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Sample records for hereditary sensory neuropathy

  1. Hereditary sensory neuropathies.

    PubMed

    Auer-Grumbach, Michaela

    2004-05-01

    Hereditary sensory neuropathies (HSNs) are a group of genetically determined peripheral neuropathies with prominent disturbance of the peripheral sensory neurons. They are characterized by sensory loss, insensitivity to pain, a variable degree of muscle weakness and wasting, as well as autonomic features. Frequent complications are foot ulcerations and infections that may lead to osteomyelitis, followed by necrosis and amputations. Consequently, the hereditary sensory neuropathies have also been termed ulceromutilating neuropathies. On the other hand, in the presence of additional motor weakness, they have been subclassified among the group of Charcot-Marie-Tooth (CMT) disorders. Sporadic and familial cases with different modes of inheritance are known to affect both children and adults. The most prevalent forms of the autosomal dominantly inherited hereditary sensory neuropathies are HSN I and CMT 2b. HSN I is associated with mutations in the SPTLC1 gene, whereas mutations in the RAB7 gene have been identified in CMT 2b. However, at least one more hitherto unknown gene responsible for autosomal-dominant hereditary sensory neuropathies must exist. Autosomal-recessive hereditary sensory neuropathies types III and IV, and probably also type V, result from mutations in the IKBKAP and NTRK1 genes. Very recently, the gene in HSN II (HSN2) has been identified. A spontaneous autosomal-recessive mutation in the Cct4 gene has been reported in the Sprague-Dawley rat strain with early onset sensory neuropathy. Although no curative treatment is available so far, and current therapy is limited to symptom relief, these molecular genetic advances in knowledge about the hereditary sensory neuropathies can be translated into clinical practice by improving diagnosis and genetic counseling. They will also be the basis for functional studies in the future. PMID:15319794

  2. Genetics Home Reference: hereditary sensory neuropathy type IA

    MedlinePlus

    ... Conditions hereditary sensory neuropathy type IA hereditary sensory neuropathy type IA Enable Javascript to view the expand/ ... PDF Open All Close All Description Hereditary sensory neuropathy type IA is a condition characterized by nerve ...

  3. Hereditary sensory neuropathy type I

    PubMed Central

    Auer-Grumbach, Michaela

    2008-01-01

    Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7) identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin

  4. Hereditary sensory neuropathy type I.

    PubMed

    Auer-Grumbach, Michaela

    2008-01-01

    Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7) identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin

  5. Molecular genetics of hereditary sensory neuropathies.

    PubMed

    Auer-Grumbach, Michaela; Mauko, Barbara; Auer-Grumbach, Piet; Pieber, Thomas R

    2006-01-01

    Hereditary sensory neuropathies (HSN), also known as hereditary sensory and autonomic neuropathies (HSAN), are a clinically and genetically heterogeneous group of disorders. They are caused by neuronal atrophy and degeneration, predominantly affecting peripheral sensory and autonomic neurons. Both congenital and juvenile to adulthood onset is possible. Currently, the classification of the HSN depends on the mode of inheritance, age at onset, and clinical presentation. Hallmark features are progressive sensory loss, chronic skin ulcers, and other skin abnormalities. Spontaneous fractures and neuropathic arthropathy are frequent complications and often necessitate amputations. Autonomic features vary between different subgroups. Distal muscle weakness and wasting may be present and is sometimes so prominent that it becomes difficult to distinguish HSN from Charcot-Marie-Tooth syndrome. Recent major advances in molecular genetics have led to the identification of seven gene loci and six-disease causing genes for autosomal-dominant and autosomal-recessive HSN. These genes have been shown to play roles in lipid metabolism and the regulation of intracellular vesicular transport, but also a presumptive transcriptional regulator, a nerve growth factor receptor, and a nerve growth factor have been described among the causative genes in HSN. Nevertheless, it remains unclear how mutations in the known genes lead to the phenotype of HSN. In this review, we summarize the recent progress of the molecular genetics of the HSN and the implicated genes. PMID:16775373

  6. Hereditary Neuropathies

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Hereditary Neuropathies Information Page Synonym(s): Neuropathy - Hereditary Table of Contents ( ... and Information Publicaciones en Español What are Hereditary Neuropathies? Hereditary neuropathies are a group of inherited disorders ...

  7. Mutation in FAM134B causing severe hereditary sensory neuropathy

    PubMed Central

    Murphy, Sinead M; Davidson, Gabrielle L; Brandner, Sebastian; Houlden, Henry; Reilly, Mary M

    2013-01-01

    The hereditary sensory and autonomic neuropathies (HSAN) are rare inherited neuropathies presenting with sensory loss and complications, including ulcers, infections, osteomyelitis and amputations. Usually, sensory symptoms predominate although motor involvement can occur. Autonomic features may be minimal (then hereditary sensory neuropathy, HSN, is preferred). HSAN has been classified into five subtypes depending on clinical presentation.1 Hereditary sensory and autonomic neuropathy II (HSANII or HSNII) is an early onset, autosomal recessive sensory neuropathy with ulcero-mutilating complications due to mutations in the HSN2 isoform of the WNK1 gene.2 Recently, a similar phenotype was described in a Saudi-Arabian family, and a homozygous nonsense mutation found in a new gene, FAM134B (family with sequence similarity 134, member B), encoding a newly identified Golgi protein. The index case in this family was initially thought to have leprosy. Three additional families (out of 75 patients) with similar phenotypes were found to have homozygous loss of function mutations in FAM134B.3 Here, we report the clinical and pathological findings in a further patient with HSNII due to a homozygous mutation in FAM134B. PMID:21115472

  8. SPTLC1 is mutated in hereditary sensory neuropathy, type 1.

    PubMed

    Bejaoui, K; Wu, C; Scheffler, M D; Haan, G; Ashby, P; Wu, L; de Jong, P; Brown, R H

    2001-03-01

    Hereditary sensory neuropathy type 1 (HSN1, MIM 162400; ref. 1) genetically maps to human chromosome 9q22 (refs. 2-4). We report here that the gene encoding a subunit of serine palmitoyltransferase is located within the HSN1 locus, expressed in dorsal root ganglia (DRG) and mutated in HSN1. PMID:11242106

  9. Painless Ulcers and Fissures of Toes: Hereditary Sensory Neuropathy, Not Leprosy

    PubMed Central

    Rao, Angoori Gnaneshwar

    2016-01-01

    Hereditary sensory neuropathies (HSN) are rare genetically determined neuropathies. They often manifest as painless injuries in children. We present HSN in a 5-year-old boy who presented with recurrent fissuring and ulceration involving both great toes. PMID:26955138

  10. Natural history and biomarkers in hereditary sensory neuropathy type 1

    PubMed Central

    Fridman, Vera; Oaklander, Anne louise; David, William S; Johnson, Elise A; Pan, Jessica; Novak, Peter; Brown, Robert H; Eichler, Florian S

    2015-01-01

    Introduction: Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is most commonly caused by missense mutations in SPTLC1. In this study we mapped symptom progression and compared the utility of outcomes. Methods: We administered retrospective surveys of symptoms and analyzed results of nerve conduction, autonomic function testing (AFT), and PGP9.5-immunolabeled skin biopsies. Results: The first symptoms were universally sensory and occurred at a median age of 20 years (range 14–54 years). The onset of weakness, ulcers, pain, and balance problems followed sequentially. Skin biopsies revealed universally absent epidermal innervation at the distal leg with relative preservation in the thigh. Neurite density was highly correlated with total Charcot-Marie-Tooth Examination Score (CMTES; r2 = −0.8) and median motor amplitude (r2 = −0.75). Conclusions: These results confirm sensory loss as the initial symptom of HSAN1 and suggest that skin biopsy may be the most promising biomarker for future clinical trials. Muscle Nerve, 2015 Muscle Nerve 51: 489–495, 2015 PMID:25042817

  11. Hereditary sensory and autonomic neuropathies: types II, III, and IV.

    PubMed

    Axelrod, Felicia B; Gold-von Simson, Gabrielle

    2007-01-01

    The hereditary sensory and autonomic neuropathies (HSAN) encompass a number of inherited disorders that are associated with sensory dysfunction (depressed reflexes, altered pain and temperature perception) and varying degrees of autonomic dysfunction (gastroesophageal reflux, postural hypotention, excessive sweating). Subsequent to the numerical classification of four distinct forms of HSAN that was proposed by Dyck and Ohta, additional entities continue to be described, so that identification and classification are ongoing. As a group, the HSAN are rare diseases that affect both sexes. HSAN III is almost exclusive to individuals of Eastern European Jewish extraction, with incidence of 1 per 3600 live births. Several hundred cases with HSAN IV have been reported. The worldwide prevalence of HSAN type II is very low. This review focuses on the description of three of the disorders, HSAN II through IV, that are characterized by autosomal recessive inheritance and onset at birth. These three forms of HSAN have been the most intensively studied, especially familial dysautonomia (Riley-Day syndrome or HSAN III), which is often used as a prototype for comparison to the other HSAN. Each HSAN disorder is likely caused by different genetic errors that affect specific aspects of small fiber neurodevelopment, which result in variable phenotypic expression. As genetic tests are routinely used for diagnostic confirmation of HSAN III only, other means of differentiating between the disorders is necessary. Diagnosis is based on the clinical features, the degree of both sensory and autonomic dysfunction, and biochemical evaluations, with pathologic examinations serving to further confirm differences. Treatments for all these disorders are supportive. PMID:17915006

  12. Central motor conduction in hereditary motor and sensory neuropathy and hereditary spastic paraplegia.

    PubMed

    Cruz Martínez, A; Tejada, J

    1999-09-01

    Conduction of the central motor pathways (CMCT) by magnetic stimulation of the motor cortex (TMS) was performed in 17 patients with hereditary motor sensory neuropathy (HMSN) and 2 siblings with hereditary spastic paraplegia (HSP). CMCT was prolonged in two patients with HMSN I with associated pyramidal features and in two subjects with HMSN II without clinical pyramidal signs. CMCT may be abnormal in HMSN due to central motor pathways involvement or altered spinal excitability with increased synaptic delay. CMCT was normal in the upper limbs in patients with HSP but increased in the legs. Diagnostic yield of TMS increased in less disabled cases with HSP when selective conduction at the spinal level (C7-S1) was calculated. Abnormal spinal conduction in HSP is consistent with degeneration of the crossed corticospinal tracts at the thoracic level found in neuropathologic observations.

  13. Genes for Hereditary Sensory and Autonomic Neuropathies: A Genotype-Phenotype Correlation

    ERIC Educational Resources Information Center

    Rotthier, Annelies; Baets, Jonathan; De Vriendt, Els; Jacobs, An; Auer-Grumbach, Michaela; Levy, Nicolas; Bonello-Palot, Nathalie; Kilic, Sara Sebnem; Weis, Joachim; Nascimento, Andres; Swinkels, Marielle; Kruyt, Moyo C.; Jordanova, Albena; De Jonghe, Peter; Timmerman, Vincent

    2009-01-01

    Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant ("SPTLC1"…

  14. Exclusion of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) as a common cause for hereditary sensory neuropathy.

    PubMed

    Dawkins, Jennifer L; Brahmbhatt, Sonal; Auer-Grumbach, Michaela; Wagner, Klaus; Hartung, Hans-Peter; Verhoeven, Kristien; Timmerman, Vincent; De Jonghe, Peter; Kennerson, Marina; LeGuern, Eric; Nicholson, Garth A

    2002-10-01

    Recently point mutations in the SPTLC1 subunit of serine palmitoyltransferase have been shown to cause the common form of dominant hereditary sensory neuropathy (HSN1). Serine palmitoyltransferase (SPT) is a heterodimeric molecule made up of two subunits, SPTLC1 and SPTLC2. Twelve index patients from families with presumed genetic sensory neuropathies were screened for SPTLC2 mutations. These families comprised six multigenerational families, including two previously reported families not linked to the SPTLC1 locus on chromosome 9 and one multigenerational family with a complicated hereditary sensory neuropathy syndrome with associated palmar plantar keratosis, ataxia and spastic paraplegia. The remaining families included one consanguineous family with presumed recessive HSN with two affected siblings, one case of congenital sensory neuropathy and four sporadic cases with adult onset sensory neuropathy. No mutations in the SPTLC2 gene were found in any family. These results suggest that SPTLC2 mutations are not a common cause for genetic sensory neuropathies. PMID:12207934

  15. [Hereditary sensory and autonomic neuropathy type II A: early neurological and skeletal findings].

    PubMed

    Esmer, C; Díaz Zambrano, S; Santos Díaz, M A; González Huerta, L M; Cuevas Covarrubias, S A; Bravo Oro, A

    2014-04-01

    The hereditary sensory and autonomic neuropathies are genetic disorders characterized by the loss of sensation including pain, tactile and temperature. Its clinical and molecular features vary widely; the symptoms may begin from birth or be noticed in the first or second decade, with different types of complications of trauma to the extremities such as ulcers, mutilations and acral amputations. They are classified into six groups from I to VI, determined by the abnormality in eleven genes leading to phenotypic variations in the age of onset and the presence or absence of dysautonomia signs. With the exception of type I, all are autosomal recessive. The type II of these neuropathies is characterized by insensitivity to pain, heat and proprioception. We describe three members of a Mexican family with WNK1 gene mutation that caused hereditary neuropathy IIA.

  16. Hereditary motor-sensory neuropathy (HMSN): possible X-linked dominant inheritance.

    PubMed

    Phillips, L H; Kelly, T E; Schnatterly, P; Parker, D

    1985-04-01

    The inheritance of the hereditary motor and sensory neuropathies (HMSN) is usually autosomal dominant. We studied a kinship with a pattern of X-linked dominant inheritance. The phenotype was similar to HMSN of the "intermediate" type. Men were more severely affected than women, and hypertrophic nerves were not found. Nerve conduction was very slow in men, but it was mildly slow or normal in women. No male-to-male transmission was found in six generations.

  17. Late-onset hereditary sensory neuropathy type I due to SPTLC1 mutation: autopsy findings.

    PubMed

    Lindahl, Andrea J; Lhatoo, Sam D; Campbell, Malcolm J; Nicholson, Garth; Love, Seth

    2006-12-01

    There is little published information on the autopsy findings in hereditary sensory neuropathy type I (HSN I), and none in genetically confirmed cases. We report the neuropathological findings in a 93-year-old woman with a disease of unusually late onset, who was part of a large HSN I kindred and in whom genetic analysis confirmed an SPTLC1 T399G mutation. PMID:16271825

  18. Genetics Home Reference: hereditary sensory and autonomic neuropathy type V

    MedlinePlus

    ... that primarily affects the sensory nerve cells (sensory neurons), which transmit information about sensations such as pain, ... in the development and survival of nerve cells (neurons), including sensory neurons. The NGFβ protein functions by ...

  19. Genetics Home Reference: hereditary sensory and autonomic neuropathy type II

    MedlinePlus

    ... that primarily affects the sensory nerve cells (sensory neurons), which transmit information about sensations such as pain, ... the sensations of pain, temperature, and touch (sensory neurons). The mutations involved in HSAN2A result in an ...

  20. Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I).

    PubMed

    Houlden, Henry; King, Rosalind; Blake, Julian; Groves, Mike; Love, Seth; Woodward, Cathy; Hammans, Simon; Nicoll, James; Lennox, Graham; O'Donovan, Dominic G; Gabriel, Carolyn; Thomas, P K; Reilly, Mary M

    2006-02-01

    Hereditary sensory and autonomic neuropathy type I (HSAN I) is the most frequent type of hereditary neuropathy that primarily affects sensory neurons. The genetic locus for HSAN I has been mapped to chromosome 9q22.1-22.3 and recently the gene was identified as SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1. Sequencing in HSAN I families have previously identified mutations in exons 5, 6 and 13 of this gene. We analysed the SPTLC1 gene for mutations in 8 families with HSAN I, 60 individuals with sporadic sensory neuropathy, 6 HSAN II families, 20 Charcot-Marie-Tooth type I families and 20 families with Charcot-Marie-Tooth type II. Six HSAN I families and a single sporadic neuropathy case had an identical SPTLC1 mutation. No mutations were found in the other groups. Genetic haplotyping across the HSAN I critical region in 5 families and the sporadic case suggested a common founder. Several characteristics, previously not widely recognized were identified, including lack of penetrance of the SPTLC1 mutation in some individuals, variability in age of onset along with an earlier age of onset in younger generations, in some patients surprisingly early and often severe motor involvement and an earlier onset characterized by motor involvement with demyelinating features in males compared to females in 4 families. The sensory findings were often disassociated with prominent pain and temperature loss. Neurophysiology mainly showed a sensory axonal neuropathy but in many individuals there was electrical evidence of demyelination. Sural nerve biopsies from six affected individuals and the post-mortem findings in 1 case showed mainly axonal loss. This in depth study on the phenotype of HSAN I in 6 families and a single sporadic case with a common founder identifies a number of poorly recognized features in this disorder and highlights the clinical heterogeneity both within and between families suggesting the influence of other genetic and acquired

  1. SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I.

    PubMed

    Verhoeven, K; Coen, K; De Vriendt, E; Jacobs, A; Van Gerwen, V; Smouts, I; Pou-Serradell, A; Martin, J J; Timmerman, V; De Jonghe, P

    2004-03-23

    Hereditary sensory neuropathy type I (HSN I) is an autosomal dominant ulceromutilating disorder of the peripheral nervous system characterized by progressive sensory loss. HSN I locus maps to chromosome 9q22.1-22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long-chain base subunit 1 (SPTLC1). A novel missense mutation in exon 13 of the SPTLC1 gene (c.1160G-->C; p.G387A) in twin sisters with a severe HSN I phenotype is reported. PMID:15037712

  2. Hereditary Sensory Neuropathy Type I: Haplotype Analysis Shows Founders in Southern England and Europe

    PubMed Central

    Nicholson, G. A.; Dawkins, J. L.; Blair, I. P.; Auer-Grumbach, M.; Brahmbhatt, S. B.; Hulme, D. J.

    2001-01-01

    Hereditary sensory neuropathy type I (HSN1) is the most common dominantly inherited degenerative disorder of sensory neurons. The gene mutation was mapped to chromosome 9 in a large Australian family, descended from an ancestor from southern England who was a convict. Dawkins et al. recently reported gene mutations in the SPTLC1 gene, in this and other families. The first description of hereditary sensory neuropathy, by Hicks, was in a family from London and Exeter. To determine if the families in the present study that have SPTLC1 mutations are related to English families with HSN1 and, possibly, to the family studied by Hicks, we performed haplotype analysis of four Australian families of English extraction, four English families, and one Austrian family. Three Australian families of English extraction and three English families (two of whom have been described elsewhere) had the 399T→G SPTLC1 mutation, the same chromosome 9 haplotype, and the same phenotype. The Australian and English families may therefore have a common founder who, on the basis of historical information, has been determined to have lived in southern England prior to 1800. The sensorimotor neuropathy phenotype caused by the 399T→G SPTLC1 mutation is the same as that reported by Campbell and Hoffman and, possibly, the same as that originally described by Hicks. PMID:11479835

  3. Hereditary sensory neuropathy type I: haplotype analysis shows founders in southern England and Europe.

    PubMed

    Nicholson, G A; Dawkins, J L; Blair, I P; Auer-Grumbach, M; Brahmbhatt, S B; Hulme, D J

    2001-09-01

    Hereditary sensory neuropathy type I (HSN1) is the most common dominantly inherited degenerative disorder of sensory neurons. The gene mutation was mapped to chromosome 9 in a large Australian family, descended from an ancestor from southern England who was a convict. Dawkins et al. recently reported gene mutations in the SPTLC1 gene, in this and other families. The first description of hereditary sensory neuropathy, by Hicks, was in a family from London and Exeter. To determine if the families in the present study that have SPTLC1 mutations are related to English families with HSN1 and, possibly, to the family studied by Hicks, we performed haplotype analysis of four Australian families of English extraction, four English families, and one Austrian family. Three Australian families of English extraction and three English families (two of whom have been described elsewhere) had the 399T-->G SPTLC1 mutation, the same chromosome 9 haplotype, and the same phenotype. The Australian and English families may therefore have a common founder who, on the basis of historical information, has been determined to have lived in southern England prior to 1800. The sensorimotor neuropathy phenotype caused by the 399T-->G SPTLC1 mutation is the same as that reported by Campbell and Hoffman and, possibly, the same as that originally described by Hicks. PMID:11479835

  4. Genetics Home Reference: hereditary sensory and autonomic neuropathy type IE

    MedlinePlus

    ... by impaired function of nerve cells called sensory neurons, which transmit information about sensations such as pain, ... understood, the enzyme may help regulate nerve cell (neuron) maturation and specialization (differentiation), the ability of neurons ...

  5. Neurofilament light mutation causes hereditary motor and sensory neuropathy with pyramidal signs.

    PubMed

    Hashiguchi, Akihiro; Higuchi, Yujiro; Nomura, Miwa; Nakamura, Tomonori; Arata, Hitoshi; Yuan, Junhui; Yoshimura, Akiko; Okamoto, Yuji; Matsuura, Eiji; Takashima, Hiroshi

    2014-12-01

    To identify novel mutations causing hereditary motor and sensory neuropathy (HMSN) with pyramidal signs, a variant of Charcot-Marie-Tooth disease (CMT), we screened 28 CMT and related genes in four members of an affected Japanese family. Clinical features included weakness of distal lower limb muscles, foot deformity, and mild sensory loss, then late onset of progressive spasticity. Electrophysiological studies revealed widespread neuropathy. Electron microscopic analysis showed abnormal mitochondria and mitochondrial accumulation in the neurons and Schwann cells. Brain magnetic resonance imaging (MRI) revealed an abnormally thin corpus callosum. In all four, microarrays detected a novel heterozygous missense mutation c.1166A>G (p.Y389C) in the gene encoding the light-chain neurofilament protein (NEFL), indicating that NEFL mutations can result in a HMSN with pyramidal signs phenotype. PMID:25583183

  6. Hereditary sensory neuropathy type 1 in a Portuguese family-electrodiagnostic and autonomic nervous system studies.

    PubMed

    Geraldes, Ruth; de Carvalho, Mamede; Santos-Bento, Mariana; Nicholson, Garth

    2004-12-15

    Hereditary sensory and autonomic neuropathy type 1 (HSAN 1) is a dominantly inherited disorder; its gene locus is mapped on chromosome 9q22. Three different missense mutations (C133Y, C133W and V144D) have been described in 11 families from Australia, England and Austria. Common clinical features have been found in these families. We report the clinical and electrophysiological features of three members of a large Portuguese family with HSAN 1 and the C133Y missense mutation. The affected members showed typical clinical features. Electrophysiological findings were consistent with a distal axonal predominantly sensory neuropathy with motor involvement, in three different severity stages. No autonomic involvement was detected in sudomotor and cardiovascular tests. This report documents the lesion of the motor nerve fibers in this disease, as well as the preservation of the autonomic nervous system function, therefore suggesting that HSNA is an inappropriate name for this disorder. PMID:15546589

  7. Facial nerve dysfunction in hereditary motor and sensory neuropathy type I and III.

    PubMed

    Glocker, F X; Rösler, K M; Linden, D; Heinen, F; Hess, C W; Lücking, C H

    1999-09-01

    Facial nerve function was studied in 19 patients with hereditary motor and sensory neuropathy type I (HMSN I) and 2 patients with hereditary motor and sensory neuropathy type III (HMSN III, Déjérine-Sottas), and compared to that in 24 patients with Guillain-Barré syndrome (GBS). The facial nerve was stimulated electrically at the stylomastoid fossa, and magnetically in its proximal intracanalicular segment. Additionally, the face-associated motor cortex was stimulated magnetically. The facial nerve motor neurography was abnormal in 17 of 19 HMSN I patients and in both HMSN III patients, revealing moderate to marked conduction slowing in both the extracranial and intracranial nerve segments, along with variable reductions of compound muscle action potential (CMAP) amplitudes. The facial nerve conduction slowing paralleled that of limb nerves, but was not associated with clinical dysfunction of facial muscles, because none of the HMSN I patients had facial palsy. Conduction slowing was most severe in the HMSN III patients, but only slight facial weakness was present. In GBS, conduction slowing was less marked, but facial weakness exceeded that in HMSN patients in all cases. We conclude that involvement of the facial nerve is common in HMSN I and HMSN III. It affects the intra- and extracranial part of the facial nerve and is mostly subclinical. PMID:10454715

  8. Hereditary Sensory and Autonomic Neuropathy Type IV in 9 Year Old Boy: A Case Report

    PubMed Central

    AZADVARI, Mohaddeseh; EMAMI RAZAVI, Seyedeh Zahra; KAZEMI, Shahrbanoo

    2016-01-01

    Objective The Hereditary Sensory and Autonomic neuropathy (HSAN) is a rare group of neuropathies that affects the Sensory and Autonomic nervous system. The patients do not have the ability of sensing different sensations such as pain and temperature, which tends to lead to different injuries. In addition, due to autonomic involvement, the patients suffer from fluctuation in body temperature periodically and lack of precipitation. HSAN is divided into 5 types according to the age of onset, clinical features, and inheritance. Our case was a 9-yr old boy from cousin parents. He had some developmental delay and history of recurrent fever and convulsion in the first year of his life. Gradually, other symptoms added to patient’ feature such as multiple painless skin ulcers, tooth loss, destruction of toes and fingers. In electrodiagnostic study, we found decreased amplitude of sensory nerves, while the other studies were normal. Laboratory test and imaging studies were also normal. All clinical and paraclinical findings were in favor of HSAN type IV. There is no cure for such patients; as a result, these patients and their families need receiving appropriate education and timely rehabilitation services. PMID:27247588

  9. Hereditary Sensory and Autonomic Neuropathy Type IV in 9 Year Old Boy: A Case Report.

    PubMed

    Azadvari, Mohaddeseh; Emami Razavi, Seyedeh Zahra; Kazemi, Shahrbanoo

    2016-01-01

    Objective The Hereditary Sensory and Autonomic neuropathy (HSAN) is a rare group of neuropathies that affects the Sensory and Autonomic nervous system. The patients do not have the ability of sensing different sensations such as pain and temperature, which tends to lead to different injuries. In addition, due to autonomic involvement, the patients suffer from fluctuation in body temperature periodically and lack of precipitation. HSAN is divided into 5 types according to the age of onset, clinical features, and inheritance. Our case was a 9-yr old boy from cousin parents. He had some developmental delay and history of recurrent fever and convulsion in the first year of his life. Gradually, other symptoms added to patient' feature such as multiple painless skin ulcers, tooth loss, destruction of toes and fingers. In electrodiagnostic study, we found decreased amplitude of sensory nerves, while the other studies were normal. Laboratory test and imaging studies were also normal. All clinical and paraclinical findings were in favor of HSAN type IV. There is no cure for such patients; as a result, these patients and their families need receiving appropriate education and timely rehabilitation services. PMID:27247588

  10. Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation.

    PubMed

    Rotthier, Annelies; Baets, Jonathan; De Vriendt, Els; Jacobs, An; Auer-Grumbach, Michaela; Lévy, Nicolas; Bonello-Palot, Nathalie; Kilic, Sara Sebnem; Weis, Joachim; Nascimento, Andrés; Swinkels, Marielle; Kruyt, Moyo C; Jordanova, Albena; De Jonghe, Peter; Timmerman, Vincent

    2009-10-01

    Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant (SPTLC1 and RAB7) and five genes for autosomal recessive forms of HSAN (WNK1/HSN2, NTRK1, NGFB, CCT5 and IKBKAP). We performed a systematic mutation screening of the coding sequences of six of these genes on a cohort of 100 familial and isolated patients diagnosed with HSAN. In addition, we screened the functional candidate gene NGFR (p75/NTR) encoding the nerve growth factor receptor. We identified disease-causing mutations in SPTLC1, RAB7, WNK1/HSN2 and NTRK1 in 19 patients, of which three mutations have not previously been reported. The phenotypes associated with mutations in NTRK1 and WNK1/HSN2 typically consisted of congenital insensitivity to pain and anhidrosis, and early-onset ulcero-mutilating sensory neuropathy, respectively. RAB7 mutations were only found in patients with a Charcot-Marie-Tooth type 2B (CMT2B) phenotype, an axonal sensory-motor neuropathy with pronounced ulcero-mutilations. In SPTLC1, we detected a novel mutation (S331F) corresponding to a previously unknown severe and early-onset HSAN phenotype. No mutations were found in NGFB, CCT5 and NGFR. Overall disease-associated mutations were found in 19% of the studied patient group, suggesting that additional genes are associated with HSAN. Our genotype-phenotype correlation study broadens the spectrum of HSAN and provides additional insights for molecular and clinical diagnosis. PMID:19651702

  11. Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2

    PubMed Central

    Murphy, Sinéad M.; Ernst, Daniela; Wei, Yu; Laurà, Matilde; Liu, Yo-Tsen; Polke, James; Blake, Julian; Winer, John; Houlden, Henry; Hornemann, Thorsten

    2013-01-01

    Objective: To describe the clinical and neurophysiologic phenotype of a family with hereditary sensory and autonomic neuropathy type 1 (HSANI) due to a novel mutation in SPTLC2 and to characterize the biochemical properties of this mutation. Methods: We screened 107 patients with HSAN who were negative for other genetic causes for mutations in SPTLC2. The biochemical properties of a new mutation were characterized in cell-free and cell-based activity assays. Results: A novel mutation (A182P) was found in 2 subjects of a single family. The phenotype of the 2 subjects was an ulcero-mutilating sensory-predominant neuropathy as described previously for patients with HSANI, but with prominent motor involvement and earlier disease onset in the first decade of life. Affected patients had elevated levels of plasma 1-deoxysphingolipids (1-deoxySLs). Biochemically, the A182P mutation was associated with a reduced canonical activity but an increased alternative activity with alanine, which results in largely increased 1-deoxySL levels, supporting their pathogenicity. Conclusion: This study confirms that mutations in SPTLC2 are associated with increased deoxySL formation causing HSANI. PMID:23658386

  12. Sporadic hereditary motor and sensory neuropathies: Advances in the diagnosis using next generation sequencing technology.

    PubMed

    Fallerini, Chiara; Carignani, Giulia; Capoccitti, Giorgio; Federico, Antonio; Rufa, Alessandra; Pinto, Anna Maria; Rizzo, Caterina Lo; Rossi, Alessandro; Mari, Francesca; Mencarelli, Maria Antonietta; Giannini, Fabio; Renieri, Alessandra

    2015-12-15

    Hereditary motor and sensory neuropathies (HMSN) are genetically heterogeneous disorders affecting peripheral motor and sensory functions. Many different pathogenic variants in several genes involved in the demyelinating, the axonal and the intermediate HMSN forms have been identified, for which all inheritance patterns have been described. The mutation screening currently available is based on Sanger sequencing and is time-consuming and relatively expensive due to the high number of genes involved and to the absence of mutational hot spots. To overcome these limitations, we have designed a custom panel for simultaneous sequencing of 28 HMSN-related genes. We have applied this panel to three representative patients with variable HMSN phenotype and uncertain diagnostic classifications. Using our NGS platform we rapidly identified three already described pathogenic heterozygous variants in MFN2, MPZ and DNM2 genes. Here we show that our pre-custom platform allows a fast, specific and low-cost diagnosis in sporadic HMSN cases. This prompt diagnosis is useful for providing a well-timed treatment, establishing a recurrence risk and preventing further investigations poorly tolerated by patients and expensive for the health system. Importantly, our study illustrates the utility and successful application of NGS to mutation screening of a Mendelian disorder with extreme locus heterogeneity.

  13. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort.

    PubMed

    Davidson, G L; Murphy, S M; Polke, J M; Laura, M; Salih, M A M; Muntoni, F; Blake, J; Brandner, S; Davies, N; Horvath, R; Price, S; Donaghy, M; Roberts, M; Foulds, N; Ramdharry, G; Soler, D; Lunn, M P; Manji, H; Davis, M B; Houlden, H; Reilly, M M

    2012-08-01

    The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.

  14. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort

    PubMed Central

    Davidson, G. L.; Murphy, S. M.; Polke, J. M.; Laura, M.; Salih, M. A. M.; Muntoni, F.; Blake, J.; Brandner, S.; Davies, N.; Horvath, R.; Price, S.; Donaghy, M.; Roberts, M.; Foulds, N.; Ramdharry, G.; Soler, D.; Lunn, M. P.; Manji, H.; Davis, M. B.; Houlden, H.; Reilly, M. M.

    2013-01-01

    The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN. PMID:22302274

  15. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort.

    PubMed

    Davidson, G L; Murphy, S M; Polke, J M; Laura, M; Salih, M A M; Muntoni, F; Blake, J; Brandner, S; Davies, N; Horvath, R; Price, S; Donaghy, M; Roberts, M; Foulds, N; Ramdharry, G; Soler, D; Lunn, M P; Manji, H; Davis, M B; Houlden, H; Reilly, M M

    2012-08-01

    The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN. PMID:22302274

  16. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss

    PubMed Central

    Klein, Christopher J.; Botuyan, Maria-Victoria; Wu, Yanhong; Ward, Christopher J.; Nicholson, Garth A.; Hammans, Simon; Hojo, Kaori; Yamanishi, Hiromitch; Karpf, Adam R.; Wallace, Douglas C.; Simon, Mariella; Lander, Cecilie; Boardman, Lisa A.; Cunningham, Julie M.; Smith, Glenn E.; Litchy, William J.; Boes, Benjamin; Atkinson, Elizabeth J.; Middha, Sumit; Dyck, P. James; Parisi, Joseph E.; Mer, Georges; Smith, David I.; Dyck, Peter J.

    2011-01-01

    DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability1-3. DNA mismatch repair, cell cycle regulation in post-mitotic neurons4,5 and neurogenesis6 are influenced by DNA methylation. Here we show mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy (HSAN1) with dementia and hearing loss7,8. Exome sequencing led to the identification of DNMT1 mutation c.A1484G (p.Tyr495Cys) in two American and one Japanese kindreds and a triple nucleotide change c.1470TCC-1472ATA (p.Asp490Glu-Pro491Tyr) in one European kindred. All mutations are within the targeting sequence (TS) domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase, leading to global hypomethylation and site specific hypermethylation. Our study demonstrates DNMT1 mutations cause aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases. PMID:21532572

  17. Targeted High-Throughput Sequencing Identifies Mutations in atlastin-1 as a Cause of Hereditary Sensory Neuropathy Type I

    PubMed Central

    Guelly, Christian; Zhu, Peng-Peng; Leonardis, Lea; Papić, Lea; Zidar, Janez; Schabhüttl, Maria; Strohmaier, Heimo; Weis, Joachim; Strom, Tim M.; Baets, Jonathan; Willems, Jan; De Jonghe, Peter; Reilly, Mary M.; Fröhlich, Eleonore; Hatz, Martina; Trajanoski, Slave; Pieber, Thomas R.; Janecke, Andreas R.; Blackstone, Craig; Auer-Grumbach, Michaela

    2011-01-01

    Hereditary sensory neuropathy type I (HSN I) is an axonal form of autosomal-dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Unrecognized, these can result in delayed wound healing and osteomyelitis, necessitating distal amputations. To elucidate the genetic basis of an HSN I subtype in a family in which mutations in the few known HSN I genes had been excluded, we employed massive parallel exon sequencing of the 14.3 Mb disease interval on chromosome 14q. We detected a missense mutation (c.1065C>A, p.Asn355Lys) in atlastin-1 (ATL1), a gene that is known to be mutated in early-onset hereditary spastic paraplegia SPG3A and that encodes the large dynamin-related GTPase atlastin-1. The mutant protein exhibited reduced GTPase activity and prominently disrupted ER network morphology when expressed in COS7 cells, strongly supporting pathogenicity. An expanded screen in 115 additional HSN I patients identified two further dominant ATL1 mutations (c.196G>C [p.Glu66Gln] and c.976 delG [p.Val326TrpfsX8]). This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders. PMID:21194679

  18. Hereditary sensory and autonomic neuropathy type I in a Chinese family: British C133W mutation exists in the Chinese.

    PubMed

    Bi, Hongyan; Gao, Yunying; Yao, Sheng; Dong, Mingrui; Headley, Alexander Peter; Yuan, Yun

    2007-10-01

    Hereditary sensory and autonomic neuropathy type I (HSAN I) is an autosomal dominant disorder of the peripheral nervous system characterized by marked progressive sensory loss, with variable autonomic and motor involvement. The HSAN I locus maps to chromosome 9q22.1-22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long chain base subunit 1 (SPTLC1). Sequencing in HSAN I families have previously identified mutations in exons 5, 6 and 13 of this gene. Here we report the clinical, electrophysiological and pathological findings of a proband in a Chinese family with HSAN I. The affected members showed almost typical clinical features. Electrophysiological findings showed an axonal, predominantly sensory, neuropathy with motor and autonomic involvement. Sural nerve biopsy showed loss of myelinated and unmyelinated fibers. SPTLC1 mutational analysis revealed the C133W mutation, a mutation common in British HSAN I families. PMID:18018475

  19. Hereditary motor and sensory neuropathies: Understanding molecular pathogenesis could lead to future treatment strategies.

    PubMed

    Jerath, Nivedita U; Shy, Michael E

    2015-04-01

    Inherited peripheral neuropathies, like many other degenerative disorders, have been challenging to treat. At this point, there is little specific therapy for the inherited neuropathies other than genetic counseling as well as symptomatic treatment and rehabilitation. In the past, ascorbic acid, progesterone antagonists, and subcutaneous neurotrophin-3 (NT3) injections have demonstrated improvement in animal models of CMT 1A, the most common inherited neuropathy, but have failed to translate any effect in humans. Given the difficulty in treatment, it is important to understand the molecular pathogenesis of hereditary neuropathies in order to strategize potential future therapies. The hereditary neuropathies are in an era of molecular insight and over the past 20 years, more than 78 subtypes of Charcot Marie Tooth disease (CMT) have been identified and extensively studied to understand the biological pathways in greater detail. Next generation molecular sequencing has also improved the diagnosis as well as the understanding of CMT. A greater understanding of the molecular pathways will help pave the way to future therapeutics of CMT. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. PMID:25108281

  20. Disturbances in affective touch in hereditary sensory & autonomic neuropathy type III.

    PubMed

    Macefield, Vaughan G; Norcliffe-Kaufmann, Lucy; Löken, Line; Axelrod, Felicia B; Kaufmann, Horacio

    2014-07-01

    Hereditary sensory and autonomic neuropathy type III (HSAN III, Riley-Day syndrome, Familial Dysautomia) is characterised by elevated thermal thresholds and an indifference to pain. Using microelectrode recordings we recently showed that these patients possess no functional stretch-sensitive mechanoreceptors in their muscles (muscle spindles), a feature that may explain their lack of stretch reflexes and ataxic gait, yet patients have apparently normal low-threshold cutaneous mechanoreceptors. The density of C-fibres in the skin is markedly reduced in patients with HSAN III, but it is not known whether the C-tactile afferents, a distinct type of low-threshold C fibre present in hairy skin that is sensitive to gentle stroking and has been implicated in the coding of pleasant touch are specifically affected in HSAN III patients. We addressed the relationship between C-tactile afferent function and pleasant touch perception in 15 patients with HSAN III and 15 age-matched control subjects. A soft make-up brush was used to apply stroking stimuli to the forearm and lateral aspect of the leg at five velocities: 0.3, 1, 3, 10 and 30 cm/s. As demonstrated previously, the control subjects rated the slowest and highest velocities as less pleasant than those applied at 1-10 cm/s, which fits with the optimal velocities for exciting C-tactile afferents. Conversely, for the patients, ratings of pleasantness did not fit the profile for C-tactile afferents. Patients either rated the higher velocities as more pleasant than the slow velocities, with the slowest velocities being rated unpleasant, or rated all velocities equally pleasant. We interpret this to reflect absent or reduced C-tactile afferent density in the skin of patients with HSAN III, who are likely using tactile cues (i.e. myelinated afferents) to rate pleasantness of stroking or are attributing pleasantness to this type of stimulus irrespective of velocity.

  1. The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy.

    PubMed

    Suriyanarayanan, Saranya; Auranen, Mari; Toppila, Jussi; Paetau, Anders; Shcherbii, Maria; Palin, Eino; Wei, Yu; Lohioja, Tarja; Schlotter-Weigel, Beate; Schön, Ulrike; Abicht, Angela; Rautenstrauss, Bernd; Tyynismaa, Henna; Walter, Maggie C; Hornemann, Thorsten; Ylikallio, Emil

    2016-03-01

    Hereditary sensory and autonomic neuropathy 1 (HSAN1) is an autosomal dominant disorder that can be caused by variants in SPTLC1 or SPTLC2, encoding subunits of serine palmitoyl-CoA transferase. Disease variants alter the enzyme's substrate specificity and lead to accumulation of neurotoxic 1-deoxysphingolipids. We describe two families with autosomal dominant HSAN1C caused by a new variant in SPTLC2, c.547C>T, p.(Arg183Trp). The variant changed a conserved amino acid and was not found in public variant databases. All patients had a relatively mild progressive distal sensory impairment, with onset after age 50. Small fibers were affected early, leading to abnormalities on quantitative sensory testing. Sural biopsy revealed a severe chronic axonal neuropathy with subtotal loss of myelinated axons, relatively preserved number of non-myelinated fibers and no signs for regeneration. Skin biopsy with PGP9.5 labeling showed lack of intraepidermal nerve endings early in the disease. Motor manifestations developed later in the disease course, but there was no evidence of autonomic involvement. Patients had elevated serum 1-deoxysphingolipids, and the variant protein produced elevated amounts of 1-deoxysphingolipids in vitro, which proved the pathogenicity of the variant. Our results expand the genetic spectrum of HSAN1C and provide further detail about the clinical characteristics. Sequencing of SPTLC2 should be considered in all patients presenting with mild late-onset sensory-predominant small or large fiber neuropathy. PMID:26573920

  2. Mutations in the SPTLC2 Subunit of Serine Palmitoyltransferase Cause Hereditary Sensory and Autonomic Neuropathy Type I

    PubMed Central

    Rotthier, Annelies; Auer-Grumbach, Michaela; Janssens, Katrien; Baets, Jonathan; Penno, Anke; Almeida-Souza, Leonardo; Van Hoof, Kim; Jacobs, An; De Vriendt, Els; Schlotter-Weigel, Beate; Löscher, Wolfgang; Vondráček, Petr; Seeman, Pavel; De Jonghe, Peter; Van Dijck, Patrick; Jordanova, Albena; Hornemann, Thorsten; Timmerman, Vincent

    2010-01-01

    Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations. Mutations in the first subunit of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I. The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway. However, different studies suggest the implication of other genes in the pathology of HSAN-I. Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients. No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families presenting with a typical HSAN-I phenotype. We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo. Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine. Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I. PMID:20920666

  3. A Locus for Hereditary Sensory Neuropathy with Cough and Gastroesophageal Reflux on Chromosome 3p22-p24

    PubMed Central

    Kok, C.; Kennerson, M. L.; Spring, P. J.; Ing, A. J.; Pollard, J. D.; Nicholson, G. A.

    2003-01-01

    Hereditary sensory neuropathy type I (HSN I) is a group of dominantly inherited degenerative disorders of peripheral nerve in which sensory features are more prominent than motor involvement. We have described a new form of HSN I that is associated with cough and gastroesophageal reflux. To map the chromosomal location of the gene causing the disorder, a 10-cM genome screen was undertaken in a large Australian family. Two-point analysis showed linkage to chromosome 3p22-p24 (Zmax=3.51 at recombination fraction (θ) 0.0 for marker D3S2338). A second family with a similar phenotype shares a different disease haplotype but segregates at the same locus. Extended haplotype analysis has refined the region to a 3.42-cM interval, flanked by markers D3S2336 and D3S1266. PMID:12870133

  4. [Leber's hereditary optic neuropathy].

    PubMed

    Hilo, Wasseem; Jabaly-Habib, Haneen; Modi, Naftali; Briscoe, Daniel

    2013-08-01

    Lebers hereditary optic neuropathy (LHON) is a maternally inherited disease characterized by subacute severe visual loss in both eyes, which usually manifests in young adulthood. The disease has maternal inheritance due to mitochondrial DNA mutation. The final diagnosis is genetic. There is still no proven treatment, but there is significant progress in developments on the genetics of the disease to reach gene therapy. In this article we review the latest literature relevant to this disease.

  5. Molecular basis of hereditary neuropathies.

    PubMed

    Chance, P F

    2001-05-01

    Inherited disorders of peripheral nerves represent a common group of neurologic diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B) and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0 or MPZ) gene. The molecular defect in CMT1C is unknown. X-linked Charcot-Marie-Tooth neuropathy (CMTX), which has clinical features similar to CMT1, is associated with mutations in the connexin32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is an axonal neuropathy, also of undetermined cause. Forms of CMT2 map to chromosome 1p36 (CMT2A), chromosome 3p (CMT2B), chromosome 7p (CMT2D), and to chromosome 8p21 (CMT2E). Dejerine-Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile-onset, demyelinating polyneuropathy syndrome that may be associated with point mutations in either the PMP22 gene or the P0 gene and shares considerable clinical and pathologic features with CMT1. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and results from reduced expression of the PMP22 gene. CMT1A and HNPP are reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis. Other rare forms of demyelinating peripheral neuropathies map to chromosomes 8q, 10q, and 11q. Hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) is an autosomal dominant disorder causing painful, recurrent brachial plexopathies

  6. Genetics Home Reference: Leber hereditary optic neuropathy

    MedlinePlus

    ... Conditions Leber hereditary optic neuropathy Leber hereditary optic neuropathy Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Leber hereditary optic neuropathy (LHON) is an inherited form of vision loss. ...

  7. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.

    PubMed

    Dawkins, J L; Hulme, D J; Brahmbhatt, S B; Auer-Grumbach, M; Nicholson, G A

    2001-03-01

    Hereditary sensory neuropathy type I (HSN1) is the most common hereditary disorder of peripheral sensory neurons. HSN1 is an autosomal dominant progressive degeneration of dorsal root ganglia and motor neurons with onset in the second or third decades. Initial symptoms are sensory loss in the feet followed by distal muscle wasting and weakness. Loss of pain sensation leads to chronic skin ulcers and distal amputations. The HSN1 locus has been mapped to chromosome 9q22.1-22.3 (refs. 3,4). Here we map the gene SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, to this locus. Mutation screening revealed 3 different missense mutations resulting in changes to 2 amino acids in all affected members of 11 HSN1 families. We found two mutations to be located in exon 5 (C133Y and C133W) and one mutation to be located in exon 6 of SPTLC1 (V144D). All families showing definite or probable linkage to chromosome 9 had mutations in these two exons. These mutations are associated with increased de novo glucosyl ceramide synthesis in lymphoblast cell lines in affected individuals. Increased de novo ceramide synthesis triggers apoptosis and is associated with massive cell death during neural tube closure, raising the possibility that neural degeneration in HSN1 is due to ceramide-induced apoptotic cell death. PMID:11242114

  8. KIF1A, an Axonal Transporter of Synaptic Vesicles, Is Mutated in Hereditary Sensory and Autonomic Neuropathy Type 2

    PubMed Central

    Rivière, Jean-Baptiste; Ramalingam, Siriram; Lavastre, Valérie; Shekarabi, Masoud; Holbert, Sébastien; Lafontaine, Julie; Srour, Myriam; Merner, Nancy; Rochefort, Daniel; Hince, Pascale; Gaudet, Rébecca; Mes-Masson, Anne-Marie; Baets, Jonathan; Houlden, Henry; Brais, Bernard; Nicholson, Garth A.; Van Esch, Hilde; Nafissi, Shahriar; De Jonghe, Peter; Reilly, Mary M.; Timmerman, Vincent; Dion, Patrick A.; Rouleau, Guy A.

    2011-01-01

    Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare autosomal-recessive disorder characterized by peripheral nerve degeneration resulting in a severe distal sensory loss. Although mutations in FAM134B and the HSN2 exon of WNK1 were associated with HSANII, the etiology of a substantial number of cases remains unexplained. In addition, the functions of WNK1/HSN2 and FAM134B and their role in the peripheral nervous system remain poorly understood. Using a yeast two-hybrid screen, we found that KIF1A, an axonal transporter of synaptic vesicles, interacts with the domain encoded by the HSN2 exon. In parallel to this screen, we performed genome-wide homozygosity mapping in a consanguineous Afghan family affected by HSANII and identified a unique region of homozygosity located on chromosome 2q37.3 and spanning the KIF1A gene locus. Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype. Subsequent sequencing of KIF1A in a series of 112 unrelated patients with features belonging to the clinical spectrum of ulcero-mutilating sensory neuropathies revealed truncating mutations in three additional families, thus indicating that mutations in KIF1A are a rare cause of HSANII. Similarly to WNK1 mutations, pathogenic mutations in KIF1A were almost exclusively restricted to an alternatively spliced exon. This study provides additional insights into the molecular pathogenesis of HSANII and highlights the potential biological relevance of alternative splicing in the peripheral sensory nervous system. PMID:21820098

  9. Identification of dietary alanine toxicity and trafficking dysfunction in a Drosophila model of hereditary sensory and autonomic neuropathy type 1.

    PubMed

    Oswald, Matthew C W; West, Ryan J H; Lloyd-Evans, Emyr; Sweeney, Sean T

    2015-12-15

    Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is characterized by a loss of distal peripheral sensory and motorneuronal function, neuropathic pain and tissue necrosis. The most common cause of HSAN1 is due to dominant mutations in serine palmitoyl-transferase subunit 1 (SPT1). SPT catalyses the condensation of serine with palmitoyl-CoA, the initial step in sphingolipid biogenesis. Identified mutations in SPT1 are known to both reduce sphingolipid synthesis and generate catalytic promiscuity, incorporating alanine or glycine into the precursor sphingolipid to generate a deoxysphingoid base (DSB). Why either loss of function in SPT1, or generation of DSBs should generate deficits in distal sensory function remains unclear. To address these questions, we generated a Drosophila model of HSAN1. Expression of dSpt1 bearing a disease-related mutation induced morphological deficits in synapse growth at the larval neuromuscular junction consistent with a dominant-negative action. Expression of mutant dSpt1 globally was found to be mildly toxic, but was completely toxic when the diet was supplemented with alanine, when DSBs were observed in abundance. Expression of mutant dSpt1 in sensory neurons generated developmental deficits in dendritic arborization with concomitant sensory deficits. A membrane trafficking defect was observed in soma of sensory neurons expressing mutant dSpt1, consistent with endoplasmic reticulum (ER) to Golgi block. We found that we could rescue sensory function in neurons expressing mutant dSpt1 by co-expressing an effector of ER-Golgi function, Rab1 suggesting compromised ER function in HSAN1 affected dendritic neurons. Our Drosophila model identifies a novel strategy to explore the pathological mechanisms of HSAN1.

  10. Identification of dietary alanine toxicity and trafficking dysfunction in a Drosophila model of hereditary sensory and autonomic neuropathy type 1

    PubMed Central

    Oswald, Matthew C. W.; West, Ryan J. H.; Lloyd-Evans, Emyr; Sweeney, Sean T.

    2015-01-01

    Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is characterized by a loss of distal peripheral sensory and motorneuronal function, neuropathic pain and tissue necrosis. The most common cause of HSAN1 is due to dominant mutations in serine palmitoyl-transferase subunit 1 (SPT1). SPT catalyses the condensation of serine with palmitoyl-CoA, the initial step in sphingolipid biogenesis. Identified mutations in SPT1 are known to both reduce sphingolipid synthesis and generate catalytic promiscuity, incorporating alanine or glycine into the precursor sphingolipid to generate a deoxysphingoid base (DSB). Why either loss of function in SPT1, or generation of DSBs should generate deficits in distal sensory function remains unclear. To address these questions, we generated a Drosophila model of HSAN1. Expression of dSpt1 bearing a disease-related mutation induced morphological deficits in synapse growth at the larval neuromuscular junction consistent with a dominant-negative action. Expression of mutant dSpt1 globally was found to be mildly toxic, but was completely toxic when the diet was supplemented with alanine, when DSBs were observed in abundance. Expression of mutant dSpt1 in sensory neurons generated developmental deficits in dendritic arborization with concomitant sensory deficits. A membrane trafficking defect was observed in soma of sensory neurons expressing mutant dSpt1, consistent with endoplasmic reticulum (ER) to Golgi block. We found that we could rescue sensory function in neurons expressing mutant dSpt1 by co-expressing an effector of ER–Golgi function, Rab1 suggesting compromised ER function in HSAN1 affected dendritic neurons. Our Drosophila model identifies a novel strategy to explore the pathological mechanisms of HSAN1. PMID:26395456

  11. Hereditary Sensory Neuropathy Type 1 Is Caused by the Accumulation of Two Neurotoxic Sphingolipids*♦

    PubMed Central

    Penno, Anke; Reilly, Mary M.; Houlden, Henry; Laurá, Matilde; Rentsch, Katharina; Niederkofler, Vera; Stoeckli, Esther T.; Nicholson, Garth; Eichler, Florian; Brown, Robert H.; von Eckardstein, Arnold; Hornemann, Thorsten

    2010-01-01

    HSAN1 is an inherited neuropathy found to be associated with several missense mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT). SPT catalyzes the condensation of serine and palmitoyl-CoA, the initial step in the de novo synthesis of sphingolipids. Here we show that the HSAN1 mutations induce a shift in the substrate specificity of SPT, which leads to the formation of the two atypical deoxy-sphingoid bases (DSBs) 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine. Both metabolites lack the C1 hydroxyl group of sphinganine and can therefore neither be converted to complex sphingolipids nor degraded. Consequently, they accumulate in the cell, as demonstrated in HEK293 cells overexpressing mutant SPTLC1 and lymphoblasts of HSAN1 patients. Elevated DSB levels were also found in the plasma of HSAN1 patients and confirmed in three groups of HSAN1 patients with different SPTLC1mutations. The DSBs show pronounced neurotoxic effects on neurite formation in cultured sensory neurons. The neurotoxicity co-occurs with a disturbed neurofilament structure in neurites when cultured in the presence of DSBs. Based on these observations, we conclude that HSAN1 is caused by a gain of function mutation, which results in the formation of two atypical and neurotoxic sphingolipid metabolites. PMID:20097765

  12. Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids.

    PubMed

    Penno, Anke; Reilly, Mary M; Houlden, Henry; Laurá, Matilde; Rentsch, Katharina; Niederkofler, Vera; Stoeckli, Esther T; Nicholson, Garth; Eichler, Florian; Brown, Robert H; von Eckardstein, Arnold; Hornemann, Thorsten

    2010-04-01

    HSAN1 is an inherited neuropathy found to be associated with several missense mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT). SPT catalyzes the condensation of serine and palmitoyl-CoA, the initial step in the de novo synthesis of sphingolipids. Here we show that the HSAN1 mutations induce a shift in the substrate specificity of SPT, which leads to the formation of the two atypical deoxy-sphingoid bases (DSBs) 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine. Both metabolites lack the C(1) hydroxyl group of sphinganine and can therefore neither be converted to complex sphingolipids nor degraded. Consequently, they accumulate in the cell, as demonstrated in HEK293 cells overexpressing mutant SPTLC1 and lymphoblasts of HSAN1 patients. Elevated DSB levels were also found in the plasma of HSAN1 patients and confirmed in three groups of HSAN1 patients with different SPTLC1 mutations. The DSBs show pronounced neurotoxic effects on neurite formation in cultured sensory neurons. The neurotoxicity co-occurs with a disturbed neurofilament structure in neurites when cultured in the presence of DSBs. Based on these observations, we conclude that HSAN1 is caused by a gain of function mutation, which results in the formation of two atypical and neurotoxic sphingolipid metabolites. PMID:20097765

  13. [Leber's hereditary optic neuropathy].

    PubMed

    Leo-Kottler, B; Wissinger, B

    2011-12-01

    Leber's hereditary optic neuropathy (LHON) is a rare disease primarily affecting the retinal ganglion cells. In most cases patients with LHON develop permanent visual loss with a large central scotoma in the visual field of both eyes. The optic disc becomes partially or completely pale. At the onset of the disease many patients are considered to suffer from an optic neuritis and are treated under the diagnostic and therapeutic regimen of optic neuritis. LHON is mostly only considered when high dose cortisone therapy fails to be effective or the second eye is affected. Thereafter, molecular genetic analysis will prove LHON in these cases. Detailed anamnesis including pedigree analysis in combination with observance of the peripapillary microangiopathic alterations at the fundus will help to speed up the diagnosis of LHON, but even after exact clinical and molecular genetic diagnosis of LHON some aspects of the disease still remain a mystery today.

  14. Biochemical Characterization of Mutants in Chaperonin Proteins CCT4 and CCT5 Associated with Hereditary Sensory Neuropathy*

    PubMed Central

    Sergeeva, Oksana A.; Tran, Meme T.; Haase-Pettingell, Cameron; King, Jonathan A.

    2014-01-01

    Hereditary sensory neuropathies are a class of disorders marked by degeneration of the nerve fibers in the sensory periphery neurons. Recently, two mutations were identified in the subunits of the eukaryotic cytosolic chaperonin TRiC, a protein machine responsible for folding actin and tubulin in the cell. C450Y CCT4 was identified in a stock of Sprague-Dawley rats, whereas H147R CCT5 was found in a human Moroccan family. As with many genetically identified mutations associated with neuropathies, the underlying molecular basis of the mutants was not defined. We investigated the biochemical properties of these mutants using an expression system in Escherichia coli that produces homo-oligomeric rings of CCT4 and CCT5. Full-length versions of both mutant protein chains were expressed in E. coli at levels approaching that of the WT chains. Sucrose gradient centrifugation revealed chaperonin-sized complexes of both WT and mutant chaperonins, but with reduced recovery of C450Y CCT4 soluble subunits. Electron microscopy of negatively stained samples of C450Y CCT4 revealed few ring-shaped species, whereas WT CCT4, H147R CCT5, and WT CCT5 revealed similar ring structures. CCT5 complexes were assayed for their ability to suppress aggregation of and refold the model substrate γd-crystallin, suppress aggregation of mutant huntingtin, and refold the physiological substrate β-actin in vitro. H147R CCT5 was not as efficient in chaperoning these substrates as WT CCT5. The subtle effects of these mutations are consistent with the homozygous disease phenotype, in which most functions are carried out during development and adulthood, but some selective function is lost or reduced. PMID:25124038

  15. Novel mutation in the replication focus targeting sequence domain of DNMT1 causes hereditary sensory and autonomic neuropathy IE.

    PubMed

    Yuan, Junhui; Higuchi, Yujiro; Nagado, Tatsui; Nozuma, Satoshi; Nakamura, Tomonori; Matsuura, Eiji; Hashiguchi, Akihiro; Sakiyama, Yusuke; Yoshimura, Akiko; Takashima, Hiroshi

    2013-03-01

    DNMT1, encoding DNA methyltransferase 1 (Dnmt1), is a critical enzyme which is mainly responsible for conversion of unmethylated DNA into hemimethylated DNA. To date, two phenotypes produced by DNMT1 mutations have been reported, including hereditary sensory and autonomic neuropathy (HSAN) type IE with mutations in exon 20, and autosomal dominant cerebellar ataxia, deafness, and narcolepsy caused by mutations in exon 21. We report a sporadic case in a Japanese patient with loss of pain and vibration sense, chronic osteomyelitis, autonomic system dysfunctions, hearing loss, and mild dementia, but without definite cerebellar ataxia. Electrophysiological studies revealed absent sensory nerve action potential with nearly normal motor nerve conduction studies. Brain magnetic resonance imaging revealed mild diffuse cerebral and cerebellar atrophy. Using a next-generation sequencing system, 16 candidate genes were analyzed and a novel missense mutation, c.1706A>G (p.His569Arg), was identified in exon 21 of DNMT1. Our findings suggest that mutation in exon 21 of DNMT1 may also produce a HSAN phenotype. Because all reported mutations of DNMT1 are concentrated in exons 20 and 21, which encode the replication focus targeting sequence (RFTS) domain of Dnmt1, the RFTS domain could be a mutation hot spot.

  16. Hereditary sensory and autonomic neuropathy types 4 and 5: Review and proposal of a new rehabilitation method.

    PubMed

    Yozu, Arito; Haga, Nobuhiko; Funato, Tetsuro; Owaki, Dai; Chiba, Ryosuke; Ota, Jun

    2016-03-01

    Although pain is unpleasant, it should serve as a reminder for individuals to avoid similar damaging incidents in the future. Hereditary sensory and autonomic neuropathy (HSAN) includes genetic disorders involving various sensory and autonomic dysfunctions. They are classified by the mode of inheritance, clinical features, and related genes. HSAN type 4 (HSAN-4) and type 5 (HSAN-5) are characterized by insensitivity to pain and thermal sensation. Further, HSAN-4 is accompanied by decreased sweating and intellectual disabilities. These characteristics of HSAN-4 and -5 result in many clinical features, such as pediatric, psychiatric, orthopedic, oral, dermatological, and ophthalmological problems. Orthopedic problems include destructive injuries such as multiple fractures and joint dislocation. Studies on gait have shown greater speed and higher heel contact angular velocity in HSAN-4 and -5 patients compared with controls. Studies on grasp-lift-holding tasks have shown higher grasp force and fluctuations in acceleration of the object. We believe that these findings represent outcomes of deficient motor learning. We propose a new rehabilitation method for patients with HSAN-4 and -5, with the aim of decreasing their destructive injuries. PMID:26562335

  17. Early-onset severe hereditary sensory and autonomic neuropathy type 1 with S331F SPTLC1 mutation.

    PubMed

    Suh, Bum Chun; Hong, Young Bin; Nakhro, Khriezhanuo; Nam, Soo Hyun; Chung, Ki Wha; Choi, Byung-Ok

    2014-02-01

    Hereditary sensory and autonomic neuropathy type I (HSAN I) is an autosomal dominant disease characterized by prominent sensory impairment, resulting in foot ulcers or amputations and has a juvenile to adult onset. The major underlying causes of HSAN I are mutations in SPTLC1, which encodes the first subunit of serine palmitoyltransferase (SPT). To date, there have been no reports with regard to an HSAN patient of Korean origin. In this report we discussed an HSAN I patient with a missense mutation in SPTLC1 (c.992C>T: p.S331F). The patient had noticed frequent falls, lower leg weakness and hand tremors at age five. The patient also presented with foot ulcers, muscle hypotrophy, cataracts, hoarseness, vocal cord palsy and respiratory difficulties and succumbed to the condition at the age of 28 years. In accordance with previous reports, a mutation in Ser331 in the present patient was associated with early-onset and a severe phenotype. Therefore, Ser331 in SPTLC1 is a crucial amino acid, which characterizes the HSAN I phenotype. PMID:24247255

  18. Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis

    PubMed Central

    Bejaoui, Khemissa; Uchida, Yoshikazu; Yasuda, Satoshi; Ho, Mengfatt; Nishijima, Masahiro; Brown, Robert H.; Holleran, Walter M.; Hanada, Kentaro

    2002-01-01

    Hereditary sensory neuropathy type 1 (HSN1) is a dominantly inherited degenerative disorder of the peripheral nerves. HSN1 is clinically and genetically heterogeneous. One form arises from mutations in the gene SPTLC1 encoding long-chain base 1 (LCB1), one of two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the initial step of sphingolipid synthesis. We have examined the effects of the mutations C133Y and C133W, which we have identified in two HSN1 families, on the function of SPT. Although in HSN1 lymphoblasts, the C133Y and C133W mutations do not alter the steady-state levels of LCB1 and LCB2 subunits, they result in reduced SPT activity and sphingolipid synthesis. Moreover, in a mutant Chinese hamster ovary (CHO) cell strain with defective SPT activity due to a lack of the LCB1 subunit, these mutations impair the ability of the LCB1 subunit to complement the SPT deficiency. Furthermore, the overproduction of either the LCB1C133Y or LCB1C133W subunit inhibits SPT activity in CHO cells despite the presence of wild-type LCB1. In addition, we demonstrate that in CHO cells the mutant LCB1 proteins, similar to the normal LCB1, can interact with the wild-type LCB2 subunit. These results indicate that the HSN1-associated mutations in LCB1 confer dominant negative effects on the SPT enzyme. PMID:12417569

  19. Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis.

    PubMed

    Bejaoui, Khemissa; Uchida, Yoshikazu; Yasuda, Satoshi; Ho, Mengfatt; Nishijima, Masahiro; Brown, Robert H; Holleran, Walter M; Hanada, Kentaro

    2002-11-01

    Hereditary sensory neuropathy type 1 (HSN1) is a dominantly inherited degenerative disorder of the peripheral nerves. HSN1 is clinically and genetically heterogeneous. One form arises from mutations in the gene SPTLC1 encoding long-chain base 1 (LCB1), one of two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the initial step of sphingolipid synthesis. We have examined the effects of the mutations C133Y and C133W, which we have identified in two HSN1 families, on the function of SPT. Although in HSN1 lymphoblasts, the C133Y and C133W mutations do not alter the steady-state levels of LCB1 and LCB2 subunits, they result in reduced SPT activity and sphingolipid synthesis. Moreover, in a mutant Chinese hamster ovary (CHO) cell strain with defective SPT activity due to a lack of the LCB1 subunit, these mutations impair the ability of the LCB1 subunit to complement the SPT deficiency. Furthermore, the overproduction of either the LCB1C133Y or LCB1C133W subunit inhibits SPT activity in CHO cells despite the presence of wild-type LCB1. In addition, we demonstrate that in CHO cells the mutant LCB1 proteins, similar to the normal LCB1, can interact with the wild-type LCB2 subunit. These results indicate that the HSN1-associated mutations in LCB1 confer dominant negative effects on the SPT enzyme. PMID:12417569

  20. Autosomal dominant hereditary sensory neuropathy with chronic cough and gastro-oesophageal reflux: clinical features in two families linked to chromosome 3p22-p24.

    PubMed

    Spring, Penelope J; Kok, Cindy; Nicholson, Garth A; Ing, Alvin J; Spies, Judith M; Bassett, Mark L; Cameron, John; Kerlin, Paul; Bowler, Simon; Tuck, Roger; Pollard, John D

    2005-12-01

    Autosomal dominant hereditary sensory neuropathy (HSN I) is a clinically and genetically heterogeneous group of disorders, and in some families it is due to mutations in the serine palmitoyltransferase (SPTLC1) gene. We have characterized two families with HSN I associated with cough and gastro-oesophageal reflux (GOR). From a large Australian family, 27 individuals and from a smaller family, 11 individuals provided clinical information and blood for genetic analysis. Affected individuals had an adult onset of paroxysmal cough, GOR and distal sensory loss. Cough could be triggered by noxious odours or by pressure in the external auditory canal (Arnold's ear-cough reflex). Other features included throat clearing, hoarse voice, cough syncope and sensorineural hearing loss. Neurophysiological and pathological studies demonstrated a sensory axonal neuropathy. Gastric emptying studies were normal, and autonomic function and sweat tests were either normal or showed distal hypohidrosis. Cough was likely to be due to a combination of denervation hypersensitivity of the upper airways and oesophagus, and prominent GOR. Most affected individuals were shown on 24 h ambulatory oesophageal pH monitoring to have multiple episodes of GOR, closely temporally associated with coughing. Hoarse voice was probably attributable to acid-induced laryngeal damage, and there was no evidence of vocal cord palsy. No other cause for cough was found on most respiratory or otorhinological studies. Linkage to chromosome 3p22-p24 has been found in both families, with no evidence of linkage to loci for known HSN I, autosomal dominant hereditary motor and sensory neuropathy, hereditary GOR or triple A syndrome. These families represent a genetically novel variant of HSN I, with a distinctive cough owing to involvement of the upper aerodigestive tract. PMID:16311270

  1. Mutations in the yeast LCB1 and LCB2 genes, including those corresponding to the hereditary sensory neuropathy type I mutations, dominantly inactivate serine palmitoyltransferase.

    PubMed

    Gable, Ken; Han, Gongshe; Monaghan, Erin; Bacikova, Dagmar; Natarajan, Mukil; Williams, Robert; Dunn, Teresa M

    2002-03-22

    It was recently demonstrated that mutations in the human SPTLC1 gene, encoding the Lcb1p subunit of serine palmitoyltransferase (SPT), cause hereditary sensory neuropathy type I . As a member of the subfamily of pyridoxal 5'-phosphate enzymes known as the alpha-oxoamine synthases, serine palmitoyltransferase catalyzes the committed step of sphingolipid synthesis. The residues that are mutated to cause hereditary sensory neuropathy type I reside in a highly conserved region of Lcb1p that is predicted to be a catalytic domain of Lcb1p on the basis of alignments with other members of the alpha-oxoamine synthase family. We found that the corresponding mutations in the LCB1 gene of Saccharomyces cerevisiae reduce serine palmitoyltransferase activity. These mutations are dominant and decrease serine palmitoyltransferase activity by 50% when the wild-type and mutant LCB1 alleles are coexpressed. We also show that serine palmitoyltransferase is an Lcb1p small middle dotLcb2p heterodimer and that the mutated Lcb1p proteins retain their ability to interact with Lcb2p. Modeling studies suggest that serine palmitoyltransferase is likely to have a single active site that lies at the Lcb1p small middle dotLcb2p interface and that the mutations in Lcb1p reside near the lysine in Lcb2p that is expected to form the Schiff's base with the pyridoxal 5'-phosphate cofactor. Furthermore, mutations in this lysine and in a histidine residue that is also predicted to be important for pyridoxal 5'-phosphate binding to Lcb2p also dominantly inactivate SPT similar to the hereditary sensory neuropathy type 1-like mutations in Lcb1p. PMID:11781309

  2. Genetics Home Reference: hereditary neuropathy with liability to pressure palsies

    MedlinePlus

    ... hereditary neuropathy with liability to pressure palsies hereditary neuropathy with liability to pressure palsies Enable Javascript to ... Download PDF Open All Close All Description Hereditary neuropathy with liability to pressure palsies is a disorder ...

  3. Genetics Home Reference: distal hereditary motor neuropathy, type II

    MedlinePlus

    ... hereditary motor neuropathy, type II distal hereditary motor neuropathy, type II Enable Javascript to view the expand/ ... Open All Close All Description Distal hereditary motor neuropathy, type II is a progressive disorder that affects ...

  4. Genetics Home Reference: distal hereditary motor neuropathy, type V

    MedlinePlus

    ... hereditary motor neuropathy, type V distal hereditary motor neuropathy, type V Enable Javascript to view the expand/ ... Open All Close All Description Distal hereditary motor neuropathy, type V is a progressive disorder that affects ...

  5. Characterization of two mutations in the SPTLC1 subunit of serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathy type I.

    PubMed

    Rotthier, Annelies; Penno, Anke; Rautenstrauss, Bernd; Auer-Grumbach, Michaela; Stettner, Georg M; Asselbergh, Bob; Van Hoof, Kim; Sticht, Heinrich; Lévy, Nicolas; Timmerman, Vincent; Hornemann, Thorsten; Janssens, Katrien

    2011-06-01

    Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy leading to progressive distal sensory loss and severe ulcerations. Mutations in SPTLC1 and SPTLC2, encoding the two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the first and rate-limiting step in the de novo synthesis of sphingolipids, have been reported to cause HSAN-I. Here, we demonstrate that the SPTLC1 mutations p.S331F and p.A352V result in a reduction of SPT activity in vitro and are associated with increased levels of the deoxysphingoid bases 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine in patients' plasma samples. Stably expressing p.S331F-SPTLC1 HEK293T cell lines likewise show accumulation of deoxysphingoid bases, but this accumulation is not observed in HEK293T cells overexpressing p.A352V-SPTLC1. These results confirm that the increased formation of deoxysphingoid bases is a key feature for HSAN-I as it is associated with all pathogenic SPTLC1 and SPTLC2 mutations reported so far, but also warrant for caution in the interpretation of in vitro data. PMID:21618344

  6. Identification of a Novel Gene (HSN2) Causing Hereditary Sensory and Autonomic Neuropathy Type II through the Study of Canadian Genetic Isolates

    PubMed Central

    Lafrenière, Ronald G.; MacDonald, Marcia L. E.; Dubé, Marie-Pierre; MacFarlane, Julie; O’Driscoll, Mary; Brais, Bernard; Meilleur, Sébastien; Brinkman, Ryan R.; Dadivas, Owen; Pape, Terry; Platon, Christèle; Radomski, Chris; Risler, Jenni; Thompson, Jay; Guerra-Escobio, Ana-Maria; Davar, Gudarz; Breakefield, Xandra O.; Pimstone, Simon N.; Green, Roger; Pryse-Phillips, William; Goldberg, Y. Paul; Younghusband, H. Banfield; Hayden, Michael R.; Sherrington, Robin; Rouleau, Guy A.; Samuels, Mark E.

    2004-01-01

    Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons. We identified two large pedigrees segregating the disorder in an isolated population living in Newfoundland and performed a 5-cM genome scan. Linkage analysis identified a locus mapping to 12p13.33 with a maximum LOD score of 8.4. Haplotype sharing defined a candidate interval of 1.06 Mb containing all or part of seven annotated genes, sequencing of which failed to detect causative mutations. Comparative genomics revealed a conserved ORF corresponding to a novel gene in which we found three different truncating mutations among five families including patients from rural Quebec and Nova Scotia. This gene, termed “HSN2,” consists of a single exon located within intron 8 of the PRKWNK1 gene and is transcribed from the same strand. The HSN2 protein may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells. PMID:15060842

  7. Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates.

    PubMed

    Lafreniere, Ronald G; MacDonald, Marcia L E; Dube, Marie-Pierre; MacFarlane, Julie; O'Driscoll, Mary; Brais, Bernard; Meilleur, Sebastien; Brinkman, Ryan R; Dadivas, Owen; Pape, Terry; Platon, Christele; Radomski, Chris; Risler, Jenni; Thompson, Jay; Guerra-Escobio, Ana-Maria; Davar, Gudarz; Breakefield, Xandra O; Pimstone, Simon N; Green, Roger; Pryse-Phillips, William; Goldberg, Y Paul; Younghusband, H Banfield; Hayden, Michael R; Sherrington, Robin; Rouleau, Guy A; Samuels, Mark E

    2004-05-01

    Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons. We identified two large pedigrees segregating the disorder in an isolated population living in Newfoundland and performed a 5-cM genome scan. Linkage analysis identified a locus mapping to 12p13.33 with a maximum LOD score of 8.4. Haplotype sharing defined a candidate interval of 1.06 Mb containing all or part of seven annotated genes, sequencing of which failed to detect causative mutations. Comparative genomics revealed a conserved ORF corresponding to a novel gene in which we found three different truncating mutations among five families including patients from rural Quebec and Nova Scotia. This gene, termed "HSN2," consists of a single exon located within intron 8 of the PRKWNK1 gene and is transcribed from the same strand. The HSN2 protein may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells.

  8. Oral l-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1

    PubMed Central

    Garofalo, Kevin; Penno, Anke; Schmidt, Brian P.; Lee, Ho-Joon; Frosch, Matthew P.; von Eckardstein, Arnold; Brown, Robert H.; Hornemann, Thorsten; Eichler, Florian S.

    2011-01-01

    Hereditary sensory and autonomic neuropathy type 1 (HSAN1) causes sensory loss that predominantly affects the lower limbs, often preceded by hyperpathia and spontaneous shooting or lancinating pain. It is caused by several missense mutations in the genes encoding 2 of the 3 subunits of the enzyme serine palmitoyltransferase (SPT). The mutant forms of the enzyme show a shift from their canonical substrate l-serine to the alternative substrate l-alanine. This shift leads to increased formation of neurotoxic deoxysphingolipids (dSLs). Our initial analysis showed that in HEK cells transfected with SPTLC1 mutants, dSL generation was modulated in vitro in the presence of various amino acids. We therefore examined whether in vivo specific amino acid substrate supplementation influenced dSL levels and disease severity in HSAN1. In mice bearing a transgene expressing the C133W SPTLC1 mutant linked to HSAN1, a 10% l-serine–enriched diet reduced dSL levels. l-serine supplementation also improved measures of motor and sensory performance as well as measures of male fertility. In contrast, a 10% l-alanine–enriched diet increased dSL levels and led to severe peripheral neuropathy. In a pilot study with 14 HSAN1 patients, l-serine supplementation similarly reduced dSL levels. These observations support the hypothesis that an altered substrate selectivity of the mutant SPT is key to the pathophysiology of HSAN1 and raise the prospect of l-serine supplementation as a first treatment option for this disorder. PMID:22045570

  9. Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1.

