P.10 Compound CACNA1S heterozygosity resulting in a novel phenotype of congenital myopathy and early onset periodic paralysis: report of two probands

Abstract

Skeletal muscle contraction is mediated by excitation-contraction coupling (ECC), a process involving the rapid elevation of cytosolic calcium. L-type voltage gated calcium channels located on T-tubule membranes are the voltage sensors of ECC. The dihydropyridine receptor (DHPR) contains the pore forming basic functional elements of these calcium channels and is encoded by the <i>CACNA1S</i> gene. Recessive mutations in the <i>CACNA1S</i> gene have been recently reported with a severe congenital myopathy and facial involvement. We describe two sisters with compound heterozygous mutations involving the <i>CACNA1S</i> gene. Both had neonatal hypotonia, muscle weakness, and delayed motor milestones. Prior to one year of age, periodic paralysis was evident as episodic flaccidity and loss of postural control. Periodic paralysis episodes continued to occur most notably with cold exposure, lasting around 10 minutes each. Lab evaluation revealed normal CPK. Electrophysiological evaluation revealed normal motor and sensory nerve conduction studies, and normal long exercise testing. Limb cooling and cold provocation led to clinical weakness and a drop in motor amplitude. Magnetic resonance imaging of the older sister showed symmetrical tigroid pattern fat replacement and atrophy of bilateral gluteus maximus muscles. Targeted next generation sequencing revealed two variants in the <i>CACNA1S</i> gene: both c.3526-2A>G and c.2831G>A (p.Cys944Tyr) are not described in the gnomAD database. Both variants co-segregated into affected sisters and Sanger sequencing revealed that c.3526-2A>G was inherited from the unaffected mother and c.2831G>A from the unaffected father, thus revealing a recessive pattern of inheritance. The c.3526-2A>G is expected to disrupt the acceptor splice site of intron 27 by <i>in silico</i> analysis, whereas the c.2831G>A variant replaces a highly conserved cysteine residue with tyrosine at codon 944 in the DIII-S5 of the Cav1.1 protein. This novel phenotype of a milder congenital recessive myopathy and early onset periodic paralysis expands the phenotypic spectrum of <i>CACNA1S</i> gene mutations.