Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three unrelated, sporadic patients with muscle coenzyme Q10 (CoQ10) deficiency presented at 32, 29, and 6 years of age with proximal muscle weakness and elevated serum creatine kinase (CK) and lactate levels, but without myoglobinuria, ataxia, or seizures. Muscle biopsy showed lipid storage myopathy, combined deficiency of respiratory chain complexes I and III, and CoQ10 levels below 50% of normal. Oral high-dose CoQ10 supplementation improved muscle strength dramatically and normalized serum CK.
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PMID:Coenzyme Q10 deficiency and isolated myopathy. 1643 67

Myoclonus epilepsy with ragged red fibers (MERRF) is one of the major mitochondrial encephalomyopathies. Its main clinical features are myoclonus epilepsy, ataxia, and myopathy with ragged red fibers. Whereas there is a close correlation between MERRF syndrome and the A8344G mutation of mitochondrial DNA, the reverse is not true. In fact, this mutation is also responsible for various other syndromes, such as Leigh syndrome, spinocerebellar degeneration, atypical Charcot-Marie-Tooth disease, and multiple truncal lipomas. We describe a child with the A8344G mutation of mitochondrial DNA and an unusual clinical, neuroradiologic, and biochemical phenotype, characterized by early-onset, nonprogressive cerebellar ataxia, and subclinical myoclonias in association with bilateral putaminal necrosis on magnetic resonance imaging and a reduction in complex V activity. Our case confirms the existence of a relationship between alteration in adenosine triphosphatase activity and basal ganglia involvement. We recommend that the possibility of a mitochondrial pathology should always be taken into consideration in the presence of bilateral symmetric lesions of the basal ganglia, even when the typical clinical picture is lacking. (J Child Neurol 2006;21:79-82).
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PMID:Bilateral putaminal necrosis associated with the mitochondrial DNA A8344G myoclonus epilepsy with ragged red fibers (MERRF) mutation: an infantile case. 1655 60

Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding of the recurrence risks. Mutations were identified in 38 cases, with the majority being sporadic compound heterozygotes. Eighty-nine DNA sequence changes were identified, including 2 predicted to alter a splice site, 1 predicted to cause a premature stop codon and 13 predicted to cause novel amino acid substitutions. The majority of children had a mutation in the linker region, often 1399G-->A (A467T), and a mutation affecting the polymerase domain. Others had mutations throughout the gene, and 11 had 3 or more substitutions. The clinical presentation ranged from the neonatal period to late adult life, with an overlapping phenotypic spectrum from severe encephalopathy and liver failure to late-onset external ophthalmoplegia, ataxia, myopathy and isolated muscle pain or epilepsy. There was a strong gender bias in children, with evidence of an environmental interaction with sodium valproate. POLG1 mutations cause an overlapping clinical spectrum of disease with both dominant and recessive modes of inheritance. 1399G-->A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.
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PMID:Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. 1680 39

The case of a 63-year-old woman who presented with status epilepticus, coma and hypoventilation is reported. A primary neurological cause was considered. Hypothermia led to further investigations and a diagnosis of severe hypothyroidism. The neurological complications of hyperthyriodism include alteration in mental status with slowness, decreased concentration and lethargy, headache, cranial nerve palsies, dysarthria, hoarseness, myopathy, neuropathy, reflex changes, ataxia, and psychotic episodes. Our patient suffered from a rare consequence of severe hypothyroidism presenting with status epilepticus and she died despite treatment. To our knowledge this is the second patient to be reported with myxoedema coma with this kind of presentation. Despite therapeutic options, there is a high mortality rate.
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PMID:Status epilepticus caused by a myxoedema coma. 1712 58

Mitochondrial DNA (mtDNA) is maternally inherited. After birth, secondary mtDNA defects can arise. MtDNA depletion is a reduction in the amount of mtDNA in particular tissues. Multiple deletions of mtDNA accumulate as somatic mutations in mainly postmitotic tissues. These disorders of mtDNA maintenance frequently show Mendelian inheritance. Positional cloning has identified several genes involved in the control of mtDNA stability. Recessive mutations in the genes ECGF1, dGK, TK2, SUCLA2 and POLG cause mtDNA depletion syndromes (MDS). Generally, MDS has infantile onset tissue specific features. Mutations in the genes ECGF1, ANT1, C10orf2 and POLG are associated with multiple mtDNA deletions. The nature of these mutations is dominant in ANT1, C10orf2 and POLG and recessive in ECGF1, C10orf2 and POLG. Mutations in these genes frequently cause progressive external ophthalmoplegia (PEO). However clinical heterogeneity results in different neurological syndromes with considerable overlap. The most common features are PEO, neuropathy, myopathy, ataxia, epilepsy and hepatopathy.
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PMID:Autosomal disorders of mitochondrial DNA maintenance. 1689 56

The ataxia mutation (axJ) is a recessive neurological mutation that results in reduced growth, ataxia, and hindlimb muscle wasting in mice. The axJ gene encodes ubiquitin-specific protease 14 (Usp14), a deubiquitinating enzyme (DUB) that associates with the proteasome via its ubiquitin-like (Ubl) domain and is involved in processing ubiquitin chains. Analysis of Usp14 gene products demonstrated that Usp14 undergoes alternative pre-mRNA splicing to produce a full-length form of Usp14 that is capable of binding proteasomes and a form that contains a deletion in the Ubl domain. The full-length form of Usp14 is the only form that appears to be reduced in the axJ mice. Transgenic rescue of the axJ mice with neuronal-specific expression of Usp14 demonstrated that the full-length form of Usp14 was sufficient to restore viability and motor system function to the axJ mice. Biochemical analysis showed that the ubiquitin hydrolyase activity of this form of Usp14 is dependent on the presence of proteasomes, and neuronal expression of full-length Usp14 was able to restore the levels of monomeric ubiquitin in the brains of axJ mice. However, the axJ-rescued mice still displayed the Purkinje cell axonal swellings that are seen in the axJ mice, indicating that this cerebellar alteration is not the primary cause of the axJ movement disorders. These results show that the motor defects observed in the axJ mice are attributable to a neuropathic disease rather than to a muscular disorder and suggest that changes in proteasomal function may contribute to neurological dysfunction in the axJ mice.
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PMID:Transgenic rescue of ataxia mice with neuronal-specific expression of ubiquitin-specific protease 14. 1707 71

