Genetics Home Reference: congenital fiber-type disproportion

Congenital fiber-type disproportion is a disorder that primarily affects skeletal muscles, which are muscles that the body uses for movement. People with this disorder typically experience muscle weakness (myopathy) throughout the body. Sometimes the weakness includes the muscles of the face and muscles that control eye movement (ophthalmoplegia). Many affected individuals also have droopy eyelids (ptosis). Some people have joint deformities (contractures) and an abnormal curvature of the spine. Approximately 30 percent of people with this disorder experience serious breathing problems related to weakness of muscles needed for breathing. People who experience these breathing problems only when they are asleep usually use a detachable mask to help them breathe (non-invasive mechanical ventilation). About 30 percent of people have difficulty swallowing due to muscle weakness in the throat. Rarely, people with this condition have a weakened and enlarged heart muscle (dilated cardiomyopathy).

The severity of congenital fiber-type disproportion varies widely. Some affected individuals experience severe muscle weakness at birth and die in infancy, while others have only mild muscle weakness that begins in adulthood. Most often, the signs and symptoms of this condition appear before age 1. The first sign of this condition is usually weak muscle tone (hypotonia) and difficulty holding the head steady. Most affected children learn to walk and remain active, although they have less stamina than their peers. However, some individuals never learn to walk. Rarely, people with this condition have a progressive decline in muscle strength over time. These individuals may lose the ability to walk and require wheelchair assistance.

Congenital fiber-type disproportion is thought to be a rare condition, although its prevalence is unknown.

Mutations in the TPM3 , ACTA1 , and SEPN1 genes can cause congenital fiber-type disproportion. TPM3 gene mutations are the most common cause of this disorder. The genes that cause congenital fiber-type disproportion provide instructions for making proteins that are involved in the tensing of muscle fibers (muscle contraction). Changes in proteins produced from the TPM3, ACTA1, or SEPN1 genes may lead to impaired muscle contraction, resulting in muscle weakness.

Skeletal muscle is made up of two types of muscle fibers: type I (slow twitch fibers) and type II (fast twitch fibers). Normally, type I and type II fibers are the same size. In people with congenital fiber-type disproportion, type I skeletal muscle fibers are significantly smaller than type II skeletal muscle fibers. It is unclear whether the small type I skeletal muscle fibers contribute to the muscle weakness seen in this disorder.

Some people with congenital fiber-type disproportion do not have identified mutations in the TPM3, ACTA1, or SEPN1 genes. In these individuals, the cause of the disorder is unknown.

Read more about the ACTA1 , SEPN1 , and TPM3 genes.

Congenital fiber-type disproportion has several different inheritance patterns.

When this condition is caused by mutations in the ACTA1 gene, it is 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. When congenital fiber-type disproportion is caused by mutations in the ACTA1 gene, it is usually the result of a new mutation and occurs in people with no history of the disorder in their family.

Cases of congenital fiber-type disproportion that result from mutations in the SEPN1 gene have an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means both copies of the 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.

When this condition is caused by mutations in the TPM3 gene, it can be inherited in either an autosomal dominant or autosomal recessive pattern. Most cases of the autosomal dominant type result from new mutations in the TPM3 gene and occur in people with no history of the disorder in their family.

In rare cases, this condition can be inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. The gene or genes on the X chromosome that cause X-linked congenital fiber-type disproportion have not been identified. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. Because females have two copies of the X chromosome, one altered copy of the gene in each cell usually leads to less severe symptoms in females than in males. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

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