Phenylketonuria as a balanced polymorphism: the nature of the heterozygote advantage

Woolf, L. I.; McBean, Michelle; Woolf, F. M.; Cahalanf, S. F.

doi:10.1111/j.1469-1809.1975.tb00635.x

Cited by 38 publications

(22 citation statements)

References 20 publications

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“…Finally, in view of the molecular data summarized below, genetic drift and recurrent mutation alone are also not sufficient to explain the high incidence of PKU in Europe. These data support previous suggestions [Woolf et al, 1975;Woolf, 1976;Saugstad, 1977] of an important role for overdominant selection in PKU.…”

Section: Introductionsupporting

confidence: 81%

“…A number of possible albeit controversial selective mechanisms have been discussed [Vogel, 1984]. Thus, female carriers of PKU could be shown both to have lower [Woolf et al, 1975;Woolf, 1976Woolf, , 1978 and higher [Saugstad, 1973;Blyumina, 1974] rates of spontaneous miscarriages than controls. In addition, birth weight in the nonaffected children of PKU carriers has been reported to be increased [Saugstad, 1977], although not consistently so [Smith et al, 1978], when compared to control children.…”

Section: Introductionmentioning

confidence: 99%

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A role for overdominant selection in phenylketonuria? Evidence from molecular data

Krawczak

Zschocke

2003

Hum. Mutat.

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For the PKU Special IssueTo date, the reason is unknown for the high prevalence of phenylalanine hydroxylase (PAH) mutations causing phenylketonuria (PKU) in extant European populations. However, molecular genetic data generated over the last decade suggest that the concomitant excess of (unaffected) PKU carriers is at least in part the result of overdominant selection (''heterozygous advantage''). Such selection would have acted upon several different mutations in different historical populations. The exact nature of the underlying selective mechanism is unknown; its elucidation requires further investigation. Hum Mutat 21:394-397,

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Section: Introductionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

A role for overdominant selection in phenylketonuria? Evidence from molecular data

Krawczak

Zschocke

2003

Hum. Mutat.

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“…A comparison of data on gestational pathology in our study and that by Woolf (1975) seems to reveal a similar pattern; the findings of Saugstad (1973) that there was evidently a higher incidence of pathology during pregnancy and delivery in the population of PKU heterozygotes is thus controversial. Despite amino acid imbalance found in the pregnant heterozygotes for phenylketonuric-especialIy an evident decrease (36 %) in plasma tyrosine concentration with an accompanying slight decrease in phenylalanine values, which remain above the normal value in a healthy population (Nowaczewska et al, 1981)-the results of our study do not confirm the hypothesis that there is damage to the developing central nervous system of the fetus.…”

Section: Discussionsupporting

confidence: 65%

Influence of the phenylketonuric heterozygote on the developing fetus

Cabalska¹,

Miesowicz²,

Zorska³

et al. 1981

J of Inher Metab Disea

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Physical development scores and clinical condition were evaluated in 403 newborn of phenylketonuric (PKU) heterozygotes. No significant differences were found between this group and the progeny of women from a healthy population. Analysis of mental development scores in 82 non-PKU children age 3-14 years born to heterozygous mothers revealed normal values of psychometric tests.Phenylketonuria follows an autosomal-recessive pattern of inheritance. Partially deficient phenylalanine hydroxylase activity in phenylketonuric (PKU) heterozygotes is manifested by a moderately increased phenylalanine and decreased plasma tyrosine concentration. These abnormalities seem not to have any evident influence on their psychosomatic condition.The problem still to be discussed is the possible influence of disturbed amino acid equilibrium in body fluids on the intrauterine environment, and in consequence on the developing fetus. The aim of the present study was to evaluate the biological value of newborn offspring of PKU heterozygotes and mental developmerit of their healthy non-PKU children. A thorough anamnesis of gestation, the perinatal period and previous pregnancies was performed. MATERIALS AND METHODSThe analysed material includes the offspring of 200 obligatory phenylketonuric heterozygotes-mothers of PKU patients, ascertained by the newborn-screening programme and confirmed by verifying examinations-or patients diagnosed late with clinical symptoms of mental retardation. The total number of children born to these women was 403. Out of this number 238 (58.8%) were PKU patients and 167 (41.2 %) their healthy siblings.Biological maturity of newborn infants was evaluated on the basis of physical development parameters (body weight and length), by Apgar score or in cases of its absence by the evaluation of a paediatrician. The above parameters were analysed separately in PKU homozygotes and in their healthy siblings. The latter group was subdivided as far as possible into heterozygotes, and healthy homozygotes.Heterozygotes were identified with previously elaborated methods: Phe/Tyr and Phe2/Tyr scores based on a single determination of phenylalanine and tyrosine in blood serum and/or plasma, or by phenylalanine tolerance tests followed by a discrimatory analaysis of the results achieved (Duczyfiska et al., 1979(Duczyfiska et al., , 1980.Mental development was evaluated with the Brunet-Lezine psychometric test in children up to 3 years, with the Terman-Merrill test between 3 and 7 years and with the Wechsler Intelligence Scale for Children [WISCJ at school age. Attempts were made to separate heterozygotes from healthy homozygotes in these examinations. RESULTSThe total number of pregnancies analysed was 441; an average of 2.2 per mother. Of these, in 393 (89.1%) the course of pregnancy was regular and in 15 (3.4%) pathology of various types was found. In 35 cases (7.5 %) pregnancy was terminated by spontaneous abortion.Out of 441 pregnancies, 403 (91.4 %) were terminated by deliveries of alive and full-term newborns. The number...

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“…Heterozygosity for phenylketonuria does not appear to dispose individuals to a greater frequency of mental retardation (Perry, 1965). Woolf et al, (1975) proposed that female heterozygote carriers of the gene may have enhanced fertility.…”

mentioning

confidence: 99%

The costs and benefits of screening for PKU in Wisconsin

Barden

Kessel

Schuett

1984

Biodemography and Social Biology

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A comprehensive benefit-cost analysis of the screening program to detect newborns with PKU in Wisconsin is presented. Classic PKU is a genetic disorder which, if undetected and untreated during the first few weeks of life, generally results in mental retardation and a variety of other abnormal conditions. Monetary costs of the detection and treatment program were compared with the projected benefits (avoided costs) that result from the prevention of the mental retardation associated with the disorder. Future costs and benefits were determined using a 4 per cent, 7 per cent, and 10 per cent rate of discount. Net benefits (benefits-costs) for detecting and treating one individual with PKU were $208,000 ($292,000-$84,000) using the 7 per cent rate of discount. Net benefits for detecting four individuals with PKU per year in Wisconsin totaled $832,000, a large rate of return on a relatively small investment. The issue of the potential economic implications of maternal PKU is briefly discussed.

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Phenylketonuria as a balanced polymorphism: the nature of the heterozygote advantage

Cited by 38 publications

References 20 publications

A role for overdominant selection in phenylketonuria? Evidence from molecular data

A role for overdominant selection in phenylketonuria? Evidence from molecular data

Influence of the phenylketonuric heterozygote on the developing fetus

The costs and benefits of screening for PKU in Wisconsin

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