Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Duchenne Muscular Dystrophy is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • DMD
  • dystrophinopathy
  • pseudohypertrophic myopathy

Disorder Subdivisions

  • None

General Discussion

Summary

Duchenne muscular dystrophy (DMD) is a rare muscle disorder but it is one of the most frequent genetic conditions affecting approximately 1 in 3,500 male births worldwide. It is usually recognized between three and six years of age. DMD is characterized by weakness and wasting (atrophy) of the muscles of the pelvic area followed by the involvement of the shoulder muscles. As the disease progresses, muscle weakness and atrophy spread to affect the trunk and forearms and gradually progress to involve additional muscles of the body. The disease is progressive and most affected individuals require a wheelchair by the teenage years. Serious life-threatening complications may ultimately develop including disease of the heart muscle (cardiomyopathy) and breathing (respiratory) difficulties.



DMD is caused by changes (mutations) of the DMD gene on the X chromosome. The gene regulates the production of a protein called dystrophin that is found in association with the inner side of the membrane of skeletal and cardiac muscle cells. Dystrophin is thought to play an important role in maintaining the structure of these muscle cells.



Introduction

DMD is classified as a dystrophinopathy. The dystrophinopathies are a spectrum of muscle diseases, each caused by alterations in the dystrophin gene. The severe end of the spectrum is known as Duchenne muscular dystrophy and the less severe as Becker muscular dystrophy.



The dystrophinopathies belong to a large group of diseases known as the muscular dystrophies. These disorders are characterized by specific changes (e.g. variation of muscle fiber size, muscle fiber necrosis and inflammation) in muscle biopsy. The clinical hallmarks include the weakness and wasting of various voluntary muscles of the body. Approximately 30 different conditions make up the muscular dystrophies. The diseases affect different muscles and have different ages of onset, severity and inheritance patterns.

Symptoms

DMD usually becomes apparent early during childhood. Affected children develop weakness and wasting (atrophy) of the muscles closest to the trunk (proximal muscles) such as those of the upper legs and pelvic area and upper arms and shoulder area. As the disease progresses, muscle weakness and atrophy spread to affect the lower legs, forearms, neck and trunk. The rate of progression is quite similar from case to case but individual variation may happen.



In children with DMD, initial findings may include delays in reaching developmental milestones such as sitting or standing without assistance; toe walking; an unusual, waddling manner of walking (gait); difficulty climbing stairs or rising from a sitting position; and repeated falling. Toddlers and young children may seem awkward and clumsy and may exhibit abnormal enlargement of the calves due to scarring of muscles (pseudohypertrophy). Parents may be falsely encouraged by an apparent improvement between the ages of 3 and 5, but this may be due to natural growth and development. As the disease progresses, additional abnormalities may develop such as progressive curvature of the spine (scoliosis or lordosis), wasting of thigh and pectoral muscles, and abnormal fixation of certain joints (contractures). A contracture occurs when thickening and shortening of tissue such as muscle fibers causes deformity and restricts movement of affected areas, especially the joints. Without treatment, , leg braces may be needed by age 8-9 to assist affected individuals to walk. By approximately ages 10 to 12, most affected individuals require a wheelchair.



Children with DMD have reduced bone density and an increased risk of developing fractures of certain bones, such as hips and spine. Many affected individuals will display mild to moderate degrees of non-progressive intellectual impairment and learning disabilities.



By the late teens, DMD may also be characterized by additional potentially life-threatening complications including weakness and deterioration of the heart muscle (cardiomyopathy). Cardiomyopathy can result in impairment in the ability of the heart to pump blood, irregular heartbeats (arrhythmias), and heart failure. Another serious complication associated with DMD is weakness and deterioration of muscles in the rib cage. This can result in an increased susceptibility to respiratory infections (e.g., pneumonia), difficulty coughing, and, ultimately, respiratory failure.



Involvement of muscles within the gastrointestinal tract may result in dysmotility, a condition in which the passage of food through the digestive tract usually because of slow and uncoordinated movements of the muscles of the digestive tract. Gastrointestinal dysmotility may result in constipation and diarrhea.

Causes

DMD is inherited as an X-linked disease. 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.



Some females who inherit a single copy of the disease gene for DMD (gene carriers or heterozygotes) may exhibit some of the symptoms associated with the disease such as weakness of certain muscles, especially those of the arms, legs, and back. Carrier females who develop symptoms of DMD are also at risk for developing heart abnormalities, which may present as exercise intolerance or shortness of breath. If left untreated, heart abnormalities can cause life-threatening complications in such affected females.



DMD is caused by mutations of the DMD gene located on the short arm (p) of the X chromosome (Xp21.2). 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 Xp21.2" refers to band 21.2 on the short arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.



