OUP user menu

Ivar Asbjörn Følling
Discovered Phenylketonuria (PKU)

Jason Gonzalez, Monte S. Willis MD, PhD
DOI: http://dx.doi.org/10.1309/LM62LVV5OSLUJOQF 118-119 First published online: 1 February 2010

Ivar Asbjörn Følling (1888–1973)

Dr. Asbjörn Følling, a Norwegian biochemist and physician, first published the description of phenylketonuria (PKU) as a cause of mental retardation in 1934.1 Moreover, this study reported a laboratory test to confirm this metabolic disease, which was later determined to be an autosomal recessive metabolic disorder. Subsequent work by other investigators would determine that diet modification would drastically improve the outcome and prevent the onset of mental retardation. The discovery of PKU was a fundamentally important discovery for the fields of biochemistry, genetics, metabolism, and medicine.

Phenylketonuria (PKU) is a genetic disorder due to the inability to metabolize the amino acid phenylalanine. This is due to mutations leading to a deficiency in the enzyme phenylalanine hydroxylase. The disease occurs in approximately 1 in 10,000 children,2 and the prevalence is slightly higher among people of Irish and West Scottish descent.2 Some have suggested an ecologic advantage of heterozygotes, protecting them from the negative health consequences of consuming moldy food, as the wet climates of Ireland and West Scotland have a higher risk of mold contamination.3

Born Ivar Asbjörn Følling on August 23, 1888, he was raised on a farm in northern Norway. He was the youngest of five children.4,5 The farm was located eight miles from the nearest town of Steinkjer and 50 miles from the Trondheim. Starting at the age of five, he recalled spending much of his childhood working.6 While summers were spent working on the farm, he was allowed to attend school during the winter, where classes were held in a one-room school house two miles away, every other day.6 After graduating in the ninth grade, he did not return to full-time work on the farm as most of the other students did, he instead expressed an interest in continuing his education. With his family’s support, he moved to Trondheim to live with his older sister and complete high school. He subsequently attended the Technical College of Norway in Trondheim, majoring in chemical engineering.4,7 He went on to study medicine in Oslo, paying his way through small loans and by teaching chemistry at the dental college.4,7 He completed his medical training in 1922 and began work at the University Hospital, while continuing to teach and do research at the dental college. Upon receiving a Rockefeller Foundation Fellowship in 1928 to study metabolic diseases in the United States, he studied at Harvard, Yale, Johns Hopkins, and Mayo.4,7 He returned to work in Norway in 1929, and in 1930 concentrated his studies on metabolism and physiology in Colorado with Dr. Lawrence Henderson, a biochemist and physicist from Harvard. In 1934, Dr. Følling became professor of physiology and biochemistry at the Oslo veterinary college as a researcher and instructor.4,7

In Oslo, where Dr. Følling practiced, Borgny and Harry Egeland had two children, ages four and six, with progressive mental retardation in 1934. The children expressed physical debilitations beyond overt mental handicaps. The youngest had difficulty sitting upright, was unable to feed himself, and had pronounced involuntary eye movement.1 The parents increasingly noticed an odor associated with both children.4,7 While the children had been evaluated by numerous doctors over the years, none of these inquiries identified an explanation for the children’s condition. During a discussion with one of these physicians, Mr. Egeland was given Dr. Følling’s name because of his expertise in metabolic disorders.5

Upon routine testing of the children’s urine for ketones, Dr. Følling found some irregularities. The test for ketones at the time was aqueous ferric chloride. When added to urine in the absence of ketones, ferric chloride turns red-brown; if ketones are present the mixture turns purple. Surprisingly, the addition of ferric chloride to the Egeland children’s urine turned dark green and faded over time.8 Aware that some substances, such as aspirin, interfered with this test, it was repeated a week later with the same results.8 It took another six weeks (and 20 L of the children’s urine) to identify the interfering substance as phenylpyruvic acid.8 Dr. Følling hypothesized the children’s mental retardation was due to the presence of phenylpyruvic acid by testing other impaired children. He collected urine from more than 400 institutionalized patients in the Oslo area and identified eight additional people, including two siblings, with the phenylpyruvic acid in their urine.1 These patients also had additional similarities including a stooping figure, spastic gait, and severe mental impairments.1 The findings were submitted to Zeitschrift fur Physiologische Chemie only six months after his first contact with the Egelands.

How did he do that? The identification of the unknown substance in the Egeland children’s urine was a process well known to chemistry. The substance was extracted through a series of reactions, the final product was tested for its ability to give the characteristic ferric chloride reaction (purple color change). After six recrystalizations, the melting point of the substance able to produce this reaction became constant, suggesting a single chemical present. Further chemical analysis determined the substance was organic (9C, 8H, 3O) and contained a benzene ring. Along with additional reaction characteristics, it was determined the substance was most likely phenylpyruvic acid.1

The increased levels of phenylalanine and its metabolites (ie, phenylpyruvic acid) in PKU exert their toxicity exclusively on the central nervous system (CNS). This toxicity is believed to be a result of either: (a) direct neuronal damage by phenylalanine and its metabolites; or (b) indirect CNS damage by competing with neurotransmitter precursors such as tyrosine and tryptophan, resulting in lower dopamine, serotonin, epinephrine, and norepinephrine needed for brain function.7,9,10 Even in patients treated early in the disease, a small reduction in executive ability has been identified.11

Until the mid-1950s, PKU was considered an unfortunate cause of mental retardation. In 1953, the role of dietary phenylalanine on the severity of PKU was discovered.12 Infants with PKU were subsequently treated with low phenylalanine diets to prevent the onset of mental retardation.13 Successful use of this diet necessitated implementation before mental debilitation occurred. Efforts to screen newborns for PKU were initiated in the early 1960s. In 1984, the genetic basis of PKU was identified as mutations in the phenylalanine hydroylase (PAH) gene.14

Dr. Følling received numerous awards for his work on PKU. King Haakon VII of Norway and the National Scientific Society awarded him the first Fridtjot Nansen medal in 1950. He was also made an honorary member of the Norwegian Medical Society. He was honored with the first Joseph P. Kennedy International Award in Mental Retardation in 1962 presented by President John F. Kennedy. Dr. Følling suffered a serious stroke at the age of 80 and died four years later in 1973. He is honored in Norway to this day for his contributions by the reference of PKU as Følling’s disease. His contributions to metabolic disease, genetics, and clinical chemistry make him a luminary in laboratory medicine.

References

View Abstract