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17-01-2012 | Genetics | Article

Two-tier system detects Duchenne muscular dystrophy in newborns


Free abstract

MedWire News: US researchers have developed a two-tier system for screening for Duchenne muscular dystrophy (DMD) in dried blood spot samples from newborns.

The system minimizes false-positive testing and uses predetermined levels of creatine kinase (CK) to predict mutations in the DMD gene, report Jerry Mendell (Ohio State University, Columbus) and colleagues.

The researchers explain that CK levels are elevated at birth in individuals with DMD, but it has been difficult to justify newborn screening (NBS) for the condition because of the lack of evidence that early treatment improves the outcome of affected newborns.

"Nevertheless, recent advances in diagnostic testing methods and promising molecular-based therapies for DMD have re-kindled interest in establishing a pathway for NBS for DMD," they add.

Writing in the Annals of Neurology, Mendell and team describe how they developed a new two-tier DMD screening method that comprises initial dried blood spot screening for CK followed by DNA isolation and DMD gene analysis on the same dried blood spot.

In phase I of the study the researchers used a fluorometric assay to establish a population-based range of CK in newborns using 30,547 anonymous dried blood spot samples.

They found no significant difference in the mean values between males (251.52 U/L) and females (246.39 U/L) with a minimal effect related to birthweight.

Based on the mean values, the researchers initially set the threshold for DMD mutation screening at CK levels of 600 U/L (three standard deviations from the mean).

Using this criteria, the team screened a further 6926 newborns (phase II) and identified 110 with CK levels at or above 600 U/L. All of these babies underwent DNA analyses, but only two had DMD mutations.

Of note, both of the newborns with DMD mutations had a CK level at or above 2000 U/L.

The researchers therefore increased the screening threshold to 750 U/L for phase III of their study, which included an additional 10,936 newborn boys. Of these, 58 had elevated CK but only one carried a DMD mutation, and his CK was again above 2000 U/L.

Increasing the CK threshold from 600 U/L to 750 U/L reduced the false-positive rate from 1.6% to 0.5%, and decreased the number of newborn males requiring DNA testing by 68%, Mendell and co-authors report.

In the final phase of the study the team screened dried blood spots from an additional 19,884 newborn boys. There were 308 with a CK level above 750 U/L and 10 with a CK level above 2000 U/L.

Three boys had DMD mutations, all with CK levels above 2000 U/L. Further screening revealed that two of the remaining seven boys with CK levels above 2000 U/L had limb-girdle muscular dystrophy gene mutations affecting SGCB (sarcoglycan, beta) and FKRP (fukutin-related protein).

The researchers calculated that adding CK testing to the full battery of tests performed on dried blood spots cost approximately US$ 1.00 (€ 0.79).

However, this could be reduced further if additional studies prove that that the CK threshold for DNA testing could be elevated even higher, to 1000 U/L, for example.

The researchers conclude: "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."

By Laura Cowen

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