Duchenne and Becker Muscular
Dystrophy

Overview

Duchenne muscular dystrophy (DMD) is an aggressive and lethal neuromuscular disorder that is characterized by proximal muscle weakness and wasting. The X-linked disease affects boys of all ethnic origins. DMD has a worldwide estimated prevalence of 1 in 3500 live male births.^1,2,3 Approximately 8,000 males in the United States (19 to 95 people per million) are affected with DMD, with a world-wide prevalence of an estimated 63 people per million.^4,5 Females are typically carriers of the DMD gene mutation and are not clinically affected.

The first symptoms of DMD are usually observed before the age of 5 years. Affected individuals may fall frequently and have a waddling gate. Muscle weakness in the hips and proximally in the legs typically occurs in the early stages. Other early stage symptoms include difficulty running, walking on toes (caused by a shortening of the Achilles’ tendon), and pressing hands to the thighs when attempting to rise from the floor or from a chair (Gower’s sign).³

DMD is caused by mutations to the Xp21 gene, the gene that codes for the dystrophin protein. Dystrophin is a muscle cell structural protein that resides beneath the sarcolemma, the plasma membrane that covers the outer surface of a muscle fiber. The dystrophin protein stabilizes the muscle during muscle contraction by anchoring muscle filaments to the sarcolemma.⁶ In DMD, mutations to the Xp21 gene result in the production of non-functioning dystrophin proteins or no dystrophin production at all.⁷

The lack of functioning dystrophin proteins prevents the normal contraction of muscle. When the muscles contract abnormally, the muscle cells become damaged. As the body attempts to repair the damage, it replaces the damaged muscle tissue with scar tissue. Affected individuals typically exhibit hypertrophy, in which muscles appear much larger than normal. Calf hypertrophy (Figure 1) is a common clinical sign of DMD.⁷

DMD affects the skeletal (voluntary) muscles, but also affects smooth (involuntary) muscles, such as the heart and diaphragm. Approximately 95% of DMD-affected individuals have cardiac involvement by the time of death. Cardiac problems include ECG abnormalities, arrhythmias, myocardial dilatation and myocardial thickening.⁸

Dystrophin-related abnormalities in the brain may cause subtle cognitive and behavioral deficits. Approximately 33% of affected individuals have a learning disability; few have severe retardation. Cognitive deficits are not progressive in DMD.⁷

As DMD progresses, weakness extends to the neck flexors, proximal arm muscles, ankle dorsiflexors and respiratory muscles. Between the ages of 7 to 11 years, affected individuals typically become wheelchair bound.⁸ Weakening or contracture (joint or tendon restriction) of the back muscles can lead to severe scoliosis.

Respiratory function is typically normal during the first decade. Damage to the diaphragm muscle, however, may decrease respiratory function in the second decade, leading to decreased blood oxygen levels. Deterioration of muscles used in coughing may prevent the clearance of lung secretions, thus allowing for bacterial and viral growth in the lungs.⁷ Death due to respiratory or cardiac complications typically occurs late in the second decade or early in the third decade.

Diagnosis

In addition to a positive family history of X-linked recessive inheritance, the clinical findings that support the diagnosis of DMD in males are progressive muscular weakness (proximal rather than distal in the early stage of the disorder), calf hypertrophy, onset of symptoms before the age of five years and wheelchair dependency before the age of 13 years. Cardiomyopathy can also be a presenting feature.⁶

The differential diagnosis of DMD includes myopathic disorders, facioscapulohumeral muscular dystrophy and limb girdle muscular dystrophy.⁹

Measuring the level of the enzyme creatine kinase (CK) in the bloodstream is useful for the screening of preclinical cases of DMD. Large quantities of CK (as much as 50 to 100 times the normal rate) are found in the blood stream as a result of damage to skeletal muscles in the early stage of the disorder.

Approximately 66% of disease-causing mutations in Xp21 are caused by large deletions and duplications. Most deletions can be detected by multiplex PCR, which amplifies approximately 25 of the gene's exons from DNA acquired from a blood sample. If the deletion or duplication is not identified though DNA testing, a muscle biopsy may confirm the diagnosis. Histological features include variability in muscle fiber size, large fibers, hyper-contracted fibers and groups of atrophic, degenerating and regenerating fibers. Endomysial fibrosis (the development of scar tissue on the connective tissue sheath that surrounds a muscle fiber) is present. Immunostaining confirms the absence of the dystrophin protein.³

To detect a small mutation, cDNA (obtained from muscle mRNA) may be generated and sequenced. A prenatal diagnosis of DMD can be done through the study of chorionic villi samples (from 10 to 11 weeks gestation) or from cultured amniotic fluid cells (16 to 18 weeks gestation).³

Genetics and counseling

Genetic defects in the Xp21 gene are associated with the two major muscular dystrophy phenotypes: DMD, and a less aggressive form that typically has a later onset, Becker muscular dystrophy (BMD).

