Multiminicore disease is a disorder that primarily affects muscles used for movement (skeletal muscles). This condition causes muscle weakness and related health problems that range from mild to life-threatening.

Researchers have identified at least four forms of multiminicore disease, which can be distinguished by their characteristic signs and symptoms. The forms of multiminicore disease are the classic form, the progressive form with hand involvement, the antenatal form with arthrogryposis, and the ophthalmoplegic form.

The classic form accounts for about 75 percent of cases of multiminicore disease. This form causes muscle weakness beginning in infancy or early childhood. The muscles of the torso and neck (axial muscles) are most affected with arm and leg muscles less so. Muscle weakness causes affected infants to appear "floppy" (hypotonic) and they may have feeding problems early in life. Muscle weakness can delay the development of motor skills such as sitting, standing, and walking. In this form, the muscles of the ribcage and spine become stiff. In addition, the muscles needed for breathing are weak. This combination of muscle weakness and stiffness leads to severe or life-threatening respiratory problems. Almost all children with the classic form develop an abnormal curvature of the spine (scoliosis), which appears during childhood and steadily worsens over time.

The progressive form with hand involvement causes muscle weakness and looseness of the joints (joint laxity) in the arms and hands. Individuals with this form may experience muscle pain (myalgia) or extreme fatigue in response to physical activity (exercise intolerance). This form accounts for about 10 percent of cases of multiminicore disease.

The antenatal form with arthrogryposis is characterized by stiff, rigid joints throughout the body (arthrogryposis) and distinctive facial features. Weakness in the muscles needed for breathing can result in breathing problems for affected individuals. This form also accounts for about 10 percent of cases of multiminicore disease.

The ophthalmoplegic form of multiminicore disease is characterized by paralysis of the eye muscles (external ophthalmoplegia). This can lead to abnormal eye movements and droopy eyelids (ptosis). This form of the condition can also cause weakness in the muscles close to the center of the body (proximal muscles), such as those of the upper arms and legs. The ophthalmoplegic form accounts for 5 to 10 percent of cases of multiminicore disease.

Many people with multiminicore disease also have an increased risk of developing a severe reaction to certain drugs used during surgery and other invasive procedures. This reaction is called malignant hyperthermia. Malignant hyperthermia occurs in response to some anesthetic gases, which are used to block the sensation of pain, either given alone or in combination with a muscle relaxant that is used to temporarily paralyze a person during a surgical procedure. If given these drugs, people at risk of malignant hyperthermia may experience a rapid increase in heart rate (tachycardia) and body temperature (hyperthermia), abnormally fast breathing (tachypnea), muscle rigidity, breakdown of muscle fibers (rhabdomyolysis), and increased acid levels in the blood and other tissues (acidosis). The complications of malignant hyperthermia can be life-threatening unless they are treated promptly.

Multiminicore disease gets its name from small, disorganized areas called minicores, which are found in skeletal muscle cells of many affected individuals. These abnormal regions can only been seen when muscle tissue is viewed under a microscope. Minicores are often present in cells with few or no mitochondria, which are the energy-producing centers within cells. Although the presence of minicores can help doctors diagnose multiminicore disease, it is unclear how they are related to muscle weakness and the other features of this condition.

Variants (also known as mutations) in the SELENON and RYR1 genes have been found to cause about half of all cases of multiminicore disease.

About 30 percent of cases of multiminicore disease, primarily the classic form, are caused by variants in the SELENON gene. This gene provides instructions for making a protein called selenoprotein N. This protein is highly active in many tissues before birth and may be involved in the formation of muscle tissue (myogenesis). The protein may also be important for normal muscle function after birth, although it is active at much lower levels in adult tissues. This protein is thought to play a role in maintaining an appropriate balance of calcium (calcium homeostasis) in cells. Calcium plays an important role in muscle movement. It is unclear, however, how variants in the SELENON gene lead to muscle weakness and the other features of multiminicore disease.

An estimated 20 percent of multiminicore disease, primarily the non-classic forms, are caused by variants in the RYR1 gene. The RYR1 gene provides instructions for making a protein called ryanodine receptor 1. This protein plays an essential role in skeletal muscles. For the body to move normally, these muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by the flow of charged atoms (ions) into muscle cells. The ryanodine receptor 1 protein forms a channel that releases calcium ions stored within muscle cells. The resulting increase in calcium ion concentration inside muscle cells stimulates muscle fibers to contract, allowing the body to move.

