PDE2A – Intellectual developmental disorder with paroxysmal dyskinesia or seizures

Intellectual developmental disorder with paroxysmal dyskinesia or seizures is an ultra-rare childhood-onset autosomal recessive movement disorder characterized by episodic dyskinesia, global developmental delay, impaired cognition, progressive psychomotor deterioration and/or drug-refractory seizures. Patients typically present in infancy or early childhood, with onset ranging from three months to seven years (PMID:37317634). Clinical overlap among symptoms and variability in choreodystonia severity and dyskinesia onset complicate diagnosis. Early genetic diagnosis can guide management and prognostication. Recent efforts have focused on identifying causative genes to improve understanding of disease mechanism and to enable targeted testing. Phosphodiesterase 2A (PDE2A) has emerged as a candidate based on recent case series.

In 2023, whole-exome sequencing of six affected individuals from three consanguineous Pakistani families identified a novel homozygous missense variant, c.1514T>C (p.Phe505Ser) (PMID:37317634), in NM_002599.4 of PDE2A. The variant was absent from population databases and predicted deleterious by multiple in silico tools. Segregation analysis confirmed that c.1514T>C segregated with disease status in all six individuals across three pedigrees. The families shared a 3.16 Mb haplotype at 11q13.4, supporting a founder effect. This report increases the total number of patients with PDE2A-related disease to twelve and expands the mutational spectrum to six variants (PMID:37317634). The observed genetic evidence meets ClinGen criteria for a strong contribution based on multiple unrelated probands, segregation data and a founder variant.

The inheritance pattern of PDE2A-related paroxysmal dyskinesia is autosomal recessive, consistent with loss of function of cyclic nucleotide phosphodiesterase. Homozygous individuals exhibit early-onset dyskinesia and cognitive impairment, whereas heterozygous carriers are asymptomatic. No de novo or dominant-negative variants have been reported to date, and no conflicting allelic data have been described. The gene under review encodes an enzyme highly expressed in basal ganglia medium spiny neurons, supporting tissue-specific vulnerability. The variant c.1514T>C affects a conserved phenylalanine residue within the catalytic domain, likely disrupting enzymatic activity. Together, these observations support a pathogenic mechanism of loss-of-function due to biallelic missense alterations.

Functional studies in patient-derived fibroblasts demonstrated abnormal mitochondrial morphology compared to controls, suggesting impaired energy metabolism or altered cyclic nucleotide signaling (PMID:37317634). Mitochondrial dysfunction may contribute to progressive psychomotor decline and seizure susceptibility. While direct enzymatic assays on p.Phe505Ser are pending, analogous loss-of-function variants in PDE2A have shown decreased hydrolytic activity in other movement disorders. Experimental concordance across cellular models strengthens the hypothesis of haploinsufficiency as the pathogenic mechanism. No rescue experiments have been reported, leaving room for future in vitro validation. These findings provide moderate-level functional support under ClinGen guidelines.

No studies to date have reported conflicting evidence or alternative gene associations for intellectual developmental disorder with paroxysmal dyskinesia beyond PDE2A. The uniform absence of disease in heterozygous parents and the recurrence of the same homozygous variant in multiple families minimizes the likelihood of phenocopies. Additional gene-disease resources and population data remain limited due to the ultra-rare nature of this condition. Future investigations including knock-in animal models and enzymatic activity assays will be critical to delineate the exact pathophysiological cascade. Nonetheless, the current genetic and cellular data coalesce into a robust association. Clinicians should consider PDE2A sequencing when encountering recessive early-onset dyskinesia with cognitive impairment.

In summary, biallelic PDE2A variants, particularly the founder c.1514T>C (p.Phe505Ser), cause an autosomal recessive movement disorder with intellectual disability, paroxysmal dyskinesia and seizures. Genetic evidence from six patients in three families, segregation analysis and a shared haplotype meet ClinGen “Strong” criteria. Functional assessment demonstrating mitochondrial abnormalities provides “Moderate” support for a loss-of-function mechanism. No conflicting evidence has emerged to challenge this relationship. Incorporation of PDE2A into diagnostic gene panels will improve molecular diagnoses and facilitate genetic counselling. PDE2A testing is thus recommended in patients with early-onset syndromic dyskinesia and cognitive delay.

References

• Clinical genetics • 2023 • A homozygous founder variant in PDE2A causes paroxysmal dyskinesia with intellectual disability. PMID:37317634

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