Actin-accumulation myopathy is a disorder that primarily affects skeletal muscles, which are muscles that the body uses for movement. People with actin-accumulation myopathy have severe muscle weakness (myopathy) and poor muscle tone (hypotonia) throughout the body. Signs and symptoms of this condition are apparent in infancy and include feeding and swallowing difficulties, a weak cry, and difficulty with controlling head movements. Affected babies are sometimes described as "floppy" and may be unable to move on their own.

The severe muscle weakness that occurs in actin-accumulation myopathy also affects the muscles used for breathing. Individuals with this disorder may take shallow breaths (hypoventilate), especially during sleep, resulting in a shortage of oxygen and a buildup of carbon dioxide in the blood. Frequent respiratory infections and life-threatening breathing difficulties can occur. Because of the respiratory problems, most affected individuals do not survive past infancy. Those who do survive have delayed development of motor skills such as sitting, crawling, standing, and walking.

The name actin-accumulation myopathy derives from characteristic accumulations in muscle cells of filaments composed of a protein called actin. These filaments can be seen when muscle tissue is viewed under a microscope.

Actin-accumulation myopathy is caused by a mutation in the ACTA1 gene. This gene provides instructions for making a protein called skeletal alpha (α)-actin, which is a member of the actin protein family found in skeletal muscles. Actin proteins are important for cell movement and the tensing of muscle fibers (muscle contraction). Thin filaments made up of actin molecules and thick filaments made up of another protein called myosin are the primary components of muscle fibers and are important for muscle contraction. 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.

ACTA1 gene mutations that cause actin-accumulation myopathy may affect the way the skeletal α-actin protein 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.

In some people with actin-accumulation myopathy, no ACTA1 gene mutations have been identified. The cause of the disorder in these individuals is unknown.

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

Actin-accumulation myopathy is an autosomal dominant condition, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases are not inherited; they result from new (de novo) mutations in the gene and occur in people with no history of the disorder in their family.

Actin-accumulation myopathy is a rare disorder that has been identified in only a small number of individuals. Its exact prevalence is unknown.