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Dentatorubral‐pallidoluysian atrophy: Clinical features are closely related to unstable expansions of trinucleotide (CAG) repeat
Author(s) -
Ikeuchi Takeshi,
Koide Reiji,
Tanaka Hajime,
Onodera Osamu,
Igarashi Shuichi,
Takahashi Hitoshi,
Kondo Rui,
Ishikawa Atsushi,
Tomoda Akemi,
Miike Teruhisa,
Ihara Yuetsu,
Hayabara Toshiyuki,
Isa Fumiko,
Tanabe Hitoshi,
Tokiguchi Susumu,
Hayashi Masataka,
Shimizu Natsue,
Ikuta Fusahiro,
Naito Haruhiko,
Tsuji Shoji
Publication year - 1995
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410370610
Subject(s) - progressive myoclonus epilepsy , trinucleotide repeat expansion , myoclonus , ataxia , age of onset , atrophy , spinocerebellar ataxia , epilepsy , choreoathetosis , medicine , allele , degenerative disease , pathology , disease , genetics , biology , dystonia , psychiatry , gene
Abstract Dentatorubral‐pallidoluysian atrophy is an autosomal dominant neurodegenerative disease characterized by various combinations of ataxia, choreoathetosis, myoclonus, epilepsy, and dementia as well as a wide range of ages at onset. A specific unstable trinucleotide repeat expansion in a gene on the short arm of chromosome 12 was recently identified as the pathogenic mutation for this disease. We investigated how the degree of expansion of the CAG repeat affects the clinical manifestations of dentatorubral‐pallidoluysian atrophy. The size of the expanded alleles was well correlated with the age at onset ( r = ‐0.696, p < 0.001). Patients with the progressive myoclonus epilepsy phenotype had larger expansions (62‐79 repeats) and an earlier age at onset (onset before age 21). Furthermore, most of the patients with the progressive myoclonus epilepsy phenotype inherited their expanded alleles from their affected fathers. On the other hand, patients with the non‐progressive myoclonus epilepsy phenotype showed smaller expansions (54‐67 repeats) and a later age at onset (onset at or after age 21). Detailed analyses of clinical features demonstrated that ataxia, involuntary movement of either myoclonus or choreoathetosis, and intellectual decline are cardinal features of dentatorubral‐pallidoluysian atrophy, with myoclonus and epilepsy being observed more frequently in patients with an earlier age at onset. Thus the wide variation in clinical manifestations of dentatorubral‐pallidoluysian atrophy can now be clearly explained based on the degree of CAG repeat expansion, which strongly indicates that the expanded alleles are intimately involved in the neuronal degeneration in dentatofugal and pallidofugal systems.