Analysis of CAG trinucleotide expansion associated with Machado-Joseph disease

There are currently some types of autosomal dominant cerebellar ataxias such as Machado-Joseph disease (MJD), spinocerebellar ataxia types 1-5 (SCA1-5), or hereditary dentatorubropallidoluysian atrophy. It is very important for these ataxias to be clinically differentiated, but that is sometimes difficult. In particular, the differential diagnosis between MJD and SCA1 is thought to be the most difficult. Recently, both MJD and SCA1 have been proven to be related to expansions of CAG trinucleotide in their causative genes. In this study, 20 cases of MJD in 13 unrelated Japanese families were genetically and clinically examined in comparison with 20 cases of age at onset- and duration-matched Japanese SCA1. The CAG repeat number of expanded MJD and SCA1 alleles was 72.2 +/- 3.1 (mean +/- SD, n = 20) and 47.3 +/- 4.4 (n = 20), respectively, and each repeat size was inversely correlated with age at onset in both MJD and SCA1. The repeat number in leukocytes increased from parents to children with acceleration of age at onset (anticipation) in MJD. In MJD, the number of CAG repeats in the expanded allele was lower in sperm than that of leukocytes, but was more in SCA1. However, the number of peaks in the expanded allele was greater in sperm than in leukocytes in both MJD and SCA1 (increased mosaicism level). MJD was clinically characterized by a relatively higher frequency of ocular signs such as eyelid retraction, bulging eyes, ophthalmoparesis, and nystagmus, spasticity in lower limbs, and sensory and urinary disturbances in contrast to the SCA1 patients except for slow eye movement. These results indicate that the expanded CAG repeat and clinical features are correlated in both MJD and SCA1, and MJD can be differentiated from SCA1 by clinical characteristics mentioned above as well as DNA analysis.