Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals

Saida K 1 , Maroofian R 2 , Sengoku T 3 , Mitani T 4 , Pagnamenta AT 5 , Marafi D 6 Show all authors , Zaki MS 7 , O'Brien TJ 8 , Karimiani EG 9 , Kaiyrzhanov R 2 , Takizawa M 1 , Ohori S 1 , Leong HY 10 , Akay G 4 , Galehdari H 11 , Zamani M 11 , Romy R 12 , Carroll CJ 12 , Toosi MB 13 , Ashrafzadeh F 14 , Imannezhad S 15 , Malek H 16 , Ahangari N 16 , Tomoum H 17 , Gowda VK 18 , Srinivasan VM 18 , Murphy D 19 , Dominik N 2 , Elbendary HM 7 , Rafat K 7 , Yilmaz S 20 , Kanmaz S 20 , Serin M 20 , Krishnakumar D 21 , Gardham A 21 , Maw A 22 , Rao TS 23 , Alsubhi S 24 , Srour M 25 , Buhas D 26 , Jewett T 27 , Goldberg RE 27 , Shamseldin H 28 , Frengen E 29 , Misceo D 29 , Strømme P 30 , Magliocco Ceroni JR 31 , Kim CA 31 , Yesil G 32 , Sengenc E 33 , Guler S 34 , Hull M 35 , Parnes M 35 , Aktas D 36 , Anlar B 37 , Bayram Y 38 , Pehlivan D 39 , Posey JE 4 , Alavi S 40 , Madani Manshadi SA 41 , Alzaidan H 42 , Al-Owain M 42 , Alabdi L 43 , Abdulwahab F 28 , Sekiguchi F 1 , Hamanaka K 1 , Fujita A 1 , Uchiyama Y 44 , Mizuguchi T 1 , Miyatake S 45 , Miyake N 46 , Elshafie RM 47 , Salayev K 48 , Guliyeva U 49 , Alkuraya FS 50 , Gleeson JG 51 , Monaghan KG 52 , Langley KG 52 , Yang H 52 , Motavaf M 53 , Safari S 53 , Alipour M 54 , Ogata K 3 , Brown AEX 8 , Lupski JR 55 , Houlden H 2 , Matsumoto N 56

Affiliations 

  • 1 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • 2 Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
  • 3 Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
  • 5 NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
  • 6 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait
  • 7 Department of Clinical Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
  • 8 MRC London Institute of Medical Sciences, London, United Kingdom; Faculty of Medicine, Institute of Clinical Sciences, Imperial College London, London, United Kingdom
  • 9 Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, United Kingdom; Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran
  • 10 Genetics Department, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
  • 11 Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
  • 12 Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, United Kingdom
  • 13 Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
  • 14 Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  • 15 Department of Pediatric Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  • 16 Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
  • 17 Department of Pediatrics, Ain Shams University, Cairo, Egypt
  • 18 Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India
  • 19 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
  • 20 Division of Pediatric Neurology, Department of Pediatrics, Ege University Faculty of Medicine, Izmir, Turkey
  • 21 North West Thames Regional Genetics Service, Northwick Park Hospital, London, United Kingdom
  • 22 Department of Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
  • 23 Department of Paediatrics, Luton and Dunstable University Hospital, Luton, United Kingdom
  • 24 Division of Pediatric Neurology, Departments of Pediatrics, McGill University, Montreal, Quebec, Canada
  • 25 Division of Pediatric Neurology, Departments of Pediatrics, McGill University, Montreal, Quebec, Canada; Research Institute of the McGill University Health Center (MUHC), Montreal, Quebec, Canada
  • 26 Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Center (MUHC), Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada
  • 27 Department of Pediatrics, Section on Medical Genetics, Wake Forest University School of Medicine, Winston-Salem, NC
  • 28 Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  • 29 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway
  • 30 Division of Pediatric and Adolescent Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
  • 31 Genetic Unit, Instituto da Crianca, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
  • 32 Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
  • 33 Department of Pediatric Neurology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
  • 34 Department of Child Neurology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
  • 35 Texas Children's Hospital, Houston, TX
  • 36 Damagen Genetic Diagnostic Center, Ankara, Turkey
  • 37 Department of Pediatric Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey
  • 38 Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
  • 39 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Texas Children's Hospital, Houston, TX; Division of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX
  • 40 Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
  • 41 Meybod Genetic Research Center, Meybod, Yazd, Iran
  • 42 Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  • 43 Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
  • 44 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan
  • 45 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Japan
  • 46 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
  • 47 Kuwait Medical Genetic Centre, Ministry of Health, Kuwait
  • 48 Department of Neurology, Azerbaijan Medical University, Baku, Azerbaijan
  • 49 MediClub Hospital, Baku, Azerbaijan
  • 50 Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
  • 51 Department of Neurosciences, University of California San Diego, San Diego, CA; Rady Children's Institute for Genomic Medicine, San Diego, CA
  • 52 GeneDx, Gaithersburg, MD
  • 53 Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • 54 Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
  • 55 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Texas Children's Hospital, Houston, TX; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Baylor College of Medicine, Houston, TX
  • 56 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address: [email protected]
Genet Med, 2023 Jan;25(1):90-102.
PMID: 36318270 DOI: 10.1016/j.gim.2022.09.010

Abstract

PURPOSE: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype-phenotype correlations in individuals with biallelic SLC18A2 variants.

METHODS: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype-phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm- and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies.

RESULTS: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global developmental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involvement (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities.

CONCLUSION: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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