Bhatia, KP

De Pablo-Fernandez, E

Djamshidian, A

Doherty, KM

Holton, JL

Lees, AJ

Limousin, P

Ling, H

Revesz, T

Warner, TT

PubMed

UCL Discovery

LETTERConcomitant fragileX-associated tremor ataxiasyndrome and Parkinson’sdisease: a clinicopathologicalreport of two casesINTRODUCTIONParkinsonism is common in fragileX-associated tremor/ataxia syndrome(FXTAS) but its underlying pathophysiologyremains unknown. Our group reported apatient with FXTAS and parkinsonism, andin vivo evidence of presynaptic and postsy-naptic nigrostriatal dysfunction.1 We reportthe histological ﬁndings of this case (case 1)and another case with dual pathologies ofFXTAS and Lewy body Parkinson’s disease(PD).METHODSGenetic testing for FXTAS was requested inseven cases from the Queen Square BrainBank for Neurological Disorders (QSBB)based on the characteristic radiological‘middle cerebellar peduncle’ (MCP) sign(case 1, diagnosis conﬁrmed in life) andhistological ﬁndings of round, eosinophilicp62-positive neuronal intranuclear inclu-sions in the hippocampus or unexplainedcerebellar degeneration (6 postmortemcases were tested). Two cases were positivefor FMR1 premutation and both showedhistological features of FXTAS and PD. TheQSBB brain donor programme wasapproved by a Research Ethics Committeeand written consent for research wasobtained from all cases.CASE REPORTSCase 1A 68-year-old man presented with a10-year history of slowly progressiveright-hand tremor. There was no familyhistory of neurological disorders or mentalretardation. Examination showed hypomi-mia, asymmetric rest and kinetic tremor,rigidity, mild bradykinesia and inability totandem walk. The patient was diagnosedwith tremor-predominant PD but did notrespond to L-dopa (600 mg/day). Over thenext few years he developed mild cognitiveimpairment, gait ataxia and intentiontremor. Brain MRI demonstrated the MCPsign and diffuse atrophy. Genetic analysisconﬁrmed FMR1 premutation with 87 CGGexpansion. 123I-FP-CIT SPECT revealedasymmetric reduced tracer uptake with theright side more affected. D2 receptor(123I) IBZM-SPECT (IBZM) scan showedslightly reduced tracer uptake bilaterally.There was clinical and neurophysiologicalevidence of large ﬁbre axonal peripheralneuropathy. The patient’s University ofPennsylvania Smell Identiﬁcation Test(UPSIT) score was 25/40 (severe hypos-mia: 19–25). His condition graduallydeteriorated and he died of pneumonia atage 72.Case 2A 21-year-old man was diagnosed withschizophrenia and his symptoms respondedwell to long-term ﬂuphenazine. At the ageof 35, he developed a right-hand tremorinitially attributed to the neuroleptic treat-ment. The tremor persisted despite switch-ing ﬂuphenazine to olanzapine 5 mg/dayand administering anticholinergics (orphe-nadrine and procyclidine). His tremorremained stable and only began to deterior-ate at age 51 along with the onset of slurredspeech and dragging of right leg.Examination showed mild hypomimia,hypophonia, restricted downgaze, slow ver-tical saccades, jaw and tongue tremor, inter-mittent right-sided predominant handtremor, bradykinesia and cogwheel rigidity.Olanzapine was replaced by quetiapine200 mg/day and L-dopa (300 mg/day) wasadministered without any improvement.Brain MRI showed global atrophy withoutthe MCP sign. At age 58, his symptomsrapidly deteriorated with severe handtremor and frequent falls requiring a wheel-chair. 123I-FP-CIT SPECT demonstratedasymmetrical reduction of tracer uptake inputamen and left caudate. A clinical diagno-sis of progressive supranuclear palsy (PSP)was made due to the rapid motor deterior-ation, postural instability, restriction ofdowngaze and absence of L-dopa response.He died of pulmonary embolism at age 59.Neuropathological ﬁndings promptedgenetic testing and the identiﬁcation ofFMR1 gene premutation with 100 CGGexpansions.NEUROPATHOLOGICAL EXAMINATIONIn both cases, histological examinationdemonstrated widespread p62-positiveand ubiquitin-positive and 1C2-negativeneuronal and glial intranuclear inclusionswith mild Purkinje cell depletion consist-ent with FXTAS. There was loss of pig-mented neurons in the substantia nigrawith α-synuclein-positive Lewy bodies, inkeeping with PD. Lewy body pathologyconformed to Braak stage 5 in case 1 andstage 3 in case 2. Age-related neuroﬁbril-lary tangle pathology was also noted inboth cases (Braak and Braak stage II incase 1 and stage I in case 2). An acute leftmiddle cerebral artery territory infarctionwas observed in case 2.DISCUSSIONIn the literature, only 13 of 29 (45%)cases with FMR1 premutation and parkin-sonism had abnormal dopamine trans-porter scans (see online supplementarytable) and it is likely that these 13 casesmay have had concomitant PD pathologyakin