DMD is inherited as recessive X-linked disorder due to mutations in the gene for dystrophin at Xp21. The dystrophin gene is the largest human gene, with 2.5 megabases and 79 exons. The large size of the gene and the spontaneous mutation rate of each base pair within the gene results in a high number of unique mutations.⁵

Large deletions in the dystrophin gene may prevent the production of dystrophin altogether in some affected individuals. Other types of mutations, such as stop, splicing, duplications and small deletions disrupt the reading frame during dystrophin protein production, resulting in the truncated, degraded protein molecule that is seen in the DMD phenotype.⁵ Deletions that involve the brain distal isoform Dp140 have been associated with the intellectual impairment seen in a relatively small number of DMD cases that also have intellectual impairment associated with the disorder.¹⁰

DMD is inherited in an X-linked recessive manner; therefore, males are affected almost exclusively. A woman can inherit the DMD mutation (and thus become a carrier) from her mother, (who is also a carrier) or from her mother or father if either of them have somatic mosaicism or germline mosaicism. Carriers are typically unaffected; 76% of carriers show no symptoms, while fewer than 20% experience mild to moderate muscle weakness or left ventricle dilation.¹⁰

A woman who may be unaffected but has an affected son and at least one other affected maternal relative is a carrier. If a woman has no family history of DMD and only one affected son, the son may have developed de novo DMD. However, approximately 66% of mothers of sons with DMD but no family history of DMD are carriers.

If a woman has no family history of DMD, but has more than one affected son, the mother may have developed a de nova mutation and is a carrier. She may have passed the mutation to her sons through a germline mutation or germline mosaicism. If a woman has no family history of DMD and is not a carrier, yet has an affected son, the son may have developed a de nova mutation.¹⁰

Affected males typically do not reproduce, either because of the degree of their debilitation or because they die prior to reaching reproductive age.

Children of a carrier female have a 50% chance of inheriting the mutation. Sons who inherit the DMD mutation will be affected with the disorder, while daughters who inherit the mutation will be carriers. Therefore, a woman with the DMD mutation has a 25% chance of having an affected child with each pregnancy.¹⁰

A family history that includes DMD is a strong indicator of the potential for DMD to affect subsequent generations. Therefore, genetic testing and counseling is critically important for family members of affected individuals.

Treatment and management

There is no cure for DMD, but drugs can modestly slow the progression of the disease. Prednisone, a corticosteroid, is the primary pharmacological therapy. The mechanism by which prednisone slows the decline of muscle function is undetermined, however, research indicates that prednisone decreases the rate of muscle breakdown and increases the production of insulin-like growth factor (ILGF-I), which may promote the repair and regeneration of muscle cells.¹¹

Prednisone has a number of side effects, including weight gain, growth inhibition, Cushingoid appearance (moon face), hirsutism (excessive hair growth), behavioral changes, fractures, hypertension (high blood pressure) and diabetes. Because of the serious side affects associated with prednisone, researchers continue to search for other medications that slow the progression of DMD. Recent studies have examined the effectiveness of deflazacort (an oxazolone derivative of prednisone) and oxandrolone (an anabolic steroid). Weight gain has been found to be less frequent with the use of deflazacort than prednisone. However, asymptomatic cataracts occur more frequently with deflazacort. Neither deflazacort nor oxandrolone is currently available in the United States.¹¹

Multiple studies have investigated different prednisone dosage regimens. The lowest effective daily dose of prednisone is 0.75 mg/kg daily. Additional studies evaluating different dose and frequency regimens suggest that 0.75 mg/kg daily for the first 10 days of each month may be as effective as daily dosing and may also decrease the incidence and severity of side effects.^11,12

Managing the secondary disorders associated with DMD, such as contractures, respiratory difficulties, scoliosis, cardiomyopathy and obesity is important for the quality of life of an affected individual, and in some cases, the prolongation of life.

Weight control. Weight gain is a common side effect of prednisone. Obesity stresses an affected individual’s already stressed musculature, joints and tendons, thus making weight control a significant goal of DMD disease management. Studies in the use of topiramate, an antiepileptic agent that also causes weight loss, indicate that it may potentially prove effective as part of a weight loss program for person’s affected with neuromuscular disorders.¹³

Physical therapy. A physical therapy program can reduce the incidence of contractures and promote mobility.

Surgical intervention. Because scoliosis can be extremely painful and cause secondary pulmonary complications, DMD-affected individuals frequently undergo surgical procedures to fuse vertebrae or have a mental rod inserted in the spine to straighten the spinal column.^7,8

Pulmonary and heart monitoring. Affected individuals should be monitored for evidence of respiratory problems and cardiomyopathy.

