Bardakjian, Tanya M.

Ehrlich, Debra

Goldstein, David S.

Gonzalez-Alegre, Pedro

Isonaka, Risa

Kokkinis, Angela D.

Liang, Tsao-Wei

Narendra, Derek P.

Nguyen, Diana

Schindler, Alice B.

Jefferson Digital Commons

Thomas Jefferson University Jefferson Digital Commons Department of Neurology Faculty Papers Department of Neurology 6-4-2019 Peripheral synucleinopathy in a DJ1 patient with Parkinson disease, cataracts, and hearing loss Derek P. Narendra National Institute of Neurological Disorders and Stroke; University of Pennsylvania Risa Isonaka National Institute of Neurological Disorders and Stroke Diana Nguyen National Institute of Neurological Disorders and Stroke Alice B. Schindler National Institute of Neurological Disorders and Stroke Angela D. Kokkinis National Institute of Neurological Disorders and Stroke See next page for additional authors Follow this and additional works at: https://jdc.jefferson.edu/neurologyfp  Part of the Neurology Commons Let us know how access to this document benefits you Recommended Citation Narendra, Derek P.; Isonaka, Risa; Nguyen, Diana; Schindler, Alice B.; Kokkinis, Angela D.; Ehrlich, Debra; Bardakjian, Tanya M.; Goldstein, David S.; Liang, Tsao-Wei; and Gonzalez-Alegre, Pedro, "Peripheral synucleinopathy in a DJ1 patient with Parkinson disease, cataracts, and hearing loss" (2019). Department of Neurology Faculty Papers. Paper 189. https://jdc.jefferson.edu/neurologyfp/189 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Department of Neurology Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: JeffersonDigitalCommons@jefferson.edu. Authors Derek P. Narendra, Risa Isonaka, Diana Nguyen, Alice B. Schindler, Angela D. Kokkinis, Debra Ehrlich, Tanya M. Bardakjian, David S. Goldstein, Tsao-Wei Liang, and Pedro Gonzalez-Alegre This article is available at Jefferson Digital Commons: https://jdc.jefferson.edu/neurologyfp/189 CLINICAL/SCIENTIFIC NOTESPeripheral synucleinopathy in a DJ1 patient withParkinson disease, cataracts, and hearing lossDerek P. Narendra, MD, PhD, Risa Isonaka, PhD, Diana Nguyen, BS, Alice B. Schindler, MS, CGC,Angela D. Kokkinis, BSN, RN, Debra Ehrlich, MD, MS, Tanya M. Bardakjian, MS, CGC,David S. Goldstein, MD, PhD, Tsao-Wei Liang, MD, and Pedro Gonzalez-Alegre, MD, PhDNeurology® 2019;92:1113-1115. doi:10.1212/WNL.0000000000007614CorrespondenceDr. Narendraderek.narendra@nih.govWhereas Parkinson disease (PD) is usually sporadic, PD with onset under 50 years old can beassociated with genetic abnormalities, including rare biallelic mutations in the DJ1 gene(PARK7).1 The DJ1 phenotype is incompletely described and has been presumed to be similarto the Parkin (PARK2) phenotype, in which atypical clinical features are usually absent, and, incontrast to idiopathic PD, synucleinopathy is lacking and olfaction preserved.2 Whether DJ1patients have peripheral synucleinopathy and olfactory dysfunction has been unknown.MethodsFor immunofluorescence microscopy, 3-mm punch biopsies from the C2 area of the posteriorneck were fixed in Zamboni fixative, cryosectioned into 10-μm slices, and immunostained fortyrosine hydroxylase (Pel-Freez Biologicals, Rogers, AR) (red), α-synuclein (Santa Cruz Bio-technology, Santa Cruz, CA) (green), and smooth muscle actin (ACTA2; Santa Cruz Bio-technology) (blue). Fibroblast cell lines were also established. A colocalization index for α-synucleinand tyrosine hydroxylase was calculated from confocal images using Fiji (NIH, Bethesda, MD).Normalized mean deviation product (nMDP) values for colocalization were tabulated from −0.1 to+1.0, and the colocalization index calculated as log (0.1 + + nMDP [0.3–1.0]).Standard protocol approvals, registrations, and patient consentsAll participants provided written informed consent before participation in the research study,which was approved by the National Institute of Neurological Disorders and Stroke in-stitutional review board.ResultsWe report a 35-year-old man with PD and compound heterozygous DJ1mutations. In his mid-20s, he developed a left-hand resting tremor that progressed over years, followed by loss ofmobility, disability, and speech difficulties. His symptoms responded to levodopa, promptinga diagnosis of PD, supported by DaT imaging (figure, A). At the time of evaluation, the patienthad resting tremor, bradykinesia, rigidity, postural instability, motor fluctuations, and dyski-nesia. The patient’s examination was notable also for eyelid opening apraxia, hyperreflexia,extensor plantar reflex responses bilaterally, and pseudobulbar affect (video 1). The patient wasanosmic by the University of Pennsylvania Smell Identification Test (UPSIT; score 16/40). Sixpatients with early-onset PD from our clinic cohort with biallelic Parkin mutations had higherUPSIT scores (mean 32.8; range 26–38; figure, B). In addition to his neurologic presentation,he had sensorineural hearing loss on audiometry and visual difficulties that improved afterbilateral cataract surgery at the age of 33.Testing for a panel of PD-related genes (Next-Generation Sequencing, Invitae, CA) revealed 2previously unreported DJ1 variants (deletion [exon 4]; c.105dupT [p.Ala36Cysfs*12] [NM_007262.4]). Parental testing showed these were on opposite chromosomes (figure, C). No DJ1From the National Institute of Neurological Disorders and Stroke (D.P.N., R.I., D.N., A.S., A.K., D.E., D.S.G.), NIH, Bethesda, MD; Department of Neurology (D.P.N., T.M.B., P.G.