Phenomenology and clinical course of movement disorder in GNAO1 variants: Results from an analytical review

Schirinzi, Tommaso; Garone, Giacomo; Travaglini, Lorena; Vasco, Gessica; Galosi, Serena; Ríos, Loreto; Castiglioni, Claudia; Barassi, Claudia; Battaglia, Domenica; Gambardella, Maria Luigia; Cantonetti, Laura; Graziola, Federica; Marras, Carlo Efisio; Castelli, Enrico; Bertini, Enrico; Capuano, Alessandro; Leuzzi, Vincenzo

doi:10.1016/j.parkreldis.2018.11.019

Cited by 66 publications

(78 citation statements)

References 29 publications

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“…As predicted, the Gnao1+/G203R (G203R) mutant mice exhibited motor coordination and gait abnormalities as well as enhanced seizure susceptibility in pentylenetrazol (PTZ) kindling studies (Feng et al, 2019). The R209H mutations is one of the most common pathogenic GNAO1 mutations (Schirinzi et al, 2018). Patients with de novo, heterozygous R209H mutations in GNAO1 display severe choreoathetosis and dystonia but do not exhibit seizures ( Supplemental Table 1).…”

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confidence: 68%

“…Effective treatments are a key goal as patients with the R209H mutation experience repeated hospitalizations (Ananth et al, 2016;Marecos et al, 2018;Schirinzi et al, 2018). Deep brain stimulation in the internal globus pallidus has proven effective in GNAO1 patients in attenuating MD (Kulkarni et al, 2016;Sanem et al, 2016;Honey et al, 2018;Koy et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…It was recognized in 2016 that some GNAO1 mutations result in movement disorders without epilepsy (Kulkarni et al, 2016;Saitsu et al, 2016). To date there are over 70 published cases of children with mutations in GNAO1 presenting with early infantile epileptic encephalopathy (EIEE17: OMIM 615473) and/or neurodevelopmental disorder with involuntary movements (NEDIM: OMIM 617493) (Nakamura et al, 2013;Consortium et al, 2014;Law et al, 2015;Talvik et al, 2015;Ananth et al, 2016;Consortium, 2016;Dhamija et al, 2016;Gawlinski et al, 2016;Kulkarni et al, 2016;Marcé-Grau et al, 2016;Menke et al, 2016;Saitsu et al, 2016;Sanem et al, 2016;Arya et al, 2017;Danti et al, 2017;Sakamoto et al, 2017;Schorling et al, 2017;Blumkin et al, 2018;Bruun, 2018;Gerald et al, 2018;Honey et al, 2018;Koy et al, 2018;Marecos et al, 2018;Okumura et al, 2018;Rim et al, 2018;Schirinzi et al, 2018;Takezawa et al, 2018;Waak et al, 2018;Xiong et al, 2018;Meredith et al, 2019). This article has not been copyedited and formatted.…”

Section: Introductionmentioning

confidence: 99%

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Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

Larrivee

Feng

Quinn

et al. 2020

J Pharmacol Exp Ther

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Section: Downloaded Frommentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

Larrivee

Feng

Quinn

et al. 2020

J Pharmacol Exp Ther

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“…As predicted, the Gnao1 +/G203R (G203R) mutant model exhibited motor coordination and gait abnormalities as well as enhanced seizure susceptibility in pentylenetrazol (PTZ) kindling studies [35]. The R209H mutations is one of the most common pathogenic GNAO1 mutations [9]. Patients with de novo, heterozygous R209H mutations in GNAO1 display severe choreoathetosis and dystonia but do not present with seizures [5,7,12,13,17,18].…”

Section: Introductionmentioning

confidence: 72%

“…Effective treatments are a key goal as patients with the R209H mutation experience multiple incidents of hospitalizations [7,9,13]. Deep brain stimulation in the globus pallidus has proven effective in GNAO1 patients in attenuating MD [5,16,21,25].…”

