PDE10A Mutation as an Emerging Cause of Childhood-Onset Hyperkinetic Movement Disorders: A Review of All Published Cases

Abstract

Cyclic nucleotide phosphodiesterase (PDE) enzymes catalyze the breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which act as intracellular second messengers for signal transduction pathways and modulate various processes in the central nervous system. Recent discoveries that mutations in genes encoding different PDEs, including PDE10A, are responsible for rare forms of chorea in children led to the recognition of an emerging role of PDEs in the field of pediatric movement disorders. A comprehensive literature review of all reported cases of PDE10A mutations in PubMed and Web of Science was performed in English. We included eight studies, describing 31 patients harboring a PDE10A mutation and exhibiting a hyperkinetic movement disorder with onset in infancy or childhood. Mutations in both GAF-A, GAF-B regulatory domains and outside the GAF domains of the PDE10A gene have been reported to cause hyperkinetic movement disorders. In general, patients with homozygous mutations in either GAF-A domain of PDE10A present with a more severe phenotype and at an earlier age but without any extensive abnormalities of the striata compared with patients with dominant variants in GAF-B domain, indicating that dominant and recessive mutations have different pathogenic mechanisms. PDE10A plays a key role in regulating control of striato-cortical movement. Comprehension of the molecular mechanisms within the cAMP and cGMP signaling systems caused by PDE10A mutations may inform novel therapeutic strategies that could alleviate symptoms in young patients affected by these rare movement disorders.

Keywords

PDE10A mutation - hyperkinetic movement disorder - chorea - children - pediatric

Authors Roles

1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the first draft, B. Review and Critique.

S.K.: 1A, 1B, 1C, 2A; G.X.: 1B, 2B, P.B.: 2B, V.C.A.: 1C, 2B, P.C.: 1C, 2B, G.M.H.: 2B.

Disclosures

The authors declare that there are no additional disclosures to report.

Statement: The work was performed at Medical School, University of Cyprus.

Publication History

Received: 21 November 2023

Accepted: 01 March 2024

Accepted Manuscript online:
05 March 2024

Article published online:
26 March 2024

• References

• 1 Erro R, Mencacci NE, Bhatia KP. The emerging role of phosphodiesterases in movement disorders. Mov Disord 2021; 36 (10) 2225-2243
• 2 Whiteley EL, Tejeda GS, Baillie GS, Brandon NJ. PDE10A mutations help to unwrap the neurobiology of hyperkinetic disorders. Cell Signal 2019; 60: 31-38
• 3 Lakics V, Karran EH, Boess FG. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 2010; 59 (06) 367-374
• 4 Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 2006; 58 (03) 488-520
• 5 Azuma R, Ishikawa K, Hirata K. et al. A novel mutation of PDE8B gene in a Japanese family with autosomal-dominant striatal degeneration. Mov Disord 2015; 30 (14) 1964-1967
• 6 Doummar D, Dentel C, Lyautey R. et al. Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia. Eur J Hum Genet 2020; 28 (10) 1403-1413
• 7 Seeger TF, Bartlett B, Coskran TM. et al. Immunohistochemical localization of PDE10A in the rat brain. Brain Res 2003; 985 (02) 113-126
• 8 Nishi A, Kuroiwa M, Miller DB. et al. Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J Neurosci 2008; 28 (42) 10460-10471
• 9 Beazely MA, Watts VJ. Regulatory properties of adenylate cyclases type 5 and 6: A progress report. Eur J Pharmacol 2006; 535 (1-3): 1-12
• 10 Chen YZ, Matsushita MM, Robertson P. et al. Autosomal dominant familial dyskinesia and facial myokymia: single exome sequencing identifies a mutation in adenylyl cyclase 5. Arch Neurol 2012; 69 (05) 630-635
• 11 Mencacci NE, Erro R, Wiethoff S. et al. ADCY5 mutations are another cause of benign hereditary chorea. Neurology 2015; 85 (01) 80-88
• 12 Mencacci NE, Kamsteeg EJ, Nakashima K. et al. De novo mutations in PDE10A cause childhood-onset chorea with bilateral striatal lesions. Am J Hum Genet 2016; 98 (04) 763-771
• 13 Diggle CP, Sukoff Rizzo SJ, Popiolek M. et al. Biallelic mutations in PDE10A lead to loss of striatal PDE10A and a hyperkinetic movement disorder with onset in infancy. Am J Hum Genet 2016; 98 (04) 735-743
• 14 Esposito S, Carecchio M, Tonduti D. et al. A PDE10A de novo mutation causes childhood-onset chorea with diurnal fluctuations. Mov Disord 2017; 32 (11) 1646-1647
• 15 Narayanan DL, Deshpande D, Das Bhowmik A, Varma DR, Dalal A. Familial choreoathetosis due to novel heterozygous mutation in PDE10A. Am J Med Genet A 2018; 176 (01) 146-150
• 16 Fujishige K, Kotera J, Michibata H. et al. Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). J Biol Chem 1999; 274 (26) 18438-18445
• 17 Loughney K, Snyder PB, Uher L, Rosman GJ, Ferguson K, Florio VA. Isolation and characterization of PDE10A, a novel human 3′, 5′-cyclic nucleotide phosphodiesterase. Gene 1999; 234 (01) 109-117
• 18 Ma LL, Wang YY, Yang ZH, Huang D, Weng H, Zeng XT. Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: what are they and which is better?. Mil Med Res 2020; 7 (01) 7
• 19 Miyatake S, Koshimizu E, Shirai I. et al. A familial case of PDE10A-associated childhood-onset chorea with bilateral striatal lesions. Mov Disord 2018; 33 (01) 177-179
• 20 Niccolini F, Mencacci NE, Yousaf T. et al. PDE10A and ADCY5 mutations linked to molecular and microstructural basal ganglia pathology. Mov Disord 2018; 33 (12) 1961-1965
• 21 Bohlega S, Abusrair AH, Al-Qahtani Z. et al. Expanding the genotype-phenotype landscape of PDE10A-associated movement disorders. Parkinsonism Relat Disord 2023; 108: 105323
• 22 Gross-Langenhoff M, Hofbauer K, Weber J, Schultz A, Schultz JE. cAMP is a ligand for the tandem GAF domain of human phosphodiesterase 10 and cGMP for the tandem GAF domain of phosphodiesterase 11. J Biol Chem 2006; 281 (05) 2841-2846
• 23 Tejeda GS, Whiteley EL, Deeb TZ. et al. Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme. Proc Natl Acad Sci U S A 2020; 117 (01) 677-688
• 24 Knopp C, Häusler M, Müller B. et al. PDE10A mutation in two sisters with a hyperkinetic movement disorder—response to levodopa. Parkinsonism Relat Disord 2019; 63: 240-242
• 25 Wang H, Liu Y, Hou J, Zheng M, Robinson H, Ke H. Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci U S A 2007; 104 (14) 5782-5787
• 26 Bonate R, Kurek G, Hrabak M. et al. Phosphodiesterase 10A (PDE10A): regulator of dopamine agonist-induced gene expression in the striatum. Cells 2022; 11 (14) 2214
• 27 Delnomdedieu M, Tan Y, Ogde A, Berger Z, Reilmann R. A randomized, double-blind, placebo-controlled Phase II Efficacy and Safety Study of the PDE10A inhibitor PF-02545920 in Huntington Disease (AMARYLLIS). Mov Disord 2018; 33 (02) x
• 28 Deng WT, Kolandaivelu S, Dinculescu A. et al. Cone phosphodiesterase-6γ′ subunit augments cone PDE6 holoenzyme assembly and stability in a mouse model lacking both rod and cone PDE6 catalytic subunits. Front Mol Neurosci 2018; 11: 233