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Title: | Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals |
Authors: | SAIDA, Ken; MAROOTAIN, Reza; SENGOKU, Toru; MITANI, Tadahiro; PAGNAMENTA, Alistair T.; MARAFI, Dana; ZAKI, Maha S.; O'BRIAN, 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; STROMME, Petter; CERONI, Jose Ricardo Magliocco; KIM, Chong Ae; YESIL, Gozde; SENGENC, Esma; GULER, Serhat; HULL, Mariam; PARNES, Mered; AKTAS, Dilek; ANLAR, Banu; BAYRAM, Yavuz; PEHLIVAN, Davut; POSEY, Jennifer E.; ALAYI, Shahryar; MANSHADI, Seyed Ali Madani; 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, Andre E. X.; LUPSKI, James R.; HOULDEN, Henry; MATSUMOTO, Naomichi |
Citation: | GENETICS IN MEDICINE, v.25, n.1, p.90-102, 2023 |
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 develop-mental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involve-ment (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.(c) 2022 American College of Medical Genetics and Genomics. |
Appears in Collections: | Artigos e Materiais de Revistas Científicas - FM/MPE Artigos e Materiais de Revistas Científicas - LIM/36 |
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