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Innovations in Testing for a Rare Genetic Disease—Pompe Disease

Researchers have developed methods that could significantly improve accuracy of testing for a rare genetic disorder called Pompe disease. Pompe disease results from lack of a protein called acid α-glucosidase (typically abbreviated GAA), and causes progressive muscle weakness, enlarged heart, and other problems—and in severe cases can lead to death in early childhood. Fortunately, the disease is treatable, particularly if GAA deficiency is identified early. Because the disease can cause significant, irreversible damage before symptoms are apparent, it is of great importance to be able to screen newborn children to identify those who would benefit from treatment.

A currently available screening method uses a chemical that becomes fluorescent when acted on by GAA. This screen can clearly distinguish individuals with normal GAA from individuals who have severe Pompe. However, some people are born with intermediate levels of GAA activity. These individuals may have a milder form of Pompe in which symptoms manifest later in development, but they also may not have the disease at all. Because the fluorescence test cannot clearly differentiate these groups from one another, some babies may be treated for Pompe unnecessarily. To get around this problem, researchers developed methods that can distinguish much more subtle differences in GAA activity. In one new study, they used a test method they estimated to be 15 times more sensitive to differences in GAA activity than is the fluorescent method. Using dried blood samples from males and females, including 11 people with early onset Pompe, 12 with more mild, later onset Pompe, and 230 with GAA levels that are lower than normal, but who have no disease, the new screening method correctly identified all of the people who have the disease, while incorrectly identifying just 4 percent of the healthy individuals who have intermediate GAA levels as having possible Pompe disease. That is, there were no false negatives, while there was a very low rate of false positives. In contrast, the fluorescence method had a much higher rate of false positives, incorrectly identifying about 90 percent of samples with intermediate levels of GAA as being from individuals with possible Pompe disease. The new method could be scaled up to allow rapid screening of dried blood spots from newborns, suggesting it could be practical as a standard infant screen for the disease.

Infants with the most severe, early-onset form of Pompe disease require more aggressive treatment than do babies with the milder, late-onset form. To enhance the ability to distinguish small differences in GAA activity, scientists developed a similar test, adding an additional step, and using fresh samples of leukocytes (white blood cells), rather than dried blood spots. This approach yields about a 700-fold improvement in sensitivity relative to the fluorescence method. Because this method requires a fresh blood sample, it is less suitable for initial screening of a large population of newborns than the version that utilizes dried blood spots. But with the more sensitive assay the researchers could clearly distinguish individuals with early-onset from those with late-onset Pompe. Even this highly sensitive approach identified a few individuals with low GAA levels but no symptoms as having possible late-onset Pompe. This suggests that some people may need more GAA than others to maintain health. Further research may be warranted to determine what factors affect susceptibility to late-onset Pompe in people with intermediate levels of GAA.

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