What is the definition of Tubular Aggregate Myopathy?
Tubular aggregate myopathy is a disorder that affects the skeletal muscles. Signs and symptoms typically begin in childhood and worsen over time. The leg muscles are most often affected, but the arm muscles may also be involved. Symptoms include muscle pain, cramping, weakness or stiffness; and exercise-induced muscle fatigue. Affected individuals may have an unusual walking style (gait) or difficulty running, climbing stairs, or getting up from a squatting position. Some individuals develop contractures. This condition may be caused by mutations in the STIM1 or ORAI1 genes. It is usually inherited in an autosomal dominant manner, but autosomal recessive inheritance has also been reported.
What are the alternative names for Tubular Aggregate Myopathy?
- Myopathy, tubular aggregate
What are the causes for Tubular Aggregate Myopathy?
Tubular aggregate myopathy (TAM) may be caused by mutations in the STIM1 or ORAI1 genes. The STIM1 gene gives the body instructions to make a protein involved in controlling when calcium ions enter cells. The protein recognizes low ion levels and stimulates the flow of ions into the cell, which amongst other things, stimulates muscle tensing. STIM1 gene mutations that cause TAM lead to the STIM1 protein always being "active," so it is continuously stimulating the entry of calcium ions regardless of ion levels. The protein encoded by the ORAI1 gene is part of a calcium channel on the cell membrane, which is activated by the STIM1 protein when calcium stores are low. Exactly how mutations in these genes lead to the specific symptoms of TAM is still being studied.
What are the symptoms for Tubular Aggregate Myopathy?
The signs and symptoms of tubular aggregate myopathy (TAM) can vary from person to person. Symptoms typically begin in childhood or adolescence and worsen over time. However, onset in adulthood has been reported. The leg muscles are most often affected, but the arm muscles may also be involved. The facial muscles are usually not affected. Symptoms include muscle pain, cramping, weakness or stiffness; and exercise-induced muscle fatigue. Affected individuals may have an unusual walking style (gait); difficulty running, climbing stairs, or getting up from a squatting position; and frequent falls. Some individuals develop contractures.
What are the current treatments for Tubular Aggregate Myopathy?
Currently, we are unaware of any targeted therapies for tubular aggregate myopathy. There is very limited information in the medical literature regarding the treatment or management of this condition. Supportive therapies may be recommended depending on the severity of symptoms and associated complications. High dose steroids were reported to be effective in one case of myopathy with tubular aggregates in 1991, but the reasons why were unclear.
What is the outlook (prognosis) for Tubular Aggregate Myopathy?
The symptoms and severity of tubular aggregate myopathy (TAM) can vary from person to person, even within the same family. Some individuals may even appear asymptomatic. In general, the disorder is slowly progressive and chronic. We are not aware of information in the literature regarding the life expectancy of people with TAM. However, we did not come across any reports of a shortened lifespan in affected individuals.
How is Tubular Aggregate Myopathy diagnosed?
Currently, the diagnosis of tubular aggregate myopathy (TAM) is made by identifying tubular aggregates in a muscle biopsy (the "hallmark" of TAM). Tubular aggregates are clumps of tube-like structures formed by the abnormal build-up of proteins. Other tests that may be used to support or rule out the diagnosis (or conditions with overlapping symptoms) include a blood test for creatine kinase (CK) levels or MRI of the muscles. If you are interested in being evaluated or finding out more about the diagnosis of TAM, we recommend asking your doctor for a referral to a specialist with experience in diagnosing myopathies and other muscle disorders.
Genetic testing for TAM may be possible, as currently there are 2 genes known to be responsible for TAM - the STIM1 and ORAI1 genes. However, some people with TAM do not have mutations in either of these genes. Additionally, specific mutations in these genes may alternatively be responsible for other disorders. The Genetic Testing Registry (GTR) provides information about the genetic tests available for TAM. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about genetic testing should contact a health care provider or a genetics professional.
Is Tubular Aggregate Myopathy an inherited disorder?
Tubular aggregate myopathy (TAM) is usually inherited in an autosomal dominant manner, but autosomal recessive inheritance has also been reported.
Autosomal dominant inheritance means that having a mutation in only one copy of the responsible gene in each cell is enough to cause features of the condition. In some cases, an affected person inherits the mutated gene from an affected parent. In other cases, the mutation occurs for the first time in a person with no family history of the condition. This is called a de novo mutation. When a person with a mutation that causes an autosomal dominant condition has children, each child has a 50% (1 in 2) chance to inherit that mutation. Mutations in the STIM1 and ORAI1 genes have been shown to cause autosomal dominant TAM.
Autosomal recessive inheritance means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. Affected people inherit one mutated copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:
- 25% chance to be affected
- 50% chance to be an unaffected carrier like each parent
- 25% chance to be unaffected and not a carrier
To our knowledge, the gene, or genes, responsible for autosomal recessive TAM have not yet been identified.
People with personal questions about the genetic cause and inheritance of this condition are encouraged to speak with a genetic counselor or other genetics professional. A genetics professional can help by:
- thoroughly evaluating the family history
- addressing questions and concerns
- assessing recurrence risks
- facilitating genetic testing if desired