SummaryEmery-Dreifuss muscular dystrophy (EDMD) is a rare, often slowly progressive genetic disorder affecting the muscles of the arms, legs, face, neck, spine and heart. The disorder consists of the clinical triad of weakness and degeneration (atrophy) of certain muscles, joints that are fixed in a flexed or extended position (contractures), and abnormalities affecting the heart (cardiomyopathy). Major symptoms may include muscle wasting and weakness particularly in arms and lower legs (humeroperoneal regions) and contractures of the elbows, Achilles tendons, and upper back muscles. In some cases, additional abnormalities may be present. In most cases, EDMD is inherited as an X-linked or autosomal dominant disease. In extremely rare cases, autosomal recessive inheritance has been reported. Although EDMD has different modes of inheritance, the symptoms are nearly the same.
IntroductionEDMD belongs to a group of rare genetic muscle disorders known as the muscular dystrophies. These disorders are characterized by weakness and atrophy of various voluntary muscles of the body. Approximately 30 different disorders make up the muscular dystrophies. The disorders affect different muscles and have different ages of onset, severity and inheritance patterns.
The age of onset, severity, and progression of EDMD varies greatly from case to case, even among individuals of the same family. Some affected individuals may experience childhood onset with rapid disease progression and severe complications; others may experience adult onset and a slowly progressive course.
EDMD is associated with the clinical triad of contractures, muscle weakness, and heart disease. A contracture occurs when thickening and shortening of tissue causes deformity and restricts movement of affected areas, especially the joints. The elbows and Achilles tendons are the most common sites for contractures. Contractures are often the first sign in X-linked EDMD and may occur early during childhood. In autosomal dominant EDMD contractures usually develop after the onset of muscle weakness.
Progressive muscle weakness and degeneration (atrophy) usually develops during late childhood or early adolescence usually in the upper arms and lower legs (humero-peroneal regions). Weakness and atrophy of legs muscles may cause affected children to walk on their toes and may result in an abnormal waddling gait. Muscle weakness affecting the arms may cause various problems such as difficulty in raising the arms above the head.
Eventually, the muscles of the thigh and hips may become involved making it difficult to climb stairs. The neck, shoulder girdle, and forearms may eventually become involved and the spine may become rigid. As affected individuals age, they may experience limited mobility of the neck. Mild weakness of facial muscles has also been reported. Abnormal curvature of spine (scoliosis) may also occur.
Muscle weakness and atrophy is usually slowly progressive during the first three decades of life. Eventually, it may become more rapid. Some individuals with autosomal dominant EDMD may eventually lose the ability to walk (ambulate) and require a wheelchair. Loss of ambulation is rare in X-linked EDMD.
Heart abnormalities are the third prominent feature of EDMD and may result in serious complications. Although onset can vary, heart abnormalities usually develop after the second decade of life. Affected individuals may develop disease of the heart muscles (cardiomyopathy) potentially resulting in palpitations, fatigue, poor exercise tolerance, and an impaired ability of the heart to pump blood. Some individuals may experience conduction defects resulting in irregular heartbeats (arrhythmias) or heart block.
Heart block is characterized by interference with the transfer of the electrical nerve impulses (conduction) that regulate the normal, rhythmic, pumping action of the heart muscle. The normal heart has four chambers. The two upper chambers are the atria and the two lower chambers are the ventricles. Within the right atrium of a normal heart is a natural pacemaker that initiates and controls the heartbeat. The electrical stimulus travels from the pacemaker (sinoatrial or SA node) to the ventricles along a very specific path consisting of conducting tissue and known as the AV (atrioventricular) node. As long as the electrical impulse is transmitted normally, the heart behaves normally. If the transmission of the signal is impeded, the blocked transmission is known as a heart block or an AV block.
Heart blocks are categorized according to the degree of impairment. The severity of such conduction abnormalities varies among individuals with EDMD. In the mild form of heart block, the two upper chambers of the heart (atria) beat normally, but the contractions of the two lower chambers (ventricles) lag slightly behind. In the more severe forms, only a half to a quarter of the atrial beats are conducted to the ventricles. In complete heart block, the atria and ventricles beat separately. In some cases, heart block may lead to blackouts (syncope), breathlessness, and/or irregular heartbeats (arrhythmias). In severe cases, sudden death is possible.
