EP247: Pathogenic variant in valosin-containing protein causing inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia

Abstract

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD, OMIM: 167320) is a rare multisystem degenerative autosomal dominant disorder which is characterized by adult onset proximal and distal muscle weakness, early-onset Paget disease and premature frontotemporal dementia. Pathogenic variants in the VCP gene are responsible for the majority of the cases, although there have been reported cases secondary to pathogenic variants in the HNRNPA1 and HNRNPA 2B genes. Phenotypically, proximal muscle myopathy is the earliest and most common symptom. Paget’s disease and frontotemporal dementia are the second and third most common phenotypes, with approximately one-half and one-third of patients developing each, respectively. Dilated cardiomyopathy has been described in some families with IBMPFD later on in the disease. Following diagnosis, baseline evaluations that are recommended include assessment of muscle strength, echocardiogram, pulmonary function tests, bone scan studies followed by x-rays and neuropsychological studies of behavior and mental status. Use of a multi-disciplinary team is beneficial; treatment is aimed at symptomatic management of muscular dystrophy, Paget’s disease and surveillance of cardiac, lung, bone and neurologic functions. Average lifespan in patients diagnosed with IBMPFD is 50-60 years old. A 38-year-old male was referred for genetics evaluation in consideration of a suspected hereditary neuromuscular disorder. The patient had a past medical history of a tremor, both resting and intentional, in addition to congenital bicuspid aortic valve diagnosed in childhood. Symptoms emerged 3 years prior to presentation with progressive proximal muscle weakness and cognitive dysfunction characterized by difficulty spelling words, difficulty recalling names and performing simple math calculations. The patient also reported small joint pain of the hands, chronic back pain, and headaches. Family history was notable for affected maternal family members. His mother passed away at age 50 due to neuromuscular problems, with muscle weakness manifesting in her 40s, progressive in nature, eventually requiring a walker a couple of years prior to passing. The patient’s maternal grandfather also passed away in his 50s. He had progressive neuromuscular disease and was wheelchair bound. His maternal great-grandfather, as well as two great aunts, also had progressive neuromuscular disease. Diagnostic evaluation included EMG, identifying median motor nerve latency with prolongation of the sensory action potential; CPK level was slightly elevated at 370 U/L and metabolic was non-diagnostic. Comprehensive metabolic panel was notable for elevated alanine transferase, aspartate aminotransferase, and alkaline phosphatase levels, at 145 IU/L, 267 IU/L and 150 IU/L respectively. MRI of the spine, previously performed due to chronic back pain, was notable for mottled signal in the L4 region, suggestive of hemangioma or Paget’s disease of the bone. Genetic testing included a chromosomal microarray analysis which identified a 15q13.1q13.2 microdeletion, which is a variant of uncertain significance and not associated with known disorders. Subsequent neuromuscular disorder gene panel testing identified a heterozygous pathogenic change in the VCP gene, NM_007126.3:c.463C>T p.(Arg155Cys), which is associated with IBMPFD. On discussion of the results, the patient was encouraged to continue care with his current care team, as well as to establish care with a tertiary care center. Screening and diagnostic tests included a nuclear bone scan, which was consistent with Paget’s disease of the bone. The patient was advised to discuss the results of his testing with family members at risk and to seek genetic counseling and testing. IBMPFD is a rare genetic disorder, with a broad range of differentials, including limb-girdle muscular dystrophy (LGMD), amyotrophic lateral sclerosis (ALS), and other muscular dystrophies. It is likely that IBMPFD is under-diagnosed, as many individuals are misdiagnosed with ALS or another type of dystrophy. It is important to recognize the potential presence of IBMPFD in the differential of patients presenting with muscular dystrophies, given that early recognition can lead to earlier diagnosis and treatment implementation. Additionally, extended genetic testing for family members at risk can help identify heterozygote individuals and provide resources for appropriate supportive treatment and surveillance. Further research into the field will also potentially yield novel therapies and provide more detailed characterization of the different phenotypes of the disorder.