Objective: GNAO1 is located on chromosome 16q12.2 and encodes Gα0 subunit of the heterotrimeric guanine-binding protein necessary for neuronal signaling. It is thought that loss-of-function GNAO1 alleles are associated with epilepsy whereas gain-of-function GNAO1 alleles lead to movement disorders. Exacerbation of hyperkinetic movement disorders has been described in other patients with GNAO1 mutations and the role of DBS both electively and emergently is becoming increasingly recognized.

Background: Monozygotic twin males born at 38 week gestation began displaying both motor and speech delays at approximately 8-9 months. By 36 months of age, choreatheotoid movements of the mouth and distal extremities were noted in both. Movements became more pronounced during acute illnesses, which often necessitated prolonged hospitalizations involving mechanical ventilation, anesthesia and neuromuscular blockade. Various medications including benzodiazepines, benztropine, risperidone, tetrabenazine, topiramate and levetiracetam were used in order to abolish hyperkinetic movements without significant benefit. Previous neuroimaging revealed bilateral frontal volume loss in both cases. Previous extensive testing including PET scans, MR spectroscopy, muscle biopsies, cerebrospinal fluid analysis and metabolic testing was unrevealing. EEG did not reveal any epileptiform activity during movements in either case. Previous genetic testing demonstrated a variant of unclear significance in MED12 gene. This gene has been implicated in several X-linked disorders including Lujan-Fryns syndrome and Opitz-Kaveggia syndrome which have overlapping phenotypes including intellectual impairment, dysmorphic facial features and hypotonia.

Method: At age 20, both brothers underwent deep brain stimulation (DBS) targeting the globus pallidus and experienced marked improvement. At age 20, whole exome sequencing with mtDNA studies revealed the same novel heterozygous de novo pathogenic variant in the GNAO1 gene (c.736G>A, p.Glu246Lys) in both brothers. Both parents were negative for this gene variant.

Results: Choreoatheoid movements of both monozygotic twins improved significantly following pallidal DBS.

Conclusion: Neurodevelopmental disorders with involuntary movements are becoming increasingly recognized as GNAO1 mutation-associated neurological disorders and DBS should perhaps be considered earlier in the course to prevent prolonged hospitalizations and other potential complications.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-gno1-mutation-in-monozygotic-twins-responsive-to-dbs/