De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions

Abstract

Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions 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 modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.

Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome

“…Clinical trio‐based WES of Family 1 and WGS of the Israeli probands and their parents (Family 2) were performed as previously described 9, 10. Immortalized lymphoblastoid cell lines were used for RNA extraction, reverse transcription polymerase chain reaction (RT‐PCR) analysis, and semiquantitative RT‐PCR assay.…”

Imaging in Parkinson's Disease

“…Positive evidence on the role of PDE10A in movement disorders comes from recent genetic studies on PDE10A gene mutations (Diggle et al, 2016;Mencacci et al, 2016). Patients with homozygous (Diggle et al, 2016) and heterozygous (Mencacci et al, 2016) PDE10A mutation present with benign childhood-onset chorea that may be followed by adult-onset levodopa-responsive parkinsonism (Mencacci et al, 2016 (Pagano, Niccolini, Fusar-Poli, et al, 2017;Pagano, Niccolini, & Politis, 2016a, 2016b spanning from far-onset premanifest stages (Niccolini, Foltynie, et al, 2015;Niccolini, Haider, et al, 2015) to early manifest (Russell et al, 2014(Russell et al, , 2016 and advanced (Ahmad et al, 2014) manifest HDGECs. Thus, PDE10A activity is critical for the control of movements and for neuronal survival and could serve as a novel therapeutic target for manipulation with pharmacotherapy in the neuropathological salient circuits, which promote neuronal survival and control of movements.…”

A familial case of PDE10A‐associated childhood‐onset chorea with bilateral striatal lesions

“…[1][2][3] Studies have shown that peripheral vibrotactile stimulation accesses central sensory networks and produces a characteristic cortical response. 4 In this study, we investigated the tolerability and efficacy of peripheral vibrotactile coordinated reset stimulation (PVCRS) 5 in 5 subjects with idiopathic Parkinson's disease (PD).…”

“…2,3 Recently, de novo mutations in PDE10A were identified in 3 individuals with childhood-onset, scarcely progressive chorea and bilateral striatal lesions identified by MRI. 4 Here, we present a Japanese family with BHC having a PDE10A mutation over three generations (Fig. 1A).…”

“…Although p.Phe300Leu does not affect its basal catalytic activity, it severely disrupts the stimulatory effect mediated by cAMP binding to the GAF-B domain. 4 The clinical picture provided by our family implies a clinical consequence of simple PDE10A inhibition, which has been targeted for basal ganglia diseases.…”