Inclusion Body Myositis (IBM) is a condition of progressive muscle weakness and wasting that primarily develops in individuals over 50. The disease’s origins are complex, involving a combination of factors. Its name comes from “inclusion bodies,” which are abnormal clumps of protein that accumulate inside muscle cells.
The Two Forms of Inclusion Body Myositis
Inclusion Body Myositis encompasses two distinct conditions. The most prevalent type is sporadic Inclusion Body Myositis (sIBM), which appears at random and is not directly passed down through families. It manifests later in life, usually after age 50, and causes a slow decline in muscle strength. Because sIBM involves muscle inflammation, it is classified as a form of myositis.
A much rarer category is hereditary inclusion body myopathy (hIBM), a group of muscle disorders caused by specific inherited genetic mutations. Unlike sIBM, the hereditary forms often show symptoms earlier, sometimes in a person’s 20s or 30s. The term “myopathy” is used because significant muscle inflammation is not a primary feature, distinguishing its underlying process from sIBM.
Genetic Susceptibility in Sporadic IBM
The development of sporadic IBM is not caused by a single faulty gene, but certain genetic factors can increase a person’s risk. This genetic predisposition means an individual is more susceptible to the disease, not that they are guaranteed to develop it. The strongest known genetic risk factor is linked to the human leukocyte antigen (HLA) system, a group of genes that helps the immune system distinguish the body’s proteins from foreign invaders.
A specific variant, HLA-DR3, is significantly more common in people with sIBM compared to the general population. This association suggests the immune system plays a part in the disease process. The presence of this allele is thought to make an individual more prone to the autoimmune activity seen in sIBM, where the body’s immune cells mistakenly attack muscle tissue.
The HLA-DR3 allele is a risk factor, not a direct cause. Many people carry this genetic variant and live their entire lives without developing sIBM. Conversely, some individuals diagnosed with sIBM do not carry the HLA-DR3 allele. Researchers are investigating other genes that may contribute to this susceptibility, but the link to the HLA region remains the most well-established genetic association.
Direct Inheritance in Hereditary IBM
In contrast to the sporadic form, hereditary inclusion body myopathies (hIBM) are caused directly by mutations in a single gene passed from parents to their children. These conditions are very rare and follow predictable inheritance patterns.
Some forms of hIBM are passed down in an autosomal recessive pattern. This means a person must inherit two copies of the mutated gene—one from each parent—to develop the disorder. If they inherit only one copy, they are a “carrier” but do not show symptoms. An example of this is GNE myopathy, a type of hIBM caused by mutations in the GNE gene.
Other hereditary myopathies follow an autosomal dominant pattern. In these cases, inheriting just one copy of the mutated gene is enough to cause the disease. A person with such a condition has a 50% chance of passing the gene to each of their children. One example is a rare syndrome known as IBMPFD, which is caused by mutations in the VCP gene.
How Genes Influence the Disease Process
The connection between genes and muscle damage in IBM involves two parallel processes: an autoimmune attack and a degenerative pathway. The “inclusion bodies” that characterize the condition are clumps of misfolded proteins that accumulate and are believed to disrupt normal cell function. Proteins such as amyloid-beta and TDP-43, also associated with neurodegenerative disorders, build up to form these inclusions.
The genetic link to the HLA system in sporadic IBM points directly to the autoimmune component. These genes regulate the immune response, and certain variants like HLA-DR3 appear to make muscle fibers a target for immune cells. This inflammatory process contributes to the muscle damage and weakness. Simultaneously, the degenerative process unfolds inside the muscle fibers, leading to the protein aggregation that is a key element in the gradual wasting of muscle tissue.
Genetic Testing and Family Considerations
The role of genetic testing in IBM depends on which form of the disease is suspected. For the vast majority of patients with the common sporadic form (sIBM), genetic testing is not a standard part of the diagnostic process. Testing for susceptibility genes like HLA-DR3 is confined to research settings and is not used to confirm a diagnosis because the gene is only a risk factor.
The situation is different for the rare hereditary inclusion body myopathies (hIBM). In cases where a doctor suspects a hereditary form due to an early age of onset or a family history, targeted genetic testing can be very useful. Identifying a specific mutation in a gene like GNE can confirm the diagnosis of that particular hIBM. This confirmation allows for accurate genetic counseling for the patient and their relatives, which can inform their personal health and family planning decisions.