A previously unreported ELOVL4 frameshift variant in a patient with early severe cognitive decline, parkinsonism, and cerebellar ataxia

Abstract

Rationale: Spinocerebellar ataxia type 34 is a rare autosomal dominant ataxia associated with heterozygous elongation of very long-chain fatty acids protein 4 (ELOVL4) variants. Parkinsonism and severe early cognitive impairment are uncommon, and frameshift variants remain poorly characterized. Patient concerns: A 35-year-old man presented with a 5-year history of progressive cognitive decline, bradykinesia, resting tremor, dysarthria, gait instability, and severe constipation. Diagnoses: Examination showed bilateral resting tremor, rigidity, limb and gait ataxia, and hyperreflexia. The Movement Disorder Society–Unified Parkinson’s Disease Rating Scale Part III score was 60, and the Scale for the Assessment and Rating of Ataxia score was 21. Cognitive testing showed severe impairment (Mini-Mental State Examination, 10; Montreal Cognitive Assessment, 8). Brain magnetic resonance imaging demonstrated marked cerebellar and generalized cerebral atrophy, and susceptibility-weighted imaging showed reduced dorsolateral nigral hyperintensity. Whole-exome sequencing identified a previously unreported heterozygous ELOVL4 frameshift variant, NM_022726.4:c.766_767delinsG (p.Ile256AlafsTer28). The clinical genetic testing report classified the variant as a variant of uncertain significance. Its predicted truncating effect and the patient’s phenotypic overlap with ELOVL4-related ataxia supported its consideration as a potentially clinically relevant candidate variant. However, Sanger confirmation and family segregation analysis were unavailable. Interventions: The patient received eperisone hydrochloride, levodopa/benserazide, piribedil prolonged-release tablets, adenosyl cobalamin, and vitamin B1. Outcomes: During 1 year of telephone and video follow-up, he reported mild improvement in tremor, gait difficulty, and rigidity, whereas dysarthria, slowing of eye movements, and constipation worsened. Repeat standardized assessments were unavailable. Lessons: This case describes a previously unreported ELOVL4 frameshift variant in a patient with cerebellar ataxia, parkinsonism, severe cognitive impairment, and autonomic dysfunction. Genetic testing may facilitate differentiation of hereditary ataxia from atypical degenerative syndromes. Additional molecular validation, segregation analysis, and functional studies are required to establish pathogenicity and genotype–phenotype relationships.