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

Ken Saida; Reza Maroofian; Toru Sengoku; Tadahiro Mitani; Alistair T. Pagnamenta; Dana Marafi; Maha S. Zaki; Thomas J. O’Brien; Ehsan Ghayoor Karimiani; Rauan Kaiyrzhanov; Marina Takizawa; Sachiko Ohori; Huey Yin Leong; Gulsen Akay; Hamid Galehdari; Mina Zamani; Ratna Romy; Christopher J. Carroll; Mehran Beiraghi Toosi; Farah Ashrafzadeh; Shima Imannezhad; Hadis Malek; Najmeh Ahangari; Hoda Tomoum; Vykuntaraju K. Gowda; Varunvenkat M. Srinivasan; David Murphy; Natalia Dominik; Hasnaa M. Elbendary; Karima Rafat; Sanem Yilmaz; Seda Kanmaz; Mine Serin; Deepa Krishnakumar; Alice Gardham; Anna Maw; Tekki Sreenivasa Rao; Sarah Alsubhi; Myriam Srour; Daniela Buhas; Tamison Jewett; Rachel E. Goldberg; Hanan Shamseldin; Eirik Frengen; Doriana Misceo; Petter Strømme; José Ricardo Magliocco Ceroni; Chong Ae Kim; Gozde Yesil; Esma Sengenc; Serhat Guler; Mariam Hull; Mered Parnes; Dilek Aktas; Banu Anlar; Yavuz Bayram; Davut Pehlivan; Jennifer E. Posey; Shahryar Alavi; Seyed Ali Madani Manshadi; Hamad Alzaidan; Mohammad Al-Owain; Lama Alabdi; Ferdous Abdulwahab; Futoshi Sekiguchi; Kohei Hamanaka; Atsushi Fujita; Yuri Uchiyama; Takeshi Mizuguchi; Satoko Miyatake; Noriko Miyake; Reem M. Elshafie; Kamran Salayev; Ulviyya Guliyeva; Fowzan S. Alkuraya; Joseph G. Gleeson; Kristin G. Monaghan; Katherine G. Langley; Hui Yang; Mahsa Motavaf; Saeid Safari; Mozhgan Alipour; Kazuhiro Ogata; André E.X. Brown; James R. Lupski; Henry Houlden; Naomichi Matsumoto

doi:10.1016/j.gim.2022.09.010

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

Journal article

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

Ken Saida, Reza Maroofian, Toru Sengoku, Tadahiro Mitani, Alistair T. Pagnamenta, Dana Marafi, Maha S. Zaki, Thomas J. O’Brien, Ehsan Ghayoor Karimiani, Rauan Kaiyrzhanov, …

Genetics in medicine, Vol.25(1), pp.90-102

01/2023

DOI: https://doi.org/10.1016/j.gim.2022.09.010

PMID: 36318270

Abstract

Brain monoamine vesicular transport disease

Dopamine agonist

Dystonia

SLC18A2

VMAT2

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. 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. 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. These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders. [Display omitted]