    PubMed

    Garofalo, Kevin; Penno, Anke; Schmidt, Brian P; Lee, Ho-Joon; Frosch, Matthew P; von Eckardstein, Arnold; Brown, Robert H; Hornemann, Thorsten; Eichler, Florian S

    2011-12-01

    Hereditary sensory and autonomic neuropathy type 1 (HSAN1) causes sensory loss that predominantly affects the lower limbs, often preceded by hyperpathia and spontaneous shooting or lancinating pain. It is caused by several missense mutations in the genes encoding 2 of the 3 subunits of the enzyme serine palmitoyltransferase (SPT). The mutant forms of the enzyme show a shift from their canonical substrate L-serine to the alternative substrate L-alanine. This shift leads to increased formation of neurotoxic deoxysphingolipids (dSLs). Our initial analysis showed that in HEK cells transfected with SPTLC1 mutants, dSL generation was modulated in vitro in the presence of various amino acids. We therefore examined whether in vivo specific amino acid substrate supplementation influenced dSL levels and disease severity in HSAN1. In mice bearing a transgene expressing the C133W SPTLC1 mutant linked to HSAN1, a 10% L-serine–enriched diet reduced dSL levels. L-serine supplementation also improved measures of motor and sensory performance as well as measures of male fertility. In contrast, a 10% L-alanine–enriched diet increased dSL levels and led to severe peripheral neuropathy. In a pilot study with 14 HSAN1 patients, L-serine supplementation similarly reduced dSL levels. These observations support the hypothesis that an altered substrate selectivity of the mutant SPT is key to the pathophysiology of HSAN1 and raise the prospect of l-serine supplementation as a first treatment option for this disorder.

  10. Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1.

    PubMed

    Garofalo, Kevin; Penno, Anke; Schmidt, Brian P; Lee, Ho-Joon; Frosch, Matthew P; von Eckardstein, Arnold; Brown, Robert H; Hornemann, Thorsten; Eichler, Florian S

    2011-12-01

    Hereditary sensory and autonomic neuropathy type 1 (HSAN1) causes sensory loss that predominantly affects the lower limbs, often preceded by hyperpathia and spontaneous shooting or lancinating pain. It is caused by several missense mutations in the genes encoding 2 of the 3 subunits of the enzyme serine palmitoyltransferase (SPT). The mutant forms of the enzyme show a shift from their canonical substrate L-serine to the alternative substrate L-alanine. This shift leads to increased formation of neurotoxic deoxysphingolipids (dSLs). Our initial analysis showed that in HEK cells transfected with SPTLC1 mutants, dSL generation was modulated in vitro in the presence of various amino acids. We therefore examined whether in vivo specific amino acid substrate supplementation influenced dSL levels and disease severity in HSAN1. In mice bearing a transgene expressing the C133W SPTLC1 mutant linked to HSAN1, a 10% L-serine–enriched diet reduced dSL levels. L-serine supplementation also improved measures of motor and sensory performance as well as measures of male fertility. In contrast, a 10% L-alanine–enriched diet increased dSL levels and led to severe peripheral neuropathy. In a pilot study with 14 HSAN1 patients, L-serine supplementation similarly reduced dSL levels. These observations support the hypothesis that an altered substrate selectivity of the mutant SPT is key to the pathophysiology of HSAN1 and raise the prospect of l-serine supplementation as a first treatment option for this disorder. PMID:22045570

  11. Salvage procedures in lower-extremity trauma in a child with hereditary motor and sensory neuropathy type I: a case report

    PubMed Central

    2012-01-01

    Introduction Fractures of the lower extremity are a common type of childhood injury and many can be treated without surgery. Dislocated and open fractures are an indication for fracture stabilization via either intramedullary nailing or, in the case of complicated fractures, external fixation. But if complications are likely because of diseases and disabilities (for example, a neuropathy) that can complicate the post-operative procedure and rehabilitation, what options does one have? Case presentation We report a nine-year-old Caucasian girl who had hereditary motor and sensory neuropathy type I and who was admitted with a grade I open tibia fracture after a fall from a small height. Plain radiographs showed a dislocated tibia and fibula fracture. An open reduction with internal fixation with a compression plate osteosynthesis was performed, and soft tissue debridement combined with an external fixateur was undertaken. Three months later, she was re-admitted with localized swelling and signs of a local soft tissue infection in the middle of her tibia. Plain radiographs showed a non-union of the tibia fracture, and microbiological analysis confirmed a wound infection with cefuroxime-sensitive Staphylococcus aureus. Because of the non-union, the osteosynthesis was replaced with an Ilizarov external fixateur, and appropriate antibiotic therapy was initiated. Four months after the initial accident, the fracture was consolidated and we removed the external fixateur. Conclusions If there is a pre-existing neuropathy and if disease makes it difficult for a child to follow all post-operative instructions, salvage procedures should be kept in mind in case of complications. There are multiple therapeutic options, including osteosynthesis, intramedullary nailing systems, cast therapy, or an external fixateur like the Ilizarov or Taylor spatial frame system. The initial use of an external fixateur such as an Ilizarov or Taylor spatial frame in patients with pre

  12. A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.

    PubMed

    Hornemann, Thorsten; Penno, Anke; Richard, Stephane; Nicholson, Garth; van Dijk, Fleur S; Rotthier, Annelies; Timmerman, Vincent; von Eckardstein, Arnold

    2009-04-01

    Hereditary sensory neuropathy type 1 (HSAN I) is an autosomal dominant inherited neurodegenerative disorder of the peripheral nervous system associated with mutations in the SPTLC1 subunit of the serine palmitoyltransferase (SPT). Four missense mutations (C133W, C133Y, V144D and G387A) in SPTLC1 were reported to cause HSAN I. SPT catalyses the condensation of Serine and Palmitoyl-CoA, which is the first and rate-limiting step in the de novo synthesis of ceramides. Earlier studies showed that C133W and C133Y mutants have a reduced activity, whereas the impact of the V144D and G387A mutations on the human enzyme was not tested yet. In this paper, we show that none of the HSAN I mutations interferes with SPT complex formation. We demonstrate that also V144D has a reduced SPT activity, however to a lower extent than C133W and C133Y. In contrast, the G387A mutation showed no influence on SPT activity. Furthermore, the growth phenotype of LY-B cells--a SPTLC1 deficient CHO cell line--could be reversed by expressing either the wild-type SPTLC1 or the G387A mutant, but not the C133W mutant. This indicates that the G387A mutation is most likely not directly associated with HSAN I. These findings were genetically confirmed by the identification of a nuclear HSAN family which showed segregation of the G387A variant as a non-synonymous SNP. PMID:19132419

  13. Hereditary neuropathy with liability to pressure palsies presenting with sciatic neuropathy

    PubMed Central

    Topakian, Raffi; Wimmer, Sibylle; Pischinger, Barbara; Pichler, Robert

    2014-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal-dominant disorder associated with recurrent mononeuropathies following compression or trivial trauma. Reports on sciatic neuropathy as the presenting manifestation of HNPP are very scarce. We report on a 21-year-old previously healthy man who was admitted with sensorimotor deficits in his left leg. He had no history of preceding transient episodes of weakness or sensory loss. Clinical and electrophysiological examinations were consistent with sciatic neuropathy. Cerebrospinal fluid investigation and MRI of the nerve roots, plexus, and sciatic nerve did not indicate the underlying aetiology. When extended electrophysiological tests revealed multiple subclinical compression neuropathies in the upper limbs, HNPP was contemplated and eventually confirmed by genetic testing. PMID:25326571

  14. DNA testing in hereditary neuropathies.

    PubMed

    Murphy, Sinéad M; Laurá, Matilde; Reilly, Mary M

    2013-01-01

    The inherited neuropathies are a clinically and genetically heterogeneous group of disorders in which there have been rapid advances in the last two decades. Molecular genetic testing is now an integral part of the evaluation of patients with inherited neuropathies. In this chapter we describe the genes responsible for the primary inherited neuropathies. We briefly discuss the clinical phenotype of each of the known inherited neuropathy subgroups, describe algorithms for molecular genetic testing of affected patients and discuss genetic counseling. The basic principles of careful phenotyping, documenting an accurate family history, and testing the available genes in an appropriate manner should identify the vast majority of individuals with CMT1 and many of those with CMT2. In this chapter we also describe the current methods of genetic testing. As advances are made in molecular genetic technologies and improvements are made in bioinformatics, it is likely that the current time-consuming methods of DNA sequencing will give way to quicker and more efficient high-throughput methods, which are briefly discussed here.

  15. Cochleo-saccular degeneration in one of three sisters with hereditary deafness, absent gastric motility, small bowel diverticulitis and progressive sensory neuropathy.

    PubMed

    Igarashi, M; MacRae, D; O-Uchi, T; Alford, B R

    1981-01-01

    This is a report of cochleo-saccular degeneration found in temporal bones from a patient who had suffered from slowly progressive and total sensorineural deafness which had an inherited origin. At age 8, this patient began to complain of hearing loss, and by age 10 she was totally deaf. The patient was 1 of 3 female siblings who have suffered from an exactly identical progressive disease: deafness, absent gastric motility, small bowel diverticulitis and ulceration, and sensory neuropathy. The temporal bone pathology found in this case was the degenerative change in the cochlear duct and sacculus. No pathology was found in the utriculus and semicircular canals. PMID:6937848

  16. Neuropathic pain in hereditary peripheral neuropathy

    PubMed Central

    Jeong, Na Young; Shin, Youn Ho; Jung, Junyang

    2013-01-01

    Charcot-Marie-Tooth (CMT) disease is the most common inherited motor and sensory neuropathy. Previous studies have shown that neuropathic pain is an occasional symptom of CMT referred by CMT patients. However, neuropathic pain is not considered a significant symptom in CMT patient and no researchers have studied profoundly the pathophysiology of neuropathic pain in CMT. Here, we highlight the relationship between CMT disease and neuropathic pain via previous several studies. PMID:24278891

  17. Leber hereditary optic neuropathy in Australia.

    PubMed

    Mackey, D A; Buttery, R G

    1992-08-01

    Leber hereditary optic neuropathy (LHON) presents with sudden onset of visual loss mainly in young adult males. LHON is not uncommon in Australia, accounting for 2% of invalid blind pensions. We have identified 20 unrelated families carrying mitochondrial DNA mutations associated with LHON and 135 of 291 individuals with documented LHON are currently alive in Australia. The mean age of onset of visual loss for males was 26 years and for females 27 years, with a range from six to 65 years. The mean risk of visual loss was 20% for males and 4% for females. There are over 1750 male and female carriers living in Australia who have not yet lost vision; 600 carriers are under 24 years of age. The expected number of new cases of blindness from LHON is three to four per year. PMID:1449769

  18. Idebenone for Leber's hereditary optic neuropathy.

    PubMed

    Gueven, N

    2016-03-01

    Idebenone is a rapidly absorbed, safe and well-tolerated drug and is currently the only clinically proven treatment option for Leber's hereditary optic neuropathy (LHON) patients. Idebenone (Raxone®) is approved by the European Medicines Agency for the treatment of LHON and has been available on the European market since 2015. Due to its molecular mode of action of bypassing the defective mitochondrial complex I, idebenone leads to improved energy supply and a functional recovery of retinal ganglion cells during the acute stage of the disease, thereby preventing further vision loss and promoting recovery of vision. Thus, commencing treatment shortly after the onset of symptoms is likely to have the best therapeutic effect, a hypothesis that is supported by the available clinical data. PMID:27186591

  19. Idebenone for Leber's hereditary optic neuropathy.

    PubMed

    Gueven, N

    2016-03-01

    Idebenone is a rapidly absorbed, safe and well-tolerated drug and is currently the only clinically proven treatment option for Leber's hereditary optic neuropathy (LHON) patients. Idebenone (Raxone®) is approved by the European Medicines Agency for the treatment of LHON and has been available on the European market since 2015. Due to its molecular mode of action of bypassing the defective mitochondrial complex I, idebenone leads to improved energy supply and a functional recovery of retinal ganglion cells during the acute stage of the disease, thereby preventing further vision loss and promoting recovery of vision. Thus, commencing treatment shortly after the onset of symptoms is likely to have the best therapeutic effect, a hypothesis that is supported by the available clinical data.

  20. Progressive auditory neuropathy in patients with Leber's hereditary optic neuropathy

    PubMed Central

    Ceranic, B; Luxon, L

    2004-01-01

    Objective: To investigate auditory neural involvement in patients with Leber's hereditary optic neuropathy (LHON). Methods: Auditory assessment was undertaken in two patients with LHON. One was a 45 year old woman with Harding disease (multiple-sclerosis-like illness and positive 11778mtDNA mutation) and mild auditory symptoms, whose auditory function was monitored over five years. The other was a 59 year old man with positive 11778mtDNA mutation, who presented with a long standing progressive bilateral hearing loss, moderate on one side and severe to profound on the other. Standard pure tone audiometry, tympanometry, stapedial reflex threshold measurements, stapedial reflex decay, otoacoustic emissions with olivo-cochlear suppression, auditory brain stem responses, and vestibular function tests were undertaken. Results: Both patients had good cochlear function, as judged by otoacoustic emissions (intact outer hair cells) and normal stapedial reflexes (intact inner hair cells). A brain stem lesion was excluded by negative findings on imaging, recordable stapedial reflex thresholds, and, in one of the patients, olivocochlear suppression of otoacoustic emissions. The deterioration of auditory function implied a progressive course in both cases. Vestibular function was unaffected. Conclusions: The findings are consistent with auditory neuropathy—a lesion of the cochlear nerve presenting with abnormal auditory brain stem responses and with normal inner hair cells and the cochlear nucleus (lower brain stem). The association of auditory neuropathy, or any other auditory dysfunction, with LHON has not been recognised previously. Further studies are necessary to establish whether this is a consistent finding. PMID:15026512

  1. Leber hereditary optic neuropathy: current perspectives

    PubMed Central

    Meyerson, Cherise; Van Stavern, Greg; McClelland, Collin

    2015-01-01

    Leber hereditary optic neuropathy (LHON) is one of the most common inherited optic neuropathies causing bilateral central vision loss. The disorder results from point mutations in mitochondrial DNA and subsequent mitochondrial dysfunction. The primary cell type that is lost in LHON is the retinal ganglion cell, which is highly susceptible to disrupted ATP production and oxidative stress. Inheritance of LHON follows that of mitochondrial genetics, and it has a highly variable clinical phenotype, as other genetic and environmental factors also play a role. Although LHON usually presents with isolated vision loss, some patients suffer other neurological sequelae. For ill-defined reasons, male LHON mutation carriers are more affected than females. Most LHON patients remain legally blind, but a small proportion can experience spontaneous partial recovery, often within the first year of symptom onset. Unfortunately, at this time there are no established curative interventions and treatment is largely supportive. Patients should be offered low vision services and counseled on mitigating risk factors for additional vision loss, such as smoking and consuming alcohol. Encouraging treatments currently undergoing investigation includes ubiquinone analogs, such as idebenone, as well as gene therapy and stem cells to restore ATP synthesis and provide neuroprotection to surviving retinal ganglion cells. PMID:26170609

  2. [Designation criteria for Leber's hereditary optic neuropathy].

    PubMed

    Nakamura, Makoto; Mimura, Osamu; Wakakura, Masato; Inatani, Masaru; Nakazawa, Toru; Shiraga, Fumio

    2015-05-01

    Designation criteria for Leber's hereditary optic neuropathy (LHON) have been established by a working group for retino-choroidal and optic atrophy funded by the Ministry of Health, Labor, and Welfare (MHLW) of Japan in collaboration with the Japanese Neuro-ophthalmology Society. The criteria are composed of three major symptoms and three ancillary test findings. According to the number and the combination of these symptoms and findings, subjects are classified into definite, probable, and possible LHON cases and asymptomatic carriers. The major symptoms include bilateral involvement with a time-lag, a papillomacular bundle atrophy, both characteristic optic disc findings at the acute phase. In the ancillary testings, mitochondrial DNA mutations specific for LHON are detailed with a table listing the mutation loci being attached. To enhance readers' understanding of description of the major symptoms and ancillary test findings, explanatory remarks on 11 parameters are supplemented. The establishment of the criteria facilitates epidemiological survey of LHON by MHLW and contributes to improvement of welfare for patients with LHON in Japan.

  3. Foot Pad Skin Biopsy in Mouse Models of Hereditary Neuropathy

    PubMed Central

    Dacci, Patrizia; Dina, Giorgia; Cerri, Federica; Previtali, Stefano Carlo; Lopez, Ignazio Diego; Lauria, Giuseppe; Feltri, Maria Laura; Bolino, Alessandra; Comi, Giancarlo; Wrabetz, Lawrence; Quattrini, Angelo

    2010-01-01

    Numerous transgenic and knockout mouse models of human hereditary neuropathies have become available over the past decade. We describe a simple, reproducible, and safe biopsy of mouse skin for histopathological evaluation of the peripheral nervous system (PNS) in models of hereditary neuropathies. We compared the diagnostic outcome between sciatic nerve and dermal nerves found in skin biopsy (SB) from the hind foot. A total of five animal models of different Charcot-Marie-Tooth neuropathies, and one model of congenital muscular dystrophy associated neuropathy were examined. In wild type mice, dermal nerve fibers were readily identified by immunohistochemistry, light, and electron microscopy and they appeared similar to myelinated fibers in sciatic nerve. In mutant mice, SB manifested myelin abnormalities similar to those observed in sciatic nerves, including hypomyelination, onion bulbs, myelin outfolding, redundant loops, and tomacula. In many strains, however, SB showed additional abnormalities—fiber loss, dense neurofilament packing with lower phosphorylation status, and axonal degeneration—undetected in sciatic nerve, possibly because SB samples distal nerves. SB, a reliable technique to investigate peripheral neuropathies in human beings, is also useful to investigate animal models of hereditary neuropathies. Our data indicate that SB may reveal distal axonal pathology in mouse models and permits sequential follow-up of the neuropathy in an individual mouse, thereby reducing the number of mice necessary to document pathology of the PNS. © 2010 Wiley-Liss, Inc. PMID:20878767

  4. Genetic spectrum of hereditary neuropathies with onset in the first year of life

    PubMed Central

    Baets, Jonathan; Deconinck, Tine; De Vriendt, Els; Zimoń, Magdalena; Yperzeele, Laetitia; Van Hoorenbeeck, Kim; Peeters, Kristien; Spiegel, Ronen; Parman, Yesim; Ceulemans, Berten; Van Bogaert, Patrick; Pou-Serradell, Adolf; Bernert, Günther; Dinopoulos, Argirios; Auer-Grumbach, Michaela; Sallinen, Satu-Leena; Fabrizi, Gian Maria; Pauly, Fernand; Van den Bergh, Peter; Bilir, Birdal; Battaloglu, Esra; Madrid, Ricardo E.; Kabzińska, Dagmara; Kochanski, Andrzej; Topaloglu, Haluk; Miller, Geoffrey; Jordanova, Albena; Timmerman, Vincent

    2011-01-01

    Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine–Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot–Marie–Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot–Marie–Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot–Marie–Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset. PMID:21840889

  5. Genetic spectrum of hereditary neuropathies with onset in the first year of life.

    PubMed

    Baets, Jonathan; Deconinck, Tine; De Vriendt, Els; Zimoń, Magdalena; Yperzeele, Laetitia; Van Hoorenbeeck, Kim; Peeters, Kristien; Spiegel, Ronen; Parman, Yesim; Ceulemans, Berten; Van Bogaert, Patrick; Pou-Serradell, Adolf; Bernert, Günther; Dinopoulos, Argirios; Auer-Grumbach, Michaela; Sallinen, Satu-Leena; Fabrizi, Gian Maria; Pauly, Fernand; Van den Bergh, Peter; Bilir, Birdal; Battaloglu, Esra; Madrid, Ricardo E; Kabzińska, Dagmara; Kochanski, Andrzej; Topaloglu, Haluk; Miller, Geoffrey; Jordanova, Albena; Timmerman, Vincent; De Jonghe, Peter

    2011-09-01

    Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine-Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot-Marie-Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot-Marie-Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset. PMID:21840889

  6. Deficiency of thiosulphate sulphurtransferase (rhodanese) in Leber's hereditary optic neuropathy.

    PubMed Central

    Poole, C J; Kind, P R

    1986-01-01

    Leber's hereditary optic neuropathy is a rare cause of progressive visual failure. Its cause is unknown, but one hypothesis is that patients have a defect in the detoxication of cyanide. One of the enzymes used in this detoxication is thiosulphate sulphurtransferase (rhodanese). The activity of this enzyme was measured in the rectal mucosa of a group of subjects with Leber's hereditary optic neuropathy, and it was found to be considerably reduced compared with that in a group of controls (p less than 0.001). This finding supports the hypothesis of an inborn error of cyanide detoxication in this condition. PMID:3085790

  7. Visual Rehabilitation of Persons with Leber's Hereditary Optic Neuropathy.

    ERIC Educational Resources Information Center

    Rudanko, S.-L.

    1995-01-01

    This article presents results of a noncontrolled clinical study of 20 persons with Leber's hereditary optic neuropathy who were treated from 1976 to 1990 at the Low Vision Centre of the Finnish Federation of the Visually Handicapped. The importance of early functional visual rehabilitation is emphasized, as is the use of low vision aids to help…

  8. Glaucoma progression associated with Leber's hereditary optic neuropathy.

    PubMed

    Nucci, Carlo; Martucci, Alessio; Mancino, Raffaele; Cerulli, Luciano

    2013-02-01

    The purpose of this article is to describe a case of open-angle glaucoma progression associated with Leber's hereditary optic neuropathy. Single case analysis method is used. A 53-year-old woman with a previous diagnosis of glaucoma presented with progressive visual field loss. Complete ophthalmological examination and blood tests were negative for other concomitant diseases. Genetic counseling revealed mitochondrial DNA mutation compatible with the diagnosis of Leber's hereditary optic neuropathy. In conclusion, the case describes the concomitant occurrence of open-angle glaucoma and Leber's optic neuropathy. We hypothesize that the two diseases may have a cumulative effect on oxidative stress and retinal ganglion cell death with the consequent rapid progression of visual impairment. Screening for mitochondrial DNA mutations may be requested in patients with glaucoma who, despite pharmacologically controlled intraocular pressure, show rapid progression of the disease.

  9. Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy.

    PubMed

    Giordano, Carla; Montopoli, Monica; Perli, Elena; Orlandi, Maurizia; Fantin, Marianna; Ross-Cisneros, Fred N; Caparrotta, Laura; Martinuzzi, Andrea; Ragazzi, Eugenio; Ghelli, Anna; Sadun, Alfredo A; d'Amati, Giulia; Carelli, Valerio

    2011-01-01

    Leber's hereditary optic neuropathy, the most frequent mitochondrial disease due to mitochondrial DNA point mutations in complex I, is characterized by the selective degeneration of retinal ganglion cells, leading to optic atrophy and loss of central vision prevalently in young males. The current study investigated the reasons for the higher prevalence of Leber's hereditary optic neuropathy in males, exploring the potential compensatory effects of oestrogens on mutant cell metabolism. Control and Leber's hereditary optic neuropathy osteosarcoma-derived cybrids (11778/ND4, 3460/ND1 and 14484/ND6) were grown in glucose or glucose-free, galactose-supplemented medium. After having shown the nuclear and mitochondrial localization of oestrogen receptors in cybrids, experiments were carried out by adding 100 nM of 17β-oestradiol. In a set of experiments, cells were pre-incubated with the oestrogen receptor antagonist ICI 182780. Leber's hereditary optic neuropathy cybrids in galactose medium presented overproduction of reactive oxygen species, which led to decrease in mitochondrial membrane potential, increased apoptotic rate, loss of cell viability and hyper-fragmented mitochondrial morphology compared with control cybrids. Treatment with 17β-oestradiol significantly rescued these pathological features and led to the activation of the antioxidant enzyme superoxide dismutase 2. In addition, 17β-oestradiol induced a general activation of mitochondrial biogenesis and a small although significant improvement in energetic competence. All these effects were oestrogen receptor mediated. Finally, we showed that the oestrogen receptor β localizes to the mitochondrial network of human retinal ganglion cells. Our results strongly support a metabolic basis for the unexplained male prevalence in Leber's hereditary optic neuropathy and hold promises for a therapeutic use for oestrogen-like molecules.

  10. Leber's hereditary optic neuropathy associated with multiple sclerosis: Harding's syndrome.

    PubMed

    Parry-Jones, A R; Mitchell, J D; Gunarwardena, W J; Shaunak, S

    2008-04-01

    We describe a 32-year-old woman with sequential, severe, painless visual loss in one eye and then the other, and three temporally distinct episodes of neurological disturbance suggestive of demyelination in the spinal cord. She was positive for the T14484C mutation in the mitochondrial genome, one of three common mutations causing Leber's hereditary optic neuropathy. In addition, MRI identified areas of demyelination within the periventricular white matter of the brain and within the spinal cord. The coexistence of multiple sclerosis and Leber's hereditary optic neuropathy (Harding's syndrome) is known to occur more often than would be expected by chance; therefore, screening for the Leber's mutations in multiple sclerosis patients with severe visual loss should be considered because this has important prognostic and genetic implications.

  11. A review of primary hereditary optic neuropathies.

    PubMed

    Votruba, M; Aijaz, S; Moore, A T

    2003-01-01

    The primary inherited optic neuropathies are a heterogeneous group of disorders that result in loss of retinal ganglion cells, leading to the clinical appearance of optic atrophy. They affect between 1:10,000 to 1:50,000 people. The main clinical features are a reduction in visual acuity, colour vision abnormalities, centro-caecal visual field defects and pallor of the optic nerve head. Electrophysiological testing shows a normal flash electroretinogram, absent or delayed pattern visually evoked potentials suggestive of a conduction deficit and N95 waveform reduction on the pattern electroretinogram, consistent with a primary ganglion cell pathology. The primary inherited optic neuropathies may be sporadic or familial. The mode of inheritance may be autosomal dominant, autosomal recessive, X-linked recessive or mitochondrial. Within each of these groups, the phenotypic characteristics vary in such features as the mode and age of onset, the severity of the visual loss, the colour deficit and the overall prognosis. A number of different genes (most as yet unidentified) in both nuclear and mitochondrial genomes, underlie these disorders. The elucidation of the role of the encoded proteins will improve our understanding of basic mechanisms of ganglion cell development, physiology and metabolism and further our understanding of the pathophysiology of optic nerve disease. It will also improve diagnosis, counselling and management of patients, and eventually lead to the development of new therapeutic modalities.

  12. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies

    PubMed Central

    2014-01-01

    PMP22 related neuropathies comprise (1) PMP22 duplications leading to Charcot-Marie-Tooth disease type 1A (CMT1A), (2) PMP22 deletions, leading to Hereditary Neuropathy with liability to Pressure Palsies (HNPP), and (3) PMP22 point mutations, causing both phenotypes. Overall prevalence of CMT is usually reported as 1:2,500, epidemiological studies show that 20-64% of CMT patients carry the PMP22 duplication. The prevalence of HNPP is not well known. CMT1A usually presents in the first two decades with difficulty walking or running. Distal symmetrical muscle weakness and wasting and sensory loss is present, legs more frequently and more severely affected than arms. HNPP typically leads to episodic, painless, recurrent, focal motor and sensory peripheral neuropathy, preceded by minor compression on the affected nerve. Electrophysiological evaluation is needed to determine whether the polyneuropathy is demyelinating. Sonography of the nerves can be useful. Diagnosis is confirmed by finding respectively a PMP22 duplication, deletion or point mutation. Differential diagnosis includes other inherited neuropathies, and acquired polyneuropathies. The mode of inheritance is autosomal dominant and de novo mutations occur. Offspring of patients have a chance of 50% to inherit the mutation from their affected parent. Prenatal testing is possible; requests for prenatal testing are not common. Treatment is currently symptomatic and may include management by a rehabilitation physician, physiotherapist, occupational therapist and orthopaedic surgeon. Adult CMT1A patients show slow clinical progression of disease, which seems to reflect a process of normal ageing. Life expectancy is normal. PMID:24646194

  13. Increased lipid droplet accumulation associated with a peripheral sensory neuropathy.

    PubMed

    Marshall, Lee L; Stimpson, Scott E; Hyland, Ryan; Coorssen, Jens R; Myers, Simon J

    2014-04-01

    Hereditary sensory neuropathy type 1 (HSN-1) is an autosomal dominant neurodegenerative disease caused by missense mutations in the SPTLC1 gene. The SPTLC1 protein is part of the SPT enzyme which is a ubiquitously expressed, critical and thus highly regulated endoplasmic reticulum bound membrane enzyme that maintains sphingolipid concentrations and thus contributes to lipid metabolism, signalling, and membrane structural functions. Lipid droplets are dynamic organelles containing sphingolipids and membrane bound proteins surrounding a core of neutral lipids, and thus mediate the intracellular transport of these specific molecules. Current literature suggests that there are increased numbers of lipid droplets and alterations of lipid metabolism in a variety of other autosomal dominant neurodegenerative diseases, including Alzheimer's and Parkinson's disease. This study establishes for the first time, a significant increase in the presence of lipid droplets in HSN-1 patient-derived lymphoblasts, indicating a potential connection between lipid droplets and the pathomechanism of HSN-1. However, the expression of adipophilin (ADFP), which has been implicated in the regulation of lipid metabolism, was not altered in lipid droplets from the HSN-1 patient-derived lymphoblasts. This appears to be the first report of increased lipid body accumulation in a peripheral neuropathy, suggesting a fundamental molecular linkage between a number of neurodegenerative diseases. PMID:24711860

  14. Mitochondrial DNA Mutation Associated with Leber's Hereditary Optic Neuropathy

    NASA Astrophysics Data System (ADS)

    Wallace, Douglas C.; Singh, Gurparkash; Lott, Marie T.; Hodge, Judy A.; Schurr, Theodore G.; Lezza, Angela M. S.; Elsas, Louis J.; Nikoskelainen, Eeva K.

    1988-12-01

    Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.

  15. Leber Hereditary Optic Neuropathy: Bringing the Lab to the Clinic.

    PubMed

    Rasool, Nailyn; Lessell, Simmons; Cestari, Dean M

    2016-01-01

    Leber hereditary optic neuropathy (LHON) was the first clinically characterized mitochondrial disorder. Since its first description in 1871, much has been discovered regarding the genetics and pathophysiology of the disease. This has enabled the development of in vitro cell and animal models that can be used to try to determine not only the effects of the genetic mutation upon the clinical phenotype but to also test potential novel therapies. Treatments for LHON have ranged from vitamins and minerals to immunosuppressants and, more recently, targeted gene therapy. This article reviews the pathophysiology and clinical features of LHON with a focus on translational research. PMID:26959136

  16. Leber Hereditary Optic Neuropathy Associated with Bilateral Macular Holes

    PubMed Central

    Shimada, Yoshiaki; Horiguchi, Masayuki

    2016-01-01

    ABSTRACT Leber hereditary optic neuropathy (LHON) causes visual loss, predominantly in healthy young men. We recently examined a patient who previously had bilateral macular holes and subsequently developed LHON at 74 years of age. Although his central scotomas were initially attributed to the macular holes, his visual acuity declined following an initial improvement after operative closure of the macular holes; thus, other diagnoses, including LHON, were considered. Furthermore, macular optical coherence tomography (OCT) images remained unchanged in this time. A mitochondrial genetic analysis identified a 11778G→A mutation. From this case, we propose that LHON remains in the differential diagnosis even in older patients, as has previously been reported. PMID:27335507

  17. [Genetics of neuropathies].

    PubMed

    Gess, B; Schirmacher, A; Young, P

    2013-02-01

    Hereditary neuropathies belong to the most common neurogenetic disorders. They appear mostly as sensory and motor neuropathies but there are also pure sensory, pure motor as well as sensory and autonomic hereditary neuropathies. In clinical practice, knowledge of hereditary neuropathies is important in order to recognize them among polyneuropathies and achieve a successful genetic diagnosis. The molecular genetics of hereditary neuropathies are very heterogeneous with currently more than 40 known disease-causing genes. The 4 most common genes account for almost 90% of the genetically diagnosed hereditary neuropathies. In this review article we provide an overview of the currently known genes and propose a rational genetic work-up protocol of the most common genes.

  18. Genetic evaluation of inherited motor/sensory neuropathy.

    PubMed

    Chance, Phillip F

    2004-01-01

    Inherited disorders of peripheral nerves represent a common group of neurologic diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B), chromosome 16 (CMT1C) and chromosome 10 (CMT1D). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-p12. In rare patients it may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (Po or MPZ) gene. Mutations in the SIMPLE gene cause CMT1C, and CMT1D is the result of mutations in the early response 2 (ERG2 or Krox-20) gene. An X-linked form of CMT1 (CMT1X) maps to Xq13 and is associated with mutations in the connexin32 (Cx32) gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is an axonal neuropathy that maps to chromosome 1p35-p36 (CMT2A), chromosome 3q13-q22 (CMT2B), chromosome 7p14 (CMT2D), chromosome 8p21 (CMT2E), chromosome 1q22-q23 (CMT2F) or chromosome 3q13 (CMT2G). Two X-linked forms of CMT2 have been reported (CMT2XA and CMT2XB), but the genes remain unidentified. An area that has recently expanded is the identification of autosomal recessive forms of CMT type 1 and 2. Of the eight recessive forms of CMT1 that have been identified to date, only two have been fully characterized at the molecular level (CMT1 AR B 1 and CMT1 AR D). Point mutations were found in the myotubularin-related protein-2 (MTM2) gene for CMT1 AR B1. CMT1 AR D is the result of point mutations in the N-myc downstream-regulated gene 1 (NDRG1). Dejerine-Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile-onset demyelinating polyneuropathy syndrome that may be associated with point mutations in either the PMP22 gene, PO gene, EGR2 gene or the PRX gene (for the recessive form). It shares considerable clinical and

  19. Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: a review.

    PubMed

    Auer-Grumbach, Michaela; De Jonghe, Peter; Verhoeven, Kristien; Timmerman, Vincent; Wagner, Klaus; Hartung, Hans-Peter; Nicholson, Garth A

    2003-03-01

    Hereditary sensory neuropathies (HSNs) are rare disorders characterized by progressive distal sensory loss, predominantly affecting the lower limbs. Foot ulcers, severe skin and bone infections, arthropathy, and amputations are frequent and feared complications. Occasionally, patients complain of spontaneous shooting or lancinating pain. Autonomic fibers can be affected to a variable degree. Patients with HSN can also have severe distal weakness, and some HSN variants have therefore been classified among the hereditary motor and sensory neuropathies (HMSNs). Molecular genetic studies of autosomal dominant inherited neuropathies with prominent sensory loss and ulceromutilating features have assigned the genetic loci for HMSN type 2B (Charcot-Marie-Tooth syndrome type 2B) and HSN type 1 to chromosomes 3q13-22 and 9q22.1-22.3, respectively. However, some families with HSN have been excluded for linkage to these loci, suggesting further genetic heterogeneity. Recently, disease-causing mutations in the SPTLC1 gene have been identified in patients with HSN type 1. In this review, we discuss the hallmark features associated with the distinct genetic subtypes of autosomal dominant inherited HSN and provide genotype-phenotype correlations. PMID:12633143

  20. [Leber's hereditary optic neuropathy after head trauma: a case report].

    PubMed

    Hayashi, Shintaro; Okamoto, Koichi

    2011-10-01

    A previously healthy 34-year-old man sustained multiple skull fractures in a traffic accident. Radiological findings and visual field examination did not detect any abnormality. Shortly after the accident, he noticed blurred vision in both eyes. Six months after the accident, he gradually developed disturbance of visual acuity in the right eye. His best corrected visual acuity (BCVA) was 0.8 OD and 1.2 OS and brain MRI did not show any abnormality, while Humphrey visual field analysis demonstrated right homonymous hemianopsia. Two months after the initial presentation, his BCVA showed 0.1 OD and 0.08 OS. Visual field examination suggested that both right homonymous hemianopsia and left blind spot had become enlarged. Mitochondrial DNA analysis demonstrated G11,778A mutation and a diagnosis of Leber's hereditary optic neuropathy (LHON) was made. A few reports have documented mild acute insult to the head or blunt optic trauma as triggers of optic neuropathy in subjects with LHON. Although, the precise mechanism of LHON following trauma remains unknown, it appears that an acute insult may be sufficient to precipitate neuropathy in the optic nerve already compromised by mitochondrial dysfunction. Asymptomatic carriers should be advised to avoid possible precipitating factors such as head trauma.

  1. Multiple sclerosis associated with Leber's Hereditary Optic Neuropathy.

    PubMed

    Palace, Jacqueline

    2009-11-15

    The cause of multiple sclerosis is unknown although it is recognised to involve an inflammatory process associated with demyelinating plaques and more widespread neurodegeneration. It appears to have become progressively more common in females which is further discussed in this issue, and genetic factors, as identified to date, appear to play only a moderate role. One curious observation is that Leber's Hereditary Optic Neuropathy (LHON), a rare genetic syndrome, presents clinically overwhelmingly in males, but can be associated with an MS-like illness and when it does it occurs mainly in females. It is interesting to examine this further to assess if this could give us any clues as to the pathogenesis of MS.

  2. Therapeutic strategies for Leber's hereditary optic neuropathy: A current update.

    PubMed

    Gueven, Nuri; Faldu, Dharmesh

    2013-11-01

    Leber's hereditary optic neuropathy (LHON) is a rare mitochondrial retinopathy, caused by mutations in subunits of complex I of the respiratory chain, which leads to elevated levels of oxidative stress and an insufficient energy supply. This molecular pathology is thought to be responsible for the dysfunction and eventual apoptotic loss of retinal ganglion cells in the eye, which ultimately results in blindness. Many strategies, ranging from neuroprotectants, antioxidants, anti-apoptotic- and anti-inflammatory compounds have been tested with mixed results. Currently, the most promising compounds are short-chain quinones that have been shown to protect the vision of LHON patients during the early stages of the disease. This commentary gives a brief overview on the current status of tested therapeutics and also addresses future developments such as the use of gene therapy that hopefully will provide safe and efficient therapy options for all LHON patients.

  3. Leber's Hereditary Optic Neuropathy: The Mitochondrial Connection Revisited.

    PubMed

    Abu-Amero, Khaled K

    2011-01-01

    Our current understanding of Leber's hereditary optic neuropathy (LHON)-mitochondrial connection falls short of comprehensive. Twenty years of intensive investigation have yielded a wealth of information about mitochondria, the mitochondrial genome, the metabolism of the optic nerve and other structures, and the phenotypic variability of classic LHON. However, we still cannot completely explain how primary LHON mutations injure the optic nerve or why the optic nerve is particularly at risk. We cannot explain the incomplete penetrance or the male predominance of LHON, the typical onset in young adult life without warning, or the synchronicity of visual loss. Moreover, primary LHON mutations clearly are not present in every family with the LHON phenotype (including multigenerational maternal inheritance), and they are present in only a minority of individuals who have the LHON optic neuropathy phenotype without a family history. All lines of evidence point to abnormalities of the mitochondria as the direct or indirect cause of LHON. Therefore, the mitochondria-LHON connection needs to be revisited and examined closely. This review will attempt to do that and provide an update on various aspects of LHON.

  4. Auditory function in individuals within Leber's hereditary optic neuropathy pedigrees.

    PubMed

    Rance, Gary; Kearns, Lisa S; Tan, Johanna; Gravina, Anthony; Rosenfeld, Lisa; Henley, Lauren; Carew, Peter; Graydon, Kelley; O'Hare, Fleur; Mackey, David A

    2012-03-01

    The aims of this study are to investigate whether auditory dysfunction is part of the spectrum of neurological abnormalities associated with Leber's hereditary optic neuropathy (LHON) and to determine the perceptual consequences of auditory neuropathy (AN) in affected listeners. Forty-eight subjects confirmed by genetic testing as having one of four mitochondrial mutations associated with LHON (mt11778, mtDNA14484, mtDNA14482 and mtDNA3460) participated. Thirty-two of these had lost vision, and 16 were asymptomatic at the point of data collection. While the majority of individuals showed normal sound detection, >25% (of both symptomatic and asymptomatic participants) showed electrophysiological evidence of AN with either absent or severely delayed auditory brainstem potentials. Abnormalities were observed for each of the mutations, but subjects with the mtDNA11778 type were the most affected. Auditory perception was also abnormal in both symptomatic and asymptomatic subjects, with >20% of cases showing impaired detection of auditory temporal (timing) cues and >30% showing abnormal speech perception both in quiet and in the presence of background noise. The findings of this study indicate that a relatively high proportion of individuals with the LHON genetic profile may suffer functional hearing difficulties due to neural abnormality in the central auditory pathways.

  5. Transcriptomic analyses of genes and tissues in inherited sensory neuropathies.

    PubMed

    Sapio, Matthew R; Goswami, Samridhi C; Gross, Jacklyn R; Mannes, Andrew J; Iadarola, Michael J

    2016-09-01

    Inherited sensory neuropathies are caused by mutations in genes affecting either primary afferent neurons, or the Schwann cells that myelinate them. Using RNA-Seq, we analyzed the transcriptome of human and rat DRG and peripheral nerve, which contain sensory neurons and Schwann cells, respectively. We subdivide inherited sensory neuropathies based on expression of the mutated gene in these tissues, as well as in mouse TRPV1 lineage DRG nociceptive neurons, and across 32 human tissues from the Human Protein Atlas. We propose that this comprehensive approach to neuropathy gene expression leads to better understanding of the involved cell types in patients with these disorders. We also characterize the genetic "fingerprint" of both tissues, and present the highly tissue-specific genes in DRG and sciatic nerve that may aid in the development of gene panels to improve diagnostics for genetic neuropathies, and may represent specific drug targets for diseases of these tissues. PMID:27343803

  6. Hereditary Neuropathy with Liability to Pressure Palsy Presenting as an Acute Brachial Plexopathy: A Lover's Palsy

    PubMed Central

    Wedderburn, Sarah; Pateria, Puraskar; Panegyres, Peter K.

    2014-01-01

    It is generally regarded that patients with hereditary neuropathy to pressure palsies, due to a deletion in the PMP22 gene, show recurrent pressure palsy and generalised peripheral neuropathy (pes cavus and hammer toes sometimes develop). Brachial plexopathy is rarely identified as a first presentation of hereditary neuropathy to pressure palsies. We describe a young man who developed a painless flail upper limb with a clinical diagnosis of a brachial plexopathy after his partner slept on his arm – a PMP22 deletion was found. His father, who had a symmetrical polyneuropathy without recurrent mononeuropathies, shared the PMP22 deletion. PMID:25685136

  7. Reversible isolated sensory axonal neuropathy due to cobalamin deficiency.

    PubMed

    Dalla Torre, Chiara; Lucchetta, Marta; Cacciavillani, Mario; Campagnolo, Marta; Manara, Renzo; Briani, Chiara

    2012-03-01

    Vitamin B(12) deficiency causes a wide range of hematological, gastrointestinal, and neurological manifestations. The most common neurological complication is subacute combined degeneration, sometimes associated with polyneuropathy. Isolated peripheral neuropathy due to cyanocobalamin deficiency is less frequent, and thus it may be overlooked. We describe 2 patients with isolated sensory axonal neuropathy secondary to vitamin B(12) deficiency who had complete clinical and electrophysiological recovery after cyanocobalamin replacement. Testing for serum vitamin B(12) and its metabolites should be done in any distal symmetric neuropathy.

  8. Pes cavus and hereditary neuropathies: when a relationship should be suspected.

    PubMed

    Piazza, S; Ricci, G; Caldarazzo Ienco, E; Carlesi, C; Volpi, L; Siciliano, G; Mancuso, M

    2010-12-01

    The hereditary peripheral neuropathies are a clinically and genetically heterogeneous group of diseases of the peripheral nervous system. Foot deformities, including the common pes cavus, but also hammer toes and twisting of the ankle, are frequently present in patients with hereditary peripheral neuropathy, and often represent one of the first signs of the disease. Pes cavus in hereditary peripheral neuropathies is caused by imbalance between the intrinsic muscles of the foot and the muscles of the leg. Accurate clinical evaluation in patients with pes cavus is necessary to exclude or confirm the presence of peripheral neuropathy. Hereditary peripheral neuropathies should be suspected in those cases with bilateral foot deformities, in the presence of family history for pes cavus and/or gait impairment, and in the presence of neurological symptoms or signs, such as distal muscle hypotrophy of limbs. Herein, we review the hereditary peripheral neuropathies in which pes cavus plays a key role as a "spy sign," discussing the clinical and molecular features of these disorders to highlight the importance of pes cavus as a helpful clinical sign in these rare diseases. PMID:20963465

  9. Gene–environment interactions in Leber hereditary optic neuropathy

    PubMed Central

    Kirkman, Matthew Anthony; Yu-Wai-Man, Patrick; Korsten, Alex; Leonhardt, Miriam; Dimitriadis, Konstantin; De Coo, Ireneaus F.; Klopstock, Thomas

    2009-01-01

    Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm this to be the case. LHON has no treatment, so identifying environmental triggers is the key to disease prevention, whilst potentially revealing new mechanisms amenable to therapeutic manipulation. To address this issue, we conducted a large, multicentre epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary pathogenic mtDNA mutations: m.3460G>A, m.11778G>A and m.14484T>C. A comprehensive history of exposure to smoking, alcohol and other putative environmental insults was collected using a structured questionnaire. We identified a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93% in men who smoked. There was a trend towards increased visual failure with alcohol, but only with a heavy intake. Based on these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake. PMID:19525327

  10. Idebenone: A Review in Leber's Hereditary Optic Neuropathy.

    PubMed

    Lyseng-Williamson, Katherine A

    2016-05-01

    Idebenone (Raxone(®)), a short-chain benzoquinone, is the only disease-specific drug approved to treat visual impairment in adolescents and adults with Leber's hereditary optic neuropathy (LHON), a rare genetic mitochondrial disease that causes rapid and progressive bilateral vision loss. The mechanism of action of idebenone involves its antioxidant properties and ability to act as a mitochondrial electron carrier. Idebenone overcomes mitochondrial complex I respiratory chain deficiency in patients with LHON by transferring electrons directly to mitochondrial complex III (by-passing complex I), thereby restoring cellular energy (ATP) production and re-activating inactive-but-viable retinal ganglion cells, which ultimately prevents further vision loss and promotes vision recovery. The approval of idebenone in the treatment of LHON was based on the overall data from a randomized clinical trial, a follow-up study and real-world data. Taken together, these studies provide convincing evidence that oral idebenone 900 mg/day for 24 weeks has persistent beneficial effects in preventing further vision impairment and promoting vision recovery in patients with LHON relative to the natural course of the disease. Therefore, idebenone is a valuable agent to treat visual impairment in adolescents and adults with LHON. PMID:27071925

  11. [Leber's hereditary optic neuropathy - phenotype, genetics, therapeutic options].

    PubMed

    Gallenmüller, C; Klopstock, T

    2014-03-01

    Leber's hereditary optic neuropathy is a rare genetic disorder affecting the retinal ganglion cells leading to a persistent severe bilateral loss of visual acuity within weeks or months. Males are much more likely to be affected than females, disease onset in most cases takes place between age 15 and 35 years. The disease is caused by point mutations in the mitochondrial DNA. The penetrance of the disease is incomplete, i.e., not all mutation carriers develop clinical symptoms. The phenotype is relatively uniform, but age at onset, severity and prognosis may vary even within the same family. Environmental and endocrine factors, optic disc anatomy as well as mitochondrial and nuclear genetic factors are discussed to influence penetrance as well as interindividual and intrafamilial variability. However, only cigarette smoking and excessive alcohol consumption have been shown to trigger disease onset. The disease is characterised by a central visual field defect, impaired colour vision and fundoscopically a peripapillary microangiopathy in the acute phase. Most patients end up after some months with a severe visual loss below 0.1 and in most cases there is no significant improvement of visual acuity in the course. In rare cases patients experience a mostly partial visual recovery which depends on the type of mutation. For confirmation of the diagnosis a detailed ophthalmological examination with fundoscopy, family history and genetic analysis of the mitochondrial DNA is needed. To date, there is no proven causal therapy, but at early disease stages treatment with idebenone can be tried.

  12. Novel therapeutic approaches for Leber's hereditary optic neuropathy.

    PubMed

    Iyer, Shilpa

    2013-03-01

    Many human childhood mitochondrial disorders result from abnormal mitochondrial DNA (mtDNA) and altered bioenergetics. These abnormalities span most of the mtDNA, demonstrating that there are no "unique" positions on the mitochondrial genome that when deleted or mutated produce a disease phenotype. This diversity implies that the relationship between mitochondrial genotype and clinical phenotype is very complex. The origins of clinical phenotypes are thus unclear, fundamentally difficult-to-treat, and are usually clinically devastating. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and mortality. Vitamin supplements and pharmacological agents have been used in isolated cases and clinical trials, but the efficacy of these interventions is unclear. In spite of recent advances in the understanding of the pathogenesis of mitochondrial diseases, a cure remains elusive. An optimal cure would be gene therapy, which involves introducing the missing gene(s) into the mitochondria to complement the defect. Our recent research results indicate the feasibility of an innovative protein-transduction ("protofection") technology, consisting of a recombinant mitochondrial transcription factor A (TFAM) that avidly binds mtDNA and permits efficient targeting into mitochondria in situ and in vivo. Thus, the development of gene therapy for treating mitochondrial disease offers promise, because it may circumvent the clinical abnormalities and the current inability to treat individual disorders in affected individuals. This review aims to focus on current treatment options and future therapeutics in mitochondrial disease treatment with a special emphasis on Leber's hereditary optic neuropathy.

  13. Idebenone: A Review in Leber's Hereditary Optic Neuropathy.

    PubMed

    Lyseng-Williamson, Katherine A

    2016-05-01

    Idebenone (Raxone(®)), a short-chain benzoquinone, is the only disease-specific drug approved to treat visual impairment in adolescents and adults with Leber's hereditary optic neuropathy (LHON), a rare genetic mitochondrial disease that causes rapid and progressive bilateral vision loss. The mechanism of action of idebenone involves its antioxidant properties and ability to act as a mitochondrial electron carrier. Idebenone overcomes mitochondrial complex I respiratory chain deficiency in patients with LHON by transferring electrons directly to mitochondrial complex III (by-passing complex I), thereby restoring cellular energy (ATP) production and re-activating inactive-but-viable retinal ganglion cells, which ultimately prevents further vision loss and promotes vision recovery. The approval of idebenone in the treatment of LHON was based on the overall data from a randomized clinical trial, a follow-up study and real-world data. Taken together, these studies provide convincing evidence that oral idebenone 900 mg/day for 24 weeks has persistent beneficial effects in preventing further vision impairment and promoting vision recovery in patients with LHON relative to the natural course of the disease. Therefore, idebenone is a valuable agent to treat visual impairment in adolescents and adults with LHON.

  14. Two Cases of Elderly-Onset Hereditary Neuropathy with Liability to Pressure Palsy Manifesting Bilateral Peroneal Nerve Palsies

    PubMed Central

    Kawaguchi, Norihiko; Suzuki, Naoki; Tateyama, Maki; Takai, Yoshiki; Misu, Tatsuro; Nakashima, Ichiro; Itoyama, Yasuto; Aoki, Masashi

    2012-01-01

    Hereditary neuropathy with liability to pressure palsy (HNPP) is characterized by recurrent focal neuropathies, which usually become symptomatic in the second or third decade of life. However, clinical phenotypic heterogeneity among patients with HNPP has recently been reported. Certain patients show polyneuropathy-type diffuse nerve injuries, whereas others remain asymptomatic at older ages. We present two cases of elderly-onset bilateral peroneal nerve palsies with diffuse muscle weakness in the lower limbs and glove-and-stocking type sensory disturbance. Both patients were diagnosed with HNPP by genetic analyses that detected deletions of chromosome 17p11.2 in peripheral myelin protein 22 genes. Their clinical courses suggested that the Japanese sitting style termed ‘seiza’, a way of sitting on the floor with the lower legs crossed under the thighs, was a precipitating factor for the bilateral peroneal nerve palsies. PMID:23185166

  15. Evidence for retrochiasmatic tissue loss in Leber's hereditary optic neuropathy.

    PubMed

    Barcella, Valeria; Rocca, Maria A; Bianchi-Marzoli, Stefania; Milesi, Jacopo; Melzi, Lisa; Falini, Andrea; Pierro, Luisa; Filippi, Massimo

    2010-12-01

    Patients with Leber's hereditary optic neuropathy (LHON) have loss of central vision with severe damage of small-caliber fibers of the papillomacular bundle and optic nerve atrophy. The aim of this study was to define the presence and topographical distribution of brain grey matter (GM) and white matter (WM) injury in LHON patients using voxel-based morphometry (VBM). The correlation of such changes with neuro-ophthalmologic findings and measurements of peripapillary retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) was also assessed. Dual-echo and fast-field echo scans were acquired from 12 LHON patients and 12 matched controls. VBM analysis was performed using SPM5 and an ANCOVA model. A complete neuro-ophthalmologic examination, including standardized automated Humphrey perimetry as well as average and temporal peripapillary RNFL thickness measurements were obtained in all the patients. Compared with controls, average peripapillary RNFL thickness was significantly decreased in LHON patients. LHON patients also had significant reduced GM volume in the bilateral primary visual cortex, and reduced WM volume in the optic chiasm, optic tract, and several areas located in the optic radiations (OR), bilaterally. Visual cortex and OR atrophy were significantly correlated with average and temporal peripapillary RNFL thickness (P < 0.001; r values ranging from 0.76 to 0.89). Brain damage in patients with LHON is not limited to the anterior visual pathways, but extends posteriorly to the OR and the primary visual cortex. Such a damage to the posterior parts of the visual pathways may be due either to trans-synaptic degeneration secondary to neuroaxonal damage in the retina and optic nerve or to local mitochondrial dysfunction.

  16. Secondary post-geniculate involvement in Leber's hereditary optic neuropathy.

    PubMed

    Rizzo, Giovanni; Tozer, Kevin R; Tonon, Caterina; Manners, David; Testa, Claudia; Malucelli, Emil; Valentino, Maria Lucia; La Morgia, Chiara; Barboni, Piero; Randhawa, Ruvdeep S; Ross-Cisneros, Fred N; Sadun, Alfredo A; Carelli, Valerio; Lodi, Raffaele

    2012-01-01

    Leber's hereditary optic neuropathy (LHON) is characterized by retinal ganglion cell (RGC) degeneration with the preferential involvement of those forming the papillomacular bundle. The optic nerve is considered the main pathological target for LHON. Our aim was to investigate the possible involvement of the post-geniculate visual pathway in LHON patients. We used diffusion-weighted imaging for in vivo evaluation. Mean diffusivity maps from 22 LHON visually impaired, 11 unaffected LHON mutation carriers and 22 healthy subjects were generated and compared at level of optic radiation (OR). Prefrontal and cerebellar white matter were also analyzed as internal controls. Furthermore, we studied the optic nerve and the lateral geniculate nucleus (LGN) in post-mortem specimens obtained from a severe case of LHON compared to an age-matched control. Mean diffusivity values of affected patients were higher than unaffected mutation carriers (P<0.05) and healthy subjects (P<0.01) in OR and not in the other brain regions. Increased OR diffusivity was associated with both disease duration (B = 0.002; P<0.05) and lack of recovery of visual acuity (B = 0.060; P<0.01). Post-mortem investigation detected atrophy (41.9% decrease of neuron soma size in the magnocellular layers and 44.7% decrease in the parvocellular layers) and, to a lesser extent, degeneration (28.5% decrease of neuron density in the magnocellular layers and 28.7% decrease in the parvocellular layers) in the LHON LGN associated with extremely severe axonal loss (99%) in the optic nerve. The post-geniculate involvement in LHON patients is a downstream post-synaptic secondary phenomenon, reflecting de-afferentation rather than a primary neurodegeneration due to mitochondrial dysfunction of LGN neurons.

  17. Sympathetic skin response in acute sensory ataxic neuropathy.

    PubMed

    Arunodaya, G R; Taly, A B; Swamy, H S

    1995-05-01

    Sympathetic skin response (SSR) is a recently described objective method of studying sudomotor sympathetic nerve function and has been studied in a variety of peripheral neuropathies. We report SSR changes in nine patients with acute sensory ataxic neuropathy (ASAN). All had severe sensory and mild motor nerve conduction abnormalities; five had dysautonomia. SSR, elicited by electric shock and cough stimuli, was absent in three patients. Latency was normal in all when SSR was present. Two patients had SSR amplitude of 0.2 mV or less. Absence of SSR did not correlate with dysautonomia, absence of sensory nerve action potential or motor nerve conduction abnormalities. Follow up SSR studies revealed return of absent SSR in one patient over a period of 3 months, despite persistence of ataxia. To our knowledge, this is the first report of SSR changes in ASAN.

  18. Novel use of idebenone in Leber's hereditary optic neuropathy in Hong Kong.

    PubMed

    Cheng, S W; Ko, C H; Yau, S K; Mak, Chloe; Yuen, Y F; Lee, C Y

    2014-10-01

    We report a case of a young Chinese male presenting with sequential, painless, bilateral visual loss in Hong Kong. He was diagnosed to have Leber's hereditary optic neuropathy with genetic workup showing G11778A mutation with over 80% heteroplasmy. He was started on idebenone treatment 11 months after onset of the binocular disease. To our best knowledge, this is the first case of Leber's hereditary optic neuropathy treated with idebenone in Hong Kong. The recent evidence of the diagnosis and treatment of this devastating disease is reviewed.

  19. Vision improvement in a Taiwanese (Han Chinese) family with Leber's hereditary optic neuropathy.

    PubMed

    Lin, Hong-Zin; Pang, Cheng-Yoong; Chen, Shee-Ping; Tsai, Rong-Kung

    2012-12-01

    In this report, we describe a Taiwanese (Han Chinese) family with Leber's hereditary optic neuropathy. The family carried a mitochondrial DNA mutation (mtDNA m.14484T>C) associated with spontaneous visual improvement. A 15-year-old boy from this family was diagnosed with Leber's hereditary optic neuropathy 6 months after losing his vision. His vision recovered after 8 months of supportive treatment. His mother, older brother, and two sisters also had the same mutation and had previously experienced vision loss. In this family, there was no male predominance.

  20. An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients

    ClinicalTrials.gov

    2015-04-28

    Charcot Marie Tooth Disease (CMT); Hereditary Sensory and Motor Neuropathy; Nerve Compression Syndromes; Tooth Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System

  1. Mitochondrial dysfunction in distal axons contribute to HIV sensory neuropathy

    PubMed Central

    Lehmann, Helmar C.; Chen, Weiran; Borzan, Jasenka; Mankowski, Joseph; Höke, Ahmet

    2010-01-01

    Objective Accumulation of mitochondrial DNA (mtDNA) damage has been associated with aging and abnormal oxidative metabolism. We hypothesized that in human immunodeficiency virus associated sensory neuropathy (HIV-SN), damaged mtDNA accumulates in distal nerve segments and that a spatial pattern of mitochondrial dysfunction contribute to the distal degeneration of sensory nerve fibers. Methods We measured levels of common deletion mutations in mtDNA and expression levels of mitochondrial respiratory chain complexes of matched proximal and distal nerve specimens from patients with and without HIV-SN. In mitochondria isolated from peripheral nerves of simian immunodeficiency virus (SIV) infected macaques, a model of HIV-SN, we measured mitochondrial function and generation of reactive oxygen species. Results We identified increased levels of mtDNA common deletion mutation in post-mortem sural nerves of patients with HIV-SN as compared to uninfected patients or HIV patients without sensory neuropathy. Furthermore, we found that common deletion mutation in mtDNA was more prevalent in distal sural nerves compared to dorsal root ganglia. In a primate model of HIV-SN, freshly isolated mitochondria from sural nerves of macaques infected with a neurovirulent strain of SIV showed impaired mitochondrial function compared to mitochondria from proximal nerve segments. Interpretation Our findings suggest that mtDNA damage accumulates in distal mitochondria of long axons, especially in patients with HIV-SN, and that this may lead to reduced mitochondrial function in distal nerves relative to proximal segments. Although our findings are based on HIV-SN, if confirmed in other neuropathies, these observations could explain the length-dependent nature of most axonal peripheral neuropathies. PMID:21280080

  2. Dendritic cell dysfunction and diabetic sensory neuropathy in the cornea

    PubMed Central

    Gao, Nan; Yan, Chenxi; Lee, Patrick; Sun, Haijing

    2016-01-01

    Diabetic peripheral neuropathy (DPN) often leads to neurotrophic ulcerations in the cornea and skin; however, the underlying cellular mechanisms of this complication are poorly understood. Here, we used post-wound corneal sensory degeneration and regeneration as a model and tested the hypothesis that diabetes adversely affects DC populations and infiltration, resulting in disrupted DC-nerve communication and DPN. In streptozotocin-induced type 1 diabetic mice, there was a substantial reduction in sensory nerve density and the number of intraepithelial DCs in unwounded (UW) corneas. In wounded corneas, diabetes markedly delayed sensory nerve regeneration and reduced the number of infiltrating DCs, which were a major source of ciliary neurotrophic factor (CNTF) in the cornea. While CNTF neutralization retarded reinnervation in normal corneas, exogenous CNTF accelerated nerve regeneration in the wounded corneas of diabetic mice and healthy animals, in which DCs had been locally depleted. Moreover, blockade of the CNTF-specific receptor CNTFRα induced sensory nerve degeneration and retarded regeneration in normal corneas. Soluble CNTFRα also partially restored the branching of diabetes-suppressed sensory nerve endings and regeneration in the diabetic corneas. Collectively, our data show that DCs mediate sensory nerve innervation and regeneration through CNTF and that diabetes reduces DC populations in UW and wounded corneas, resulting in decreased CNTF and impaired sensory nerve innervation and regeneration. PMID:27064280

  3. Hereditary Neuropathy With Liability to Pressure Palsies: A Single-Center Experience in Southern Brazil

    PubMed Central

    Lorenzoni, Paulo José; Kay, Cláudia Suemi Kamoi; Cavalet, Cristiane; Arndt, Raquel C.; Werneck, Lineu Cesar; Scola, Rosana Herminia

    2016-01-01

    The spectrum of clinical and electrophysiological features in hereditary neuropathy with liability to pressure palsies (HNPP) is broad. We analyze a series of Brazilian patients with HNPP. Correlations between clinical manifestations, laboratory features, electrophysiological analyze, histological and molecular findings were done. In five cases, more than one episode occurred before diagnosis. Median nerve in the carpal tunnel at the wrist, ulnar nerve in its groove at the elbow, fibular nerve in the head of the fibula at the knee, radial nerve in its groove of the humerus and suprascapular nerve in its notch at the supraspinous fossa were found as focal neuropathies. One patient presented with persistent writer’s cramp after ulnar nerve palsy. Nerve conduction studies showed focal neuropathy in all patients and concomitant generalized symmetrical neuropathy in eight patients. Molecular analysis of the PMP22 gene detected deletion of the 1.5-Mb fragment in all patients. PMID:27761228

  4. Complicated hereditary spastic paraplegia with peripheral neuropathy, optic atrophy and mental retardation.

    PubMed

    Miyama, S; Arimoto, K; Kimiya, S; Tomi, H

    2000-08-01

    An 8-year old girl with a not previously described type of complicated hereditary spastic paraplegia (HSP) is presented. Spasticity in her lower limbs had already been recognized during infancy and worsened progressively. Severe delay in mental development was observed. Peripheral neuropathy and optic atrophy developed at 5 years of age. On brain magnetic resonance imaging, an abnormally thin corpus callosum was observed. Involvement of the fasciculus gracilis was suggested by somatosensory evoked potentials. To our knowledge, there has been no reported case of complicated HSP with peripheral neuropathy, optic atrophy and mental retardation so far. We postulate that our patient is a sporadic case of not previously described complicated HSP. PMID:11071149

  5. Successful chemotherapy in a male patient with malignant lymphoma and Leber's hereditary optic neuropathy (LHON).

    PubMed

    Zanssen, Stefanie; Buse, Gerhard

    2003-04-01

    Leber's hereditary optic neuropathy (LHON) is a bilateral subacute optic neuropathy caused by hereditary missense mutations of the mitochondrial genome. Primary mutations are located at nucleotide positions 11778, 3460, and 14484 in genes encoding subunits of complex I of the respiratory chain. It has been suggested that degenerative changes in the optic nerve might be mediated by apoptosis. Therefore, we hypothesized that patients affected with LHON might show altered sensitivity to cytotoxic drugs. Here we report the case of a LHON patient carrying the 11778 mutation who required chemotherapy for malignant lymphoma. Using in vitro assays, we found that the patient's peripheral blood mononuclear cells did not show altered vulnerability to cytotoxic drugs. The patient was treated with combination chemotherapy and consolidating radiotherapy, leading to complete remission without inappropriately severe acute or chronic side effects. These data indicate that the 11778 mutation does not change cellular response to cytotoxic drugs in a clinically apparent manner.

  6. Leber's hereditary optic neuropathy mutations associated with infantile-onset myoclonic epilepsy.

    PubMed

    Frye, Richard E

    2011-06-01

    Epilepsy syndromes with onset in the first year of life, especially when they include myoclonic features, have special significance since they are associated with long-term developmental and neurological abnormalities. Dravet's severe myoclonic epilepsy in infancy is especially interesting as it is associated with fever-provoked seizures and mutations in the alpha subunit of the sodium channel (SCN1A) in about one-third of the cases. Here, we report 2 children who had clinical features of severe myoclonic epilepsy of infancy without mutations in the SCN1A gene who were found to have mitochondrial DNA mutations associated with Leber's hereditary optic neuropathy. These 2 children demonstrated markers of mitochondrial dysfunction, drug-resistant epilepsy, and dysfunction of nonneurological systems. These cases demonstrate that mitochondrial DNA mutations, especially those associated with Leber's hereditary optic neuropathy, should be considered in cases of myclonic epilepsy starting in infancy, especially when mutations in the SCN1A gene are not found.

  7. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy.

    PubMed

    Klopstock, Thomas; Yu-Wai-Man, Patrick; Dimitriadis, Konstantinos; Rouleau, Jacinthe; Heck, Suzette; Bailie, Maura; Atawan, Alaa; Chattopadhyay, Sandip; Schubert, Marion; Garip, Aylin; Kernt, Marcus; Petraki, Diana; Rummey, Christian; Leinonen, Mika; Metz, Günther; Griffiths, Philip G; Meier, Thomas; Chinnery, Patrick F

    2011-09-01

    Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated. PMID:21788663

  8. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy.

    PubMed

    Klopstock, Thomas; Yu-Wai-Man, Patrick; Dimitriadis, Konstantinos; Rouleau, Jacinthe; Heck, Suzette; Bailie, Maura; Atawan, Alaa; Chattopadhyay, Sandip; Schubert, Marion; Garip, Aylin; Kernt, Marcus; Petraki, Diana; Rummey, Christian; Leinonen, Mika; Metz, Günther; Griffiths, Philip G; Meier, Thomas; Chinnery, Patrick F

    2011-09-01

    Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

  9. Distal hereditary motor neuropathy type 7B with Dynactin 1 mutation.

    PubMed

    Hwang, Sun Hee; Kim, Eun Ja; Hong, Young Bin; Joo, Jaesoon; Kim, Sung Min; Nam, Soo Hyun; Hong, Hyun Dae; Kim, Seung Hyun; Oh, Kiwook; Lim, Jeong-Geun; Cho, Jeong Hee; Chung, Ki Wha; Choi, Byung-Ok

    2016-10-01

    Mutations in the Dynactin 1 (DCTN1) gene have been demonstrated to result in various neurodegenerative diseases, including distal hereditary motor neuropathy type 7B (dHMN7B), Perry syndrome, amyotrophic lateral sclerosis and amyotrophic lateral sclerosis‑frontotemporal dementia. However, since the first dHMN7B patient with a DCTN1 mutation was described in 2003, to the best of our knowledge no further cases have been reported. In the present study, the DCTN1 p.G59S mutation was identified in two unrelated families from a total of 24 Korean families with dHMN, by whole exome sequencing. Codon 59 appears to be the mutational hot spot in the DCTN1 gene, as all described dHMN7B patients to date have harbored an identical p.G59S mutation. The families of the present study with the DCTN1 mutation had a milder disease with a later onset compared with the previously described patients. No affected family members exhibited facial muscle weakness or bulbar involvement. One family member demonstrated vocal cord palsy as the initial sign of disease; however, in the other family hand muscle weakness was the first major symptom. No affected patients demonstrated sensory loss or upper motor neuron involvements. Although this is only the second report of dHMN7B resulting from a DCTN1 mutation, the frequency of the DCTN1 mutation was not low in the Korean population examined, and clinical heterogeneities were observed in patients with the DCTN1 mutation. Therefore, it may be beneficial to screen all dHMN patients for the DCTN1 mutation.

  10. Distal hereditary motor neuropathy type 7B with Dynactin 1 mutation.

    PubMed

    Hwang, Sun Hee; Kim, Eun Ja; Hong, Young Bin; Joo, Jaesoon; Kim, Sung Min; Nam, Soo Hyun; Hong, Hyun Dae; Kim, Seung Hyun; Oh, Kiwook; Lim, Jeong-Geun; Cho, Jeong Hee; Chung, Ki Wha; Choi, Byung-Ok

    2016-10-01

    Mutations in the Dynactin 1 (DCTN1) gene have been demonstrated to result in various neurodegenerative diseases, including distal hereditary motor neuropathy type 7B (dHMN7B), Perry syndrome, amyotrophic lateral sclerosis and amyotrophic lateral sclerosis‑frontotemporal dementia. However, since the first dHMN7B patient with a DCTN1 mutation was described in 2003, to the best of our knowledge no further cases have been reported. In the present study, the DCTN1 p.G59S mutation was identified in two unrelated families from a total of 24 Korean families with dHMN, by whole exome sequencing. Codon 59 appears to be the mutational hot spot in the DCTN1 gene, as all described dHMN7B patients to date have harbored an identical p.G59S mutation. The families of the present study with the DCTN1 mutation had a milder disease with a later onset compared with the previously described patients. No affected family members exhibited facial muscle weakness or bulbar involvement. One family member demonstrated vocal cord palsy as the initial sign of disease; however, in the other family hand muscle weakness was the first major symptom. No affected patients demonstrated sensory loss or upper motor neuron involvements. Although this is only the second report of dHMN7B resulting from a DCTN1 mutation, the frequency of the DCTN1 mutation was not low in the Korean population examined, and clinical heterogeneities were observed in patients with the DCTN1 mutation. Therefore, it may be beneficial to screen all dHMN patients for the DCTN1 mutation. PMID:27573046

  11. Congenital optic nerve anomalies and hereditary optic neuropathies

    PubMed Central

    Heidary, Gena

    2014-01-01

    Congenital and hereditary optic nerve anomalies represent a significant cause of visual dysfunction. While some optic nerve abnormalities affect the visual system alone, others may be associated with neurologic and systemic findings. Correct identification of the optic nerve disease therefore is crucial both for developing a treatment plan with respect to visual rehabilitation, but also for initiating the appropriate multidisciplinary evaluation. The purpose of this review is to highlight common examples of congenital and inherited optic nerve abnormalities in an effort to familiarize the clinician with salient clinical features of these diseases and to review important systemic testing when relevant. PMID:27625883

  12. Congenital optic nerve anomalies and hereditary optic neuropathies.

    PubMed

    Heidary, Gena

    2014-12-01

    Congenital and hereditary optic nerve anomalies represent a significant cause of visual dysfunction. While some optic nerve abnormalities affect the visual system alone, others may be associated with neurologic and systemic findings. Correct identification of the optic nerve disease therefore is crucial both for developing a treatment plan with respect to visual rehabilitation, but also for initiating the appropriate multidisciplinary evaluation. The purpose of this review is to highlight common examples of congenital and inherited optic nerve abnormalities in an effort to familiarize the clinician with salient clinical features of these diseases and to review important systemic testing when relevant. PMID:27625883

  13. Identification of two novel KIF5A mutations in hereditary spastic paraplegia associated with mild peripheral neuropathy.

    PubMed

    López, Eva; Casasnovas, Carlos; Giménez, Javier; Santamaría, Raúl; Terrazas, Jesús M; Volpini, Víctor

    2015-11-15

    Spastic paraplegia type 10 (SPG10) is a rare form of autosomal dominant hereditary spastic paraplegia (AD-HSP) due to mutations in KIF5A, a gene encoding the neuronal kinesin heavy-chain involved in axonal transport. KIF5A mutations have been associated with a wide clinical spectrum, ranging from pure HSP to isolated peripheral nerve involvement or complicated HSP phenotypes. Most KIF5A mutations are clustered in the motor domain of the protein that is necessary for microtubule interaction. Here we describe two Spanish families with an adult onset complicated AD-HSP in which neurological studies revealed a mild sensory neuropathy. Intention tremor was also present in both families. Molecular genetic analysis identified two novel mutations c.773 C>T and c.833 C>T in the KIF5A gene resulting in the P258L and P278L substitutions respectively. Both were located in the highly conserved kinesin motor domain of the protein which has previously been identified as a hot spot for KIF5A mutations. This study adds to the evidence associating the known occurrence of mild peripheral neuropathy in the adult onset SPG10 type of AD-HSP. PMID:26403765

  14. Identification of two novel KIF5A mutations in hereditary spastic paraplegia associated with mild peripheral neuropathy.

    PubMed

    López, Eva; Casasnovas, Carlos; Giménez, Javier; Santamaría, Raúl; Terrazas, Jesús M; Volpini, Víctor

    2015-11-15

    Spastic paraplegia type 10 (SPG10) is a rare form of autosomal dominant hereditary spastic paraplegia (AD-HSP) due to mutations in KIF5A, a gene encoding the neuronal kinesin heavy-chain involved in axonal transport. KIF5A mutations have been associated with a wide clinical spectrum, ranging from pure HSP to isolated peripheral nerve involvement or complicated HSP phenotypes. Most KIF5A mutations are clustered in the motor domain of the protein that is necessary for microtubule interaction. Here we describe two Spanish families with an adult onset complicated AD-HSP in which neurological studies revealed a mild sensory neuropathy. Intention tremor was also present in both families. Molecular genetic analysis identified two novel mutations c.773 C>T and c.833 C>T in the KIF5A gene resulting in the P258L and P278L substitutions respectively. Both were located in the highly conserved kinesin motor domain of the protein which has previously been identified as a hot spot for KIF5A mutations. This study adds to the evidence associating the known occurrence of mild peripheral neuropathy in the adult onset SPG10 type of AD-HSP.

  15. Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy.

    PubMed

    Giordano, Carla; Iommarini, Luisa; Giordano, Luca; Maresca, Alessandra; Pisano, Annalinda; Valentino, Maria Lucia; Caporali, Leonardo; Liguori, Rocco; Deceglie, Stefania; Roberti, Marina; Fanelli, Francesca; Fracasso, Flavio; Ross-Cisneros, Fred N; D'Adamo, Pio; Hudson, Gavin; Pyle, Angela; Yu-Wai-Man, Patrick; Chinnery, Patrick F; Zeviani, Massimo; Salomao, Solange R; Berezovsky, Adriana; Belfort, Rubens; Ventura, Dora Fix; Moraes, Milton; Moraes Filho, Milton; Barboni, Piero; Sadun, Federico; De Negri, Annamaria; Sadun, Alfredo A; Tancredi, Andrea; Mancini, Massimiliano; d'Amati, Giulia; Loguercio Polosa, Paola; Cantatore, Palmiro; Carelli, Valerio

    2014-02-01

    Leber's hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber's hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber's hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies.

  16. HSMNR belongs to the most frequent types of hereditary neuropathy in the Czech Republic and is twice more frequent than HMSNL.

