Emery-Dreifuss Muscular Dystrophy: A Triad of Challenges

Emery-Dreifuss Muscular Dystrophy: A Triad of Challenges

While there are different phenotypes of EDMD depending on the pattern of inheritance, each subtype is unified by a clinical triad of joint deformities, muscle weakness in the upper arms and lower legs, and cardiac disease.

Brief Summary of Disease
Muscular dystrophy refers to a group of nine inherited, non-inflammatory muscular disorders, which result from rare genetic mutations.1 Emery – Dreifuss Muscular Dystrophy (EDMD) is an extremely rare subtype, with a worldwide incidence of one in one-hundred thousand.1 While there are different phenotypes of EDMD depending on the pattern of inheritance, each subtype is unified by a clinical triad of joint deformities, muscle weakness in the upper arms and lower legs, and cardiac disease.2 Alan Emery and Fred Dreifuss used these three defining characteristics to first identify EDMD as a separate disease entity from other muscular dystrophies in 1966.1 Those with EDMD can have a normal life expectancy, although likely cardiac complications can lead to sudden death later on in life. Early detection and diagnosis are therefore critical to prevent against these complications and improve the prognosis of the disease.1,2,3


Etiology & Pathology
While numerous genes have been identified to cause EDMD, the clinical symptoms and manifestations of the disease are consistent regardless of the gene mutated.4 The three genes responsible for a majority of EDMD cases are EMD, LMNA and FHL1.5 EDMD inheritance patterns have shown to be X-linked recessive, autosomal dominant and more rarely, autosomal recessive. Mutations in either the EMD or FHL1 genes result in an X-linked recessive inheritance pattern. Males are affected by X-linked recessive disorders (and thus EDMD) much more frequently than females. It is possible for females who carry only one altered copy of the gene to develop heart problems or mild muscle weakness over time, but they usually do not experience the same muscle weakness and wasting that is characteristic of EDMD. Mutations in the LMNA gene often lead to autosomal dominant inheritance, however the disease can also be inherited in an autosomal recessive pattern in more rare cases.2,4

While numerous genes have been identified to cause EDMD, the clinical symptoms and manifestations of the disease are consistent regardless of the gene mutated.


In the manifestation of EDMD, each of the mutated genes encodes for a protein which interacts with the nuclear envelope to generate the common EDMD phenotype.2 However, the exact mechanism behind this expression of the disease for each protein is unknown. The nuclear envelope, composed of the inner and outer nuclear membranes, separates the genome from the cytoplasm and defines the nucleus of the cell. While playing an important role in nuclear structural support, the nuclear envelope also plays a critical role in the organization of genetic material and gene expression.6 Nearly two-thirds of EDMD patients with an X-linked inheritance pattern have a mutation in the EDMD gene. This mutation causes a defect in emerin, a single membrane-spanning protein which is expressed at the inner nuclear membrane. In muscle cells, an emerin-nuclear protein complex localizes at the nuclear envelope and acts to stabilize the nuclear membrane during mechanical stress generated by muscle contraction.2


Mutations in the LMNA gene are the most commonly known cause of autosomal dominant cases of EDMD, although some autosomal recessive inheritance has also been described.2 LMNA encodes for the nuclear envelope proteins lamins A and C. More specifically, lamins A and C comprise the nuclear lamina, which lies on the inner surface of the inner nuclear membrane. In addition to providing mechanical support, the lamina regulates DNA replication and cell division, organizes chromatin, and anchors nuclear pore complexes embedded in the nuclear envelope.7


Symptoms
Some of the earliest symptoms of EDMD are joint deformities called contractures, which typically become apparent during adolescence.3 Contractures restrict joint movement in the elbows, ankles or neck. Early signs of the disease also include “toe-walking” due to shortening of the Achilles tendon, as well as difficulty bending the elbows due to flexion contractures.2 The majority of affected individuals also experience muscle weakness and wasting of shoulder, upper arm, and calf muscles. Progression of muscle weakness typically occurs slowly and may not become a source of difficulty until later on in life.3 In addition to orthopaedic effects, almost everyone with EDMD will develop heart problems by early adulthood. Cardiac complications can include: cardiac conduction defects, arrhythmias, palpitations, heart failure and an increased risk of sudden death.4


Diagnosis
Prompt diagnosis of EDMD is essential, yet challenging. General muscular dystrophy is diagnosed by analyzing patient history and performing physical examinations. Special care must be taken to determine whether the patient’s weakness results from a problem in the muscles themselves, or in the nerves that control them. Origin of weakness can typically be pinpointed by a physical exam, but electromyography tests may be done if required. A major issue with diagnosis is that even with the unique triad, EDMD can still be very difficult to distinguish from other muscular dystrophies. Muscle biopsy and subsequent tests can be used to provide information about specific muscle proteins and whether they are present in the right amounts or in the right location. However, genetic tests are the most useful in analyzing genes for particular defects which cause EDMD. Correct diagnosis can assist in predicting the likely course of the disease and can help families to assess the risk of passing the disease on to their offspring based off of inheritance patterns.3 Prompt diagnosis is also essential to help detect cardiac complications early via electrocardiography, which is crucial in preventing against the life-threatening heart problems associated with EDMD during early adulthood.1


While there is presently no cure for EDMD, early diagnosis and interventions are essential in improving the well-being of patients.