to the two cases in this series. On theother hand, IBZM scans were only avail-able in four cases with FMR1 premutationincluding our case and all had abnormalﬁndings (see online supplementary table).We propose that postsynaptic dopamin-ergic striatal pathway dysfunction isresponsible for parkinsonism in indivi-duals with FXTAS. FMR1 premutationcarriers with an abnormal dopaminetransporter scan probably signiﬁes thepresence of concomitant PD pathologyand may have a rapidly progressivedisease course due to the dual patholo-gies. These patients may beneﬁt from L-dopa therapy.Of the 22 FXTAS cases with post-mortem data (table 1), concomitantpathologies were identiﬁed in nine cases(41%): four had Alzheimer’s diseasepathology,2 one had multiple sclerosis(MS)2 and four had PD pathology includ-ing the two cases presented here.2 3It is difﬁcult to ascertain the exact contri-bution of each pathology to the clinicalcourse of parkinsonism in our cases. In case2, the long-term use of neuroleptics compli-cated the clinical picture, thus the long-standing hand tremor could have beencaused by a combination of FTXAS andneuroleptics. However, at age 51, thedeterioration of hand tremor, relentlessprogression of parkinsonism and the onsetof typical features of PD including jaw andtongue tremor collectively marked theonset of an additional underlying neurode-generative process of PD. Both cases had arelatively benign course in the ﬁrst decadeof symptom onset followed by rapidly pro-gressive parkinsonism and motor disabilityleading to death. This rapid deterioration isatypical for either FXTAS or PD. Indeed,the clinical diagnosis for case 2 was revisedto PSP. Among the four patients with dualFXTAS and PD pathology in the litera-ture,2 3 the time from onset to use ofwalking aid (median: 7.5 years) and lifeexpectancy (median: 11 years) are muchshorter than in other patients with isolatedFXTAS, in whom the median time towalking aid is 15 years and median survivalis 21 years.4 These data suggest that thesynergistic effect of more than one neuro-degenerative condition might haveJ Neurol Neurosurg Psychiatry Month 2014 Vol 0 No 0 1PostScript JNNP Online First, published on December 4, 2014 as 10.1136/jnnp-2014-309460Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence. group.bmj.com on March 19, 2015 - Published by http://jnnp.bmj.com/Downloaded from contributed to an accelerated diseasecourse. Carriers of FMR1 premutation withconcomitant Alzheimer’s disease,2 hetero-zygous Parkin mutation5 or MS2 have beenreported and these secondary pathologicalprocesses have been postulated to modulatethe effect of FMR1 premutation.Eduardo De Pablo-Fernandez,1,2Karen M Doherty,1,2 Janice L Holton,1,2,3Tamas Revesz,1,2 Atbin Djamshidian,1Patricia Limousin,3,4 Kailash P Bhatia,3,4Thomas T Warner,1,2,3 Andrew J Lees,1,2Helen Ling1,21Reta Lila Weston Institute of Neurological Studies, UCLInstitute of Neurology, London, UK2Queen Square Brain Bank for Neurological Disorders,UCL Institute of Neurology, London, UK3National Hospital for Neurology and Neurosurgery,Queen Square, UCL Hospitals NHS Foundation Trust,London, UK4Sobell Department of Motor Neuroscience, UCLInstitute of Neurology, London, UKCorrespondence to Dr Helen Ling, Reta Lila WestonInstitute of Neurological Studies, UCL Institute ofNeurology, 1 Wakeﬁeld Street, London WC1N 1PJ, UK;h.ling@ucl.ac.ukAcknowledgements The authors thank Dr ThomasinAndrews for providing clinical information regarding case 2.Contributors ED-PF contributed to project conceptionand organisation, and data collection, and wrote theﬁrst draft; KMD contributed to project conception andorganisation, and data collection, and criticallyreviewed the manuscript; JLH and TR performedhistological analysis, contributed to pathology contentand critically reviewed the manuscript; AD, PL, KPB,TTW and AJL contributed to clinical assessment,diagnostic process and critically reviewed themanuscript; HL contributed to project conception andorganisation, and critically reviewed the manuscript.Competing interests None.Patient consent Obtained.Ethics approval The brain donor programme of theQSBB was approved by a London Multi-Centre ResearchEthics Committee and tissue is stored under a licensefrom the Human Tissue Authority. Consent for use oftissue for research was obtained from donors and/ortheir next of kin.Provenance and peer review Not commissioned;externally peer reviewed.