    PubMed

    Šafka Brožková, D; Haberlová, J; Mazanec, R; Laštůvková, J; Seeman, P

    2016-08-01

    Hereditary motor and sensory neuropathy type Russe (HMSNR), also called CMT4G, is an autosomal recessive inherited peripheral neuropathy (IPN) caused by a founder mutation in the HK1 gene. HMSNR affects only patients with Roma origin, similar to the better known HMSN type Lom clarified earlier. By testing IPN patients with Roma origin, we realized that HMSNR affects surprisingly many patients in the Czech Republic. HMSNR is one of the most frequent types of IPN in this country and appears to be twice more frequent than HMSNL. Pronounced lower limb atrophies and severe deformities often lead to walking inability in even young patients, but hands are usually only mildly affected even after many years of disease duration. The group of 20 patients with HMSNR presented here is the first report about the prevalence of HMSNR from central Europe. PMID:26822750

  17. Evaluation of Leber's hereditary optic neuropathy patients prior to a gene therapy clinical trial

    PubMed Central

    Yang, Shuo; Yang, Hong; Ma, Si-qi; Wang, Shuai-shuai; He, Heng; Zhao, Min-jian; Li, Bin

    2016-01-01

    Abstract Gene therapy may be a promising approach for the treatment of Leber hereditary optic neuropathy. The aim of this study was to evaluate patients with this condition who were recruited into an upcoming gene therapy clinical trial and to assess any changes in the detection parameters to provide support for the clinical trial. Sixteen patients with Leber hereditary optic neuropathy were evaluated using visual function tests 12 months before the initiation of gene therapy. Then, the results of visual acuity (VA), visual field (VF), RNFL (retinal nerve fiber layer) thickness, and Pattern-reversal Visual evoked potential (PR-VEP) were compared and analyzed. A total of 32 eyes of 16 patients were evaluated. Based on the best-corrected visual acuity (BCVA), 24 eyes were relatively stable compared with the baseline evaluation, and 8 eyes had significant changes, including 5 eyes that showed improvement and 3 eyes that showed impairment. In all eyes, the changes in the best-corrected visual acuity were significantly correlated with the changes in the visual field index (VFI), mean defect (MD), and P100 of the visual evoked potential. In the eyes with relatively stable BCVA and those with an obvious improvement in the BCVA, only the visual mean defect showed a significant change; the other indicators were not significantly different. Aside from the patients showing a tendency of spontaneous improvement, the others were in accordance with the requirement. The effects of Leber hereditary optical neuropathy (LHON) gene therapy should be evaluated primarily based on visual acuity. Additionally, visual field, neural fiber thickness, and electrophysiology should be considered in the evaluation. PMID:27749593

  18. DNA analysis in Finnish patients with hereditary neuropathy with liability to pressure palsies (HNPP).

    PubMed Central

    Silander, K; Halonen, P; Sara, R; Kalimo, H; Falck, B; Savontaus, M L

    1994-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is a dominantly inherited disorder that presents as recurrent mononeuropathies precipitated by apparently trivial traumas. The presence of a deletion in 17p11.2 was analysed in 13 Finnish families with HNPP. The deletion was found in all patients who were neurologically and neurophysiologically confirmed to have HNPP. In the problematic cases the detection of the gene defect is the method of choice in the diagnosis of HNPP. Analysis of DNA can also be used to detect clinically unaffected family members. Images PMID:7931393

  19. Identification of small molecules that improve ATP synthesis defects conferred by Leber's hereditary optic neuropathy mutations.

    PubMed

    Datta, Sandipan; Tomilov, Alexey; Cortopassi, Gino

    2016-09-01

    Inherited mitochondrial complex I mutations cause blinding Leber's hereditary optic neuropathy (LHON), for which no curative therapy exists. A specific biochemical consequence of LHON mutations in the presence of trace rotenone was observed: deficient complex I-dependent ATP synthesis (CIDAS) and mitochondrial O2 consumption, proportional to the clinical severity of the three primary LHON mutations. We optimized a high-throughput assay of CIDAS to screen 1600 drugs to 2, papaverine and zolpidem, which protected CIDAS in LHON cells concentration-dependently. TSPO and cAMP were investigated as protective mechanisms, but a conclusive mechanism remains to be elucidated; next steps include testing in animal models.

  20. Leber's hereditary optic neuropathy masquerading as optic neuritis with spontaneous visual recovery.

    PubMed

    Hsu, Tsui-Kang; Wang, An-Guor; Yen, May-Yung; Liu, Jorn-Hon

    2014-01-01

    We report a case of Leber's hereditary optic neuropathy (LHON) masquerading as optic neuritis with late visual recovery. A 28-year-old man had gradual visual loss in both eyes for two weeks. Visual acuity was 0.4 in the right eye and 0.7 in the left. Fundus examination revealed hyperaemic discs in each eye. Fluorescein angiography revealed dye leakage at both optic discs in the late phase. Static perimetry (Humphrey 30-2) revealed bilateral relative central scotomata. Magnetic resonance imaging of the optic nerves was normal and his lumbar puncture showed normal opening pressure. He received steroid pulse therapy for three days. Nevertheless, vision in his right eye deteriorated to 0.1 one month later and left vision worsened to 0.05 six months later. Fifteen months after onset, his vision began to improve. At 21 months, his vision recovered to 0.9 R and 1.0 L. Peripheral blood DNA sequencing revealed 14484 mutation of mitochondrial DNA (mtDNA). Visual recovery can occur in patients with Leber's hereditary optic neuropathy with mtDNA 14484 mutation. LHON could be misdiagnosed as optic neuritis in some cases. Molecular examination of mtDNA mutation can confirm the diagnosis of LHON in clinically controversial patients. We should keep in mind the diagnosis of LHON when optic neuritis shows poor response to pulse therapy.

  1. Oxidative phosphorylation differences between mitochondrial DNA haplogroups modify the risk of Leber's hereditary optic neuropathy.

    PubMed

    Gómez-Durán, Aurora; Pacheu-Grau, David; Martínez-Romero, Iñigo; López-Gallardo, Ester; López-Pérez, Manuel J; Montoya, Julio; Ruiz-Pesini, Eduardo

    2012-08-01

    Leber's hereditary optic neuropathy is a maternally inherited optic atrophy caused by mitochondrial DNA point mutations. Previous epidemiological studies have shown that individuals from mitochondrial genetic backgrounds (haplogroups) J/Uk and H have a higher and a lower risk, respectively, of suffering this disorder. To analyze the bases of these associations at cellular and molecular levels, functional studies with cybrids provide high quality evidence. Cybrids from haplogroup J contain less mitochondrial deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and synthesize a smaller amount of mitochondrial DNA-encoded polypeptides than those from haplogroup H. Haplogroup J cybrids also display lower oxygen consumption, mitochondrial inner membrane potential and total adenosine-5'-triphosphate (ATP) levels. Moreover, mitochondrial DNA levels correlate with many parameters of the oxidative phosphorylation system. These results suggest that the mitochondrial DNA amount determines oxidative phosphorylation capacity and, along with other recently published observations, support the possibility that mitochondrial DNA levels may be responsible for the bias of the disorder toward males, for the incomplete penetrance of mutations causing Leber's hereditary optic neuropathy and for the association of the disease with particular mitochondrial DNA haplogroups.

  2. A mitochondrial DNA mutation as a cause of Leber's hereditary optic neuropathy.

    PubMed

    Singh, G; Lott, M T; Wallace, D C

    1989-05-18

    Leber's hereditary optic neuropathy is a maternally inherited disease associated with the late onset of bilateral loss of central vision and cardiac dysrhythmias. The maternal inheritance is explained by the mitochondrial origin of the disease. Analysis of the sequence of a mitochondrial DNA has indicated that a single nucleotide change at position 11778 is associated with this disease. This mutation converts the 340th amino acid of NADH dehydrogenase subunit 4 from an arginine to a histidine and eliminates an SfaNI endonuclease restriction site. A survey of restriction-fragment-length polymorphisms in the mitochondrial DNA of three independent families with this disease (an American black and two white European families) and 10 controls confirmed that this SfaNI site is associated with the disease. A phylogenetic tree for mitochondrial DNA polymorphism and sequence variants from three probands with Leber's disease and four controls was constructed, and the mutation at position 11778 was found to be associated with two mitochondrial DNA backgrounds--an American black mitochondrial DNA and a European mitochondrial DNA. Thus, this mutation must have arisen twice independently. Since the mutation correlated with symptoms of Leber's disease in both cases, these findings indicate that the mutation is a cause of the disease. This genetic analysis has identified the specific point mutation in the mitochondrial DNA that results in Leber's hereditary optic neuropathy. PMID:2566116

  3. Relative Contribution of Mutations in Genes for Autosomal Dominant Distal Hereditary Motor Neuropathies: A Genotype-Phenotype Correlation Study

    ERIC Educational Resources Information Center

    Dierick, Ines; Baets, Jonathan; Irobi, Joy; Jacobs, An; De Vriendt, Els; Deconinck, Tine; Merlini, Luciano; Van den Bergh, Peter; Rasic, Vedrana Milic; Robberecht, Wim; Fischer, Dirk; Morales, Raul Juntas; Mitrovic, Zoran; Seeman, Pavel; Mazanec, Radim; Kochanski, Andrzej; Jordanova, Albena; Auer-Grumbach, Michaela; Helderman-van den Enden, A. T. J. M.; Wokke, John H. J.; Nelis, Eva; De Jonghe, Peter; Timmerman, Vincent

    2008-01-01

    Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; "glycyl-tRNA synthetase (GARS)," "dynactin 1 (DCTN1)," "small heat shock 27 kDa protein 1 (HSPB1),"…

  4. Strength-duration curve: a measure for assessing sensory deficit in peripheral neuropathy.

    PubMed Central

    Friedli, W G; Meyer, M

    1984-01-01

    By using an isolated constant current stimulator producing true square-wave pulses, sensory strength-duration curves were obtained at various sites by percutaneous electrical stimulation. Strength-duration curves derived from normal groups were compared to those of patients with peripheral neuropathy. Stimulus strength at sensory threshold was shown to be a reproducible measure of sensory deficit, increasing parallel to the degree of axonal failure found by conventional methods. This may be useful as a complementary method in assessing peripheral neuropathy. PMID:6323634

  5. Cisplatin induced sensory neuropathy is prevented by vascular endothelial growth factor-A.

    PubMed

    Vencappa, Samanta; Donaldson, Lucy F; Hulse, Richard P

    2015-01-01

    Increased patient survival is a mark of modern anti-cancer therapy success. Unfortunately treatment side-effects such as neurotoxicity are a major long term concern. Sensory neuropathy is one of the common toxicities that can arise during platinum based chemotherapy. In many cases the current poor understanding of the neurological degeneration and lack of suitable analgesia has led to high incidences of patient drop out of treatment. VEGF-A is a prominent neuroprotective agent thus it was hypothesised to prevent cisplatin induced neuropathy. Systemic cisplatin treatment (lasting 3 weeks biweekly) resulted in mechanical allodynia and heat hyperalgesia in mice when compared to vehicle control. PGP9.5 sensory nerve fibre innervation was reduced in the plantar skin in the cisplatin treated group versus vehicle control mice. The cisplatin induced sensory neurodegeneration was associated with increased cleaved caspase 3 expression as well as a reduction in Activating Transcription Factor 3 and pan VEGF-A expression in sensory neurons. VEGF-A165b expression was unaltered between vehicle and cisplatin treatment. rhVEGF-A165a and rhVEGF-A165b both prevented cisplatin induced sensory neurodegeneration. Cisplatin exposure blunts the regenerative properties of sensory neurons thus leading to sensory neuropathy. However, here it is identified that administration of VEGF-A isoform subtypes induce regeneration and prevent cell death and are therefore a possible adjunct therapy for chemotherapy induced neuropathy. PMID:26279748

  6. Cisplatin induced sensory neuropathy is prevented by vascular endothelial growth factor-A

    PubMed Central

    Vencappa, Samanta; Donaldson, Lucy F; Hulse, Richard P

    2015-01-01

    Increased patient survival is a mark of modern anti-cancer therapy success. Unfortunately treatment side-effects such as neurotoxicity are a major long term concern. Sensory neuropathy is one of the common toxicities that can arise during platinum based chemotherapy. In many cases the current poor understanding of the neurological degeneration and lack of suitable analgesia has led to high incidences of patient drop out of treatment. VEGF-A is a prominent neuroprotective agent thus it was hypothesised to prevent cisplatin induced neuropathy. Systemic cisplatin treatment (lasting 3 weeks biweekly) resulted in mechanical allodynia and heat hyperalgesia in mice when compared to vehicle control. PGP9.5 sensory nerve fibre innervation was reduced in the plantar skin in the cisplatin treated group versus vehicle control mice. The cisplatin induced sensory neurodegeneration was associated with increased cleaved caspase 3 expression as well as a reduction in Activating Transcription Factor 3 and pan VEGF-A expression in sensory neurons. VEGF-A165b expression was unaltered between vehicle and cisplatin treatment. rhVEGF-A165a and rhVEGF-A165b both prevented cisplatin induced sensory neurodegeneration. Cisplatin exposure blunts the regenerative properties of sensory neurons thus leading to sensory neuropathy. However, here it is identified that administration of VEGF-A isoform subtypes induce regeneration and prevent cell death and are therefore a possible adjunct therapy for chemotherapy induced neuropathy. PMID:26279748

  7. Mechanisms of disease: a molecular genetic update on hereditary axonal neuropathies.

    PubMed

    Züchner, Stephan; Vance, Jeffery M

    2006-01-01

    Hereditary axonal peripheral neuropathies comprise a genetically heterogeneous group of disorders that are clinically subsumed under the name of Charcot-Marie-Tooth (CMT) disease type 2 (CMT2). Historically, two classes of CMT have been differentiated: demyelinating forms of CMT (CMT1), in which nerve conduction velocities are decreased, and the axonal CMT2 forms, in which nerve conduction velocities are preserved. Recently, a number of genes that are defective in patients with the main forms of CMT2 have been identified. The molecular dissection of cellular functions of the related gene products has only just begun, and detailed pathophysiological models are still lacking. The known CMT2-related genes represent key players in these pathways, however, and are likely to provide powerful tools for identifying targets for future therapeutic intervention. PMID:16932520

  8. Gene-Based Therapies for Leber Hereditary Optic Neuropathy. Hype or Hope?

    PubMed

    Mackey, David A; Kearns, Lisa S; Hewitt, Alex W

    2016-01-01

    Leber hereditary optic neuropathy has now joined Leber congenital amaurosis in the list of genetic eye diseases undergoing gene therapy clinical trials. Although a dramatic response to treatment would be welcome, a minor improvement in vision is a major challenge in efficacy assessment, given this may occur spontaneously as part of the natural history of minor recovery in some patients. Thus, we must await the outcome of adequately powered clinical trials to know if the treatment is effective, particularly given the likely high cost of such therapeutic interventions in the future. We need global cooperation to ensure that the most suitable patients are enrolled in these trials and that support is provided for participants who need to travel from the Asia-Pacific region to Europe or North America if there are no local arms of these trials. PMID:27488066

  9. Differential cerebro spinal fluid proteome investigation of Leber hereditary optic neuropathy (LHON) and multiple sclerosis.

    PubMed

    D'Aguanno, Simona; Barassi, Alessandra; Lupisella, Santina; d'eril, Gianlodovico Melzi; Del Boccio, Piero; Pieragostino, Damiana; Pallotti, Francesco; Carelli, Valerio; Valentino, Maria Lucia; Liguori, Rocco; Avoni, Patrizia; Bernardini, Sergio; Gambi, Domenico; Urbani, Andrea; Federici, Giorgio

    2008-01-01

    Leber's hereditary optic neuropathy (LHON) is a genetic disease leading to the loss of central vision and optic nerve atrophy. The existence of occasional cases of LHON patients developing a Multiple Sclerosis (MS)-like illness and the hypothesis that mtDNA variants may be involved in MS suggest the possibility of some common molecular mechanisms linking the two diseases. We have pursued a comparative proteomics approach on cerebrospinal fluid (CSF) samples from LHON and MS patients, as well as healthy donors by employing 2-DE gel separations coupled to MALDI-TOF-MS and nLC-MS/MS investigations. 7 protein spots showed significant differential distribution among the three groups. Both CSF of LHON or MS patients are characterized by lower level of transthyretin dimer adduct while a specific up regulation of Apo A-IV was detected in LHON CSF.

  10. Long-term evaluation of Leber's hereditary optic neuropathy-like symptoms in rotenone administered rats.

    PubMed

    Zhang, Li; Liu, Laura; Philip, Ann L; Martinez, Juan C; Guttierez, Juan C; Marella, Mathieu; Patki, Gaurav; Matsuno-Yagi, Akemi; Yagi, Takao; Thomas, Biju B

    2015-01-12

    Leber's hereditary optic neuropathy (LHON) is an inherited disorder affecting the retinal ganglion cells (RGCs) and their axons that lead to the loss of central vision. This study is aimed at evaluating the LHON symptoms in rats administered with rotenone microspheres into the superior colliculus (SC). Optical coherence tomography (OCT) analysis showed substantial loss of retinal nerve fiber layer (RNFL) thickness in rotenone injected rats. Optokinetic testing in rotenone treated rats showed decrease in head-tracking response. Electrophysiological mapping of the SC surface demonstrated attenuation of visually evoked responses; however, no changes were observed in the ERG data. The progressive pattern of disease manifestation in rotenone administered rats demonstrated several similarities with human disease symptoms. These rats with LHON-like symptoms can serve as a model for future investigators to design and implement reliable tests to assess the beneficial effects of therapeutic interventions for LHON disease.

  11. Structure and stability of internodal myelin in mouse models of hereditary neuropathy.

    PubMed

    Avila, Robin L; Inouye, Hideyo; Baek, Rena C; Yin, Xinghua; Trapp, Bruce D; Feltri, M Laura; Wrabetz, Lawrence; Kirschner, Daniel A

    2005-11-01

    Peripheral neuropathies often result in abnormalities in the structure of internodal myelin, including changes in period and membrane packing, as observed by electron microscopy (EM). Mutations in the gene that encodes the major adhesive structural protein of internodal myelin in the peripheral nervous system of humans and mice--P0 glycoprotein--correlate with these defects. The mechanisms by which P0 mutations interfere with myelin packing and stability are not well understood and cannot be provided by EM studies that give static and qualitative information on fixed material. To gain insights into the pathogenesis of mutant P0, we used x-ray diffraction, which can detect more subtle and dynamic changes in native myelin, to investigate myelin structure in sciatic nerves from murine models of hereditary neuropathies. We used mice with disruption of one or both copies of the P0 gene (models of Charcot-Marie-Tooth-like neuropathy [CMT1B] or Dejerine-Sottas-like neuropathy) and mice with a CMT1B resulting from a transgene encoding P0 with an amino terminal myc-tag. To directly test the structural role of P0, we also examined a mouse that expresses P0 instead of proteolipid protein in central nervous system myelin. To link our findings on unfixed nerves with EM results, we analyzed x-ray patterns from unembedded, aldehyde-fixed nerves and from plastic-embedded nerves. From the x-ray patterns recorded from whole nerves, we assessed the amount of myelin and its quality (i.e. relative thickness and regularity). Among sciatic nerves having different levels of P0, we found that unfixed nerves and, to a lesser extent, fixed but unembedded nerves gave diffraction patterns of sufficient quality to distinguish periods, sometimes differing by a few Angstroms. Certain packing abnormalities were preserved qualitatively by aldehyde fixation, and the relative amount and structural integrity of myelin among nerves could be distinguished. Measurements from the same nerve over time

  12. X-inactivation pattern in multiple tissues from two Leber's hereditary optic neuropathy (LHON) patients.

    PubMed

    Pegoraro, Elena; Vettori, Andrea; Valentino, Maria L; Molon, Annamaria; Mostacciuolo, Maria L; Howell, Neil; Carelli, Valerio

    2003-05-15

    The more frequent manifestation of ophthalmological abnormalities in males, relative to females, is an unexplained feature of Leber's hereditary optic neuropathy (LHON) that suggests an X-linked modifying gene acting in concert with the pathogenic LHON mitochondrial DNA (mtDNA) mutation. In addition, segregation analysis of the optic neuropathy in LHON pedigrees was compatible with the presence of a recessive-modifying gene on chromosome X. According to this two-locus model, females would be affected only if homozygous or if they were susceptible to skewed X-inactivation. Attempts both to localize the putative LHON-modifying gene by linkage analysis and to find an excess of skewed X-inactivation in affected females were unsuccessful, although the inactivation pattern was only studied in DNA isolated from blood cells. We had the opportunity to analyze a wide range of tissues at autopsy, including the optic nerves and the retina, from two LHON female patients. We found no evidence of skewed X-inactivation in the affected tissues, thus weakening further the hypothesized involvement of a specific X chromosome locus in the pathophysiological expression of LHON.

  13. Peripheral sensory neuropathy is associated with altered postocclusive reactive hyperemia in the diabetic foot

    PubMed Central

    Barwick, Alex L; Tessier, John W; Janse de Jonge, Xanne; Ivers, James R; Chuter, Vivienne H

    2016-01-01

    Objective This study examined whether the presence of peripheral sensory neuropathy or cardiac autonomic deficits is associated with postocclusive reactive hyperemia (reflective of microvascular function) in the diabetic foot. Research design and methods 99 participants with type 2 diabetes were recruited into this cross-sectional study. The presence of peripheral sensory neuropathy was determined with standard clinical tests and cardiac autonomic function was assessed with heart rate variation testing. Postocclusive reactive hyperemia was measured with laser Doppler in the hallux. Multiple hierarchical regression was performed to examine relationships between neuropathy and the peak perfusion following occlusion and the time to reach this peak. Results Peripheral sensory neuropathy predicted 22% of the variance in time to peak following occlusion (p<0.05), being associated with a slower time to peak but was not associated with the magnitude of the peak. Heart rate variation was not associated with the postocclusive reactive hyperemia response. Conclusions This study found an association between the presence of peripheral sensory neuropathy in people with diabetes and altered microvascular reactivity in the lower limb. PMID:27486520

  14. A case of neuromyelitis optica harboring both anti-aquaporin-4 antibodies and a pathogenic mitochondrial DNA mutation for Leber's hereditary optic neuropathy.

    PubMed

    Shiraishi, Wataru; Hayashi, Shintaro; Kamada, Takashi; Isobe, Noriko; Yamasaki, Ryo; Murai, Hiroyuki; Ohyagi, Yasumasa; Kira, Jun-ichi

    2014-02-01

    We report the first case of definite neuromyelitis optica (NMO) with a pathogenic mitochondrial DNA (mtDNA) mutation for Leber's hereditary optic neuropathy (LHON) (G11778A point mutation). A 36-year-old Japanese woman had experienced recurrent neurological symptoms originating from involvements of the optic nerves and spinal cord. She finally lost her bilateral vision, and spastic paraparesis and sensory disturbances below the T6 level remained despite intensive immunotherapies. Brain and spinal magnetic resonance imaging (MRI) revealed T2-high-intensity lesions in the optic nerves and thoracic spinal cord, but no lesions in the brain. A blood examination revealed positivity for both anti-aquaproin-4 antibodies and an LHON mtDNA mutation.

  15. [Skin biopsy and quantitative sensory testing can contribute to small fibre neuropathy diagnostics].

    PubMed

    Krøigård, Thomas; Karlsson, Pall; Finnerup, Nanna Brix; Sindrup, Søren Hein; Jensen, Troels Staehelin

    2016-06-20

    Nerve conduction studies are normal in small fibre neuropathy and special methods such as skin biopsies or quantitative sensory testing are required for diagnosis. In skin biopsies, nerve fibres are stained immunohistochemically and loss of distal nerve endings can be quantified directly. Assessment of thermal detection thresholds is used to evaluate the function of the sensory thermal pathways, but cannot discriminate between central and peripheral lesions. Small fibre neuropathy is often associated with potentially treatable diseases, and treatment of neuropathic pain may be required.

  16. Multifocal Motor Neuropathy, Multifocal Acquired Demyelinating Sensory and Motor Neuropathy and Other Chronic Acquired Demyelinating Polyneuropathy Variants

    PubMed Central

    Barohn, Richard J.; Katz, Jonathan

    2014-01-01

    Chronic acquired demyelinating neuropathies (CADP) are an important group of immune neuromuscular disorders affecting myelin. These are distinct from chronic inflammatory demyelinating polyneuropathy (CIDP). Classically, CIDP is characterized by proximal and distal weakness, large fiber sensory loss, elevated cerebrospinal fluid (CSF) protein content, demyelinating changes nerve conduction studies or nerve biopsy, and response to immunomodulating treatment. In this chapter we discuss CADP with emphasis on multifocal motor neuropathy (MMN), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), distal acquired demyelinating symmetric (DADS) neuropathy and conclude with less common variants. While each of these entities has distinctive laboratory and electrodiagnostic features that aid in their diagnosis, clinical characteristics are of paramount importance in diagnosing specific conditions and determining the most appropriate therapies. Unlike CIDP, MMN is typically asymmetric and affects only the motor nerve fibers. MMN is a rare disease that presents chronically, over several years of progression affecting the arms are more commonly than the legs. Men are more likely than women to develop MMN. MADSAM should be suspected in patients who have weakness and loss of sensation in primarily one arm or leg which progresses slowly over several months to years. It is important in patient with multifocal demyelinating clinical presentation to distinguish MMN from MADSAM since corticosteroids are not effective in MMN where the mainstay of therapy is intravenous gammaglobulin (IVIg). DADS can be subdivided into DADS-M (associated woth M-protein) and DADS-I which is idioapthic. While DADS-I patients respond somewhat to immunotherapy, DADS-M patients present with distal predominant sensorimotor demyelinating neuropathy phenotype and are notoriously refractory to immunotherapies regardless of antibodies to myelin-associated glycoprotein (MAG). Our knowledge

  17. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) associated to hereditary neuropathy with liability to pressure palsies (HNPP) and revealed after influenza AH1N1 vaccination.

    PubMed

    Remiche, Gauthier; Abramowicz, Marc; Mavroudakis, Nicolas

    2013-12-01

    Neurological complications of AH1N1 vaccination such as Guillain-Barré syndrome were described in the previous years. Several reports suggest that hereditary neuropathies may be a predisposing factor for immune-mediated neuropathies. We report the case of a 54-year-old female who developed chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) 5 weeks after AH1N1 vaccination. She had no previous neurological history, but neurophysiological features led us to suspect an underlying hereditary neuropathy. PMP22 gene analysis showed a typical deletion, confirming the diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP). We observed a significant clinical and neurophysiological improvement of the neuropathy after intravenous immunoglobulin treatment. This is, to our knowledge, the first reported case of CIDP potentially triggered by AH1N1 vaccination. This and previous observations suggest that genetic-determined neuropathies could predispose to the occurrence of immune-mediated neuropathies. One must recall the possibility of a superimposed hereditary neuropathy like HNPP in patients with a clinical presentation of CIDP, especially when positive family history or unexpected neurophysiological features are present.

  18. Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1.

    PubMed Central

    Flanigan, K.; Gardner, K.; Alderson, K.; Galster, B.; Otterud, B.; Leppert, M. F.; Kaplan, C.; Ptácek, L. J.

    1996-01-01

    The hereditary ataxias represent a clinically and genetically heterogeneous group of neurodegenerative disorders. Various classification schemes based on clinical criteria are being replaced as molecular characterization of the ataxias proceeds; so far, seven distinct autosomal dominant hereditary ataxias have been genetically mapped in the human genome. We report linkage to chromosome 16q22.1 for one of these genes (SCA4) in a five-generation family with an autosomal dominant, late-onset spinocerebellar ataxia; the gene is tightly linked to the microsatellite marker D16S397 (LOD score = 5.93 at theta = .00). In addition, we present clinical and electrophysiological data regarding the distinct and previously unreported phenotype consisting of ataxia with the invariant presence of a prominent axonal sensory neuropathy. PMID:8755926

  19. Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia

    SciTech Connect

    De Vries, D.D.; Oost, B.A. van; Went, L.N.; Bruyn, G.W.

    1996-04-01

    A rare form of Leber hereditary optic neuropathy (LHON) that is associated with hereditary spastic dystonia has been studied in a large Dutch family. Neuropathy and ophthalmological lesions were present together in some family members, whereas only one type of abnormality was found in others. mtDNA mutations previously reported in LHON were not present. Sequence analysis of the protein-coding mitochondrial genes revealed two previously unreported mtDNA mutations. A heteroplasmic A{yields}G transition at nucleotide position 11696 in the ND4 gene resulted in the substitution of an isoleucine for valine at amino acid position 312. A second mutation, a homoplasmic T{yields}A transition at nucleotide position 14596 in the ND6 gene, resulted in the substitution of a methionine for the isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy revealed a severe complex I deficiency, providing a link between these unique mtDNA mutations and this rare, complex phenotype including Leber optic neuropathy. 80 refs., 2 figs., 3 tabs.

  20. Multiplex MALDI-TOF MS detection of mitochondrial variants in Brazilian patients with hereditary optic neuropathy

    PubMed Central

    Matilde da Silva-Costa, Sueli; Balieiro, Juliane Cristina; Fernandes, Marcela Scabello Amaral; Alves, Rogério Marins; Guerra, Andrea Trevas Maciel; Marcondes, Ana Maria; Sartorato, Edi Lúcia

    2016-01-01

    Purpose Leber hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by bilateral vision loss. More than 95% of LHON cases are associated with one of the three main mtDNA mutations: G11778A, T14484C, and G3460A. The other 5% of cases are due to other rare mutations related to the disease. The aim of this study was to identify the prevalence and spectrum of LHON mtDNA mutations, including the haplogroup, in a cohort of Brazilian patients with optic neuropathy and to evaluate the usefulness of iPLEX Gold/matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) technology in detecting LHON mutations. Methods We analyzed a total of 101 patients; 67 had a clinical diagnosis of LHON and 34 had optic neuropathy of unknown etiology. Direct sequencing and iPLEX Gold/MALDI-TOF MS were used to screen for the most common pathogenic point mutations in LHON, together with the rare mutations G3733A, C4171A, T10663C, G14459A, C14482G, A14495G, C14568T, and C14482A. Results We identified mutations in 36 patients, of whom 83.3% carried the G11778A mutation and 16.7% carried the T14484C mutation. In individuals with mutations, the haplogroups found were L1/L2, L3, C, R, U, D, and H. Rare mutations were not detected in any of the patients analyzed. Conclusions The frequencies of the main LHON mutations were similar to those previously reported for Latin America. A different frequency was found only for the A3460G mutation. The most frequent haplogroups identified were of African origin. The iPLEX Gold/MALDI-TOF MS technology proved to be highly accurate and efficient for screening mutations and identifying the haplogroups related to LHON. The MassArray platform, combined with other techniques, enabled definitive diagnosis of LHON in 36% (36/101) of the cases studied. PMID:27582625

  1. Skin biopsy and quantitative sensory testing do not predict response to lidocaine patch in painful neuropathies.

    PubMed

    Herrmann, David N; Pannoni, Valerie; Barbano, Richard L; Pennella-Vaughan, Janet; Dworkin, Robert H

    2006-01-01

    Predictors of response to neuropathic pain treatment in patients with painful distal sensory neuropathies are lacking. The 5% lidocaine patch is believed to exert its effects on neuropathic pain via a local stabilizing effect on cutaneous sensory afferents. As such, it provides a model to assess whether the status of epidermal innervation as determined by skin biopsy or quantitative sensory testing (QST) of small- and large-diameter sensory afferents might serve as predictors of response to topical, locally active treatment. In this study we assessed associations between epidermal nerve fiber (ENF) densities, sensory nerve conduction studies (NCS), QST, and response to a 5% lidocaine patch in patients with painful distal sensory neuropathies. We observed no association between distal leg epidermal and subepidermal innervation and response to the lidocaine patch. Several patients with complete loss of distal leg ENF showed a response to the lidocaine patch. Similarly we observed no consistent association between treatment response and QST for vibration, cooling, warm, heat-pain, and cold-pain thresholds, or distal sensory NCS. Thus, distal-leg skin biopsy, QST, and sensory NCS cannot be used to identify patients with painful polyneuropathy likely to respond to a lidocaine patch in clinical practice. Further studies are required to clarify precisely the mechanism and site of action of the lidocaine patch in patients with peripheral neuropathic pain.

  2. A quantitative sensory analysis of peripheral neuropathy in colorectal cancer and its exacerbation by oxaliplatin chemotherapy.

    PubMed

    de Carvalho Barbosa, Mariana; Kosturakis, Alyssa K; Eng, Cathy; Wendelschafer-Crabb, Gwen; Kennedy, William R; Simone, Donald A; Wang, Xin S; Cleeland, Charles S; Dougherty, Patrick M

    2014-11-01

    Peripheral neuropathy caused by cytotoxic chemotherapy, especially platins and taxanes, is a widespread problem among cancer survivors that is likely to continue to expand in the future. However, little work to date has focused on understanding this challenge. The goal in this study was to determine the impact of colorectal cancer and cumulative chemotherapeutic dose on sensory function to gain mechanistic insight into the subtypes of primary afferent fibers damaged by chemotherapy. Patients with colorectal cancer underwent quantitative sensory testing before and then prior to each cycle of oxaliplatin. These data were compared with those from 47 age- and sex-matched healthy volunteers. Patients showed significant subclinical deficits in sensory function before any therapy compared with healthy volunteers, and they became more pronounced in patients who received chemotherapy. Sensory modalities that involved large Aβ myelinated fibers and unmyelinated C fibers were most affected by chemotherapy, whereas sensory modalities conveyed by thinly myelinated Aδ fibers were less sensitive to chemotherapy. Patients with baseline sensory deficits went on to develop more symptom complaints during chemotherapy than those who had no baseline deficit. Patients who were tested again 6 to 12 months after chemotherapy presented with the most numbness and pain and also the most pronounced sensory deficits. Our results illuminate a mechanistic connection between the pattern of effects on sensory function and the nerve fiber types that appear to be most vulnerable to chemotherapy-induced toxicity, with implications for how to focus future work to ameloirate risks of peripheral neuropathy. PMID:25183707

  3. Leber's hereditary optic neuropathy is associated with mitochondrial ND6 T14502C mutation

    SciTech Connect

    Zhao, Fuxin; Guan, Minqiang; Zhou, Xiangtian; Yuan, Meixia; Liang, Ming; Liu, Qi; Liu, Yan; Zhang, Yongmei; Yang, Li; Tong, Yi; Wei, Qi-Ping; Sun, Yan-Hong; Qu, Jia; and others

    2009-11-20

    We report here the clinical, genetic, and molecular characterization of three Chinese families with Leber's hereditary optic neuropathy (LHON). There were variable severity and age of onset in visual impairment among these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of complete mitochondrial genomes in these pedigrees showed the homoplasmic T14502C (I58V) mutation, which localized at a highly conserved isoleucine at position 58 of ND6, and distinct sets of mtDNA polymorphisms belonging to haplogroups M10a, F1a1, and H2. The occurrence of T14502C mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. Here, mtDNA variants I187T in the ND1, A122V in CO1, S99A in the A6, and V254I in CO3 exhibited an evolutionary conservation, indicating a potential modifying role in the development of visual impairment associated with T14502C mutation in those families. Furthermore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic manifestation of the LHON-associated T14502C mutation in these Chinese families.

  4. Leber's hereditary optic neuropathy is associated with mitochondrial ND1 T3394C mutation

    SciTech Connect

    Liang, Min; Guan, Minqiang; Zhao, Fuxing; Zhou, Xiangtian; Yuan, Meixia; Tong, Yi; Yang, Li; Wei, Qi-Ping; Sun, Yan-Hong; Lu, Fan; Qu, Jia; and others

    2009-06-05

    We report here the clinical, genetic and molecular characterization of four Chinese families with Leber's hereditary optic neuropathy (LHON). There were variable severity and age-of-onset in visual impairment among these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of complete mitochondrial genomes in these pedigrees showed the homoplasmic T3394C (Y30H) mutation, which localized at a highly conserved tyrosine at position 30 of ND1, and distinct sets of mtDNA polymorphisms belonging to haplogroups D4b and M9a. The occurrence of T3394C mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. However, there was the absence of functionally significant mtDNA mutations in these four Chinese pedigrees carrying the T3394C mutation. Therefore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic expression of the LHON-associated T3394C mutation.

  5. Smoking as an aetiological factor in a pedigree with Leber's hereditary optic neuropathy

    PubMed Central

    Tsao, K.; Aitken, P.; Johns, D.

    1999-01-01

    BACKGROUND/AIMS—Leber's hereditary optic neuropathy (LHON) is a mitochondrial DNA mediated disease which causes severe visual deficits. Although expressivity of the disease is 100%, penetrance is variable, and environmental factors may influence risk of becoming symptomatic. The causative relation between cigarette smoking and disease penetrance was examined.
METHODS—The incidence of smoking in 65 age matched family members of one LHON pedigree was retrospectively obtained. Smoking in groups which expressed disease was compared with those which did not. Male subgroups were analysed separately in addition to combined sex groups.
RESULTS—The association between smoking and disease penetrance was significant in all subgroups (p values from p=0.0009 to p=0.0001, 95% confidence intervals). Disease penetrance was higher in males than females. The association was weaker in the male group than combined sex groups (p values from p=0.0146 to p=0.0008, 95% confidence intervals), probably because of elimination of female asymptomatic non-smokers in the comparison groups. The association was strengthened in older age groups and in groups which smoked more heavily.
CONCLUSIONS—Smoking is significantly associated with disease penetrance in this LHON pedigree. Degree of smoking and number of years smoked correlate with increased risk of developing symptoms.

 PMID:10216058

  6. Hereditary Neuropathy with Liability to Pressure Palsies Masked by Previous Gunshots and Tuberculosis

    PubMed Central

    Gencik, Martin; Finsterer, Josef

    2015-01-01

    Objectives. Although hereditary neuropathy with liability to pressure palsies (HNPP) presents with a distinct phenotype on history, clinical exam, and nerve conduction studies, it may be masked if diagnostic work-up suggests other causes. Case Report. In a 37-year-old male with pseudoradicular lumbar pain, neurological exam revealed sore neck muscles, peripheral facial nerve palsy, right anacusis and left hypoacusis, hemihypesthesia of the right face, mild distal quadriparesis, diffuse wasting, and generally reduced tendon reflexes. He had a history of skull fracture due to a gunshot behind the right ear and tuberculosis for which he had received adequate treatment for 3 years; MRI revealed a disc prolapse at C6/7 and Th11/12. Nerve conduction studies were indicative of demyelinating polyneuropathy with conduction blocks. Despite elevated antinuclear antibodies and elevated CSF-protein, HNPP was diagnosed genetically after having excluded vasculitis, CIDP, radiculopathy, and the side effects of antituberculous treatment. Conclusions. HNPP may manifest with mild, painless, distal quadriparesis. The diagnosis of HNPP may be blurred by a history of tuberculosis, tuberculostatic treatment, hepatitis, and the presence of elevated CSF-protein. PMID:26640726

  7. [Molecular diagnosis of hereditary neuropathies such as Charcot-Marie-Tooth disease].

    PubMed

    Pouget, J

    2004-02-01

    During the last decade, molecular biology has demonstrated the extraordinary heterogeneity of genetic abnormalities in Charcot-Marie-Tooth disease (CMT). The main phenotypes are either of the demyelinating or axonal type, transmitted with dominant or recessive autosomal inheritance. X-linked CMT is less rare than it was initially described and is often misdiagnosed as autosomal dominant type. Linked phenotypes are Dejerine-Sottas disease, congenital hypomyelinization and hereditary neuropathy with susceptibility to pressure palsies. Each phenotype can be due to different genotypes and concerned genes are numerous. Conversely, each genotype can express different phenotypes. Molecular diagnostic strategy of CMT is mainly baised on three elements: - phenotypic expertise which is based on the analysis of the inheritance mode and on electrophysiological data, which are peculiar in CMTX - knowledge of respective occurrence of the different genotypes and phenotypes which is increasing - technical feasibility of molecular biology methods which is important to consider, even though progress are fastly coming. According to these considerations, a strategy is proposed for molecular diagnosis of CMT. PMID:15034475

  8. Clinical Expression of Leber Hereditary Optic Neuropathy Is Affected by the Mitochondrial DNA–Haplogroup Background

    PubMed Central

    Hudson, Gavin ; Carelli, Valerio ; Spruijt, Liesbeth ; Gerards, Mike ; Mowbray, Catherine ; Achilli, Alessandro ; Pyle, Angela ; Elson, Joanna ; Howell, Neil ; La Morgia, Chiara ; Valentino, Maria Lucia ; Huoponen, Kirsi ; Savontaus, Marja-Liisa ; Nikoskelainen, Eeva ; Sadun, Alfredo A. ; Salomao, Solange R. ; Belfort Jr., Rubens ; Griffiths, Philip ; Man, Patrick Yu Wai ; de Coo, Rene F. M. ; Horvath, Rita ; Zeviani, Massimo ; Smeets, Hubert J. T. ; Torroni, Antonio ; Chinnery, Patrick F. 

    2007-01-01

    Leber hereditary optic neuropathy (LHON) is due primarily to one of three common point mutations of mitochondrial DNA (mtDNA), but the incomplete penetrance implicates additional genetic or environmental factors in the pathophysiology of the disorder. Both the 11778G→A and 14484T→C LHON mutations are preferentially found on a specific mtDNA genetic background, but 3460G→A is not. However, there is no clear evidence that any background influences clinical penetrance in any of these mutations. By studying 3,613 subjects from 159 LHON-affected pedigrees, we show that the risk of visual failure is greater when the 11778G→A or 14484T→C mutations are present in specific subgroups of haplogroup J (J2 for 11778G→A and J1 for 14484T→C) and when the 3460G→A mutation is present in haplogroup K. By contrast, the risk of visual failure is significantly less when 11778G→A occurs in haplogroup H. Substitutions on MTCYB provide an explanation for these findings, which demonstrate that common genetic variants have a marked effect on the expression of an ostensibly monogenic mtDNA disorder. PMID:17668373

  9. MRI in Leber's hereditary optic neuropathy: the relationship to multiple sclerosis

    PubMed Central

    Matthews, Lucy; Enzinger, Christian; Fazekas, Franz; Rovira, Alex; Ciccarelli, Olga; Dotti, Maria Teresa; Filippi, Massimo; Frederiksen, Jette L; Giorgio, Antonio; Küker, Wilhelm; Lukas, Carsten; Rocca, Maria A; De Stefano, Nicola; Toosy, Ahmed; Yousry, Tarek; Palace, Jacqueline

    2015-01-01

    Background Leber's hereditary optic neuropathy (LHON) and a multiple sclerosis (MS)-like illness appear to coexist 50 times more frequently than would be expected by chance. This association of LHON and MS (LMS) raises an important question about whether there could be a common pathophysiological mechanism involving mitochondrial dysfunction. Objective The primary aim was to define MRI features of LMS and LHON, and to assess the proportions of individuals displaying features typical of MS. Secondarily, we investigated the effect of gender on the risk of developing white matter lesions in the context of LHON. Methods A blinded standardised review of conventional brain MRIs of 30 patients with MS, 31 patients with LHON and 11 patients with LMS was conducted by three independent experts in the field. MS-like MRI features were assessed. Results All patients with LMS and 26% of patients with LHON had white matter lesions. Of these, all patients with LMS and 25% with LHON were found to have an MRI appearance typical of MS. Female patients with LHON had a significantly greater risk of having white matter lesions consistent with MS compared with male patients (relative risk 8.3). Conclusions A blinded review of conventional brain MRIs shows that patients with LMS have a scan appearance indistinguishable from MS. Mitochondrial dysfunction could be a common pathophysiological pathway in the formation of white matter lesions. There appears to be a strong female influence on the radiological appearance as well as clinical development of MS in patients with LHON. PMID:25053773

  10. Targeting estrogen receptor β as preventive therapeutic strategy for Leber's hereditary optic neuropathy.

    PubMed

    Pisano, Annalinda; Preziuso, Carmela; Iommarini, Luisa; Perli, Elena; Grazioli, Paola; Campese, Antonio F; Maresca, Alessandra; Montopoli, Monica; Masuelli, Laura; Sadun, Alfredo A; d'Amati, Giulia; Carelli, Valerio; Ghelli, Anna; Giordano, Carla

    2015-12-15

    Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease characterized by degeneration of retinal ganglion cells (RGCs) and consequent optic nerve atrophy. Peculiar features of LHON are incomplete penetrance and gender bias, with a marked male prevalence. Based on the different hormonal metabolism between genders, we proposed that estrogens play a protective role in females and showed that these hormones ameliorate mitochondrial dysfunction in LHON through the estrogen receptors (ERs). We also showed that ERβ localize to the mitochondria of RGCs. Thus, targeting ERβ may become a therapeutic strategy for LHON specifically aimed at avoiding or delaying the onset of disease in mutation carriers. Here, we tested the effects of ERβ targeting on LHON mitochondrial defective metabolism by treating LHON cybrid cells carrying the m.11778G>A mutation with a combination of natural estrogen-like compounds that bind ERβ with high selectivity. We demonstrated that these molecules improve cell viability by reducing apoptosis, inducing mitochondrial biogenesis and strongly reducing the levels of reactive oxygen species in LHON cells. These effects were abolished in cells with ERβ knockdown by silencing receptor expression or by using specific receptor antagonists. Our observations support the hypothesis that estrogen-like molecules may be useful in LHON prophylactic therapy. This is particularly important for lifelong disease prevention in unaffected LHON mutation carriers. Current strategies attempting to combat degeneration of RGCs during the acute phase of LHON have not been very effective. Implementing a different and preemptive approach with a low risk profile may be very helpful.

  11. Efficacy and Safety of rAAV2-ND4 Treatment for Leber's Hereditary Optic Neuropathy.

    PubMed

    Wan, Xing; Pei, Han; Zhao, Min-jian; Yang, Shuo; Hu, Wei-kun; He, Heng; Ma, Si-qi; Zhang, Ge; Dong, Xiao-yan; Chen, Chen; Wang, Dao-wen; Li, Bin

    2016-02-19

    Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited disease leading to blindness. A mitochondrial DNA point mutation at the 11778 nucleotide site of the NADH dehydrogenase subunit 4 (ND4) gene is the most common cause. The aim of this study was to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) in LHON patients carrying the G11778A mutation. Nine patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 9 months. Ophthalmologic examinations of visual acuity, visual field, and optical coherence tomography were performed. Physical examinations included routine blood and urine. The visual acuity of the injected eyes of six patients improved by at least 0.3 log MAR after 9 months of follow-up. In these six patients, the visual field was enlarged but the retinal nerve fibre layer remained relatively stable. No other outcome measure was significantly changed. None of the nine patients had local or systemic adverse events related to the vector during the 9-month follow-up period. These findings support the feasible use of gene therapy for LHON.

  12. A Female Patient with Down Syndrome and Low-Penetrance Leber's Hereditary Optic Neuropathy.

    PubMed

    Frousiakis, Starleen E; Pouw, Andrew E; Karanjia, Rustum; Sadun, Alfredo A

    2014-09-01

    We present the case of a 19-year-old female with a history of Down syndrome (DS) who was referred to our neuro-ophthalmology clinic for evaluation of Leber's hereditary optic neuropathy (LHON). The patient's family history was significant for a known G11778A mutation in a maternal relative, consistent with LHON. The patient was also positive for the G11778A mutation; however, the genotype demonstrated low penetrance in the pedigree, with only 1 out of 10 adult male offspring showing signs or symptoms of the disease. Mitochondrial mutations implicated in LHON have been shown to impair complex I of the electron transport chain and thereby reducing the effective generation of adenosine triphosphate and increasing the production of toxic reactive oxygen species. Although the partial or complete triplicate of chromosome 21 constitutes the etiology of DS, some of the pleiotropic phenotypes of the syndrome have been attributed to oxidative stress and mitochondrial dysfunction. Given the low penetrance of the mutation and the patient's sex, this case illustrates the possibility that the mitochondrial mutation demonstrated increased penetrance due to pre-existing mitochondrial dysfunction related to DS.

  13. White Matter Changes in Two Leber's Hereditary Optic Neuropathy Pedigrees: 12-Year Follow-Up.

    PubMed

    Jančić, Jasna; Dejanović, Ivana; Radovanović, Saša; Ostojić, Jelena; Kozić, Duško; Đurić-Jovičić, Milica; Samardžić, Janko; Ćetković, Mila; Kostić, Vladimir

    2016-01-01

    We are presenting two Leber's hereditary optic neuropathy (LHON) pedigrees with abnormal magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (H-MRS) findings but without neurological manifestation associated with LHON. The study included 14 LHON patients and 41 asymptomatic family members from 12 genealogically unrelated families. MRI showed white matter involvement and H-MRS exhibited metabolic anomalies within 12 LHON families. Main outcome measures were abnormal MRI and H-MRS findings in two pedigrees. MRI of the proband of the first pedigree showed a single demyelinating lesion in the right cerebellar hemisphere, while the proband of the second family displayed multiple supratentorial and infratentorial lesions, compatible with the demyelinating process, and both the absolute choline (Cho) concentration and Cho/creatinine ratio were increased. MRI and H-MRS profiles of both affected and unaffected mitochondrial DNA mutation carriers suggest more widespread central nervous involvement in LHON. Although even after 12 years our patients did not develop neurological symptoms, MRI could still be used to detect possible changes during the disease progression.

  14. Mitochondrial ND3 as the novel causative gene for Leber hereditary optic neuropathy and dystonia.

    PubMed

    Wang, Kang; Takahashi, Yuji; Gao, Zong-Liang; Wang, Guo-Xiang; Chen, Xian-Wen; Goto, Jun; Lou, Jin-Ning; Tsuji, Shoji

    2009-10-01

    Leber hereditary optic neuropathy and dystonia (LDYT) is a mitochondrial disorder associated with variable combinations of vision loss and progressive generalized dystonia. LDYT is a unique oxidative phosphorylation disorder caused by mutations in mitochondrial ND6 or ND4 gene. In this paper, we describe a Chinese family with 18 LDYT patients. The comprehensive nucleotide sequence analysis of the entire mitochondrial genome using resequencing microarray revealed a mutation (mtND3*10197A (m.10197G>A)) substituting a threonine for a highly conserved alanine at codon 47 of MTND3 on the background of haplogroup D4b. Quantitative analysis of the heteroplasmy of the mutation revealed a homoplasmy in the leukocytes of all the affected individuals on the maternal side. This is the first description of the ND3 mutation causing LDYT. The mtND3*10197A (m.10197G>A) mutation has recently been described in French and Korean patients with Leigh syndrome. These findings suggest that the clinical presentations associated with the mtND3*10197A (m.10197G>A) mutation (ND3) are much wider, encompassing those of LDYT and Leigh syndrome. PMID:19458970

  15. Efficacy and Safety of rAAV2-ND4 Treatment for Leber's Hereditary Optic Neuropathy.

    PubMed

    Wan, Xing; Pei, Han; Zhao, Min-jian; Yang, Shuo; Hu, Wei-kun; He, Heng; Ma, Si-qi; Zhang, Ge; Dong, Xiao-yan; Chen, Chen; Wang, Dao-wen; Li, Bin

    2016-01-01

    Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited disease leading to blindness. A mitochondrial DNA point mutation at the 11778 nucleotide site of the NADH dehydrogenase subunit 4 (ND4) gene is the most common cause. The aim of this study was to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) in LHON patients carrying the G11778A mutation. Nine patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 9 months. Ophthalmologic examinations of visual acuity, visual field, and optical coherence tomography were performed. Physical examinations included routine blood and urine. The visual acuity of the injected eyes of six patients improved by at least 0.3 log MAR after 9 months of follow-up. In these six patients, the visual field was enlarged but the retinal nerve fibre layer remained relatively stable. No other outcome measure was significantly changed. None of the nine patients had local or systemic adverse events related to the vector during the 9-month follow-up period. These findings support the feasible use of gene therapy for LHON. PMID:26892229

  16. White Matter Changes in Two Leber's Hereditary Optic Neuropathy Pedigrees: 12-Year Follow-Up.

    PubMed

    Jančić, Jasna; Dejanović, Ivana; Radovanović, Saša; Ostojić, Jelena; Kozić, Duško; Đurić-Jovičić, Milica; Samardžić, Janko; Ćetković, Mila; Kostić, Vladimir

    2016-01-01

    We are presenting two Leber's hereditary optic neuropathy (LHON) pedigrees with abnormal magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (H-MRS) findings but without neurological manifestation associated with LHON. The study included 14 LHON patients and 41 asymptomatic family members from 12 genealogically unrelated families. MRI showed white matter involvement and H-MRS exhibited metabolic anomalies within 12 LHON families. Main outcome measures were abnormal MRI and H-MRS findings in two pedigrees. MRI of the proband of the first pedigree showed a single demyelinating lesion in the right cerebellar hemisphere, while the proband of the second family displayed multiple supratentorial and infratentorial lesions, compatible with the demyelinating process, and both the absolute choline (Cho) concentration and Cho/creatinine ratio were increased. MRI and H-MRS profiles of both affected and unaffected mitochondrial DNA mutation carriers suggest more widespread central nervous involvement in LHON. Although even after 12 years our patients did not develop neurological symptoms, MRI could still be used to detect possible changes during the disease progression. PMID:26540208

  17. Corneal confocal microscopy reveals trigeminal small sensory fiber neuropathy in amyotrophic lateral sclerosis

    PubMed Central

    Ferrari, Giulio; Grisan, Enrico; Scarpa, Fabio; Fazio, Raffaella; Comola, Mauro; Quattrini, Angelo; Comi, Giancarlo; Rama, Paolo; Riva, Nilo

    2014-01-01

    Although subclinical involvement of sensory neurons in amyotrophic lateral sclerosis (ALS) has been previously demonstrated, corneal small fiber sensory neuropathy has not been reported to-date. We examined a group of sporadic ALS patients with corneal confocal microscopy, a recently developed imaging technique allowing in vivo observation of corneal small sensory fibers. Corneal confocal microscopy (CCM) examination revealed a reduction of corneal small fiber sensory nerve number and branching in ALS patients. Quantitative analysis demonstrated an increase in tortuosity and reduction in length and fractal dimension of ALS patients’ corneal nerve fibers compared to age-matched controls. Moreover, bulbar function disability scores were significantly related to measures of corneal nerve fibers anatomical damage. Our study demonstrates for the first time a corneal small fiber sensory neuropathy in ALS patients. This finding further suggests a link between sporadic ALS and facial-onset sensory and motor neuronopathy (FOSMN) syndrome, a rare condition characterized by early sensory symptoms (with trigeminal nerve distribution), followed by wasting and weakness of bulbar and upper limb muscles. In addition, the finding supports a model of neurodegeneration in ALS as a focally advancing process. PMID:25360111

  18. Acute motor-sensory axonal neuropathy with hyperreflexia in Guillain-Barré syndrome.

    PubMed

    Tosun, Ayşe; Dursun, Şiar; Akyildiz, Utku Ogan; Oktay, Seçil; Tataroğlu, Cengiz

    2015-04-01

    Guillain-Barré syndrome is an acute inflammatory autoimmune polyradiculoneuritis. Progressive motor weakness and areflexia are essential for its diagnosis. Hyperreflexia has rarely been reported in the early healing period of Guillain-Barré syndrome following Campylobacter jejuni infection in patients with acute motor axonal neuropathy with antiganglioside antibody positivity. In this study, we report a 12-year-old girl presenting with complaints of inability to walk, numbness in hands and feet, and hyperactive deep tendon reflexes since the onset of the clinical picture, diagnosed with acute motor-sensory axonal neuropathy type of Guillain-Barré syndrome.

  19. Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial.

    PubMed

    Koilkonda, Rajeshwari D; Yu, Hong; Chou, Tsung-Han; Feuer, William J; Ruggeri, Marco; Porciatti, Vittorio; Tse, David; Hauswirth, William W; Chiodo, Vince; Boye, Sanford L; Lewin, Alfred S; Neuringer, Martha; Renner, Lauren; Guy, John

    2014-04-01

    IMPORTANCE We developed a novel strategy for treatment of Leber hereditary optic neuropathy (LHON) caused by a mutation in the nicotinamide adenine dinucleotide dehydrogenase subunit IV (ND4) mitochondrial gene. OBJECTIVE To demonstrate the safety and effects of the gene therapy vector to be used in a proposed gene therapy clinical trial. DESIGN AND SETTING In a series of laboratory experiments, we modified the mitochondrial ND4 subunit of complex I in the nuclear genetic code for import into mitochondria. The protein was targeted into the organelle by agency of a targeting sequence (allotopic expression). The gene was packaged into adeno-associated viral vectors and then vitreally injected into rodent, nonhuman primate, and ex vivo human eyes that underwent testing for expression and integration by immunohistochemical analysis and blue native polyacrylamide gel electrophoresis. During serial follow-up, the animal eyes underwent fundus photography, optical coherence tomography, and multifocal or pattern electroretinography. We tested for rescue of visual loss in rodent eyes also injected with a mutant G11778A ND4 homologue responsible for most cases of LHON. EXPOSURE Ocular infection with recombinant adeno-associated viral vectors containing a wild-type allotopic human ND4 gene. MAIN OUTCOMES AND MEASURES Expression of human ND4 and rescue of optic neuropathy induced by mutant human ND4. RESULTS We found human ND4 expressed in almost all mouse retinal ganglion cells by 1 week after injection and ND4 integrated into the mouse complex I. In rodent eyes also injected with a mutant allotopic ND4, wild-type allotopic ND4 prevented defective adenosine triphosphate synthesis, suppressed visual loss, reduced apoptosis of retinal ganglion cells, and prevented demise of axons in the optic nerve. Injection of ND4 in the ex vivo human eye resulted in expression in most retinal ganglion cells. Primates undergoing vitreal injection with the ND4 test article and followed up for 3

  20. Point mutations associated with Leber hereditary optic neuropathy in a Latvian population

    PubMed Central

    Baumane, Kristine; Zalite, Solveiga; Ranka, Renate; Zole, Egija; Pole, Ilva; Sepetiene, Svetlana; Laganovska, Guna; Baumanis, Viesturs; Pliss, Liana

    2013-01-01

    Purpose To study mutations associated with Leber hereditary optic neuropathy (LHON) in patients suspected of having this mitochondrial disorder in a Latvian population. Additional aims were to determine the heteroplasmy status of all non-synonymous polymorphisms identified in the current study and to identify the mitochondrial haplogroups of the studied participants because these factors may contribute to the manifestation of LHON. Methods Twelve patients, including patients in two families, were enrolled in the current study. LHON was suspected based on the findings of ophthalmologic examinations. In clinically affected individuals, the presence of all previously reported LHON-associated mutations was assessed with sequencing analysis. Additionally, the SURVEYOR endonuclease assay was used to detect heteroplasmy. The mitochondrial haplogroups were identified with restriction analysis and the sequencing of hypervariable segment 1. Results In one family (mother and son), there was one primary LHON-associated mutation, G11778A. In addition, one rare previously reported LHON-associated polymorphism, A13637G, was detected in two unrelated patients. A non-synonymous polymorphism at T6253C was found in one individual. This mutation was reported in the background of the 3460 mutation among LHON patients in a Chinese population. No non-synonymous point mutations in mitochondrial DNA were found in five of the study participants. Conclusions Molecular analysis of 12 patients with suspected LHON confirmed the diagnosis in four patients and allowed the use of appropriate prophylactic measures and treatment. Further investigations and additional studies of different populations are necessary to confirm the role of the non-synonymous polymorphisms A13637G and T6253C in the manifestation of LHON and the associations of these polymorphisms with mitochondrial haplogroups and heteroplasmy. PMID:24319328

  1. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.

    PubMed Central

    Howell, N; Bindoff, L A; McCullough, D A; Kubacka, I; Poulton, J; Mackey, D; Taylor, L; Turnbull, D M

    1991-01-01

    Biochemical and molecular genetic evidence is presented that in six independent pedigrees the development of Leber hereditary optic neuropathy (LHON) is due to the same primary mutation in the mitochondrial ND1 gene. A LHON family from the Newcastle area of Great Britain was analyzed in depth to determine the mitochondrial genetic etiology of their disease. Biochemical assays of mitochondrial electron transport in organelles isolated from the platelet/white-blood-cell fraction have established that the members of this family have a substantial and specific lowering of flux through complex I (NADH-ubiquinone oxidoreductase). To determine the site of the primary mitochondrial gene mutation in this pedigree, all seven mitochondrial complex I genes were sequenced, in their entirety, from two family members. The primary mutation was identified as a homoplasmic transition at nucleotide 3460, which results in the substitution of threonine for alanine at position 52 of the ND1 protein. This residue occurs within a very highly conserved hydrophilic loop, is invariantly alanine or glycine in all ND1 proteins, and is adjacent to an invariant aspartic acid residue. This is only the second instance in which both a biochemical abnormality and a mitochondrial gene mutation have been identified in an LHON pedigree. The sequence analysis of the ND81 gene was extended to a further 11, unrelated LHON pedigrees that had been screened previously and found not to carry the mitochondrial ND4/R340H mutation. The ND1/A52T mutation at nucleotide 3460 was found in five of these 11 pedigrees. In contrast, this sequence change was not found in any of the 47 non-LHON controls. The possible role of secondary complex I mutations in the etiology of LHON is also addressed in these studies. PMID:1928099

  2. Neuron-Specific Enolase Is Elevated in Asymptomatic Carriers of Leber's Hereditary Optic Neuropathy

    PubMed Central

    Yee, Kenneth M.; Ross-Cisneros, Fred N.; Lee, Jeong Goo; Da Rosa, Arlon Bastos; Salomao, Solange R.; Berezovsky, Adriana; Belfort, Rubens; Chicani, Filipe; Moraes-Filho, Milton; Sebag, Jerry; Carelli, Valerio; Sadun, Alfredo A.

    2012-01-01

    Purpose. Neuron-specific enolase (NSE) is a biomarker for neuronal stress. Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease affecting retinal ganglion cells (RGC). These RGCs and their axons in the retinal nerve fiber layer (RNFL) and optic nerve head may show subclinical pathology in unaffected mutation carriers, or undergo cell death in affected patients. We hypothesize that increased levels of blood NSE may characterize LHON carriers as a biomarker of ongoing RGC stress. Methods. Serum was obtained from 74 members of a Brazilian pedigree with LHON carrying the homoplasmic 11778/ND4 mitochondrial DNA mutation. Classified by symptoms and psychophysical metrics, 46/74 patients were unaffected mutation “carriers,” 14/74 were “affected,” and 14/74 were “off-pedigree” controls. Serum NSE levels were determined by ELISA specific for the γ subunit of NSE. Results. Serum NSE concentrations in carriers (27.17 ± 39.82 μg/L) were significantly higher than affected (5.66 ± 4.19 μg/L; P = 0.050) and off-pedigree controls (6.20 ± 2.35 μg/L; P = 0.047). Of the 14/46 (30.4 %) carriers with significantly elevated NSE levels (mean = 75.8 ± 42.3 μg/L), 9/14 (64.3%) were male. Furthermore, NSE levels were nearly three times greater in asymptomatic male carriers (40.65 ± 51.21 μg/L) than in asymptomatic female carriers (15.85 ± 22.27 μg/L; P = 0.034). Conclusions. Serum NSE levels are higher in LHON carriers compared with affected and off-pedigree individuals. A subgroup of mostly male carriers had significantly elevated serum NSE levels. Thus, male carriers are at higher risk for LHON-related neuronal stress. PMID:22893673

  3. Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation.

    PubMed Central

    Harding, A E; Sweeney, M G; Govan, G G; Riordan-Eva, P

    1995-01-01

    Eighty-nine index patients from 85 families were defined as having Leber hereditary optic neuropathy (LHON) by the presence of one of the mtDNA mutations at positions 11778 (66 families), 3460 (8 families), or 14484 (11 families). There were 62 secondary cases. Overall, 64% of index cases had a history of similarly affected relatives. The ratios of affected males to affected females were 3.7:1 (11778), 4.3:1 (3460), and 7.7:1 (14484). The 95th centile for age at onset of symptoms was close to 50 years in index, secondary, male, and female patients. There were no differences in the distributions of age at onset between different mutation groups, between index and secondary cases, or between males and females, apart from this being slightly later in all female patients than in male 11778 patients. There was no significant correlation between age at onset in index cases and that in their affected siblings or cousins. Heteroplasmy (< 96% mutant mtDNA) was detected in 4% of affected subjects (67%-90% mutant mtDNA) and in 13.6% of 140 unaffected relatives (< 5%-90% mutant mtDNA). Analysis of all pedigrees, excluding sibships < 50 years of age and index cases, indicated recurrence risks of 30%, 8%, 46%, 10%, 31%, and 6%, respectively, to the brothers, sisters, nephews, nieces, and male and female matrilineal first cousins of index cases. Affected females were more likely to have affected children, particularly daughters, than were unaffected female carriers. The pedigree data were entirely compatible with the previously proposed X-linked susceptibility locus, with a gene frequency of .08, penetrance of .11 in heterozygous females, and 40% of affected females being homozygous, the remainder being explained by heterozygosity and disadvantageous X inactivation. PMID:7611298

  4. Diagnostic approach to peripheral neuropathy

    PubMed Central

    Misra, Usha Kant; Kalita, Jayantee; Nair, Pradeep P.

    2008-01-01

    Peripheral neuropathy refers to disorders of the peripheral nervous system. They have numerous causes and diverse presentations; hence, a systematic and logical approach is needed for cost-effective diagnosis, especially of treatable neuropathies. A detailed history of symptoms, family and occupational history should be obtained. General and systemic examinations provide valuable clues. Neurological examinations investigating sensory, motor and autonomic signs help to define the topography and nature of neuropathy. Large fiber neuropathy manifests with the loss of joint position and vibration sense and sensory ataxia, whereas small fiber neuropathy manifests with the impairment of pain, temperature and autonomic functions. Electrodiagnostic (EDx) tests include sensory, motor nerve conduction, F response, H reflex and needle electromyography (EMG). EDx helps in documenting the extent of sensory motor deficits, categorizing demyelinating (prolonged terminal latency, slowing of nerve conduction velocity, dispersion and conduction block) and axonal (marginal slowing of nerve conduction and small compound muscle or sensory action potential and dennervation on EMG). Uniform demyelinating features are suggestive of hereditary demyelination, whereas difference between nerves and segments of the same nerve favor acquired demyelination. Finally, neuropathy is classified into mononeuropathy commonly due to entrapment or trauma; mononeuropathy multiplex commonly due to leprosy and vasculitis; and polyneuropathy due to systemic, metabolic or toxic etiology. Laboratory investigations are carried out as indicated and specialized tests such as biochemical, immunological, genetic studies, cerebrospinal fluid (CSF) examination and nerve biopsy are carried out in selected patients. Approximately 20% patients with neuropathy remain undiagnosed but the prognosis is not bad in them. PMID:19893645

  5. Visual and somatosensory evoked potentials and F-wave latency measurements in hereditary neuropathy with liability to pressure palsies.

    PubMed

    Strenge, H; Soyka, D; Tackmann, W

    1982-01-01

    Pattern shift visual evoked potentials (VEPs), cervical and cortical somatosensory evoked responses (SEPs) and motor conduction velocities studied by F-wave latency measurements were investigated in two family members with hereditary neuropathy with liability to pressure palsies (HN-PP). In both cases in VEPs and SEP conduction times N13-N20 were normal. A bilateral pathological increase of latencies of early SEP components, N9-N13 transit times and F-wave latencies revealed a lesion in the proximal parts of the median nerves close to the spinal cord in the older patient. These abnormalities emphasize the close relationship of HN-PP with hereditary polyradiculopathy (Mayer 1975). PMID:6174708

  6. Dorsal Root Ganglia Sensory Neuronal Cultures: a tool for drug discovery for peripheral neuropathies

    PubMed Central

    Melli, Giorgia; Höke, Ahmet

    2010-01-01

    Background Peripheral neuropathies affect many people worldwide and are caused by or associated with a wide range of conditions, both genetic and acquired. Current therapies are directed at symptomatic control because no effective regenerative treatment exists. Primary challenge is that mechanisms that lead to distal axonal degeneration, a common feature of all peripheral neuropathies, are largely unknown. Objective/Methods To address the role and specific characteristics of dorsal root ganglia (DRG) derived sensory neuron culture system as a useful model in evaluating the pathogenic mechanisms of peripheral neuropathies and examination and validation of potential therapeutic compounds. A thorough review of the recent literature was completed and select examples of the use of DRG neurons in different peripheral neuropathy models were chosen to highlight the utility of these cultures. Conclusion Many useful models of different peripheral neuropathies have been developed using DRG neuronal culture and potential therapeutic targets have been examined, but so far none of the potential therapeutic compounds have succeeded in clinical trials. In recent years, focus has changed to evaluation of axon degeneration as the primary outcome measure advocating a drug development strategy starting with phenotypic drug screening, followed by validation in primary complex co-cultures and animal models. PMID:20657751

  7. Afferent Visual Pathway Affection in Patients with PMP22 Deletion-Related Hereditary Neuropathy with Liability to Pressure Palsies

    PubMed Central

    Rinnenthal, Jan Leo; Zimmermann, Hanna; Mikolajczak, Janine; Oberwahrenbrock, Timm; Papazoglou, Sebastian; Pfüller, Caspar F.; Schinzel, Johann; Tackenberg, Björn; Paul, Friedemann; Hahn, Katrin; Bellmann-Strobl, Judith

    2016-01-01

    Background The PMP22 gene encodes a protein integral to peripheral myelin. Its deletion leads to hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is not expressed in the adult central nervous system, but previous studies suggest a role in CNS myelin development. The objective of this study was to identify potential structural and functional alterations in the afferent visual system in HNPP patients. Methods Twenty HNPP patients and 18 matched healthy controls (HC) were recruited in a cross-sectional study. Participants underwent neurological examination including visual acuity, visual evoked potential (VEP) examination, optical coherence tomography (OCT), and magnetic resonance imaging with calculation of brain atrophy, regarding grey and white matter, and voxel based morphometry (VBM), in addition answered the National Eye Institute’s 39-item Visual Functioning Questionnaire (NEI-VFQ). Thirteen patients and 6 HC were additionally examined with magnetic resonance spectroscopy (MRS). Results All patients had normal visual acuity, but reported reduced peripheral vision in comparison to HC in the NEI-VFQ (p = 0.036). VEP latency was prolonged in patients (P100 = 103.7±5.7 ms) in comparison to healthy subjects (P100 = 99.7±4.2 ms, p = 0.007). In OCT, peripapillary retinal nerve fiber layer thickness RNFL was decreased in the nasal sector (90.0±15.5 vs. 101.8±16.5, p = 0.013), and lower nasal sector RNFL correlated with prolonged VEP latency (Rho = -0.405, p = 0.012). MRS revealed reduced tNAA (731.4±45.4 vs. 814.9±62.1, p = 0.017) and tCr (373.8±22.2 vs. 418.7±31.1, p = 0.002) in the visual cortex in patients vs. HC. Whole brain volume, grey and white matter volume, VBM and metabolites in a MRS sensory cortex control voxel did not differ significantly between patients and HC. Conclusion PMP22 deletion leads to functional, metabolic and macro-structural alterations in the afferent visual system of HNPP patients. Our data suggest a

  8. Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies.

    PubMed

    Oaklander, Anne Louise

    2016-01-01

    The best-known peripheral neuropathies are those affecting the large, myelinated motor and sensory fibers. These have well-established immunological causes and therapies. Far less is known about the somatic and autonomic "small fibers"; the unmyelinated C-fibers, thinly myelinated A-deltas, and postganglionic sympathetics. The small fibers sense pain and itch, innervate internal organs and tissues, and modulate the inflammatory and immune responses. Symptoms of small-fiber neuropathy include chronic pain and itch, sensory impairment, edema, and skin color, temperature, and sweating changes. Small-fiber polyneuropathy (SFPN) also causes cardiovascular, gastrointestinal, and urological symptoms, the neurologic origin of which often remains unrecognized. Routine electrodiagnostic study does not detect SFPN, so skin biopsies immunolabeled to reveal axons are recommended for diagnostic confirmation. Preliminary evidence suggests that dysimmunity causes some cases of small-fiber neuropathy. Several autoimmune diseases, including Sjögren and celiac, are associated with painful small-fiber ganglionopathy and distal axonopathy, and some patients with "idiopathic" SFPN have evidence of organ-specific dysimmunity, including serological markers. Dysimmune SFPN first came into focus in children and teenagers as they lack other risk factors, for example diabetes or toxic exposures. In them, the rudimentary evidence suggests humoral rather than cellular mechanisms and complement consumption. Preliminary evidence supports efficacy of corticosteroids and immunoglobulins in carefully selected children and adult patients. This paper reviews the evidence of immune causality and the limited data regarding immunotherapy for small-fiber-predominant ganglionitis, regional neuropathy (complex regional pain syndrome), and distal SFPN. These demonstrate the need to develop case definitions and outcome metrics to improve diagnosis, enable prospective trials, and dissect the mechanisms of

  9. Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies.

    PubMed

    Oaklander, Anne Louise

    2016-01-01

    The best-known peripheral neuropathies are those affecting the large, myelinated motor and sensory fibers. These have well-established immunological causes and therapies. Far less is known about the somatic and autonomic "small fibers"; the unmyelinated C-fibers, thinly myelinated A-deltas, and postganglionic sympathetics. The small fibers sense pain and itch, innervate internal organs and tissues, and modulate the inflammatory and immune responses. Symptoms of small-fiber neuropathy include chronic pain and itch, sensory impairment, edema, and skin color, temperature, and sweating changes. Small-fiber polyneuropathy (SFPN) also causes cardiovascular, gastrointestinal, and urological symptoms, the neurologic origin of which often remains unrecognized. Routine electrodiagnostic study does not detect SFPN, so skin biopsies immunolabeled to reveal axons are recommended for diagnostic confirmation. Preliminary evidence suggests that dysimmunity causes some cases of small-fiber neuropathy. Several autoimmune diseases, including Sjögren and celiac, are associated with painful small-fiber ganglionopathy and distal axonopathy, and some patients with "idiopathic" SFPN have evidence of organ-specific dysimmunity, including serological markers. Dysimmune SFPN first came into focus in children and teenagers as they lack other risk factors, for example diabetes or toxic exposures. In them, the rudimentary evidence suggests humoral rather than cellular mechanisms and complement consumption. Preliminary evidence supports efficacy of corticosteroids and immunoglobulins in carefully selected children and adult patients. This paper reviews the evidence of immune causality and the limited data regarding immunotherapy for small-fiber-predominant ganglionitis, regional neuropathy (complex regional pain syndrome), and distal SFPN. These demonstrate the need to develop case definitions and outcome metrics to improve diagnosis, enable prospective trials, and dissect the mechanisms of

  10. An update on the causes, assessment and management of third division sensory trigeminal neuropathies.

    PubMed

    Carter, E; Yilmaz, Z; Devine, M; Renton, T

    2016-06-24

    Introduction Sensory neuropathies of the mandibular division of the trigeminal (V3) nerve can be debilitating, causing difficulty with daily function. It has a variety of causes, including iatrogenic injury, usually caused by third molar removal, local anaesthetic administration, implant placement or endodontic treatment. Non-iatrogenic causes include infection, primary or secondary neoplasia and various medical conditions.Objective To review the aetiology, evaluation and management of V3 neuropathy in a retrospective case-series of patients referred to a specialist nerve injury clinic over an eight-year period, particularly focusing on the non-iatrogenic causes of this presentation.Methods A retrospective analysis of the case notes of 372 patients referred to the specialist nerve injury clinic between 2006 and 2014 was carried out to establish the cause of the neuropathy and subsequent management or referral. The assessment protocol of trigeminal neuropathy used in the clinic is also outlined.Results Most patients (89.5%) presented with neuropathy due to iatrogenic injury. Of the non-iatrogenic causes (10.5%), malignancy accounted for a fifth of presentations, and infection almost two-fifths, demonstrating the importance of prompt identification of a cause and management by the clinician, or referral to the appropriate specialty. Other, more rare causes are also presented, including multiple sclerosis, sickle-cell anaemia and Paget's disease, highlighting the importance to the clinician of considering differential diagnoses.Conclusions This case series demonstrates the less frequent, but nevertheless important, non-iatrogenic causes which clinicians should consider when assessing patients with trigeminal neuropathy. PMID:27338902

  11. Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy.

