Successful Lisdexamfetamine Treatment for Behavioral Arrests, Paroxysmal Nonkinesiogenic Dyskinesia, and Attention Deficits Due to a Previously Unreported KCNMA1 Variant

Abstract

Disease-causing variants in KCNMA1 are associated with a spectrum of epilepsy and/or movement disorders, often with additional developmental issues or intellectual impairment. Monoallelic gain-of-function variants often lead to paroxysmal nonkinesigenic dyskinesia (PNKD). While the treatment mechanism is unknown, dextroamphetamine and its prodrug lisdexamfetamine have been shown to successfully control the debilitating PNKD with up to several hundred daily incidents in one patient with the KCNMA1 (NM_001161352.2) c.1606A > C p.(Asn536His) and six patients with the c.3158A > G p.(Asn1053Ser) variant. Via exome sequencing, a monoallelic KCNMA1 c.2367C > A, p.(Asp789Glu) variant was detected in a 7-year-old girl with daily behavioral arrests, tremors, and drop attacks/PNKD occurring every 8 weeks. The girl had moderate difficulties in mainstream school and experienced challenges in her social life as she was easily fatigued. Additionally, she was heat-intolerant and unable to sweat. Lisdexamfetamine treatment led to cessation of the neuro(psycho)logical symptoms, better functioning in daily life and at school during more than 2 years of follow-up. This report illustrates the importance of an exact, genetic diagnosis for successful individual treatment. It adds another previously unreported variant in KCNMA1. Furthermore, this case increases the evidence for a broader treatment effect of lisdexamfetamine for KCNMA1 variants beyond its known effects on the control of muscle tone, in this case illustrated by better social interaction, improved attention/school performance, and mood. Finally, the previously unreported findings of heat intolerance and inability to sweat may extend the phenotypic spectrum associated with KCNMA1 variants.

Keywords

rare disease - treatment - concentration - exome - epilepsy - movement disorder

^‡ Equal contribution.

Publikationsverlauf

Eingereicht: 23. Juni 2025

Angenommen: 25. Juli 2025

Artikel online veröffentlicht:
14. August 2025

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