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)

Friedreich's ataxia (FRDA) is the most frequent cause of recessive ataxias. Neurological examination shows oculo-motor ataxia, dysarthria, limbs ataxia, tendon areflexia, pyramidal signs and sensory deficits. Extra-neurological involvement consists in osteoarticular deformities, cardiomyopathy and diabetes mellitus. Neurological deficits and osteoarticular deformities both contribute to the gait disorder, which is the main disabling deficit. In 98% of the cases, a trinucleotide repeat is found in chromosome 9. Gene implicated in FRDA codes for a protein called frataxin. Experimental studies have revealed iron accumulation in mitochondria of neurons and cardiomyocytes, suggesting that frataxin plays a determinant role in intramitochondrial iron homeostasis. These discoveries are now considered as a clue for new strategies of treatment in this hereditary disease.
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PMID:[Friedreich's ataxia: recent developments and prospects for treatment]. 1033

Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is caused in 94% of cases by homozygous expansions of an unstable GAA repeat localised in intron 1 of the X25 gene. We have investigated this mutation in five Brazilian patients: four with typical FRDA findings and one patient with atypical manifestations, who was considered to have some other form of cerebellar ataxia with retained reflexes. The GAA expansion was detected in all these patients. The confirmation of FRDA diagnosis in the atypical case may be pointing out, as in other reports, that clinical spectrum of Friedreich's ataxia is broader than previously recognised and includes cases with intact tendon reflexes.
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PMID:Clinical and molecular studies in five Brazilian cases of Friedreich ataxia. 1034 15

We analyzed the clinical and genetic aspects of 28 FRDA patients from 20 families. 19 families were consanguineous. The onset was between 4 and 13 1/2 years of age (mean 15.4 +/- 6.2). Three patients presented with cardiomyopathy, one with weakness, and the rest with ataxia. There were two patients with preserved lower-limb deep tendon reflexes. Sensory nerve action potentials were reduced in 14/14 patients. Cardiac echograms were abnormal in 17/19 cases, and this was between 6 and 16 years of age (mean 10.1 +/- 3.5). Four families were multiplex. Clinical intra-familial variability was observed. Increased GAA repeats of the X25 gene were found in 27/28 patients studied, all in a homozygous state. 88.9% of patients had a smaller allele larger than 500 repeats, and 66.7% had more than 700 repeats. The patient who did not have increased GAA repeats in both alleles had peculiar findings. Significant correlation of expansion was obtained for the early onset, and cardiomyopathy as the onset.
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PMID:Clinical and genetic correlate in childhood onset Friedreich ataxia. 1040 88

We estimated the relative contributions of known ataxia genes (SCA1, 2, 3, 6, 7 and X25) in the patient population sent to our DNA diagnostic laboratory for diagnostic testing. Approximately 28% of these patients had an abnormal triplet repeat expansion in one of these ataxia genes (3% for SCA1, 8% for SCA2, 11% for SCA3/MJD, 2% for SCA6, 3% for SCA7, and 1.5% for X25). The lack of abnormal repeat expansions in the majority of ataxis patients tested suggests that the molecular defects associated with most ataxia cases are currently undetermined and that this population includes both familial and sporadic cases. In contrast, of the patients submitted for genetic testing for Friedrich's ataxia (FRDA), 44% (69/157) showed at least one expansion in the X25 gene, indicating that FRDA accounts for a significant proportion of the recessively inherited ataxias and appears to have a high rate of accurate clinical diagnosis. On the basis of our DNA studies, we propose a comprehensive and efficient approach for molecular analysis of ataxia patients.
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PMID:Estimated contribution of known ataxia genes in ataxia patients undergoing DNA testing. 1046 57

Fourteen patients with classical features of Friedreich's ataxia (FRDA) were examined. The clinical diagnosis of FRDA was afterwards confirmed in all patients by the appropriate DNA investigation which showed markedly increased amounts of GAA repeats on both alleles of the frataxin gene. None of our patients presented with atypical features such as late-onset FRDA, FRDA with retained deep tendon reflexes or with a very slow course. Five of them are not yet confined to a wheelchair. But for 1 patient who died at age 36 years and had the largest number of GAA repeats on both alleles, there was no significant correlation between number of repeats in the shortest allele, age at onset, age at wheelchair dependence, duration of the disease and main clinical signs. All patients but 3 had between 500 and 1,050 GAA repeats. The 3 patients with, respectively, 400, 450 and 500 repeats on the shortest allele had a clinical course comparable to the other patients. Even in the case of variations in the number of repeats in the same sibship, there were only modest differences between the siblings concerning age at onset of the disease, symptoms and signs and age at wheelchair dependence. There were no qualitative differences in the main clinical features and laboratory investigations in the full-blown phase of the disorder. Molecular biology has become a major element in the diagnosis of FRDA. DNA testing for FRDA should be applied to every case of idiopathic autosomal recessive or sporadic ataxia. However, the clinical features of FRDA remain fully characteristic in many patients and keep their diagnostic value.
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PMID:Classical Friedreich's ataxia and its genotype. 1047 83