    PubMed

    Yang, Shuo; Ma, Si-Qi; Wan, Xing; He, Heng; Pei, Han; Zhao, Min-Jian; Chen, Chen; Wang, Dao-Wen; Dong, Xiao-Yan; Yuan, Jia-Jia; Li, Bin

    2016-08-01

    Leber's hereditary optic neuropathy (LHON) is a disease that leads to blindness. Gene therapy has been investigated with some success, and could lead to important advancements in treating LHON. This was a prospective, open-label trial involving 9 LHON patients at Tongji Hospital, Wuhan, China, from August 2011 to December 2015. The purpose of this study was to evaluate the long-term outcomes of gene therapy for LHON. Nine LHON patients voluntarily received an intravitreal injection of rAAV2-ND4. Systemic examinations and visual function tests were performed during the 36-month follow-up period to determine the safety and efficacy of this gene therapy. Based on successful experiments in an animal model of LHON, 1 subject also received an rAAV2-ND4 injection in the second eye 12months after gene therapy was administered in the first eye. Recovery of visual acuity was defined as the primary outcome of this study. Changes in the visual field, visual evoked potential (VEP), optical coherence tomography findings, liver and kidney function, and antibodies against AAV2 were defined as secondary endpoints. Eight patients (Patients 2-9) received unilateral gene therapy and visual function improvement was observed in both treated eyes (Patients 4, 6, 7, and 8) and untreated eyes (Patients 2, 3, 4, 6 and 8). Visual regression fluctuations, defined as changes in visual acuity greater than or equal to 0.3 logMAR, were observed in Patients 2 and 9. Age at disease onset, disease duration, and the amount of remaining optic nerve fibers did not have a significant effect on the visual function improvement. The visual field and pattern reversal VEP also improved. The patient (Patient 1) who received gene therapy in both eyes had improved visual acuity in the injected eye after the first treatment. Unfortunately, visual acuity in this eye decreased 3months after he received gene therapy in the second eye. Animal experiments suggested that ND4 expression remains stable in the

  12. A retrospective analysis of characteristics of visual field damage in patients with Leber's hereditary optic neuropathy.

    PubMed

    Ran, Ruijin; Yang, Shuo; He, Heng; Ma, Shiqi; Chen, Zhiqi; Li, Bin

    2016-01-01

    The objective of this study is to investigate the characteristics and the evolution of visual field damage caused by Leber's hereditary optic neuropathy (LHON) and to provide clinical data for the diagnosis of LHON. Parameters of visual field in 32 consecutive patients (49 eyes) with LHON who were confirmed by genetic diagnostic tests were retrospectively measured within 1 week, between three to six months, and at six months after onset. Visual field defects revealed central scotoma in 26 eyes (53.1 %), paracentral scotoma in 12 eyes (24.5 %), ceco-central defects in 6 eyes (12.2 %), blind spot enlargenment in 3 eyes (6.1 %), quadrantanopia in 2 eyes (4.1 %) within 1 week after onset. After 3 to 6 months, ceco-central defects were detected in 22 eyes (44.9 %), central isopter constriction in 10 eyes (20.4 %), hemianopia or quadrantanopia in 5 eyes (10.2 %), central scotoma in 4 eyes (8.2 %), and paracentral scotoma in 1 eye (2.0 %). After 6 months, central isopter constriction was observed in 18 eyes (36.7 %), diffuse defects in 21 eyes (42.9 %), ceco-central defects in 3 eyes (6.1 %), hemianopia or quadrantanopia in 5 eyes (10.2 %), and central scotoma in 2 eyes (4.1 %). LHON at different stages was characterized by different focal visual field defects: visual field defects in LHON patients within 1 week after onset were mostly central or paracentral scotoma, which was enlarged around the ceco-central defect, or connected to form a blind spot after 3-6 months. Diffuse and central isopter constriction defects were usually developed after 6 months. Damages firstly appeared in papillomacular bundle and gradually expanded outward. These characteristics of visual field defects reported in this study might provide a clinical basis for better diagnosis of LHON.

  13. The debut of a rational treatment for an inherited neuropathy?

    PubMed Central

    Scherer, Steven S.

    2011-01-01

    Hereditary neuropathies are common neurological conditions characterized by progressive loss of motor and/or sensory function. There are no effective treatments. Among the many causes of hereditary neuropathies are dominant mutations in serine palmitoyltransferase, long chain base subunit 1 (SPTLC1), which cause hereditary sensory and autonomic neuropathy type 1 (HSAN1). By incorporating l-alanine in place of l-serine, the mutant HSAN1–associated serine palmitoyltransferase generates deoxysphingolipids, which are thought to be neurotoxic. In this issue of the JCI, Garofalo and colleagues report that oral l-serine reverses the accumulation of deoxysphingolipids in humans with HSAN1 and in a transgenic mouse model. As oral l-serine reduces the severity of neuropathy in the mouse model of HSAN1, these data suggest a rational candidate therapy for this devastating condition. PMID:22045569

  14. The debut of a rational treatment for an inherited neuropathy?

    PubMed

    Scherer, Steven S

    2011-12-01

    Hereditary neuropathies are common neurological conditions characterized by progressive loss of motor and/or sensory function. There are no effective treatments. Among the many causes of hereditary neuropathies are dominant mutations in serine palmitoyltransferase, long chain base subunit 1 (SPTLC1), which cause hereditary sensory and autonomic neuropathy type 1 (HSAN1). By incorporating L-alanine in place of L-serine, the mutant HSAN1–associated serine palmitoyltransferase generates deoxysphingolipids, which are thought to be neurotoxic. In this issue of the JCI, Garofalo and colleagues report that oral L-serine reverses the accumulation of deoxysphingolipids in humans with HSAN1 and in a transgenic mouse model. As oral L-serine reduces the severity of neuropathy in the mouse model of HSAN1, these data suggest a rational candidate therapy for this devastating condition. PMID:22045569

  15. The relationship of nerve fibre pathology to sensory function in entrapment neuropathy.

    PubMed

    Schmid, Annina B; Bland, Jeremy D P; Bhat, Manzoor A; Bennett, David L H

    2014-12-01

    Surprisingly little is known about the impact of entrapment neuropathy on target innervation and the relationship of nerve fibre pathology to sensory symptoms and signs. Carpal tunnel syndrome is the most common entrapment neuropathy; the aim of this study was to investigate its effect on the morphology of small unmyelinated as well as myelinated sensory axons and relate such changes to somatosensory function and clinical symptoms. Thirty patients with a clinical and electrophysiological diagnosis of carpal tunnel syndrome [17 females, mean age (standard deviation) 56.4 (15.3)] and 26 age and gender matched healthy volunteers [18 females, mean age (standard deviation) 51.0 (17.3)] participated in the study. Small and large fibre function was examined with quantitative sensory testing in the median nerve territory of the hand. Vibration and mechanical detection thresholds were significantly elevated in patients with carpal tunnel syndrome (P<0.007) confirming large fibre dysfunction and patients also presented with increased thermal detection thresholds (P<0.0001) indicative of C and Aδ-fibre dysfunction. Mechanical and thermal pain thresholds were comparable between groups (P>0.13). A skin biopsy was taken from a median nerve innervated area of the proximal phalanx of the index finger. Immunohistochemical staining for protein gene product 9.5 and myelin basic protein was used to evaluate morphological features of unmyelinated and myelinated axons. Evaluation of intraepidermal nerve fibre density showed a striking loss in patients (P<0.0001) confirming a significant compromise of small fibres. The extent of Meissner corpuscles and dermal nerve bundles were comparable between groups (P>0.07). However, patients displayed a significant increase in the percentage of elongated nodes (P<0.0001), with altered architecture of voltage-gated sodium channel distribution. Whereas neither neurophysiology nor quantitative sensory testing correlated with patients' symptoms or

  16. The relationship of nerve fibre pathology to sensory function in entrapment neuropathy

    PubMed Central

    Schmid, Annina B.; Bland, Jeremy D. P.; Bhat, Manzoor A.

    2014-01-01

    Surprisingly little is known about the impact of entrapment neuropathy on target innervation and the relationship of nerve fibre pathology to sensory symptoms and signs. Carpal tunnel syndrome is the most common entrapment neuropathy; the aim of this study was to investigate its effect on the morphology of small unmyelinated as well as myelinated sensory axons and relate such changes to somatosensory function and clinical symptoms. Thirty patients with a clinical and electrophysiological diagnosis of carpal tunnel syndrome [17 females, mean age (standard deviation) 56.4 (15.3)] and 26 age and gender matched healthy volunteers [18 females, mean age (standard deviation) 51.0 (17.3)] participated in the study. Small and large fibre function was examined with quantitative sensory testing in the median nerve territory of the hand. Vibration and mechanical detection thresholds were significantly elevated in patients with carpal tunnel syndrome (P < 0.007) confirming large fibre dysfunction and patients also presented with increased thermal detection thresholds (P < 0.0001) indicative of C and Aδ-fibre dysfunction. Mechanical and thermal pain thresholds were comparable between groups (P > 0.13). A skin biopsy was taken from a median nerve innervated area of the proximal phalanx of the index finger. Immunohistochemical staining for protein gene product 9.5 and myelin basic protein was used to evaluate morphological features of unmyelinated and myelinated axons. Evaluation of intraepidermal nerve fibre density showed a striking loss in patients (P < 0.0001) confirming a significant compromise of small fibres. The extent of Meissner corpuscles and dermal nerve bundles were comparable between groups (P > 0.07). However, patients displayed a significant increase in the percentage of elongated nodes (P < 0.0001), with altered architecture of voltage-gated sodium channel distribution. Whereas neither neurophysiology nor quantitative sensory testing correlated with patients

  17. The relationship of nerve fibre pathology to sensory function in entrapment neuropathy.

    PubMed

    Schmid, Annina B; Bland, Jeremy D P; Bhat, Manzoor A; Bennett, David L H

    2014-12-01

    Surprisingly little is known about the impact of entrapment neuropathy on target innervation and the relationship of nerve fibre pathology to sensory symptoms and signs. Carpal tunnel syndrome is the most common entrapment neuropathy; the aim of this study was to investigate its effect on the morphology of small unmyelinated as well as myelinated sensory axons and relate such changes to somatosensory function and clinical symptoms. Thirty patients with a clinical and electrophysiological diagnosis of carpal tunnel syndrome [17 females, mean age (standard deviation) 56.4 (15.3)] and 26 age and gender matched healthy volunteers [18 females, mean age (standard deviation) 51.0 (17.3)] participated in the study. Small and large fibre function was examined with quantitative sensory testing in the median nerve territory of the hand. Vibration and mechanical detection thresholds were significantly elevated in patients with carpal tunnel syndrome (P<0.007) confirming large fibre dysfunction and patients also presented with increased thermal detection thresholds (P<0.0001) indicative of C and Aδ-fibre dysfunction. Mechanical and thermal pain thresholds were comparable between groups (P>0.13). A skin biopsy was taken from a median nerve innervated area of the proximal phalanx of the index finger. Immunohistochemical staining for protein gene product 9.5 and myelin basic protein was used to evaluate morphological features of unmyelinated and myelinated axons. Evaluation of intraepidermal nerve fibre density showed a striking loss in patients (P<0.0001) confirming a significant compromise of small fibres. The extent of Meissner corpuscles and dermal nerve bundles were comparable between groups (P>0.07). However, patients displayed a significant increase in the percentage of elongated nodes (P<0.0001), with altered architecture of voltage-gated sodium channel distribution. Whereas neither neurophysiology nor quantitative sensory testing correlated with patients' symptoms or

  18. [Optic nerve swelling and gadolinium contrast enhancement on magnetic resonance imaging in the subacute stage of Leber's hereditary optic neuropathy: a case report].

    PubMed

    Furuki, Misako; Ohkubo, Takuya; Ota, Kiyobumi; Ishikawa, Kinya; Yokota, Takanori; Mizusawa, Hidehiro

    2012-01-01

    We report the case of a 50-year-old man with subacute onset of bilateral visual field loss and visual acuity loss. His visual acuity was 0.07 OD/0.09 OS and Goldmann perimetry showed central scotomas. The optic fundi were normal bilaterally. Magnetic resonance imaging (MRI) showed hyperintensity in the right optic nerve on T(2) weighted imaging and swelling of the optic chiasm with slight enhancement of the bilateral optic nerves and the optic chiasm on gadolinium-enhanced imaging. Since sensory disturbance in the left hand and leg was noted in addition to the visual problem, multiple sclerosis (MS) was suspected initially. The patient was treated with intravenous methylprednisolone (1,000 mg/day), plasma exchange therapy, and immunosuppressant therapy. However, his visual disturbance did not improve. He had a history of deafness and family history of visual disturbance, because of which we performed an analysis of mitochondrial DNA. G11778A point mutation was found, and a diagnosis of Leber's hereditary optic neuropathy (LHON) was made. Although gadolinium contrast enhancement and swelling of the optic nerve are rare, this case shows that these findings are not in conflict with LHON. The present case also suggests that mitochondrial dysfunction may trigger the onset of MS-like extraocular symptoms in patients with LHON.

  19. The modified ultrasound pattern sum score mUPSS as additional diagnostic tool for genetically distinct hereditary neuropathies.

    PubMed

    Grimm, Alexander; Rasenack, Maria; Athanasopoulou, Ioanna M; Dammeier, Nele Maria; Lipski, Christina; Wolking, Stefan; Vittore, Debora; Décard, Bernhard F; Axer, Hubertus

    2016-02-01

    The objective of this study is to evaluate the nerve ultrasound characteristics in genetically distinct inherited neuropathies, the value of the modified ultrasound pattern sum score (mUPSS) to differentiate between the subtypes and the correlation of ultrasound with nerve conduction studies (NCS), disease duration and severity. All patients underwent a standardized neurological examination, ultrasound, and NCS. In addition, genetic testing was performed. Consequently, mUPSS was applied, which is a sum-score of cross-sectional areas (CSA) at predefined anatomical points in different nerves. 31 patients were included (10xCharcot-Marie-Tooth (CMT)1a, 3xCMT1b, 3xCMTX, 9xCMT2, 6xHNPP [Hereditary neuropathy with liability to pressure palsies]). Generalized, homogeneous nerve enlargement and significantly increased UPS scores emphasized the diagnosis of demyelinating neuropathy, particularly CMT1a and CMT1b. The amount of enlargement did not depend on disease duration, symptom severity, height and weight. In CMTX the nerves were enlarged, as well, however, only in the roots and lower limbs, most prominent in men. In CMT2 no significant enlargement was detectable. In HNPP the CSA values were increased at entrapped sites, and not elsewhere. However, a distinction from CMT1, which also showed enlarged CSA values at entrapment sites, was only possible by calculating the entrapment ratios and entrapment score. The mUPSS allowed distinction between CMT1a (increased UPS scores, entrapment ratios <1.0) and HNPP (low UPS scores, entrapment ratios >1.4), while CMT1b and CMTX showed intermediate UPS types and entrapment ratios <1.0. Although based on few cases, ultrasound revealed consistent and homogeneous nerve alteration in certain inherited neuropathies. The modified UPSS is a quantitative tool, which may provide useful information for diagnosis, differentiation and follow-up evaluation in addition to NCS and molecular testing.

  20. Medical marijuana for HIV-associated sensory neuropathy: legal and ethical issues.

    PubMed

    Larriviere, Daniel G

    2014-10-01

    The number of states legalizing medical marijuana is increasing. Medical marijuana is possibly effective therapy for HIV-associated sensory neuropathy. Despite legalization at the state level, however, the current and contradictory federal drug enforcement policy creates the risk that physicians who recommend medical marijuana to their patients will lose their ability to prescribe medications. The federal-state tension has legal and ethical implications for neurologists who receive a request for medical marijuana from their patients since neurologists must strive to both relieve suffering and obey relevant laws. Recommendation of medical marijuana by neurologists to their patients is ethically permissible but is not ethically mandatory.

  1. A novel RAB7 mutation associated with ulcero-mutilating neuropathy.

    PubMed

    Houlden, Henry; King, Rosalind H M; Muddle, John R; Warner, Thomas T; Reilly, Mary M; Orrell, Richard W; Ginsberg, Lionel

    2004-10-01

    There are two known autosomal dominant genes for the hereditary ulcero-mutilating neuropathies: SPTLC1 (hereditary sensory neuropathy type 1) and RAB7 (Charcot-Marie-Tooth disease type 2B). We report a family with autosomal dominant ulcero-mutilating neuropathy, developing in the teens and characterized by ulcers, amputations, sensory involvement in the feet but no motor features. Sequencing the RAB7 gene showed a novel heterozygous A to C mutation, changing asparagine to threonine at codon 161. The mutation is situated adjacent to a previously identified valine to methionine mutation at codon 162, implying a hotspot for mutations in the highly conserved C terminus of RAB7. PMID:15455439

  2. Features of mtDNA mutation patterns in European pedigrees and sporadic cases with leber hereditary optic neuropathy

    SciTech Connect

    Obermaier-Kusser, B.; Schubring, S.; Paprotta, A.; Meitinger, T.; Jaksch, M.; Gerbitz, K.D.; Lorenz, B.; Zerres, K.; Meire, F.; Cochaux, P.

    1994-11-01

    Leber hereditary optic neuropathy (LHON) is maternally transmitted and is characterized by bilateral loss of central vision in young adults as a result of optic nerve degeneration. Fifteen transition mutations located in different genes for the mitochondrially encoded subunits of respiratory chain complexes have been associated thus far with the disease. Genetic studies have led to the classification of the pathogenic significance of these different mutations. However, more research is required to determine the causality of the mutations and the penetrance of the disease. The present study compares studies of populations of different ethnic origins, namely European LHON pedigrees and sporadic cases, in order to elucidate the pathogenic mechanisms involved. 21 refs., 2 figs., 1 tab.

  3. Gene therapy for mitochondrial diseases: Leber Hereditary Optic Neuropathy as the first candidate for a clinical trial.

    PubMed

    Cwerman-Thibault, Hélène; Augustin, Sébastien; Ellouze, Sami; Sahel, José-Alain; Corral-Debrinski, Marisol

    2014-03-01

    Mitochondrial disorders cannot be ignored anymore in most medical disciplines; indeed their minimum estimated prevalence is superior to 1 in 5000 births. Despite the progress made in the last 25 years on the identification of gene mutations causing mitochondrial pathologies, only slow progress was made towards their effective treatments. Ocular involvement is a frequent feature in mitochondrial diseases and corresponds to severe and irreversible visual handicap due to retinal neuron loss and optic atrophy. Interestingly, three clinical trials for Leber Congenital Amaurosis due to RPE65 mutations are ongoing since 2007. Overall, the feasibility and safety of ocular Adeno-Associated Virus delivery in adult and younger patients and consistent visual function improvements have been demonstrated. The success of gene-replacement therapy for RPE65 opens the way for the development of similar approaches for a broad range of eye disorders, including those with mitochondrial etiology such as Leber Hereditary Optic Neuropathy (LHON).

  4. Evidence for Detrimental Cross Interactions between Reactive Oxygen and Nitrogen Species in Leber's Hereditary Optic Neuropathy Cells

    PubMed Central

    Santini, Paolo

    2016-01-01

    Here we have collected evidence suggesting that chronic changes in the NO homeostasis and the rise of reactive oxygen species bioavailability can contribute to cell dysfunction in Leber's hereditary optic neuropathy (LHON) patients. We report that peripheral blood mononuclear cells (PBMCs), derived from a female LHON patient with bilateral reduced vision and carrying the pathogenic mutation 11778/ND4, display increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS), as revealed by flow cytometry, fluorometric measurements of nitrite/nitrate, and 3-nitrotyrosine immunodetection. Moreover, viability assays with the tetrazolium dye MTT showed that lymphoblasts from the same patient are more sensitive to prolonged NO exposure, leading to cell death. Taken together these findings suggest that oxidative and nitrosative stress cooperatively play an important role in driving LHON pathology when excess NO remains available over time in the cell environment. PMID:26881022

  5. Previously Unclassified Mutation of mtDNA m.3472T>C: Evidence of Pathogenicity in Leber's Hereditary Optic Neuropathy.

    PubMed

    Sheremet, N L; Nevinitsyna, T A; Zhorzholadze, N V; Ronzina, I A; Itkis, Y S; Krylova, T D; Tsygankova, P G; Malakhova, V A; Zakharova, E Y; Tokarchuk, A V; Panteleeva, A A; Karger, E M; Lyamzaev, K G; Avetisov, S E

    2016-07-01

    Leber's hereditary optic neuropathy (LHON) refers to a group of mitochondrial diseases and is characterized by defects of the mitochondrial electron transport chain and decreased level of oxidative phosphorylation. The list of LHON primary mtDNA mutations is regularly updated. In this study, we describe the homoplasmic nucleotide substitution m.3472T>C in the MT-ND1 (NADH-ubiquinone oxidoreductase chain 1) gene and specific changes in cell metabolism in a patient with LHON and his asymptomatic sister. To confirm the presence of mutation-related mitochondrial dysfunction, respiration of skin fibroblasts and platelets from the patient and his sister was studied, as well as the mitochondrial potential and production of reactive oxygen species in the skin fibroblasts. In addition, based on characteristics of the toxic effect of paraquat, a new approach was developed for detecting the functional activity of complex I of the mitochondrial respiratory chain.

  6. Evidence for Detrimental Cross Interactions between Reactive Oxygen and Nitrogen Species in Leber's Hereditary Optic Neuropathy Cells.

    PubMed

    Falabella, Micol; Forte, Elena; Magnifico, Maria Chiara; Santini, Paolo; Arese, Marzia; Giuffrè, Alessandro; Radić, Kristina; Chessa, Luciana; Coarelli, Giulia; Buscarinu, Maria Chiara; Mechelli, Rosella; Salvetti, Marco; Sarti, Paolo

    2016-01-01

    Here we have collected evidence suggesting that chronic changes in the NO homeostasis and the rise of reactive oxygen species bioavailability can contribute to cell dysfunction in Leber's hereditary optic neuropathy (LHON) patients. We report that peripheral blood mononuclear cells (PBMCs), derived from a female LHON patient with bilateral reduced vision and carrying the pathogenic mutation 11778/ND4, display increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS), as revealed by flow cytometry, fluorometric measurements of nitrite/nitrate, and 3-nitrotyrosine immunodetection. Moreover, viability assays with the tetrazolium dye MTT showed that lymphoblasts from the same patient are more sensitive to prolonged NO exposure, leading to cell death. Taken together these findings suggest that oxidative and nitrosative stress cooperatively play an important role in driving LHON pathology when excess NO remains available over time in the cell environment.

  7. A prototype haptic feedback system for lower-limb prostheses and sensory neuropathy.

    PubMed

    Fan, Richard E; Culjat, Martin O; King, Chih-Hung; Franco, Miguel L; Sedrak, Mark; Bisley, James W; Dutson, Erik P; Grundfest, Warren S

    2008-01-01

    Lower-limb sensory loss as a result of peripheral neuropathy or amputation results in sub-optimal movement and an increased incidence of injury. While the adoption of lower-limb prostheses and therapeutic footwear can reduce tissue injury and support movement, the fundamental problem of sensory loss continues to exist. A prototype haptic feedback system has been developed to aid in the recovery of lower-limb sensation due to these causes. Thin-film force sensors placed at the critical points for gait and balance functions collect essential force data, which is delivered to the user via pneumatically controlled balloon inflation. It is postulated that the use of this system will increase the tactile awareness of a patient's lower-limb or prosthesis, and when used in concert with modern rehabilitation techniques will create a method that will reduce the duration and improve the quality of lower-limb rehabilitation, especially in gait and balance functions.

  8. Amplitude of sensory nerve action potential in early stage diabetic peripheral neuropathy: an analysis of 500 cases.

    PubMed

    Zhang, Yunqian; Li, Jintao; Wang, Tingjuan; Wang, Jianlin

    2014-07-15

    Early diagnosis of diabetic peripheral neuropathy is important for the successful treatment of diabetes mellitus. In the present study, we recruited 500 diabetic patients from the Fourth Affiliated Hospital of Kunming Medical University in China from June 2008 to September 2013: 221 cases showed symptoms of peripheral neuropathy (symptomatic group) and 279 cases had no symptoms of peripheral impairment (asymptomatic group). One hundred healthy control subjects were also recruited. Nerve conduction studies revealed that distal motor latency was longer, sensory nerve conduction velocity was slower, and sensory nerve action potential and amplitude of compound muscle action potential were significantly lower in the median, ulnar, posterior tibial and common peroneal nerve in the diabetic groups compared with control subjects. Moreover, the alterations were more obvious in patients with symptoms of peripheral neuropathy. Of the 500 diabetic patients, neural conduction abnormalities were detected in 358 cases (71.6%), among which impairment of the common peroneal nerve was most prominent. Sensory nerve abnormality was more obvious than motor nerve abnormality in the diabetic groups. The amplitude of sensory nerve action potential was the most sensitive measure of peripheral neuropathy. Our results reveal that varying degrees of nerve conduction changes are present in the early, asymptomatic stage of diabetic peripheral neuropathy.

  9. [The mitochondrial ND5 T12338C mutation may be associated with Leber's hereditary optic neuropathy in two Chinese families].

    PubMed

    Ji, Yan-Chun; Liu, Xiao-Ling; Zhao, Fu-Xin; Zhang, Juan-Juan; Zhang, Yu; Zhou, Xiang-Tian; Qu, Jia; Guan, Min-Xin

    2011-04-01

    Leber's hereditary optic neuropathy (LHON) associated with mitochondrial DNA mutation is a maternally inherited eye disease. We reported here the clinical, genetic and molecular characterization of two Han Chinese families with Leber's hereditary optic neuropathy. Ophthalmologic examinations revealed that the variable severity and age-of-onset in visual impairment among probands and other matrilineal relatives of these families. Strikingly, there were extremely low penetrances of visual impairment in these families. Sequence analysis of complete mitochondrial genomes in these pedigrees identified the homoplasmic ND4 G11696A and ND5 T12338C mutation and distinct sets of polymorphism belonging to haplogroups F2. It is well known that mitochondrial DNA ND4 G11696A is associated with LHON. The ND5 T12338C mutation resulted in replacement of the first amino acid, translation-initiating methionine with a threonine, and shortening two amino acids of ND5. This mutation also locates in two nucleotides adjacent to the 3' end of the tRNALeu(Cun). Thus, this mutation may alter structural formation and stabilization of functional tRNA, thereby leading to a failure in protein synthesis and mitochondrial dysfunction involved in visual impairment. Therefore, the ND4 G11696A and ND5 T12338C mutation is likely associated with LHON in these two Chinese families. But these families exhibited extremely low penetrances of visual impairment. It suggests that other factors, such as nuclear modifier gene(s) or environmental factor(s), may play a role in the phenotypic expression of the LHON-associated ND4 G11696A and ND5 T12338C mutation.

  10. Subacute autonomic and sensory neuropathy closely related to cytomegalovirus infection preceded by frequent syncopal attacks.

    PubMed

    Nakao, Koichi; Namekawa, Michito; Kondo, Soichi; Ono, Sayaka; Nakano, Imaharu

    2016-08-31

    A 73-year-old woman who had hypertension developed a slight fever and general malaise with laboratory-proven hepatic dysfunction as well as frequent syncopal attacks 3 months before admission to our hospital. One month later, she developed urinary retention and distal limb numbness. Upon admission, her neurological examination showed reduced limb tendon reflexes, glove and stocking-type numbness, and diminished senses of touch, temperature, pain, and distal leg vibration and position. Serum cytomegalovirus (CMV) IgM antibody and CMV IgG antibody were elevated on admission, and both decreased thereafter, confirming CMV infection. No serum anti-ganglioside antibody was detected. Cerebrospinal fluid revealed a mild pleocytosis and elevated proteins. Compound muscle action potential (CMAP) amplitudes of the tibial and peroneal nerve were slightly reduced. Sensory nerve action potential (SNAP) amplitudes of the median and ulnar nerves were reduced, and sural SNAP was not evoked. Systolic blood pressure dropped 48 mmHg when the patient assumed a standing position from a supine one, demonstrating orthostatic hypotension, and a cold pressor test was abnormal, both indicating an obvious hypofunction of the sympathetic nerve. The postganglionic autonomic nerve appeared to be damaged because the accumulation of [(123)I] meta-iodobenzylguanidine was reduced on myocardial scintigraphy. These findings combined together led us to make a diagnosis of subacute autonomic and sensory neuropathy associated with CMV infection in this case. Following an eventless administration of oral fludrocortisones, intravenous immuno-globulin (IVIg) was given after one month of the hospitalization with a remarkable reduction of the syncope. This case is instructive in two points. One is that there may be a couple of months with syncope alone before the sensory disturbance appearance, and the other is that IVIg may be considerably effective for the patient-annoying syncopes. To our knowledge, this

  11. Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy.

    PubMed

    Lupo, Vincenzo; García-García, Francisco; Sancho, Paula; Tello, Cristina; García-Romero, Mar; Villarreal, Liliana; Alberti, Antonia; Sivera, Rafael; Dopazo, Joaquín; Pascual-Pascual, Samuel I; Márquez-Infante, Celedonio; Casasnovas, Carlos; Sevilla, Teresa; Espinós, Carmen

    2016-03-01

    Charcot-Marie-Tooth disease is characterized by broad genetic heterogeneity with >50 known disease-associated genes. Mutations in some of these genes can cause a pure motor form of hereditary motor neuropathy, the genetics of which are poorly characterized. We designed a panel comprising 56 genes associated with Charcot-Marie-Tooth disease/hereditary motor neuropathy. We validated this diagnostic tool by first testing 11 patients with pathological mutations. A cohort of 33 affected subjects was selected for this study. The DNAJB2 c.352+1G>A mutation was detected in two cases; novel changes and/or variants with low frequency (<1%) were found in 12 cases. There were no candidate variants in 18 cases, and amplification failed for one sample. The DNAJB2 c.352+1G>A mutation was also detected in three additional families. On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJB2 c.352+1G>A mutation may be a founder event. Our gene panel allowed us to perform a very rapid and cost-effective screening of genes involved in Charcot-Marie-Tooth disease/hereditary motor neuropathy. Our diagnostic strategy was robust in terms of both coverage and read depth for all of the genes and patient samples. These findings demonstrate the difficulty in achieving a definitive molecular diagnosis because of the complexity of interpreting new variants and the genetic heterogeneity that is associated with these neuropathies.

  12. Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjögren's syndrome.

    PubMed

    Griffin, J W; Cornblath, D R; Alexander, E; Campbell, J; Low, P A; Bird, S; Feldman, E L

    1990-03-01

    Thirteen patients, 11 women and 2 men, developed sensory and autonomic neuronopathies in association with features of primary Sjögren's syndrome. In 11, Sjögren's syndrome had not been previously diagnosed at the time of neurological presentation. All had prominent loss of kinesthesia and proprioception. Pain and thermal sensibility were less severely affected. Most had evidence of autonomic insufficiency. In some this was severe, with Adie's pupils, fixed tachycardia, and orthostatic hypotension. The course ranged from an abrupt, devastating onset to indolent progression over years. Stabilization or functional improvement occurred in 6 patients, 2 of whom received no drug therapy. Sensory nerve conduction studies and examination of nerve biopsy specimens demonstrated a wide spectrum in the severity of loss of large myelinated fibers. The cutaneous nerves of 6 patients had perivascular mononuclear infiltrates without necrotizing arteritis. Examination of biopsy specimens of dorsal root ganglia in 3 patients revealed lymphocytic (T-cell) infiltration in the dorsal roots and ganglia, with focal clusters around neurons. In the more mildly affected ganglia, individual sensory neurons were undergoing degeneration. In the most advanced case, very few neurons remained. The possibility of Sjögren's syndrome should be considered in patients, especially women, who develop acute, subacute, or chronic sensory and autonomic neuropathies, with ataxia and kinesthetic loss.

  13. The influence of diabetic peripheral neuropathy on local postural muscle and central sensory feedback balance control.

    PubMed

    Toosizadeh, Nima; Mohler, Jane; Armstrong, David G; Talal, Talal K; Najafi, Bijan

    2015-01-01

    Poor balance control and increased fall risk have been reported in people with diabetic peripheral neuropathy (DPN). Traditional body sway measures are unable to describe underlying postural control mechanism. In the current study, we used stabilogram diffusion analysis to examine the mechanism under which balance is altered in DPN patients under local-control (postural muscle control) and central-control (postural control using sensory cueing). DPN patients and healthy age-matched adults over 55 years performed two 15-second Romberg balance trials. Center of gravity sway was measured using a motion tracker system based on wearable inertial sensors, and used to derive body sway and local/central control balance parameters. Eighteen DPN patients (age = 65.4±7.6 years; BMI = 29.3±5.3 kg/m2) and 18 age-matched healthy controls (age = 69.8±2.9; BMI = 27.0±4.1 kg/m2) with no major mobility disorder were recruited. The rate of sway within local-control was significantly higher in the DPN group by 49% (healthy local-controlslope = 1.23±1.06×10-2 cm2/sec, P<0.01), which suggests a compromised local-control balance behavior in DPN patients. Unlike local-control, the rate of sway within central-control was 60% smaller in the DPN group (healthy central-controlslope-Log = 0.39±0.23, P<0.02), which suggests an adaptation mechanism to reduce the overall body sway in DPN patients. Interestingly, significant negative correlations were observed between central-control rate of sway with neuropathy severity (rPearson = 0.65-085, P<0.05) and the history of diabetes (rPearson = 0.58-071, P<0.05). Results suggest that in the lack of sensory feedback cueing, DPN participants were highly unstable compared to controls. However, as soon as they perceived the magnitude of sway using sensory feedback, they chose a high rigid postural control strategy, probably due to high concerns for fall, which may increase the energy cost during extended period of standing; the adaptation mechanism

  14. The Influence of Diabetic Peripheral Neuropathy on Local Postural Muscle and Central Sensory Feedback Balance Control

    PubMed Central

    2015-01-01

    Poor balance control and increased fall risk have been reported in people with diabetic peripheral neuropathy (DPN). Traditional body sway measures are unable to describe underlying postural control mechanism. In the current study, we used stabilogram diffusion analysis to examine the mechanism under which balance is altered in DPN patients under local-control (postural muscle control) and central-control (postural control using sensory cueing). DPN patients and healthy age-matched adults over 55 years performed two 15-second Romberg balance trials. Center of gravity sway was measured using a motion tracker system based on wearable inertial sensors, and used to derive body sway and local/central control balance parameters. Eighteen DPN patients (age = 65.4±7.6 years; BMI = 29.3±5.3 kg/m2) and 18 age-matched healthy controls (age = 69.8±2.9; BMI = 27.0±4.1 kg/m2) with no major mobility disorder were recruited. The rate of sway within local-control was significantly higher in the DPN group by 49% (healthy local-controlslope = 1.23±1.06×10-2 cm2/sec, P<0.01), which suggests a compromised local-control balance behavior in DPN patients. Unlike local-control, the rate of sway within central-control was 60% smaller in the DPN group (healthy central-controlslope-Log = 0.39±0.23, P<0.02), which suggests an adaptation mechanism to reduce the overall body sway in DPN patients. Interestingly, significant negative correlations were observed between central-control rate of sway with neuropathy severity (rPearson = 0.65-085, P<0.05) and the history of diabetes (rPearson = 0.58-071, P<0.05). Results suggest that in the lack of sensory feedback cueing, DPN participants were highly unstable compared to controls. However, as soon as they perceived the magnitude of sway using sensory feedback, they chose a high rigid postural control strategy, probably due to high concerns for fall, which may increase the energy cost during extended period of standing; the adaptation mechanism

  15. A patient with PMP22-related hereditary neuropathy and DBH-gene-related dysautonomia.

    PubMed

    Bartoletti-Stella, Anna; Chiaro, Giacomo; Calandra-Buonaura, Giovanna; Contin, Manuela; Scaglione, Cesa; Barletta, Giorgio; Cecere, Annagrazia; Garagnani, Paolo; Tieri, Paolo; Ferrarini, Alberto; Piras, Silvia; Franceschi, Claudio; Delledonne, Massimo; Cortelli, Pietro; Capellari, Sabina

    2015-10-01

    Recurrent focal neuropathy with liability to pressure palsies is a relatively frequent autosomal-dominant demyelinating neuropathy linked to peripheral myelin protein 22 (PMP22) gene deletions. The combination of PMP22 gene mutations with other genetic variants is known to cause a more severe phenotype than expected. We present the case of a patient with severe orthostatic hypotension since 12 years of age, who inherited a PMP22 gene deletion from his father. Genetic double trouble was suspected because of selective sympathetic autonomic disturbances. Through exome-sequencing analysis, we identified two novel mutations in the dopamine beta hydroxylase gene. Moreover, with interactome analysis, we excluded a further influence on the origin of the disease by variants in other genes. This case increases the number of unique patients presenting with dopamine-β-hydroxylase deficiency and of cases with genetically proven double trouble. Finding the right, complete diagnosis is crucial to obtain adequate medical care and appropriate genetic counseling. PMID:26410747

  16. [A case or Leber hereditary optic neuropathy (LHON): differential diagnosis with post inflammatory atrophy of nerve II using the mtDNA analysis].

    PubMed

    Lubos, Leszek; Wajgt, Andrzej; Maciejowski, Maciej; Mroczek-Tońska, Katarzyna; Bartnik, Ewa; Dziekanowska, Danuta

    2003-01-01

    The Leber hereditary optic neuropathy (LHON) is a disease due to a mtDNA mutation. The disorder results from enzymatic perturbations in the mitochondrial respiratory chain. Clinically the LHON may present as a progressive axonal atrophy of the optic nerves with or without other neurological symptoms. The process of reaching the diagnosis of the LHON by means of the molecular analysis of mtDNA is discussed.

  17. Diagnosing and treating HIV-associated sensory neuropathy: a global perspective.

    PubMed

    Cherry, Catherine L; Wadley, Antonia L; Kamerman, Peter R

    2016-04-01

    HIV-associated sensory neuropathy (HIV-SN) is a common complication of HIV and remains highly prevalent even with modern HIV management strategies, causing debilitating pain in millions globally. We review HIV-SN diagnosis and management. We suggest most HIV-SN cases are easily recognized using clinical screening tools, with physician assessment and/or specialized testing prioritized for atypical cases. Management aims to prevent further nerve damage and optimize symptom control. Symptom relief is difficult and rarely complete, with a lack of proven pharmacological strategies. Work is needed to clarify optimal use of available medications. This includes understanding the marked placebo effect in HIV-SN analgesic trials and exploring 'responder phenotypes'. Limited data support nondrug strategies including hypnosis, meditation, psychology, physical activity and a positive therapeutic relationship. PMID:26988147

  18. Measurement of Systemic Mitochondrial Function in Advanced Primary Open-Angle Glaucoma and Leber Hereditary Optic Neuropathy.

    PubMed

    Van Bergen, Nicole J; Crowston, Jonathan G; Craig, Jamie E; Burdon, Kathryn P; Kearns, Lisa S; Sharma, Shiwani; Hewitt, Alex W; Mackey, David A; Trounce, Ian A

    2015-01-01

    Primary Open Angle Glaucoma (POAG) is a common neurodegenerative disease characterized by the selective and gradual loss of retinal ganglion cells (RGCs). Aging and increased intraocular pressure (IOP) are glaucoma risk factors; nevertheless patients deteriorate at all levels of IOP, implying other causative factors. Recent evidence presents mitochondrial oxidative phosphorylation (OXPHOS) complex-I impairments in POAG. Leber Hereditary Optic Neuropathy (LHON) patients suffer specific and rapid loss of RGCs, predominantly in young adult males, due to complex-I mutations in the mitochondrial genome. This study directly compares the degree of OXPHOS impairment in POAG and LHON patients, testing the hypothesis that the milder clinical disease in POAG is due to a milder complex-I impairment. To assess overall mitochondrial capacity, cells can be forced to produce ATP primarily from mitochondrial OXPHOS by switching the media carbon source to galactose. Under these conditions POAG lymphoblasts grew 1.47 times slower than controls, whilst LHON lymphoblasts demonstrated a greater degree of growth impairment (2.35 times slower). Complex-I enzyme specific activity was reduced by 18% in POAG lymphoblasts and by 29% in LHON lymphoblasts. We also assessed complex-I ATP synthesis, which was 19% decreased in POAG patients and 17% decreased in LHON patients. This study demonstrates both POAG and LHON lymphoblasts have impaired complex-I, and in the majority of aspects the functional defects in POAG were milder than LHON, which could reflect the milder disease development of POAG. This new evidence places POAG in the spectrum of mitochondrial optic neuropathies and raises the possibility for new therapeutic targets aimed at improving mitochondrial function.

  19. Measurement of Systemic Mitochondrial Function in Advanced Primary Open-Angle Glaucoma and Leber Hereditary Optic Neuropathy

    PubMed Central

    Van Bergen, Nicole J; Crowston, Jonathan G.; Craig, Jamie E.; Burdon, Kathryn P.; Kearns, Lisa S.; Sharma, Shiwani; Hewitt, Alex W.; Mackey, David A.; Trounce, Ian A.

    2015-01-01

    Primary Open Angle Glaucoma (POAG) is a common neurodegenerative disease characterized by the selective and gradual loss of retinal ganglion cells (RGCs). Aging and increased intraocular pressure (IOP) are glaucoma risk factors; nevertheless patients deteriorate at all levels of IOP, implying other causative factors. Recent evidence presents mitochondrial oxidative phosphorylation (OXPHOS) complex-I impairments in POAG. Leber Hereditary Optic Neuropathy (LHON) patients suffer specific and rapid loss of RGCs, predominantly in young adult males, due to complex-I mutations in the mitochondrial genome. This study directly compares the degree of OXPHOS impairment in POAG and LHON patients, testing the hypothesis that the milder clinical disease in POAG is due to a milder complex-I impairment. To assess overall mitochondrial capacity, cells can be forced to produce ATP primarily from mitochondrial OXPHOS by switching the media carbon source to galactose. Under these conditions POAG lymphoblasts grew 1.47 times slower than controls, whilst LHON lymphoblasts demonstrated a greater degree of growth impairment (2.35 times slower). Complex-I enzyme specific activity was reduced by 18% in POAG lymphoblasts and by 29% in LHON lymphoblasts. We also assessed complex-I ATP synthesis, which was 19% decreased in POAG patients and 17% decreased in LHON patients. This study demonstrates both POAG and LHON lymphoblasts have impaired complex-I, and in the majority of aspects the functional defects in POAG were milder than LHON, which could reflect the milder disease development of POAG. This new evidence places POAG in the spectrum of mitochondrial optic neuropathies and raises the possibility for new therapeutic targets aimed at improving mitochondrial function. PMID:26496696

  20. A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology

    SciTech Connect

    Mackey, D. ); Howell, N. )

    1992-12-01

    The Tas2 and Vic2 Australian families are affected with a variant of Leber hereditary optic neuropathy (LHON). The risk of developing the optic neuropathy shows strict maternal inheritance, and the opthalmological changes in affected family members are characteristic of LHON. However, in contrast to the common form of the disease, members of these two families show a high frequency of vision recovery. To ascertain the mitochondrial genetic etiology of the LHON in these families, both (a) the nucleotide sequences of the seven mitochondrial genes encoding subunits of respiratory-chain complex I and (b) the mitochondrial cytochrome b gene were determined for representatives of both families. Neither family carries any of the previously identified primary mitochondrial LHON mutations: ND4/11778, ND1/3460, or ND1/4160. Instead, both LHON families carry multiple nucleotide changes in the mitochondrial complex I genes, which produce conservative amino acid changes. From the available sequence data, it is inferred that the Vic2 and Tas2 LHON families are phylogenetically related to each other and to a cluster of LHON families in which mutations in the mitochondrial cytochrome b gene have been hypothesized to play a primary etiological role. However, sequencing analysis establishes that the Vic2 and Tas2 LHON families do not carry these cytochrome b mutations. There are two hypotheses to account for the unusual mitochondrial genetic etiology of the LHON in the Tas2 and Vic2 LHON families. One possibility is that there is a primary LHON mutation within the mitochondrial genome but that it is at a site that was not included in the sequencing analyses. Alternatively, the disease in these families may result from the cumulative effects of multiple secondary LHON mutations that have less severe phenotypic consequences. 29 refs., 3 figs., 3 tabs.

  1. Laryngeal and phrenic nerve involvement in a patient with hereditary neuropathy with liability to pressure palsies (HNPP).

    PubMed

    Cortese, A; Piccolo, G; Lozza, A; Schreiber, A; Callegari, I; Moglia, A; Alfonsi, E; Pareyson, D

    2016-07-01

    Lower cranial and phrenic nerve involvement is exceptional in hereditary neuropathy with liability to pressure palsies (HNPP). Here we report the occurrence of reversible laryngeal and phrenic nerve involvement in a patient with HNPP. The patient recalled several episodes of reversible weakness and numbness of his feet and hands since the age of 30 years. His medical history was uneventful, apart from chronic obstructive pulmonary disease (COPD). At age 44, following severe weight loss, he presented with progressive dysphonia and hoarseness. EMG of cricoarytenoid and thyroarytenoid muscles and laryngeal fibroscopy confirmed vocal cord paralysis. These speech disturbances gradually regressed. Two years later, he reported rapidly worsening dyspnea. Electroneurography showed increased distal latency of the right phrenic nerve and diaphragm ultrasonography documented reduced right hemi-diaphragm excursion. Six months later and after optimization of CODP treatment, his respiratory function had improved and both phrenic nerve conduction and diaphragm excursion were completely restored. We hypothesize that chronic cough and nerve stretching in the context of CODP, together with severe weight loss, may have triggered the nerve paralysis in this patient. Our report highlights the need for optimal management of comorbidities such as CODP as well as careful control of weight in HNPP patients to avoid potentially harmful complications. PMID:27241821

  2. Correlation between PMP-22 messenger RNA expression and phenotype in hereditary neuropathy with liability to pressure palsies.

    PubMed

    Schenone, A; Nobbio, L; Caponnetto, C; Abbruzzese, M; Mandich, P; Bellone, E; Ajmar, F; Gherardi, G; Windebank, A J; Mancardi, G

    1997-12-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a deletion in chromosome 17p11.2, which includes the gene for the peripheral myelin protein 22 (PMP-22). A "gene dosage" effect is probably the mechanism underlying HNPP, but the amount of PMP-22 mRNA in sural nerves of HNPP patients is highly variable and the role of PMP-22 underexpression in impairing myelination has yet to be clarified. We have studied 6 genetically proven HNPP patients, to evaluate the relationship between PMP-22 mRNA levels, and clinical, neurophysiological, and neuropathological findings. Underexpression of PMP-22 mRNA correlates with disease severity and with mean axon diameter and g ratio, but not with myelin thickness, number of "tomacula," or nerve conduction parameters. Our findings further confirm that underexpression of PMP-22 is the main pathogenetic mechanism underlying the severity of clinical symptoms and signs in HNPP. Smaller axons in sural nerves of HNPP patients with lower PMP-22 levels suggests that underexpression of PMP-22 may also affect axon development.

  3. Leber's hereditary optic neuropathy is associated with the mitochondrial ND4 G11696A mutation in five Chinese families

    SciTech Connect

    Zhou Xiangtian |; Wei Qiping; Yang Li; Tong Yi |; Zhao Fuxin; Lu Chunjie; Qian Yaping; Sun Yanghong; Lu Fan; Qu Jia |. E-mail: jqu@wzmc.net; Guan Minxin ||. E-mail: min-xin.guan@cchmc.org

    2006-02-03

    We report here the clinical, genetic, and molecular characterization of five Chinese families with Leber's hereditary optic neuropathy (LHON). Clinical and genetic evaluations revealed the variable severity and age-of-onset in visual impairment in these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to the identical ND4 G11696A mutation associated with LHON. Indeed, this mutation is present in homoplasmy only in the maternal lineage of those pedigrees but not other members of these families. In fact, the occurrence of the G11696A mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. Furthermore, the N405D in the ND5 and G5820A in the tRNA{sup Cys}, showing high evolutional conservation, may contribute to the phenotypic expression of G11696A mutation in the WZ10 pedigree. However, there was the absence of functionally significant mtDNA mutations in other four Chinese pedigrees carrying the G11696A mutation. Therefore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic expression of the LHON-associated G11696A mutation in these Chinese pedigrees.

  4. Leber's hereditary optic neuropathy is associated with the mitochondrial ND6 T14484C mutation in three Chinese families

    SciTech Connect

    Sun Yanhong; Wei Qiping; Zhou Xiangtian; Qian Yaping; Zhou Jian; Lu Fan; Qu Jia . E-mail: jqu@wzmc.net; Guan Minxin . E-mail: min-xin.guan@cchmc.org

    2006-08-18

    We report here the clinical, genetic, and molecular characterization of three Chinese families with maternally transmitted Leber's hereditary optic neuropathy (LHON). Clinical and genetic evaluations revealed the variable severity and age-of-onset in visual impairment in these families. In the affected matrilineal relatives, the loss of central vision is bilateral, the fellow eye becoming affected either simultaneously (45%) or sequentially (55%). The penetrances of vision loss in these pedigrees were 27%, 50%, and 60%, respectively. The age-at-onset of vision loss in these families was 14, 19, and 24 years, respectively. Furthermore, the ratios between affected male and female matrilineal relatives were 1:1, 1:1.2, and 1:2, respectively. Mutational analysis of mitochondrial DNA revealed the presence of homoplasmic ND6 T14484C mutation, which has been associated with LHON. The incomplete penetrance and phenotypic variability implicate the involvement of nuclear modifier gene(s), environmental factor(s) or mitochondrial haplotype(s) in the phenotypic expression of the LHON-associated T14484C mutation in these Chinese pedigrees.

  5. Haplogroup Effects and Recombination of Mitochondrial DNA: Novel Clues from the Analysis of Leber Hereditary Optic Neuropathy Pedigrees

    PubMed Central

    Carelli, Valerio; Achilli, Alessandro; Valentino, Maria Lucia; Rengo, Chiara; Semino, Ornella; Pala, Maria; Olivieri, Anna; Mattiazzi, Marina; Pallotti, Francesco; Carrara, Franco; Zeviani, Massimo; Leuzzi, Vincenzo; Carducci, Carla; Valle, Giorgio; Simionati, Barbara; Mendieta, Luana; Salomao, Solange; Belfort, Rubens; Sadun, Alfredo A.; Torroni, Antonio

    2006-01-01

    The mitochondrial DNA (mtDNA) of 87 index cases with Leber hereditary optic neuropathy (LHON) sequentially diagnosed in Italy, including an extremely large Brazilian family of Italian maternal ancestry, was evaluated in detail. Only seven pairs and three triplets of identical haplotypes were observed, attesting that the large majority of the LHON mutations were due to independent mutational events. Assignment of the mutational events into haplogroups confirmed that J1 and J2 play a role in LHON expression but narrowed the association to the subclades J1c and J2b, thus suggesting that two specific combinations of amino acid changes in the cytochrome b are the cause of the mtDNA background effect and that this may occur at the level of the supercomplex formed by respiratory-chain complexes I and III. The families with identical haplotypes were genealogically reinvestigated, which led to the reconnection into extended pedigrees of three pairs of families, including the Brazilian family with its Italian counterpart. The sequencing of entire mtDNA samples from the reconnected families confirmed the genealogical reconstruction but showed that the Brazilian family was heteroplasmic at two control-region positions. The survey of the two sites in 12 of the Brazilian subjects revealed triplasmy in most cases, but there was no evidence of the tetraplasmy that would be expected in the case of mtDNA recombination. PMID:16532388

  6. Compression of Root Level in a Patient with Hereditary Neuropathy with Liability to Pressure Palsy Diagnosed by Magnetic Resonance Imaging.

    PubMed

    Park, Donghwi; Ryu, Ju Seok; Kim, Ki-Jeong

    2016-09-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by acute, painless, and recurrent mononeuropathies that are secondary to compression or minor trauma. This case is the first to report an intraspinal compression of the radicular nerve by schwannoma in a patient with HNPP. A 66-year-old woman developed left foot drop and paresthesia of the lateral aspects of left distal lower leg. An electromyography showed left L5 radiculopathy and severe peripheral polyneuropathy. A lumbosacral magnetic resonance imaging revealed a radicular nerve in the intradural and extramedullary space being compressed by schwannoma. She previously had symptoms of foot drop several years ago, and HNPP was confirmed by peripheral myelin protein 22 deletion. She was surgically treated for L5 radiculopathy, which might have been caused by a traction of the nerve root by schwannoma at the intradural and extramedullary space. After surgical treatment, her symptoms of foot drop had improved from zero grade to IV+ grade within 4 weeks. The occurrence of HNPP and schwannoma in the same patient may be coincidental, but it is tempting to speculate that they share a common genetic basis. Therefore, for patients with HNPP, it is important to consider not only an electrophysiologic study but also a magnetic resonance imaging to locate the exact pathologic site.

  7. Characteristic features of hereditary neuropathy with liability to pressure palsy (HNPP) presenting with brachial plexopathy in soldiers.

    PubMed

    Kim, Kyoung-Eun

    2014-11-15

    A brachial plexus lesion is not common in hereditary neuropathy with liability to pressure palsy (HNPP). We report the clinical and electrodiagnostic features of young soldiers with HNPP presenting with brachial plexopathy. By reviewing 2year medical records from Korean military hospitals, we identified soldiers with brachial plexus lesions. Among them, patients diagnosed with HNPP were determined and clinical and electrophysiological findings were compared between HNPP and non-HNPP patients with a brachial plexus lesion. Thirteen patients (6.8%) were diagnosed with HNPP among 189 patients with a brachial plexus lesion. Push-ups, as either a punishment or an exercise, was the most frequent preceding event in HNPP patients (76.9%), whereas it was rare in non-HNPP patients. The distal motor latency of the median nerve showed the highest sensitivity (90.9%) and specificity (100%) for HNPP in patients with a brachial plexus lesion. In conclusion, HNPP should be suspected in patients with brachial plexopathy if brachial plexopathy develops after push-ups or if the distal motor latency of median nerves is prolonged.

  8. Inner retinal contributions to the multifocal electroretinogram: patients with Leber's hereditary optic neuropathy (LHON). Multifocal ERG in patients with LHON.

    PubMed

    Kurtenbach, Anne; Leo-Kottler, Beate; Zrenner, Eberhart

    2004-05-01

    In this study we examine the multifocal electroretinogram (mfERG) recorded from patients suffering from Leber's hereditary optic neuropathy (LHON), a degeneration of the ganglion cell and nerve fibre layers of the retina. We compared the mfERGs recorded from 11 patients with LHON, to those from 11 control subjects. The pattern ERG (PERG) was additionally performed with 9 of the patients. MfERGs were recorded and analysed using the VERIS 3.01 system with a stimulus of 103 equal-sized hexagons. For analysis, hexagons were grouped according to distance from the optic nerve head (ONH) and according to distance from the fovea. Two significant differences were found between the waveforms of the two groups: In the first order kernel, the control group showed a component around 34 ms that decreased with distance from the ONH. This component was reduced in the LHON group of subjects. In the second order (first slice) kernel, the patient group was missing features that decrease with distance from the fovea in the control group. PERG amplitudes showed a significant correlation with the amplitude of the second order mfERG kernel. The results show that the damage to ganglion cells and nerve fibres caused by LHON can be detected in mfERG recordings and indicate that activity from the inner retina can contribute significantly to first and second order waveforms.

  9. Leber's hereditary optic neuropathy (LHON) pathogenic mutations induce mitochondrial-dependent apoptotic death in transmitochondrial cells incubated with galactose medium.

    PubMed

    Ghelli, Anna; Zanna, Claudia; Porcelli, Anna Maria; Schapira, Anthony H V; Martinuzzi, Andrea; Carelli, Valerio; Rugolo, Michela

    2003-02-01

    Leber's hereditary optic neuropathy (LHON), a maternally inherited form of central vision loss, is associated with mitochondrial DNA pathogenic point mutations affecting different subunits of complex I. We here report that osteosarcoma-derived cytoplasmic hybrids (cybrid) cell lines harboring one of the three most frequent LHON pathogenic mutations, at positions 11778/ND4, 3460/ND1, and 14484/ND6, undergo cell death when galactose replaces glucose in the medium, contrary to control cybrids that maintain some growth capabilities. This is a well known way to produce a metabolic stress, forcing the cells to rely on the mitochondrial respiratory chain to produce ATP. We demonstrate that LHON cybrid cell death is apoptotic, showing chromatin condensation and nuclear DNA laddering. Moreover, we also document the mitochondrial involvement in the activation of the apoptotic cascade, as shown by the increased release of cytochrome c into the cytosol in LHON cybrid cells as compared with controls. Cybrids bearing the 3460/ND1 and 14484/ND6 mutations seemed more readily prone to undergo apoptosis as compared with the 11778/ND4 mutation. In conclusion, LHON cybrid cells forced by the reduced rate of glycolytic flux to utilize oxidative metabolism are sensitized to an apoptotic death through a mechanism involving mitochondria.

  10. Efficacy and Safety of rAAV2-ND4 Treatment for Leber’s Hereditary Optic Neuropathy

    PubMed Central

    Wan, Xing; Pei, Han; Zhao, Min-jian; Yang, Shuo; Hu, Wei-kun; He, Heng; Ma, Si-qi; Zhang, Ge; Dong, Xiao-yan; Chen, Chen; Wang, Dao-wen; Li, Bin

    2016-01-01

    Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited disease leading to blindness. A mitochondrial DNA point mutation at the 11778 nucleotide site of the NADH dehydrogenase subunit 4 (ND4) gene is the most common cause. The aim of this study was to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) in LHON patients carrying the G11778A mutation. Nine patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 9 months. Ophthalmologic examinations of visual acuity, visual field, and optical coherence tomography were performed. Physical examinations included routine blood and urine. The visual acuity of the injected eyes of six patients improved by at least 0.3 log MAR after 9 months of follow-up. In these six patients, the visual field was enlarged but the retinal nerve fibre layer remained relatively stable. No other outcome measure was significantly changed. None of the nine patients had local or systemic adverse events related to the vector during the 9-month follow-up period. These findings support the feasible use of gene therapy for LHON. PMID:26892229

  11. Minocycline, a possible neuroprotective agent in Leber's hereditary optic neuropathy (LHON): studies of cybrid cells bearing 11,778 mutation.

    PubMed

    Haroon, Mohammad Fahad; Fatima, Ambrin; Schöler, Susanne; Gieseler, Anne; Horn, Thomas F W; Kirches, Elmar; Wolf, Gerald; Kreutzmann, Peter

    2007-12-01

    Leber's hereditary optic neuropathy (LHON) is a retinal neurodegenerative disorder caused by mitochondrial DNA point mutations. Complex I of the respiratory chain affected by the mutation results in a decrease in ATP and an increase of reactive oxygen species production. Evaluating the efficacy of minocycline in LHON, the drug increased the survival of cybrid cells in contrast to the parental cells after thapsigargin-induced calcium overload. Similar protection was observed by treatment with cyclosporine A, a blocker of the mitochondrial permeability transition pore (mPTP). Ratiometric Ca(2+) imaging reveals that acetylcholine/thapsigargin triggered elevation of the cytosolic calcium concentration is alleviated by minocycline and cyclosporine A. The mitochondrial membrane potential of LHON cybrids was significantly conserved and the active-caspase-3/procaspase-3 ratio was decreased in both treatments. Our observations show that minocycline inhibits permeability transition induced by thapsigargin in addition to its antioxidant effects. In relation with its high safety profile, these results would suggest minocycline as a promising neuroprotective agent in LHON.

  12. Idebenone protects against retinal damage and loss of vision in a mouse model of Leber's hereditary optic neuropathy.

    PubMed

    Heitz, Fabrice D; Erb, Michael; Anklin, Corinne; Robay, Dimitri; Pernet, Vincent; Gueven, Nuri

    2012-01-01

    Leber's hereditary optic neuropathy (LHON) is an inherited disease caused by mutations in complex I of the mitochondrial respiratory chain. The disease is characterized by loss of central vision due to retinal ganglion cell (RGC) dysfunction and optic nerve atrophy. Despite progress towards a better understanding of the disease, no therapeutic treatment is currently approved for this devastating disease. Idebenone, a short-chain benzoquinone, has shown promising evidence of efficacy in protecting vision loss and in accelerating recovery of visual acuity in patients with LHON. It was therefore of interest to study suitable LHON models in vitro and in vivo to identify anatomical correlates for this protective activity. At nanomolar concentrations, idebenone protected the rodent RGC cell line RGC-5 against complex I dysfunction in vitro. Consistent with the reported dosing and observed effects in LHON patients, we describe that in mice, idebenone penetrated into the eye at concentrations equivalent to those which protected RGC-5 cells from complex I dysfunction in vitro. Consequently, we next investigated the protective effect of idebenone in a mouse model of LHON, whereby mitochondrial complex I dysfunction was caused by exposure to rotenone. In this model, idebenone protected against the loss of retinal ganglion cells, reduction in retinal thickness and gliosis. Furthermore, consistent with this protection of retinal integrity, idebenone restored the functional loss of vision in this disease model. These results support the pharmacological activity of idebenone and indicate that idebenone holds potential as an effective treatment for vision loss in LHON patients.

  13. Mitochondrial tRNA(Thr) A15951G mutation may not be associated with Leber's Hereditary Optic Neuropathy.

    PubMed

    Zhang, Xi; Yu, Shuaishuai; Tu, Yunhai; Huang, Wenjie

    2016-07-01

    Mutation in mitochondrial DNA (mtDNA) has been found to play an important role in the pathogenesis of Leber's Hereditary Optic Neuropathy (LHON). Three primary mutations, the ND4 G11778A, ND6 T14484C, and ND1 G3460A, have been found to account more than 90% of LHON patients in many families worldwide. In addition to the mutations in genes encoding the respiratory chain complex I, reports concerning the mt-tRNA gene mutations associated with LHON have increased, some pathogenic mutations caused the failure in mt-tRNA metabolism, thereby worsened the mitochondrial dysfunction that is responsible for LHON. Recently, the A15951G mutation in mt-tRNA(Thr) gene has been reported to be a "modified" factor in increasing the penetrance and expressivity of LHON-associated ND4 G11778A mutation in three Chinese families. However, evolutionary conservation analysis of this mutation suggested a poor conservation index and the pathogenicity scoring system showed that this mutation was a neutral polymorphism.

  14. Characteristic features of hereditary neuropathy with liability to pressure palsy (HNPP) presenting with brachial plexopathy in soldiers.

    PubMed

    Kim, Kyoung-Eun

    2014-11-15

    A brachial plexus lesion is not common in hereditary neuropathy with liability to pressure palsy (HNPP). We report the clinical and electrodiagnostic features of young soldiers with HNPP presenting with brachial plexopathy. By reviewing 2year medical records from Korean military hospitals, we identified soldiers with brachial plexus lesions. Among them, patients diagnosed with HNPP were determined and clinical and electrophysiological findings were compared between HNPP and non-HNPP patients with a brachial plexus lesion. Thirteen patients (6.8%) were diagnosed with HNPP among 189 patients with a brachial plexus lesion. Push-ups, as either a punishment or an exercise, was the most frequent preceding event in HNPP patients (76.9%), whereas it was rare in non-HNPP patients. The distal motor latency of the median nerve showed the highest sensitivity (90.9%) and specificity (100%) for HNPP in patients with a brachial plexus lesion. In conclusion, HNPP should be suspected in patients with brachial plexopathy if brachial plexopathy develops after push-ups or if the distal motor latency of median nerves is prolonged. PMID:25175852

  15. An Inversion Disrupting FAM134B Is Associated with Sensory Neuropathy in the Border Collie Dog Breed

    PubMed Central

    Forman, Oliver P.; Hitti, Rebekkah J.; Pettitt, Louise; Jenkins, Christopher A.; O’Brien, Dennis P.; Shelton, G. Diane; De Risio, Luisa; Quintana, Rodrigo Gutierrez; Beltran, Elsa; Mellersh, Cathryn

    2016-01-01

    Sensory neuropathy in the Border Collie is a severe neurological disorder caused by the degeneration of sensory and, to a lesser extent, motor nerve cells with clinical signs starting between 2 and 7 months of age. Using a genome-wide association study approach with three cases and 170 breed matched controls, a suggestive locus for sensory neuropathy was identified that was followed up using a genome sequencing approach. An inversion disrupting the candidate gene FAM134B was identified. Genotyping of additional cases and controls and RNAseq analysis provided strong evidence that the inversion is causal. Evidence of cryptic splicing resulting in novel exon transcription for FAM134B was identified by RNAseq experiments. This investigation demonstrates the identification of a novel sensory neuropathy associated mutation, by mapping using a minimal set of cases and subsequent genome sequencing. Through mutation screening, it should be possible to reduce the frequency of or completely eliminate this debilitating condition from the Border Collie breed population. PMID:27527794

  16. An Inversion Disrupting FAM134B Is Associated with Sensory Neuropathy in the Border Collie Dog Breed.

    PubMed

    Forman, Oliver P; Hitti, Rebekkah J; Pettitt, Louise; Jenkins, Christopher A; O'Brien, Dennis P; Shelton, G Diane; De Risio, Luisa; Quintana, Rodrigo Gutierrez; Beltran, Elsa; Mellersh, Cathryn

    2016-01-01

    Sensory neuropathy in the Border Collie is a severe neurological disorder caused by the degeneration of sensory and, to a lesser extent, motor nerve cells with clinical signs starting between 2 and 7 months of age. Using a genome-wide association study approach with three cases and 170 breed matched controls, a suggestive locus for sensory neuropathy was identified that was followed up using a genome sequencing approach. An inversion disrupting the candidate gene FAM134B was identified. Genotyping of additional cases and controls and RNAseq analysis provided strong evidence that the inversion is causal. Evidence of cryptic splicing resulting in novel exon transcription for FAM134B was identified by RNAseq experiments. This investigation demonstrates the identification of a novel sensory neuropathy associated mutation, by mapping using a minimal set of cases and subsequent genome sequencing. Through mutation screening, it should be possible to reduce the frequency of or completely eliminate this debilitating condition from the Border Collie breed population. PMID:27527794

  17. Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy.

    PubMed

    Lupo, Vincenzo; García-García, Francisco; Sancho, Paula; Tello, Cristina; García-Romero, Mar; Villarreal, Liliana; Alberti, Antonia; Sivera, Rafael; Dopazo, Joaquín; Pascual-Pascual, Samuel I; Márquez-Infante, Celedonio; Casasnovas, Carlos; Sevilla, Teresa; Espinós, Carmen

    2016-03-01

    Charcot-Marie-Tooth disease is characterized by broad genetic heterogeneity with >50 known disease-associated genes. Mutations in some of these genes can cause a pure motor form of hereditary motor neuropathy, the genetics of which are poorly characterized. We designed a panel comprising 56 genes associated with Charcot-Marie-Tooth disease/hereditary motor neuropathy. We validated this diagnostic tool by first testing 11 patients with pathological mutations. A cohort of 33 affected subjects was selected for this study. The DNAJB2 c.352+1G>A mutation was detected in two cases; novel changes and/or variants with low frequency (<1%) were found in 12 cases. There were no candidate variants in 18 cases, and amplification failed for one sample. The DNAJB2 c.352+1G>A mutation was also detected in three additional families. On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJB2 c.352+1G>A mutation may be a founder event. Our gene panel allowed us to perform a very rapid and cost-effective screening of genes involved in Charcot-Marie-Tooth disease/hereditary motor neuropathy. Our diagnostic strategy was robust in terms of both coverage and read depth for all of the genes and patient samples. These findings demonstrate the difficulty in achieving a definitive molecular diagnosis because of the complexity of interpreting new variants and the genetic heterogeneity that is associated with these neuropathies. PMID:26752306

  18. Evaluation of peripheral neuropathy. Part III: vasculitic, infectious, inherited, and idiopathic neuropathies.

    PubMed

    Kelly, John J

    2005-01-01

    In this, the third of a 3-part series on peripheral neuropathy, the syndromes of vasculitic, infectious, inherited, and idiopathic neuropathy are discussed. Vasculitis is a frequent cause of neuropathy in the setting of a connective tissue disease. The infectious neuropathies most likely to be encountered in the United States are those due to varicella-zoster virus, human immunodeficiency virus, Lyme disease, hepatitis C virus, and, most recently, West Nile virus. Inherited neuropathies are divided into 2 main types: predominant motor or predominant sensory. The former are generally classed as the Charcot-Marie-Tooth diseases and the latter as the hereditary sensory neuropathies. Each category has a number of different subtypes. If the results of routine screening tests are negative, the clinician must consider special testing for unusual disorders, including evaluations for underlying autoimmune or malignant disorders, genetic tests for inherited neuropathies, and other unusual or selectively ordered tests. These tests are very expensive and should be ordered only after the common causes of neuropathy are excluded. Unless the neuropathy can be substantially alleviated or cured, symptomatic treatment (most often for pain) plays a significant role for these patients.

  19. Inherited peripheral neuropathy.

    PubMed

    Keller, M P; Chance, P F

    1999-01-01

    Hereditary disorders of the peripheral nerves constitute a group of frequently encountered neurological diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is genetically heterogeneous and characterized by demyelination with moderately to severely reduced nerve conduction velocities, absent muscle stretch reflexes and onion bulb formation. Genetic loci for CMT1 map to chromosome 17 (CMT1A), chromosome 1 (CMT1B), and another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1 B result from point mutations in the myelin protein zero (Po or MPZ) gene. The molecular defect in CMT1 C is unknown. Mutations in the early growth response 2 gene (EGR2) are also associated with demyelinating neuropathy. Other rare forms of demyelinating peripheral neuropathies map to chromosome 8q, 10q, and 11q. X-linked Charcot-Marie-Tooth neuropathy (CMTX), which has clinical features similar to CMT1, is associated with mutations in the connexin32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is characterized by normal or mildly reduced nerve conduction velocity with decreased amplitude and axonal loss without hypertrophic features. One form of CMT2 maps to chromosome 1 p36 (CMT2A), another to chromosome 3p (CMT2B) and another to 7p (CMT2D). Dejerine-Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile-onset demyelinating polyneuropathy that may be associated with point mutations in either the PMP22 gene or the Po gene and shares considerable clinical and pathological features with CMT1. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and results from reduced

  20. Bilateral Vestibulopathy Aggravates Balance and Gait Disturbances in Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis: A Case Report.

    PubMed

    van Leeuwen, Roeland B; Smits, Bart W; Rodenburg, Richard J; van Engelen, Baziel G

    2016-09-01

    In patients with a triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO), the presenting features are mainly ataxia or ptosis. SANDO patients often have impaired balance and gait, which is not surprising considering the combination of sensory ataxic neuropathy, and additional symptoms like cerebellar ataxia and limb girdle weakness. We describe a SANDO patient who noticed an increasingly impaired balance and gait, without any dizziness. Neurological investigation revealed an external ophthalmeplegia and a cerebellar ataxia; the head impulse test was not reliable because of eye movement disorders. The caloric reflex tests showed lack of responses on both sides, compatible with severe bilateral vestibulopathy. Making the diagnosis of bilateral vestibulopathy in SANDO patients may have implications for the management of the patient, because specific vestibular rehabilitation can improve gaze and postural stability. PMID:27552387

  1. c-Jun activation in Schwann cells protects against loss of sensory axons in inherited neuropathy

    PubMed Central

    Hantke, Janina; Carty, Lucy; Wagstaff, Laura J.; Turmaine, Mark; Wilton, Daniel K.; Quintes, Susanne; Koltzenburg, Martin; Baas, Frank; Mirsky, Rhona

    2014-01-01

    Charcot–Marie–Tooth disease type 1A is the most frequent inherited peripheral neuropathy. It is generally due to heterozygous inheritance of a partial chromosomal duplication resulting in over-expression of PMP22. A key feature of Charcot–Marie–Tooth disease type 1A is secondary death of axons. Prevention of axonal loss is therefore an important target of clinical intervention. We have previously identified a signalling mechanism that promotes axon survival and prevents neuron death in mechanically injured peripheral nerves. This work suggested that Schwann cells respond to injury by activating/enhancing trophic support for axons through a mechanism that depends on upregulation of the transcription factor c-Jun in Schwann cells, resulting in the sparing of axons that would otherwise die. As c-Jun orchestrates Schwann cell support for distressed neurons after mechanical injury, we have now asked: do Schwann cells also activate a c-Jun dependent neuron-supportive programme in inherited demyelinating disease? We tested this by using the C3 mouse model of Charcot–Marie–Tooth disease type 1A. In line with our previous findings in humans with Charcot–Marie–Tooth disease type 1A, we found that Schwann cell c-Jun was elevated in (uninjured) nerves of C3 mice. We determined the impact of this c-Jun activation by comparing C3 mice with double mutant mice, namely C3 mice in which c-Jun had been conditionally inactivated in Schwann cells (C3/Schwann cell-c-Jun−/− mice), using sensory-motor tests and electrophysiological measurements, and by counting axons in proximal and distal nerves. The results indicate that c-Jun elevation in the Schwann cells of C3 nerves serves to prevent loss of myelinated sensory axons, particularly in distal nerves, improve behavioural symptoms, and preserve F-wave persistence. This suggests that Schwann cells have two contrasting functions in Charcot–Marie–Tooth disease type 1A: on the one hand they are the genetic source of

  2. Sensory, psychological, and metabolic dysfunction in HIV-associated peripheral neuropathy: A cross-sectional deep profiling study

    PubMed Central

    Phillips, Tudor J.C.; Brown, Matthew; Ramirez, Juan D.; Perkins, James; Woldeamanuel, Yohannes W.; Williams, Amanda C. de C.; Orengo, Christine; Bennett, David L.H.; Bodi, Istvan; Cox, Sarah; Maier, Christoph; Krumova, Elena K.; Rice, Andrew S.C.

    2014-01-01

    HIV-associated sensory neuropathy (HIV-SN) is a frequent complication of HIV infection and a major source of morbidity. A cross-sectional deep profiling study examining HIV-SN was conducted in people living with HIV in a high resource setting using a battery of measures which included the following: parameters of pain and sensory symptoms (7 day pain diary, Neuropathic Pain Symptom Inventory [NPSI] and Brief Pain Inventory [BPI]), sensory innervation (structured neurological examination, quantitative sensory testing [QST] and intraepidermal nerve fibre density [IENFD]), psychological state (Pain Anxiety Symptoms Scale-20 [PASS-20], Depression Anxiety and Positive Outlook Scale [DAPOS], and Pain Catastrophizing Scale [PCS], insomnia (Insomnia Severity Index [ISI]), and quality of life (Short Form (36) Health Survey [SF-36]). The diagnostic utility of the Brief Peripheral Neuropathy Screen (BPNS), Utah Early Neuropathy Scale (UENS), and Toronto Clinical Scoring System (TCSS) were evaluated. Thirty-six healthy volunteers and 66 HIV infected participants were recruited. A novel triumvirate case definition for HIV-SN was used that required 2 out of 3 of the following: 2 or more abnormal QST findings, reduced IENFD, and signs of a peripheral neuropathy on a structured neurological examination. Of those with HIV, 42% fulfilled the case definition for HIV-SN (n = 28), of whom 75% (n = 21) reported pain. The most frequent QST abnormalities in HIV-SN were loss of function in mechanical and vibration detection. Structured clinical examination was superior to QST or IENFD in HIV-SN diagnosis. HIV-SN participants had higher plasma triglyceride, concentrations depression, anxiety and catastrophizing scores, and prevalence of insomnia than HIV participants without HIV-SN. PMID:24973717

  3. Sensory, psychological, and metabolic dysfunction in HIV-associated peripheral neuropathy: A cross-sectional deep profiling study.

