Natural History of Alternating Hemiplegia of Childhood: Vulnerabilities in Early Childhood and Predictive Factors for Long‐Term Outcomes

Abstract

Objective: The natural history of the most common ATP1A3-related disease, alternating hemiplegia of childhood (AHC), has not been determined. We investigated three hypotheses: (1) AHC worsens over time; (2) several novel factors correlate with long-term outcomes; and (3) AHC manifests high mortality. Methods: In a large cross-sectional study with a nested period of prospective 1–3-year follow-up, 115 patients (0.3–46.0 years old, 9 centers/5 countries) were evaluated using across-center-standardized protocol and validated scales. Univariable and multivariable linear-mixed-effects models with random intercepts and random slopes for age, adjusted for confounding variables, allowed for the determination of the effect of age throughout the total age range of patients studied. Results: Course: We identified a distinction between two periods, namely the period of early childhood (age 1–5 years) and the period of later childhood to mid-adulthood. Intellectual and non-paroxysmal disability indexes (IDS, NPDI) scores as well as the Vineland Adaptive Behavior Composite and its subscales worsened during early childhood, but not in the period after that. The extent of motor skills impairment did not differ with age in either period. Within the PDI (paroxysmal disability index) scores, dystonia severity scores did not differ with age in either period; however, plegia severity scores did improve with age after 5 years of age. Prognostic variables included the following: (1) Epilepsy was associated with worse NPDI, intellectual, and fine and gross motor skills. (2) Worse early life PDI and NPDI scores were significantly associated with worse respective scores at the latest follow-up. (3) Worse early life NPDI scores were also associated with worse IDS and fine and gross motor scores at the latest follow-up. (4) D801N mutation was associated with worse PDI. (4) E815K mutation was associated with worse IDS. Mortality was 1.12 deaths/100 patient-years and 6.5 sudden unexpected death in epilepsy (SUDEP) deaths/1000 patient-years. Interpretation: AHC is a progressive disease, and early childhood is the vulnerable period. We identified several novel prognostic indicators and a mortality rate, which provide critical information not only regarding prognostication, counseling, and underlying pathophysiology but also for planning therapeutic studies.