Mutations inSCN4A: A Rare but Treatable Cause of Recurrent Life-Threatening Laryngospasm

Abstract

Laryngospasm is a rare but potentially life-threatening occurrence in infants and usually has infective, allergic, metabolic, or anatomic causes. Underlying genetic conditions are rarely considered. Mutations in SCN4A encoding the voltage-gated sodium channel NaV1.4 have been implicated in a wide spectrum of neuromuscular disorders with variable onset, ranging from a rare form of congenital myasthenic syndrome to both hypokalemic and hyperkalemic forms of periodic paralysis and paramyotonia congenita. Here we report on 3 unrelated patients without family history presenting with recurrent, life-threatening episodes of laryngospasm from the first months of life. Clinical features more typically associated with SCN4A-related disorders such as generalized muscle hypertrophy with clinical or electrical myotonia evolved later in life. All patients were found to be heterozygous for the same SCN4A mutation, c.3917G>A; p.Gly1306Glu. Treatment with carbamazepine resulted in complete abolition of recurrent laryngospasm and alleviated symptoms associated with myotonia and muscle stiffness. We conclude that SCN4A mutations ought to be considered in the differential diagnosis of recurrent infantile laryngospasm because timely institution of treatment can be life-saving.

Sodium Channelopathies of Skeletal Muscle

“…A diverse variety of clinical subtypes have been described, depending on the severity (e.g. myotonia permanens for severe dysfunction that may compromise breathing (Singh et al, 2014)) or on precipitating factors (e.g. potassium-aggravated myotonia (Heine et al, 1993)).…”

Skeletal Muscle Channelopathies

“…In the SCN4A patients, these symptoms include abnormal gait, leg cramps, eyelid or extraocular myotonia, strabismus, stridor, and choking episodes. Episodic neonatal and infantile laryngospasm in these patients occur rarely, but can be life-threatening and respond remarkably well to carbamazepine [35]. The CLCN1 patients may have a Bfunny gait,f requent falls, and below average running compared to peers.…”

Flecainide-Responsive Myotonia Permanens With SNEL Onset: A New Case and Literature Review

“…In 2014, Singh et al 16 reported on 3 unrelated patients, heterozygous for the G1306E mutation, presenting at birth with recurrent life-threatening episodes of laryngospasms. Generalized muscle hypertrophy with clinical or electrical myotonia appeared later.…”