The allelic disorders rapid-onset dystonia-parkinsonism

(RDP), alternating hemiplegia of childhood

(AHC), and CAPOS/CAOS syndrome (cerebellar

ataxia, areflexia, pes cavus, optic atrophy, and sensorineural

deafness) are caused by ATP1A3 mutations.1–3

Intermediate RDP-AHC phenotypes are

emerging. Positional mutations 274, 583, 867, and

923 lead to both RDP and AHC, suggesting different

pathomechanisms.4,5 The E818K mutation underlies

all reported cases of CAPOS/CAOS, including an

AHC-CAPOS overlap syndrome.6 We report a family

with features of all 3 ATP1A3-spectrum disorders

Fawcett, K

Hanna, MG

Heger, A

Houlden, H

Jaffer, F

Kingston, H

Sims, D

Sisodiya, SM

Neurology Genetics

PubMed

The allelic disorders rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and CAPOS/CAOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural deafness) are caused by ATP1A3 mutations.1,–,3 Intermediate RDP-AHC phenotypes are emerging. Positional mutations 274, 583, 867, and 923 lead to both RDP and AHC, suggesting different pathomechanisms.4,5 The E818K mutation underlies all reported cases of CAPOS/CAOS, including an AHC-CAPOS overlap syndrome.6 We report a family with features of all 3 ATP1A3-spectrum disorders

Oxford University Research Archive (ORA)

Familial childhood-onset progressive cerebellar syndrome associated with the ATP1A3 mutation

