Limb-girdle muscular dystrophy

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Limb-girdle muscular dystrophy

Definition

Limb-girdle muscular dystrophy encompasses a diverse group of hereditary degenerative muscle disorders characterized by weakness and deterioration of the skeletal muscles.

Description

The term limb-girdle muscular dystrophy (LGMD) is used to describe a group of muscular dystrophies that

Genetic causes of the limb-girdle muscular dystrophies
Type Mode of Inheritance Gene Involved Chromosomal Location
*Alpha-sarcoglycanopathy Recessive LGMD2D (SGCA) 17
*Beta-sarcoglycanopathy Recessive LGMD2E (SGCB) 4
*Gamma-sarcoglycanopathy Recessive LGMD2C (SGCG) 13
*Delta-sarcoglycanopathy Recessive LGMD2F (SGCD) 5
Calpainopathy Recessive LGMD2A (CAPN3) 15
Dysferlinopathy Recessive LGMD2B (DYSF) 2
Telethoninopathy Recessive LGMD2G 17
LGMD2H Recessive LGMD2H 9
LGMD2I Recessive LGMD2I 19
LGMD1A Dominant LGMD1A 5
LGMD1B Dominant LGMD1B 1
Caveolinopathy Dominant LGMD1C (CAV3) 3
LGMD1D Dominant LGMDID 6
LGMD1E Dominant   7
Bethlem myopathy Dominant COL6A1 21
  Dominant COL6A2 21
  Dominant COL6A3 2
*Each type of sarcoglycanopathy can result from a gene change that results in complete absence of sarcoglycan protein or decreased amounts of sarcoglycan protein.

cause a muscle deterioration that primarily affects the voluntary muscles around the limb girdle. The muscles of the limb girdle include those around the shoulders and hips. As the disease develops, the distal muscles of the limbs can be affected. In some cases the muscles of the heart can also be affected. There are at least 15 different LGMD that each have a different range of symptoms. Each of the muscular dystrophies result in an absent, deficient or abnormal protein that is required for normal structure and function of the muscles. It can be difficult to differentiate LGMD from other muscular dystrophies and muscle disorders which can also result in a weakness in the limb girdle.

Genetic profile

Each type of limb-girdle muscular dystrophy (LGMD) is caused by changes in a different type of gene that produces a protein normally involved in the functioning of the skeletal muscles (see table 1). Each gene is found at a specific location on a chromosome. We inherit two of each type of gene, one from our mother and one from our father. Each type of gene produces a specific type of protein. A change (mutation) in a gene can cause it to produce abnormal protein, an increased or decreased amount of normal protein or can cause it to stop producing protein altogether. Abnormal or decreased amounts of skeletal muscle proteins can affect the development or functioning of the muscle cells, causing the symptoms of LGMD. Most forms of LGMD are autosomal recessive although some rare forms are autosomal dominant.

An autosomal recessive form of LGMD is caused by a change in both genes of a pair. One of the changed genes is inherited from the egg cell of the mother and one of the changed genes is inherited from the sperm cell of the father. Parents who have a child with an autosomal recessive form of LGMD are called carriers, since they each possess one changed LGMD gene and one unchanged LGMD gene. Carriers do not have any symptoms since they have one unchanged gene, which produces enough normal protein to prevent the symptoms of LGMD. Each child born to parents who are both carriers for the same type of LGMD, has a 25% chance of having LGMD, a 50% chance of being a carrier and a 25% chance of being neither a carrier nor affected with LGMD. Parents who are carriers for different types of LGMD are not at increased risk for having affected children.

The autosomal dominant forms of LGMD are caused by a change in only one gene of a pair. Sometimes this changed gene is inherited from either the mother or the father. If the changed gene is inherited, then each sibling of the person with LGMD has a 50% chance of inheriting the condition. Sometimes the change occurs spontaneously when the egg and sperm come together to form the first cell of the baby. In this case other relatives, such as siblings, are not at increased risk for inheriting LGMD. A person with an autosomal dominant form of LGMD has a 50% chance of passing the condition on to his or her

Frequency of limb–girdle muscular dystrophies
Type Frequency Most Common In:
Alpha-sarcoglycanopathy   None
Beta-sarcoglycanopathy Majority with severe disease— Amish
Gamma-sarcoglycanopathy 10% of those with mild disease North Africans; Gypsies
Delta-sarcoglycanopathy   Brazilian
Calpainopathy Approximately 10%—30% Amish; La Reunion Isle.; Basque (Spain); Turkish
Dysferlinopathy Approximately 10% Libyan Jews
Telethoninopathy Rare Italian
LGMD2H Unknown Unknown
LGMD2I Unknown Unknown
LGMD1A Rare Unknown
LGMD1B Rare Unknown
Caveolinopathy Rare Unknown
LGMD1D Rare Unknown
LGMD1E Rare Unknown
Bethlem myopathy Rare Unknown

children. Some people who posses an autosomal dominant LGMD gene change do not have any symptoms.

