Inclusion Body Myopathy With Paget Disease Of Bone And/or Frontotemporal Dementia

Clinical 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. 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, and paraphasic errors, with minimal impairment of episodic memory; later stages are characterized 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, 56 years. Dilated cardiomyopathy, amyotrophic lateral sclerosis, and Parkinson disease are now known to be part of the spectrum of findings associated with IBMPFD.

Diagnosis/testing.

The diagnosis of IBMPFD is established in a proband with typical clinical findings and a heterozygous pathogenic variant in HNRNPA1, HNRNPA2B1, or VCP identified by molecular genetic testing.

Management.

Treatment of manifestations: Weight control to avoid obesity; physical therapy and stretching exercises to promote mobility and prevent contractures; mechanical aids (canes, walkers, orthotics, wheelchairs) for ambulation/mobility; surgical intervention for foot deformity and scoliosis; respiratory aids when indicated; social and emotional support; assisted living arrangements for muscle weakness and/or dementia; bisphosphonates to relieve pain and disability from PDB.

Surveillance: At periodic intervals: echocardiogram and ECG to monitor for evidence of cardiomyopathy; pulmonary function studies; sleep study; alkaline phosphatase, skeletal x-rays and bone scans to monitor for PDB onset and effectiveness of therapy; assessment of behavior and mental status.

Genetic counseling.

IBMPFD is inherited in an autosomal dominant manner. An estimated 80% of affected individuals have an affected parent; approximately 20% have the disorder as a result of a de novo pathogenic variant. Each child of an individual with IBMPFD has a 50% chance of inheriting the pathogenic variant. Once the IBMPFD-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Inclusion body or nonspecific myopathy associated with Paget disease of bone with or without frontotemporal dementia (IBMPFD) should be suspected in individuals with a combination of the following findings.

Myopathy that is usually proximal, progressive, and adult-onset:

• Serum CK concentration is normal to mildly elevated (mean: 195 U/L; range: 40-1145 U/L; normal range: 20-222 U/L).
• EMG (electromyogram) shows myopathic changes, and neuropathic changes including acute and chronic denervation.

Skeletal muscle pathology is typically nonspecific (both light microscopy and electron microscopy). On light microscopy, findings characteristic of inclusion body myopathy consisting of rimmed vacuoles and cytoplasmic TAR DNA-binding protein 43 (TDP-43) and ubiquitin-positive inclusions may be visible in some fibers; the inclusions appear with time and can be observed at a later stage of the disease in some individuals.

Paget disease of bone (PDB), suspected in individuals with spine or hip pain, bony tenderness, reduced height, pathologic fractures, long-bone or cranial-bone deformity, or hearing loss resulting from eighth-nerve compression by calvarial bony overgrowth. The diagnosis of PDB can be established with the following findings:

• Elevated serum alkaline phosphatase concentration (mean: 359 U/L; range: 58-1724 U/L; normal range: 30-130 U/L)
• Elevated urine concentrations of pyridinoline (PYD) and deoxypyridinoline (DPD):
  • Mean PYD: 153 IU/L (normal: 31.1 IU/L)
  • Mean DPD: 40 IU/L (normal: 6.8 IU/L)
  Note: The DPD/PYD ratio is not significantly different between affected persons (0.291) and normal controls (0.214).
• Bone findings – either of the following:
  • 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.
  • 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., lack of personal/social awareness, perseveration, disinhibition), early expressive or receptive language dysfunction, and relative preservation of memory, orientation, and praxis [Miller et al 1997]. Brain MRI studies reveal atrophy of anterior temporal and frontal lobes.

Establishing the Diagnosis

The diagnosis of IBMPFD is established in a proband with typical clinical findings and a heterozygous pathogenic variant in HNRNPA1, HNRNPA2B1, or VCP identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, single-gene testing) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of IBMPFD is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of IBMPFD has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Inclusion body myopathy associated with Paget disease of bone 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 Paget disease of bone (PDB), and premature frontotemporal dementia (FTD).

Death typically occurs in the sixth or seventh decade from progressive respiratory failure.

