About VCP Disease

 

Educational information for providers

What is IBMPFD?

VCP Disease primarily manifests as IBMPFD, which identifies the three primary disorders originally associated with the disease:  Inclusion Body Myopathy, Paget's Disease of Bone, and Frontotemporal Dementia.  A person with IBMPFD may have one, two, or all of these disorders.  IBMPFD is recognized globally as a rare disease with the following designations:  OMIM #167320 and ICD-11 Code 4A41.21.

 

Researchers also categorize this disease as Multisystem Proteinopathy (MSP1) because it is a protein disorder that affects multiple body systems. 

 

This disease is a rare, adult-onset, neuromuscular disease caused by any one of several possible variants in a gene called Valosin Containing Protein (VCP or p97). The clinical features typically include one or a combination of the following: myopathy, early–onset Paget’s disease of bone, and premature frontotemporal dementia. VCP Disease is progressive and death typically occurs in the 50s and 60s from respiratory and cardiac failure. 

Inheritance and Genetics

VCP Disease is an autosomal dominant disorder. It is estimated that 80% of affected people also have an affected parent and 20% occurs de novo or without recognized family history. Penetrance is almost complete (approximately 90%), but onset is age-related. Symptoms will typically be recognized by doctors in the 40s or 50s although subtle symptoms may be recognized by the patients as early as their 20s or 30s. Expression is variable between families as well as within the same family.

Mutations in one gene, Valosin Containing Protein (VCP or p97), is known to cause the majority of IBMPFD, but other genes have recently been found causing similar clinical features. VCP is located at 9p13 - p12, and there is evidence that VCP is involved in a number of cellular activities including cell cycle control, membrane fusion, the ubiquitin-proteasome mediated degradation, endoplasmic reticulum-associated degradation and mitochondrial function.

Clinical Diagnosis

A patient with a mutation in the VCP gene may have one or a combination of these manifestations. Symptoms may include:

  1. Myopathy: Family studies have found myopathy in 90% of people with IBMPFD. Muscle atrophy is usually progressive, and most people will eventually need to use a wheelchair and other mechanical aids for mobility. The proximal muscles are usually affected before the distal muscles of the legs and arms. The myopathy may clinically resemble limb-girdle (LG) or facio-scapulo-humeral (FSH) muscular dystrophy. Myopathy can also affect the cardiac and respiratory systems, leading to earlier death.

    • Myopathy Evaluation:  Serum CK concentration, electromyogram, skeletal muscle histology and MRI.

  2. Paget’s disease of bone (PDB): Paget’s disease of bone is caused by problems with bone turnover. Symptoms of PDB include bone pain, localized bone enlargement, deformation of the long bones, and deafness from eighth-nerve compression. Family studies have found PDB in 50% of people with IBMPFD, usually with an earlier onset (mean age of 42 years) than is seen with isolated PDB.

    • PDB Evaluation: Serum alkaline phosphatase concentration, urine concentrations of pyridinoline and deoxypyridinoline, and skeletal radiographs or radionuclide bone scans.

  3. Frontotemporal dementia (FTD) affects reasoning, personality, and language. Memory is relatively preserved until the later stages of the disorder. In family studies approximately 30% of people with IBMPFD have FTD.

    • FTD Evaluation: comprehensive neurological assessment and imaging.

  4. Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's disease): ALS occurs in approximately 10% or more of individuals with VCP Disorder. Symptoms include increased muscle tone, weakness, muscle wasting, muscle cramps, and difficulty swallowing and speaking.

    • ALS Evaluation: comprehensive neurological assessment.

  5. Other:  A few patients have been shown to have hereditary spastic paraplegia, Charcot-Marie-Tooth disease, cardiomyopathy, cataracts, and neuropathy.

 

Approximately 12% of patients are affected with all three features listed above, 50% of affected people have two of the features, 30% have apparently isolated myopathy, and 8% have apparently isolated PDB or FTD.

Treatment and Therapy

Management of the disease involves an interdisciplinary healthcare team that includes Genetics, Cardiology, Neurology, physical therapy, and psychosocial support for patients and caregivers. There are treatments to help lessen, delay, or eliminate some of the symptoms of PDB. There are also some therapies for maintaining quality of life for as long as possible and slowing the rate of decline.

  1. Myopathy: Quality of life therapies include using assisted living devices like wheelchairs, walkers, canes, toilet lifts, and lift chairs as well as respiratory aids. Patients should have regular echocardiograms to monitor for signs of cardiomyopathy. The need of respiratory aids may also develop. Weight control is important for general health and easier ambulation.  Supportive therapies include physical therapy, and stretching exercises promote both mobility and general physical health. For example, exercises might reduce susceptibility to breathing problems and pneumonia. A research study sponsored by UF Health suggests a guideline for amount of exercise and PT for a person with VCP-related Myopathy. 

