CASE REPORT * ETUDE DE CAS

Undiagnosed phenylketonuria in adult women:a hidden public health problemWilliam B. Hanley, MD, FRCPC; Joe T.R. Clarke, MD, PhD, FRCPC; Wanda E. Schoonheyt, RN

T he devastating effects of untreated maternalphenylketonuria (PKU) on the fetus are wellknown.' Over 90% of the offspring of women

with classic PKU untreated during pregnancy havebeen mentally retarded and 73% microcephalic. Inaddition, 50% have exhibited intrauterine growthretardation, and 17% have had serious congenitalheart anomalies. Prevention of this PKU embryopa-thy appears to be possible through early diagnosisand treatment with dietary phenylalanine restrictionthroughout pregnancy.2

The certainty of serious disabling congenitalanomalies in the offspring of women with PKU,along with the potential for prevention throughtreatment during pregnancy, emphasizes the impor-tance of recognizing PKU among women of repro-ductive age. Most younger women with PKU willhave been identified through newborn screeningprograms. However, those over 25 years of age, bornbefore the advent of large-scale screening, mighthave escaped detection, especially if they were notrecognized to be mentally retarded as a result of thedisease. Although the incidence of profound mentalretardation among people with untreated PKU hasgenerally been thought to be very high our experi-ence suggests that there is a significant number ofwomen with PKU who are of normal or near-normalintelligence and would be at risk for having seriouslyhandicapped children if their condition were notrecognized. We report five such cases and discuss theimplications for the management of PKU.

Case reports

The women described here presented to us overan 8-year period after referral by pediatric neurolo-gists and geneticists who suspected maternal PKU

embryopathy because the mothers had multiple mi-crocephalic, mentally retarded infants and apparent-ly never a normal child. The salient historical andclinical data are shown in Table 1.

In every case the fasting plasma phenylalanineconcentration, determined by means of ion-exchangechromatography with an automatic amino acidanalyser, was consistently greater than 900 ,mol/L.In cases 3 and 5 the women had a plasma phenylala-nine level consistent with their being classified ashaving "atypical (mild) PKU".

In this small sample of PKU patients the rela-tion between the plasma phenylalanine level and theintelligence quotient (IQ) was weak. Three of thewomen were considered to have normal intelligence(IQ greater than 85), one was found to have border-line intelligence (IQ 75), and one was mildly mental-ly handicapped (IQ 67). All had completed at leastsome years of high school, held responsible jobs andwere considered good mothers. None was suspectedby her family or physician to be intellectually handi-capped.

Comments

In 1960 Knox,' after reviewing 466 cases ofuntreated PKU, concluded that 99% of the patientswere mentally retarded (IQ less than 80) and that88% had an IQ of less than 40. Partington6 reportedthat 74 of 75 patients with untreated PKU inOntario were mentally retarded; 66 (88%) had an IQof less than 41. In Australia Pitt7 indicated that only2 of 53 people with untreated PKU were regarded ashaving normal intelligence and 1 borderline intelli-gence; 42 were moderately to profoundly retarded.These experiences and those of others worldwidehave indicated that untreated PKU is associated

From the Division ofClinical Genetics, Department ofPediatrics, and the Department ofNursing, Hospitalfor Sick Children andUniversity of Toronto

Reprint requests to: Dr. William B. Hanley, Director, PKU Programme, Division of Clinical Genetics, Hospitalfor Sick Children, 555University Ave., Toronto, Ont. MSG IX8

CAN MED ASSOC J 1990; 143 (6) 513

with a high incidence of mental retardation, usuallysevere.

