Congenital fiber-type disproportion

Congenital fiber-type disproportion is a disorder that primarily affects skeletal muscles, which are muscles the body uses for movement. People with this disorder typically experience muscle weakness (myopathy) throughout the body, particularly in the muscles of the shoulders, upper arms, hips, and thighs. Weakness can also affect the muscles of the face and muscles that control eye movement (ophthalmoplegia), sometimes causing droopy eyelids (ptosis). Affected people may have joint deformities (contractures) and an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Approximately 30 percent of people with this disorder experience mild to severe breathing problems related to weakness of muscles needed for breathing. Some people who experience these breathing problems require extra support and use a detachable mask (noninvasive mechanical ventilation) to help them breathe at night, and occasionally during the day as well. About 30 percent of affected individuals 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. It is estimated that up to 25 percent of affected individuals experience severe muscle weakness at birth and die in infancy or childhood. Others have only mild muscle weakness that becomes apparent in adulthood. Most often, the signs and symptoms of this condition appear by age 1. The first signs of this condition are usually decreased muscle tone (hypotonia) and muscle weakness. Muscle weakness generally does not worsen over time, and in some cases it may improve. Although motor skills such as standing and walking may be delayed, many affected children eventually learn to walk. These individuals often have less stamina than their peers, but they remain active. 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, RYR1 and SEPN1 genes can cause congenital fiber-type disproportion. These genes provide instructions for making proteins that are involved in the tensing of muscle fibers (muscle contraction). Changes in these proteins may lead to impaired muscle contraction, resulting in muscle weakness. TPM3 gene mutations are the most common cause of congenital fiber-type disproportion.

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, RYR1 or SEPN1 genes. In these individuals, the cause of the disorder is unknown. Researchers are looking for other genes that are associated with congenital fiber-type disproportion.

Read more about the ACTA1, RYR1, 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 usually occurs 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 often 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 RYR1 or 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 occur in either an autosomal dominant or autosomal recessive pattern. Many 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 or may cause no symptoms at all. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.