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
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.
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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 Ozaki et al., 2015
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- Authors
- Ozaki, K., Doi, H., Mitsui, J., Sato, N., Iikuni, Y., Majima, T., Yamane, K., Irioka, T., Ishiura, H., Doi, K., Morishita, S., Higashi, M., Sekiguchi, T., Koyama, K., Ueda, N., Miura, Y., Miyatake, S., Matsumoto, N., Yokota, T., Tanaka, F., Tsuji, S., Mizusawa, H., & Ishikawa, K.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Yokohama City University (JP)
- The University of Tokyo (JP)
- Ohta Atami Hospital (JP)
- Yokosuka Kyosai Hospital (JP)
- Tokyo Metropolitan Neurological Hospital (JP)
- Fujisawa City Hospital (JP)
- Tokyo Metropolitan Komagome Hospital (JP)
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2015-07-01
- Volume
- 72
- Issue
- 7
- Pages
- 797
- ISSN
- 2168-6149 (ISSN-L)
- OpenAlex
- W2164495642
- Cited by
- 81
- References
- 45
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 5 · 2023: 10 · 2022: 8 · 2021: 15 · 2020: 10 · 2019: 6 · 2018: 10 · 2017: 6 · 2016: 3
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (15K09344, 25461287)
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- spinocerebellar ataxia, ELOVL4, novel mutations, hot cross bun sign, multiple system atrophy, erythrokeratodermia variabilis, cerebellar ataxia, pontine atrophy, missense mutations, Japanese family, linkage analysis, haplotype analysis
- MeSH terms
- Adult, Amino Acid Sequence, Ataxia, Eye Proteins, Female, Humans, Male, Membrane Proteins, Middle Aged, Molecular Sequence Data, Mutation, Pedigree, Skin Diseases, Genetic, Spinocerebellar Ataxias
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