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NICHD Mission and Scientific Accomplishments: Phenylketonuria (PKU)

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​Effective, Low-Cost Screening of Newborns Eliminates a Major Cause of Intellectual Disability

In 1934, Norwegian doctor Asbjörn Fölling discovered phenylketonuria (PKU), a rare disease that, if left untreated in newborns, causes intellectual disability, seizures, and deafness. In 1939, research showed that PKU was an inherited disorder that resulted from the body's inability to break down (metabolize) the amino acid phenylalanine (Phe), a common part of many proteins. The extra Phe  built up in the blood and body tissues and prevented normal brain development, which often resulted in intellectual disability.

Through his efforts to understand PKU, Dr. Fölling discovered that a certain chemical called phenylpyruvic acid, which was present in the urine of people with untreated PKU, turned green in the presence of another chemical, ferric chloride. This reaction provided the first test for PKU. Most infants, only a few days old, did not have enough of the chemical in their urine for the test to detect PKU. So, although the test was useful for detecting PKU, this detection was usually too late to prevent damage.

By 1953, researchers had developed a special low-protein diet for people with PKU that allowed normal development if started right after birth. However, because early detection was not available, most infants and children did not begin the diet in time to prevent the effects of PKU. Mass screening of newborns seemed impossible at the time—too costly and too invasive.

In the early 1960s, researcher Dr. Robert Guthrie developed a simple, inexpensive blood test that could screen for PKU. By pricking an infant's heel to get a drop of blood, placing it on a piece of paper, and seeing whether it contained enough Phe to allow a certain kind of bacteria to grow, physicians could determine whether that infant had PKU. This single discovery made possible both early detection and mass screening. Researchers supported by the federal Children's Bureau determined that Dr. Guthrie’s PKU test for newborns was safe and effective. As a result, in 1963, Massachusetts became the first state to pass a law requiring PKU testing for all newborns.

Soon after, NICHD led research on the safety and effectiveness of a restricted diet to treat PKU among newborns who had been identified using the new screening test. Researchers followed the intellectual development of infants who had been diagnosed with PKU and who had been given the low-Phe diet since their diagnosis. This follow-up research clearly demonstrated the diet’s effectiveness in improving outcomes for those with PKU.

By the 1970s, screening for PKU was commonplace throughout the nation. Upon diagnosis, children were placed on the special diet until at least age 5, which allowed for normal brain development.

​But that's not the end of the PKU story.

As more people with PKU developed normally , many of them began starting families, which raised a new issue of PKU and pregnancy. In 1980, researchers in Boston demonstrated an association between blood Phe levels during pregnancy and intellectual disability, heart problems, miscarriage, low birth weight, and other problems in children of women with PKU. These problems were linked to exposure to high Phe levels in the womb. Based on the findings, some predicted that the incidence of new cases of PKU-related intellectual disability would return to its former level within one generation.

In response , NICHD initiated a collaborative study to evaluate the efficacy of a Phe-restricted diet during or before pregnancy in reducing the health problems in babies born to mothers with PKU. Findings from this research showed that continuing diet therapy prevented intellectual disability and other health problems . If women continued the special diet therapy just prior to and during pregnancy, it was likely that they would deliver healthy babies, free of deficits or other medical problems related to PKU.

Screening newborn infants for PKU, now required in all states, in combination with immediate initiation of the special low-protein diet, has virtually eliminated PKU as a cause of intellectual disability in the United States. Research findings show that staying on the diet therapy throughout life enhances the health of those with PKU .

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