The PKU Paradox: A Short History of a Genetic Disease

Chapter 8. The Perplexing Problem of Maternal PKU

140 CHAPTER EIGHT The Perplexing Problem of Maternal PKU F F F In the words of a New England Journal of Medicine editorial in the mid-1960s, “The solution of one problem often begets new ones,” and the history of PKU prevention is a case in point: “The oldest early-treated phenylketonuric girls are now more than ten years of age. Mental retardation due to phenylketonuria is waning as a result of existing programs; however, a significant incidence of retardation secondary to maternal phenylketonuria threatens unless some of these problems are solved within the next eight years.”1 Before the advent of mass screening, most women with severe forms of PKU were childless because they were institutionalized or had been sterilized or simply because of the condition itself.2 But the fertility of women diagnosed in infancy and placed on a protein-restricted diet is nearly normal. In the early years of screening for PKU, most clinicians assumed that it was safe to discontinue the diet in childhood, so nearly all women in the first cohort to be treated had terminated the diet by the time they became pregnant, and few continued to be seen at a metabolic clinic. Indeed, women who had discontinued the diet at a very young age might not have remembered why they had been treated or even the name of the condition.3 Nor were systems established to track these women; after all, PKU was seen as an The Perplexing Problem of Maternal PKU 141 acute and curable condition, not, as it turned out, a chronic one. For these women, however, their fetuses were at risk because, at high levels, phenylalanine is an extremely potent teratogen. Circulating in the maternal blood of women with PKU, it is actively transported across the placenta, resulting in a maternal-fetal phenylalanine ratio of about 1:1.5.4 Children born to such women rarely have PKU, since only about 1 in 120 offspring inherit the responsible gene from both parents. But these children were often found to be multiply impaired, although initially it was uncertain just what proportion were affected and in what specific ways and to what degree. It is commonly said that this harm was an unanticipated consequence of the success of screening, and the magnitude of the problem of maternal PKU (MPKU) certainly did come as a shock.5 But the possibility that damage to the offspring of mothers with PKU could be a serious complication of screening had been recognized as early as the mid-1960s, and the issue was discussed within the US Children’s Bureau and in leading medical journals throughout the 1960s and 1970s. Følling himself wrote in 1971 that it is a “worrying fact that phenylketonuric mothers may give birth to mentally retarded children who suffer in utero, so that postnatal treatment comes too late. We may become responsible for the occurrence of more mental retardation than we prevent. At present, however, we can do nothing but continue the treatment of phenylketonuric patients, and hopefully await the further elucidation of this condition.”6 Yet discussions of dietary management only rarely addressed the issue, which was also absent from legislative hearings and the many expositions on screening in the popular press. Not until the 1980s were the risks confirmed and a prospective, large-scale study organized to examine whether damage to offspring could be prevented if women with PKU were to resume the low-phe diet. FIRST SUSPICIONS AND RESPONSES As early as 1956, Charles Dent, in London, called attention to the case of a woman with PKU whose three children, with unknown 142 The PKU Paradox but presumably different fathers, were all severely mentally impaired from birth, despite having no abnormal amino acids in their urine.7 Dent’s hypothesis that the brain insult occurred in utero as the result of toxic blood phenylalanine levels in the mother made little stir at the time—not surprisingly, given that it was published in a volume of conference proceedings, antedated development of the Guthrie test, and was immediately followed by George Jervis’s remark that a phenylketonuric patient under no dietary restriction at his institution had delivered two normal children. But in 1963, a group led by C. Charlton Mabry at the University of Kentucky published high-profile reports of mothers with PKU whose children were mentally retarded but did not have the disease.8...