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Muscular Dystrophies:

Emery-Dreifuss

 

Definition

Emery-Dreifuss muscular dystrophy (EDMD) is a rare childhood-onset degenerative muscle disease seen almost exclusively in males. Emery-Dreifuss muscular dystrophy is characterized by a classic triad of symptoms. These include early-onset contractures, very slow progressive muscle weakness and degeneration involving the upper arms and lower legs, and cardiac (heart) muscle disease.

Description

Emery-Dreifuss muscular dystrophy affects the arms, legs, spine, face, neck, and heart. This disease is characterized by contractures of the elbows and the Achilles tendons at an early age, slowly progressive muscle wasting and weakness, and life potentially life-threatening heart muscle disease. Intelligence is normal, however physical problems may be severe.

Symptoms and disease severity may vary between individuals. Three modes of inheritance exist: X-linked, autosomal dominant, and autosomal recessive. The symptoms of the autosomal dominant and X-linked forms of the disease are identical, however the autosomal dominant form appears to have a later onset of symptoms.

Genetic profile

Emery Dreifuss muscular dystrophy is inherited in different ways in different families. Most commonly EDMD is inherited in an X-linked recessive manner. Autosomal dominant inheritance of EDMD is also well characterized. Only one case of autosomal recessive inheritance of EDMD has been reported.

Rarely a new mutation causing EDMD can also occur, causing disease in a person with no family history. This is called a sporadic occurrence and is the ressult of a new change in a gene (new mutation) in that individual. New mutations account for approximately 10% of cases of EDMD.

X-linked recessive form

Emery-Dreifuss muscular dystrophy is usually inherited in an X-linked recessive manner. EDMD is the third most common type of X-linked muscular dystrophy. Symptoms begin in the first decade of life. A tendency to walk on the toes is often one of the first signs of EDMD. Muscle weakness first affects the lower extremities usually at age four or five.

X-linked diseases map to the human X chromosome, a sex chromosome. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. Because males only have one X chromosome, they only require one X-linked disease gene to display disease. Since females have two X chromosomes, the effect of one X-linked recessive disease gene is masked by the disease gene's normal counterpart on her other X chromosome.

In classic X-linked inheritance males are affected, presenting full clinical symptoms of the disease. Females are usually not affected. Affected fathers can never pass X-linked diseases to their sons. However, affected fathers always pass X-linked disease genes to their daughters. Females who inherit the faulty gene but do not show the disease are known as carriers. Female carriers of X-linked EDMD have a 50% chance to pass the disease-causing gene to each of their children.

It is unusual for female carriers of an X-linked disease to show symptoms of the disease. In X-linked EDMD, carrier females can exhibit certain symptoms of the disease. Females have two X chromosomes in each of their body cells. Very early on in fetal development, one X chromosome in each cell of a female is inactivated. The pattern of inactivation is random, so carrier females may express the disease-causing gene in some of their cells. An estimated 10–20% of female carriers of X-linked EDMD display varying symptoms of the disease. Female carriers can display the dangerous heart symptoms of EDMD. Less commonly, carrier females may show late-onset muscle weakness.

In 1994 it was recognized that the X-linked recessive form of Emery-Dreifuss muscular dystrophy is caused by changes, or mutations, in a gene now known as EMD or STA. This gene is located on the long arm of the human X chromosome at a location designated as Xq28. The STA gene is approximately 2,100 base pairs in length. This gene codes for emerin, an amino acid protein.

Emerin is an important protein normally found on the inner nuclear membrane of skeletal, cardiac, and smooth muscle cells as well as in other tissues. Emerin is missing from the nuclear membranes of males affected with X-linked EDMD. Emerin is not altered in other neuromuscular disorders.

Autosomal dominant form

In some families, Emery-Dreifuss muscular dystrophy may be inherited in an autosomal dominant pattern. Autosomal dominant EDMD is known as Emery-Dreifuss muscular dystrophy 2 (EDMD2), Hauptmann-Thannhauser muscular dystrophy, and Scapuloilioperoneal atrophy with cardiopathy. Autosomal dominant disorders affect both sexes equally. In autosomal dominant conditions a person, male or female, requires only one faulty gene to produce disease. There are no unaffected carriers of EDMD2. In families with EDMD2, both males and females can be affected and father to son inheritance of the disease can occur. Every child of a person affected with EDMD2 has a 50% chance of inheriting the disease.