Sims, David

Heger, Andreas

Oxford University Research Archive

Clinical/ScientificNotesFatima Jaffer, MRCPKatherine Fawcett, PhDDavid Sims, PhDAndreas Heger, PhDHenry Houlden, FRCPMichael G. Hanna, FRCPHelen Kingston, PhDSanjay M. Sisodiya, FRCPNeurol Genet2017;3:e145; doi: 10.1212/NXG.0000000000000145FAMILIAL CHILDHOOD-ONSET PROGRESSIVECEREBELLAR SYNDROME ASSOCIATED WITHTHE ATP1A3 MUTATIONThe allelic disorders rapid-onset dystonia-parkinson-ism (RDP), alternating hemiplegia of childhood(AHC), and CAPOS/CAOS syndrome (cerebellarataxia, areflexia, pes cavus, optic atrophy, and senso-rineural deafness) are caused by ATP1A3 muta-tions.1–3 Intermediate RDP-AHC phenotypes areemerging. Positional mutations 274, 583, 867, and923 lead to both RDP and AHC, suggesting differentpathomechanisms.4,5 The E818K mutation underliesall reported cases of CAPOS/CAOS, including anAHC-CAPOS overlap syndrome.6 We report a familywith features of all 3 ATP1A3-spectrum disorders.Case report. The proband (II-3; figure, A) is 49years old, born at 32 weeks of gestation with pre-eclampsia complicating pregnancy. Developmentwas delayed, walking at 28 months with progressivegait ataxia, and speaking at 30 months. Hypertoniaand choreoathetosis were present at this time. Aged 5years, she developed fever-induced acute-onset gen-eralized hypotonia and dysarthria. Motor weaknesspersisted for 8 months, requiring neurorehabilitationto reacquire independent ambulation. Aged 6 years,she developed limb incoordination and dysarthria,worsening during febrile illnesses. Childhood-onsetpainful limb spasms and stimulus-sensitive fingermyoclonus were reported. At 30 years, she notedfurther worsening of dysarthria and ataxia. Exami-nation at 49 years revealed short stature, low-set ears,scoliosis, and pes planus. She had marked cerebellarsigns with dysarthria, dysmetria, square wave jerks,intention tremor, and gait ataxia and spasticity withpreserved muscle strength, choreoathetosis, fingermyoclonus, and cervical dystonia. Reflexes wereabsent and sensation intact. Fundoscopy and hearingwere normal. MRI showed cerebellar atrophy.Individual III-2 was delivered at term and had de-layed development, sitting at age 10 months, speak-ing at 18 months, and walking at 27 months withataxia. At 30 months, she transiently lost the abilityto walk, with upper limb ataxia, lasting 3 weeks aftera febrile illness. She had another episode after Vari-cella zoster infection, with acute-onset generalizedhypotonia, dysarthria, and dysphagia lasting for 1month, followed by slow recovery. Examination atage 5.5 years showed persistent cerebellar signs withdysarthria, gait, and limb ataxia. She continues tohave episodic cerebellar deterioration during intercur-rent illness, with a recovery period of 1–2 days andcomplete return to baseline function. Examination at20 years showed dysarthria, dysmetria, square wavejerks, gait ataxia, spasticity with normal musclestrength, global hyporeflexia with down-going plantarresponses, and normal sensation. Athetoid movementof the hands, finger myoclonus, and scoliosis werepresent. There was no visual or hearing impairment.Brain MRI shows nonspecific mild periventricularwhite-matter changes and normal cerebellar volume.Individual IV-1 presented at age 8 months withgeneralized weakness during a febrile illness, taking3 weeks to recover and be able to sit independentlyagain. She started walking at age 17 months, and at2 years, was ataxic and unable to walk independently.Vision and hearing were normal.Mutation analysis for spinocerebellar ataxias 1, 2,3, 5, 7, and 17, dentatorubral-pallidoluysian atrophy,ferritin light chains, and common mitochondrialDNA mutations in the proband were negative, aswere plasma acylcarnitine profile, lactate, ammonia,and amino acids. Whole-exome sequencing revealeda deleterious missense mutation, c.2267G.A;p.Arg756His (R756H), in ATP1A3, confirmed bySanger sequencing and shown to segregate with thedisease (figure, B).Discussion. Infantile-onset RDP with motor delayand initial fluctuations evolving into persistent dysto-nia and ataxia is reported with R756H mutations.7With the exception of IV-1, our patients presentedwith motor delay prior to paroxysmal motor symp-toms, with a protracted recovery period, consistentwith this picture. The development of a progressivecerebellar syndrome with superimposed fever-induced fluctuation is a key clinical feature in allthree affected members of our family as is globalhyporeflexia, suggesting some features also ofCAPOS/CAOS syndrome, without visual or auditoryinvolvement. Development of gait ataxia precedingepisodic features broadens the phenotype away fromCAPOS/CAOS and infantile-onset RDP.Neurology.org/ng Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1CAPOS are associated with pes cavus: recently,cases without are reported.3 Our proband has flat feet,and she and her daughter have scoliosis, extending themusculoskeletal phenotype of ATP1A3-spectrumsyndromes. The age at onset in this family fits withCAPOS/CAOS and AHC, and the development ofpyramidal signs and an extrapyramidal disorderobserved is more in keeping with nonparoxysmalAHC/RDP features. Overall, the phenotypic presen-tation has features of all three ATP1A3-spectrumdisorders. The early-onset cerebellar ataxia prior toparoxysmal symptoms and extended musculoskeletalinvolvement is novel. Early MRI is unavailable: how-ever, cerebellar atrophy in adulthood is observed inFigure Pedigree and genetics(A) Family pedigree: no clinical information is available on the parents of the proband; Sanger sequencing confirmed the presence of c.2267G.A;p.Arg756His (indicated