▸ Additional material is published online only. To viewplease visit the journal online (http://dx.doi.org/10.1136/jnnp-2014-309460).Open Access This is an Open Access articledistributed in accordance with the Creative CommonsAttribution Non Commercial (CC BY-NC 4.0) license,which permits others to distribute, remix, adapt, buildupon this work non-commercially, and license theirderivative works on different terms, provided theoriginal work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/To cite De Pablo-Fernandez E, Doherty K M,Holton JL, et al. J Neurol Neurosurg PsychiatryPublished Online First: [please include Day Month Year]doi:10.1136/jnnp-2014-309460Received 10 September 2014Revised 7 November 2014Accepted 13 November 2014J Neurol Neurosurg Psychiatry 2014;0:1–2.doi:10.1136/jnnp-2014-309460REFERENCES1 Healy DG, Bressman S, Dickson J, et al. Evidence forpre and postsynaptic nigrostriatal dysfunction in thefragile X tremor-ataxia syndrome. Mov Disord2009;24:1245–7.2 Tassone F, Greco CM, Hunsaker MR, et al.Neuropathological, clinical and molecular pathology infemale fragile X premutation carriers with and withoutFXTAS. Genes Brain Behav 2012;11:577–85.3 Greco CM, Berman RF, Martin RM, et al.Neuropathology of fragile X-associated tremor/ataxiasyndrome (FXTAS). Brain 2006;129(Pt 1):243–55.4 Leehey MA, Berry-Kravis E, Min SJ, et al. Progressionof tremor and ataxia in male carriers of the FMR1premutation. Mov Disord 2007;22:203–6.5 Hedrich K, Pramstaller PP, Stubke K, et al.Premutations in the FMR1 gene as a modifying factorin Parkin-associated Parkinson’s disease? Mov Disord2005;20:1060–2.6 Greco CM, Hagerman RJ, Tassone F, et al. Neuronalintranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain2002;125:1760–71.7 Louis E, Moskowitz C, Friez M, et al. Parkinsonism,dysautonomia, and intranuclear inclusions in a fragileX carrier: a clinical-pathological study. Mov Disord2006;21:420–5.Table 1 Features of 22 reported postmortem FXTAS casesDuration fromonset (years)CCGrepeats MCP signAdditionalneuropathologicalfindingsWheelchair DeathGreco et al3; 11 males6 6 10 113 – –– 13 80 – –NA 5 80 Y –13 14 71 – PD12 19 105 – –7 13 77 Y –5 6 88 Y –NA 3 92 – –13 16 88 Y –4 6 93 Y –NA 1 65 – –Tassone et al2; 8 females NA NA 70 – –– 10 80 N AD (B&B V-VI)– 6 87 – –– 14 75 Y MS– 7 65 – AD (B&B V-VI)4 7 – N AD (B&B V-VI)4 6 59 N PD– 8 78 – AD (B&B V-VI)Louis et al; 1 male7 7 9 90 – –Present series: De Pablo-Fernandezet al; 2 males13 14 72 Y PD (Braak 5)7 8 100 N PD (Braak 3)Total: 8 females; 14 males 8 9 Y64% (7/11)AD, Alzheimer disease; B&B, Braak and Braak stage for Alzheimer; Braak, Braak stage for Parkinson’s disease; FXTAS,fragile X-associated tremor/ataxia syndrome; MCP, middle cerebellar peduncle; MS, multiple sclerosis; N, no; NA, notapplicable; PD, Parkinson’s disease; Y, yes.2 J Neurol Neurosurg Psychiatry Month 2014 Vol 0 No 0PostScriptgroup.bmj.com on March 19, 2015 - Published by http://jnnp.bmj.com/Downloaded from clinicopathological report of two casesataxia syndrome and Parkinson's disease: a Concomitant fragile X-associated tremorT Warner, Andrew J Lees and Helen LingRevesz, Atbin Djamshidian, Patricia Limousin, Kailash P Bhatia, Thomas Eduardo De Pablo-Fernandez, Karen M Doherty, Janice L Holton, Tamas published online December 4, 2014J Neurol Neurosurg Psychiatry  http://jnnp.bmj.com/content/early/2014/12/04/jnnp-2014-309460Updated information and services can be found at: These include:MaterialSupplementary htmlhttp://jnnp.bmj.com/content/suppl/2014/12/04/jnnp-2014-309460.DC1.Supplementary material can be found at: References #BIBLhttp://jnnp.bmj.com/content/early/2014/12/04/jnnp-2014-309460This article cites 5 articles, 1 of which you can access for free at: Open Accesshttp://creativecommons.org/licenses/by-nc/4.0/non-commercial. See: provided the original work is properly cited and the use isnon-commercially, and license their derivative works on different terms, permits others to distribute, remix, adapt, build upon this workCommons Attribution Non Commercial (CC BY-NC 4.0) license, which This is an Open Access article distributed in accordance with the CreativeserviceEmail alertingbox at the top right corner of the online article. Receive free email alerts when new articles cite this article. Sign up in theCollectionsTopic Articles on similar topics can be found in the following collections  (157)Open accessNoteshttp://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:http://journals.bmj.com/cgi/reprintformTo order reprints go to:http://group.bmj.com/subscribe/To subscribe to BMJ go to:group.bmj.com on March 19, 2015 - Published by http://jnnp.bmj.com/Downloaded from 

Concomitant fragile X-associated tremor ataxia syndrome and Parkinson's disease: a clinicopathological report of two cases.

http://dx.doi.org/10.1136/jnnp-2014-309460

Concomitant fragile X-associated tremor ataxia syndrome and Parkinson's disease: a clinicopathological report of two cases.

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