Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals.
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Saida Ken, Maroofian Reza, Sengoku Toru, Mitani Tadahiro, Pagnamenta Alistair T, Marafi Dana, Zaki Maha S, O'Brien Thomas J, Karimiani Ehsan Ghayoor, Kaiyrzhanov Rauan, Takizawa Marina, Ohori Sachiko, Leong Huey Yin, Akay Gulsen, Galehdari Hamid, Zamani Mina, Romy Ratna, Carroll Christopher J, Toosi Mehran Beiraghi, Ashrafzadeh Farah, Imannezhad Shima, Malek Hadis, Ahangari Najmeh, Tomoum Hoda, Gowda Vykuntaraju K, Srinivasan Varunvenkat M, Murphy David, Dominik Natalia, Elbendary Hasnaa M, Rafat Karima, Yilmaz Sanem, Kanmaz Seda, Serin Mine, Krishnakumar Deepa, Gardham Alice, Maw Anna, Rao Tekki Sreenivasa, Alsubhi Sarah, Srour Myriam, Buhas Daniela, Jewett Tamison, Goldberg Rachel E, Shamseldin Hanan, Frengen Eirik, Misceo Doriana, Strømme Petter, Magliocco Ceroni José Ricardo, Kim Chong Ae, Yesil Gozde, Sengenc Esma, Guler Serhat, Hull Mariam, Parnes Mered, Aktas Dilek, Anlar Banu, Bayram Yavuz, Pehlivan Davut, Posey Jennifer E, Alavi Shahryar, Madani Manshadi Seyed Ali, Alzaidan Hamad, Al-Owain Mohammad, Alabdi Lama, Abdulwahab Ferdous, Sekiguchi Futoshi, Hamanaka Kohei, Fujita Atsushi, Uchiyama Yuri, Mizuguchi Takeshi, Miyatake Satoko, Miyake Noriko, Elshafie Reem M, Salayev Kamran, Guliyeva Ulviyya, Alkuraya Fowzan S, Gleeson Joseph G, Monaghan Kristin G, Langley Katherine G, Yang Hui, Motavaf Mahsa, Safari Saeid, Alipour Mozhgan, Ogata Kazuhiro, Brown André E X, Lupski James R, Houlden Henry, Matsumoto Naomichi
Аннотация
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.