How Did It All Begin?
First use of the term “Inborn Errors of Metabolism.” Coined by Archibald Garrod, who in 1902 showed insight into the inheritance of specific chemical defects in metabolism and demonstrated that an enzyme deficiency can be inherited and lead to disease.
Dr. Asbjorn Folling of Norway discovered PKU, a rare hereditary disease in newborns in which the enzyme that processes the amino acid phenylalanine is defective or missing, leading to its accumulation in the child’s blood which damages the infant’s developing nervous system. If not treated within the first few weeks of life it can cause mental retardation, seizures, tremors, behavioral disorders, and some forms of mental illness. Dr. Folling discovered that phenlpyruvic acid, excreted in the urine of individuals with untreated PKU, turns green in the presence of ferric chloride. Although this test was reliable in verifying PKU as a cause of mental retardation, it was not an effective tool in prevention because not enough phenylalanine may build up in the urine within the first few days after birth, so detection occurs too late to prevent damage. Only infants with a family history of PKU were tested. Mass screening seemed impossible at the time.
George A. Jervis demonstrated that the disease was inherited and that unusually high levels of phenylalanine were present in PKU patients.
About 15 years passed before the next big step occurred. Horst Bickel of Germany, working with colleagues in Birmingham, England, developed a low-phenylalanine diet for the first treatment of PKU. All proteins contain phenylalanine. The phenylalanine-free diet was developed by first removing all the essential amino acid, then putting a very strictly controlled amount back, in order for growth and development to occur without damage. The diet improves the behavior of those already with PKU and actually prevents mental retardation if started before any damage occurs. Early detection was still a major problem that needed to be solved, as mass screening seemed impractical.
Dr. Willard Centerwall of Los Angeles began the “wet diaper test,” the first step towards mass screening for PKU. It was no longer necessary to collect urine samples and send them to a lab for diagnosis. Pediatricians could perform this test in their office.
While still working in cancer research, Dr. Guthrie was introduced to PKU by Dr. Robert Warner in Buffalo, NY and asked to develop a simple test to monitor the blood phenylalanine level in patients being treated with the diet. Blood tests were accurate but it was cumbersome to draw a vial of blood from each infant and send it to the lab for results. Dr. Guthrie’s test produced accurate results and was a pivotal point in newborn screening history, but his biggest contribution was the dried blood spot, which made mass screening of all newborns possible. A prick of the heel and a piece of filter paper impregnated with blood revolutionized the testing process. “It was a very simple idea, like inventing a safety pin, but it made possible the testing of every newborn baby before leaving the maternity hospital,” he said in 1990.
After the blood dries, small circles are punched out so the phenylalanine levels can be determined. At first this punching process was done by hand, but with the invention of the Punch Index Machine by Robert Phillips in 1964 (which automated the process), mass screening became even easier. Phillips’ machine punched four discs simultaneously from the blood spots and placed them on trays. Dr. Guthrie suggested four discs from one blood spot to save the others for additional testing.
Working in his lab at Children’s Hospital and at the University of Buffalo, Dr. Guthrie developed and/or collaborated on tests for 30 different conditions, all of which could be applied to the single newborn blood screening specimen originally collected for only PKU screening. Not all have been practical but at least six have been important, including: galatosemia, maple syrup urine disease and homocystinuria. The test for sickle cell anemia, which was developed in Guthrie’s lab by Dr. Michael Garrick and published in 1973, was also applied to the blood specimen.
“The Guthrie Test,” as it became known as, was ready to be implemented. A trial involving nearly 3,000 residents was done at the Newark State Institution near Rochester, NY.
In the fall of that year Dr. Guthrie gave a talk about PKU to the Association for Retarded Children in Jamestown, N.Y. A few days later, his lab began to receive filter-paper specimens of blood from newborn infants in two Jamestown hospitals. Mass newborn screening had arrived.
A Life magazine article appeared in January about the newborn screening test. Pictures included Dr. Guthrie and NARC PKU poster children.
Also in 1962, a national trial in 29 states was funded by the U.S. Children’s Bureau, particularly for projects to prevent mental retardation, because of the influence of President John F. Kennedy, who had a sister with retardation. At Dr. Guthrie’s urging, adult participants in a sheltered workshop in Buffalo collated and packaged test kits. The Erie County Department of Health adopted the Guthrie test and the first infant with PKU was discovered in Niagara Falls, NY, after only 800 tests were done a miraculous event that increased support for and encouraged the practicality of mass newborn screening.
Dr. Guthrie’s method of testing was finally published in Pediatrics.
In January, the Guthrie Test became mandatory in New York State.