In families with EDMD2, affected members exhibit a later onset of the same symptoms as someone affected with X-linked EDMD. Symptoms begin between the ages of 17 and 42. EDMD2 and X-linked EDMD are caused by changes in different genes on different chromosomes.

Muscle biopsy of people with EDMD2 are found to have normal emerin levels. In families with EDMD2, the disease is caused by changes, or mutations, in a gene known as Lamin A/C, or LMNA. Lamin A/C is located in a specific area on the long arm of chromosome 1 known as 1q21.2.

Lamin A/C codes for two proteins, lamins A and C. Like emerin, these lamins are associated with the nuclear membrane. People with autosomal dominant EDMD2 have normal levels of emerin and low levels of these lamin proteins. Emerin and these lamins form an important protein complex in a cell's nuclear membrane. The exact role of this complex is unclear. Scientists theorize that this important complex of proteins stabilizes the nuclear membrane and plays a role in regeneration of muscle fibers.

Autosomal recessive form

As of early 2001 a single case of autosomal recessively inherited EDMD has been documented. EDMD of autosomal recessive inheritance has been named Emery-Dreifuss muscular dystrophy 3 (EDMD3). For someone to be affected with an autosomal recessive disease they must inherit two copies of a disease-causing gene, one from each parent. A parent who has only one gene associated with autosomal recessive EDMD is not affected by the disease and is known as a carrier of the disease. Two carriers of autosomal recessive EDMD have a 25% chance to have a child affected with the disorder in each pregnancy.

Like EDMD2, EDMD3 is caused by mutations in the Lamin A/C gene located on the long arm of chromosome 1 at an area designated as 1q21.2. The single known mutation associated with EDMD3 has not been found to also lead to EDMD2.

The single known patient with autosomal recessively inherited EDMD (EDMD3) displayed symptoms similar to those of X-linked and autosomal dominant EDMD without any heart involvement. He had difficulties when he started walking at 14 months of age. At five years of age, his contractures were so severe that he could not stand. At age 40, he was confined to a wheelchair and exhibited severe widespread muscle wasting. He displayed normal intelligence and did not have any heart problems. His carrier parents had no heart, skeletal, or muscle abnormalities.

Demographics

X-linked EDMD is estimated to occur in one in 100,000 births. EDMD2 and EDMD3 are far less common. Only one case of EDMD3 has been documented.

Only males exhibit full symptoms of X-linked EDMD. EDMD2 and EDMD3 may occur in males and females. X-linked EDMD and EDMD2 have been documented in many countries. There does not appear to be a single founder of these diseases, as many families have distinctly different backgrounds and different diseasecausing mutations.

Signs and symptoms

Emery-Dreifuss muscular dystrophy is recognized by a classic triad of symptoms: contractures at a young age, progressive muscle weakness and degeneration involving the upper arms and lower legs, and cardiac (heart) muscle disease.

Contractures

Contractures, or frozen joints, are a hallmark of all forms of EDMD. A contracture is the abnormal shortening of a body part, usually a muscle or a tendon. This shortening creates joint deformity. Contractures usually begin in childhood or adolescence before any muscle weakness is evident. In most cases, contractures are recognized before patients reach 10 years of age.

Contractures may display as flexion or extension deformities. In a flexion contracture a muscle or tendon remains abnormally flexed, permanently bending a body part at a joint. In an extension contracture a muscle or tendon remains abnormally extended, not allowing a body part to bend at a joint. Affected persons cannot control these contractures and cannot release them at will. Contractures are treated with stretching, physical therapy, bracing, and surgery.

People affected with EDMD often have flexion contractures of the elbows and ankles. Elbow contractures force the elbow to remain bent at an angle. Contractures of the Achilles tendons, or heel cords, force the feet to remain in a pointed toe position. Children with EDMD often walk on their toes due to heel cord contractures. Neck and trunk contractures may also occur, restricting movement of the neck or the entire spine. Scoliosis is commonly found in patients with EDMD.

Muscle weakness and degeneration

Muscle weakness and degeneration are slowly progressive, affecting a distinct pattern of muscles. This pattern includes the muscles of the upper arms and the muscles of the lower legs. The biceps (inner upper arm), triceps (outer upper arm), tibialis anterior (inner lower leg), and peroneal (outer lower leg) muscles are commonly involved. Later, the muscles of the shoulder girdle and pelvic girdle, the shoulder and hip area muscles that stabilize and support the attachment of the arms and legs, may also be affected. Additionally, the highly specialized muscle of the heart is at risk for weakness and degeneration.

