tips and tricks

• Keep dystrophin deficiency in the differential diagnosis for both muscle and cognitive complaints.
  
• Think of a dystrophinopathy in any male or female at any age presenting with an elevated CK or unexplained transaminases, exertional myalgias, myoglobinuria, or proximal weakness with or without diaphragm weakness or cardiomyopathy.
  
• Dystrophin deficiency is also a consideration in children and adults presenting with cognitive dysfunction (e.g. delayed language development, autism, learning disorders, attention-deficit hyperactivity disorder and impaired intelligence).

Clinical Presentations

Duchenne Muscular Dystrophy

The classic presentation of DMD includes delayed gross motor milestones, difficulty running, and increasing falls in young boys. Examination shows calf pseudohypertrophy, and proximal hip girdle weakness manifested by a waddling gait and use of a Gower maneuver to get up from a supine position. Serum CK is markedly elevated (20–200 times normal). Many affected boys will also have cognitive dysfunction. Diagnosis is made between 3 and 5 years of age.

Progression is relentless, with loss of ambulation occurring by 12 years of age. Weakness of the diaphragm begins while boys are ambulatory and annual pulmonary function testing should be initiated early. With transition to a wheelchair, progressive kyphoscoliosis significantly worsens respiratory function. Monitoring for progressive scoliosis is essential in nonambulatory patients because some individuals may need spinal fusion to help maintain their respiratory function. Ultimately, it is the chronic respiratory failure that is the primary cause of death in DMD, typically in the late 20s or early 30s. Early involvement of pulmonologists is essential. The introduction of noninvasive ventilation (NIV) has altered the natural history and has extended the survival of boys with DMD well into adulthood. Nocturnal ventilation is useful for symptoms of ineffective ventilation such as morning headaches, reduced energy and appetite, nocturnal anxiety, and nightmares. Cough assist devices can help patients with poor cough to clear secretions and prevent infections. Tracheostomy and assisted mechanical ventilation may be pursued by some patients and families late in the disease course.

All boys with DMD develop signs of cardiac involvement, usually with asymptomatic tachycardia. An electrocardiogram (EKG) commonly shows sinus tachycardia, prominent Q waves, right ventricular hypertrophy, and a short P–R interval. Echocardiography with cardiology evaluation is recommended annually from age 10. Management may include angiotensin-converting enzyme (ACE) inhibitors and β blockers.

However, less than 40% of individuals with DMD will be symptomatic from a cardiac standpoint, likely related to the decreased demand on the heart after the transition to a wheelchair.

Optimal care for DMD requires a well-coordinated multidisciplinary healthcare team that anticipates and manages the multisystemic manifestations and complications of DMD. Glucocorticoids (prednisone 0.75 mg/kg per day and deflazacort 0.9 mg/kg per day) slow the decline of muscle strength and function in boys with DMD. Observational cohort data suggest that ambulation is prolonged in boys treated with glucocorticoids and benefit is maintained once nonambulatory, with a reduced risk of scoliosis, a slower deterioration in pulmonary function, and potential benefits to the heart. Despite this, there is marked variability in clinical practice with regard to dosing regimens and time to initiate treatment. Recent recommendations suggest individualized treatment based on consideration of functional status (start once no longer gaining in motor skills), age (>2 years but <8 years of age), and after assessment of risk factors for the many side effects of steroids. Similarly, there are no stopping rules; dosing may be adjusted to minimize side effects such as weight gain, mood and behavior changes, cataracts, and long bone and vertebral compression fractures. It remains common for young men with advanced DMD to continue their steroid regimen indefinitely. Seasonal flu shots are recommended in all boys and they should be supplemented with vitamin D if the serum 25-hydroxy-vitamin D is low.

Initiation of nocturnal ventilation requires coordination and provision of resources in the home and community, along with education of patients and families. Advanced care planning is critical for facilitating shared decision-making, and should be introduced early and revisited regularly in a systematic manner.

Becker Dystrophy

In contrast to the fairly stereotypical presentation in DMD, there is a highly variable presentation with BMD. Any male at any age presenting with a symmetric limb–girdle pattern weakness should be tested for a dystrophinopathy, even in the absence of a positive family history. Although many affected males present in adolescence, onset of muscle weakness in the fourth and fifth decades and beyond is well described. Early involvement of the quadriceps in men aged over 40 may erroneously suggest the diagnosis of inclusion body myositis if a dystrophinopathy is not considered. In general, the older the age of symptomatic onset is, the milder the disease. There may also be learning difficulties, and attention and behavioral problems in adolescents and men with BMD.

By clinical consensus, patients with a dystrophinopathy who remain ambulatory past the age of 16 years are said to have BMD. Adolescent boys who lose the ability to walk independently between 12 and 16 years of age were historically classified as having an intermediate phenotype between DMD and BMD. However the use of glucocorticoids has blurred this distinction.

Similar to DMD, all affected individuals should be screened with pulmonary function tests (seated and repeated supine) and cardiac investigations biannually. Symptomatic cardiac involvement secondary to dilated cardiomyopathy and/or arrhythmia is much more likely in men with BMD. EKG findings are similar to those seen in DMD. Referral to cardiology is indicated in all symptomatic individuals and management may require the use of ACE inhibitors and β blockers. Relatively preserved limb muscle strength likely permits more dynamic activity and increased cardiac demand. Importantly, cardiac failure may be the initial manifestation in some patients. Chronic respiratory failure secondary to diaphragm involvement and ineffective nighttime ventilation may also lead to right heart failure and management involves initiation of nocturnal assisted ventilation. Life expectancy is reduced for men with significant involvement of the heart or diaphragm.