Demographics

The incidence of LGMD is not known since it can have a wide range of symptoms and is difficult to differentiate from other muscular disorders. Some forms of LGMD are found more commonly in people of a certain ethnic background (see table 2). LGMD is found equally in men and women.

Signs and symptoms

Each type of LGMD has a different range of symptoms (see table 3). The symptoms can even vary between individuals with the same type of LGMD. The age of onset of symptoms varies tremendously and can range from infancy to adulthood. The most common symptom of LGMD is muscle weakness and deterioration involving the muscles around the hips and shoulders. The disorder progresses at a different rate in different people. The progression and extent of muscle deterioration cannot be predicted, although individuals with an onset of the disorder in adulthood may have a slower progression and milder symptoms.

The first noticeable symptom of LGMD is often a "waddling" gait due to weakness of the hip and leg muscles. Difficulties in rising from a chair or toilet seat and difficulties in climbing stairs are common. Eventually walking may become so difficult that a wheelchair or scooter is necessary for locomotion. Enlargement or a decrease in size of the calf muscles can also be seen. Contractures and muscle cramps are experienced by some individuals with LGMD. The limited mobility associated with LGMD can result in muscle soreness and joint pain.

Lifting heavy objects, holding the arms outstretched and reaching over the head can become difficult because of weaknesses in the shoulder muscles. Some individuals with LGMD may even eventually have difficulties swallowing and feeding themselves. Sometimes the back muscles can become weakened and result in scoliosis (curvature of the spine).

LGMD can occasionally result in a weakening of the heart muscles and/or the respiratory muscles. Some people may experience a weakening of the heart muscles called a cardiomyopathy. Others may develop a conduction defect, an abnormality in the electrical system of the heart that regulates the heartbeat. A weakening of the muscles necessary for respiration can cause breathing difficulties. LGMD does not affect the brain and the ability to reason and think. Individuals with LGMD also maintain normal bladder and bowel control and sexual functioning.

Diagnosis

There is no single test available to diagnose LGMD. A diagnosis is based on clinical symptoms, physical examinations, and a variety of tests. The doctor will often first take a medical history to establish the type of symptoms experienced and the pattern of muscle weakness. He or she will usually ask questions about the family history to see whether other family members have similar symptoms.

It is necessary for the doctor to establish whether the weakness is due to problems with the muscles or due to

Symptoms of the limb-girdle muscular dystrophies
Type Age of Onset Early Symptoms Late Symptoms
*Sarcoglycanopathy (complete deficiency) 3–15 years (8.5 average) Proximal weakness Contractures
    Difficulty walk/run Curvature in the spine
    Enlarged calf muscles Wheelchair bound
      Possible cardiac conduction defect
      Dilated cardiomyopathy
**Sarcoglycanopathy (partial deficiency Adolescence/Young adulthood Muscle cramp  
Calpainopathy 2–40 years (8–15 average) Intolerance to exercise Wheelchair bound
    Proximal weakness  
    Jutting backwards of shoulder blades (scapular winging)  
    Decreased size of calf muscles  
    Contractures  
    Curvature in the spine  
Dysferlinopathy 17–23 years Some patients have distal weakness and some have proximal weakness  
    Inability to tip-toe  
    Difficulties walk/run  
Telethoninopathy Early teens   Wheelchair bound
LGMD2H 8–27 years   Wheelchair bound
LGMD2I 1.5–27 years   Wheelchair bound
LGMD1A 18–35 years Proximal leg and arm weakness Distal weakness
    Tight Achilles tendon  
    Problems with articulation of speech  
    Nasal sounding speech  
LGMD1B 4–38 years (50% onset childhood) Proximal lower limb weakness Contractures
      Irregular heart beat
      Sudden death due to cardiac problems (if untreated)
LGMD1D <25 years Proximal muscle weakness All patients remain able to walk
    Cardiac conduction defect  
    Dilated cardiomyopathy  
LGMD1E 9–49 years (30 average) Proximal lower and upper limb muscle weakness Contractures
      Difficulties swallowing
Caveolinopathy Approx. 5 years Mild to moderate proximal weakness  
    Muscle cramping  
    Enlargement of the calf muscles  
    Some have no symptoms  
Bethlem myopathy <2 years Floppy muscles in infancy 2/3 of patents are wheelchair bound
    Proximal muscle weakness by age 50
    Contractures  
* Includes alpha, beta, gamma and delta sarcoglycanopathies that result in complete absence of a sarcoglycan protein
**Includes alpha, beta, gamma and delta sarcoglycanopathies that result in decreased amounts of a sarcoglycan protein

a problem with the nerves that control the muscles. Sometimes this can be accomplished through a physical examination. Testing called electromyography is often performed to establish whether the weakness is nerve or muscle based. During electromyography a needle electrode is inserted into the muscle. Electromyography measures the electrical activity of the muscle in response to stimulation by the nerves.