Prognosis
Genetic and clinical screening of family members is needed as it plays an important role in the early recognition of family members at risk. While there is presently no cure for EDMD, early diagnosis and interventions are essential in improving the well-being of patients.2 With early recognition, contractures can be minimized through physical therapy and stretching exercises. Surgery can also be done to release contractures, however surgical procedures are challenging due to the tendency of the contractures to recur. 3 Early detection of cardiac complications is also crucial for timely interventions such as pacemaker implantation to help prevent against sudden cardiac death.1 Depending on the severity of the disease, with a dedication to physical treatment and cardiac interventions, EDMD is not likely to affect one’s lifespan.3


Children
Though typically occurring during adolescence, joint contractures that are characteristic of EDMD can begin to manifest in early childhood. If a child displays contractures or muscle weakness in the characteristic EDMD areas, they should be tested for the disease as early recognition and supportive treatment are key in reducing orthopedic complications. As cardiac complications typically do not occur until adulthood, childhood treatment focuses primarily on physical therapy. This can include range of motion and stretching exercises to help limit problems with stiff joints. Again, while surgery can also release contractures and help mobility, a child may need several surgeries as the contractures may reoccur.2,3 Due to the differing inheritance patterns associated with EDMD, the likelihood of an EDMD patient’s offspring having the disease is variable. With the common X-linked inheritance pattern, female carriers of the disorder have an equal twenty-five percent chance of having a carrier daughter like themselves, a non-carrier daughter, a son affected with the disease or an unaffected son. If a male with the X-linked disorder is able to reproduce, he will pass the mutated gene on to all daughters as carriers, but not to any of his sons. On the other hand, with autosomal dominant inheritance the risk of passing the mutated gene from the affected parent to the offspring is fifty percent for each pregnancy (with an equal risk for males and females). For the extremely rare autosomal recessive pattern of inheritance, two carrier parents have a fifty percent chance of having a child who is a carrier for the mutated gene and a twenty-five percent chance of having an affected child.4,8 Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been previously identified in a family member. Though there is no treatment for the disease, this early recognition can aid in creating a plan for appropriate therapy interventions in the future.9


Current Research
Unique therapies based on individual genetic makeup are widely thought to be the basis for an EDMD cure.1,2 This is because the exact mechanism behind how each unique protein interacts with the nuclear envelope to cause EDMD symptoms is currently unknown.2 Researchers believe that gaining a deeper understanding of all the possible mutations which can lead to the disease will help them to uncover this mystery.1,2 Due to the large number of genetic mutations that can cause EDMD, the disease has been identified as a key example of the need for the Precision Medicine Initiative. Developed by the United States government in 2015, this initiative stresses the need to move away from the “one size fits all” approach and rather strives to develop novel therapies based on an individual’s genetic complement.2 The precision method is hoped to help researchers to better understand the mechanisms by which EDMD occurs as well as to improve the ability to predict which treatments will work best for specific patients in the future.10


The precision method is hoped to help researchers to better understand the mechanisms by which EDMD occurs as well as to improve the ability to predict which treatments will work best for specific patients in the future.

Relevant Resources
The Muscular Dystrophy Association is a great resource for families and friends of people affected by EDMD. The organization provides detailed information on the disease, current research and medical management. It also provides ways for supporters to get involved or make donations to help in the search for a cure for EDMD.3 By raising awareness for this disease, one day we will hopefully have the genetic information needed to develop the novel therapy that EDMD patients require.


Works Cited:

1. Ekabe CJ, Kehbila J, Sama CB, Kadia BM, Abanda MH, Monekosso GL. Occurrence of Emery-Dreifuss muscular dystrophy in a rural setting of Cameroon: A case report and review of the literature. BMC Research Notes, 2017;10(36). doi:10.1186/s13104-016-2363-1

2. Pillers DA, Von Bergen NH. Emery–dreifuss muscular dystrophy: A test case for precision medicine. The Application of Clinical Genetics, 2016;9:27-32. doi:10.2147/TACG.S75028

3. The Muscular Dystrophy Association. Emery-Dreifuss Muscular Dystrophy, 2018. https://www.mda.org/disease/emery-dreifuss-muscular-dystrophy.

4. Genetics Home Reference. Emery-Dreifuss Muscular Dystrophy, 2018. https://ghr.nlm.nih.gov/condition/emery-dreifuss-muscular-dystrophy#genes.

5. Kegel M. Emery-Dreifuss Muscular Dystrophy seen as ideal candidate for Precision Medicine Initiative. Muscular Dystrophy News Today, 2016. https://musculardystrophynews.com/2016/03/01/emery-dreifuss-muscular-dystrophy-ideal-target-for-precision-medicine/

6. Dultz E & Ellenberg J. Quick Guide: Nuclear Envelope. Current Biology, 2006;17(5):154-156. doi:10.1016/j.cub.2006.12.035

7. Polychronidou M, Grobhans J. Determining nuclear shape: The role of farnesylated nuclear membrane proteins. Nucleus, 2011;2(1):17-23. doi:10.4161/nucl.13992

8. National Organization for Rare Disorders. Emery Dreifuss Muscular Dystrophy, 2018. https://rarediseases.org/rare-diseases/emery-dreifuss-muscular-dystrophy/

9. Bonne G, Leturcq F, Yaou RB. Emery-Dreifuss Muscular Dystrophy. GeneReviews, 2015.10(3):157. https://www.ncbi.nlm.nih.gov/books/NBK1436/

10. Genetics Home Reference. What are some potential benefits of precision medicine and the Precision Medicine Initiative? 2018. https://ghr.nlm.nih.gov/primer/precisionmedicine/potentialbenefits


Cite This Article:

Wyslobicky M., Chan G., Lewis K., Palczewski K, Ho J. Emery-Dreifuss Muscular Dystrophy: A Triad of Challenges. Illustrated by Huicochea Munoz M.F. Rare Disease Review. November 2019. DOI:10.13140/RG.2.2.25651.37926.

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