• High frequency of new mutations
• Allelic heterogeneity
• Manifesting carriers
• Phenotypic variability
Major Phenotypic Features
• Age at onset: Childhood
• Muscle weakness
• Calf pseudohypertrophy
• Mild intellectual compromise
• Elevated serum creatine kinase level
History and Physical Findings
A.Y., a 6-year-old boy, was referred for mild developmental delay. He had difficulty climbing stairs, running, and participating in vigorous physical activities; he had decreased strength and endurance. His parents, two brothers, and one sister were all healthy; no other family members were similarly affected. On examination, he had difficulty jumping onto the examination table, a Gowers sign (a sequence of maneuvers for rising from the floor; Fig. C-14), proximal weakness, a waddling gait, tight heel cords, and apparently enlarged calf muscles. His serum creatine kinase level was 50-fold higher than normal. Because the history, physical examination findings, and elevated creatine kinase level strongly suggested a myopathy, A.Y. was referred to the neurogenetics clinic for further evaluation. Results of his muscle biopsy showed marked variation of muscle fiber size, fiber necrosis, fat and connective tissue proliferation, and no staining for dystrophin. On the basis of these results, A.Y. was given a provisional diagnosis of Duchenne muscular dystrophy, and he was tested for deletions of the dystrophin gene; he was found to have a deletion of exons 45 through 48. Subsequent testing showed his mother to be a carrier. The family was therefore counseled that the risk for affected sons was 50%, the risk for affected daughters was low but dependent on skewing of X inactivation, and the risk for carrier daughters was 50%. Because her carrier status placed her at a high risk for cardiac complications, the mother was referred for a cardiac evaluation.
FIGURE C-14 Drawing of a boy with Duchenne muscular dystrophy rising from the ground, illustrating the Gowers maneuver. See Sources & Acknowledgments.
Disease Etiology and Incidence
Duchenne muscular dystrophy (DMD, MIM 310200) is a panethnic, X-linked progressive myopathy caused by mutations within the DMD gene. It has an incidence of approximately 1 in 3500 male births.
DMD encodes dystrophin, an intracellular protein that is expressed predominantly in smooth, skeletal, and cardiac muscle as well as in some brain neurons (see Chapter 12). In skeletal muscle, dystrophin is part of a large complex of sarcolemma-associated proteins that confers stability to the sarcolemma (see Fig. 12-20).
DMD mutations that cause DMD include large deletions (60% to 65%), large duplications (5% to 10%), and small deletions, insertions, or nucleotide changes (25% to 30%). Most large deletions occur in one of two hot spots. Nucleotide changes occur throughout the gene, predominantly at CpG dinucleotides. De novo mutations arise with comparable frequency during oogenesis and spermatogenesis; most of the de novo large deletions arise during oogenesis, whereas most of the de novo nucleotide changes arise during spermatogenesis.
Mutations causing a dystrophin null phenotype effect more severe muscle disease than mutant DMD alleles expressing partially functional dystrophin. A consistent genotype-phenotype correlation has not been defined for the intellectual impairment.
Phenotype and Natural History
DMD is a progressive myopathy resulting in muscle degeneration and weakness. Beginning with the hip girdle muscles and neck flexors, the muscle weakness progressively involves the shoulder girdle and distal limb and trunk muscles. Although occasionally manifesting in the newborn period with hypotonia or failure to thrive, male patients usually present between the ages of 3 and 5 years with gait abnormalities. By 5 years of age, the majority of patients use a Gowers maneuver and have calf pseudohypertrophy, that is, enlargement of the calf through replacement of muscle by fat and connective tissue. By 12 years of age, most patients are confined to a wheelchair and have or are developing contractures and scoliosis. Most die of impaired pulmonary function and pneumonia; the median age at death is 18 years.
Nearly 95% of patients with DMD have some cardiac compromise (dilated cardiomyopathy, electrocardiographic abnormalities, or both), and 84% have demonstrable cardiac involvement at autopsy. Chronic heart failure develops in nearly 50% of patients. Rarely, cardiac failure is the presenting complaint for patients with DMD. Although dystrophin is also present in smooth muscle, smooth muscle complications are rare. These complications include gastric dilatation, ileus, and bladder paralysis.
Patients with DMD have an average IQ approximately 1 standard deviation below the mean, and nearly one third have some degree of intellectual disability. The basis of this impairment has not been established.
The age at onset and the severity of DMD in females depend on the degree of skewing of X inactivation (see Chapter 6). If the X chromosome carrying the mutant DMD allele is active in most cells, females develop signs of DMD; if the X chromosome carrying the normal DMD allele is predominantly active, females have few or no symptoms of DMD. Regardless of whether they have clinical symptoms of skeletal muscle weakness, most carrier females have cardiac abnormalities, such as dilated cardiomyopathy, left ventricle dilatation, and electrocardiographic changes.
The diagnosis of DMD is based on family history and either DNA analysis or muscle biopsy to test for immunoreactivity for dystrophin.
Currently there are no curative treatments of DMD, although improved symptomatic management has increased the average longevity from late childhood to early adulthood. The objectives of therapy are slowing of disease progression, maintenance of mobility, prevention and correction of contractures and scoliosis, weight control, and optimization of pulmonary and cardiac function. Glucocorticoid therapy can slow the progression of DMD for several years. Several experimental therapies, including gene transfer, are under investigation. Most patients also require extensive counseling to deal with the psychological effects of having a chronic fatal disease.
One third of mothers who have a single affected son will not themselves be carriers of a mutation in the DMD gene (see Chapter 16). Determination of the carrier state in females in the approximately 30% to 35% of DMD families with a point mutation or small indel has proved difficult in the past because of the large number of exons in the dystrophin gene. Advances in DNA sequencing, however, have made targeted exome sequencing much more effective. Counseling of recurrence risk must take into account the high rate of germline mosaicism (currently estimated to be 14%).
If a mother is a carrier, each son has a 50% risk for DMD and each daughter has a 50% risk for inheriting the DMD mutation. Reflecting the random nature of X chromosome inactivation, daughters inheriting the DMD mutation have a low risk for DMD; however, for reasons not fully understood, their risk for cardiac abnormalities may be as high as 50% to 60%. If a mother is apparently not a carrier by DNA testing, she still has an approximately 7% risk for having a boy with DMD due to germline mosaicism (see Chapter 7). Counseling and possibly prenatal diagnosis are indicated for these mothers.
Questions for Small Group Discussion
1. Why is DMD considered a genetic lethal condition? What features define a condition as being genetically lethal?
2. Discuss what mechanisms may cause a gender bias in different types of mutation. Name several diseases other than DMD in which this occurs. In particular, discuss the mechanism and high frequency of mutations at CpG dinucleotides during spermatogenesis.
3. How is the rate of germline mosaicism determined for a disease? Name several other diseases with a high rate of germline mosaicism.
4. Contrast the phenotype of Becker muscular dystrophy with DMD. What is the postulated basis for the milder phenotype of Becker muscular dystrophy?
Darras BT, Miller DT, Urion DK. Dystrophinopathies. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1119/.
Fairclough RJ, Wood MJ, Davies KE. Therapy for Duchenne muscular dystrophy: renewed optimism from genetic approaches. Nat Rev Genet. 2013;14:373–378.
Shieh PB. Muscular dystrophies and other genetic myopathies. Neurol Clin. 2013;31:1009–1029.