2. Academic Validation
  3. An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

  • Genet Med. 2021 Apr;23(4):740-750. doi: 10.1038/s41436-020-01027-3.
Sacha Ferdinandusse 1,  Kirsty McWalter 2,  Heleen Te Brinke 3,  Lodewijk IJlst 3,  Petra M Mooijer 3,  Jos P N Ruiter 3,  Alida E M van Lint 3,  Mia Pras-Raves 3 4 5,  Eric Wever 3 4 5,  Francisca Millan 2,  Maria J Guillen Sacoto 2,  Amber Begtrup 2,  Mark Tarnopolsky 6,  Lauren Brady 6,  Roger L Ladda 7,  Susan L Sell 7,  Catherine B Nowak 8,  Jessica Douglas 8,  Cuixia Tian 9,  Elizabeth Ulm 10,  Seth Perlman 11,  Arlene V Drack 12,  Karen Chong 13,  Nicole Martin 13,  Jennifer Brault 14,  Elly Brokamp 14,  Camilo Toro 15,  William A Gahl 15,  Ellen F Macnamara 15,  Lynne Wolfe 15,  Undiagnosed Diseases Network,  Quinten Waisfisz 16,  Petra J G Zwijnenburg 16,  Alban Ziegler 17,  Magalie Barth 17,  Rosemarie Smith 18,  Sara Ellingwood 18,  Deborah Gaebler-Spira 19,  Somayeh Bakhtiari 20,  Michael C Kruer 20,  Antoine H C van Kampen 5 21,  Ronald J A Wanders 3,  Hans R Waterham 3,  David Cassiman 22,  Frédéric M Vaz 23
Affiliations

Affiliations

  • 1 Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands. [email protected].
  • 2 GeneDx, Gaithersburg, MD, USA.
  • 3 Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
  • 4 Core Facility Metabolomics, Amsterdam UMC, Amsterdam, The Netherlands.
  • 5 Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • 6 Department of Pediatrics, McMaster University Children's Hospital, Hamilton, ON, Canada.
  • 7 Department of Pediatrics, Penn State Children's Hospital, Hershey, PA, USA.
  • 8 The Feingold Center for Children, Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
  • 9 Division of Neurology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 10 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 11 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
  • 12 Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA.
  • 13 Mount Sinai Hospital, Department of Obstetrics and Gynecology, Prenatal Diagnosis and Medical Genetics Program, Toronto, ON, Canada.
  • 14 Vanderbilt University Medical Center, Department of Pediatrics, Nashville, TN, USA.
  • 15 NIH Undiagnosed Diseases Program, Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
  • 16 Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • 17 Genetic department, University Hospital Angers, Angers, France.
  • 18 Division of Genetics, Department of Pediatrics, Maine Medical Center, Portland, ME, USA.
  • 19 Feinberg Northwestern University School of Medicine, Shirley Ryan Ability Lab, Chicago, IL, USA.
  • 20 Barrow Neurological Institute, Phoenix Children's Hospital and University of Arizona College of Medicine, Phoenix, AZ, USA.
  • 21 Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
  • 22 Department of Gastroenterology-Hepatology, Metabolic Center, University Hospitals Leuven, Leuven, Belgium.
  • 23 Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands. [email protected].
PMID: 33239752 DOI: 10.1038/s41436-020-01027-3
Abstract

Purpose: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).

Methods: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 Enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.

Results: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.

Conclusion: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.

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