ELOVL5 – Spinocerebellar Ataxia Type 38

ELOVL5 encodes a fatty-acid elongase highly expressed in cerebellar Purkinje cells. Spinocerebellar ataxia type 38 (SCA38, MONDO:0014417) is an autosomal-dominant neurodegenerative disorder characterized by adult-onset cerebellar ataxia, nystagmus, and peripheral sensory involvement. Initial linkage in an Italian pedigree localized SCA38 to chr6p and identified a missense variant, c.689G>T (p.Gly230Val), segregating in the index family and two additional unrelated Italian kindreds (n = 3 families) ([PMID:25065913]). A second variant, c.214C>G (p.Leu72Val), was found in an independent French family ([PMID:25065913]).

Subsequent exome sequencing in a five-member kindred spanning two generations confirmed segregation of c.698A>G (p.Tyr233Cys) in four affected relatives with gait ataxia, downbeat nystagmus and vestibular impairment, and demonstrated serum docosahexaenoic acid (DHA) deficiency responsive to 26-week DHA supplementation with clinical improvement ([PMID:32314013]). A larger study of 21 affected individuals from the original three Italian families all harbored c.689G>T (p.Gly230Val); onset was in the fourth decade with universal nystagmus and progressive gait and limb ataxia, frequent pes cavus and hyposmia, and later dysarthria, dysphagia, ophthalmoparesis and sensory neuronopathy ([PMID:27143115]).

Functional assays demonstrate that p.Gly230Val alters subcellular localization with Golgi accumulation, reduces serum arachidonic acid and DHA in patients, and fails to distribute to the endoplasmic reticulum as wild-type does ([PMID:25065913]). In patient fibroblasts, p.Gly230Val shows decreased ELOVL5 expression, Golgi enlargement and increased proteasomal degradation. Overexpression of p.Gly230Val in mouse cortical neurons triggers an unfolded protein response and reduces cell viability, while homology modeling reveals a disrupted intramolecular disulfide bond in Loop 2–Loop 6, a hotspot shared with SCA34 variants ([PMID:37199746]).

Together, >25 probands across five unrelated families, autosomal-dominant segregation in multiple affected relatives, and concordant biochemical, cellular and structural data support a definitive gene-disease relationship for ELOVL5 and SCA38. Key Take-home: Genetic testing for ELOVL5 variants informs diagnosis and suggests DHA supplementation as a potential therapeutic strategy.

References

• American Journal of Human Genetics • 2014 • ELOVL5 mutations cause spinocerebellar ataxia 38. PMID:25065913
• Parkinsonism & Related Disorders • 2016 • Clinical and neuroradiological features of spinocerebellar ataxia 38 (SCA38). PMID:27143115
• Journal of Neurology • 2020 • Contributions to the study of spinocerebellar ataxia type 38 (SCA38). PMID:32314013
• Human Genetics • 2023 • Spinocerebellar ataxia 38: structure-function analysis shows ELOVL5 G230V is proteotoxic, conformationally altered and a mutational hotspot. PMID:37199746

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