Awakening‐Related Bouts of Severe Opisthotonos in GNAO1

GNAO1 encodes the α subunit of heterotrimeric guanine nucleotide‐binding protein, a membrane protein widely expressed in the central nervous system involved in signal transduction. Pathogenic variants in GNAO1 cause an autosomal dominant condition characterized by epilepsy, global developmental delay, chorea, and dystonia. Severe exacerbations triggered by infections or surgeries have often been reported. ¹ We present a patient with a GNAO1 pathogenic variant and severe opisthotonos triggered by awakening.

Our patient is a 10‐year‐old female. She was born by an emergency C‐section due to non‐reassuring fetal heart tones and needed to be observed in the neonatal intensive care unit, briefly. She developed epilepsy during infancy and was treated with prednisolone, phenobarbital, topiramate, and lamotrigine. Currently, she is kept on a low dose of lamotrigine due to persistent abnormalities on the EEG but has been seizure‐free for several years. Developmental delays were noted in infancy. She is not able to crawl or walk, has minimal use of her hands, and does not speak. She has limited non‐verbal communication. Initially required G‐tube feedings but she currently feeds by mouth. The G‐tube is only used for medications for ease of administration.

She has generalized dystonia and chorea with frequent episodes of severe opisthotonos (Video 1). These episodes happen almost exclusively in transitions from sleep to arousal. It's unclear if they happen out of sleep or immediately after waking up. They also happen after naps. No other triggers, including illnesses or surgeries, are reported. Baclofen, clonazepam, botulinum toxin injections, and trihexyphenidyl had limited benefits. Levodopa worsened the dystonic episodes, while Gabapentin improved their frequency and severity.

Video 1.

Segment 1 shows the patient at baseline. Segment 2 shows the patient during an acute exacerbation.

She had an extensive non‐diagnostic metabolic and genetic workup when she was 2 years old. A brain MRI at 22 months old showed a paucity of myelination. A repeat brain MRI at 6 years old showed completion of myelination and mild prominence of bilateral frontal horns of the lateral ventricles (Fig. 1). Her last EEG at 5 years old showed very frequent 1.5 Hz generalized spike and slow‐wave runs and diffuse slowing and no electrographic correlate of the opisthotonus. A Cerebral Palsy genetic panel found a GNAO1 pathogenic variant (c.143C > T).

Fig. 1.

Brain MRI.

Sleep was one of the classic triggers of paroxysmal dyskinesias until most cases were found to be epileptic in origin. However, ADCY5 has recently emerged as a common cause of non‐epileptic sleep‐triggered dyskinesias. ² Other causes of sleep‐related dyskinesias include PRRT2, anti‐NMDAR encephalitis, and stroke. ³ , ⁴ , ⁵ A polysomnography study reported that dyskinesias in ADCY5 emerged after arousals from sleep, and not during sleep. ⁶ Recently, GNB1 has been associated with awakening‐induced paroxysmal dyskinesias. ⁷ Our patient also presented with dramatic bouts of worsening dystonia upon awakening.

GNAO1, ADCY5, and GNB1 are part of a pathway that affects the homeostasis of cAMP. ¹ , ⁷ Awakening‐dyskinesias in ADCY5 may result from an imbalance in the striatal medium spiny neurons between adenosine and dopamine. ⁶ Adenosine also promotes sleep, and the wake‐promoting effects of caffeine are driven by adenosine receptors. ⁶ Caffeine has been effective in ADCY5‐related dyskinesias and also had positive effects in dyskinesias in a GNAO1 animal model. ² , ⁸

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Patient Evaluation: A. Organization, B. Video Documentation; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

A.Z.V.: 1A, 1B, 2A, 2B, 3A, 3B

M.D.: 1C, 2A, 3B

L.T.: 1C, 2A, 3B

M.M.: 1C, 2A, 3B

A.G.: 1C, 2A, 3B

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. We confirm that patient consent has been sought and allowed for this case report and its publication. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: Dr. Zea Vera has received research support from the Tourette Association of America, American Brain Foundation, and American Academy of Neurology. He is part of the editorial team of the Neurology: Clinical Practice Journal. Dr. DiSabella receives funding from clinical trials from Amgen, Lilly, Biohaven, and Lundbeck. He serves as an editor for Neurology in Clinical Practice, Annals of Child Neurology Society, and Pediatric Neurology. Dr. Gropman receives grant NIH funding from NCATs, NICHD, NIDDK and funding from HRSA, as well as from the O'Malley scholars fund and the Kettering Fund. She receives honoraria for being an editor of Swaiman's Pediatric Neurology. She is on the editorial team of The Journal of Child Neurology and is editor in chief of Journal of Translational Genetics and Genomics (JTGG) and The Mitochondrial and Metabolic Medicine (M3) journal. The authors declare that there are no additional disclosures to report.