Congenital fiber-type disproportion is a condition that primarily affects skeletal muscles, which are muscles used for movement. People with this condition typically experience muscle weakness (myopathy), 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). Individuals with congenital fiber-type disproportion generally have a long face, a high arch in the roof of the mouth (high-arched palate), and crowded teeth.

Individuals with congenital fiber-type disproportion 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 use of a machine to help regulate their breathing at night (noninvasive mechanical ventilation), 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. In most cases, muscle weakness does not worsen over time, and in some instances 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.

Mutations in multiple genes can cause congenital fiber-type disproportion. Mutations in the TPM3, RYR1 and ACTA1 genes cause 35 to 50 percent of cases, while mutations in other genes, some known and some unidentified, are responsible for the remaining cases.

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 these proteins 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 lead to muscle weakness or are caused by muscle weakness in people with congenital fiber-type disproportion.

Normal Function

The ACTA1 gene provides instructions for making a protein called skeletal alpha (α)-actin, which is part of the actin protein family. Actin proteins are important for cell movement and the tensing of muscle fibers (muscle contraction). These proteins also help maintain the cytoskeleton, which is the structural framework that determines cell shape and organizes cell contents.

Skeletal α-actin plays an important role in skeletal muscles, which are muscles that the body uses for movement. Within skeletal muscle cells, skeletal α-actin is an essential component of structures called sarcomeres. Sarcomeres are composed of thin filaments made up of actin and thick filaments made up of another protein called myosin. Attachment (binding) and release of the overlapping thick and thin filaments allows them to move relative to each other so that the muscles can contract.

Health Conditions Related to Genetic Changes

Actin-accumulation myopathy

At least nine variants (also called mutations) in the ACTA1 gene have been identified in people with actin-accumulation myopathy. Most of these variants change single protein building blocks (amino acids) in the skeletal α-actin protein sequence.

Researchers suggest that ACTA1 gene variants that cause actin-accumulation myopathy may affect the way the actin binds to ATP. ATP is a molecule that supplies energy for cells' activities and is important in the formation of thin filaments from individual actin molecules. Dysfunctional actin-ATP binding may result in abnormal thin filament formation and impair muscle contraction, leading to muscle weakness and the other signs and symptoms of actin-accumulation myopathy.

Cap myopathy

At least one ACTA1 gene variant has been identified as a cause of cap myopathy. The variant replaces the amino acid methionine with the amino acid valine at position 47 in the protein sequence, written as Met47Val or M47V. The resulting abnormal protein may interfere with the proper assembly of thin filaments. Cap myopathy is characterized by the presence of cap-like structures in muscle cells, and these structures are composed of disorganized thin filaments. The abnormal filament structure likely impairs the ability of skeletal muscles to contract, resulting in muscle weakness and the other signs and symptoms of cap myopathy.

Congenital fiber-type disproportion

At least seven variants in the ACTA1 gene have been found to cause congenital fiber-type disproportion, a disorder that causes general muscle weakness that typically does not worsen over time. The variants that cause this condition change single amino acids in skeletal α-actin. These variants lead to the production of an abnormal actin protein, which interferes with the function of normal actin proteins in the sarcomere. As a result, the function of the sarcomere is impaired, which disrupts muscle contraction. Inefficient muscle contraction leads to muscle weakness in people with congenital fiber-type disproportion.

Intranuclear rod myopathy

At least 13 variants in the ACTA1 gene have been identified in people with intranuclear rod myopathy. These variants change single amino acids in the skeletal α-actin protein sequence.

ACTA1 gene variants that cause intranuclear rod myopathy result in rod-shaped accumulations of actin in the nucleus of muscle cells. Normally, most actin is found in the fluid surrounding the nucleus (the cytoplasm), with small amounts in the nucleus itself. Researchers suggest that the ACTA1 gene variants that cause intranuclear rod myopathy may interfere with the normal transport of actin between the nucleus and the cytoplasm, resulting in the accumulation of actin in the nucleus and the formation of intranuclear rods. Abnormal accumulation of actin in the nucleus of muscle cells and a corresponding reduction of available actin in muscle fibers may impair muscle contraction and lead to the muscle weakness seen in intranuclear rod myopathy.

A few ACTA1 gene variants that have been identified in people with intranuclear rod myopathy have also been found in people with actin-accumulation myopathy (described above). It is unclear how the same variants can cause two different conditions.

Nemaline myopathy

More than 170 variants in the ACTA1 gene have been found to cause nemaline myopathy. Nemaline myopathy is the most common muscle disorder associated with ACTA1 gene variants. Some of the variants that cause this disorder alter the structure or function of skeletal α-actin, causing the protein to cluster together and form clumps (aggregates). These aggregates interfere with the normal functioning of muscle cells. Other ACTA1 gene variants prevent the production of any skeletal α-actin, impairing the muscle cells' ability to contract. ACTA1 gene variants that cause nemaline myopathy impair muscle contraction, causing weakness and the other features of this condition.

