Episodic Choreo-Dystonic Storm in an Infantile-Onset Movement Disorder: Think of G Protein Subunit Alpha O1 Gene Defect!

Abstract

While ATPase Copper Transporting Beta (ATP7B), Dystonia-1 (DYT-1), Lysine (K) Methyl transferase 2B (KMT2B), and Adenylate Cyclase 5 (ADCY5) gene mutations are well-characterized causes of childhood-onset choreo-dystonic movement disorders, G protein subunit alpha O1 (GNAO1)-related disorders are not commonly suspected. The GNAO1 gene is crucial for neuronal transmission, and its mutation has been linked to neurodevelopmental delay, infantile-onset epilepsy, and movement disorders. To the best of our knowledge, only five Indian cases have been reported to date. We report a 9-year-old girl with predominant choreo-dystonic manifestations along with dyskinetic storm, i.e., episodes of significant worsening in involuntary movements following febrile episodes. Her brain magnetic resonance imaging (MRI) was unremarkable. She presented to us in a dyskinetic crisis, which responded to oral haloperidol. Thus, GNAO1-related disorder must be suspected in a child with developmental delay, infantile- to childhood-onset seizures with/without movement disorders, along with episodes of dyskinetic crisis related to stress or febrile episodes.

Introduction

The G protein subunit alpha O1 (GNAO1) gene encodes the synthesis of the Gα_O subunit of guanosine nucleotide-binding proteins.[1] It is extensively expressed in the brain and plays an essential role in the regulation of several neurotransmitter-related functions required for neuronal signaling and development.[1] The GNAO1 gene defect is a rare condition first reported in 2013, with more than 200 patients reported to date.[2] Symptoms usually start in infancy and range from developmental delay to epileptic encephalopathy and involuntary movements.[2] To the best of our knowledge, only five cases of GNAO1-related disorder have been reported from India [Table 1].[3,4,5,6,7] While two of these cases had primary epileptic manifestations,[3,4] the remaining three cases had predominant hyperkinetic movement disorder presentation.[5,6,7] Herein, we describe a 9-year-old girl with a GNAO1 gene defect having predominant chorea along with episodic choreo-dystonic storm.

Table 1.

Description of clinical manifestations and genotype in GNAO1 gene mutation cases reported from India

Author	Gender	Age at Presentation	Genotype	Global Developmental Delay	Seizures	Phenotypic Presentation
Chowdhury et al., 2025	Male	12 years	GNAO1 gene (c.617G>A p.Arg206Gln)	No	No	Adolescent-onset progressive generalized dystonia
Biswas et al., 2025	Male	6 years	GNAO1 (c.644G>A, p.Cys215Tyr), CP (c.131_132delTT)	No	No	Hyperkinetic movement disorder (dystonia, tremor), hypoceruloplasminemia without K-F rings
Panda et al., 2023	Male	6 months	GNAO1 (c.1033G>A, p.Ala345Thr)	No	Yes	Febrile encephalopathy-like onset, followed by refractory seizures and choreoathetoid movements
Negi et al., 2023	Female	7 months	GNAO1(c.935A>G, p.Asn312Ser)	Yes	No	West syndrome
Satish et al., 2022	Female	7 years	GNAO1 (c.736G>A, p.Glu246Lys)	Yes	Yes (single focal seizure at 7 years)	Hyperkinetic movements (dystonia, myoclonus), spasticity, dysmorphic features
Present study 2025	Female	9 years	GNAO1 (c625 C>T p.Arg 209 Cys)	Yes	No	Hyperkinetic movements (chorea with episodic choreo-dystonic storm during fever)

GNAO1: G protein subunit alpha O1

Case Report

A 9-year-old girl, with global developmental delay despite no history of perinatal insult, developed abnormal posturing of the body from the age of 18 months. Initially, she developed abnormal neck posturing in the form of intermittent neck extension, aggravated by crying and relieved by supporting the neck. She started walking with support at 2 years of age. She used to bend her left foot, turning it inwards, along with occasional toe walking of her right leg. During episodes of fever, the abnormal posturing of the neck and feet used to worsen, only to improve to the pre-febrile status once the fever subsided. She presented with a 3-day history of fever associated with significant worsening of involuntary movements in the form of abnormal flinging movements involving all four limbs: legs > hands; proximal > distal, subsiding in sleep. Despite control of the fever, the worsening of involuntary movements persisted, unlike previous episodes. Examination showed choreo-dystonic movements involving all four limbs, associated with generalized dystonia [Video 1]. Routine laboratory parameters were normal, including liver, renal, and thyroid function tests, and serum antistreptolysin O titer. Brain magnetic resonance imaging (MRI) returned nonsignificant. Whole-exome sequencing revealed a pathogenic mutation in exon 6 (c625 C>T p.Arg 209 Cys) in the GNAO1 gene, following an autosomal dominant inheritance pattern. According to the American College of Medical Genetics and Genomics guidelines, the variant has been described as pathogenic. She was started on haloperidol, 0.125 mg oral twice daily, and her chore-dystonic movements improved to the pre-febrile state over the subsequent 5 days. Haloperidol was tapered over the next month. Interestingly, she developed oculogyric crisis (OGC) following administration of haloperidol, which subsided after haloperidol was stopped [Video 1]. No further worsening was observed over the subsequent 11-month follow-up.

