IN BRIEF

A Natural History of Duchenne Muscular Dystrophy in Boys 3 to 6 Years Old

March 10, 2020
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A prospective, multicenter study following 153 boys younger than 6 years old documents disease progression of Duchenne muscular dystrophy.

Duchenne muscular dystrophy is the most common inherited neuromuscular disorder that affects all races and ethnicities. It affects males, occurring in 1/3,600 live-born infant boys. While some affected newborns may have mild hypotonia, other symptoms are rarely present at birth or in early infancy. Early gross motor developmental milestones, including rolling over, sitting and standing may be only mildly delayed making early diagnosis challenging. In fact, the average age of diagnosis is around 4 to 5 years.

Part of the reason why diagnosis occurs so late is that some of the tools used in diagnosis – such as the North Star Ambulatory Assessment (NSAA) – are only validated for populations older than 5 years.

“The first step increasing early diagnosis and treatment includes validating these tools for younger patients. And to do so, we need to fully understand what DMD looks like in boys younger than age 5. We established this prospective study to do that,” says Anne Connolly, MD, chief of the Division of Neurology at Nationwide Children’s Hospital and study author.

The multicenter research team reported the results of their study of children with DMD between ages 3 and 6 years who had been followed for at least one year.

“We hoped to establish the range of changes according to age, the possible effect of corticosteroids, and the possible effect of the site of the DMD mutation,” says Dr. Connolly, who is also professor of Pediatrics at The Ohio State University College of Medicine and a member of the Center for Gene Therapy in the Abigail Wexner Research Institute at Nationwide Children’s.

The analysis, published in Neuromuscular Disorders, showed that NSAA scores progressively increased for boys with DMD with increasing age – even beyond age 5 years. The NSAA is an ordinal scale consisting of 17 items, scored using the following criteria: 2 points – normal achievement of goal without assistance; 1 point – modified method but achieves goal independent of physical assistance of another person; 0 points – unable to achieve the goal independently.

In typically developing boys, the full scale – ability to do all 17 items independently – is reached by age 4 year. Improved ability of boys with DMD on the Northstar was associated with both the use of corticosteroids and the site of the mutation in the dystrophin gene. The boys treated with corticosteroids reached higher average NSAA scores more quickly and sustained them through the study period.

“We’ve been treating children with DMD with corticosteroids for a long time now, and this study continues to affirm that this improves outcomes. However, it should be noted that even at age 6 years, boys with DMD were rarely able to complete all 17 items,” says Dr. Connolly.

In terms of mutation location, the study supported previous data suggesting that patients with mutations downstream to exon 44 had lower baseline scores and lower magnitude of changes compared to those with mutations in the first part of the gene. Patients with mutations after exon 63 had the lowest scores.

As new therapeutic options become available and are undergoing clinical evaluation, understanding the natural history of disease progression is essential to understanding the efficacy of the therapeutic in question.

“These results support the use of the NSAA in boys from the age of 3 years to assess early changes,” says Dr. Connolly. “This work and earlier work by the MDA-DMD network group using the Bayley-3 provide potential outcomes to use in very young children to assess potential benefits of next generation therapeutics, including gene transfer, for boys with DMD.”

 

Reference:

Coratti G, Brogna C, Norcia G, Ricotti V, Abbott L, D’ Amico A, Berardinelli A, Vita GL, Lucibello S, Messina S, Manzur A, Main M, Baranello G, Arnoldi MT, Parsons J, Curry T, Connolly AM, Bertini E, Muntoni F, Pane M, Mercuri E. Longitudinal natural history in young boys with Duchenne muscular dystrophy. Neuromuscular Disorders. 2019;29:857-862.

 

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