-A.),University of Pennsylvania; Department of Neurology (T.-W.L.), Thomas Jefferson University Hospital; ad The Children’s Hospital of Philadelphia (P.G.-A.), PA.Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.MORE ONLINEVideoCopyright © 2019 American Academy of Neurology 1113Copyright © 2019 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.protein was detectable in lysates from the patient’s fibroblasts.Lysates from each parent had half of the normal DJ1 protein,establishing pathogenicity of the variants (figure, D).Immunofluorescence microscopy of skin biopsies from thepatient demonstrated substantial deposition of α-synucleinwithin tyrosine hydroxylase-positive fibers. The calculatedFigurePeripheral synucleinopathy and anosmia in apatientwith early-onset Parkinsondiseasewith biallelicDJ1mutations(A) Consecutive axial FP-CIT SPECT images demonstrate absent signal in the region of the putamen (arrows) and decreased signal in caudate heads, bilaterally(arrowheads). (B) Clinical characteristics of the DJ1 patient and 6 biallelic Parkin patients for whomUniversity of Pennsylvania Smell Identification Test (UPSIT)data were available. (C) Pedigree of DJ1 family. Filled in symbol indicates affected individual. (D) fibroblast lysates from a control adult dermal fibroblast line(ATCC), the affected patient, and his unaffected parents were separated on sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) gels andimmunoblotted for DJ1 (MBL International, Woburn, MA). (E, F) Representative confocal images (F) and quantification (E) of α-synuclein (green) withinsympathetic noradrenergic nerve fibers (red) innervating dermal piloerector muscles (blue). Normal range is based on measurements from 4 healthycontrols and 7 patients with multiple system atrophy.3 Scale bar = 20 μm. AAO = age at onset; H&Y = Hoehn & Yahr; LEDD = levodopa equivalent daily dose;UPDRS = Unified Parkinson’s Disease Rating Scale.1114 Neurology | Volume 92, Number 23 | June 4, 2019 Neurology.org/NCopyright © 2019 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.colocalization index, 2.0, was above the control range in ourseries (−1.0 to 1.3, n = 11; figure, E and F); and within therange of idiopathic PD (0.9–4.9, n = 9).3DiscussionWe identified novel compound heterozygous DJ1 mutationsin a patient with early-onset PD. A prior report of a DJ1 casenoted postmortem Lewy body pathology in the brain.4 Herewe report deposition of α-synuclein in sympathetic norad-renergic nerves in biopsied skin from a living patient. To-gether these reports support the view that DJ1/PARK7involves synucleinopathy within both the brain and thesympathetic nervous system. We also provide evidence thatolfaction can be severely compromised in DJ1/PARK7. Dataon peripheral synucleinopathy and olfaction, key phenotypicfeatures that distinguish most patients with Parkin frompatients with idiopathic PD,2 were previously missing forDJ1/PARK7 on review of the 32 reported cases (appendix e-1:doi.org/10.5061/dryad.nv892mp). These findings suggestthat the DJ1 phenotype resembles that of idiopathic PD moreclosely than that of Parkin/PARK2 PD.This case and review of the literature also underscore atypicalfeatures of theDJ1/PARK7 clinical phenotype. Early cataractswere present in 3 cases (9.1%), 2 of whom also had sensorineuralhearing loss (6.1%).5,6 The triad of early-onset PD, cataracts, andsensorineural hearing loss may be specific forDJ1/PARK7, as weare unaware of their co-occurrence in other PD cases. Recentstudies suggest that DJ1 is a deglycase, repairing cellular damagefrom reactive aldehydes and protecting against oxidative damage.Reactive aldehydes and oxidative damage are implicated in cat-aractogenesis, pointing to a possible mechanism for prematurecataract development in DJ1/PARK7.7We expand the DJ1 phenotype to include autonomic synu-cleinopathy and impaired olfaction, distinguishing it from theParkin/PARK2 phenotype. In addition, we suggest that theclinical triad of early-onset PD, cataracts, and sensorineuralhearing loss may be specific for DJ1/PARK7.Author contributionsD.P. Narendra: drafting/revising the manuscript, data acqui-sition, study concept or design, analysis or interpretation ofdata, accepts responsibility for conduct of research and finalapproval, acquisition of data, study supervision, obtainingfunding. R. Isonaka: drafting/revising the manuscript, dataacquisition, analysis or interpretation of data, accepts re-sponsibility for conduct of research and final approval, acquisitionof data, statistical analysis. D. Nguyen: data acquisition, studyconcept or design, analysis or interpretation of data, accepts re-sponsibility for conduct of research and final approval, acquisitionof data. A. Schindler: data acquisition, study concept or design,accepts responsibility for conduct of research and final ap-proval, acquisition of data, study supervision. A. Kokkinis: dataacquisition, accepts responsibility for conduct of research andfinal approval. D. Ehrlich: drafting/revising the manuscript,accepts responsibility for conduct of research and final ap-proval, acquisition of data. T.M. Bardakjian: drafting/revisingthe manuscript, data acquisition, accepts responsibility forconduct of research and final approval. D.S. Goldstein:drafting/revising the manuscript, analysis or interpretation ofdata, accepts responsibility for conduct of research and finalapproval. T.-W. Liang: drafting/revising the manuscript, dataacquisition, accepts responsibility for conduct of research andfinal approval patient referral. P. Gonzalez-Alegre: drafting/revising the manuscript, data acquisition, study concept ordesign, analysis or interpretation of data, accepts responsibilityfor conduct of research and final approval, acquisition of data,study supervision.AcknowledgmentThe authors thank Carolyn Smith, PhD, and NINDS LightMicroscopy Facility for technical assistance with confocalmicroscopy.Study fundingThis work was funded by the Intramural Research Program ofthe National Institute of Neurological Disorders and Stroke.DisclosureThe authors report no disclosures relevant to the manuscript.Go to Neurology.org/N for full disclosures.References1. Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated withautosomal recessive early-onset parkinsonism. Science 2003;299:256–259.2. Kasten M, Hartmann C, Hampf J, et al. Genotype-phenotype relations for the Par-kinson’s disease genes Parkin, PINK1,DJ1: MDSGene systematic review. Mov Disord2018;33:730–741.3. Isonaka R, Rosenberg AZ, Sullivan P, et al. Alpha-synuclein deposition within sym-pathetic noradrenergic neurons is associated with myocardial noradrenergic de-ficiency in neurogenic orthostatic hypotension. Hypertension 2019;73:910–918.4. Taipa R, Pereira C, Reis I, et al. DJ-1 linked parkinsonism (PARK7) is associated withLewy body pathology. Brain J Neurol 2016;139:1680–1687.5. Di Nottia M, Masciullo M, Verrigni D, et al. DJ-1 modulates mitochondrial responseto oxidative stress: clues from a novel diagnosis of PARK7. Clin Genet 2017;92:18–25.6. Taghavi S, Chaouni R, Tafakhori A, et al. A clinical and molecular genetic study of 50families with autosomal recessive parkinsonism revealed known and novel genemutations. Mol Neurobiol 2018;55:3477–3489.7. Richarme G, Mihoub M, Dairou J, Bui LC, Leger T, Lamouri A. Parkinsonism-associated protein DJ-1/park7 is a major protein deglycase that repairs methylglyoxal-and glyoxal-glycated cysteine, arginine, and lysine residues. J Biol Chem 2015;290:1885–1897.Neurology.org/N Neurology | Volume 92, Number 23 | June 4, 2019 1115Copyright © 2019 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.DOI 10.1212/WNL.00000000000076142019;92;1113-1115 Published Online before print April 26, 2019Neurology Derek P. Narendra, Risa Isonaka, Diana Nguyen, et al. hearing loss patient with Parkinson disease, cataracts, andDJ1Peripheral synucleinopathy in a This information is current as of April 26, 2019ServicesUpdated Information & http://n.neurology.org/content/92/23/1113.fullincluding high resolution figures, can be found at:References http://n.neurology.org/content/92/23/1113.full#ref-list-1This article cites 7 articles, 2 of which you can access for free at: Subspecialty Collections http://n.neurology.org/cgi/collection/parkinsons_disease_parkinsonismParkinson's disease/Parkinsonism http://n.neurology.org/cgi/collection/all_neuroophthalmologyAll Neuro-ophthalmology http://n.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://www.neurology.org/about/about_the_journal#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://n.neurology.org/subscribers/advertiseInformation about ordering reprints can be found online:rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.1951, it is now a weekly with 48 issues per year. Copyright © 2019 American Academy of Neurology. All ® is the official journal of the American Academy of Neurology. Published continuously sinceNeurology 

Peripheral synucleinopathy in a DJ1 patient with Parkinson disease, cataracts, and hearing loss

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Peripheral synucleinopathy in a DJ1 patient with Parkinson disease, cataracts, and hearing loss

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