Alternative titles; symbols
SNOMEDCT: 703544004; ORPHA: 52430; DO: 0111385;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9p13.3 | Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1 | 167320 | Autosomal dominant | 3 | VCP | 601023 |
A number sign (#) is used with this entry because of evidence that inclusion body myopathy with Paget disease and frontotemporal dementia-1 (IBMPFD1) is caused by heterozygous mutation in the VCP gene (601023) on chromosome 9p13.
Heterozygous mutation in the VCP gene can also cause frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; 613954), which can show overlapping clinical features.
IBMPFD is an autosomal dominant disorder characterized by incomplete penetrance of 3 main features: disabling muscle weakness (in 90%), osteolytic bone lesions consistent with Paget disease (in 51%), and frontotemporal dementia (in 32%). Muscle weakness is an isolated symptom in about 30% of patients and the presenting symptom in greater than half of patients, suggesting that IBMPFD may commonly be seen in a neuromuscular clinic without its other syndromic features (review by Weihl et al., 2009).
Genetic Heterogeneity of IBMPFD
IBMPFD2 (615422) is caused by mutation in the HNRNPA2B1 gene (600124) on chromosome 7p15. IBMPFD3 (615424) is caused by mutation in the HNRNPA1 gene (164017) on chromosome 12q13.
IBMPFD may also be referred to as FTLD-TDP (or TDP43), VCP-related, based on neuropathologic findings (MacKenzie et al., 2010).
Bucelli et al. (2015) suggested use of the designation multisystem proteinopathy (MSP) for a group of genetic disorders clinically characterized by variable penetrance of FTD, ALS, Paget disease, and myopathy, which are unified by the pathologic accumulation of ubiquitin and TDP43; see 617158.
Tucker et al. (1982) studied a large kindred with a syndrome of lower motor neuron degeneration and polyostotic skeletal disorganization resembling Paget disease of bone (PDB; see 167250). The disorder begins insidiously at about age 35 with weakness and atrophy of the leg and proximal arm muscles. Nerve conductions are normal; EMG shows muscle denervation, as does muscle biopsy. The disorder progresses to wheelchair confinement and later to bed confinement, quadriparesis, dementia, respiratory failure, and death before age 60 years. Even early in the neurologic illness, patients have coarse trabeculation, cortical thickening, and spotty sclerosis on bone x-rays; diffusely increased uptake of radionuclide and elevated heat-labile serum alkaline phosphatase. The disorder affected 6 females and 6 males in 5 sibships of 3 generations with no instance of male-to-male transmission.
Kimonis et al. (2000) described a family in which autosomal dominant limb-girdle muscular dystrophy (LGMD) was associated with early-onset Paget disease of bone PDB and cardiomyopathy. Eight of 11 affected individuals had both disorders. Onset of PDB occurred at a mean age of 35 years, with classic distribution involving the spine, pelvis, and skull. Muscle weakness and atrophy was progressive with mildly elevated to normal CPK levels. Muscle biopsy in the oldest male revealed vacuolated fibers, but in others revealed nonspecific myopathy. Affected individuals die from progressive muscle weakness and respiratory and cardiac failure in their forties to sixties.
Kovach et al. (2001) described the clinical, biochemical, radiologic, and pathologic characteristics of 49 affected individuals from the family described by Kimonis et al. (2000) and 3 other unrelated families with autosomal dominant inclusion body myopathy (IBM), PDB, and frontotemporal dementia. Ninety percent of the patients had myopathy, 43% had PDB, and 37% had premature frontotemporal dementia.
Watts et al. (2004) reported 13 families with IBMPFD, 12 from the U.S. and 1 from Canada. Among those individuals, 82% of affected individuals had myopathy, 49% had PDB, and 30% had early-onset frontotemporal dementia. The mean age at presentation was 42 years for both IBM and PDB, whereas frontotemporal dementia typically presented at age 53 years. In IBMPFD myopathic muscle and PDB osteoclasts, inclusions appear similar, suggestive of disruptions in the same pathologic pathway. Family 11 in the report by Watts et al. (2004) was originally reported by Tucker et al. (1982) (Kimonis, 2005).
