Barresi R

Clegg S

Eugenicos M

Jackson AP

Miller TD

Smart CM

Stone J

Straub V

Summers D

Newcastle University E-Prints

doi: 10.1136/jnnp.2008.148676 2009 80: 583-584J Neurol Neurosurg Psychiatry T D Miller, A P Jackson, R Barresi, et al. large pedigreefeatures including sphincter disturbance in a clinicaland frontotemporal dementia (IBMPFD): Inclusion body myopathy with Paget disease http://jnnp.bmj.com/content/80/5/583.full.htmlUpdated information and services can be found at: These include:MaterialSupplemental  http://jnnp.bmj.com/content/suppl/2009/04/03/80.5.583.DC1.htmlReferences http://jnnp.bmj.com/content/80/5/583.full.html#ref-list-1This article cites 5 articles, 1 of which can be accessed free at:serviceEmail alertingbox at the top right corner of the online article.Receive free email alerts when new articles cite this article. 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Am J Neuroradiol1999;20:1412–16.6. Tan SV, Guiloff RJ. Hypothesis on the pathogenesisof vacuolar myelopathy, dementia, and peripheralneuropathy in AIDS. J Neurol Neurosurg Psychiatry1998;65:23–8.7. Kamin SS, Petito CK. Idiopathic myelopathies withwhite matter vacuolation in non-acquiredimmunodeficiency syndrome patients. Hum Pathol1991;22:816–24.8. Mwanza J-C, Nyamabo LK, Tylleskar T, et al. Neuro-opthalmological disorders in HIV infected subjectswith neurological manifestations. Br J Opthalmol2004;88:1455–9.9. Selmaj KW, Raine CS. Tumor necrosis factormediates myelin and oligodendrocyte damage in vitro.Ann Neurol 1988;23:339–46.10. Lin XH, Kashima Y, Heller KB, et al. Animmunohistochemical study of TNF-alpha in opticnerves from AIDS patients. Curr Eye Res1997;16:1064–8.11. Aboulafia DM, Taylor L. Vacuolar myelopathy andvacuolar cerebellar leukoencephalopathy: a latecomplication of AIDS after highly active antiretroviraltherapy-induced immune reconstitution. AIDS PatientCare STDS 2002;16:579–84.Inclusion body myopathy withPaget disease and frontotemporaldementia (IBMPFD): clinicalfeatures including sphincterdisturbance in a large pedigreeAutosomal dominant inclusion body myo-pathy (IBM) associated with Paget disease ofbone (PDB) and frontotemporal dementia(FTD), or IBMPFD, is a rare recentlydescribed multisystem disorder caused bymissense mutations of the valosin-contain-ing protein (VCP) gene on chromosome9p13–p12 (OMIM 605382).1 Recognised fea-tures include proximal and distal weakness,early-onset PDB, early-onset FTD and cardi-omyopathy.1–3 Here we report the clinicalfeatures of a large affected kindred.PATIENTS AND METHODSA large extended British family was identi-fied with the condition (VS and AJ). Clinicalinformation was obtained by interviewingpatients, neurological examination of fiveliving patients and reviewing medicalrecords. Patients were investigated wherepossible with MRI of brain, spine and pelvicmuscles, neurophysiology and anorectalphysiology, muscle biopsy, AddenbrookesCognitive Examination—Revised, skull,lumbar spine and pelvic x rays, creatinekinase and alkaline phosphatase. Mutationanalysis of VCP was performed on fouraffected members and one unaffected refer-ence member from this family. GenomicDNA, extracted from peripheral blood viastandard methods, was analysed in duplicatefor each subject.RESULTSVCP mutation analysis of four affectedindividuals (II:18, III:13, III:14, III:15; onlinefigure 1) showed a heterozygous c.464GRAnucleotide substitution in exon 5 of the VCPprotein (p.R155H), a substitution notdetected in an unaffected maternal brother(II:20) confirming mutation segregationwithin the family. This mutation has beenpreviously identified.1CLINICAL FEATURESThe pedigree of this five-generation IBMPFDfamily with 18 affected members (12 men,six women) is consistent with an autosomaldominant pattern of inheritance (onlinefig 1). Affected members presented withproximal and axial weakness diagnosed asmotor neuron disease (MND) or othermuscular dystrophies (online table 1). Eightmembers then proceeded to develop demen-tia. PDB was not found in the retrospectivenotes. The mean age of muscle weaknessonset was 34 (n = 9; range 20–49). The meanduration of the illness to death, whenrecorded, was 17 years (n = 