ELOVL4 – Spinocerebellar Ataxia Type 34

Spinocerebellar ataxia type 34 (SCA34) is caused by autosomal dominant variants in ELOVL4, presenting with late-onset cerebellar ataxia and variable skin findings. Over 60 unrelated cases have been reported to date, establishing a robust case series (PMID:36696030).

Inheritance is autosomal dominant, with heterozygous missense alleles segregating in multiple kindreds, including six affected relatives in a French-Canadian family (PMID:32211516) and father–child pairs in a Japanese cohort (PMID:31105016).

The variant spectrum comprises at least five recurrent missense changes in ELOVL4; the c.698C>T (p.Thr233Met) allele is observed in multiple families and reclassified as likely pathogenic after segregation analysis (PMID:36696030).

Functional studies support a dominant-negative mechanism: mutant ELOVL4 mislocalizes from the ER, impairing very long-chain saturated fatty acid synthesis. Knock-in rat models expressing p.Trp246Gly exhibit cerebellar long-term potentiation and depression defects without overt neurodegeneration (PMID:34227061).

Clinically, affected individuals manifest gait and limb ataxia (88–77%), dysarthria (63%), nystagmus (58%), pyramidal tract signs, cognitive impairment, and universal cerebellar atrophy on MRI (PMID:36696030).

Together, multiple independent families, segregation evidence, and concordant functional models support a Strong ELOVL4–SCA34 association. ELOVL4 genetic testing is recommended for autosomal dominant ataxia irrespective of dermatological features.

References

• Cerebellum (London, England) • 2024 • Two New Families and a Literature Review of ELOVL4-Associated Spinocerebellar Ataxia Type 34 PMID:36696030
• Parkinsonism & related disorders • 2019 • Prevalence and clinicoradiological features of spinocerebellar ataxia type 34 in a Japanese ataxia cohort. PMID:31105016
• Neurology. Genetics • 2020 • Characterization of the phenotype with cognitive impairment and protein mislocalization in SCA34. PMID:32211516
• Molecular neurobiology • 2021 • W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34. PMID:34227061

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