Aggressive use of anti-congestive medications and ventilatory support can increase both the quality of life and life expectancy.^6,10 A recent study found that the quality of life as rated by affected individuals does not correlate with the level of their physical impairment nor the use of non-invasive positive pressure ventilation. The high quality of life reported by such individuals should be taken into consideration with evaluating therapeutic options.¹⁴

While the incidence of cardiomyopathy in DMD is high, it often occurs without the typical congenital heart failure symptoms. Therefore, echocardiography once every 2 years up to the age of 10 years and annually in subsequent years is recommended. In addition, because of cardiac autonomic nervous system disturbances in patients affected with DMD, a 24-hour Holter ECG record on every cardiac examination is also recommended¹⁵

Prognosis and natural history

DMD presents in early childhood with delayed milestones, including delays in sitting, standing and walking independently. The mean age of diagnosis of affected boys without a family history of DMD is four years 10 months. The first symptoms of DMD are typically gait problems, delay in walking, learning difficulties and speech problems. Proximal weakness causes a waddling gait and difficulty climbing. Affected children use the Gower maneuver to rise from a supine position. Calf muscles are hypertrophic. DMD progresses rapidly, with affected children wheelchair bound by age 12 years. The incidence of cardiomyopathy increases steadily in the teenage years, with approximately one-third of individuals being affected by age 14 year and all individuals after age 18.¹⁰ Death due to respiratory or cardiac complications typically occurs late in the second decade or early in the third decade.

Investigative therapies

A Phase I study of dystrophin plasmid-based gene therapy was recently reported and showed promising results. The small study included nine patients with either DMD or BMD who were injected via the radialis (arm) muscle with a human dystrophin plasmid (a circular, double-stranded unit of DNA) In the biopsies taken three weeks after the initial injection, dystrophin expression, albeit low, was detected in six of the nine patients (up to 6% weak, but complete sarcolemmal dystrophin staining, and up to 26% partial sarcolemmal labeling). No side effects were observed, nor any anti-dystrophin responses.¹⁶

Conclusion

DMD is a devastating disease with no known cure. Pharmacological treatment, surgical intervention, ventilatory assistance and physical therapy play an important role in managing the disease’s symptoms and associated secondary diseases. Current research in DMD is focused on more effectively managing DMD using know drugs and derivatives. Gene therapy studies, while nascent, show positive results that indicate further research is warranted.

Online Resources

• GeneReviews at GeneTests.org: An online genetics database. See the GeneReview for Dystrophinopathies (Korf BR et al). http://www.genetests.org
• Wheeless’ Textbook of Orthopaedics: An online database of the Wheeless’ Textbook of Orthopaedics. See the entry for Duchenne Muscular Dystrophy. http://www.wheelessonline.com
• Parent Project Muscular Dystrophy: An online resource of the Parent Project Muscular Dystrophy. http://www.parentprojectmd.org
• The Muscular Dystrophy Association: The online site of The Muscular Dystrophy Association. http://www.mdausa.org

References

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² Gatta V et al. Identification of deletions and duplications of the DMD gene in affected males and carrier females by multiple ligation probe amplification (MLPA). Hum Genet (2005) 117: 92–98.
³ Mukherjee, M. and Mittal, B. Muscular Dystrophies. Indian J Pediatr 2004; 71 (2):161-168.
⁴ Community Health Care; Wausau Hospital Medical Library. Muscular Dystrophy. CHC Medical Library & Patient Education Online Health Encyclopedia. Accessed August 2005. http://www.chclibrary.org/micromed/00057310.html
⁵ Emery AH, Population frequencies of inherited neuromuscular diseases - a world survey. Neuromusc Disord 1991; 1:19-29.
⁶ Reilly MM and Hanna MG. Genetic Neuromuscular Disease. J Neurol Neurosurg Psychiatry 2002;73 (Suppl II):ii12–ii21.
⁷ Parent Project Muscular Dystrophy. Understanding DMD. Parent Product Muscular Dystrophy. Accessed August 2005. http://www.parentprojectmd.org/dmd/introduction.html
⁸ Wagner KR. Genetic diseases of muscle. Neurol Clin N Am 20 (2002) 645-675.
⁹ Duchenne Muscular Dystrophy. Wheeless' Textbook of Orthopaedics (database online). Accessed August 2005. http://www.wheelessonline.com/ortho/duchenne_muscular_dystrophy
¹⁰ Korf BR et al. Dystrophinopathies. In: GeneReviews at GeneTests: Medical Genetics Information Resource online database. Updated Oct 2004. Accessed Aug 2005. http://www.genetests.org
¹¹ Ames WA, et al. The role of corticosteroids in Duchenne muscular dystrophy: a review for the anesthetist. Pediatr Anesth 2005 15:
¹² Beenakker EAC et al. Intermittent Prednisone Therapy in Duchenne Muscular Dystrophy. Arch Neurol. 2005;62:128-132.
¹³ Carter GT et al. Topiramate for Weight Reduction in Duchenne Muscular Dystrophy. Letter to the Editor. Muscle & Nerve. June 2005: 788.
¹⁴ Kohler M et al. Quality of Life, Physical Disability, and Respiratory Impairment in Duchenne Muscular Dystrophy. Am. J. Respir. Crit. Care Med. published ahead of print on June 16, 2005 as doi:10.1164/rccm.200503-322OC.
¹⁵ Kirchmann C et al. Echocardiographic and Electrocardiographic Findings of Cardiomyopathy in Duchenne and Becker–Kiener Muscular Dystrophies. Pediatr Cardiol 2005; 26:66–72.
¹⁶ Romero NB et al. Phase I Study of Dystrophin Plasmid-Based Gene Therapy in Duchenne/Becker Muscular Dystrophy. Human Gene Therapy 2004; 15:1065–1076.