Variants in the RYR1 gene change the structure and function of the ryanodine receptor 1 protein and the calcium channel that it forms. The abnormal calcium channel alters the normal flow of stored calcium ions within muscle cells. A disruption in calcium ion transport prevents muscles from contracting normally, leading to the muscle weakness characteristic of multiminicore disease. RYR1 gene variants are also associated with an increased risk of malignant hyperthermia.

It is likely that individuals with multiminicore disease who do not have a known variant in either of these two genes have variants in other genes that underlie the condition.

Normal Function

The SELENON gene (also called SEPN1) provides instructions for making a protein called selenoprotein N. This protein is part of a family of selenoproteins, which have several critical functions within the body. Selenoproteins are primarily involved in chemical reactions called oxidation-reduction reactions, which are essential for protecting cells from damage caused by unstable oxygen-containing molecules. Although the exact function of selenoprotein N is unknown, it is likely involved in protecting cells against oxidative stress. Oxidative stress occurs when unstable molecules called free radicals accumulate to levels that damage or kill cells.

Selenoprotein N is highly active in many tissues before birth and may be involved in the formation of muscle tissue (myogenesis). The protein may also be important for normal muscle function after birth, although it is active at much lower levels in adult tissues. This protein is thought to play a role in maintaining an appropriate balance of calcium (calcium homeostasis) in cells. Calcium plays an important role in muscle movement.

Health Conditions Related to Genetic Changes

Multiminicore disease

At least 17 mutations in the SELENON gene have been identified in people with the classic form of multiminicore disease. This condition is named for a distinctive abnormality in the muscle fibers called minicores (which can only be seen with a microscope). In addition, affected individuals have muscle weakness, particularly in the muscles of the torso and neck (the axial muscles); abnormal curvature of the spine (scoliosis); and serious breathing problems. Many of the genetic changes that cause classic multiminicore disease lead to the production of an abnormally short version of selenoprotein N. Other mutations change single protein building blocks (amino acids) in critical regions of the protein. The effects of changes in the structure and function of selenoprotein N are unknown, and researchers are working to determine how these changes lead to muscle weakness and the other characteristic features of classic multiminicore disease.

Rigid spine muscular dystrophy

More than a dozen SELENON gene mutations have been found to cause rigid spine muscular dystrophy 1 (RSMD1). In people with this disorder, the muscles surrounding the spine weaken and waste away (atrophy), and the joints in the spine develop deformities called contractures that restrict movement. Affected children have limited ability to move their heads up and down or side to side. They also develop scoliosis and have serious breathing problems during sleep.

The SELENON gene mutations that cause RSMD1 are thought to reduce the amount of selenoprotein N or impair its activity in cells. It is unclear how a shortage of functional selenoprotein N affects the formation of muscle tissue or the function of muscles. Researchers are working to determine why axial muscles are particularly affected by SELENON gene mutations.

Congenital fiber-type disproportion

MedlinePlus Genetics provides information about Congenital fiber-type disproportion

Other disorders

Mutations in the SELENON gene are involved in another rare muscle disorder called desmin-related myopathy with Mallory body-like inclusions. This disorder is characterized by the presence of small clusters of accumulated proteins in the muscle fibers. These abnormal regions can only be seen when muscle tissue is viewed under a microscope. The inclusions resemble an abnormality known as Mallory bodies. As in other SELENON-related muscle disorders (described above), desmin-related myopathy with Mallory body-like inclusions is characterized by axial muscle weakness, spine stiffness, scoliosis, and serious breathing problems. Because they have a similar pattern of signs and symptoms and are caused by mutations in the same gene, many researchers believe that these conditions are all part of a single syndrome with variable signs and symptoms. Together, muscle diseases caused by SELENON gene mutations are known as SELENON-related (or SEPN1-related) myopathy. It is unclear why mutations in the SELENON gene cause the different muscle fiber abnormalities that distinguish these disorders.

Other Names for This Gene

• selenoprotein N, 1
• SELN
• SEPN1
• SEPN1_HUMAN

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

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have variants. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Multiminicore disease is thought to be a rare disorder, although its incidence is unknown.