The DMD gene regulates (encodes for) the production of dystrophin, a protein that appears to play an essential role in maintaining the integrity of cell membrane in skeletal (voluntary) and cardiac muscle cells. Dystrophin is found attached to the inner side of the membrane that surrounds muscle fibers. Mutation of the DMD gene will result in absence of the dystrophin protein, leading to degeneration of muscle fibers. The body can replace (regenerate) some muscle fibers, but over time more and more muscle fiber is lost. Such degeneration leads to the symptoms and findings associated with DMD. In Becker muscular dystrophy, a related disorder, dystrophin is present, but it is truncated or only present in insufficient levels to properly perform its functions.



Although most boys with DMD inherit the abnormal gene from their mothers, some may develop the diseases as the result of a spontaneous mutation of the dystrophin gene that occurs randomly for unknown reasons (de novo or sporadic cases).

Affected Populations

DMD is the most common childhood onset form of muscular dystrophy and affects males almost exclusively. The prevalence is estimated to be 1 in every 3,500 live male births. Age of onset is usually between 3 and 5 years of age. The muscular dystrophies as a whole are estimated to affect 250,000 individuals in the United States.

Standard Therapies

Diagnosis

A diagnosis of DMD is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests including molecular genetic tests. If the genetic tests are not informative, surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers. Specialized blood tests (e.g. creatin kinase) that evaluate the presence and levels of certain proteins in muscle (immunohistochemistry) are also used.



Molecular genetic tests involve the examination of deoxyribonucleic acid (DNA) to identify specific a genetic mutation including deletions, duplications or single point mutations. Samples of blood or muscles cells may be tested. These techniques can also be used to diagnosis DMD before birth (prenatally).



Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is found in abnormally high levels when muscle is damaged. The detection of elevated CK levels (usually in the thousands or ten thousands range) can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of DMD.



In some cases, a specialized test can be performed on muscle biopsy samples that can determine the presence and levels of specific proteins within cells. Various techniques such as immunostaining, immunofluorescence or Western blot (immunoblot) can be used. These tests involve the use of certain antibodies that react to certain proteins such as dystrophin. Tissue samples from muscle biopsies are exposed to these antibodies and the results can determine whether a specific muscle protein is present in the cells and in what quantity or what size.



Treatment

No curative treatment exists for DMD. Treatments are aimed at the specific symptoms present in each individual. Treatment options should 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. Braces may be used to prevent the development of contractures. The use of mechanical aids (e.g., canes, braces, and wheelchairs) may become necessary to aid walking (ambulation).



Corticosteroids are used as standard of care to treat individuals with DMD. These drugs slow the progression of muscle weakness in affected individuals and delay the loss of ambulation by 2-3 years. Two common corticosteroid drugs used to treat individuals with DMD are prednisone and deflazacort (which is not available in the United States).



Clinical Testing and Work-Up

Children diagnosed with DMD should be monitored regularly for potential heart involvement. In some cases, severe respiratory distress may necessitate the use of ventilator to assist breathing.



Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

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.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



Contact for additional information about Duchenne muscular dystrophy:



Gyula Acsadi, MD, PhD

Associate Professor of Pediatrics

University of Connecticut, School of Medicine

Chief of Neurology Division

Connecticut Children's Medical Center

282 Washington Street

Hartford, CT. 06106

Phone: 860-545-9460

Fax: 860-545-9484

References

TEXTBOOKS

Behrman RE, Kliegman RM, Jenson HB,eds. Nelson Textbook of Pediatrics. 17th ed. Philadelphia, PA: Elsevier Saunders; 2005:2060-9.



Acsadi G. Duchenne Muscular Dystrophy. NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins: 2003:623.



JOURNAL ARTICLES

Foster K, Foster H, Dickson JG. Gene therapy progress and prospects: Duchenne muscular dystrophy. Gene Ther. 2006;13:1677-85.



Flanigan KM, von Niederhausern A, Dunn DM, et al., Rapid direct sequence analysis of the dystrophin gene. Am J Hum Genet. 2003;72:931-9.



Davies JE, Winokur TS, Aaron MF, et al., Cardiomyopathy in a carrier of Duchenne's muscular dystrophy. J Heart Lung Transplant. 2001;20:781-4.



Fenichel GM, Griggs RC, Kissel J, et al., A randomized efficacy and safety trial of oxandrolone in the treatment of Duchenne muscular dystrophy. Neurology. 2001;56:1075-9.



Dubowitz V. The muscular dystrophies--clarity or chaos? N Engl J Med. 1997;336:650-651.



Boland BJ, Silbert PL, Groover RV, Wollan PC, Silverstein MD. Skeletal, cardiac, and smooth muscle failure in Duchenne muscular dystrophy. Pediat Neurol. 1996;14:7-12.



