SCN4A-T704M突变相关正常血钾性周期性麻痹的临床与遗传学特征:中国两家系报道及表型异质性机制探讨OA

Objective To investigate the clinical features,genetic basis,and phenotypic heterogeneity mechanism of nor-mokalemic periodic paralysis(normoKPP)associated with SCN4A-T704M mutation in the Chinese population,and to clarify its basis as an independent disease subtype.Methods Two Chinese families(13 patients)with normoKPP were included,and re-lated clinical data were collected,including medical history,test results,electrophysiology,and muscle pathology.Sanger se-quencing was used to identify SCN4A gene mutations,and a family co-segregation analysis and ACMG pathogenicity rating were used to validate the pathogenicity of the mutations.A literature review was performed to compare genotype-phenotype associations,and phenotypic heterogeneity and racial differences were also compared.Results All patients carried the heterozygous mutation of c.2111C>T(p.T704M)in the SCN4A gene(SCN4A-T704M),which was in line with autosomal dominant inheritance,and the core phenotypes included disease onset in childhood(with a mean age of 1.5-10 years),paroxysmal proximal muscle weak-ness(induced by cold/hunger/strenuous exercise),and normal blood potassium during the ictal period(3.5-5.5 mmol/L),as well as gastrocnemius hypertrophy and persistent muscle weakness in some patients.Electrophysiology and muscle pathology sug-gested myogenic damage,with significant phenotypic heterogeneity within the family,and family 2 had a significantly higher mean annual number of attacks than family 1[(16.4±11.4)times/year vs(9.5±9.2)times/year].Functional speculation showed that the mutation triggered resting leakage current through defective slow inactivation of the sodium channel,resulting in an abnormally low threshold for muscle membrane excitability.Conclusion SCN4A-T704M mutation is a key pathogenic factor for normoKPP in Chinese families,and its clinical symptoms have the features of both episodic and chronic myopathy.Normal blood potassium and a lack of myotonic discharges support its attribute as an independent disease subtype.Phenotypic heterogeneity may be associated with the interaction between genetic modification and envi-ronmental factors,and calcium overload caused by so-dium channel dysfunction may be a key mechanism of muscle fiber injury.This study provides new evidence for the precise diagnosis and treatment of normoKPP.