Haubenberger et al. (2005) reported an Austrian family in which 4 sibs had autosomal dominant inclusion body myopathy and Paget disease associated with a heterozygous mutation in the VCP gene (R159H; 601023.0007). None of the affected individuals developed frontotemporal dementia even though all were over 60 years of age. Haubenberger et al. (2005) noted that only approximately 30% of patients with VCP mutations develop dementia, illustrating phenotypic variability. In a follow-up of this family, van der Zee et al. (2009) noted that 1 patient had developed dementia at age 64. Van der Zee et al. (2009) also identified the R159H mutation in affected members of 2 unrelated Belgian families. In 1 family, patients presented with frontotemporal lobar degeneration only, whereas in the other family, patients developed frontotemporal lobar degeneration, Paget disease of the bone, or both without signs of inclusion body myopathy for any of the mutation carriers. Haplotype analysis showed that the 2 families and the Austrian family reported by Haubenberger et al. (2005) were unrelated. Autopsy data of 3 patients from the 2 Belgian families showed frontotemporal lobar degeneration with numerous ubiquitin-immunoreactive, intranuclear inclusions and dystrophic neurites staining positive for TDP43 (TARDBP; 605078) protein. Van der Zee et al. (2009) commented on the high degree of clinical heterogeneity and incomplete penetrance of the disorder in different families carrying the same mutation.
Kimonis et al. (2008) reported detailed clinical features of 49 patients from 9 families with IBMPFD confirmed by genetic analysis. One family had been previously reported by Tucker et al. (1982). Forty-two (86%) patients had muscle disease, the majority of whom were initially misdiagnosed as having some other form of muscular dystrophy or spinal muscular atrophy. Weakness was distal and/or proximal, and many patients were confined to wheelchairs. Muscle biopsies showed inclusion bodies and/or rimmed vacuoles (39%) or nonspecific changes. Frontotemporal dementia was diagnosed in 13 (27%) of 49 individuals at a mean age of 57 years, of whom 3 had been originally diagnosed with Alzheimer disease (104300). Paget disease of bone was found in 28 (57%) of 49 patients at a mean age of 40 years and correlated with increased serum alkaline phosphatase. Kimonis et al. (2008) postulated that IBMPFD is underdiagnosed among patients with myopathy and/or dementia.
Viassolo et al. (2008) reported an Italian family in which 2 sibs and their mother had IBMPFD. All 3 had progressive inclusion body myopathy and rapidly progressive severe dementia, but only 1 developed Paget disease. Genetic analysis identified a heterozygous mutation in the VCP gene (R155H; 601023.0001). Several other family members were reportedly affected. Viassolo et al. (2008) discussed the implications of the incomplete penetrance of some of the features for genetic counseling.
Kim et al. (2011) reported 3 Korean sibs with IBMPFD confirmed by genetic analysis (601023.0002). The proband developed progressive dementia presenting as fluent aphasia and language difficulties with onset at age 47. She never developed myopathy, but did develop asymptomatic Paget disease with increased serum alkaline phosphatase and lytic bone lesions on imaging. Her brother developed slowly progressive proximal muscle weakness at age 50, followed by frontotemporal dementia characterized initially by comprehension defects at age 54. He never had Paget disease, although serum alkaline phosphatase was increased. A second brother developed muscle weakness at age 47, followed by Paget disease at age 53, and dementia at age 61. Brain MRI in all patients showed asymmetric atrophy in the anterior inferior and lateral temporal lobes and inferior parietal lobule with ventricular dilatation on the affected side (2 on the left, 1 on the right). Two had glucose hypometabolism in the lateral temporal and inferior parietal areas, with less involvement of the anterior temporal and frontal lobes compared to those with typical semantic dementia.
Sacconi et al. (2012) reported 2 unrelated men in their fifties who presented with a phenotype reminiscent of FSHD1 (158900) but were found to carry a heterozygous VCP mutation (R191Q; 601023.0006). One had scapuloperoneal weakness without facial involvement and increased serum creatine kinase. The second patient had facial weakness, shoulder and pelvic girdle weakness, and anterior foreleg weakness. Creatine kinase was increased 4-fold. Muscle biopsies of both patients showed mild dystrophic changes, but no inclusion bodies. Both had a myopathic pattern on EMG. One was later found to have a mild dysexecutive syndrome, but neither had evidence of Paget disease.
