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

Introduction

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 such as neurogenesis, apoptosis, and plasticity.[1] [2] [3] PDEs are encoded by 21 genes, which produce 11 distinct PDE families (PDE1–PDE11).[4] Specific PDE enzymes are highly expressed in brain regions involved in cognitive and motor functions.[3] Recent discoveries that mutations in genes encoding different PDEs, including PDE2A, PDE8B, and PDE10A, are responsible for rare forms of monogenic parkinsonism and chorea led to the recognition of an emerging role of PDEs in the field of movement disorders.[1] [2] [5] [6]

Across PDE families, phosphodiesterase 10A (PDE10A) is almost exclusively detected in the brain.[3] It is enriched in the GABAergic medium spiny neurons (MSNs) of the striatum, although reduced levels of the enzyme are also present in the cerebellum, hippocampus, and cortex.[7] Striatal cAMP activity in MSN modulates movement and is determined from the balance between its synthesis by adenylate cyclase 5 (ADCY5) and its degradation by PDE10A.[8] [9] Functional dysregulation of either gene increases cAMP levels and causes chorea and other hyperkinetic movement disorders.[10] [11] [12] [13] Indeed, the role of PDE10A in the regulation of coordinated movement has been further established by both dominant and recessive mutations in this gene as causes of childhood-onset hyperkinetic syndromes.[12] [13] [14] [15]

PDE10A gene is a large housekeeping gene (spanning over 200 kb), mapped to chromosome 6q26-q27, containing 24 exons.[16] [17] PDE10A protein has an N-amino- and a C-carboxyl-terminal region as well as two regulatory GAF domains, GAF-A and GAF-B, the latter containing an cAMP binding site.[2] Mutations in both GAF-A, GAF-B domains and outside the GAF domains have been reported to cause hyperkinetic movement disorders.[2] In this paper, we summarize all reported cases of PDE10A pathogenic mutations, leading to a hyperkinetic phenotype with onset in infancy or childhood, focusing on genotype-phenotype correlations.

Methods

A comprehensive literature review of all reported cases of PDE10A mutations was performed. We searched PubMed and Web of Science databases in English using the following search terms “PDE10A mutation” OR “PDE10A gene mutation.” The inclusion criteria comprised (1) original studies or case reports (reviews, editorials were excluded), (2) full text written in English, and (3) human subjects involved (animal or molecular studies were excluded). The included studies were assessed for their quality using Joanna Briggs Institute Critical Appraisal Checklist for Case Reports; all of them reached high score.[18] The flow chart of the studies included in this review can be seen in [Fig. 1].

Fig. 1 Flow-chart of the included studies.

Results

We included eight studies, describing 31 patients in total harboring a PDE10A mutation and exhibiting a hyperkinetic movement disorder. The majority of studies were case series and only two were case reports. Characteristics such as age, gender, age of onset, age of diagnosis, ethnicity, location of mutation, symptoms, imaging findings, and outcomes were retrieved from the included studies and can be seen in [Table 1].

Table 1 Case reports of patients with PDE10A mutations

Authors year	Gender	Age of onset	Age of diagnosis	Ethnicity	Mutation	Heterozygous/homozygous De novo/inherited	Location of mutation	Symptoms	Imaging findings	Treatment	Outcome
Mencacci et al. 2016[12]	Male	5 y	11 y	Dutch	c.1000T > C p.Phe334Leu	Heterozygous, de novo	GAF-B domain	Chorea	Slight edema of striata with restricted diffusion	n/a	n/a
Mencacci et al. 2016[12]	Female	8 y	22 y	British	c.898T > C p.Phe300Leu	Heterozygous, de novo	GAF-B domain	Chorea, anxiety	Bilateral striatal hyperintensities and atrophy	n/a	n/a
Mencacci et al. 2016[12]	Female	5 y	60 y	British	c.898T > C p.Phe300Leu	Heterozygous,de novo	GAF-B domain	Chorea affecting face and limbs Adult-onset parkinsonism	T2 hyperintensity within the posterolateral putamina	n/a	n/a
Diggle et al. 2016[13]	4 Female, 2 male (family)	Early infancy	n/a	Pakistani (consaguineous)	c.320A > G p.Tyr107Cys	Homozygous, inherited	GAF-A domain	Generalized hyperkinetic movement disorder, drooling, dysarthria	Normal MRI brain in three individuals	n/a	n/a
Diggle et al. 2016[13]	2 Male (brothers)	Early infancy	Childhood	Finnish (consaguineous)	c.346G > C p.Ala116Pro	Homozygous, inherited	GAF-A domain	Generalized hyperkinetic movement disorder, hypotonia, mild cognitive delay, dysarthria, focal epilepsy in the youngest child	Normal MRI brain	n/a	n/a
Esposito et al. 2017[14]	Male	2.5 y old	5 y	Italian	c.1000T > C, p.Phe334Leu	Heterozygous, de novo	GAF-B domain	Chorea involving the lower limbs later on generalized, upper limb dystonia	Bilateral hyperintense lesions of putamen and caudate on T2, FLAIR and DWI	Trihexyphenidyl (1 mg/d), discontinued because of behavioral changes	2 y-follow-up: no progression, unchanged brain MRI
Narayanan et al. 2017[15] 7 family members (4 female, 3 male)	Female-patient 1	5 y	24 y	Indian	c.1001Τ > G p.Phe334Cys	Heterozygous, inherited	GAF-B	Chorea starting from hands, progressed to face and head, dysarthria, difficulty in writing	Hyperintensities on T2 and FLAIR, volume loss in putamina and caudate nuclei	n/a	n/a
Narayanan et al. 2017[15]	Male-father of patient 1	3 y	60 y	Indian	c.1001Τ > G p.Phe334Cys	Heterozygous, inherited	GAF-B	Chorea	n/a	n/a	n/a
Miyatake et al. 2017[19]	4 Family members	n/a	15,43, 46, and 82 y	Japanese	c.898T > C p.Phe300Leu	Heterozygous, inherited	GAF-B	15-year-old (proband): choreatic movements around the neck 43 year-old (mother) and 46 year-old (uncle): generalized chorea 82 year-old (grandfather): generalized chorea, stammering	MRI brain proband and mother: T2 hyperintensities in the striatum, DWI restriction in the striatum of the proband, atrophy of putamen in the mother	n/a	n/a
Niccolini et al. 2018[20]	n/a	Childhood	Adult	n/a	c.199G > C resulting in p.Glu67Gln, C.1873a > T resulting in p.Ile625Phe	Compound heterozygote, inherited	N-terminal and GAF-B domain	Paroxysmal non-kinesiogenic dyskinesias	[11C]IMA107* decreased in the basal ganglia	n/a	n/a
Knopp et al. 2018[24]	Female (2 sisters)	7 and 10 months	10 mo and 6 y	Afghan	p.(Leu675Pro)	homozygous, inherited	Catalytic domain	Hypotonia, microcephaly,hyperkinetic movements, developmental delay, seizures	MRI and MR spectroscopy in both sisters: no basal ganglia abnormalities	Beneficial response of levodopa within two weeks	n/a
Bohlega et al. 2023[21]	3 Female, 2 male	Infancy	19,33,34,42 y old	Arab	p.Asp295Asn	Homozygous, inherited	GAF-B domain	Developmental and cognitive delay, chorea of face, limbs, trunk, limb dystonia, feet deformities	Normal brain MRI	No effect of levodopa	Progressive chorea

Abbreviations: DWI, diffusion weighted imaging; MRI, magnetic resonance imaging; n/a, not available, [¹¹C]IMA107*: selective radioligand for PDE10A.

Mutations in Different Domains of PDE10A Gene

Mutations in GAF-A Domain

In affected members of two unrelated consanguineous families of Pakistani and Finnish origin with infantile-onset limb and orofacial dyskinesia (IOLOD; OMIM 616921), Diggle et al identified two different homozygous missense mutations in PDE10A gene (c.320A > G resulting in p.Tyr107Cys and c.346G > C resulting in p.Ala116Pro) in exon 4 in GAF-A domain.[13] The patients suffered from a generalized hyperkinetic movement disorder with dyskinesia of the limbs and trunk as well as orofacial dyskinesia and dysarthria. There was considerable variation in severity of symptoms within the members of the family of Pakistani origin with older individuals being less severely affected. All family members had preserved cognitive performance. Interestingly, patients with mutations in the GAF-A domain had normal magnetic resonance imaging (MRI) scans.[13] However, positron emission tomography (PET) using [¹¹C]IMA107, a selective radioligand for PDE10A quantification, showed 70% decrease in striatal PDE10A expression in one subject carrying this mutation.[13] Expression of the mutation in cell lines (HEK293 cells) showed that it caused a significant decrease in PDE10A levels.[13] The degree of decrease was greater in the Finnish family than in the Pakistani family, reflecting probably a more severe phenotype.[13] Heterozygous carriers for these variants (parents of Finnish brothers) did not exhibit any symptoms. Thus, it can be assumed that the motor abnormalities produced by GAF-A mutations are the result of reduced PDE10A activity in the striatum due to reduction of protein levels.

