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), the most-common form of autosomal recessive ataxia, is inherited in most cases by a large expansion of a GAA triplet repeat in the first intron of the frataxin (X25) gene. Genetic heterogeneity in FRDA has been previously reported in typical FRDA families that do not link to the FRDA locus on chromosome 9q13. We report localization of a second FRDA locus (FRDA2) to chromosome 9p23-9p11, and we provide evidence for further genetic heterogeneity of the disease, in a family with the classic FRDA phenotype.
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PMID:Mapping of the second Friedreich's ataxia (FRDA2) locus to chromosome 9p23-p11: evidence for further locus heterogeneity. 1152 63

Ataxia with vitamin E (Vit E) defciency (AVED) is an autosomal recessive disorder caused by mutations of the alpha tocopherol transfer protein gene. The Friedreich ataxia phenotype is the most frequent clinical presentation. In AVED patients, serum Vit E levels are very low in the absence of intestinal malabsorption. As Vit E is a major antioxidant agent, Vit E deficiency is supposed to be responsible for the pathological process. Twenty-four AVED patients were fully investigated (electromyography, nerve conduction velocity (NVC) studies, somatosensory evoked potentials, cerebral computed tomography scan, sural nerve biopsy, genetic studies) and supplemented with Vit E (800 mg daily) during a 1-year period. Clinical evaluation was mainly based on the Ataxia Rating Scale (ARS) for cerebellar ataxia assessment and serum Vit E levels were monitored. Serum Vit E levels normalized and ARS scores decreased moderately but significantly suggesting clinical improvement. Better results were noted with mean disease duration < or = 15 years. Reflexes remained abolished and posterior column disturbances unchanged. Vitamin E supplementation in AVED patients stabilizes the neurological signs and can lead to mild improvement of cerebellar ataxia, especially in early stages of the disease.
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PMID:Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiency. 1155 13

Friedreich ataxia (FRDA), the most common autosomal recessive neurodegenerative disease among Europeans and people of European descent, is characterized by an early onset (usually before the age of 25), progressive ataxia, sensory loss, absence of tendon reflexes and pyramidal weakness of the legs. We have recently identified a unique group of patients whose clinical presentations are characterized by autosomal recessive inheritance, early age of onset, FRDA-like clinical presentations and hypoalbuminemia. Linkage to the FRDA locus, however, was excluded. Given the similarities of the clinical presentations to those of the recently described ataxia with oculomotor apraxia (AOA) linked to chromosome 9p13, we confirmed that the disorder of our patients is also linked to the same locus. We narrowed the candidate region and have identified a new gene encoding a member of the histidine triad (HIT) superfamily as the 'causative' gene. We have called its product aprataxin; the gene symbol is APTX. Although many HIT proteins have been identified, aprataxin is the first to be linked to a distinct phenotype.
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PMID:Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene. 1158 99

The newly recognized ataxia-ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal. It shares several neurological features with ataxia-telangiectasia, including early onset ataxia, oculomotor apraxia and cerebellar atrophy, but does not share its extraneurological features (immune deficiency, chromosomal instability and hypersensitivity to X-rays). AOA1 is also characterized by axonal motor neuropathy and the later decrease of serum albumin levels and elevation of total cholesterol. We have identified the gene causing AOA1 and the major Portuguese and Japanese mutations. This gene encodes a new, ubiquitously expressed protein that we named aprataxin. This protein is composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3'- phosphatase (PNKP), with histidine-triad (HIT) proteins and with DNA-binding C2H2 zinc-finger proteins, respectively. PNKP is involved in DNA single-strand break repair (SSBR) following exposure to ionizing radiation and reactive oxygen species. Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex. The results suggest that aprataxin is a nuclear protein with a role in DNA repair reminiscent of the function of the protein defective in ataxia-telangiectasia, but that would cause a phenotype restricted to neurological signs when mutant.
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PMID:The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. 1158

We have clinically and genetically evaluated 24 affected patients belonging to 22 Italian Friedreich ataxia (FA) families, 52 patients from 32 kindreds with proven autosomal dominant cerebellar ataxia (ADCA), 9 patients belonging to 5 families with autosomal recessive hereditary ataxia (ARCA) and 103 sporadic cases, 89 of which affected by idiopathic late onset cerebellar ataxia (ILOCA). Genotype-phenotype correlation analyses in FA patients have evidenced an inverse relationship between GAA repeat expansion length and age of onset, disease duration, and presence of cardiomyopathy. Among autosomal dominant types, spinocerebellar ataxia 2 (SCA2) genotype has been found in 31% of our ADCA families, resulting the most frequent form of ataxia. Phenotypic analysis of the various SCA subtypes evidenced a marked heterogeneity of symptoms with a substantial overlap between different syndromes.
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PMID:Clinical and genetic analysis of hereditary and sporadic ataxia in central Italy. 1171 73

