Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals
Ken Saida 1, Reza Maroofian 2, Toru Sengoku 3, Tadahiro Mitani 4, Alistair T Pagnamenta 5, Dana Marafi 6, Maha S Zaki 7, Thomas J O'Brien 8, Ehsan Ghayoor Karimiani 9, Rauan Kaiyrzhanov 2, Marina Takizawa 1, Sachiko Ohori 1, Huey Yin Leong 10, Gulsen Akay 4, Hamid Galehdari 11, Mina Zamani 11, Ratna Romy 12, Christopher J Carroll 12, Mehran Beiraghi Toosi 13, Farah Ashrafzadeh 14, Shima Imannezhad 15, Hadis Malek 16, Najmeh Ahangari 16, Hoda Tomoum 17, Vykuntaraju K Gowda 18, Varunvenkat M Srinivasan 18, David Murphy 19, Natalia Dominik 2, Hasnaa M Elbendary 7, Karima Rafat 7, Sanem Yilmaz 20, Seda Kanmaz 20, Mine Serin 20, Deepa Krishnakumar 21, Alice Gardham 21, Anna Maw 22, Tekki Sreenivasa Rao 23, Sarah Alsubhi 24, Myriam Srour 25, Daniela Buhas 26, Tamison Jewett 27, Rachel E Goldberg 27, Hanan Shamseldin 28, Eirik Frengen 29, Doriana Misceo 29, Petter Strømme 30, José Ricardo Magliocco Ceroni 31, Chong Ae Kim 31, Gozde Yesil 32, Esma Sengenc 33, Serhat Guler 34, Mariam Hull 35, Mered Parnes 35, Dilek Aktas 36, Banu Anlar 37, Yavuz Bayram 38, Davut Pehlivan 39, Jennifer E Posey 4, Shahryar Alavi 40, Seyed Ali Madani Manshadi 41, Hamad Alzaidan 42, Mohammad Al-Owain 42, Lama Alabdi 43, Ferdous Abdulwahab 28, Futoshi Sekiguchi 1, Kohei Hamanaka 1, Atsushi Fujita 1, Yuri Uchiyama 44, Takeshi Mizuguchi 1, Satoko Miyatake 45, Noriko Miyake 46, Reem M Elshafie 47, Kamran Salayev 48, Ulviyya Guliyeva 49, Fowzan S Alkuraya 50, Joseph G Gleeson 51, Kristin G Monaghan 52, Katherine G Langley 52, Hui Yang 52, Mahsa Motavaf 53, Saeid Safari 53, Mozhgan Alipour 54, Kazuhiro Ogata 3, André E X Brown 8, James R Lupski 55, Henry Houlden 2, Naomichi Matsumoto 56
Affiliations
Affiliations
1Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
2Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
3Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
5NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait.
7Department of Clinical Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
8MRC London Institute of Medical Sciences, London, United Kingdom; Faculty of Medicine, Institute of Clinical Sciences, Imperial College London, London, United Kingdom.
9Molecular 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.
10Genetics Department, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia.
11Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
12Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, United Kingdom.
13Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
14Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
15Department of Pediatric Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
16Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran.
17Department of Pediatrics, Ain Shams University, Cairo, Egypt.
18Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.
19Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
20Division of Pediatric Neurology, Department of Pediatrics, Ege University Faculty of Medicine, Izmir, Turkey.
21North West Thames Regional Genetics Service, Northwick Park Hospital, London, United Kingdom.
22Department of Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
23Department of Paediatrics, Luton and Dunstable University Hospital, Luton, United Kingdom.
24Division of Pediatric Neurology, Departments of Pediatrics, McGill University, Montreal, Quebec, Canada.
25Division of Pediatric Neurology, Departments of Pediatrics, McGill University, Montreal, Quebec, Canada; Research Institute of the McGill University Health Center (MUHC), Montreal, Quebec, Canada.
26Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Center (MUHC), Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
27Department of Pediatrics, Section on Medical Genetics, Wake Forest University School of Medicine, Winston-Salem, NC.
28Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
29Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
30Division of Pediatric and Adolescent Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway.
31Genetic Unit, Instituto da Crianca, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil.
32Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
33Department of Pediatric Neurology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey.
34Department of Child Neurology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.
35Texas Children's Hospital, Houston, TX.
36Damagen Genetic Diagnostic Center, Ankara, Turkey.
37Department of Pediatric Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
38Division 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.
39Department 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.
40Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
41Meybod Genetic Research Center, Meybod, Yazd, Iran.
42Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
43Department 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.
44Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan.
45Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Japan.
46Department 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.
47Kuwait Medical Genetic Centre, Ministry of Health, Kuwait.
48Department of Neurology, Azerbaijan Medical University, Baku, Azerbaijan.
49MediClub Hospital, Baku, Azerbaijan.
50Department 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.
51Department of Neurosciences, University of California San Diego, San Diego, CA; Rady Children's Institute for Genomic Medicine, San Diego, CA.
52GeneDx, Gaithersburg, MD.
53Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
54Functional 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.
55Department 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.
56Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address: naomat@yokohama-cu.ac.jp.
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.
Keywords: Brain monoamine vesicular transport disease; Dopamine agonist; Dystonia; SLC18A2; VMAT2.
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