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.
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