Mutations in GAF-B Domain

On the other hand, heterozygous PDE10A mutations in GAF-B domain have been implicated in a scarcely progressive childhood-onset choreatic movement disorder with bilateral striatal hyperintensity on MRI (autosomal dominant striatal degeneration-2, ADSD2; OMIM 616922).[12] [14] [15] [19] [20] All patients with mutations in the GAF-B domain met cognitive and developmental milestones. Miyatake et al reported a clinical picture similar to benign hereditary chorea.[19] Unlike GAF-A domain mutations, MRI of affected individuals showed bilateral striatal hyperintensities, while some patients[12] [14] [19] showed restricted diffusion, indicative of an active disease. Adult carriers of p.F300L mutation exhibited striatal atrophy and nigrostriatal degeneration i.a loss of neuromelanin-containing neurons within the substantia nigra.[12] In the same patients, presynaptic dopaminergic binding was reduced.[12] However, there has been recently reported an Arab family with five affected members carrying a homozygous mutation in GAF-B domain exhibiting a more severe phenotype resembling GAF-A mutations.[21] Diurnal fluctuation of choreatic movements (chorea being more severe in the morning) were reported in only few patients.[14] [21] Few patients with mutations in GAF-B domain also exhibited limb dystonia.[14] [21]

On a molecular level, GAF-B mutations probably alter the morphology of cAMP deep binding pocket, where cAMP is bound and activates the wild-type enzyme.[22] Mencacci and colleagues reported that p.F300L and p.F334L mutations did not affect the basal activity of the enzyme; however, they inhibited the cAMP-stimulatory effect for cGMP hydrolysis.[12] Therefore, these mutations may not impair basal PDE10A activity but affect the positive regulatory mechanism of cAMP binding to GAF-B domain on PDE catalytic activity.[2] [12] On the other hand, Niccolini et al in a PET study using [11C]IMA107 showed that subjects carrying the F300L mutation exhibited a significant decrease in striatal PDE10A levels.[20] Generally, mutations in the regulatory GAF domains lead to misprocessing of PDE10A enzyme, which leads to targeted degradation by the ubiquitin proteasome system or clearance by autophagy. Both mechanisms result in alteration of PDE10A activity that leads to loss of movement coordination.[23]

Mutations Outside GAF-Domains

Knopp et al described two severely affected sisters of Afghan origin with marked muscular hypotonia, hyperkinetic movements, and delay in motor development, who carried a homozygous missense mutation (p.Leu675Pro) in the C-terminal (catalytic domain) of PDE10A.[24] Both their parents (consanguineous) and healthy brother were heterozygous carriers. MRI brain and MR spectroscopy did not show any basal ganglia abnormalities. These patients, similar to mutations in the GAF-A domain, showed early manifestations of symptoms and normal brain MRI scans. Mutations within the catalytic domain of PDE10A[20] [24] probably affect the ability of the enzyme to hydrolyze cyclic nucleotides.[25] Finally, a compound heterozygous mutation in an area outside the GAF domains (c.199G > C; p.E67Q and c.1873A > T; p.I625F) has been detected in one individual with childhood onset paroxysmal nonkinesigenic dyskinesia.[20] The patient showed fronto-parietal cortical atrophy without striatal degeneration, suggesting a prominent role of PDE10A not only in the basal ganglia but in the whole motor circuit.

Interestingly, in comparison to patients with dominant (heterozygous) PDE10A mutations,[12] [14] [15] [19] 10 reported patients of three families with homozygous PDE10A mutations showed a severe phenotype with a generalized hyperkinetic movement disorder and developmental delay in some cases but no striatal lesions on MRI.[13] [24] Moreover, homozygous mutations carriers had an earlier age of onset, that is, within the first few months after birth or early infancy compared with heterozygous mutations, which became clinical apparent in the age of 2.5 to 8 years of age.

Pathophysiology of PDE10A Mutations

The PDEs most abundant in the basal ganglia are PDE1B and PDE10A, which are equally expressed in caudate nucleus.[3] PDE10A concentrations in caudate nucleus and nucleus accumbens are at least 10-fold higher than in any other CNS areas.[3] PDE10A expression is most abundant in the sensorimotor striatum, intermediate in the associative striatum and lower in the limbic striatum.[26] This might explain the fact that patients carrying a PDE10A mutation had mainly motor impairment without serious cognitive or behavioral symptoms. PDE10A is specifically found at high levels in the striatal GABAergic MSN, which receive input from the cortex and thalamus. The high expression of PDE10A in the postsynaptic region helps PDE10A to orchestrate incoming cortical glutaminergic and midbrain dopaminergic signals, regulating MSN sensitivity and influencing various behaviors including movement and motivation.[2] PDE10A is expressed in both D1R-(dopamine receptor) expressing striatonigral MSNs of the direct pathway, which promote movement, and D2R expressing striatopallidal MSNs of the indirect pathway, which inhibit movement, but it might regulate them differentially.[2] D1 receptors stimulate and D2 receptors inhibit second messenger signaling.[26] The observed hyperkinetic phenotype in humans may suggest that PDE10A mutations predominantly affect D1R-expressing MSN of the direct pathway.