    PubMed

    Phillips, Tudor J C; Brown, Matthew; Ramirez, Juan D; Perkins, James; Woldeamanuel, Yohannes W; Williams, Amanda C de C; Orengo, Christine; Bennett, David L H; Bodi, Istvan; Cox, Sarah; Maier, Christoph; Krumova, Elena K; Rice, Andrew S C

    2014-09-01

    HIV-associated sensory neuropathy (HIV-SN) is a frequent complication of HIV infection and a major source of morbidity. A cross-sectional deep profiling study examining HIV-SN was conducted in people living with HIV in a high resource setting using a battery of measures which included the following: parameters of pain and sensory symptoms (7day pain diary, Neuropathic Pain Symptom Inventory [NPSI] and Brief Pain Inventory [BPI]), sensory innervation (structured neurological examination, quantitative sensory testing [QST] and intraepidermal nerve fibre density [IENFD]), psychological state (Pain Anxiety Symptoms Scale-20 [PASS-20], Depression Anxiety and Positive Outlook Scale [DAPOS], and Pain Catastrophizing Scale [PCS], insomnia (Insomnia Severity Index [ISI]), and quality of life (Short Form (36) Health Survey [SF-36]). The diagnostic utility of the Brief Peripheral Neuropathy Screen (BPNS), Utah Early Neuropathy Scale (UENS), and Toronto Clinical Scoring System (TCSS) were evaluated. Thirty-six healthy volunteers and 66 HIV infected participants were recruited. A novel triumvirate case definition for HIV-SN was used that required 2 out of 3 of the following: 2 or more abnormal QST findings, reduced IENFD, and signs of a peripheral neuropathy on a structured neurological examination. Of those with HIV, 42% fulfilled the case definition for HIV-SN (n=28), of whom 75% (n=21) reported pain. The most frequent QST abnormalities in HIV-SN were loss of function in mechanical and vibration detection. Structured clinical examination was superior to QST or IENFD in HIV-SN diagnosis. HIV-SN participants had higher plasma triglyceride, concentrations depression, anxiety and catastrophizing scores, and prevalence of insomnia than HIV participants without HIV-SN. PMID:24973717

  4. Longitudinal study of a heteroplasmic 3460 Leber hereditary optic neuropathy family by multiplexed primer-extension analysis and nucleotide sequencing

    SciTech Connect

    Ghosh, S.S.; Fahy, E.; Bodis-Wollner, I.

    1996-02-01

    Nucleotide-sequencing and multiplexed primer-extension assays have been used to quantitate the mutant-allele frequency in 14 maternal relatives, spanning three generations, from a family that is heteroplasmic for the primary Leber hereditary optic neuropathy (LHON) mutation at nucleotide 3460 of the mitochondrial genome. There was excellent agreement between the values that were obtained with the two different methods. The longitudinal study shows that the mutant-allele frequency was constant within individual family members over a sampling period of 3.5 years. Second, although there was an overall increase in the mutant-allele frequency in successive generations, segregation in the direction of the mutant allele was not invariant, and there was one instance in which there was a significant decrease in the frequency from parent to offspring. From these two sets of results, and from previous studies of heteroplasmic LHON families, we conclude that there is no evidence for a marked selective pressure that determines the replication, segregation, or transmission of primary LHON mutations to white blood cells and platelets. Instead, the mtDNA molecules are most likely to replicate and segregate under conditions of random drift at the cellular level. Finally, the pattern of transmission in this maternal lineage is compatible with a developmental bottleneck model in which the number of mitochondrial units of segregation in the female germ line is relatively small in relation to the number of mtDNA molecules within a cell. However, this is not an invariant pattern for humans, and simple models of mitochondrial gene transmission are inappropriate at the present time. 37 refs., 4 figs., 1 tab.

  5. Cigarette toxicity triggers Leber's hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways

    PubMed Central

    Giordano, L; Deceglie, S; d'Adamo, P; Valentino, M L; La Morgia, C; Fracasso, F; Roberti, M; Cappellari, M; Petrosillo, G; Ciaravolo, S; Parente, D; Giordano, C; Maresca, A; Iommarini, L; Del Dotto, V; Ghelli, A M; Salomao, S R; Berezovsky, A; Belfort, R; Sadun, A A; Carelli, V; Loguercio Polosa, P; Cantatore, P

    2015-01-01

    Leber's hereditary optic neuropathy (LHON), the most frequent mitochondrial disease, is associated with mitochondrial DNA (mtDNA) point mutations affecting Complex I subunits, usually homoplasmic. This blinding disorder is characterized by incomplete penetrance, possibly related to several genetic modifying factors. We recently reported that increased mitochondrial biogenesis in unaffected mutation carriers is a compensatory mechanism, which reduces penetrance. Also, environmental factors such as cigarette smoking have been implicated as disease triggers. To investigate this issue further, we first assessed the relationship between cigarette smoke and mtDNA copy number in blood cells from large cohorts of LHON families, finding that smoking was significantly associated with the lowest mtDNA content in affected individuals. To unwrap the mechanism of tobacco toxicity in LHON, we exposed fibroblasts from affected individuals, unaffected mutation carriers and controls to cigarette smoke condensate (CSC). CSC decreased mtDNA copy number in all cells; moreover, it caused significant reduction of ATP level only in mutated cells including carriers. This implies that the bioenergetic compensation in carriers is hampered by exposure to smoke derivatives. We also observed that in untreated cells the level of carbonylated proteins was highest in affected individuals, whereas the level of several detoxifying enzymes was highest in carriers. Thus, carriers are particularly successful in reactive oxygen species (ROS) scavenging capacity. After CSC exposure, the amount of detoxifying enzymes increased in all cells, but carbonylated proteins increased only in LHON mutant cells, mostly from affected individuals. All considered, it appears that exposure to smoke derivatives has a more deleterious effect in affected individuals, whereas carriers are the most efficient in mitigating ROS rather than recovering bioenergetics. Therefore, the identification of genetic modifiers that

  6. Characterization of retinal nerve fiber layer thickness changes associated with Leber's hereditary optic neuropathy by optical coherence tomography.

    PubMed

    Zhang, Yixin; Huang, Houbin; Wei, Shihui; Qiu, Huaiyu; Gong, Yan; Li, Hongyang; Dai, Yanli; Jiang, Zhaocai; Liu, Zihao

    2014-02-01

    In the present study, the changes in the retinal nerve fiber layer (RNFL) thickness associated with Leber's hereditary optic neuropathy (LHON) were examined by Cirrus high definition-optical coherence tomography (OCT), and the correlation between the RNFL thickness and the best corrected visual acuity (BCVA) was evaluated. A cross-sectional study was performed. Sixty-eight eyes from patients with LHON and 30 eyes from healthy individuals were scanned. Affected eyes were divided into 5 groups according to disease duration: Group 1, ≤3 months; group 2, 4-6 months; group 3, 7-9 months; group 4, 10-12 months; and group 5, >12 months. The RNFL thickness of the temporal, superior, nasal and inferior quadrants and the 360° average were compared between the LHON groups and the control group. The eyes in groups 1 and 2 were observed to have a thicker RNFL in the superior, nasal and inferior quadrants and a higher 360°-average RNFL thickness compared with those of the control group (P<0.05), the RNFL was observed to be thinner in the temporal quadrant in groups 1 and 2. The eyes in groups 3 and 4 showed a thinner RNFL in the temporal (P=0.001), superior and inferior (both P<0.05) quadrants, and a lower 360°-average RNFL thickness as compared with controls (P=0.001). No significant correlation was identified between BCVA and RNFL thickness. RNFL thickness was observed to undergo a unique process from thickening to thinning in the patients with LHON. Changes in different quadrants occurred at different time periods and the BCVA was not found to be correlated with RNFL thickness.

  7. Patterns of white matter diffusivity abnormalities in Leber's hereditary optic neuropathy: a tract-based spatial statistics study.

    PubMed

    Milesi, Jacopo; Rocca, Maria A; Bianchi-Marzoli, Stefania; Petrolini, Melissa; Pagani, Elisabetta; Falini, Andrea; Comi, Giancarlo; Filippi, Massimo

    2012-09-01

    Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by retinal ganglion cell degeneration and optic nerve atrophy, leading to a loss of central vision. The aim of this study was to explore the topographical pattern of damage to the brain white matter (WM) tracts from patients with chronic LHON using diffusion tensor (DT) MRI and tract-based spatial statistics (TBSS). Brain dual-echo and DT MRI scans were acquired from 13 patients with chronic LHON and 25 matched controls using a 3.0 T scanner. TBSS analysis was performed using the FMRIB's Diffusion Toolbox. A complete neuro-ophthalmologic examination, including standardized automated Humphrey perimetry as well as average and temporal peripapillary retinal nerve fiber layer thickness (PRNFL) measurements, was obtained in all patients. Mean average and temporal PRNFL thicknesses were decreased significantly in LHON patients. Compared to controls, TBSS analysis revealed significant diffusivity abnormalities in these patients, which were characterized by a decreased fractional anisotropy (FA) and an increased mean diffusivity and radial diffusivity, affecting exclusively the optic tracts and optic radiations (OR). In patients, a significant correlation was found between optic tract average FA and mean visual acuity (r = 0.57, p = 0.04). In LHON patients, DT MRI reveals a microstructural alteration of the WM along the entire visual pathways, with a sparing of the other main WM tracts of the brain. Damage to the OR may be secondary either to trans-synaptic degeneration, which in turn is due to neuroaxonal loss in the retina and optic nerve, or to local mitochondrial dysfunction.

  8. Cigarette toxicity triggers Leber's hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways.

    PubMed

    Giordano, L; Deceglie, S; d'Adamo, P; Valentino, M L; La Morgia, C; Fracasso, F; Roberti, M; Cappellari, M; Petrosillo, G; Ciaravolo, S; Parente, D; Giordano, C; Maresca, A; Iommarini, L; Del Dotto, V; Ghelli, A M; Salomao, S R; Berezovsky, A; Belfort, R; Sadun, A A; Carelli, V; Loguercio Polosa, P; Cantatore, P

    2015-12-17

    Leber's hereditary optic neuropathy (LHON), the most frequent mitochondrial disease, is associated with mitochondrial DNA (mtDNA) point mutations affecting Complex I subunits, usually homoplasmic. This blinding disorder is characterized by incomplete penetrance, possibly related to several genetic modifying factors. We recently reported that increased mitochondrial biogenesis in unaffected mutation carriers is a compensatory mechanism, which reduces penetrance. Also, environmental factors such as cigarette smoking have been implicated as disease triggers. To investigate this issue further, we first assessed the relationship between cigarette smoke and mtDNA copy number in blood cells from large cohorts of LHON families, finding that smoking was significantly associated with the lowest mtDNA content in affected individuals. To unwrap the mechanism of tobacco toxicity in LHON, we exposed fibroblasts from affected individuals, unaffected mutation carriers and controls to cigarette smoke condensate (CSC). CSC decreased mtDNA copy number in all cells; moreover, it caused significant reduction of ATP level only in mutated cells including carriers. This implies that the bioenergetic compensation in carriers is hampered by exposure to smoke derivatives. We also observed that in untreated cells the level of carbonylated proteins was highest in affected individuals, whereas the level of several detoxifying enzymes was highest in carriers. Thus, carriers are particularly successful in reactive oxygen species (ROS) scavenging capacity. After CSC exposure, the amount of detoxifying enzymes increased in all cells, but carbonylated proteins increased only in LHON mutant cells, mostly from affected individuals. All considered, it appears that exposure to smoke derivatives has a more deleterious effect in affected individuals, whereas carriers are the most efficient in mitigating ROS rather than recovering bioenergetics. Therefore, the identification of genetic modifiers that

  9. Bilateral Neuropathy of Primary Sensory Neurons by the Chronic Compression of Multiple Unilateral DRGs

    PubMed Central

    Xie, Ya-Bin; Zhao, Huan; Wang, Ying; Song, Kai; Zhang, Ming; Meng, Fan-Cheng; Yang, Yu-Jie; He, Yang-Song; Kuang, Fang; You, Si-Wei; You, Hao-Jun; Xu, Hui

    2016-01-01

    To mimic multilevel nerve root compression and intervertebral foramina stenosis in human, we established a new animal model of the chronic compression of unilateral multiple lumbar DRGs (mCCD) in the rat. A higher occurrence of signs of spontaneous pain behaviors, such as wet-dog shaking and spontaneous hind paw shrinking behaviors, was firstly observed from day 1 onward. In the meantime, the unilateral mCCD rat exhibited significant bilateral hind paw mechanical and cold allodynia and hyperalgesia, as well as a thermal preference to 30°C plate between 30 and 35°C. The expression of activating transcription factor 3 (ATF3) was significantly increased in the ipsilateral and contralateral all-sized DRG neurons after the mCCD. And the expression of CGRP was significantly increased in the ipsilateral and contralateral large- and medium-sized DRG neurons. ATF3 and CGRP expressions correlated to evoked pain hypersensitivities such as mechanical and cold allodynia on postoperative day 1. The results suggested that bilateral neuropathy of primary sensory neurons might contribute to bilateral hypersensitivity in the mCCD rat. PMID:26819761

  10. Bilateral Neuropathy of Primary Sensory Neurons by the Chronic Compression of Multiple Unilateral DRGs.

    PubMed

    Xie, Ya-Bin; Zhao, Huan; Wang, Ying; Song, Kai; Zhang, Ming; Meng, Fan-Cheng; Yang, Yu-Jie; He, Yang-Song; Kuang, Fang; You, Si-Wei; You, Hao-Jun; Xu, Hui

    2016-01-01

    To mimic multilevel nerve root compression and intervertebral foramina stenosis in human, we established a new animal model of the chronic compression of unilateral multiple lumbar DRGs (mCCD) in the rat. A higher occurrence of signs of spontaneous pain behaviors, such as wet-dog shaking and spontaneous hind paw shrinking behaviors, was firstly observed from day 1 onward. In the meantime, the unilateral mCCD rat exhibited significant bilateral hind paw mechanical and cold allodynia and hyperalgesia, as well as a thermal preference to 30°C plate between 30 and 35°C. The expression of activating transcription factor 3 (ATF3) was significantly increased in the ipsilateral and contralateral all-sized DRG neurons after the mCCD. And the expression of CGRP was significantly increased in the ipsilateral and contralateral large- and medium-sized DRG neurons. ATF3 and CGRP expressions correlated to evoked pain hypersensitivities such as mechanical and cold allodynia on postoperative day 1. The results suggested that bilateral neuropathy of primary sensory neurons might contribute to bilateral hypersensitivity in the mCCD rat.

  11. Clinical and serological features of acute sensory ataxic neuropathy with antiganglioside antibodies.

    PubMed

    Rojas-García, Ricard; Querol, Luis; Gallardo, Eduard; De Luna Salva, Noemi; Juarez, Cándido; Garces, Mercedes; Fages, Eva; Casasnovas, Carlos; Illa, Isabel

    2012-06-01

    There is as yet no consensus for considering pure acute sensory ataxic neuropathy (ASAN) as a variant of Guillain-Barré syndrome (GBS). Reactivity against gangliosides sharing disialosyl epitopes has been reported in these patients. The aim of this study was to determine the spectrum of reactivity against gangliosides in ASAN and to define the clinical pattern. From our database we identified patients with suspicion of ASAN. We defined ASAN as the presence of ataxia of peripheral origin with loss of proprioception, and areflexia, absence of ophthalmoplegia and no or minimal muscle weakness. Patients who met these criteria were retrospectively reviewed for their spectrum of reactivity against gangliosides and clinical features. We identified 12 patients fulfilling pre-defined criteria for ASAN. Reactivity against gangliosides containing disialosyl epitopes was present in seven patients. Concomitant reactivity against other gangliosides was present in 6/7 patients. All patients presented good prognosis and an antecedent illness was present in nine. Our results support the previously described clinico-immunological association between ASAN and disialosyl specificity, and widen the spectrum of reactivity against gangliosides. The acute presentation with a monophasic course, and good prognosis in all cases, together with transient immunoglobulin G antiganglioside antibodies and infectious antecedent in 7/12 patients support the inclusion of ASAN as a GBS variant. PMID:22734901

  12. Very high penetrance and occurrence of Leber's hereditary optic neuropathy in a large Han Chinese pedigree carrying the ND4 G11778A mutation.

    PubMed

    Zhou, Xiangtian; Zhang, Hongxing; Zhao, Fuxin; Ji, Yanchun; Tong, Yi; Zhang, Juanjuan; Zhang, Yu; Yang, Li; Qian, Yaping; Lu, Fan; Qu, Jia; Guan, Min-Xin

    2010-08-01

    We report here the clinical, genetics and molecular characterization of a five-generation Han Chinese family with Leber's hereditary optic neuropathy (LHON). Strikingly, this family exhibits very high penetrance and occurrence of optic neuropathy. In particular, 25 (10 males/15 females) of 30 matrilineal relatives exhibited the variable severity, ranging from profound to mild of visual impairment. This penetrance of optic neuropathy in this Chinese family is much higher than those in many families with LHON worldwide. The age-at-onset for visual impairment in matrilineal relatives in this Chinese family varied from 7 to 24years old, with the average of 15 years old. Furthermore, the ratio between affected male and female matrilineal relatives is 1:1.5 in the Chinese family. This observation is in contrast with the typical features in LHON pedigrees that there was predominance of affected males in LHON in many families from different ethnic origins. Molecular analysis of mitochondrial genome identified the known ND4 G11778A mutation and 51 variants, belonging to Asian haplogroup C4a1. The absence of other known secondary LHON-associated and functionally significant mtDNA mutations in this Chinese family suggested that mitochondrial variants may not play an important role in the phenotypic manifestation of the G11778A mutation in this Chinese family. Therefore, nuclear modifier gene(s) may be responsible for very high penetrance and occurrence of optic neuropathy in this Chinese pedigree.

  13. Electrical Stimulation as an Adjunctive Treatment of Painful and Sensory Diabetic Neuropathy

    PubMed Central

    Thakral, Gaurav; Kim, Paul J.; LaFontaine, Javier; Menzies, Robert; Najafi, Bijan; Lavery, Lawrence A.

    2013-01-01

    Background The objective of this review is to evaluate the use of electrical stimulation to treat diabetic neuropathy. Application of electrical stimulation may provide a novel treatment option for large and small fiber neuropathy in persons with diabetes. Large and small nerve neuropathy alters pain, proprioception, touch perception, and motor function, which cause burning foot pain and serve as protective mechanisms from ulcerations. Methods A content search for clinical trials involving electrical stimulation, neuropathy, and diabetes was conducted through PubMed. Randomized clinical trials and prospective studies with outcome measures affecting the lower extremity function were selected for review. Results We identified eight studies in which electrical stimulation was used to treat diabetic neuropathy. Six studies evaluated small fiber neuropathy. Two studies evaluated patients with both small and large fiber neuropathy and reported significant improvement in vibration and monofilament testing and reduction in symptoms in the electrical stimulation treatment group. Six of the eight painful neuropathy studies identified significant improvement in symptoms. There were no studies that evaluated electrical stimulation to treated diabetic motor neuropathy, fall prevention or postural instability. Conclusions Electrical stimulation may be an effective alternative and adjunctive therapy to current interventions for diabetic peripheral neuropathy. PMID:24124947

  14. Mitochondria and peripheral neuropathies.

    PubMed

    Vital, Anne; Vital, Claude

    2012-12-01

    There has been considerable progress during the past 24 years in the molecular genetics of mitochondrial DNA and related nuclear DNA mutations, and more than 100 nerve biopsies from hereditary neuropathies related to mitochondrial cytopathy have been accurately examined. Neuropathies were first reported in diseases related to point mutations of mitochondrial DNA, but they proved to be a prominent feature of the phenotype in mitochondrial disorders caused by defects in nuclear DNA, particularly in 3 genes: polymerase gamma 1 (POLG1), mitofusin 2 (MFN2), and ganglioside-induced differentiation-associated protein 1 (GDAP1). Most patients have sensory-motor neuropathy, sometimes associated with ophthalmoplegia, ataxia, seizures, parkinsonism, myopathy, or visceral disorders. Some cases are caused by consanguinity, but most are sporadic with various phenotypes mimicking a wide range of other etiologies. Histochemistry on muscle biopsy, as well as identification of crystalloid inclusions at electron microscopy, may provide a diagnostic clue to mitochondriopathy, but nerve biopsy is often less informative. Nevertheless, enlarged mitochondria containing distorted or amputated cristae are highly suggestive, particularly when located in the Schwann cell cytoplasm. Also noticeable are clusters of regenerating myelinated fibers surrounded by concentric Schwann cell processes, and such onion bulb-like formations are frequently observed in neuropathies caused by GDAP1 mutations. PMID:23147504

  15. Early onset (childhood) monogenic neuropathies.

    PubMed

    Landrieu, Pierre; Baets, Jonathan

    2013-01-01

    Hereditary neuropathies (HN) with onset in childhood are categorized according to clinical presentation, pathogenic mechanism based on electrophysiology, genetic transmission and, in selected cases, pathological findings. Especially relevant to pediatrics are the items "secondary" versus "primary" neuropathy, "syndromic versus nonsyndromic," and "period of life." Different combinations of these parameters frequently point toward specific monogenic disorders. Ruling out a neuropathy secondary to a generalized metabolic disorder remains the first concern in pediatrics. As a rule, metabolic diseases include additional, orienting symptoms or signs, and their biochemical diagnosis is based on logical algorithms. Primary, motor sensory are the most frequent HN and are dominated by demyelinating autosomal dominant (AD) forms (CMT1). Other forms include demyelinating autosomal recessive (AR) forms, axonal AD/AR forms, and forms with "intermediate" electrophysiological phenotype. Peripheral motor neuron disorders are dominated by AR SMN-linked spinal muscular atrophies. (Distal) hereditary motor neuropathies represent <10% of HN but exhibit large clinical and genetic heterogeneity. Sensory/dysautonomic HN involves five classic subtypes, each one related to specific genes. However, genetic heterogeneity is larger than initially suspected. Syndromic HN distinguish "purely neurological syndromes", which are multisystemic, such as spinocerebellar atrophies +, spastic paraplegias +, etc. Peripheral neuropathy is possibly the presenting feature, including in childhood. Autosomal recessive forms, on average, start more frequently in childhood. "Multiorgan syndromes", on the other hand, are more specific to Pediatrics. AR forms, which are clearly degenerative, prompt the investigation of a large set of pleiotropic genes. Other syndromes expressed in the perinatal period are mainly developmental disorders, and can sometimes be related to specific transcription factors. Systematic

  16. Detection of the mtDNA 14484 mutation on an African-specific haplotype: Implications about its role in causing Leber hereditary optic neuropathy

    SciTech Connect

    Torroni, A.; Petrozzi, M.; Terracina, M.

    1996-07-01

    Leber hereditary optic neuropathy (LHON) is a maternally transmitted disease whose primary clinical manifestation is acute or subacute bilateral loss of central vision leading to central scotoma and blindness. To date, LHON has been associated with 18 mtDNA missense mutations, even though, for many of these mutations, it remains unclear whether they cause the disease, contribute to the pathology, or are nonpathogenic mtDNA polymorphisms. On the basis of numerous criteria, which include the specificity for LHON, the frequency in the general population, and the penetrance within affected pedigrees, the detection of associated defects in the respiratory chain, mutations at three nucleotide positions (nps), 11778 (G{r_arrow}A), 3460 (G{r_arrow}A), and 14484 (T{r_arrow}C) have been classified as high-risk and primary LHON mutations. Overall, these three mutations encompass {ge}90% of the LHON cases. 29 refs., 1 fig.

  17. Partial mitochondrial complex I inhibition induces oxidative damage and perturbs glutamate transport in primary retinal cultures. Relevance to Leber Hereditary Optic Neuropathy (LHON).

    PubMed

    Beretta, Simone; Wood, John P M; Derham, Barry; Sala, Gessica; Tremolizzo, Lucio; Ferrarese, Carlo; Osborne, Neville N

    2006-11-01

    Leber Hereditary Optic Neuropathy (LHON) is a maternally inherited form of visual loss, due to selective degeneration of retinal ganglion cells. Despite the established aetiological association between LHON and mitochondrial DNA mutations affecting complex I of the electron transport chain, the pathophysiology of this disorder remains obscure. Primary rat retinal cultures were exposed to increasing concentrations of rotenone to titrate complex I inhibition. Neural cells were more sensitive than Müller glial cells to rotenone toxicity. Rotenone induced an increase in mitochondrial-derived free radicals and lipid peroxidation. Sodium-dependent glutamate uptake, which is mostly mediated by the glutamate transporter GLAST expressed by Müller glial cells, was reduced dose-dependently by rotenone with no changes in GLAST expression. Our findings suggest that complex I-derived free radicals and disruption of glutamate transport might represent key elements for explaining the selective retinal ganglion cell death in LHON.

  18. Mitochondrial gene therapy improves respiration, biogenesis, and transcription in G11778A Leber's hereditary optic neuropathy and T8993G Leigh's syndrome cells.

    PubMed

    Iyer, Shilpa; Bergquist, Kristen; Young, Kisha; Gnaiger, Erich; Rao, Raj R; Bennett, James P

    2012-06-01

    Many incurable mitochondrial disorders result from mutant mitochondrial DNA (mtDNA) and impaired respiration. Leigh's syndrome (LS) is a fatal neurodegenerative disorder of infants, and Leber's hereditary optic neuropathy (LHON) causes blindness in young adults. Treatment of LHON and LS cells harboring G11778A and T8993G mutant mtDNA, respectively, by >90%, with healthy donor mtDNA complexed with recombinant human mitochondrial transcription factor A (rhTFAM), improved mitochondrial respiration by ∼1.2-fold in LHON cells and restored >50% ATP synthase function in LS cells. Mitochondrial replication, transcription, and translation of key respiratory genes and proteins were increased in the short term. Increased NRF1, TFAMB1, and TFAMA expression alluded to the activation of mitochondrial biogenesis as a mechanism for improving mitochondrial respiration. These results represent the development of a therapeutic approach for LHON and LS patients in the near future.

  19. Searching the co-occurrence of pathogenic mutations for Leber's hereditary optic neuropathy and hearing loss in more than 26,000 whole mitochondrial genomes.

    PubMed

    Yang, Haixin; Liu, Rui; Wang, Chuan-Chao

    2016-09-01

    The co-occurrence of pathogenic or candidate mutations for Leber's hereditary optic neuropathy (LHON) and hearing loss has long been suggested to be a rare incident. The "rare" is probably caused by inadequate database searches. In this study, we created and released a comprehensive database with detailed information of haplogroup, variants, coding sites, and potential pathogenic mutations for more than 26,000 whole mitochondrial genomes. We found the co-occurrence in more than 200 individuals including not only LHON or hearing loss patients but also individuals sampled from general populations with various haplogroup backgrounds. The results highlighted the significant importance of adequate database searching in the genetic analysis of mitochondrial disorders.

  20. Prediction of protective sensory loss, neuropathy and foot ulceration in type 2 diabetes

    PubMed Central

    Paisey, R B; Darby, T; George, A M; Waterson, M; Hewson, P; Paisey, C F; Thomson, M P

    2016-01-01

    Objectives To prospectively determine clinical and biochemical characteristics associated with the development of peripheral neuropathy, loss of protective sensation, and foot ulceration in persons with type 2 diabetes mellitus (DM) over 7 years. Research design and methods Graded monofilament (MF) testing, vibration perception threshold, and neuropathy symptom questionnaires were undertaken in 206 participants with type 2 DM without peripheral vascular disease or history of foot ulceration and 71 healthy participants without DM at baseline and after 7 years. 6 monthly glycosylated hemoglobin (HbA1c) levels and annual serum lipid profiles were measured during follow-up of those with DM. Incident foot ulceration was recorded at follow-up. Results Taller stature and higher quartiles of serum triglyceride and HbA1c levels were associated with neuropathy at follow-up (p=0.008). Remission of baseline neuropathy was observed in 7 participants at follow-up. 9 participants with type 2 DM developed foot ulcers by the end of the study, only 1 at low risk. Mean HbA1c levels were higher in those who developed foot ulceration (p<0.0001). 1 participant with neuropathy throughout developed a Charcot foot. Failure to perceive 2 or more 2, 4 and 6 g MF stimuli at baseline predicted loss of protective sensation at follow-up. Conclusions Tall stature and worse metabolic control were associated with progression to neuropathy. Mean HbA1c levels were higher in those who developed foot ulcers. Graded MF testing may enrich recruitment to clinical trials and assignation of high risk for foot ulceration. PMID:27239314

  1. Simultaneous occurrence of the 11778 (ND4) and the 9438 (COX III) mtDNA mutations in Leber hereditary optic neuropathy: Molecular, biochemical, and clinical findings

    SciTech Connect

    Oostra, R.J.; Bleeker-Wagemakers, E.M.; Zwart, R.

    1995-10-01

    Three mtDNA point mutations at nucleotide position (np) 3460, at np 11778 and at np 14484, are thought to be of primary importance in the pathogenesis of Leber hereditary optic neuropathy (LHON), a maternally inherited disease characterized by subacute central vision loss. These mutations are present in genes coding for subunits of complex I (NADH dehydrogenase) of the respiratory chain, occur exclusively in LHON maternal pedigrees, and have never been reported to occur together. Johns and Neufeld postulated that an mtDNA mutation at np 9438, in the gene coding for one of the subunits (COX III) of complex IV (cytochrome c oxidase), was also of primary importance. Johns and Neufeld (1993) found this mutation, which changed a conserved glycine to a serine, in 5 unrelated LHON probands who did not carry one of the presently known primary mutations, but they did not find it in 400 controls. However, the role of this sequence variant has been questioned in the Journal when it has been found to occur in apparently healthy African and Cuban individuals. Subsequently, Johns et al. described this mutation in two Cuban individuals presenting with optic and peripheral neuropathy. 22 refs., 1 fig., 1 tab.

  2. Severe manifestation of Leber's hereditary optic neuropathy due to 11778G>A mtDNA mutation in a female with hypoestrogenism due to Perrault syndrome.

    PubMed

    Badura-Stronka, Magdalena; Wawrocka, Anna; Zawieja, Krzysztof; Silska, Sylwia; Krawczyński, Maciej Robert

    2013-11-01

    Perrault syndrome (PS) is a rare autosomal recessive condition with ovarian dysgenesis, hearing deficit and neurological abnormalities in female patients. The molecular basis of the syndrome is heterogeneous, mutations in the HSD17B4 gene have been identified in one family and mutations in the HARS2 gene have been found in another one. We have excluded pathogenic changes in the HSD17B4 gene and in the HARS2 gene by a direct sequencing of all coding exons in a female with clinical hallmarks of PS, ataxia and mild mental retardation. In addition, the patient suffers from severe Leber's hereditary optic neuropathy (LHON) due to 11778G>A mtDNA mutation. This case is the first reported patient with PS and LHON. Possible influence of hypoestrogenism on the manifestation of optic neuropathy in this patient is discussed in the context of recent findings concerning the crucial role of estrogens in supporting the vision capacity in LHON-related mtDNA mutation carriers.

  3. [The analysis of mitochondrial DNA haplogroups and variants for Leber's hereditary optic neuropathy in Chinese families carrying the m.14484T >C mutation].

    PubMed

    Meng, Xiangjuan; Zhu, Jinping; Gao, Min; Zhang, Sai; Zhao, Fuxin; Zhang, Juanjuan; Liu, Xiaoling; Wei, Qiping; Tong, Yi; Zhang, Minglian; Qu, Jia; Guan, Minxin

    2014-04-01

    The m.14484T>C mutation in mitochondrial ND6 gene (MT-ND6) is a primary mutation underlying the development of Leber's hereditary optic neuropathy (LHON) , but by itself not enough to cause visual loss. To explore the role of mitochondrial haplogroups on the expression of LHON for the people carrying the m.14484T>C mutation, we performed systematic and extended mutational screening of MT-ND6 gene in a cohort of 1177 Han Chinese patients with LHON. A total of 67 affected subjects carried the homoplasmic m.14484T>C mutation, accounting for 5.7% of this LHON population. The penetrances of optic neuropathy among 51 pedigrees carrying the m.14484T>C mutation ranged from 5.6% to 100.0%, with the average of 21.5%. The sequence analysis of entire mitochondrial genomes of 51 probands exhibited distinct sets of polymorphisms belonging to 18 Eastern Asian haplogroups. The frequencies of haplogroup A and haplogroup F were sig-nificantly less in the LHON mtDNA samples than those in 106 Chinese controls. On the other hand, the haplogroup M10a accounted for 9.8% of the patient's mtDNA samples but was absent in 106 Chinese controls. Strikingly, the average pene-trance (46.13%) of optic neuropathy for the pedigrees carrying mitochondrial haplogroup M10a was higher than those car-rying other mtDNA haplogroups. These observations indicated that mitochondrial haplogroup M10a may increase the risk of visual loss.

  4. Randomized, Double-Blind, Crossover Trial of Amitriptyline for Analgesia in Painful HIV-Associated Sensory Neuropathy

    PubMed Central

    Dinat, Natalya; Marinda, Edmore; Moch, Shirra; Rice, Andrew S. C.; Kamerman, Peter R.

    2015-01-01

    We conducted a randomized, double-blind, placebo-controlled, crossover study at a single center in South Africa, to ascertain whether amitriptyline is an effective analgesic for painful HIV-associated sensory neuropathy of moderate to severe intensity in: i) antiretroviral drug naive individuals, and ii) antiretroviral drug users. 124 HIV-infected participants (antiretroviral drug naive = 62, antiretroviral drug users = 62) who met the study criteria for painful HIV-associated sensory neuropathy were randomized to once-daily oral amitriptyline (titrated to a median: interquartile range of 50: 25-50 mg) or placebo for six weeks, followed by a three-week washout period and subsequent treatment crossover. The primary outcome measure was change from baseline in worst pain intensity of the feet (measured by participant self-report using an 11-point numerical pain rating scale) after six weeks of treatment. 122 of 124 participants completed all study visits and were included in the analysis of the primary outcome. In the antiretroviral drug-naive group (n = 61) there was no significant difference in the mean change in pain score from baseline after six weeks of treatment with placebo or amitriptyline [amitriptyline: 2.8 (SD 3.3) vs. placebo: 2.8 (3.4)]. Similarly, there was no significant difference in the change in pain score after six weeks of treatment with placebo or amitriptyline in the antiretroviral drug-user group (n = 61) [amitriptyline: 2.7 (3.3) vs. placebo: 2.1 (2.8)]. Controlling for period effects and treatment order effects did not alter the outcome of the analyses. Nor did analyzing the intention-to-treat cohort (missing data interpolated using baseline observation carried forward) alter the outcome of the analyses. In summary, amitriptyline, at the doses used here, was no more effective than an inactive placebo at reducing pain intensity in individuals with painful HIV-associated sensory neuropathy of moderate to severe intensity, irrespective of whether

  5. Role of the DNA base excision repair protein, APE1 in cisplatin, oxaliplatin, or carboplatin induced sensory neuropathy.

    PubMed

    Kelley, Mark R; Jiang, Yanlin; Guo, Chunlu; Reed, April; Meng, Hongdi; Vasko, Michael R

    2014-01-01

    Although chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of platinum drugs, the mechanisms of this toxicity remain unknown. Previous work in our laboratory suggests that cisplatin-induced CIPN is secondary to DNA damage which is susceptible to base excision repair (BER). To further examine this hypothesis, we studied the effects of cisplatin, oxaliplatin, and carboplatin on cell survival, DNA damage, ROS production, and functional endpoints in rat sensory neurons in culture in the absence or presence of reduced expression of the BER protein AP endonuclease/redox factor-1 (APE1). Using an in situ model of peptidergic sensory neuron function, we examined the effects of the platinum drugs on hind limb capsaicin-evoked vasodilatation. Exposing sensory neurons in culture to the three platinum drugs caused a concentration-dependent increase in apoptosis and cell death, although the concentrations of carboplatin were 10 fold higher than cisplatin. As previously observed with cisplatin, oxaliplatin and carboplatin also increased DNA damage as indicated by an increase in phospho-H2AX and reduced the capsaicin-evoked release of CGRP from neuronal cultures. Both cisplatin and oxaliplatin increased the production of ROS as well as 8-oxoguanine DNA adduct levels, whereas carboplatin did not. Reducing levels of APE1 in neuronal cultures augmented the cisplatin and oxaliplatin induced toxicity, but did not alter the effects of carboplatin. Using an in vivo model, systemic injection of cisplatin (3 mg/kg), oxaliplatin (3 mg/kg), or carboplatin (30 mg/kg) once a week for three weeks caused a decrease in capsaicin-evoked vasodilatation, which was delayed in onset. The effects of cisplatin on capsaicin-evoked vasodilatation were attenuated by chronic administration of E3330, a redox inhibitor of APE1 that serendipitously enhances APE1 DNA repair activity in sensory neurons. These outcomes support the importance of the BER pathway, and particularly APE

  6. Role of the DNA Base Excision Repair Protein, APE1 in Cisplatin, Oxaliplatin, or Carboplatin Induced Sensory Neuropathy

    PubMed Central

    Kelley, Mark R.; Jiang, Yanlin; Guo, Chunlu; Reed, April; Meng, Hongdi; Vasko, Michael R.

    2014-01-01

    Although chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of platinum drugs, the mechanisms of this toxicity remain unknown. Previous work in our laboratory suggests that cisplatin-induced CIPN is secondary to DNA damage which is susceptible to base excision repair (BER). To further examine this hypothesis, we studied the effects of cisplatin, oxaliplatin, and carboplatin on cell survival, DNA damage, ROS production, and functional endpoints in rat sensory neurons in culture in the absence or presence of reduced expression of the BER protein AP endonuclease/redox factor-1 (APE1). Using an in situ model of peptidergic sensory neuron function, we examined the effects of the platinum drugs on hind limb capsaicin-evoked vasodilatation. Exposing sensory neurons in culture to the three platinum drugs caused a concentration-dependent increase in apoptosis and cell death, although the concentrations of carboplatin were 10 fold higher than cisplatin. As previously observed with cisplatin, oxaliplatin and carboplatin also increased DNA damage as indicated by an increase in phospho-H2AX and reduced the capsaicin-evoked release of CGRP from neuronal cultures. Both cisplatin and oxaliplatin increased the production of ROS as well as 8-oxoguanine DNA adduct levels, whereas carboplatin did not. Reducing levels of APE1 in neuronal cultures augmented the cisplatin and oxaliplatin induced toxicity, but did not alter the effects of carboplatin. Using an in vivo model, systemic injection of cisplatin (3 mg/kg), oxaliplatin (3 mg/kg), or carboplatin (30 mg/kg) once a week for three weeks caused a decrease in capsaicin-evoked vasodilatation, which was delayed in onset. The effects of cisplatin on capsaicin-evoked vasodilatation were attenuated by chronic administration of E3330, a redox inhibitor of APE1 that serendipitously enhances APE1 DNA repair activity in sensory neurons. These outcomes support the importance of the BER pathway, and particularly APE

  7. Neurological associations in auditory neuropathy spectrum disorder: Results from a tertiary hospital in South India

    PubMed Central

    Lepcha, Anjali; Chandran, Reni K.; Alexander, Mathew; Agustine, Ann Mary; Thenmozhi, K.; Balraj, Achamma

    2015-01-01

    Aims: To find out the prevalence and types of neurological abnormalities associated in auditory neuropathy spectrum disorder in a large tertiary referral center. Settings and Design: A prospective clinical study was conducted on all patients diagnosed with auditory neuropathy spectrum disorder in the ear, nose, and throat (ENT) and neurology departments during a 17-month period. Patients with neurological abnormalities on history and examination were further assessed by a neurologist to determine the type of disorder present. Results: The frequency of auditory neuropathy spectrum disorder was 1.12%. Sixty percent were found to have neurological involvement. This included cerebral palsy in children, peripheral neuropathy (PN), spinocerebellar ataxia, hereditary motor-sensory neuropathy, spastic paresis, and ponto-bulbar palsy. Neurological lesions did not present simultaneously with hearing loss in most patients. Sixty-six percent of patients with auditory neuropathy spectrum disorder were born of consanguineous marriages. Conclusions: There is a high prevalence of neurological lesions in auditory neuropathy spectrum disorder which has to be kept in mind while evaluating such patients. Follow-up and counselling regarding the appearance of neuropathies is therefore important in such patients. A hereditary etiology is indicated in a majority of cases of auditory neuropathy spectrum disorder. PMID:26019414

  8. Very low penetrance of Leber's hereditary optic neuropathy in five Han Chinese families carrying the ND1 G3460A mutation.

    PubMed

    Tong, Yi; Sun, Yan-Hong; Zhou, Xiangtian; Zhao, Fuxin; Mao, Yijian; Wei, Qi-ping; Yang, Li; Qu, Jia; Guan, Min-Xin

    2010-04-01

    We report here the clinical, genetic, and molecular characterization of five Han Chinese families with Leber's hereditary optic neuropathy (LHON). Strikingly, there were very low penetrances of visual impairment in these Chinese families, ranging from 4.2% to 22.2%, with an average of 10.2%. In particular, only 7 (4 males/3 females) of 106 matrilineal relatives in these families exhibited the variable severity and age-at-onset in visual dysfunction. The age-at-onset for visual impairment in matrilineal relatives in these families, varied from 20 to 25 years, with an average of 21.8 years old. Molecular analysis of mitochondrial genomes identified the homoplasmic ND1 G3460A mutation and distinct sets of variants, belonging to the Asian haplogroups B5b, C4a1, D5, F1, and R9, respectively. This suggests that the G3640A mutation occurred sporadically and multiplied through evolution of the mtDNA in China. However, there was the absence of known secondary LHON-associated mtDNA mutations in these Chinese families. Very low penetrance of visual loss in these five Chinese pedigrees strongly indicated that the G3640A mutation was itself insufficient to develop the optic neuropathy. The absence of secondary LHON mtDNA mutations suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the G3640A mutation in those Chinese families with low penetrance of vision loss. However, nuclear modifier genes, epigenetic and environmental factors appear to be modifier factors for the phenotypic manifestation of the G3640A mutation in these Chinese families.

  9. Leber's hereditary optic neuropathy caused by the homoplasmic ND1 m.3635G>A mutation in nine Han Chinese families.

    PubMed

    Zhang, Juanjuan; Jiang, Pingping; Jin, Xiaofen; Liu, Xiaoling; Zhang, Minglian; Xie, Shipeng; Gao, Min; Zhang, Sai; Sun, Yan-Hong; Zhu, Jinping; Ji, Yanchun; Wei, Qi-Ping; Tong, Yi; Guan, Min-Xin

    2014-09-01

    In this report, we investigated the molecular mechanism underlying Leber's hereditary optic neuropathy (LHON)-associated mitochondrial m.3635G>A (p.S110N, ND1) mutation. A mutational screening of ND1 gene in a cohort of 1070 Han Chinese subjects LHON identified the m.3635G>A mutation in nine Chinese families with suggestively maternally transmitted LHON. Thirty-eight (22 males/16 females) of 162 matrilineal relatives in these families exhibited the variable severity and age-at-onset of optic neuropathy. Molecular analysis of their mitochondrial genomes identified the homoplasmic m.3635G>A mutation and distinct sets of polymorphisms belonging to the Asian haplogroups G2a1, R11a, D4, R11a, M7b2, G1a, F1a1, B4, and N9a3, respectively. Using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from one Chinese family into mtDNA-less (ρ(0)) cells, we showed ~27% decrease in the activity of NADH:ubiquinone oxidoreductase (complex I) in mutant cybrids carrying the m.3635G>A mutation, compared with control cybrids. The respiratory deficiency caused by the m.3635G>A mutation results in decreased efficiency of mitochondrial ATP synthesis. These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cybrids. The data provide the direct evidence for the m.3635G>A mutation leading to LHON. Our findings may provide new insights into the understanding of pathophysiology of LHON.

  10. Cell therapy using retinal progenitor cells shows therapeutic effect in a chemically-induced rotenone mouse model of Leber hereditary optic neuropathy.

    PubMed

    Mansergh, Fiona C; Chadderton, Naomi; Kenna, Paul F; Gobbo, Oliviero L; Farrar, G Jane

    2014-11-01

    Primary mitochondrial disorders occur at a prevalence of one in 10 000; ∼50% of these demonstrate ocular pathology. Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial disorder. LHON results from retinal ganglion cell pathology, which leads to optic nerve degeneration and blindness. Over 95% of cases result from one of the three common mutations in mitochondrial genes MTND1, MTND4 and MTND6, which encode elements of the complex I respiratory chain. Various therapies for LHON are in development, for example, intravitreal injection of adeno-associated virus carrying either the yeast NDI1 gene or a specific subunit of mammalian Complex I have shown visual improvement in animal models. Given the course of LHON, it is likely that in many cases prompt administration may be necessary before widespread cell death. An alternative approach for therapy may be the use of stem cells to protect visual function; this has been evaluated by us in a rotenone-induced model of LHON. Freshly dissected embryonic retinal cells do not integrate into the ganglion cell layer (GCL), unlike similarly obtained photoreceptor precursors. However, cultured retinal progenitor cells can integrate in close proximity to the GCL, and act to preserve retinal function as assessed by manganese-enhanced magnetic resonance imaging, optokinetic responses and ganglion cell counts. Cell therapies for LHON therefore represent a promising therapeutic approach, and may be of particular utility in treating more advanced disease. PMID:24569607

  11. X-inactivation patterns in female Leber`s hereditary optic neuropathy patients do not support a strong X-linked determinant

    SciTech Connect

    Pegoraro, E.; Hoffman, E.P.; Carelli, V.; Cortelli, P.

    1996-02-02

    Leber`s hereditary optic neuropathy (LHON) accounts for about 3% of the cases of blindness in young adult males. The underlying mitochondrial pathogenesis of LHON has been well studied, with specific mitochondrial DNA (mtDNA) mutations of structural genes described and well characterized. However, enigmatic aspects of the disease are not explained by mutation data, such as the higher proportion of affected males, the later onset of the disease in females, and the presence of unaffected individuals with a high proportion of mutant mtDNA. A hypothesis which has been put forward to explain the unusual disease expression is a dual model of mtDNA and X-linked nuclear gene inheritance. If a nuclear X-linked modifier gene influences the expression of the mitochondrial-linked mutant gene then the affected females should be either homozygous for the nuclear determinant, or if heterozygous, lyonization should favor the mutant X. In order to determine if an X-linked gene predisposes to LHON phenotype we studied X-inactivation patterns in 35 females with known mtDNA mutations from 10 LHON pedigrees. Our results do not support a strong X-linked determinant in LHON cause: 2 of the 10 (20%) manifesting carriers showed skewing of X-inactivation, as did 3 of the 25 (12%) nonmanifesting carriers. 39 refs., 2 figs., 1 tab.

  12. Mitochondrial tRNAThr 15891C>G mutation was not associated with Leber's hereditary optic neuropathy in Han Chinese patients.

    PubMed

    Jiang, Zhaochang; Yu, Jinfang; Xia, Bohou; Zhuo, Guangchao

    2016-01-01

    Mutations in mitochondrial DNA (mtDNA) were the most important causes of Leber's hereditary optic neuropathy (LHON). To date, approximately 25 LHON-associated mtDNA mutations have been identified in various ethnic populations. Three primary mutations, the 3460G > A, 11778G > A and 14484T > C, in genes encoding the subunits of respiratory chain complex I, were the most common LHON-associated mtDNA mutations. Moreover, secondary mutations in mt-tRNA genes have been reported increasingly to be associated with LHON, simply due to the high mutation rates of mt-tRNAs. There is a lack of functional analysis and a poor genetic evaluation of a certain mt-tRNA mutation, which failed to meet the classic pathogenicity scoring system. As a result, how to classify a pathogenic mutation in mt-tRNA gene became important for both geneticist and clinician to diagnosis the LHON or the suspicious of LHON. In this study, we reassessed the role of a point mutation in mt-tRNA(Thr) gene which had been reported to be a mutation associated with LHON, the pathogenicity of this mutation has been discussed in this context.

  13. Cell therapy using retinal progenitor cells shows therapeutic effect in a chemically-induced rotenone mouse model of Leber hereditary optic neuropathy

    PubMed Central

    Mansergh, Fiona C; Chadderton, Naomi; Kenna, Paul F; Gobbo, Oliviero L; Farrar, G Jane

    2014-01-01

    Primary mitochondrial disorders occur at a prevalence of one in 10 000; ∼50% of these demonstrate ocular pathology. Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial disorder. LHON results from retinal ganglion cell pathology, which leads to optic nerve degeneration and blindness. Over 95% of cases result from one of the three common mutations in mitochondrial genes MTND1, MTND4 and MTND6, which encode elements of the complex I respiratory chain. Various therapies for LHON are in development, for example, intravitreal injection of adeno-associated virus carrying either the yeast NDI1 gene or a specific subunit of mammalian Complex I have shown visual improvement in animal models. Given the course of LHON, it is likely that in many cases prompt administration may be necessary before widespread cell death. An alternative approach for therapy may be the use of stem cells to protect visual function; this has been evaluated by us in a rotenone-induced model of LHON. Freshly dissected embryonic retinal cells do not integrate into the ganglion cell layer (GCL), unlike similarly obtained photoreceptor precursors. However, cultured retinal progenitor cells can integrate in close proximity to the GCL, and act to preserve retinal function as assessed by manganese-enhanced magnetic resonance imaging, optokinetic responses and ganglion cell counts. Cell therapies for LHON therefore represent a promising therapeutic approach, and may be of particular utility in treating more advanced disease. PMID:24569607

  14. A Meta-analysis of the association between different genotypes (G11778A, T14484C and G3460A) of Leber hereditary optic neuropathy and visual prognosis

    PubMed Central

    Guo, Dong-Yu; Wang, Xia-Wei; Hong, Nan; Gu, Yang-Shun

    2016-01-01

    AIM To analyze the influences of different genotypes (G11778A, T14484C and G3460A) of Leber hereditary optic neuropathy (LHON) on visual prognosis. METHODS After a systematic literature search, all relevant studies evaluating the association between the three primary mutations of LHON and visual prognosis were included. All statistical tests were calculated with Revman 5.2 and STATA 12.0. RESULTS Ten independent studies were included finally. A significant association between the three primary mutations and prognostic vision over 0.3 were found in G11778A versus T14484C [odds ratio (OR)=0.10, 95% confidence interval (CI)=0.05-0.17, P<0.001], G11778A versus G3460A (OR=0.18, 95%CI=0.09-0.37, P<0.001) and T14484C versus G3460A (OR=2.45, 95%CI=1.10-5.48, P<0.05). In addition, obtained by pairwise comparison, the vision during onset, age of onset and sex ratio of these three kinds of patients, have no statistical significance (P>0.05). CONCLUSION From pairwise comparison, we conclude that these three different genotypes of LHON are related to patients' visual prognosis. The T14484C patients might have a best prognostic vision, G3460A second, and G11778A worst. And there is little relation between the three different genotypes and patients' vision, age of onset and sex ratio. PMID:27803870

  15. Yeast NDI1 Improve Oxidative Phosphorylation Capacity and Increases Protection Against Oxidative Stress and Cell Death in Cells Carrying a Leber’s Hereditary Optic Neuropathy Mutation

    PubMed Central

    Park, Jeong Soon; Li, You-fen; Bai, Yidong

    2007-01-01

    G11778A in the subunit ND4 gene of NADH dehydrogenase complex is the most common primary mutation found in Leber’s hereditary optic neuropathy (LHON) patients. The NDI1 gene, which encodes the internal NADH -quinone oxidoreductase in Saccharomyces cerevisiae, was introduced into the nuclear genome of a mitochondrial defective human cell line, Le1.3.1, carrying the G11778A mutation. In transformant cell lines, LeNDI1-1 and -2, total and complex I-dependent respiration were fully restored and largely resistant to complex I inhibitor, rotenone, indicating a dominant role of NDI1 in the transfer of electrons in the host cells. Whereas the original mutant Le1.3.1 cell grows poorly in medium containing galactose, the transformants have a fully restored growth capacity in galactose medium, although the ATP production was not totally recovered. Furthermore, the increased oxidative stress in the cells carrying the G11778A mutation was alleviated in transformants, demonstrated by a decreased reactive oxygen species (ROS) level. Finally, transformants were also shown to be desensitized to induction to apoptosis and also exhibit greater resistance to paraquat-induced cell death. It is concluded that the yeast ND11 enzyme can improve the oxidative phosphorylation capacity in cells carrying the G11778A mutation and protect the cells from oxidative stress and cell death. PMID:17320357

  16. Two families with Leber's hereditary optic neuropathy carrying G11778A and T14502C mutations with haplogroup H2a2a1 in mitochondrial DNA.

    PubMed

    Qiao, Chen; Wei, Tanwei; Hu, Bo; Peng, Chunyan; Qiu, Xueping; Wei, Li; Yan, Ming

    2015-08-01

    The mitochondrial haplogroup has been reported to affect the clinical expression of Leber's hereditary optic neuropathy (LHON). The present study aimed to investigate the interaction between mutations and the haplogroup of mitochondrial DNA (mtDNA) in families. Two unrelated families with LHON were enrolled in the study, and clinical, genetic and molecular characterizations were determined in the affected and unaffected family members. Polymerase chain reaction direct sequencing was performed using 24 pairs of overlapping primers for whole mtDNA to screen for mutations and haplogroup. Bioinformatics analysis was performed to evaluate the pathogenic effect of these mtDNA mutations and the haplogroup. The G11778A mutation was identified in the two families. In addition, the members of family 2 exhibited the T14502C mutation and those in family 1 exhibited the T3394C and T14502C mutations, which were regarded as secondary mutations. The penetrance of visual loss in families 1 and 2 were 30.8 and 33.3%, respectively. In addition, the two families were found to be in the H2a2a1 haplogroup. In this limited sample size, it was demonstrated that the H2a2a1 haplogroup had a possible protective effect against LHON. Additional modifying factors, including environmental factors, lifestyle, estrogen levels and nuclear genes may also be important in LHON.

  17. Sensory mononeuropathies.

    PubMed

    Massey, E W

    1998-01-01

    The clinical neurologist frequently encounters patients with a variety of focal sensory symptoms and signs. This article reviews the clinical features, etiologies, laboratory findings, and management of the common sensory mononeuropathies including meralgia paresthetica, cheiralgia paresthetica, notalgia paresthetica, gonyalgia paresthetica, digitalgia paresthetica, intercostal neuropathy, and mental neuropathy. PMID:9608615

  18. Sensory Ataxic Neuropathy in Golden Retriever Dogs Is Caused by a Deletion in the Mitochondrial tRNATyr Gene

    PubMed Central

    Baranowska, Izabella; Jäderlund, Karin Hultin; Nennesmo, Inger; Holmqvist, Erik; Heidrich, Nadja; Larsson, Nils-Göran; Andersson, Göran; Wagner, E. Gerhart H.; Hedhammar, Åke; Wibom, Rolf; Andersson, Leif

    2009-01-01

    Sensory ataxic neuropathy (SAN) is a recently identified neurological disorder in golden retrievers. Pedigree analysis revealed that all affected dogs belong to one maternal lineage, and a statistical analysis showed that the disorder has a mitochondrial origin. A one base pair deletion in the mitochondrial tRNATyr gene was identified at position 5304 in affected dogs after re-sequencing the complete mitochondrial genome of seven individuals. The deletion was not found among dogs representing 18 different breeds or in six wolves, ruling out this as a common polymorphism. The mutation could be traced back to a common ancestor of all affected dogs that lived in the 1970s. We used a quantitative oligonucleotide ligation assay to establish the degree of heteroplasmy in blood and tissue samples from affected dogs and controls. Affected dogs and their first to fourth degree relatives had 0–11% wild-type (wt) sequence, while more distant relatives ranged between 5% and 60% wt sequence and all unrelated golden retrievers had 100% wt sequence. Northern blot analysis showed that tRNATyr had a 10-fold lower steady-state level in affected dogs compared with controls. Four out of five affected dogs showed decreases in mitochondrial ATP production rates and respiratory chain enzyme activities together with morphological alterations in muscle tissue, resembling the changes reported in human mitochondrial pathology. Altogether, these results provide conclusive evidence that the deletion in the mitochondrial tRNATyr gene is the causative mutation for SAN. PMID:19492087

  19. A simple oligonucleotide biochip capable of rapidly detecting known mitochondrial DNA mutations in Chinese patients with Leber's hereditary optic neuropathy (LHON).

    PubMed

    Du, Wei-Dong; Chen, Gang; Cao, Hui-Min; Jin, Qing-Hui; Liao, Rong-Feng; He, Xiang-Cheng; Chen, Da-Ben; Huang, Shu-Ren; Zhao, Hui; Lv, Yong-Mei; Tang, Hua-Yang; Tang, Xian-Fa; Wang, Yong-Qing; Sun, Song; Zhao, Jian-Long; Zhang, Xue-Jun

    2011-01-01

    Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disease. Clinically, no efficient assay protocols have been available. In this study, we aimed to develop an oligonucleotide biochip specialized for detection of known base substitution mutations in mitochondrial DNA causing LHON and to investigate frequencies of LHON relevant variants in Anhui region of China. Thirty-two pairs of oligonucleotide probes matched with the mutations potentially linked to LHON were covalently immobilized. Cy5-lablled targets were amplified from blood DNA samples by a multiplex PCR method. Two kinds of primary mutations 11778 G > A and 14484 T > C from six confirmed LHON patients were interrogated to validate this biochip format. Further, fourteen Chinese LHON pedigrees and twenty-five unrelated healthy individuals were investigated by the LHON biochip, direct sequencing and pyrosequencing, respectively. The biochip was found to be able efficiently to discriminate homoplasmic and heteroplasmic mtDNA mutations in LHON. Biochip analysis revealed that twelve of eighteen LHON symptomatic cases from the 14 Chinese pedigree harbored the mutations either 11778G > A, 14484T > C or 3460G A, respectively, accounting for 66.7%. The mutation 11778G > A in these patients was homoplasmic and prevalent (55.5%, 10 of 18 cases). The mutations 3460G > A and 3394T > C were found to co-exist in one LHON case. The mutation 13708G > A appeared in one LHON pedigree. Smaller amount of sampling and reaction volume, easier target preparation, fast and high-throughput were the main advantages of the biochip over direct DNA sequencing and pyrosequencing. Our findings suggested that primary mutations of 11778G > A, 14484T > C or 3460G > A are main variants of mtDNA gene leading to LHON in China. The biochip would easily be implemented in clinical diagnosis.

  20. Fifteen novel mutations in the mitochondrial NADH dehydrogenase subunit 1, 2, 3, 4, 4L, 5 and 6 genes from Iranian patients with Leber's hereditary optic neuropathy (LHON).

    PubMed

    Rezvani, Zahra; Didari, Elmira; Arastehkani, Ahoura; Ghodsinejad, Vadieh; Aryani, Omid; Kamalidehghan, Behnam; Houshmand, Massoud

    2013-12-01

    Leber's hereditary optic neuropathy (LHON) is an optic nerve dysfunction resulting from mutations in mitochondrial DNA (mtDNA), which is transmitted in a maternal pattern of inheritance. It is caused by three primary point mutations: G11778A, G3460A and T14484C; in the mitochondrial genome. These mutations are sufficient to induce the disease, accounting for the majority of LHON cases, and affect genes that encode for the different subunits of mitochondrial complexes I and III of the mitochondrial respiratory chain. Other mutations are secondary mutations associated with the primary mutations. The purpose of this study was to determine MT-ND variations in Iranian patients with LHON. In order to determine the prevalence and distribution of mitochondrial mutations in the LHON patients, their DNA was studied using PCR and DNA sequencing analysis. Sequencing of MT-ND genes from 35 LHON patients revealed a total of 44 nucleotide variations, in which fifteen novel variations-A14020G, A13663G, C10399T, C4932A, C3893G, C10557A, C12012A, C13934T, G4596A, T12851A, T4539A, T4941A, T13255A, T14353C and del A 4513-were observed in 27 LHON patients. However, eight patients showed no variation in the ND genes. These mutations contribute to the current database of mtDNA polymorphisms in LHON patients and may facilitate the definition of disease-related mutations in human mtDNA. This research may help to understand the disease mechanism and open up new diagnostic opportunities for LHON.

  1. A real-time ARMS PCR/high-resolution melt curve assay for the detection of the three primary mitochondrial mutations in Leber’s hereditary optic neuropathy

    PubMed Central

    Ryan, Fergus; O’Dwyer, Veronica; Neylan, Derek

    2016-01-01

    Purpose Approximately 95% of patients who are diagnosed with Leber’s hereditary optic neuropathy (LHON) have one of three mitochondrial point mutations responsible for the disease, G3460A, G11778A, and T14484C. The purpose of this study was to develop a novel multiplex real-time amplification-refractory mutation system (ARMS) PCR combined with high-resolution melt curves to identify the individual mutations involved. The study aimed to provide a more robust, cost- and time-effective mutation detection strategy than that offered with currently available methods. The assay reported in this study will allow diagnostic laboratories to avoid costly next-generation sequencing (NGS) assays for most patients with LHON and to focus resources on patients with unknown mutations that require further analysis. Methods The test uses a combination of multiplex allele-specific PCR (ARMS PCR) in combination with a high-resolution melt curve analysis to detect the presence of the mutations in G3460A, G11778A, and T14484C. PCR primer sets were designed to produce a control PCR product and PCR products only in the presence of the mutations in 3460A, 11778A, and 14484C in a multiplex single tube format. Products produce discrete well-separated melt curves to clearly detect the mutations. Results This novel real-time ARMS PCR/high-resolution melt curve assay accurately detected 95% of the mutations that cause LHON. The test has proved to be robust, cost- and time-effective with the real-time closed tube system taking approximately 1 h to complete. Conclusions A novel real-time ARMS PCR/high-resolution melt curve assay is described for the detection of the three primary mitochondrial mutations in LHON. This test provides a simple, robust, easy-to-read output that is cost- and time-effective, thus providing an alternative method to individual endpoint PCR-restriction fragment length polymorphism (RFLP), PCR followed by Sanger sequencing or pyrosequencing, and next-generation sequencing

  2. A pilot study of a plantar sensory evaluation system for early screening of diabetic neuropathy in a weight-bearing position.

    PubMed

    Ino, Shuichi; Chikai, Manabu; Takahashi, Noriyo; Ohnishi, Tadasuke; Doi, Kohki; Nunokawa, Kiyohiko

    2014-01-01

    The purpose of this study is to develop smart equipment to quantify plantar tactile sensibility for the early diagnosis and tracking of peripheral neuropathy caused by diabetes mellitus. In this paper, we offer a new testing system that is composed of a plantar tactile stimulation platform with a small moving contactor to stretch the skin tangentially, a response switch for each tactile stimulus, a motor control box, and a personal computer (PC) for psychophysical data processing. This quantitative sensory testing system has detailed measurements available and is easy to use compared with the conventional testing devices, such as von Frey monofilaments, pin-prick testing devices, and current perception threshold testers. When using our testing system in a weight-bearing position, we observed that the plantar tactile thresholds for the tangential stretching stimulus on the plantar surface of the foot ranged from approximately 10 um to 30 um for healthy subjects. However, the threshold for a subject with diabetes was nearly three times higher than that for healthy subjects. The significant difference between these values suggests that the plantar sensory evaluation system using the lateral skin stretch stimulation can be used for early diagnosis, for the accurate staging of diabetic neuropathy, and for evaluating its progression noninvasively in a clinic and at home. PMID:25570747

  3. A pilot study of a plantar sensory evaluation system for early screening of diabetic neuropathy in a weight-bearing position.

    PubMed

    Ino, Shuichi; Chikai, Manabu; Takahashi, Noriyo; Ohnishi, Tadasuke; Doi, Kohki; Nunokawa, Kiyohiko

    2014-01-01

    The purpose of this study is to develop smart equipment to quantify plantar tactile sensibility for the early diagnosis and tracking of peripheral neuropathy caused by diabetes mellitus. In this paper, we offer a new testing system that is composed of a plantar tactile stimulation platform with a small moving contactor to stretch the skin tangentially, a response switch for each tactile stimulus, a motor control box, and a personal computer (PC) for psychophysical data processing. This quantitative sensory testing system has detailed measurements available and is easy to use compared with the conventional testing devices, such as von Frey monofilaments, pin-prick testing devices, and current perception threshold testers. When using our testing system in a weight-bearing position, we observed that the plantar tactile thresholds for the tangential stretching stimulus on the plantar surface of the foot ranged from approximately 10 um to 30 um for healthy subjects. However, the threshold for a subject with diabetes was nearly three times higher than that for healthy subjects. The significant difference between these values suggests that the plantar sensory evaluation system using the lateral skin stretch stimulation can be used for early diagnosis, for the accurate staging of diabetic neuropathy, and for evaluating its progression noninvasively in a clinic and at home.

  4. Distal leg epidermal nerve fiber density as a surrogate marker of HIV-associated sensory neuropathy risk: risk factors and change following initial antiretroviral therapy.

    PubMed

    Shikuma, Cecilia M; Bennett, Kara; Ananworanich, Jintanat; Gerschenson, Mariana; Teeratakulpisarn, Nipat; Jadwattanakul, Tanate; DeGruttola, Victor; McArthur, Justin C; Ebenezer, Gigi; Chomchey, Nitiya; Praihirunkit, Pairoa; Hongchookiat, Piranun; Mathajittiphun, Pornpen; Nakamoto, Beau; Hauer, Peter; Phanuphak, Praphan; Phanuphak, Nittaya

    2015-10-01

    Distal leg epidermal nerve fiber density (ENFD) is a validated predictor of HIV sensory neuropathy (SN) risk. We assessed how ENFD is impacted by initiation of first-time antiretroviral therapy (ART) in subjects free of neuropathy and how it is altered when mitochondrial toxic nucleoside medications are used as part of ART. Serial changes in proximal thigh and distal leg ENFD were examined over 72 weeks in 150 Thai subjects randomized to a regimen of stavudine (d4T) switching to zidovudine (ZDV) at 24 weeks vs ZDV vs tenofovir (TDF) for the entire duration of study, all given in combination with nevirapine. We found individual variations in ENFD change, with almost equal number of subjects who decreased or increased their distal leg ENFD over 72 weeks and no relationship to nucleoside backbone or to development of neuropathic signs or symptoms. Lower baseline distal leg ENFD and greater increases in mitochondrial oxidative phosphorylation complex I (CI) activity were associated with larger increases in distal leg ENFD over 72 weeks. Distal leg ENFD correlated with body composition parameters (body surface area, body mass index, height) as well as with blood pressure measurements. Assessed together with a companion cross-sectional study, we found that mean distal leg ENFD in all HIV+ subjects was lower than in HIV- subjects but similar among HIV+ groups whether ART-naïve or on d4T with/without neuropathy/neuropathic symptoms. The utility of ENFD as a useful predictor of small unmyelinated nerve fiber damage and neuropathy risk in HIV may be limited in certain populations.

  5. Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy

    PubMed Central

    Sames, Lori; Moore, Allison; Arnold, Renee; Ekins, Sean

    2014-01-01

    Approximately 1 in 2500 Americans suffer from Charcot-Marie-Tooth (CMT) disease. The underlying disease mechanisms are unique in most forms of CMT, with many point mutations on various genes causing a toxic accumulation of misfolded proteins. Symptoms of the disease often present within the first two decades of life, with CMT1A patients having reduced compound muscle and sensory action potentials, slow nerve conduction velocities, sensory loss, progressive distal weakness, foot and hand deformities, decreased reflexes, bilateral foot drop and about 5% become wheelchair bound. In contrast, the ultra-rare disease Giant Axonal Neuropathy (GAN) is frequently described as a recessively inherited condition that results in progressive nerve death. GAN usually appears in early childhood and progresses slowly as neuronal injury becomes more severe and leads to death in the second or third decade. There are currently no treatments for any of the forms of CMTs or GAN. We suggest that further clinical studies should analyse electrical impedance myography as an outcome measure for CMT. Further, additional quality of life (QoL) assessments for these CMTs are required, and we need to identify GAN biomarkers as well as develop new genetic testing panels for both diseases. We propose that using the Global Registry of Inherited Neuropathy (GRIN) could be useful for many of these studies. Patient advocacy groups and professional organizations (such as the Hereditary Neuropathy Foundation (HNF), Hannah's Hope Fund (HHF), The Neuropathy Association (TNA) and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) can play a central role in educating clinicians and patients. Undertaking these studies will assist in the correct diagnosis of disease recruiting patients for clinical studies, and will ultimately improve the endpoints for clinical trials. By addressing obstacles that prevent industry investment in various forms of inherited neuropathies, we can

  6. [Screening for hereditary neuromuscular disorders with molecular genetic methods in the Roma population of Hungary].

    PubMed

    Herczegfalvi, Agnes; Pikó, Henriett; Karcagi, Veronika

    2008-11-30

    Recent medical genetic research has identified a number of novel, or previously known, but rare conditions, caused by private founder mutations. The Finnish and Ashkenazi Jew populations provide the best examples for identifying genes in unique genetic disorders. In these populations, research efforts and high-level medical services resulted in intense improvements of medical care and in organization of population-based screening programs. Hereditary disorders of the Roma populations are known for a long time. The genetic background of these diseases has been established by extensive molecular genetic studies. The Romas represent 6% of the Hungarian population and live under extremely bad health conditions. Therefore, our aim was to map the incidence of the hereditary neuromuscular disorders among the Hungarian Roma population. Moreover, we intended to provide proper information, genetic counseling and possible prevention strategies for the families at risk, which should represent a primer task in public health. Because of our experience in neuromuscular disorders, we choose six, frequent, autosomal recessive disorders for these clinical and genetic studies: hereditary motor and sensory neuropathy type Lom (HMSNL), hereditary motor and sensory neuropathy type Russe (HMSNR), congenital cataracts facial dysmorphism syndrome (CCFDN), limb-girdle muscular dystrophy 2C (LGMD2C), congenital myasthenic syndrome (CMS) and spinal muscular atrophy (SMA). Following identification of the founder mutations, the possibility of prenatal diagnosis and carrier screening for family members will contribute to the decrease of the recurrence risk for these severe, mostly untreatable disorders. PMID:19070320

  7. Peripheral Neuropathy

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Peripheral Neuropathy Information Page Condensed from Peripheral Neuropathy Fact Sheet ... Español Additional resources from MedlinePlus What is Peripheral Neuropathy? Peripheral neuropathy describes damage to the peripheral nervous ...

  8. Quantitative Sensory Analysis of Peripheral Neuropathy Produced by Colorectal Cancer and its Exacerbation by Cumulative Dose of Oxaliplatin Chemotherapy

    PubMed Central

    de Carvalho Barbosa, Mariana; Kosturakis, Alyssa K.; Eng, Cathy; Wendelschafer-Crabb, Gwen; Kennedy, William R.; Simone, Donald A.; Wang, Xin Shelley; Cleeland, Charles S.; Dougherty, Patrick M.

    2014-01-01

    The goal in this study was to determine the impact of colorectal cancer and cumulative chemotherapeutic dose on sensory function to gain mechanistic insight to the subtypes of primary afferent fibers damaged by chemotherapy. Patients with colorectal cancer underwent quantitative sensory testing (QST) before and then prior to each cycle of oxaliplatin. These data were compared to that from age- and sex-matched healthy volunteers. The patients showed significant subclinical deficits in sensory function prior to any therapy compared to healthy volunteers. Sensory deficits became more pronounced in patients with chemotherapy. Sensory deficits were most pronounced for modalities mediated by large Aβ myelinated fibers and unmyelinated C fibers whereas those modalities of sensation conveyed by thinly myelinated Aδ fibers appeared showed less sensitivity to chemotherapy. Patients with baseline sensory deficits went on to develop more symptom complaints during chemotherapy than those who had no baseline deficit. Patients who were re-tested 6 to 12 months following chemotherapy showed the most numbness and pain as well as the most pronounced sensory deficits. The pattern of effects on sensory function has clear mechanistic implications for the fibers types that are vulnerable to the toxicity of chemotherapy. PMID:25183707

  9. A New Regulatory Mechanism for Kv7.2 Protein During Neuropathy: Enhanced Transport from the Soma to Axonal Terminals of Injured Sensory Neurons.

    PubMed

    Cisneros, Elsa; Roza, Carolina; Jackson, Nieka; López-García, José Antonio

    2015-01-01

    Kv7.2 channel expression has been reported to decrease in dorsal root ganglia (DRG) following the induction of a peripheral neuropathy while other experiments show that Kv7.2 accumulates in peripheral neuromas. The mechanisms underlying these novel expression patterns are poorly understood. Here we use immunofluorescence methods to analyze Kv7.2 protein expression changes in sensory neurons following peripheral axotomy and the potential role of axonal transport. Results indicate that DRG neurons express Kv7.2 in ~16% of neurons and that this number decreases by about 65% after axotomy. Damaged neurons were identified in DRG by application of the tracer Fluoro-ruby at the site of injury during surgery. Reduction of Kv7.2 expression was particularly strong in damaged neurons although some loss was also found in putative uninjured neurons. In parallel to the decrease in the soma of axotomized sensory neurons, Kv7.2 accumulated at neuromatose fiber endings. Blockade of axonal transport with either vinblastine (VLB) or colchicine (COL) abolished Kv7.2 redistribution in neuropathic animals. Channel distribution rearrangements did not occur following induction of inflammation in the hind paw. Behavioral tests indicate that protein rearrangements within sensory afferents are essential to the development of allodynia under neuropathic conditions. These results suggest that axotomy enhances axonal transport in injured sensory neurons, leading to a decrease of somatic expression of Kv7.2 protein and a concomitant accumulation in damaged fiber endings. Localized changes in channel expression patterns under pathological conditions may create novel opportunities for Kv7.2 channel openers to act as analgesics. PMID:26696829

  10. A New Regulatory Mechanism for Kv7.2 Protein During Neuropathy: Enhanced Transport from the Soma to Axonal Terminals of Injured Sensory Neurons

    PubMed Central

    Cisneros, Elsa; Roza, Carolina; Jackson, Nieka; López-García, José Antonio

    2015-01-01

    Kv7.2 channel expression has been reported to decrease in dorsal root ganglia (DRG) following the induction of a peripheral neuropathy while other experiments show that Kv7.2 accumulates in peripheral neuromas. The mechanisms underlying these novel expression patterns are poorly understood. Here we use immunofluorescence methods to analyze Kv7.2 protein expression changes in sensory neurons following peripheral axotomy and the potential role of axonal transport. Results indicate that DRG neurons express Kv7.2 in ~16% of neurons and that this number decreases by about 65% after axotomy. Damaged neurons were identified in DRG by application of the tracer Fluoro-ruby at the site of injury during surgery. Reduction of Kv7.2 expression was particularly strong in damaged neurons although some loss was also found in putative uninjured neurons. In parallel to the decrease in the soma of axotomized sensory neurons, Kv7.2 accumulated at neuromatose fiber endings. Blockade of axonal transport with either vinblastine (VLB) or colchicine (COL) abolished Kv7.2 redistribution in neuropathic animals. Channel distribution rearrangements did not occur following induction of inflammation in the hind paw. Behavioral tests indicate that protein rearrangements within sensory afferents are essential to the development of allodynia under neuropathic conditions. These results suggest that axotomy enhances axonal transport in injured sensory neurons, leading to a decrease of somatic expression of Kv7.2 protein and a concomitant accumulation in damaged fiber endings. Localized changes in channel expression patterns under pathological conditions may create novel opportunities for Kv7.2 channel openers to act as analgesics. PMID:26696829

  11. Electrodiagnosis of peripheral neuropathy.

    PubMed

    Ross, Mark A

    2012-05-01

    Electrodiagnostic studies are an important component of the evaluation of patients with suspected peripheral nerve disorders. The pattern of findings and the features that are seen on the motor and sensory nerve conduction studies and needle electromyography can help to identify the type of neuropathy, define the underlying pathophysiology (axonal or demyelinating), and ultimately help to narrow the list of possible causes. This article reviews the electrodiagnostic approach to and interpretation of findings in patients with peripheral neuropathies.

  12. [Diabetic neuropathy].

    PubMed

    Lechleitner, Monika; Abrahamian, Heidemarie; Francesconi, Claudia; Kofler, Markus

    2016-04-01

    These are the guidelines for diagnosis and treatment of diabetic neuropathy. This diabetic late complication comprises a number of mono- and polyneuropathies, plexopathies, radiculopathies and autonomic neuropathy. The position statement summarizes characteristic clinical symptoms and techniques for diagnostic assessment of diabetic neuropathy. Recommendations for the therapeutic management of diabetic neuropathy, especially for the control of pain in sensorimotor neuropathy, are provided.

  13. Diabetic Neuropathy

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Diabetic Neuropathy Information Page Table of Contents (click to jump ... Organizations Additional resources from MedlinePlus What is Diabetic Neuropathy? Diabetic neuropathy is a peripheral nerve disorder caused ...