Friedreich ataxia (FRDA), the most common of the inherited ataxias, is an autosomal recessive degenerative disorder, characterized clinically by onset before the age of 25 of progressive gait and limb ataxia, absence of deep tendon reflexes, extensor plantar responses, and loss of position and vibration sense in the lower limbs. FRDA is caused by a GAA triplet expansion in the first intron of the FRDA gene on chromosome 9q13 in 97% of patients. The FRDA gene encodes a widely expressed 210-aa protein, frataxin, which is located in mitochondria and is severely reduced in FRDA patients. Frataxin function is still unknown but the knockout of the yeast frataxin homologue gene (YFH1) showed a severe defect of mitochondrial respiration and loss of mtDNA associated with elevated intramitochondrial iron. Here we report in vivo evidence of impaired mitochondrial respiration in skeletal muscle of FRDA patients. Using phosphorus magnetic resonance spectroscopy we demonstrated a maximum rate of muscle mitochondrial ATP production (V(max)) below the normal range in all 12 FRDA patients and a strong negative correlation between mitochondrial V(max) and the number of GAA repeats in the smaller allele. Our results show that FRDA is a nuclear-encoded mitochondrial disorder affecting oxidative phosphorylation and give a rationale for treatments aimed to improve mitochondrial function in this condition.
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PMID:Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. 1050 Jan 3

Friedreich ataxia, the most common type of inherited ataxia, is itself caused in most cases by 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 organisms 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 pathogenesis of Friedreich ataxia. 1098 12

Friedreich ataxia (FRDA) is the most common inherited ataxia. About 98% of mutant alleles have an expansion of a GAA trinucleotide repeat in intron 1 of the affected gene, FRDA. The other 2% are point mutations. Of the 17 point mutations so far described, three appear to be more common. One of these is the G130V mutation in exon 4 of FRDA. G130V, when present with an expanded GAA repeat on the other allele, is associated with an atypical FRDA phenotype. Haplotype analysis was undertaken on the four families who have been described with this mutation. The results suggest a common founder for this mutation. Although marked differences in extragenic marker haplotypes were seen in one family, similar intragenic haplotyping suggests the same mutation founder for this family with the differences explicable by two recombination events.
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PMID:G130V, a common FRDA point mutation, appears to have arisen from a common founder. 1054 3

An individual with late-onset ataxia was found to be heterozygous for an unusual (GAAGGA)65 sequence and a normal GAA repeat in the frataxin gene. No frataxin point mutation was present, excluding a form of Friedreich ataxia. (GAAGGA)65 did not have the inhibitory effect on gene expression in transfected cells shown by pathogenic GAA repeats of similar length. GAA repeats, but not (GAAGGA)65, adopt a triple helical conformation in vitro. We suggest that such a triplex structure is essential for suppression of gene expression.
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PMID:A nonpathogenic GAAGGA repeat in the Friedreich gene: implications for pathogenesis. 1056 39

Early onset cerebellar ataxia with retained tendon reflexes (EOCA) is a clinical syndrome characterised by progressive cerebellar ataxia with an onset before the age of 25 years and a wide spectrum of associated features. It is distinguished from Friedreich's ataxia (FA) mainly by the preservation of tendon reflexes, a better prognosis, and the absence of GAA expansion in the frataxin gene. Although EOCA is thought to be a hereditary disorder with an autosomal recessive mode of inheritance, genetic heterogeneity might underlie the spectrum of clinical features. In this case report we describe a patient with EOCA accompanied by pes cavus, hammer toes and peripheral neuropathy. The patient's father did not have any ataxia, but had the same foot deformities as his daughter and a slight peripheral neuropathy. The possible relationship between these clinical features is discussed.
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PMID:Early onset cerebellar ataxia with retained tendon reflexes: foot deformity in a first grade family member. 1062 55


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