Pharmacogenetic pilot study of CYP2D6 and CYP1A2 genes in Italian patients with non-dystrophic myotonia and myotonic dystrophy treated with mexiletine

Mexiletine (MXT) is the first-line anti-myotonic drug for myotonic dystrophies (MD) and non-dystrophic myotonias (NDM), metabolized by CYP2D6 and CYP1A2 enzymes. We investigated genetic variants in these genes and their influence on MXT response in Italian MD and NDM patients. Fifty patients (MD: 34, NDM: 16) were treated with MXT (200–600 mg daily) for at least two months. Based on the Myotonic Behaviour Scale (MBS) and neurological examination, 37 patients (74 %) were classified as responders (R), while 13 (26 %) were non-responders (NR). Comparison between R and NR revealed associations with 14 genetic variants (12 in CYP2D6, 2 in CYP1A2). In silico analysis suggested eQTL effects on liver and skeletal muscle gene expression. Functional annotation indicated the regulatory roles of these variants. The CYP2D6*2/*41 diplotype showed a nominal association with non-response (OR = 10.8, p = 0.049), being 11 times more frequent in NR (23 %) than in R (3 %). Most common diplotypes (CYP2D6*1/*2, *1/*1, *1/*10, *2/10) corresponded to Normal Metabolizers, while CYP2D6*10/*10, *10/*41, and *41/41 indicated intermediate metabolism, suggesting a higher risk of adverse reactions with concurrent drugs. The CYP2D6*41 allele was more frequent in NR patients than in the European population, supporting its role in MXT response variability. Our findings suggest CYP2D6 and CYP1A2 variants as potential predictors of MXT treatment response in MD and NDM patients.