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Title: Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals
Creators - without role: Ken Saida - Yokohama City University
Reza Maroofian - UCL Australia
Toru Sengoku - Yokohama City University
Tadahiro Mitani - Baylor College of Medicine
Alistair T. Pagnamenta - University of Oxford
Dana Marafi - Baylor College of Medicine
Maha S. Zaki - Department of Clinical Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
Thomas J. O’Brien - MRC London Institute of Medical Sciences
Ehsan Ghayoor Karimiani - St George's, University of London
Rauan Kaiyrzhanov - Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
Marina Takizawa - Yokohama City University
Sachiko Ohori - Yokohama City University
Huey Yin Leong - Hospital Kuala Lumpur
Gulsen Akay - Baylor College of Medicine
Hamid Galehdari - Shahid Chamran University of Ahvaz
Mina Zamani - Shahid Chamran University of Ahvaz
Ratna Romy - St George's, University of London
Christopher J. Carroll - St George's, University of London
Mehran Beiraghi Toosi - Mashhad University of Medical Sciences
Farah Ashrafzadeh - Mashhad University of Medical Sciences
Shima Imannezhad - Mashhad University of Medical Sciences
Hadis Malek - Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
Najmeh Ahangari - Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
Hoda Tomoum - Ain Shams University
Vykuntaraju K. Gowda - Indira Gandhi Institute of Child Health
Varunvenkat M. Srinivasan - Indira Gandhi Institute of Child Health
David Murphy - University College London
Natalia Dominik - Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
Hasnaa M. Elbendary - Department of Clinical Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
Karima Rafat - Department of Clinical Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
Sanem Yilmaz - Ege University
Seda Kanmaz - Ege University
Mine Serin - Ege University
Deepa Krishnakumar - Northwick Park Hospital
Alice Gardham - Northwick Park Hospital
Anna Maw - Cambridge University Hospitals NHS Foundation Trust
Tekki Sreenivasa Rao - Luton and Dunstable Hospital
Sarah Alsubhi - McGill University
Myriam Srour - McGill University
Daniela Buhas - McGill University
Tamison Jewett - Wake Forest University
Rachel E. Goldberg - Wake Forest University
Hanan Shamseldin - Genomic
Eirik Frengen - Oslo University Hospital
Doriana Misceo - Oslo University Hospital
Petter Strømme - Oslo University Hospital
José Ricardo Magliocco Ceroni - Universidade de São Paulo
Chong Ae Kim - Universidade de São Paulo
Gozde Yesil - Istanbul University
Esma Sengenc - Faculty
Serhat Guler - Istanbul University
Mariam Hull - Texas Children’s Hospital, Houston, TX
Mered Parnes - Texas Children’s Hospital, Houston, TX
Dilek Aktas - Ankara
Banu Anlar - Hacettepe University
Yavuz Bayram - Children's Hospital of Philadelphia
Davut Pehlivan - Baylor College of Medicine
Jennifer E. Posey - Baylor College of Medicine
Shahryar Alavi - University of Isfahan
Seyed Ali Madani Manshadi - Meybod Genetic Research Center, Meybod, Yazd, Iran
Hamad Alzaidan - Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Mohammad Al-Owain - Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Lama Alabdi - Genomic
Ferdous Abdulwahab - Genomic
Futoshi Sekiguchi - Yokohama City University
Kohei Hamanaka - Yokohama City University
Atsushi Fujita - Yokohama City University
Yuri Uchiyama - Yokohama City University
Takeshi Mizuguchi - Yokohama City University
Satoko Miyatake - Yokohama City University
Noriko Miyake - Yokohama City University
Reem M. Elshafie - Kuwait Medical Genetic Centre, Ministry of Health, Kuwait
Kamran Salayev - Azerbaijan Medical University
Ulviyya Guliyeva - MediClub Hospital, Baku, Azerbaijan
Fowzan S. Alkuraya - Genomic
Joseph G. Gleeson - University of California, San Diego
Kristin G. Monaghan - GeneDx, Gaithersburg, MD
Katherine G. Langley - GeneDx, Gaithersburg, MD
Hui Yang - GeneDx, Gaithersburg, MD
Mahsa Motavaf - Shahid Beheshti University of Medical Sciences
Saeid Safari - Shahid Beheshti University of Medical Sciences
Mozhgan Alipour - Shahid Beheshti University of Medical Sciences
Kazuhiro Ogata - Yokohama City University
André E.X. Brown - MRC London Institute of Medical Sciences
James R. Lupski - Baylor College of Medicine
Henry Houlden - UCL Australia
Naomichi Matsumoto - Yokohama City University
Publication Details: Genetics in medicine, Vol.25(1), pp.90-102
Publisher: Elsevier Inc
Identifiers: 9913411508331
Academic Unit: King Faisal University; Alfaisal University
Language: English
Resource Type: Journal article