Heart disorders

Heart disease associated with EDMD may be life threatening. It is, however, potentially treatable. Not all patients with EDMD develop heart involvement. Any heart involvement often becomes apparent in the second to third decade of life. In rare cases heart problems may be the first symptom of EDMD. Early recognition of heart involvement is of utmost importance as surgical placement of a pacemaker may be life saving.

EDMD is associated with cardiac conduction defects (electrical impulse problems), heart muscle degeneration, and unusual tissues (abnormal fatty and fibrous tissues) growing into the heart. Conduction defects can manifest as heart rhythm disturbances known as arrhythmias or, more seriously, heart block. Heart block is a dangerous situation where the heart is unable to respond correctly to its own electrical system. Arrhythmias and heart block can lead to fainting or even sudden death.

One uncommon type of heart conduction problem, total permanent auricular paralysis (TPAP), is relatively specific to EDMD. Scientists have found that 33% of 109 published cases of TPAP were due to EDMD.

The level of skeletal involvement in a patient with EDMD is not indicative of their level of heart involvement. Heart problems can be unpredictable, occasionally leading to sudden death without any prior symptom. In a review of 73 cases of X-linked EDMD, scientists found that 30 patients died suddenly between ages 25 and 39. Frequent careful checkups with a cardiologist (heart specialist) are necessary. Preventive surgical implantation of a pacemaker is often considered.

Female carriers of X-linked EDMD

Female carriers of X-linked EDMD may display some symptoms of disease. They can have the dangerous heart problems or, less commonly, muscle weakness. One case of sudden death of a female carrier of X-linked EDMD has been reported. It is recommended that female carriers of X-linked EDMD have regular examinations by a cardiologist.

Diagnosis

Diagnosis of EDMD is based on the classic triad of distinctive clinical symptoms seen in this disease. A diagnosis based on careful neuromuscular examination may be confirmed with muscle biopsy or DNA testing. Other special laboratory tests and neuromuscular tests may help physicians to confirm or rule out EDMD.

Creatine kinase (CK), a muscle enzyme, is often measured when symptoms of muscular dystrophy are present. CK levels are only mildly elevated in EDMD. Muscle biopsy can show microscopic changes in muscle fibers. Muscle biopsy also allows for a very practical test for X-linked EDMD where muscle tissue is stained with a chemical that binds specifically to emerin. If emerin is present, X-linked EDMD can be ruled out. If emerin is reduced or absent, X-linked EDMD is diagnosed.

Genetic testing and prenatal diagnosis for X-linked Emery-Dreifuss muscular dystrophy is available on a clinical basis. To perform DNA testing for X-linked EDMD a blood sample is required. This method of testing can diagnose female carriers of X-linked EDMD. Prenatal testing requires fetal cells obtained via amniocentesis or chorionic villus sampling. Once the specific alteration in the gene is identified in an affected family member, female relatives at risk to be carriers can be tested and prenatal diagnosis can be offered. Prenatal testing is performed on DNA extracted from fetal cells obtained by amniocentesis or chorionic villus sampling.

Treatment and management

The muscle and skeletal symptoms of EDMD are treated as they appear. People with EDMD should see a neurologist at least once a year. Stretching and working with a physical therapist is useful in preventing or delaying contractures. Occupational therapy can help patients adapt their activities and environment to their own particular needs. Ankle and foot braces are used to prevent leg deformity. Surgery may be necessary to release contractures. Exercise can help maintain muscle use and overall good health. Affected individuals may eventually require a wheelchair or other adaptive equipment.
Persons affected with EDMD require frequent, at least yearly, heart checkups with a cardiologist. Heart symptoms can appear suddenly with disastrous consequences, so patients often have a pacemaker implanted before they have had any serious heart problem. Anti-arrhythmia drugs, diuretics, ACE inhibitors, and blood thinners may help with some of the cardiovascular symptoms associated with EDMD. Heart transplant has been successful. Relatives of patients with EDMD, especially female carriers of X-linked EDMD, should also be offered yearly screening for heart involvement via electrocardiography and echocardiography.
Scientists are currently researching gene therapy as a possible treatment for EDMD. STA, the gene known to be involved in the X-linked form of EDMD, is a relatively small, less complicated gene. A small gene with a widespread product, such as STA, shows great promise for gene therapy.

Prognosis

Without serious heart involvement, most people with EDMD are expected to survive at least into middle age. Slow progression of muscle involvement allows most patients to walk and work until middle age or late adult life. Intellect is not affected.


Additional Information

OMIM Link

Neuromuscular


 


 

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