Multiplex families with multiple system atrophy.
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.


METHODS
Clinical and genetic study.


METHODS
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.


METHODS
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 alpha-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, beta isoform; PP2R2B), SCA17 (TATA box binding protein, TBP) and DRPLA (atrophin 1; ATN1), were excluded, and no mutations in the alpha-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.
Hara
Kenju
K
Departments of Neurology, Center for Bioresource-Based Researches, Brain Research Institute, Niigata University, Niigata, Japan.
Momose
Yoshio
Y
Tokiguchi
Susumu
S
Shimohata
Mitsuteru
M
Terajima
Kenshi
K
Onodera
Osamu
O
Kakita
Akiyoshi
A
Yamada
Mitsunori
M
Takahashi
Hitoshi
H
Hirasawa
Motoyuki
M
Mizuno
Yoshikuni
Y
Ogata
Katsuhisa
K
Goto
Jun
J
Kanazawa
Ichiro
I
Nishizawa
Masatoyo
M
Tsuji
Shoji
S
D000368:Aged; D001921:Brain / Q000473:pathology; D003241:Consanguinity; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D017422:Sequence Analysis, DNA; D019680:Trinucleotide Repeat Expansion; D051844:alpha-Synuclein / Q000235:genetics
D051844:alpha-Synuclein