Several poster sessions, as well as the first portion of the Sarepta Symposium, presented by Eugenio Mercuri, MD, PhD (Rome, Italy) involved the evaluation of the new natural history of Duchenne. The 6-minute walk test (6mwt) is the primary outcome for many clinical trials where maintenance of ambulation is the therapeutic focus. The North Star Ambulatory Assessment (NSAA) is being discussed as a primary outcome by some groups, especially those evaluating very young children (under 5 years), with good results ages 3.5-4 years, and very good results after 4 years.
Longitudinal evaluation of the Bayley III developmental scale for infants and very young children demonstrate that children with Duchenne function cognitively at 1 standard deviation below normal, with cognitive function remaining stable. While some skills are below normal to start and continue to decline progressively below normal (motor function), some skills begin at low normal but are only delayed, with children gaining progress over time (speech, coordination, dexterity). This is a point which need to be factored into the evaluation of functional abilities of very young children in clinical trials. It has been suggested that the shortened timed function tests (2-minute walk test) might elicit more consistent results, however this has yet to be established.
Given extended life spans, as well as interest in including non-ambulatory subjects in current and future clinical trials, many groups are developing tools and methods of evaluating upper limb performance (PUL) specific for Duchenne. These appear to be reliable after age 5 and involve three domains: shoulder dimension, elbow dimension, and distal dimensions (wrist and fingers). The Toronto group demonstrated encouraging data related to daily deflazacort use, with between 96-100% of 18-20 year olds taking daily deflazacort for more than 7 years, who had not had spinal surgery, preserved upper limb function, and maintained the ability to feed themselves. Given the new natural history of Duchenne and steroids, new and different questions will need to be addressed with new and different methodology.
Exciting developments in technologies are suggesting novel biomarkers for clinical trials and influencing care. MRI imaging, using MRI and MRS (which measures lipid and water in muscle) demonstrated that both the water and lipid component of muscle increased in people with Duchenne, the increase was more marked in patients who were not taking steroids, and that there was a strong correlation between the composition of muscle and the 6mwt. Bone mineral density and bone composition were the subjects of several posters, demonstrating that patients with Duchenne have decreased density and altered composition, and that further research into the stabilization of both is needed.
Dr. Kathy Mathews (Iowa City, IA) discussed the importance of accelerated diagnosis in Duchenne. She cited data showing that, while parents are generally concerned about symptoms of Duchenne before age three, that the diagnostic odyssey begins with the pediatrician or family provider, who delay diagnosis an average of two years. Both delayed referrals and issues around payment for diagnosis are significant barriers to diagnosis. While Dr. Jerry Mendel's group showed financial and practical feasibility of newborn screening for Duchenne, this has not been instituted in the US. Newborn screening would be the ultimate in accelerated diagnosis, but it is not without complications.
Dr. Richard Finkel (Orlando, FL) discussed the necessity for standards of care. The Care Considerations were developed with the assistance of the Centers for Disease Control and Prevention, and published in 2009, with the most current evidence and expert opinion of the time. They are recognized as only guidelines, rather than mandates for care, which are constantly moving and evolving, and do not take into consideration local, regional, and national constraints, or cultural biases. Many areas (dental and oral health, gastrointestinal, transition and palliative care, for example) were mentioned only slightly and have become major areas of concern today. Several sub-specialties have held workshops and published guidelines (cardiac, pulmonary, endocrine, orthopedics, psychosocial (transition, cognition)).
There is much more to come. We will do our best to keep the updates coming!