Objective: To provide a detailed clinical characterization of genetic disorders affecting G-protein coupled receptor signaling and cAMP metabolism

Background: Genetic disorders affecting G-protein coupled receptor (GPCRs) signaling and cAMP metabolism includes genes encoding for proteins highly expressed in CNS and involved in GPCRs signal transduction and cAMP synthesis or degradation (e.g., GNAO1, GNB1, ADCY5, GNAL PDE2A, PDE10A, and HPCA genes). While the phenotype associated to ADCY5, GPR88 and GNAL was predominantly characterized by movement disorder (MD), the other disorders present with a complex phenotype featuring MD, epilepsy, and neurodevelopmental disorders.

Method: We reviewed clinical features and genetic data of 323 patients from literature with GNAO1, ADCY5, GPR88, GNB1, PDE2A, PDE10A, and HPCA pathogenic variants.

Results: Dominant mutations in GNAO1, GNB1, and PDE2A have been associated to a complex neurological disorder characterized by a variable association of hyperkinetic MD, epilepsy, and global developmental delay (GDD) evolving into intellectual disability. GNAL, ADCY5, and GPR88 genes have not been associated with epilepsy so far.
Dyskinetic storms or minor paroxysmal choreo-dystonic spells, dystonia and/or chorea with prominent cranial involvement, orofacial dyskinesia, axial hypotonia, and impaired postural development characterize the MD phenotype of these conditions. Susceptibility to a wide range of triggers and exacerbations evolving into status dystonicus are typical. Febrile and upon awakening exacerbations of MD have been described for GNAO1, ADCY5, PDE2A, and GNB1. 
Epilepsy can be prominent in GNB1 and GNAO1 encephalopathy, while it is anecdotical in other conditions. Ohtahara, West syndrome, or malignant migrating partial epilepsy of childhood can be the epileptic presentation of GNAO1, GNB1, and PDE2A. Childhood onset focal and/or generalized epilepsies are usually milder. Febrile status epilepticus and seizures are typical of GNB1 and GNAO1. GDD and intellectual disability are observed in almost all patients with GNB1, GNAO1, PDE2A, and HPCA variants.

Conclusion: These group of disorders present with a highly recognizable phenotype with distinctive motor, epileptic, and neurodevelopmental features. The existence of a distinctive clinical phenotype prompting early detection has relevant implications for clinical and therapeutic management.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/motor-epileptic-and-developmental-phenotypes-in-genetic-disorders-affecting-g-protein-coupled-receptor-signaling-and-camp-metabolism/