Barwick, Katy

Cross, J Helen

Gibbon, Frances M

Kurian, Manju A

Smith, Martin

Steel, Dora

Vezyroglou, Aikaterini

Vogt, Julie

English

UCL Discovery

L E T T E R S : N E W O B S E R V A T I O NBoth Heterozygous andHomozygous Loss-of-FunctionJPH3 Variants Are Associated witha Paroxysmal Movement DisorderRecently, a single patient with a homozygous truncatingvariant in JPH3 and a neurodevelopmental disorder involvingparoxysmal dystonia was described.1 We report both a sec-ond individual with recessive disease and a family with amilder phenotype and autosomal dominant inheritance(Fig. 1A).Patient one, now 15 years old, was born to first-cousin par-ents with no relevant family or perinatal history. Her motherwas asymptomatic, but the medical history of her father wasunavailable. Early infant milestones were normal, but she didnot walk until 3 years old. At school, she was identified ashaving moderate intellectual disability and behavioral difficul-ties. From 6 months old, her mother noticed episodes ofabnormal body stiffening. Over time, these evolved into twoclear episode types. “Minor” episodes consisted of brief rightor occasionally left hemidystonia, which occurred severaltimes each week. “Major” episodes happened two or threetimes per month and lasted up to 30 minutes. After a similaronset, they progressed to involuntary flailing movements ofall limbs, impaired responsiveness, dysarthria, aphasia, anddrooling, sometimes associated with upward eye deviation.Although “major” episodes tended to be triggered by fatigue,there was no obvious trigger for “minor” episodes. A clinicaldiagnosis of alternating hemiplegia of childhood (AHC) wasmade. Neurological examination between episodes wasunremarkable. There was no disease progression over time.There was no clinical response to levodopa, oxcarbazepine,flunarizine, trihexyphenidyl, topiramate, or gabapentin,although prolonged episodes could be terminated with buccalmidazolam. Extensive investigation including brain magneticresonance imaging, electroencephalogram (EEG) (with cap-ture of a typical episode), and cerebrospinal fluid neurotrans-mitters was normal. Whole genome sequencing (WGS)identified a novel homozygous frameshift in JPH3(NM020655.3:c.1310delG; p.Arg437Leufs*34). ParentalDNA was not available for testing. The only other variant ofinterest was a homozygous NDUFAF5 variant(NM_024120.5:c.524A>G; p.His175Arg), which was consid-ered unlikely to be relevant because the phenotypic fit formitochondrial complex I deficiency was poor and in silicotools predicted that it was probably benign.Patient two, now 10 years old, experienced episodes oflimb, facial, and orolingual dyskinesia at least weekly fromthe age of 6 months (Video S1). These usually started in theright upper limb before becoming generalized and lasted forseveral hours. No abnormal eye movements were evident dur-ing the episodes, and there was no obvious trigger. Betweenepisodes, very mild resting dyskinesia was evident in the upperlimbs. She had moderate learning difficulties, but no behavioralissues. Again, extensive investigation was unremarkable,including EEG with capture of episodes. Several differentmedications—carbamazepine, valproate, topiramate, acetazol-amide, and trihexyphenidyl—proved ineffective. Her maternalgrandmother had experienced lifelong episodes of orofacialdyskinesia and limb posturing and had never learned to read.Her mother reported episodes of orofacial dystonia triggeredby alcohol and had a slight resting tremor. She had completedcompulsory education. The only relevant variant identified onWGS was a novel heterozygous nonsense variant in JPH3(NM020655.3:c.1014C>G; p.Tyr338*) shared by mother anddaughter: grandmaternal DNA was unavailable (Fig. 1B).JPH3 encodes junctophilin-3, a component of the junc-tional complex linking the plasma membrane with the endo-plasmic reticulum in excitable cells.2 Expression is highest inthe brain. Pathological heterozygous triplet-repeat expansionvariants (believed to cause toxic intracellular accumulation ofabnormal protein)3,4 occur in Huntington-like disease type2, characterized by adult-onset chorea, dementia and atrophyof the cortex, and basal ganglia.5 However, we believe thatthe disorder from either biallelic or heterozygous truncatingvariants is a distinct condition, mediated by loss of proteinfunction rather than toxic accumulation, and so far, appearsnon-progressive in reported cases (Fig. 1C). The gene ispredicted to be highly intolerant of loss-of-function,6 and inmice, both haploinsufficiency and knockout of JPH3 result inan abnormal motor phenotype.7 Although the association ofthe variably penetrant, heterozygous phenotype will requirefurther confirmation in additional patients, JPH3 variantsshould be considered in patients with undiagnosed complexparoxysmal movement disorders.Acknowledgments: We are grateful to the patients and their familiesfor their participation. Prof. Kurian’s research group has benefited fromgrants from the National Institute for Health Research, Rosetrees Trustand the Sir Jules Thorne Trust.