  14. Metabolic neuropathies

    MedlinePlus

    Neuropathy - metabolic ... can be caused by many different things. Metabolic neuropathy may be caused by: A problem with the ... one of the most common causes of metabolic neuropathies. People who are at the highest risk for ...

  15. Fasciculations in human hereditary disease.

    PubMed

    Finsterer, Josef; Aliyev, Rahim

    2015-06-01

    Fasciculations are a manifestation of peripheral nerve hyperexcitability in addition to myokymia, neuromyotonia, cramps, or tetany. Fasciculations occur in hereditary and non-hereditary diseases. Among the hereditary diseases, fasciculations are most frequently reported in familial amyotrophic lateral sclerosis (FALS), and spinal muscular atrophy (SMA). Among the non-hereditary diseases, fasciculations occur most frequently in peripheral nerve hyperexcitability syndromes (Isaac's syndrome, voltage-gated potassium channelopathy, cramp fasciculation syndrome, Morvan syndrome). If the cause of fasciculations remains unknown, they are called benign. Systematically reviewing the literature about fasciculations in hereditary disease shows that fasciculations can be a phenotypic feature in bulbospinal muscular atrophy (BSMA), GM2-gangliosidosis, triple-A syndrome, or hereditary neuropathy. Additionally, fasciculations have been reported in familial amyloidosis, spinocerebellar ataxias, Huntington's disease, Rett syndrome, central nervous system disease due to L1-cell adhesion molecule (L1CAM) mutations, Fabry's disease, or Gerstmann-Sträussler disease. Rarely, fasciculations may be a phenotypic feature in patients with mitochondrial disorders or other myopathies. Fasciculations are part of the phenotype in much more genetic disorders than commonly assumed. Fasciculations not only occur in motor neuron disease, but also in hereditary neuropathy, spinocerebellar ataxia, GM2-gangliosidosis, Huntington's disease, Rett syndrome, Fabry's disease, Gerstmann-Sträussler disease, mitochondrial disorders, or muscular dystrophies. PMID:25073774

  16. Peripheral neuropathy

    MedlinePlus

    Peripheral neuritis; Neuropathy - peripheral; Neuritis - peripheral; Nerve disease; Polyneuropathy ... Neuropathy is very common. There are many types and causes. Often, no cause can be found. Some ...

  17. Detection Rates of Cortical Auditory Evoked Potentials at Different Sensation Levels in Infants with Sensory/Neural Hearing Loss and Auditory Neuropathy Spectrum Disorder.

    PubMed

    Gardner-Berry, Kirsty; Chang, Hsiuwen; Ching, Teresa Y C; Hou, Sanna

    2016-02-01

    With the introduction of newborn hearing screening, infants are being diagnosed with hearing loss during the first few months of life. For infants with a sensory/neural hearing loss (SNHL), the audiogram can be estimated objectively using auditory brainstem response (ABR) testing and hearing aids prescribed accordingly. However, for infants with auditory neuropathy spectrum disorder (ANSD) due to the abnormal/absent ABR waveforms, alternative measures of auditory function are needed to assess the need for amplification and evaluate whether aided benefit has been achieved. Cortical auditory evoked potentials (CAEPs) are used to assess aided benefit in infants with hearing loss; however, there is insufficient information regarding the relationship between stimulus audibility and CAEP detection rates. It is also not clear whether CAEP detection rates differ between infants with SNHL and infants with ANSD. This study involved retrospective collection of CAEP, hearing threshold, and hearing aid gain data to investigate the relationship between stimulus audibility and CAEP detection rates. The results demonstrate that increases in stimulus audibility result in an increase in detection rate. For the same range of sensation levels, there was no difference in the detection rates between infants with SNHL and ANSD. PMID:27587922

  18. The coexistence of mitochondrial ND6 T14484C and 12S rRNA A1555G mutations in a Chinese family with Leber's hereditary optic neuropathy and hearing loss

    SciTech Connect

    Wei Qiping; Zhou Xiangtian; Yang Li; Sun Yanhong; Zhou Jian; Li Guang; Jiang, Robert; Lu Fan; Qu Jia . E-mail: jqu@wzmc.net; Guan Minxin . E-mail: min-xin.guan@cchmc.org

    2007-06-15

    We report here the clinical, genetic and molecular characterization of one three-generation Han Chinese family with Leber's hereditary optic neuropathy (LHON) and hearing loss. Four of 14 matrilineal relatives exhibited the moderate central vision loss at the average age of 12.5 years. Of these, one subject exhibited both LHON and mild hearing impairment. Sequence analysis of the complete mitochondrial genomes in the pedigree showed the presence of homoplasmic LHON-associated ND6 T14484C mutation, deafness-associated 12S rRNA A1555 mutation and 47 other variants belonging to Eastern Asian haplogroup H2. None of other mitochondrial variants was evolutionarily conserved and functional significance. Therefore, the coexistence of the A1555G mutation and T14484C mutations in this Chinese family indicate that the A1555G mutation may play a synergistic role in the phenotypic manifestation of LHON associated ND6 T14484C mutation. However, the incomplete penetrance of vision and hearing loss suggests the involvement of nuclear modifier genes and environmental factors in the phenotypic expression of these mtDNA mutations.

  19. Sensory neuron subpopulation-specific dysregulation of intracellular calcium in a rat model of chemotherapy-induced peripheral neuropathy

    PubMed Central

    Yilmaz, E; Gold, MS

    2015-01-01

    The purpose of the present study was to test the prediction that the unique manifestation of chemotherapeutic-induced peripheral neuropathy (CIPN) would be reflected in a specific pattern of changes in the regulation of the intracellular Ca2+ concentration ([Ca2+]i) in subpopulations of cutaneous neurons. To test this prediction, we characterized the pattern of changes in mechanical nociceptive threshold associated with paclitaxel administration (2 mg/kg, iv, every other day for four days), as well as the impact of target of innervation and paclitaxel treatment on the regulation of [Ca2+]i in subpopulations of putative nociceptive and non-nociceptive neurons. Neurons innervating the glabrous and hairy skin of the hindpaw as well as the thigh were identified with retrograde tracers, and fura-2 was used to assess changes in [Ca2+]i. Paclitaxel was associated with a persistent decrease in mechanical nociceptive threshold in response to stimuli applied to the glabrous skin of the hindpaw, but not the hairy skin of the hindpaw or the thigh. However, in both putative nociceptive and non-nociceptive neurons, resting [Ca2+]i was significantly lower in neurons innervating the thigh after treatment. The magnitude of the depolarization-evoked Ca2+ transient was also lower in putative non-nociceptive thigh neurons. More interestingly, while paclitaxel had no detectable influence on either resting or depolarization-evoked Ca2+ transients in putative non-nociceptive neurons, in putative nociceptive neurons there was a subpopulation- specific decrease in the duration of the evoked Ca2+ transient that was largely restricted to neurons innervating the glabrous skin. These results suggest that peripheral nerve length alone, does not account for the selective distribution of CIPN symptoms. Rather, they suggest the symptoms of CIPN reflect an interaction between the toxic actions of the therapeutic and unique properties of the neurons deleteriously impacted. PMID:25982563

  20. Diabetic neuropathy.

    PubMed

    Vinik, Aaron I; Nevoret, Marie-Laure; Casellini, Carolina; Parson, Henri

    2013-12-01

    Diabetic neuropathy (DN) is the most common and troublesome complication of diabetes mellitus, leading to the greatest morbidity and mortality and resulting in a huge economic burden for diabetes care. The clinical assessment of diabetic peripheral neuropathy and its treatment options are multifactorial. Patients with DN should be screened for autonomic neuropathy, as there is a high degree of coexistence of the two complications. A review of the clinical assessment and treatment algorithms for diabetic neuropathy, painful neuropathy, and autonomic dysfunction is provided.

  1. Amplitudes of Pain-Related Evoked Potentials Are Useful to Detect Small Fiber Involvement in Painful Mixed Fiber Neuropathies in Addition to Quantitative Sensory Testing – An Electrophysiological Study

    PubMed Central

    Hansen, Niels; Kahn, Ann-Kathrin; Zeller, Daniel; Katsarava, Zaza; Sommer, Claudia; Üçeyler, Nurcan

    2015-01-01

    To investigate the usefulness of pain-related evoked potentials (PREP) elicited by electrical stimulation for the identification of small fiber involvement in patients with mixed fiber neuropathy (MFN). Eleven MFN patients with clinical signs of large fiber impairment and neuropathic pain and ten healthy controls underwent clinical and electrophysiological evaluation. Small fiber function, electrical conductivity and morphology were examined by quantitative sensory testing (QST), PREP, and skin punch biopsy. MFN was diagnosed following clinical and electrophysiological examination (chronic inflammatory demyelinating neuropathy: n = 6; vasculitic neuropathy: n = 3; chronic axonal ­neuropathy: n = 2). The majority of patients with MFN characterized their pain by descriptors that mainly represent C-fiber-mediated pain. In QST, patients displayed elevated cold, warm, mechanical, and vibration detection thresholds and cold pain thresholds indicative of MFN. PREP amplitudes in patients correlated with cold (p < 0.05) and warm detection thresholds (p < 0.05). Burning pain and the presence of par-/dysesthesias correlated negatively with PREP amplitudes (p < 0.05). PREP amplitudes correlating with cold and warm detection thresholds, burning pain, and par-/dysesthesias support employing PREP amplitudes as an additional tool in conjunction with QST for detecting small fiber impairment in patients with MFN. PMID:26696950

  2. Neuropathy in Human and Mice with PMP22 null

    PubMed Central

    Saporta, Mario Andre; Katona, Istvan; Zhang, Xuebao; Roper, Helen P.; Carr, Louise; Macdonald, Fiona; Brueton, Louise; Blake, Julian; Suter, Ueli; Reilly, Mary M.; Shy, Michael E.; Li, Jun

    2013-01-01

    Background/Objective Haploinsufficiency of PMP22 causes hereditary neuropathy with liability to pressure palsies (HNPP). However, the biological functions of PMP22 in humans are largely unexplored due to the absence of patients with PMP22 null mutations. Design, Setting and Participants We have evaluated a 7-year-old boy with PMP22 null. Findings were compared with those from nerves of Pmp22 null mice. Results Motor and sensory deficits in the proband were non-length dependent. Weakness was found in cranial muscles, but not in the limbs. Large fiber sensory modalities were profoundly abnormal, which started prior to the maturation of myelin. This is in line with the temporal pattern of PMP22 expression predominantly in cranial motor neurons and DRG during embryonic development, becoming undetectable in adulthood. Moreover, there were conspicuous maturation defects of myelinating Schwann cells that were more significant in motor nerve fibers than in sensory nerve fibers. Conclusions Taken together, these data suggest that PMP22 is important for the normal function of neurons that express PMP22 during early development, such as cranial motor neurons and spinal sensory neurons. Moreover, PMP22 deficiency differentially affects myelination between motor and sensory nerves, which may have contributed to the unique clinical phenotype in the patient with absence of PMP22. PMID:21670407

  3. Mitochondrial protein alterations in a familial peripheral neuropathy caused by the V144D amino acid mutation in the sphingolipid protein, SPTLC1.

    PubMed

    Stimpson, Scott E; Coorssen, Jens R; Myers, Simon J

    2015-01-01

    Axonal degeneration is the final common path in many neurological disorders. Subsets of neuropathies involving the sensory neuron are known as hereditary sensory neuropathies (HSNs). Hereditary sensory neuropathy type I (HSN-I) is the most common subtype of HSN with autosomal dominant inheritance. It is characterized by the progressive degeneration of the dorsal root ganglion (DRG) with clinical symptom onset between the second or third decade of life. Heterozygous mutations in the serine palmitoyltransferase (SPT) long chain subunit 1 (SPTLC1) gene were identified as the pathogenic cause of HSN-I. Ultrastructural analysis of mitochondria from HSN-I patient cells has displayed unique morphological abnormalities that are clustered to the perinucleus where they are wrapped by the endoplasmic reticulum (ER). This investigation defines a small subset of proteins with major alterations in abundance in mitochondria harvested from HSN-I mutant SPTLC1 cells. Using mitochondrial protein isolates from control and patient lymphoblasts, and a combination of 2D gel electrophoresis, immunoblotting and mass spectrometry, we have shown the increased abundance of ubiquinol-cytochrome c reductase core protein 1, an electron transport chain protein, as well as the immunoglobulin, Ig kappa chain C. The regulation of these proteins may provide a new route to understanding the cellular and molecular mechanisms underlying HSN-I. PMID:25584079

  4. Toxic neuropathies.

    PubMed

    Misra, Usha Kant; Kalita, Jayantee

    2009-01-01

    Toxic neuropathies generally result in length dependent axonal neuropathy with the exception of diphtheria and a few toxic neuropathies. In spite of occurrence of diphtheria in India there is paucity of published reports on diphtheritic neuropathy. Arsenic neuropathy commonly occurs in Bengal and Bangladesh because of ground water contamination whereas in Punjab it is due to contamination of opium. Lead neuropathy is rare and has been reported in battery workers and silver refining workers. It produces motor neuropathy resulting in foot drop and wrist drop. Organophosphates are used as pesticides, industrial chemicals and food adulterant. Certain organophosphates such as triorthocresyl phosphate used for or oil adulteration inhibit neurotoxic esterase and result in a delayed type of axonal neuropathy. Alcohol related neuropathy is a controversial issue whether it is due to alcohol related toxicity or due to nutritional deficiencies. Indian studies have revealed that neuropathy occurs both in alcoholic and nonalcoholic cirrhosis. Hexane neuropathy is reported in screen printers and these cases highlight the need for better preventive and occupational measures. Iatrogenic toxic neuropathies have been reported with cisplatin and vincristine. Because of geographical, occupational and health related conditions toxic neuropathies are likely to be more common than reported and greater awareness is needed.

  5. Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia.

    PubMed Central

    Jun, A S; Trounce, I A; Brown, M D; Shoffner, J M; Wallace, D C

    1996-01-01

    A heteroplasmic G-to-A transition at nucleotide pair (np) 14459 within the mitochondrial DNA (mtDNA)-encoded NADH dehydrogenase subunit 6 (ND6) gene has been identified as the cause of Leber hereditary optic neuropathy (LHON) and/or pediatric-onset dystonia in three unrelated families. This ND6 np 14459 mutation changes a moderately conserved alanine to a valine at amino acid position 72 of the ND6 protein. Enzymologic analysis of mitochondrial NADH dehydrogenase (complex I) with submitochondrial particles isolated from Epstein-Barr virus-transformed lymphoblasts revealed a 60% reduction (P < 0.005) of complex I-specific activity in patient cell lines compared with controls, with no differences in enzymatic activity for complexes II plus III, III and IV. This biochemical defect was assigned to the ND6 np 14459 mutation by using transmitochondrial cybrids in which patient Epstein-Barr virus-transformed lymphoblast cell lines were enucleated and the cytoplasts were fused to a mtDNA-deficient (p 0) lymphoblastoid recipient cell line. Cybrids harboring the np 14459 mutation exhibited a 39% reduction (p < 0.02) in complex I-specific activity relative to wild-type cybrid lines but normal activity for the other complexes. Kinetic analysis of the np 14459 mutant complex I revealed that the Vmax of the enzyme was reduced while the Km remained the same as that of wild type. Furthermore, specific activity was inhibited by increasing concentrations of the reduced coenzyme Q analog decylubiquinol. These observations suggest that the np 14459 mutation may alter the coenzyme Q-binding site of complex I. PMID:8622678

  6. Profiling the mitochondrial proteome of Leber's Hereditary Optic Neuropathy (LHON) in Thailand: down-regulation of bioenergetics and mitochondrial protein quality control pathways in fibroblasts with the 11778G>A mutation.

    PubMed

    Tun, Aung Win; Chaiyarit, Sakdithep; Kaewsutthi, Supannee; Katanyoo, Wanphen; Chuenkongkaew, Wanicha; Kuwano, Masayoshi; Tomonaga, Takeshi; Peerapittayamongkol, Chayanon; Thongboonkerd, Visith; Lertrit, Patcharee

    2014-01-01

    Leber's Hereditary Optic Neuropathy (LHON) is one of the commonest mitochondrial diseases. It causes total blindness, and predominantly affects young males. For the disease to develop, it is necessary for an individual to carry one of the primary mtDNA mutations 11778G>A, 14484T>C or 3460G>A. However these mutations are not sufficient to cause disease, and they do not explain the characteristic features of LHON such as the higher prevalence in males, incomplete penetrance, and relatively later age of onset. In order to explore the roles of nuclear encoded mitochondrial proteins in development of LHON, we applied a proteomic approach to samples from affected and unaffected individuals from 3 pedigrees and from 5 unrelated controls. Two-dimensional electrophoresis followed by MS/MS analysis in the mitochondrial lysate identified 17 proteins which were differentially expressed between LHON cases and unrelated controls, and 24 proteins which were differentially expressed between unaffected relatives and unrelated controls. The proteomic data were successfully validated by western blot analysis of 3 selected proteins. All of the proteins identified in the study were mitochondrial proteins and most of them were down regulated in 11778G>A mutant fibroblasts. These proteins included: subunits of OXPHOS enzyme complexes, proteins involved in intermediary metabolic processes, nucleoid related proteins, chaperones, cristae remodelling proteins and an anti-oxidant enzyme. The protein profiles of both the affected and unaffected 11778G>A carriers shared many features which differed from those of unrelated control group, revealing similar proteomic responses to 11778G>A mutation in both affected and unaffected individuals. Differentially expressed proteins revealed two broad groups: a cluster of bioenergetic pathway proteins and a cluster involved in protein quality control system. Defects in these systems are likely to impede the function of retinal ganglion cells, and may lead

  7. Neuropathy Tests

    MedlinePlus

    ... be limited. Home Visit Global Sites Search Help? Neuropathy Share this page: Was this page helpful? Overview | ... of testing are: To diagnose the presence of neuropathy and distinguish it from other conditions that may ...

  8. Peripheral Neuropathy

    MedlinePlus

    ... can be associated with peripheral neuropathy. Metabolic and endocrine disorders impair the body’s ability to transform nutrients into ... to neuropathies as a result of chemical imbalances. Endocrine disorders that lead to hormonal imbalances can disturb normal ...

  9. Alcoholic neuropathy

    MedlinePlus

    Neuropathy - alcoholic; Alcoholic polyneuropathy ... The exact cause of alcoholic neuropathy is unknown. It likely includes both a direct poisoning of the nerve by the alcohol and the effect of poor nutrition ...

  10. High-Resolution Ultrasonography of the Superficial Peroneal Motor and Sural Sensory Nerves May Be a Non-invasive Approach to the Diagnosis of Vasculitic Neuropathy

    PubMed Central

    Üçeyler, Nurcan; Schäfer, Kristina A.; Mackenrodt, Daniel; Sommer, Claudia; Müllges, Wolfgang

    2016-01-01

    High-resolution ultrasonography (HRUS) is an emerging new tool in the investigation of peripheral nerves. We set out to assess the utility of HRUS performed at lower extremity nerves in peripheral neuropathies. Nerves of 26 patients with polyneuropathies of different etiologies and 26 controls were investigated using HRUS. Patients underwent clinical, laboratory, electrophysiological assessment, and a diagnostic sural nerve biopsy as part of the routine work-up. HRUS was performed at the sural, tibial, and the common, superficial, and deep peroneal nerves. The superficial peroneal nerve longitudinal diameter (LD) distinguished best between the groups: patients with immune-mediated neuropathies (n = 13, including six with histology-proven vasculitic neuropathy) had larger LD compared to patients with non-immune-mediated neuropathies (p < 0.05) and to controls (p < 0.001). Among all subgroups, patients with vasculitic neuropathy showed the largest superficial peroneal nerve LD (p < 0.001) and had a larger sural nerve cross-sectional area when compared with disease controls (p < 0.001). Enlargement of the superficial peroneal and sural nerves as detected by HRUS may be a useful additional finding in the differential diagnosis of vasculitic and other immune-mediated neuropathies. PMID:27064457

  11. [Atypical neuropathies associated with diabetes].

    PubMed

    Lozeron, P

    2014-12-01

    Diabetes is the leading cause of neuropathy worldwide and, due to the epidemic progression of the affection, prevalence of diabetic neuropathies will increase in the near future. Beside the typical diabetic neuropathy pattern and the common entrapment neuropathies, several unusual clinical forms have been described with either a symmetrical or an asymmetrical pattern. Treatment-induced neuropathy is an acute sensory affection most commonly related to acute glycemic control. Pain is debilitating and associated with vegetative dysfunction. Prevention is important, as resolution is often incomplete. Several patterns or asymmetrical neuropathies of inflammatory and ischemic origin were described long ago in the lower limb. They are debilitating, most often painful and require steroid treatment. Other patterns affecting the thoracolumbar region or the upper limbs or involving a painless motor deficit must be identified as specific treatments are sometimes needed. An association between diabetes and chronic inflammatory demyelinating polyneuropathy has not been demonstrated but diagnosis may be suggested due to the misleading low conduction velocities seen in classical diabetic neuropathy. Like any other patient, the diabetic patient may present a neuropathy unrelated to diabetes. To facilitate patient care, neurologists should be aware of such clinical entities. PMID:25459114

  12. North America and South America (NA-SA) neuropathy project.

    PubMed

    Pasnoor, Mamatha; Nascimento, Osvaldo J M; Trivedi, Jaya; Wolfe, Gil I; Nations, Sharon; Herbelin, Laura; de Freitas, M G; Quintanilha, Giseli; Khan, Saud; Dimachkie, Mazen; Barohn, Richard

    2013-08-01

    Peripheral neuropathy is a common neurological disorder. There may be important differences and similarities in the diagnosis of peripheral neuropathy between North America (NA) and South America (SA). Neuromuscular databases were searched for neuropathy diagnosis at two North American sites, University of Kansas Medical Center and University of Texas Southwestern Medical Center, and one South American site, Federal Fluminense University in Brazil. All patients were included into one of the six major categories: immune-mediated, diabetic, hereditary, infectious/inflammatory, systemic/metabolic/toxic (not diabetic) and cryptogenic. A comparison of the number of patients in each category was made between North America and South America databases. Total number of cases in North America was 1090 and in South America was 1034 [immune-mediated: NA 215 (19.7%), SA 191 (18%); diabetic: NA 148 (13.5%), SA 236 (23%); hereditary: NA 292 (26.7%), SA 103 (10%); infectious/inflammatory: NA 53 (4.8%), SA 141 (14%); systemic/metabolic/toxic: NA 71 (6.5%), SA 124 (12%); cryptogenic: NA 311 (28.5%), SA 239 (23%)]. Some specific neuropathy comparisons were hereditary neuropathies [Charcot-Marie-Tooth (CMT) cases] in NA 246/292 (84.2%) and SA 60/103 (58%); familial amyloid neuropathy in SA 31/103 (30%) and none in NA. Among infectious neuropathies, cases of human T-lymphotropic virus type 1 (HTLV-1) neuropathy in SA were 36/141(25%), Chagas disease in SA were 13/141(9%) and none for either in NA; cases of neuropathy due to leprosy in NA were 26/53 (49%) and in SA were 39/141(28%). South American tertiary care centers are more likely to see patients with infectious, diabetic and hereditary disorders such as familial amyloid neuropathies. North American tertiary centers are more likely to see patients with CMT. Immune neuropathies and cryptogenic neuropathies were seen equally in North America and South America.

  13. The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation.

    PubMed

    Jiang, Pingping; Jin, Xiaofen; Peng, Yanyan; Wang, Meng; Liu, Hao; Liu, Xiaoling; Zhang, Zengjun; Ji, Yanchun; Zhang, Juanjuan; Liang, Min; Zhao, Fuxin; Sun, Yan-Hong; Zhang, Minglian; Zhou, Xiangtian; Chen, Ye; Mo, Jun Qin; Huang, Taosheng; Qu, Jia; Guan, Min-Xin

    2016-02-01

    Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder. Nuclear modifier genes are proposed to modify the phenotypic expression of LHON-associated mitochondrial DNA (mtDNA) mutations. By using an exome sequencing approach, we identified a LHON susceptibility allele (c.572G>T, p.191Gly>Val) in YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase, which interacts with m.11778G>A mutation to cause visual failure. We performed functional assays by using lymphoblastoid cell lines derived from members of Chinese families (asymptomatic individuals carrying m.11778G>A mutation, or both m.11778G>A and heterozygous p.191Gly>Val mutations and symptomatic subjects harboring m.11778G>A and homozygous p.191Gly>Val mutations) and controls lacking these mutations. The 191Gly>Val mutation reduced the YARS2 protein level in the mutant cells. The aminoacylated efficiency and steady-state level of tRNA(Tyr) were markedly decreased in the cell lines derived from patients both carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The failure in tRNA(Tyr) metabolism impaired mitochondrial translation, especially for polypeptides with high content of tyrosine codon such as ND4, ND5, ND6 and COX2 in cells lines carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The YARS2 p.191Gly>Val mutation worsened the respiratory phenotypes associated with m.11778G>A mutation, especially reducing activities of complexes I and IV. The respiratory deficiency altered the efficiency of mitochondrial ATP synthesis and increased the production of reactive oxygen species. Thus, mutated YARS2 aggravates mitochondrial dysfunctions associated with the m.11778G>A mutation, exceeding the threshold for the expression of blindness phenotype. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutation and mutated nuclear-modifier YARS2.

  14. Diabetic Neuropathies

    PubMed Central

    Russell, James W.; Zilliox, Lindsay A.

    2014-01-01

    Purpose of Review: This article provides an overview for understanding the diagnosis, pathogenesis, and management of diabetic neuropathy. Recent Findings: New information about the pathogenesis of diabetic neuropathy continues to emerge, which will lead to identifying new drug targets. It is clear that the natural history of diabetic neuropathy is changing and the rate of progression is slowing. This is likely because of a combination of earlier diagnosis, improved glycemic management, and improved control of related complications such as hyperlipidemia and hypertension. Early diagnosis is critical, and small fiber neuropathy or subclinical diabetic neuropathy may be reversed or significantly improved with appropriate intervention. The American Academy of Neurology recently published guidelines for the treatment of painful diabetic neuropathy. Summary: Diabetic neuropathy is common and can present with varied clinical presentations discussed in this article. Although treatment currently focuses on pain management, attention should be paid to potential risk factors for neuropathy. For example, glycemic control, hyperlipidemia, and hypertension should be managed with diet, exercise, and medications. Class I or II clinical studies indicate that pregabalin, duloxetine, amitriptyline, gabapentin, and opioids are effective in the management of diabetic neuropathic pain. PMID:25299279

  15. Axonal loss and neuroprotection in optic neuropathies.

    PubMed

    Levin, Leonard A

    2007-06-01

    Most optic neuropathies do not have effective treatments. Examples are ischemic optic neuropathy, Leber hereditary optic neuropathy, optic neuritis, and traumatic optic neuropathy. In some cases, the pathophysiology of the optic nerve injury is not fully understood. For example, while the demyelinative aspects of optic neuritis have been studied, the mechanism by which the axonal loss occurs is less apparent. In other cases, although the pathophysiology of the optic neuropathy may be understood, there is difficulty treating the disease, for example, with traumatic optic neuropathy. In response to this therapeutic dearth, the concept of neuroprotection has arisen. Neuroprotection is a therapeutic paradigm for preventing death of neurons from injury and maintaining function. In optic neuropathies, the corresponding neuron is the retinal ganglion cell. These cells are unable to divide, and optic neuropathies irrevocably result in their death; therefore, the primary target of neuroprotection are retinal ganglion cells and their axons. This review emphasizes that most optic neuropathies are axonal and thus good targets for neuroprotection. PMID:17508035

  16. Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing

    PubMed Central

    Drew, Alexander P; Zhu, Danqing; Kidambi, Aditi; Ly, Carolyn; Tey, Shelisa; Brewer, Megan H; Ahmad-Annuar, Azlina; Nicholson, Garth A; Kennerson, Marina L

    2015-01-01

    Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype–phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identified 41 missense sequence variants in the known IPN genes in our cohort of 110 index patients. Nine variants (8%), identified in the genes MFN2, GJB1, BSCL2, and SETX, are previously reported mutations and considered to be pathogenic in these families. Twelve novel variants (11%) in the genes NEFL, TRPV4, KIF1B, BICD2, and SETX are implicated in the disease but require further evidence of pathogenicity. The remaining 20 variants were confirmed as polymorphisms (not causing the disease) and are detailed here to help interpret sequence variants identified in other family studies. Validation using segregation, normal controls, and bioinformatics tools was valuable as supporting evidence for sequence variants implicated in disease. In addition, we identified one SETX sequence variant (c.7640T>C), previously reported as a putative mutation, which we have confirmed as a nonpathogenic rare polymorphism. This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well-defined cases remains important and will account for most positive

  17. [Hereditary hemocromatosis].

    PubMed

    Franchini, Massimo; Veneri, Dino

    2004-10-01

    Hereditary hemochromatosis is a disorder of iron metabolism characterized by a progressive tissue iron overload which leads to an irreversible organ damage if it is not treated timely. The recent developments in the field of molecular medicine have radically changed the physiopathology and the diagnosis of this disease. However, transferrin saturation and serum ferritin are still the most reliable tests for the detection of subjects with hereditary hemochromatosis. Therapeutic phlebotomy is the mainstay of the treatment of hereditary hemochromatosis. If phlebotomy is started before the onset of irreversible organ damages, the life expectancy of these patients is similar to that of normal population.

  18. Gaze behaviour in hereditary prosopagnosia.

    PubMed

    Schwarzer, Gudrun; Huber, Susanne; Grüter, Martina; Grüter, Thomas; Gross, Cornelia; Hipfel, Melanie; Kennerknecht, Ingo

    2007-09-01

    Prosopagnosia is the inability to recognize someone by the face alone in the absence of sensory or intellectual impairment. In contrast to the acquired form of prosopagnosia we studied the congenital form. Since we could recently show that this form is inherited as a simple monogenic trait we called it hereditary form. To determine whether not only face recognition and neuronal processing but also the perceptual acquisition of facial information is specific to prosopagnosia, we studied the gaze behaviour of four hereditary prosopagnosics in comparison to matched control subjects. This rarely studied form of prosopagnosia ensures that deficits are limited to face recognition. Whereas the control participants focused their gaze on the central facial features, the hereditary prosopagnosics showed a significantly different gaze behaviour. They had a more dispersed gaze and also fixated external facial features. Thus, the face recognition impairment of the hereditary prosopagnosics is reflected in their gaze behaviour.

  19. Electrophysiological profile in arsenic neuropathy.

    PubMed

    Oh, S J

    1991-12-01

    Comprehensive electrophysiological studies were performed on 13 patients with arsenic neuropathy. The most prominent finding was a marked abnormality in sensory nerve conduction in the presence of moderate abnormalities in motor nerve conduction. The motor nerve conduction studies and needle EMG were typical of those seen in axonal degeneration which was confirmed by sural nerve biopsy.

  20. Hereditary angioedema

    MedlinePlus

    ... disease; HAE- Hereditary angioedema; Kallikrein inhibitor-HAE: bradykinin receptor antagonist-HAE; C1-inhibitors-HAE; Hives-HAE ... eyes, tongue, throat, or genitals Swelling of the intestines -- can be severe and lead to abdominal cramping, ...

  1. Autonomic neuropathies

    NASA Technical Reports Server (NTRS)

    Low, P. A.

    1998-01-01

    A limited autonomic neuropathy may underlie some unusual clinical syndromes, including the postural tachycardia syndrome, pseudo-obstruction syndrome, heat intolerance, and perhaps chronic fatigue syndrome. Antibodies to autonomic structures are common in diabetes, but their specificity is unknown. The presence of autonomic failure worsens prognosis in the diabetic state. Some autonomic neuropathies are treatable. Familial amyloid polyneuropathy may respond to liver transplantation. There are anecdotal reports of acute panautonomic neuropathy responding to intravenous gamma globulin. Orthostatic hypotension may respond to erythropoietin or midodrine.

  2. Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy.

    PubMed

    McCampbell, Alexander; Truong, David; Broom, Daniel C; Allchorne, Andrew; Gable, Ken; Cutler, Roy G; Mattson, Mark P; Woolf, Clifford J; Frosch, Matthew P; Harmon, Jeffrey M; Dunn, Teresa M; Brown, Robert H

    2005-11-15

    Mutations in enzymes involved in sphingolipid metabolism and trafficking cause a variety of neurological disorders, but details of the molecular pathophysiology remain obscure. SPTLC1 encodes one subunit of serine palmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis. Mutations in SPTLC1 cause hereditary sensory and autonomic neuropathy (type I) (HSAN1), an adult onset, autosomal dominant neuropathy. HSAN1 patients have reduced SPT activity. Expression of mutant SPTLC1 in yeast and mammalian cell cultures dominantly inhibits SPT activity. We created transgenic mouse lines that ubiquitously overexpress either wild-type (SPTLC1(WT)) or mutant SPTLC1 (SPTLC1(C133W)). We report here that SPTLC1(C133W) mice develop age-dependent weight loss and mild sensory and motor impairments. Aged SPTLC1(C133W) mice lose large myelinated axons in the ventral root of the spinal cord and demonstrate myelin thinning. There is also a loss of large myelinated axons in the dorsal roots, although the unmyelinated fibers are preserved. In the dorsal root ganglia, IB4 staining is diminished, whereas expression of the injury-induced transcription factor ATF3 is increased. These mice represent a novel mouse model of peripheral neuropathy and confirm the link between mutant SPT and neuronal dysfunction. PMID:16210380

  3. Hereditary Pancreatitis.

    PubMed

    Rivera Rivera, Edgardo D; Chugh, Ankur; Cordova, Jonathon; Young, Sona

    2016-02-01

    A 13-year-old boy with a strong family history of hereditary pancreatitis was found to have a PRSS1 mutation after being tested at age 5 years during his first documented incident of pancreatitis. Since then, a multidisciplinary team has been treating him for the diagnosis of hereditary pancreatitis. His pain episodes increased in severity over the past several months such that the pain began to severely interfere with his daily life. After extensive discussion, a total pancreatectomy with auto islet cell transplant was performed. He is now pain free and does not require any insulin. This leads us to the questions of what is hereditary pancreatitis and how is it diagnosed? What are the management and follow-up strategies needed for these patients? This article addresses these questions and informs the reader about this diagnosis and the importance of having a high index of clinical suspicion. PMID:26878183

  4. Which lower limb frontal plane sensory and motor functions predict gait speed and efficiency on uneven surfaces in older persons with diabetic neuropathy?

    PubMed Central

    Allet, L.; Kim, H.; Ashton-Miller, J.A.; Richardson, J.K.

    2012-01-01

    Objective To identify which frontal plane lower limb sensorimotor functions predict gait speed and efficiency (step-width-to-step-length ratio) on an uneven surface. Design Cross sectional, observational study. Setting Biomechanics research laboratory. Participants Thirty-three subjects (14; 42.4% female and 21; 63.6% with diabetic distal symmetric peripheral neuropathy), with a spectrum of lower limb sensorimotor function ranging from normal to marked diabetic neuropathy. Methods Independent variables included ankle inversion/eversion proprioceptive thresholds, and normalized measures of maximum voluntary strength and maximum rate of torque development (RTD) of hip abduction/adduction and ankle inversion/eversion. Kinematic data were obtained using an optoelectronic system as subjects walked over an uneven 10m surface. Main Outcome Measures Dependent variables included gait speed and efficiency (determined by step-width-to-step-length ratio) on an uneven surface. Results Hip adduction RTD, ankle inversion RTD, and hip abduction maximal strength predicted XY% of gait speed, with the first predicting the majority (45%). Ankle inversion RTD was the only significant predictor of gait efficiency, accounting for 46% of its variability. Age predicted neither gait speed nor efficiency. Conclusions The rapid generation of strength in the frontal plane at the hip and ankle is responsible for the successful negotiation of irregular surfaces in older persons. Age demonstrated no independent influence. Training regimens in older persons should include maneuvers that develop strength rapidly in hip adductors and ankle invertors if navigation of uneven surfaces is a functional goal. PMID:22796383

  5. Hereditary Hyperlipoproteinemias

    ERIC Educational Resources Information Center

    Nora, James J.; And Others

    1973-01-01

    Evidence and research indicate that the majority of cases of coronary artery disease represent familial disorders which are best explained by a polygenic hereditary predisposition interacting with emotional triggers such as diet and stress. Early identification is judged necessary. (Authors/JA)

  6. Cryptogenic sensory polyneuropathy.

    PubMed

    Pasnoor, Mamatha; Dimachkie, Mazen M; Barohn, Richard J

    2013-05-01

    Chronic sensory or sensorimotor polyneuropathy is a common cause for referral to neurologists. Despite extensive diagnostic testing, up to one-third of these patients remain without a known cause, and are referred to as having cryptogenic sensory peripheral neuropathy. Symptoms progress slowly. On examination, there may be additional mild toe flexion and extension weakness. Electrophysiologic testing and histology reveals axonal neuropathy. Prognosis is usually favorable, as most patients maintain independent ambulation. Besides patient education and reassurance, management is focused on pharmacotherapy for neuropathic pain and physical therapy for balance training, and, occasionally, assistive devices.

  7. Enhanced Excitability of Primary Sensory Neurons and Altered Gene Expression of Neuronal Ion Channels in Dorsal Root Ganglion in Paclitaxel-Induced Peripheral Neuropathy

    PubMed Central

    Zhang, Haijun; Dougherty, Patrick M.

    2014-01-01

    Background The mechanism of chemotherapy-induced peripheral neuropathy after paclitaxel treatment is not well understood. Given the poor penetration of paclitaxel into central nervous system, peripheral nervous system is most at risk. Methods Intrinsic membrane properties of dorsal root ganglion (DRG) neurons were studied by intracellular recordings. Multiple-gene real-time Polymerase Chain Reaction array was used to investigate gene expression of DRG neuronal ion channels. Results Paclitaxel increased the incidence of spontaneous activity from 4.8% to 27.1% in large and from 0% to 33.3% in medium-sized neurons. Paclitaxel decreased the rheobase (nA) from 1.6 ± 0.1 to 0.8 ± 0.1 in large, from 1.5 ± 0.2 to 0.6 ± 0.1 in medium-sized, and from 1.6 ± 0.2 to 1.0 ± 0.1 in small neurons. After paclitaxel, other characteristics of membrane properties in each group remained the same except that Aδ neurons showed shorter action potential fall time (ms) (1.0 ± 0.2, n = 10 vs. 1.8 ± 0.3, n = 9, paclitaxel vs. vehicle). Meanwhile, real-time polymerase chain reaction array revealed an alteration in expression of some neuronal ion channel genes including upregulation of HCN1 (fold change 1.76 ± 0.06) and Nav1.7 (1.26 ± 0.02) and downregulation of Kir channels (Kir1.1, 0.73 ± 0.05, Kir3.4, 0.66 ± 0.06) in paclitaxel-treated animals. Conclusions The increased neuronal excitability and the changes in gene expression of some neuronal ion channels in DRG may provide insight into the molecular and cellular basis of paclitaxel neuropathy, which may lead to novel therapeutic strategies. PMID:24534904

  8. Generalized pruritus preceding paraneoplastic neuropathy.

    PubMed

    Hébant, Benjamin; Miret, Nicolas; Berthelot, Lucile; Jaafar, Mohamad; Maltête, David; Lefaucheur, Romain

    2016-04-01

    Paraneoplastic syndromes are a group of rare disorders involving non-metastatic systemic effects accompanying malignancies, and occur remotely from the tumor itself. Chronic pruritus lasting more than 6 weeks can be from paraneoplastic origin. A 65-year-old woman was admitted for generalized pruritus lasting for 1 month, despite treatment with prednisolone, levocetirizine and hydroxyzine. General examination was normal. Biological data and gastroscopy were normal. One month later, the patient was readmitted for worsening of her pruritus and walking impairment, revealing a severe sensory neuropathy. Blood anti-Hu antibodies returned positive at a level of 400 (normal <100). Bronchoscopy and bronchial biopsies revealed small-cell lung carcinoma. To our knowledge, the association of generalized pruritus and paraneoplastic neuropathy has been rarely reported. Our observation raises the question of a pathophysiological continuum between pruritus and neuropathy in a paraneoplastic context. PMID:26633089

  9. N-hexane neuropathy in offset printers.

    PubMed Central

    Chang, C M; Yu, C W; Fong, K Y; Leung, S Y; Tsin, T W; Yu, Y L; Cheung, T F; Chan, S Y

    1993-01-01

    In an offset printing factory with 56 workers, 20 (36%) developed symptomatic peripheral neuropathy due to exposure to n-hexane. Another 26 workers (46%) were found to have subclinical neuropathy. The initial change in the nerve conduction study was reduced amplitude of the sensory action potentials, followed by reduced amplitude of the motor action potentials, reduction in motor conduction velocities and increase in distal latencies. These changes indicate primary axonal degeneration with secondary demyelination. Sural nerve biopsy in a severe case showed giant axonal swellings due to accumulation of 10nm neurofilaments, myelin sheath attenuation and widening of nodal gaps. The development of neuropathy bore no direct relationship to the duration of exposure, hence factors such as individual susceptibility may be important. Optic neuropathy and CNS involvement were uncommon and autonomic neuropathy was not encountered. Images PMID:8505647

  10. Animal models of HIV peripheral neuropathy

    PubMed Central

    Burdo, Tricia H; Miller, Andrew D

    2014-01-01

    The use of animal models in the study of HIV and AIDS has advanced our understanding of the underlying pathophysiologic mechanisms of infection. Of the multitude of HIV disease manifestations, peripheral neuropathy remains one of the most common long-term side effects. Several of the most important causes of peripheral neuropathy in AIDS patients include direct association with HIV infection with or without antiretroviral medication and infection with opportunistic agents. Because the pathogeneses of these diseases are difficult to study in human patients, animal models have allowed for significant advancement in the understanding of the role of viral infection and the immune system in disease genesis. This review focuses on rodent, rabbit, feline and rhesus models used to study HIV-associated peripheral neuropathies, focusing specifically on sensory neuropathy and antiretroviral-associated neuropathies. PMID:25214880

  11. [SUPRASCAPULAR NEUROPATHY].

    PubMed

    Massenet, V; Crielaard, J M

    2016-05-01

    Supra-scapular nerve (SSN) damage is a rare, but classical diagnosis that can often be overlooked since the nonspecific clinical history and examination commonly lead to the misdiagnosis of another shoulder disorder. This article details the etiopathology, the patients at risk, the reasons for consultation and the clinical aspects of suprascapular neuropathy; it also outlines its diagnostic and therapeutic approaches. PMID:27337843

  12. Peripheral neuropathies.

    PubMed

    Hanewinckel, R; Ikram, M A; Van Doorn, P A

    2016-01-01

    Peripheral neuropathies are diseases of the peripheral nervous system that can be divided into mononeuropathies, multifocal neuropathies, and polyneuropathies. Symptoms usually include numbness and paresthesia. These symptoms are often accompanied by weakness and can be painful. Polyneuropathies can be divided into axonal and demyelinating forms, which is important for diagnostic reasons. Most peripheral neuropathies develop over months or years, but some are rapidly progressive. Some patients only suffer from mild, unilateral, slowly progressive tingling in the fingers due to median nerve compression in the wrist (carpal tunnel syndrome), while other patients can be tetraplegic, with respiratory insufficiency within 1-2 days due to Guillain-Barré syndrome. Carpal tunnel syndrome, with a prevalence of 5% and incidence of 1-2 per 1000 person-years, is the most common mononeuropathy. Population-based data for chronic polyneuropathy are relatively scarce. Prevalence is estimated at 1% and increases to 7% in persons over 65 years of age. Incidence is approximately 1 per 1000 person-years. Immune-mediated polyneuropathies like Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy are rare diseases, with an annual incidence of approximately 1-2 and 0.2-0.5 per 100 000 persons respectively. Most peripheral neuropathies are more prevalent in older adults and in men, except for carpal tunnel syndrome, which is more common in women. Diabetes is a common cause of peripheral neuropathy and is associated with both mono- and polyneuropathies. Among the group of chronic polyneuropathies, in about 20-25% no direct cause can be found. These are slowly progressive axonal polyneuropathies. PMID:27637963

  13. Chemotherapy-induced peripheral neuropathy.

    PubMed

    Fehrenbacher, Jill C

    2015-01-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is common in patients receiving anticancer treatment and can affect survivability and long-term quality of life of the patient following treatment. The symptoms of CIPN primarily include abnormal sensory discrimination of touch, vibration, thermal information, and pain. There is currently a paucity of pharmacological agents to prevent or treat CIPN. The lack of efficacious therapeutics is due, at least in part, to an incomplete understanding of the mechanisms by which chemotherapies alter the sensitivity of sensory neurons. Although the clinical presentation of CIPN can be similar with the various classes of chemotherapeutic agents, there are subtle differences, suggesting that each class of drugs might induce neuropathy via different mechanisms. Multiple mechanisms have been proposed to underlie the development and maintenance of neuropathy; however, most pharmacological agents generated from preclinical experiments have failed to alleviate the symptoms of CIPN in the clinic. Further research is necessary to identify the specific mechanisms by which each class of chemotherapeutics induces neuropathy.

  14. Giant Axonal Neuropathy

    MedlinePlus

    ... Diversity Find People About NINDS NINDS Giant Axonal Neuropathy Information Page Table of Contents (click to jump ... done? Clinical Trials Organizations What is Giant Axonal Neuropathy? Giant axonal neuropathy (GAN) is a rare inherited ...

  15. Multifocal Motor Neuropathy

    MedlinePlus

    ... Diversity Find People About NINDS NINDS Multifocal Motor Neuropathy Information Page Table of Contents (click to jump ... done? Clinical Trials Organizations What is Multifocal Motor Neuropathy? Multifocal motor neuropathy is a progressive muscle disorder ...

  16. Additional Types of Neuropathy

    MedlinePlus

    ... A A Listen En Español Additional Types of Neuropathy Charcot's Joint Charcot's Joint, also called neuropathic arthropathy, ... can stop bone destruction and aid healing. Cranial Neuropathy Cranial neuropathy affects the 12 pairs of nerves ...

  17. CRYPTOGENIC SENSORY POLYNEUROPATHY

    PubMed Central

    Pasnoor, Mamatha; Dimachkie, Mazen M.; Barohn, Richard J.

    2014-01-01

    Chronic sensory or sensorimotor polyneuropathy is a common cause for referral to neurologists. Despite extensive diagnostic testing, up to one-third of these patients remain without a known cause. They are referred to as having cryptogenic sensory peripheral neuropathy (CSPN). The age of onset is variable but usually in the sixth to seventh decade of life, affecting men and women equally. CSPN symptoms progress slowly, most patients present with distal leg paresthesias or pain that progressed over years to involve the hands. On examination, there may be additional mild toe flexion and extension weakness. Electrophysiologic testing and histology reveals axonal neuropathy. Prognosis is usually favorable as most patients maintain independent ambulation. Besides patient education and reassurance, management is focused on pharmacotherapy of neuropathic pain (see Treatment of Painful Peripheral Neuropathy chapter) and physical therapy for balance training and occasionally assistive devices. PMID:23642719

  18. Nonsyndromic hereditary hearing loss.

    PubMed

    Alford, Raye L

    2011-01-01

    The etiology of hereditary hearing loss is extraordinarily complex. More than 400 genetic syndromes are associated with hearing loss and more than 140 genetic loci associated with nonsyndromic hearing loss have been mapped, with more than 60 genes identified to date. Hereditary hearing loss can be inherited as an autosomal dominant, autosomal recessive, X-linked or mitochondrial (maternally inherited) condition. The overlapping audiologic phenotypes associated with many genes and the variability and/or reduced, sometimes age-related, penetrance of some phenotypic features of syndromic hearing loss can complicate the distinction between various genetic causes of nonsyndromic hearing loss and between nonsyndromic and syndromic hearing loss, especially in childhood. Testing for individual genes associated with nonsyndromic hearing loss, beyond GJB2 which encodes Connexin 26, can become expensive and, without specific phenotypic features to guide selection of genes for testing (such as enlarged vestibular aqueducts, low frequency hearing loss or auditory neuropathy), it is not likely to yield an etiology. Advances in DNA sequencing and the rapid decline in the cost of sequencing presage the availability of testing that can identify the etiology in the majority of cases of genetic hearing loss. However, until comprehensive genetic testing of hearing loss is clinically available and cost-effective, thorough phenotypic and audiologic evaluation and careful documentation of risk factors, infectious exposures and patient and family medical history will continue to be important to efforts directed toward etiologic diagnosis. The complexities associated with interpretation of genetic test results, genetic counseling and genetic risk assessment make consultation with medical geneticists important for many patients.

  19. Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies.

    PubMed

    Lopez Sanchez, M I G; Crowston, J G; Mackey, D A; Trounce, I A

    2016-09-01

    Optic neuropathies are an important cause of blindness worldwide. The study of the most common inherited mitochondrial optic neuropathies, Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) has highlighted a fundamental role for mitochondrial function in the survival of the affected neuron-the retinal ganglion cell. A picture is now emerging that links mitochondrial dysfunction to optic nerve disease and other neurodegenerative processes. Insights gained from the peculiar susceptibility of retinal ganglion cells to mitochondrial dysfunction are likely to inform therapeutic development for glaucoma and other common neurodegenerative diseases of aging. Despite it being a fast-evolving field of research, a lack of access to human ocular tissues and limited animal models of mitochondrial disease have prevented direct retinal ganglion cell experimentation and delayed the development of efficient therapeutic strategies to prevent vision loss. Currently, there are no approved treatments for mitochondrial disease, including optic neuropathies caused by primary or secondary mitochondrial dysfunction. Recent advances in eye research have provided important insights into the molecular mechanisms that mediate pathogenesis, and new therapeutic strategies including gene correction approaches are currently being investigated. Here, we review the general principles of mitochondrial biology relevant to retinal ganglion cell function and provide an overview of the major optic neuropathies with mitochondrial involvement, LHON and ADOA, whilst highlighting the emerging link between mitochondrial dysfunction and glaucoma. The pharmacological strategies currently being trialed to improve mitochondrial dysfunction in these optic neuropathies are discussed in addition to emerging therapeutic approaches to preserve retinal ganglion cell function. PMID:27288727

  20. Hereditary Cerebellar Ataxias: A Korean Perspective

    PubMed Central

    Kim, Ji Sun; Cho, Jin Whan

    2015-01-01

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

  1. Recurrent Episodes of Stroke-Like Symptoms in a Patient with Charcot-Marie-Tooth Neuropathy X Type 1

    PubMed Central

    Wu, Ning; Said, Sarita; Sabat, Shyamsunder; Wicklund, Matthew; Stahl, Mark C.

    2015-01-01

    Charcot-Marie-Tooth disease (CMT), also known as hereditary motor sensory neuropathy, is a heterogeneous group of disorders best known for causing inherited forms of peripheral neuropathy. The X-linked form, CMTX1, is caused by mutations in the gap junction protein beta 1 (GJB1) gene, expressed both by peripheral Schwann cells and central oligodendrocytes. Central manifestations are known but are rare, and there are few case reports of leukoencephalopathy with transient or persistent neurological deficits in patients with this CMT subtype. Here, we report the case of a man with multiple male and female family members affected by neuropathy who carries a pathologic mutation in GJB1. He has experienced three transient episodes with variable neurological deficits over the course of 7 years with corresponding changes on magnetic resonance imaging (MRI). This case illustrates CMT1X as a rare cause of transient neurological deficit and demonstrates the evolution of associated reversible abnormalities on MRI over time. To the best of our knowledge, this report provides the longest period of serial imaging in a single patient with this condition in the English language literature. PMID:26955336

  2. Hereditary hemochromatosis.

    PubMed

    Franchini, Massimo; Veneri, Dino

    2005-04-01

    Hereditary hemochromatosis (HH) is a disorder of iron metabolism characterized by a progressive tissue iron overload which leads to an irreversible organ damage if it is not treated timely. The recent developments in the field of molecular medicine have radically changed the physiopathology and the diagnosis of this disease. However, transferrin saturation and serum ferritin are still the most reliable tests for the detection of subjects with HH. Therapeutic phlebotomy is the mainstay of the treatment of HH. If phlebotomy is started before the onset of irreversible organ damages, the life expectancy of these patients is similar to that of normal population.

  3. An Unusual Postoperative Neuropathy: Foot Drop Contralateral to the Lateral Decubitus Position.

    PubMed

    Morgan, Kyle Joseph; Figueroa, Juan J

    2016-09-01

    Postoperative neuropathy is often related to surgical positioning or improper padding during surgery. However, other causes should be considered, particularly when the deficit does not correlate with a positioning error. A case is presented of a 15-year-old girl who experienced postoperative foot drop contralateral to the lateral decubitus position. Further evaluation led to a clinical diagnosis of hereditary neuropathy with liability to pressure palsies that predisposed the patient to the injury. Anesthesiologists should suspect hereditary neuropathy with liability to pressure palsies in patients presenting for multiple nerve decompression surgeries and be vigilant in the perioperative handling of these susceptible individuals. PMID:27580410

  4. [Hereditary pancreatitis].

    PubMed

    Dyrla, Przemysław; Nowak, Tomasz; Gil, Jerzy; Adamiec, Cezary; Bobula, Mariusz; Saracyn, Marek

    2016-02-01

    Hereditary pancreatitis (HP) is a rare, heterogeneous familial disease and should be suspected in any patient who has suffered at least two attacks of acute pancreatitis for which there is no underlying cause and unexplained chronic pancreatitis with a family history in a first- or second degree relative. with an early onset, mostly during childhood. Genetic factors have been implied in cases of familial chronic pancreatitis. The most common are mutations of the PRSS1 gene on the long arm of the chromosome 7, encoding for the cationic trypsinogen. The inheritance pattern is autosomal dominant with an incomplete penetrance (80%). The inflammation results in repeated DNA damage, error-prone repair mechanisms and the progressive accumulation of genetic mutations. Risk of pancreatic adenocarcinoma is a major concern of many patients with hereditary chronic pancreatitis, but the individual risk is poorly defined. Better risk models of pancreatic cancer in individual patients based on etiology of pancreatitis, family history, genetics, smoking, alcohol, diabetes and the patient's age are needed. PMID:27000817

  5. Peripheral neuropathy and antiretroviral drugs.

    PubMed

    Dalakas, M C

    2001-03-01

    Patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) develop a varying degree of myopathy or neuropathy after long-term therapy. Zidovudine (AZT) causes myopathy; zalcitabine (ddC), didanosine (ddl) and lamuvidine (3TC) cause neuropathy; stavudine (d4T) and fialuridine (FIAU) cause neuropathy or myopathy and lactic acidosis. The tissue distribution of phosphorylases responsible for phosphorylation of NRTIs relates to their selective tissue toxicity. The myopathy is characterized by muscle wasting, myalgia, fatigue, weakness and elevation of CK. The neuropathy is painful, sensory and axonal. In vitro, NRTIs inhibit the gamma-DNA polymerase, responsible for replication of mtDNA, and cause mtDNA dysfunction. In vivo, patients treated with AZT, the best studied NRTI, develop a mitochondrial myopathy with mtDNA depletion, deficiency of COX (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion, as determined with in vivo MRS spectroscopy, due to impaired oxidative phosphorylation. Animals or cultured cells treated with NRTIs develop neuropathy, myopathy, or cell destruction with similar changes in the mitochondria. There is evidence that the NRTI-related neuropathy is also due to mitochondrial toxicity. The NRTIs (AZT, ddC, ddl, d4T, 3TC) contain azido groups that compete with natural thymidine triphosphate as substrates of DNA pol-gamma and terminate mtDNA synthesis. In contrast, FIAU that contains 3'-OH groups serves as an alternate substrate for thymidine triphosphate with DNA pol-gamma and is incorporated into the DNA causing permanent mtDNA dysfunction. The NRTI-induced mitochondrial dysfunction has an influence on the clinical application of these agents, especially at high doses and when combined. They have produced in humans a new category of acquired mitochondrial toxins that cause clinical manifestations resembling the genetic mitochondrial disorders.

  6. Dejerine-Sottas disease and hereditary demyelinating polyneuropathy of infancy.

    PubMed

    Plante-Bordeneuve, Violaine; Said, Gérard

    2002-11-01

    Dejerine-Sottas disease (DSD) was originally described as a hypertrophic polyneuropathy characterized by onset in infancy or early childhood in patients born to unaffected parents. The clinical features included distal sensory changes with ataxia; pes cavus, at times with kyphoscoliosis; motor deficit and atrophy predominating in the distal lower limbs and progressing toward the proximal limbs following a length-dependent pattern; palpable nerve hypertrophy; and Argyll-Robertson pupils. The morphological hallmark was the extensive nerve and root hypertrophy associated with demyelination-remyelination of surviving, originally myelinated axons and profuse Schwann-cell proliferation forming onion bulbs. Wide variations in clinical manifestations of chronic demyelinating polyneuropathies of early onset in children born to unaffected parents have now been reported, with only some of the characteristics required in the original study, and at least seven genes encoding the myelin proteins P0, PMP22, the transcriptional factor EGR2, and others have been implicated. Thus, DSD is now a component of the hereditary demyelinating polyneuropathies of infancy that also include subsets of the recently individualized CMT4 neuropathies. The presumed recessive transmission of patients with DSD should be confirmed by molecular genetic analysis, which is still negative in a significant proportion of patients. The nerve biopsy can be useful in patients in whom genealogical or DNA abnormalities in favor of a genetic disorder are missing, because in a few patients with a progressive or relapsing course the diagnosis of early-onset chronic inflammatory demyelinating polyneuropathy must be considered. PMID:12402282

  7. Abnormal Nutritional Factors in Patients Evaluated at a Neuropathy Center.

    PubMed

    Latov, Norman; Vo, Mary L; Chin, Russell L; Carey, Bridget T; Langsdorf, Jennifer A; Feuer, Naomi T

    2016-06-01

    Abnormal concentrations of nutritional factors were found in 24.1% of 187 patients with neuropathy who were newly seen at our academic neuropathy referral center over a 1-year period. All patients presented with sensory axonal or small fiber neuropathy. In 7.3%, they were present in association with at least one other identifiable cause for neuropathy. Elevated levels of pyridoxal phosphate or mercury occurred more frequently than deficiencies in vitamins B1, B12, or B6. The nutritional abnormalities are amenable to correction by dietary intervention. PMID:27224436

  8. Peripheral Neuropathy in Mouse Models of Diabetes.

    PubMed

    Jolivalt, Corinne G; Frizzi, Katie E; Guernsey, Lucie; Marquez, Alex; Ochoa, Joseline; Rodriguez, Maria; Calcutt, Nigel A

    2016-01-01

    Peripheral neuropathy is a frequent complication of chronic diabetes that most commonly presents as a distal degenerative polyneuropathy with sensory loss. Around 20% to 30% of such patients may also experience neuropathic pain. The underlying pathogenic mechanisms are uncertain, and therapeutic options are limited. Rodent models of diabetes have been used for more than 40 years to study neuropathy and evaluate potential therapies. For much of this period, streptozotocin-diabetic rats were the model of choice. The emergence of new technologies that allow relatively cheap and routine manipulations of the mouse genome has prompted increased use of mouse models of diabetes to study neuropathy. In this article, we describe the commonly used mouse models of type 1 and type 2 diabetes, and provide protocols to phenotype the structural, functional, and behavioral indices of peripheral neuropathy, with a particular emphasis on assays pertinent to the human condition. © 2016 by John Wiley & Sons, Inc. PMID:27584552

  9. Rheumatoid neuropathy: a histological and electrophysiological study

    PubMed Central

    Weller, R. O.; Bruckner, F. E.; Chamberlain, M. Anne

    1970-01-01

    Peripheral nerves in five patients with rheumatoid neuropathy were examined electrophysiologically and by sural nerve biopsy. There was close correlation between the clinical severity of the disease and the degree of nerve damage found histologically and by EMG. Group 1 patients with a mild distal sensory neuropathy showed varying degrees of axonal degeneration in the large myelinated fibres and some segmental demyelination. Group 2 patients with a severe, rapidly progressive sensori-motor neuropathy had extensive loss of myelinated fibres. In one case all the large fibres had degenerated. The second case had lost both large and small myelinated fibres together with many of the non-myelinated axons. The major nerve damage in both groups appeared to be axonal degeneration but some segmental demyelination was detected. Occlusive vascular disease in the vasa nervorum was considered to be the major cause of the nerve damage. Images PMID:4320255

  10. Diabetic autonomic neuropathy.

    PubMed

    Freeman, Roy

    2014-01-01

    Diabetes mellitus is the commonest cause of an autonomic neuropathy in the developed world. Diabetic autonomic neuropathy causes a constellation of symptoms and signs affecting cardiovascular, urogenital, gastrointestinal, pupillomotor, thermoregulatory, and sudomotor systems. Several discrete syndromes associated with diabetes cause autonomic dysfunction. The most prevalent of these are: generalized diabetic autonomic neuropathy, autonomic neuropathy associated with the prediabetic state, treatment-induced painful and autonomic neuropathy, and transient hypoglycemia-associated autonomic neuropathy. These autonomic manifestations of diabetes are responsible for the most troublesome and disabling features of diabetic peripheral neuropathy and result in a significant proportion of the mortality and morbidity associated with the disease.

  11. [Painful neuropathies and small fiber involvement].

    PubMed

    Lefaucheur, J-P

    2014-12-01

    It is customary to consider that a purely sensory and painful neuropathy accompanied by normal electroneuromyographic examination may be or must be a small fiber neuropathy. This leads to perform specific tests, such as measuring the intra-epidermal nerve fiber density on skin biopsy or neurophysiological tests, such as evoked potentials to noxious stimuli (laser) or quantification of thermal sensory thresholds. However, these tests are only sensitive to the loss of small fibers (A-delta and C), which does not reflect the mechanisms responsible for peripheral neuropathic pain. Selective loss of small sensory fibers inherently generates a sensory deficit that does not necessarily present a painful character. Also, assigning the cause of a painful neuropathy to a small fiber neuropathy has no pathophysiological sense, although there are indirect links between these two conditions. In fact, it is not possible to explain univocally peripheral neuropathic pain, which reflects complex and diverse mechanisms, involving different types of nerve fibers. In this context, the clinical and laboratory approach must be improved to better understand the underlying mechanisms. It is imperative to interpret the data provided by laboratory tests and to correlate these data to the clinical signs and symptoms presented by the patients. Thus, one must go beyond many a priori and misinterpretations that unfortunately exist in this area at present and are not based on any solid pathophysiological basis.

  12. Differential diagnosis of Charcot-Marie-Tooth disease and related neuropathies.

    PubMed

    Pareyson, D

    2004-06-01

    The diagnosis of Charcot-Marie-Tooth disease (CMT) and related neuropathies (e. g. Déjèrine-Sottas disease; hereditary neuropathy with liability to pressure palsies) appears to be easy. However, the incredible advances in molecular genetics have greatly complicated the classification of these disorders, and the proper diagnosis of the CMT subtype may be important for correct genetic counselling and prognosis. Moreover, these diseases may be confused with potentially treatable acquired and inherited neuropathies, such as dysimmune neuropathies, familial amyloid polyneuropathy, and Refsum's disease. A number of clinical, laboratory, electrophysiological, morphological and neuroradiological features that may help in the diagnostic process are reviewed in the present paper. DNA investigations are fundamental but need to be properly addressed. Currently, great interest is focused on the role of the immune system in hereditary neuropathies, and surprising findings are coming from research on animal models. PMID:15221625

  13. Axonopathy in peripheral neuropathies: Mechanisms and therapeutic approaches for regeneration.

    PubMed

    Landowski, Lila M; Dyck, P James B; Engelstad, JaNean; Taylor, Bruce V

    2016-10-01

    Peripheral neuropathies (PNs) are injuries or diseases of the nerves which arise from varied aetiology, including metabolic disease, trauma and drug toxicity. The clinical presentation depends on the type of neuropathy, and may include the loss of motor, sensory and autonomic functions, or development of debilitating neuropathic pain distal to the injury site. It can be challenging to identify the aetiology of PNs, as the clinical syndromes are often indistinct. However, the mechanisms that underlie pathological changes in peripheral neuropathy are fundamentally different, depending on the trigger. This review focuses on the axonopathy observed in two frequently encountered forms of peripheral neuropathy, diabetic neuropathy and chemotherapy-induced neuropathy. A key manifestation of axonopathy in PN is the degeneration of terminal arbors of peripheral nerves, resulting in a loss of epidermal nerve fibres and inappropriate termination of nerve endings. Many symptoms of PN arise from aberrant termination of nerve endings, and the underlying axonopathy may be non-reversible, as nerve regeneration after injury and disease is often poor, absent, or aberrant. Directed guidance of terminal arbors back into the epidermis is therefore a suggested approach to treat peripheral neuropathy. This review will outline potential strategies to enhance and guide axonal regeneration and reinnervation in the skin. Using diabetic neuropathy and chemotherapy-induced neuropathy as specific examples, this review examines the setbacks encountered with the translation of growth factors into therapeutics for human neuropathy, and suggests a number of approaches for topical drug delivery.

  14. Subacute arsenic neuropathy: clinical and electrophysiological observations.

    PubMed

    Murphy, M J; Lyon, L W; Taylor, J W

    1981-10-01

    Two patients with subacute arsenic neuropathy are described and the results of serial conduction velocity determinations from the very early stages of the illness to partial recovery are reported. Sensory and motor deficits were maximal within four weeks of the estimated time of exposure. Recovery was slow, with only partial improvement of the neurological deficits two years after onset of the illness. Progressive slowing of motor conduction velocity was observed in the first three months followed by a gradual increase in velocity thereafter. The possible mechanisms underlying the temporal profile of the electrophysiological changes are considered. The need for initiating chelation therapy before the development of the neuropathy is emphasised.

  15. Persisting nutritional neuropathy amongst former war prisoners.

    PubMed Central

    Gill, G V; Bell, D R

    1982-01-01

    Of 898 former Far East prisoners of war, assessed between 1968 and 1981, 49 (5.5%) had evidence of persisting symptomatic neurological disease dating back to their periods of malnutrition in captivity. The commonest syndromes were peripheral neuropathy (often of "burning foot" type), optic atrophy, and sensori-neural deafness. Though nutritional neuropathies disappeared soon after release in most ex-Far East prisoners of war, in some they have persisted up to 36 years since exposure to the nutritional insult. PMID:6292369

  16. Inherited Neuropathies

    PubMed Central

    Li, Jun

    2013-01-01

    With a prevalence of 1 in 2500 people, inherited peripheral nerve diseases, collectively called Charcot-Marie-Tooth disease (CMT), are among the most common inherited neurologic disorders. Patients with CMT typically present with chronic muscle weakness and atrophy in limbs, sensory loss in the feet and hands, and foot deformities. Clinical similarities between patients often require genetic testing to achieve a precise diagnosis. In this article, the author reviews the clinical and pathologic features of CMT, and demonstrates how electrodiagnostic and genetic tools are used to assist in the diagnosis and symptomatic management of the diseases. Several cases are presented to illustrate the diagnostic processes. PMID:23117945

  17. Peroneal neuropathy after weight loss.

    PubMed

    Cruz-Martinez, A; Arpa, J; Palau, F

    2000-06-01

    The objectives of this study were to evaluate the clinical and electrophysiological findings in peroneal mononeuropathies following a weight-reduction diet. Thirty patients with acute peroneal palsy and weight loss were studied. Complete nerve conduction studies (NCS) were performed in upper and lower limbs. NCS showed conduction block (CB) of the peroneal nerve at the fibular head that recovered in 29 patients within 3 weeks to 3 months. Severity of CB was correlated with clinical weakness. Three patients had abnormalities consistent with polyneuropathy (PNP). NCS in asymptomatic relatives confirmed familial neuropathy. Nerve biopsy and molecular study were consistent with hereditary neuropathy with liability to pressure palsies (HNPP). One of these peroneal palsies (6 months) recovered after neurolysis. Weight loss might be a risk factor in peroneal mononeuropathies. NCS is a tool in the diagnosis of the site and severity of the nerve injury. Testing should be considered for relatives of patients with PNP because peroneal mononeuropathies may be the first expression of HNPP.

  18. The neuropathy of erectile dysfunction.

    PubMed

    Bleustein, C B; Arezzo, J C; Eckholdt, H; Melman, A

    2002-12-01

    These studies were intended to explore the relationship between autonomic neuropathy and erectile dysfunction (ED). Sensory thresholds reflecting the integrity of both large diameter, myelinated neurons (ie pressure, touch, vibration) and small diameter axons (ie hot and cold thermal sensation) were determined on the penis and finger. Data were compared across subjects with and without ED, controlling for age, hypertension and diabetes. The correlation of specific thresholds scores and IIEF values were also examined. Seventy-three patients who visited the academic urology clinics at Montefiore hospital were evaluated. All patients were required to complete the erectile function domain of the International Index of Erectile Function (IIEF) questionnaire: 20 subjects had no complaints of ED and scored within the 'normal' range on the IIEF. Patients were subsequently tested on their index finger and glans penis for vibration (Biothesiometer), pressure (Semmes-Weinstein monofilaments), spatial perception (Tactile Circumferential Discriminator), and warm and cold thermal thresholds (Physitemp NTE-2). Sensation of the glans penis, as defined by the examined sensory thresholds, was significantly diminished in patients with ED and these differences remained significant when controlling for age, diabetes and hypertension. In contrast, thresholds on the index finger were equivalent in the ED and non-ED groups. Threshold and IIEF scores were highly correlated, consistent with an association between diminished sensation and decreasing IIEF score (worse erectile functioning). These relations also remained significant when controlling for age, diabetes and hypertension. The findings demonstrate dysfunction of large and small diameter nerve fibers in patients with ED of all etiologies. Further, the neurophysiologic measures validate the use of the IIEF as an index of ED, as objective findings of sensory neuropathy were highly correlated with worse IIEF scores. The sensory

  19. Pupillary signs in diabetic autonomic neuropathy.

    PubMed Central

    Smith, S E; Smith, S A; Brown, P M; Fox, C; Sönksen, P H

    1978-01-01

    Pupillary function was investigated in 36 insulin-dependent diabetics and 36 controls matched for age and sex. About half of the diabetics had evidence of peripheral somatic or autonomic neuropathy, or both. The diabetic patients had abnormally small pupil diameters in the dark and less fluctuation in pupil size (hippus) during continuous illumination than the controls. They also had reduced reflex responses to light flashes of an intensity adjusted for individual retinal sensitivities. The pupillary findings were compared with results of five tests of cardiovascular function and five tests of peripheral sensory and motor nerve function. Almost all the patients with autonomic neuropathy had pupillary signs, which we therefore conclude are a common manifestation of diabetic autonomic neuropathy. PMID:709128

  20. Pathogenesis and treatment of immune-mediated neuropathies.

    PubMed

    Lehmann, Helmar C; Meyer Zu Horste, Gerd; Kieseier, Bernd C; Hartung, Hans-Peter

    2009-07-01

    Immune-mediated neuropathies represent a heterogeneous spectrum of peripheral nerve disorders that can be classified according to time course, predominant involvement of motor/sensory fibers, distribution of deficits and paraclinical parameters such as electrophysiology and serum antibodies. In the last few years, significant advances have been achieved in elucidating underlying pathomechanisms, which made it possible to identify potential therapeutic targets. In this review, we discuss the latest development in pathogenesis and treatment of immune-mediated neuropathies.

  1. Facioscapulohumeral muscular dystrophy and Charcot-Marie-Tooth neuropathy 1A - evidence for “double trouble” overlapping syndromes

    PubMed Central

    2013-01-01

    Background We report on a patient with genetically confirmed overlapping diagnoses of CMT1A and FSHD. This case adds to the increasing number of unique patients presenting with atypical phenotypes, particularly in FSHD. Even if a mutation in one disease gene has been found, further genetic testing might be warranted in cases with unusual clinical presentation. Case presentation The reported 53 years old male patient suffered from walking difficulties and foot deformities first noticed at age 20. Later on, he developed scapuloperoneal and truncal muscle weakness, along with atrophy of the intrinsic hand and foot muscles, pes cavus, claw toes and a distal symmetric hypoesthesia. Motor nerve conduction velocities were reduced to 20 m/s in the upper extremities, and not educible in the lower extremities, sensory nerve conduction velocities were not attainable. Electromyography showed both, myopathic and neurogenic changes. A muscle biopsy taken from the tibialis anterior muscle showed a mild myopathy with some neurogenic findings and hypertrophic type 1 fibers. Whole-body muscle MRI revealed severe changes in the lower leg muscles, tibialis anterior and gastrocnemius muscles were highly replaced by fatty tissue. Additionally, fatty degeneration of shoulder girdle and straight back muscles, and atrophy of dorsal upper leg muscles were seen. Taken together, the presenting features suggested both, a neuropathy and a myopathy. Patient’s family history suggested an autosomal dominant inheritance. Molecular testing revealed both, a hereditary motor and sensory neuropathy type 1A (HMSN1A, also called Charcot-Marie-Tooth neuropathy 1A, CMT1A) due to a PMP22 gene duplication and facioscapulohumeral muscular dystrophy (FSHD) due to a partial deletion of the D4Z4 locus (19 kb). Conclusion Molecular testing in hereditary neuromuscular disorders has led to the identification of an increasing number of atypical phenotypes. Nevertheless, finding the right diagnosis is crucial

  2. Abnormal calcium homeostasis in peripheral neuropathies

    PubMed Central

    Fernyhough, Paul; Calcutt, Nigel A.

    2010-01-01

    Abnormal neuronal calcium (Ca2+) homeostasis has been implicated in numerous diseases of the nervous system. The pathogenesis of two increasingly common disorders of the peripheral nervous system, namely neuropathic pain and diabetic polyneuropathy, has been associated with aberrant Ca2+ channel expression and function. Here we review the current state of knowledge regarding the role of Ca2+ dyshomeostasis and associated mitochondrial dysfunction in painful and diabetic neuropathies. The central impact of both alterations of Ca2+ signalling at the plasma membrane and also intracellular Ca2+ handling on sensory neuron function is discussed and related to abnormal endoplasmic reticulum performance. We also present new data highlighting sub-optimal axonal Ca 2+ signalling in diabetic neuropathy and discuss the putative role for this abnormality in the induction of axonal degeneration in peripheral neuropathies. The accumulating evidence implicating Ca2+ dysregulation with both painful and degenerative neuropathies, along with recent advances in understanding of regional variations in Ca2+ channel and pump structures, makes modulation of neuronal Ca2+ handling an increasingly viable approach for therapeutic interventions against the painful and degenerative aspects of many peripheral neuropathies. PMID:20034667

  3. Novel mutation in spacer region of POLG associated with ataxia neuropathy spectrum and gastroparesis.

    PubMed

    Bostan, Alionka; Glibert, Gerald; Dachy, Bernard; Dan, Bernard

    2012-09-25

    Clinical expression of POLG mutations is largely variable. We present a patient with a new mutation in spacer region of mitochondrial polymerase gamma protein (P765T). The clinical picture is characterized by the presence of sensory-ataxic neuropathy, ophthalmoplegia, dysarthria and gastroparesis, which had not been previously observed in ataxia neuropathy spectrum. PMID:22805437

  4. Peripheral Neuropathy: Symptoms and Signs

    MedlinePlus

    ... Research News Make a Difference Symptoms of Peripheral Neuropathy Print This Page Peripheral Neuropathy symptoms usually start ... slowly over many years. The symptoms of peripheral neuropathy often include: A sensation of wearing an invisible “ ...

  5. Genetic and phenotypic characterization of complex hereditary spastic paraplegia

    PubMed Central

    Kara, Eleanna; Tucci, Arianna; Manzoni, Claudia; Lynch, David S.; Elpidorou, Marilena; Bettencourt, Conceicao; Chelban, Viorica; Manole, Andreea; Hamed, Sherifa A.; Haridy, Nourelhoda A.; Federoff, Monica; Preza, Elisavet; Hughes, Deborah; Pittman, Alan; Jaunmuktane, Zane; Brandner, Sebastian; Xiromerisiou, Georgia; Wiethoff, Sarah; Schottlaender, Lucia; Proukakis, Christos; Morris, Huw; Warner, Tom; Bhatia, Kailash P.; Korlipara, L.V. Prasad; Singleton, Andrew B.; Hardy, John; Wood, Nicholas W.; Lewis, Patrick A.

