Kokoro Ozaki1, Hiroshi Doi2, Jun Mitsui3, Nozomu Sato1, Yoichiro Iikuni4, Takamasa Majima5, Kiyomi Yamane4, Takashi Irioka5, Hiroyuki Ishiura3, Koichiro Doi6, Shinichi Morishita6, Miwa Higashi1, Teruhiko Sekiguchi7, Kazuo Koyama8, Naohisa Ueda2, Yoshiharu Miura9, Satoko Miyatake10, Naomichi Matsumoto10, Takanori Yokota1, Fumiaki Tanaka2, Shoji Tsuji3, Hidehiro Mizusawa11, Kinya Ishikawa1. 1. Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan. 2. Department of Neurology and Stroke Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan. 3. Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, Japan. 4. Department of Neurology, Neurological Institute, Ohta-Atami Hospital, Koriyama, Fukushima, Japan. 5. Department of Neurology, Yokosuka Kyosai Hospital, Yokosuka, Kanagawa, Japan. 6. Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan. 7. Department of Neurology, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, Japan. 8. Department of Neurology, Fujisawa City Hospital, Fujisawa, Kanagawa, Japan. 9. Department of Neurology, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, Bunkyo, Tokyo, Japan. 10. Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan. 11. Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan11The National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Abstract
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.
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.
Authors: Anna I Wernick; Ronald L Walton; Alexandra I Soto-Beasley; Shunsuke Koga; Yingxue Ren; Michael G Heckman; Lukasz M Milanowski; Rebecca R Valentino; Naveen Kondru; Ryan J Uitti; William P Cheshire; Zbigniew K Wszolek; Dennis W Dickson; Owen A Ross Journal: Neurosci Lett Date: 2021-02-15 Impact factor: 3.046
Authors: Blake R Hopiavuori; Ferenc Deák; Joseph L Wilkerson; Richard S Brush; Nicole A Rocha-Hopiavuori; Austin R Hopiavuori; Kathryn G Ozan; Michael T Sullivan; Jonathan D Wren; Constantin Georgescu; Luke Szweda; Vibhudutta Awasthi; Rheal Towner; David M Sherry; Robert E Anderson; Martin-Paul Agbaga Journal: Mol Neurobiol Date: 2017-11-22 Impact factor: 5.590
Authors: Bokkyoo Jun; Pranab K Mukherjee; Aram Asatryan; Marie-Audrey Kautzmann; Jessica Heap; William C Gordon; Surjyadipta Bhattacharjee; Rong Yang; Nicos A Petasis; Nicolas G Bazan Journal: Sci Rep Date: 2017-07-13 Impact factor: 4.379