Friedreich's ataxia: Point mutations and clinical presentation of compound heterozygotes

Abstract

Friedreich's ataxia is the most common inherited ataxia. Ninety‐six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy‐terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino‐terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early‐onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele. Ann Neurol 1999;45:200–206

Selected missense mutations impair frataxin processing in Friedreich ataxia

“…FRDA G130V patients also have significantly lower occurrence of cardiomyopathy, scoliosis, and diabetes, and they surpass other point mutation carrying subjects on composite performance measures. As suggested in single cases previously, this demonstrates that FRDA patients with FXN G130V demonstrate greater neurological function and decreased disease severity at a similar length of disease duration 8, 10, 11, 15, 23, 24, 25, 26, 27, 28, 29. Patients with I154F mutations have clinical severities intermediate between other patients with point mutations and G130V patients, matching the data from cellular models of the molecular consequences of these mutants.…”

“…In general, patients carrying G130V mutations have milder phenotypes in single case reports and small series. In contrast, individuals with mutations in W155R and R165C have much more severe phenotypes 9, 10, 11, 12…”

“…Many missense mutations in the C‐terminus end of FXN have been identified in FRDA, yet, few have been characterized in vivo or in situ. Some are proposed to disrupt mRNA expression (various splice site mutations such as c.165 + 1 G>A and c.384 −2 A>G),11, 12 translation initiation (c.1A>T, c.2T>C, c.2delT, c.3 g>T, c.3G>A), or protein folding (L106S) 9, 13, 14, 15. These should produce little to no functional protein, and their associated phenotype should be severe in conjunction with a long GAA repeat on the other FXN allele.…”

Lateral-flow immunoassay for the frataxin protein in Friedreich’s ataxia patients and carriers

“…The remaining cases are all compound heterozygotes in which one FXN allele contains an expanded GAA repeat while the second allele carries a deleterious point mutation [8,9]. Most individuals carry only small numbers of GAA repeats in the frataxin gene, with most (> 80%), carrying "small normal" (6)(7)(8)(9)(10)(11)(12) repeats and the remainder carrying "large normal" repeats [10]. To date, the functional role and pathological consequences, if any, of these small normal and large normal repeats is still unknown.…”

Crystal Structure of Human Frataxin

“…Most patients are homozygous for a GAA trinucleotide repeat expansion in the first intron (4), which causes the DNA to be sticky (5) and leads to decreased transcription and diminished protein production (6). Fewer patients have a point mutation in one allele and an increase in GAA repeats in the other allele (7), confirming that Friedreich's ataxia is due to loss of function.…”