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -© 2022 The Authors. Movement Disorders published by Wiley Periodi-cals LLC on behalf of International Parkinson and Movement DisorderSociety.This is an open access article under the terms of the CreativeCommons Attribution License, which permits use, distribution andreproduction in any medium, provided the original work is properlycited.Key Words: alternating hemiplegia of childhood, dyskinesia, dystonia,JPH3, paroxysmal movement disorder*Correspondence to: Professor Manju Kurian, NIHR ResearchProfessor and UCL Professor of Neurogenetics, Honorary ConsultantPaediatric Neurologist, Zayed Centre for Research into Rare Disease inChildren, UCL Great Ormond Street Institute of Child Health, 20 GuilfordStreet, WC1N 1DZ, London, UK; E-mail: manju.kurian@ucl.ac.ukReceived: 21 June 2022; Revised: 9 August 2022; Accepted: 29August 2022Published online in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.29250Movement Disorders, 2022 1 15318257, 0, Downloaded from https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.29250 by University College London UCL Library Services, Wiley Online Library on [26/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseDora Steel, BMBCh,1,2 Aikaterini Vezyroglou, MD,1,2Katy Barwick, PhD,1 Martin Smith, MBBS,3 Julie Vogt, MD,4Frances M. Gibbon, MB, ChB,5 J. Helen Cross, PhD,1,2 andManju A. Kurian, PhD1,2*1Developmental Neurosciences, Zayed Centre for Research intoRare Disease in Children, UCL Great Ormond Street Institute ofChild Health, London, United Kingdom, 2Department of Neurology,Great Ormond Street Hospital, London, United Kingdom,3Department of Paediatric Neurology, Oxford University HospitalsNHS Foundation Trust, London, United Kingdom, 4West MidlandsRegional Genetics Service, Birmingham Women and Children’sHospital NHS Foundation Trust, Birmingham, United Kingdom, and5Noah’s Ark Children’s Hospital for Wales, Cardiff and ValeUniversity Health Board, Cardiff, Wales, United KingdomFunding InformationProfessor Kurian’s laboratory receives funding from theNational Institute for Health Research and the Sir Jules ThornCharitable Trust.Data Availability StatementWe are unable to make patients’ full genomic data availableunder the terms of our ethical approval but are happy to sharedetails of methods and laboratory or clinical results on request.References1. Bourinaris T, Athanasiou A, Efthymiou S, Wiethoff S, Salpietro V,Houlden H. Allelic and phenotypic heterogeneity in Junctophillin-3related neurodevelopmental and movement disorders. Eur J HumGenet 2021;29(6):1027–1031.2. Takeshima H, Komazaki S, Nishi M, Iino M, Kangawa K.Junctophilins: a novel family of junctional membrane complex pro-teins. Mol Cell 2000;6(1):11–22.3. Wilburn B, Rudnicki DD, Zhao J, et al. An antisense CAG repeattranscript at JPH3 locus mediates expanded polyglutamine proteintoxicity in Huntington’s disease-like 2 mice. Neuron 2011;70(3):427–440.4. Krench M, Cho RW, Littleton JT. A drosophila model of Huntingtondisease-like 2 exhibits nuclear toxicity and distinct pathogenic mecha-nisms from Huntington disease. Hum Mol Genet 2016;25(15):3164–3177.5. Holmes SE, O’Hearn E, Rosenblatt A, et al. A repeat expansion inthe gene encoding junctophilin-3 is associated with Huntingtondisease-like 2. Nat Genet 2001;29(4):377–378.6. Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraintspectrum quantified from variation in 141,456 humans. Nature 2020;581:434–443.7. Seixas AI, Holmes SE, Takeshima H, et al. Loss of junctophilin-3 con-tributes to Huntington disease-like 2 pathogenesis. Ann Neurol 2012;71(2):245–257.Supporting DataAdditional Supporting Information may be found in theonline version of this article at the publisher’s web-site.(A)(C)(B)FIG. 1. (A) Pedigrees for families 1 and 2. Circle: female; square: male; diamond: sex unknown; P: current pregnancy; black circle or square: affectedindividual; double horizontal line: consanguineous union. (B) Electrophoretogram of Sanger sequencing showing heterozygous variant present in patient2 and her mother, indicated by blue arrow. (C) Schematic diagram of the JPH3 gene. MORN, membrane occupation and recognition nexus repeatdomain; TM, transmembrane domain. Site of previously published variants and variants reported here is indicated by arrows. [Color figure can beviewed at wileyonlinelibrary.com]2 Movement Disorders, 2022S T E E L E T A L 15318257, 0, Downloaded from https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.29250 by University College London UCL Library Services, Wiley Online Library on [26/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseSGML and CITI Use OnlyDO NOT PRINTAuthor Roles(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design,B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.D.S.: 1A, 1C, 3AA.V.: 1C, 3BK.B.: 1C, 3BM.S.: 3BH.C.: 3BM.A.K.: 1A, 1B, 3BFinancial DisclosuresNone of the authors has any financial disclosures relevant to the research. Financial relationships are listed below.D.S. is employed by UCL with a salary paid by a grant from the National Institute for Health Research. A.V. isemployed by UCL. K.B. is employed by UCL. M.S. is employed by the Oxford Radcliffe Hospitals National HealthService (NHS) Foundation Trust. J.V. is employed by the Birmingham Women and Children’s Hospitals NHS Foun-dation Trust. F.G. is employed by the Cardiff and Vale University Health Board. H.C. is employed by UCL withgrants from various organizations. M.A.K. is employed by UCL. M.A.K.’s research group receives grants from theNational Institute of Health Research; Rosetrees Fund; Great Ormond Street Hospital Charity; LifeArc; and the SirJules Thorn Trust. 15318257, 0, Downloaded from https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.29250 by University College London UCL Library Services, Wiley Online Library on [26/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Both Heterozygous and Homozygous Loss-of-Function JPH3 Variants Are Associated with a Paroxysmal Movement Disorder

https://discovery.ucl.ac.uk/10158173/1/Both%20Heterozygous%20and%20Homozygous%20Loss%20of%20Function%20JPH3%20Variants%20Are%20Associated.pdf

Both Heterozygous and Homozygous Loss-of-Function JPH3 Variants Are Associated with a Paroxysmal Movement Disorder

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