Abstract
Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease resulting in severe respiratory derangements. As such, DMD patients are at a high risk of nocturnal hypoventilation, thereby requiring nocturnal ventilation (NV). To this end, NV is an important clinical milestone in the management of DMD. Emerging evidence suggests that ß2 adrenergic receptors (ADRB2) may play a role in determining respiratory function, whereby more functional ADRB2 genotype variants (e.g., Gly16) are associated with improved pulmonary function and respiratory muscle strength. These findings suggest that the more functional ADRB2 genotype may help to preserve respiratory function in patients with DMD. The purpose of this study was to identify the influence of ADRB2 genotype on the risk of NV use in DMD. Data from the CINRG Duchenne Natural History Study including 175 DMD patients (3–25 yrs) were analyzed focusing on ADRB2 genotype variants. Time-to-event analyses were used to examine differences in the age at prescription of full-time NV use between genotypes. There were no differences between genotype groups in age, height, weight, corticosteroid use, proportion of ambulatory patients, or age at loss of ambulation. DMD patients expressing the Gly16 polymorphism had a significantly (P < 0.05) lower mean age at NV prescription compared with those patients expressing the Arg16 polymorphism (21.80 ± 0.59 yrs. vs 25.91 ± 1.31 yrs., respectively). In addition, a covariate-adjusted Cox model revealed that the Gly16 variant group possessed a 6.52-fold higher risk of full-time NV use at any given age compared with the Arg16 polymorphism group. These data suggest that genetic variations in the ADRB2 gene may influence the age at which DMD patients are first prescribed NV, whereby patients with the Gly16 polymorphism are more likely to require NV assistance at an earlier age than their Arg16 counterparts.
Highlights
It is estimated that 32% of Duchenne muscular dystrophy (DMD) patients suffer from nighttime alveolar hypoventilation as a result of sleep-disordered breathing [1]
DMD participants with the Gly16 polymorphism demonstrated a higher risk (P < 0.05) of use of nocturnal ventilation (NV) at any given age compared with those expressing the Arg16 polymorphism (21.80 ± 0.59 yrs. vs 25.91 ± 1.31 yrs., respectively)
The original hypothesis of this study was that DMD patients with the Gly16 polymorphism would have a reduced risk of using NV at any given age compared with those patients expressing the Arg16 polymorphism
Summary
It is estimated that 32% of Duchenne muscular dystrophy (DMD) patients suffer from nighttime alveolar hypoventilation as a result of sleep-disordered breathing [1]. Respiratory muscle weakness in DMD is characterized by a progressive loss in the ability to generate respiratory pressures, resulting in severe ventilatory derangements [6, 7]. Decreases in respiratory pressure and airflow generation can be attributed to a primary weakness of the diaphragm secondary to intramuscular remodeling in DMD [6]. This remodeling is characterized by an increased resting diaphragm thickness due to an infiltration and deposition of non-contractile elements (pseudo-hypertrophy), concomitant with the loss of sarcomeres in series [8, 9]. Due to the progressive nature of respiratory weakness in DMD, it is imperative that therapeutic targets are identified to slow respiratory muscle degradation, and decrease the risk of NV prescription
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