Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone

Kimonis, Virginia; Kovach, Margaret J.; Waggoner, Brook; Leal, Suzanne M.; Salam, Ambar A.; Rimer, Lisa; Davis, Kyle; Khardori, Romesh; Gelber, David A.

doi:10.1097/00125817-200007000-00006

Cited by 123 publications

(174 citation statements)

References 33 publications

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“…5 Although there has been no report of TDP-43 pathology in Pagetoid bone from patients with IBMPFD (perhaps no one has yet looked), ultrastructural analysis of bone from patients with IBMPFD demonstrates tubulofilamentous inclusions similar to the inclusions identifiable in muscle tissue. 1,8,13,25 The role of TDP-43, hnRNPA2B1, and hnRNPA1 in disease pathogenesis is strongly supported by the fact that missense mutations in any of the 3 genes is sufficient to cause ALS or MSP. 5,[26][27][28] The significance of defining the phenotypic overlap between IBMPFD and ALS is best understood in the context of the recent discovery that mutations in HNRNPA2B1 and HNRNPA1 are novel genetic causes of MSP.…”

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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“…Mutations in the valocin-containing protein (VCP) gene cause inclusion body myopathy with early-onset Paget disease of the bone and frontotemporal dementia (IBMPFD; OMIM ID 167320), which is an adult-onset disorder caused [Kimonis et al, 2000;Kimonis et al, 2011]. Ninety-two percent of individuals develop myopathy with a mean age of onset being 42 years.…”

Section: Discussionmentioning

confidence: 99%

Report of two patients and further characterization of interstitial 9p13 deletion—A rare but recurrent microdeletion syndrome?

Niemi

Kwan

Hudgins

et al. 2012

American J of Med Genetics Pt A

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To date, an interstitial deletion of 9p13 has been described only two times in the medical literature. These reports were based on routine chromosomal analysis. We report on two additional patients with an interstitial deletion of 9p13 further defined on array CGH who share clinical features with the other two patients previously described. Our first patient is a 16-year-old girl with a 5.9 Mb deletion at 9p13.3-9p13.1, initially detected on routine karyotype analysis and further characterized on array CGH. Our second patient is a 7½-year-old boy with a 4.8 Mb deletion also at 9p13.3-9p13.1. Patients with 9p13 deletion appear to have mild to moderate developmental delay, social and interactive personality, behavior issues such as attention deficit-hyperactivity disorder, short stature, prominent antihelices, hypoplastic nails, and precocious/early puberty. Our 16-year-old patient is the oldest patient described thus far. This report further characterizes this condition and helps to delineate the long-term prognosis in these patients.

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“…Rimmed vacuolar inclusions were noted in ∼35% of muscle biopsy specimens analyzed from the 13 families. Electron microscopy of biopsy samples from individuals with IBMPFD showed atrophic and vacuolated muscle fibers containing abundant nuclear and cytoplasmic, paired helical filaments with congophilia, accumulations of phosphorylated tau, apolipoprotein E and excessive β-amyloid precursor protein epitopes 1,2 .…”

Section: Methodsmentioning

confidence: 99%

“…1). IBMPFD features adult-onset proximal and distal muscle weakness (clinically resembling limb girdle muscular dystrophy), early-onset PDB in most cases and 'premature' FTD 2 .…”

mentioning

confidence: 99%

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein

et al. 2004

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Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) is a dominant progressive disorder that maps to chromosome 9p21.1-p12. We investigated 13 families with IBMPFD linked to chromosome 9 using a candidate-gene approach. We found six missense mutations in the gene encoding valosincontaining protein (VCP, a member of the AAA-ATPase superfamily) exclusively in all 61 affected individuals. Haplotype analysis indicated that descent from two founders in two separate North American kindreds accounted for IBMPFD in ~50% of affected families. VCP is associated with a variety of cellular activities, including cell cycle control, membrane fusion and the ubiquitin-proteasome degradation pathway. Identification of VCP as causing IBMPFD has important implications for other inclusion-body diseases, including myopathies, dementias and Paget disease of bone (PDB), as it may define a new common pathological ubiquitin-based pathway.Hereditary inclusion body myopathy (IBM) associated with PDB and frontotemporal dementia (FTD), or IBMPFD, is a rare, complex and ultimately lethal autosomal dominant disorder (OMIM 605382; ref. 1). IBMPFD features adult-onset proximal and distal muscle weakness (clinically resembling limb girdle muscular dystrophy), early-onset PDB in most cases and 'premature' FTD 2 . Although the disorder was mapped to chromosome 9p21-p12, the genetic basis was not known.Within 13 families (12 from the United States and 1 from Canada, Fig. 1 and Supplementary Fig. 1 online), 82% of individuals had myopathy, 49% had PDB and 30% had early-onset FTD. The mean age of presentation was 42 years for both IBM and PDB, whereas FTD typically presented at age 53 years. In IBMPFD myopathic muscle and PDB osteoclasts, inclusions appear similar, suggestive of disruptions in the same pathological pathway.Haplotype analysis of the families with IBMPFD identified two ancestral, disease-associated haplotypes, distinguishing families 1, 3, 7 and 16 (group A) from families 2 and 5 (group B), both groups of Northern European ancestry ( Table 1

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Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone

Cited by 123 publications

References 33 publications

Motor neuron involvement in multisystem proteinopathy

Motor neuron involvement in multisystem proteinopathy

Report of two patients and further characterization of interstitial 9p13 deletion—A rare but recurrent microdeletion syndrome?

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein

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