Expanding the Clinical Phenotype Associated With ELOVL4 Mutation: Study of a Large French-Canadian Family With Autosomal Dominant Spinocerebellar Ataxia and Erythrokeratodermia
Abstract
IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: A total of 32 individuals from the family have undergone complete neurologic and dermatologic examinations. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.
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ELOVL4 mutations cause spinocerebellar ataxia, impaired neural development, neuronal dysfunction, hyper-excitability, seizures, juvenile macular degeneration in autosomal dominant STGD3, and early functional defects in RPE and PRCs.
“ELOVL4 mutations cause spinocerebellar ataxia (Bourassa et al., 2015; Cadieux-Dion et al., 2014; Ozaki et al., 2015) impaired neural development, neuronal dysfunction, hyper-excitability, seizures (Agbaga, 2016; Aldahmesh et al., 2011) juvenile macular degeneration in autosomal dominant STGD3, with loss of central vision, progressive degeneration of the macula and peripheral retina (Agbaga et al.,”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Cadieux-Dion et al., 2014
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A New<i>ELOVL4</i>Mutation in a Case of Spinocerebellar Ataxia With Erythrokeratodermia
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- Authors
- Cadieux-Dion, M., Turcotte-Gauthier, M., Noreau, A., Martin, C., Meloche, C., Gravel, M., Drouin, C. A., Rouleau, G. A., Nguyen, D. K., & Cossette, P.
- Affiliations
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Notre Dame Hospital, University of Montreal, Montreal, Quebec, Canada
- Montreal Neurological Institute and Hospital (CA)
- Hôpital Notre-Dame (CA)
- Department of Dermatology, Grand Portage Hospital, Rivière du Loup, Quebec, Canada
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2014-04-01
- Volume
- 71
- Issue
- 4
- Pages
- 470
- ISSN
- 2168-6149 (ISSN-L)
- OpenAlex
- W1990141561
- Cited by
- 124
- References
- 28
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 12 · 2023: 11 · 2022: 11 · 2021: 18 · 2020: 8 · 2019: 8 · 2018: 11 · 2017: 12 · 2016: 8 · 2015: 9 · 2014: 5
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
- Keywords
- ELOVL4, autosomal dominant spinocerebellar ataxia, erythrokeratodermia variabilis, heterozygous mutation, very long chain fatty acid elongation, genotype-phenotype correlation, clinical phenotype, linkage analysis, exome sequencing, skin barrier formation, neurodegenerative diseases
- MeSH terms
- Amino Acid Sequence, Eye Proteins, Female, Genetic Carrier Screening, Humans, Male, Membrane Proteins, Molecular Sequence Data, Pedigree, Phenotype, Quebec, Cohort Studies, Mutation, Missense, Spinocerebellar Ataxias, Erythrokeratodermia Variabilis
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