Symptom Burden and Patient Priorities in Alternating Hemiplegia of Childhood

ABSTRACT Objective Our aim was to quantify symptom burden and caregiver priorities in alternating hemiplegia of childhood (AHC), where intermittent and heterogeneous symptoms complicate endpoint development. Methods We conducted a cross‐sectional caregiver‐reported study of 186 participants with a 6‐month recall. Caregivers reported symptom presence, frequency, duration, and priorities for mitigation. Episode frequency and duration were multiplied to estimate monthly burden of each paroxysmal symptom across the cohort and subgroups stratified by gene, ATP1A3 genotype, age, and sex. Results Caregivers prioritized elimination of paroxysmal over non‐paroxysmal symptoms; catastrophic episodes, seizures, dystonia, and plegia were highest priorities. Median individual paroxysmal burden was 52 h/month. Paroxysmal burden was dominated by plegia and dystonia (10 and 3 h/month). Symptoms varied with age, gene, and genotype. The ATP1A3 D801N variant was associated with longer, higher‐burden plegia, dystonia, and episodes of breathing or swallowing difficulties, whereas the E815K variant was associated with shorter, more frequent seizures, plegia, and spells of reduced consciousness. Adults experienced shorter, more frequent plegia and dystonia episodes, while seizure frequency declined with age. ATP1A3 patients had higher prevalence of seizures and motor impairment; non‐ ATP1A3 patients had a higher prevalence of autonomic and non‐motor features. Seizure burden was not correlated with plegia or dystonia burden. Composite burden measures did not preserve subgroup differences observed for individual symptoms. Interpretation Integrating symptom burden, subpopulation specificity, and patient priorities can guide endpoint selection in AHC. Endpoints capturing how patients experience symptoms may improve sensitivity to treatment effects. This approach may inform endpoint selection in other rare diseases lacking natural history data.