Discussion

Our patient presented with global developmental delay, along with infantile-onset, progressive, cervical-onset, generalized, combined dystonia associated with chorea precipitated by fever. GNAO1 gene defects affect brain development and functioning. Patients mostly present with developmental delay, epileptic encephalopathy, and multiple movement disorders, with a predominance of dystonia and chorea. Stress-associated dyskinetic storms have been reported in several patients with GNAO1-related disorder.[2,8]

Children with GNAO1 gene defects are often misdiagnosed as having cerebral palsy, neurotransmitter defects, or mitochondrial disorders, and many times undergo invasive tests like muscle biopsy and lumbar tap.[2] Moreover, the features also overlap with other infantile- and childhood-onset movement disorders, including Torsin 1 A (TOR1A), Lysine (K) Methyl transferase 2B (KMT2B), and Adenylate Cyclase 5 (ADCY5) gene mutations. However, clinical clues may help rule out these differentials. While predominant motor delay and dystonic posturing are common in TOR1A mutation, global developmental delay and seizures are less common.[9] The KMT2B gene mutation presents primarily with lower-limb-onset generalized dystonia and usually lacks associated seizures or episodic worsening.[10] The ADCY5 gene mutation has periodic exacerbations, with dyskinesias and axial hypotonia being predominant features that become more prominent during sleep.[11]

In a recent report summarizing clinical characteristics of 86 patients with GNAO 1-related disorder, developmental delay (100%), movement disorders (89%), and epilepsy (53%) were the most common manifestations. Both movement disorders and epilepsy were seen in 41% of patients. The study reported hypotonia in about 91% of cases.[12] Several patients (around 40%) suffer episodic dyskinetic crises, including chorea storms, precipitated by stress or illness,[2,8] as was seen in our patient. The literature review revealed nine cases of ocular movement abnormalities (i.e., saccades alterations, nystagmus, OGC, downward gaze palsy, and fixation deficit with head nodding) in GNAO1-related disorders. Among these, the incidence of OGC is unknown.[13] OGC in our patient occurred after starting haloperidol, which could be the likely culprit.

The pathogenesis of dyskinetic crisis seen in patients with GNAO1-related disorder is not completely understood, and it is considered a result of dopaminergic dysfunction in the basal ganglia, where the Gα_O gene is an important regulator.[14] There are multiple other conditions, such as DYT-1, Wilson’s disease, and mitochondrial disorders like Leigh syndrome, which are associated with worsening of movement disorders with fever and stress.[15] These conditions are usually associated with dystonic crisis, while GNAO1-related disorder can have dystonic crisis or dyskinetic crisis, including choreo-ballismus.

While brain MRI may be normal in patients with GNAO1-related disorder, several abnormalities, including diffuse atrophy, thinned corpus callosum, and basal ganglia involvement, have also been reported.[12] Our patient has a normal brain MRI. No specific clinico-radiological correlation has been reported in previous studies.

The GNAO1 gene mutation is autosomal dominant in inheritance. Several types of genetic mutations have been reported in GNAO1, with genotypic–phenotypic correlation. The most common variant is c.607G>A (14.8%) which presents with developmental and epileptic encephalopathy. The c.625C>T variant seen in our patient is found in about 6% of cases and presents with neurodevelopmental disorder with involuntary movements.[2] Our patient had a mutation in exon 6 (c625 C>T p.Arg209Cys) in the GNAO1 gene, which has been described in two patients reported by Koy et al.[8] Unlike our patient, both of these patients reported by Koy et al. had epilepsy. While one of their patients had infantile-onset generalized progressive choreo-dystonia similar to our patient, the onset of choreoathetosis and dystonia in their second patient was at 11 years of age. Interestingly, both these patients demonstrated a good response to deep brain stimulation (DBS) targeting the global pallidus internus.[8] The dyskinetic crisis in our patient improved with medical management, and her parents refused DBS.

Conclusion

GNAO1-related disorders are relatively rare, less suspected, and underreported. This disorder should be suspected in a patient with developmental delay, infantile- to childhood-onset movement disorders, with or without seizures, along with episodic exacerbations of involuntary movements due to stress or febrile episodes.

Declaration of patient’s consent

The patient is a minor. Her father provided consent for video and publication. The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and that due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.