Associations between multiple system atrophy and polymorphisms of SLC1A4, SQSTM1, and EIF4EBP1 genes.

Multiple system atrophy (MSA) is an adult-onset sporadic neurodegenerative disease. Although the etiology of MSA remains obscure, recent studies suggest that oxidative stress is associated with the pathogenesis of MSA. The aim of this study was to evaluate genetic associations between the candidate genes involved in oxidative stress and MSA in a case-control study. We examined 119 Japanese patients with MSA and 123 controls, and genotyped single-nucleotide polymorphisms (SNPs) of the following eight genes: CCAAT/enhancer-binding protein homologous protein, activating transcription factor 3, CCAAT/enhancer-binding protein-beta, sequestosome 1 (SQSTM1), cysteinyl-tRNA synthetase, solute carrier family 1A4 (SLC1A4), activating transcription factor 4, and eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1). SLC1A4 SNP +28833 (V398I, rs759458, genotype: Pc = 0.0186, allele: Pc = 0.0303, Pc: P-value with Bonferroni correction), two major haplotypes of SLC1A4 "T-C-C-G" and "T-C-T-A" (Pc = 0.0261 and 0.000768), two-SNP haplotypes of SQSTM1 "C-T" and "A-T" (Pc = 0.0136 and 0.0369), and the most common haplotype of EIF4EBP1 "C-T-G-C" (Pc = 0.0480) showed significant associations. This study revealed genetic associations of SLC1A4, SQSTM1, and EIF4EBP1 with MSA. These results may lend genetic support to the hypothesis that oxidative stress is associated with the pathogenesis of MSA.

MSA-C is the predominant clinical phenotype of MSA in Japan: analysis of 142 patients with probable MSA.

We investigated the clinical features and mode of disease progression in 142 patients with probable multiple system atrophy (MSA) according to the Consensus Criteria. The subjects included 84 men and 58 women with a mean age at onset of 58.2+/-7.1 years (range: 38-79 years). Cerebellar signs were detected in 87.3% of these patients at the time of initial examination, and were found in 95.1% of them at latest follow-up. MSA-C was diagnosed in 83.8% of the patients at their first examination. Parkinsonism was initially detected in 28.9% of the patients, increasing to 51.4% at the latest follow-up. Among all of the subjects, only 16.2% were classified as having MSA-P on initial examination. At the latest follow-up, parkinsonian features had become predominant over cerebellar features in 24.6% of the 65 patients with MSA-C who were followed for more than 3 years. Although parkinsonism usually masked the signs of cerebellar involvement in MSA-C patients, none of the patients with MSA-P at an early stage showed predominance of cerebellar features at the latest follow-up. Parkinsonism is the predominant feature of MSA among Western patients, even at an early stage, but this study showed that cerebellar deficits are the main feature in Japanese patients. This difference of disease manifestations between ethnic groups suggests that genetic factors may influence the clinical phenotype of MSA.

Heredity in multiple system atrophy.

We investigated the family histories of 157 Japanese patients with probable or possible multiple system atrophy (MSA). A family history of neurodegenerative disorders was only detected in three MSA patients (1.9%). We evaluated these patients by careful neurological examination, neuroimaging studies, and genetic studies to exclude hereditary spinocerebellar ataxia with a similar clinical phenotype to MSA. The results indicated that one of them had a family history of MSA. Although the familial presence of neurodegenerative disorders is rare in MSA patients, the existence of such cases suggests that MSA may have a genetic background.