Clinical Variability
Abrahao et al. (2016) reported a Brazilian family in which 2 brothers and their father had different clinical manifestations of VCP-related neurologic disease. The proband presented in his forties with proximal muscle weakness associated with dystrophic features, myofibrillar disorganization, and rimmed vacuoles on muscle biopsy, consistent with a diagnosis of IBMPFD1, but without Paget disease or dementia. His affected brother presented in his late thirties with lower motor neuron-predominant ALS without signs of Paget disease or frontotemporal dementia, and their father presented at age 66 with behavioral variant frontotemporal dementia without signs of myopathy, Paget disease, or ALS (see 613954). The findings emphasized the extreme phenotypic variability associated with VCP mutations, even within the same family.
Neuropathologic Findings
Schroder et al. (2005) reported a patient with frontotemporal dementia (FTD) and inclusion body myopathy caused by mutation in the VCP gene (601023.0002). There was no evidence of Paget disease. Neuropathologic examination showed cortical atrophy and widespread neuronal loss; subcortical neuronal loss was less severe. The cerebral and cerebellar white matter had severe astrogliosis. Surviving cortical pyramidal neurons contained VCP- and ubiquitin (see 191321)-positive intranuclear inclusions and displayed cytoplasmic autofluorescence consistent with lipofuscin. Nuclear inclusions were not seen in astrocytes, oligodendrocytes, or microglial cells. Western blot analysis showed a single 97-kD band corresponding to normal-sized VCP that was similar to control brains. Schroder et al. (2005) concluded that mutant VCP causes a novel form of frontotemporal dementia, distinct from tau (MAPT; 157140)-associated FTD (see 600274), characterized by neuronal nuclear inclusions containing ubiquitin and VCP. The authors suggested that mutant VCP interferes with ubiquitin-dependent pathways, leading to abnormal intracellular and intranuclear protein aggregation.
The transmission pattern of IBMPFD1 in the families reported by Kimonis et al. (2008) was consistent with autosomal dominant inheritance with variable expressivity and incomplete penetrance of some features.
In a family with autosomal dominant LGMD associated with early-onset PDB and cardiomyopathy, Kimonis et al. (2000) excluded autosomal dominant and recessive LGMD, PDB, and cardiomyopathy loci. They argued that their linkage analysis data indicated a unique locus in this family.
By linkage analysis, Kovach et al. (2001) localized autosomal dominant IBM with PDB and frontotemporal dementia to a 1.08- to 6.46-cM critical interval on 9p13.3-p12. The maximum lod score generated from the combined genotype data was 9.29 for marker D91791.
Watts et al. (2004) performed haplotype analysis of 13 families with IBMPFD and identified 2 ancestral disease-associated haplotypes, distinguishing families 1, 3, 7, and 16 (group A) from families 2 and 5 (group B). Both groups were of northern European ancestry. The predominant IBMPFD haplotype of group A includes a core haplotype flanked by D9S1118 and D9S234, probably transmitted from a shared ancestor. Watts et al. (2004) identified 6 missense mutations in the valosin-containing protein (VCP; 601023) in these families. Families 1, 3, 4, 7, 10, 15, and 16 shared the R155H mutation in exon 5 (601023.0001); families 2 and 5 had an R155C mutation (601023.0002); and family 11 had an R155P mutation (601023.0005). Thus, 10 of the 13 families with IBMPFD had an amino acid change at codon 155 in VCP, which therefore seems to be a mutation hotspot. In addition, 1 family had a missense mutation at codon 232 (601023.0003), another at codon 95 (601023.0004), and another at codon 191 (601023.0006).
In 2 Brazilian brothers and their father with different clinical manifestations of VCP-related neurologic disease, Abrahao et al. (2016) identified a heterozygous missense mutation in exon 3 of the VCP gene (N91Y; 601023.0012). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with a neurologic phenotype in the family. The variant was not present in the Exome Variant Server or ExAC databases, or in 1000 control Brazilian exomes. Functional studies of the variant were not performed, but it was predicted to be pathogenic. The proband had features of IBMPFD1 without Paget disease or FTD, his brother had features of ALS without Paget disease or FTD, and their father had isolated behavioral variant FTD without features of myopathy, Paget disease, or ALS. The findings emphasized the extreme phenotypic variability associated with VCP mutations, even within the same family.
