Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016719 (Friedreich's ataxia)
 2,098 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical features of 115 patients from 90 families with Friedreich's ataxia are described. Onset of symptoms was before the age of 25 (mean 10.52) years in all the index cases. An analysis of early cases suggested that limb and truncal ataxia and absent tendon reflexes in the legs were the only consistent diagnostic criteria within five years of presentation. Dysarthria, signs of pyramidal tract dysfunction in the legs and loss of joint position and vibration sense are not necessarily present during the first five years of symptoms, but appear to develop eventually in all cases. Scoliosis and ECG evidence of cardiomyopathy were found in over two-thirds of the patients studied; pes cavus, distal amyotrophy, optic atrophy, nystagmus and deafness were all less frequent. The disorder was gradually progressive in all cases. The mean age of losing the ability to walk was 25 years; 95 per cent were chair-bound by the age of 44 years. About 10 per cent of the patients had diabetes mellitus which was controlled by oral hypoglycaemic drugs in one quarter. Diabetes appeared to be associated with a higher incidence of optic atrophy and deafness. Diabetes also clustered within sibships; the risk of an individual with Friedreich's ataxia developing diabetes if an affected sib has it is over 40 per cent. Similarly, cardiomyopathy ran true within affected members of the same sibship, but there were instances of discordance which suggest that the development of the non-neurological features of Friedreich's ataxia may be controlled by modifying genes rather than heterogeneity of the main gene. Segregation analysis and an increased consanguinity rate amongst parents of patients (5.55 per cent) confirmed that this disorder is of autosomal recessive inheritance. A study of 101 first degree relatives of the patients with Friedreich's ataxia failed to demonstrate any neurological or electrocardiographic abnormalities which could be ascribed to the heterozygous state.
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PMID:Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. 727 14

Twenty patients are described with a distinctive clinical syndrome characterised by progressive cerebellar ataxia developing within the first two decades. This is associated with dysarthria, pyramidal signs in the limbs, normal or increased knee jerks and upper limb reflexes and in some instances sensory loss. Inheritance is probably autosomal recessive in the majority, if not all, of the cases. The preservation of tendon reflexes distinguishes this disorder from Friedreich's ataxia. Other important differences from Friedreich's ataxia are absence of optic atrophy, cardiomyopathy, diabetes mellitus and severe skeletal deformity. The prognosis was better in the present series than in cases of Friedreich's ataxia; patients remained ambulant, on average, for more than 10 years longer.
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PMID:Early onset cerebellar ataxia with retained tendon reflexes: a clinical and genetic study of a disorder distinct from Friedreich's ataxia. 727 63

Friedreich's ataxia (FA) is a progressive, spinocerebellar degenerative disease. Onset is generally in the second decade of life, occurring as a neurologic degenerative process. Most, if not all, patients have an associated cardiomyopathy, which is frequently the cause of death. We studied two siblings who had FA with acute cardiomyopathy at 3 and 5 years of age, respectively, and in whom the classic nervous system signs developed, only later. The diagnosis of FA should be considered in patients of any age who have unexplained cardiomyopathy.
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PMID:Friedreich's ataxia with acute cardiomyopathy. 736 3

Absence of lower limb tendon reflexes has been considered an essential diagnostic criterion for Friedreich's ataxia (FA). However, preservation of knee and ankle jerks has been reported in a few patients. Linkage analysis to FA locus (FRDA) on chromosome 9q13-21.1 was performed in 11 patients from 6 families with FA phenotype, including cardiomyopathy, but retained reflexes (FARR). A maximal lod score of 3.38 at recombination fraction theta equal to 0.00 was obtained demonstrating that FARR maps to the FRDA locus. These results suggest that FARR is a variant phenotype of FA.
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PMID:Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreich's ataxia locus on chromosome 9q. 769 35

We describe two patients with Friedreich's ataxia whose presenting symptomatology was for years progressive tabetic ataxia. Based upon the initial clinical, electrophysiological and nerve biopsy data, a diagnosis of idiopathic sensory neuropathy was established. Subsequent examination of the kin showed that three sisters of case 1 had Friedreich's ataxia. Upon serial clinical and electrocardiographic study, both patients eventually developed a florid Friedreich's ataxia, including cardiomyopathy. Our findings indicate that at onset Friedreich's ataxia may be indistinguishable from sensory neuropathy and also that serial examination and investigation of kinship are essential steps for accurate diagnosis.
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PMID:Friedreich's ataxia presenting with pure sensory ataxia: a long-term follow-up study of two patients. 848 91

