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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 Selway,
  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

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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
[Supporting_information_JNNP_submitted_4_2017.pdf]

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_supp.JPG]
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 …

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