A blood test that measures the amount of creatine kinase is often performed. Creatine kinase is an enzyme that is produced by damaged muscle. High levels of creatine kinase suggest that the muscle is being destroyed, but do not indicate the cause of the damage. The most common causes of increased creatine kinase are muscular dystrophy and an inflammation of the muscle.

A muscle biopsy will often be performed if LGMD is suspected. During the muscle biopsy, a small amount of muscle is surgically removed. The muscle sample is examined under the microscope to check for changes that are characteristic of muscular dystrophies. The amount and type of muscle proteins present in the sample of muscle can sometimes help to confirm a diagnosis of LGMD and can sometimes indicate the type of LGMD.

A diagnosis can be difficult to make since there are many types of LGMD and a wide range of symptoms. It can also be difficult to differentiate LGMD from other muscular dystrophies that have similar symptoms such as Becker and Duchenne muscular dystrophy . Anyone suspected of having LGMD should, therefore, consider undergoing testing for other types of muscular dystrophies.

As of 2001, DNA testing for the different forms of LGMD is not available through clinical laboratories. DNA testing is difficult since there are many genes and types of gene changes that can cause LGMD. Some research laboratories are looking for the gene changes that cause LGMD and may detect the gene change or changes responsible for LGMD in a particular individual. DNA testing may be performed on a sample of blood cells or a sample of muscle cells. If an autosomal dominant gene change is detected in someone with LGMD then both of his or her parents can be tested to see if the gene change was inherited. If the gene change was inherited then siblings can be tested to see if they have inherited the changed gene. If autosomal recessive gene changes are detected then relatives such as siblings can be tested to see if they are carriers.

Prenatal testing for LGMD is only available if DNA testing has detected an autosomal dominant LGMD gene change in one parent or an autosomal recessive gene change in both parents. Cells for prenatal testing are obtained through an amniocentesis or chorionic villus sampling. These cells are analyzed for the LGMD gene change or changes that were found in one or both parents.

Treatment and management

Physical therapy and exercises can often help keep the muscles and joints mobile and prevent contractures. Muscle and joint pain can be treated through exercise, warm baths and pain medications. Surgical treatment of complications such as a curved spine may be necessary. Breathing exercises can sometimes help if breathing becomes difficult. If breathing independently becomes impossible then a portable mechanical ventilator can be used. A wheelchair or scooter can help when walking becomes difficult. Medications are often prescribed for cardiomyopathies and heart conduction defects. A device such as a pacemaker that creates normal contractions of the heart muscle may be necessary for some people with heart muscle abnormalities.

Gene therapy may one day cure LGMD. Gene therapy introduces unchanged copies of a LGMD gene into the muscle cells. The goal of therapy is for the normal LGMD gene to produce normal protein that will allow the muscle cells to function normally. As of 2001 gene therapy clinical trials have been temporarily halted but they are likely to continue in the near future. It will take quite a few years, however, for gene therapy to become a viable way to treat LGMD.

Prognosis

The prognosis of LGMD varies tremendously. Most people with LGMD, however do not have severe symptoms and most experience a normal lifespan. Cardiac and respiratory difficulties can, however, decrease the lifespan.

Resources

PERIODICALS

Bushby K. "The limb-girdle muscular dystrophies—multiple genes, multiple mechanisms." Human Molecular Genetics 8 (1999): 1875–1882.

Bushby K. "Making sense of the limb-girdle muscular dystrophies." Brain 122 (1999): 1403–1420.

Sunada, Yoshide. "The Muscular Dystrophies." ContempNeurol Ser 57, no. 5 (2000): 77–103.

Zatz, M., M. Vainzof, and M.R. Passos-Bueno. "Limb-girdle muscular dystrophy: one gene with different phenotypes, one phenotype with different genes." Current Opinion in Neurology 13, no. 5 (October 2000): 511–517.

ORGANIZATIONS

Muscular Dystrophy Association—Canada. 2345 Yonge St., Suite 900, Toronto, ONT M4P 2E5. Canada (416) 488-2699. [email protected] <http://www.mdac.ca/main.html>.

Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717. <http://www.mdausa.org>.

Muscular Dystrophy Campaign. 7-11 Prescott Place, London, SW4 6BS. UK +44(0) 7720 8055. [email protected] <http://www.muscular-dystrophy.org>.

WEBSITES

Hoffman, Eric, Cheryl Scacheri, and Elena Pegoraro. "Limb-Girdle Muscular Dystrophy Overview." Gene Clinics <http://www.geneclinics.org/profiles/lgmd-overview/index.html>. (2 February 2001).

Lisa Maria Andres, MS, CGC