Genotype-dependent response to combined levodopa/benserazide and trihexyphenidyl in pediatric genetic dystonia

BACKGROUND: Genetic etiologies underlie a substantial proportion of pediatric dystonia, but whether treatment response to combined dopaminergic and anticholinergic therapy varies by genotype remains unknown. METHODS: This retrospective cohort study analyzed 36 children with genetically confirmed dystonia, classified into three subgroups: PANK2 (n = 7), channelopathies (SCN1A/SCN2A/SCN3A/SCN1B, KCNQ2; n = 6), and other monogenic etiologies (n = 23; 19 distinct genes). All received levodopa/benserazide and trihexyphenidyl combination therapy for 16 weeks. Outcomes included Barry-Albright Dystonia Scale (BADS), Gross Motor Function Measure-88 (GMFM-88), Quality of Upper Extremity Skills Test (QUEST), and Cerebral Palsy Quality of Life Questionnaire (CP-QOL). RESULTS: Treatment response was genotype-dependent. PANK2 patients showed excellent improvement (ΔBADS -6.6 ± 3.0; ΔGMFM-88 + 49.6 ± 45.8). Other monogenic patients showed moderate improvement comparable to our cerebral palsy cohort (ΔBADS -6.1 ± 1.9; ΔGMFM-88 + 32.2 ± 26.5). Channelopathy patients derived minimal benefit (ΔBADS -3.5 ± 1.2; ΔGMFM-88 + 6.2 ± 2.9; p < 0.001 compared to both other groups). All six patients with status dystonicus (all in the other monogenic group) responded excellently. Adverse event rates were comparable across groups (p = 0.61). CONCLUSIONS: Genotype determines treatment response to levodopa/benserazide and trihexyphenidyl in pediatric genetic dystonia. PANK2 and most other monogenic etiologies respond well, while channelopathies derive minimal benefit. Genotype, not severity, guides therapy.