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)

Ataxia with vitamin E deficiency (AVED), or familial isolated vitamin E deficiency, is a rare autosomal recessive neurodegenerative disease characterized clinically by symptoms with often striking resemblance to those of Friedreich ataxia. We recently have demonstrated that AVED is caused by mutations in the gene for alpha-tocopherol transfer protein (alpha-TTP). We now have identified a total of 13 mutations in 27 families. Four mutations were found in >=2 independent families: 744delA, which is the major mutation in North Africa, and 513insTT, 486delT, and R134X, in families of European origin. Compilation of the clinical records of 43 patients with documented mutation in the alpha-TTP gene revealed differences from Friedreich ataxia: cardiomyopathy was found in only 19% of cases, whereas head titubation was found in 28% of cases and dystonia in an additional 13%. This study represents the largest group of patients and mutations reported for this often misdiagnosed disease and points to the need for an early differential diagnosis with Friedreich ataxia, in order to initiate therapeutic and prophylactic vitamin E supplementation before irreversible damage develops.
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PMID:Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. 946 7

Friedreich ataxia (FRDA) is an autosomal recessive, neurodegenerative disease, characterized by progressive gait and limb ataxia, dysarthria, lower-limb areflexia, Babinski sign, loss of position and vibration senses, cardiomyopathy, and carbohydrate intolerance. It is the most common inherited ataxia, and is associated with a GAA triplet repeat expansion in the first intron of the X25 gene on the long arm of chromosome 9. We present a case whose clinical diagnosis was initially confounded by the mildness of the ataxic phenotype and a family history of multiple sclerosis. Evaluation of the X25 gene revealed that the patient was homozygous for the GAA triplet repeat expansion, pathognomonic of FRDA. Investigation of her sural nerve biopsy revealed a significantly smaller expansion size, constituting the first direct demonstration of somatic mosaicism involving the nervous system in FRDA. We speculate that a similar contraction in pathologically affected tissues could be the molecular basis for the mildness of the ataxia.
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PMID:A mild case of Friedreich ataxia: lymphocyte and sural nerve analysis for GAA repeat length reveals somatic mosaicism. 948 68

Ataxia with vitamin E deficiency is an autosomal recessive condition associated with a defect in the a-tocopherol transfer protein. Clinically it manifests as a progressive ataxia with a phenotype resembling that of Friedreich's ataxia. There is some evidence that progression of neurological symptoms is prevented by vitamin E therapy. A patient is described who was given a clinical diagnosis of Friedreich's ataxia. Molecular genetic analysis showed the absence of the frataxin gene expansion. Subsequent vitamin E assay showed deficiency and a diagnosis of ataxia with vitamin E deficiency was made. It is recommended that all patients with ataxia of unknown cause should have vitamin E deficiency excluded. When a diagnosis of Friedreich's ataxia is considered patients should have frataxin analysis in addition. Further, neurologists should be aware that ataxia with vitamin E deficiency may present as "mutation negative" Friedreich's ataxia.
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PMID:Ataxia with isolated vitamin E deficiency presenting as mutation negative Friedreich's ataxia. 952 51

Friedreich's ataxia is the most common hereditary ataxia and is frequently associated with disturbances of glucose metabolism. This autosomal recessive disease is caused by the decreased expression of a mitochondrial protein, frataxin, encoded by the X25 gene. Homozygous expansion of a GAA repeat in the first intron of X25 inhibits frataxin expression and is associated with clinical disease. We evaluated whether heterozygous expansions of the triplet repeat in the frataxin gene X25 may be associated with NIDDM in two genetically distinct populations--one in Germany (n = 358) and the other in the U.S. (n = 292)--using a polymerase chain reaction-based assay. Intermediate expansions (10-36 repeats), which are longer than normal but not sufficient for the appearance of the ataxia phenotype, were found in 24.7 and 27.3% of these two NIDDM cohorts compared with 7.6 and 6.3% of the matched control subjects (both P < 0.001). The odds ratios were 3.36 (95% CI 1.72-6.55) for the German group and 4.01 (2.08-7.74) for the U.S. group. Therefore, we conclude that the X25/frataxin GAA repeat polymorphism is associated with NIDDM in a frequency higher than any other mutation heretofore described. Further studies are needed to elucidate the possible role of frataxin in the pathogenesis of NIDDM.
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PMID:An association between NIDDM and a GAA trinucleotide repeat polymorphism in the X25/frataxin (Friedreich's ataxia) gene. 958 63

The hereditary ataxias comprise a complex group of neurological disorders involving the cerebellum and its connections. Several classifications based on clinical and/or pathological data have been only partially successful. Recent progress in molecular genetics has identified the genic loci of hereditary ataxias and has allowed a more precise diagnosis of distinct genetic diseases. Trinucleotide repeat expansions has been recognized as a mechanism of disease in some autosomal dominant spinocerebellar ataxias (ADCA) (SCA1 to SCA7), including Machado-Joseph disease/SCA3, probably the most common form of ADCA in South Brazil, and Friedreich ataxia (GAA expansion-chromosome 9p). Familial alpha-tocopherol deficiency (chromosome 8q) may have a Friedreich ataxia phenotype and responds to the oral supplementation with vitamin E. Familial episodic ataxias with (EA1-chromosome 12p) and without (chromosome 19p-EA2) myokimia were identified, the first one caused by point mutations in the gene encoding the KCNA1 potassium voltage-gated channel. The gene responsible for ataxia-teleangiectasia (chromosome 11q) was found to encode a putative DNA binding protein kinase (ATM), related to the cell cycle control. One to 3% of the population are heterozygotic ATM gen carry and pose a higher risk of cancer when exposed to ionizing radiation. Molecular biology has provided us with useful tools to diagnosis and genetic counseling and, hopefully, will provide us with a better understanding of the pathogenesis and eventual treatment of the several forms of hereditary ataxias.
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PMID:[Hereditary cerebellar ataxias: from hammer to genetics]. 962 25

