<p>Hypomyelinating spastic dyskinesia and ichthyosis caused by a homozygous splice site mutation leading to exon skipping in ELOVL1</p>

Abstract

Introduction: Next generation sequencing technologies allow detection of very rare pathogenic gene variants and uncover cerebral palsy. Herein, we describe two siblings with cerebral palsy due to ELOVL1 splice site mutation in autosomal recessive manner. ELOVL1 catalyzes fatty acid elongation to produce very long-chain fatty acids (VLCFAs; > C21), most of which are components of sphingolipids such as ceramides and sphingomyelins. Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies & nbsp;Methods: We have studied a consanguineous family with whole exome sequencing (WES) and performed in depth analysis of cryptic splicing on the molecular level using RNA. Comprehensive analysis of ceramides in the skin stratum corneum of patients using liquid chromatography-tandem mass spectrometry (LC-MS/MS). ELOVL1 protein structure was computationally modelled.& nbsp;Results: The novel c.376-2A > G (ENST00000372458.8) homozygous variant in the affected siblings causes exon skipping. Comprehensive analysis of ceramides in the skin stratum corneum of patients using LC-MS/MS demonstrated significant shortening of fatty acid moieties and severe reduction in the levels of acylceramides.& nbsp;& nbsp;Discussion:It has recently been shown that disease associated variants ofELOVL1segregate in an autosomal dominant manner.However, our study for the first time demonstrates an alternative autosomal recessive inheritance model forELOVL1. In conclu-sion, we suggest that in ultra-rare diseases, being able to identify the inheritance patterns of the disease-associated gene or genes canbe an important guide to identifying the molecular mechanism of genetic cerebral palsy. (C) 2022 The Japanese Society of Child Neurology Published by Elsevier B.V. All rights reserved.