  2. Paget’s disease: Oral bisphosphonate treatment (e.g. Reclast) is effective at rebuilding normal bone and treating the pain associated with the condition by reducing the alkaline phosphatase concentration.

  3. Frontotemporal Dementia: There is no medication that has been approved specifically to treat FTD. Patients should meet with a neurologist to discuss FTD management which might include therapies to mitigate symptoms or off-label medications.  For patients with FTD, additional resources and support can be found with the Association for Frontotemporal Dementia https://www.theaftd.org/

  4. Amyotrophic Lateral Sclerosis:  Currently, Riluzole is the only drug that slows down the progression of ALS.  Several new therapies are undergoing research.

  5. Supplements:  Some patients have reported to have consulted with a licensed nutritionist to develop a personalized wellness plan.  Patients also report that using supplements that promote mitochondrial and nerve health has been beneficial. 

  6. Support: Social and emotional support systems are often extremely valuable for patients, their caregivers, and family members. The non-profit patient advocacy group, Cure VCP Disease, Inc., provides peer-to-peer support and education, and its Facebook page is @curevcpdisease.  There is a closed Facebook group, @ibmpfd- patients, family and friends and a patient support portal, rareconnect.org.

Treatments of Manifestations

Myopathy:

  • Weight control to avoid obesity.

  • Physical therapy and stretching exercises to promote mobility and prevent contractures.

  • Occupational therapy and use of mechanical aids (i.e. canes, walkers, orthotics, scooters, wheelchairs) as needed to promote mobility and ambulation.

  • Surgical intervention as needed for orthopedic complications (i.e. foot deformity, scoliosis).

  • Use of respiratory aids if indicated.

  • Social and emotional support and stimulation to maximize sense of social involvement and productivity and to offset the possible social isolation.

  • Assisted living arrangements as necessitated by muscle weakness and/or dementia.

 

Paget's disease of bone:

  • Treatment with potent bisphosphonates can decrease alkaline phospatase concentration and relive pain and disability.

Evaluations following Initial Diagnosis

To establish the extent of the disease , the below evaluations are recommended to establish a baseline (if not performed as part of the evaluation that led to the diagnosis).

  • Muscle:  Assessment of muscle strength, muscle wasting and tendon reflexes.  EMG and/or muscle biopsy may be necessary.

  • Cardiac:  Baseline echocardiogram and ECG

  • Lungs:  Baseline pulmonary function studies

  • Bone:  Blood alkaline phosphatase, urine pyridinoline studies, and bone scan studies followed by skeletal x-ray to evaluate distribution and severity of Paget's disease of the bone.

  • Neurologic:  Baseline neuropsychological studies of behavior and mental status

  • Other:  Consultation with clinical geneticist and/or counselor

Evaluations recommended for Surveillance

  • Muscle:  Assessment of muscle strength, muscle wasting and tendon reflexes.

  • Cardiac:  Echocardiogram and ECG to monitor for evidence of cardiomyopathy.  If normal, reevaluate at 2-3 year intervals or if symptomatic.

  • Lungs:  Pulmonary function studies annually.  Sleep studies as needed.

  • Bone:  Annual alkaline phospatase.  If alkaline phospahtase increases or symptoms of pain or bony deformity observed, skeletal x-rays and/or bone scans to monitor therapy and (if symptomatic) PDB.

  • Neurologic:  Asssessment of behavior and mental status every 2-3 years.

Genetic Testing

Purpose of VCP Genetic Testing:

VCP Disease has often been misdiagnosed clinically. Finding a mutation in VCP is the only conclusive way to establish an accurate diagnosis.  An accurate diagnosis gives information and opportunities for:

  • Screening guidelines for potentially affected systems (e.g. echocardiograms, PDB evaluation) permitting earlier treatment of these conditions

  • Lifestyle changes for the patient (e.g. changes in diet, nutrition, and exercise)

  • The choice to participate in research to learn more about VCP Disease

  • Accurate recurrence risk counseling or identification of at-risk family members

  • Pre-symptomatic testing for family members who are at risk

  • Prenatal testing through amniocentesis or chorionic villus sampling (CVS)

  • Pre-implantation genetic diagnosis (PGD) in conjunction with in vitro fertilization (IVF) for families who wish to have only pregnancies that do not carry a familial VCP mutation

Risks of VCP Genetic Testing:

As with other adult onset disorders, pre-symptomatic patients require psychological preparation before testing, including in depth discussion of their reasons for testing and how both positive and negative results would affect their lives. Discussing the implications of testing will allow the patient to make a fully informed decision about whether or not to proceed.

Genetic privacy and discrimination issues have been a large area of concern, especially among people seeking pre-symptomatic genetic testing. The passage of the Genetic Information Nondiscrimination Act (GINA) of 2008 now provides protection against health insurance and employment discrimination based on genetic information. However, this law does not cover life, disability, or long-term care insurance and does not apply to members of the military. It is also still relatively new and has not yet been tested in court, so the extent of GINA’s protection is still not well established. Patients should still think carefully about how their DNA test result might impact their employment and insurance. In addition, it is important to allow sufficient time before ordering the test for the patient to make any necessary financial or insurance arrangements.

