Cardiopulmonary phenotypic variability and discordance in Duchenne
muscular dystrophy
Abstract
Neuromuscular respiratory medicine has traditionally focused on
mechanically assisted lung ventilation and mucus clearance. These
therapies have prolonged survival for patients with Duchenne muscular
dystrophy (DMD). However, the field is rapidly evolving in a new
direction: it is being revolutionized by molecular and genetic
therapies. A good correlation between a patient’s dystrophin mutation
and his cardiopulmonary phenotype would allow accurate prediction of
patient prognosis and would facilitate the design of studies that assess
new DMD therapies. Instead, patient prognosis and the design of valid
therapeutic studies are complicated by cardiopulmonary phenotypic
discordance and variability, by which a notable proportion of DMD
patients have unexpectedly good or poor cardiopulmonary function. The
likely cause of phenotypic variability and discordance is genetic
modifiers. Once the modifiers that affect cardiopulmonary function are
better understood, it should be possible to create a personalized
genetic profile that accurately predicts the prognosis of each
individual DMD patient. This would allow investigators to assess the
effect of new therapies in the context of each patient’s particular
cardiopulmonary natural history. Amplification of beneficial
cardiopulmonary genetic modifiers and blocking of detrimental modifiers
is a promising strategy for creating new DMD therapies. When patients
with chronic respiratory failure are treated with assisted ventilation,
cardiac function determines their survival. Therefore, prioritizing new
cardiac therapies is most likely to prolong patient survival. By
focusing on these topics we aim to move neuromuscular respiratory
medicine beyond assisted ventilation and coughing and into the age of
translational medicine.