A Novel Mutation in ELOVL4 Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia A Broadened Spectrum of SCA34

被引:68
作者
Ozaki, Kokoro [1 ]
Doi, Hiroshi [2 ]
Mitsui, Jun [3 ]
Sato, Nozomu [1 ]
Iikuni, Yoichiro [4 ]
Majima, Takamasa [5 ]
Yamane, Kiyomi [4 ]
Irioka, Takashi [5 ]
Ishiura, Hiroyuki [3 ]
Doi, Koichiro [6 ]
Morishita, Shinichi [6 ]
Higashi, Miwa [1 ]
Sekiguchi, Teruhiko [7 ]
Koyama, Kazuo [8 ]
Ueda, Naohisa [2 ]
Miura, Yoshiharu [9 ]
Miyatake, Satoko [10 ]
Matsumoto, Naomichi [10 ]
Yokota, Takanori [1 ]
Tanaka, Fumiaki [2 ]
Tsuji, Shoji [3 ]
Mizusawa, Hidehiro [1 ,11 ]
Ishikawa, Kinya [1 ]
机构
[1] Tokyo Med & Dent Univ, Dept Neurol & Neurol Sci, Grad Sch Med & Dent Sci, Bunkyo Ku, Tokyo 1138519, Japan
[2] Yokohama City Univ, Dept Neurol & Stroke Med, Grad Sch Med, Yokohama, Kanagawa 232, Japan
[3] Univ Tokyo, Dept Neurol, Grad Sch Med, Bunkyo Ku, Tokyo, Japan
[4] Ohta Atami Hosp, Neurol Inst, Dept Neurol, Koriyama, Fukushima, Japan
[5] Yokosuka Kyosai Hosp, Dept Neurol, Yokosuka, Kanagawa, Japan
[6] Univ Tokyo, Dept Computat Biol, Grad Sch Frontier Sci, Kashiwa, Chiba, Japan
[7] Tokyo Metropolitan Neurol Hosp, Dept Neurol, Fuchu, Tokyo, Japan
[8] Fujisawa City Hosp, Dept Neurol, Fujisawa, Kanagawa, Japan
[9] Komagome Hosp, Tokyo Metropolitan Canc & Infect Dis Ctr, Dept Neurol, Bunkyo Ku, Tokyo, Japan
[10] Yokohama City Univ, Dept Human Genet, Grad Sch Med, Yokohama, Kanagawa 232, Japan
[11] Natl Ctr Hosp, Natl Ctr Neurol & Psychiat, Kodaira, Tokyo, Japan
基金
日本学术振兴会; 日本科学技术振兴机构;
关键词
TRANSMEMBRANE PROTEIN TOPOLOGY; MULTIPLE SYSTEM ATROPHY; HIDDEN MARKOV MODEL; GENE; MECHANISM; IDENTIFICATION;
D O I
10.1001/jamaneurol.2015.0610
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
IMPORTANCE Although mutations in 26 causative genes have been identified in the spinocerebellar ataxias (SCAs), the causative genes in a substantial number of families with SCA remain unidentified. OBJECTIVE To identify the causative gene of SCA in 2 Japanese families with distinct neurological symptoms and radiological presentations. DESIGN, SETTING, AND PARTICIPANTS Clinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997. MAIN OUTCOMES AND MEASURES Results of neurological examinations and radiological evaluations. The causative mutation was identified using genome-wide linkage analysis and next-generation sequencing. RESULTS Affected members (9 of 11 members [81.8%]) showed slowly progressive cerebellar ataxia (all 9 members [100%]), ocular movement disturbance (all 9 members [100%]), and pyramidal tract signs (8 of 9 members [88.9%]) with an age at onset between the second and sixth decades of life. Besides cerebellar and pontine atrophy, magnetic resonance imaging of the brain revealed the hot cross bun sign (4 of 6 members [66.7%]), pontine midline linear hyperintensity (2 of 6 members [33.3%]), or high intensity in the middle cerebellar peduncle (1 of 6 members [16.7%]), which are all reminiscent of multiple system atrophy in tested patients. Using linkage analysis combined with exome and whole-genome sequencing, we identified a novel heterozygous mutation in the ELOVL fatty acid elongase 4 (ELOVL4) gene (c.736T>G, p.W246G) in both families. Haplotype analysis indicated that it was unlikely that these 2 Japanese families shared a common ancestor. Although a missense mutation in ELOVL4 (c.504G>C, p.L168F) was recently reported to be associated with SCA with erythrokeratodermia variabilis (SCA34) in a French-Canadian family, signs of erythrokeratodermia variabilis were absent in our families. CONCLUSIONS AND RELEVANCE Combined with the results of the family with SCA34 reported previously, this report confirms that mutations in ELOVL4 can cause dominantly inherited neurodegeneration severely affecting the cerebellum and brainstem. We should be aware that the presence of multiple system atrophy-like features on magnetic resonance imaging scans, together with cerebellar and brainstem atrophy, suggests SCA34, even when erythrokeratodermia variabilis is absent. The present study further broadened the spectrum of the clinical presentations of SCA34 associated with mutations in ELOVL4, which is involved in the biosynthesis of very long-chain fatty acids.
引用
收藏
页码:797 / 805
页数:9
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