by *) in the ATP1A3 gene in all affected family members and was absent in unaffected family members, II-1 and III-3 (indicatedby [-]). (B) Validation of mutation by Sanger sequencing. Chromatograms showing segregation of the variant with disease: present in affected familymembers II-3, III-2, and IV-1 and absent in II-1 and III-3. (C) Mutation map of the ATP1A3 gene. ATP1A3 mutation map showing all published mutationsassociated with rapid-onset dystonia-parkinsonism (RDP) (top panel), CAPOS/CAOS (top panel; highlighted in green), and alternating hemiplegia of childhood(AHC) (bottom panel). Mutations underlined indicate frequently reported variants associated with the disease; mutations in our patients are indicated in red;amino acid positions 274, 583, 923, and 801 highlighted in blue are mutated in both RDP and AHC; * indicates intronic splice-site variant c.2542 11G.A.2 Neurology: Geneticsthe proband, suggesting possible progression anddevelopment of fixed deficits observed in other neu-rologic channelopathies.Reporting unique ATP1A3-spectrum phenotypesfacilitates genotype-phenotype correlation, althoughsome phenotypic aspects may escape detection, di-rects functional studies and possible therapeutic tar-gets. We propose that ATP1A3 mutation analysis isconsidered in patients with delayed motor develop-ment and childhood- or early-onset progressive cere-bellar syndromes with superimposed acute motorfluctuations.From the Department of Neurosciences (F.J.), King’s College Hos-pital, London; MRC Centre for Neuromuscular Diseases andDepartment of Molecular Neuroscience (F.J., H.H., M.G.H.),UCL Institute of Neurology; MRC Computational GenomicsAnalysis and Training Programme (K.F., D.S., A.H.), Universityof Oxford; Central Manchester University Hospitals (H.K.); andNIHR UCLH Biomedical Research Centre (S.M.S.), Departmentof Clinical and Experimental Epilepsy, UCL Institute of Neurology,Queen Square, UK.Author contributions: Dr. Jaffer: study concept and design, acquisi-tion of data, genetic analysis, interpretation of data, and manuscriptdraft. Dr. Fawcett, Dr. Sims, and Dr. Heger: genetic analysis andinterpretation of data. Prof. Houlden: study concept and design andcritical revision of manuscript. Prof. Hanna: study conceptand design and critical revision of manuscript for important intel-lectual content. Dr. Kingston: clinical data collection and criticalrevision of manuscript for important intellectual content. Prof.Sisodiya: study concept and design, critical revision of manuscriptfor important intellectual content, and study supervision.Study funding: K.F., D.S., and A.H. are funded by the MedicalResearch Council (UK) Computational Genomics Analysis andTraining programme (G1000902). S.M.S. is supported by the Epi-lepsy Society, UK. The work was partly undertaken at UCLH/UCLwhich received a proportion of funding from the Department ofHealth’s NIHR Biomedical Research Centres funding scheme.Disclosure: Dr. Jaffer and Dr. Fawcett report no disclosures. Dr. Simshas received research support from MRC (H4R00700, 2016–2018).Dr. Heger is/has been employed by Genomics. Prof. Houlden hasreceived research support from Medical Research Council (MRC)UK, BRT, MDA USA, Muscular Dystrophy UK, Rosetrees Trust,Wellcome Trust, National Institute for Health (NIHR) UCL/UCLH BRC, the Dystonia Medical Research Foundation (DMRF),The Parkinson’s Disease Foundation (PDF), National Organisationfor Rare Disorders (NORD), and The Brain Research Trust (BRT).Prof. Hanna has received research support from MRC and TheMyositis Support Group. Dr. Kingston reports no disclosures.Prof. Sisodiya has received funding for travel and/or speaker honorariafrom UCB Pharma, Eisai, and Nutricia; has served on the editorialboards of Epileptic Disorders and Practical Neurology; has receivedresearch support from UCB Pharma, NIH, European Commission,Wellcome Trust, Epilepsy Action, and Dravet Syndrome UK; and isa patron of AHC UK. Go to Neurology.org/ng for full disclosure forms.The Article Processing Charge was funded by the MRC via UCL OpenAccess office.This is an open access article distributed under the terms of theCreative Commons Attribution License 4.0 (CC BY), which permitsunrestricted use, distribution, and reproduction in any medium, pro-vided the original work is properly cited.Received November 13, 2016. Accepted in final form February 21,2017.Correspondence to Prof. Sisodiya: s.sisodiya@ucl.ac.uk1. Rosewich H, Ohlenbusch A, Huppke P, et al. The expand-ing clinical and genetic spectrum of ATP1A3-related disor-ders. Neurology 2014;82:945–955.2. Demos MK, Van Karnebeek CDM, Ross CJD, et al. Anovel current mutation in ATP1A3 causes CAPOS syn-drome. Orphanet J Rare Dis 2014;9:15.3. Heimer G, Sadaka Y, Israelian L, et al. CAOS-episodiccerebellar ataxia, areflexia, optic atrophy, and sensorineuralhearing loss: a third allelic disorder of the ATP1A3 gene.J Child Neurol 2015;30:1749–1756.4. Sasaki M, Ishii A, Saito Y, Hirose S. Intermediate formbetween alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism. Mov Disord 2014;29:153–154.5. Nicita F, Travaglini L, Sabatini S, et al. Childhood-onsetATP1A3-related conditions: report of two new cases ofphenotypic spectrum. Parkinsonism Relat Disord 2016;30:81–82.6. Rosewich H, Weise D, Ohlenbusch A, Gärtner J,Brockmann K. Phenotypic overlap of alternating hemiplegiaof childhood and CAPOS syndrome. Neurology 2014;83:861–863.7. Brashear A, Mink JW, Hill DF, et al. ATP1A3 mutations ininfants: a new rapid-onset dystonia-Parkinsonism pheno-type characterized by motor delay and ataxia. Dev MedChild Neurol 2012;54:1065–1067.Neurology: Genetics 3

