Objective: Presenting the case of a patient with a GNAO1 mutation who exhibited severe movement disorder and underwent GPi-DBS

Background: GNAO1 mutations manifest in two clinical profiles: severe early-infantile epileptic encephalopathy and a neurodevelopmental disorder with involuntary movements. The GNAO1 gene encodes the α-subunit of a guanine nucleotide-binding protein crucial for cAMP metabolism in the CNS, particularly in the striatum. These mutations lead to various neurological syndromes, including movement disorders, psychomotor delay, intellectual disability, and epilepsy in infancy. Choreoathetosis is a hallmark, and the movements may evolve to status dystonicus. While severe cases are common, milder forms may present in childhood or adolescence

Method: A child with a history of dyskinesia was examined at a movement disorder and neurogenetics reference center.

Results: A 10-year-old girl presented with hypotonia and stereotypic jerks in her lower extremities since 5 months old. Born at term without relevant family history, she experienced developmental delays, with limited speech and motor skills. By age 4, jerk frequency increased, along with dystonic postures, especially during emotional stress. At 9, dyskinetic and choreoathetotic movements worsened, along with dystonic hand and lower limb contractions. No seizures were reported. Hospitalized for pneumonia, continuous dyskinetic movements impaired her nutrition and hygiene, resulting in neurological regression. Various medications were ineffective. Neurological examination revealed refractory involuntary movements, orofacial dyskinesia, and increased muscle tone. Creatine phosphokinase levels were elevated, with normal brain MRI and EEG. Next-generation sequencing identified a GNAO1 mutation, confirming GNAO1-related neurodevelopmental disorder. Due to dyskinetic status triggered by pneumonia, she underwent bilateral GPi-DBS placement, leading to significant improvement postoperatively

Conclusion: Our case underscores the severity of GNAO1-related neurodevelopmental disorder with involuntary movements. While dystonia is well-documented, choreic and dyskinetic features appear particularly indicative of GNAO1 deficiency. Challenges in terminology and symptomatology description exist, but hyperkinetic movements alongside developmental delay and susceptibility to triggers help diagnose GNAO1 deficiency.

References: 1. Wirth T, Garone G, Kurian MA, et al. Highlighting the Dystonic Phenotype Related to GNAO1. Mov Disord. 2022 Jul;37(7):1547-1554. doi: 10.1002/mds.29074. Epub 2022 Jun 20. PMID: 35722775; PMCID: PMC9545634.

2. Novelli M, Galosi S, Zorzi G, Martinelli S, Capuano A, et al. GNAO1-related movement disorder: An update on phenomenology, clinical course, and response to treatments. Parkinsonism Relat Disord. 2023 Jun;111:105405. doi: 10.1016/j.parkreldis.2023.105405. Epub 2023 Apr 29. PMID: 37142469.

3. Saitsu, H., Fukai, R., Ben-Zeev, B. et al. Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay. Eur J Hum Genet 24, 129–134 (2016). https://doi.org/10.1038/ejhg.2015.92

4. Waak M, Mohammad SS, Coman D, et al. GNAO1-related movement disorder with life-threatening exacerbations: movement phenomenology and response to DBS. Journal of Neurology, Neurosurgery & Psychiatry 2018;89:221-222.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gnao1-related-neurodevelopmental-disorder-with-involuntary-movements-inducing-a-dyskinetic-status/