The Friedreich's ataxia mutation may originate from a premutation and shows size reduction when transmitted from parent to affected child

Most trinucleotide repeat mutations cause dominant or X linked neurological disorders and show progressive increase in size from affected parent to affected child, the basis of phenotypic anticipation. Friedreich's ataxia (FA) is a recessive disorder in which gene dysfunction is due to an expansion of a GAA trinucleotide repeat in intron one which reduces mRNA and protein levels. We confirm that the severity of the disorder in our population depends upon the repeat length of the smaller allele, to a point where those with smaller alleles may be mis-diagnosed with other conditions such as spastic paraparesis. Two brothers were found to be heterozygou1; for the expansion and a point mutation (G to T) which leads to G130V. These patients have an atypical clinical phenotype. From studying 81 transmissions.we demonstrate that the repeat number of the expansion in FA usually decreases in size from parent to affected child, and that this affect is particularly marked in the paternal allele. No expanded alleles were found in the range between 22 and 332 trinucleotides with one important exception, a carrier with an intermediate repeat size of approximately 100. When this allele was transmitted to the affected child, the repeat increased in size either probably to 538 or possible to 1036. Analysis of a sperm sample from this carrier showed a major band for the expanded allele of 320 repeats. These data suggest that there may be a premutation for Friedrelch's ataxia carriers, similar to that demonstrated for FraX-A and that expansion occurs in two stages, the first during meiosis followed by a second mitotic expansion

A duplication at chromosome 11q12.2–11q12.3 is associated with spinocerebellar ataxia type 20

Spinocerebellar ataxia type 20 (SCA20) has been linked to chromosome 11q12, but the underlying genetic defect has yet to be identified. We applied single-nucleotide polymorphism genotyping to detect structural alterations in the genomic DNA of patients with SCA20. We found a 260 kb duplication within the previously linked SCA20 region, which was confirmed by quantitative polymerase chain reaction and fiber fluorescence in situ hybridization, the latter also showing its direct orientation. The duplication spans 10 known and 2 unknown genes, and is present in all affected individuals in the single reported SCA20 pedigree. While the mechanism whereby this duplication may be pathogenic remains to be established, we speculate that the critical gene within the duplicated segment may be DAGLA, the product of which is normally present at the base of Purkinje cell dendritic spines and contributes to the modulation of parallel fiber-Purkinje cell synapses

Absence of linkage of ABO blood group locus to familial tuberous sclerosis

A mutation leading to tuberous sclerosis was linked to the ABO blood group locus (9q34) on the long arm of chromosome 9. In an effort to confirm this assignment, nine multigenerational families with tuberous sclerosis, comprising 126 sampled individuals, were assessed for linkage of the ABO locus to tuberous sclerosis. Two-point linkage analysis and multilocus linkage analysis were used to evaluate linkage between tuberous sclerosis and the markers ABO, MCT136, and AblK2. Linkage of ABO to tuberous sclerosis was excluded for a distance of 20 centimorgans (cM) encompassing the region of the ABO locus. There was no evidence for genetic heterogeneity within this data set. Using 23 polymorphic markers, exclusion mapping demonstrated only a 1% probability that the tuberous sclerosis locus was on the distal short arm of chromosome 9 and provided no evidence in support of a tuberous sclerosis locus on the remainder of chromosome 9 including the area of the ABO locus