Duchenne muscular dystrophy (DMD) is a rare disease; however, it is the most common form of inherited muscle disease in childhood with an incidence of 1 in 3,500 live male births
2 and prevalence of 1.7 to 4.2 cases per 100,000 people.
1
Pathogenesis
DMD is an X-linked recessive disease, characterized by progressive deterioration of muscle mass in boys. In 70% to 80% of the cases a genetic link can be identified; the remainder of the cases are the result of “de-novo” mutation.
3 Mutations in the DMD gene (Xp21.2) are most often caused by a deletion or duplication of a promoter region which leads to frameshift-type mutation and formation of nonsense dystrophin which undergoes rapid degradation. The result of this mutation is an absence (or insufficient levels) of dystrophin protein in muscle tissue. This lack of function results in the inability to shield muscle from mechanical stress during repeated contractions. As such the cell membrane becomes disrupted leading to cell death. At the tissue level, the repeated breakdown of cellular integrity leads to prolonged inflammation process and ultimately fibrosis and fat deposition of the muscles. Dystrophin protein is also found in cardiac muscle tissue; therefore, DMD patients are at risk for dilated cardiomyopathy.
Clinical Presentation
In the first few years of life, muscle regeneration is excellent; however, as the child ages, muscle tissue degeneration outpaces their ability to replace it. This is particularly true in proximal muscles. The first symptoms usually appear between 2 and 3 years of age. The symptoms may include flat feet, delay in motor milestones including walking, pseudohypertrophy of the calves, balance issues, and clumsiness. The so-called “Gower’s” sign is present when the child uses his hands to push up off the legs to aid the weak legs in standing. The plurality of patients will achieve the ability to walk; however, gait is characterized by a broad base of support, and toe walking is common. Flexion contractures of hips and knees and equinus contractures of the ankles are common as weakness progresses, eventually leading to the patient being restricted to a wheelchair. Hip flexion contractures will lead to lumbar hyperlordosis and scoliosis. Proximal muscle weakness in the upper limbs is manifested by difficulty with shoulder elevation during feeding. Cardiac and respiratory failure will ultimately lead to the patients’ demise typically in the third decade of life.
Management
The general goals for the management of DMD patients are the preservation of function, maintaining bone health, and reducing contractures. The orthopaedic surgeon’s role is to assist neurology and physical medicine by providing assessment and treatment of contractures, scoliosis, fractures, and optimization of bone health. Lengthening of muscles to produce braceable feet to preserve ambulatory function is critical as it can potentially decrease the rate of obesity and osteoporosis which is seen in later stage disease.
Disease severity dictates treatment methods. Ambulatory patients use orthoses to facilitate walking assist during longer distances; contractures (mostly of the ankle) are addressed by surgical lengthening followed by casting and physical therapy. Administration of long-term corticosteroids has been shown to improve muscle strength, delay the loss of ambulation, preserve upper limb and respiratory functions, and decrease the need for spinal fusion for scoliosis.
5,6 In nonambulatory patients, great effort is directed at maintaining joint range of motion. Physical therapy and orthoses are used to delay the onset of contractures. Contractures of the lower limbs are addressed to maintain comfortable sitting and free movement of hip and knee joints. Scoliosis is addressed early with posterior spinal instrumented fusion to sustain an upright posture and decrease the work of breathing. In contrast to other disorders, spinal fusion is often encouraged much earlier in DMD than other disorders (as early as 20°) because of the natural history of cardiopulmonary decline shortly after scoliosis presents.
Pharmacological treatments including corticosteroids have been used in DMD patients in the last decade with great success. They have revolutionized the treatment of Duchenne’s boys and prolonged their lives and in some cases their independence.
5 Theoretically, steroids may have an anti-inflammatory effect, which delays the muscle degeneration process while not explicitly addressing the underlying pathology.
3 However, these medications can exacerbate osteoporosis in these patients. Fractures are extremely common, particularly as the disease progresses. More recently with a better understanding of the genetic pathogenesis, the goal of treatment has been directed toward of mutation-specific drugs. Examples include ataluren and eteplirsen. Ataluren targets a stop codon in the mature mRNA of the dystrophin gene; it blocks the stop codon and allows mRNA translation to be completed, so a functional protein is produced. Eteplirsen specifically recognizes exon 51 in the pre-mRNA sequence (which become the stop codon on mRNA); by binding the pre-mRNA it changes the splicing process allowing mRNA-reading to become in-frame and allows a functional protein to be formed.
Cardiac and pulmonary function should be assessed in DMD patients. Cardiologists and Pulmonologists are critical members of the team particularly in its later stages where patients experience such multisystem organ decline. Consultation with these specialists is vital before surgery because of the limited pulmonary reserve. Additionally, malignant hyperthermia is associated with muscle disease, so vigilance on the part of anesthesia and the surgical team is needed.