De Ridder et al. (2020) reported a 36-year-old Belgian man with onset of IBMPFD1 at age 29 years who carried a homozygous R159H mutation in the VCP gene (601023.0007). His 63-year-old father, who carried the mutation in heterozygous state, had a similar myopathic phenotype with later onset at age 58. His 60-year-old mother, who was also heterozygous for the mutation, was clinically unaffected. The proband presented with progressive proximal muscle weakness with possible neurogenic features and high serum creatine kinase; an asymptomatic Paget bone lesion was later identified. Neither patient had dementia. Functional studies of the variant were not performed, but proteomic analysis of skeletal muscle from the proband and his father, as well as from 3 additional patients with VCP-related myopathy, showed changes in upstream regulators involved in myogenesis, muscle regeneration, oxidative stress, endoplasmic reticulum stress, stress granules, and the unfolded protein response. The findings indicated that homozygosity for this VCP mutation is viable and that the key features of the disorder are still present, although the overall phenotype may be more severe with earlier onset.
Mehta et al. (2013) analyzed clinical and biochemical markers from a database of 190 individuals from 27 families harboring 10 missense mutations in the VCP gene. Among these, 145 mutation carriers were symptomatic and 45 were presymptomatic. The most common clinical feature (in 91% of patients) was onset of myopathic weakness at a mean age of 43 years. Paget disease of the bone was found in 52% of patients at a mean age of 41 years. Frontotemporal dementia occurred in 30% of patients at a mean age of 55 years. Significant genotype-phenotype correlations were difficult to establish because of small numbers. However, patients with the R155C mutation had a more severe phenotype with an earlier onset of myopathy and Paget disease, as well as decreased survival, compared to those with the R155H mutation. A diagnosis of ALS was found in at least 13 (8.9%) individuals from the 27 families, including 10 patients with the R155H mutation, and 5 (3%) patients were diagnosed with Parkinson disease.
Al-Obeidi et al. (2018) studied 231 individuals from 36 families carrying 15 different heterozygous VCP mutations. Of these individuals, 187 were clinically symptomatic and 44 were presymptomatic carriers. The cohort of patients were of various ethnicities, including European, Brazilian, Hispanic/Apache, and an African-American. Most (90%) of symptomatic patients presented with myopathy at a mean age of 43 years (range, 20-70 years). Paget disease of bone was identified in 42% of patients with a mean age at onset of 41 years (range, 23-65 years), and dementia was diagnosed in 29.4% of patients at a mean age of 55.9 years (range, 30-80 years). When possible to ascertain, the dementia included sociobehavioral and language changes, as well as loss of executive function. Sixteen (8.6%) of patients were diagnosed with ALS associated with upper and lower motor neuron degeneration. Some patients were diagnosed with Parkinson disease (3.8%) or Alzheimer disease (2.1%). Although VCP mutations are associated with a triad of symptoms, only 10% of patients had the 3 features of myopathy, bone disease, and dementia. After stratification by mutation type, there were no apparent genotype/phenotype correlations, although the R159C mutation was associated with a slightly later age at onset of myopathy (57 years) compared to other mutations. Functional studies of the variants were not performed. The authors emphasized the enormous phenotypic heterogeneity both between and within families.
Weihl et al. (2007) found that transgenic mice overexpressing the R155H mutation became progressively weaker in a dose-dependent manner starting at 6 months of age. There was abnormal muscle pathology, with coarse internal architecture, vacuolation and disorganized membrane morphology with reduced caveolin-3 (CAV3; 601253) expression at the sarcolemma. Even before animals displayed measurable weakness, there was an increase in ubiquitin-containing protein inclusions and high molecular weight ubiquitinated proteins. These findings suggested a dysregulation in protein degradation.
Custer et al. (2010) developed and characterized transgenic mice with ubiquitous expression of wildtype and disease-causing versions of human VCP/p97. Mice expressing VCP/p97 harboring the mutations R155H (601023.0001) or A232E (601023.0003) exhibited progressive muscle weakness, and developed inclusion body myopathy including rimmed vacuoles and TDP43 pathology. The brain showed widespread TDP43 (605078) pathology, and the skeleton exhibited severe osteopenia accompanied by focal lytic and sclerotic lesions in vertebrae and femur. In vitro studies indicated that mutant VCP caused inappropriate activation of the NF-kappa-B (see 164011) signaling cascade, which could contribute to the mechanism of pathogenesis in multiple tissues including muscle, bone, and brain.
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