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Movement disorders
Letter
GNAO1-related movement disorder with life-threatening exacerbations: movement phenomenology and response to DBS
  1. Michaela Waak1,2,
  2. Shekeeb S Mohammad3,4,5,
  3. David Coman1,2,6,
  4. Kate Sinclair1,2,
  5. Lisa Copeland1,2,
  6. Peter Silburn7,
  7. Terry Coyne7,
  8. Jim McGill1,
  9. Mary O’Regan8,9,
  10. Richard Selway10,11,
  11. Joseph Symonds8,9,
  12. Padraic Grattan-Smith3,
  13. Jean-Pierre Lin10,11,
  14. Russell C Dale4,
  15. Stephen Malone1
  1. 1 Department of Neuroscience, Rehabilitation and Metabolic Medicine, Lady Cilento Children’s Hospital, South Brisbane, Queensland, Australia
  2. 2 School of Medicine, University of Queensland, Brisbane, Queensland, Australia
  3. 3 Department of Neurology, Children’s Hospital at Westmead, Sydney, New South Wales, Australia
  4. 4 Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia
  5. 5 School of Medicine, University of Sydney, Sydney, New South Wales, Australia
  6. 6 School of Medicine, Griffith University, Brisbane, Queensland, Australia
  7. 7 Asia-Pacific Centre for Neuromodulation, Queensland Brain Institute, Brisbane, Queensland, Australia
  8. 8 Paediatric Neurosciences Research Group, Fraser of Allander Neurosciences Unit, Royal Hospital for Children, Glasgow, UK
  9. 9 University of Glasgow, Glasgow, UK
  10. 10 Complex Motor Disorders Service, Children’s Neurosciences, Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, King’s Health Partners, London, UK
  11. 11 Department of Neurosurgery, King’s College Hospital NHS Foundation Trust, London, UK
  1. Correspondence to Dr. Michaela Waak; schuechtiwaak{at}gmx.de; Michaela.Waak{at}health.qld.gov.au

https://doi.org/10.1136/jnnp-2017-315653

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    Background

    GNAO1 (OMIM 139311) encodes a Gα0CNS protein responsible for regulation of GABA-B and α2-receptors, and neurotransmitter release. Mutations of GNAO1 are reported in patients with epileptic encephalopathy (EE) at times with a movement disorder (MD); some display severe hyperkinetic movements without EE, three underwent Deep Brain Stimulation (DBS) with reduction in exacerbations.1–4 (see online supplementary table 3, supporting information (SI)).

    Supplementary Material

    Supplementary table 1

    Methods

    We describe the MD phenomenology and course in three patients identified from neurology services in Brisbane and Glasgow with GNAO1-related MD, highlighting effectiveness of DBS in exacerbations.

    Informed consent was obtained. Four MD specialists reviewed videos (baseline, exacerbations, post-DBS) using a Proforma (SI) and reached a consensus on movement phenomenology.

    Results

    All patients had global delay, central hypotonia and MD noted in early life (see online supplementary table 1, patient synopsis, SI). Patient 3 initially showed bradykinesia, rigidity and dystonia; patient 1 resting tremor. All had been diagnosed with dyskinetic Cerebral Palsy (CP), without substantive MRI findings. Medication for baseline MD had variable efficacy (see online supplementary table 2, SI). MRI demonstrated mild progressive atrophy over 6 years in two patients (see online supplementary figure 1, SI). MRI during an exacerbation revealed restricted diffusion in the internal capsules and splenium (corpus callosum) in one (figure 1).

    Supplementary Material

    Supplementary figure 1
    Figure 1
    Figure 1

    Response to Deep Brain Stimulation (DBS) and MRI changes. PICU - Pediatric Intensive Care Unit.

    Whole exome sequencing identified de novo heterozygous mutations in the GNAO1 gene in all three patients, confirmed with Sanger sequencing.

    MD phenomenology

    Dominant baseline MD varied between patients; agreed features included chorea, orofaciolingual dyskinesia (n=2) and dystonia (n=1). During exacerbations all patients had violent mixed hyperkinesis (chorea, dystonia and orofaciolingual dyskinesia). Following DBS implantation movements significantly improved, but with residual chorea, orofaciolingual dyskinesia (n=2) and dystonia (n=3) (SI, online supplementary video).

    Supplementary Material

    Supplementary video 1

    Patients had severe episodic exacerbations (1–10 months duration), requiring a median of 5 intensive care admissions (figure 1). Chorea and ballism caused joint dislocations and superficial injuries, orofacial dyskinesia and bruxism caused orolingual injury. Illnesses were thought as triggers but fever often occurred without infective symptoms. Hyperthermia and rhabdomyolysis caused dehydration and prerenal failure. Movements impaired communication, motor function, sleep and exacerbated hypotonia. Maximal supportive care was required (median 15 medications trialled); clonazepam, tetrabenazine, phenobarbitone and intrathecal baclofen were of partial benefit, high-dose clonidine stabilised patient 3 (see online supplementary table 2, SI). Due to the severe movements, implantation of DBS was performed.

