Miyoshi myopathy is a muscle disorder that begins with weakness in the muscles that are located away from the center of the body (distal muscles), such as those in the legs. During early to mid-adulthood, affected individuals typically begin to experience muscle weakness and wasting (atrophy) in one or both calves. If only one leg is affected, the calves appear different in size (asymmetrical). Calf weakness can make it difficult to stand on tiptoe.

As Miyoshi myopathy slowly worsens, the muscle weakness and atrophy spread up the leg to the muscles in the thigh and buttock and can also involve the upper arm and shoulder muscles. Eventually, affected individuals may have difficulty climbing stairs or walking for an extended period of time. Some people with Miyoshi myopathy may eventually need wheelchair assistance.

Rarely, abnormal heart rhythms (arrhythmias) have developed in people with Miyoshi myopathy. Individuals with Miyoshi myopathy have highly elevated levels of an enzyme called creatine kinase (CK) in their blood, which often indicates muscle disease.

Miyoshi myopathy is caused by mutations in the DYSF or ANO5 gene. When Miyoshi myopathy is caused by ANO5 gene mutations it is sometimes referred to as distal anoctaminopathy; when this condition is caused by DYSF gene mutations it is known as a dysferlinopathy. The DYSF and ANO5 genes provide instructions for making proteins primarily found in muscles that are used for movement (skeletal muscles). The protein produced from the DYSF gene, called dysferlin, is found in the thin membrane called the sarcolemma that surrounds muscle fibers. Dysferlin is thought to aid in repairing the sarcolemma when it becomes damaged or torn due to muscle strain.

The ANO5 gene provides instructions for making a protein called anoctamin-5. This protein is located within the membrane of a cell structure called the endoplasmic reticulum, which is involved in protein production, processing, and transport. Anoctamin-5 is thought to act as a channel, allowing charged chlorine atoms (chloride ions) to flow in and out of the endoplasmic reticulum. The regulation of chloride flow within muscle cells plays a role in controlling muscle tensing (contraction) and relaxation.

DYSF and ANO5 gene mutations often result in a decrease or elimination of the corresponding protein. A lack of dysferlin leads to a reduced ability to repair damage done to the sarcolemma of muscle fibers. As a result, damage accumulates and leads to atrophy of the muscle fiber. It is unclear why this damage leads to the specific pattern of weakness and atrophy that is characteristic of Miyoshi myopathy. The effects of the loss of anoctamin-5 are also unclear. While chloride is necessary for normal muscle function, it is unknown how a lack of this chloride channel causes the signs and symptoms of Miyoshi myopathy.

Normal Function

The DYSF gene provides instructions for making a protein called dysferlin. This protein is found in the thin membrane called the sarcolemma that surrounds muscle fibers. Dysferlin is thought to aid in repairing the sarcolemma when it becomes damaged or torn due to muscle strain. Researchers suggest that dysferlin may also be involved in the formation of new muscle fibers (regeneration) and in inflammation, but little is known about these functions.

Health Conditions Related to Genetic Changes

Limb-girdle muscular dystrophy

More than 140 mutations in the DYSF gene that can cause limb-girdle muscular dystrophy type 2B have been identified. Limb-girdle muscular dystrophy is a group of related disorders characterized by muscle weakness and wasting (atrophy), particularly in the shoulders, hips, thighs, and upper arms. Muscle problems caused by DYSF gene mutations, such as limb-girdle muscular dystrophy type 2B and others (see below), are called dysferlinopathies.

DYSF gene mutations may disrupt the function of the dysferlin protein and interfere with the muscle repair process. Studies suggest that inefficient repair of damaged muscle fibers may lead to inflammation and degeneration of muscles, resulting in muscle weakness.

Miyoshi myopathy

More than 100 mutations in the DYSF gene have been found to cause Miyoshi myopathy. This condition is a muscle disorder that is characterized by progressive weakness and atrophy of muscles that are away from the center of the body (distal muscles), particularly those in the legs. The DYSF gene mutations identified in people with Miyoshi myopathy change single amino acids in the dysferlin protein, which impairs the protein's function or results in the production of a nonfunctional protein. A common cause of the condition in people of Japanese ancestry is a mutation that replaces the amino acid tryptophan with the amino acid cysteine at position 999 in dysferlin (written Trp999Cys or W999C).

A lack of normal dysferlin leads to a reduced ability to repair damage done to the sarcolemma of muscle fibers. As a result, damage accumulates and leads to atrophy of the muscle fiber. It is unclear why the DYSF gene mutations that cause Miyoshi myopathy lead to the specific pattern of weakness and atrophy that is characteristic of this disorder.

Some researchers consider Miyoshi myopathy to be a variant of limb-girdle muscular dystrophy (see above) rather than a separate disorder because they are caused by mutations in the same gene and have overlapping signs and symptoms.

Other disorders

DYSF gene mutations also cause another dysferlinopathy called distal myopathy with anterior tibial onset. In this condition, the muscle weakness is most apparent in the muscles of the lower legs. This condition first becomes apparent in a muscle called tibialis anterior, which is located at the front of the lower leg and helps to flex the foot. Distal myopathy with anterior tibial onset later affects the muscles of the upper leg, and affected individuals eventually require wheelchair assistance.

