1. Introduction

The GNAO1 gene encodes the α-subunit of the heterotrimeric G protein Go, which plays a key role in neuronal signaling and synaptic transmission. Pathogenic variants in GNAO1 have been increasingly recognized as a cause of severe neurodevelopmental disorders characterized by variable combinations of developmental delay, epileptic seizures, and hyperkinetic movement disorders [1-3].

Since the first descriptions of GNAO1-related disease, the phenotypic spectrum has expanded substantially. While some patients present with developmental and epileptic encephalopathy, others exhibit predominantly movement disorder phenotypes, including dystonia, choreoathetosis, and paroxysmal hyperkinesia, with absent or delayed epilepsy [2,4]. This phenotypic variability complicates clinical diagnosis, particularly when routine neurophysiological studies are non-diagnostic.

Electroencephalographic findings in GNAO1-associated disorders are notably heterogeneous and may range from normal recordings to severe epileptiform abnormalities, depending on age and clinical phenotype [1,5]. Consequently, EEG findings may be variable and should be interpreted in the broader clinical context.In this context, whole-exome sequencing has become an essential diagnostic tool, enabling etiological clarification and supporting individualized management strategies.

Here, we describe a clinical case from Uzbekistan of a child with a severe neurodevelopmental disorder associated with a de novo GNAO1 variant, illustrating diagnostic challenges and the importance of genetic testing in guiding clinical decision-making.

2. Case Presentation

The patient is a 6-year-old child with a severe neurodevelopmental disorder characterized by global developmental delay and prominent movement abnormalities.

Early psychomotor development was markedly delayed. Head control was achieved after the first year of life, independent sitting at approximately 18 months, and independent walking was not attained. Assisted ambulation became possible after the age of 2 years. Speech development remained severely limited.

From early childhood, the patient exhibited pronounced involuntary movements, including generalized hyperkinesia and dystonia. Recurrent paroxysmal dystonic crises were observed, lasting up to 30 minutes. These episodes were frequently triggered or exacerbated by external factors such as increased ambient temperature and were accompanied by autonomic manifestations, including facial flushing and excessive sweating. Prior to the onset of confirmed epileptic seizures, these paroxysmal events raised diagnostic concern for epilepsy; however, their clinical presentation was atypical and suggested a non-epileptic movement-related origin.

At the age of 3 years, the patient developed epileptic seizures. The events occurred predominantly during sleep and were characterized by sudden eye opening followed by brief generalized jerking movements. Seizure duration was approximately 5 minutes, and episodes initially occurred daily. Antiseizure therapy with valproate and levetiracetam was initiated.

Neuroimaging

Brain magnetic resonance imaging performed in early childhood demonstrated delayed myelination of the cerebral white matter and diffuse widening of the subarachnoid spaces in the frontal and temporal regions. No focal structural abnormalities were identified.

Electroencephalography

At the age of 4 years, video-electroencephalography performed during clinical evaluation did not capture clinical events. No epileptiform discharges were recorded, and background activity was appropriate for the patient’s age. At the time of assessment, there was no electroencephalographic confirmation of epilepsy.

At the age of 5 years, overnight video-EEG monitoring demonstrated preserved background activity and physiological sleep architecture. Interictally, epileptiform discharges were observed in the frontal regions. A brief clinical episode characterized by stereotyped hand movements and forced laughter was recorded; however, EEG interpretation during this event was limited by movement-related artifacts.

Six months later, repeat overnight video-EEG monitoring again demonstrated preserved background rhythms and normal sleep organization. Epileptiform abnormalities were detected predominantly in the right frontal regions. No habitual clinical events were captured.

Genetic Findings

Whole-exome sequencing identified a heterozygous missense variant in GNAO1 (NM_020988.3: c.749T>C), classified as likely pathogenic based on established variant interpretation criteria and concordance with the patient’s phenotype. Segregation analysis confirmed the variant to be de novo. The molecular finding was considered causative and was subsequently confirmed by Sanger sequencing.

Therapeutic Considerations

Given the predominance of severe hyperkinetic movements and dystonic crises, a genotype-oriented therapeutic approach was considered. Treatment with tetrabenazine was considered as a targeted option for management of dystonic episodes, with careful attention to cardiac safety and electrocardiographic monitoring.

3. Discussion

This case represents a GNAO1-related neurodevelopmental disorder with a phenotype dominated by severe movement disorder and dystonic crises, followed by the later development of epilepsy. Such a clinical course reflects the well-recognized phenotypic heterogeneity of GNAO1-associated disease, in which epilepsy may be absent, delayed, or secondary to prominent movement abnormalities.

An important aspect of this case is the temporal dissociation between early paroxysmal movement phenomena and the later onset of epileptic seizures. Prior to the age of 3 years, the patient exhibited paroxysmal events with atypical semiology that mimicked seizures but were more consistent with movement-related episodes. This diagnostic overlap is well documented in GNAO1-related disorders and represents a frequent source of clinical uncertainty.

EEG findings in our patient evolved over time. While electroencephalography performed during the initial evaluation did not demonstrate epileptiform abnormalities, subsequent overnight video-EEG recordings revealed intermittent epileptiform discharges predominantly involving the frontal regions.

Previous studies have shown that EEG patterns in GNAO1-associated disorders are highly heterogeneous and may range from normal recordings to focal or multifocal epileptiform discharges, as well as more severe encephalopathic patterns depending on age and epilepsy phenotype [1,5,6].

This variability underscores the importance of repeated neurophysiological assessment in patients with suspected genetic epilepsies and movement disorders.

Identification of a de novo likely pathogenic GNAO1 variant provided crucial etiological clarification in this patient. Molecular diagnosis supported differentiation between epileptic seizures and non-epileptic paroxysmal movement phenomena and enabled a shift toward genotype-informed management. In recent years, targeted therapeutic strategies, including dopamine-depleting agents such as tetrabenazine, have demonstrated benefit in reducing the severity and frequency of dystonic crises in selected patients with GNAO1-associated movement disorders [3,7].

In clinical settings with limited access to early genetic testing, delayed diagnosis may result in prolonged empirical treatment and misinterpretation of paroxysmal events. This case underscores the importance of incorporating whole-exome sequencing into the diagnostic evaluation of children with complex movement disorders, developmental delay, and paroxysmal symptoms, even when neurophysiological findings are non-diagnostic.

4. Conclusions

This clinical case contributes to the growing body of evidence on GNAO1-related neurodevelopmental disorders and highlights their phenotypic diversity. The variability of EEG findings and overlapping paroxysmal manifestations underscore the importance of comprehensive clinical and genetic evaluation. Early molecular diagnosis plays a central role in etiological clarification and individualized patient management.