title: A Novel Mutation in ELOVL4 Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia: A Broadened Spectrum of SCA34.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Clinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997.
  
  
  METHODS
  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
  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.affiliation: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan.
authors.forename: Kokoro
authors.initials: K
authors.lastname: Ozaki
authors.affiliation: Department of Neurology and Stroke Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Doi
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Mitsui
authors.affiliation: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Sato
authors.affiliation: Department of Neurology, Neurological Institute, Ohta-Atami Hospital, Koriyama, Fukushima, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iikuni
authors.affiliation: Department of Neurology, Yokosuka Kyosai Hospital, Yokosuka, Kanagawa, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Majima
authors.affiliation: Department of Neurology, Neurological Institute, Ohta-Atami Hospital, Koriyama, Fukushima, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Yamane
authors.affiliation: Department of Neurology, Yokosuka Kyosai Hospital, Yokosuka, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Irioka
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishiura
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Doi
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Morishita
authors.affiliation: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Higashi
authors.affiliation: Department of Neurology, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Sekiguchi
authors.affiliation: Department of Neurology, Fujisawa City Hospital, Fujisawa, Kanagawa, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Koyama
authors.affiliation: Department of Neurology and Stroke Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Ueda
authors.affiliation: Department of Neurology, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, Bunkyo, Tokyo, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Yokota
authors.affiliation: Department of Neurology and Stroke Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: 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.
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, Bunkyo, Tokyo, Japan.
authors.forename: Kinya
authors.initials: K
authors.lastname: Ishikawa
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001259:Ataxia / Q000175:diagnosis* / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012873:Skin Diseases, Genetic / Q000175:diagnosis* / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C418975:ELOVL4 protein, human; D005136:Eye Proteins; D008565:Membrane Proteins