Severe upper airway dysfunction in GNAO1-related disorders

TL;DR

This study highlights the severe upper airway dysfunction in patients with GNAO1-related disorders, leading to life-threatening complications and poor outcomes despite interventions.

Contribution

The study emphasizes the critical role of upper airway dysfunction in GNAO1-related disorders and calls for improved therapeutic strategies.

Findings

All four patients exhibited severe hypotonia and hyperkinetic movement disorders, leading to life-threatening respiratory complications.

Interventions like DBS and tracheostomy did not effectively address airway or swallowing dysfunction.

All patients died at a young age due to respiratory complications, underscoring the high mortality rate in this condition.

Abstract

GNAO1-related disorders (GNAO1-RD) encompass a wide phenotypic spectrum, including muscular hypotonia, movement disorders (MD), epilepsy, developmental delay, and intellectual disability. MD often presents with dystonia and choreoathetosis, and dyskinetic crises can lead to life-threatening conditions. Despite increasing reports, limited information exists on the impact of upper airway dysfunction in GNAO1-RD patients. This study examines the implications of muscular hypotonia on upper airway function and subsequent clinical outcomes.

This study includes four patients, three from the GNAO1 registry in Germany, with data collected from medical records including neurological examinations, EEG recordings, genetics, imaging studies, and video documentation of dyskinetic movements and respiratory symptoms. Treatment interventions and clinical outcomes were documented.

The study involved four patients (three males and one female) aged between 15 months and 12 years, all of whom were within the severe spectrum of GNAO1-RD. All patients exhibited severe hypotonia and hyperkinetic MD, leading to recurrent dyskinetic crises. Respiratory complications included an inspiratory stridor and airway obstructions. All patients died at young age (2.4, 2.8, 7.8 and 12 years) due to respiratory complications. Despite interventions such as DBS and tracheostomy, clinical outcomes remained poor.

Upper airway dysfunction significantly contributes to the high morbidity and mortality in GNAO1-RD patients. Current therapeutic options are limited; while DBS can be life-saving during acute crises, it does not address swallowing or airway dysfunction effectively. Multimodal approaches and larger, multicenter trials are needed to improve outcomes for these patients.

The online version contains supplementary material available at 10.1186/s13052-025-02150-0.

Full text

Introduction

GNAO1-related disorders (GNAO1-RD) encompass a wide phenotypic spectrum, including muscular hypotonia, movement disorders (MD), epilepsy, developmental delay and intellectual disability [1, 2]. MD usually manifests during infancy, presenting with predominantly severe hypotonia combined with dystonia and choreoathetosis. Dyskinetic crises [3], or paroxysmal exacerbations of the MD, can occur spontaneously or be triggered by infections, pain, or emotional distress. These episodes can be life-threatening and are a cardinal feature of the disease in many patients [4]. Although milder and later-onset phenotypes have been identified [5], most reported cases exhibit a severe form of the disease, characterized by recurrent dyskinetic crises and substantial impairment in motor function, cognition, speech, swallowing, and sleep [6].

GNAO1-RD patients face a notable risk of mortality during early childhood [7], often due to refractory epilepsy or dyskinetic crises. Recurrent respiratory tract infections and severe dysphagia significantly increase the risk of aspiration, leading to significant clinical deterioration in these patients [8]. Another potential cause of respiratory dysfunction may be autonomic respiratory control dysfunction or obstructive sleep apnoea (OSA), as seen in other patients with epileptic encephalopathies. Dysfunction of the autonomic nervous system can interfere with the normal regulation of breathing, leading to issues such as apnea, hypoventilation, and irregular breathing episodes [9, 10]. Despite an increasing number of case reports and a broader understanding of the clinical spectrum of GNAO1-RD, there remains limited information on the impact of upper respiratory tract dysfunction in these patients. Therefore, this study aims to examine the implications of muscular hypotonia on upper airway function and subsequent clinical outcomes.

Methods

Three out of the four patients are enrolled in the GNAO1 registry in Germany, approved by the Ethics Committee of the Medical Faculty of the University of Cologne under identification number 19–19280. The parents of one patient residing outside Germany retrospectively consented to the publication of the case of their child. Prior to study participation, all participants gave informed consent. Clinical data were collected from medical records, including detailed histories, neurological examinations, electroencephalogram (EEG) recordings, genetics, and imaging studies where available. Video documentation of dyskinetic movements and respiratory symptoms, such as inspiratory stridor, was also reviewed. Treatment interventions, such as pharmacological management and surgical procedures, and clinical outcomes were documented. All patients underwent laryngotracheoscopy and bronchoscopy under spontaneous breathing.

