P.293 - Classic congenital myopathy with recessive mutations in genes encoding ion channels: clinical phenotype and good response to acetazolamide

Abstract

We present data on 2 children with congenital myopathy due to mutations in genes encoding ion-channels. First, is a 10-year-old boy with neonatal hypotonia with lower limb contractures, bulbar and facial weakness, ophthalmoplegia, ptosis with maximal functional ability to sit independently. He uses NIV since the age of 7. He has periodic short-lived episodes where he loses head-control, develops slurred speech but remains conscious. Triggers include rest, hot weather, fasting, and illness. Exercise testing and CK were normal. Muscle MRI and biopsy showed changes compatible with congenital myopathy. Compound heterozygous mutations (p.Q1265H & p.E100K) were identified in CACNA1S gene using whole exome sequencing. p.E100K in isolation would predict a periodic paralysis phenotype. With acetazolamide, his periodic symptoms completely resolved and he gained some overall muscle strength over 1 year. Second, is a 16-year-old girl with neonatal-onset hypotonia, facial, axial and proximal weakness, hip, knee and ankle contractures with respiratory and feeding difficulties. She has ophthalmoplegia and uses NIV since the age of 6 and needed scoliosis surgery at 13. From the age of 12, she describes marked diurnal fluctuation in strength with short-lived episodic weakness during febrile illnesses, exertion and on hot days. She has significant fatigability. CK, stimulation SFEMG and exercise test were normal. Muscle biopsy and muscle MRI showed features of congenital myopathy. Compound heterozygous mutations were identified in SCN4A using whole exome sequencing. p.R1135C is reported previously with periodic paralysis. Treatment with salbutamol reduced fatigue. With acetazolamide, her periodic weakness and fluctuation in symptoms significantly improved. This report demonstrates the role of genetic evaluation in ion-channel related congenital myopathies. Mutations in specific regions of the channel may predict fluctuant symptoms and can help identify those who could be offered acetazolamide. These conditions present a diagnostic challenge as classical congenital myopathy mimics.