Efforts to classify the hereditary ataxias by their clinical and neuropathological phenotypes are troubled by excessive heterogeneity. Linkage analysis opened the door to a new approach with the methods of molecular biology. The classic form of autosomal recessive ataxia, Friedreich's ataxia (FA), is now known to be due to an intronic expansion of a guanine-adenine-adenine (GAA)-trinucleotide repeat. The autosomal dominant ataxias such as olivopontocerebellar atrophy (OPCA), familial cortical cerebellar atrophy (FCCA), and Machado-Joseph disease (MJD) have been renamed the spinocerebellar ataxias (SCA). Specific gene loci are indicated as SCA-1, SCA-2, SCA-3, SCA-4, SCA-5, SCA-6, and SCA-7. In 5 of them (SCA-1, SCA-2, SCA-3, SCA-6, and SCA-7), expanded cytosine-adenine-guanine (CAG)-trinucleotide repeats and their abnormal gene products cause the ataxic condition. The most common underlying loci for olivopontocerebellar atrophy (OPCA) are SCA-1 and SCA-2, although other genotypes may be added in the future. A major recent advance was the identification of the gene for SCA-3 and MJD, and the high prevalence of this form of autosomal dominant ataxia. In FA and the SCA with expanded CAG-trinucleotide repeats, clinical and neuropathological severity are inversely correlated with the lengths of the repeats. Anticipation in the dominant ataxias can now be explained by lengthening of the repeats in successive generations. Progress is being made in the understanding of the pathogenesis of FA and SCA as the absent or mutated gene products are studied by immunocytochemistry in human and transgenic murine brain tissue. In FA, frataxin is diminished or absent, and an excess of mitochondrial iron may cause the illness of the nervous system and the heart. In SCA-3, abnormal ataxin-3 is aggregated in neuronal nuclei, and in SCA-6, a mutated alpha1A-calcium channel protein is the likely cause of abnormal calcium channel function in Purkinje cells and in the death of these neurons.
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PMID:The hereditary ataxias. 963 Feb 33

One of us (MP) learned about the mapping of Huntington disease gene to chromosome 4 from the late Dr. Anita Harding. She got the news over the phone from her London office during a visit to Italy for a meeting on hereditary ataxias. In Britain, they receive Nature at least a week earlier than us. Dr. Harding was very excited, and she immediately said that that was the way to go if we wanted to understand the causes of hereditary ataxias, classify these diseases in a rational way, and eventually find a treatment. At that time, the challenge seemed, and indeed was, formidable. No clue was then available about the genetic basis of what Dr. Harding aptly called "hereditary ataxias of unknown cause," their classification was confused and controversial, and all attempts to find specific biochemical abnormalities had failed. Fourteen years later, the success of the molecular genetic studies is astounding. The defective genes have been identified for Friedreich ataxia, the major recessive "hereditary ataxia of unknown cause," and for five dominantly inherited "hereditary ataxias of unknown cause." Three more dominant ataxia genes have been mapped. The molecular pathogenesis of the dominant ataxias begins to be unraveled and animal models have been and are being developed. Information is also quickly accumulating about the defective protein in Friedreich ataxia. Direct molecular diagnosis is now possible. Classification has been revolutionized. Diagnostic criteria are being redefined in the light of the molecular discoveries. The goal of this review, dedicated to the memory of the late Dr. Harding, is to offer a concise summary of current knowledge about the molecular genetics of some of the hereditary ataxias that used to be classified as of "unknown cause."
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PMID:Molecular genetics of the hereditary ataxias. 967 5

Friedreich ataxia, the most frequent cause of inherited ataxia, is due in most cases to a large expansion of an intronic GAA repeat, resulting in decreased expression of the target frataxin gene. The autosomal recessive inheritance of the disease gives this triplet repeat mutation some unique features of natural history and evolution. Frataxin is a mitochondrial protein that has homologues in yeast and even in gram negative bacteria. Yeast deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. This suggests that Friedreich ataxia is caused by mitochondrial dysfunction and free radical toxicity.
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PMID:Molecular genetics and pathogenesis of Friedreich ataxia. 971 60

The hereditary ataxias are a group of inherited neurodegenerative disorders characterized by progressive ataxia that results from degeneration of the cerebellum and its afferent and efferent connections. Recent molecular research has led not only to the discovery of a number of causative mutations, but also shed light on the likely mechanisms by which these mutations cause the respective phenotypes. In Friedreich's ataxia (FRDA), the most common type of autosomal recessive ataxia, the loss of a mitochondrial protein, frataxin, results in overload of mitochondrial iron and oxidative stress. The autosomal dominant ataxias, spinocerebellar ataxia type I (SCAI), SCA2, SCA3 and SCA7, are caused by inheritance of an unstable, expanded CAG trinucleotide repeat. These disorders are assumed to be due to a novel deleterious function of the extended polyglutamine sequences within the proteins encoded by the respective genes. Recent observations in transgenic mice and in human post-mortem tissue suggest that the extended proteins are transported into the nucleus of neurons where they form intranuclear inclusions that disrupt normal nuclear function. In another group of dominant disorders, episodic ataxia type I and type 2 (EA-I, EA-2) and SCA6, the mutations affect genes that code for ion channels.
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PMID:Genes involved in hereditary ataxias. 973 50

Friedreich's ataxia is the most common inherited ataxia. Ninety-six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy-terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele.
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PMID:Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes. 998 22


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