The activation of these pathways within the striatum relies on the tuning of intracellular second messenger molecules, cAMP and cGMP. Binding of dopamine to D1R triggers cAMP synthesis and neural excitability.[2] PDEs terminate such second messenger signaling by degrading cyclic nucleotides.[26] PDE10A might function as a “brake” for MSN activation, in case of high intracellular levels of cAMP. Indeed, there is increasing evidence that abnormal cyclic nucleotide signaling in basal ganglia circuitry can contribute to the development of movement disorders.[1] Interestingly, both GNAL and ADCY5 mutations that cause hyperkinetic movement disorders result in alteration of cAMP synthesis, that is, GNAL mutations result in reduced cAMP synthesis while the majority of pathogenic ADCY5 mutations increase cAMP production.[1] This indicates that regulation of cAMP plays an important role in the pathophysiology of genetic hyperkinetic movement disorders. [Fig. 2] shows the molecular mechanisms of PDE10A enzyme.

Fig. 2 Cellular mechanisms of PDE10A in medium spiny neurons Abbreviations: PDE10A: Phosphodiesterase 10A enzyme, D1R: dopamine D1 receptor, D2R: dopamine D2 receptor, ATP: Adenosine triphosphate, GTP: Guanosine-5′-triphosphate, cAMP: cyclic adenosine monophosphate, cGMP: Cyclic guanosine monophosphate, ADCY5: Adenylate Cyclase 5 protein Abnormal cyclic nucleotide signaling in basal ganglia circuitry can contribute to the development of hyperkinetic movement disorders. Striatal cAMP in medium spiny neurons (MSN) is determined from the balance between its synthesis by ADCY5 and its degradation by PDE10A. PDE10A is expressed in both D1Rexpressing striatonigral MSNs of the direct pathway (shown on green background) and D2R expressing striatopallidal MSNs of the indirect pathway (shown on red background). The activation of these pathways within the striatum relies on the tuning of the intracellular second messenger molecules, cAMP and cGMP.

Possible Treatments for PDE10A Mutation Carriers

Studying PDEs linked to monogenic movement disorders contributes to better understanding of their role in disease pathogenesis and eventually treatment.[1] Using a PDE10A-specific radioligand, Diggle et al demonstrated a 70% reduction in striatal PDE10A signal, independent of total striatal volume loss.[13] This argues that the elevation of PDE10A levels in these hyperkinetic disorders might have beneficial clinical effect. A therapeutic approach would be to enhance PDE10A activity, an opposite approach to that of AMARYLLIS study,[27] where PDE10A was inhibited. A possible way to enhance PDE10A would be viral transfer of PDE genes to specific brain regions. This strategy is currently being used for PDE6 in the retina where loss of PDE6 activity causes retinal degeneration.[28] Pharmacological strategies targeting manipulation of cAMP levels in MSNs by either modulating their synthesis or degradation may also be promising therapeutic options for chorea and other movement disorders.[1] This could be achieved by using compounds that potentially lock PDE10A in an active formation similar to that when cAMP is bound to GAF domain.[2]

Niccolini et al 2018 showed reduced PDE10A and DAT expression in the basal ganglia as well as loss of neuromelanin-containing neurons in the substantia nigra in PDE10A mutation carriers. The reduced [¹²³I]FP-CIT uptake observed in PDE10A mutation carriers could reflect a decrease of dopamine producing cells in the substantia nigra. Indeed, loss of neuromelanin-containing neurons in the substantia nigra was found in an older patient with c.898T > C PDE10A mutation, who developed parkinsonism.[12] Tractography showed increased substantia nigra fractional anisotropy, suggesting a prodromal dysfunction of substantia nigra neurons.[20] Therefore, PDE10A mutations may affect the function and later on survival of presynaptic dopaminergic neurons.[20] Knopp et al was the only paper reporting that levodopa had favorable effect on two severely affected sisters (levodopa/decarboxylase inhibitor 1/0.25 and 0.25/0.06 mg/kg/d) with a homozygous mutation in the c-terminal of PDE10A.[24] On the other hand, dopamine depletion decreases the expression of PDE10A resulting in increase in cAMP signaling.[26] Therefore, dopamine depleting agents do not seem a plausible therapeutic approach for these particular hyperkinetic movement disorders.

Conclusion

In this paper, we summarized all reported cases of PDE10A pathogenic mutations, leading to a hyperkinetic phenotype with onset in infancy or childhood. In general, patients with homozygous mutations in either GAF-A domain or c-terminal 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.[1] At this moment there are no comparisons of GAF-A versus GAF-B mutations across any model system. These studies may help to understand how the two classes of mutation cause disease and eventually how they might be treated. 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.

Conflicts of Interest

None declared.

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.

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

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Publication History

Received: 21 November 2023

Accepted: 01 March 2024

Accepted Manuscript online:
05 March 2024

Article published online:
26 March 2024