In most cases, EDMD is inherited as an X-linked recessive trait. EDMD may also be inherited as an autosomal dominant trait. Autosomal recessive inheritance is extremely rare, but has been reported in at least one family. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq28” refers to band 28 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
Investigators have determined that the X-linked form of EDMD is caused by disruption or changes (mutations) of the EMD (also known as STA) gene located on the long arm of the X chromosome (Xq28). The EMD gene encodes a muscle protein known as emerin. Emerin is found in most cell types of the body and skeletal and cardiac muscle have particularly high expression levels.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals typically carry a number of abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Investigators have determined that the autosomal dominant and autosomal recessive forms of EDMD are caused by mutations of the same gene located on the long arm of the chromosome 1 (1q21.2). The gene is known as the LMNA gene and encodes the proteins lamin A and lamin C. Interestingly, mutations in this gene also cause a variety of other human diseases, including limb-girdle muscular dystrophy, dilated cardiomyopathy, Dunnigan-type familial partial lipodystrophy, and the premature aging disease Hutchinson-Gilford progeria syndrome.
EDMD can also result from mutations in the nuclear envelope proteins nesprin-1 and -2, which also directly interact with emerin. Mutations in the SUN-domain proteins SUN1 and SUN2, which form a complex with nesprins to connect the nucleus to the cytoskeleton, can also cause EDMD. These findings suggest that disruption in the LINC (Linker between nucleoskeleton and cytoskeleton) complex can contribute to the muscular phenotype in EDMD.
Lastly, some cases of EDMD have been attributed to mutations in the FHL1 gene, also known as LUMA, a nuclear membrane protein that binds to emerin At the same time, more than half of all EDMD patients have no identifiable mutations in the above genes, suggesting that additional genes/mutations must be responsible for EDMD. Consequently, substantial efforts are underway to identify additional genes that cause EDMD and the underlying disease mechanism.
The overall prevalence of EDMD is unknown. The X-linked form is estimated to affect 1 in 100,000 people in the general population. EDMD is believed to be the third most common form of muscular dystrophy. X-linked EDMD is fully expressed in males only. Approximately 10-20 percent of female carriers for X-linked EDMD will develop heart conduction defects and/or muscle weakness. The autosomal dominant and recessive forms of EDMD affect males and females in equal numbers.
Approximately 250,000 individuals in the United States are affected by some form of muscular dystrophy.
A diagnosis of X-linked EDMD is based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms (contractures, myopathy, heart defects, etc.), surgical removal and microscopic study (biopsy) of affected tissue, and specialized tests such as immunodetection and molecular genetic testing.
Through immunodetection, physicians can determine the presence and levels of certain proteins such as emerin in tissue samples obtained from affected individuals. Various techniques such as immunofluorescence or Western blot can be used. These tests involve the use of certain antibodies that react to certain proteins. Samples taken from tissue biopsies are exposed to these antibodies and the results can determine whether a specific protein such as emerin is present and in what quantity. In approximately 95 percent of individuals with X-linked EDMD emerin is absent.
Molecular genetic testing involves the examination of deoxyribonucleic acid (DNA) to identify specific a genetic mutation.
The diagnosis of autosomal dominant or recessive EDMD is based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings, and molecular genetic testing. Immunodetection cannot be used to aid in the diagnosis of the autosomal forms of EDMD because the associated proteins, lamin A and C, are not absent in affected individuals. However, mislocalization of emerin, i.e., an abnormal distribution of emerin within the cell, can often be indicative of mutations in lamins A and C.
Additional tests that may be used to aid in the diagnosis of EDMD include specialized blood tests and a test that assesses the health of muscles and the nerves that control muscles (electromyography). Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of EDMD.
During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy.
Individuals with EDMD may receive an electrocardiogram, a test that records the heart’s electrical impulses and may reveal abnormal electrical patterns.
No specific treatment exists for EDMD. Treatment is aimed at the specific symptoms present in each individual. Treatment options may include physical therapy and active and passive exercise to build muscle strength and prevent contractures. Surgery may be recommended in some cases to treat contractures or scoliosis. The use of mechanical aids (e.g., canes, braces, and wheelchairs) may become necessary to aid walking (ambulation).
Clinical Testing and Work-Up
Children diagnosed with EDMD should be monitored regularly for potential heart involvement. In the case of serious heart involvement, cardiac pacemakers may be implanted and treatment with antiarrhythmic drugs may become necessary.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Heart transplantation has been attempted in individuals with EDMD with serious cases of heart involvement. More research is required to determine the long-term outcome of this procedure on individuals with this form of muscular dystrophy.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
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