Friedreich ataxia is an autosomal recessive neurodegenerative disorder. The genetic homogeneity to the FRDA locus on chromosome 9q13-21.1 has been observed in families from different ancestries. We report a Spanish family with two affected and three unaffected children. The segregated classical Friedreich ataxia did not show the expected linkage. The analysis focusses on flanking markers FR1, FR2, FR7 and FR5, excluding linkage 1 cM around the FRDA locus. The unique clinical hallmark in this family was the absence of cardiomyopathy after a long-term follow-up in the two affected children. In both patients serum vitamin E levels were normal. The present observations support the existence of a second locus in Friedreich ataxia, and we suggest that this form could be clinically characterized by the absence of muscular heart disease.
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PMID:A family segregating a Friedreich ataxia phenotype that is not linked to the FRDA locus. 864 4

Friedreich ataxia (FA) is associated with the expansion of a GAA trinucleotide repeat in the first intron of the X25 gene. We found both alleles expanded in 67 FA patients from 48 Italian families. Five patients from three families were compound heterozygotes with expansion on one allele and an isoleucine-->phenylalanine change at position 154 on the other one. We found neither expansions nor point mutations in three patients. The length of FA alleles ranged from 201 to 1,186 repeat units, with no overlap with the normal range, and showed a negatively skewed distribution with a peak between 800 and 1,000 repeats. The FA repeat showed meiotic instability with a median variation of 150 repeats. The lengths of both larger and smaller alleles in each patient inversely correlated with age at onset of the disorder. Smaller alleles showed the best correlation, accounting for approximately 50% of the variation of age at onset. Mean allele length was significantly higher in patients with diabetes and in those with cardiomyopathy.
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PMID:The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. 875 56

The gene for Friedreich ataxia (FRDA), an autosomal-recessive neurodegenerative disease, remains elusive. The current candidate region of about 150 kb lies between loci FR2 and F8101 near the D9S15/D9S5 linkage group at 9q13-21.1. Linkage homogeneity between classical FRDA and a milder, slowly progressive Acadian variant (FRDA-Acad) has been demonstrated. An extended D9S15-D9S5 haplotype (C6) predominates in FRDA-Acad chromosomes from Louisiana. We studied 10 Acadian families from New Brunswick, Canada. In eight families, affected individuals conformed to the clinical description of FRDA-Acad; in one, 2 sibs presented with spastic ataxia (SPA-Acad). In the last family, 2 sibs had FRDA-Acad, and one had SPA-Acad. We found that SPA-Acad is linked to the FRDA gene region. The C6 haplotype and a second major haplotype (B7) were identified. The same ataxia-linked haplotypes segregated with both FRDA-Acad and SPA-Acad in two unrelated families. The parental origins of these haplotypes were different. Our observation of different phenotypes associated with the same combination of haplotypes may point to the influence of the parent of origin on gene expression, indicate the effect of modifier genes, or reflect the presence of different mutations on the same haplotypes. Our findings underline the need to investigate families with autosomal-recessive ataxias for linkage to the FRDA region, despite lack of key diagnostic manifestations such as cardiomyopathy or absent deep-tendon reflexes.
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PMID:Friedreich ataxia in Acadian families from eastern Canada: clinical diversity with conserved haplotypes. 887 Sep 28

The gene responsible for Friedreich's ataxia, a disease characterized by neurodegeneration and cardiomyopathy, has recently been cloned and its product designated frataxin. A gene in Saccharomyces cerevisiae was characterized whose predicted protein product has high sequence similarity to the human frataxin protein. The yeast gene (yeast frataxin homolog, YFH1) encodes a mitochondrial protein involved in iron homeostasis and respiratory function. Human frataxin also was shown to be a mitochondrial protein. Characterizing the mechanism by which YFH1 regulates iron homeostasis in yeast may help to define the pathologic process leading to cell damage in Friedreich's ataxia.
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PMID:Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. 918 83

The Friedreich ataxia (FA) mutation has recently been identified as an unstable trinucleotide GAA repeat present 7-22 times in the normal population but amplified as many as > 1,000 times in FA. Since it is an autosomal recessive disease, FA does not show typical features observed in other dynamic mutation disorders, such as genetic anticipation. We have analyzed the GAA repeat in 104 FA patients and 163 carrier relatives previously defined by linkage analysis. The GAA expansion was detected in all patients, most (94%) of them being homozygous for the mutation. We have demonstrated that clinical variability in FA is related to the size of the expanded alleles: milder forms of the disease-late-onset FA and FA with retained reflexes-are associated with shorter expansions, especially with the smaller of the two expanded alleles. Absence of cardiomyopathy is also associated with shorter alleles. Dynamics of the GAA repeat has been investigated in 212 parent-offspring pairs. Meiotic instability showed a sex bias: paternally transmitted alleles tend to decrease in a linear way that depends on the paternal expansion size, whereas maternal alleles can either increase or decrease. A different pattern of intergenerational variation was also observed, depending on the genetic status of the sib: patients had shorter expansions than were seen in heterozygous carriers. This finding has been interpreted as a postzygotic event. Finally, we have observed that the size of the expansion remains constant in the population through carriers.
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PMID:Phenotype correlation and intergenerational dynamics of the Friedreich ataxia GAA trinucleotide repeat. 924 90


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