Motor, epileptic, and developmental phenotypes in genetic disorders affecting G protein coupled receptors-cAMP signaling

Abstract

Over the last years, a constantly increasing number of genetic diseases associated with epilepsy and movement disorders have been recognized. An emerging group of conditions in this field is represented by genetic disorders affecting G-protein-coupled receptors (GPCRs)–cAMP signaling. This group of postsynaptic disorders includes genes encoding for proteins highly expressed in the central nervous system and involved in GPCR signal transduction and cAMP production (e.g., GNAO1, GNB1, ADCY5, GNAL, PDE2A, PDE10A, and HPCA genes). While the clinical phenotype associated with ADCY5 and GNAL is characterized by movement disorder in the absence of epilepsy, GNAO1, GNB1, PDE2A, PDE10A, and HPCA have a broader clinical phenotype, encompassing movement disorder, epilepsy, and neurodevelopmental disorders. We aimed to provide a comprehensive phenotypical characterization of genetic disorders affecting the cAMP signaling pathway, presenting with both movement disorders and epilepsy. Thus, we reviewed clinical features and genetic data of 203 patients from the literature with GNAO1, GNB1, PDE2A, PDE10A, and HPCA deficiencies. Furthermore, we delineated genotype–phenotype correlation in GNAO1 and GNB1 deficiency. This group of disorders presents with a highly recognizable clinical phenotype combining distinctive motor, epileptic, and neurodevelopmental features. A severe hyperkinetic movement disorder with potential life-threatening exacerbations and high susceptibility to a wide range of triggers is the clinical signature of the whole group of disorders. The existence of a distinctive clinical phenotype prompting diagnostic suspicion and early detection has relevant implications for clinical and therapeutic management. Studies are ongoing to clarify the pathophysiology of these rare postsynaptic disorders and start to design disease-specific treatments.

Multi-cohort comprehensive analysis unveiling the clinical value and therapeutic effect of <i>GNAL</i> in glioma

“…Therefore, the experimental verification of the relationship between GNAL expression and immune cell expression, chemotherapy response, or immunotherapy response in gliomas is imperative. Although the analysis of pathway enrichment revealed that GNAL was associated with several immune-related pathways, there may be other pathways in which GNAL plays an important role, such as the closely related cAMP signaling pathway [ 64 ]. Studies have demonstrated that the cAMP, which acts as a second signaling molecule, can inhibit the progression of glioma [ 65 ], and decreased expression of GNAL may be the main reason for the dysregulation of this pathway in glioma.…”

GNB1 Encephalopathy: Clinical Case Report and Literature Review

“…GNB1 encephalopathy (GNB1-E) is a rare genetic disease caused by pathogenic variants in the G Protein Subunit Beta 1 (GNB1) gene. Only around 68 cases of this disease have been reported to this day worldwide [1][2][3][4]. Characterizing symptoms for GNB1-E are developmental delay, intellectual disability, and various neurological symptoms.…”

Severity of GNAO1‐Related Disorder Correlates with Changes in G‐Protein Function

“…8,14 However, growing evidence suggests the severity of the disease lies on a spectrum with intermediate clinical phenotypes. 15 Although a few studies have examined genotypephenotype correlation in GNAO1-related disorders, [16][17][18] natural history data or severity scores have not been developed, nor have prognostic factors been identified. Defining subgroups of patients with GNAO1-related disorders by severity is a prerequisite for designing more precise natural history studies to identify domains and windows for potential therapeutic interventions, and to plan clinical trials.…”

“…Recent progress in this area suggests that GNAO1-associated variants perturb Gαo function by different mechanisms, including loss-offunction, dominant-negative, and debatable gainof-function effects, which ultimately lead to GNAO1related disorders. 11,15,18,20,[23][24][25][26] Yet, our understanding of the molecular pathology of GNAO1 and its relationship with the disease symptomatology is far from complete, and many disease-causing variants remain to be characterized.…”

“…This has led to the description of two recognized OMIM phenotypes: (1) developmental and epileptic encephalopathy 17 (OMIM#615473), 5–10 and (2) neurodevelopmental disorder with involuntary movements (OMIM#617493) 8,14 . However, growing evidence suggests the severity of the disease lies on a spectrum with intermediate clinical phenotypes 15 …”