Objective: To identify the underlying genetic abnormality in three sporadic unrelated cases presenting with chorea and bilateral striatal abnormalities on cerebral MRI.

Background: Chorea is a major feature of several inherited neurological disorders. Functional dysregulation of striatal GABAergic medium spiny neurons (MSNs), which form the main basal ganglia output projections, is considered to underlie the pathophysiology of the choreic movements.

Methods: Whole exome sequencing was performed in all three cases and in the unaffected parents of case 1 and 2. Filtering of variants focused on de novo dominant or recessive mutations. We determined the overlap for damaging mutations (defined as nonsense, frameshift, canonical splice site, predicted damaging missense mutations based on CADD scores >20) with a minor allele frequency <1% in Exome Aggregation Consortium and in an in-house database containing >10,000 individuals.

Results: All three cases presented in early-childhood with a scarcely progressive movement disorder dominated by chorea. Developmental milestones were normal and there were no other major neurological features, in particular intellectual disability or cognitive decline. Brain MRI consistently showed in all three cases striking bilateral T2 hyperintensity within the striatum, which is an atypical finding for BHC and is more often observed in metabolic and mitochondrial diseases affecting the basal ganglia. All cases were identified to carry a de novo heterozygous mutation in PDE10A (p.Phe300Leu in two cases and p.Phe334Leu in one case), encoding a phospodiesterase highly and selectively expressed in MSNs. PDE10A contributes to the regulation of the intracellular levels of cAMP and cGMP. Both mutations affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modelling shows that the mutated residues are located deep into the binding pocket, where they are likely to alter cAMP-binding properties.

Conclusions: The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signalling in MSNs, and highlights the crucial role of striatal cAMP signalling in the regulation of basal ganglia circuitry. The pharmacological modulation of this pathway may offer promising aetiologically-targeted treatments for chorea and other hyperkinetic disorders.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/de-novo-mutations-in-pde10a-cause-childhood-onset-chorea-with-bilateral-striatal-lesions/