Genotype and phenotype analysis of Friedreich's ataxia compound heterozygous patients

Abstract

Friedreich's ataxia is caused by mutations in the FRDA gene that encodes frataxin, a nuclear-encoded mitochondrial protein. Most patients are homozygous for the expansion of a GAA triplet repeat within the FRDA gene, but a few patients show compound heterozygosity for a point mutation and the GAA-repeat expansion. We analyzed DNA samples from a cohort of 241 patients with autosomal recessive or isolated spinocerebellar ataxia for the GAA triplet expansion. Patients heterozygous for the GAA expansion were screened for point mutations within the FRDA coding region. Molecular analyses included the single-strand conformation polymorphism analysis, direct sequencing, and linkage analysis with FRDA locus flanking markers. Seven compound heterozygous patients were identified. In four patients, a point mutation that predicts a truncated frataxin was detected. Three of them associated classic early-onset Friedreich's ataxia with an expanded GAA allele greater than 800 repeats. The other patient associated late-onset disease at the age of 29 years with a 350-GAA repeat expansion. In two patients manifesting the classical phenotype, no changes were observed by single-strand conformation polymorphism (SSCP) analysis. Linkage analysis in a family with two children affected by an ataxic syndrome, one of them showing heterozygosity for the GAA expansion, confirmed no linkage to the FRDA locus. Most point mutations in compound heterozygous Friedreich's ataxia patients are null mutations. In the present patients, clinical phenotype seems to be related to the GAA repeat number in the expanded allele. Complete molecular definition in these patients is required for clinical diagnosis and genetic counseling.

Heart and Nervous System Pathology in Compound Heterozygous Friedreich Ataxia

“…The deletion in one allele of the FXN gene reported here (compound heterozygous FA case 1) probably caused a truncated, functionally deficient protein. In this and other "null" mutations, transcription of the expanded allele may be expected to generate normal frataxin, though at an insufficient amount (2,4). The deletion of exon 5 in the compound heterozygous FA case 2 is similar to that in a previously reported heterozygous FA patient (14).…”

The Molecular Basis of Iron-induced Oligomerization of Frataxin and the Role of the Ferroxidation Reaction in Oligomerization

“…Friedreich ataxia has been shown to be associated in most patients with reduced levels of frataxin, caused by expanded GAA repeats in the first intron of the gene encoding the protein (7). In addition, several mutations in the frataxin gene have been found to lead to Friedreich ataxia (7)(8)(9)(10)(11)(12).…”

Friedreich’s Ataxia: A New Mutation in Two Compound Heterozygous Siblings with Unusual Clinical Onset

“…Various authors [10][11][12][13] have reported an incidence of 2-5% of compound heterozygosity among patients affected by FA.…”

“…Suppression of frataxin expression by GAA expansion is not complete and appears to be proportional to repeat length. Accordingly, expansion size in patients who are homozygous for GAA repeat expansion inversely correlates with age at onset, disease severity and the time of wheelchair confinement [12][13][14][15] . Some authors even correlate larger triplet expansion with increased frequency of cardiomyopathy [12] .…”