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)

With the availability of a simple molecular test that distinguishes Friedreich ataxia, the most frequent form of inherited ataxia, from other recessive ataxias, it now becomes possible to unravel the genetic heterogeneity of the latter. We have now localised two genes causing autosomal recessive spinocerebellar ataxia in two consanguineous families. In the first family, the four affected Japanese sibs had spinocerebellar ataxia associated with elevated levels of serum creatine kinase, gamma-globulin, and alpha-foetoprotein. Homozygosity over a 20 cM region allowed to demonstrate linkage at 9q33.3-34.3 with a lod score of 3.0. Genotyping two unrelated Japanese patients from first degree consanguineous parents revealed that one was homozygous for the same region but did not share the biochemical features. In the second family, an Israeli uncle and a niece were affected by an early-onset recessive ataxia and subsequently developed hearing impairment and optic atrophy. Homozygosity over a 17 cM region allowed demonstration of linkage at 6p21-23 with a lod score of 3.25. These two localisations of autosomal recessive ataxia genes represent a first step toward the identification of genetically homogenous, non-Friedreich, ataxic patients and subsequent cloning of the genes.
Eur J Hum Genet 2000 Dec
PMID:Homozygosity mapping of spinocerebellar ataxia with cerebellar atrophy and peripheral neuropathy to 9q33-34, and with hearing impairment and optic atrophy to 6p21-23. 1117 88

The expansion of triplet repeat sequences is an initial step in the disease etiology of a number of hereditary neurological disorders in humans. Diseases such as myotonic dystrophy, Huntington's, several spinocerebellar ataxias, fragile X syndrome, and Friedreich's ataxia are caused by the expansions of CTG.CAG, CGG.CCG, or GAA.TTC repeats. The mechanisms of the expansion process have been investigated intensely in E. coli, yeast, transgenic mice, mammalian cell culture, and in human clinical cases. Whereas studies from 1994-1999 have implicated DNA replication and repair at the paused synthesis sites due to the unusual conformations of the triplet repeat sequences, recent work has shown that homologous recombination (gene conversion) is a powerful mechanism for generating massive expansions, in addition to, or in concert with, replication and repair.
IUBMB Life 2000 Dec
PMID:Genetic instabilities of triplet repeat sequences by recombination. 1132 7

Many of autosomal dominant spinocerebellar ataxias (SCA) are now shown to result from the expansion of unstable trinucleotide repeats. In most SCAs, these repeats are present within coding sequences of the causative genes and translated into polyglutamine tracts. In this overview clinical and molecular genetic features of newly identified group of diseases in this category are briefly summarized. Expanded polyglutamine repeats are supposed to mediate some toxic effects on a certain population of neurons that result in neuronal dysfunction. The current progress in these molecular biological studies on their pathophysiology is also reviewed. In Japan, Friedreich ataxia with intoronic GAA repeat expansions has not been known. Instead, early onset ataxia with Friedreich phenotype, associated with ocular motor apraxia in childhood and with hypoalbuminemia in adult, is the predominant ataxia with Friedreich phenotype, the causative mutation of which was very recently identified.
Rinsho Shinkeigaku 2001 Dec
PMID:[Hereditary ataxias-overview]. 1223 12

Ataxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia. The gene APTX, which encodes aprataxin, has been identified recently. We studied a large series of 158 families with non-Friedreich progressive ARCA. We identified 14 patients (nine families) with five different missense or truncating mutations in the aprataxin gene (W279X, A198V, D267G, W279R, IVS5+1), four of which were new. We determined the relative frequency of AOA1 which is 5%. Mutation carriers underwent detailed neurological, neuropsychological, electrophysiological, oculographic and biological examinations, as well as brain imaging. The mean age at onset was 6.8 +/- 4.8 years (range 2-18 years). Cerebellar ataxia with cerebellar atrophy on MRI and severe axonal sensorimotor neuropathy were present in all patients. In contrast, oculomotor apraxia (86%), hypoalbuminaemia (83%) and hypercholesterolaemia (75%) were variable. Choreic movements were frequent at onset (79%), but disappeared in the course of the disease in most cases. However, a remarkably severe and persistent choreic phenotype was associated with one of the mutations (A198V). Cognitive impairment was always present. Ocular saccade initiation was normal, but their duration was increased by the succession of multiple hypometric saccades that could clinically be confused with 'slow saccades'. We emphasize the phenotypic variability over the course of the disease. Cerebellar ataxia and/or chorea predominate at onset, but later on they are often partially masked by severe neuropathy, which is the most typical symptom in young adults. The presence of chorea, sensorimotor neuropathy, oculomotor anomalies, biological abnormalities, cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich's ataxia on a clinical basis. The frequency of chorea at onset suggests that this diagnosis should also be considered in children with chorea who do not carry the IT15 mutation responsible for Huntington's disease.
Brain 2003 Dec
PMID:Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies. 1450 70

Frataxin protein controls iron availability in mitochondria and reduced levels lead to the human disease, Friedreich's ataxia (FRDA). The molecular aspects of disease progression are not well understood. We developed a highly regulatable promoter system for expressing frataxin in yeast to address the consequences of chronically reduced amounts of this protein. Shutting off the promoter resulted in changes normally associated with loss of frataxin including iron accumulation within the mitochondria and the induction of mitochondrial petite mutants. While there was considerable oxidative damage to mitochondrial proteins, the petites were likely due to accumulation of mitochondrial DNA lesions and subsequent DNA loss. Chronically reduced frataxin levels resulted in similar response patterns. Furthermore, nuclear DNA damage was detected in a rad52 mutant, deficient in double-strand break repair. We conclude that reduced frataxin levels, which is more representative of the disease state, results in considerable oxidative damage in both mitochondrial and nuclear DNA.
Hum Mol Genet 2003 Dec 15
PMID:Reduction in frataxin causes progressive accumulation of mitochondrial damage. 1457 Jul 13

