Myoclonus‐dystonia caused by <i>GNB1</i> mutation responsive to deep brain stimulation

Jones, Hannah; Morales‐Briceño, Hugo; Barwick, Katy; Lewis, Jennifer; Sanchis‐Juan, Alba; Raymond, F. Lucy; Stewart, Kirsty; Waugh, Mary‐Clare; Mahant, Neil; Kurian, Manju A.; Dale, Russell C.; Mohammad, Shekeeb S

doi:10.1002/mds.27708

Cited by 26 publications

(31 citation statements)

References 7 publications

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“…We found that one Gprotein subunit, GNB1, was significantly decreased in all the regions. Missense, splice-site and frameshift variants in the GNB1 gene are associated with multiple neurological phenotypes, including seizures in most cases [75][76][77][78][79][80]. Mice harboring the GNB1 K78R human pathogenic recapitulate many clinical features, including developmental delay, motor and cognitive deficits, and absence-like generalized seizures, and that cellular models displayed extended bursts of firing followed by extensive recovery periods [81].…”

Section: Discussionmentioning

confidence: 99%

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Pires

Leitner

Drummond

et al. 2020

Preprint

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Epilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioral disorders, and increased mortality from direct (e.g., Sudden Unexpected Death in Epilepsy [SUDEP], accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signaling networks associated with epilepsy, we examined the proteome of brain samples from epilepsy and control cases. Label-free quantitative mass spectrometry (MS) was performed on the hippocampal CA1-3 region, frontal cortex, and dentate gyrus microdissected from epilepsy and control cases (n=14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1-3 region, 296 proteins in the frontal cortex, and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signaling, and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G-protein Subunit Beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G-protein subunit signaling and G-protein–coupled receptors (GPCRs) in epilepsy. Our results provide insights into the molecular mechanisms underlying epilepsy, which may allow for novel targeted therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Pires

Leitner

Drummond

et al. 2020

Preprint

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“…STN-DBS was found to be efficacious in two patients with GCH1 variants for parkinsonism and motor fluctuations following long-term treatment with levodopa (134). A case report of GNB1-related myoclonus dystonia showed an initial marked response to GPi-DBS (135). KCTD17-related myoclonus dystonia is known to have an excellent response to GPi-DBS (136), including an improvement in orolingual dyskinesia and speech (137).…”

Section: Other Genetic Causes Of Dystoniamentioning

confidence: 99%

Pallidal Deep Brain Stimulation for Monogenic Dystonia: The Effect of Gene on Outcome

Tisch

Kumar

2021

Front. Neurol.

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Globus pallidus internus deep brain stimulation (GPi DBS) is the most effective intervention for medically refractory segmental and generalized dystonia in both children and adults. Predictive factors for the degree of improvement after GPi DBS include shorter disease duration and dystonia subtype with idiopathic isolated dystonia usually responding better than acquired combined dystonias. Other factors contributing to variability in outcome may include body distribution, pattern of dystonia and DBS related factors such as lead placement and stimulation parameters. The responsiveness to DBS appears to vary between different monogenic forms of dystonia, with some improving more than others. The first observation in this regard was reports of superior DBS outcomes in DYT-TOR1A (DYT1) dystonia, although other studies have found no difference. Recently a subgroup with young onset DYT-TOR1A, more rapid progression and secondary worsening after effective GPi DBS, has been described. Myoclonus dystonia due to DYT-SCGE (DYT11) usually responds well to GPi DBS. Good outcomes following GPi DBS have also been documented in X-linked dystonia Parkinsonism (DYT3). In contrast, poorer, more variable DBS outcomes have been reported in DYT-THAP1 (DYT6) including a recent larger series. The outcome of GPi DBS in other monogenic isolated and combined dystonias including DYT-GNAL (DYT25), DYT-KMT2B (DYT28), DYT-ATP1A3 (DYT12), and DYT-ANO3 (DYT24) have been reported with varying results in smaller numbers of patients. In this article the available evidence for long term GPi DBS outcome between different genetic dystonias is reviewed to reappraise popular perceptions of expected outcomes and revisit whether genetic diagnosis may assist in predicting DBS outcome.

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“…Homozygous loss of Gnb1 in mice is embryonically lethal with affected embryos showing abnormal brain morphology and defects in neural precursor differentiation and proliferation (Okae & Iwakura, 2010). In humans, variants in this gene have been associated with a neurodevelopmental disorder (NDD; OMIM: 616973, Mental retardation, autosomal dominant 42) with patients presenting with global developmental delay, hypotonia, and epilepsy (Brett et al, 2017; Endo et al, 2020; Hemati et al, 2018; Jones et al, 2019; Lohmann et al, 2017; Peng et al, 2019; Petrovski et al, 2016; Steinrucke et al, 2016; Szczaluba et al, 2018). Other prevalent phenotypes reported include brain abnormalities, ophthalmological disorders, growth restriction, movement disorders, and non‐specific dysmorphisms (Revah‐Politi, Sands, Colombo, Goldstein, & Anyane‐Yeboa, 1993).…”

Section: Introductionmentioning

confidence: 99%

Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder

Schultz‐Rogers

Masuho

Vairo

et al. 2020

Molec Gen & Gen Med

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The gene GNB1 (guanine nucleotide binding protein (G protein), beta polypeptide 1; OMIM: 616973 and OMIM:613065) encodes the Gβ subunit of a heterotrimeric G-protein complex which additionally includes Gα and Gγ subunits. This complex functions to transduce a variety of intracellular signaling cascades (Ford et al., 1998). Homozygous loss of Gnb1 in mice is embryonically lethal with affected embryos showing abnormal brain morphology and defects in neural precursor

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Myoclonus‐dystonia caused by GNB1 mutation responsive to deep brain stimulation

Cited by 26 publications

References 7 publications

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Pallidal Deep Brain Stimulation for Monogenic Dystonia: The Effect of Gene on Outcome

Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder

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