English

UCL Discovery

Clinical/ScientificNotesFatima Jaffer, MRCPKatherine Fawcett, PhDDavid Sims, PhDAndreas Heger, PhDHenry Houlden, FRCPMichael G. Hanna, FRCPHelen Kingston, PhDSanjay M. Sisodiya, FRCPNeurol Genet2017;3:e145; doi: 10.1212/NXG.0000000000000145FAMILIAL CHILDHOOD-ONSET PROGRESSIVECEREBELLAR SYNDROME ASSOCIATED WITHTHE ATP1A3 MUTATIONThe allelic disorders rapid-onset dystonia-parkinson-ism (RDP), alternating hemiplegia of childhood(AHC), and CAPOS/CAOS syndrome (cerebellarataxia, areflexia, pes cavus, optic atrophy, and senso-rineural deafness) are caused by ATP1A3 muta-tions.1–3 Intermediate RDP-AHC phenotypes areemerging. Positional mutations 274, 583, 867, and923 lead to both RDP and AHC, suggesting differentpathomechanisms.4,5 The E818K mutation underliesall reported cases of CAPOS/CAOS, including anAHC-CAPOS overlap syndrome.6 We report a familywith features of all 3 ATP1A3-spectrum disorders.Case report. The proband (II-3; figure, A) is 49years old, born at 32 weeks of gestation with pre-eclampsia complicating pregnancy. Developmentwas delayed, walking at 28 months with progressivegait ataxia, and speaking at 30 months. Hypertoniaand choreoathetosis were present at this time. Aged 5years, she developed fever-induced acute-onset gen-eralized hypotonia and dysarthria. Motor weaknesspersisted for 8 months, requiring neurorehabilitationto reacquire independent ambulation. Aged 6 years,she developed limb incoordination and dysarthria,worsening during febrile illnesses. Childhood-onsetpainful limb spasms and stimulus-sensitive fingermyoclonus were reported. At 30 years, she notedfurther worsening of dysarthria and ataxia. Exami-nation at 49 years revealed short stature, low-set ears,scoliosis, and pes planus. She had marked cerebellarsigns with dysarthria, dysmetria, square wave jerks,intention tremor, and gait ataxia and spasticity withpreserved muscle strength, choreoathetosis, fingermyoclonus, and cervical dystonia. Reflexes wereabsent and sensation intact. Fundoscopy and hearingwere normal. MRI showed cerebellar atrophy.Individual III-2 was delivered at term and had de-layed development, sitting at age 10 months, speak-ing at 18 months, and walking at 27 months withataxia. At 30 months, she transiently lost the abilityto walk, with upper limb ataxia, lasting 3 weeks aftera febrile illness. She had another episode after Vari-cella zoster infection, with acute-onset generalizedhypotonia, dysarthria, and dysphagia lasting for 1month, followed by slow recovery. Examination atage 5.5 years showed persistent cerebellar signs withdysarthria, gait, and limb ataxia. She continues tohave episodic cerebellar deterioration during intercur-rent illness, with a recovery period of 1–2 days andcomplete return to baseline function. Examination at20 years showed dysarthria, dysmetria, square wavejerks, gait ataxia, spasticity with normal musclestrength, global hyporeflexia with down-going plantarresponses, and normal sensation. Athetoid movementof the hands, finger myoclonus, and scoliosis werepresent. There was no visual or hearing impairment.Brain MRI shows nonspecific mild periventricularwhite-matter changes and normal cerebellar volume.Individual IV-1 presented at age 8 months withgeneralized weakness during a febrile illness, taking3 weeks to recover and be able to sit independentlyagain. She started walking at age 17 months, and at2 years, was ataxic and unable to walk independently.Vision and hearing were normal.Mutation analysis for spinocerebellar ataxias 1, 2,3, 5, 7, and 17, dentatorubral-pallidoluysian atrophy,ferritin light chains, and common mitochondrialDNA mutations in the proband were negative, aswere plasma acylcarnitine profile, lactate, ammonia,and amino acids. Whole-exome sequencing revealeda deleterious missense mutation, c.2267G.A;p.Arg756His (R756H), in ATP1A3, confirmed bySanger sequencing and shown to segregate with thedisease (figure, B).Discussion. Infantile-onset RDP with motor delayand initial fluctuations evolving into persistent dysto-nia and ataxia is reported with R756H mutations.7With the exception of IV-1, our patients presentedwith motor delay prior to paroxysmal motor symp-toms, with a protracted recovery period, consistentwith this picture. The development of a progressivecerebellar syndrome with superimposed fever-induced