Phosphodiesterase 10A (PDE10A) controls body movements by regulating cyclic adenosine monophosphate signaling in the basal ganglia. Two classes of PDE10A variants are reported with distinctive genotype-phenotype correlation. The autosomal recessive mutations in the GAF-A and catalytic domains are associated with compromised membrane localization, and manifested with infantile onset chorea, developmental, and cognition delay with normal brain MRI.  Conversely, autosomal dominant mutations in the GAF-B domain cause protein aggregates which results in childhood onset chorea in the context of normal cognition and development despite striatal nigral lesions. Herein, we report four cases of PDE10A-related chorea in a native Arab family with biallelic mutations in PDE10A.

Phenotypic characteristics of affected family members with PDE10A mutations were recorded, in addition to Sanger sequencing and in silico analysis to identify the mutations.

Four individuals from a consanguineous family affected with PDE10A mutations were observed for up to 40 years. Although these individuals displayed a clinical phenotype attributed to the recessive GAF-A mutations, they revealed an autosomal recessive GAF-B mutation (c.883G>A:p. D295N; p.Asp295Asn) that was segregated from all affected individuals. In addition to chorea, we observed peculiar foot deformities and pronounced social phobia. In silico structural analysis suggested that the GAF-B mutation blocked allosteric PDE10A activation. The resulting lack of PDE10A activity without protein aggregation photocopies GAF-A mutations but is achieved through a distinct mechanism.

Collectively, our work explains the recessive and dominant phenotypes of known variants and expands the genotype-phenotype landscape of PDE10A-associated movement disorders.