    2016-01-01

    generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35) (4/97) and two in ZFYVE26/SPG15. Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson’s disease-associated gene ATP13A2, neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes. PMID:27217339

  6. Inherited Peripheral Neuropathies

    PubMed Central

    Saporta, Mario A.; Shy, Michael E.

    2013-01-01

    SYNOPSIS Charcot Marie Tooth disease (CMT) is a heterogeneous group of inherited peripheral neuropathies in which the neuropathy is the sole or primary component of the disorder, as opposed to diseases in which the neuropathy is part of a more generalized neurological or multisystem syndrome. Due to the great genetic heterogeneity of this condition, it can be challenging for the general neurologist to diagnose patients with specific types of CMT. Here, we review the biology of the inherited peripheral neuropathies, delineate major phenotypic features of the CMT subtypes and suggest strategies for focusing genetic testing. PMID:23642725

  7. Giant axonal neuropathy: a rare inherited neuropathy with simple clinical clues

    PubMed Central

    Kamate, Mahesh; Ramakrishna, Shashikala; Kambali, Shweta; Mahadevan, Anita

    2014-01-01

    Giant axonal neuropathy (GAN) is a rare hereditary neurodegenerative disorder characterised by accumulation of excess neurofilaments in the axons of peripheral and central nervous systems, which hampers signal transmission. It usually manifests in infancy and early childhood and is slowly progressive. Those affected with GAN have characteristic curly kinky hair, everted feet and a crouched gait, which suggest the diagnosis in most cases. We describe twin children who presented with difficulty in walking and an abnormal gait since they began walking; clinical clues such as hair changes led us to the final diagnosis. PMID:25216920

  8. Early Electrophysiological Abnormalities and Clinical Neuropathy

    PubMed Central

    Hyllienmark, Lars; Alstrand, Nils; Jonsson, Björn; Ludvigsson, Johnny; Cooray, Gerald; Wahlberg-Topp, Jeanette

    2013-01-01

    OBJECTIVE The aim of this study was to elucidate whether subclinical nerve dysfunction as reflected by neurophysiological testing predicts the development of clinical neuropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Fifty-nine patients were studied twice with neurophysiological measurements at baseline and at follow-up. At baseline, patients were 15.5 ± 3.22 years (range 7–22 years) of age, and duration of diabetes was 6.8 ± 3.3 years. At follow-up, patients were 20–35 years of age, and disease duration was 20 ± 5.3 years (range 10–31 years). RESULTS At baseline, patients showed modestly reduced nerve conduction velocities and amplitudes compared with healthy subjects, but all were free of clinical neuropathy. At follow-up, clinical neuropathy was present in nine (15%) patients. These patients had a more pronounced reduction in peroneal motor nerve conduction velocity (MCV), median MCV, and sural sensory nerve action potential at baseline (P < 0.010–0.003). In simple logistic regression analyses, the predictor with the strongest association with clinical neuropathy was baseline HbA1c (R2 = 48%, odds ratio 7.9, P < 0.002) followed by peroneal MCV at baseline (R2 = 38%, odds ratio 0.6, P < 0.006). With the use of a stepwise forward analysis that included all predictors, first baseline HbA1c and then only peroneal MCV at baseline entered significantly (R2 = 61%). Neuropathy impairment assessment showed a stronger correlation with baseline HbA1c (ρ = 0.40, P < 0.002) than with follow-up HbA1c (ρ = 0.034, P < 0.007). CONCLUSIONS Early defects in nerve conduction velocity predict the development of diabetic neuropathy. However, the strongest predictor was HbA1c during the first years of the disease. PMID:23723354

  9. Painful Traumatic Trigeminal Neuropathy.

    PubMed

    Rafael, Benoliel; Sorin, Teich; Eli, Eliav

    2016-08-01

    This article discusses neuropathic pain of traumatic origin affecting the trigeminal nerve. This syndrome has been termed painful traumatic trigeminal neuropathy by the International Headache Society and replaces atypical odontalgia, deafferentation pain, traumatic neuropathy, and phantom toothache. The discussion emphasizes the diagnosis and the early and late management of injuries to the trigeminal nerve and subsequent painful conditions.

  10. Treatment of peripheral neuropathies.

    PubMed Central

    Hallett, M; Tandon, D; Berardelli, A

    1985-01-01

    There are three general approaches to treatment of peripheral neuropathy. First, an attempt should be made to reverse the pathophysiological process if its nature can be elucidated. Second, nerve metabolism can be stimulated and regeneration encouraged. Third, even if the neuropathy itself cannot be improved, symptomatic therapy can be employed. This review outlines the options available for each approach. PMID:3003254

  11. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice.

    PubMed

    Trammell, Samuel A J; Weidemann, Benjamin J; Chadda, Ankita; Yorek, Matthew S; Holmes, Amey; Coppey, Lawrence J; Obrosov, Alexander; Kardon, Randy H; Yorek, Mark A; Brenner, Charles

    2016-01-01

    Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies. PMID:27230286

  12. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice

    PubMed Central

    Trammell, Samuel A.J.; Weidemann, Benjamin J.; Chadda, Ankita; Yorek, Matthew S.; Holmes, Amey; Coppey, Lawrence J.; Obrosov, Alexander; Kardon, Randy H.; Yorek, Mark A.; Brenner, Charles

    2016-01-01

    Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD+ metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP+ and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies. PMID:27230286

  13. [Past, present, and future in Leber's hereditary optic neuropathy].

    PubMed

    Oguchi, Y

    2001-12-01

    Leber's disease is a disease of optic atrophy first reported by Theodor Leber in 1871. Since then, 130 years have passed. Recently, several new findings about the pathology, causes, and heredity of this disease have been made. In 1988 Wallace and others reported a new mutation of 11778 base pairs of mtDNA of patients with Leber's disease. Since then, the study of this disease has progressed remarkably. In this review clinical studies on Leber's disease which were carried out in our department from 1990 are summarized. 1. Genetic diagnosis and clinics Two hundred and twenty-four cases were examined, including patients at our hospital, for the 8 years between 1990 and 1998. Among them, 72 cases were diagnosed as Leber's disease. There were 3 cases (4%) of 3460 mutations, 63 cases(83%) of 11778 mutations, and 6 cases(8%) of 14484 mutations as primary mutations. The reasons for performing the genetic diagnosis were mostly the need for a definite diagnosis of Leber's disease and research on the genesis of optic nerve atrophy of unknown origin. Concerning the secondary mutations, it was confirmed that these mutations were polymorphic as seen in European and American patients. There is a problem of heteroplasmy about the mtDNA mutation. We developed a simple and exact method to evaluate heteroplasmy by using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). In a study of peripheral blood samples in one family, Leber's disease does not appear under conditions of less than 60% mtDNA mutation. As for the three kinds of mutation in Leber's disease, cases of recovery of a visual acuity of 0.3 and above were only 7% in 11778 mutations, but 38% in 3460 mutations and 50% in 14484 mutations. It is assumed that visual prognosis depends on the kind of mutation. 2. Characteristics of visual evoked potential(VEP) In pattern VEP in the acute stage, latency was not delayed very much, but the amplitude was low. On the other hand, in the acute stage of optic neuritis, the latency was very much delayed and the amplitude was diminished. Therefore, I deduced that not only demyelination of the optic nerve fibers but also papilla-macula bundle defects may play an important role. In flash VEP, only the amplitude was low, but latency was normal. 3. Image analysis of the optic nerve In high resolution T2-weighted fast spin-echo magnetic resonance imaging(MRI), the image of the optic nerve can be clearly demonstrated within a short operation time. In MRI in the acute stage of Leber's disease, the image of the optic nerve appeared almost normal. But in the course of time, patients with Leber's disease showed markedly high signals in the optic nerve on the T2-weighted fast spin-echo MRI, and in the atrophic stage the image of the optic nerve showed thinning. The results in this study support the hypothesis that a primary lesion in Leber's disease may be intraocular. 4. Possibility of therapy at the present time The effectiveness of using idebenone combined with vitamin B2, vitamin C, and isopropyl unoprostone(Rescula) for recovery of the circulation of the optic nerve head for patients in the acute stage was compared with untreated patients. In patients with visual acuity of 0.3 and more, there was no statistical difference between the two groups. The recovery interval up to 0.3 was significantly shorter in the treated group than in the untreated group. I suggest that this kind of treatment may aid spontaneous recovery. Among 15 cases of Leber's disease which occurred in the patients teens, at least one eye in 8 cases(53%) recovered to 0.3 or more. Among the 8 recovered cases, 5 cases were from the treated group. On the other hand, 6 cases were treated and 5 cases recovered visual acuity. It is said that the patients developing the disease at younger ages have a tendency toward visual recovery. Pharmacological treatment can aid recovery. 5. Visual function after the recovery of visual acuity The recovery of visual acuity in Leber's disease has the characteristics of fenestrated central scotoma. The visual acuity can be recovered by the appearance of a small part of sensitive area inside the absolute central scotoma. This phenomenon coincides with the results of VEP which does not recover in spite of recovery of vision. Good visual acuity or bad visual acuity depends not only on the recovery of the total area of the central part but on the existence of an area with good sensitivity. In the results of a Humphrey visual field analyzer(10-2) obtained from 8 recovering patients, the part nasal to the fovea was more sensitive than the temporal area. In the early stage of visual recovery, scanning laser ophthalmoscope(SLO) microperimetry can detect this sensitive area, and with the enlargement of this sensitive area, the Humphrey visual field analyzer(10-2) can also detect this recovery area. 6. Strategy for gene therapy We have succeeded in cloning a human retina-specific amine oxidase gene which was found specifically in retinal ganglion cells. By using this promoter, we are now developing a vector specific to the ganglion cells. The fact that there is spontaneous recovery shows the possibility that some papillamacular bundle may exist. In Leber's disease, retinal ganglion cells may die from the mechanism of apoptosis. Therefore it may be possible to treat this disease by transferring the apoptosis block gene to ganglion cells for protection, and to protect the cells from death by apoptosis. PMID:11802455

  14. Traumatic optic neuropathy.

    PubMed

    Steinsapir, K D; Goldberg, R A

    1994-01-01

    Knowledge concerning the pathophysiologic mechanisms of traumatic optic neuropathy is limited. The optic nerve is a tract of the brain. Therefore, the cellular and biochemical pathophysiology of brain and spinal cord trauma and ischemia provide insight into mechanisms that may operate in traumatic optic neuropathy. The dosage of methylprednisolone (30 mg/kg/6 hours) which was successful in the National Acute Spinal Cord Injury Study 2 (NASCIS 2) evolved from the unique pharmacology of corticosteroids as antioxidants. The management of traumatic optic neuropathy rests on an accurate diagnosis which begins with a comprehensive clinical assessment and appropriate neuroimaging. The results of medical and surgical strategies for treating this injury have not been demonstrated to be better than those achieved without treatment. The spinal cord is a mixed grey and white matter tract of the brain in contrast to the optic nerve which is a pure white matter tract. The treatment success seen with methylprednisolone in the NASCIS 2 study may not generalize to the treatment of traumatic optic neuropathy. Conversely, if the treatment does generalize to the optic nerve, NASCIS 2 data suggests that treatment must be started within eight hours of injury, making traumatic optic neuropathy one of the true ophthalmic emergencies. Given the uncertainties in the treatment, ophthalmologists involved in the management of traumatic optic neuropathy are encouraged to participate in the collaborative study of traumatic optic neuropathy.

  15. Dejerine-Sottas neuropathy with multiple nerve roots enlargement and hypomyelination associated with a missense mutation of the transmembrane domain of MPZ/P0.

    PubMed

    Simonati, Alessandro; Fabrizi, Gian Maria; Taioli, Federica; Polo, Alberto; Cerini, Roberto; Rizzuto, Nicolò

    2002-09-01

    In a patient affected with a slowly progressive, severe form of Dejerine-Sottas syndrome, symmetric enlargement of cranial nerves and focal hypertrophy of cervical and caudal roots were detected following MRI. Neuropathological features of the sural nerve disclosed a dramatic loss of myelinated fibres, with skewed-to-the-left, unimodal distribution of the few residual fibres, consistent with the diagnosis of congenital hypomyelination neuropathy. Genetic analysis revealed this condition to be associated with a heterozygous G to A transition at codon 167 in the exon 4 of the MPZ/P0 gene causing a Gly138Arg substitution in the transmembrane domain of the mature MPZ/P0 protein. Focal enlargement of the nerve trunks in demyelinating, hereditary motor and sensory neuropathies (HMSN) was previously reported in both asymptomatic and symptomatic cases with root compression, but peculiar to this case is the diffuse involvement of both cranial and spinal nerves. We believe that the relevance of nerve trunk hypertrophy in HMSN is probably underevaluated: therefore MRI investigation of the head and spine should be included in the diagnostic study of selected HMSN patients. Molecular analysis of peripheral myelin genes will help to rule out misdiagnosed cases. PMID:12242557

  16. Acetylator phenotype in diabetic neuropathy.

    PubMed

    McLaren, E H; Burden, A C; Moorhead, P J

    1977-07-30

    The proportions of slow and fast acetylators in a group of diabetics with symptomatic peripheral neuropathy were compared with those in a group of diabetics who had had the disease for at least 10 years without developing neuropathy. There was a significantly higher proportion of fast acetylators in the group of diabetics without neuropathy than in those with neuropathy or in the normal population. Hence genetic factors separate from the diabetic diathesis may determine the development of neuropathy in any particular diabetic.

  17. Hereditary Hemochromatosis (For Parents)

    MedlinePlus

    ... buildup can be prevented. Doctors usually diagnose iron overload with these blood tests: serum ferritin : measures the ... disease. previous continue Treatment Doctors treat the iron overload from hereditary hemochromatosis by regularly drawing blood to ...

  18. Hereditary Hemorrhagic Telangiectasia - HHT

    MedlinePlus

    ... Throughout Body Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic disorder that affects about one in 5,000 people and causes arterial blood to flow directly into the veins, creating weakened ballooned vessels that can rupture. Interventional radiologists ...

  19. Hereditary Gingival Fibromatosis

    ERIC Educational Resources Information Center

    Nevin, N. C.

    1971-01-01

    Case studies of two siblings suffering from a gum disorder in which enlargement of the gingival mucosa is caused by a fibrosis. The disorder in the two children was felt to be an hereditary recessive trait. (CD)

  20. Hereditary Spastic Paraplegia

    MedlinePlus

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

  1. [Hereditary movement disorders].

    PubMed

    Schulz, J B

    2007-12-01

    Hereditary movement disorders comprise a group of genetically defined diseases characterized by an impaired control of movements, ataxia and/or spasticity. Affected individuals are disabled, their quality of life significantly reduced and their life expectancy shortened. One or more genetic causes have been identified for many of these diseases, including Huntington's disease, Wilson's disease, spinocerebellar ataxias, recessive ataxias, hereditary spastic paraplegia and hereditary dystonias. Due to their characteristic molecular and biochemical pathogenesis, these rare diseases can often serve as models for more common disorders such as Alzheimer's disease or Parkinson's disease. The primary tasks of the German Network of Hereditary Movement Disorders (GeNeMove), funded by the German Ministry for Education and Research (BMBF), are to co-ordinate basic scientific research and clinical research into rare hereditary movement disorders and to improve the cooperation between the German centers specializing in hereditary movement disorders. For each of the diseases in its scope, GeNeMove works at creating standardized documentation of symptoms and the disease's progressive course over time; developing rating scales for clinical examinations and guidelines for therapy; improving genetic testing; fostering genetic research; and collecting samples of DNA, tissue, CSF and blood from sufferers of the disease for biobanks.

  2. Permanent Peripheral Neuropathy

    PubMed Central

    Higgins, Elizabeth

    2014-01-01

    The health risks and side effects of fluoroquinolone use include the risk of tendon rupture and myasthenia gravis exacerbation, and on August 15, 2013, the Food and Drug Administration updated its warning to include the risk of permanent peripheral neuropathy. We present a case of fluoroquinolone-induced peripheral neuropathy in a patient treated for clinically diagnosed urinary tract infection with ciprofloxacin antibiotic. PMID:26425618

  3. Diabetic neuropathy in children.

    PubMed

    Mah, Jean K; Pacaud, Danièle

    2014-01-01

    The worldwide burden of diabetes and its complications in children continues to increase due to the rise in type 1 and type 2 diabetes. Although overt diabetic neuropathy is rarely present in children and adolescents with diabetes, subclinical diabetic neuropathy has been estimated to occur in approximately half of all children with type 1 diabetes with a duration of 5 years or longer and up to 25% of pediatric patients with newly diagnosed diabetes have abnormal findings on nerve conduction studies. The present review on the state of pediatric diabetic neuropathy covers the definition, prevalence, pathogenesis, diagnosis, risk factors, and possible treatment approaches specific to children and adolescents with diabetes. It also highlights the many unknowns in this field. Nonetheless, new emerging interventions that can either prevent or delay the progression of diabetic microvascular and macrovascular complications may become available in the near future. Until specific interventions for diabetic neuropathy are available for use in children, it will be hard to justify screening for neuropathy other than through clinical assessment. Meanwhile, the search for quicker, easily administered, and quantifiable tests for diabetic neuropathy and efforts to establish valid pediatric norms for well-established measures used in adults will need to continue.

  4. Peripheral neuropathy after hair dye exposure: a case report.

    PubMed

    Deeb, Wissam; Cachia, David; Quinn, Colin; Salameh, Johnny

    2014-06-01

    We present a case of length-dependent sensory axonal polyneuropathy due to lead exposure from a cosmetic product. Serial follow-ups showed a direct relationship between the lead level, clinical symptoms, and the polyneuropathy. Our patient had a relatively short-term exposure to lead after misusing a hair dye on his beard. Nerve conduction studies showed a predominantly axonal sensory neuropathy that correlated with lead blood levels and reached 3 times the upper limit of normal. The patient had an unexpected sensory predominant neuropathy. He had a full recovery after stopping the lead-containing product. Blood lead levels were noted to be below previously reported toxic levels. No other systemic signs of lead toxicity were noted. This could be related to the mucosal route of absorption inducing a reversible injury at lower than previously reported lead levels and after a shorter duration of exposure. PMID:24872215

  5. Dystonin/Bpag1 is a necessary endoplasmic reticulum/nuclear envelope protein in sensory neurons

    SciTech Connect

    Young, Kevin G.; Kothary, Rashmi

    2008-09-10

    Dystonin/Bpag1 proteins are cytoskeletal linkers whose loss of function in mice results in a hereditary sensory neuropathy with a progressive loss of limb coordination starting in the second week of life. These mice, named dystonia musculorum (dt), succumb to the disease and die of unknown causes prior to sexual maturity. Previous evidence indicated that cytoskeletal defects in the axon are a primary cause of dt neurodegeneration. However, more recent data suggests that other factors may be equally important contributors to the disease process. In the present study, we demonstrate perikaryal defects in dorsal root ganglion (DRG) neurons at stages preceding the onset of loss of limb coordination in dt mice. Abnormalities include alterations in endoplasmic reticulum (ER) chaperone protein expression, indicative of an ER stress response. Dystonin in sensory neurons localized in association with the ER and nuclear envelope (NE). A fusion protein ofthe dystonin-a2 isoform, which harbors an N-terminal transmembrane domain, associated with and reorganized the ER in cell culture. This isoform also interacts with the NE protein nesprin-3{alpha}, but not nesprin-3{beta}. Defects in dt mice, as demonstrated here, may ultimately result in pathogenesis involving ER dysfunction and contribute significantly to the dt phenotype.

  6. Periaxin mutations cause a broad spectrum of demyelinating neuropathies.

    PubMed

    Takashima, Hiroshi; Boerkoel, Cornelius F; De Jonghe, Peter; Ceuterick, Chantal; Martin, Jean-Jacques; Voit, Thomas; Schröder, J-Michael; Williams, Anna; Brophy, Peter J; Timmerman, Vincent; Lupski, James R

    2002-06-01

    Previous studies have demonstrated that apparent loss-of-function mutations in the periaxin gene cause autosomal recessive Dejerine-Sottas neuropathy or severe demyelinating Charcot-Marie-Tooth disease. In this report, we extend the associated phenotypes with the identification of two additional families with novel periaxin gene mutations (C715X and R82fsX96) and provide detailed neuropathology. Each patient had marked sensory involvement; two siblings with a homozygous C715X mutation had much worse sensory impairment than motor impairment. Despite early disease onset, these siblings with the C715X mutation had relatively slow disease progression and adult motor impairment typical of classic demyelinating Charcot-Marie-Tooth neuropathy. In contrast, a patient with the homozygous R82fsX96 mutation had a disease course consistent with Dejerine-Sottas neuropathy. The neuropathology of patients in both families was remarkable for demyelination, onion bulb and occasional tomacula formation with focal myelin thickening, abnormalities of the paranodal myelin loops, and focal absence of paranodal septate-like junctions between the terminal loops and axon. Our study indicates a prominent sensory neuropathy resulting from periaxin gene mutations and suggests a role for the carboxyl terminal domain of the periaxin protein. PMID:12112076

  7. Neuropathological alterations in diabetic truncal neuropathy: evaluation by skin biopsy

    PubMed Central

    Lauria, G.; McArthur, J.; Hauer, P.; Griffin, J.; Cornblath, D.

    1998-01-01

    OBJECTIVES—To describe the neuropathological features in skin biopsies from patients with diabetic truncal neuropathy.
METHODS—Three patients with diabetic truncal neuropathy underwent skin biopsies from both symptomatic and asymptomatic regions of the chest and trunk. After local anaesthesia, biopsies were performed using a 3 mm diameter punch device (Acupunch). Intraepidermal nerve fibres (IENFs), the most distal processes of small myelinated and unmyelinated nerve fibres, were identified after staining with PGP 9.5 as previously described.
RESULTS—Diabetes was diagnosed at the time of the neurological presentation in two, and one was a known diabetic patient. All three had associated sensory-motor polyneuropathy. In all, skin biopsies showed a marked reduction of both epidermal and dermal nerve fibres in the symptomatic dermatomes, compared with skin from asymptomatic truncal areas. In one patient, a follow up skin biopsy when symptoms had improved showed a return of IENFs.
CONCLUSIONS—In diabetic truncal neuropathy, skin biopsies from symptomatic regions show a loss of IENFs. After clinical recovery, there is a return of the IENF population, suggesting that improvement occurs by nerve regeneration. These findings suggest that sensory nerve fibre injury in diabetic truncal neuropathy is distal to or within the sensory ganglia. Skin biopsy provides a possible tool for understanding the pathophysiology of the disease.

 PMID:9810952

  8. Severe peripheral neuropathy after exposure to monosodium methyl arsonate.

    PubMed

    Hessl, S M; Berman, E

    1982-05-01

    A case of severe peripheral neuropathy after several days of exposure to a pesticide spray containing monosodium methyl arsonate (MSMA) is reported. The clinical manifestations of symmetrical peripheral neuropathy with stocking-glove sensory deficit, decreased position sense, decreased and absent deep tendon reflexes, and muscle wasting are consistent with those described in other cases of arsenic intoxication. The anemia, leukopenia, and bone marrow changes of dyserythropoiesis in this case are also similar to those previously described with arsenic intoxication. The authors discuss the possible contribution of toxicity from exposure to other pesticides.

  9. Genetics Home Reference: hereditary hyperekplexia

    MedlinePlus

    ... Rarely, infants with hereditary hyperekplexia experience recurrent seizures (epilepsy). The signs and symptoms of hereditary hyperekplexia typically ... limb movements during sleep. Affected individuals who have epilepsy have the disorder throughout their lives. Related Information ...

  10. Genetics Home Reference: hereditary hemochromatosis

    MedlinePlus

    ... increase the excretion of iron, excess iron can overload and eventually damage tissues and organs. For this reason, hereditary hemochromatosis is also called an iron overload disorder. Early symptoms of hereditary hemochromatosis are nonspecific ...

  11. Sensory Guillain-Barré syndrome and related disorders: an attempt at systematization.

    PubMed

    Uncini, Antonino; Yuki, Nobuhiro

    2012-04-01

    The possibility that some patients diagnosed with an acute sensory neuropathy could actually have Guillain-Barré syndrome (GBS) has been repeatedly advanced in the literature, but the number of cases reported is small. The reports have shown different clinical presentations and electrophysiological findings and are variously named, thus generating terminological and nosological confusion. We operatively defined sensory GBS as an acute, monophasic, widespread neuropathy characterized clinically by exclusive sensory symptoms and signs that reach their nadir in a maximum of 6 weeks without related systemic disorders and other diseases or conditions. We reviewed the literature through searches of PubMed from 1980 to March 2011 and our own files. On the basis of the size of fibers involved and the possible site of primary damage, we propose tentatively classifying sensory GBS and related disorders into three subtypes: acute sensory demyelinating polyneuropathy; acute sensory large-fiber axonopathy-ganglionopathy; and acute sensory small-fiber neuropathy-ganglionopathy.

  12. Early onset Charcot-Marie-Tooth neuropathy type 2A and severe developmental delay: expanding the clinical phenotype of MFN2-related neuropathy.

    PubMed

    Tufano, Maria; Cappuccio, Gerarda; Terrone, Gaetano; Manganelli, Fiore; Pisciotta, Chiara; Geroldi, Alessandro; Capponi, Simona; Del Giudice, Ennio

    2015-12-01

    Charcot-Marie-Tooth (CMT) syndromes are a group of clinically heterogeneous disorders of the peripheral nervous system. Mutations of mitofusin 2 (MFN2) have been recognized to be associated with CMT type 2A (CMT2A). CMT2A is primarily an axonal disorder resulting in motor and sensory neuropathy. We report a male child with psychomotor delay, dysmorphic features, and weakness of lower limbs associated with electrophysiological features of severe, sensory-motor, axonal neuropathy. The patient was diagnosed with early onset CMT2A and severe psychomotor retardation associated with c.310C>T mutation (p.R104W) in MFN2 gene. CMT2A should be considered in patients with both axonal sensory-motor neuropathy and developmental delay.

  13. Peripheral neuropathies in Sjögren's syndrome: a critical update on clinical features and pathogenetic mechanisms.

    PubMed

    Pavlakis, P P; Alexopoulos, H; Kosmidis, M L; Mamali, I; Moutsopoulos, H M; Tzioufas, A G; Dalakas, M C

    2012-08-01

    Sjögren's syndrome is a systemic autoimmune disease that, apart from exocrine glands, may affect every organ or system. Involvement of different sections of the peripheral nervous system results in a wide spectrum of neuropathic manifestations. Based on distinct clinical, electrophysiological and histological criteria, the types of neuropathies seen in Sjögren's syndrome include: a) pure sensory which presents with distal symmetric sensory loss due to axonal degeneration of sensory fibers; sensory ataxia due to loss of proprioceptive large fibers (ganglionopathy); or with painful dysethesias (small fiber sensory neuropathy) due to degeneration of cutaneous axons. The latter appears to be the most common neuropathy in Sjögren's syndrome and requires skin biopsy for diagnosis to document loss or reduction of nerve fiber density; b) sensorimotor polyneuropathy affecting sensory and motor axons, often associated with severe systemic or pro-lymhomatous manifestations, such as palpable purpura and cryoglobulinemia, and c) rare types that include autoimmune demyelinating neuropathy, mononeuropathy, mononeuropathy multiplex and autonomic neuropathy. In this review, the frequency, prevalence and diagnostic criteria for each neuropathy subset are discussed and possible pathogenetic mechanisms are outlined.

  14. Inherited peripheral neuropathies due to mitochondrial disorders.

    PubMed

    Cassereau, J; Codron, P; Funalot, B

    2014-05-01

    Mitochondrial disorders (MIDs) are frequently responsible for neuropathies with variable severity. Mitochondrial diseases causing peripheral neuropathies (PNP) may be due to mutations of mitochondrial DNA (mtDNA), as is the case in MERRF and MELAS syndromes, or to mutations of nuclear genes. Secondary abnormalities of mtDNA (such as multiple deletions of muscle mtDNA) may result from mitochondrial disorders due to mutations in nuclear genes involved in mtDNA maintenance. This is the case in several syndromes caused by impaired mtDNA maintenance, such as Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO) due to recessive mutations in the POLG gene, which encodes the catalytic subunit of mtDNA polymerase (DNA polymerase gamma), or Mitochondrial Neuro-Gastro-Intestinal Encephalomyopathy (MNGIE), due to recessive mutations in the TYMP gene, which encodes thymidine phosphorylase. The last years have seen a growing list of evidence demonstrating that mitochondrial bioenergetics and dynamics might be dysfunctional in axonal Charcot-Marie-Tooth disease (CMT2), and these mechanisms might present a common link between dissimilar CMT2-causing genes.

  15. Ischemic optic neuropathy.

    PubMed

    Athappilly, Geetha; Pelak, Victoria S; Mandava, Naresh; Bennett, Jeffrey L

    2008-10-01

    Ischemic optic neuropathy is the most frequent cause of vision loss in middle age. Clinical and laboratory research studies have begun to clarify the natural history, clinical presentation, diagnostic criteria and pathogenesis of various ischemic nerve injuries. As a result, physicians are acquiring new tools to aid in the diagnosis and potential treatment of ischemic nerve injury. The aim of this review is to examine recent data on anterior and posterior ischemic optic neuropathy and to provide a framework for physicians to manage and counsel affected individuals. PMID:18826805

  16. Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies.

    PubMed

    Gonzalez, Sergio; Berthelot, Jade; Jiner, Jennifer; Perrin-Tricaud, Claire; Fernando, Ruani; Chrast, Roman; Lenaers, Guy; Tricaud, Nicolas

    2016-03-01

    Schwann cells produce myelin sheath around peripheral nerve axons. Myelination is critical for rapid propagation of action potentials, as illustrated by the large number of acquired and hereditary peripheral neuropathies, such as diabetic neuropathy or Charcot-Marie-Tooth diseases, that are commonly associated with a process of demyelination. However, the early molecular events that trigger the demyelination program in these diseases remain unknown. Here, we used virally delivered fluorescent probes and in vivo time-lapse imaging in a mouse model of demyelination to investigate the underlying mechanisms of the demyelination process. We demonstrated that mitochondrial calcium released by voltage-dependent anion channel 1 (VDAC1) after sciatic nerve injury triggers Schwann cell demyelination via ERK1/2, p38, JNK, and c-JUN activation. In diabetic mice, VDAC1 activity was altered, resulting in a mitochondrial calcium leak in Schwann cell cytoplasm, thereby priming the cell for demyelination. Moreover, reduction of mitochondrial calcium release, either by shRNA-mediated VDAC1 silencing or pharmacological inhibition, prevented demyelination, leading to nerve conduction and neuromuscular performance recovery in rodent models of diabetic neuropathy and Charcot-Marie-Tooth diseases. Therefore, this study identifies mitochondria as the early key factor in the molecular mechanism of peripheral demyelination and opens a potential opportunity for the treatment of demyelinating peripheral neuropathies. PMID:26878172

  17. Clinicopathological and genetic study of early-onset demyelinating neuropathy.

    PubMed

    Parman, Yesim; Battaloglu, Esra; Baris, Ibrahim; Bilir, Birdal; Poyraz, Mürüvvet; Bissar-Tadmouri, Nisrine; Williams, Anna; Ammar, Nadia; Nelis, Eva; Timmerman, Vincent; De Jonghe, Peter; Najafov, Ayaz; Necefov, Ayaz; Deymeer, Feza; Serdaroglu, Piraye; Brophy, Peter J; Said, G

    2004-11-01

    Autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4), Dejerine-Sottas disease and congenital hypomyelinating neuropathy are variants of hereditary demyelinating neuropathy of infancy, a genetically heterogeneous group of disorders. To explore the spectrum of early-onset demyelinating neuropathies further, we studied the clinicopathological and genetic aspects of 20 patients born to unaffected parents. In 19 families out of 20, consanguinity between the parents or presence of an affected sib suggested autosomal recessive transmission. Screening of various genes known to be involved in CMT4 revealed six mutations of which five are novel. Four of these novel mutations occurred in the homozygous state and include: one in GDAP1, one in MTMR2, one in PRX and one in KIAA1985. One patient was heterozygous for a novel MTMR2 mutation and still another was homozygous for the founder mutation, R148X, in NDRG1. All patients tested negative for mutations in EGR2. Histopathological examination of nerve biopsy specimens showed a severe, chronic demyelinating neuropathy, with onion bulb formation, extensive demyelination of isolated fibres and axon loss. We did not discern a specific pattern of histopathology that could be correlated to mutations in a particular gene. PMID:15469949

  18. Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies

    PubMed Central

    Berthelot, Jade; Jiner, Jennifer; Perrin-Tricaud, Claire; Fernando, Ruani; Chrast, Roman; Lenaers, Guy

    2016-01-01

    Schwann cells produce myelin sheath around peripheral nerve axons. Myelination is critical for rapid propagation of action potentials, as illustrated by the large number of acquired and hereditary peripheral neuropathies, such as diabetic neuropathy or Charcot-Marie-Tooth diseases, that are commonly associated with a process of demyelination. However, the early molecular events that trigger the demyelination program in these diseases remain unknown. Here, we used virally delivered fluorescent probes and in vivo time-lapse imaging in a mouse model of demyelination to investigate the underlying mechanisms of the demyelination process. We demonstrated that mitochondrial calcium released by voltage-dependent anion channel 1 (VDAC1) after sciatic nerve injury triggers Schwann cell demyelination via ERK1/2, p38, JNK, and c-JUN activation. In diabetic mice, VDAC1 activity was altered, resulting in a mitochondrial calcium leak in Schwann cell cytoplasm, thereby priming the cell for demyelination. Moreover, reduction of mitochondrial calcium release, either by shRNA-mediated VDAC1 silencing or pharmacological inhibition, prevented demyelination, leading to nerve conduction and neuromuscular performance recovery in rodent models of diabetic neuropathy and Charcot-Marie-Tooth diseases. Therefore, this study identifies mitochondria as the early key factor in the molecular mechanism of peripheral demyelination and opens a potential opportunity for the treatment of demyelinating peripheral neuropathies. PMID:26878172

  19. Hereditary Hearing Loss.

    ERIC Educational Resources Information Center

    Tran, LenhAnh P.; Grundfast, Kenneth M.

    1997-01-01

    This article discusses inheritance patterns in hearing loss, epidemiology, clues to genetic causes, locating genes that cause hereditary disorders, genes related to hearing loss disorders in individuals with Usher syndrome, Waardenburg syndrome, Treacher-Collins syndrome, Branchio-oto-renal and Pendred syndromes, and the significance of finding…

  20. Hereditary and metabolic myelopathies.

    PubMed

    Hedera, Peter

    2016-01-01

    Hereditary and metabolic myelopathies are a heterogeneous group of neurologic disorders characterized by clinical signs suggesting spinal cord dysfunction. Spastic weakness, limb ataxia without additional cerebellar signs, impaired vibration, and positional sensation are hallmark phenotypic features of these disorders. Hereditary, and to some extent, metabolic myelopathies are now recognized as more widespread systemic processes with axonal loss and demyelination. However, the concept of predominantly spinal cord disorders remains clinically helpful to differentiate these disorders from other neurodegenerative conditions. Furthermore, metabolic myelopathies are potentially treatable and an earlier diagnosis increases the likelihood of a good clinical recovery. This chapter reviews major types of degenerative myelopathies, hereditary spastic paraplegia, motor neuron disorders, spastic ataxias, and metabolic disorders, including leukodystrophies and nutritionally induced myelopathies, such as vitamin B12, E, and copper deficiencies. Neuroimaging studies usually detect a nonspecific spinal cord atrophy or demyelination of the corticospinal tracts and dorsal columns. Brain imaging can be also helpful in myelopathies caused by generalized neurodegeneration. Given the nonspecific nature of neuroimaging findings, we also review metabolic or genetic assays needed for the specific diagnosis of hereditary and metabolic myelopathies. PMID:27430441

  1. Clinical description of toxic neuropathies.

    PubMed

    Little, Ann A; Albers, James W

    2015-01-01

    Toxic neuropathy, although rare, is an important consideration in the setting of a known or suspected toxic exposure in the workplace or other environment. This chapter discusses the clinical and electrodiagnostic evaluation of peripheral neuropathies, highlighting findings that direct further workup and may point to specific toxins as etiology. The difficulty of establishing causality of a toxin in relation to peripheral neuropathy is discussed; guidelines for establishing causality are presented. Examples of common industrial toxins are listed, including their typical industrial uses and their mechanisms of action in producing neuropathy. Characteristic clinical presentations of specific toxic neuropathies are highlighted with selected case studies. PMID:26563794

  2. Acetylator phenotype in diabetic neuropathy.

    PubMed Central

    McLaren, E H; Burden, A C; Moorhead, P J

    1977-01-01

    The proportions of slow and fast acetylators in a group of diabetics with symptomatic peripheral neuropathy were compared with those in a group of diabetics who had had the disease for at least 10 years without developing neuropathy. There was a significantly higher proportion of fast acetylators in the group of diabetics without neuropathy than in those with neuropathy or in the normal population. Hence genetic factors separate from the diabetic diathesis may determine the development of neuropathy in any particular diabetic. PMID:871863

  3. Molecular genetics and biology of inherited peripheral neuropathies: a fast-moving field.

    PubMed

    Nelis, E; Timmerman, V; De Jonghe, P; Van Broeckhoven, C; Rautenstrauss, B

    1999-09-01

    The recent progress of molecular genetics has considerably increased our knowledge about the underlying disease mechanism of inherited peripheral neuropathies. Mutations in three genes coding for the myelin proteins peripheral myelin protein 22, myelin protein zero and connexin 32 and in one gene coding for the transcription factor early growth response 2 element are associated with Charcot-Marie-Tooth type 1 and 2, hereditary neuropathy with liability to pressure palsies, Dejerine-Sottas syndrome and congenital hypomyelination. This review focuses on the correlation of the different human phenotypes associated with distinct mutations with those found in cellular and animal models. PMID:10541586

  4. Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease.

    PubMed

    Souayah, Nizar; Ajroud-Driss, Senda; Sander, Howard W; Brannagan, Thomas H; Hays, Arthur P; Chin, Russell L

    2009-12-01

    Neuropathy following vaccination has been reported; however, biopsy-confirmed small fiber neuropathy has not been described. We report five patients who developed paresthesias within one day to two months following vaccination for rabies, varicella zoster, or Lyme disease. On examination, there was mild sensory loss in distal extremities, preserved strength, normal or minimally abnormal electrodiagnostic findings, and decreased epidermal nerve fiber densities per skin biopsy. Empiric immunomodulatory therapy was tried in two patients and was ineffective. All patients' symptoms have improved, but persist. We conclude that an acute or subacute, post-vaccination small fiber neuropathy may occur and follow a chronic course.

  5. Rare cause of paraparesis: bilateral obturator neuropathy after hysterosalpingectomy.

    PubMed

    López-Blanco, Roberto; Mejía-Jiménez, Inmaculada; de Fuenmayor-Fernández de la Hoz, Carlos Pablo; Ruiz-Morales, Juan

    2015-01-01

    Bilateral obturator nerve injury during pelvic surgery is an infrequent cause of lower limb paraparesis. We report the case of a 45-year-old woman with a large uterine leiomyoma who underwent simple total hysterectomy and bilateral salpingectomy. At 24 h after the surgery, the patient noticed loss of muscle strength when adducting both legs. She had no problem with other movements and no sensory or sphincter abnormalities. Neurological examination confirmed that there was loss of strength only in the adductor muscles, with preserved sensory function and reflexes, suggesting bilateral obturator nerve involvement. Pelvic MRI showed a small postsurgical haematoma in the Douglas recess, but far from the obturator nerves. 2 weeks later, electromyography showed positive sharp waves and low motor unit recruitment in the adductor magnus muscles, confirming acute, bilateral obturator nerve neuropathy. The few cases of bilateral obturator neuropathy that have been reported were mostly related to abdominopelvic interventions. PMID:26689250

  6. Peripheral neuropathy induced by combination chemotherapy of docetaxel and cisplatin.

    PubMed Central

    Hilkens, P. H.; Pronk, L. C.; Verweij, J.; Vecht, C. J.; van Putten, W. L.; van den Bent, M. J.

    1997-01-01

    Docetaxel, a new semisynthetic taxoid that has demonstrated promising activity as an antineoplastic agent, was administered in combination with cisplatin to 63 patients in a dose-escalating study. As both drugs were known to be potentially neurotoxic, peripheral neurotoxicity was prospectively assessed in detail. Neuropathy was evaluated by clinical sum-score for signs and symptoms and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to the National Cancer Institute's 'Common Toxicity Criteria'. The docetaxel-cisplatin combination chemotherapy induced a predominantly sensory neuropathy in 29 (53%) out of 55 evaluable patients. At cumulative doses of both cisplatin and docetaxel above 200 mg m(-2), 26 (74%) out of 35 patients developed a neuropathy which was mild in 15, moderate in ten and severe in one patient. Significant correlations were present between both the cumulative dose of docetaxel and cisplatin and the post-treatment sum-score of neuropathy (P < 0.01) as well as the post-treatment VPT (P < 0.01). The neurotoxic effects of this combination were more severe than either cisplatin or docetaxel as single agent at similar doses. PMID:9020489

  7. Charcot-marie-tooth disease and related neuropathies: molecular basis for distinction and diagnosis.

    PubMed

    Pareyson, D

    1999-11-01

    Great advances have been made in understanding the molecular basis of Charcot-Marie-Tooth disease (CMT) and related neuropathies, namely Dejerine-Sottas disease (DSD), hereditary neuropathy with liability to pressure palsies (HNPP) and congenital hypomyelination (CH). The number of newly uncovered mutations and identified genetic loci is rapidly increasing, and, as a consequence, the classification of these disorders is becoming more complicated. Molecular genetics, animal models, and transfected cell studies are shedding light on function and dysfunction of proteins involved in hereditary myelinopathies-peripheral myelin protein 22 (PMP22), myelin protein zero (PO), connexin 32 (Cx32), and early growth response 2 (EGR2). Gene dosage effect, loss of function, gain of toxic function, and dominant negative effect are possible mechanisms whereby different gene mutations may exert their detrimental action on peripheral nerves. A tentative rational approach to clinical and molecular diagnosis based on genotype-phenotype correlation analysis is described. PMID:10514227

  8. Automated Peripheral Neuropathy Assessment Using Optical Imaging and Foot Anthropometry.

    PubMed

    Siddiqui, Hafeez-U R; Spruce, Michelle; Alty, Stephen R; Dudley, Sandra

    2015-08-01

    A large proportion of individuals who live with type-2 diabetes suffer from plantar sensory neuropathy. Regular testing and assessment for the condition is required to avoid ulceration or other damage to patient's feet. Currently accepted practice involves a trained clinician testing a patient's feet manually with a hand-held nylon monofilament probe. The procedure is time consuming, labor intensive, requires special training, is prone to error, and repeatability is difficult. With the vast increase in type-2 diabetes, the number of plantar sensory neuropathy sufferers has already grown to such an extent as to make a traditional manual test problematic. This paper presents the first investigation of a novel approach to automatically identify the pressure points on a given patient's foot for the examination of sensory neuropathy via optical image processing incorporating plantar anthropometry. The method automatically selects suitable test points on the plantar surface that correspond to those repeatedly chosen by a trained podiatrist. The proposed system automatically identifies the specific pressure points at different locations, namely the toe (hallux), metatarsal heads and heel (Calcaneum) areas. The approach is generic and has shown 100% reliability on the available database used. The database consists of Chinese, Asian, African, and Caucasian foot images.

  9. Automated Peripheral Neuropathy Assessment Using Optical Imaging and Foot Anthropometry.

    PubMed

    Siddiqui, Hafeez-U R; Spruce, Michelle; Alty, Stephen R; Dudley, Sandra

    2015-08-01

    A large proportion of individuals who live with type-2 diabetes suffer from plantar sensory neuropathy. Regular testing and assessment for the condition is required to avoid ulceration or other damage to patient's feet. Currently accepted practice involves a trained clinician testing a patient's feet manually with a hand-held nylon monofilament probe. The procedure is time consuming, labor intensive, requires special training, is prone to error, and repeatability is difficult. With the vast increase in type-2 diabetes, the number of plantar sensory neuropathy sufferers has already grown to such an extent as to make a traditional manual test problematic. This paper presents the first investigation of a novel approach to automatically identify the pressure points on a given patient's foot for the examination of sensory neuropathy via optical image processing incorporating plantar anthropometry. The method automatically selects suitable test points on the plantar surface that correspond to those repeatedly chosen by a trained podiatrist. The proposed system automatically identifies the specific pressure points at different locations, namely the toe (hallux), metatarsal heads and heel (Calcaneum) areas. The approach is generic and has shown 100% reliability on the available database used. The database consists of Chinese, Asian, African, and Caucasian foot images. PMID:26186748

  10. Non HFE related hereditary haemochromatosis.

    PubMed

    Sharma, S K; Mangudkar, Sangram; Rathod, Mehul; Verma, Amrita; Phanikumar, R L V; Garg, Subodh; Dhakne, Ajinkya; Barure, Ramdas

    2014-03-01

    Hereditary hemochromatosis (HH) is manifested as iron overload in different organs due to homozygosity of a single autosomal mutation. Two different mutations C282Y and H63D in the HFE gene have been associated with hereditary hemochromatosis cases. This disease is seen in northern european populations, but in India it is a rare disease. We report a young male with severe abnormalty of liver functions due to Non HFE related Hereditary Hemochromatosis.

  11. Increasing cutaneous afferent feedback improves proprioceptive accuracy at the knee in patients with sensory ataxia.

    PubMed

    Macefield, Vaughan G; Norcliffe-Kaufmann, Lucy; Goulding, Niamh; Palma, Jose-Alberto; Fuente Mora, Cristina; Kaufmann, Horacio

    2016-02-01

    Hereditary sensory and autonomic neuropathy type III (HSAN III) features disturbed proprioception and a marked ataxic gait. We recently showed that joint angle matching error at the knee is positively correlated with the degree of ataxia. Using intraneural microelectrodes, we also documented that these patients lack functional muscle spindle afferents but have preserved large-diameter cutaneous afferents, suggesting that patients with better proprioception may be relying more on proprioceptive cues provided by tactile afferents. We tested the hypothesis that enhancing cutaneous sensory feedback by stretching the skin at the knee joint using unidirectional elasticity tape could improve proprioceptive accuracy in patients with a congenital absence of functional muscle spindles. Passive joint angle matching at the knee was used to assess proprioceptive accuracy in 25 patients with HSAN III and 9 age-matched control subjects, with and without taping. Angles of the reference and indicator knees were recorded with digital inclinometers and the absolute error, gradient, and correlation coefficient between the two sides calculated. Patients with HSAN III performed poorly on the joint angle matching test [mean matching error 8.0 ± 0.8° (±SE); controls 3.0 ± 0.3°]. Following application of tape bilaterally to the knee in an X-shaped pattern, proprioceptive performance improved significantly in the patients (mean error 5.4 ± 0.7°) but not in the controls (3.0 ± 0.2°). Across patients, but not controls, significant increases in gradient and correlation coefficient were also apparent following taping. We conclude that taping improves proprioception at the knee in HSAN III, presumably via enhanced sensory feedback from the skin.

  12. Diabetic Neuropathy: Mechanisms to Management

    PubMed Central

    Edwards, James L.; Vincent, Andrea; Cheng, Thomas; Feldman, Eva L.

    2014-01-01

    Neuropathy is the most common and debilitating complication of diabetes and results in pain, decreased motility, and amputation. Diabetic neuropathy encompasses a variety of forms whose impact ranges from discomfort to death. Hyperglycemia induces oxidative stress in diabetic neurons and results in activation of multiple biochemical pathways. These activated pathways are a major source of damage and are potential therapeutic targets in diabetic neuropathy. Though therapies are available to alleviate the symptoms of diabetic neuropathy, few options are available to eliminate the root causes. The immense physical, psychological, and economic cost of diabetic neuropathy underscores the need for causally targeted therapies. This review covers the pathology, epidemiology, biochemical pathways, and prevention of diabetic neuropathy, as well as discusses current symptomatic and causal therapies and novel approaches to identify therapeutic targets. PMID:18616962

  13. Genetics Home Reference: ataxia neuropathy spectrum

    MedlinePlus

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

  14. Genetics Home Reference: small fiber neuropathy

    MedlinePlus

    ... Home Health Conditions small fiber neuropathy small fiber neuropathy Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Small fiber neuropathy is a condition characterized by severe pain attacks ...

  15. [Hereditary angioedema causing colocolic intussusception].

    PubMed

    Sanchez, A; Ecochard, A; Maestracci, M; Rodiere, M

    2008-03-01

    Hereditary angioedema is a rare, autosomal dominant disease inherited. The cause is a quantitative or qualitative congenital deficit in C1 inhibitor. Various clinical symptoms, in particular of sub-cutaneous, upper airways and digestive origin, have been described. Life threatening conditions may be observed. Little information is available on digestive tract localization corresponding to intestinal intussusception associated with hereditary angioedema in children. We report a case of hereditary angioedema observed in a 15-years-old girl who presented such features. We propose a review of the literature and discuss the curative treatment of digestive crisis in children with hereditary angioedema.

  16. Arsenical peripheral neuropathy.

    PubMed

    Mathew, Liberty; Vale, Allister; Adcock, Jane E

    2010-02-01

    A 49-year-old white man returned urgently to the UK after spending 3 months in Goa. He had a several week history of vomiting, weight loss, a widespread desquamating skin rash, and symptoms and signs of a progressive painful sensorimotor neuropathy. He had a mild normocytic anaemia and lymphopenia. Nerve conduction studies revealed a severe predominantly axonal large fibre sensorimotor neuropathy, confirmed on subsequent sural nerve biopsy. Once he had left Goa most of his symptoms started to rapidly settle although the neuropathic symptoms remained severe. Arsenic poisoning was suspected. A spot urine arsenic concentration was 300 microg/l, confirming the diagnosis. He was treated with chelation therapy. Deliberate arsenic poisoning was highly likely.

  17. Diabetic autonomic neuropathy.

    PubMed

    Clarke, B F; Ewing, D J; Campbell, I W

    1979-10-01

    This review attempts to outline the present understanding of diabetic autonomic neuropathy. The clinical features have been increasinly recognised but knowledge of the localization and morphology of the lesions and their pathogenesis remains fragmentary. A metabolic causation as postulated in somatic nerves accords best with clinical observations. Most bodily systems, particularly the cardiovascular, gastrointestinal and urogenital, are involved with added disturbances of thermoregulatory function and pupillary reflexes. Possible effects on neuroendocrine and peptidergic secretion and respiratory control await definition. Current interest centres around the development of a new generation of tests of autonomic nerve function that are simple, non-invasive, reproducible and allow precision in diagnosis and accurate quantitation. Most are based on cardiovascular reflexes and abnormality in them is assumed to reflect autonomic damage elsewhere. Probably no single test suffices and a battery of tests reflecting both parasympathetic and sympathetic function is preferable. Little is known of the natural history. The prevalence may be greater than previously suspected and although symptoms are mild in the majority, a few develop florid features. The relation of control and duration of diabetes to the onset and progression of autonomic neuropathy is not clearly established. Once tests of autonomic function become abnormal they usually remain abnormal. Symptomatic autonomic neuropathy carries a greatly increased mortality rate possibly due to indirect mechanisms such as renal failure and direct mechanisms such as cardio-resiratory arrest. Improved treatment of some of the more disabling symptoms has been possible in recent years. PMID:387501

  18. Hereditary Hemorrhagic Telangiectasia.

    PubMed

    Parambil, Joseph G

    2016-09-01

    Hereditary hemorrhagic telangiectasia (HHT) is an underrecognized and underdiagnosed autosomal-dominant angiodysplasia that has an estimated prevalence of 1 in 5000 individuals, with variable clinical presentations even within family members with identical mutations. The most common manifestations are telangiectasias of the skin and nasal mucosa. However, HHT can often be complicated by the presence of arteriovenous malformations and telangiectasias in the lungs, brain, gastrointestinal tract, and liver that are often silent and can lead to life-threatening complications of stroke and hemorrhage. This article reviews HHT for the pulmonologist, who is not uncommonly the first practitioner to encounter these patients. PMID:27514597

  19. Myanmarese Neuropathy: Clinical Description of Acute Peripheral Neuropathy Detected among Myanmarese Refugees in Malaysia.

    PubMed

    Fu Liong, Hiew; Santhi, Datuk Puvanarajah; Shanthi, Viswanathan; Mohd Hanip, Rafia

    2014-01-01

    Background. Since 2008, we have observed an increasing number of Myanmarese refugees in Malaysia being admitted for acute/subacute onset peripheral neuropathy. Most of them had a preceding history of starvation. Methods. We retrospectively studied the clinical features of all Myanmarese patients admitted with peripheral neuropathy from September 2008 to January 2014. Results. A total of 24 patients from the Chin, Rohingya, and Rakhine ethnicities (mean age, 23.8 years; male, 96%) had symmetrical, ascending areflexic weakness with at least one additional presenting symptom of fever, lower limb swelling, vomiting, abdominal pain, or difficulty in breathing. Twenty (83.3%) had sensory symptoms. Ten (41.6%) had cranial nerve involvement. Nineteen patients had cerebrospinal fluid examinations but none with evidence of albuminocytological dissociation. Neurophysiological assessment revealed axonal polyneuropathy, predominantly a motor-sensory subtype. Folate and vitamin B12 deficiencies were detected in 31.5% of them. These findings suggested the presence of a polyneuropathy related to nutrition against a backdrop of other possible environmental factors such as infections, metabolic disorders, or exposure to unknown toxin. Supportive treatment with appropriate vitamins supplementation improved functional outcome in most patients. Conclusion. We report a spectrum of acquired reversible neurological manifestations among Myanmarese refugees likely to be multifactorial with micronutrient deficiencies playing an important role in the pathogenesis. PMID:27350989

  20. Myanmarese Neuropathy: Clinical Description of Acute Peripheral Neuropathy Detected among Myanmarese Refugees in Malaysia

    PubMed Central

    Santhi, Datuk Puvanarajah; Mohd Hanip, Rafia

    2014-01-01

    Background. Since 2008, we have observed an increasing number of Myanmarese refugees in Malaysia being admitted for acute/subacute onset peripheral neuropathy. Most of them had a preceding history of starvation. Methods. We retrospectively studied the clinical features of all Myanmarese patients admitted with peripheral neuropathy from September 2008 to January 2014. Results. A total of 24 patients from the Chin, Rohingya, and Rakhine ethnicities (mean age, 23.8 years; male, 96%) had symmetrical, ascending areflexic weakness with at least one additional presenting symptom of fever, lower limb swelling, vomiting, abdominal pain, or difficulty in breathing. Twenty (83.3%) had sensory symptoms. Ten (41.6%) had cranial nerve involvement. Nineteen patients had cerebrospinal fluid examinations but none with evidence of albuminocytological dissociation. Neurophysiological assessment revealed axonal polyneuropathy, predominantly a motor-sensory subtype. Folate and vitamin B12 deficiencies were detected in 31.5% of them. These findings suggested the presence of a polyneuropathy related to nutrition against a backdrop of other possible environmental factors such as infections, metabolic disorders, or exposure to unknown toxin. Supportive treatment with appropriate vitamins supplementation improved functional outcome in most patients. Conclusion. We report a spectrum of acquired reversible neurological manifestations among Myanmarese refugees likely to be multifactorial with micronutrient deficiencies playing an important role in the pathogenesis. PMID:27350989

  1. Role of A3 adenosine receptor in diabetic neuropathy.

    PubMed

    Yan, Heng; Zhang, Enshui; Feng, Chang; Zhao, Xin

    2016-10-01

    Neuropathy is the most common diabetic complication. Although the A1 and A2A adenosine receptors are important pharmacological targets in alleviating diabetic neuropathy, the role of the A3 adenosine receptor remains unknown. Because the A3 adenosine receptor regulates pain induced by chronic constriction injury or chemotherapy, its stimulation might also attenuate diabetic neuropathy. This study examines the effects of systemic treatment with the A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-d-ribofuranuronamide (IB-MECA) on diabetic neuropathy and explores the putative mechanisms underlying its pharmacological effects. We show that IB-MECA alleviated mechanical hyperalgesia and thermal hypoalgesia in mice 2 weeks but not 4 weeks after streptozocin (STZ) treatment. Furthermore, IB-MECA prevented the reduction in sciatic motor nerve conduction velocity and sensory nerve conduction velocity in diabetic mice 2 weeks but not 4 weeks after STZ treatment. Similarly, IB-MECA inhibited the activation of nuclear factor-κB and decreased the generation of tumor necrosis factor-α in the spinal cord of mice 2 weeks but not 4 weeks after STZ treatment. These phenomena were associated with reduction of A3 adenosine receptor expression in the spinal cord after long-term diabetes. Our results suggest that the A3 adenosine receptor plays a critical role in regulating diabetic neuropathy and that reduction in A3 adenosine receptor expression/function might contribute to the progression of diabetic neuropathy. © 2016 Wiley Periodicals, Inc.

  2. Hereditary hemochromatosis of tongue.

    PubMed

    Al Wayli, Hessa; Rastogi, Sanjay; Verma, Neha

    2011-01-01

    Hereditary hemochromatosis (HH) refers to several inherited disorders of iron metabolism leading to tissue iron overload. Classical HH is associated with mutations in HFE (C282Y homozygotes or C282Y/H63D compound heterozygotes) and is almost exclusively found in populations of northern European descent. Non-HFE-associated HH is caused by mutations in other recently identified genes involved in iron metabolism. Hepcidin is an iron regulatory hormone that inhibits ferroportin-mediated iron export from enterocytes and macrophages. Defective hepcidin gene expression or function may underlie most forms of HH. Target organs and tissues affected by HH include the liver, heart, pancreas, joints, and skin, with cirrhosis and diabetes mellitus representing late signs of disease in patients with markedly elevated liver iron concentration. Recently, we have encountered the rare representation of this disease of the oral cavity associated with generalized burning sensation of the tongue. The diagnosis was established accidently, from the lab investigations, otherwise the patient was healthy and free from classical signs and symptoms of the disease. The patient was adequately treated by phlebotomy. To conclude, all patients with a chief complaint of burning sensation of the oral cavity and tongue should be adequately screened for hereditary hemochromatosis to prevent the associated mortality and morbidity with the hemochromatosis.

  3. Subacute diabetic proximal neuropathy

    NASA Technical Reports Server (NTRS)

    Pascoe, M. K.; Low, P. A.; Windebank, A. J.; Litchy, W. J.

    1997-01-01

    OBJECTIVE: To evaluate the clinical, electrophysiologic, autonomic, and neuropathologic characteristics and the natural history of subacute diabetic proximal neuropathy and its response to immunotherapy. MATERIAL AND METHODS: For the 12-year period from 1983 to 1995, we conducted a retrospective review of medical records of Mayo Clinic patients with diabetes who had subacute onset and progression of proximal weakness. The responses of treated versus untreated patients were compared statistically. RESULTS: During the designated study period, 44 patients with subacute diabetic proximal neuropathy were encountered. Most patients were middle-aged or elderly, and no sex preponderance was noted. The proximal muscle weakness often was associated with reduced or absent lower extremity reflexes. Associated weight loss was a common finding. Frequently, patients had some evidence of demyelination on nerve conduction studies, but it invariably was accompanied by concomitant axonal degeneration. The cerebrospinal fluid protein concentration was usually increased. Diffuse and substantial autonomic failure was generally present. In most cases, a sural nerve biopsy specimen suggested demyelination, although evidence of an inflammatory infiltrate was less common. Of 12 patients who received treatment (with prednisone, intravenous immune globulin, or plasma exchange), 9 had improvement of their conditions, but 17 of 29 untreated patients (59%) with follow-up also eventually had improvement, albeit at a much slower rate. Improvement was usually incomplete. CONCLUSION: We suggest that the entity of subacute diabetic proximal neuropathy is an extensive and severe variant of bilateral lumbosacral radiculoplexopathy, with some features suggestive of an immune-mediated cause. It differs from chronic inflammatory demyelinating polyradiculoneuropathy in that most cases have a more restricted distribution and seem to be monophasic and self-limiting. The efficacy of immunotherapy is unproved

  4. Isoniazid induced motor-dominant neuropathy.

    PubMed

    Arsalan, Rabeeya; Sabzwari, Saniya

    2015-10-01

    Isoniazid though a very effective treatment for tuberculosis can cause severe motor-dominant neuropathy which can be reversible with pyridoxine supplementation. A 45-year-old female diagnosed with psoas abscess, culture positive for mycobacterium tuberculosis, was started on anti- tuberculous treatment with four drugs, including isoniazid at a dose of 5 mg/kg/day. Three months later she developed severe motor weakness of lower limbs with loss of ankle and knee reflexes. She was treated with vitamin B6 injections and isoniazid treatment was continued. Her motor weakness gradually improved in a few months, but mild sensory impairment persisted even after two years. There is need for vigilance regarding neurological effects of isoniazid in seemingly low-risk individuals in whom development of symptoms should raise the suspicion about slow acetylator status. Timely therapeutic intervention with high-dose vitamin B6 can reduce the long-term morbidity associated with this easily reversible condition. PMID:26440850

  5. Cardiovascular autonomic neuropathy

    PubMed Central

    McCarty, Niamh

    2016-01-01

    Cardiovascular autonomic neuropathy often goes unrecognized. We present a case of a 22-year-old man with multiple manifestations of this disease, including weakness, dizziness, fatigue, tachycardia, abnormal QTc, and orthostasis, which occurred 2 years after his type 1 diabetes diagnosis. He exhibited parasympathetic denervation with resting tachycardia and exercise intolerance but also had evidence of orthostatic hypotension, which suggests sympathetic denervation. He did not have complete cardiovascular autonomic reflex testing, which would have been helpful, but improved with aggressive diabetes treatment and the increase of beta-blockade. It is important to identify these patients to understand their signs and symptoms and consider appropriate therapies. PMID:27034552

  6. Cardiovascular autonomic neuropathy.

    PubMed

    McCarty, Niamh; Silverman, Barry

    2016-04-01

    Cardiovascular autonomic neuropathy often goes unrecognized. We present a case of a 22-year-old man with multiple manifestations of this disease, including weakness, dizziness, fatigue, tachycardia, abnormal QTc, and orthostasis, which occurred 2 years after his type 1 diabetes diagnosis. He exhibited parasympathetic denervation with resting tachycardia and exercise intolerance but also had evidence of orthostatic hypotension, which suggests sympathetic denervation. He did not have complete cardiovascular autonomic reflex testing, which would have been helpful, but improved with aggressive diabetes treatment and the increase of beta-blockade. It is important to identify these patients to understand their signs and symptoms and consider appropriate therapies. PMID:27034552

  7. Hereditary Pancreatic and Hepatobiliary Cancers

    PubMed Central

    Haddad, Ashraf; Kowdley, Gopal C.; Pawlik, Timothy M.; Cunningham, Steven C.

    2011-01-01

    Hereditary etiologies of pancreatic and hepatobiliary cancers are increasingly recognized. An estimated >10% of pancreatic and increasing number of hepatobiliary cancers are hereditary. The cumulative risk of hereditary pancreatic cancer ranges from measurable but negligible in cystic fibrosis to a sobering 70% in cases of hereditary pancreatitis. Candidates for pancreatic cancer surveillance are those with a risk pancreatic cancer estimated to be >10-fold that of the normal population. Screening for pancreatic cancer in high-risk individuals is typically performed by endoscopic ultrasound and should begin at least 10 years prior to the age of the youngest affected relative. Disease states known to be associated with increased risk of hepatocellular cancer include hereditary hemochromatosis, autoimmune hepatitis, porphyria, and α1-antitrypsin deficiency, with relative risks as high as 36-fold. Although much less is known about hereditary bile-duct cancers, Muir-Torre syndrome and bile salt export pump deficiency are diseases whose association with hereditary carcinogenesis is under investigation. PMID:22312493

  8. Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment.

    PubMed

    Mo, Michelle; Erdelyi, Ildiko; Szigeti-Buck, Klara; Benbow, Jennifer H; Ehrlich, Barbara E

    2012-11-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect that occurs in many patients undergoing chemotherapy. It is often irreversible and frequently leads to early termination of treatment. In this study, we have identified two compounds, lithium and ibudilast, that when administered as a single prophylactic injection prior to paclitaxel treatment, prevent the development of CIPN in mice at the sensory-motor and cellular level. The prevention of neuropathy was not observed in paclitaxel-treated mice that were only prophylactically treated with a vehicle injection. The coadministration of lithium with paclitaxel also allows for administration of higher doses of paclitaxel (survival increases by 60%), protects against paclitaxel-induced cardiac abnormalities, and, notably, does not interfere with the antitumor effects of paclitaxel. Moreover, we have determined a mechanism by which CIPN develops and have discovered that lithium and ibudilast inhibit development of peripheral neuropathy by disrupting the interaction between paclitaxel, neuronal calcium sensor 1 (NCS-1), and the inositol 1,4,5-trisphosphate receptor (InsP3R) to prevent treatment-induced decreases in intracellular calcium signaling. This study shows that lithium and ibudilast are candidate therapeutics for the prevention of paclitaxel-induced neuropathy and could enable patients to tolerate more aggressive treatment regimens.

  9. Diabetic corneal neuropathy.

    PubMed Central

    Schultz, R O; Peters, M A; Sobocinski, K; Nassif, K; Schultz, K J

    1983-01-01

    Corneal epithelial lesions can be found in approximately one-half of asymptomatic patients with diabetes mellitus. These lesions are transient and clinically resemble the keratopathy seen in staphylococcal keratoconjunctivitis. Staphylococcal organisms, however, can be isolated in equal percentages from diabetic patients without keratopathy. Diabetic peripheral neuropathy was found to be related to the presence of diabetic keratopathy after adjusting for age with analysis of covariance. The strongest predictor of both keratopathy and corneal fluorescein staining was vibration perception threshold in the toes (P less than 0.01); and the severity of keratopathy was directly related to the degree of diminution of peripheral sensation. Other predictors of keratopathy were: reduced tear breakup time (P less than 0.03), type of diabetes (P less than 0.01), and metabolic status as indicated by c-peptide fasting (P less than 0.01). No significant relationships were found between the presence of keratopathy and tear glucose levels, endothelial cell densities, corneal thickness measurements, the presence of S epidermidis, or with duration of disease. It is our conclusion that asymptomatic epithelial lesions in the nontraumatized diabetic cornea can occur as a manifestation of generalized polyneuropathy and probably represent a specific form of corneal neuropathy. Images FIGURE 1 FIGURE 2 FIGURE 3 PMID:6676964

  10. Hereditary pancreatitis for the endoscopist.

    PubMed

    Patel, Milan R; Eppolito, Amanda L; Willingham, Field F

    2013-03-01

    Hereditary pancreatitis shares a majority of clinical and morphologic features with chronic alcoholic pancreatitis, but may present at an earlier age. The term hereditary pancreatitis has primarily been associated with mutations in the serine protease 1 gene (PRSS1) which encodes for cationic trypsinogen. PRSS1 mutations account for approximately 68-81% of hereditary pancreatitis. Mutations in other genes, primarily serine protease inhibitor Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) are also associated with hereditary pancreatitis. While chronic alcoholic pancreatitis may develop in the fourth or fifth decades, patients with hereditary pancreatitis may develop symptoms in the first or second decades of life. Hereditary pancreatitis is diagnosed either by detecting a causative gene mutation or by the presence of chronic pancreatitis in two first-degree or three second-degree relatives, in two or more generations, without precipitating factors and with a negative workup for known causes. Patients with hereditary pancreatitis may have recurrent acute pancreatitis and may develop pancreatic exocrine and endocrine insufficiency. Hereditary pancreatitis may involve premature trypsinogen activation or decreased control of trypsin. Recurrent inflammation can lead to acute pancreatitis and subsequently to chronic pancreatitis with parenchymal calcification. There is a markedly increased risk of pancreatic carcinoma compared with the general population. Patients are often referred for evaluation of pancreatitis, biliary or pancreatic ductal dilatation, jaundice, biliary obstruction, pancreatic duct stone or stricture, pancreatic pseudocysts, and for evaluation for malignancy. Medical treatment includes pancreatic enzyme supplementation, nutritional supplementation, diabetes management, and palliation of pain. Patients should avoid tobacco use and alcohol exposure. Hereditary pancreatitis is reviewed and recommendations for

  11. [Hereditary and familial colorectal cancer].

    PubMed

    Balaguer, Francesc

    2014-09-01

    Up to 5% of all colorectal cancer cases are caused by a known hereditary syndrome. These hereditary types often need a higher degree of clinical suspicion to be diagnosed and require specific and specialized management. In addition, diagnosing hereditary colorectal cancer has significant consequences not only for the patient, for whom there are effective preventative measures, but also for their families, who could be carriers of the condition. The most significant advances in the field of colorectal cancer have come from the diagnosis and characterization of these syndromes.

  12. Hereditary gingival fibromatosis

    PubMed Central

    Chaurasia, Akhilanand

    2014-01-01

    Hereditary gingival fibromatosis (HGF) is a rare condition that can occur as an isolated disease, chromosomal abnormality, or as part of a number of syndromes. The gingival enlargement in HGF can be so severe that it can cover the crowns of teeth completely, causing severe functional derangement and facial disfigurement. Through review of literature revealed that HGF is usually an autosomal dominant condition, however the recessive forms are also reported. The hyperplastic gingiva is firm on palpation and has normal color with abundant stippling on the adjacent gingiva. The buccal and lingual gingiva may be involved in both the mandible and maxilla. The degrees of gingival enlargement show both intra- and interindividual variations. Here, an interesting case report of massive HGF has been presented. PMID:25298717

  13. Hereditary gingival fibromatosis

    PubMed Central

    Dhadse, Prasad Vijayrao; Yeltiwar, Ramareddy Krishnarao; Pandilwar, Prashant K.; Gosavi, Suchitra R.

    2012-01-01

    Hereditary gingival fibromatosis is a rare benign oral condition characterised by slow and progressive enlargement of both maxillary and mandibular attached gingiva. It may develop as an isolated disorder but can feature along with a syndrome. A case of 12 year old female child who presented with generalised severe gingival overgrowth, involving both the arches and covering almost the entire dentition, and had all the teeth remaining invisible within the confinement of gingival tissues. The excess gingival tissue, in this non-syndromic case was removed by conventional gingivectomy using local as well as general anaesthesia. The post-operative result was uneventful and the patient appearance improved considerably. Good aesthetic result was achieved to allow patient to practice oral hygiene measures. After treatment regular recall visits are necessary in order to evaluate oral hygiene and stability of periodontal treatment. PMID:23492855

  14. Acute Onset Sensory Polyneuropathy Due to Metronidazole Therapy.

    PubMed

    Singh, Jitendra; Atam, Virendra; Dinkar, Anju

    2015-09-01

    Metronidazole is associated with numerous neurologic complications, including peripheral neuropathy particularly in patients; those are on high doses of metronidazole for prolonged period. We hereby report a case of liver abscess that developed sensory polyneuropathy following 11 days of metronidazole therapy at low cumulative dose. PMID:27608880

  15. Subacute sensory neuronopathy secondary to dorsal root ganglionitis in primary Sjögren's syndrome.

    PubMed

    Malinow, K; Yannakakis, G D; Glusman, S M; Edlow, D W; Griffin, J; Pestronk, A; Powell, D L; Ramsey-Goldman, R; Eidelman, B H; Medsger, T A

    1986-10-01

    Sensory neuropathies, particularly trigeminal neuropathy, have been recognized as neurological complications of Sjögren's syndrome, but the pathogenesis has not been established. We describe a woman with primary Sjögren's syndrome who developed a progressive debilitating subacute sensory neuronopathy. Results of electrophysiological studies were consistent with involvement of the trigeminal and dorsal root ganglia. A thoracic dorsal root ganglion biopsy showed lymphocytic infiltration and degeneration of ganglion cells. We believe that this is the first description of biopsy-documented dorsal root ganglionitis in a subacute sensory neuronopathy associated with Sjögren's syndrome and that the finding suggests an immunopathogenic basis.

  16. Practical rules for electrodiagnosis in suspected multifocal motor neuropathy.

    PubMed

    Bromberg, Mark B; Franssen, Hessel

    2015-03-01

    Multifocal motor neuropathy (MMN) with conduction block (CB) is a rare chronic immune-mediated neuropathy, but important to diagnose as it is treatable. The key features in prototypic MMN are electrodiagnostic demonstration of focal CB away from common sites of entrapment and normal sensory conduction across these sites. However, there are challenges in distinguishing CB from the effects of abnormal temporal dispersion. Consensus electrodiagnostic criteria, reinforced by modeling studies, are available to support definite or probable CB. In addition, consideration of technical issues can guard against false-positive and false-negative conclusions. These include limb temperature, stimulus site, inadvertent stimulating electrode movement, and supramaximal and submaximal responses, as well as the possibility of Martin-Gruber anastamosis. Robust evidence supports the treatment of MMN with intravenous immunoglobulin, and guidelines have been developed. Application of practical and simple rules including a 4-step diagnostic algorithm can help practitioners correctly diagnose this treatable condition and improve patient outcomes.

  17. Indirect traumatic optic neuropathy.

    PubMed

    Singman, Eric L; Daphalapurkar, Nitin; White, Helen; Nguyen, Thao D; Panghat, Lijo; Chang, Jessica; McCulley, Timothy

    2016-01-01

    Indirect traumatic optic neuropathy (ITON) refers to optic nerve injury resulting from impact remote to the optic nerve. The mechanism of injury is not understood, and there are no confirmed protocols for prevention, mitigation or treatment. Most data concerning this condition comes from case series of civilian patients suffering blunt injury, such as from sports- or motor vehicle-related concussion, rather than military-related ballistic or blast damage. Research in this field will likely require the development of robust databases to identify patients with ITON and follow related outcomes, in addition to both in-vivo animal and virtual human models to study the mechanisms of damage and potential therapies. PMID:26759722

  18. Radiation optic neuropathy

    SciTech Connect

    Kline, L.B.; Kim, J.Y.; Ceballos, R.

    1985-08-01

    Following surgery for pituitary adenoma, radiation therapy is an accepted treatment in reducing tumor recurrence. However, a potential therapeutic complication is delayed radionecrosis of perisellar neural structures, including the optic nerves and chiasm. This particular cause of visual loss, radiation optic neuropathy (RON), has not been emphasized in the ophthalmologic literature. Four cases of RON seen in the past five years are reported. Diagnostic criteria include: (1) acute visual loss (monocular or binocular), (2) visual field defects indicating optic nerve or chiasmal dysfunction, (3) absence of optic disc edema, (4) onset usually within three years of therapy (peak: 1-1 1/2 years), and (5) no computed tomographic evidence of visual pathway compression. Pathologic findings, differential diagnosis and therapy will be discussed in outlining the clinical profile of RON.

  19. Suprascapular neuropathy in pitchers.

    PubMed

    Ringel, S P; Treihaft, M; Carry, M; Fisher, R; Jacobs, P

    1990-01-01

    The clinical features and preoperative and postoperative electrodiagnostic studies were reviewed in two professional pitchers with a suprascapular neuropathy. These studies demonstrate that denervation of the infraspinatus and/or supraspinatus muscle is not always due to entrapment of the nerve at the suprascapular or spinoglenoid notches, as is often proposed. Similar studies in healthy pitchers during spring training and again at midseason demonstrate that slowing of suprascapular nerve conduction is detectable in some cases as the season progresses. Sagittal sections of a cadaver with the arm fixed in the acceleration phase of the pitching motion demonstrate five possible sites of trauma to the suprascapular nerve. Mechanisms proposed to explain these progressive, but potentially reversible, changes include consideration of biomechanical factors as well as anatomical features. An alternative hypothesis to nerve trauma that explains this symptom complex is intimal damage to the axillary or suprascapular artery and subsequent production of microemboli which become trapped in the suprascapular nerve vasa nervorum.

