Tubular aggregate myopathy

Alternate names

Myopathy, tubular aggregate

Definition

Tubular aggregate myopathy is a disorder that primarily affects the skeletal muscles, which are muscles the body uses for movement.

Epidemiology

Tubular aggregate myopathy is a rare disorder. Its prevalence is unknown.

Cause

• Tubular aggregate myopathy can be caused by mutations in the STIM1 gene.
• The protein produced from this gene is involved in controlling the entry of positively charged calcium atoms (calcium ions) into cells.
• The STIM1 protein recognizes when calcium ion levels are low and stimulates the flow of ions into the cell through special channels in the cell membrane called calcium-release activated calcium (CRAC) channels.
• In muscle cells, the activation of CRAC channels by STIM1 is thought to help replenish calcium stores in a structure called the sarcoplasmic reticulum.
• STIM1 may also be involved in the release of calcium ions from the sarcoplasmic reticulum.
• This release of ions stimulates muscle tensing (contraction).

Gene mutations

• The STIM1 gene mutations involved in tubular aggregate myopathy lead to production of a STIM1 protein that is constantly turned on (constitutively active), which means it continually stimulates calcium ion entry through CRAC channels regardless of ion levels.
• It is unknown how constitutively active STIM1 leads to the muscle weakness characteristic of tubular aggregate myopathy.
• Evidence suggests that the tubular aggregates are composed of proteins that are normally part of the sarcoplasmic reticulum.
• Although the mechanism is unknown, some researchers speculate that the aggregates are the result of uncontrolled calcium levels in muscle cells, possibly due to abnormal STIM1 activity.
• Mutations in other genes, some of which have not been identified, are also thought to cause some cases of tubular aggregate myopathy.

Inheritance

• Most cases of tubular aggregate myopathy, including those caused by STIM1 gene mutations, are inherited in an autosomal dominant pattern. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, the mutation is passed through generations in a family. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.
• Rarely, tubular aggregate myopathy is inherited in an autosomal recessive pattern, which means both copies of a gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Researchers are still working to determine which gene or genes are associated with autosomal recessive tubular aggregate myopathy.

Onset

Signs and symptoms typically begin in childhood and worsen over time.

Signs and symptoms

• 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.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• EMG: myopathic abnormalities
• Fatiguable weakness of proximal limb muscles
• Muscle fiber tubular inclusions
• Muscle spasm
• Myalgia(Muscle ache)

30%-79% of people have these symptoms

• Centrally nucleated skeletal muscle fibers
• Increased variability in muscle fiber diameter

5%-29% of people have these symptoms

• Abnormal pupil morphology(Abnormality of the pupil)
• External ophthalmoplegia(Paralysis or weakness of muscles within or surrounding outer part of eye)
• Flexion contracture(Flexed joint that cannot be straightened)
• Nyctalopia(Night blindness)
• Respiratory insufficiency(Respiratory impairment)
• Type 2 muscle fiber atrophy

Diagnosis

• 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.

Treatment

• 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.

NIH genetic and rare disease info

• NIH info on Tubular aggregate myopathy

Tubular aggregate myopathy is a rare disease.

Tubular aggregate myopathy Resources
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