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GNAO1 Encephalopathy Broadening the Phenotype and Evaluating Treatment and Outcome

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GNAO1 Encephalopathy Broadening the Phenotype and Evaluating Treatment and Outcome GNAO1 encephalopathy Broadening the phenotype and evaluating treatment and outcome Federica Rachele Danti, ABSTRACT MD Objective: To describe better the motor phenotype, molecular genetic features, and clinical Serena Galosi, MD course of GNAO1-related disease. Marta Romani, PhD Methods: We reviewed clinical information, video recordings, and neuroimaging of a newly iden- Martino Montomoli, MD tified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected Keren J. Carss, PhD‡ by next-generation sequencing techniques. F. Lucy Raymond, PhD‡ – Elena Parrini, PhD Results: Patients first presented in early childhood (median age of presentation 10 months, range 0 48 Claudia Bianchini, BSc months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment Tony McShane, MD with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder pheno- Russell C. Dale, PhD type, featuring moderate developmental delay associated with complex stereotypies, mainly facial Shekeeb S. Mohammad, dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, MD such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading Ubaid Shah, MD to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was Neil Mahant, FRACP, effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was PhD life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyper- Joanne Ng, MBChB kinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Struc- Amy McTague, MBChB tural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident Rajib Samanta, MD in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. Gayatri Vadlamani, MD Conclusions: Our findings support the causative role of GNAO1 mutations in an expanded spec- Enza Maria Valente, MD, trum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers PhD and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful Vincenzo Leuzzi, MD, treatments for dyskinesia. Neurol Genet 2017;3:e143; doi: 10.1212/NXG.0000000000000143 PhD Manju A. Kurian, MD, GLOSSARY PhD, MRCPCH* CK 5 creatine kinase; DBS 5 deep brain stimulation; EOEE 5 early-onset epileptic encephalopathy; EVS 5 Exome Variant 5 5 5 – Renzo Guerrini, MD, Server; ExAC Exome Aggregation Consortium; GATK Genome Analysis Toolkit; GPCR Gprotein coupled receptor; WES 5 whole-exome sequencing; WGS 5 whole-genome sequencing. FRCP* De novo GNAO1 mutations (MIM 139311) were initially identified in children with early- onset epileptic encephalopathy (EOEE) and severe developmental delay,1–3 with later develop- Correspondence to 1,4–6 Dr. Guerrini: ment of dyskinetic movement disorders and in children exhibiting developmental delay and [email protected] severe dyskinesia without seizures.7,8 *These authors have contributed equally to this work. ‡These authors are members of the National Institute for Health Research (NIHR) Bioresource Rare Diseases Consortium. From the Department of Paediatrics, Child Neurology and Psychiatry (F.R.D., S.G., V.L.), Sapienza University of Rome, Italy; Molecular Neurosciences, Developmental Neurosciences Programme (F.R.D., J.N., A.M., M.A.K.), University College London Institute of Child Health, UK; Supplemental data Department of Neurology (F.R.D., J.N., A.M., M.A.K.), Great Ormond Street Hospital for Children, London, UK; GENOMA Group (M.R.), at Neurology.org/ng Molecular Genetics Laboratory, Rome, Italy; Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories (M.M., E.P., C.B., R.G.), Neuroscience Department, A Meyer Children’s Hospital, University of Florence, Italy; Department of Haematology (K.J.C.), University of Cambridge, NHS Blood and Transplant Centre, UK; NIHR Bioresource Rare Diseases (K.J.C., F.L.R.), University of Cambridge, UK; Department of Neurology (N.M.), Westmead Hospital, Sydney, Australia; Childrens Hospital Oxford (T.M.), John Radcliffe Hospital, UK; Institute for Neuroscience and Muscle Research (R.C.D., S.S.M., U.S.), the Children’s Hospital at Westmead, University of Sydney, Australia; Department of Medical Genetics (F.L.R.), Cambridge Institute for Medical Research, University of Cambridge, UK; Department of Neurology (R.S.), University Hospitals Leicester NHS Trust, UK; Department of Paediatric Neurology (G.V.), Leeds Teaching Hospitals NHS Trust, UK; Section of Neurosciences (E.M.V.), Department of Medicine and Surgery, University of Salerno, Italy; and Neurogenetics Unit (E.M.V.), IRCCS Fondazione Santa Lucia, Rome, Italy. Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by the EU FP7 Program–“Desire” Project. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Neurology.org/ng Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology 1 GNAO1 encodes a subclass (Gao) of the including base calling, primary filtering of low-quality Ga subunit of heterotrimeric guanine reads and probable artefacts, and annotation of variants was applied. nucleotide-binding proteins and is highly For all patients, variants reported as validated polymor- expressed in the brain and involved in the reg- phisms with a minor allele frequency .0.01 (1%) in publicly ulation of neuronal excitability and neurotrans- available human variation resources (including dbSNP144, mission. Mutations in GNAO1 and other NHLBI GO Exome Sequencing Project, UK10, 1000 Ge- nomes, Exome Variant Server [EVS], and Exome Aggregation G-protein subunits (GNAL), adenylyl cyclase Consortium [ExAC] browser) and variants present in in-house (ADCY5), cyclic nucleotide phosphodiesterase control individuals were filtered out. In silico prediction of the (PDE10A), and G protein–coupled receptor mutation pathogenicity was performed using ANNOVAR and 9 the dbNSFP database (v3.0a) (sites.google.com/site/jpopgen/ (GPCR) (GPR88) in early-onset movement dbNSFP). Putative causative variants were validated by Sanger disorders, support the notion that disruption sequencing and investigated in the probands’ parents to deter- of the G-protein-cAMP pathway axis is a key mine whether the mutations were inherited or had occurred contributor to the pathophysiology of dystonia de novo. and chorea. Although the pathophysiologic Standard protocol approvals, registrations, and patient mechanisms underlying such genetic move- consents. Written informed consent to disclose clinical infor- ment disorders remain yet to be elucidated, mation, neuroimaging, and video footage was obtained from all parents/guardians of the 7 participants. Informed consent impaired modulation or transduction of trans- for genetic testing was obtained according to the local institu- membrane signaling, presynaptic autoinhibi- tional policy. tory effects, and altered neuronal excitability are all putative disease mechanisms that might RESULTS Genetic analysis. We identified 7 patients explain the co-occurrence of multiple neuro- carrying 6 different GNAO1 (GenBank accession logic manifestations such as epilepsy and number NM_020988) mutations; all the variants hyperkinesia. occurred de novo and 4 are previously unreported Here, we report 7 newly identified patients (table, figure 1). with GNAO1 mutations, with the aim of char- In patient 1, we detected the novel c.139A G [p.(Ser47Gly)] missense variant, located in the N- acterizing in detail the clinical phenotype, terminal domain of the protein. In patients 2 and 4, response to treatment and outcome, as well we identified the c.625C.T [p.(Arg209Cys)] mis- as associated brain MRI features. sense variant. This variant has previously been re- ported in 1 patient with developmental delay, – METHODS Molecular genetic testing. Patients 1 3, 6, intellectual disability, and severe chorea, associated and 7 were studied using whole-exome/genome (WES/ with the later onset of complex partial seizures.5 In WGS) sequencing. For patient 1, WES was performed on 1 . a SOLiD 5500XL sequencing platform (Life Technologies, patient 3, we observed the novel c.723 1G A Foster City, CA). Short reads were mapped against the intronic variant, and in patient 5, the novel GRCh37/hg19 human assembly by means of LifeScope soft- c.167T.C [p.(Ile56Thr)] missense variant, ware (Life Technologies). Variants were detected using the located in the N-terminal domain of the protein. Haplotype Caller software package of the Genome Analysis In patient 6, we detected the c.118G.C Toolkit (GATK) suite and filtered to include only variants [p.(Gly40Arg)] missense mutation, located in the covered by at least 10 reads with mapping quality values exceeding 30. For patients 2, 3, and 6, WGS was performed N-terminal domain of the protein. A different with Illumina TruSeq DNA PCR-FreeSamplePreparationkit mutation leading to the same amino acid change on an Illumina Hiseq 2500 sequencing
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