Phenylketonuria (PKU) and the Guthrie test

Blood screening for phenylketonuria. Guthrie R. JAMA. 1961;178(8):863. doi:10.1001/jama.1961.03040470079019.
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Phenylketonuria (PKU) is one of the most well-known inborn metabolic diseases in the medical field due to the fascinating growth of its research over the years. It’s mechanisms of disease was first discovered by I. Asbjørn Følling in 1935 who found that patients displaying symptoms such as intellectual disability, epilepsy, seizures, eczema, light pigmentation, and a musty odour, were unable to metabolise an essential amino acid called phenylalanine. While phenylalanine is typically metabolised into another amino acid called tyrosine by an enzyme called phenylalanine hydroxylase (PAH), PKU individuals had a deficiency in this enzyme, leading to neurotoxic accumulation of phenylpyruvic acid. Thankfully, a simple treatment was discovered by Dr Horst Bickel and his team in 1953 that could prevent this neurotoxic accumulation by restricting the amount of phenylalanine in the diet. If implemented from birth, PKU individuals would develop normally with minimal symptoms.
Early diagnosis became important to ensure that the benefits of the treatment could be fully utilised. During the early 1960s, this was done via a urine ferric chloride test which involved adding a few drops of the patient’s urine to a ferric chloride solution to detect the presence of phenylpyruvic acid. If the individual has PKU, the solution would turn blue-green. However, this test was not sensitive enough, inspiring Dr. Robert Guthrie to develop a new test called the Guthrie test in 1961. Using a few drops of the patient’s blood soaked onto a filter paper, a bacterial inhibition assay would be conducted. If phenylpyruvic acid is present in the blood, it would inhibit the inhibition of a bacteria called Bacillus subtilis ATTCC 6051 by β-2-tienylalanine, allowing bacterial growth.
Using the Guthrie test, PKU became the first genetic disorder that newborns were screened for and it inspired the development of other similar genetic testing and eventually led to the implementation of universal newborn screening worldwide, thus helping the lives of many people. Therefore, while PKU screening has now evolved to use other methods, the Guthrie test marks an important part of medical history.
Creator: Denise Koh
References:
Bickel H, Gerrard J, Hickmans EM. Preliminary Communication. Lancet. 1953;262(3790):812-813.
Brosco JP, Paul DB. The political history of PKU: reflections on 50 years of newborn screening. Pediatrics. 2013;132(6):987-989.
Følling IA. The excretion of phenylpyruvic acid in the urine as a metabolic anomaly in connection with imbecility. Zeitschr Physiol Chem. 1934;227:169-176.
Gonzalez J, Willis MS. Robert Guthrie, MD, PhD: Clinical Chemistry/Microbiology. Lab Med. 2009;40(12):748-749.
Guthrie R. Blood screening for phenylketonuria. JAMA. 1961;178(8):863.
Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics. 1963;32:338-343.
van Spronsen FJ, Blau N, Harding C, Burlina A, Longo N, Bosch AM. Phenylketonuria. Nat Rev Dis Primers. 2021;7(1):36.
Surtees R, Blau N. The neurochemistry of phenylketonuria. Eur J Pediatr. 2000;159 Suppl 2:S109-13.