Promising new therapies have begun to emerge for Duchenne muscular dystrophy (DMD), and that has researchers beginning to think about getting them to newborns at the earliest possible time. Now, a new study shows that newborn screening to identify at birth those carrying the gene for DMD can be done practically, accurately, and inexpensively. The results have experts wondering whether it is time to develop a comprehensive screening program for the disease, to ensure it is in place when any new therapy is approved.
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For the study, whose findings appeared Jan. 12 in an advance online edition of the Annals of Neurology, Jerry Mendell, MD, director of the Center for Gene Therapy at the Research Institute of Nationwide Children's Hospital in Columbus, OH, and colleagues, used a two-stage screen, first to identify newborns with high creatine kinase and then to follow up with genetic testing for dystrophin mutations.
“The most powerful arguments for newborn screening,” Dr. Mendell said, are the recent advances in exon skipping strategies, which he called “the most promising treatment.” Within the past two years, two teams of European researchers have shown than oligonucleotides aimed at the most common mutation can restore dystrophin to the muscle membrane, and, according to one trial, may even provide clinically meaningful improvements in ambulation. Dr. Mendell is now conducting a blinded trial of this strategy. Mutation suppression and gene delivery strategies are also in development.
“We think there will be a treatment that can be introduced early in the disease, and we wanted to develop a means of screening boys early that could take advantage of potential early treatments,” he said.
High creatine kinase (CK) in the blood is characteristic of newborns with DMD, but it is nonspecific, since it may be caused by multiple other conditions, including birth trauma. It remains high in DMD, while dropping in most other newborn conditions, but families often don't return for a second blood test. Direct genetic testing is highly specific, but current costs prevent it from being used as a first-pass screen.
Dr. Mendell tested for CK in blood spots collected for other disease screens, and performed a genetic test on those with highly elevated CK. He conducted several screenings — first working with 30,000 samples from the Ohio Department of Health, then 7,000 newborns from Columbus and Cincinnati hospitals, 11,000 samples statewide (all boys), and 20,000 newborn boys, from a pooled samples of over 37,000. (See the table, “Screening Results: Duchenne Muscular Dystrophy” for the results in the different samples.)
Among the entire tested population, the researchers found a total of 308 samples with CK over 750 U/L. They also found 10 new samples with CK over 2000 U/L, and three new DMD mutations, for a total of six in the entire population.
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The cost of CK testing was minimal, Dr. Mendell said, with no more than a dollar of materials, and a small marginal labor cost, since all newborns are screened for up to several dozen disorders using the same set of blood spots. Costs could come down even further with a higher CK threshold. “I think we could easily go to 1000 units per liter,” based on the results from this study. DNA testing was an additional $150 in materials, although the cost is likely to continue to fall as technology improves, and may fall further if widespread screening is adopted.
A future publication from this study will look at the ethical issues involved in screening for DMD. “The critical question is how an early diagnosis impacts the family,” Dr. Mendell said. Some concern has been raised whether receiving such a grave diagnosis at birth would lead parents to emotionally distance themselves from the newborn.
“I've been doing muscular dystrophy research for about 40 years, and I'm very involved in developing treatments,” Dr. Mendell said. “But if I leave no other legacy in this field, I'd like to make sure we have a pathway for newborn screening so if we have a treatment, that we can really make a difference.”
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“This is a valuable study that provides important information,” said Thomas Bird, MD, professor of medicine, neurology, and medical genetics at the University of Washington in Seattle, who also serves on the editorial advisory board of Neurology Today. But it raises several issues that will deserve attention in the future, he said.
Not every DMD case identified will be eligible for exon-skipping therapy, should it be approved, he continued. Current strategies employ an oligonucleotide that can address only 13 percent of DMD cases. The field is currently divided about the right time to offer corticosteroid therapy: Should it be offered as early as possible, or not until symptoms become manifest?
However, he said, “Newborn screening would be valuable for Duchenne muscular dystrophy simply on the basis of family planning. I think it's very important for a woman to know that she's a carrier of Duchenne, and she needs to be able to take that into consideration before she has another pregnancy. To me that's a compelling reason for doing the testing,” although, he noted, “it's not compelling to some people and to some states.”
How all these issues will factor into the eventual decision-making process at the federal and state levels will be closely watched as effective therapies for DMD move closer to reality.
“This is an important study,” said Valerie Cwik, MD, interim president of the Muscular Dystrophy Association, in an interview with Neurology Today. “It shows that population-based newborn screening is feasible for Duchenne muscular dystrophy, and it gives us some good information about how to conduct such a screening program.”
Regarding whether right now is the time to develop a full national screening program, she said, “We are probably not there yet with Duchenne, but certainly with everything that is on the horizon with this disorder, we probably will be in the not-too-distant future.”
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R. Rodney Howell, MD, professor of pediatrics at the Miller School of Medicine at the University of Miami, also praised the study. However, he noted, a much larger screening trial is likely to be needed before nationwide screening is implemented. A recent pilot trial of screening for severe combined immunodeficiency enrolled a million newborns, he said.
Dr. Howell served until recently as the first chair of the Secretary's Advisory Committee on Heritable Diseases in Newborns and Children, the federal panel that, since 2004, has advised the Health and Human Services Secretary on newborn screening. He noted that while the ultimate decision on which diseases to screen for rests with each state, states look to the recommendations of the Committee, and “as a result, about 98 percent of all babies in the country are screened for a panel of diseases similar to those in the committee's recommendation.”
Regarding the concern over emotional distancing from a DMD diagnosis at birth, he noted, “There is no evidence that I am aware of that indicates that if you have a child with Duchenne and you know on day one that he has Duchenne, that you reject that child. There is just no evidence for that.”
Dr. Howell called the recent results of oligonucleotide therapy in DMD reported last year in the Lancet “pretty compelling evidence that there may be a treatment on the horizon.” Based on those results, he said, “I would hope someone would nominate Duchenne for consideration” to the committee. While more clinical therapeutic trials are needed, he thinks it would be valuable to begin developing the infrastructure needed for screening while those trials are being completed. “You would not want to lose a year. You want newborn screening up and running at the time we have a treatment.”
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• Cirak S, Arechavala-Gomeza V, Muntoni F, et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet
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