ADCY5 and GNAO1: pediatric early onset chorea with paroxysmal events

Oliver Maier Children’s Hospital of Eastern Switzerland. Deprtment of child neurology, development and rehabilitation (KER-Zentrum) , St. Gallen, Switzerland

Introduction: Heterozygous mutations in the GNAO1 (OMIM 139311), encoding the subunit of the heterotrimeric guanine nucleotide- binding (G ) were first described as a cause of early infantile epileptic encephalopathy (EIEE) in 2013. Subsequent reports have broadened the spectrum of clinical presentation including prominent dyskinesia and intellectual disability with few or no seizures. Paroxysmal attacks of chorea and dyskinesia can be triggered by fever or emotions. ADCY5 mutations (OMIM 600293) have been recently identified as an important cause of early-onset hyperkinetic movement disorders with paroxysmal chorea and dystonia. ADCY5 codes for adenylate type 5, which is strongly expressed in the striatum. This protein interacts with Gαolf, which is encoded by GNAL, a gene involved in primary dystonia. ADCY5 integrates signals from multiple receptors, including adenosine A2A and D1 and D2 dopamine receptors. The pathophysiology likely involves increased adenylate cyclate activity, thereby affecting within the striatum.

Case reports: GNAO1: We report a now 6 year old girl that presented at the age of 1 year with severe muscular hypotonia and developmental delay. After the age of 2 years she developed severe dyskinetic movement disorder with paroxysmal life- threatening episodes of choreoathetoid crisis induced by fever and emotions. Genetic analysis showed de novo mutation in GNAO1 gene (c.736G>A p.Glu246Lys). She has only mild epilepsy.

Early age until 2 year of age: Severe muscular hypotonia and developmental delay, no epilepsy, cranial MRI with slight frontal cortical atrophy, infrequent seizures. From age 2 years severe dyskinetc, choreatic movement disorder, no seizures

(photos with permission of parents)

ADCY5: We report a now 17 year old girl who presented from early childhood with muscular hypotonia and choreathetosis with paroxysmal choreoathethotic events. EEG and cMRI were normal. There was only minimal improvement with medications as clonazepame. No improvement on levodopa or carbamazepine. Good improvement of the movement disorder with Deep brain stimulation (DBS) performed at the age of 15 years. Genetic analysis showed de novo mutation c.125C>T, p.Arg418Trp At the early age muscular hypotonia and hyperkinetic movements with paroxysmal hyperkinetic events. Good

improvement with DBS (last photo)

(photos with permission of parents)

Conclusion: Clinical phenotype GNAO1 ADCY1 Hyperkinetc movements Dykinesia, Chorea Dyskinesia, Chorea GNAO1 and ADCY are two distinct movement disorders characterized by involuntary movements Paroxysmal events tiggered by fever, emotions, with and without trigger, day with paroxysmal events. Cranial MRI is usually day and night normal. Deep brain stimulation could be effective in Developmental delay Moderate to severe moderate both GNAO1 and ADCY5 related movement Epilepsy epileptic encephalopathy no frequent disorders. MRI Normal to moderate atrophy normal

Literature: Therapy (selection) Clonidine, tetrabenazine, Benzodiazepine, • Koy et al., J Neurol Sci, 2018: Deep brain stimulation is effective in pediatric patients with GNAO1 associated severe hyperkinesia • Dy et al.: J Child Neurology, 2016: Treatment of ADCY5-associated dystonia, chorea, and hyperkinetic disorders with deep brain stimulation DBS carbamazepine, • Carecchio et al: Parkinsonism and related disordes 2017: ADCY5-related movement disorders: frequency, disease course and phenotypic variability in a cohort of paediatric patients tetabenazine, DBS • Méneret et al: Revue neurologique 2016: Paroxysmal movement disorders: an update • Feng et al., Neurology 2017: Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations • Parson et al., Neurology 2017: Epileptic encephalopathy, movement disorder, and the yin and yang of GNAO1 function Inheritance Autosomal-dominant Autosomal-dominant

EACD Paris 23.-25.5.2019