Bushby KMD, Appleton R, Anderson LVB, et al. Deletion status and intellectual impairment in Duchenne muscular dystrophy. Dev Med Child Neurol. 1995;37:260-269.



Barbujani G, Russo A, Danieli GA, et al. Segregation analysis of 1885 DMD families: significant departure from the expected proportion of sporadic cases. Hum Genet. 1990;84: 522-526.



Mendell JR, Moxley RT, Griggs RC, et al. Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy. N Engl J Med. 1989;320:1592-1597.



INTERNET

Darras BT, MD, Miller DT, Urion DK. (Updated November 23, 2011). Dystrophinopathies. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2012. Available at http://www.genetests.org. Accessed August 31, 2012.



Nair DG, Mellion ML. Dystrophinopathies. Emedicine. http://emedicine.medscape.com/article/1173204-overview. Updated June 27, 2012. Accessed August 31, 2012.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Muscular Dystrophy, Duchenne Type; DMD. Entry No: 310200. Last Edited May 8, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed August 31, 2012.

Resources

March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Tel: (888)663-4637

Email: Askus@marchofdimes.com

Internet: http://www.marchofdimes.com



Parent Project Muscular Dystrophy

401 Hackensack Avenue, 9th Floor

Hackensack, NJ 07601

USA

Tel: (201)944-9985

Fax: (201)944-9987

Tel: (800)714-5437

Email: info@parentprojectmd.org

Internet: http://www.parentprojectmd.org



Muscular Dystrophy Association

3300 East Sunrise Drive

Tucson, AZ 85718-3208

USA

Tel: (520)529-2000

Fax: (520)529-5300

Tel: (800)572-1717

Email: mda@mdausa.org

Internet: http://www.mda.org/



Muscular Dystrophy Canada

2345 Yonge Street Suite 900

Toronto

Ontario, M4P 2E5

Canada

Tel: 4164880030

Fax: 4164887523

Tel: 866MUSCLE8

Email: info@muscle.ca

Internet: http://www.muscle.ca



Muscular Dystrophy Campaign

61 Southwark Street

London, SE1 0HL

United Kingdom

Tel: 02078034800

Email: info@muscular-dystrophy.org

Internet: http://www.muscular-dystrophy.org



NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/



Society for Muscular Dystrophy Information International

P.O. Box 7490

Bridgewater

Nova Scotia, B4V 2X6

Canada

Tel: 9026853961

Fax: 9026853962

Email: smdi@auracom.com

Internet: http://www.nsnet.org/smdi/



European Alliance of Neuromuscular Disorders Associations

MDG Malta 4

Gzira Road

Gzira, GAR 04

Malta

Tel: 0035621346688

Fax: 0035621318024

Email: eamda@hotmail.com

Internet: http://www.eamda.net



New Horizons Un-Limited, Inc.

811 East Wisconsin Ave

P.O. Box 510034

Milwaukee, WI 53203

USA

Tel: (414)299-0124

Fax: (414)347-1977

Email: horizons@new-horizons.org

Internet: http://www.new-horizons.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Let Them Hear Foundation

1900 University Avenue, Suite 101

East Palo Alto, CA 94303

Tel: (650)462-3174

Fax: (650)462-3144

Email: info@letthemhear.org

Internet: http://www.letthemhear.org



DuchenneConnect

Emory University, Department of Human Genetics

2165 N. Decatur Road

Atlanta, GA 30033

Tel: (404)778-0553

Fax: (404)935-0636

Email: coordinator@duchenneconnect.org

Internet: http://www.duchenneconnect.org



CureDuchenne

1400 Quail Street, Suite 110

Newport Beach, CA 92660

USA

Tel: (949)872-2552

Fax: (949)872-2568

Email: debra@cureduchenne.org

Internet: http://www.CureDuchenne.org



Muscular Dystrophy Association of Kosovo

Str"Ardian Krasnici N:6/22

Prishtina, 10000

Republic of Kosovo

Tel: 38138247721

Fax: 38138247721

Email: gimi_mda@yahoo.com



Child Neurology Foundation

2000 West 98th Street

Bloomington, MN 55431

USA

Tel: (952)641-6100

Fax: (952)881-6276

Tel: (877)263-5430

Email: jstone@childneurologyfoundation.org

Internet: http://www.childneurologyfoundation.org



Medical Home Portal

Dept. of Pediatrics

University of Utah

P.O. Box 581289

Salt Lake City, UT 84158

Tel: (801)587-9978

Fax: (801)581-3899

Email: mindy.tueller@utah.edu

Internet: http://www.medicalhomeportal.org



For a Complete Report

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