Nacer Abbas

Patients with spinocerebellar ataxia 3 (SCA3) and Machado-Joseph disease (MJD) carry an expanded CAG repeat in the MJD1 gene. One hundred twenty families of different geographic origin with autosomal dominant cerebellar ataxia (ADCA) type I were tested. Thirty-four families (126 patients) carried an expanded CAG repeat. The expanded and the normal allele did not overlap and the repeat was unstable during transmission, with variation in the size of the CAG length ranging from -8 to +5 and a mean expansion of 0.86 repeats without differences according to the parental sex. There was a combined effect of the number of CAG repeats of the expanded and normal allele on the age at onset, which accounted for 70% of its variability. The length of the CAG repeat influenced the frequency of clinical signs associated with cerebellar ataxia, such as abnormal tendon reflexes or decreased vibration sense, whereas the interindividual variation of supranuclear ophthalmoplegia, sphincter and swallowing difficulties, and amyotrophy was mostly determined by different disease durations. We compared the clinical profile of 91 SCA3/MJD patients with 51 SCA1 and 32 SCA2 patients. There were striking differences between the SCA3/MJD and SCA2 but not with SCA1 groups of patients. Despite their clinical similarities, distinct neuropathological features were observed in 2 SCA3/MJD and 2 SCA1 patients.

Charcot-Marie-Tooth disease type 1A (CMT1A) is a common autosomal dominant demyelinating neuropathy that is associated with a 1.5 megabase (Mb) tandem DNA duplication in chromosome 17p11.2-p12. Hereditary neuropathy with liability to pressure palsies (HNPP, tomaculous neuropathy) is another less frequently diagnosed autosomal dominant neuropathy and is associated with a 1.5 Mb deletion in chromosome 17p11.2-12. Meiotic unequal crossover is a proposed mechanism for the generation of both the duplication in CMT1A and the deletion in HNPP. CMT1A-REP is a repeat that flanks the region which is duplicated/deleted in CMT1A/HNPP. The CMT1A-REP repeat sequence may mediate unequal crossover through misalignment of the homologous, repeated sequences. Three copies of the CMT1A-REP repeat are present on stably inherited CMT1A duplication chromosomes. In this report, molecular analysis in multiple patients detected three copies of the CMT1A-REP sequence on both inherited and de novo CMT1A duplication chromosomes, and one copy of the CMT1A-REP repeat on the deleted chromosome in both inherited and de novo HNPP. These observations support the hypothesis that a reciprocal recombination mechanism involving the CMT1A-REP is responsible for the generation of both the duplicated and deleted chromosomes, and document the first examples in humans of Mendelian syndromes resulting from the reciprocal products of unequal exchange involving large intra-chromosomal segments.