Other Names for This Gene

• ACTA
• ACTS_HUMAN
• alpha skeletal muscle actin
• ASMA

Genomic Location

Normal Function

The RYR1 gene provides instructions for making a protein called ryanodine receptor 1 (also called the RYR1 channel). This protein is part of a group of related proteins called ryanodine receptors, which form channels that, when turned on (activated), release positively charged calcium atoms (ions) from storage within cells. RYR1 channels play a critical role in muscles used for movement (skeletal muscles).

For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by an increase in the concentration of calcium ions inside muscle cells.

RYR1 channels are located in the membrane surrounding a structure in muscle cells called the sarcoplasmic reticulum. This structure stores calcium ions when muscles are at rest. In response to certain signals, the RYR1 channel releases calcium ions from the sarcoplasmic reticulum into the cell fluid. The resulting increase in calcium ion concentration in muscle cells stimulates muscles to contract, allowing the body to move. The process by which electrical signals trigger muscle contraction is called excitation-contraction (E-C) coupling.

Health Conditions Related to Genetic Changes

Central core disease

More than 100 mutations in the RYR1 gene have been identified in people with central core disease. This condition is characterized by muscle weakness, primarily affecting the muscles near the center of the body (proximal muscles), such as the muscles in the upper legs and hips. Affected individuals also have an increased risk of malignant hyperthermia (described below).

Most of the RYR1 gene mutations involved in central core disease affect single protein building blocks (amino acids) in critical regions of the ryanodine receptor 1 protein. These mutations change the structure of the RYR1 channel, which alters the normal flow of stored calcium ions within muscle cells. A disruption in calcium ion release prevents muscles from contracting normally, leading to the muscle weakness characteristic of central core disease.

Researchers have proposed two mechanisms to explain how RYR1 gene mutations underlie muscle weakness in people with central core disease. Some genetic changes cause the RYR1 channel to be "leaky," allowing calcium ions to flow slowly but continually out of the sarcoplasmic reticulum. The leaky channels greatly reduce the amount of stored calcium ions. As a result, not enough calcium ions are available in the sarcoplasmic reticulum to trigger muscle contractions. Muscle weakness results from the inability of skeletal muscles to contract appropriately.

Other RYR1 gene mutations change the structure of the RYR1 channel in a way that impedes the normal flow of calcium ions. Although the sarcoplasmic reticulum stores plenty of these ions, the receptor cannot release them in response to the usual signals. Without enough calcium ions flowing out of the sarcoplasmic reticulum at the appropriate time, muscles cannot contract normally and muscle weakness results. This mechanism is known as E-C uncoupling.

Congenital fiber-type disproportion

At least 11 mutations in the RYR1 gene have been found to cause congenital fiber-type disproportion, a disorder that causes general muscle weakness that typically does not worsen over time. Some mutations change single amino acids in the ryanodine receptor 1 protein. Other RYR1 gene mutations create a premature stop signal in the instructions for making the receptor, resulting in an abnormally short, nonfunctional protein. Researchers suspect that disruption of the RYR1 channel may play a role in the muscle weakness and other features of congenital fiber-type disproportion, although the role of RYR1 gene mutations in this condition is unclear.

It is not yet clear whether people with congenital fiber-type disproportion caused by RYR1 gene mutations have an increased risk of malignant hyperthermia (described below).

Malignant hyperthermia

RYR1 gene mutations are the most common genetic risk factor for malignant hyperthermia. Malignant hyperthermia is a severe reaction to particular anesthetic drugs that are often used during surgery and other invasive procedures. The reaction involves a high fever (hyperthermia), a rapid heart rate (tachycardia), muscle rigidity, breakdown of muscle fibers (rhabdomyolysis), and increased acid levels in the blood and other tissues (acidosis). Complications can be life-threatening without prompt treatment.

At least 48 mutations in the RYR1 gene are known to increase the risk of malignant hyperthermia in people without features of a muscle disorder (such as central core disease, described above, or multiminicore disease, described below). Most of these mutations change single amino acids in important regions of the ryanodine receptor 1 protein. These mutations alter the structure of the RYR1 channel, causing it to open more easily and close more slowly in response to certain drugs (particularly some anesthetic gases and a type of muscle relaxant used during surgery). As a result, large amounts of calcium ions are released from the sarcoplasmic reticulum inside muscle cells. An overabundance of calcium ions activates processes that generate heat (leading to increased body temperature) and produce excess acid (leading to acidosis). An increase in calcium ion concentration within muscle cells also causes skeletal muscles to contract abnormally, which leads to muscle rigidity.

