Severe neonatal episodic laryngospasm due to de novo
            <i>SCN4A</i>
            mutations

Lion‐François, Laurence; Mignot, Cyril; Vicart, Savine; Manel, Véronique; Sternberg, Damien; Landrieu, P.; Lesca, Gaëtan; Broussolle, E.; Villemeur, Thierry Billette de; Napuri, Sylvia; Portes, Vincent Des; Fontaine, Bertrand

doi:10.1212/wnl.0b013e3181ed9e96

Cited by 70 publications

(61 citation statements)

References 10 publications

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“…One infant who was not treated in time with either carbamazepine or mexiletine died due to respiratory arrest during an apneic episode. A de novo A799S missense mutation of the Na v 1.4 channel was found in this patient (Lion-Francois et al, 2010; Simkin et al, 2011). This mutation is located on the S6 transmembrane segment of domain II and results in such a severe phenotype by shifting the steady state of activation in a hyperpolarizing direction, slowing the kinetics of fast inactivation and deactivation, and dramatically increasing channel open probability (Simkin et al, 2011).…”

Section: Skeletal Muscle Pathophysiologymentioning

confidence: 75%

“…Recently a novel Na v 1.4 myotonia mutation was identified causing severe neonatal episodic laryngospasm (SNEL) found to be lethal in newborns (Lion-Francois et al, 2010). These newborns presented with episodic apneas and apparent life threatening events that included myotonia of the laryngeal muscles preventing proper ventilation.…”

Section: Skeletal Muscle Pathophysiologymentioning

confidence: 99%

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Skeletal muscle Na+ channel disorders

Simkin¹

2011

Front. Pharmacol.

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Five inherited human disorders affecting skeletal muscle contraction have been traced to mutations in the gene encoding the voltage-gated sodium channel Nav1.4. The main symptoms of these disorders are myotonia or periodic paralysis caused by changes in skeletal muscle fiber excitability. Symptoms of these disorders vary from mild or latent disease to incapacitating or even death in severe cases. As new human sodium channel mutations corresponding to disease states become discovered, the importance of understanding the role of the sodium channel in skeletal muscle function and disease state grows.

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Section: Skeletal Muscle Pathophysiologymentioning

confidence: 75%

Section: Skeletal Muscle Pathophysiologymentioning

confidence: 99%

Skeletal muscle Na+ channel disorders

Simkin¹

2011

Front. Pharmacol.

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“…Recently, severe neonatal episodic laryngospasm, a form of life-threatening myotonia, has been associated with SCN4A mutations (G1306E, T1313M and A799S) 51 52. Functional work via patch-clamp techniques showed that the A799S mutation promoted the channel open state with sustained activity leading to hyperexcitability of laryngeal muscles which could be lethal during infancy 52…”

Section: Subsectionsmentioning

confidence: 99%

Genotype phenotype associations across the voltage-gated sodium channel family

et al. 2014

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Mutations in genes encoding voltage-gated sodium channels have emerged as the most clinically relevant genes associated with epilepsy, cardiac conduction defects, skeletal muscle channelopathies and peripheral pain disorders. Geneticists in partnership with neurologists and cardiologists are often asked to comment on the clinical significance of specific mutations. We have reviewed the evidence relating to genotype phenotype associations among the best known voltage-gated sodium channel related disorders. Comparing over 1300 sodium channel mutations in central and peripheral nervous system, heart and muscle, we have identified many similarities in the genetic and clinical characteristics across the voltage-gated sodium channel family. There is evidence, that the level of impairment a specific mutation causes can be anticipated by the underlying physico-chemical property change of that mutation. Across missense mutations those with higher Grantham scores are associated with more severe phenotypes and truncating mutations underlie the most severe phenotypes. Missense mutations are clustered in specific areas and are associated with distinct phenotypes according to their position in the protein. Inherited mutations tend to be less severe than de novo mutations which are usually associated with greater physico-chemical difference. These findings should lead to a better understanding of the clinical significance of specific voltage-gated sodium channel mutations, aiding geneticists and physicians in the interpretation of genetic variants and counselling individuals and their families.

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“…The extreme cramps in the tongue muscles are also peculiar . Myotonia in the tongue muscles is well known, but impressive painful cramps and contraction, as seen in these patients, have not been recognized.…”

Section: Discussionmentioning

confidence: 99%