Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals
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Authors
Saida, K
Maroofian, R
Sengoku, T
Mitani, T
Pagnamenta, A.T
Marafi, D
Zaki, M.S
O'Brien, T.J
Karimiani, E.G
Kaiyrzhanov, R
Issue Date
2023
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Scientific Paper
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Research Subject Categories::MEDICINE::Dermatology and venerology,clinical genetics, internal medicine::Internal medicine::Paediatric medicine , Research Subject Categories::MEDICINE::Dermatology and venerology,clinical genetics, internal medicine::Clinical genetics
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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.
Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
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Saida K, Maroofian R, Sengoku T, et al. Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals. Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2023 Jan;25(1):90-102. DOI: 10.1016/j.gim.2022.09.010. PMID: 36318270.
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https://www.sciencedirect.com/science/article/pii/S1098360022009480?via%3Dihub