Anne Koy, Sebahattin Cirak, Victoria Gonzalez, Kerstin Becker, Thomas Roujeau, Christophe Milesi, Julien Baleine, Gilles Cambonie, Alain Boularan, Frederic Greco, Pierre-Francois Perrigault, Claude Cances, Nathalie Dorison, Diane Doummar, Agathe Roubertie, Christophe Beroud, Friederike Körber, Burkhard Stüve, Stephan Waltz, Cyril Mignot, Caroline Nava, Mohammad Maarouf, Philippe Coubes, Laura Cif

Exacerbation of hyperkinesia is a life-threatening complication of dyskinetic movement disorders, which can lead to multi-organ failure and even to death. GNAO1 has been recently identified to be involved in the pathogenesis of early infantile epileptic encephalopathy and movement disorders. Patients with GNAO1 mutations can present with a severe, progressive hyperkinetic movement disorder with prolonged life-threatening exacerbations, which are refractory to most anti-dystonic medication. The objective was to investigate the evolution of symptoms and the response to deep brain stimulation of the globus pallidus internus (GPi-DBS) in patients with different GNAO1 mutations. We report six patients presenting with global motor retardation, reduced muscle tone and recurrent episodes of severe, life-threatening hyperkinesia with dystonia, choreoathetosis, and ballism since early childhood. Five of them underwent GPi-DBS. The genetic workup revealed mutations in GNAO1 for all six patients. These encompass a new splice site mutation (c.723+1G>T) in patient 1, a new missense mutation (c.610G>C; p.Gly204Arg) in patient 2, a heterozygous mutation (c.625>T; p.Arg209Cys) in patients 3 and 4, and a heterozygous mutation (c.709G>A; p.Glu237Lys) in patients 5 and 6. By intervention with GPi-DBS the severe paroxysmal hyperkinetic exacerbations could be stopped in five patients. One patient is still under evaluation for neuromodulation. In complex movement disorders of unsolved etiology clinical WES can rapidly streamline pathogenic genes. We identified two novel GNAO1 mutations. GPi-DBS can be an effective and life-saving treatment option for patients with GNAO1 mutations and has to be considered early.