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.
In IBMPFD, the diagnosis of muscle disease is based on serum CK concentration, electromyogram (EMG), and skeletal muscle histology; the diagnosis of PDB is based on serum alkaline phosphatase (ALP) concentration, urine concentrations of pyridinoline (PYD) and deoxypyridinoline (DPD), and skeletal radiographs or radionuclide scan; and the diagnosis of FTD is based on on comprehensive neuropsychological assessment. Molecular genetic testing of VCP, the only gene in which mutations are known to cause IBMPFD, is available clinically.
IBMPFD is inherited in an autosomal dominant manner. An estimated 80% of affected individuals have an affected parent; approximately 20% have a de novo mutation. Each child of an individual with IBMPFD has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.