8; range 10–30). A detailed summary of the currentclinical features and investigations and thosefrom the retrospective notes for this largepedigree are presented in online table 1. Fourmembers of the pedigree were found to havedilated cardiomyopathy following echocar-diography, two with mild shortness ofbreath on exertion. All affected membershave been treated with angiotensin-convert-ing enzyme inhibitors, one patient withsymptomatic improvement.Five members of the extended pedigreehad symptoms of sphincter disturbancepresenting as urge incontinence (n = 5),Figure 1 MRI from members of the reported pedigree. (A) T2-weighted coronal image of II:18.There is moderate atrophy of the left temporal lobe cortex. (B) T2-weighted sagittal image of thethoracolumbar spine in the same subject showing marked atrophy of the distal cord. (C) FLAIR axialimage of III:14 demonstrating scattered white matter high signal in the white matter. (D) Fatsuppressed T2 coronal imaging of the pelvis and upper thigh in III:14 demonstrating markedasymmetrical wasting of the adductor and hamstring muscles on the left side (black arrowheads)compared with the more normal right side (white arrowheads).PostScriptJ Neurol Neurosurg Psychiatry May 2009 Vol 80 No 5 583 group.bmj.com on June 21, 2010 - Published by jnnp.bmj.comDownloaded from faecal incontinence (n = 4) or erectile dys-function (n = 3; all male patients). Anorectalelectrophysiology was performed in twopatients, both consistent with bilateralpudendal neuropathies (Web table 1). MRIstudies (fig 1) showed: scattered cerebralwhite matter hyperintensities in all threepatients in whom this test was performed;asymmetrical left frontotemporal atrophyconsistent with clinical FTD and an atrophiccord especially around the conus in II:18;and fatty change and atrophy of the glutealmuscles and low muscle volume in thequadriceps and hamstring groups in III:14.A muscle biopsy from II:14 is shown inonline fig 2.DISCUSSIONIBMPFD presents as a multisystem disorderaffecting brain, skeletal and cardiac muscle,3spinal cord and bone.1 4 The R155H muta-tion, an arginine-to-histidine substitution inthe N-terminal CDC48 domain of the VCPprotein, results in loss of VCP function5 andis found exclusively in individuals affectedwith IBMPFD.1 Clinical reports of thisdisease are scarce.1 2 4 Family membersusually presented with proximal weakness,progressing to wheelchair disability andpremature death. The average age of muscleweakness onset, as a familial average, was34, contrasting with previous studies (432and 574). The dementia frequency withinthis pedigree was 44% compared with 30%,170%,4 and 100%4 in other studies. As somepatients may have prematurely died ofmyopathy- or cardiomyopathy-related com-plications, it was difficult to assess FTDpenetrance.Four out of five investigated members ofthis pedigree had echocardiographic featuresof cardiomyopathy.3 This is the first clinicaldescription of cardiomyopathy in a molecu-larly confirmed VCP mutation. Recentpostmortem findings have found a dilatedand hypertrophic cardiomyopathy in onepatient with IBMPFD.3The new observation in this pedigree isthe presence of prominent sphincter distur-bance involving bladder, bowel and erectilefunction in all five assessed pedigree mem-bers. Other factors could partially explainthese symptoms: for example, functionalobstructive defaecation may be partlyresponsible for the clinical picture of puden-dal neuropathy seen in III:13. However, thisis associated with a reduction in sphinctertone, a feature not seen during anorectalphysiology. Moreover, III:15 had pudendalneuropathy with no history of longstandingconstipation. In III:13, III:14 and III:15,erectile failure may be partly explained bypsychogenic factors. Nonetheless, the simi-larity of sphincter symptoms between allpatients and in particular four relativelyyoung patients (III:3, III:13, III:14, III:15) isstriking. We therefore conclude thatIBMPFD is likely to be associated withsphincter disturbance. The presence ofspinal cord atrophy in one patient (II:18)and previous work showing ubiquitin-posi-tive nuclear inclusion bodies in the spinalcord in IBMPFD4 suggest that sphincterdisturbance in