    Patients 1 and 2 received Vercise Rechargeable DBS (Boston Scientific, ages 10 and 6 years); patient 3 ACTIVA RC DBS (Medtronic Inc, age 13 years). Bilateral Globus Pallidus Internus (GPi) was targeted with all patients receiving bilateral monopolar stimulation at last follow-up.

    No exacerbations requiring intensive care unit (ICU) admission were seen following DBS (figure 1), and improved quality of life and functioning was observed in all.

    Postoperative complications included stimulator site infection (patient 1), and lead displacement requiring reinsertion (patient 2).

    Discussion

    We described the fluctuating, hyperkinetic movement phenomenology in patients with GNAO1 mutations without EE, the insufficient response to medical therapies and response to DBS. The pattern of exacerbations with violent movements appears characteristic for this disorder, and is responsible for significant morbidity. The prominent orofaciolingual dyskinesia3 4 causes orolingual injury and hypersalivation, worsening exacerbations.

    Chorea features in other paediatric-onset monogeneic MD syndromes including ADCY5, FOXG1, ARX and SCN8A, although the constellation of features (global hypotonia, relatively spared cognition, normal head circumference) helps to differentiate GNAO1.

    Our patients share severe developmental delay, hypotonia, an MD and the ‘investigative odyssey.’ Severe motor disturbance appears to mirror the severity of the MD, with authors implicating the MD as a contributor to motor delay.2 GNAO1 may display a genotype–phenotypic correlation, demonstrated in other genetic MDs, but this requires further validation. Patient 3 has late-onset seizures, a feature seen in another reported case with an identical mutation.1 Despite differences in MD at baseline, consistent features are fluctuating nature, severity, treatment resistance and orofaciolingual dyskinesia especially in exacerbations.

    GNAO1 may be progressive, witnessed by decline in patients with EE, postnatal death in mouse models, worsening movement exacerbations, MRI changes (including new changes during exacerbation, seen in patient 2 and others)2 4 and postmortem findings.2 Two reported patients have died during exacerbations,2 emphasising the severity and need for effective intervention.

    Agents targeting calcium channels may have a therapeutic role and topiramate has been used successfully.5 Topiramate and valproate appeared to increase dyskinesia in patient 3, but helped in patient 1, with no effect in others.2 The clonidine effect seen in patient 3 might be explained by the regulatory role of GNAO1 on α2-receptors. High-dose tetrabenazine partially improved chorea in patient 2, others report a similar response.2

    DBS allowed rapid discharge from ICU, and a sustained short-term benefit in MD, others noting similar improvement.3 4 DBS has not provided complete remission for movements, with two patients having short exacerbations managed medically. Patient 2 had increased movements with lead dislodgment, and return to baseline when replaced, emphasising effectiveness of neurostimulation. Improved level of function, quality of life and healthcare cost benefits are apparent and worth examining further with validated scale scores not used in this study.

    Another limitation is the use of a qualitative scale for movement assessment lacking external validation; the Abnormal Involuntary Movement Scale could be considered in future.

    The clinical features and movement phenomenology of GNAO1 may alert clinicians to the diagnosis, our cohort suggesting that milder cases exist which may remain indistinguishable from other ‘MRI-negative dyskinetic CP’ until there is an exacerbation. Recognition may direct therapies, and in patients with exacerbations DBS should be considered early. Long-term effectiveness of DBS in GNAO1 is unknown, but it appears effective in reducing life-threatening exacerbations.

    Acknowledgments

    The authors thank the patients and families involved in this study. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available at http://decipher.sanger.ac.uk and via email at decipher@sanger.ac.uk.

    References

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    Footnotes

    • Contributors All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing or revision of the manuscript. Furthermore, each author certifies that this material or similar material has not been and will not be submitted to or published in any other publication before its appearance in the Journal of Neurology, Neurosurgery and Psychiatry. Author roles: 1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique. MW: 1C, 2A, 2B, 2C, 3A, 3B. SSM: 1C, 2C, 3B. DC: 3B. KS: 3B. LC: 3B. PS: 3B. TC: 3B. JM: 3B. MOR: 3B. RS: 3B. JS: 3B. PGS: 1C, 3B. JPL: 1C, 3B. RCD: 1C, 3B. SM: 1C, 2C, 3B. All persons who have made substantial contributions to the work reported in the manuscript (eg, technical help, writing and editing assistance, general support), but who do not meet the criteria for authorship, are named in the Acknowledgements section. If we have not included an acknowledgement, then that indicates we have not received substantial contributions from non-authors.

    • Funding Funding for the project was provided by the Wellcome Trust.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Ethics comittee LCCH.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement All additional unpublished data from the study will be provided as supplemental material, so it can be accessed with the publication.