Donkervoort, S;
Mohassel, P;
Laugwitz, L;
Zaki, MS;
Kamsteeg, E-J;
Maroofian, R;
Chao, KR;
Verschuuren-Bemelmans, CC;
Horber, V;
Fock, AJM;
et al.
Donkervoort, S; Mohassel, P; Laugwitz, L; Zaki, MS; Kamsteeg, E-J; Maroofian, R; Chao, KR; Verschuuren-Bemelmans, CC; Horber, V; Fock, AJM; McCarty, RM; Jain, MS; Biancavilla, V; McMacken, G; Nalls, M; Voermans, NC; Elbendary, HM; Snyder, M; Cai, C; Lehky, TJ; Stanley, V; Iannaccone, ST; Foley, AR; Lochmüller, H; Gleeson, J; Houlden, H; Haack, TB; Horvath, R; Bönnemann, CG
(2020)
Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.
Am J Med Genet A, 182 (10).
pp. 2272-2283.
ISSN 1552-4833
https://doi.org/10.1002/ajmg.a.61765
SGUL Authors: Maroofian, Reza
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Abstract
Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin-2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS-disease gene and expands its clinical and genetic spectrum to include recessive loss-of-function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.
Item Type: |
Article
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Additional Information: |
This is the peer reviewed version of the following article: Donkervoort, S, Mohassel, P, Laugwitz, L, et al. Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome. Am J Med Genet Part A. 2020; 182A: 2272– 2283, which has been published in final form at https://doi.org/10.1002/ajmg.a.61765. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited. |
Keywords: |
SYT2, congenital myasthenic syndrome, neuromuscular junction, presynaptic CMS, synaptotagmins, Adolescent, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Humans, Male, Muscle Hypotonia, Muscle Weakness, Mutation, Missense, Myasthenic Syndromes, Congenital, Pedigree, Phenotype, Synaptic Transmission, Synaptotagmin II, Humans, Muscle Weakness, Muscle Hypotonia, Myasthenic Syndromes, Congenital, Genetic Predisposition to Disease, Pedigree, Synaptic Transmission, Phenotype, Mutation, Missense, Adolescent, Child, Child, Preschool, Female, Male, Synaptotagmin II, congenital myasthenic syndrome, neuromuscular junction, presynaptic CMS, synaptotagmins, SYT2, SYT2, congenital myasthenic syndrome, neuromuscular junction, presynaptic CMS, synaptotagmins, 1103 Clinical Sciences, 0604 Genetics |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
Am J Med Genet A |
ISSN: |
1552-4833 |
Language: |
eng |
Dates: |
Date | Event |
---|
15 September 2020 | Published | 10 August 2020 | Published Online | 13 June 2020 | Accepted |
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Publisher License: |
Publisher's own licence |
Projects: |
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PubMed ID: |
32776697 |
Web of Science ID: |
WOS:000557415300001 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/113592 |
Publisher's version: |
https://doi.org/10.1002/ajmg.a.61765 |
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