Clinical and genetic features of SCN4A-T704M mutation-related normokalemic periodic paralysis：A report of two Chinese families and mechanism of phenotypic heterogeneity
10.19845/j.cnki.zfysjjbzz.2026.0012
- VernacularTitle: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
- Author:
Qianqian XIONG
1
;
Xueming LI
2
Author Information
1. 江西省丰城市人民医院神经内科， 江西 丰城 331100
2. 南昌大学第二附属医院全科医学科， 江西 南昌 330000
- Publication Type:Journal Article
- Keywords:
Normokalemic periodic paralysis;
SCN4A-T704M mutation;
Phenotypic heterogeneity;
Sodium channel disease
- From:
Journal of Apoplexy and Nervous Diseases
2026;43(1):70-75
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the clinical features， genetic basis， and phenotypic heterogeneity mechanism of normokalemic 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 related clinical data were collected， including medical history， test results， electrophysiology， and muscle pathology. Sanger sequencing 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 weakness （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 suggested 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 environmental factors， and calcium overload caused by sodium channel dysfunction may be a key mechanism of muscle fiber injury. This study provides new evidence for the precise diagnosis and treatment of normoKPP.
