Familial choreoathetosis due to novel heterozygous mutation in <i>PDE10A</i>

Narayanan, Dhanya Lakshmi; Deshpande, Dipti; Bhowmik, Aneek Das; Varma, Dandu Ravi; Dalal, Ashwin

doi:10.1002/ajmg.a.38507

Cited by 12 publications

(19 citation statements)

References 15 publications

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“…Nevertheless, DBS performed in the patient reported by Salpietro et al showed improvement in the first weeks after chronic stimulation but followed by a very little improvement of PD without functional amelioration [ 16 ]. These data indicate that a better understanding of the PDE2A variants consequences on basal ganglia and connected brain structures is needed to adapt DBS therapeutic approach to PDE2A -related disorders [ 17 – 19 ].…”

Section: Discussionmentioning

confidence: 99%

Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia

Doummar

Dentel²,

Lyautey

et al. 2020

Eur J Hum Genet

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Cause of complex dyskinesia remains elusive in some patients. A homozygous missense variant leading to drastic decrease of PDE2A enzymatic activity was reported in one patient with childhood-onset choreodystonia preceded by paroxysmal dyskinesia and associated with cognitive impairment and interictal EEG abnormalities. Here, we report three new cases with biallelic PDE2A variants identified by trio whole-exome sequencing. Mitochondria network was analyzed after Mitotracker™ Red staining in control and mutated primary fibroblasts. Analysis of retrospective video of patients’ movement disorder and refinement of phenotype was carried out. We identified a homozygous gain of stop codon variant c.1180C>T; p.(Gln394*) in PDE2A in siblings and compound heterozygous variants in young adult: a missense c.446C>T; p.(Pro149Leu) and splice-site variant c.1922+5G>A predicted and shown to produce an out of frame transcript lacking exon 22. All three patients had cognitive impairment or developmental delay. The phenotype of the two oldest patients, aged 9 and 26, was characterized by childhood-onset refractory paroxysmal dyskinesia initially misdiagnosed as epilepsy due to interictal EEG abnormalities. The youngest patient showed a proven epilepsy at the age of 4 months and no paroxysmal dyskinesia at 15 months. Interestingly, analysis of the fibroblasts with the biallelic variants in PDE2A variants revealed mitochondria network morphology changes. Together with previously reported case, our three patients confirm that biallelic PDE2A variants are a cause of childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy.

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Section: Discussionmentioning

confidence: 99%

Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia

Doummar

Dentel²,

Lyautey

et al. 2020

Eur J Hum Genet

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“…Heterozygous PDE10A mutations have been recently implicated in a childhood‐onset nonprogressive choreic syndrome with bilateral striatal hyperintensity on MRI. 8 , 95 , 96 , 97 All identified missense mutations (p.F300L, p.F334L/C) have been demonstrated to recurrently affect amino acid residues that are completely conserved down to invertebrate species and are located in the GAF‐B domain, likely altering the morphology of the cAMP binding pocket. 8 Interestingly, in vitro studies showed that these mutations do not substantially impair basal PDE10A activity but severely affect the positive regulatory mechanism of cAMP binding to the GAF‐B domain on PDE catalytic activity.…”

Section: Huntington's Diseasementioning

confidence: 99%

The Emerging Role of Phosphodiesterases in Movement Disorders

2021

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A BS TRACT: Cyclic nucleotide phosphodiesterase (PDE) enzymes catalyze the hydrolysis and inactivation of the cyclic nucleotides cyclic adenosine monophosphate and cyclic guanosine monophosphate, which act as intracellular second messengers for many signal transduction pathways in the central nervous system. Several classes of PDE enzymes with specific tissue distributions and cyclic nucleotide selectivity are highly expressed in brain regions involved in cognitive and motor functions, which are known to be implicated in neurodegenerative diseases, such as Parkinson's disease and Huntington's disease. The indication that PDEs are intimately involved in the pathophysiology of different movement disorders further stems from recent discoveries that mutations in genes encoding different PDEs, including PDE2A, PDE8B, and PDE10A, are responsible for rare forms of monogenic parkinsonism and chorea. We here aim to provide a translational overview of the preclinical and clinical data on PDEs, the role of which is emerging in the field of movement disorders, offering a novel venue for a better understanding of their pathophysiology. Modulating cyclic nucleotide signaling, by either acting on their synthesis or on their degradation, represents a promising area for development of novel therapeutic approaches. The study of PDE mutations linked to monogenic movement disorders offers the opportunity of better understanding the role of PDEs in disease pathogenesis, a necessary step to successfully benefit the treatment of both hyperkinetic and hypokinetic movement disorders.

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“…To support the role of PDE10A, three different families with PDE10A gene mutations have been reported with a choreic phenotype and striatal abnormalities [ [84] , [85] , [86] ]. They have shown decreased binding not only at the striatum but also at the caudate, the thalamus, and some cortical areas.…”

Section: Mechanisms Of Pathogenesis In Hdmentioning

confidence: 99%

Huntington disease: Advances in the understanding of its mechanisms

Gatto

Rojas

Persi

et al. 2020

Clinical Parkinsonism & Related Disorders

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Huntington disease (HD) is a devastating monogenic autosomal dominant disorder. HD is caused by a CAG expansion in exon 1 of the gene coding for huntingtin, placed in the short arm of chromosome 4. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract. Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unraveling mechanisms are still unknown. This practical and brief review summarizes some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis.

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Familial choreoathetosis due to novel heterozygous mutation in PDE10A

Cited by 12 publications

References 15 publications

Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia

Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia

The Emerging Role of Phosphodiesterases in Movement Disorders

Huntington disease: Advances in the understanding of its mechanisms

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