Undiagnosed phenylketonuria in adult women: a hidden public health problem William B. Hanley, MD, FRCPC; Joe T.R. Clarke, MD, PhD, FRCPC; Wanda E. Schoonheyt, RN T he devastating effects of untreated maternal phenylketonuria (PKU) on the fetus are well known.' Over 90% of the offspring of women with classic PKU untreated during pregnancy have been mentally retarded and 73% microcephalic. In addition, 50% have exhibited intrauterine growth retardation, and 17% have had serious congenital heart anomalies. Prevention of this PKU embryopathy appears to be possible through early diagnosis and treatment with dietary phenylalanine restriction throughout pregnancy.2 The certainty of serious disabling congenital anomalies in the offspring of women with PKU, along with the potential for prevention through treatment during pregnancy, emphasizes the importance of recognizing PKU among women of reproductive age. Most younger women with PKU will have been identified through newborn screening programs. However, those over 25 years of age, born before the advent of large-scale screening, might have escaped detection, especially if they were not recognized to be mentally retarded as a result of the disease. Although the incidence of profound mental retardation among people with untreated PKU has generally been thought to be very high our experience suggests that there is a significant number of women with PKU who are of normal or near-normal intelligence and would be at risk for having seriously handicapped children if their condition were not recognized. We report five such cases and discuss the implications for the management of PKU.

embryopathy because the mothers had multiple microcephalic, mentally retarded infants and apparently never a normal child. The salient historical and clinical data are shown in Table 1. In every case the fasting plasma phenylalanine concentration, determined by means of ion-exchange chromatography with an automatic amino acid analyser, was consistently greater than 900 ,mol/L. In cases 3 and 5 the women had a plasma phenylalanine level consistent with their being classified as having "atypical (mild) PKU". In this small sample of PKU patients the relation between the plasma phenylalanine level and the intelligence quotient (IQ) was weak. Three of the women were considered to have normal intelligence (IQ greater than 85), one was found to have borderline intelligence (IQ 75), and one was mildly mentally handicapped (IQ 67). All had completed at least some years of high school, held responsible jobs and were considered good mothers. None was suspected by her family or physician to be intellectually handicapped.


In 1960 Knox,' after reviewing 466 cases of untreated PKU, concluded that 99% of the patients were mentally retarded (IQ less than 80) and that 88% had an IQ of less than 40. Partington6 reported that 74 of 75 patients with untreated PKU in Ontario were mentally retarded; 66 (88%) had an IQ of less than 41. In Australia Pitt7 indicated that only 2 of 53 people with untreated PKU were regarded as Case reports having normal intelligence and 1 borderline intelliThe women described here presented to us over gence; 42 were moderately to profoundly retarded. an 8-year period after referral by pediatric neurolo- These experiences and those of others worldwide gists and geneticists who suspected maternal PKU have indicated that untreated PKU is associated

From the Division of Clinical Genetics, Department of Pediatrics, and the Department of Nursing, Hospitalfor Sick Children and University of Toronto

Reprint requests to: Dr. William B. Hanley, Director, PKU Programme, Division of Clinical Genetics, Hospitalfor Sick Children, 555 University Ave., Toronto, Ont. MSG IX8 CAN MED ASSOC J 1990; 143 (6)


with a high incidence of mental retardation, usually severe. The association of severe mental retardation with untreated PKU was, however, based primarily on surveys of mentally retarded people, many of whom were in institutions, and the data were therefore subject to a strong bias of ascertainment.5 The incidence of severe mental retardation in people with untreated PKU may be lower than previously thought. In 1966 Bessman8 suggested that as many as half of the people with untreated PKU were mentally normal or near normal, a view that has stimulated considerable debate. In 1969 Berman and associates9 described 15 patients with previously unrecognized and untreated PKU detected only after younger siblings were found to have the condition through screening. Four of the 15 had a normal IQ (greater than 85), 3 had borderline intelligence (IQ 70 to 85), and 4 were mildly or moderately retarded (IQ 50 to 70); only the remaining 4 were severely retarded (IQ less than 50). Among an estimated 250 000 adults undergoing serologic testing for syphilis in Massachusetts only 3 were found to have previously unrecognized and untreated PKU.'0 All three were mentally handicapped. They were living in the community and were sexually active; two were women who had mentally retarded offspring. In another study 2 of 67 274 apparently healthy adults in Ontario were found to have previously unrecognized PKU: 1 had classic PKU and the other atypical;" both were intellectually normal. In Saskatchewan an estimated 120 000 people from whom samples of serum were obtained for premarital testing for syphilis over 10 years were tested for PKU; S women with previously undiagnosed PKU were discovered.'2 In Oregon Buist and collaborators,'3 during prenatal screening among 33 000 women in 1962-63 and 260 000 in 1975-79, discovered 10 with previously unknown hereditary hyperphenylalaninemia (1 case

