On the Scent: The Discovery of PKU

U.S. President John F. Kennedy and Dr. Asbjørn Følling, with some of the other recipients of the first Joseph P. Kennedy International Award in Mental Retardation, awarded in December 1962. Credit: Willard R. Centerwall.

U.S. President John F. Kennedy and Dr. Asbjørn Følling, with some of the other recipients of the first Joseph P. Kennedy International Award in Mental Retardation, awarded in December 1962. (Willard R. Centerwall)

How many mentally impaired people had this urinary anomaly, he wondered. Using his simple ferric chloride test as a screening tool, Følling checked the urine of 420 patients at institutions around Oslo, finding eight who tested positive for phenylpyruvic acid. Only five months after Borgny’s initial visit he prepared a report on the 10 total cases of this previously unrecognized disease. He termed the condition imbecillitas phenylpyrouvica. Eventually it would come to be called phenylketonuria, or PKU, a disease that affects 1 out of every 15,000 babies in the United States. In his report, he postulated that since the same rare condition tended to affect siblings, this genetic defect was probably recessively inherited.

Diagnosis did not help the Egelands. Dag died a couple of years later, though Liv survived into her forties, living in an institution. Harry died young, while Borgny lived into her eighties, knowing that her struggles eventually benefited other families.

Simple and Striking

A dozen years later British psychiatrist and geneticist Lionel Penrose observed that the test for phenylpyruvic acid in urine “is so simple and striking that the failure of clinicians to observe the reaction until so recently is puzzling, except on the basis of the difficulty of obtaining specimens from subjects of low mental grade.” Still, as Penrose added in his inaugural lecture at University College London, Følling’s discovery inspired a surge of urine testing of mentally deficient patients in institutions, with reports of findings published in succession in the United Kingdom, France, the United States, Switzerland, and Canada. A single neurophysiologist at a mental institution in New York State tested over 8,000 patients in the mid-1930s.

Penrose’s comment is especially striking considering that in 1934 he published a paper on four related patients having a rare, previously unrecognized, recessive form of inherited mental deficiency. After seeing Følling’s paper Penrose went back and tested the urine of the surviving patient from his study. He found phenylpyruvic acid. So Penrose himself was one of the many physicians who “puzzlingly” failed to observe the ferric chloride reaction in the urine of people with PKU!

Why then did Følling succeed where others failed? The simple ferric chloride test was not an unusual one. But there were many simple colorimetric tests he might have chosen. And none of the available tests, including ferric chloride, had ever been associated with mental retardation. Følling had already done two tests for diabetes and kidney trouble. Why do another?

One possible answer is that Følling was sleuthing, and it took his nose as both a doctor and a chemist to solve the puzzle. From his medical training he knew that certain characteristic smells were sometimes associated with disease. Plus he had the added advantage of being an experienced bench chemist familiar with a range of chemical odors. In pondering the children’s scent he would want to test for substances or conditions that could produce distinct smells. And diabetic ketosis is associated with a distinct scent, albeit a sweet one. Following his nose Følling perhaps took an intuitive stab at finding distinct odor-causing compounds and found something unexpected—a previously unrecognized disease. His intuition led to an elegantly simple test for screening large numbers of mentally deficient patients quickly and cheaply. This innovation fueled PKU research for at least the next two decades.

A Cure for Mental Retardation?

As a metabolic expert, Følling immediately recognized that the phenylpyruvic acid in urine was likely connected to a metabolic problem. In his 1934 paper he speculated that PKU was caused by an inherited error in metabolizing an essential amino acid called phenylalanine, which had a chemical structure almost identical to that of phenylpyruvic acid. In turn Penrose seized on Følling’s supposition that PKU was an inborn error of metabolism. If that theory were true, then PKU was an inherited defect of the liver, not the brain, and so might be treated with a phenylalanine-free diet. Granted, this disease was relatively rare, and a successful therapy would only help limited numbers of patients. But the revolutionary idea that a simple diet could treat a form of mental deficiency was irresistible. Penrose rushed to try it.