Analyzing the type of mutation in the DMD gene combined with assessing motor milestones may help better distinguish Duchenne muscular dystrophy (DMD) from Becker muscular dystrophy (BMD) early in life, a study found.
Combining both approaches had better predictive power than using either alone, and could mean that children will be able to received targeted treatment sooner.
The findings “significantly improved the early diagnosis rate of DMD and provided a new tool for earlier diagnosis,” the researchers wrote, adding, “these two indicators are stable, easy to obtain, and have the potential to be widely promoted in the future.”
The study, “Walking alone milestone combined reading-frame rule improves early prediction of Duchenne muscular dystrophy,” was published in Frontiers in Pediatrics.
Mutations in the DMD gene are responsible for both DMD and BMD,and in most cases are caused by the deletion or duplication of stretches of DNA. Mutations associated with Duchenne lead to a complete lack of the dystrophin protein and a more severe disease presentation compared with Becker, which results in either lower amounts of working dystrophin protein or a dysfunctional protein and milder symptoms.
Distinguishing between the two early on is critical to ensure access to the right treatments. “Early intervention is essential, but early identification of DMD/BMD is the first step,” the researchers wrote.
The reading-frame rule is one way of predicting whether a particular DMD mutation will be associated with Duchenne or Becker. Essentially, it determines whether a mutation disrupts the DNA code’s reading frame or not.
The building blocks of DNA, called nucleotides, are “read” in groups of three during protein production. If a mutation disrupts this reading frame, it’s called an out-of-frame mutation. This type of mutation usually means the protein can’t be produced at all, resulting in DMD. But if a mutation is “in-frame” and these trios can still be read, but with some changes, some functional dystrophin might still be produced, although it’s likely shorter than normal. This is associated with BMD.
But the rule isn’t foolproof and some cases can’t be distinguished that way.
Children with DMD show delays in certain motor milestones, such as walking, crawling, or sitting up, raising the possibility that such milestones could be used to distinguish DMD from BMD early in life.
Researchers in China evaluated whether using the reading-frame rule and walking milestones together might have better predictive power than relying on one alone.
The study included 152 boys diagnosed with DMD and 17 with BMD at the Children’s Hospital Affiliated to Zhengzhou University from 2014 to 2021. Those who lost the ability to walk and required a wheelchair by age 16 met the diagnostic criteria for DMD, whereas those who were still able to walk at 16 were diagnosed with BMD.
The mean age of DMD onset was 3.9, with age at diagnosis at 6.8 years. Age of BMD onset was 6.5 and of diagnosis at 7.1 years. Boys with DMD had significantly higher blood levels of creatine kinase, a marker of muscle damage.
Data from the participants were retrospectively evaluated to determine whether each had met the walking alone milestone, defined as an ability to walk alone before 18 months of age (a year and a half).
The mean age of independent walking was 12.9 months, or just over a year, for BMD boys, and 18.0 months for DMD boys — a significant difference between the two groups. All the boys in the BMD group met the walk alone milestone, while 93 boys with DMD (61.2%) didn’t.
Genetic analyses revealed a DNA deletion was responsible for most DMD and BMD cases, accounting for all 17 BMD and 136 DMD cases. Remaining DMD cases were caused by a duplication of DNA. A majority of boys with BMD (12 out of 17) had an in-frame mutation, while a large majority of DMD patients — 132 of 152 — had an out-of frame mutation. This means that 85.2% of cases were in line with the reading frame rule.
Among all deletion cases, the most frequent were deletions in a single exon (28.1%) — the DNA bits that have information to make proteins. A total of 106 cases (69.3%) had six or fewer exon deletions.
“Although the reading frame helps predict the severity of skeletal muscle weakness, there is still some … variability within the prediction,” the researchers wrote. “Therefore, we combined the reading-frame rule and gross motor milestone.”
Using the reading-frame rule and walking alone milestone together had better predictive power for a DMD versus BMD diagnosis than either approach alone. Together, they had a diagnostic rate of 93.49%, compared with 85.2% with the reading-frame rule alone and 60.09% with walking alone.
“We believe that the combined index of the above two variables might have application potential for early DMD prediction,” the researchers wrote, noting that both approaches are easy for doctors to obtain and are not costly. The researchers said further studies with larger samples and in more regions would help to verify their findings.