title: Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia.
abstract: OBJECTIVE
  The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders with significant genetic heterogeneity. Despite the identification of 20 SCA genes, the cause of the disorder in a significant proportion of families with SCA remains unexplained. In 1972, a French-Canadian family segregating a combination of SCA and erythrokeratodermia variabilis (EKV) in an autosomal dominant fashion was described.
  
  
  OBJECTIVE
  To map and identify the causative gene in this large family with SCA and EKV using a combination of linkage analysis and whole-exome sequencing.
  
  
  METHODS
  A total of 32 individuals from the family have undergone complete neurologic and dermatologic examinations.
  
  
  METHODS
  Mutations in ELOVL4 have been reported in families with macular degeneration. Recently, homozygous mutations were found in patients with ichthyosis, spastic paraplegia, and severe neurodevelopmental defects. In the present study, we report on a heterozygote mutation in ELOVL4 in affected individuals from the family with SCA and EKV. The mutation segregates with a milder phenotype consisting of early-onset patches of erythema and hyperkeratosis, as well as SCA manifesting in the fourth or fifth decade of life.
  
  
  RESULTS
  We describe the mapping and the identification of a c.504G>C transversion in ELOVL4 resulting in the p.L168F substitution. We also provide clinical characterization of the phenotypes in 19 mutation carriers.
  
  
  CONCLUSIONS
  We report, to our knowledge, the first mutation in ELOVL4 that is associated with SCA and EKV. This gene encodes a member of the elongase family, which is responsible for the elongation of very long-chain fatty acids (at least 26 carbons). These fatty acids participate in a wide variety of physiological functions, including skin barrier formation and peroxisome β-oxidation. Overall, these results provide additional insight into the pathogenesis of these complex neurodegenerative disorders.
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Notre Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Cadieux-Dion
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Notre Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Maude
authors.initials: M
authors.lastname: Turcotte-Gauthier
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Noreau
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Notre Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Martin
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Notre Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Meloche
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Notre Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Micheline
authors.initials: M
authors.lastname: Gravel
authors.affiliation: Department of Dermatology, Grand Portage Hospital, Rivière du Loup, Quebec, Canada.
authors.forename: Christian Allen
authors.initials: CA
authors.lastname: Drouin
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Notre Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Dang Khoa
authors.initials: DK
authors.lastname: Nguyen
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Notre Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cossette
mesh_terms: D000595:Amino Acid Sequence; D015331:Cohort Studies; D056266:Erythrokeratodermia Variabilis / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011792:Quebec / Q000208:ethnology; D020754:Spinocerebellar Ataxias / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*
chemical_list: C418975:ELOVL4 protein, human; D005136:Eye Proteins; D008565:Membrane Proteins