Effect of phenotypic heterogeneity
Another important factor potentially confounding the interpretation of
aggregate results of intervention studies on respiratory outcomes is
phenotypic heterogeneity. This variability has been recognized for years18 and can manifest as markedly different timing and
value maximum VC as well as rate of decline. Neve, in a study of 33 CS
naïve DMD subjects identified subphenotypes requiring NIV either prior
to, or after age 17 40. The former was identified by
an earlier (age 11.5 to 13) and lower peak VC and SNIP and more rapid
decline. In a study using the STRIDE nonsense mutation (nmDMD) cohort,
investigators found no correlation in 181 patients between disease
severity and exon location of the nonsense mutation. There was a large
degree of phenotypic variability despite of having identical dystrophin
mutations 41. Birnkrant has identified highly
discordant cardiopulmonary function in brothers with DMD and identical
dystrophin mutations and identified 8 of 15 patients (53%) with a
shared genotype who had discordant cardiopulmonary function23,42. Clinical manifestations were not related to the
dystrophin mutation. In a cohort of over 200 patients, Magri, as well,
noted the absence of correlation of pulmonary, cardiac or motor
phenotype with dystrophin genotype, with the exception of neurocognitive
function being related to more distal mutations 43.
Being unable to predict the natural evolution of cardiopulmonary
function in a portion of the population despite common genotype could
pose a significant confounding issue when assessing the impact of
emerging therapies in DMD. Rather than being the true treatment effect,
such beneficial or adverse observations might simply be due to more
favorable or unfavorable phenotype.