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

Miller, Thomas D.; Jackson, Andrew P.; Barresi, Rita; Smart, CM; Eugenicos, Maria; Summers, David; Clegg, Shona; Straub, Volker; Stone, Jon

doi:10.1136/jnnp.2008.148676

Cited by 36 publications

(32 citation statements)

References 5 publications

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“…As such, the term IBMPFD seems overly restrictive. IBMPFD-ALS is similarly cumbersome and probably inadequate given the rare, but well-described, involvement of other organ systems including cardiac, 13 hepatic, 14 visual, 14 auditory, 15 sensory, 16 and autonomic systems, 17 as well as emerging evidence that mutations in VCP may infrequently manifest as Parkinson disease, [18][19][20] hereditary spastic paraplegia, 21 or cerebellar ataxia. 22 Instead, we propose to change the name of this syndrome from IBMPFD to multisystem proteinopathy (MSP), using the nomenclature of MSP1 for disease caused by mutations in VCP, MSP2 when due to mutations in HNRNPA2B1, 5 MSP3 when caused by HNRNPA1 mutations, 5 and MSP4 when due to mutations in the as yet unidentified gene.…”

Section: Resultsmentioning

confidence: 99%

Motor neuron involvement in multisystem proteinopathy

et al. 2013

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Objective: To explore the putative connection between inclusion body myopathy, Paget disease, frontotemporal dementia (IBMPFD) and motor neuron disease (MND).Methods: Clinical, genetic, and EMG characterization of 17 patients from 8 IBMPFD families.Results: Limb weakness was the most common clinical manifestation (present in 15 patients, median onset age 38 years, range 25-52), with unequivocal evidence of upper motor neuron dysfunction in 3. EMG, abnormal in all 17, was purely neurogenic in 4, purely myopathic in 6, and mixed neurogenic/myopathic in 7. Cognitive/behavioral impairment was detected in at least 8. Mutations in VCP (R155H, R159G, R155C) were identified in 6 families, and in hnRNPA2B1 (D290V) in another family. The genetic cause in the eighth family has not yet been identified. Conclusion:Mutations in at least 4 genes may cause IBMPFD, and its phenotypic spectrum extends beyond IBM, Paget disease, and frontotemporal dementia (FTD). Weakness, the most common and disabling manifestation, may be caused by muscle disease or MND. The acronym IBMPFD is, therefore, insufficient to describe disorders due to VCP mutations or other recently identified IBMPFD-associated genes. Instead, we favor the descriptor multisystem proteinopathy (MSP), which encompasses both the extended clinical phenotype and the previously described prominent pathologic feature of protein aggregation in affected tissues. The nomenclature MSP1, MSP2, and MSP3 may be used for VCP-, HNRNPA2B1-, and HNRNPA1-associated disease, respectively. Genetic defects in MSP implicate a range of biological mechanisms including RNA processing and protein homeostasis, both with potential relevance to the pathobiology of more common MNDs such as amyotrophic lateral sclerosis (ALS) and providing an additional link between ALS and FTD. Neurology Inclusion body myopathy (IBM) with Paget disease and frontotemporal dementia (IBMPFD) is a rare multisystem degenerative disorder named after the organ systems originally recognized to be affected-muscle, bone, and brain. Mutations in the valosin-containing protein (VCP) gene were the first identified cause of IBMPFD, 1,2 but reports of families without linkage to chromosome 9 established the genetic heterogeneity of the disorder.3,4 It has recently emerged that mutations in the HNRNPA2B1 (chromosome 7) and HNRNPA1 (chromosome 12) genes account for some families with IBMPFD. 5 We first raised the possibility of a connection between IBMPFD and amyotrophic lateral sclerosis (ALS) after mutations in the VCP gene were identified in patients with familial ALS.6 Interestingly, the original report of IBMPFD 7 almost 30 years ago described it as a "familial disorder of combined lower motor neuron degeneration and skeletal disorganization"; the presence of fasciculations, EMG evidence of chronic reinnervation, and muscle biopsy showing grouped atrophy all pointing toward a primarily neurogenic process. This family was subsequently found to have an R155Q mutation in the VCP gene. 8 Since the original description, var...

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Section: Resultsmentioning

confidence: 99%

Motor neuron involvement in multisystem proteinopathy

et al. 2013

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“…Except in myotonic dystrophy type 1 (DM1) [9][10][11][12] , incontinence is rarely reported in myopathies [13][14][15] . Nevertheless, it is a disabling condition in social as well as in professional life [16] .…”

Section: Methodsmentioning

confidence: 99%

Incontinence in Late-Onset Pompe Disease: An Underdiagnosed Treatable Condition

et al. 2012

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“…However, a third patient from a Canadian family carrying a A232E mutation-whose clinical picture was mistaken for limb girdle muscle dystrophy and PBD-had an electrophysiological workup suggestive of axonal sensory neuropathy in the legs 4. Finally, Miller et al10 reported two patients with pudendal neuropathy in a large British pedigree with a p.R155H mutation.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the phenotypic expression of a mutation can vary so widely that carriers of the same mutation in a single affected family can have completely different symptoms: for example, one member might have PDB and FTD while his or her siblings might have only IBM 4. To complete the confusion, even two family members with IBM can exhibit a marked variability in the patterns of muscle weakness,7 or atypical features such as pyramidal tract dysfunction [mimicking spastic paraplegia or amyotrophic lateral sclerosis (ALS)], sensory motor axonal neuropathy, Parkinsonism, sensorineural hearing loss, cataract, cardiomyopathy, liver steatosis, sphincter disturbances, or erectile dysfunction 3,8,9,10…”

Section: Introductionmentioning

confidence: 99%

Involvement of Peripheral and Central Nervous Systems in a Valosin-Containing Protein Mutation

et al. 2014

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BackgroundInclusion-body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD) is a rare, late-onset autosomal disorder arising from missense mutations in a gene coding for valosin-containing protein.Case ReportWe report the case of a man carrying the previously described p.Arg159His mutation, who had an unusual axonal sensorimotor neuropathy as the first clinical manifestation of IBMPFD, and for whom diagnosis only became clear 8 years later when the patient developed frontotemporal dementia.ConclusionsPeripheral neuropathy is a rare manifestation of IBMPFD. This underdiagnosed disorder should be considered when a patient develops dementia or has signs of Paget's disease.

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

Cited by 36 publications

References 5 publications

Motor neuron involvement in multisystem proteinopathy

Motor neuron involvement in multisystem proteinopathy

Incontinence in Late-Onset Pompe Disease: An Underdiagnosed Treatable Condition

Involvement of Peripheral and Central Nervous Systems in a Valosin-Containing Protein Mutation

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