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.
- SNEL —
- severe neonatal episodic laryngospasm
Skeletal muscle sodium channelopathies are rare ion channel diseases that usually present as childhood-onset dominant disorders. They may manifest as potassium-aggravated myotonia, including myotonia fluctuans, moderate myotonia, myotonia permanens, acetazolamide-responsive myotonia, and painful myotonia. These types of sodium channel myotonias do not produce muscle weakness, but they do share some overlapping clinical features (eg, muscle stiffness, hypertrophy).1–4 They can affect either children or adult patients; newborns may manifest with severe neonatal episodic laryngospasm (SNEL) characterized by muscle hypotonia and recurrent episodes of laryngospasm, followed by apnea. SNEL exhibits a spontaneous decrease in frequency and duration; this clinical phase is usually followed by myotonia (ie, myotonia permanens or paramyotonia congenita).5 The standard treatment for myotonia is based on carbamazepine, mexiletine, and, more recently, flecainide6–8 or other sodium channel blockers.9,10 All of these drugs act by reducing the involuntary high-frequency action potential bursts responsible for muscle stiffness, without blocking voluntary physiologic muscle activity.6,7
Recently, a case of myotonia permanens, linked to a G1306E mutation in the SCN4A gene, was reported to be dramatically responsive to flecainide treatment.8 The patient presented with focal and ocular muscle myotonia at birth but had neither laryngospasm nor apneic episodes, confirming the clinical variability of patients carrying the G1306E mutation.11
The present article describes the case of an 8-year-old girl who was affected by myotonia permanens with an SNEL onset who responded positively to flecainide.
The proband was examined at 15 months of age because of concerns regarding slightly increased creatine kinase levels (509 U/L). She was the second child from nonconsanguineous parents; family history was unremarkable for neuromuscular disorders. The infant was born via cesarean delivery at 37 weeks’ gestation. At birth, her weight was 3200 g, and length was 50 cm.
The child presented as a floppy infant with flebile crying, impaired swallowing, and difficulty breathing with respiratory distress requiring oxygen therapy. At 6 months of age, the patient manifested with severe muscle stiffness and apneic episodes induced by intense crying. Dysmorphic facial features were present as a high forehead, down-slanting palpebral fissures, low-set ears, high-arched palate, short neck, and barrel chest. Because of recurrent episodes of apnea, she was admitted several times to the hospital. During the first 6 years of life, the patient’s apnea manifested less frequently, whereas her stiffness became more disabling and exacerbated by cold temperatures and rest.
At 15 months of age, the patient had poor facial movements, with periorbital and extraocular myotonia, generalized muscle hypertrophy, and stiffness, mainly at paraspinal muscles with a positive Gowers’sign; no myotonia was present either at the hands or after percussion. An electromyography revealed intense generalized myotonia. Steinert disease was ruled out based on results of molecular analysis. Muscle biopsy samples evidenced nonspecific features with normal perlecan expression. SCN4A gene molecular analysis disclosed the presence of p.G1306E in a heterozygous state; this change, not found in asymptomatic parents, suggested a de novo mutation.
Carbamazepine (20 mg/kg/d) was started, with a slight improvement in symptoms. After withdrawal of carbamazepine, acetazolamide (125 mg/d) plus mexiletine (15 mg/kg/d) were administered but with no defined improvements. After these attempts, the patient was again prescribed carbamazepine.
Since 6 years of age, the patient’s apneic episodes have been reduced, presenting only while she is crying. She later developed difficulties opening her fists or eyes, walking after prolonged rest, or performing sudden motor activities. Stiffness strongly influenced her posture; she developed a forced internal rotation of the glenohumeral joint, with difficulty in shoulder elevation and kyphosis (Figs 1A and 1B). She managed to perform the functional chair test in 30 seconds and the 10-m Timed Up and Go Test in 42 seconds. Her psychological profile revealed that she was very shy, with poor participation in all environmental activities. Spine radiograph, brain MRI, cardiac assessment, and muscle MRI results were normal. Carbamazepine (200 mg/d) was then stopped and flecainide immediately started. At that time, the patient was 8 years old and weighed 35 kg. After the first 4 days, the dosage was progressively increased from 25 to 100 mg, but the patient transitorily experienced malaise. In the following week, her stiffness decreased, allowing a marked improvement in internal rotation of the glenohumeral joint. The patient was then able to raise her arms above her head. In addition, from a psychological point of view, she started to interact better with physicians and caregivers.
After an additional 2 months of treatment, results of the functional chair test improved to 12 seconds, and the 10-m Timed Up and Go Test was performed in 18 seconds. The patient is currently taking flecainide, with no adverse effects.
