Chen, Z

Houlden, H

Sullivan, R

Vandrovcova, J

Yau, WY

English

UCL Discovery

REPLY TO LETTERReply: Genetic heterogeneity of neuronal intranuclearinclusion disease. What about the infantile variant?Wai Yan Yau1 , Zhongbo Chen1,2 , Roisin Sullivan1 , Jana Vandrovcova1 & Henry Houlden1,31Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom2Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom3Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, United KingdomCorrespondenceWai Yan Yau, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UnitedKingdom. Tel: +44 (0)203 4484249; E-mail: wai.yau.17@ucl.ac.ukFunding InformationW.Y.Y. receives a PhD studentship from Ataxia UK and Rosetree Trust and funding from a Nicholas Blair MDSANZ traveling fellowship. R.S.receives funding from MRC. Z.C. is supported by a clinical fellowship from the Leonard Wolfson Foundation. We are grateful to the MedicalResearch Council (MRC), The Wellcome Trust Synaptopathies award, MRC Centre grant (G0601943), Ataxia UK, The Rosetrees Trust, BrainResearch UK, UCL ODA/LMIC award, The MSA Trust, MDUK, The Muscular Dystrophy Association (MDA). This research was also supported bythe UCL/UCLH National Institute for Health Research University College London Hospitals Biomedical Research Centre.Received: 11 February 2021; Accepted: 11 February 2021doi: 10.1002/acn3.51330We thank Sikora et al. for their interest in our work andtheir letter that highlighted the distinctive clinical mani-festations and disease trajectory of infantile neuronalintranuclear inclusion disease (iNIID).1 The authors pro-vided a summary of all published cases of iNIID and hasdemonstrated that iNIID is a rapidly progressive neurode-generative disorder across different ethnicities with com-plex phenotypes; the unifying features in these patientswere ataxia and cerebellar atrophy. None of the patientslived beyond ten years old. In comparison, dementia,neuropathy, myopathy, leukoencephalopathy and othermovement disorders are more common clinical manifes-tations of juvenile and adult-onset NIID carrying theGGC repeat expansion in NOTCH2NLC and their diseasecourse usually spans decades.2,3 Although neuronalintranuclear inclusions were found throughout tissues inthe nervous system and other organs, patients with iNIIDdo not have typical MRI findings of hyperintensity in thecorticomedullary junction on diffusion-weightedsequences and typical NIIs on skin biopsy.We concede that our study and algorithm predomi-nantly focused on juvenile and adult-onset NIID, partlydue to the rarity of reported iNIID.4 The report of theEuropean infant with iNIID who was also tested nega-tive for the NOTCH2NLC GGC repeat expansionstrengthens our proposal that NIID is a geneticallyheterogeneous disease.5 NIID patients of European des-cent likely carry the same trinucleotide repeat at a dif-ferent genetic locus, analogous to the recent discoveryof a pentanucleotide expansion in six different geneticloci responsible for benign adult familial myoclonic epi-lepsy in different ethnic populations.6 Inherent attributesof repeat expansion disorders may also explain the dif-ference in the phenotypes between infantile and juvenile/adult-onset NIID. We hypothesize that iNIID patientsmay carry a much larger repeat expansion or they maycarry biallelic expansions of the same repeat. The clini-cal disease heterogeneity can be seen in other repeatexpansion disorders such as spinocerebellar ataxia 3: alarger CAG repeat expansion manifests with childhood-onset spasticity and parkinsonism without ataxia whilsta shorter repeat allele causes ataxia and peripheral neu-ropathy at a later age.7,8 However, we agree with Sikoraet al that iNIID may also be a distinct genetic disorderto juvenile and adult-onset NIID. Figure 1 provides asimplified overview of current understandings in differ-ent forms of NIID. Future collaboration and analysis ofmutation-negative cases of NIID will be paramount insolving this genetic conundrum and help patientsachieve a genetic diagnosis.ª 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological AssociationThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use anddistribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.1AcknowledgmentsW.Y.Y. receives a PhD studentship from Ataxia UK andRosetree Trust and funding from a Nicholas BlairMDSANZ traveling fellowship. R.S. receives funding fromMRC. Z.C. is supported by a clinical fellowship from theLeonard Wolfson Foundation. We are grateful to theMedical Research Council (MRC), The Wellcome TrustSynaptopathies award, MRC Centre grant (G0601943),Ataxia UK, The Rosetrees Trust, Brain Research UK, UCLODA/LMIC award, The MSA Trust, MDUK, The Muscu-lar Dystrophy Association (MDA). This research was alsosupported by the UCL/UCLH National Institute forHealth Research University College London HospitalsBiomedical Research Centre.Authors’ ContributionsWYY, ZC, RS, JV and HH contributed to drafting thetext, preparing the figures and critical review of the finalmanuscript.Conflict of InterestThe authors declare no competing interests.Data Availability StatementNot applicable.References1. Sikora J, Jedlickova I, Pristoupilova A, et al. Geneticheterogeneity of neuronal intranuclear inclusion disease.What about the infantile variant? Ann Clin Transl Neurol2021. https://doi.org/10.1002/acn3.512222. Ishiura H, Shibata S, Yoshimura J, et al. Noncoding CGGrepeat expansions in neuronal intranuclear inclusiondisease, oculopharyngodistal myopathy and an overlappingdisease. Nat Genet 2019;51:1222–1232.3. Sone J, Mitsuhashi S, Fujita A, et al. Long-read sequencingidentifies GGC repeat expansions in NOTCH2NLCassociated with neuronal intranuclear inclusion disease. NatGenet 2019;51:1215–1221.4. Chen Z, Yan Yau W, Jaunmuktane Z, et al. Neuronalintranuclear inclusion disease is genetically heterogeneous.Ann Clin Transl Neurol 2020;7:1716–1725.5. Jedlickova I, Pristoupilova A, Hulkova H, et al.NOTCH2NLC CGG repeats are not expanded and skinbiopsy was negative in an infantile patient with neuronalintranuclear inclusion disease. J Neuropathol Exp Neurol2020;79:1065–1071.Figure 1. An overview of current understanding in the clinico-pathologico-genetic correlation of infantile-, juvenile- and adult-onset NIID.2 ª 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological AssociationAnn Clin Transl Neurol6. Ishiura H, Tsuji S. Advances in repeat expansion diseasesand a new concept of repeat motif-phenotype correlation.Curr Opin Genet Dev 2020;65:176–185.7. Lu CS, Chang HC, Kuo PC, et al. The parkinso-nian phenotype of spinocerebellar ataxia type 3 in aTaiwanese family. Parkinsonism Relat Disord 2004;10:369–373.8. Riess O, Rub U, Pastore A, et al. SCA3: neurologicalfeatures, pathogenesis and animal models. Cerebellum2008;7:125–137.ª 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association 3Ann Clin Transl Neurol

Reply: Genetic heterogeneity of neuronal intranuclear inclusion disease. What about the infantile variant?

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Reply: Genetic heterogeneity of neuronal intranuclear inclusion disease. What about the infantile variant?

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