Disease progression with BMD largely seen only in adults: Study
Becker's natural history observed in 83 people, ages 5 to 76, for three years
Disease progression with Becker muscular dystrophy (BMD) varies considerably, and depends on a patient’s age — with progression largely seen only in adults — and type of mutation, a three-year study of BMD’s natural history shows.
“We … provide evidence that decline/improvement in function would be hard to measure in patients less than 18 years of age,” the researchers wrote, noting that this and other evidence may be of importance to clinical trials.
The study, “Findings from the Longitudinal CINRG Becker Natural History Study,” was published in the Journal of Neuromuscular Diseases.
Aiming to better understand a more slowly progressive muscular dystrophy
BMD is caused by mutations in the DMD gene that lead to shortage of working dystrophin, an essential protein for muscle health, resulting in progressive muscle weakness and wasting. Most disease-causing mutations are deletions of one or more exons — segments along the DNA strand that contain the instructions to make proteins.
Natural history studies are paramount in understanding how a disease progresses in the absence of treatment. Aiming to add to knowledge of BMD through longer term follow-up, researchers in the U.S. and Canada analyzed data covering 83 BMD patients followed for three years as part of the Cooperative International Neuromuscular Research Group (CINRG) Becker natural history study.
The longer follow-up aims to lead to a “better understanding of the disease course and thus inform patient clinical care,” the researchers wrote. It also helps to inform clinical trial design by assessing functional outcomes in people of varying ages and backgrounds.
Patients were divided into two groups, younger (32 patients, range 5-18 years) and older than 18 years old (51 patients, range 18-76 years), some able to walk independently. Assistive devices were more commonly used by older participants (mean age of 40.7) than by ambulatory ones (mean age of 24.2).
Nine patients were wheelchair dependent prior to entering the study.
Participants, being followed at sites across the U.S. and in Canada, Italy, the U.K., were categorized according to the type of mutation: a group with deletions in exons 45-47, another with deletions in exons 45-48, and a third and smaller group with all other deletions.
Symptom onset occurred at a median age of 7, whereas a disease diagnosis (either by a muscle biopsy and/or genetic analysis) was conducted at a median age of 12.9.
A total of 19 patients were treated with corticosteroids at some point in their life, including 10 during the study. “Sustained use of corticosteroids is less common in BMD as compared to DMD [Duchenne muscular dystrophy],” the researchers wrote.
Although annual assessments were planned, 75 participants were evaluated once during follow-up, 61 twice, and 39 three times.
Two participants lost the ability to walk during follow-up, one at age 35 and another at age 46.
Some poorer test scores noted in people with deletions in exons 45-47
Motor function, evaluated using the North Star Ambulatory Assessment (NSAA, where higher scores indicate better function), worsened in adults after age 18.
The same trend was seen in four other measures of muscle health: the time to run or walk 10 meters, the six-minute walk distance (6MWD), the time to stand from a supine position — lying with the face and torso facing up — and the time to climb four stairs (CLIMBVEL).
Patients younger than 18 had high NSAA scores, with stable or improved performance in the other tests through childhood and adolescence. Overall, this suggests that muscle function is largely stable up to age 18, the scientists said.
At the start of the study (baseline), motor tests showed strong correlations particularly in adults. “The stronger correlation magnitudes in adults compared to youth suggests more heterogeneity [variability] in outcome capabilities in those less than 18 years,” the researchers wrote.
In contrast, correlations of motor outcomes with age were weaker, which suggests “that level of function may be a more suitable trial eligibility criterion than age,” they added.
A further analysis of the different functional tests — the 6MWD, NSAA score, and CLIMBVEL — confirmed a statistically significant decline as adults aged.
Those with deletions in exons 45-47 did poorer than the group with rarer deletions in NSAA scores and the time to run or walk 10 meters test. However, researchers noted that the group with rarer deletions was younger on average. No notable differences were found between patients with deletions in exons 45-47 and those in exons 45-48.
Age significantly associated with outcome performance in adults, and lung function, assessed by a measure called percentage predicted forced vital capacity, declined with age.
Overall, findings show that in BMD patients, progressive muscle function loss varies according to age and type of mutations. “Disease progression seems to largely manifest in adulthood for BMD,” the researchers wrote.
These insights could prove useful for clinical trials, namely “enrollment criteria, importance of placebo control, efficacy determination, and sample size calculations,” they concluded.