Hereditary myopathy with early respiratory failure (HMERF) is an inherited disease that affects muscles used for movement (skeletal muscles) and muscles that are needed for breathing (respiratory muscles).

The major signs and symptoms of HMERF usually appear in adulthood, often in the mid-thirties. Among the earliest signs of the condition are breathing problems and difficulty walking. Weakness of the respiratory muscles, particularly the diaphragm (the muscle that separates the organs in the abdomen from those in the chest), causes breathing problems. This weakness worsens over time and can lead to life-threatening respiratory failure. Some affected individuals have weakness of muscles of the lower leg and foot, which makes it difficult to lift the toes while walking, a condition known as foot drop. Other muscles that become weak in people with HMERF include those of the hips, thighs, upper arms, and neck.

When viewed under a microscope, muscle fibers from affected individuals contain abnormal structures called cytoplasmic bodies. In many cases, the cytoplasmic bodies are arranged side-by-side in a ring inside the muscle fiber, resembling a necklace (necklace cytoplasmic bodies).

HMERF is caused by mutations in the TTN gene. This gene provides instructions for making a protein called titin. Titin plays an important role in muscles the body uses for movement (skeletal muscles) and in heart (cardiac) muscle.

Within muscle cells, titin is an essential component of structures called sarcomeres. Sarcomeres are the basic units of muscle contraction; they are made of proteins that generate the mechanical force needed for muscles to contract. Titin has several functions within sarcomeres. One of its most important jobs is to act as a backbone in these structures, providing structure, flexibility, and stability. Titin also plays a role in chemical signaling and in assembling new sarcomeres.

The TTN gene mutations responsible for HMERF lead to the production of an altered version of the titin protein that cannot fold into its normal 3-dimensional shape. Researchers are studying how abnormally folded titin contributes to the muscle damage that underlies the signs and symptoms of HMERF. It is unclear why these effects are usually limited to skeletal muscles and respiratory muscles, and do not involve cardiac muscle.

Rarely, people with the characteristic features of HMERF do not have identified mutations in the TTN gene. In these cases, the genetic cause of the condition is unknown.

Normal Function

The TTN gene provides instructions for making a very large protein called titin. This protein plays an important role in skeletal muscles, which the body uses for movement, and in heart (cardiac) muscle. Slightly different versions (called isoforms) of titin are made from the TTN gene in different muscles.

Within muscle cells, titin is an essential component of structures called sarcomeres. Sarcomeres are the basic units of muscle tensing (contraction); they are made of proteins that generate the mechanical force needed for muscles to contract. Titin has several functions within sarcomeres. One of the protein's main jobs is to provide structure, flexibility, and stability to these cell structures. Titin interacts with other muscle proteins, including actin and myosin, to keep the components of sarcomeres in place as muscles contract and relax. Titin also contains a spring-like region that allows muscles to stretch. Additionally, researchers have found that titin plays a role in chemical signaling and in assembling new sarcomeres.

Health Conditions Related to Genetic Changes

Centronuclear myopathy

Several variants (also known as mutations) in the TTN gene have been found to cause centronuclear myopathy, a condition that is characterized by muscle weakness (myopathy) in the skeletal muscles. Most of these variants alter the way the gene's instructions are used to produce titin, resulting in production of an abnormal protein with reduced or altered activity in muscle cells. Other variants prevent the production of titin protein. It is unclear how TTN gene variants cause centronuclear myopathy, but it is likely that a shortage of normal titin protein leads to dysfunction of the sarcomere. Abnormal sarcomeres prevent muscle cells from contracting and relaxing normally, resulting in the muscle weakness that is characteristic of centronuclear myopathy.

Early-onset myopathy with fatal cardiomyopathy

Variants in the TTN gene have been identified in people with early-onset myopathy with fatal cardiomyopathy (EOMFC), an inherited disease that affects both skeletal and cardiac muscle. These genetic changes occur near the end of the TTN gene and lead to the production of an abnormally short version of the titin protein. The defective protein disrupts the function of sarcomeres, preventing skeletal and cardiac muscle from developing and working normally. These muscle abnormalities underlie the characteristic features of EOMFC, including skeletal muscle weakness and a form of heart disease called dilated cardiomyopathy.

Familial dilated cardiomyopathy

Many TTN gene variants have been found to cause familial dilated cardiomyopathy, a condition that weakens and enlarges the heart, preventing it from pumping blood efficiently. Signs and symptoms of familial dilated cardiomyopathy typically begin in mid-adulthood and result in heart failure. TTN gene variants account for approximately one-quarter of all cases of familial dilated cardiomyopathy. These variants result in the production of an abnormal titin protein, particularly isoforms that are found in cardiac muscle. It is unclear how the altered protein causes familial dilated cardiomyopathy, but it likely impairs sarcomere function and disrupts chemical signaling. Changes in sarcomere function reduce the heart's ability to contract, weakening cardiac muscle and leading to the signs and symptoms of familial dilated cardiomyopathy.

