title: Gene dosage effect in spinocerebellar ataxia type 6 homozygotes: A clinical and neuropathological study.
abstract: Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disorder. However, it remains unclear whether SCA6 shows a gene dosage effect, defined by earlier age-of-onset in homozygotes than heterozygotes. Herein, we retrospectively analyzed four homozygous SCA6 subjects from our single institution cohort of 120 SCA6 subjects. We also performed a neuropathological investigation into an SCA6 individual with compound heterozygous expansions. In the 116 heterozygotes, there was an inverse correlation of age-of-onset with the number of CAG repeats in the expanded allele, and with the total number of CAG repeats, in both normal and expanded alleles. The age-of-onset in the four homozygotes was within the 95% confidence interval of the age-of-onset versus the repeat-lengths correlations determined in the 116 heterozygotes. Nevertheless, all homozygotes had earlier onset than their parents, and showed rapid disease progression. Neuropathology revealed neuronal loss, as well as α1A-calcium channel protein aggregates in Purkinje cells, a few α1A-calcium channel protein aggregates in the neocortex and basal ganglia, and neuronal loss in Clarke's column and the globus pallidus not seen in heterozygotes. These data suggest a mild clinical and neuropathological gene dosage effect in SCA6 subjects.
authors.affiliation: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Soga
authors.affiliation: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; The Center for Personalized Medicine for Healthy Aging, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Electronic address: pico.nuro@tmd.ac.jp.
authors.forename: Kinya
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Department of Neurology, Kawaguchi Kogyo General Hospital, 1-18-15 Aoki, Kawaguchi, Saitama 332-0031, Japan.
authors.forename: Tokuro
authors.initials: T
authors.lastname: Furuya
authors.affiliation: Department of Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; Department of Cellular Neurobiology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Tadatsune
authors.initials: T
authors.lastname: Iida
authors.affiliation: Department of Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; Laboratory of Pathology, Department of Clinical Laboratory Medicine, Bunkyo Gakuin University Graduate School of Health Care Science, 2-4-1 Mukogaoka, Bunkyo-ku, Tokyo 113-0023, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Ando
authors.affiliation: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Kiyobumi
authors.initials: K
authors.lastname: Ota
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Hokkaido, Japan; Department of Surgical Pathology, Hokkaido University Hospital, Hokkaido University, North 14, West 5, Kita-ku, Sapporo 060-8648, Hokkaido, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kanno-Okada
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Hokkaido, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Pathology, Shiga Medical Center for Adults, 5-4-30 Moriyama, Moriyama, Shiga 524-8524, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shintaku
authors.affiliation: Department of Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Eishi
authors.affiliation: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; The National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8551, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
authors.affiliation: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Yokota
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000473:pathology*; D015220:Calcium Channels / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D019680:Trinucleotide Repeat Expansion; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type
keywords: Age-of-onset; Aggregation; Gene dosage; Homozygous; Neuropathology; Spinocerebellar ataxia type 6