Predominantly myalgic phenotype caused by the c.3466G>A p.A1156T mutation in SCN4A gene

Abstract

Objective:To characterize the clinical phenotype in patients with p.A1156T sodium channel mutation.Methods:Twenty-nine Finnish patients identified with the c.3466G>A p.A1156T mutation in the SCN4A gene were extensively examined. In a subsequent study, 63 patients with similar myalgic phenotype and with negative results in myotonic dystrophy type 2 genetic screening (DM2-neg group) and 93 patients diagnosed with fibromyalgia were screened for the mutation. Functional consequences of the p.A1156T mutation were studied in HEK293 cells with whole-cell patch clamp.Results:The main clinical manifestation in p.A1156T patients was not myotonia or periodic paralysis but exercise- and cold-induced muscle cramps, muscle stiffness, and myalgia. EMG myotonic discharges were detected in most but not all. Electrophysiologic compound muscle action potentials exercise test showed variable results. The p.A1156T mutation was identified in one patient in the DM2-neg group but not in the fibromyalgia group, making a total of 30 patients so far identified. Functional studies of the p.A1156T mutation showed mild attenuation of channel fast inactivation.Conclusions:The unspecific symptoms of myalgia stiffness and exercise intolerance without clinical myotonia or periodic paralysis in p.A1156T patients make the diagnosis challenging. The symptoms of milder SCN4A mutations may be confused with other similar myalgic syndromes, including fibromyalgia and myotonic dystrophy type 2.

Pain in SCN4A Mutated P.A1156T muscle sodium channelopathy—a postal survey

“…There is evidence that EMG abnormalities in patients with myalgia can differentiate an underlying channelopathy from nonspecific myalgic syndromes . In our patients with the p.A1156T mutation, initial EMG studies showed either myotonic discharges or increased insertional activity, as described previously …”

“…Most SCN4A mutations cause gain‐of‐function defects, either disrupted inactivation or enhanced activation . Mildly attenuated fast inactivation by the p.A1156T channel, demonstrated by functional studies, does not cause clinical myotonia or paramyotonia, although myotonic discharges have been detected by electromyography (EMG) in most such patients . Pain has been reported in various proportions of myotonia patients with different SCN4A mutations …”

“…We recently reported a series of 30 new patients with this mutation, and described the clinical consequences of this mutation. These patients presented with widespread pain, muscular stiffness, and exercise and cold‐induced cramps, but without signs of clinical myotonia, paramyotonia, or periodic paralyses . According to the ExAC database, the frequency of the p.A1156T mutation in the Finnish population is 60 in 100,000, meaning that there are more than 3,000 mutation carriers and (due to the adult onset of symptoms) approximately 1,000 affected individuals in Finland …”

“…7 According to the ExAC database, the frequency of the p.A1156T mutation in the Finnish population is 60 in 100,000, meaning that there are more than 3,000 mutation carriers and (due to the adult onset of symptoms) approximately 1,000 affected individuals in Finland. 7 Muscular pain is a frequent symptom in nondystrophic myotonias, as reported by approximately 80% of these patients. 8,9 The severity of symptoms of SCN4A-related myotonias can vary from very mild ones producing minimal or no interference with daily life to ones that have a severe impact.…”

Possible role of SCN4A skeletal muscle mutation in apnea during seizure

“…Infants with SCN4A-related myotonia can appear outwardly healthy but present acutely with recurrent episodes of generalized stiffening of the trunk and limbs, apnea, and cyanosis (due to respiratory and laryngeal muscle myotonia-causing laryngospasm) which may be accompanied by bradycardia and loss of consciousness. [13][14][15] We hypothesize that SCN4A mutation may contribute to apnea during the physiological stress of seizures. An erroneous diagnosis of generalized epilepsy is frequently made in these infants.…”