Ataxia and peripheral neuropathy are the most common neurological manifestations of gluten sensitivity. Myopathy is a less common and poorly characterized additional neurological manifestation of gluten sensitivity. We present our experience with 13 patients who presented with symptoms and signs suggestive of a myopathy and in whom investigation led to the diagnosis of gluten sensitivity. Three of these patients had a neuropathy with or without ataxia in addition to the myopathy. The mean age at onset of the myopathic symptoms was 54 years. Ten patients had neurophysiological evidence of myopathy. Inflammatory myopathy was the most common finding on neuropathological examination. One patient had basophilic rimmed vacuoles suggestive of inclusion-body myositis. Six patients received immunosuppressive treatment in addition to starting on a gluten-free diet; five improved and one remained unchanged. Among seven patients not on immunosuppressive treatment, four showed clinical improvement of the myopathy with a gluten-free diet. The improvement was also associated with reduction or normalization of serum creatine kinase level. The myopathy progressed in one patient who refused the gluten-free diet. Myopathy may be another manifestation of gluten sensitivity and is likely to have an immune-mediated pathogenesis. A gluten-free diet may be a useful therapeutic intervention.
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PMID:Myopathy associated with gluten sensitivity. 1714 94

We describe a patient who presented with parkinsonism associated with the A8344G myoclonus epilepsy, ataxia, and myopathy with ragged red fibers mutation in the tRNA(Lys) gene. In addition, neurogenic changes and mitochondrial myopathy with ragged red fibers were observed. Neither myoclonus epilepsy nor other clinical signs described in association with A8344G were noted. Similar to previously reported patients with parkinsonism and mtDNA deletions, the symptoms of our patient responded favorably to levodopa therapy.
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PMID:Parkinson syndrome, neuropathy, and myopathy caused by the mutation A8344G (MERRF) in tRNALys. 1720 Apr 93

During February-April 2004, an estimated 400-500 free-ranging elk (Cervus elaphus) developed paresis, became recumbent, and died or were euthanized in the Red Rim Wildlife Habitat Management Area (RRWHMA), Wyoming, USA. Elk were found in sternal recumbency, alert and responsive, but unable to rise. Their condition progressed to lateral recumbency followed by dehydration, obtundation, and death. Gross lesions were limited to degenerative myopathy, with pallor and streaking in skeletal muscles. Microscopically, affected muscles had degenerative lesions of varying duration, severity, and distribution, some with early mineralization and attempts at regeneration. Diagnostic testing ruled out common infectious, inflammatory, toxic, and traumatic causes. Tumbleweed shield lichen (Xanthoparmelia chlorochroa) was found in the area and in the rumen of several elk. This lichen was collected and fed to three captive elk. Two of these elk exhibited signs of ataxia, which rapidly progressed to weakness and recumbency after 7 and 10 days on this diet, respectively, and a degenerative myopathy, consistent with lesions observed in the elk affected at RRWHMA, was observed. All remaining elk migrated from the RRWHMA during the spring and no subsequent losses have been documented.
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PMID:Paresis and death in elk (Cervus elaphus) due to lichen intoxication in Wyoming. 1769 88

The cardiofaciocutaneous (CFC) syndrome is characterized by congenital heart defect, developmental delay, peculiar facial appearance with bitemporal constriction, prominent forehead, downslanting palpebral fissures, curly sparse hair and abnormalities of the skin. CFC syndrome phenotypically overlaps with Noonan and Costello syndromes. Mutations of several genes (PTPN11, HRAS, KRAS, BRAF, MEK1 and MEK2), involved in the mitogen-activated protein kinase (MAPK) pathway, have been identified in CFC-Costello-Noonan patients. Coenzyme Q10 (CoQ10), a lipophilic molecule present in all cell membranes, functions as an electron carrier in the mitochondrial respiratory chain, where it transports electrons from complexes I and II to complex III. CoQ10 deficiency is a rare treatable mitochondrial disorder with various neurological (cerebellar ataxia, myopathy, epilepsy, mental retardation) and extraneurological (cardiomyopathy, nephropathy) signs that are responsive to CoQ10 supplementation. We report the case of a 4-year-old girl who presented a CFC syndrome, confirmed by the presence of a pathogenic R257Q BRAF gene mutation, together with a muscular CoQ10 deficiency. Her psychomotor development was severely impaired, hindered by muscular hypotonia and ataxia, both improving remarkably after CoQ10 treatment. This case suggests that there is a functional connection between the MAPK pathway and the mitochondria. This could be through the phosphorylation of a nuclear receptor essential for CoQ10 biosynthesis. Another hypothesis is that K-Ras, one of the proteins composing the MAPK pathway, might be recruited into the mitochondria to promote apoptosis. This case highlights that CoQ10 might contribute to the pathogenesis of CFC syndrome.
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PMID:Cardiofaciocutaneous (CFC) syndrome associated with muscular coenzyme Q10 deficiency. 1770 71


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