IBMPFD could arise fromboth spinal cord and nerve pathology.Brain MRI demonstrated a mild excess ofwhite matter abnormalities in all threeexamined. Right temporal lobe atrophy andcord atrophy were seen in an older patient,correlating with her clinical FTD. This is inagreement with one other MRI brain studyof IBMPFD,3 while another described pro-gressive cerebral atrophy with prominentcallosal and frontal white matter loss.5Spinal cord atrophy is a previously unde-scribed feature of IBMPFD and is consistentwith pathological findings of spinal cordinclusion bodies.4 A recent report describesMRI muscle findings in IBMPFD of ‘‘fattydegeneration’’ throughout predominantlyproximal muscle groups,3 in agreement withcurrent findings.Members of this pedigree had been pre-viously given other diagnoses includingvarious muscular dystrophies and spinalmuscular atrophy. MND had been diag-nosed in some patients because of denerva-tion on neurophysiology (online table 1).In conclusion, IBMPFD is a multisystemdisorder, which should be considered in thedifferential diagnosis of autosomal domi-nant neuromuscular disorders, especiallywhen there is a prominent history ofdementia or ‘‘MND.’’ Sphincter involve-ment is a likely associated clinical featureof the disease.T D Miller,1 A P Jackson,2 R Barresi,3 C M Smart,1M Eugenicos,4 D Summers,1 S Clegg,5 V Straub,3J Stone11 Department Clinical Neurosciences, University ofEdinburgh, Western General Hospital, Edinburgh, UK; 2 MRCHuman Genetics Unit, Western General Hospital, Edinburgh,UK; 3 Institute of Human Genetics, University of Newcastleupon Tyne, International Centre for Life, Newcastle uponTyne, UK; 4 Gastrointestinal Unit, Western General Hospital,Edinburgh, UK; 5 South East of Scotland Clinical GeneticsService, Western General Hospital, Edinburgh, UKCorrespondence to: Dr J Stone, Department ClinicalNeurosciences, University of Edinburgh, Western GeneralHospital, Crewe Road, Edinburgh EH4 2XU, UK;jon.stone@ed.ac.ukAcknowledgements: L Strain is thanked for technical helpin establishing the VCP mutation analysis.Funding: None.Competing interests: None.Patient consent: Obtained.c An additional table and figures are published online only athttp://jnnp.bmj.com/content/vol80/issue5Received 5 March 2008Revised 4 June 2008Accepted 8 July 2008J Neurol Neurosurg Psychiatry 2009;80:583–584.doi:10.1136/jnnp.2008.148676REFERENCES1. Watts GDJ, Wymer J, Kovach MJ, et al. Inclusionbody myopathy associated with Paget disease of boneand frontotemporal dementia is caused by mutantvalosin-containing protein. Nat Genet 2004;36:377–81.2. Kovach MJ, Waggoner B, Leal SM, et al. Clinicaldelineation and localization to chromosome 9p13.3–p12 of a unique dominant disorder in four families:hereditary inclusion body myopathy, Paget disease ofbone, and frontotemporal dementia. Mol Genet Metab2001;74:458–75.3. Hubbers CU, Clemen CS, Kesper K, et al. Pathologicalconsequences of VCP mutations on human striatedmuscle. Brain 2006;130:381–93.4. Guyant-Marechal L, Laquerriere A, Duyckaerts C, etal. Valosin-containing protein gene mutations: clinicaland neuropathologic features. Neurology2006;67:644–51.5. Krause S, Göhringer T, Walter MC, et al. Brain imagingand neuropsychology in late-onset dementia due to anovel mutation (R93C) of valosin-containing protein.Clin Neuropathol 2007;26:232–40.CORRECTIONdoi:10.1136/jnnp.2008.158303corr1M P T Lunn, H J Willison. Diagnosis andtreatment of inflammatory neuropathies (JNeurol Neurosurg Psychiatry 2009;80:249–58).There is a dosage error in this paper. In thelast paragraph on page 255 the dose ofprednisolone should be 1mg/kg not 1g/kg asprinted.PostScript584 J Neurol Neurosurg Psychiatry May 2009 Vol 80 No 5 group.bmj.com on June 21, 2010 - Published by jnnp.bmj.comDownloaded from 

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Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD): clinical features including sphincter disturbance in a large pedigree

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Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD): clinical features including sphincter disturbance in a large pedigree

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