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Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.

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.

SUBMITTER: Donkervoort S

PROVIDER: S-EPMC7959540 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.

Donkervoort Sandra S Mohassel Payam P Laugwitz Lucia L Zaki Maha S MS Kamsteeg Erik-Jan EJ Maroofian Reza R Chao Katherine R KR Verschuuren-Bemelmans Corien C CC Horber Veronka V Fock Annemarie J M AJM McCarty Riley M RM Jain Minal S MS Biancavilla Victoria V McMacken Grace G Nalls Matthew M Voermans Nicol C NC Elbendary Hasnaa M HM Snyder Molly M Cai Chunyu C Lehky Tanya J TJ Stanley Valentina V Iannaccone Susan T ST Foley A Reghan AR Lochmüller Hanns H Gleeson Joseph J Houlden Henry H Haack Tobias B TB Horvath Rita R Bönnemann Carsten G CG

American journal of medical genetics. Part A 20200810 10

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 imp ...[more]

PMID: 32776697

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Project description:Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.

Dataset Information

Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.

Publications

Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.

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