Phenylketonuria

   (PKU)

   In 1934, Norwegian biochemist Ivor Asbjorn Folling (1888–1973) discovered, in research published in Hoppe-Seyler’s Zeitschrift für physiologische Chemie, that a cause of mental retardation—one of the so-called "inborn errors of metabolism"—was a genetic inability to metabolize the amino acid L-phenylalanine. As a result, toxic amounts of a metabolite of phenylalanine accumulated in the brain, causing a disease known as phenylketonuria (PKU)—so-called because the ketone metabolite phenylpyruvic acid in the urine has a peculiar smell and turns green in the presence of ferric chloride (phenylpyruvic acid was known, somewhat cruelly, to insiders as "the idiot acid").

   PKU turned out to have a significant genetic source. In 1935, Lionel S. Penrose (1898–1972), a physician on staff at the Royal Eastern Counties’ Institution at Colchester—an asylum for mental retardation—studied the genetics of mental retardation (MR) by carefully interviewing the families of 1280 patients; in research published in the Lancet in 1935, he found that PKU was inherited as an autosomal recessive trait. In 1953, Horst Bickel (1918–2000)* and co-workers at the Children’s Hospital in Birmingham described in the Lancet the success of a diet low in phenylalanine in reducing PKU. In 1963, Robert Guthrie (1916–1995) at the Children’s Hospital in Buffalo, New York, announced in Pediatrics a simple screeing test for PKU that entailed inhibiting the growth of bacteria. Then, Seymour Kaufman (1924–), chief of the Laboratory of Neurochemistry at the National Institute of Mental Health, wrapped up a virtual lifetime of doing basic research on the biochemistry of PKU by introducing folinic acid in 1987 in the treatment of one form of PKU that is caused by a lacking coenzyme; this research was published in the Journal of Pediatrics. This whole chain of research from Folling’s discovery on has touched off a hunt for other biological causes of mental retardation. (Indeed, some observers consider PKU the only established abnormality in psychiatry.)