  20. Low Levels of NDRG1 in Nerve Tissue Are Predictive of Severe Paclitaxel-Induced Neuropathy

    PubMed Central

    Sundar, Raghav; Jeyasekharan, Anand D.; Pang, Brendan; Soong, Richie Chuan Teck; Kumarakulasinghe, Nesaretnam Barr; Ow, Samuel Guan Wei; Ho, Jingshan; Lim, Joline Si Jing; Tan, David Shao Peng; Wilder-Smith, Einar P. V.; Bandla, Aishwarya; Tan, Stacey Sze Hui; Asuncion, Bernadette Reyna; Fazreen, Zul; Hoppe, Michal Marek; Putti, Thomas Choudary; Poh, Lay Mui; Goh, Boon Cher; Lee, Soo-Chin

    2016-01-01

    Introduction Sensory peripheral neuropathy caused by paclitaxel is a common and dose limiting toxicity, for which there are currently no validated predictive biomarkers. We investigated the relationship between the Charcot-Marie-Tooth protein NDRG1 and paclitaxel-induced neuropathy. Methods/Materials Archived mammary tissue specimen blocks of breast cancer patients who received weekly paclitaxel in a single centre were retrieved and NDRG1 immunohistochemistry was performed on normal nerve tissue found within the sample. The mean nerve NDRG1 score was defined by an algorithm based on intensity of staining and percentage of stained nerve bundles. NDRG1 scores were correlated with paclitaxel induced neuropathy Results 111 patients were studied. 17 of 111 (15%) developed severe paclitaxel-induced neuropathy. The mean nerve NDRG1 expression score was 5.4 in patients with severe neuropathy versus 7.7 in those without severe neuropathy (p = 0.0019). A Receiver operating characteristic (ROC) curve analysis of the mean nerve NDRG1 score revealed an area under the curve of 0.74 (p = 0.0013) for the identification of severe neuropathy, with a score of 7 being most discriminative. 13/54 (24%) subjects with an NDRG1 score < = 7 developed severe neuropathy, compared to only 4/57 (7%) in those with a score >7 (p = 0.017). Conclusion Low NDRG1 expression in nerve tissue present within samples of surgical resection may identify subjects at risk for severe paclitaxel-induced neuropathy. Since nerve biopsies are not routinely feasible for patients undergoing chemotherapy for early breast cancer, this promising biomarker strategy is compatible with current clinical workflow. PMID:27716814

  1. Peripheral Neuropathy and Agent Orange

    MedlinePlus

    ... registry health exam . Research on peripheral neuropathy and herbicides The Health and Medicine Division (HMD) (formally known ... acute or subacute onset may be associated with herbicide exposure. Based on this evidence, VA presumed an ...

  2. Mitochondrial optic neuropathies – Disease mechanisms and therapeutic strategies

    PubMed Central

    Yu-Wai-Man, Patrick; Griffiths, Philip G.; Chinnery, Patrick F.

    2011-01-01

    Leber hereditary optic neuropathy (LHON) and autosomal-dominant optic atrophy (DOA) are the two most common inherited optic neuropathies in the general population. Both disorders share striking pathological similarities, marked by the selective loss of retinal ganglion cells (RGCs) and the early involvement of the papillomacular bundle. Three mitochondrial DNA (mtDNA) point mutations; m.3460G>A, m.11778G>A, and m.14484T>C account for over 90% of LHON cases, and in DOA, the majority of affected families harbour mutations in the OPA1 gene, which codes for a mitochondrial inner membrane protein. Optic nerve degeneration in LHON and DOA is therefore due to disturbed mitochondrial function and a predominantly complex I respiratory chain defect has been identified using both in vitro and in vivo biochemical assays. However, the trigger for RGC loss is much more complex than a simple bioenergetic crisis and other important disease mechanisms have emerged relating to mitochondrial network dynamics, mtDNA maintenance, axonal transport, and the involvement of the cytoskeleton in maintaining a differential mitochondrial gradient at sites such as the lamina cribosa. The downstream consequences of these mitochondrial disturbances are likely to be influenced by the local cellular milieu. The vulnerability of RGCs in LHON and DOA could derive not only from tissue-specific, genetically-determined biological factors, but also from an increased susceptibility to exogenous influences such as light exposure, smoking, and pharmacological agents with putative mitochondrial toxic effects. Our concept of inherited mitochondrial optic neuropathies has evolved over the past decade, with the observation that patients with LHON and DOA can manifest a much broader phenotypic spectrum than pure optic nerve involvement. Interestingly, these phenotypes are sometimes clinically indistinguishable from other neurodegenerative disorders such as Charcot-Marie-Tooth disease, hereditary spastic

  3. Effect of Atibalamula and Bhumyamalaki on thirty-three patients of diabetic neuropathy

    PubMed Central

    Patel, Kalapi; Patel, Manish; Gupta, S N

    2011-01-01

    Diabetic neuropathy is a relatively early and common complication affecting approximately 30% of diabetic patients. According to Ayurvedic principles there is involvement of Vata and Pitta Dosa in diabetic neuropathy. Bhumyamalaki (Phyllanthus niruri) is a plant which shows possibility to pacify these two Dosas. Another plant Atibala (Abutilon indicum) has also Vata pacifying qualities. Present study has been carried out to study the effects of Bhumyamalaki and Atibala on 33 patients of diabetic neuropathy. All the patients have been given Bhumyamalaki Churna 3 g twice a day and decoction of 10 g of Atibala-mula twice a day for 30 days. Neuropathy analyzer machine has been used for exact recording of sensory perception of vibration, cold and hot sensations before and after treatment. Changes in numbness, tingling, burning sensation and pain in lower limbs have also been assessed before and after treatment. Results have been analyzed statistically by applying the ‘t’ test. It can be stated from the results that use of Bhumyamalaki and Atibalamula in the patients of diabetic neuropathy can revert the diminished sensory perception and can reduce the symptoms significantly. PMID:22529650

  4. Effect of Atibalamula and Bhumyamalaki on thirty-three patients of diabetic neuropathy.

    PubMed

    Patel, Kalapi; Patel, Manish; Gupta, S N

    2011-07-01

    Diabetic neuropathy is a relatively early and common complication affecting approximately 30% of diabetic patients. According to Ayurvedic principles there is involvement of Vata and Pitta Dosa in diabetic neuropathy. Bhumyamalaki (Phyllanthus niruri) is a plant which shows possibility to pacify these two Dosas. Another plant Atibala (Abutilon indicum) has also Vata pacifying qualities. Present study has been carried out to study the effects of Bhumyamalaki and Atibala on 33 patients of diabetic neuropathy. All the patients have been given Bhumyamalaki Churna 3 g twice a day and decoction of 10 g of Atibala-mula twice a day for 30 days. Neuropathy analyzer machine has been used for exact recording of sensory perception of vibration, cold and hot sensations before and after treatment. Changes in numbness, tingling, burning sensation and pain in lower limbs have also been assessed before and after treatment. Results have been analyzed statistically by applying the 't' test. It can be stated from the results that use of Bhumyamalaki and Atibalamula in the patients of diabetic neuropathy can revert the diminished sensory perception and can reduce the symptoms significantly. PMID:22529650

  5. Corneal Confocal Microscopy Detects Neuropathy in Subjects With Impaired Glucose Tolerance

    PubMed Central

    Asghar, Omar; Petropoulos, Ioannis N.; Alam, Uazman; Jones, Wendy; Jeziorska, Maria; Marshall, Andrew; Ponirakis, Georgios; Fadavi, Hassan; Boulton, Andrew J.M.; Tavakoli, Mitra

    2014-01-01

    OBJECTIVE Impaired glucose tolerance (IGT) represents one of the earliest stages of glucose dysregulation and is associated with macrovascular disease, retinopathy, and microalbuminuria, but whether IGT causes neuropathy is unclear. RESEARCH DESIGN AND METHODS Thirty-seven subjects with IGT and 20 age-matched control subjects underwent a comprehensive evaluation of neuropathy by assessing symptoms, neurological deficits, nerve conduction studies, quantitative sensory testing, heart rate variability deep breathing (HRVdb), skin biopsy, and corneal confocal microscopy (CCM). RESULTS Subjects with IGT had a significantly increased neuropathy symptom profile (P < 0.001), McGill pain index (P < 0.001), neuropathy disability score (P = 0.001), vibration perception threshold (P = 0.002), warm threshold (P = 0.006), and cool threshold (P = 0.03), with a reduction in intraepidermal nerve fiber density (P = 0.03), corneal nerve fiber density (P < 0.001), corneal nerve branch density (P = 0.002), and corneal nerve fiber length (P = 0.05). No significant difference was found in sensory and motor nerve amplitude and conduction velocity or HRVdb. CONCLUSIONS Subjects with IGT have evidence of neuropathy, particularly small-fiber damage, which can be detected using skin biopsy and CCM. PMID:24969581

  6. [Advances in hereditary hemochromatosis].

    PubMed

    Nardi, Graciela; Cadiz, Claudia; Lachman, J; Cornelio, Cecilia

    2003-01-01

    Hereditary hemocromatosis (HH) is a genetic disease with a recessive autosomic pattern, in which inadequate iron (Fe) absorption is made by the intestinal cell. As consequence of that process, takes place a progressive accumulation of metal in different organs, predominantly in the liver. This leads to an alteration of liver structure and function: cirrhosis and hepatocarcinoma (1). The gene implied in this pathology was identified (HFE) in 1996. This codes a similar molecule to the mayor histocompatibility complex type 1(MHC-T1 like) that can modulate the transport of PE binding the transferrin receptor. This progress allows a deep understanding of the molecular and cellular biology of the homeostasis of the Fe and its alterations in the NH. The diagnosis of disease by means of a genetic test let to carry out a familiar screening and to detect asymptomatic carriers. This makes possible to begin the appropriate treatment at early stages of the disease in order to avoid its consequences and offering a better quality of life to these patients.

  7. Hereditary fructose intolerance.

    PubMed Central

    Ali, M; Rellos, P; Cox, T M

    1998-01-01

    Hereditary fructose intolerance (HFI, OMIM 22960), caused by catalytic deficiency of aldolase B (fructose-1,6-bisphosphate aldolase, EC 4.1.2.13), is a recessively inherited condition in which affected homozygotes develop hypoglycaemic and severe abdominal symptoms after taking foods containing fructose and cognate sugars. Continued ingestion of noxious sugars leads to hepatic and renal injury and growth retardation; parenteral administration of fructose or sorbitol may be fatal. Direct detection of a few mutations in the human aldolase B gene on chromosome 9q facilitates the genetic diagnosis of HFI in many symptomatic patients. The severity of the disease phenotype appears to be independent of the nature of the aldolase B gene mutations so far identified. It appears that hitherto there has been little, if any, selection against mutant aldolase B alleles in the population: in the UK, approximately 1.3% of neonates harbour one copy of the prevalent A149P disease allele. The ascendance of sugar as a major dietary nutrient, especially in western societies, may account for the increasing recognition of HFI as a nutritional disease and has shown the prevalence of mutant aldolase B genes in the general population. The severity of clinical expression correlates well with the immediate nutritional environment, age, culture, and eating habits of affected subjects. Here we review the biochemical, genetic, and molecular basis of human aldolase B deficiency in HFI, a disorder which responds to dietary therapy and in which the principal manifestations of disease are thus preventable. Images PMID:9610797

  8. Hereditary pancreatitis: current perspectives.

    PubMed

    Raphael, Kara L; Willingham, Field F

    2016-01-01

    Hereditary pancreatitis (HP) is a rare cause of acute, recurrent acute, and chronic pancreatitis. It may present similarly to other causes of acute and chronic pancreatitis, and often there has been a protracted evaluation prior to the diagnosis of HP. Since it was first described in 1952, multiple genetic defects that affect the action of digestive enzymes in the pancreas have been implicated. The most common mutations involve the PRSS1, CFTR, SPINK1, and CTRC genes. New mutations in these genes and previously unrecognized mutations in other genes are being discovered due to the increasing use of next-generation genomic sequencing. While the inheritance pathways of these genetic mutations may be variable and complex, sometimes involving coinheritance of other mutations, the clinical presentation of patients tends to be similar. Interactions with environmental triggers often play a role. Patients tend to present at an early age (prior to the second decade of life) and have a significantly increased risk for the development of pancreatic adenocarcinoma. Patients with HP may develop sequelae of chronic pancreatitis such as strictures and fluid collections as well as exocrine and endocrine insufficiency. Management of patients with HP involves avoidance of environmental triggers, surveillance for pancreatic adenocarcinoma, medical therapy for endocrine and exocrine insufficiency, pain management, and endoscopic or surgical treatment for complications. Care for affected patients should be individualized, with an emphasis on early diagnosis and multidisciplinary involvement to develop a comprehensive treatment strategy. PMID:27555793

  9. Hereditary pancreatitis: current perspectives

    PubMed Central

    Raphael, Kara L; Willingham, Field F

    2016-01-01

    Hereditary pancreatitis (HP) is a rare cause of acute, recurrent acute, and chronic pancreatitis. It may present similarly to other causes of acute and chronic pancreatitis, and often there has been a protracted evaluation prior to the diagnosis of HP. Since it was first described in 1952, multiple genetic defects that affect the action of digestive enzymes in the pancreas have been implicated. The most common mutations involve the PRSS1, CFTR, SPINK1, and CTRC genes. New mutations in these genes and previously unrecognized mutations in other genes are being discovered due to the increasing use of next-generation genomic sequencing. While the inheritance pathways of these genetic mutations may be variable and complex, sometimes involving coinheritance of other mutations, the clinical presentation of patients tends to be similar. Interactions with environmental triggers often play a role. Patients tend to present at an early age (prior to the second decade of life) and have a significantly increased risk for the development of pancreatic adenocarcinoma. Patients with HP may develop sequelae of chronic pancreatitis such as strictures and fluid collections as well as exocrine and endocrine insufficiency. Management of patients with HP involves avoidance of environmental triggers, surveillance for pancreatic adenocarcinoma, medical therapy for endocrine and exocrine insufficiency, pain management, and endoscopic or surgical treatment for complications. Care for affected patients should be individualized, with an emphasis on early diagnosis and multidisciplinary involvement to develop a comprehensive treatment strategy. PMID:27555793

  10. Hereditary pancreatitis: current perspectives.

    PubMed

    Raphael, Kara L; Willingham, Field F

    2016-01-01

    Hereditary pancreatitis (HP) is a rare cause of acute, recurrent acute, and chronic pancreatitis. It may present similarly to other causes of acute and chronic pancreatitis, and often there has been a protracted evaluation prior to the diagnosis of HP. Since it was first described in 1952, multiple genetic defects that affect the action of digestive enzymes in the pancreas have been implicated. The most common mutations involve the PRSS1, CFTR, SPINK1, and CTRC genes. New mutations in these genes and previously unrecognized mutations in other genes are being discovered due to the increasing use of next-generation genomic sequencing. While the inheritance pathways of these genetic mutations may be variable and complex, sometimes involving coinheritance of other mutations, the clinical presentation of patients tends to be similar. Interactions with environmental triggers often play a role. Patients tend to present at an early age (prior to the second decade of life) and have a significantly increased risk for the development of pancreatic adenocarcinoma. Patients with HP may develop sequelae of chronic pancreatitis such as strictures and fluid collections as well as exocrine and endocrine insufficiency. Management of patients with HP involves avoidance of environmental triggers, surveillance for pancreatic adenocarcinoma, medical therapy for endocrine and exocrine insufficiency, pain management, and endoscopic or surgical treatment for complications. Care for affected patients should be individualized, with an emphasis on early diagnosis and multidisciplinary involvement to develop a comprehensive treatment strategy.

  11. The roles of oxidative stress and antioxidant treatment in experimental diabetic neuropathy.

    PubMed

    Low, P A; Nickander, K K; Tritschler, H J

    1997-09-01

    Oxidative stress is present in the diabetic state. Our work has focused on its presence in peripheral nerves. Antioxidant enzymes are reduced in peripheral nerves and are further reduced in diabetic nerves. That lipid peroxidation will cause neuropathy is supported by evidence of the development of neuropathy de novo when normal nerves are rendered alpha-tocopherol deficient and by the augmentation of the conduction deficit in diabetic nerves subjected to this insult. Oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia auto-oxidation. The indexes of oxidative stress include an increase in nerve, dorsal root, and sympathetic ganglia lipid hydroperoxides and conjugated dienes. The most reliable and sensitive index, however, is a reduction in reduced glutathione. Experimental diabetic neuropathy results in myelinopathy of dorsal roots and a vacuolar neuropathy of dorsal root ganglion. The vacuoles are mitochondrial; we posit that lipid peroxidation causes mitochondrial DNA mutations that increase reduced oxygen species, causing further damage to mitochondrial respiratory chain and function and resulting in a sensory neuropathy. Alpha-lipoic acid is a potent antioxidant that prevents lipid peroxidation in vitro and in vivo. We evaluated the efficacy of the drug in doses of 20, 50, and 100 mg/kg administered intraperitoneally in preventing the biochemical, electrophysiological, and nerve blood flow deficits in the peripheral nerves of experimental diabetic neuropathy. Alpha-lipoic acid dose- and time-dependently prevented the deficits in nerve conduction and nerve blood flow and biochemical abnormalities (reductions in reduced glutathione and lipid peroxidation). The nerve blood flow deficit was 50% (P < 0.001). Supplementation dose-dependently prevented the deficit; at the highest concentration, nerve blood flow was not different from that of control nerves. Digital nerve conduction underwent a dose-dependent improvement at

  12. Riley-Day syndrome

    MedlinePlus

    Familial dysautonomia; Hereditary sensory and autonomic neuropathy - type III (HSAN III) ... Saunders; 2012:chap 76. Klein CJ. The inherited neuropathies. Neurol Clin . 2007;25:173-207. PMID: 17324725 ...

  13. Electrodiagnosis of brachial plexopathies and proximal upper extremity neuropathies.

    PubMed

    Simmons, Zachary

    2013-02-01

    This article describes the normal anatomy of the brachial plexus and its major terminal branches, as well as the major causes and clinical presentations of lesions of these structures. An approach to electrodiagnosis of brachial plexopathies and proximal upper extremity neuropathies is provided, with an emphasis on those nerve conduction studies and portions of the needle examination, which permit localization of lesions to specific trunks, cords, and terminal branches. The importance of specific sensory nerve conduction studies for differentiating plexopathies from radiculopathies and mononeuropathies is emphasized.

  14. Luteolin improves the impaired nerve functions in diabetic neuropathy: behavioral and biochemical evidences.

    PubMed

    Li, Ming; Li, Qiang; Zhao, Qingsong; Zhang, Jinchao; Lin, Jiang

    2015-01-01

    Peripheral neuropathies are a major cause of morbidity in patients with diabetes mellitus. Up to now, drugs for improving the impaired nerve functions has been lacking for diabetic neuropathy. The antioxidant and neuroprotective effects of luteolin make it an attractive candidate for diabetic neuropathy. The present study was designed to investigate the putative beneficial effect of luteolin on diabetic neuropathy. Diabetic rats were intraperitoneally treated with daily luteolin (50 mg/kg, 100 mg/kg and 200 mg/kg) or vehicle for 3 weeks from the 28(th) day after streptozotocin injection. Behavioral, electrophysiological and biochemical studies were performed to evaluate the effect of luteolin on the impaired nerve functions in diabetic neuropathy. It was found that luteolin dose dependently alleviated abnormal sensation, improved nerve conduction velocities and nerve blood flow in diabetic rats. Biochanical analysis showed that luteolin significantly lowered the reactive oxygen species production and malondialdehyde level, as well as increased antioxidants activities in a dose dependent manner. In addition, luteolin significantly up-regulated the protein levels of nuclear factor-E2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) in diabetic nerves. Taken together, luteolin is capable of improving diabetes-induced deficit in motor and sensory functions, which could be attributable, at least in part, to its Nrf2-dependent antioxidant capacity. The findings in the present study highlight the therapeutic value of luteolin for diabetic neuropathy.

  15. Luteolin improves the impaired nerve functions in diabetic neuropathy: behavioral and biochemical evidences

    PubMed Central

    Li, Ming; Li, Qiang; Zhao, Qingsong; Zhang, Jinchao; Lin, Jiang

    2015-01-01

    Peripheral neuropathies are a major cause of morbidity in patients with diabetes mellitus. Up to now, drugs for improving the impaired nerve functions has been lacking for diabetic neuropathy. The antioxidant and neuroprotective effects of luteolin make it an attractive candidate for diabetic neuropathy. The present study was designed to investigate the putative beneficial effect of luteolin on diabetic neuropathy. Diabetic rats were intraperitoneally treated with daily luteolin (50 mg/kg, 100 mg/kg and 200 mg/kg) or vehicle for 3 weeks from the 28th day after streptozotocin injection. Behavioral, electrophysiological and biochemical studies were performed to evaluate the effect of luteolin on the impaired nerve functions in diabetic neuropathy. It was found that luteolin dose dependently alleviated abnormal sensation, improved nerve conduction velocities and nerve blood flow in diabetic rats. Biochanical analysis showed that luteolin significantly lowered the reactive oxygen species production and malondialdehyde level, as well as increased antioxidants activities in a dose dependent manner. In addition, luteolin significantly up-regulated the protein levels of nuclear factor-E2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) in diabetic nerves. Taken together, luteolin is capable of improving diabetes-induced deficit in motor and sensory functions, which could be attributable, at least in part, to its Nrf2-dependent antioxidant capacity. The findings in the present study highlight the therapeutic value of luteolin for diabetic neuropathy. PMID:26617718

  16. Sensory analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sensory evaluation can answer questions about a product that instruments cannot. The human subject is the instrument, and data can provide a wealth of information for a product developer, or results can be very variable and erroneous if all the precautions to minimize bias and external noise are no...

  17. Sensory Dysfunction

    MedlinePlus

    ... to Web version Sensory Dysfunction Overview Why are smell and taste important? Your senses of smell and taste let you fully enjoy the scents ... bitter and sour. Flavor involves both taste and smell. For example, because a person is able to ...

  18. Canadian hereditary angioedema guideline.

    PubMed

    Betschel, Stephen; Badiou, Jacquie; Binkley, Karen; Hébert, Jacques; Kanani, Amin; Keith, Paul; Lacuesta, Gina; Yang, Bill; Aygören-Pürsün, Emel; Bernstein, Jonathan; Bork, Konrad; Caballero, Teresa; Cicardi, Marco; Craig, Timothy; Farkas, Henriette; Longhurst, Hilary; Zuraw, Bruce; Boysen, Henrik; Borici-Mazi, Rozita; Bowen, Tom; Dallas, Karen; Dean, John; Lang-Robertson, Kelly; Laramée, Benoît; Leith, Eric; Mace, Sean; McCusker, Christine; Moote, Bill; Poon, Man-Chiu; Ritchie, Bruce; Stark, Donald; Sussman, Gordon; Waserman, Susan

    2014-01-01

    Hereditary angioedema (HAE) is a disease which is associated with random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased Health Related Quality of Life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada is neither optimal nor uniform across the country. It lags behind other countries where there are more organized models for HAE management, and where additional therapeutic options are licensed and available for use. The objective of this guideline is to provide graded recommendations for the management of patients in Canada with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. It is anticipated that by providing this guideline to caregivers, policy makers, patients and their advocates, that there will be an improved understanding of the current recommendations regarding management of HAE and the factors that need to be considered when choosing therapies and treatment plans for individual patients. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency physicians, gastroenterologists, dentists and otolaryngologists, who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.

  19. Crucifixion and median neuropathy

    PubMed Central

    Regan, Jacqueline M; Shahlaie, Kiarash; Watson, Joseph C

    2013-01-01

    Crucifixion as a means of torture and execution was first developed in the 6th century B.C. and remained popular for over 1000 years. Details of the practice, which claimed hundreds of thousands of lives, have intrigued scholars as historical records and archaeological findings from the era are limited. As a result, various aspects of crucifixion, including the type of crosses used, methods of securing victims to crosses, the length of time victims survived on the cross, and the exact mechanisms of death, remain topics of debate. One aspect of crucifixion not previously explored in detail is the characteristic hand posture often depicted in artistic renditions of crucifixion. In this posture, the hand is clenched in a peculiar and characteristic fashion: there is complete failure of flexion of the thumb and index finger with partial failure of flexion of the middle finger. Such a “crucified clench” is depicted across different cultures and from different eras. A review of crucifixion history and techniques, median nerve anatomy and function, and the historical artistic depiction of crucifixion was performed to support the hypothesis that the “crucified clench” results from proximal median neuropathy due to positioning on the cross, rather than from direct trauma of impalement of the hand or wrist. PMID:23785656

  20. Genetics Home Reference: hereditary diffuse gastric cancer

    MedlinePlus

    ... JT, van Hillegersberg R, Dekker E, Oliveira C, Cats A, Hoogerbrugge N; Dutch Working Group on Hereditary ... JH, van Hillegersberg R, Ligtenberg M, Bleiker E, Cats A; Dutch Working Group on Hereditary Gastric Cancer. ...

  1. Physical examination of upper extremity compressive neuropathies.

    PubMed

    Popinchalk, Samuel P; Schaffer, Alyssa A

    2012-10-01

    A thorough history and physical examination are vital to the assessment of upper extremity compressive neuropathies. This article summarizes relevant anatomy and physical examination findings associated with upper extremity compressive neuropathies.

  2. Mixed or immune complex cryoglobulinaemia and neuropathy

    PubMed Central

    Cream, J. J.; Hern, J. E. C.; Hughes, R. A. C.; Mackenzie, I. C. K.

    1974-01-01

    Three patients with peripheral neuropathy and mixed or immune complex cryoglobulinaemia are reported. The significance of mixed cryoglobulinaemia and the pathogenesis of the peripheral neuropathy are discussed. Images PMID:4360402

  3. Recent advances in hereditary hemochromatosis.

    PubMed

    Franchini, Massimo; Veneri, Dino

    2005-06-01

    Hereditary hemochromatosis, a very common genetic defect in the Caucasian population, is characterized by progressive tissue iron overload which leads to irreversible organ damage if it is not treated in a timely manner. Recent developments in the field of molecular medicine have radically improved the understanding of the physiopathology and diagnosis of this disease. However, transferrin saturation and serum ferritin are still the most reliable tests for identifying subjects with hereditary hemochromatosis. Therapeutic phlebotomy is the mainstay of the treatment of this disease and the life expectancy of these patients is similar to that of the normal population if phlebotomy is started before the onset of irreversible organ damage. In this review we discuss the genetics, pathophysiology, diagnosis, clinical features, and management of hereditary hemochromatosis.

  4. Peripheral neuropathy: the importance of rare subtypes

    PubMed Central

    Callaghan, Brian C.; Price, Ray S.; Chen, Kevin S.; Feldman, Eva L.

    2016-01-01

    Importance Peripheral neuropathy is a prevalent condition that usually warrants a thorough history and examination, but limited diagnostic evaluation. Rare localizations of peripheral neuropathy, however, often require more extensive diagnostic testing and different treatments. Objective To describe rare localizations of peripheral neuropathy, including the appropriate diagnostic evaluation and available treatments. Evidence Review References were identified from PubMed searches with an emphasis on systematic reviews and randomized clinical trials. Articles were also identified through the use of the author's own files. Search terms included common rare neuropathy localizations and their causes, as well as epidemiology, pathophysiology, diagnosis, and treatment. Findings Diffuse, non-length dependent neuropathies, multiple mononeuropathies, polyradiculopathies, plexopathies, and radiculoplexus neuropathies are rare peripheral neuropathy localizations that often require extensive diagnostic testing. Atypical neuropathy features, such as acute/subacute onset, asymmetry, and/or motor predominant signs, are frequently present. The most common diffuse, non-length dependent neuropathies are Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and amyotrophic lateral sclerosis (ALS). Effective disease modifying therapies exist for many diffuse, non-length dependent neuropathies including GBS, CIDP, MMN, and some paraprotein-associated demyelinating neuropathies. Vasculitic neuropathy (multiple mononeuropathy) also has efficacious treatment options, but definitive evidence of a treatment effect for IgM anti-MAG neuropathy and diabetic amyoptrophy (radiculoplexus neuropathy) is lacking. Conclusions and Relevance Recognition of rare localizations of periperhal neuropathy is essential given the implications for diagnostic testing and treatment. Electrodiagnostic studies are an important early step in the

  5. Peripheral neuropathy and parkinsonism: a large clinical and pathogenic spectrum.

    PubMed

    Vital, Anne; Lepreux, Sebastien; Vital, Claude

    2014-12-01

    Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism, but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa-induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism. PMID:25582874

  6. Entrapment neuropathies in diabetes mellitus

    PubMed Central

    Rota, Eugenia; Morelli, Nicola

    2016-01-01

    Neuropathy is a common complication of diabetes mellitus (DM) with a wide clinical spectrum that encompasses generalized to focal and multifocal forms. Entrapment neuropathies (EN), which are focal forms, are so frequent at any stage of the diabetic disease, that they may be considered a neurophysiological hallmark of peripheral nerve involvement in DM. Indeed, EN may be the earliest neurophysiological abnormalities in DM, particularly in the upper limbs, even in the absence of a generalized polyneuropathy, or it may be superimposed on a generalized diabetic neuropathy. This remarkable frequency of EN in diabetes is underlain by a peculiar pathophysiological background. Due to the metabolic alterations consequent to abnormal glucose metabolism, the peripheral nerves show both functional impairment and structural changes, even in the preclinical stage, making them more prone to entrapment in anatomically constrained channels. This review discusses the most common and relevant EN encountered in diabetic patient in their epidemiological, pathophysiological and diagnostic features.

  7. Paraproteinemic neuropathy: a practical review.

    PubMed

    Rison, Richard A; Beydoun, Said R

    2016-01-01

    The term paraproteinemic neuropathy describes a heterogeneous set of neuropathies characterized by the presence of homogeneous immunoglobulin in the serum. An abnormal clonal proliferation of B-lymphocytes or plasma cells, which may or may not occur in the context of a hematologic malignancy, produces the immunoglobulins in excess. If malignancy is identified, treatment should be targeted to the neoplasm. Most cases, however, occur as monoclonal gammopathy of undetermined significance. Few prospective, randomized, placebo-controlled trials are available to inform the management of paraproteinemic neuropathies. Clinical experience combined with data from smaller, uncontrolled studies provide a basis for recommendations, which depend on the specific clinical setting in which the paraprotein occurs. In this review, we provide a clinically practical approach to diagnosis and management of such patients. PMID:26821540

  8. Entrapment neuropathies in diabetes mellitus

    PubMed Central

    Rota, Eugenia; Morelli, Nicola

    2016-01-01

    Neuropathy is a common complication of diabetes mellitus (DM) with a wide clinical spectrum that encompasses generalized to focal and multifocal forms. Entrapment neuropathies (EN), which are focal forms, are so frequent at any stage of the diabetic disease, that they may be considered a neurophysiological hallmark of peripheral nerve involvement in DM. Indeed, EN may be the earliest neurophysiological abnormalities in DM, particularly in the upper limbs, even in the absence of a generalized polyneuropathy, or it may be superimposed on a generalized diabetic neuropathy. This remarkable frequency of EN in diabetes is underlain by a peculiar pathophysiological background. Due to the metabolic alterations consequent to abnormal glucose metabolism, the peripheral nerves show both functional impairment and structural changes, even in the preclinical stage, making them more prone to entrapment in anatomically constrained channels. This review discusses the most common and relevant EN encountered in diabetic patient in their epidemiological, pathophysiological and diagnostic features. PMID:27660694

  9. Entrapment neuropathies in diabetes mellitus.

    PubMed

    Rota, Eugenia; Morelli, Nicola

    2016-09-15

    Neuropathy is a common complication of diabetes mellitus (DM) with a wide clinical spectrum that encompasses generalized to focal and multifocal forms. Entrapment neuropathies (EN), which are focal forms, are so frequent at any stage of the diabetic disease, that they may be considered a neurophysiological hallmark of peripheral nerve involvement in DM. Indeed, EN may be the earliest neurophysiological abnormalities in DM, particularly in the upper limbs, even in the absence of a generalized polyneuropathy, or it may be superimposed on a generalized diabetic neuropathy. This remarkable frequency of EN in diabetes is underlain by a peculiar pathophysiological background. Due to the metabolic alterations consequent to abnormal glucose metabolism, the peripheral nerves show both functional impairment and structural changes, even in the preclinical stage, making them more prone to entrapment in anatomically constrained channels. This review discusses the most common and relevant EN encountered in diabetic patient in their epidemiological, pathophysiological and diagnostic features.

  10. Entrapment neuropathies in diabetes mellitus.

    PubMed

    Rota, Eugenia; Morelli, Nicola

    2016-09-15

    Neuropathy is a common complication of diabetes mellitus (DM) with a wide clinical spectrum that encompasses generalized to focal and multifocal forms. Entrapment neuropathies (EN), which are focal forms, are so frequent at any stage of the diabetic disease, that they may be considered a neurophysiological hallmark of peripheral nerve involvement in DM. Indeed, EN may be the earliest neurophysiological abnormalities in DM, particularly in the upper limbs, even in the absence of a generalized polyneuropathy, or it may be superimposed on a generalized diabetic neuropathy. This remarkable frequency of EN in diabetes is underlain by a peculiar pathophysiological background. Due to the metabolic alterations consequent to abnormal glucose metabolism, the peripheral nerves show both functional impairment and structural changes, even in the preclinical stage, making them more prone to entrapment in anatomically constrained channels. This review discusses the most common and relevant EN encountered in diabetic patient in their epidemiological, pathophysiological and diagnostic features. PMID:27660694

  11. Warfarin improves neuropathy in monoclonal gammopathy of undetermined significance.

    PubMed

    Henry Gomez, Teny; Holkova, Beata; Noreika, Danielle; Del Fabbro, Egidio

    2016-01-01

    We report a case of a 60-year-old man who was referred to a palliative care clinic with monoclonal gammopathy of undetermined significance (MGUS)-associated neuropathy, responding to a therapeutic trial of warfarin. Electromyography showed distal symmetric sensory axonal neuropathy. The patient reported having had improvement of his neuropathic symptoms while taking warfarin postoperatively for thromboprophylaxis 1 year prior, and recurrence of his symptoms after the warfarin was discontinued. The patient was rechallenged with a trial of warfarin, targeting an international normalised ratio of 1.5-2.0. His pain scores decreased from 5/10 to 3/10 at 1 month and symptom improvement was maintained through 24 months of follow-up. Warfarin had a remarkable impact on our patient's symptoms and quality of life. The mechanisms mediating the symptomatic benefit with warfarin are unclear; however, a placebo effect is unlikely. Further studies may help guide the use of warfarin for MGUS-associated neuropathy. PMID:27317760

  12. Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy.

    PubMed

    Huang, Jianying; Han, Chongyang; Estacion, Mark; Vasylyev, Dymtro; Hoeijmakers, Janneke G J; Gerrits, Monique M; Tyrrell, Lynda; Lauria, Giuseppe; Faber, Catharina G; Dib-Hajj, Sulayman D; Merkies, Ingemar S J; Waxman, Stephen G

    2014-06-01

    Sodium channel Nav1.9 is expressed in peripheral nociceptive neurons, as well as visceral afferents, and has been shown to act as a threshold channel. Painful peripheral neuropathy represents a significant public health challenge and may involve gain-of-function variants in sodium channels that are preferentially expressed in peripheral sensory neurons. Although gain-of-function variants of peripheral sodium channels Nav1.7 and Nav1.8 have recently been found in painful small fibre neuropathy, the aetiology of peripheral neuropathy in many cases remains unknown. We evaluated 459 patients who were referred for possible painful peripheral neuropathy, and confirmed the diagnosis of small fibre neuropathy in a cohort of 393 patients (369 patients with pure small fibre neuropathy, and small fibre neuropathy together with large fibre involvement in an additional 24 patients). From this cohort of 393 patients with peripheral neuropathy, we sequenced SCN11A in 345 patients without mutations in SCN9A and SCN10A, and found eight variants in 12 patients. Functional profiling by electrophysiological recordings showed that these Nav1.9 mutations confer gain-of-function attributes to the channel, depolarize resting membrane potential of dorsal root ganglion neurons, enhance spontaneous firing, and increase evoked firing of these neurons. Our data show, for the first time, missense mutations of Nav1.9 in individuals with painful peripheral neuropathy. These genetic and functional observations identify missense mutations of Nav1.9 as a cause of painful peripheral neuropathy. PMID:24776970

  13. Novel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathy

    PubMed Central

    Zimanyi, Christina M.; Aisenberg, William; Bears, Breanne; Chen, Dong-Hui; Day, John W.; Bird, Thomas D.; Siskind, Carly E.; Gaudet, Rachelle; Sumner, Charlotte J.

    2015-01-01

    Objective: To characterize 2 novel TRPV4 mutations in 2 unrelated families exhibiting the Charcot-Marie-Tooth disease type 2C (CMT2C) phenotype. Methods: Direct CMT gene testing was performed on 2 unrelated families with CMT2C. A 4-fold symmetric tetramer model of human TRPV4 was generated to map the locations of novel TRPV4 mutations in these families relative to previously identified disease-causing mutations (neuropathy, skeletal dysplasia, and osteoarthropathy). Effects of the mutations on TRPV4 expression, localization, and channel activity were determined by immunocytochemical, immunoblotting, Ca2+ imaging, and cytotoxicity assays. Results: Previous studies suggest that neuropathy-causing mutations occur primarily at arginine residues on the convex face of the TRPV4 ankyrin repeat domain (ARD). Further highlighting the key role of this domain in TRPV4-mediated hereditary neuropathy, we report 2 novel heterozygous missense mutations in the TRPV4-ARD convex face (p.Arg237Gly and p.Arg237Leu). Generation of a model of the TRPV4 homotetramer revealed that while ARD residues mutated in neuropathy (including Arg237) are likely accessible for intermolecular interactions, skeletal dysplasia–causing TRPV4 mutations occur at sites suggesting disruption of intramolecular and/or intersubunit interactions. Like previously described neuropathy-causing mutations, the p.Arg237Gly and p.Arg237Leu substitutions do not alter TRPV4 subcellular localization in transfected cells but cause elevations of cytosolic Ca2+ levels and marked cytotoxicity. Conclusions: These findings expand the number of ARD residues mutated in TRPV4-mediated neuropathy, providing further evidence of the central importance of this domain to TRPV4 function in peripheral nerve. PMID:27066566

  14. Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies.

    PubMed

    Carelli, Valerio; Ross-Cisneros, Fred N; Sadun, Alfredo A

    2002-05-01

    Selective degeneration of the smallest fibers (papillo-macular bundle) of the human optic nerve occurs in a large number of optic neuropathies characterized primarily by loss of central vision. The pathophysiology that underlies this peculiar pattern of cell involvement probably reflects different forms of genetic and acquired mitochondrial dysfunction. Maternally inherited Leber's hereditary optic neuropathy (LHON), dominant optic atrophy (Kjer disease), the optic atrophy of Leigh's syndrome, Friedreich ataxia and a variety of other conditions are examples of inherited mitochondrial disorders with different etiologies. Tobacco-alcohol amblyopia (TAA), the Cuban epidemic of optic neuropathy (CEON) and other dietary (Vitamins B, folate deficiencies) optic neuropathies, as well as toxic optic neuropathies such as due to chloramphenicol, ethambutol, or more rarely to carbon monoxide, methanol and cyanide are probably all related forms of acquired mitochondrial dysfunction. Biochemical and cellular studies in LHON point to a partial defect of respiratory chain function that may generate either an ATP synthesis defect and/or a chronic increase of oxidative stress. Histopathological studies in LHON cases and a rat model mimicking CEON revealed a selective loss of retinal ganglion cells (RGCs) and the corresponding axons, particularly in the temporal-central part of the optic nerve. Anatomical peculiarities of optic nerve axons, such as the asymmetric pattern of myelination, may have functional implications on energy dependence and distribution of mitochondrial populations in the different sections of the nerve. Histological evidence suggests impaired axonal transport of mitochondria in LHON and in the CEON-like rat model, indicating a possible common pathophysiology for this category of optic neuropathies. Histological evidence of myelin pathology in LHON also suggests a role for oxidative stress, possibly affecting the oligodendrocytes of the optic nerves.

  15. Peripheral neuropathy caused by methaqualone.

    PubMed

    Marks, P; Sloggem, J

    1976-01-01

    Three patients are described who each received methaqualone and developed signs and symptoms of peripheral neuropathy. The subsequent improvement after cessation of methaqualone was highly suggestive or a direct toxic action of the drug or one of its metabolites. In one patient methaqualone was recommended with reappearance of signs and symptoms of peripheral neuropathy. Again cessation of the drug caused disappearance of these signs. There was no evidence whatsoever of any electrolyte or metabolic disturbance or any other pathology which might have given rise to this symptom complex. In addition, no other drugs were prescribed besides methaqualone.

  16. Different intracellular pathomechanisms produce diverse Myelin Protein Zero neuropathies in transgenic mice.

    PubMed

    Wrabetz, Lawrence; D'Antonio, Maurizio; Pennuto, Maria; Dati, Gabriele; Tinelli, Elisa; Fratta, Pietro; Previtali, Stefano; Imperiale, Daniele; Zielasek, Jurgen; Toyka, Klaus; Avila, Robin L; Kirschner, Daniel A; Messing, Albee; Feltri, M Laura; Quattrini, Angelo

    2006-02-22

    Missense mutations in 22 genes account for one-quarter of Charcot-Marie-Tooth (CMT) hereditary neuropathies. Myelin Protein Zero (MPZ, P0) mutations produce phenotypes ranging from adult demyelinating (CMT1B) to early onset [Déjérine-Sottas syndrome (DSS) or congenital hypomyelination] to predominantly axonal neuropathy, suggesting gain of function mechanisms. To test this directly, we produced mice in which either the MpzS63C (DSS) or MpzS63del (CMT1B) transgene was inserted randomly, so that the endogenous Mpz alleles could compensate for any loss of mutant P0 function. We show that either mutant allele produces demyelinating neuropathy that mimics the corresponding human disease. However, P0S63C creates a packing defect in the myelin sheath, whereas P0S63del does not arrive to the myelin sheath and is instead retained in the endoplasmic reticulum, where it elicits an unfolded protein response (UPR). This is the first evidence for UPR in association with neuropathy and provides a model to determine whether and how mutant proteins can provoke demyelination from outside of myelin. PMID:16495463

  17. Drug therapy for hereditary cancers

    PubMed Central

    2011-01-01

    Tumors arising in patients with hereditary cancer syndromes may have distinct drug sensitivity as compared to their sporadic counterparts. Breast and ovarian neoplasms from BRCA1 or BRCA2 mutation carriers are characterized by deficient homologous recombination (HR) of DNA, that makes them particularly sensitive to platinum compounds or inhibitors of poly (ADP-ribose) polymerase (PARP). Outstandingly durable complete responses to high dose chemotherapy have been observed in several cases of BRCA-related metastatic breast cancer (BC). Multiple lines of evidence indicate that women with BRCA1-related BC may derive less benefit from taxane-based treatment than other categories of BC patients. There is virtually no reports directly assessing drug response in hereditary colorectal cancer (CRC) patients; studies involving non-selected (i.e., both sporadic and hereditary) CRC with high-level microsatellite instability (MSI-H) suggest therapeutic advantage of irinotecan. Celecoxib has been approved for the treatment of familial adenomatous polyposis (FAP). Hereditary medullary thyroid cancers (MTC) have been shown to be highly responsive to a multitargeted tyrosine kinase inhibitor vandetanib, which exerts specific activity towards mutated RET receptor. Given the rapidly improving accessibility of DNA analysis, it is foreseen that the potential predictive value of cancer-associated germ-line mutations will be increasingly considered in the future studies. PMID:21819606

  18. Diabetic gastrointestinal autonomic neuropathy: current status and new achievements for everyday clinical practice.

    PubMed

    Gatopoulou, A; Papanas, N; Maltezos, E

    2012-09-01

    Gastrointestinal symptoms occur frequently among patients with diabetes mellitus and are associated with considerable morbidity. Diabetic gastrointestinal autonomic neuropathy represents a complex disorder with multifactorial pathogenesis, which is still not well understood. It appears to involve a spectrum of metabolic and cellular changes that affect gastrointestinal motor and sensory control. It may affect any organ in the digestive system. Clinical manifestations are often underestimated, and therefore autonomic neuropathy should be suspected in all diabetic patients with unexplained gastrointestinal symptoms. Advances in technology have now enabled assessment of gastrointestinal motor function. Moreover, novel pharmacological approaches, along with endoscopic and surgical treatment options, contribute to improved outcomes. This review summarises the progress achieved in diabetic gastrointestinal autonomic neuropathy during the last years, focusing on clinical issues of practical importance to the everyday clinician. PMID:22863425

  19. Molecular alterations resulting from frameshift mutations in peripheral myelin protein 22: implications for neuropathy severity.

    PubMed

    Johnson, J S; Roux, K J; Fletcher, B S; Fortun, J; Notterpek, L

    2005-12-15

    Alterations in peripheral myelin protein 22 (PMP22) expression are associated with a heterogeneous group of hereditary demyelinating peripheral neuropathies. Two mutations at glycine 94, a single guanine insertion or deletion in PMP22, result in different reading frameshifts and, consequently, an extended G94fsX222 or a truncated G94fsX110 protein, respectively. Both of these autosomal dominant mutations alter the second half of PMP22 and yet are linked to clinical phenotypes with distinct severities. The G94fsX222 is associated with hereditary neuropathy with liability to pressure palsies, whereas G94fsX110 causes severe neuropathy diagnosed as Dejerine-Sottas disease or Charcot-Marie-Tooth disease type IA. To investigate the subcellular changes associated with the G94 frameshift mutations, we expressed epitope-tagged forms in primary rat Schwann cells. Biochemical and immunolabeling studies indicate that, unlike the wild-type protein, which is targeted for the plasma membrane, frameshift PMP22s are retained in the cell, prior to reaching the medial Golgi compartment. Similar to Wt-PMP22, both frameshift mutants are targeted for proteasomal degradation and accumulate in detergent-insoluble, ubiquitin-containing aggregates upon inhibition of this pathway. The extended frameshift PMP22 shows the ability to form spontaneous aggregates in the absence of proteasome inhibition. On the other hand, Schwann cells expressing the truncated protein proliferate at a significantly higher rate than Schwann cells expressing the wild-type or the extended PMP22. In summary, these results suggest that a greater potential for PMP22 aggregation is associated with a less severe phenotype, whereas dysregulation of Schwann cell proliferation is linked to severe neuropathy. PMID:16273544

  20. Irritative and sensory disturbances in oral implantology. Literature review.

    PubMed

    Palma-Carrió, Cristina; Balaguer-Martínez, Jose; Peñarrocha-Oltra, David; Peñarrocha-Diago, María

    2011-11-01

    The aim of this study was to review irritative and sensory disturbances following placement of dental implants. A literature search was made of PubMed for articles published between 2000 and 2010. Studies that reported sensory disturbances directly caused by the placement of dental implants were included. Sensory deficits or trigeminal neuropathy are caused by damage to the third branch of the trigeminal nerve during surgery. This manifests in the immediate postoperative period as a sensory deficit not usually associated with pain and generally transient. The literature reviewed reported irritative and sensory disturbances caused during surgery, after surgery, and as a result of complications. Postoperative pain appears after oral surgery as a result of inflammation associated with damage to tissue during surgery. Pain due to postoperative complications following implant placement was classified as neurogenic pain, peri-implant pain and bone pain.

  1. Inactivation of TNF-α ameliorates diabetic neuropathy in mice

    PubMed Central

    Yamakawa, Isamu; Terashima, Tomoya; Katagi, Miwako; Oi, Jiro; Urabe, Hiroshi; Sanada, Mitsuru; Kawai, Hiromichi; Chan, Lawrence; Yasuda, Hitoshi; Maegawa, Hiroshi; Kimura, Hiroshi

    2011-01-01

    Tumor necrosis factor (TNF)-α is a potent proinflammatory cytokine involved in the pathogenesis of diabetic neuropathy. We inactivated TNF-α to determine if it is a valid therapeutic target for the treatment of diabetic neuropathy. We effected the inactivation in diabetic neuropathy using two approaches: by genetic inactivation of TNF-α (TNF-α−/− mice) or by neutralization of TNF-α protein using the monoclonal antibody infliximab. We induced diabetes using streptozotocin in wild-type and TNF-α−/− mice. We measured serum TNF-α concentration and the level of TNF-α mRNA in the dorsal root ganglion (DRG) and evaluated nerve function by a combination of motor (MNCV) and sensory (SNCV) nerve conduction velocities and tail flick test, as well as cytological analysis of intraepidermal nerve fiber density (IENFD) and immunostaining of DRG for NF-κB p65 serine-276 phosphorylated and cleaved caspase-3. Compared with nondiabetic mice, TNF-α+/+ diabetic mice displayed significant impairments of MNCV, SNCV, tail flick test, and IENFD as well as increased expression of NF-κB p65 and cleaved caspase-3 in their DRG. In contrast, although nondiabetic TNF-α−/− mice showed mild abnormalities of IENFD under basal conditions, diabetic TNF-α−/− mice showed no evidence of abnormal nerve function tests compared with nondiabetic mice. A single injection of infliximab in diabetic TNF-α+/+ mice led to suppression of the increased serum TNF-α and amelioration of the electrophysiological and biochemical deficits for at least 4 wk. Moreover, the increased TNF-α mRNA expression in diabetic DRG was also attenuated by infliximab, suggesting infliximab's effects may involve the local suppression of TNF-α. Infliximab, an agent currently in clinical use, is effective in targeting TNF-α action and expression and amelioration of diabetic neuropathy in mice. PMID:21810933

  2. Neuropathy in arsenic toxicity from groundwater arsenic contamination in West Bengal, India.

    PubMed

    Mukherjee, Subhash Chandra; Rahman, Mohammad Mahmudur; Chowdhury, Uttam Kumar; Sengupta, Mrinal Kumar; Lodh, Dilip; Chanda, Chitta Ranjan; Saha, Kshitish Chandra; Chakraborti, Dipankar

    2003-01-01

    Large number of people from 9 out of 18 districts of West Bengal, India are endemically exposed to arsenic contaminated groundwater due to drinking of tubewell water containing arsenic level above World Health Organization's maximum permissible limit of 50 microg/L. From our ongoing studies on neurological involvement in patients of arsenicosis from different districts of West Bengal, we report our findings in a total of 451 patients of three districts (Murshidabad, Nadia, and Burdwan), comprising 267 males and 184 females with age ranging from 11 to 79 years. They all had arsenical skin lesions, positive biomarkers and identified source of arsenic contaminated water drinking. Peripheral neuropathy was the predominant neurological complication in these patients affecting 154 (37.3%) of 413 patients of Group 1 and 33 (86.8%) of 38 patients of Group 2. Other possible causes and alternative explanations of neuropathy were excluded. The temporal profile in most of the cases (154 of Group 1) were of chronic affection while the 33 patients of Group 2 developed both neuropathy and dermopathy subacutely. Subacutely affected Group 2 patients had much higher incidence of neuropathy. Paresthesias and pains in the distal parts of extremities were much higher in incidence in Group 2 (73.7% and 23.7% respectively) than in Group 1 (18.4% and 11.1%). Distal limb weakness or atrophy was evident in 7.3% in Group 1 and 10.5% in Group 2. Overall, sensory features were more common than motor features in patients of neuropathy and sensory neuropathy was diagnosed in 30% and 76.3% and sensorimotor in 7.3% and 10.5% respectively in Group 1 and Group 2 subjects. Nerve conduction and electromyographic studies performed in 88 cases revealed dysfunction of sensory nerve in 45% and 27% and of motor nerve in 20% and 16.7% of patients with moderate degree and mild degree of clinical neuropathies respectively. Evoked potential studies performed in 20 patients were largely normal except for two

  3. Inflammation: therapeutic targets for diabetic neuropathy.

    PubMed

    Zhou, Jiyin; Zhou, Shiwen

    2014-02-01

    There are still no approved treatments for the prevention or of cure of diabetic neuropathy, and only symptomatic pain therapies of variable efficacy are available. Inflammation is a cardinal pathogenic mechanism of diabetic neuropathy. The relationships between inflammation and the development of diabetic neuropathy involve complex molecular networks and processes. Herein, we review the key inflammatory molecules (inflammatory cytokines, adhesion molecules, chemokines) and pathways (nuclear factor kappa B, JUN N-terminal kinase) implicated in the development and progression of diabetic neuropathy. Advances in the understanding of the roles of these key inflammatory molecules and pathways in diabetic neuropathy will facilitate the discovery of the potential of anti-inflammatory approaches for the inhibition of the development of neuropathy. Specifically, many anti-inflammatory drugs significantly inhibit the development of different aspects of diabetic neuropathy in animal models and clinical trials.

  4. Phrenic neuropathy in arsenic poisoning.

    PubMed

    Bansal, S K; Haldar, N; Dhand, U K; Chopra, J S

    1991-09-01

    A patient presented with acute arsenic neuropathy with asymmetric bilateral phrenic nerve involvement. The clinical and roentgenographic observations of phrenic nerve dysfunction were confirmed by prolonged phrenic nerve conduction time. The patient made a significant recovery with d-penicillamine therapy.

  5. Functioning of patients with multifocal motor neuropathy.

    PubMed

    Erdmann, Peter G; Lindeman, Eline; Cats, Elisabeth A; van den Berg, Leonard H

    2010-06-01

    Patients with multifocal motor neuropathy (MMN) have slowly progressive, predominantly distal asymmetric limb weakness without sensory loss. While previous studies have investigated the impact of MMN on body functions and structures, relatively little is known about the impact of patients' weakness on daily functioning. The aim of the present cross-sectional study, involving 47 patients with MMN, was to evaluate determinants of patients' functioning. Most patients showed not only muscle weakness but also fatigue, limited dexterity, and limited walking ability. Regression models showed that age, hand aids, and muscle strength scores together explained 54% of the variance in dexterity scores, which in turn explained 8% of the variance in patients' scores for autonomy indoors. Age, the use of walking aids, and muscle strength scores together explained 58% of the variance in walking ability scores, which in turn explained 18% of the variance in patients' scores for autonomy indoors and 7% of the variance in patients' scores for autonomy outdoors. Assessment of determinants of patient functioning may make it possible to tailor interventions to address these aspects and thereby improve patients' functioning in daily life. PMID:20626774

  6. Micturition disturbance in acute idiopathic autonomic neuropathy

    PubMed Central

    Sakakibara, R; Uchiyama, T; Asahina, M; Suzuki, A; Yamanishi, T; Hattori, T

    2004-01-01

    Objective: To define the nature of micturition disturbance in patients with acute idiopathic autonomic neuropathy (AIAN). Methods: Micturitional symptoms were observed during hospital admissions and the in outpatient clinics in six patients with clinically definite AIAN (typical form in four, cholinergic variant in one, autonomic-sensory variant in one). Urodynamic studies included medium-fill water cystometry, external sphincter electromyography, and a bethanechol test. Results: Four patients had urinary retention and two had voiding difficulty as the initial presentation. Patients with retention became able to urinate within a week (two to seven days). The major symptoms at the time of urodynamic studies (three weeks to four months after disease onset in most cases) were voiding difficulty and nocturnal frequency. None had urinary incontinence. Complete recovery from the micturition disturbance took from three months to >18 years. The recovery period was shorter in a patient with cholinergic variant, and it was longer in two patients who had a longer duration of initial urinary retention. Micturition disturbance tended to improve earlier than orthostatic hypotension. The major urodynamic abnormalities were detrusor areflexia on voiding (5), denervation supersensitivity to bethanechol (3); low compliance detrusor (1); and impaired bladder sensation (2). None had neurogenic motor unit potentials of the external sphincter muscles. Conclusions: In patients with AIAN, urinary retention and voiding difficulty are common initial presentations. The underlying mechanisms seem to be pre- and postganglionic cholinergic dysfunction with preservation of somatic sphincter function. The bladder problems tend to improve earlier than orthostatic hypotension. PMID:14742606

  7. Painful Diabetic Neuropathy: Prevention or Suppression?

    PubMed

    Todorovic, S M

    2016-01-01

    Pain-sensing sensory neurons (nociceptors) of the dorsal root ganglia (DRG) and dorsal horn (DH) can become sensitized (hyperexcitable) in response to pathological conditions such as diabetes, which in turn may lead to the development of painful peripheral diabetic neuropathy (PDN). Because of incomplete knowledge about the mechanisms underlying painful PDN, current treatment for painful PDN has been limited to somewhat nonspecific systemic drugs that have significant side effects or potential for abuse. Recent studies have established that several ion channels in DRG and DH neurons are dysregulated and make a previously unrecognized contribution to sensitization of pain responses by enhancing excitability of nociceptors in animal models of type 1 and type 2 PDN. Furthermore, it has been reported that targeting posttranslational modification of nociceptive ion channels such as glycosylation and methylglyoxal metabolism can completely reverse mechanical and thermal hyperalgesia in diabetic animals with PDN in vivo. Understanding details of posttranslational regulation of nociceptive channel activity may facilitate development of novel therapies for treatment of painful PDN. We argue that pharmacological targeting of the specific pathogenic mechanism rather than of the channel per se may cause fewer side effects and reduce the potential for drug abuse in patients with diabetes. PMID:27133151

  8. Corneal Confocal Microscopy Detects Small Fibre Neuropathy in Patients with Upper Gastrointestinal Cancer and Nerve Regeneration in Chemotherapy Induced Peripheral Neuropathy.

    PubMed

    Ferdousi, Maryam; Azmi, Shazli; Petropoulos, Ioannis Nikolaos; Fadavi, Hassan; Ponirakis, Georgios; Marshall, Andrew; Tavakoli, Mitra; Malik, Imaan; Mansoor, Wasat; Malik, Rayaz Ahmed

    2015-01-01

    There are multiple neurological complications of cancer and its treatment. This study assessed the utility of the novel non-invasive ophthalmic technique of corneal confocal microscopy in identifying neuropathy in patients with upper gastrointestinal cancer before and after platinum based chemotherapy. In this study, 21 subjects with upper gastrointestinal (oesophageal or gastric) cancer and 21 healthy control subjects underwent assessment of neuropathy using the neuropathy disability score, quantitative sensory testing for vibration perception threshold, warm and cold sensation thresholds, cold and heat induced pain thresholds, nerve conduction studies and corneal confocal microscopy. Patients with gastro-oesophageal cancer had higher heat induced pain (P = 0.04) and warm sensation (P = 0.03) thresholds with a significantly reduced sural sensory (P<0.01) and peroneal motor (P<0.01) nerve conduction velocity, corneal nerve fibre density (CNFD), nerve branch density (CNBD) and nerve fibre length (CNFL) (P<0.0001). Furthermore, CNFD correlated significantly with the time from presentation with symptoms to commencing chemotherapy (r = -0.54, P = 0.02), and CNFL (r = -0.8, P<0.0001) and CNBD (r = 0.63, P = 0.003) were related to the severity of lymph node involvement. After the 3rd cycle of chemotherapy, there was no change in any measure of neuropathy, except for a significant increase in CNFL (P = 0.003). Corneal confocal microscopy detects a small fibre neuropathy in this cohort of patients with upper gastrointestinal cancer, which was related to disease severity. Furthermore, the increase in CNFL after the chemotherapy may indicate nerve regeneration.

  9. Corneal Confocal Microscopy Detects Small Fibre Neuropathy in Patients with Upper Gastrointestinal Cancer and Nerve Regeneration in Chemotherapy Induced Peripheral Neuropathy

    PubMed Central

    Ferdousi, Maryam; Azmi, Shazli; Petropoulos, Ioannis Nikolaos; Fadavi, Hassan; Ponirakis, Georgios; Marshall, Andrew; Tavakoli, Mitra; Malik, Imaan; Mansoor, Wasat; Malik, Rayaz Ahmed

    2015-01-01

    There are multiple neurological complications of cancer and its treatment. This study assessed the utility of the novel non-invasive ophthalmic technique of corneal confocal microscopy in identifying neuropathy in patients with upper gastrointestinal cancer before and after platinum based chemotherapy. In this study, 21 subjects with upper gastrointestinal (oesophageal or gastric) cancer and 21 healthy control subjects underwent assessment of neuropathy using the neuropathy disability score, quantitative sensory testing for vibration perception threshold, warm and cold sensation thresholds, cold and heat induced pain thresholds, nerve conduction studies and corneal confocal microscopy. Patients with gastro-oesophageal cancer had higher heat induced pain (P = 0.04) and warm sensation (P = 0.03) thresholds with a significantly reduced sural sensory (P<0.01) and peroneal motor (P<0.01) nerve conduction velocity, corneal nerve fibre density (CNFD), nerve branch density (CNBD) and nerve fibre length (CNFL) (P<0.0001). Furthermore, CNFD correlated significantly with the time from presentation with symptoms to commencing chemotherapy (r = -0.54, P = 0.02), and CNFL (r = -0.8, P<0.0001) and CNBD (r = 0.63, P = 0.003) were related to the severity of lymph node involvement. After the 3rd cycle of chemotherapy, there was no change in any measure of neuropathy, except for a significant increase in CNFL (P = 0.003). Corneal confocal microscopy detects a small fibre neuropathy in this cohort of patients with upper gastrointestinal cancer, which was related to disease severity. Furthermore, the increase in CNFL after the chemotherapy may indicate nerve regeneration. PMID:26430773

  10. Alternative Quantitative Tools in the Assessment of Diabetic Peripheral and Autonomic Neuropathy.

    PubMed

    Vinik, A I; Casellini, C; Névoret, M-L

    2016-01-01

    Here we review some seldom-discussed presentations of diabetic neuropathy, including large fiber dysfunction and peripheral autonomic dysfunction, emphasizing the impact of sympathetic/parasympathetic imbalance. Diabetic neuropathy is the most common complication of diabetes and contributes additional risks in the aging adult. Loss of sensory perception, loss of muscle strength, and ataxia or incoordination lead to a risk of falling that is 17-fold greater in the older diabetic compared to their young nondiabetic counterparts. A fall is accompanied by lacerations, tears, fractures, and worst of all, traumatic brain injury, from which more than 60% do not recover. Autonomic neuropathy has been hailed as the "Prophet of Doom" for good reason. It is conducive to increased risk of myocardial infarction and sudden death. An imbalance in the autonomic nervous system occurs early in the evolution of diabetes, at a stage when active intervention can abrogate the otherwise relentless progression. In addition to hypotension, many newly recognized syndromes can be attributed to cardiac autonomic neuropathy such as orthostatic tachycardia and bradycardia. Ultimately, this constellation of features of neuropathy conspire to impede activities of daily living, especially in the patient with pain, anxiety, depression, and sleep disorders. The resulting reduction in quality of life may worsen prognosis and should be routinely evaluated and addressed. Early neuropathy detection can only be achieved by assessment of both large and small- nerve fibers. New noninvasive sudomotor function technologies may play an increasing role in identifying early peripheral and autonomic neuropathy, allowing rapid intervention and potentially reversal of small-fiber loss.

  11. Corneal Confocal Microscopy to Assess Diabetic Neuropathy: An Eye on the Foot

    PubMed Central

    Tavakoli, Mitra; Petropoulos, Ioannis N.; Malik, Rayaz A.

    2013-01-01

    Accurate detection and quantification of human diabetic peripheral neuropathy are important to define at-risk patients, anticipate deterioration, and assess new therapies. Easily performed clinical techniques such as neurological examination, assessment of vibration perception or insensitivity to the 10 g monofilament only assess advanced neuropathy, i.e., the at-risk foot. Techniques that assess early neuropathy include neurophysiology (which assesses only large fibers) and quantitative sensory testing (which assesses small fibers), but they can be highly subjective while more objective techniques, such as skin biopsy for intra-epidermal nerve fiber density quantification, are invasive and not widely available. The emerging ophthalmic technique of corneal confocal microscopy allows quantification of corneal nerve morphology and enables clinicians to diagnose peripheral neuropathy in diabetes patients, quantify its severity, and potentially assess therapeutic benefit. The present review provides a detailed critique of the rationale, a practical approach to capture images, and a basis for analyzing and interpreting the images. We also critically evaluate the diagnostic ability of this new noninvasive ophthalmic test to diagnose diabetic and other peripheral neuropathies. PMID:24124944

  12. A clinical decision support system with an integrated EMR for diagnosis of peripheral neuropathy.

    PubMed

    Kunhimangalam, Reeda; Ovallath, Sujith; Joseph, Paul K

    2014-04-01

    The prevalence of peripheral neuropathy in general population is ever increasing. The diagnosis and classification of peripheral neuropathies is often difficult as it involves careful clinical and electro-diagnostic examination by an expert neurologist. In developing countries a large percentage of the disease remains undiagnosed due to lack of adequate number of experts. In this study a novel clinical decision support system has been developed using a fuzzy expert system. The study was done to provide a solution to the demand of systems that can improve health care by accurate diagnosis in limited time, in the absence of specialists. It employs a graphical user interface and a fuzzy logic controller with rule viewer for identification of the type of peripheral neuropathy. An integrated medical records database is also developed for the storage and retrieval of the data. The system consists of 24 input fields, which includes the clinical values of the diagnostic test and the clinical symptoms. The output field is the disease diagnosis, whether it is Motor (Demyelinating/Axonopathy) neuropathy, sensory (Demyelinating/Axonopathy) neuropathy, mixed type or a normal case. The results obtained were compared with the expert's opinion and the system showed 93.27 % accuracy. The study aims at showing that Fuzzy Expert Systems may prove useful in providing diagnostic and predictive medical opinions. It enables the clinicians to arrive at a better diagnosis as it keeps the expert knowledge in an intelligent system to be used efficiently and effectively.

  13. Significant response to lacosamide in a patient with severe chemotherapy-induced peripheral neuropathy.

    PubMed

    Ibrahim, Samar A; Albany, Zhanna; Albany, Constantine

    2015-05-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity of potentially curative cancer therapy regimens. Cisplatin is the class of chemotherapy agent that has a broad spectrum of activity against several solid tumors, but it induces sensory neuropathy of upper and lower extremities. Cisplatin-induced peripheral neuropathy is usually in a "gloves and socks" distribution that can persist for months or years after completion of chemotherapy treatment. If the pain is severe, it affects the patient's long-term quality of life and can potentially result in chemotherapy dose reduction or treatment discontinuation. The mechanism of CIPN is not well understood, and a number of pathophysiological mechanisms have been proposed to explain the phenomenon. Although many therapies have been investigated for the prevention or treatment of CIPN, there is currently no accepted proven therapy. Here we report a case in which lacosamide alleviated painful CIPN symptoms. Lacosamide is an anticonvulsant drug that blocks the voltage-gated sodium channels in the neurons and may also be a promising novel candidate for the prevention and treatment of chemotherapy-induced peripheral neuropathy. Preclinical data support the role of lacosamide protective effect in a rat model of chemotherapy-induced neuropathy, randomized clinical trial is needed.

  14. The Pain in Neuropathy Study (PiNS): a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy

    PubMed Central

    Themistocleous, Andreas C.; Ramirez, Juan D.; Shillo, Pallai R.; Lees, Jonathan G.; Selvarajah, Dinesh; Orengo, Christine; Tesfaye, Solomon; Rice, Andrew S.C.; Bennett, David L.H.

    2016-01-01

    Abstract Disabling neuropathic pain (NeuP) is a common sequel of diabetic peripheral neuropathy (DPN). We aimed to characterise the sensory phenotype of patients with and without NeuP, assess screening tools for NeuP, and relate DPN severity to NeuP. The Pain in Neuropathy Study (PiNS) is an observational cross-sectional multicentre study. A total of 191 patients with DPN underwent neurological examination, quantitative sensory testing, nerve conduction studies, and skin biopsy for intraepidermal nerve fibre density assessment. A set of questionnaires assessed the presence of pain, pain intensity, pain distribution, and the psychological and functional impact of pain. Patients were divided according to the presence of DPN, and thereafter according to the presence and severity of NeuP. The DN4 questionnaire demonstrated excellent sensitivity (88%) and specificity (93%) in screening for NeuP. There was a positive correlation between greater neuropathy severity (r = 0.39, P < 0.01), higher HbA1c (r = 0.21, P < 0.01), and the presence (and severity) of NeuP. Diabetic peripheral neuropathy sensory phenotype is characterised by hyposensitivity to applied stimuli that was more marked in the moderate/severe NeuP group than in the mild NeuP or no NeuP groups. Brush-evoked allodynia was present in only those with NeuP (15%); the paradoxical heat sensation did not discriminate between those with (40%) and without (41.3%) NeuP. The “irritable nociceptor” subgroup could only be applied to a minority of patients (6.3%) with NeuP. This study provides a firm basis to rationalise further phenotyping of painful DPN, for instance, stratification of patients with DPN for analgesic drug trials. PMID:27088890

  15. The Pain in Neuropathy Study (PiNS): a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy.

    PubMed

    Themistocleous, Andreas C; Ramirez, Juan D; Shillo, Pallai R; Lees, Jonathan G; Selvarajah, Dinesh; Orengo, Christine; Tesfaye, Solomon; Rice, Andrew S C; Bennett, David L H

    2016-05-01

    Disabling neuropathic pain (NeuP) is a common sequel of diabetic peripheral neuropathy (DPN). We aimed to characterise the sensory phenotype of patients with and without NeuP, assess screening tools for NeuP, and relate DPN severity to NeuP. The Pain in Neuropathy Study (PiNS) is an observational cross-sectional multicentre study. A total of 191 patients with DPN underwent neurological examination, quantitative sensory testing, nerve conduction studies, and skin biopsy for intraepidermal nerve fibre density assessment. A set of questionnaires assessed the presence of pain, pain intensity, pain distribution, and the psychological and functional impact of pain. Patients were divided according to the presence of DPN, and thereafter according to the presence and severity of NeuP. The DN4 questionnaire demonstrated excellent sensitivity (88%) and specificity (93%) in screening for NeuP. There was a positive correlation between greater neuropathy severity (r = 0.39, P < 0.01), higher HbA1c (r = 0.21, P < 0.01), and the presence (and severity) of NeuP. Diabetic peripheral neuropathy sensory phenotype is characterised by hyposensitivity to applied stimuli that was more marked in the moderate/severe NeuP group than in the mild NeuP or no NeuP groups. Brush-evoked allodynia was present in only those with NeuP (15%); the paradoxical heat sensation did not discriminate between those with (40%) and without (41.3%) NeuP. The "irritable nociceptor" subgroup could only be applied to a minority of patients (6.3%) with NeuP. This study provides a firm basis to rationalise further phenotyping of painful DPN, for instance, stratification of patients with DPN for analgesic drug trials. PMID:27088890

  16. [Hereditary hearing loss: genetic counselling].

    PubMed

    Cabanillas Farpón, Rubén; Cadiñanos Bañales, Juan

    2012-01-01

    The aim of this review is to provide an updated overview of hereditary hearing loss, with special attention to the etiological diagnosis of sensorineural hearing loss, the genes most frequently mutated in our environment, the techniques available for their analysis and the clinical implications of genetic diagnosis. More than 60% of childhood sensorineural hearing loss is genetic. In adults, the percentage of hereditary hearing loss is unknown. Genetic testing is the highest yielding test for evaluating patients with sensorineural hearing loss. The process of genetic counselling is intended to inform patients and their families of the medical, psychological and familial implications of genetic diseases, as well as the risks, benefits and limitations of genetic testing. The implementation of any genetic analysis must be always preceded by an appropriate genetic counselling process.

  17. A Novel CSF1R Mutation in a Patient with Clinical and Neuroradiological Features of Hereditary Diffuse Leukoencephalopathy with Axonal Spheroids.

    PubMed

    Di Donato, Ilaria; Stabile, Carmen; Bianchi, Silvia; Taglia, Ilaria; Mignarri, Andrea; Salvatore, Simona; Giorgio, Elisa; Brusco, Alfredo; Simone, Isabella; Dotti, Maria Teresa; Federico, Antonio

    2015-01-01

    Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant cerebral white matter degeneration leading to progressive cognitive and motor dysfunction. The peripheral nervous system is generally spared. Recently, mutations in the colony-stimulating factor-1 receptor (CSF1R) gene have been shown to be associated with HDLS. Here we report a new case of HDLS, carrying a mutation in CSF1R and manifesting rapidly progressive dementia and peripheral neuropathy.

  18. An overview of hereditary pancreatitis.

    PubMed

    Rebours, Vinciane; Lévy, Philippe; Ruszniewski, Philippe

    2012-01-01

    Hereditary pancreatitis is a rare cause of chronic pancreatitis. The prevalence was evaluated to 0.3/100000 in Western Countries. Genetic disorders are due to mutations of the PRSS1 gene on the long arm of the chromosome 7, encoding for the cationic trypsinogen. The inheritance pattern is autosomal dominant with an incomplete penetrance (80%). Since 1996, more than 30 mutations were found. The three more common mutations are R122H, N29I and A16V. First symptoms begin since childhood, mainly before 10 years old. Main symptoms are pancreatic pain and acute pancreatitis (>70%). CP morphological changes as pancreatic calcifications are diagnosed at a median age of 22-25 years. Exocrine and endocrine pancreatic insufficiency occurred in 34% and 26% at a median age of 29 and 38 years. No clinical differences exist according to the mutation type. No excess of mortality in hereditary pancreatitis population compared to general population was found, despite a real risk of cancer. The cumulative risks of pancreatic cancer at 50, 60 and, 75 years are 10%, 18.7% and, 53.5%, respectively. The relative risk of cancer increases in smokers and is evaluated to 8.55. Hereditary pancreatitis diagnosis permits to propose an adapted management in expert centres.

  19. Dorsal root ganglia microenvironment of female BB Wistar diabetic rats with mild neuropathy.

    PubMed

    Zochodne, D W; Ho, L T; Allison, J A

    1994-12-01

    Abnormalities in the microenvironment of dorsal root ganglia (DRG) might play a role in the pathogenesis of sensory abnormalities in human diabetic neuropathy. We examined aspects of DRG microenvironment by measuring local blood flow and oxygen tension in the L4 dorsal root ganglia of female BB Wistar (BBW) diabetic rats with mild neuropathy. The findings were compared with concurrent measurements of local sciatic endoneurial blood flow and oxygen tension. Diabetic rats were treated with insulin and underwent electrophysiological, blood flow and oxygen tension measurements at either 7-11 or 17-23 weeks after the development of glycosuria. Nondiabetic female BB Wistar rats from the same colony served as controls. At both ages, BBW diabetic rats had significant abnormalities in sensory, but not motor conduction compared to nondiabetic controls. Sciatic endoneurial blood flow in the diabetic rats of both ages was similar to control values, but the older (17-23 week diabetic) BBW diabetic rats had a selective reduction in DRG blood flow. Sciatic endoneurial oxygen tensions were not significantly altered in the diabetic rats. DRG oxygen tension appeared lowered in younger (7-11 week diabetic) but not older (17-23 week diabetic) BBW rats. Our findings indicate that there are important changes in the DRG microenvironment of diabetic rats with selective sensory neuropathy. PMID:7699389

  20. Dorsal root ganglia microenvironment of female BB Wistar diabetic rats with mild neuropathy.

    PubMed

    Zochodne, D W; Ho, L T; Allison, J A

    1994-12-01

    Abnormalities in the microenvironment of dorsal root ganglia (DRG) might play a role in the pathogenesis of sensory abnormalities in human diabetic neuropathy. We examined aspects of DRG microenvironment by measuring local blood flow and oxygen tension in the L4 dorsal root ganglia of female BB Wistar (BBW) diabetic rats with mild neuropathy. The findings were compared with concurrent measurements of local sciatic endoneurial blood flow and oxygen tension. Diabetic rats were treated with insulin and underwent electrophysiological, blood flow and oxygen tension measurements at either 7-11 or 17-23 weeks after the development of glycosuria. Nondiabetic female BB Wistar rats from the same colony served as controls. At both ages, BBW diabetic rats had significant abnormalities in sensory, but not motor conduction compared to nondiabetic controls. Sciatic endoneurial blood flow in the diabetic rats of both ages was similar to control values, but the older (17-23 week diabetic) BBW diabetic rats had a selective reduction in DRG blood flow. Sciatic endoneurial oxygen tensions were not significantly altered in the diabetic rats. DRG oxygen tension appeared lowered in younger (7-11 week diabetic) but not older (17-23 week diabetic) BBW rats. Our findings indicate that there are important changes in the DRG microenvironment of diabetic rats with selective sensory neuropathy.