Friedreich's ataxia, the most common autosomal recessive inherited ataxia, is characterized by progressive gait and limb ataxia. Friedreich's ataxia is known for its occurrence within the first or second decade of life and is associated with hypertrophic cardiomyopathy, and in some cases with diabetes. Genetically, it is identified by the expression of an unstable trinucleotide GAA repeat expansion located in the first intron of the X25 gene on chromosome 9. Two brothers with very late adult-onset ataxia, and their unaffected sister, were examined for the clinical presentation of FA and for the presence of the mutated FA gene. The relationship of the expanded gene sequence to the severity of disease and age of onset were evaluated. Clinical examination revealed that the two brothers had mild ataxia and proprioceptive loss, with age of onset between 60 and 70 years of age. DNA from peripheral blood nucleated cells demonstrated a small homozygous expansion, with approximately 120-130 GAA repeats in the X25 gene in both patients. The expanded repeats were interrupted either with GAAGAG, GAAGGA, or GAAGAAAA sequences. The unaffected sister carried a normal FA genotype with 8-uninterrupted GAA repeat, observed by sequence analysis. In addition, the levels of FA gene transcript in both brothers were relatively lower than that in the unaffected sister. No detectable cardiomyopathy or diabetes was observed. Phenotypic diversity of FA is increasingly expanding. The age of onset and the structure of GAA repeat expansion plays an important role in determining the clinical features and the differential diagnosis of FA. The confirmation of the FA gene mutation in the atypical case, broadens the clinical spectrum of FA, and supports the idea that patients with even a mild form of ataxia of late adult onset should be considered for molecular testing.
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PMID:Sequence variation in GAA repeat expansions may cause differential phenotype display in Friedreich's ataxia. 1174 52

Around a quarter of Friedreich ataxia (FA) patients, despite being homozygous for GAA expansion within the FRDA gene, show atypical presentations. Our aim is to describe the case of three brothers with long-term follow-up suffering from late onset FA manifested with spastic ataxia. The three patients belong to a family with occipital dysplasia (OD) and Chiari I malformation previously reported by us. We have carried out serial examinations since 1977. Electrophysiological and neuroimaging studies, and molecular genetic analyses of hereditary ataxias are available in all three patients. Onset of symptoms occurred between 25 and 35 years. The clinical picture consisted of progressive spastic gait, truncal and limb ataxia, dysarthria, nystagmus, hyperreflexia with knee and ankle clonus and extensor plantar response, and mild hypopallesthesia. Ages at present vary between 50 and 59. One patient is wheelchair-bound but the other two are able to walk with support. Leaving OD aside, skeletal anomalies are not prominent. All three patients showed cardiomyopathy. MR imaging revealed atrophy of the cerebellum and spinal cord. Motor and sensory nerve conduction velocities were normal. Central conduction time of both motor and sensory pathways was delayed or unobtainable. All three patients were homozygous for the GAA expansion, the smaller expanded allele ranging between 131 and 156 repeats. Four heterozygotic carriers were detected among non-ataxic relatives including one with OD; furthermore, an asymptomatic OD patient showed normal genotype. We conclude that adult onset spastic ataxia is a distinctive FA phenotype associated with minimal GAA expansion. This phenotype represents a new cause of selective distal degeneration of central sensory axons. The present concurrence of OD and FA reflects coincidental cosegregation of two different inherited disorders.
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PMID:Friedreich ataxia with minimal GAA expansion presenting as adult-onset spastic ataxia. 1180 70

A number of ataxias have been shown to result from defects in mitochondrial function. The genes responsible for Friedreich ataxia (FRDA) and for X-linked sideroblastic anemia with ataxia are nuclear genes that encode mitochondrial proteins. These genes, which are highly conserved in species as diverse as humans and yeast, play a role in mitochondrial iron metabolism and in the formation of iron-sulfur clusters. Defects in vitamin E metabolism, due to mutations in tocopherol transfer protein (TTP), also result in ataxia. It is hypothesized that the biochemical feature common to these ataxias is increased oxidant damage either through increased oxidants or decreased anti-oxidants.
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PMID:Spinocerebellar ataxias due to mitochondrial defects. 1185 Jan 12

The discovery of the genetic cause of Friedreich ataxia has significantly affected our understanding of the disorder at both the clinical and basic science levels. Friedreich ataxia results from a deficiency of functional frataxin, a protein that appears to be involved in mitochondrial iron homeostasis. This leads to iron accumulation and mitochondrial abnormalities with consequent oxidant damage. The clinical spectrum of Friedreich ataxia has also expanded with the recognition of broader phenotypic features, including the absence of classical Friedreich ataxia features, later age at onset, and spasticity instead of ataxia. Although no proven therapy is yet available, antioxidants are a potential method for therapeutic intervention.
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PMID:Friedreich ataxia: effects of genetic understanding on clinical evaluation and therapy. 1243 76

Fifteen Moroccan families with a phenotype resembling Friedreich Ataxia (FA) were studied. Seven families (13 patients) had the 744 del A mutation in the alpha-tocopherol transfer protein (alpha-TTP) gene, characteristic of ataxia with vitamin E deficiency (AVED). The other eight families (16 patients) had GAA expansions in the first intron of the frataxin gene. The clinical differences between the two groups differed. AVED caused by the 744 del A could be distinguished by head titubation, lower frequency of the neuropathy and slower disease progression, decreased visual activity and retinitis pigmentosa, which has also been associated with a His(101) Gln missense mutation in the alpha-TTP gene. The neurological disorder associated with vitamin E deficiency can be improved by the alpha-tocopherol treatment.
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PMID:Clinical comparison between AVED patients with 744 del A mutation and Friedreich ataxia with GAA expansion in 15 Moroccan families. 1203 60


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