fluctuation is a key clinical feature in allthree affected members of our family as is globalhyporeflexia, suggesting some features also ofCAPOS/CAOS syndrome, without visual or auditoryinvolvement. Development of gait ataxia precedingepisodic features broadens the phenotype away fromCAPOS/CAOS and infantile-onset RDP.Neurology.org/ng Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1CAPOS are associated with pes cavus: recently,cases without are reported.3 Our proband has flat feet,and she and her daughter have scoliosis, extending themusculoskeletal phenotype of ATP1A3-spectrumsyndromes. The age at onset in this family fits withCAPOS/CAOS and AHC, and the development ofpyramidal signs and an extrapyramidal disorderobserved is more in keeping with nonparoxysmalAHC/RDP features. Overall, the phenotypic presen-tation has features of all three ATP1A3-spectrumdisorders. The early-onset cerebellar ataxia prior toparoxysmal symptoms and extended musculoskeletalinvolvement is novel. Early MRI is unavailable: how-ever, cerebellar atrophy in adulthood is observed inFigure Pedigree and genetics(A) Family pedigree: no clinical information is available on the parents of the proband; Sanger sequencing confirmed the presence of c.2267G.A;p.Arg756His (indicated by *) in the ATP1A3 gene in all affected family members and was absent in unaffected family members, II-1 and III-3 (indicatedby [-]). (B) Validation of mutation by Sanger sequencing. Chromatograms showing segregation of the variant with disease: present in affected familymembers II-3, III-2, and IV-1 and absent in II-1 and III-3. (C) Mutation map of the ATP1A3 gene. ATP1A3 mutation map showing all published mutationsassociated with rapid-onset dystonia-parkinsonism (RDP) (top panel), CAPOS/CAOS (top panel; highlighted in green), and alternating hemiplegia of childhood(AHC) (bottom panel). Mutations underlined indicate frequently reported variants associated with the disease; mutations in our patients are indicated in red;amino acid positions 274, 583, 923, and 801 highlighted in blue are mutated in both RDP and AHC; * indicates intronic splice-site variant c.2542 11G.A.2 Neurology: Geneticsthe proband, suggesting possible progression anddevelopment of fixed deficits observed in other neu-rologic channelopathies.Reporting unique ATP1A3-spectrum phenotypesfacilitates genotype-phenotype correlation, althoughsome phenotypic aspects may escape detection, di-rects functional studies and possible therapeutic tar-gets. We propose that ATP1A3 mutation analysis isconsidered in patients with delayed motor develop-ment and childhood- or early-onset progressive cere-bellar syndromes with superimposed acute motorfluctuations.From the Department of Neurosciences (F.J.), King’s College Hos-pital, London; MRC Centre for Neuromuscular Diseases andDepartment of Molecular Neuroscience (F.J., H.H., M.G.H.),UCL Institute of Neurology; MRC Computational GenomicsAnalysis and Training Programme (K.F., D.S., A.H.), Universityof Oxford; Central Manchester University Hospitals (H.K.); andNIHR UCLH Biomedical Research Centre (S.M.S.), Departmentof Clinical and Experimental Epilepsy, UCL Institute of Neurology,Queen Square, UK.Author contributions: Dr. Jaffer: study concept and design, acquisi-tion of data, genetic analysis, interpretation of data, and manuscriptdraft. Dr. Fawcett, Dr. Sims, and Dr. Heger: genetic analysis andinterpretation of data. Prof. Houlden: study concept and design andcritical revision of manuscript. Prof. Hanna: study conceptand design and critical revision of manuscript for important intel-lectual content. Dr. Kingston: clinical data collection and criticalrevision of manuscript for important intellectual content. Prof.Sisodiya: study concept and design, critical revision of manuscriptfor important intellectual content, and study supervision.Study funding: K.F., D.S., and A.H. are funded by the MedicalResearch Council (UK) Computational Genomics Analysis andTraining programme (G1000902). S.M.S. is supported by the Epi-lepsy Society, UK. The work was partly undertaken at UCLH/UCLwhich received a proportion of funding from the Department ofHealth’s NIHR Biomedical Research Centres funding scheme.Disclosure: Dr. Jaffer and Dr. Fawcett report no disclosures. Dr. Simshas received research support from MRC (H4R00700, 2016–2018).Dr. Heger