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Multiplex Families With Multiple System Atrophy
Kenju Hara, MD, PhD;
Yoshio Momose, MD, PhD;
Susumu Tokiguchi, MD, PhD;
Mitsuteru Shimohata, MD, PhD;
Kenshi Terajima, MD, PhD;
Osamu Onodera, MD, PhD;
Akiyoshi Kakita, MD, PhD;
Mitsunori Yamada, MD, PhD;
Hitoshi Takahashi, MD, PhD;
Motoyuki Hirasawa, MD, PhD;
Yoshikuni Mizuno, MD, PhD;
Katsuhisa Ogata, MD, PhD;
Jun Goto, MD, PhD;
Ichiro Kanazawa, MD, PhD;
Masatoyo Nishizawa, MD, PhD;
Shoji Tsuji, MD, PhD
Arch Neurol. 2007;64(4):545-551.
Background Multiple system atrophy (MSA) has been considered a sporadic disease, without patterns of inheritance.
Objective To describe the clinical features of 4 multiplex families with MSA, including clinical genetic aspects.
Design Clinical and genetic study.
Setting Four departments of neurology in Japan.
Patients Eight patients in 4 families with parkinsonism, cerebellar ataxia, and autonomic failure with age at onset ranging from 58 to 72 years. Two siblings in each family were affected with these conditions.
Main Outcome Measures Clinical evaluation was performed according to criteria by Gilman et al. Trinucleotide repeat expansion in the responsible genes for the spinocerebellar ataxia (SCA) series and for dentatorubral-pallidoluysian atrophy (DRPLA) was evaluated by polymerase chain reaction. Direct sequence analysis of coding regions in the  -synuclein gene was performed.
Results Consanguineous marriage was observed in 1 of 4 families. Among 8 patients, 1 had definite MSA, 5 had probable MSA, and 2 had possible MSA. The most frequent phenotype was MSA with predominant parkinsonism, observed in 5 patients. Six patients showed pontine atrophy with cross sign or slitlike signal change at the posterolateral putaminal margin or both on brain magnetic resonance imaging. Possibilities of hereditary ataxias, including SCA1 (ataxin 1, ATXN1), SCA2 (ATXN2), Machado-Joseph disease/SCA3 (ATXN1), SCA6 (ATXN1), SCA7 (ATXN7), SCA12 (protein phosphatase 2, regulatory subunit B, β isoform; PP2R2B), SCA17 (TATA box binding protein, TBP) and DRPLA (atrophin 1; ATN1), were excluded, and no mutations in the -synuclein gene were found.
Conclusions Findings in these multiplex families suggest the presence of familial MSA with autosomal recessive inheritance and a genetic predisposition to MSA. Molecular genetic approaches focusing on familial MSA are expected to provide clues to the pathogenesis of MSA.
Author Affiliations: Departments of Neurology (Drs Hara, Shimohata, Terajima, and Nishizawa) and Pathology (Drs Yamada and Takahashi), and Genome Science Branch (Dr Onodera) and Resource Branch for Brain Disease Research (Dr Kakita), Center for Bioresource-Based Researches, Brain Research Institute, Niigata University, Niigata; Division of Neuroscience, Department of Neurology, Graduate School of Medicine, University of Tokyo (Drs Momose, Ogata, Goto, and Tsuji), Department of Neurology, Juntendo University School of Medicine (Drs Hirasawa and Mizuno), and National Center of Neurology and Psychiatry (Dr Kanazawa), Tokyo; and Department of Neurology, Toi Clinic, Shizuoka (Dr Tokiguchi); Japan.
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Second consensus statement on the diagnosis of multiple system atrophy
Gilman et al.
Neurology 2008;71:670-676.
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