Many other changes in the RYR1 gene have been described in people with an increased risk of malignant hyperthermia. It is unclear, however, whether these variations are directly related to malignant hyperthermia risk.

Multiminicore disease

More than 20 mutations in the RYR1 gene have been found to cause atypical forms of multiminicore disease. Multiminicore disease is characterized by muscle weakness, and the atypical forms can have additional features. The condition is also associated with an increased risk of malignant hyperthermia (described above).

RYR1 gene mutations involved in multiminicore disease change single amino acids in the ryanodine receptor 1 protein, which alters the structure and function of the protein. The effects of these changes are unclear. Some mutations may reduce the amount of ryanodine receptor 1 protein produced by the cell or lead to an unstable version of the protein. Other mutations may interfere with the normal regulation of the RYR1 channel. Researchers believe that some RYR1 gene mutations change the shape of the channel in such a way that calcium ions cannot flow through properly. A disruption in calcium ion transport prevents muscles from contracting normally, leading to the muscle weakness characteristic of multiminicore disease.

Centronuclear myopathy

MedlinePlus Genetics provides information about Centronuclear myopathy

Other Names for This Gene

• CCD
• MHS
• MHS1
• PPP1R137
• ryanodine receptor 1 (skeletal)
• ryanodine receptor type1
• RYDR
• RYR
• RYR-1
• RYR1_HUMAN
• sarcoplasmic reticulum calcium release channel
• skeletal muscle ryanodine receptor
• Skeletal muscle-type ryanodine receptor
• SKRR

Genomic Location

Normal Function

The TPM3 gene provides instructions for making a protein called slow muscle alpha (α)-tropomyosin, which is part of the tropomyosin protein family. Tropomyosin proteins regulate the tensing of muscle fibers (muscle contraction) by controlling the binding of two muscle proteins, myosin and actin. In non-muscle cells, tropomyosin proteins play a role in controlling cell shape.

Slow muscle α-tropomyosin is found in skeletal muscles, which are the muscles used for movement. Skeletal muscle is made up of two types of muscle fibers: type I (slow twitch fibers) and type II (fast twitch fibers). Slow muscle α-tropomyosin is found only in type I fibers. Type I fibers are the primary component of skeletal muscles that are resistant to fatigue. For example, muscles involved in posture, such as the neck muscles that hold the head steady, are made predominantly of type I fibers. Slow muscle α-tropomyosin helps regulate muscle contraction in type I skeletal muscle fibers.

Health Conditions Related to Genetic Changes

Cap myopathy

At least two TPM3 gene mutations have been identified in people with cap myopathy. These mutations replace the protein building block (amino acid) arginine with the amino acids cysteine or histidine at position 168 of the protein sequence, written as Arg168Cys or Arg168His (also written as R168C or R168H). The specific effects of these TPM3 gene mutations are unclear, but researchers suggest they may interfere with normal actin-myosin binding, impairing muscle contraction and resulting in the muscle weakness that occurs in cap myopathy.

Congenital fiber-type disproportion

At least 10 mutations in the TPM3 gene have been found to cause congenital fiber-type disproportion, a disorder that causes general muscle weakness that typically does not worsen over time. TPM3 gene mutations appear to be the most common cause of this disorder. These mutations change single amino acids in slow muscle α-tropomyosin and are thought to impair the protein's ability to interact with myosin and actin within type I skeletal muscle fibers, disrupting muscle contraction. Inefficient muscle contraction leads to muscle weakness in people with congenital fiber-type disproportion.

Nemaline myopathy

Mutations in the TPM3 gene are also associated with a condition called nemaline myopathy. People with nemaline myopathy typically have muscle weakness throughout their body, including the muscles of the face, neck, and limbs. When nemaline myopathy is caused by mutations in the TPM3 gene, affected individuals typically have muscle weakness at birth or beginning in early childhood. TPM3 gene mutations account for a small percentage of all cases of nemaline myopathy.

Other Names for This Gene

• cytoskeletal tropomyosin TM30
• FLJ41118
• heat-stable cytoskeletal protein 30 kDa
• hscp30
• TM-5
• TM3
• TPM3_HUMAN
• TRK
• tropomyosin alpha-3 chain
• tropomyosin gamma

Genomic Location

Congenital fiber-type disproportion can have multiple 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.

Most other cases of congenital fiber-type disproportion, including those caused by mutations in the RYR1 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.

In rare cases, this condition can be inherited in an X-linked pattern, although the gene or genes associated with X-linked congenital fiber-type disproportion have not been identified. 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. 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.

It is estimated that 40 percent of individuals with congenital fiber-type disproportion have an affected relative.

Currently we are not aware of new therapies, drugs, supplements, or vitamins to cure or effectively treat congenital fiber-type disproportion. Supportive treatment may involve orthopedic treatments, as well as physical, occupational or speech therapy.

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