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


Clinical Management

Poster Number: 83


Sandra Donkervoort MS, CGC, Payam Mohassel MD, Lucia Laugwitz , Maha Zaki , Erik-Jan Kamsteeg , Reza Maroofian , Katherine Chao , Corien Verschuuren-Bemelmans , Veronka Horber , Annemarie Fock , Riley McCarty , Minal Jain , Victoria Biancavi , Grace McMacken , Matthew Nalls , Nicol Voermans , Hasnaa Elbendary , Molly Snyder , Chunyu Cai , Tanya Lehky MD, Valentina Stanley , Susan Iannaccone , A Reghan Foley MD, PhD, Hanns Lochmüller , Joseph Gleeson MD, Henry Houlden , Tobias Haack , Rita Horvath , Carsten Bönnemann MD


1. National Institutes of Health, 2. NINDS, NIH, 11. National Institutes of Health/National Institute of Neurological Disorders and Stroke, 12. Rehabilitation Medicine Department, Clinical Research Center, NIH, Bethesda, MD, USA, 13. National Institutes of Health, 20. National Institutes of Health, EMG Section, 22. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA, 23. NINDS, NIH, 24. Children’s Hospital of Eastern Ontario Research Institute, 28. NINDS/NIH, Bethesda, MD

Background: 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 (NMJ). 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. An understanding of the underlying molecular mechanism of NMJ dysfunction is imperative for a rational therapeutic choice to be made and to avoid inadvertent worsening of the condition in patients with SYT2-related disease. Objectives: To 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. Results: Given SYT2's role at the presynaptic NMJ, treatment with an acetylcholinesterase inhibitor was pursued in three patients who subsequently showed clinical improvement with increased strength and function. Conclusions: 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.