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Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD): clinical features including sphincter disturbance in a large pedigree
  1. T D Miller1,
  2. A P Jackson2,
  3. R Barresi3,
  4. C M Smart1,
  5. M Eugenicos4,
  6. D Summers1,
  7. S Clegg5,
  8. V Straub3,
  9. J Stone1
  1. 1
    Department Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, UK
  2. 2
    MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK
  3. 3
    Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Newcastle upon Tyne, UK
  4. 4
    Gastrointestinal Unit, Western General Hospital, Edinburgh, UK
  5. 5
    South East of Scotland Clinical Genetics Service, Western General Hospital, Edinburgh, UK
  1. Dr J Stone, Department Clinical Neurosciences, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK; jon.stone{at}ed.ac.uk

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Autosomal dominant inclusion body myopathy (IBM) associated with Paget disease of bone (PDB) and frontotemporal dementia (FTD), or IBMPFD, is a rare recently described multisystem disorder caused by missense mutations of the valosin-containing protein (VCP) gene on chromosome 9p13–p12 (OMIM 605382).1 Recognised features include proximal and distal weakness, early-onset PDB, early-onset FTD and cardiomyopathy.13 Here we report the clinical features of a large affected kindred.

PATIENTS AND METHODS

A large extended British family was identified with the condition (VS and AJ). Clinical information was obtained by interviewing patients, neurological examination of five living patients and reviewing medical records. Patients were investigated where possible with MRI of brain, spine and pelvic muscles, neurophysiology and anorectal physiology, muscle biopsy, Addenbrookes Cognitive Examination—Revised, skull, lumbar spine and pelvic x rays, creatine kinase and alkaline phosphatase. Mutation analysis of VCP was performed on four affected members and one unaffected reference member from this family. Genomic DNA, extracted from peripheral blood via standard methods, was analysed in duplicate for each subject.

RESULTS

VCP mutation analysis of four affected individuals (II:18, III:13, III:14, III:15; online figure 1) showed a heterozygous c.464G→A nucleotide substitution in exon 5 of the VCP protein (p.R155H), a substitution not detected in an unaffected maternal brother (II:20) confirming mutation segregation within the family. This mutation has been previously identified.1

CLINICAL FEATURES

The pedigree of this five-generation IBMPFD family with 18 affected …

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