Clinical Delineation and Localization to Chromosome 9p13.3–p12 of a Unique Dominant Disorder in Four Families: Hereditary Inclusion Body Myopathy, Paget Disease of Bone, and Frontotemporal Dementia

Kovach, Margaret J.; Waggoner, Brook; Leal, Suzanne M.; Gelber, David A.; Khardori, Romesh; Levenstien, Mark A; Shanks, Christy A.; Gregg, Gregory; Al‐Lozi, Muhammad; Miller, Timothy M.; Rakowicz, Wojtek; Lopate, Glenn; Florence, J.; Glosser, Guila; Simmons, Zachary; Morris, John C.; Whyte, Michael P.; Pestronk, Alan; Kimonis, Virginia

doi:10.1006/mgme.2001.3256

Cited by 184 publications

(175 citation statements)

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“…We extracted peripheral blood DNA using the PureGene DNA isolation kit (Gentra Systems). IBMPFD linkage to chromosome 9p21.1-p12 was known in four families 2 and confirmed in the nine new kindreds. We constructed the disease-associated haplotype for each family to identify the critical locus 2 .…”

Section: Methodsmentioning

confidence: 67%

“…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%

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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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Section: Methodsmentioning

confidence: 67%

Section: Methodsmentioning

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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“…However, FTD affected only 30% of patients in our previous clinical study, with an average age of onset of 55 years. 1,2 The majority of these patients also had pre-existing IBM and/or PDB. Since not all affected individuals survive to age 55 because of severe myopathy, early death in some subjects with IBM may have led to an underestimate of the FTD phenotype.…”

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confidence: 99%

APOE is a potential modifier gene in an autosomal dominant form of frontotemporal dementia (IBMPFD)

Mehta

Watts

Adamson

et al. 2007

Genetics in Medicine

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Purpose: Inclusion-body myopathy, Paget's disease of bone and frontotemporal dementia is an adult-onset autosomal dominant illness (IBMPFD) caused by mutations in the valosin-containing protein (VCP) on chromosome 9p21.1-p12. The penetrance of the gene is 82% for myopathy, 49% for Paget's disease, but may be as low as 30% for frontotemporal dementia. Modifier genes could account for decreased frontotemporal dementia penetrance. In this study apolipoprotein-E (APOE) was evaluated for this role in IBMPFD families based on its known modifier effect in Alzheimer's disease. Methods: From a database of 231 members of 15 families, 174 had APOE genotype available for analysis. Logistic regressions on APOE genotype and frontotemporal dementia were performed, using appropriate covariates. Results and Conclusion: FTD was associated with APOE 4 genotype (P ϭ 0.0002), myopathy (P ϭ 0.0006), and age (P ϭ 0.01), but not microtubule associated protein tau (MAPT) H2 haplotype (P ϭ 0.5) or gender (0.09) after adjustment for membership in pedigrees with at least one APOE 4 genotype. These data suggest a potential link between APOE 4 genotype and the specific form of frontotemporal dementia found in IBMPFD. The molecular basis of this link bears further investigation. We did not observe an association of frontotemporal dementia and H2 MAPT haplotype. Genet Med 2007:9(1):9-13.

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“…The existence of many cases of familial FTD that have neither tau mutations nor tau pathology is strong evidence that additional genes for familial FTD are likely to be discovered (40 ). Genetic heterogeneity in familial FTD is also supported by the fact that genetic linkage to chromosomes 3 and 9 has been found for clinical FTD variants (41)(42)(43).…”

Section: Genetics Of Frontotemporal Dementiamentioning

confidence: 99%

Familial Frontotemporal Dementia: From Gene Discovery to Clinical Molecular Diagnostics

et al. 2003

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Genetic testing is important for diagnosis and prediction of many diseases. The development of a clinical genetic test can be rapid for common disorders, but for rare genetic disorders this process can take years, if it occurs at all. We review the path from gene discovery to development of a clinical genetic test, using frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) as an example of a complex, rare genetic condition. An Institutional Review Boardapproved multidisciplinary research program was developed to identify patients with familial frontotemporal dementia. Genetic counseling is provided and DNA obtained to identify mutations associated with FTDP-17. In some cases it may be appropriate for individuals to be given the opportunity to learn information from the research study to prevent unnecessary diagnostic studies or the utilization of inappropriate therapies, and to make predictive testing possible. Mutations identified in a research laboratory must be confirmed in a clinical laboratory to be used clinically. To facilitate the development of clinical genetic testing for a rare disorder, it is useful for a research laboratory to partner with a clinical laboratory. Most clinical molecular assays are developed in research laboratories and must be properly validated. We conclude that the transition of genetic testing for rare diseases from the research laboratory to the clinical laboratory requires a validation process that maintains the quality-control elements necessary for genetic testing but is flexible enough to permit testing to be developed for the benefit of patients and families.

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Clinical Delineation and Localization to Chromosome 9p13.3–p12 of a Unique Dominant Disorder in Four Families: Hereditary Inclusion Body Myopathy, Paget Disease of Bone, and Frontotemporal Dementia

Cited by 184 publications

References 53 publications

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

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

APOE is a potential modifier gene in an autosomal dominant form of frontotemporal dementia (IBMPFD)

Familial Frontotemporal Dementia: From Gene Discovery to Clinical Molecular Diagnostics

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