The association of severe mental retardationwith untreated PKU was, however, based primarilyon surveys of mentally retarded people, many ofwhom were in institutions, and the data were there-fore subject to a strong bias of ascertainment.5 Theincidence of severe mental retardation in peoplewith untreated PKU may be lower than previouslythought. In 1966 Bessman8 suggested that as many ashalf of the people with untreated PKU were mentallynormal or near normal, a view that has stimulatedconsiderable debate. In 1969 Berman and associates9described 15 patients with previously unrecognizedand untreated PKU detected only after youngersiblings were found to have the condition throughscreening. Four of the 15 had a normal IQ (greaterthan 85), 3 had borderline intelligence (IQ 70 to 85),and 4 were mildly or moderately retarded (IQ 50 to70); only the remaining 4 were severely retarded (IQless than 50). Among an estimated 250 000 adultsundergoing serologic testing for syphilis in Massa-chusetts only 3 were found to have previouslyunrecognized and untreated PKU.'0 All three werementally handicapped. They were living in the com-munity and were sexually active; two were womenwho had mentally retarded offspring. In anotherstudy 2 of 67 274 apparently healthy adults inOntario were found to have previously unrecognizedPKU: 1 had classic PKU and the other atypical;"both were intellectually normal. In Saskatchewan anestimated 120 000 people from whom samples ofserum were obtained for premarital testing for syphi-lis over 10 years were tested for PKU; S women withpreviously undiagnosed PKU were discovered.'2 InOregon Buist and collaborators,'3 during prenatalscreening among 33 000 women in 1962-63 and260 000 in 1975-79, discovered 10 with previouslyunknown hereditary hyperphenylalaninemia (1 case

in 29 300 births); 7 had classic PKU and 3 mildervariants of the disease.

Other studies targeted specifically at unrecog-nized maternal PKU support these findings.Guttler'4 estimated that there were as many as 100women with undiagnosed PKU in Denmark; Scottand colleagues,'5 after screening 10 000 Glasgowwomen for PKU during prenatal evaluation, found 1such woman, who had normal intelligence. In Massa-chusetts Levy and Waisbren' tested 453 118 umbili-cal cord blood samples over 10 years and discovered22 women with previously undiagnosed, untreatedhyperphenylalaninemia (1 case in 20 596 births).Only two had classic PKU; however, although onewas mentally retarded (IQ 45) the other was intellec-tually normal (IQ 94). Of the remaining 20, 11 hadatypical PKU (plasma phenylalanine level 750 to1200 ,umol/L) and 9 benign hyperphenylalaninemia(plasma phenylalanine level less than 750 ,umol/L).Reporting the experience of the maternal PKUcollaborative study in Europe and Australia Drogariand coworkers'6 stated that 23 of 50 women withPKU had not been identified through screening or asa result of mental retardation; 8 were discoveredduring routine antenatal screening, 14 after the birthof an abnormal child and 1 after the birth of asecond child with PKU. In another study 6 of 18affected infants were born to women with previouslyunrecognized PKU. 17

The incidence of previously undiagnosed mater-nal PKU, determined on the basis of surveys ofapparently healthy adults in many areas includingCanada, has been estimated to be about 1 in 30 000population (Table 2). Since the overall incidence ofPKU in North America, as determined throughnewborn screening, is about 1 in 15 000 as many ashalf the adults with untreated PKU would be missedif detection were based on the occurrence of severemental retardation.

Tatle 1 Characteristics of five women with previously unrecognized phenylketonuria (PKU,

Case Year of Age. Plasma phenylalanine--i.: diagnosis yr Ievel pumol/L*

1981 22

-19871988-19,88

Intelligencequotient

1543

352664

1989 36

13749981588

1152

107i75±85.

90t

Obstetrichistory

G 4, P2.SA 1.SB 1

G2. P2G 2, P2G 8, P4,SA 4

G 2. P2

Outcome of offspring

One infant born with IUGRand MC - died at 16 mo:one living child with MC anndelayed speech

Two children with MC and MRTwo children with MC and MRFour children with MC and MFP

Two children with IUGR. MCand MR

. a.. :t4tC1VitiP para- SA,. spontanPeos abortinor SB stillbirth IUGR intrauterine growth retardation MC M lcrocephaly andn MR cit.etard4atiorNormal piasma 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,:'.f-.tFii^.ciiFl

514 CAN MED ASSOC J 1990; 143 (6)

Our experience, along with that reported fromcentres worldwide, suggests that the ascertainment ofcases of PKU in women over 25 years of age on thebasis of severe mental retardation is likely to beincomplete. Data for 1986 from Statistics Canadahave shown that 68.6% of the 364 813 live birthsreported in Canada that year were to women over 24years of age.'8 If the incidence of unrecognized PKUis as high as 1 in 30 000 eight affected infants mayhave been born in 1986.

