Inclusion Body Myopathy with Paget Disease of Bone and / or Frontotemporal Dementia

Disease characteristics. Inclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB, and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. Cardiac failure and cardiomyopathy have been observed in later stages. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, paraphasic errors, and relative preservation of memory, and later stages by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease and PDB is 42 years; for FTD, 55 years.


Bone findings:
Skeletal radiographs reveal diagnostic changes of coarse trabeculation; cortical thickening; and spotty sclerosis in the skull, pelvis, spine, and scapula that later becomes widespread.Radiographic findings of PDB are typically present ten to 15 years before the diagnosis of PDB can be made based on clinical findings.

OR
Radionuclide scan shows focally increased bony uptake (a more sensitive indicator of PDB than skeletal radiographs).
Frontotemporal dementia (FTD), diagnosed by comprehensive neuropsychological assessment that reveals behavioral alteration (e.g., personal/social unawareness, perseveration, disinhibition), early expressive or receptive language dysfunction, and relative preservation of memory, orientation, and praxis [Miller et al 1997]: Imaging studies reveal atrophy of anterior temporal and frontal lobes.

Molecular Genetic Testing
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Gene.VCP, encoding valosin-containing protein (VCP), a member of the AAA-ATPase superfamily, is the only gene known to be associated with inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD).

Note:
In all families with IBMPFD that link to 9p, VCP mutations have been identified.In families with isolated PDB that link to 9p, VCP mutations have not been identified [Lucas et al 2006].
Other loci.Several families who meet diagnostic criteria for IBMPFD have not had VCP mutations or shown linkage to 9p21.2 [Authors, unpublished data], suggesting genetic heterogeneity for this disorder.

Clinical testing
Custom mutation analysis.Mutations identified in a research laboratory can be confirmed in clinical laboratories that provide custom mutation analysis.

Research testing
Targeted mutation analysis.Using a panel of the ten known mutations * , mutations would be identified in 27/37 (70%) of probands [Author, personal observation].7/1/2007 1:00 PM p.Leu198Trp, p.Asn387His Sequence analysis.A VCP mutation has been identified in all families with IBMPFD that link to 9p (see Table 2 for the specific mutations identified) [Author, personal observation].

Genetically Related (Allelic) Disorders
No other phenotypes are known to be associated with mutations in VCP.

Natural History
Inclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB in most cases, and premature frontotemporal dementia (FTD).
The association of inclusion body myopathy and frontotemporal dementia was established by Kovach et al (2001) among 49 affected individuals from the original family described by Kimonis et al (2000) and three other unrelated families.Frontotemporal dementia.FTD is a degenerative condition of the frontal and anterior temporal lobes that differs from the dementia seen in disorders such as Alzheimer disease (see Alzheimer Disease Overview), Pick disease, and Creutzfeldt-Jakob disease (see Prion Diseases).The areas of the brain affected by FTD control reasoning, personality, movement, speech, social graces, and language; memory is preserved.
Among those studied, features were consistent with frontotemporal dementia.In the early stages, dysnomia, dyscalculia, comprehension deficits, and paraphasic errors were evident.Adjusting for aphasia, episodic memory is minimally impaired in the early stages.Progressive aphasia with inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia are noted.
In families studied thus far, approximately 30% of affected individuals had frontotemporal dementia.Mean age at diagnosis of dementia was 55 years (range: 42-61 years).Several individuals were in advanced stages of dementia when diagnosed with IBMPFD.
Other phenotypes associated with mutations in VCP include isolated: Proximal limb-girdle myopathy Paget disease of bone Dementia [Kimonis et al 2000 ;Kovach et al 2001 ;Haubenberger et al 2005 ;Schroder et al 2005 ;Guyant-Marechal et al 2006 ;Hübbers et al 2007 ;Kimonis et al, in press] Neuropathology.A systematic analysis of the neuropathologic changes in eight persons with IBMPFD and VCP mutations revealed a novel pattern of ubiquitin pathology, characterized by ubiquitin-positive neuronal intranuclear inclusions, dystrophic neuritis, and rare intracytoplasmic inclusions.The ubiquitin pathology was abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus.Only rare inclusions were detected with antibodies to VCP and TDP-43 [Forman et al 2006, Neumann et al 2007].These findings support the hypothesis that neuropathologic changes associated with VCP gene mutations result from impairment of ubiquitin-based degradation pathways.

