A Patient with Paramyotonia Congenita Due to a Novel SCN4A Gene Mutation.

Topic:

Other

Poster Number: P213

Author(s):

Carlos Lara, MD, University of Chicago, Zachary Osborn, MD, University of Chicago, Shubadra Priyadarshini, MD, University of Chicago, Betty Soliven, MD, University of Chicago, Kourosh Rezania, MD, University of Chicago

Background: SCN4A-gene mutations encode an abnormal α-subunit of the voltage-gated sodium channel 1.4(NaV1.4) can be associated with paroxysmal abnormal skeletal muscle excitability leading to stiffness, delayed muscle relaxation, and transient paralysis. Paramyotonia Congenita (PMC) is a rare, highly penetrant autosomal dominant disease resulting from the gain of function of the SCN4A gene. PMC’s presentation is characterized by paradoxical delayed relaxation (paramyotonia) of the facial, tongue, and hand muscles after repeated contraction and cold exposure, with electrical myotonia on EMG. More than 70 skeletal-muscle-associated-disease mutations of SCN4A have been identified. Functional expression studies could result in a better understanding of the genotype-phenotype association of the allelic disorders of the muscle sodium channelopathies.

Case presentation: We present a 24-year-old Caucasian male with episodic muscle stiffness, difficulty with hand-relaxation, and eye-opening since his early teens. Symptoms exacerbate with stress, caffeine, and exercise, worsening in winter months. His father reports similar symptoms. Physical examination showed normal muscle tone without weakness, myotonia, or paramyotonia at baseline but decreased hand relaxation after 2-minute cooling. Thyroid function and ionized serum calcium were normal, with elevated CK 499 U/L. NCS was normal. Electromyography showed generalized myotonic discharges, becoming less prominent after hand cooling and supporting the diagnosis of PMC. Genetic sequencing showed a novel heterozygous mutation of the SCN4A gene in the exon 24, c.5024A>G expected to disrupt protein function with a PPV of 95%. Exon 24 of the SCN4 is highly conserved and is a hotspot for pathogenic mutations. To this date, this variant has not been reported and is not present in population database.

Discussion: This case of intermittent muscle stiffness showed hallmark clinical and electrophysiological features of PMC with a mild phenotype, not previously reported genetic mutation of the SCN4A gene in the exon 24,c.5024A>G.