The PKU Paradox: A Short History of a Genetic Disease

Chapter 1. The Discovery of PKU as a Metabolic Disorder

CHAPTER ONE The Discovery of PKU as a Metabolic Disorder F F F A NEW “INBORN ERROR OF METABOLISM” Borgny Egeland gave birth to her first child, a daughter named Liv, in Norway in 1927. Like Carol Buck, Liv Egeland seemed fine in early infancy but was slow to begin to talk. Consulting the family doctor, this mother, too, was assured there was no cause for concern. A brother, Dag, born when Liv was 3 years old, also seemed healthy at birth but would soon develop symptoms more severe than his sister’s. Liv learned to speak a few words and exhibited a spastic gait and seemingly random movements; in contrast, Dag gradually lost interest in his surroundings and was never able to talk, walk, chew solid food, or even sit up by himself. Noticing a strong musty odor to the body and urine of both children, which could not be eliminated no matter how often they were bathed, the parents wondered whether it might be related to their developmental problems. But neither their family physician nor any of a host of other doctors, herbalists, and other healers could identify either the strange odor or the cause of their children’s ills. Colleagues of Borgny Egeland’s husband, Harry, a dentist, suggested that the parents contact Ivar Asbjørn Følling (1888–1973), a physician and biochemist with a strong interest in metabolic disease. As it turned out, Borgny Egeland’s sister occasionally saw 10 Følling socially and so was asked, when an opportunity arose, to tell him about the children’s retardation and inquire whether he thought it might be linked to their peculiar musty odor. Følling later explained that, although he had no real expectation of being able to help, he did not want to disappoint the mother and so offered to examine Liv and Dag, if she would bring the children and a urine sample to his laboratory.1 That fortuitous connection would have far-reaching consequences . Følling was one of the few Norwegians well trained in both chemistry and medicine, and as such, he was well positioned to appreciate that diseases could result from failures of metabolism , could be identified biochemically, and could be inherited as Mendelian recessives. In 1927–28, Følling had been awarded a Rockefeller Foundation fellowship that funded study at Harvard University, where he worked with biochemist-physiologist Lawrence J. Henderson. After further studies at several prominent US institutions, including work at the Rockefeller Institute with Donald Van Slyke, one of the founders of clinical chemistry, Følling returned to Norway to assume a faculty position at the University of Oslo.2 As an academically oriented biochemist, Følling was familiar with Archibald Garrod’s concept of “inborn errors of metabolism” (what we would now refer to as inherited metabolic disorders), an expression Garrod coined to describe a group of conditions that “apparently result from the failure of some step or other in the series of chemical changes that constitute metabolism.”3 In his landmark 1902 paper “The Incidence of Alkaptonuria: A Study in Chemical Individuality,” a copy of which was later found in Følling’s attic, Garrod claimed that the condition known colloquially as “black urine disease” was due, not to intestinal microorganisms , but to a more or less harmless chemical aberration whose pattern of transmission could be accounted for by Mendel ’s laws of heredity.4 More generally, Garrod argued that in their chemistry as much as in their physical structure, no two individuals of a species are identical. Most differences, whether physical or chemical, are slight, but some are very marked—as in the case of The Discovery of PKU as a Metabolic Disorder 11 12 The PKU Paradox supernumerary digits or the metabolic condition alkaptonuria.5 In the Croonian Lectures delivered to the Royal Society of Physicians in 1908 and published the following year as Inborn Errors of Metabolism, Garrod identified three other such “metabolic sports” linked to enzyme deficiencies—albinism, cystinuria, and pentosuria —and demonstrated that they were inherited as Mendelian autosomal recessives. When the Egelands brought their children to Følling’s lab, he applied his skills as a chemist as well as a physician. As a routine part of the examination, he added a few drops of ferric chloride to the children’s urine, at that time a standard test for the detection of ketones in...