Results

Case 1 was a male patient who manifested with generalized seizures at the age of six weeks, with rapidly increasing frequency from thereon. A genetic panel for Early Infantile Epileptic Encephalopathy (EIEE) revealed a missense variant in GNAO1. He showed developmental delay and severe muscular hypotonia with a lack of head control. At six months of age, he manifested choreoathetosis of the limbs and persistent orofacial dyskinesia. Dystonia was present in the trunk, leading to recurrent opisthotonos. Apart from EIEE, a profound feeding problem due to severe dysphagia was prominent. At the age of eight months, he developed an increasing inspiratory stridor in the supine position with recurrent oxygen desaturation episodes (Supplementary Material 2). A laryngotracheoscopy with a rigid laryngoscope was performed under spontaneous breathing (Supplementary Material 3). The examination did not reveal any structural alterations or tracheo-laryngeal narrowing, suggesting that the stridor was secondary to muscular hypotonia of the upper airways. Due to a lack of therapeutic options, he was dependent on continuous head fixation in an upright position and oxygen therapy to improve his breathing. Unfortunately, the patient’s clinical conditions deteriorated constantly due to recurrent infections of the upper airways, with dyskinetic crisis necessitating numerous hospitalizations. Colonization of the nasal and throat regions with Klebsiella pneumoniae and 3MRGN Enterobacter was detected. In the course of a further severe respiratory infection, the patient died due to combined pulmonary and renal failure in a palliative outpatient setting.

Case 2 was a 15-month-old male with neurodevelopmental encephalopathy and MD due to a GNAO1 de novo variant. Since birth, he experienced intermittent dyskinetic movements of the limbs with tongue protrusion. At the age of 4 months, the MD became aggravated by the onset of paroxysmal choreoathetosis and dystonia of the limbs and trunk with opisthotonos, general irritability, and excessive drooling. He suffered from several episodes of daily dyskinetic crises (0–8 episodes per day) with hyperkinesia of the limbs and the head, which worsened with stress and tactile stimulation. He had never any seizures; his psychomotor development was delayed with no motor milestones reached and impaired cognition. In the following, he was suffering from continuous hyperkinetic involuntary movements accompanied by severe central muscular hypotonia. Treatment with clonazepam led to a remarkable improvement in the MD. At the age of twelve months, he manifested an inspiratory stridor. In the following weeks, his respiratory condition deteriorated continuously, leading to a hospital admission and requiring respiratory support through noninvasive ventilation. The laryngotracheoscopy revealed moderate pharyngo-tracheomalacia, muscular hypotonia of the upper airways, and adenoid hypertrophy. Treatment with local steroids was started to reduce the hypertrophy, but the stridor persisted. In the following, he experienced recurrent respiratory infections with hospital admission, and deceased due to a severe pneumonia without detection of pathogens.

Case 3 was a male patient, born spontaneously at term. He manifested muscular hypotonia with a profound developmental delay. During the first year of life, the boy developed a severe hyperkinetic MD comprising dystonia and generalized choreoathetosis, with recurrent life-threatening dyskinetic crises requiring admission to the intensive care unit. Due to a persistent, severe dyskinetic crisis, Deep Brain Stimulation of the globus pallidus internus (Gpi-DBS) was performed as an emergency intervention as well as a tracheostomy at the age of eight years. Thereafter, the dyskinetic crisis stopped, and the MD improved. In the genetic testing, the missense variant in GNAO1 could be identified. In the following days, he manifested a stridor at rest, which increased with the deterioration of the MD. Despite the tracheostomy, obstructions of the airways continued to occur, originating in the lower airways, which led to multiple hypoxic spells requiring reanimation. He was diagnosed with severe dynamic trachea-bronchomalacia, characterized by recurrent total collapse of the left main bronchus. Pseudomonas aeruginosa sensitive to ciprofloxacin was identified in the tracheal secretions. Permanent continuous positive airway pressure (CPAP) ventilation was not tolerated and led to exacerbations of the MD. The tolerable oxygen flow therapy could not stop the obstructive apnea, and the boy died at the age of 12 in a nursing home.

