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

TitleBrain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals.
Publication TypeJournal Article
Year of Publication2023
AuthorsSaida, K, Maroofian, R, Sengoku, T, Mitani, T, Pagnamenta, AT, Marafi, D, Zaki, MS, O'Brien, TJ, Karimiani, EGhayoor, Kaiyrzhanov, R, Takizawa, M, Ohori, S, Leong, HYin, Akay, G, Galehdari, H, Zamani, M, Romy, R, Carroll, CJ, Toosi, MBeiraghi, Ashrafzadeh, F, Imannezhad, S, Malek, H, Ahangari, N, Tomoum, H, Gowda, VK, Srinivasan, VM, Murphy, D, Dominik, N, Elbendary, HM, Rafat, K, Yilmaz, S, Kanmaz, S, Serin, M, Krishnakumar, D, Gardham, A, Maw, A, Rao, TSreenivasa, Alsubhi, S, Srour, M, Buhas, D, Jewett, T, Goldberg, RE, Shamseldin, H, Frengen, E, Misceo, D, Strømme, P, Ceroni, JRicardo Ma, Kim, CAe, Yesil, G, Sengenc, E, Guler, S, Hull, M, Parnes, M, Aktas, D, Anlar, B, Bayram, Y, Pehlivan, D, Posey, JE, Alavi, S, Manshadi, SAli Madani, Alzaidan, H, Al-Owain, M, Alabdi, L, Abdulwahab, F, Sekiguchi, F, Hamanaka, K, Fujita, A, Uchiyama, Y, Mizuguchi, T, Miyatake, S, Miyake, N, Elshafie, RM, Salayev, K, Guliyeva, U, Alkuraya, FS, Gleeson, JG, Monaghan, KG, Langley, KG, Yang, H, Motavaf, M, Safari, S, Alipour, M, Ogata, K, Brown, AEX, Lupski, JR, Houlden, H, Matsumoto, N
JournalGenet Med
Date Published2023 Jan
KeywordsAmines, Animals, Brain, Brain Diseases, Caenorhabditis elegans, Dystonia, Humans, Movement Disorders, Rats, Vesicular Monoamine Transport Proteins

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.

Alternate JournalGenet Med
PubMed ID36318270
Grant ListK08 HG008986 / HG / NHGRI NIH HHS / United States
MC_UP_1102/6 / MRC_ / Medical Research Council / United Kingdom
MR/S005021/1 / MRC_ / Medical Research Council / United Kingdom
/ DH_ / Department of Health / United Kingdom
MC-A658-5TY30 / MRC_ / Medical Research Council / United Kingdom
T32 GM007526 / GM / NIGMS NIH HHS / United States
MR/S01165X/1 / MRC_ / Medical Research Council / United Kingdom
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
G0601943 / MRC_ / Medical Research Council / United Kingdom