The maturation of iron-sulfur (Fe/S) proteins in eukaryotes has been intensively studied in yeast. Hardly anything is known so far about the process in higher eukaryotes, even though the high conservation of the yeast maturation components in most Eukarya suggests similar mechanisms. Here, we developed a cell culture model in which the RNA interference (RNAi) technology was used to deplete a potential component of Fe/S protein maturation, frataxin, in human HeLa cells. This protein is lowered in humans with the neuromuscular disorder Friedreich's ataxia (FRDA). Upon frataxin depletion by RNAi, the enzyme activities of the mitochondrial Fe/S proteins, aconitase and succinate dehydrogenase, were decreased, while the activities of non-Fe/S proteins remained constant. Moreover, Fe/S cluster association with the cytosolic iron-regulatory protein 1 was diminished. In contrast, no alterations in cellular iron uptake, iron content and heme formation were found, and no mitochondrial iron deposits were observed upon frataxin depletion. Hence, iron accumulation in FRDA mitochondria appears to be a late consequence of frataxin deficiency. These results demonstrate (i) that frataxin is a component of the human Fe/S cluster assembly machinery and (ii) that it plays a role in the maturation of both mitochondrial and cytosolic Fe/S proteins.
Hum Mol Genet 2004 Dec 01
PMID:Iron-sulfur protein maturation in human cells: evidence for a function of frataxin. 1550 95

We report on a Friedreich's ataxia (FA) family with 3 affected siblings with markedly different phenotypic presentations, including one with spastic paraplegia. Molecular analysis showed midsize GAA repeat expansion sizes in all 3 individuals. Gait spasticity in FA, although rare, has been described in a few patients who are compound heterozygotes for a point mutation, or who had GAA expansions of less than 200 repeats. The occurrence of spastic paraplegia in our family, in the presence of homozygous midsize GAA repeat expansions, is an unusual finding. Spasticity can be the main feature in both sporadic and familial patients with FA, either as an isolated finding, or in addition to other neurological abnormalities, and should be included as a rare feature in the clinical spectrum of FA. This family also demonstrates that in FA, marked intrafamilial phenotypic variability can arise in the presence of similar GAA expansion sizes. Therefore, in familial FA, the disease course in relatives therefore cannot be predicted solely from repeat length. Factors such as somatic mosaicism, repeat interruptions, modifying mutations and environmental factors must also be considered.
Mov Disord 2004 Dec
PMID:Striking intrafamilial phenotypic variability and spastic paraplegia in the presence of similar homozygous expansions of the FRDA1 gene. 1551 25

Friedreich ataxia patients are homozygous for expanded GAA triplet-repeats containing 66 to 1,700 triplets. We report two patients with delayed-onset, hyperreflexia and gradually progressive disease. Both were heterozygous for large expansions and also carried alleles with 44 and 66 triplet-repeats, respectively. Due to somatic instability, 15% (GAA-44) and 75% (GAA-66) of cells contained alleles with >/=66 triplet-repeats, constituting a plausible mechanism for their mild phenotype. A sibling with a stable GAA-37 allele and a large expansion was clinically normal. Instability of borderline alleles confers a risk for Friedreich ataxia, and the range of pathogenic alleles is broader than previously recognized.
Ann Neurol 2004 Dec
PMID:Friedreich ataxia in carriers of unstable borderline GAA triplet-repeat alleles. 1556 8

Very late-onset Friedreich's ataxia (VLOFA) is characterized by symptomatic onset after 40 years of age and, usually, a benign phenotype. We describe a sporadic case with onset at 53 years of age and a novel VLOFA phenotype mimicking multiple system atrophy (MSA) of cerebellar type associated with minimal GAA1 expansion. We detected several atypical features for a diagnosis of MSA, which should alert to the possibility of an inherited ataxia.
Mov Disord 2005 Dec
PMID:Very late-onset Friedreich's ataxia with minimal GAA1 expansion mimicking multiple system atrophy of cerebellar type. 1609 10

Clinicians require scientifically rigorous, clinically meaningful rating scales to evaluate the health impact of disease and treatment that cannot be measured using conventional laboratory instruments. This study evaluated the psychometric properties of the International Cooperative Ataxia Rating Scale (ICARS), a commonly used clinician-rated measure, in Friedreich's ataxia (FRDA). People with confirmed FRDA were assessed by using the ICARS. Two assumptions of its measurement model were tested: the legitimacy of reporting ICARS scores in FRDA, and the acceptability, reliability, and validity of total and subscale scores. Seventy-seven people with FRDA were assessed. The ICARS total score effectively satisfied all psychometric criteria tested. The posture and gait disturbances subscale also performed well. The other three subscales did not pass standard criteria for tests of scaling assumptions, reliability, and validity. This small study recommends only the use of the ICARS total score as a measure of FRDA. However, the extent to which this score quantifies the true extent of FRDA remains uncertain as our validity testing was limited, partly by the lack of appropriate validating measures. Further validity testing, and examination of responsiveness, is required before the ICARS can be recommended as an outcome measure for treatment trials of FDRA.
Mov Disord 2005 Dec
PMID:International Cooperative Ataxia Rating Scale (ICARS): appropriate for studies of Friedreich's ataxia? 1611 19


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