in 29 300 births); 7 had classic PKU and 3 milder variants of the disease. Other studies targeted specifically at unrecognized maternal PKU support these findings. Guttler'4 estimated that there were as many as 100 women with undiagnosed PKU in Denmark; Scott and colleagues,'5 after screening 10 000 Glasgow women for PKU during prenatal evaluation, found 1 such woman, who had normal intelligence. In Massachusetts Levy and Waisbren' tested 453 118 umbilical cord blood samples over 10 years and discovered 22 women with previously undiagnosed, untreated hyperphenylalaninemia (1 case in 20 596 births). Only two had classic PKU; however, although one was mentally retarded (IQ 45) the other was intellectually normal (IQ 94). Of the remaining 20, 11 had atypical PKU (plasma phenylalanine level 750 to 1200 ,umol/L) and 9 benign hyperphenylalaninemia (plasma phenylalanine level less than 750 ,umol/L). Reporting the experience of the maternal PKU collaborative study in Europe and Australia Drogari and coworkers'6 stated that 23 of 50 women with PKU had not been identified through screening or as a result of mental retardation; 8 were discovered during routine antenatal screening, 14 after the birth of an abnormal child and 1 after the birth of a second child with PKU. In another study 6 of 18 affected infants were born to women with previously unrecognized PKU. 17 The incidence of previously undiagnosed maternal PKU, determined on the basis of surveys of apparently healthy adults in many areas including Canada, has been estimated to be about 1 in 30 000 population (Table 2). Since the overall incidence of PKU in North America, as determined through newborn screening, is about 1 in 15 000 as many as half the adults with untreated PKU would be missed if detection were based on the occurrence of severe mental retardation.

Tatle 1 Characteristics of five women with previously unrecognized phenylketonuria (PKU, Cas e --i.:



Year of diagnosis

Age. yr

Plasma phenylalanine Ievel pumol/L*




-1987 1988

35 26

1374 998


-19, 88







a..P : t4tC1Viti para- SA,.

spontanPeos abortinor SB

Intelligence quotient

G 4, P2. SA 1. SB 1

75± 90t

stillbirth IUGR

ptenylalanine ievel is less. tharn 120 mol/t..ietermined with the tuse of the revised Wechsler Adult Intelligence Scale. tDeterm-ned with irncuEse of Raver, s Sta.ridard Proqressive Mar ce,:'

Normal piasma

.f-.tFii^.ciiFl 514

CAN MED ASSOC J 1990; 143 (6)

Obstetric history

G2. P2 G 2, P2 G 8, P4, SA 4 G 2. P2

Outcome of offspring One infant born with IUGR and MC - died at 16 mo: one living child with MC ann delayed speech Two children with MC and MR Two children with MC and MR Four children with MC and MFP Two children with IUGR. MC and MR

intrauterine growth retardation MC


lcrocephaly andn



Our experience, along with that reported from centres worldwide, suggests that the ascertainment of cases of PKU in women over 25 years of age on the basis of severe mental retardation is likely to be incomplete. Data for 1986 from Statistics Canada have shown that 68.6% of the 364 813 live births reported in Canada that year were to women over 24 years of age.'8 If the incidence of unrecognized PKU is as high as 1 in 30 000 eight affected infants may have been born in 1986. Projections of the magnitude of the problem are inherently inaccurate because the necessary calculations are based on certain assumptions (e.g., birth rates among women over 24 years, fecundity, likelihood that infants with maternal PKU embryopathy would be missed and accuracy of the estimated incidence of unrecognized PKU). As the number of women in that age group who have not been tested for PKU in the neonatal period falls, the incidence of maternal PKU embryopathy due to unrecognized PKU will inevitably decrease sharply over the next 10 years. Using projected birth rates among women over 24 years and the estimated incidence of unrecognized PKU among women of reproductive age we estimated that as many as 40 infants would be affected in that 10-year period. Factors that would increase the incidence of PKU embryopathy include an increase in the birth rate among older women, as has happened in the United States,'9 and an increase in the numbers of immigrants from countries with no newborn PKU screening program. In addition, some women with treated PKU will inevitably be lost to follow-up and may not seek appropriate medical care during pregnancy. Estimates of the magnitude of the problem in the United States are more difficult to derive. Since the overall incidence of PKU in the population is comparable to that in Canada20 the total number of affected infants might be 400 or more over the next 10 years. The large population of black people, in whom PKU is rare, and the large overall proportion of infants born to women less than 24 years of age may tend to decrease the incidence.2' On the other hand, the late introduction of newborn PKU screening programs in many states and the relatively large losses to follow-up22-24 likely will increase the overall risk. Large-scale newborn screening for PKU had

