Q&A: Experts encourage implementation of newborn screening for Duchenne muscular dystrophy

Better screening protocols and new, potentially more effective treatments have created “an opportune time” for the implementation of newborn screening for Duchenne muscular dystrophy, according to a viewpoint published in JAMA Neurology.

The systematic implementation of newborn screening for Duchenne muscular dystrophy would allow for identification of affected infants earlier in the disease course and, therefore, the use of systematic testing of earlier interventions, according to the authors. The “ultimate hope” of such an approach, they noted, would be improvements in longitudinal clinical outcomes.

“Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy; despite improved screening diagnostic techniques and novel U.S. FDA–approved treatment options, DMD is not screened for at birth beyond investigational studies,” Stephen M. Chrzanowski, MD, PhD, a resident in the department of neurology at Boston Children’s Hospital, and colleagues wrote. “Currently, the mean age at diagnosis of DMD is 4.4 years. Intuitively, presymptomatic treatment may yield improved outcomes, but this remains an unresolved issue warranting further investigation.”

Healio Neurology spoke with Chrzanowski to learn more about the factors that have enabled the potential implementation of systematic newborn screening for DMD as well as the issues that “must be addressed” to achieve this effort.

Healio Neurology: What prompted this paper?

Chrzanowski: Our motivation for composing this paper revolves around the premise that earlier detection of DMD may lead to earlier treatment, and thus, hypothetically better longitudinal outcomes in this population. While logical in theory, much research needs to first be done to confirm this hypothesis. Several criteria are required for a disease to be on the newborn screening panel, which DMD previously did not meet. Such criteria include the following:

• A disease is so serious that a lack of treatment would result in significant morbidity or death;
• Treatment in the pre-symptomatic or early symptomatic period should lead to better outcomes compared with the usual clinical care;
• A reliable screening test must be available and accessible to the general neonatal population;
• Adequate confirmatory tests must be available to eliminate false-positive results;
• The test results must be able to be available and communicated to a clinician who can provide timely intervention; and
• Following diagnosis, effective treatment should be readily accessible.

Previously, treatment for DMD was limited to symptomatic management, though now new disease-modifying molecular therapies are available to a portion of the population. With the emergence of adequate screening techniques and new treatment options that may be more efficacious with earlier administration, it is an opportune time to systematically implement DMD newborn screening.

Healio Neurology: Does newborn screening for DMD occur currently at all — and, if so, in what circumstances?

Chrzanowski: Newborn screening for DMD is available, but currently only on a research basis, and it is not universally widespread in the United States.

Healio Neurology: How do the FDA approvals of both a screening immunoassay and exon-skipping antisense oligonucleotides contribute to the rationale for screening?

Chrzanowski: The approval of both a screening assay and several exon skipping antisense oligonucleotides is very fortuitous in timing for the DMD community. Having adequately sensitive and specific screening initial screening assays for DMD means there is now a reliable screening test that can "screen-in" DMD. Subsequent confirmatory genetic tests serve to confirm true-positive tests and screen out false-positive tests.

Keeping track of the DMD therapy pipeline is excitingly exhausting because of the rapid development of so many novel therapeutics. Right now, the four exon-skipping antisense oligonucleotides available (Exondys 51, Vyondys 53, Viltepso and Amondys 45) are applicable to approximately 30% of the DMD population. However, as more disease-modifying therapies continue to advance through the clinical trial pipeline, one may anticipate that additional therapeutics will be available to more individuals affected by DMD.

The availability of a readily accessible screening assay, in conjunction with more FDA-approved therapeutics, support the discussion of newborn screening for DMD.

Healio Neurology: What are some of the biggest issues related to newborn screening for DMD?

Chrzanowski: This is a very important question and one that we must anticipate prior to possibly moving forward with newborn screening for DMD. The first issue that I anticipate arises with the inherent imperfection of any test. Though the initial screening test appears sensitive, it may miss some cases of DMD, leading to later diagnosis. Also, I anticipate that 'false-positives' — a positive initial newborn screening test with negative confirmatory genetic testing — may lead to anxiety and uncertainty, especially if diseases without treatment are identified.

Beyond the anticipated pitfalls of the screening tests, logistically, ensuring adequate systems are in place for appropriate follow-up and management of these patients requires an adequate number of pediatric neuromuscular specialists, genetic counselors and geneticists, and there is currently considerable regional variability of these professionals across the United States.

Healio Neurology: What strategies do you propose in your Viewpoint for implementing this type of screening?

Chrzanowski: To become widely adopted in numerous states, newborn screening for DMD should be added to the Recommended Uniform Screening Panel (RUSP) for newborn screening. To facilitate a successful screening program, an adequate infrastructure of providers, from the nursery to primary care pediatricians to neuromuscular specialists, must be streamlined. Clear management plans are needed for how to follow up with positive test results in a uniform manner.

Healio Neurology: How practical would the implementation of this screening be?

Chrzanowski: Currently, the RUSP lists 61 disorders that are recommended for states to screen for as a part of their respective newborn screening programs. However, each state has their own individual newborn screening panels. Adding DMD to the list of RUSP-recommended diseases would be minimally disruptive to patients and families that benefit from the current newborn screening protocols, as such practices have been in place for years. Newborn screening for DMD likely would increase the workload of pediatric neuromuscular specialists and geneticists, as more tests will require more interpretation, management and follow-up. Furthermore, there is the potential stress for families who have false-positive results. Lastly, each state may need to find the funding to add an additional test to their respective newborn screening panels, which may impact state-level decisions.

Healio Neurology: Is there anything else you would like to elaborate on?

Chrzanowski: While we hypothesize that earlier diagnosis will lead to earlier treatments and thus better outcomes, further research is warranted to investigate this hypothesis. Potential treatment in a younger population of boys with DMD will be novel and it is too early to anticipate what longitudinal studies may reveal. However, to make this all happen, we must develop an adequate infrastructure to appropriately manage and treat this younger population with pre-symptomatic disease.

Reference:

Chrzanowski SM, et al. JAMA Neurol. 2021;doi:10.1001/jamaneurol.2021.1782.