Pharmacogenetics of myotonic hNav1.4 sodium channel variants situated near the fast inactivation gate

Farinato, Alessandro; Altamura, Concetta; Imbrici, Paola; Maggi, Lorenzo; Bernasconi, Pia; Mantegazza, Renato; Pasquali, Livia; Siciliano, Gabriele; Monaco, Mauro Lo; Vial, Christophe; Sternberg, Damien; Carratù, Maria Rosaria; Conte, Diana; Desaphy, Jean-François

doi:10.1016/j.phrs.2019.01.004

Cited by 29 publications

(24 citation statements)

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“…Some previous functional studies have demonstrated how the location of the mutations in the different channel domains deeply influences the clinical severity and response to therapy producing major differences among patients sharing the same gene defect but different mutations. On the other hand, different phenotypes have also been described in patients with the same mutation, suggesting that modifier genes and environmental condition might influence the clinical features of individual patients [37,38]. We found 12 novel genetic variants.…”

Section: Discussionmentioning

confidence: 69%

Non-dystrophic myotonias: clinical and mutation spectrum of 70 German patients

et al. 2020

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Introduction Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in a large German cohort. Methods We retrospectively identified all patients with genetically confirmed NDM diagnosed in our center. The following data were analyzed: demographics, family history, muscular features, cardiac involvement, CK, EMG, genotype, other tested genes, treatment perceived efficacy. Results 70 patients (age 40.2 years ± 14.9; 52.8% males) were included in our study (48 NDM-CLCN1, 22 NDM-SCN4A). The most frequent presenting symptoms were myotonia (NDM-CLCN1 83.3%, NDM-SCN4A 72.2%) and myalgia (NDM-CLCN1 57.4%, NDM-SCN4A 52.6%). Besides a more prominent facial involvement in NDM-SCN4A and cold-sensitivity in NDM-CLCN1, no other significant differences were observed between groups. Cardiac arrhythmia or conduction defects were documented in sixNDM-CLCN1 patients (three of them requiring a pacemaker) and one patient with NDM-SCN4A. CK was normal in 40% of patients. Myotonic runs in EMG were detected in 89.1% of CLCN1 and 78.9% of SCN4A. 50% of NDM-CLCN1 patients had the classic c.2680C>T (p.Arg894*) mutation. 12 new genetic variants are reported. About 50% of patients were not taking any anti-myotonic drug at the last follow-up. The anti-myotonic drugs with the best patient’s perceived efficacy were mexiletine and lamotrigine. Conclusion This study highlights the relevant clinical overlap between NDM-CLCN1 and NDM-SCN4A patients and warrants the use of early and broad genetic investigation for the precise identification of the NDM subtype. Besides the clinical and genetic heterogeneity, the limited response to current anti-myotonic drugs constitutes a continuing challenge.

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Section: Discussionmentioning

confidence: 69%

Non-dystrophic myotonias: clinical and mutation spectrum of 70 German patients

et al. 2020

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“…Three mutations (p.N1180I, p.N1297S, and p.F1298C) found in six patients were already reported and associated to non-dystrophic myotonias ( Table 2 ) ( 13 , 14 ). Of note, p.N1297S was found in our cohort in two patients also carrying the p.F167L variant in CLCN1 gene, which probably mitigated the severe effect of the mutation in the Nav1.4 channel, as already reported ( 8 ).…”

Section: Resultsmentioning

confidence: 87%

Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients

et al. 2020

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Background: Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis. Methods: We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A. Maggi et al. SCN4A-Clinical Molecular and Features Results: PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM (p < 0.01) and in Hyper/NormoPP than in HypoPP2 (p = 0.02). Cold-induced myotonia was more frequently observed in PMC (n = 34) than in SCM (n = 23) (p = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP (n = 4), SCM (n = 5), and PMC (n = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC (p < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains. Conclusions: Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum.

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“…For the severe SNEL cases, treatment can be transformative. There is some in vitro evidence that in these cases the sodium channel blocker flecainide may be the most effective choice for the common SNEL mutation, G1306E 75,76 . Even in the recessive disorders there is some evidence of efficacy from similar therapies and the possibility of treatment should always be considered, even when the examination suggests fixed weakness 7,77 .…”

Section: Skeletal Muscle Sodium Channelopathiesmentioning

confidence: 99%

Muscle and brain sodium channelopathies: genetic causes, clinical phenotypes, and management approaches

Matthews

Balestrini

Sisodiya

et al. 2020

The Lancet Child & Adolescent Health

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Voltage gated sodium channels are essential for excitability of skeletal muscle fibres and neurones. An increasing number of disabling or fatal paediatric neurological disorders linked to mutations of voltage gated sodium channel genes are recognised. Muscle phenotypes include episodic paralysis, myotonia, neonatal hypotonia, respiratory compromise, laryngospasm/stridor, congenital myasthenia and myopathy. Recent evidence suggests a possible link between sodium channel dysfunction and sudden infant death. Increasingly recognised brain sodium channelopathy phenotypes include several epilepsy disorders and complex encephalopathies. Together these early onset muscle and brain phenotypes have a significant morbidity and an appreciable mortality rate but there have been significant advances in understanding the pathophysiological mechanisms underlying them and these have helped to identify effective targeted therapies. The availability of effective treatments underlines the importance of increasing clinical awareness and the need to achieve a precise genetic diagnosis. Here, we describe the expanded range of phenotypes of muscle and brain sodium channelopathies and the underlying knowledge regarding mechanisms of sodium channel dysfunction. We outline a diagnostic approach and review the available treatment options.

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Pharmacogenetics of myotonic hNav1.4 sodium channel variants situated near the fast inactivation gate

Cited by 29 publications

References 50 publications

Non-dystrophic myotonias: clinical and mutation spectrum of 70 German patients

Non-dystrophic myotonias: clinical and mutation spectrum of 70 German patients

Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients

Muscle and brain sodium channelopathies: genetic causes, clinical phenotypes, and management approaches

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