First report of a VAMP1 associated pre-synaptic congenital myasthenic syndrome from South-East Asia

Abstract

Biallelic mutations in VAMP1, a member of synaptobrevin family have been reported previously to cause a rare form of pre-synaptic congenital myasthenic syndrome (CMS) in two middle-eastern families. We present a case of pre-synaptic CMS from Southern India with VAMP1 novel mutation identified by clinical exome sequencing (CES).Infomed consent obtained. A 5-year-old girl born to consanguineous parentage and delivered by LSCS for absent labour pains, developed respiratory distress and feeding difficulty postnatally requiring oxygen supplementation. Profound hypotonia, muscle weakness and ophthalmoparesis was observed during neonatal period. After 9 months of ryle’s tube feeding, percutaneous endoscopic gastrostomy (PEG) was performed. Fatigable ptosis, hypophonia and frequent lower respiratory tract infections were noticed from 2 years of age. She did not attain motor mile stones but attained normal mental milestones. Examination revealed myopathic facies, ophthalmoparesis, bifacial and bulbar weakness, contractures at ankle and knee, kyphoscoliosis and areflexia. Her elder sister died in neonatal period following meconium aspiration and respiratory distress. Her maternal cousin, a 12-year-old boy is reported to have fatiguable ocular, limb and bulbar weakness. Creatine kinase level was 366 IU/L. Child did not co-operate for repetitive nerve stimulation test. CES revealed a homozygous frameshift mutation c.66delT (p.Gly23AlafsTer6) in exon 2 of VAMP1 resulting in loss of v-SNARE domain important for vesicle docking at NMJ. Child showed mild improvement in neck, truncal movements and voice after 2 weeks of oral salbutamol and pyridostigmine. This is the first case report of VAMP1 pre-synaptic CMS from south-east Asia.