We report details of the seventh SNEL patient with a G1306E mutation in the SCN4A gene manifesting with early and severe clinical presentation, which initially made the diagnosis difficult. Neonatal forms of skeletal muscle channelopathies are rarely reported, and they are related to 5 different mutations (Table 1). In 2006, Colding-Jørgensen et al11 first described 2 unrelated patients with myotonia permanens caused by a G1306E mutation, presenting only with severe myotonia but no laryngospasm at birth, raising the question if diagnosis of SNEL would have been missed in the neonatal period. In 2008, Gay et al12 described a newborn harboring the p.N1297K mutation with facial dysmorphisms, muscle hypertrophy, severe constipation, psychomotor delay, and recurrent cold-induced episodes of muscle weakness and myotonia, leading to severe hypoxia and apnea followed by loss of consciousness. The patient improved with oral mexiletine treatment but died at 20 months of a broncopulmonary infection. In the same year, Matthews et al5 reported on 6 patients carrying the p.I693T change who presented at birth with hypotonia, impaired suckling, oxygen desaturation and generalized muscle paralysis, later developing a PMC phenotype. Two years later, Lion-Francois et al10 described 3 SNEL patients with episodic laryngospasm and facial and limb myotonia: 2 harbored the p.G1306E mutation and 1 the p.Ala799Ser mutation. The 2 patients with the p.G1306E mutation responded to sodium channel blockers (mexiletine and carbamazepine) and survived; the other patient with the p.Ala799Ser mutation was not treated and died of respiratory failure. In 2011, Matthews et al13 reported on another patient with SNEL with the p.Thr1313Met mutation, presenting with neonatal stridor and feeding difficulties. The patient had been treated since 4 years of age with mexiletine, with a successful response. In 2012, Desaphy et al8 described a newborn boy with a severe phenotype characterized by ocular and facial myotonia, diffuse painful myotonia, muscle hypertrophy, and forced internal rotation of the glenohumeral joint with difficult elevation of shoulders. He harbored the p.G1306E mutation, inherited from the mother. Since early childhood, he had been treated with mexiletine, with limited effects. Having already demonstrated the in vitro beneficial effects of flecainide on that specific mutation,14 the authors decided to administer, for the first time, flecainide in mother and son, and a marked improvement in symptoms was noted.13
In 2013, Caietta et al15 reported on 2 other SNEL patients with a p.G1306E de novo mutation. One patient presenting with laryngospasm, stiffness, and an athletic appearance was treated with mexiletine, with partial improvement of stiffness. During early childhood, he experienced episodes of diplopia, strabismus, dysphagia after cold drinks, and generalized muscle contractions that improved with physical exercise. The patient was treated with acetazolamide combined with mexiletine and demonstrated clinical improvement. The second patient had experienced, since birth, breathing difficulties and daily episodes of apnea with stridor followed by cyanosis, bradycardia, generalized stiffness, and facial contraction. He was treated with carbamazepine, with amelioration of laryngospasm.
In 2014, Singh et al16 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. These patients were treated with carbamazepine; their laryngospasm disappeared, and improvements in myotonia and muscle stiffness were noted.
As illustrated in the aforementioned cases, the absence or late appearance of muscle hypertrophy in patients with myotonia secondary to SCN4A mutations makes an early diagnosis difficult, thus delaying proper treatment. Differential diagnosis is crucial and could include, in newborns, laryngomalacia, gastroesophageal reflux, myotonic dystrophy type 1, Schwartz-Jampel syndrome, and myasthenic syndromes caused by mutation of the SCN4A sodium channel.17–19
Furthermore, it is noteworthy that the p.G1306E mutation is located in the intracellular loop between domains III and IV of the protein, which acts as a fast inactivation gate, quickly occluding the channel pore after activation. At this site, 3 substitutions (G1306A/V/E) have been associated with myotonia, with different severity.20,21 However, in these forms, response to treatments is highly variable. In fact, even though flecainide and mexiletine exhibit a similar mechanism of blocking skeletal muscle sodium channels, flecainide reportedly inhibits some mutant channels more efficiently than mexiletine.14,15 Although flecainide has been shown to be an effective human voltage-gated sodium channel blocker in vitro, its clinical use as an antimyotonic agent has rarely been reported.8,22 Indeed, it has been shown previously that flecainide was more efficient than mexiletine in blocking functionally expressed G1306E channels, likely because of a positive shift of channel availability voltage dependence induced by the mutation.14
We report on a new case of myotonia permanens with SNEL onset, confirming the clinical variability of sodium channelopathies. Even in cases with a negative family history, it is important to consider SNEL in newborns displaying hypotonia, feeding difficulties, stridor, and apneic episodes, especially when myotonic bursts are shown on electromyography.
An early diagnosis of SNEL is crucial because efficient treatments are available that may reduce laryngospasm and prevent muscular and cerebral derangement. In this case, as previously reported,8 treatment with flecainide was initiated early in childhood. However, although this drug has been successfully used in newborns with cardiac arrhythmias,23,24 it has not yet been used in SNEL. Consequently, it is possible that SNEL might respond to flecainide, thus providing a valid alternative to mexiletine or carbamazepine, but this hypothesis needs to be proven. A precise pharmacologic characterization of sodium channel mutants could help clinicians to better choose a drug for patients with various mutations.
The authors thank the TELETHON Foundation for having funded the project N. GGP14096 (entitled “Preclinical Evaluation of Pharmacogenetics and New Therapeutic Options in Nondystrophic Myotonias Toward Personalized Medicine”).
- Accepted December 18, 2015.
- Address correspondence to Simona Portaro, MD, PhD, IRCCS Centro Neurolesi “Bonino Pulejo,” SS 113, Via Palermo, c. da Casazza, 98124, Messina, Italy. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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- Copyright © 2016 by the American Academy of Pediatrics