To see whether kinetic assays of lipoamide dehydrogenase could be used for carrier detection or preclinical diagnosis, Michaelis-Menten constants (KmL and KmH) for the enzyme were determined in platelets from families with a form of recessive Friedreich ataxia and low activities of the enzyme.
The activity of lipoamide dehydrogenase was abnormally heat-labile in homogenized platelets from seven patients with as recessive ataxia conforming to the syndrome of Friedreich ataxia or clinical variants.
The FA gene has been shown to be in close linkage with the two chromosome 9 markers D9S5 and D9S15, and linkage disequilibrium between FA and D9S15 has been detected in French families by Hanauer et al.
This suggests that both marker loci are less than 1 cM from the FRDA gene and that a small number of mutations account for the majority of FA cases in the French population studied.
Chamberlain et al. have assigned the gene for Friedreich ataxia (FA), a recessive neurodegenerative disorder, to chromosome 9, and have proposed a regional localization in the proximal short arm (9p22-cen), on the basis of linkage to D9S15 and to interferon-beta (IFNB), the latter being localized in 9p22.
Corrected insulin responses, CIR = I x 100/G (G-70) (I = insulin, G = glucose), were not different from controls, whereas peripheral insulin activities, A = 10(4)/Ip Gp (p = values of I and G at peak glucose concentration), were significantly decreased (FA, 0.66 +/- 0.11, P less than .001; parents, 0.63 +/- 0.06, P less than .001; siblings, 0.72 +/- 0.09, P less than .01; v controls, 1.52 +/- 0.19), indicating the presence of insulin resistance in patients and first-degree relatives.
Corrected insulin responses, CIR = I x 100/G (G-70) (I = insulin, G = glucose), were not different from controls, whereas peripheral insulin activities, A = 10(4)/Ip Gp (p = values of I and G at peak glucose concentration), were significantly decreased (FA, 0.66 +/- 0.11, P less than .001; parents, 0.63 +/- 0.06, P less than .001; siblings, 0.72 +/- 0.09, P less than .01; v controls, 1.52 +/- 0.19), indicating the presence of insulin resistance in patients and first-degree relatives.
By analysis of crossovers in key recombinant families and by homozygosity analysis of inbred families, the Friedreich ataxia (FRDA) locus was localized in a 300-kb interval between the X104 gene and the microsatellite marker FR8 (D9S888).
The observation that some patients with only mild-to-moderate hypertension exhibit gross left ventricular hypertrophy (LVH) similar to the inherited hypertrophic cardiomyopathies such as familial hypertrophic cardiomyopathy (FHC) and Friedreich's ataxia (FA) has prompted us to investigate the hypothesis that genetic factors associated with excessive myocardial hypertrophy, viz. mutations in FHC and FA genes alter the hypertrophic response of the heart to pressure overload.
The STM7 gene on chromosome 9 was recently 'excluded' as a candidate for Friedreich's ataxia following the identification of an expanded intronic GAA triplet repeat in the adjacent gene, X25, in patients with the disease.
Friedreich ataxia (FA), the most frequent cause of recessive ataxia, is attributable, in most cases, to a large expansion of an intronic GAA repeat, resulting in decreased expression of the target frataxin gene.
In contrast, in one family with typical Friedreich's ataxia phenotype we did not find an expanded allele; this suggests that there can be either point mutations in the X25 gene on both chromosomes or locus heterogeneity in Friedreich's ataxia.
The most common mutation causing Friedreich ataxia (FRDA), an autosomal recessive neurodegenerative disease, is the hyperexpansion of a polymorphic GAA triplet repeat localized within an Alu sequence (GAA-Alu) in the first intron of the frataxin (X25) gene.