Mexiletine prevents transient heart failure in a polymicrogyria child with an ATP1A3 variant: a case report

Abstract Background Several variants in ATP1A3, a gene encoding the α3-subunit of Na+/K+ adenosine triphosphatase (Na–K–ATPase), are reportedly involved in polymicrogyria. Some cases exhibit transient heart failure (HF); however, its underlying mechanism and prevention strategy remain unknown. Case summary The patient was a 5-year-old female who suffered from intractable seizures since birth and was diagnosed with polymicrogyria based on a head magnetic resonance imaging scan. Whole-exome sequencing identified a de novo heterozygous ATP1A3 variant, c.2976_2978del, p.(Asp992del). At 4 years of age, she experienced transient HF for the first time. Because bradycardia could trigger transient HF, we administered cilostazol. However, her bradycardia and subsequent transient HF recurred every few months. Therefore, mexiletine was initiated as an upstream therapy. During 1.5 years of follow-up, she has not experienced HF except once when she could not take mexiletine because of vomiting. Discussion Loss of function of the Na–K–ATPase caused high concentrations of intracellular Na+ and subsequent increments in Ca2+ via the Na+/Ca2+ exchanger in the steady state. An augmentation of the late Na+ current (INa, L) due to bradycardia may have led to further increments of intracellular Na+ and Ca2+, causing myocardial stunning. Based on the proposed pathophysiological mechanism, we selected mexiletine, which blocks Na+ channels particularly in the inactivated state, reducing INa, L and the subsequent Ca2+ overload. Mexiletine was administered safely, successfully preventing transient HF.