Genotype-Phenotype Correlations
Clinical, radiologic, biochemical, and mutation data were analyzed in 103 individuals from 14 families: Individuals with the p.Arg155Cys mutation had an earlier age of onset of IBM (p=0.01) and those with the p.Arg155His mutation had a later onset of PDB (p<0.05) compared to the others [Watts et al, in preparation].
A mutation in the main catalytic D1 ATPase domain of VCP (p.Ala232Glu) essential for hexamer formation was found in a single family with a more aggressive type of disease.
Because of the range of phenotypes associated with mutations in VCP, several studies have looked at modifier genes: From a database of 231 members of 15 families, 174 had APOE genotype available for regression analysis.Analysis of the data suggests a potential link between APOE e4 genotype and the frontotemporal dementia found in IBMPFD [Mehta et al 2007].

Penetrance
Penetrance is almost complete; however, it is age related.
Penetrance by phenotype (Figure 1) Presence of all three major manifestations: 12% of affected individuals Presence of only two major manifestations in any combination: 50% of affected individuals Each of the three major manifestations as an apparently isolated finding: Myopathy (IBM): 30% Paget disease of bone (PDB): 5% Frontotemporal dementia (FTD): 3%

Prevalence
IBMPFD is rare; the true prevalence is unknown.Twenty-six families have been studied by the authors, who believe the disorder to be underdiagnosed.

Differential Diagnosis
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory.-ED.
The differential diagnosis of inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) includes the following disorders: Limb-girdle muscular dystrophy (LGMD).Because the muscle biopsy is nonspecific in the majority of individuals with IBMPFD, the disorder has been labeled as an LGMD.Scapuloperoneal myopathy (SPM) (also known as scapuloperoneal muscular dystrophy (SPMD) or scapuloperoneal syndrome, myopathic type).Scapuloperoneal syndromes are heterogeneous.They are characterized by weakness in the distribution of the shoulder girdle and peroneal muscles.Scapuloperoneal myopathy can resemble FSHD clinically.The locus for SPMD has been assigned to 12q [Wilhelmsen et al 1996].

Amyotrophic lateral sclerosis (ALS).
Because of asymmetric involvement and association of both distal and proximal muscle groups, individuals with IBMPFD have been misdiagnosed as ALS.

Paget disease of bone (PDB).
Genetic heterogeneity is found [Cody et al 1997, Hocking et al 2002, Laurin et al 2002].Germline mutations of the gene encoding sequestosome 1 have been implicated in Paget disease of bone.A mutation hot spot (p.Pro392Leu) was identified in the ubiquitin-associated domain (UBA) that accounts for 16% of simplex cases (i.e., a single occurrence in a family) and 46% of familial cases in the French Canadian population.
Frontotemporal dementia (FTD) causes a substantial proportion of primary degenerative dementia occurring before age 65 years [Chow et al 1999].7/1/2007 1:00 PM Frontotemporal dementia with parkinsonism-17 (FTDP-17) is a presenile dementia affecting the frontal and temporal cortex and some subcortical nuclei.Clinical presentation is variable.Individuals may present with slowly progressive behavioral changes, language disturbances, and/or extrapyramidal signs.Some present with rigidity, bradykinesia, supranuclear palsy, and saccadic eye movement disorders.Symptoms usually start between ages 40 and 60 years, but may occur earlier or later.Disease duration is usually between five and ten years, but occasionally may be up to 20 to 30 years.The disease progresses over a few years into a profound dementia with mutism.MAPT encoding microtubule-associated protein tau is the only gene known to be associated with FTDP-17.Inheritance is autosomal dominant [Hutton et al 1998].
Alzheimer disease .Imaging studies in IBMPFD reveal atrophy of anterior temporal and frontal lobes.By contrast, more widespread atrophy or perfusion deficits, for example involving parietal lobes, are more compatible with Alzheimer disease.
Other disorders.An autosomal dominant disorder associated with progressive myopathy of a limb-girdle distribution, bone fragility, poor healing of long bones, premature graying with thin hair, thin skin, hernias, and clotting disorders that may resemble IBMPFD has been described in a single family [Mehta et al 2006].Skeletal radiographs demonstrate coarse trabeculation, patchy sclerosis, cortical thickening, and narrowing of medullary cavities.A genome-wide scan mapped the disorder to chromosome 9p21-p22, the region in which diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) also maps, suggesting possible allelic heterogeneity [Watts et al 2005].
Waggoner et al ( 2002) reported a ten-member family with autosomal dominant PDB and a scapuloperoneal type of muscular dystrophy.Molecular analyses excluded all known loci for Paget disease of bone, scapuloperoneal muscular dystrophy (SPMD), facioscapulohumeral muscular dystrophy (FSHD), amyotrophic lateral sclerosis (ALS), Bethlem myopathy , two forms of autosomal dominant limb-girdle muscular dystrophy (LGMD), and the critical region for LGMD or HIBM/PDB on chromosome 9p21.1-q12.A genome-wide search identified linkage to chromosome 16q 22.3-q24.1 [Watts et al, in preparation], a locus known to contain a quantitative trait locus (QTL) [Ralston et al 2005].
Nasu Hakola disease (also known as PLOSL) is a presenile dementia associated with loss of myelin, basal ganglia calcification, and bone cysts.It is caused by recessively inherited mutations in the two genes TREM2 and DAP12, which encode subunits of a cell membrane-associated receptor complex [Paloneva et al 2002].

