G.P.139: Congenital myasthenic syndrome due to novel choline acetyltransferase (ChAT) gene mutations in Kadazandusun family from Borneo

Abstract

Pathogenic mutations of the choline acetyltransferase (ChAT) gene alters its function and causes reduced synthesis of acetylcholine and its depletion in synaptic vesicles. This results in a rare presynaptic form of congenital myasthenic syndrome which presents at birth or in infancy characterised by apnoeic attacks. We present Kadazandusun family, an ethnic group native to Sabah, in north Borneo, with ChAT deficiency in which 5 of 6 siblings of non-consanguineous parents were affected. 2 died in their infancy from apnoeic atatacks while another sibling died at the age of 12 years from a severe apnoeic episode after an intercurrent infection. We reviewed 2 brothers, the eldest and the 4th at 24 and 18 years of age respectively, although both had presented in infancy with bilateral ptosis and limb weakness. The elder brother had episodes of apnoea and weakness on exposure to cold well water in their village. A congenital myasthenic syndrome was suspected and both brothers were treated on pyridostigmine after positive Tensilon tests and negative acetylcholine receptor antibody tests. On review, both had muscle weakness after moderate to severe exertion and repetitive nerve stimulation test of the abductor digiti minimi, which was normal at rest, showed sustained decremental response after prolonged 5 min stimulation at 10 Hz. Screening of the ChAT gene showed compound heterozygous mutation in both brothers, c.1069G>C and c.2263_2265delTCT in exons 6 and 15 respectively. Each parent was heterozygous for one of the mutations, which were not seen in any of 50 normal controls obtained from the native population of Sabah. In summary, we present a Kadazandusun family with ChAT deficiency congenital myasthenic syndrome, in which, 3 affected siblings died from apnoeic episodes, while another 2 survived to adulthood. This variable severity could be attributed to treatment with pyridostigmine as well as recognised improvement with age in this condition.