Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) is a condition that can affect the muscles, bones, and brain.

The first symptom of IBMPFD is often muscle weakness (myopathy), which typically appears in mid-adulthood. Weakness first occurs in muscles of the hips and shoulders, making it difficult to climb stairs and raise the arms above the shoulders. As the disorder progresses, weakness develops in other muscles in the arms and legs. Muscle weakness can also affect respiratory and heart (cardiac) muscles, leading to life-threatening breathing difficulties and heart failure.

About half of all adults with IBMPFD develop a disorder called Paget disease of bone. This disorder causes bones to grow larger and weaker than normal. Paget disease of bone most often affects bones of the hips, spine, and skull, and the long bones of the arms and legs. Bone pain, particularly in the hips and spine, is usually the major symptom of Paget disease. Other complications of Paget disease of bone depend on which bones are affected. Rarely, this condition can weaken bones so much that they break (fracture).

In about one-third of people with IBMPFD, the disorder also affects the brain. IBMPFD is associated with a brain condition called frontotemporal dementia, which becomes noticeable in a person's forties or fifties. People with frontotemporal dementia initially may have trouble speaking, remembering words and names (dysnomia), and using numbers (dyscalculia). Over time, the condition damages parts of the brain that control reasoning, personality, social skills, speech, and language. Personality changes, loss of judgment, and inappropriate social behavior are also hallmarks of the disease. As the dementia worsens, affected people ultimately become unable to speak, read, or care for themselves.

Additional features that rarely occur in IBMPFD include a severe and progressive muscular disease called amyotrophic lateral sclerosis and progressive problems with movement and balance (Parkinson's disease).

People with IBMPFD usually live into their fifties or sixties.

Variants (also known as mutations) in the VCP gene are the main cause of IBMPFD. The VCP gene provides instructions for making an enzyme called valosin-containing protein, which has a wide variety of functions within cells. One of its most critical jobs is to help break down (degrade) proteins that are abnormal or no longer needed.

Variants in the VCP gene alter the structure of valosin-containing protein, impairing its ability to break down other proteins. As a result, excess and abnormal proteins build up in muscle, bone, and brain cells. The proteins form clumps that interfere with the normal functions of these cells. It remains unclear how damage to muscle, bone, and brain cells leads to the specific features of IBMPFD.

In individuals with IBMPFD who do not have identified VCP variants, the condition may be caused by rare variants in specific genes or remain unknown. IBMPFD is sometimes known as mutlisystem proteinopathy, often distinguished by its genetic cause. For example, when the condition is caused by VCP gene variants, it is called VCP-associated multisystem proteinopathy (VCP MSP).

Normal Function

The VCP gene provides instructions for making an enzyme called valosin-containing protein. This enzyme is found throughout the body and has a wide variety of functions within cells. It is involved in cell division, joining (fusing) membranes within cells, reassembling cell structures after cells have divided, preventing the self-destruction of cells (apoptosis), and repairing damaged DNA.

Valosin-containing protein is part of the ubiquitin-proteasome system, which is the machinery that breaks down (degrades) unneeded proteins within cells. This system provides quality control by disposing of damaged, misshapen, and excess proteins. It also regulates the level of proteins involved in several critical cell activities, such as the timing of cell division and growth. Researchers believe that most of the functions of valosin-containing protein are directly or indirectly related to the ubiquitin-proteasome system.

Health Conditions Related to Genetic Changes

Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia

Many variants (also known as mutations) in the VCP gene have been identified in people who have inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD). This rare disease causes muscle weakness (myopathy) and can also include a painful bone condition called Paget disease of bone and a brain condition called frontotemporal dementia that worsens over time.

The variants associated with IBMPFD each change a single protein building block (amino acid) in valosin-containing protein. Changes in the structure of this enzyme impair its ability to break down other proteins as part of the ubiquitin-proteasome system. As a result, excess and abnormal proteins build up in muscle, bone, and brain cells. The proteins form clumps (aggregates) that interfere with the normal functions of these cells. It remains unclear how damage to muscle, bone, and brain cells leads to the specific features of IBMPFD.

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis

Charcot-Marie-Tooth disease

MedlinePlus Genetics provides information about Charcot-Marie-Tooth disease

Other Names for This Gene

• 15S Mg(2+)-ATPase p97 subunit
• CDC48
• IBMPFD
• MGC131997
• MGC148092
• MGC8560
• p97
• TER ATPase
• TERA
• TERA_HUMAN

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the altered gene from one affected parent.

Although the prevalence of IBMPFD is unknown, this condition is rare. It has been diagnosed in several hundred people worldwide.