What is Emery-Dreifuss Muscular Dystrophy?
EDMD is a progressive form of muscular dystrophy named after Professors Alan Emery and Fritz Dreifuss. Emery and Dreifuss together first described the disorder — including the clinical features and typical progression — among a Virginia family in the 1960s. The EDMD subtype they described is X-linked (affecting males), which was subsequently shown to be caused by mutations in the EMD gene encoding the protein emerin. Autosomal dominant inheritance (affecting males and females equally) was later described and shown to be caused by mutations in the LMNA gene encoding lamin A/C. Very rare mutations in other genes have also been linked to EDMD.
The features of EDMD, which make it unique and different from other muscular dystrophies, are the early development of muscle contractures, the distribution of muscle weakness and wasting (atrophy), and cardiac involvement. The onset of symptoms, severity, and progression of disease can vary greatly between affected people, even those within the same family. The presence and severity of these manifestations vary by EDMD subtype — as classified by the gene mutation causing the disease — and the individual. Because symptoms can vary from person to person and may be mistaken for other neuromuscular conditions, including other inherited muscular dystrophies or myopathies, EDMD can be difficult to diagnose. An EDMD diagnosis is typically based on a combination of clinical symptoms and genetic testing.
Clinical symptoms
EDMD affects the joints, the skeletal muscles, and the heart and lead to a triad of symptoms that are common to most of those with the disease:
Early contractures
Progressive muscle weakness and atrophy
Cardiac conduction abnormalities/cardiomyopathy
While the age of onset is variable, the joint symptoms commonly present in childhood — usually by age 10 — and involve contractures (shortening of tendons) of the elbows, heels, and posterior neck/spine, restricting movement in these areas and worsening over time. Such contractures are common at a late stage in most muscle wasting diseases and result from inactivity. But in EDMD, muscle contractures develop very early or before there is any marked muscle weakness.
Most affected individuals also experience muscle weakness and wasting that worsen slowly over time, beginning in muscles that make up the shoulders and upper arms and lower legs (‘scapulo-humeroperoneal’) and later sometimes affecting muscles in the neck and hips.
Cardiac involvement is the most serious and important aspect of EDMD, making it particularly important to diagnose early. It usually appears as muscle weakness progresses, but may occur before there is any significant weakness or even any muscle involvement at all. In many affected by the disorder there is evidence of cardiac involvement by the age of 30. This involvement includes
conduction defects: abnormalities of the electrical signals that control the heartbeat, such as sinus bradycardia, prolongation of the PR interval on electrocardiography (first degree heart block), or complete heart block
dilated cardiomyopathy: weakening and enlargement of the heart
arrhythmias: abnormal heart rhythms, such as atrial tachyarrhythmias (such as atrial fibrillation), atrial standstill, and ventricular tachyarrhythmias.
Symptoms include palpitations, an unusually slow heartbeat, pre-syncope and syncope (fainting), tiredness and breathlessness, heart failure symptoms, and an increased risk of debilitating stroke or sudden death.
Causes/Genetics
Researchers have identified several genes that, when defective, cause EDMD. Most X-linked cases are caused by mutations in EMD encoding emerin (EDMD1). Most autosomal dominant cases are caused by mutations in LMNA encoding lamin A/C (EDMD2). Mutations in other genes can very rarely cause EDMD (EDMD 3-7). These genes have been assigned to specific EDMD subtypes in the Online Mendelian Inheritance in Man (OMIM) database:
Other genes that have been associated with EDMD-like disease features are TOR1AIP1, SUN1 and SUN2, as well as TTNN. Of the identified subtypes, perhaps 40% of EDMD cases are those effected by EMD or LMNA mutations. The exact prevalence of all subtypes of EDMD is unknown, but EDMD1cases are estimated to affect 1 in 100,000 people. EDMD2 may be even more common.
EDMD subtypes are also distinguished by their pattern of inheritance: X-linked, autosomal dominant, and autosomal recessive. EDMD1 and EDMD 6 are X-linked forms of EDMD, which is inherited from the mother (the “carrier”) and primarily affects males. All the sons of an affected male will be unaffected but all his daughters will be carriers. The daughter of an X-linked EDMD carrier has a 50/50 chance of also being a carrier, and on average each son has a 50/50 chance of being affected. Some women who are genetic carriers for X-linked EDMD may have a low risk for cardiac problems, such as conduction abnormalities and sudden death, often in the absence of any significant muscle weakness and atrophy.
Mutations in the LMNA gene cause both the autosomal dominant (EDMD2) and, extremely rarely, autosomal recessive (EDMD3) subtypes. In EDMD2, the disease can be inherited from either parent and is usually inherited in a dominant way, meaning that only one copy of the defective gene is enough to cause the disease — in both male and female offspring. On average each son or daughter of an affected parent has a 50/50 chance of also becoming affected. In the case of autosomal recessive EDMD3, a child must inherit two copies of the mutated gene, one from each biological parent, to be affected by the disease. Additionally, there is a 50% chance a child inherits only one copy of the mutated gene and is a carrier.
Sometimes X-linked and autosomal dominant cases EDMD will appear out of the blue, with no pattern of inheritance. This form of the disease occurs randomly because of a new spontaneous mutation in the affected individual, who may then later pass the disorder on to his or her children.