Many patients with DBMD develop short stature, disordered weight, and osteoporosis. The DMD gene encodes multiple dystrophin (Dp) isoforms. Isoform transcription is determined by mutation position. Differential Dp isoform disruption could underlie phenotypic variability in endocrine and bone health complications.
To investigate associations between Dp isoform disruption and short stature, underweight, obesity, and low areal bone mineral density (aBMD) among individuals with DBMD from the population-based Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet).
We analyzed 382 males with DBMD from 6 US surveillance regions (CO/IA/21 western counties in NY/33 counties of NC/SC/UT), born and diagnosed during 01/01/2000-12/31/2015, with genetic testing results. DMD mutation position and exon involvement were used to predict Dp isoform disruption (Dp427/Dp260/Dp140/Dp116/Dp71). Cases were categorized 1 to 5 based upon the number of disrupted isoforms. Height (ht), weight (wt), and body mass index (BMI) Z-scores for age were calculated using 2000 CDC reference data. aBMD Z-scores were abstracted from dual-energy X-ray absorptiometry reports. Outcomes were short stature [height=Z≤-2], underweight [BMI=Z<-1.64], obesity [BMI=Z≥1.64], and low aBMD [aBMD=Z≤-2]). One-way ANOVA and chi-square (Fisher-exact) were used where appropriate. Results Isoform distributions were: 1(28%), 2(17%), 3(45%), 4(4%), and 5(6%). Mean ht-Z differed by isoform disruption, ranging from -1.5±1.4 (5 disrupted) to -0.8±1.1 (1 disrupted), p<0.0001. The frequency of short stature ranged from 40% (5 disrupted) to 13% (1 disrupted), p<0.0001. Significant differences were seen for wt-Z and BMI-Z, but not aBMD-Z. The frequency of obesity and underweight ranged from 27% (5 disrupted) to 10% (4 disrupted), p=0.01, and 7% (4 disrupted) to 2% (1 disrupted), p=0.04, respectively. Multivariable analyses accounting for steroid exposure are underway. Conclusion Significant associations between Dp isoform disruption and height, weight and BMI were identified. Notably, the frequency of short stature and obesity were greatest in cases with 5 disrupted Dp isoforms.