A 39-yr-old female with potassium-aggravated myotonia due to p.Q1633E in SCN4A experienced painful muscle stiffness triggered by exercise, potassium-rich fruits, and cold exposure, which progressed into a rigid state. Needle electromyography (EMG) during muscle stiffness showed synchronous, rhythmic, and regular activities starting at ∼60 Hz and ∼6 mV. A 37-yr-old male with myotonia permanens due to a splicing-affecting indel variant in intron 21 of SCN4A experienced cold-induced myotonia. EMG recordings during muscle stiffness showed similar synchronous, rhythmic, and regular activities starting at ∼80 Hz and 6.5 mV. In both patients, the frequencies and amplitudes were gradually decreased with relief of muscle stiffness. In either patient, single motor unit potentials by spontaneous activity were not explicitly recognized. In both patients, the activities produced a characteristic sound which, while similar in pitch to the "dive bomber" sound of classical myotonia, lacked its typical waxing and waning quality. The activities were similar to the Piper rhythm that was originally reported in fatigued normal muscle. Visual inspection of EMG activities in the literature revealed that similar Piper rhythm-like EMG activities were presented in Satoyoshi disease, myotonia permanens, paramyotonia congenita, and a rare form of nondystrophic myotonia. In Satoyoshi disease and fatigued normal skeletal muscle, the activities during muscle stiffness were less than 60 Hz, whereas in sodium channelopathies, they started at 60 Hz or higher, which may be a hallmark of hyperexcitability of the muscle membrane in sodium channelopathies.NEW & NOTEWORTHY In two patients with sodium channel myotonia representing potassium-aggravated myotonia and myotonia permanens, needle EMG showed Piper rhythm-like activities during muscle stiffness. Inspection of EMG recordings in the literature revealed similar Piper rhythm-like EMG activities in Satoyoshi disease, myotonia permanens, paramyotonia congenita, and a rare form of nondystrophic myotonia. Piper rhythm-like EMG activities starting at 60 Hz or higher, synchronizing with muscle stiffness, may be a hallmark of hyperexcitability of muscle membrane in sodium channelopathies.

Non-dystrophic myotonias are a group of rare neuromuscular diseases linked to SCN4A or CLCN1. Among the subtypes, myotonia permanens, associated with the Gly1306Glu variant of SCN4A, is a relatively less frequent but more severe form. Most reports of non-dystrophic myotonias describe European populations. Therefore, to expand the genetic and phenotypic spectrum of this disorder, we evaluated 30 Chilean patients with non-dystrophic myotonias for associated variants and clinical characteristics. SCN4A variants were observed in 28 (93%) of patients, including 25 (83%) with myotonia permanens due to the Gly1306Glu variant. Myotonia permanens was inherited in 24 (96%) patients; the mean age of onset was 6 months, and the initial symptoms were orbicularis oculi myotonia in 17 (74%) patients and larynx myotonia in 12 (52%) patients. The extraocular muscles were involved in 11 (44%) patients, upper limbs in 20 (80%), and lower limbs in 21 (84%). Thirteen (52%) patients experienced recurrent pain and 10 (40%) patients reported limitations in daily life activities. Carbamazepine reduced myotonia in eight treated patients. The high frequency of the Gly1306Glu variant in SCN4A in Chilean patients suggests a founder effect and expands its phenotypic spectrum.

Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life. Clinical neurophysiology and genetic analysis were performed. Using existing functional expression data we determined the sodium window by integration. In 10 unrelated patients who were believed to have epilepsy, respiratory disease or Schwartz-Jampel syndrome, we made the same prima facie diagnosis and detected the same heterologous Nav1.4-G1306E channel mutation as for our first myotonia permanens patient published in 1993. Eight mutations were de-novo, two were inherited from the affected parent each. Seven patients improved with age, one had a benign phenotype from birth, and two died of respiratory complications. The clinical features age-dependently varied with severe neonatal episodic laryngospasm in childhood and myotonia throughout life. Weakness of varying degrees was present. The responses to cold, exercise and warm-up were different for lower than for upper extremities. Spontaneous membrane depolarization increased frequency and decreased size of action potentials; self-generated repolarization did the opposite. The overlapping of steady-state activation and inactivation curves generated a 3.1-fold window area for G1306E vs. normal channels. Residue G1306 Neonatal laryngospasm and unusual distribution of myotonia, muscle hypertrophy, and weakness encourage direct search for the G1306E mutation, a hotspot for de-novo mutations. Successful therapy with the sodium channel blocker flecainide is due to stabilization of the inactivated state and special effectiveness for enlarged window currents. Our G1306E collection is the first genetically clarified case series from newborn period to adulthood and therefore helpful for counselling.

We performed a clinical, functional, and pharmacologic characterization of the novel p.P1158L Nav1.4 mutation identified in a young girl presenting a severe myotonic phenotype. Wild-type hNav1.4 channel and P1158L mutant were expressed in tsA201 cells for functional and pharmacologic studies using patch-clamp. The patient shows pronounced myotonia, slowness of movements, and generalized muscle hypertrophy. Because of general discomfort with mexiletine, she was given flecainide with satisfactory response. In vitro, mutant channels show a slower current decay and a rightward shift of the voltage dependence of fast inactivation. The voltage dependence of activation and slow inactivation were not altered. Mutant channels were less sensitive to mexiletine, whereas sensitivity to flecainide was not altered. The reduced inhibition of mutant channels by mexiletine was also observed using clinically relevant drug concentrations in a myotonic-like condition. Clinical phenotype and functional alterations of P1158L support the diagnosis of myotonia permanens. Impairment of fast inactivation is consistent with the possible role of the channel domain III S4-S5 loop in the inactivation gate docking site. The reduced sensitivity of P1158L to mexiletine may have contributed to the unsatisfactory response of the patient. The success of flecainide therapy underscores the usefulness of in vitro functional studies to help in the choice of the best drug for each individual.

Sodium channel myotonias are inherited muscle diseases linked to mutations in the voltage-gated sodium channel. These diseases may also affect newborns with variable symptoms. More recently, severe neonatal episodic laryngospasm (SNEL) has been described in a small number of patients. A timely diagnosis of SNEL is crucial because a specific treatment is now available that will likely reduced laryngospasm and improve vital and cerebral outcomes. We report here on an 8-year-old girl who had presented, at birth, with SNEL who subsequently developed myotonia permanens starting at age 3 years. Results of molecular analysis revealed a de novo SCN4A G1306E mutation. The girl was treated with carbamazepine, acetazolamide, and mexiletine, with little improvement; after switching her treatment to flecainide, she experienced a dramatic reduction in muscle stiffness and myotonic symptoms as well as an improvement in behavior.