Other Names for This Gene

• DYSF_HUMAN
• dysferlin, limb girdle muscular dystrophy 2B (autosomal recessive)
• dystrophy-associated fer-1-like 1
• fer-1-like protein 1
• FER1L1
• FLJ00175
• FLJ90168
• LGMD2B

Genomic Location

Normal Function

The ANO5 gene provides instructions for making a protein called anoctamin-5. While the specific function of this protein is not well understood, it belongs to a family of proteins, called anoctamins, that act as chloride channels. Chloride channels, which transport negatively charged chlorine atoms (chloride ions) in and out of cells, play a key role in a cell's ability to generate and transmit electrical signals. Studies suggest that most anoctamin proteins function as chloride channels that are turned on (activated) in the presence of positively charged calcium atoms (calcium ions); these channels are known as calcium-activated chloride channels. The mechanism for this calcium activation is unclear. Anoctamin proteins are also involved in maintaining the membrane that surrounds cells and repairing the membrane if it gets damaged.

The anoctamin-5 protein is most abundant in muscles used for movement (skeletal muscles). For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. The regulation of chloride flow within muscle cells plays a role in controlling muscle contraction and relaxation.

The anoctamin-5 protein is also found in other cells including heart (cardiac) muscle cells and bone cells. Studies have suggested that the anoctamin-5 protein may be important for the development of muscle and bone before birth.

Health Conditions Related to Genetic Changes

Gnathodiaphyseal dysplasia

At least three ANO5 gene mutations have been identified in people with a bone disorder called gnathodiaphyseal dysplasia, which leads to fragile bones, jaw problems, and other skeletal abnormalities. The ANO5 gene mutations that cause gnathodiaphyseal dysplasia change single protein building blocks (amino acids) in the anoctamin-5 protein. It is unclear how these mutations lead to the signs and symptoms of gnathodiaphyseal dysplasia, or why they primarily affect bones while other ANO5 gene mutations cause muscle disorders. Researchers suggest that the mutations may affect the way cells process calcium, an important mineral in bone development and growth.

Limb-girdle muscular dystrophy

More than 40 mutations in the ANO5 gene have been identified in people with limb-girdle muscular dystrophy type 2L. Limb-girdle muscular dystrophy is a group of related disorders characterized by muscle weakness and wasting (atrophy), particularly in the shoulders, hips, thighs, and upper arms.

The ANO5 gene mutations identified in people with limb-girdle muscular dystrophy type 2L change single amino acids in the anoctamin-5 protein sequence, disrupt how genetic information is pieced together to make a blueprint for producing the protein, or result in a premature stop signal that leads to an abnormally short protein. One of the mutations adds an extra DNA building block (nucleotide) to the ANO5 gene (written as 191dupA) and is believed to be a relatively common cause of limb-girdle muscular dystrophy in people with northern European ancestry. This mutation alters the instructions used to make the anoctamin-5 protein, leading to a premature stop signal that would produce an abnormally short protein. Instead, a cellular error-catching mechanism called nonsense-mediated decay prevents the protein from being produced at all.

ANO5 gene mutations that eliminate or impair the role of the anoctamin-5 protein as a chloride channel likely lead to impaired muscle function, resulting in the signs and symptoms of limb-girdle muscular dystrophy.

Miyoshi myopathy

At least 10 mutations in the ANO5 gene have been found to cause Miyoshi myopathy. When caused by mutations in this gene, the condition is also known as distal anoctaminopathy. Miyoshi myopathy is a muscle disorder that is characterized by progressive weakness and atrophy of muscles that are away from the center of the body (distal muscles), particularly those in the legs. The ANO5 gene mutations identified in people with Miyoshi myopathy change single amino acids in the anoctamin-5 protein or result in the production of an abnormally short protein that is quickly broken down.

These mutations result in the production of little or no anoctamin-5 protein. The effects of the loss of anoctamin-5 are unclear. While chloride is necessary for normal muscle function, it is unknown how a lack of this chloride channel causes the signs and symptoms of Miyoshi myopathy.

The 191dupA mutation that can cause limb-girdle muscular dystrophy (described above) is also a common cause of Miyoshi myopathy in individuals of northern European ancestry. It is not known why the 191dupA mutation can result in different patterns of signs and symptoms. Miyoshi myopathy caused by ANO5 gene mutations is likely a variation of limb-girdle muscular dystrophy because it is caused by mutations in the same gene, and in some cases even by the same mutation.

Other Names for This Gene

• ANO5_HUMAN
• anoctamin-5
• GDD1
• gnathodiaphyseal dysplasia 1 protein
• integral membrane protein GDD1
• LGMD2L
• TMEM16E
• transmembrane protein 16E

Genomic Location

• Muscle weakness and atrophy (wasting), most marked in the distal parts of the legs, especially the gastrocnemius (calf) and soleus (Achilles tendon) muscles, specially in young adults
• Inability to stand on tiptoe, retaining the ability to stand on the heels
• Slow progression of weakness and atrophy spreading to the thighs and gluteal muscles, at which time climbing stairs, standing, and walking become difficult
• Mildly loss of muscular mass in forearms with decrease in grip strength; the small muscles of the hands are not affected
• Weakness of the shoulder girdle muscles, which may occur on one side than the other.

• Mid- to late-childhood or early-adult onset of signs and symptoms
• Early and predominant involvement of the calf muscles
• Slow progression
• Elevation of serum creatine kinase (CK) concentration, often 10-100 times normal
• Primarily myogenic pattern on EMG (electromyography)
• Biopsy evidence of a chronic, active myopathy without rimmed vacuoles

• Physical therapy and stretching exercises to promote mobility and prevent contractures
• Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility
• Surgical intervention as needed for orthopedic complications such as foot deformity and scoliosis
• Use of respiratory aids when indicated
• Social and emotional support