Management Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD), the following evaluations are recommended: Assessment of muscle strength, muscle wasting and tendon reflexes.EMG and/or muscle biopsy may be necessary.
Baseline pulmonary function studies Cardiac evaluation by echocardiogram and ECG Blood alkaline phosphatase, urine pyridinoline studies and, if indicated, skeletal x-ray or bone scan studies to evaluate distribution and severity of Paget disease of the bone Baseline neuropsychological studies of behavior and mental status

Treatment of Manifestations
Myopathy.Management should be tailored to each individual.A general approach to appropriate management can prolong survival and improve quality of life.This general approach is based on 7/1/2007 1:00 PM the typical progression and complications of individuals with LGMD as described by McDonald et al (1995) and Bushby (1999).
Weight control to avoid obesity Physical therapy and stretching exercises to promote mobility and prevent contractures Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility Surgical intervention as needed for orthopedic complications such as foot deformity and scoliosis Use of respiratory aids when indicated Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in these disorders [Eggers & Zatz 1998] Assisted living arrangements as necessitated by muscle weakness and/or dementia Paget disease of bone.Treatment with the following potent bisphosphonates can reduce the alkaline phosphatase concentration and relieve pain and disability:

Testing of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation
Search ClinicalTrials.govfor access to information on clinical studies for a wide range of diseases and conditions.Note: There may not be clinical trials for this disorder.

Other
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources.See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals.The Resources section may include disease-specific and/or umbrella support organizations.

Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the 7/1/2007 1:00 PM nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members.This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional.To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.-ED.

Mode of Inheritance
Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) is inherited in an autosomal dominant manner.

Parents of a proband
Approximately 80% of individuals diagnosed with IBMPFD have an affected parent.
A proband with IBMPFD may have the disorder as the result of a new gene mutation.The proportion of cases caused by de novo mutations is an estimated 20% or greater.
Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical evaluation by a neurologist familiar with myopathic disorders in addition to laboratory evaluation of CPK and alkaline phosphatase concentrations.
Note: Although approximately 80% of individuals diagnosed with IBMPFD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband
The risk to the sibs of the proband depends upon the genetic status of the proband's parents.If a parent of the proband is affected, the risk to the sibs is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
Offspring of a proband.Each child of an individual with IBMPFD has a 50% chance of inheriting the mutation.
Other family members of a proband.The risk to other family members depends upon the status of the proband's parents.If a parent is found to be affected, his or her family members are at risk.

Related Genetic Counseling Issues
Considerations in families with an apparent de novo mutation.When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation.However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.

Family planning.
The optimal time for determination of genetic risk is before pregnancy.It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use.Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only.See DNA Banking for a list of laboratories offering this service.
Prenatal Testing 7/1/2007 1:00 PM No laboratories offering molecular genetic testing for prenatal diagnosis for IBMPFD are listed in the GeneTests Laboratory Directory.However, prenatal testing may be available for families in which the disease-causing mutation has been identified.For laboratories offering custom prenatal testing, see .
Requests for prenatal testing for adult-onset conditions such as IBMPFD are not common.Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis.Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified.For laboratories offering PGD, see .