Hereditary myopathy with early respiratory failure

Several variants in the TTN gene have been found to cause hereditary myopathy with early respiratory failure (HMERF), an inherited disease that affects muscles used for movement (skeletal muscles) and muscles that are needed for breathing (respiratory muscles). These variants change single DNA building blocks (nucleotides) in a region of the TTN gene called exon 344. These changes alter a region of the titin protein called the FN3 119 domain and are thought to impair the folding of the titin protein into its normal 3-dimensional shape. Researchers are studying how abnormally folded titin contributes to the muscle damage underlying the signs and symptoms of HMERF. It is unclear why these effects are usually limited to certain skeletal muscles and respiratory muscles, and do not involve cardiac muscle.

Limb-girdle muscular dystrophy

A small number of TTN gene variants have been found to cause limb-girdle muscular dystrophy type 2J (LGMD2J). Limb-girdle muscular dystrophy is a group of related disorders characterized by weakness and wasting of skeletal muscles, particularly in the shoulders, hips, and limbs. LGMD2J is a type of limb-girdle muscular dystrophy that has been identified primarily in the Finnish population. The genetic change found in this population deletes several amino acids and replaces them with other amino acids at the end of the titin protein. This complex variant, known as FINmaj, causes LGMD2J when it occurs in both copies of the TTN gene. The FINmaj variant may disrupt titin's interactions with other proteins that are needed to maintain muscle fibers. Loss of muscle fibers causes muscles to weaken and waste away over time, resulting in the signs and symptoms of limb-girdle muscular dystrophy.

Tibial muscular dystrophy

Several variants in the TTN gene have been identified in people with tibial muscular dystrophy, a condition that primarily affects the muscles at the front of the lower leg. The FINmaj variant (described above) has been found to cause tibial muscular dystrophy in all affected people of Finnish descent. Other TTN gene variants cause tibial muscular dystrophy in non-Finnish European populations. This condition is caused by variants that occur in one copy of the TTN gene.

Researchers predict that the TTN gene variants responsible for tibial muscular dystrophy, including FINmaj, alter the ability of the titin protein to interact with other proteins within sarcomeres. These alterations likely impair muscle fiber maintenance or muscle contraction, causing muscles to weaken and waste away over time. It is unclear why the resulting weakness is usually limited to muscles in the lower legs in tibial muscular dystrophy.

Researchers are working to determine why some conditions resulting from TTN gene variants predominantly affect cardiac muscle, some predominantly affect skeletal muscle, and some affect both. They suspect that these differences may be related to the location of variants in the TTN gene and how they affect the many versions of titin that are produced in different muscles.

Arrhythmogenic right ventricular cardiomyopathy

MedlinePlus Genetics provides information about Arrhythmogenic right ventricular cardiomyopathy

Familial hypertrophic cardiomyopathy

MedlinePlus Genetics provides information about Familial hypertrophic cardiomyopathy

Other disorders

TTN gene variants can cause muscle problems that begin before or soon after birth. Scientists suggest that early-onset forms of titin-related muscle disorders be grouped as congenital titinopathy. Often, fetuses with this condition move less than normal in the uterus. Affected babies may have low muscle tone (hypotonia) or joint deformities that limit their ability to move (contractures). Babies and children with congenital titinopathy can have muscle weakness in the neck, arms, or legs which usually worsens slowly, and they often learn to walk later than their peers. Abnormal side-to-side curvature of the spine (scoliosis) and difficulty breathing also commonly occur, and they can worsen rapidly. Some individuals with congenital titinopathy have heart problems. It is not clear how TTN gene variants affect the titin protein and cause congenital titinopathy. Researchers suspect that the version (isoform) of the titin protein affected by the gene variant may help determine the set of features in affected individuals.

Other Names for This Gene

• CMH9
• CMPD4
• CONNECTIN
• EOMFC
• LGMD2J
• MYLK5
• TITIN_HUMAN
• TMD

Genomic Location

HMERF is typically inherited in an autosomal dominant pattern, which means one copy of the altered TTN gene in each cell is sufficient to cause the disorder. An affected person usually has one parent with the condition.

In rare cases, a specific mutation in one copy of the TTN gene leads to mild signs and symptoms of the condition, such as respiratory problems that begin later than is typical in HMERF with no other muscle weakness. However, family members who have the mutation in both copies of the gene have severe features of HMERF.

HMERF is a rare condition with an unknown prevalence. It has been found in populations worldwide.