Severe neonatal non‐dystrophic myotonia secondary to a novel mutation of the voltage‐gated sodium channel (<i>SCN4A</i>) gene

Gay, Sébastien; Dupuis, Delphine S.; Faivre, Laurence; Masurel‐Paulet, Alice; Labenne, M.; Colombani, Marina; Soichot, P.; Huet, Frédéric; Hainque, Bernard; Sternberg, Damien; Fontaine, Bertrand; Gouyon, Jean‐Bernard; Thauvin‐Robinet, Christel

doi:10.1002/ajmg.a.32141

Cited by 58 publications

(51 citation statements)

References 16 publications

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“…Now, there is evidence that certain SCN4A genotypes are associated with a severe neonatal phenotype. A fatal case of myotonia with significant respiratory muscle involvement was described in an infant with a de novo N1297K mutation (Gay et al, 2008). We observed the I693T mutation linked to spontaneously resolving neonatal hypotonia with variable feeding and respiratory difficulties in four unrelated families (Matthews et al, 2008a).…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 78%

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

Matthews

Fialho

Tan

et al. 2009

Brain

194

226

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The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.

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Section: Genotype-phenotype Correlationsmentioning

confidence: 78%

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

Matthews

Fialho

Tan

et al. 2009

Brain

194

226

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“…In 2006, Colding-Jørgensen et al 11 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 al 12 described a newborn harboring the p.N1297K mutation with facial dysmorphisms, muscle hypertrophy, e2…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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“…SNEL as the initial presentation of sodium muscle channelopathy has already been reported. [6][7][8] Correct diagnosis is crucial given the possibility of fatal outcome, although the G1306E mutation seems to have better prognosis than N1297K 7 or A799S. 8 The condition may be easily mistaken for laryngomalacia or gastroesophageal reflux, as was the case in our patients; such misdiagnosis could clearly be deleterious, eventually leading to unnecessary surgery or repeated hospitalization in the neonatal period.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4] It has been shown recently that these can manifest as neonatal disorders, either hypotonia or stridor 5,6 or potentially severe episodic apnea. 7,8 In particular, de novo mutations may be responsible for severe cases with no family history. 7,8 Therapeutic agents, such as sodium channel blockers, are available for those disorders and can help in treating neonatal manifestations.…”

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confidence: 99%

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Diagnosis and Outcome of SCN4A-Related Severe Neonatal Episodic Laryngospasm (SNEL): 2 New Cases

Caietta

Milh

Sternberg³

et al. 2013

Pediatrics

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Mutations of SCN4A encoding the skeletal muscle sodium channel Nav 1.4 cause several types of disease, including sodium channel myotonias. The latter may be responsible for neonatal symptoms, including severe neonatal episodic laryngospasm (SNEL). Establishing the diagnosis of SCN4A-related SNEL early in the neonatal period is crucial because treatment is available that can reduce laryngospasm and improve vital and cerebral outcome. We report 2 new unrelated French patients who presented with SNEL. The first patient was initially diagnosed with laryngomalacia and underwent laryngeal surgery in the neonatal period before being diagnosed with myotonia at 14 months of age. The episodes of laryngospasm disappeared spontaneously, although occasional circumstances such as cold exposure could trigger laryngeal reactions; in addition, he developed myotonia corresponding to an adult myotonia permanens phenotype. This patient is now 24 years old and leading a normal life. The second patient was initially diagnosed with gastroesophageal reflux, then SNEL; his condition improved with carbamazepine treatment, and he is now 6 months old. The diagnostic sequence in both patients was the same: first, severe episodic apneic attacks necessitating hospitalization occurring in the first week of life; second, observation of muscle hypertrophy and peripheral hypertonia with a clear myotonic pattern on electromyogram (at 14 and 3 months of age, respectively); third, genetic testing revealing de novo SCN4A G1306E mutation. Both patients have had good therapeutic response to sodium channel blockers (carbamazepine or mexiletine). Pediatrics 2013;132:e784-e787 AUTHORS:

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Severe neonatal non‐dystrophic myotonia secondary to a novel mutation of the voltage‐gated sodium channel (SCN4A) gene

Cited by 58 publications

References 16 publications

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

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

Diagnosis and Outcome of SCN4A-Related Severe Neonatal Episodic Laryngospasm (SNEL): 2 New Cases

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