Synaptotagmins are a family of synaptic proteins that are primarily involved in calcium-regulated synaptic vesicle exocytosis.  While the best characterized member of this family is synaptotagmin 1 (Syt 1), synaptotagmin 2 (Syt 2) is the isoform expressed at the mammalian neuromuscular junction.

Defects in SYT2 have been linked to a presynaptic CMS and motor neuropathies. However, to date only dominant forms of the disease have been described.

The affected 2 year old girl had profound weakness and areflexia with moderate bulbar deficit. Repetitive nerve stimulation revealed an extreme reduction of compound muscle action potential amplitudes at rest, with a striking facilitation followed by a progressive decline at fast stimulation rates. These findings were reminiscent, but not identical to those seen in the Lambert Eaton Myasthenic Syndrome.  3,4 diaminopyridine and pyridostigmine were effective to ameliorate muscle fatigue, but albuterol was ineffective. Muscle biopsy showed muscle fiber type disproportion and a fiber type 1 predominance. WES revealed the homozygous mutation c.1191delG, p.Arg397Serfs*37 in SYT2, which was present in the heterozygous state in each one of her healthy parents.

Modeling of the mutation demonstrated that Arg397Serfs*37 disrupts a highly conserved amino acid sequence at the bottom face of the C2B domain not directly involved in calcium-binding, but crucial for synaptotagmin-SNARE interaction and exocytosis.

A homozygous mutation in SYT2 that alters a domain of synaptotagmin 2  not directly involved in calcium-binding, but essential for synaptotagmin-SNARE interaction, results in a CMS. This CMS variant is severe and manifests early in life, but it can be significantly ameliorated by 3,4 diaminopyridine and pyridostigmine.