begun in Canada25 and most of the United States20 by 1965. Screening in Britain and the rest of Europe was not established until the late 1960s.26 The incidence of PKU in Europe appears to be 50% higher than that in North America.202627 Along with the later start in newborn screening, the number of fetuses at risk might be substantially higher in Europe than in North America over the next 10 to 15 years. If our estimate is correct that as many as half the women with PKU born before the advent of widespread newborn screening may have sufficient intelligence to escape clinical detection before the birth of an affected infant, then until such women are beyond reproductive age screening should be considered to include all adult women before pregnancy occurs.28 Even after women born before the screening was introduced are beyond reproductive age the risk of mental retardation due to PKU embryopathy may be considerable for several years. Until then we recommend that any woman bearing a child with these stigmata (microcephaly and mental retardation) should have her plasma phenylalanine level measured, particularly if she has never had a normal child or has had more than one affected child. Consideration should be given to methods of screening women for PKU who may have escaped newborn screening (i.e., those over age 25 and recent immigrants) or were previously known but lost to follow-up. The American Public Health Association has underscored the seriousness of the problem in a resolution for improved efforts to locate and counsel young women with PKU regarding the risks of

maternal PKU embryopathy.29 We thank Drs. Andrew Plioplys, Division of Neurology, Hospital for Sick Children, Donald T. Whelan, McMaster University, Hamilton, Ont., and Jacqueline Siegel-Bartelt and the late Linda Stevens, Division of Clinical Genetics, Hospital for Sick Children, Department of Genetics, Hospital for Sick- Children, for referring their patients to us.

This work was supported in part by grant 6606-3265 from the National Health Research and Development Program, Department of National Health and Welfare, and grant 1-HD-4-2809 from the US National Institute of Child Health and Development.

Table 2: Detection of maternal PKU through premarital, prenatal and cord blood screening

Type of

Study Zaleski et al12 Buist et al 3 Scott et al'5

Location Saskatchewan

Levy et al'


Oregon Glasgow

screening Premarital

Prenatal Prenatal Cord blood

No. of women tested 120 000* 293 000 10 000 453 118

No. of cases of PKU 5 10 1 22

Incidence 1:24 000* 1:29 300 1:10 000 1:20 596

*Estimated. CAN MED ASSOC J 1990; 143 (6)


References 1. Levy HL, Waisbren SE: Effects of untreated maternal phenylketonuria and hyperphenylalaninemia on the fetus. N Engi J Med 1983; 309: 1269-1274 2. Lenke RR, Levy HL: Maternal phenylketonuria and hyperphenylalaninemia. An international survey of outcome of treated and untreated pregnancies. N Engl J Med 1980; 303: 1202- 1208 3. Wechsler D: Wechsler Adult Intelligence Scale - Revised, Psychological Corp, New York, 1981: 156 4. Raven JC: Guide to the Standard Progressive Matrices, Univ Printing House, Cambridge, England, 1960: 26 5. Knox WE: An evaluation of the treatment of phenylketonuria with diets low in phenylalanine. Pediatrics 1960; 26: 1 -11 6. Partington MW: Variations in intelligence in phenylketonuria. Can Med Assoc J 1962; 86: 736-743 7. Pitt D: The natural history of untreated phenylketonuria. Med JAust 1971; 1: 378-383 8. Bessman SP: Legislation and advances in medical knowledge - Acceleration or inhibition? J Pediatr 1966; 69: 334-338 9. Berman JL, Cunningham GC, Day RW et al: Causes for high phenylalanine with normal tyrosine in newborn screening programs. Am J Dis Child 1969; 117: 54-65 10. Levy HL, Karolkewicz V, Houghton SA et al: Screening the "normal" population in Massacchusetts for phenylketonuria. NEnglJMed 1970; 282: 1455-1458 11. Advisory Committee on Inborn Errors of Metabolism to the Ontario Ministry of Health: Phenylketonuria variants in Ontario. Can MedAssoc J 1976; 115: 509-512 12. Zaleski LA, Casey RE, Zaleski W: Maternal phenylketonuria: dietary treatment during pregnancy. Can Med Assoc J 1979; 121: 1591-1594 13. Buist NRM, Lis EL, Tuerck JM et al: Maternal phenylketonuria [C]. Lancet 1979; 2: 589 14. Guttler F: Hyperphenylalaninaemia: diagnosis and classification of the phenylalanine hydroxylase deficiency in childhood. Acta Paediatr Scand 1980; 280 (suppl): 1-80 15. Scott TM, Morton Fyfe W, McKay Hart D: Maternal phenylketonuria: abnormal baby despite low phenylalanine diet during pregnancy. Arch Dis Child 1980; 55: 634-649 16. Drogari E, Smith I, Beasley M et al: Timing of strict diet in