Projections of the magnitude of the problem areinherently inaccurate because the necessary calcula-tions are based on certain assumptions (e.g., birthrates among women over 24 years, fecundity, likeli-hood that infants with maternal PKU embryopathywould be missed and accuracy of the estimatedincidence of unrecognized PKU). As the number ofwomen in that age group who have not been testedfor PKU in the neonatal period falls, the incidenceof maternal PKU embryopathy due to unrecognizedPKU will inevitably decrease sharply over the next10 years. Using projected birth rates among womenover 24 years and the estimated incidence of unrec-ognized PKU among women of reproductive age weestimated that as many as 40 infants would beaffected in that 10-year period. Factors that wouldincrease the incidence of PKU embryopathy includean increase in the birth rate among older women, ashas happened in the United States,'9 and an increasein the numbers of immigrants from countries withno newborn PKU screening program. In addition,some women with treated PKU will inevitably belost to follow-up and may not seek appropriatemedical care during pregnancy.

Estimates of the magnitude of the problem inthe United States are more difficult to derive. Sincethe overall incidence of PKU in the population iscomparable to that in Canada20 the total number ofaffected infants might be 400 or more over the next10 years. The large population of black people, inwhom PKU is rare, and the large overall proportionof infants born to women less than 24 years of agemay tend to decrease the incidence.2' On the otherhand, the late introduction of newborn PKU screen-ing programs in many states and the relatively largelosses to follow-up22-24 likely will increase the overallrisk. Large-scale newborn screening for PKU had

begun in Canada25 and most of the United States20by 1965. Screening in Britain and the rest of Europewas not established until the late 1960s.26 Theincidence of PKU in Europe appears to be 50%higher than that in North America.202627 Along withthe later start in newborn screening, the number offetuses at risk might be substantially higher inEurope than in North America over the next 10 to15 years.

If our estimate is correct that as many as halfthe women with PKU born before the advent ofwidespread newborn screening may have sufficientintelligence to escape clinical detection before thebirth of an affected infant, then until such womenare beyond reproductive age screening should beconsidered to include all adult women before preg-nancy occurs.28 Even after women born before thescreening was introduced are beyond reproductiveage the risk of mental retardation due to PKUembryopathy may be considerable for several years.Until then we recommend that any woman bearing achild with these stigmata (microcephaly and mentalretardation) should have her plasma phenylalaninelevel measured, particularly if she has never had anormal child or has had more than one affectedchild. Consideration should be given to methods ofscreening women for PKU who may have escapednewborn screening (i.e., those over age 25 and recentimmigrants) or were previously known but lost tofollow-up. The American Public Health Associationhas underscored the seriousness of the problem in aresolution for improved efforts to locate and counselyoung women with PKU regarding the risks ofmaternal PKU embryopathy.29

We thank Drs. Andrew Plioplys, Division of Neurology,Hospital for Sick Children, Donald T. Whelan, McMasterUniversity, Hamilton, Ont., and Jacqueline Siegel-Barteltand the late Linda Stevens, Division of Clinical Genetics,Hospital for Sick Children, Department of Genetics,Hospital for Sick- Children, for referring their patients tous.

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

Table 2: Detection of maternal PKU through premarital, prenatal and cord blood screeningType of No. of women No. of cases

Study Location screening tested of PKU Incidence

Zaleski et al12 Saskatchewan Premarital 120 000* 5 1:24 000*Buist et al 3 Oregon Prenatal 293 000 10 1:29 300Scott et al'5 Glasgow Prenatal 10 000 1 1:10 000Levy et al' Massachusetts Cord blood 453 118 22 1:20 596

*Estimated.

CAN MED ASSOC J 1990; 143 (6) 515

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23. Ahn SS, Cunningham GC, Mordaunt VL: Twenty-two yearslater: California's maternal PKU program [abstr]. In SkeelsMR, Buist NRM, Tuerck JM (eds): Neonatal Screening.Proceedings of the 6th National Neonatal Screening Sympo-sium, May 22-25, 1988, Portland, Oregon: 139-140

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What is man?

To me man is a thickened node in the web ofa universe offorces which, ever repetitivelyand 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 theinvisible strands of heredity to every form of life that ever lived; and his fundamentaldrives and compulsive activities go back to the first piece of life that ever appeared onearth. He is packed with chemical factories, his every cell a better chemist and physicistthan all the Nobel prize laureates put together. He is immersed in age-old and everchanging socialforces that compress, enhance, destroy, or deform his trends. At every stephe is beset by conflict between his biology and his sociology.... Somehow there is aconstant 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 transitfrom conception to that catalytic dispersal, perhaps reassemblage, called death.

- Abraham Myerson (1881-1948)

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