Recently Al-Obeidi et al [2018] studied 231 individuals (118 males and 113 females) from 36 families and found that myopathy, PDB, and FTD were present in 90%, 42%, and 30% of the individuals, respectively, beginning at an average age of 43, 41, and 56 years, respectively. Intra- and interfamilial variability is observed in this disorder.

Myopathy. In families studied thus far, 90% of affected individuals had proximal limb-girdle weakness.

• Diagnosis was at a mean age of 43 years (range: 3-61 years; typically 20s-40s).
• Muscle weakness is usually proximal, involving the hip and shoulder girdle muscles; however, several individuals have had initial weakness of the muscles of the hands and feet.
• Affected individuals experience difficulty walking upstairs and raising the arms above the shoulders.
• The gait is typically waddling and the stance lordotic.
• Weakness progresses and other limb and respiratory muscle groups become involved over time. Many affected individuals become wheelchair bound.
• Muscle biopsy findings:
  • Light microscopy of muscle biopsy reveals nonspecific changes: variability in fiber size, type I fiber predominance, and atrophic and hypertrophic fibers. Fibers may contain single or multiple vacuoles. Rimmed vacuoles and cytoplasmic ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions visible in some fibers are characteristic of inclusion body myopathy [Weihl et al 2008]. The inclusions appear with time and can be observed at a later stage of the disease in some individuals. In advanced cases, severe degenerative muscle changes and fatty replacement of muscle fibers may be noted. Inflammatory cells are absent.
  • Electron microscopy may show nonspecific cytoplasmic changes. The characteristic inclusions, composed of randomly oriented tubulofilaments roughly 15-21 nm in diameter, are seen in muscle nuclei and in cytoplasm. In one family, atrophic and vacuolated muscle fibers containing abundant cytoplasmic-paired helical filaments with epitopes of phosphorylated tau, congophilia, abnormal accumulation of β-amyloid precursor protein (βAPP) epitopes, and accumulation of apolipoprotein E (ApoE) were observed [Alvarez et al 1998].

Paget disease of bone (PDB). In families studied by Al-Obeidi et al [2018], 42% of affected individuals had PDB. The mean age at diagnosis was 41 years (range: 31-61 years). PDB was often asymptomatic, but was diagnosed based on the serum concentration of alkaline phosphatase and bone scans; therefore, it may be underdiagnosed.

PDB involves focal areas of increased bone turnover that lead to complications such as bone pain, localized painful enlargement and deformity of the long bones, pathologic fractures (rare), and deafness. PDB typically manifests as spine and/or hip pain.

Frontotemporal dementia (FTD). 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 Genetic Prion Disease). 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 by Al-Obeidi et al [2018], approximately 30% of affected individuals had dementia. Mean age at diagnosis of dementia was 56 years (range: 30-86 years). This was a cross-sectional study and several individuals were not old enough to have developed FTD. Several individuals were in advanced stages of dementia when diagnosed with IBMPFD and detailed evaluation of the FTD was not possible in them.

Dilated cardiomyopathy. In several individuals in the first family originally reported by Kimonis et al [2000] with limb-girdle myopathy and Paget disease of bone, cardiac failure and cardiomyopathy were noted in the later stages of the disease. Hübbers et al [2007] reported dilated cardiomyopathy characterized by ubiquitin-positive cytoplasmic aggregates and nuclear inclusions in an affected woman. This relatively uncommon finding was most recently reported in four of 18 affected individuals in a large family [Miller et al 2009]. See Dilated Cardiomyopathy Overview.

Amyotrophic lateral sclerosis (ALS). Al-Obeidi et al [2018] reported that approximately 10% of individuals with IBMPFD had a previous diagnosis of ALS. Benatar et al [2013] conducted a systematic EMG characterization of 17 individuals with a diagnosis of IBMPFD from eight families and found that the EMG was abnormal in all individuals. The abnormality was purely neurogenic in four and mixed neurogenic/myopathic in seven individuals; thus, motor neuron involvement as characteristic of ALS was identified in 11/17 (65%) of the participants.

