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

Keit Men Wong; Reza Maroofian; Kolja Meier; Susann Diegmann; Tinatin Tkemaladze; Javeria Raza Alvi; Behnoosh Tasharrofi; Stephanie Efthymiou; Alexander Munchau; G Christoph Korenke; Naif Almontashiri; Wafaa Eyaid; Amna Kashgari; Modhi Alotaibi; Jutta Gärtner; Brenda Huppke; Mostafa Asadollahi; Gocha Chikvinidze; Mohammad Keramatipour; Tipu Sultan; Holger Thiele; Peter Nürnberg; Markus H Gräler; Henry Houlden; Peter Huppke

doi:10.1002/mds.30258

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

Mov Disord. 2025 Jul 1. doi: 10.1002/mds.30258. Online ahead of print.

Authors

Keit Men Wong^{1

2

3}, Reza Maroofian⁴, Kolja Meier⁵, Susann Diegmann⁵, Tinatin Tkemaladze^{6

7}, Javeria Raza Alvi⁸, Behnoosh Tasharrofi⁹, Stephanie Efthymiou⁴, Alexander Munchau¹⁰, G Christoph Korenke¹¹, Naif Almontashiri^{12

13}, Wafaa Eyaid^{14

15

16}, Amna Kashgari¹⁶, Modhi Alotaibi¹⁷, Jutta Gärtner⁵, Brenda Huppke^{1

2}, Mostafa Asadollahi⁹, Gocha Chikvinidze¹⁸, Mohammad Keramatipour⁹, Tipu Sultan⁸, Holger Thiele¹⁹, Peter Nürnberg¹⁹, Markus H Gräler^{20

21

22}, Henry Houlden⁴, Peter Huppke^{1

2}

Affiliations

¹ Department of Neuropediatrics, Jena University Hospital, Jena, Germany.
² Center for Rare Diseases, Jena University Hospital, Jena, Germany.
³ School of Pharmacy, University of Wyoming, Laramie, Wyoming, USA.
⁴ Department of Neuromuscular Diseases, Queen Square, Institute of Neurology, University College London, London, United Kingdom.
⁵ Department of Pediatrics and Pediatric Neurology and German Center for Child and Adolescent Health (DZKJ), University Medical Center Göttingen, Georg August University Göttingen, Göttingen, Germany.
⁶ Division of Clinical Genetics, Givi Zhvania Pediatric University Clinic, Tbilisi State Medical University, Tiblisi, Georgia.
⁷ Department of Molecular and Medical Genetics, Tbilisi State Medical University, Tbilisi, Georgia.
⁸ Department of Pediatric Neurology, Children's Hospital and Institute of Child Health, Lahore, Pakistan.
⁹ Watson Genetic Laboratory, Tehran, Iran.
¹⁰ Institute of Systems Motor Science and Center for Rare Diseases, University of Lübeck, Lübeck, Germany.
¹¹ Section of Neonatology and Pediatric Intensive Care, Department of Pediatrics, School VI-School of Medicine and Health Sciences, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany.
¹² College of Applied Medical Sciences and Center for Genetics and Inherited Diseases, Taibah University, Madinah, Kingdom of Saudi Arabia.
¹³ Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
¹⁴ Department of Clinical Genetics and Precision Medicine, King Abdulaziz Medical City, Riyadh, Kingdom of Saudi Arabia.
¹⁵ Department of Medical Genomics, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia.
¹⁶ College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia.
¹⁷ Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
¹⁸ Department of Child Neurology, I. Tsitsishvili Children's New Clinic, Tbilisi, Georgia.
¹⁹ Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
²⁰ Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
²¹ Center for Molecular Biomedicine (CMB), Jena University Hospital, Jena, Germany.
²² Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.

PMID: 40590574
DOI: 10.1002/mds.30258

Abstract

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.

Keywords: ELOVL1; head tremor; ichthyosis; leukodystrophy; myoclonus.