Congenital myasthenic syndrome is a group of conditions characterized by muscle weakness (myasthenia) that worsens with physical exertion. The muscle weakness typically begins in early childhood but can also appear in adolescence or adulthood. Facial muscles, including muscles that control the eyelids, muscles that move the eyes, and muscles used for chewing and swallowing, are most commonly affected. However, any of the muscles used for movement (skeletal muscles) can be affected in this condition. Due to muscle weakness, affected infants may have feeding difficulties. Development of motor skills such as crawling or walking may be delayed. The severity of the myasthenia varies greatly, with some people experiencing minor weakness and others having such severe weakness that they are unable to walk.

Some individuals have episodes of breathing problems that may be triggered by fevers or infection. Severely affected individuals may also experience short pauses in breathing (apnea) that can lead to a bluish appearance of the skin or lips (cyanosis).

Mutations in many genes can cause congenital myasthenic syndrome. Mutations in the CHRNE gene are responsible for more than half of all cases. A large number of cases are also caused by mutations in the RAPSN, CHAT, COLQ, and DOK7 genes. All of these genes provide instructions for producing proteins that are involved in the normal function of the neuromuscular junction. The neuromuscular junction is the area between the ends of nerve cells and muscle cells where signals are relayed to trigger muscle movement.

Gene mutations lead to changes in proteins that play a role in the function of the neuromuscular junction and disrupt signaling between the ends of nerve cells and muscle cells. Disrupted signaling between these cells results in an impaired ability to move skeletal muscles, muscle weakness, and delayed development of motor skills. The respiratory problems in congenital myasthenic syndrome result from impaired movement of the muscles of the chest wall and the muscle that separates the abdomen from the chest cavity (the diaphragm).

Mutations in other genes that provide instructions for proteins involved in neuromuscular signaling have been found to cause some cases of congenital myasthenic syndrome, although these mutations account for only a small number of cases. Some people with congenital myasthenic syndrome do not have an identified mutation in any of the genes known to be associated with this condition.

Normal Function

The CHRNE gene provides instructions for making the epsilon (ε) component (subunit) of the acetylcholine receptor (AChR) protein. The AChR protein is found in the membrane of skeletal muscle cells and plays a critical role in the neuromuscular junction, which is the area where signaling between nerve and muscle cells occurs. Signaling between nerve and muscle cells is necessary for movement. The AChR protein consists of five subunits, each of which is produced from a different gene. The subunits are assembled into the AChR protein in the endoplasmic reticulum, a cell structure involved in protein processing and transport, before being transported to the cell membrane. There are two major forms of the AChR protein, a fetal type that is present before birth and an adult type. The ε subunit is found only in the adult AChR protein. At about the 33rd week of pregnancy, the ε subunit replaces the gamma (γ) subunit (found only in fetal AChR) to form adult AChR protein.

Health Conditions Related to Genetic Changes

Congenital myasthenic syndrome

More than 90 mutations in the CHRNE gene have been found to cause congenital myasthenic syndrome. Most of these mutations replace one DNA building block (nucleotide) in the gene, but other mutations add or delete small sections of DNA. These mutations can lead to the production of an altered ε subunit. A change in the ε subunit leads to an increase in AChR protein signaling or a decrease in AChR protein signaling, which impairs cell-to-cell communication at the neuromuscular junction. Decreased signaling can lead to a decrease in muscle movement and cause weakness, while an increase in signaling can damage muscle cells and cause weakness. Problems with communication between nerve and muscle cells can lead to the signs and symptoms of congenital myasthenic syndrome, including muscle weakness and delayed development of motor skills such as crawling and walking. Some people with CHRNE mutations seem to have a milder course of the disease compared with other affected individuals, likely because the fetal γ subunit (active at low levels after birth) can partially compensate for the lack of ε subunit in the adult AChR protein.

Other Names for This Gene

• acetylcholine receptor subunit epsilon
• ACHE_HUMAN
• AchR epsilon subunit
• ACHRE
• cholinergic receptor, nicotinic epsilon
• cholinergic receptor, nicotinic, epsilon
• cholinergic receptor, nicotinic, epsilon (muscle)
• cholinergic receptor, nicotinic, epsilon polypeptide

Genomic Location

This condition is most commonly inherited in an autosomal recessive pattern, which 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.

Rarely, this condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

The prevalence of congenital myasthenic syndrome is unknown. At least 600 families with affected individuals have been described in the scientific literature.