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. 2023 Jan;25(1):90-102.
doi: 10.1016/j.gim.2022.09.010. Epub 2022 Oct 31.

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
Free article

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

Ken Saida et al. Genet Med. 2023 Jan.
Free article

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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