An earlier study by Johnson et al [2010] identified a pathogenic variant in VCP in five of 289 (1%-2%) cases of familial ALS. The parent of one proband died at age 58 years with dementia, parkinsonism, Paget disease, and upper-limb muscle weakness, findings that strongly suggested IBMPFD. In another individual with a pathogenic variant in VCP and diagnosis of ALS, neuropsychological testing performed within one year of symptom onset suggested mild frontal lobe dysfunction. The study findings widened the spectrum of clinical findings associated with IBMPFD to include ALS. See Amyotrophic Lateral Sclerosis Overview.

Parkinson disease (PD). PD is now known to be a feature of IBMPFD. Spina et al [2013] reported affected individuals with PD, but complete details were lacking. Al-Obeidi et al [2018] reported an incidence of 3.8% of Parkinson disease in a cohort of 231 individuals. Individuals with PD in IBMPFD tend to have classic symptoms and respond well to standard treatment [Chan et al 2012]. More recently, Regensburger et al [2017] reported an individual with VCP-related multisystem proteinopathy presenting as early-onset PD.

Other phenotypic features including hepatic steatosis, cataracts, sensorimotor axonal neuropathy, pyramidal tract dysfunction, sphincter disturbance, and sensorineural hearing loss have been reported [Haubenberger et al 2005, Guyant-Maréchal et al 2006, Hübbers et al 2007, Djamshidian et al 2009, Miller et al 2009, Kumar et al 2010].

Neuropathology. VCP-related IBMPFD represents a novel class of neurodegenerative diseases called TDP-43 proteinopathies. Neuropathologic findings associated with IBMPFD include ubiquitin-positive neuronal intranuclear inclusions, dystrophic neuritis, and rare intracytoplasmic inclusions. These findings are abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus [Forman et al 2006, Neumann et al 2007, van der Zee et al 2009].

IBMPFD associated with pathogenic variants in either HNRNPA2B1 or HNRNPA1 has similar neuropathologic findings.

Genotype-Phenotype Correlations

Al-Obeidi et al [2018] analyzed clinical, radiologic, biochemical, and pathogenic variant data in 231 individuals from 36 families with 15 different pathogenic variants in VCP. Inter- and intrafamilial variability made establishing correlations difficult. No significant genotype-phenotype correlations were identified.

No major differences are noted in the IBMPFD phenotype associated with pathogenic variants in either HNRNPA or HNRNPA2B1 except that the Paget disease of the bone seen with a pathogenic variant in HNRNPA2B1 is much more severe and involves the extremities – unlike the distribution in VCP-related disease, in which the sites of predilection are the spine, hip, pelvis, skull, and scapulae with relative sparing of the extremities [Waggoner et al 2002, Kim et al 2013]

Penetrance

Penetrance is almost complete; however, it is age related.

Penetrance by phenotype (see Figure 1).There is marked intra- and interfamilial variability in severity, age of onset, distribution of weakness, and presence or absence of Paget disease, myopathy, and cognitive impairment [Al-Obeidi et al 2018]:

Figure 1.

IBMPFD phenotypes FTD = frontotemporal dementia; IBM = inclusion body myopathy; IBMPFD = inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia; PDB = Paget disease of bone

• Presence of all three major manifestations: 10% 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:
  • Inclusion body myopathy: 37%
  • Paget disease of bone: 5%
  • Frontotemporal dementia: 3%

Prevalence

IBMPFD is rare; the true prevalence is unknown. A study from the UK estimated a prevalence of approximately 1:300,000, although this was not a population ascertainment and the true incidence may be higher. Because previous studies have shown that individuals receive a diagnosis after a diagnostic odyssey of several years and are typically seen by numerous specialists in a number of disciplines (neurology, rheumatology, endocrinology, pain management, genetics), this disorder is considered to be significantly underdiagnosed. As the spectrum of disorders associated with pathogenic variants in VCP expands (as indicated by the number of worldwide publications) it is anticipated that the disorder will be increasingly recognized.

Very few families have been reported with IBMPFD associated with a pathogenic variant in either HNRNPA1 or HNRNPA2B1; thus no estimates of prevalence are available.

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 evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Individuals benefit from care by a multidisciplinary team including: a neuromuscular specialist, endocrinologist with expertise in Paget disease, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and medical geneticist/genetic counselor.

Surveillance

Agents/Circumstances to Avoid

Individuals and their families should be educated about safety precautions and environmental modification in the home and at work.

Evaluation 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.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.