relation to foetal damage in maternal phenylketonuria. Lancet 1987; 2: 927-930 17. Naughten E, Kiely B, Saul I: Maternal hyperphenylalaninemia: a preventable cause of childhood morbidity and mortality [abstr]. In Abstracts of the 8th Congress of the

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International Association for the Scientific Study of Mental Deficiency, Dublin, August 21-25, 1988, International Association for the Scientific Study of Mental Deficiency, Dublin, 1988 Births and Deaths, 1986 (Vital Statistics and Health Status ser), cat no 84-204 (annual), vol 1, Statistics Canada, Ottawa, 1988: 20-21 Wegman ME: Annual summary of vital statistics - 1988. Pediatrics 1989; 84: 943-956 Tiwary CM: Proposed guidelines for screening for metabolic and endocrine diseases of dependent neonates of the U.S. armed forces. Clin Pediatr (Phila) 1987; 26: 349-354 Statistical Abstract of the United States: 1989, 109th ed, US Bureau of the Census, Washington, 1989: 62 Waisbren SE, Doherty LB, Bailey IV et al: The New England maternal PKU project: identification of at-risk women. Am J Public Health 1988; 78: 789-792 Ahn SS, Cunningham GC, Mordaunt VL: Twenty-two years later: California's maternal PKU program [abstr]. In Skeels MR, Buist NRM, Tuerck JM (eds): Neonatal Screening. Proceedings of the 6th National Neonatal Screening Symposium, May 22-25, 1988, Portland, Oregon: 139-140 Gill AE, Amador PS: A retrospective of newborn screening for PKU in New York State, 1965-1986. Ibid: 133-134 Haworth JC, Miller JR, Scriver CR: Screening, counselling and treatment of hereditary metabolic disease: a survey of resources in Canada. Can Med Assoc J 1974; 111: 1147-1153 Working Party of the Council of Europe to Study Hereditary Metabolic Diseases: Collective results of mass screening for inborn errors in eight European countries. Acta Paediatr Scand 1973; 62: 413-416 Ferreira P: Current Canadian newborn screening practices. Pediatr Med Q 1989; 3: 111-120 Ludar AS, Greene CL: Maternal phenylketonuria and hyperphenylalaninemia: implications for medical practice in the United States. Am J Obstet Gynecol 1989; 161: 1102-1105 Preventing birth defects from maternal phenylketonuria [policy statement 8907]. Am J Public Health 1990; 80: 228

What is man? To me man is a thickened node in the web of a universe offorces which, ever repetitively and ever anew, flow in and out of him; he is part of an ecology that involves plants, animals, climate, soil, and all kinds of radiant forces and chemicals. He is united by the invisible strands of heredity to every form of life that ever lived; and his fundamental drives and compulsive activities go back to the first piece of life that ever appeared on earth. He is packed with chemical factories, his every cell a better chemist and physicist than all the Nobel prize laureates put together. He is immersed in age-old and ever changing socialforces that compress, enhance, destroy, or deform his trends. At every step he is beset by conflict between his biology and his sociology.... Somehow there is a constant and shifting balance offorces in which hormones, ferments, enzymes, memories, ideas, emotions, and moods all play a part; and all of this is an unexplainable transit from conception to that catalytic dispersal, perhaps reassemblage, called death. -


CAN MED ASSOC J 1990; 143 (6)

Abraham Myerson (1881-1948)

Undiagnosed phenylketonuria in adult women: a hidden public health problem.

CASE REPORT * ETUDE DE CAS Undiagnosed phenylketonuria in adult women: a hidden public health problem William B. Hanley, MD, FRCPC; Joe T.R. Clarke,...
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