A case report of a novel GNB1 pathogenic variant and the response to deep brain stimulation

Rožmarić, Gloria; Hero, Mario; Rački, Valentino; Vuletić, Vladimira; Chudy, Darko; Peterlin, Borut

doi:10.1007/s13760-022-01883-7

Cited by 4 publications

(4 citation statements)

References 6 publications

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“…In some cases, attention-deficit hyperactivity disorder, nystagmus, strabismus, cortical visual impairment, and autistic characteristics were observed (Petrovski et al, 2016 ; Revah-Politi et al, 2020 ). GNB1 mutations have been found in several tens of cases so far (Lansdon and Saunders, 2021 ; RoŽmarić et al, 2022 ), and approximately 75% of GNB1 mutations affect residues in exon 6 or exon 7.…”

Section: Introductionmentioning

confidence: 99%

Epilepsy in a mouse model of GNB1 encephalopathy arises from altered potassium (GIRK) channel signaling and is alleviated by a GIRK inhibitor

Colombo

Reddy

Petri

et al. 2023

Front. Cell. Neurosci.

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De novo mutations in GNB1, encoding the Gβ1 subunit of G proteins, cause a neurodevelopmental disorder with global developmental delay and epilepsy, GNB1 encephalopathy. Here, we show that mice carrying a pathogenic mutation, K78R, recapitulate aspects of the disorder, including developmental delay and generalized seizures. Cultured mutant cortical neurons also display aberrant bursting activity on multi-electrode arrays. Strikingly, the antiepileptic drug ethosuximide (ETX) restores normal neuronal network behavior in vitro and suppresses spike-and-wave discharges (SWD) in vivo. ETX is a known blocker of T-type voltage-gated Ca2+ channels and G protein-coupled potassium (GIRK) channels. Accordingly, we present evidence that K78R results in a gain-of-function (GoF) effect by increasing the activation of GIRK channels in cultured neurons and a heterologous model (Xenopus oocytes)—an effect we show can be potently inhibited by ETX. This work implicates a GoF mechanism for GIRK channels in epilepsy, identifies a new mechanism of action for ETX in preventing seizures, and establishes this mouse model as a pre-clinical tool for translational research with predicative value for GNB1 encephalopathy.

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Section: Introductionmentioning

confidence: 99%

Epilepsy in a mouse model of GNB1 encephalopathy arises from altered potassium (GIRK) channel signaling and is alleviated by a GIRK inhibitor

Colombo

Reddy

Petri

et al. 2023

Front. Cell. Neurosci.

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“…Movement disorder is frequent in patients with GNB1 pathogenic variants (23 individuals), usually dystonia and/or ataxia. Dystonia has been reported in 12 patients and was found to be more commonly associated with the p.Ile80Thr, p.Leu95Pro, p.Asp118Tyr, and p.Asp118Gly substitutions ( 22 – 25 , 28 , 30 , 34 ). Myoclonus with dystonia has been reported in two patients ( 23 , 29 ), suggesting a myoclonus–dystonia phenotype.…”

Section: Resultsmentioning

confidence: 99%

“…Levodopa administration was not effective in one patient ( 24 , 30 ). Deep brain stimulation (DBS) improved dystonia in two patients ( 30 , 34 ).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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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.

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“…If dystonia predominates in the clinical picture, the isolated dystonia may be taken into consideration. e gene mutations include DYT-TO-R1A, DYT-KMT2B, DYT-THAP1, DYT-ANO3, DYT-GNAL, DYT-HPCA, DYT-TUBB4A, DYT-PRKRA, and novel variants such as DYT-GNB1 (12,13). e majority of isolated dystonias have autosomal dominant inheritance (12).…”

Section: Geneticsmentioning

confidence: 99%

Dystonia and deep brain stimulation: correlation between genetic mutation and clinical outcome

Rožmarić¹,

Hero²,

Rački³

et al. 2022

Rad Hrvatske akademije znanosti i umjetnosti

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Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions, leading to abnormal involuntary movements or postures. Although the pathogenesis of dystonia is not entirely understood, lack of intracortical inhibition, aberrant sensory integration and derangement of neural plasticity are known to contribute. Etiologically, dystonia can be idiopathic, acquired or hereditary, most commonly occurring with TOR1A, THAP1, GCH1, and KMT2B mutations. e classi cation of dystonia is based on two main axes: clinical features (Axis I) and etiology (Axis II). When it comes to treatment a variety of therapeutic options are available, including oral medication therapy, intramuscular injections of botulinum neurotoxins (BoNTs), physical and occupational therapy and invasive neurosurgical treatment. Deep brain stimulation (DBS) is an established neurosurgical treatment for medication-refractory dystonia. As more evidence suggests that DBS treatment outcomes may be related to a hereditary basis, genotype determination is an important factor to consider in patient selection and prognostic counselling.

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A case report of a novel GNB1 pathogenic variant and the response to deep brain stimulation

Cited by 4 publications

References 6 publications

Epilepsy in a mouse model of GNB1 encephalopathy arises from altered potassium (GIRK) channel signaling and is alleviated by a GIRK inhibitor

Epilepsy in a mouse model of GNB1 encephalopathy arises from altered potassium (GIRK) channel signaling and is alleviated by a GIRK inhibitor

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

Dystonia and deep brain stimulation: correlation between genetic mutation and clinical outcome

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