THE COOPERATIVE INTERNATIONAL NEUROMUSCULAR RESEARCH GROUP DUCHENNE NATURAL HISTORY STUDY: GLUCOCORTICOID TREATMENT PRESERVES CLINICALLY MEANINGFUL FUNCTIONAL MILESTONES AND REDUCES RATE OF DISEASE PROGRESSION AS MEASURED BY MANUAL MUSCLE TESTING AND OTHER COMMONLY USED CLINICAL TRIAL OUTCOME MEASURES

Duchenne muscular dystrophy (DMD) is an X-linked degenerative disorder of the dystrophin protein that causes progressive muscle weakness, usually leading to death in early adulthood.1 DMD is the most common neuromuscular disease of childhood and occurs with an incidence of about 30 per 100,000 live-born males across all ethnic groups.2 Although it is accepted that a majority of cases of DMD are inherited, studies have demonstrated that between 20% and 50% of DMD cases in various populations are the result of spontaneous mutations.3–6 The course of physical impairment is severe and inexorably progressive, and its description has varied little since Meryon’s and Duchenne’s early descriptions of the disease in the mid-19th century.7,8 In early childhood, motor developmental milestones are delayed and, by 4–5 years of age, these children rise from the floor in the classic adaptive standing pattern first described by Gowers,9 have increasing difficulty climbing stairs, and begin to have frequent falls. Muscles show a classic pattern of pseudohypertrophy, most notably in the calf muscles. With disease progression, boys begin to walk with a characteristic waddling gait with compensatory lumbar lordosis, shortened stride length, and widened base of support, which advances to a point where they require constant physical support and stabilization.10,11 Mean age to loss of ambulation in steroid-naive children is between ages 9 and 10 years.12–16 Over the ensuing years, patients typically develop worsening contractures, scoliosis, and progressive impairment of respiratory and cardiac function. From the earliest reports until the 1960s, death has typically occurred in the early to mid-teens due to respiratory complications or cardiac failure, but advances in preventive and supportive respiratory and cardiac therapies have led to a median survival in the middle to late twenties and growing chances of survival into the thirties for patients who receive aggressive care.13 Clinical trials have demonstrated that administering glucocorticoid (GC) therapy improves strength within weeks to a few months, and that these increases in strength can preserve ambulation for up to 2–3 years longer than for steroid-naive patients.17–22 However, few studies have assessed the long-term impact of GC-mediated improvements on maintaining strength, preserving function, and developing or preventing secondary health conditions. The aims of this study were to: (1) assess baseline levels of impairment and prevalence of secondary conditions from age 2 years to adulthood; and (2) evaluate the effect of chronic GCs in DMD on: (a) preservation of functional capabilities using a novel composite functional “milestone” scale scale showing clinically meaningful mobility and upper limb abilities; (b) progression of strength loss based on manual muscle testing versus historical reports of strength loss in steroid-naive patients; and (c) preservation of respiratory function based on pulmonary function tests (PFTs) across the age span.