Efficient System Developed for DMD Newborn Screening

Researchers have developed a new, two-step process for screening newborn babies for Duchenne MD and possibly other muscular dystrophies

Article Highlights:
  • Screening newborn babies for elevated serum creatine kinase (CK) levels and then testing those with high CK for Duchenne MD-causing gene mutations using the same dried blood spot appears feasible and cost-effective.
  • There is some evidence that starting corticosteroid treatment earlier in the DMD disease course than is usually possible would be beneficial.
  • Recent advances in research may bolster support for newborn screening for DMD, so that newly developed treatments can be given earlier in life.
  • Regulatory agencies will be involved in making the final decisions about newborn screening for MD; the new study provides a pathway for its implementation.
  • A podcast on this topic is available; see Podcast Explores Newborn Screening for DMD.
by Margaret Wahl on March 2, 2012 - 9:37am

Update 5/21/12: A podcast on this topic is now available; see Podcast Explores Newborn Screening for DMD.

Researchers at Nationwide Children’s Hospital in Columbus, Ohio, working with the DNA Sequencing Core Facility at the University of Utah, have developed an approach to newborn screening for Duchenne muscular dystrophy (DMD).

The program is potentially ready for implementation but requires approval from regulatory agencies.

The usual criterion for screening newborns for a genetic disorder in the United States is the availability of an effective treatment that can and should be started early in life. Until now, DMD hasn't met that standard, but some believe that the disease is at or near that point now.

"Whether treatment has advanced to the point of justifying newborn screening for DMD requires assessment through state and federal agencies with appropriate jurisdiction," the investigators write in this new study. "If and when an early therapy that improves the health outcome for individuals with DMD becomes available, our study serves as a model for implementation of newborn screening for DMD."

The research team, coordinated by neurologist Jerry Mendell at Nationwide Children's and geneticist Robert Weiss at the University of Utah, released its findings online in Annals of Neurology Jan. 12, 2012.

MDA research grantees were part of the team

Mendell, a neurologist specializing in neuromuscular diseases, is a longtime MDA research grantee, although MDA did not fund this particular study. Mendell has three current MDA research grants related to DMD and one related to limb-girdle muscular dystrophy (LGMD).

Kevin Flanigan, a geneticist specializing in neuromuscular diseases at Nationwide, is also an author on this study and has received significant MDA research support.

The effort was funded and facilitated by the National Center on Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention (CDC), with important contributions from the Ohio Department of Health.

Screening test for high CK and follow-up DNA testing performed on single blood sample

The investigators have developed a two-step process for screening all newborns for DMD and have tested it in 37,749 newborn boys and 18,763 newborn girls. DMD is an X-linked genetic disease that affects males almost exclusively, but there are other forms of muscular dystrophy, including LGMD, that affect both sexes. The researchers wanted to apply the screening method to some of those as well.

The two-step strategy involves first screening for elevations of an enzyme called creatine kinase (CK) in the blood; and then, in those babies with high CK levels, performing DNA testing for mutations in the dystrophin gene, which are the underlying cause of DMD.

CK is an enzyme that leaks out of damaged muscle cells into the circulation, where it can be measured through a blood test. Although CK is markedly elevated in DMD and some other MDs, it also canbe higher than normal because of muscle injury, including injury during the birth process.

Normal values for serum CK are between 60 and 400 international units per liter. The researchers on this study determined that samples with CK levels of 750 units per liter or higher should undergo DNA testing for DMD. Setting the level lower, they determined, would likely lead to too many "false positives," or CK levels that were temporarily raised for reasons other than muscular dystrophy.

For babies with serum CK levels above the cutoff point, DNA testing of the dystrophin gene was conducted, using highly sophisticated technology designed to detect even the smallest mutations (changes) anywhere in the dystrophin gene.

Of note is that the methodology the investigators developed allows both the CK level and the DNA testing to be conducted on the same dried blood spot, derived from a heel stick of each infant at 24 to 48 hours of age.

The state of Ohio currently screens newborns for 35 genetic disorders, using dried blood spots taken from one heel stick.

Adding the CK screening test to the battery of tests already performed on newborn blood samples in Ohio did not require any additional blood samples to be drawn and added a very small amount to the cost of screening. (Approximately $1 in raw materials was added to the cost for each newborn.)

The DNA testing, in those babies with markedly elevated CK levels, was conducted on the same blood spot, with no need for an additional blood draw. (Each of these DNA tests added $150 per baby to the cost of testing.)

Previous attempts at screening newborns for DMD, conducted mostly outside the United States, have required at least one additional blood draw from a baby following the finding of an elevated CK level; and many previous studies have found a high rate of false-positive CK elevations.

All those with MD-causing genetic mutations had CK levels of at least 2,000 units per liter

In the 37,749 newborn boys screened for serum CK elevation, the investigators found 308 (0.8 percent) with levels above 750 units per liter; and 10 (0.03 percent) had levels above 2,000 units per liter.

All those with levels of 750 or higher were tested for mutations in the dystrophin gene, and six (0.02 percent) were found to have them. All those who were found to have dystrophin mutations had CK levels of at least 2,000 units per liter (suggesting to researchers that the cutoff point for DNA testing potentially could be raised).

Seven newborn boys had CK levels of at least 2,000 units but did not have dystrophin mutations. Their blood samples underwent further testing to look for mutations in various genes that can cause LGMD. Two of the seven boys with very high CK had such mutations.

Among the 18,763 newborn females screened, the researchers found CK levels of 750 or greater in 242 (1.3 percent), with two (0.01 percent) showing CK levels of at least 2,000. None of the females was found to have a dystrophin mutation. However, one (whose CK was at least 2,000) was found to have an LGMD-causing gene mutation.

The investigators say this initial study suggests that the threshold for DNA testing could be raised even higher — to at least 1,000 units per liter — improving the potential cost-benefit ratio for this type of screening.

Development of new therapies may provide support for screening newborns for DMD

"The results of our study support the two-tier system of analysis for newborn screening for DMD, perhaps in a way even more satisfying than anticipated," Mendell, Weiss and colleagues write.

They cite the promising results obtained in recent trials of exon-skipping therapies in development for DMD as possible support for newborn screening for this disease, since early treatment with exon-skipping compounds is likely to be more effective than treatment that begins after considerable muscle damage has occurred.

The researchers also cite a recommendation from the CDC in 2009 that corticosteroids (such as prednisone or deflazacort) be started before a child's motor skills have begun to decline as evidence that DMD newborn screening and treatment within the first few years of life could be beneficial in this disease.

"If the development of promising therapies for DMD continues to proceed at its current pace," the authors of this study note, "newborn screning could be on the horizon for this disease, not only in the USA, but also in other countries of the world."

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