Saida, K;
Maroofian, R;
Sengoku, T;
Mitani, T;
Pagnamenta, AT;
Marafi, D;
Zaki, MS;
... Matsumoto, N; + view all
(2023)
Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals.
Genetics in Medicine
, 25
(1)
pp. 90-102.
10.1016/j.gim.2022.09.010.
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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.
| Type: | Article |
|---|---|
| Title: | Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.gim.2022.09.010 |
| Publisher version: | http://dx.doi.org/10.1016/j.gim.2022.09.010 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Brain monoamine vesicular transport disease, Dopamine agonist, Dystonia, SLC18A2, VMAT2, Humans, Animals, Rats, Caenorhabditis elegans, Vesicular Monoamine Transport Proteins, Brain Diseases, Movement Disorders, Dystonia, Amines, Brain |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10184407 |
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