Molecular Genetics
Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information.-ED.Normal gene product: The 97-kd valosin-containing protein is a member of the type II AAA ATPases (ATPases Associated with a variety of Activities), characterized by the presence of two conserved ATPase domains, also called AAA domains.Similar to other AAA proteins, VCP is an enzymatic machine.It catalyzes ATP hydrolysis to generate energy and uses the energy to perform mechanical work in cells.VCP is involved in an unusually wide variety of functions and is associated with distinct and crucial cell protein pathways, namely cell cycle control homotypic membrane fusion, nuclear envelope reconstruction, postmitotic organelle reassembly, and ubiquitin-dependent protein degradation [Rabouille et al 1998, Hetzer et al 2001, Rabinovich et al 2002].VCP forms a homohexamer and binds to several different adapter proteins, enabling VCP to target specific substrates for degradation [Kondo et al 1997, Meyer et al 2000].VCP plays a critical role in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway during the "quality control process" that selectively eliminates aberrant proteins in the secretory pathway [Jarosch et al 2002].This pathway also targets destruction of protein substrates dislocated from the ER to the cytosol, where ubiquitination and degradation occur by the 26S proteasome [Dai & Li 2001].Growing evidence implicates VCP in neuronal degeneration.Several in vitro studies, using

Molecular Genetics of Inclusion
Abnormal gene product: VCP mutations in families with IBMPFD cluster in the N-terminal CDC48 domain, involved in ubiquitin binding[Dai & Li 2001, Rape et al 2001].This highly structured domain forms two distinct regions -the double barrel (amino acids 25-106) and the four-stranded barrel (amino acids 112-186) -connected by a short linker region (amino acids 107-111).VCP forms a homohexamer in which the D1/D2 domains bind in a head-to-tail ring[Zhang et al 2000], allowing the N-terminal domain to undergo conformational changes without affecting the stability of the homohexamer ring structure.VCP missense mutations causing IBMPFD disrupt either the double barrel (p.Arg93Cys, p.Arg95Gly/Cys), or the four-stranded barrel (p.Arg155Cys/His/Pro, p.Arg159His), or the flexible linker (p.Arg191Gln; family 13).Hence, the affected ubiquitin-binding domain may possibly impair N-terminal domain binding of specific partner proteins.Most of the mutated residues are adjacent and potentially interact with each other (p.Arg155-p.Asn387, p.Arg159-p.Ala232 and p.Arg191-p.Leu198), suggesting that these residues may have a similar and specific function within the VCP homohexamer.

Table 1
summarizes molecular genetic testing for this disorder.

Table 1 . Molecular Genetic Testing Used in Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia Test Method Mutations Detected Mutation Detection Frequency 1 Test Availability
1. Proportion of affected individuals with a mutation(s) as classified by gene/locus, phenotype, population group, genetic mechanism, and/or test method 2. In families who meet diagnostic criteria for IBMPFD and show linkage to 9p21.1-p12 ). IBM2 is characterized by adult-onset, slowly progressive distal muscle weakness that begins with gait disturbance and foot drop secondary to anterior tibialis muscle weakness.Weakness eventually includes the hand and thigh muscles, but commonly spares the quadriceps muscles, even in advanced disease.Affected individuals are usually wheelchair bound approximately 20 years after onset.If quadriceps sparing is incomplete, loss of ambulation tends to occur earlier.Muscle histopathology typically shows rimmed vacuoles and characteristic filamentous inclusions.The gene GNE, which encodes the bifunctional enzyme [Askanas & Engel 2002]e 2-epimerase/N-acetylmannosamine kinase, is the only gene associated with IBM2.Inheritance is autosomal recessive[Eisenberg et al 2001].Sporadic inclusion-body myositis (sIBM) is the most common acquired muscle disease inCaucasians over age 50 years.Pathologically it is characterized by inflammatory, degenerative, and mitochondrial changes that interact in an as-yet-unknown manner to cause progressive muscle degeneration and weakness.The cause is unknown, but it is thought to involve a complex interplay between environmental factors, genetic susceptibility, and aging[Askanas & Engel 2002].Facioscapulohumeral muscular dystrophy (FSHD) FSHD typically presents before age 20 years with weakness of the facial muscles and the stabilizers of the scapula or the dorsiflexors of the foot.Severity is variable.Weakness is slowly progressive and approximately 20% of affected individuals eventually require a wheelchair.Life expectancy is not shortened.Inheritance is autosomal dominant.

Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia
OMIM Entries

Genomic Databases for Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia
Normal allelic variants: VCP has 17 exons.Pathologic allelic variants:Mutations in the 27 families studied to date are summarized in Table2.Mutations in all but one family cluster in the N-terminal CDC48 domain involved in ubiquitin binding.7/1/2007 1:00 PM