Clinical Guidance

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

Source: GeneReviews — "Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia"

Penetrance

Penetrance is almost complete; however, it is age related. Penetrance by phenotype .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 :

• 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%

Source: GeneReviews — "Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia"

Diagnostic Criteria

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.

Source: GeneReviews — "Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia"

Differential Diagnosis

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. GNE-related myopathy 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.

Source: GeneReviews — "Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia"

Management Guidelines

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 (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 2. Recommended Evaluations Following Initial Diagnosis in Individuals with IBMPFD System/Concern | Evaluation Muscle | Assessment of muscle strength, muscle wasting, tendon reflexes. EMG /or muscle biopsy may be necessary. Cardiac | Baseline echocardiogram EKG Lungs | Baseline pulmonary function studies Bone | Blood alkaline phosphatase, urine pyridinoline studies, bone scan studies followed by skeletal x-ray to evaluate distribution severity of Paget disease of bone Neurologic | Baseline neuropsychological studies of behavior mental status Other | Consultation w/clinical geneticist /or genetic counselor 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. Table 3. Treatment of Manifestations in Individuals with IBMPFD

Source: GeneReviews — "Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia"

Clinical Guidance

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

Source: GeneReviews — "Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia"

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.

Source: GeneReviews — "Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia"

Surveillance Guidelines

Table 4. Recommended Surveillance for Individuals with IBMFD

Source: GeneReviews — "Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia"