Natural history of respiratory function in DMD
A major measure of lung function is absolute vital capacity (VC), which
rises from age 7 and usually peaks between 12 and 14 years and then
declines due to progressive muscle weakness. While absolute VC continues
to rise, the percentage of ideal or predicted VC (VC%pred) declines in
a linear fashion reaching about 80% predicted at age 1013. Hence, gradually falling VC%pred values include
absolute values which occur before, at and following peak VC. Some
investigators suggest that the identification of absolute values before,
at and following peak VC may be best to assess the effect of
interventions 14. In a large cohort study the VC of
untreated individuals peaked at 1.85 liters at age 12 to 13 yrs and
began to decline when VC%pred fell to 60-70% 15.
Rates of decline of VC%pred per year have varied in the literature
between as little as 5% (ages 5 to 24 yrs) 16 to as
much as 10.7% (ages 12 to 15 yrs) 17. Following peak
VC, absolute decline in ml/yr varies between 118 14and 180 mls/yr 18 with subsequently both FVC and
VC%pred reaching an asymptotic floor after 20 years of age14-16,19,20. Without ventilatory support, a more
favorable prognosis is associated with a higher, later peak and a more
gradual decline in VC 21. Consensus guidelines
recommend lung volume recruitment strategies at VC 60%pred,
mechanically assisted coughing at 50%pred and NIV below 50%pred22. A VC of less than 1 liter has been associated with
a 5 year survival of only 8% without respiratory supports18. At VCs below a liter (680cc) up to 24 hour
respiratory support, preferably noninvasively, may be required. As such,
disease modifying therapies have the goal of increasing and delaying the
peak VC and reducing the post-plateau rate of decline. The more or less
linear decline of VC%pred as an outcome measure may not be as sensitive
to change as a result of interventions, as absolute VC13.
Phenotypic differences in pulmonary function and therefore clinical
outcomes have been recognized for years. Phillips identified a longer
surviving population who experienced peak VC at a median of 2 years
later, 13 vs. 15 years and a slower yearly decline in VC%pred, 6% vs,
7.8% 18 and other investigators have divided DMD
populations in to cohorts with different outcomes and survival related
to the number of mutations upstream to exon 30 23.
Even within the same genotype heterogeneity exists and needs to be
considered in the evaluation of emerging therapies 23.