Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.
Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.
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DOI：
10.1002/ajmg.a.61765
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Bönnemann CG
中科院分区：
文献类型：
--
作者：
Donkervoort S;Mohassel P;Laugwitz L;Zaki MS;Kamsteeg EJ;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
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, and with electrodiagnostic findings 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.
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影响因子：
2
作者：
Maselli, Ricardo A.;van der Linden, Helio, Jr.;Ferns, Michael
通讯作者：
Ferns, Michael
影响因子：
5.3
作者：
Nagy, G;Kim, JH;Sorensen, JB
通讯作者：
Sorensen, JB
影响因子：
3.3
作者：
Nicole S;Azuma Y;Bauché S;Eymard B;Lochmüller H;Slater C
通讯作者：
Slater C
影响因子：
2.3
作者：
Hogrel, Jean-Yves
通讯作者：
Hogrel, Jean-Yves
影响因子：
3.1
作者：
Montes-Chinea, Nataly, I;Guan, Zhuo;Saporta, Mario A.
通讯作者：
Saporta, Mario A.