P 411. GNAO1-Associated Hyperkinetic-Dystonic Movement Disorder and Developmental Delay in a 14-Year-Old Girl

Background: Several dystonic movement disorders in childhood are associated with cerebral palsy due to basal ganglia lesions. Primary dystonia is rare with DYT1-associated dystonia, the most common variant. Over the past couple of years, several pathogenic variants causing dystonia have been described. We report on a 14-year-old girl with hyperkinetic-dystonic movement disorder and psychomotor retardation.

Case Report: After uneventful pregnancy and delivery, the girl showed a nonprogressive developmental delay and a variable dystonic-hyperkinetic movement disorder with exacerbations, mostly triggered by infections. Multiple magnetic resonance imaging (MRI) scans and cerebrospinal fluid analyses including neurotransmitter diagnostics were unremarkable. Walking was possible if supported by a walking frame. Active speech was not achieved but the patient communicated through a speech-generating device. The first dystonic state with rhabdomyolysis and consecutive renal failure occurred at the age of 10 years triggered by a soft tissue infection. Deep sedation with intubation and assisted ventilation was necessary to control the movements. The current episode of dystonic state accompanied by rhabdomyolysis was triggered by orthopaedic surgery. The girl showed distinct dystonic-hyperkinetic movements requiring a balanced sedation with continuous clonidine and midazolam infusions and single doses of morphine and propofol.Oral tetrabenazine was added stepwise with a slow improvement of the clinical symptoms and normalization of creatine kinase and myoglobin concentrations. A repeat MRI showed no alterations of the basal ganglia or signs of metal accumulation. We initiated a genetic work-up using next-generation sequencing and a dystonia panel. The analysis showed heterozygosity for a probably pathogenic variant within the GNAO1 gene, causing a nonconservative exchange of an amino acid (c.626G>T;p.(Arg209Leu). Both parents do not carry the mutation. The detected variant has not been described in the literature but the other variants within the same codon in patients with similar symptoms.

The GNAO1 gene is encoding a G-protein subunit and mutations in this gene were first described in 2013 causing an epileptic encephalopathy and later also in combination with a hyperkinetic-dystonic movement disorder with developmental delay. Until now 40 patients with GNAO1 mutations have been described. It has been suggested that the epileptic encephalopathy phenotype is mainly affecting girls and the movement disorder predominantly boys, but cases of girls with developmental delay and movement disorder have also been reported. There is no standard therapy until now—clonidine, tetrabenazine, and deep brain stimulation have been used with variable success.