Section: Discussionmentioning

confidence: 99%

Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

Larrivee

Feng

Quinn

et al. 2019

Preprint

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Neurodevelopmental disorder with involuntary movements (NEDIM, OMIM: 617493) is a severe, early onset neurological condition characterized by a delay in psychomotor development, hypotonia, and hyperkinetic involuntary movements. Heterozygous de novo mutations in the GNAO1 gene cause NEDIM. Gαo, the gene product of GNAO1, is the alpha subunit of Go, a member of the heterotrimeric Gi/o family of G-proteins. Go is found abundantly throughout the brain but the pathophysiological mechanisms linking Gαo functions to clinical manifestations of GNAO1-related disorders are still poorly understood. One of the most common mutant alleles among the GNAO1 encephalopathies is the c.626G>A or p.Arg209His (R209H) mutation. We developed heterozygous knock-in Gnao1+/R209H mutant mice using CRISPR/Cas9 methodology to assess whether a mouse model could replicate aspects of the NEDIM clinical pattern. Mice carrying the R209H mutation exhibited increased locomotor activity and a modest gait abnormality at 8-12 weeks. In contrast to mice carrying other mutations in Gnao1, the Gnao1+/R209H mice did not show enhanced seizure susceptibility. Levels of protein expression in multiple brain regions were unchanged from WT mice but the nucleotide exchange rate of mutant R209H Gαo was 9 times faster than WT. The atypical neuroleptic risperidone has shown efficacy in a patient with the R209H mutation. It also alleviated the hyperlocomotion phenotype observed in our mouse model but suppressed locomotion in WT mice as well. In this study, we show that Gnao1+/R209H mice mirror elements of the patient phenotype and respond to an approved pharmacological agent.

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Molecular Diagnostic Yield of Exome Sequencing in Patients With Cerebral Palsy

Moreno-De-Luca

Millan²,

Pesacreta

et al. 2021

JAMA

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IMPORTANCE Cerebral palsy is a common neurodevelopmental disorder affecting movement and posture that often co-occurs with other neurodevelopmental disorders. Individual cases of cerebral palsy are often attributed to birth asphyxia; however, recent studies indicate that asphyxia accounts for less than 10% of cerebral palsy cases.OBJECTIVE To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy. DESIGN, SETTING, AND PARTICIPANTSA retrospective cohort study of patients with cerebral palsy that included a clinical laboratory referral cohort with data accrued between 2012 and 2018 and a health care-based cohort with data accrued between 2007 and 2017.EXPOSURES Exome sequencing with copy number variant detection. MAIN OUTCOMES AND MEASURESThe primary outcome was the molecular diagnostic yield of exome sequencing. RESULTS Among 1345 patients from the clinical laboratory referral cohort, the median age was 8.8 years (interquartile range, 4.4-14.7 years; range, 0.1-66 years) and 601 (45%) were female. Among 181 patients in the health care-based cohort, the median age was 41.9 years (interquartile range, 28.0-59.6 years; range, 4.8-89 years) and 96 (53%) were female. The molecular diagnostic yield of exome sequencing was 32.7% (95% CI, 30.2%-35.2%) in the clinical laboratory referral cohort and 10.5% (95% CI, 6.0%-15.0%) in the health care-based cohort. The molecular diagnostic yield ranged from 11.2% (95% CI, 6.4%-16.2%) for patients without intellectual disability, epilepsy, or autism spectrum disorder to 32.9% (95% CI, 25.7%-40.1%) for patients with all 3 comorbidities. Pathogenic and likely pathogenic variants were identified in 229 genes (29.5% of 1526 patients); 86 genes were mutated in 2 or more patients (20.1% of 1526 patients) and 10 genes with mutations were independently identified in both cohorts (2.9% of 1526 patients).CONCLUSIONS AND RELEVANCE Among 2 cohorts of patients with cerebral palsy who underwent exome sequencing, the prevalence of pathogenic and likely pathogenic variants was 32.7% in a cohort that predominantly consisted of pediatric patients and 10.5% in a cohort that predominantly consisted of adult patients. Further research is needed to understand the clinical implications of these findings.

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Phenomenology and clinical course of movement disorder in GNAO1 variants: Results from an analytical review

Cited by 66 publications

References 29 publications

Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

Molecular Diagnostic Yield of Exome Sequencing in Patients With Cerebral Palsy

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