About VCP Disease

IBMPFD educational information for providers

What is IBMPFD?

IBMPFD stands for: Inclusion Body Myopathy associated with Paget’s disease of bone and/or Frontotemporal Dementia. IBMPFD is a rare adult onset genetic disease caused by any one of several possible mutations in a gene called Valosin Containing Protein (VCP or p97). The clinical features include one or a combination of the following: myopathy, early–onset Paget’s disease of bone, and premature frontotemporal dementia. IBMPFD is progressive and death typically occurs in the 50s and 60s from respiratory and cardiac failure.

IBMPFD Inheritance and Genetics

IBMPFD is an autosomal dominant disorder. It is estimated that 80% of affected people also have an affected parent and 20% of IBMPFD 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 of IBMPFD 

People with IBMPFD may have one or a combination of the four main features. 

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 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.

 

Approximately 12% of people with IBMPFD 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

Unfortunately, there is no cure for IBMPFD. 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: There is no direct treatment for 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. Supportive therapies include physical therapy and stretching exercises to promote mobility and general physical health. For example, exercises might reduce susceptibility to breathing problems and pneumonia. Research studies may be available to investigate the effects of exercise or medications.

  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. People with IBMPFD should meet with a neurologist to discuss FTD management which might include therapies to mitigate symptoms or off-label medications.

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

  5. Other: Social and emotional support systems are often extremely valuable for patients, their caregivers, and family members. There is a non-profit patient advocacy group, Cure VCP Disease, Inc., with its website as www.curevcp.org, and its Facebook page is curevcpdisease.  There is a closed Facebook group, ibmpfd- patients, family and friends and a patient support portal, rareconnect.org.

Genetic Testing

Purpose of VCP Genetic Testing:

IBMPFD 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  IBMPFD

  • 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.

Ordering the VCP 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

  • 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.

 
 
 
 
 

Medical Resources

IBMPFD GENE CARD​

The Weizmann Institute of Science has established a database which aims at providing a quick overview of the current available biomedical information.  Attached is the link to the associated gene cards for IBMPFD.

MEDICAL PUBLICATIONS

This links to a database of medical publications related to IBMPFD from the US National Library of Medicine on pub med.gov.

VCP GENE CARD

The Weizmann Institute of Science has established a database which aims at providing a quick overview of the current available biomedical information.  Attached is the link to the associated gene cards for the VCP gene.

MEDICAL PAPER FOR IBMPFD

 

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

A comprehensive report that you can take to your doctors 

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EIN NO.: 82-4368871