Case 4 Starting from the third day of life, this girl presented with focal seizures and subsequently a status epilepticus. Development was delayed, and abnormal hyperkinetic movements were observed since the first months of life. Furthermore, intermittent muscular hypotonia and sleep disturbances were prominent. Due to severe feeding problems and swallowing difficulties due to muscular hypotonia, a gastrostomy and later a jejunal feeding tube were performed. Exome analysis revealed a missense GNAO1 de novo variant. The movement disorder worsened over time, with recurrent severe dyskinetic crises. As a result, she underwent Gpi-DBS implantation at the age of three years, with an initial improvement in hyperkinesia. However, the girl started to exhibit significant impairment due to frequent vomiting of mucous secretion, often resulting in choking episodes. She experienced recurrent episodes of upper airway obstruction, likely due to mucous obstruction due to weak coughing in the context of muscular hypotonia, impaired coordination of swallowing, irregular, involuntary tongue movements, and excessive drooling. After several unsuccessful therapeutic approaches, including glycopyrronium bromide, anticholinergic drugs, dopamine antagonists, and botulinum toxin injections in the parotid gland, a tracheostomy was performed to protect her from aspirations of mucous secretions due to severe dysphagia. With the tracheostomy, there were no further aspirations, but vomiting persisted, and the need for mechanical suction increased. At the age of five, she underwent a fundoplication surgery with beneficial effects on the frequency of vomiting and hypersalivation. A colonization with 3MRGN Escherichia coli of the tracheal secretions was found. Death occurred at the age of 7.8 years due to acute respiratory distress syndrome (ARDS) resulting from a an Influenza A infection.

Table 1 resumes genetic findings, clinical and radiological features of the four patients.

Severity score is attached in Supplementary Material 1.

Table 1. Genetic variants and clinical features of the patientsPatGen.Variant in GNAO1reference sequence: NM_138736.3Respiratory Symptom (onset in m)and treatmentEpileptic symptoms(ILAE classification of seizures 2017) and treatmentEEGMovement disorder and treatmentSpeech and feedingImagingGNAO1-RD Severity scoreOutcomeFirst publishedP1c.607G > A/p.G203RStridor (8), MH of the UA.Head fixation in upright positionand oxygen therapyNeo: generalised motor onset; later focal and generalised motor onset;LEV: frequency reduction.(6 m)no pathologic findingsDY trunk, mouth, MH, nystagmus. DCCZP -> DY+,GAB increased alertness,CL –> on demandAnarthria;PEGMRI (1 m):no pathologic findings11,25Deceased(2.4 y) Thiel et al., 2022P2c.607G > A/p.G203RStridor (12), pharyngo-tracheomalacia,MH of the UA and adenoid hypertrophyLocal corticosteroids,non-invasive ventilationNone(7 m and 15 m)no pathologic findingsDY limbs, trunk, CH, DC; MHBZD -> DY+,GAB ineffectiveAnarthria;PEGMRI (7 m)no pathologic findings8,75Deceased(2.8 y)Domínguez-Carral, Jana et al. 2023P3c.607G > A/p.G203RStridor (96), severe dynamic trachea-bronchomalaciatracheostomy, CPAP ventilationNone(8 y)no pathologic findingsDY generalised; CH; MH; DC;NystagmusTHP: partial effectBaclofen: DY+;BZD & CL–> on demandCannabis short effect;DBS(8 y): + on CH; no more DCDysarthria;PEGMRI (72 m): EV; pseudotumour cerebri8,5Deceased(12 y) Thiel et al., 2022P4c.170 A > C/p.H57PStridor (3) MH of the UA, severe dysphagia; involuntary tongue movements, excessive drooling & repeated vomiting of mucus.GB, anticholinergic drugs, DA and botulinum toxin injections in the parotid gland: all ineffective.Tracheostomy & fundoplication ->reduction vomiting and hypersalivationNeo: focal motor onset; 3 y SE; later no SZ anymore;CZP, TPM: frequency reduction(3 y)no pathologic findingsGeneralised DY; increasing CH; MHBZD -> DY+;Baclofen & GAB ineffective;CL on demandDBS(36 m): + on DY and CH, no more DCAnarthria;PEGCT(40 m): ATMRI(36 m): AT, EV9,75Deceased(7.8y) Thiel et al., 2022+: Positive effect, AT cerebral and cerebellar atrophy, BZD benzodiazepines, CH Chorea, CL Chloral hydrate, CZP Clonazepam, DA dopamine antagonists, DBS Deep brain stimulation, DC Dyskinetic crisis, DY Dystonia, EV Enlarged Ventricles, GAB Gabapentin, GB Glycopyrronium bromide, LEV Levetiracetam, m Months, MD Movement disorder, MH Muscular hypotonia, neo Neonatal, PEG percutaneous endoscopic gastrostomy, SE Status epilepticus, SZ Seizures, THP Trihexyphenidyl, TPM Topiramate, UA Upper respiratory airways, y Years

Discussion

The four cases presented in this study illustrate the severe end of the phenotypic spectrum of GNAO1-RD, characterized by profound motor impairment and global developmental delay and all died at a young age. Three of the patients carried the c.607G > A/p.G203R pathogenic variant, which is known to be associated with the most severe phenotypes.

