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

Abstract

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.

Intrafamilial Phenotypic Variability in Friedreich Ataxia Associated With a G130V Mutation in the FRDA Gene

“…3 He was the offspring of two unrelated Irish parents who had no symptoms of ataxia or neurologic disease.…”

“…3,5,14 Subject III:1 was estimated to have approximately 954 GAA repeats and subject III:2 was estimated to have 917 GAA repeats on one allele of chromosome 9, but the GAA repeat number on the other allele was normal in both subjects. The diffuse PCR product associated with the GAA expansion in subject III:2 overlapped the expansion in subject III:1 on agarose gel electrophoresis (data not shown).…”

Determination of Genotypic and Phenotypic Characteristics of Friedreich’s Ataxia and Autosomal Dominant Spinocerebellar Ataxia Types 1, 2, 3, and 6

“…Milbrandt et al (31) determined 63% had scoliosis and 24.5% had hyperkyphos in a series of 77 patients. Previous studies have indicated that foot deformity prevalence was between 55% and 90% (32,33,34,35). In all of our cases, skeletal deformities consisting of one or more of such deformities (pes cavus, kyphoscoliosis, and dome palate) were detected.…”

Very‐late‐onset Friedreich ataxia with disturbing head tremor and without spinal atrophy—A case report

“…Head tremor as a cerebellar sign was once thought to be rare in FA, 2 but recent reports concerning the frequency of various clinical manifestations in different FA phenotypes revealed an unexpectedly high prevalence of head tremor among patients with typical FA. 7 In contrast, head tremor has been described only in exceptional cases of atypical FA. 7 Although involvement of the pyramidal tract, as more commonly seen in patients with late onset forms of FA, was confirmed in our patient by transcranial magnetic stimulation, MRI revealed no atrophy or other abnormality of the spinal cord.…”

“…7 In contrast, head tremor has been described only in exceptional cases of atypical FA. 7 Although involvement of the pyramidal tract, as more commonly seen in patients with late onset forms of FA, was confirmed in our patient by transcranial magnetic stimulation, MRI revealed no atrophy or other abnormality of the spinal cord. Most patients with typical or atypical FA have been found to have significant cervical cord atrophy 1,8 ; the absence of this finding in our case is unusual.…”