is/has been employed by Genomics. Prof. Houlden hasreceived research support from Medical Research Council (MRC)UK, BRT, MDA USA, Muscular Dystrophy UK, Rosetrees Trust,Wellcome Trust, National Institute for Health (NIHR) UCL/UCLH BRC, the Dystonia Medical Research Foundation (DMRF),The Parkinson’s Disease Foundation (PDF), National Organisationfor Rare Disorders (NORD), and The Brain Research Trust (BRT).Prof. Hanna has received research support from MRC and TheMyositis Support Group. Dr. Kingston reports no disclosures.Prof. Sisodiya has received funding for travel and/or speaker honorariafrom UCB Pharma, Eisai, and Nutricia; has served on the editorialboards of Epileptic Disorders and Practical Neurology; has receivedresearch support from UCB Pharma, NIH, European Commission,Wellcome Trust, Epilepsy Action, and Dravet Syndrome UK; and isa patron of AHC UK. Go to Neurology.org/ng for full disclosure forms.The Article Processing Charge was funded by the MRC via UCL OpenAccess office.This is an open access article distributed under the terms of theCreative Commons Attribution License 4.0 (CC BY), which permitsunrestricted use, distribution, and reproduction in any medium, pro-vided the original work is properly cited.Received November 13, 2016. Accepted in final form February 21,2017.Correspondence to Prof. Sisodiya: s.sisodiya@ucl.ac.uk1. Rosewich H, Ohlenbusch A, Huppke P, et al. The expand-ing clinical and genetic spectrum of ATP1A3-related disor-ders. Neurology 2014;82:945–955.2. Demos MK, Van Karnebeek CDM, Ross CJD, et al. Anovel current mutation in ATP1A3 causes CAPOS syn-drome. Orphanet J Rare Dis 2014;9:15.3. Heimer G, Sadaka Y, Israelian L, et al. CAOS-episodiccerebellar ataxia, areflexia, optic atrophy, and sensorineuralhearing loss: a third allelic disorder of the ATP1A3 gene.J Child Neurol 2015;30:1749–1756.4. Sasaki M, Ishii A, Saito Y, Hirose S. Intermediate formbetween alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism. Mov Disord 2014;29:153–154.5. Nicita F, Travaglini L, Sabatini S, et al. Childhood-onsetATP1A3-related conditions: report of two new cases ofphenotypic spectrum. Parkinsonism Relat Disord 2016;30:81–82.6. Rosewich H, Weise D, Ohlenbusch A, Gärtner J,Brockmann K. Phenotypic overlap of alternating hemiplegiaof childhood and CAPOS syndrome. Neurology 2014;83:861–863.7. Brashear A, Mink JW, Hill DF, et al. ATP1A3 mutations ininfants: a new rapid-onset dystonia-Parkinsonism pheno-type characterized by motor delay and ataxia. Dev MedChild Neurol 2012;54:1065–1067.Neurology: Genetics 3DOI 10.1212/NXG.00000000000001452017;3; Neurol Genet Fatima Jaffer, Katherine Fawcett, David Sims, et al. mutationATP1A3Familial childhood-onset progressive cerebellar syndrome associated with the This information is current as of March 27, 2017ServicesUpdated Information & http://ng.neurology.org/content/3/2/e145.full.htmlincluding high resolution figures, can be found at:References http://ng.neurology.org/content/3/2/e145.full.html##ref-list-1This article cites 7 articles, 0 of which you can access for free at: Subspecialty Collections http://ng.neurology.org//cgi/collection/gait_disorders_ataxiaGait disorders/ataxia http://ng.neurology.org//cgi/collection/cerebellumCerebellum http://ng.neurology.org//cgi/collection/all_movement_disordersAll Movement Disordersfollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://ng.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://ng.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:reserved. Online ISSN: 2376-7839.Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.. All rightsan open-access, online-only, continuous publication journal. Copyright Copyright © 2017 The Author(s). is an official journal of the American Academy of Neurology. Published since April 2015, it isNeurol Genet 

ORA - Oxford University Research Archive

Fatima Jaffer

Katherine Fawcett

David Sims

Andreas Heger

Henry Houlden

Michael G. Hanna

Helen Kingston

Sanjay M. Sisodiya

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Familial childhood-onset progressive cerebellar syndrome associated with the <i>ATP1A3</i> mutation

http://dx.doi.org/10.1212/NXG.0000000000000145

Familial childhood-onset progressive cerebellar syndrome associated with the ATP1A3 mutation

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