Abstract
BACKGROUND: Breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in basal ganglia cells through hydrolysis of diesteric bonds, primarily by PDE10A and PDE1B, is essential for normal human movement. While biallelic loss-of-function variants in PDE10A are known to cause hyperkinetic movement disorders, the role of PDE1B in human disease has not been characterized. OBJECTIVES: We aimed to define the phenotypic and molecular characteristics of a novel autosomal recessive disorder caused by biallelic PDE1B variants. METHODS: Clinical phenotyping by senior geneticists and neurologists, followed by whole exome sequencing, segregation analysis (Sanger sequencing), and molecular studies, including mini-gene splicing assays and protein studies in transfected HEK293 cells. RESULTS: Seven affected individuals from five unrelated pedigrees presented with an apparently autosomal recessive disorder characterized by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with developmental delay and intellectual disability. Biallelic PDE1B variants were identified in all affected individuals: three truncating (p.Q45*, p.Q86*, p.S298Afs*6) and three splicing variants (c.594 + 2 T>G, c.735 + 5G>A, c.837-1G>C). Functional studies confirmed that the truncating variants caused loss of the catalytic domain, resulting in truncated or absent functional protein. Splicing variants led to exon skipping, frameshifts, and catalytic domain disruption. These findings establish a causative link between biallelic PDE1B variants and the observed clinical phenotype. CONCLUSIONS: Biallelic loss-of-function variants in PDE1B underlie a novel early-onset movement disorder resembling the phenotype associated with PDE10A deficiency. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.