Congenital type disproportion fibrous (fiber-type disproportion Congenital) - Genes ACTA1, MYH7, RYR1, TPM2 and TPM3

The fiber type disproportion is a congenital disorder that mainly affects skeletal muscles. The severity of the disease is highly variable. It is estimated that up to 25% have severe muscle weakness at birth, which can cause death in infancy or childhood. Other people have only mild muscle weakness manifested in adulthood. In general, the first signs of the disease include hypotonia and muscle weakness. The weakness is usually worse over time and in some cases can improve. Although motor skills such as standing and walking may be delayed, many affected children learn to walk with time. In rare cases, people with this disease have a progressive decrease in muscle strength. These people may lose the ability to walk and require a wheelchair.

People usually present throughout the body myopathy, especially in the muscles of the shoulders, arms, hips and thighs. Weakness may also affect the muscles of the face and the muscles that control eye movement, causing ophthalmoplegia and ptosis. Other signs and symptoms may include contractures, lordosis, or scoliosis. Approximately 30% of people with this disorder have respiratory problems and difficulty swallowing. Some people who have respiratory problems requiring mechanical ventilation. Rarely, people with congenital fibrous disproportion have dilated cardiomyopathy.

This may be due to mutations in multiple genes. Mutations in TPM3 (tropomyosin 3), RYR1 (ryanodine receptor 1) and ACTA1 genes (actin, alpha 1, skeletal muscle) are responsible for 35 to 50 percent of cases, while mutations in other genes, some known (TPM2 (tropomyosin 2 (beta)) and MYH7 (myosin, heavy chain 7, cardiac muscle, beta)) and some unidentified, are responsible for the remaining cases. The genes responsible for development of type disproportion fibrous congenital encode the synthesis of proteins that are involved in muscle contraction. Changes in these proteins alter muscle contraction, resulting in muscle weakness. Skeletal muscle consists of two types of muscle fibers: type I (slow-twitch fibers) and type II (fast-twitch fibers). Typically, the fibers of type I and type II are the same size. In people with congenital fibrous disproportion, the skeletal muscle fiber type I are significantly lower than skeletal muscle fibers of type II.

The ACTA1 (actin, alpha 1, skeletal muscle) gene, located on the long arm of chromosome 1 (1q42.13), encodes a protein called ?-actin skeleton. Actin proteins are important for cell movement and muscle contraction. These proteins also help maintain the cytoskeleton. The protein encoded by the gene ACTA1, plays an important role in skeletal muscles. Inside the skeletal muscle cells, it is an essential component of the sarcomeres. Sarcomeres compounds comprise thin actin filaments and myosin filaments composed thick. This binding allows them to move relative to each other so that muscles to contract. They have identified at least 7 ACTA1 mutations in the gene in people with the disease. These mutations change amino acids in the protein, which probably impairs the ability of the protein to function normally. As a result, muscle contraction is interrupted, leading to muscle weakness and other characteristics of the disease.

The RYR1 gene (ryanodine receptor 1), located on the long arm of chromosome 19 (19q13.1), encoding the ryanodine receptor 1. This protein is part of a family of ryanodine receptors, which are channels for the transport of ions calcium inside cells. These channels play a critical role in skeletal muscles. For the body to move normally, skeletal muscles must contract and relax in a coordinated manner. Muscle contractions are caused by the flow of positively charged, including calcium ions in muscle cells. When muscles are at rest, the calcium ions are stored in the sarcoplasmic reticulum within each muscle cell. In response to certain signals, the channel RYR1 releases calcium ions from the sarcoplasmic reticulum in the cytoplasm. The resulting increase in the concentration of calcium ions stimulates the muscle fibers to contract, allowing the body to move. They have identified at least 7 RYR1 mutations in the gene responsible for the disease. Some mutations change the amino acids in ryanodine receptor 1. Other mutations, creating a premature stop signal in the receiver coding, which results in an abnormally short, nonfunctional protein. Although the role of RYR1 gene mutations in this disease is unclear, it is likely that disruption of RYR1 channel can play a role in muscle weakness and other characteristics of the disease.

The gene TPM3 (tropomyosin 3), located on the long arm of chromosome 1 (1q21.2), encodes a ?-tropomyosin 3 protein called which is part of the family of proteins tropomyosin. These proteins regulate muscle contraction by controlling the joining of two muscle, actin and myosin proteins. In non-muscle cells, tropomyosin proteins play a role in the control of cell shape. The protein encoded by the gene TPM3 found in skeletal muscles. They have identified at least 10 mutations in the gene TPM3 in people with congenital fibrous disproportion. These mutations change the amino acids in ?-tropomyosin 3. It is likely that these mutations compromise the ability of the protein to interact with actin and myosin in the interior of the fibers of skeletal muscle type I, disrupting muscle contraction and therefore, it causes muscle weakness.

Depending on the gene involved, this disease has different inheritance patterns. In general, when the disease is it due to mutations in the gene ACTA1, it is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient for alteration is expressed. Often, the disease can be caused by a new mutation in the gene ACTA1 and occurs in people with no history of disease in your family. Most cases of type disproportion other fibrous congenital, including cases due to mutations in the RYR1 gene have an autosomal recessive inheritance pattern. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. When the disease is due to mutations in the gene TPM3, it may run in either an autosomal recessive pattern or autosomal dominant.

In rare cases, congenital fibrous type disproportion can be inherited with an X-linked pattern A disease is X-linked, if the mutated gene that is expressed on the X chromosome, one of the two sex chromosomes in each cell. In males, an altered copy of the gene in each cell is sufficient for alteration is expressed. Because women have two copies of the X chromosome, one altered copy of the gene in each cell usually causes less severe symptoms in women than in men and may cause no symptoms at all. A feature of the X-linked inheritance is that fathers can not pass X-linked traits to their sons chromosome.

Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with fibrous congenital disproportion, by complete PCR amplification of the exons of ACTA1, MYH7, RYR1, TPM2 and TPM3 genes, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).