VP.42 Clinical characteristics, molecular genetics and long-term clinical outcomes in 43 patients with congenital myasthenia syndrome due to RAPSYN mutation

Abstract

Congenital myasthenic syndromes (CMS) are a group of rare inherited disorders of neuromuscular transmission. Rapsyn (receptor-associated protein of the synapse) is a post-synaptic protein that binds to the acetylcholine receptor (AChR) subunits and has a crucial role in AChR clustering at the post synaptic membrane. We describe the clinical characteristics, molecular genetic findings, and long-term clinical outcomes in 43 patients with CMS due to <i>RAPSYN</i> mutations seen at three UK specialist neuromuscular centres. 43 patients (20 females) with confirmed <i>RAPSYN</i> mutations and at least one follow-up visit were included. Median age at last follow up was 18 years (range 4-73 years). Symptoms at onset, included arthrogryposis 41%, ptosis 44%, respiratory involvement 48%, limb weakness/motor delay 67% and feeding difficulties 62%. Recurrent apnoea was the commonest respiratory symptom, 46% required short term and 7% required long-term respiratory support for apnoea management. 32% patients required nasogastric or gastrostomy feeding. Typical pattern of weakness was ptosis, facial weakness, axial, generalised or proximal weakness in limbs. 95% patients had ptosis, 62% patients had a divergent/ convergent squint and ophthalmoplegia was absent in all but one. All patients achieved independent ambulation, median age in 27 patients was 16 months (range 12- 48 months). At last follow up, all but one patient was independently ambulant. At last follow up 25% patients had no CMS features, 37% only ptosis and remainder had mild limb weakness. All patients were on normal oral diet except one who remained on mixture of oral and gastrostomy feeds since childhood. Patients who required long-term respiratory support in childhood were weaned off it successfully and no patient had respiratory crisis after 7 years of age. Except for 2, all patients had N88K mutation (homozygous in 14 patients). All but one patient was on treatment. Pyridostigmine was first line with good response in all treated patients, 28% required additional 3,4 diaminopyridine and 2% salbutamol. Two patients were able to reduce treatment in 2nd/3rd decade. In summary, this is the largest cohort of RAPSYN patients with clinical and genetic characteristics and also long-term outcome which was of consistent clinical improvements after 1st decade and stability in adult life in majority of patients, a crucial information for treating clinicians, patients and families.