Severe hyperkinetic MD, leading to recurrent dyskinetic crises, is a hallmark feature of GNAO1-RD and a significant predictor of mortality [11–13]. The patients described exhibited pronounced hyperkinetic MD with distinctive orofacial involvement, impaired tongue coordination, and swallowing difficulties. In addition, muscle hypotonia and impaired postural control, which are early indicators of GNAO1-RD, contributed to the life-threatening respiratory distress [14].

The management of both hyperkinesia and central hypotonia poses significant challenges. Pharmaceutical treatment for dystonia and choreoathetosis can exacerbate resting muscular hypotonia [15], while hypersalivation, a common side effect of benzodiazepine therapy, further impairs upper airway function [16]. DBS has shown beneficial effects primarily on limb hyperkinesia in GNAO1-RD [8], yet its impact on orofacial hyperkinesia and hypotonia remains limited [14].

Upper airway dysfunction in all the described patients led to profound discomfort and frequent hospitalizations. The therapeutic approach involved multidisciplinary assessments, including laryngotracheoscopy, to identify treatable causes, consistent with guidelines from the International Pediatric Otorhinolaryngology Group (IPOG) for laryngomalacia [17]. Laryngeal dystonia (LD) with inspiratory stridor, potentially treatable with antidystonic medications or botulinum toxin injections into the vocal cords, was considered a differential diagnosis. This condition has been documented in cerebral palsy [18], and it can be hypothesized that it could cause stridor in GNAO1-RD. However, a definite diagnosis often requires fiberoptic laryngoscopy in an awake patient to detect vocal cord adduction during inspiration in the presence of generalized dystonia, as examination under anesthesia may obscure the pathophysiology of the stridor.

Nevertheless, there is considerable overlap between the patterns of inspiratory stridor in laryngomalacia and LD. In both conditions, inspiratory stridor worsens when patients are agitated and improves when they are relaxed. In this context, one may speculate that in case 3, overlapping dystonic airway obstructions may have prevented the patient from benefiting from a tracheostomy. Laryngomalacia, characterized by hypotonic narrowing of the upper airways, emerged as a major contributor to stridor and upper airway dysfunction in GNAO1-RD patients. Interestingly, early stridor onset has been linked to reduced survival in other conditions marked by hypotonia, such as multiple system atrophy [19].

In addition to upper airway disorders, lower airway abnormalities, central control of ventilation, autonomic dysfunction, and sleep-related breathing disorders can contribute to respiratory dysfunction in complex neuronal disorders [20]. To examine these features in GNAO1 might be of future relevance.

Brain structural deficits may be linked to disruptions in respiratory rhythm generation, as seen in chronic obstructive pulmonary disease and OSA [21, 22]. Regional changes in gray matter have been correlated with autonomic dysfunction in Parkinson’s disease (PD) [23] and autonomic failure has been proposed as a contributing factor to respiratory dysfunction in PD [24] and in patients with epileptic encephalopathies [8]. All but one of the patients discussed above had normal brain imaging, and no gray matter changes could be assessed in any of them. To assess this hypothesis in the future in GNAO1-RD, advanced brain imaging methods should be performed in larger cohorts, and polysomnographic evaluations could be useful to rule out the presence of sleep-related respiratory disorders.

Here we underscore the high morbidity and mortality associated with upper airway involvement in severely affected GNAO1-RD patients. Current therapeutic options are limited; while Gpi-DBS may be life-saving during acute dyskinesis crises, it has no proven efficacy in managing swallowing or upper airway dysfunction [25]. Respiratory muscle therapy through targeted speech interventions has shown promise in alleviating obstructive sleep apnea related to hypotonia [26], but its application in severely affected patients remains challenging. Tracheostomy was performed in cases 3 and 4, and although it did not uniformly yield beneficial outcomes, in severe affected patients, such as those with c.607G > A/p.G203R pathogenic variant, an early invasive approach could be considered to prevent the progressive deterioration of the airway function.

This study is limited by its small sample size of only four patients, which may not fully capture the variability of the GNAO1-RD spectrum. Additionally, the retrospective nature of the case reviews and the reliance on medical records in cases 2 and 3 may introduce bias or incomplete data.

Conclusion

We conclude that upper airway involvement in severely affected GNAO1-RD patients should not be underestimated and may serve as a predictor of reduced survival, exacerbated by the current lack of effective therapies. Clinicians should adopt a multimodal approach involving diverse specialties and diagnostic tools like laryngotracheoscopy to address this critical aspect of patient care. Future research efforts should prioritize larger, multicenter prospective trials to enhance the management and outcomes of these complex, disabled patients with GNAO1-RD.

Supplementary Information

Supplementary Material 1.

Supplementary Material 2.

Supplementary Material 3.

Supplementary Material 4.