Key Insights Into BMD, DMD Could Revolutionize Clinical Care and Trials

Appendicular lean mass (ALM) and ALM index (ALMI) show promise as surrogate markers for disease severity in patients who have Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD), with implications that could have an impact on clinical care decision and clinical trial designs, experts wrote in Journal of Cachexia, Sarcopenia and Muscle.

Their retrospective review covered 499 patients who had DMD (466 with typical DMD, 33 with intermediate DMD [DMDI]) and 46 patients who had BMD, all male. Ages were equivalent, ranging from 5 to 23 years and 5 to 21 years, respectively. All of the children had been seen at Cincinnati Children’s Comprehensive Neuromuscular Care Center between January 1, 2009, and March 31, 2017. Their longitudinal ALM was measured by dual energy X-ray absorptiometry, which evaluated bone health and body composition as part of the annual standard-of-care protocol for patients who have DMD and BMD. Diagnosis of DMD or BMD was confirmed via presence of a dystrophin gene mutation or muscle biopsy dystrophin findings, and soft tissue mass was used to measure lean body mass.

DNA concept art | Image credit: nobeastsofierce - stock.adobe.com

“We hypothesized that patients with typical DMD and DMDI, who have earlier onset of progressive loss of muscle strength and motor function, have lower muscle mass as compared with pediatric patients with BMD, who have no functional mobility deficits as defined by functional mobility criteria," they wrote.

Previous research from these same investigators illustrated ALM and ALMI progressively declined in male patients who have DMD, but that data lack on these potential makers’ utility for DMDI and BMD.

Most DXA scans (2460) were seen among patients with typical DMD; 171 scans took place among those with DMDI, and 137 among those with BMD. The median patient age for a DXA scan was youngest among the patients with DMD (11.0 [range, 5.0-22.8] years) vs BMD (11.6 [range, 5.1-21.1] years) and a group of 693 control patients (13.9 [range, 5.0-12.8] years).

Thirty-six percent of the patients living with DMD had received either growth hormone (19%) or testosterone (14%). No patients living with BMD received glucocorticoids.

Median body mass index (BMI) Z-score was highest among the patients with DMD, at 1.1 (range, –0.2 to 3.5) and lowest among the patients with BMD, at 0.5 (range, ­2.7 to 2.7); the healthy controls had a Z-score of 0.3 (range, ­2.9 to 2.6). The corresponding height-for-age Z-score for each patient group was –2.1 (range, –7.4 to 2.2), –0.2 (range, –2.4 to 2.8), and 0.1 (range, –2.5 to 3.0). Patients living with DMD had the highest median percentage of whole body fat (37%) compared with the healthy controls who had 23.1% whole body fat; the patients with BMD had 29.1% whole body fat.

An analysis that looked at mutation location in DMD found that mutations at exons 45-62 were the most common type, followed by exons 1-30, 31-44, and 63-79, at 253, 159, 73, and 12, respectively. Total DXA scans corresponded with these totals, at 1132, 772, 373, and 52.

When considering age-related trajectories of ALM and ALMI, the study authors observed these results among the DMD, BMD, and control groups:

• Consistent ALM and ALMI gains for the healthy controls
• Patients with BMD had parallel gains in ALM and ALMI vs controls until adolescence, after which Z-scores were within 2 SD
• Patients with DMD saw steady declines in their mean ALM Z-scores starting with age 7, with a drop below –2.0 by age 10 years; by age 13 years, height-adjusted ALMI Z-scores reached the same mark

Also for age-related trajectories of ALM and ALMI, these results were seen for a comparison among patients with either typical DMD or DMDI and BMD:

• For patients with BMD, the highest rate of ALMI change took place between ages 10 to younger than 14 years, at 0.27 kg/m² (DMD vs BMD and DMDI vs BMD, both P < .0001); the corresponding ALM rate of change was 1.86 kg (DMD vs BMD and DMDI vs BMD, both P < .0001)
• For patients with typical DMD, these rates were 0.16 kg/m² (DMD vs BMD, P = .7086; DMDI vs BMD, P = .9316) and 0.66 kg (DMD vs BMD, P = .3643; DMDI vs BMD, P = .5081) before age 7 years
• For patients with intermediate DMD, the rates again were highest before age 7 years, at 0.20 kg/m² (DMD vs BMD, P = .7086; DMDI vs BMD, P = .9316) and 0.74 kg(DMD vs BMD, P = .3643; DMDI vs BMD, P = .5081)

A final analysis that compared ALMI outcomes by exon grouping mutation just among the patients with DMD found the greatest overall declines in ALMI were seen in connection with exons 63-79 (–0.45 kg/m²) after age 10 years compared with exons 45-62 and a drop of –0.32 kg/m² at 20 years or older, exons 31-44 and a drop of –0.21 kg/m² at 20 years or older, and exons 1-30 and a drop of –0.12 kg/m² at age 14 to younger than 20 years.

The authors highlighted that their findings add to current knowledge of the relationships between ALM/ALMI and DMD and BMD, with the ALMI findings, in particular, reflecting earlier-onset muscle weakness in patients with DMD vs BMD.

“Our findings further support the potential use of ALM and ALMI as surrogate biomarkers to characterize the severity of BMD and DMD, to inform genotype-phenotype correlations, clinical care decisions, and clinical trial designs and outcomes," they concluded.

Reference

Wong BL, Summer S, Horn PS, et a. Appendicular lean mass index changes in patients with Duchenne muscular dystrophy and Becker muscular dystrophy. J Cachexia Sarcopenia Muscle. Published online October 25, 2023. doi:10.1002/jcsm.13357