It was the 1950’s. A physician, Dr. Robert Warner, was working tirelessly to rehabilitate children with mental retardation at a clinic in Buffalo, New York. Some of these children were born by perfectly normal/uneventful delivery, cried immediately after birth and seemed to be normal, like every other baby for the first few months of their lives. But as the days passed by, they began to show some neurological symptoms like tics and subtle seizures and before anything could be done, it was too late. The damage to the brain was already done and it would prove to be a permanent, irreparable one.  It became increasingly daunting for Dr. Robert Warner to explain to the parents the reason behind mental retardation of their apparently normal child. But, prevention is always better than cure and Dr. Warner understood the importance of this more than anyone else. So he roped in Dr. Robert Guthrie, a microbiologist and asked him to devise a test that would pick up this debilitating disease in the new born at an early age so as to prevent the neurological damage. Dr. Guthrie returned back in just three days with his prototype test – the Guthrie heel prick test, a test that dramatically brought down the incidence of this debilitating disease, Phenylketonuria and also opened a whole new concept of neonatal screening for diseases in the developed countries.

Phenylketonuria is an inherited error in the metabolism of the amino acid phenylalanine.

Phenylalanine is an essential amino acid which cannot be synthesised by the body and has to be mandatorily supplemented in the diet through meat and dairy products. Normally, phenylalanine would be metabolised to tyrosine by the enzyme Phenylalanine Hydroxylase.(Click here to read how this reaction can lead to the phenomenon "Death by Chocolate"!)

Deficiency of the enzyme or the co-factor Tetrahydrobiopterin (BH4) can lead to accumulation of excessive amounts of phenylalanine in the body. As long as the baby is in-utero, the excess phenylalanine is metabolised by the mother. But once the baby is on its own, phenylalanine begins to accumulate in the newborn’s blood. Well, the more the merrier, right? Unfortunately, not in this case. Tyrosine and all those other metabolites down the road, solely depend upon phenylalanine. A road block in the conversion process would mean deficiency of tyrosine, DOPA and dopamine. DOPA is also required for synthesis of Melanin, the pigment which gives colour to the skin. Hence babies with phenylketonuria have a lighter complexion than normal.

But a slight variation in the skin tone is not the glaring problem. The bigger problem is mental retardation. Now the reason for mental retardation is not completely known. But it is believed that the higher levels of phenylalanine in the blood saturates the amino acid transporters in the blood brain barrier and competitively prevents other amino acids like tryptophan from entering the brain. This deranged level of amino acids in the brain affects the synthesis of neurotransmitters and leads to CNS damage.

Can the mental retardation be prevented? Absolutely. Thanks to the Guthrie test.

Like a true microbiologist, Dr. Guthrie once again used his culture plates to his rescue. He designed a culture plate with the bacteria Bacillus subtilis, the growth of which was inhibited by a chemical but could be reversed by excessive amount of phenylalanine in the patient’s blood acting as a fuel. He collected blood sample by pricking the heel of the newborn, blotted it on a filter paper and simply put the paper on the culture plate and let the excess phenylalanine do the rest of the job. Why specifically the heel? For the simple reason that Dr. Guthrie realised it is essential to save the peripheral veins for IV access if required in the neonatal intensive care. More importantly, the blood sample was drawn 24-48 hours after feeding the baby and not immediately after birth, in order to avoid false negative results.

Now-a-days, more precise and quantitative methods (fluorometric and tandem mass spectrometry) have replaced the Guthrie test for diagnosing hyper-phenylalaninemia. But the Guthrie test was indeed one of a kind. It paved way to develop tests to screen other inborn errors of metabolism and Dr. Guthrie was widely regarded as the father of neonatal screening.

Once the condition is diagnosed, it is also essential to differentiate the cause – deficiency of phenylalanine hydroxylase or deficiency of the cofactor BH4. The treatment is simple - avoid phenylalanine rich foods or supplement synthetic BH4 life long, depending on the cause.

And thats how a simple screening method and prompt dietary advice made a world of difference to millions of children around the world.