Generalized chorea in two patients harboring the Friedreich's ataxia gene trinucleotide repeat expansion

Hanna, Michael G.; Davis, Mary B.; Sweeney, Mary G.; Noursadeghi, Mahdad; Ellis, Christopher J.; Elliot, Perry; Wood, Nicholas W.; Marsden, C. D.

doi:10.1002/mds.870130223

Cited by 46 publications

(24 citation statements)

References 5 publications

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“…One patient presented with titubation, and another with "leg spasms", which are uncommon presenting symptoms of typical FA [1]. Patient 1 had choreiform movements of the hands and face, which has been previously described in FA [18], and is still ambulatory with assistance at 48 years of age. Nerve conduction studies revealed a severe sensory axonal neuropathy with a median nerve MCV of 42 m/s.…”

Section: Atypical Negative Patientsmentioning

confidence: 99%

Typical Friedreich's ataxia without GAA expansions and GAA expansions without typical Friedreich's ataxia

et al. 2000

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We clinically assessed and performed polymerase chain reaction analysis for the GAA trinucleotide repeat expansion in 103 patients from 73 families in Ireland, with a prior clinical diagnosis of Friedreich's ataxia (FA) or an unclassified progressive ataxic syndrome. The patients were classified as "typical" or "atypical" FA according to Harding's mandatory clinical diagnostic criteria. All patients underwent blood glucose analysis, and electrocardiography and echocardiography was performed in 99 and 101 patients, respectively. Mutation screening for expanded CAG trinucleotide repeats, associated with spinocerebellar ataxia (SCA) 1, 2, 3 and 6 was performed in 86 patients overall, including all GAA negative patients. Forty-nine of 56 typical patients and 13 of 47 atypical patients were either homozygous or heterozygous for the GAA expansion. Seven patients with a typical FA phenotype were negative for the GAA expansion. Although one of these patients had vitamin E deficiency, and two had raised alpha-fetoprotein levels, three other GAA negative patients with a typical FA phenotype had no other identifiable cause for their ataxia, once again raising the possibility of locus heterogeneity in FA. It is also possible that these patients have two point mutations in the X25 gene, or that they have another ataxic syndrome mimicking the FA phenotype. Two families who were homozygous for the GAA expansion exhibited intrafamilial phenotypic variability. Only one GAA negative patient had the SCA 3 mutation, and this was the only patient in the study with a possible autosomal dominant inheritance pattern. In the homozygous GAA population typical patients had significantly more repeats on the smaller allele than atypical patients, and there was an inverse relationship between the number of repeats on the smaller allele and the age at presentation. There was also an inverse relationship between the repeat size on both the larger and the smaller of the two alleles and the age at becoming wheelchair bound. There was no significant relationship between repeat size and the other indices of disease severity, including the presence or absence of diabetes or cardiomyopathy. This is the first large study of an Irish population with progressive ataxia that has shown a similar phenotype/genotype relationship to studies of FA in other European and non-European populations. The relatively low sensitivity and specificity of Harding's clinical diagnostic criteria must be appreciated when clinically assessing patients with a progressive ataxic syndrome. Although molecular genetic analysis now plays an essential role in diagnosis and classification, patients with a typical FA phenotype without any identifiable cause for their ataxia exist.

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Section: Atypical Negative Patientsmentioning

confidence: 99%

Typical Friedreich's ataxia without GAA expansions and GAA expansions without typical Friedreich's ataxia

et al. 2000

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“…Chorea as a presenting feature of FRDA has been reported in 2 patients who were homozygous for the GAA repeat expansion. 14 The case we present here therefore has broadened the spectrum of FRDA genotype associated with chorea. It also suggests that all cases of idiopathic recessive or sporadic ataxia should undergo genetic tested for FRDA.…”

Section: Discussionmentioning

confidence: 94%

Friedreich's ataxia with chorea and myoclonus caused by a compound heterozygosity for a novel deletion and the trinucleotide GAA expansion

Zhu

Burke²,

Leslie

et al. 2002

Movement Disorders

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Friedreich's ataxia (FRDA) is the most common hereditary ataxia, affecting about 1 in 50,000 individuals. It is caused by mutations in the frataxin gene; 98% of cases have homozygous expansions of a GAA trinucleotide in intron 1 of the frataxin gene. The remaining 2% of patients are compound heterozygotes, who have a GAA repeat expansion in one allele and a point mutation in the other allele. FRDA patients with point mutation have been suggested to have atypical clinical features. We present a case of compound heterozygotes in a FRDA patient who has a deletion of one T in the start codon (ATG) of the frataxin gene and a GAA repeat expansion in the other allele. The patient presented with chorea and subsequently developed FRDA symptoms. The disease in this case is the result of both a failure of initiation of translation and the effect of the expansion. This novel mutation extends the range of point mutations seen in FRDA patients, and also broadens the spectrum of FRDA genotype associated with chorea.

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“…As the phenotypic match becomes smaller, the odds of a positive test also decline [65,71,72]. But, with the most common genetic syndromes (Ataxia telangiectasia in the 2-to 10-year-old sporadic cerebellar group, Friedreich's ataxia in the 10-to 25-yearold sporadic spinocerebellar group, and SCA 1, 2, 3, and 6 in the later-onset ataxias) it is reasonable to test with even very atypical phenotypes, which have been reported for all of these [60,63,64,73]. Certain clinical features may be so characteristic of a particular condition, that even in the absence of anything else, the physician should look for that condition.…”

Section: Is the Ataxic Phenotype Consistent With A Genetic Cause?mentioning

confidence: 95%

“…FRDA1 has some phenotypic variability, with milder phenotypes being seen proportional to the amount of functional protein produced by the least abnormal allele (smallest GAA repeat or milder missense mutation [59]). Onset after the age of 25 years (and into the 7th decade) [60], retained reflexes or isolated spasticity [61][62][63], and chorea [64] have all been reported; however, these are rare (less than 10% of cases). The patient with a phenotype more like typical Friedreich's ataxia will be more likely to test positive for the GAA expansion [65].…”

Section: Genotype/phenotype Studiesmentioning

confidence: 96%

Spinocerebellar degenerations: An update

Perlman

2002

Curr Neurol Neurosci Rep

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Over the past decade, the spinocerebellar degenerations have gone from a diverse group of loosely defined phenotypes to a family of diseases with many identifiable genotypes and the promise of gene-specific treatments. The evaluation of the spinocerebellar ataxias has been simplified, and the counseling of patients and families has been enhanced by the growing number of molecular diagnostic tests now available. Management strategies remain symptomatic and focused on rehabilitation, with empirical use of antioxidants based on research in other neurogenetic diseases.

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Generalized chorea in two patients harboring the Friedreich's ataxia gene trinucleotide repeat expansion

Cited by 46 publications

References 5 publications

Typical Friedreich's ataxia without GAA expansions and GAA expansions without typical Friedreich's ataxia

Typical Friedreich's ataxia without GAA expansions and GAA expansions without typical Friedreich's ataxia

Friedreich's ataxia with chorea and myoclonus caused by a compound heterozygosity for a novel deletion and the trinucleotide GAA expansion

Spinocerebellar degenerations: An update

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