Genetic Testing of At-risk Family Members:

  • Symptomatic individuals: In a family with an established diagnosis, it is appropriate to consider testing of symptomatic individuals regardless of age. A proper diagnosis allows for symptomatic individuals to get needed help, support and treatment.  An individual should take into consideration social, financial, life insurance, and disability insurance implications prior to genetic testing.

  • Asymptomatic at-risk relatives:  Predictive testing for at-risk relatives is possible once the pathogenic variant has been identified in an affected family member. Because of the individualized nature of predictive testing, consultation with a genetic counselor or clinical geneticist prior to and following testing is recommended.

  • Minors:  For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

Ordering the VCP Variant Test:

There are a number of options to order genetic testing of VCP. Physicians can order full sequencing of the VCP gene, or targeted sequencing of exons where mutations are most often found. Turnaround time is usually within 3 weeks for each tier of testing ordered.

VCP Gene Testing Options

  • Testing of a known familial mutation  

  • Next generation panel testing can be arranged by a physician at a number of laboratories such as

  • Reproductive Testing:  Prenatal testing can be arranged through laboratories. Prenatal testing may require advance notice to set up before the prenatal sample is collected.

Sample Requirements and Turnaround Time:

VCP testing can be performed on 3-10 cc of blood drawn in a lavender top (EDTA) tube, saliva, or buccal samples. Specimen requirements may vary among labs

 

Interpreting VCP Results:

  1. Positive: A known pathogenic mutation in VCP has been identified in the patient. A positive result may confirm the diagnosis in a person who meets clinical criteria. It may provide a pre-symptomatic diagnosis for an unaffected individual. If an unaffected individual has a positive result, there is a 90% chance that he or she will experience one or more of the features of IBMPFD.  Onset of symptoms is age-dependent.

  2. Negative:  No mutation has been identified in the exons examined. This result is interpreted differently depending on the purpose of testing.

    • Affected Individual: Mutations will be found in approximately 70% of people who meet clinical criteria for IBMPFD. The other 30% of clinically affected people may have mutations that the test is not designed to detect or they may have mutations in another gene that has not yet been identified. Please feel free to contact the lab to discuss options.  Your patient may wish to participate in research  studies.

    • Unaffected individual in a family with a known mutation: If a family mutation in VCP has already been identified, a negative result means that the person does not have the genetic change that causes IBMPFD.

    • Unaffected individual in a family without a known mutation: If there is a strong clinical presentation and family history consistent with IBMPFD but no mutation has been identified, then a negative result decreases the chance that the patient will be affected with IBMPFD. However, the result is not as meaningful if a familial mutation has not been found. It is possible that the family may have a type of mutation in VCP that the test is not designed to detect or they may have a mutation in another gene that has not yet been identified.

  3. Variant of Unknown Significance:  A variant of unknown significance (VOUS) is a change in the VCP gene that has not previously been associated with IBMPFD. This result means that no data exists to support whether or not the variant is benign or a mutation that can cause IBMPFD. The lab evaluates the variant to determine the type of mutation, amino acid change, level of conservation, etc. and provide this information in the report. Your patient may wish to participate in research studies to further investigate the finding.

Genetic Counseling:

Genetic Counseling is recommended to explain the implications of a result to patients and their families. To find a genetics professional in your area go to: GeneTests (www.genetests.org); or the National Society of Genetic Counselors (www.nsgc.org); or the Genetic and Rare Disease Information Center (www.genome.gov); or the Genetic Alliance (www.geneticalliance.org).

Research

  • Patients can register on the CoRDS patient registry at www.curevcp.org.  The purpose of the registry is to provide data on the disease so that a treatment and cure can be found.  It will assist researchers who are looking for trial participants.

  • Research studies may be available through research match.

References

  • Kimonis V. Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia. 2007 May 25 [Updated 2019 Sep 12]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1476/

  • National Genetics 2004 Apr;36(4):377-81. Epub 2004 Mar 21. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.

 
 
 
 

Resources and References

IBMPFD GENE CARD​

Overview of the current available biomedical information and  gene card for IBMPFD.

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VCP GENE CARD

Overview of the current available biomedical information and gene card for the VCP gene.

OMIM® - Online Mendelian Inheritance in Man

 

This links to the IBMPFD entry, OMIM #167320.  OMIM is a comprehensive, authoritative compendium of human genes and genetic phenotypes.  IBMPFD is now recognized with an ICD Code- ICD-11 Code 4A41.21.

MEDICAL PUBLICATIONS

Medical publications related to IBMPFD from the NIH National Library of Medicine on pubmed.gov.

MEDICAL PAPER FOR CLINICIANS

 

by Virginia Kimonis, MD, Sandra Donkervoort, MS, CGC, and Giles Watts, PhD.