A clinical prediction rule for myotonia permanens associated with the SCN4A p.Gly1306Glu variant

Myotonia permanens (MP), a life-threatening condition, is prevalent in Chile, and is frequently associated with the SCN4A p.Gly1306Glu variant (exon 22), likely due to a founder effect in this population. Low clinical suspicion and the high cost of genetic testing contribute to delayed diagnosis and impaired quality of life. This study aimed to develop a clinical prediction rule (CPR) for early MP-p.Gly1306Glu detection specially in Chile, and confirm diagnosis through genetic testing.

This cross-sectional study was conducted at five Chilean hospitals and included healthy controls and patients with non-dystrophic myotonia (NDM). Participants were classified as controls, MP-p.Gly1306Glu, or non-permanens myotonia (NPM). Diagnosis was confirmed by SCN4A exon 22 sequencing or a gene panel (SCN4A, CLCN1). Fisher's exact test and logistic regression were used to identify clinical predictors of MP.

A total of 19 controls and 17 patients with NDM (MP-p.Gly1306Glu/NPM = 8/9; mean age: 36 years) were included. Four predictors of MP-p.Gly1306Glu were identified: eyelid myotonia before age 2 (predictive value [PV] = 100%), myotonic discharges ≥28/30 s (PV = 95%), laryngospasm before age 2 (PV = 94%), and generalized myotonia before age 5 (PV = 88%). If all four predictors are present, MP-p.Gly1306Glu is highly probable and SCN4A exon 22 sequencing is recommended. If one to three predictors are present, targeted sequencing or a gene panel is advised, depending on clinical context.

This CPR may facilitate early diagnosis of MP-p.Gly1306Glu and improve clinical outcomes, especially in Chile, and possibly other resource-limited settings, by guiding timely genetic confirmation and management. These predictors may support diagnostic criteria for MP/NPM, and guide future clinical trial design.