The Genetic Landscape of Complex Childhood‐Onset Hyperkinetic Movement Disorders

ABSTRACT Background and Objective The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early‐onset, monogenic hyperkinetic movement disorders. Methods Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria. Results One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism‐dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5‐, ATP1A3‐, FOXG1‐, NKX2.1‐, SLC2A1‐, GNAO1‐, and PDE10A‐related disorders; and stereotypies were a prominent feature in FOXG1‐ and GNAO1‐related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P