Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis

BACKGROUND: Very long chain fatty acids (VLCFAs) are an integral component of myelin and the epidermal water barrier. Variants in genes encoding enzymes responsible for catalyzing the first and rate limiting step in the production of VLCFAs, elongation of VLCFAs (ELOVLs), underlie a novel group of metabolic disorders. OBJECTIVES: The goal was to describe the clinical phenotype and disturbance in VLCFA metabolism associated with variants in the ELOV1 gene. METHODS: The following methods were employed: Exome sequencing, clinical phenotyping, magnetic resonance imaging (MRI), metabolomics, liquid chromatography-tandem mass spectrometry, fatty acid elongation assay. RESULTS: We, here, describe seven patients with autosomal recessive variants in ELOVL1. Common clinical features included ichthyosis (5/7), developmental delay (7/7), progressive spasticity (7/7), nystagmus (5/6), and a complex movement disorder characterized by pronounced head tremor (7/7), myoclonus (6/7), and dysarthria (6/6). Brain MRI revealed non-progressive hypomyelination (6/6) and hypoplasia of the corpus callosum (5/6). Plasma VLCFA analysis in one patient showed reduced concentrations of C24:0 and C26:0. Biochemical analysis of fibroblasts from this patient revealed elongation defects in VLCFA synthesis and dysregulation of other ELOVL enzymes. CONCLUSIONS: We show that biallelic variants in ELOVL1 are associated with a unique and recognizable phenotype of hypomyelinating leukodystrophy, ichthyosis, and a complex movement disorder including progressive spasticity, head tremor, and myoclonus. Biochemical analyses confirmed a defect in VLCFA synthesis. Variants in genes encoding enzymes involved in the elongation of VLCFAs are a novel group of metabolic disorders with overlapping symptoms. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.