenone and deferiprone, caspase expression decreased while antioxidant gene expression, as well as frataxin expression, increased. Regarding epigenetic mechanisms, the frataxin gene was hypermethylated, compared to the healthy counterparts, in the upstream GAA repetitive region. Of the three DNA methyltransferases, DNMT1 but not DNMT3׳s gene expression was higher in FRDA cells. In conclusion, our data show that FRDA cells present altered expression of genes related to cell cycle, oxidative stress and iron homeostasis which may be implicated in the increased apoptotic levels. Also, the altered expression is in a certain degree normalized in the presence of idebenone and deferiprone.

  2. Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia.

    PubMed

    Abeti, Rosella; Uzun, Ebru; Renganathan, Indhushri; Honda, Tadashi; Pook, Mark A; Giunti, Paola

    2015-09-01

    Friedreich's ataxia (FRDA) is an autosomal recessive disorder, caused by reduced levels of the protein frataxin. This protein is located in the mitochondria, where it functions in the biogenesis of iron-sulphur clusters (ISCs), which are important for the function of the mitochondrial respiratory chain complexes. Moreover, disruption in iron biogenesis may lead to oxidative stress. Oxidative stress can be the cause and/or the consequence of mitochondrial energy imbalance, leading to cell death. Fibroblasts from two FRDA mouse models, YG8R and KIKO, were used to analyse two different categories of protective compounds: deuterised poly-unsaturated fatty acids (dPUFAs) and Nrf2-inducers. The former have been shown to protect the cell from damage induced by lipid peroxidation and the latter trigger the well-known Nrf2 antioxidant pathway. Our results show that the sensitivity to oxidative stress of YG8R and KIKO mouse fibroblasts, resulting in cell death and lipid peroxidation, can be prevented by d4-PUFA and Nrf2-inducers (SFN and TBE-31). The mitochondrial membrane potential (ΔΨm) of YG8R and KIKO fibroblasts revealed a difference in their mitochondrial pathophysiology, which may be due to the different genetic basis of the two models. This suggests that variable levels of reduced frataxin may act differently on mitochondrial pathophysiology and that these two cell models could be useful in recapitulating the observed differences in the FRDA phenotype. This may reflect a different modulatory effect towards cell death that will need to be investigated further.

  3. 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

  4. Hereditary myokymia and paroxysmal ataxia linked to chromosome 12 is responsive to acetazolamide.

    PubMed Central

    Lubbers, W J; Brunt, E R; Scheffer, H; Litt, M; Stulp, R; Browne, D L; van Weerden, T W

    1995-01-01

    A sixth family with autosomal dominantly inherited myokymia and paroxysmal ataxia is described. The syndrome in this family is linked to the recently discovered locus for inherited myokymia and paroxysmal ataxia on the human chromosome 12p, and a missense mutation is shown in the KCNA1 gene. The attacks of ataxia in this family compare well with those of previously described families and similarly are precipitated by kinesigenic stimuli, exertion, and startle. Responsiveness of these attacks to low dose acetazolamide is confirmed, but some loss of efficacy occurs with prolonged treatment, and side effects are notable. Although not all affected family members showed my