Detection by Phenylalanine Tolerance Tests of Heterozygous Carriers of Phenylketonuria

Kw, Driscoll; Dy, Hsia; We, Knox; Troll, Walter

doi:10.1038/1781239a0

Cited by 133 publications

(27 citation statements)

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“…Extensive family studies (10,11) have shown that this disease is inherited as an autosomal recessive trait with complete penetrance. Hence the parents must be heterozygous carriers and might be expected to show some abnormality by analogy with the situation in phenylketonuria (30). This has in fact proved to be the case.…”

Section: Resultsmentioning

confidence: 99%

Studies of Red-Cell Stromal Lipids in Tay-Sachs Disease and Other Lipidoses*

Balint¹,

Spitzer²,

Kyriakides³

1963

J. Clin. Invest.

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Section: Resultsmentioning

confidence: 99%

Studies of Red-Cell Stromal Lipids in Tay-Sachs Disease and Other Lipidoses*

Balint¹,

Spitzer²,

Kyriakides³

1963

J. Clin. Invest.

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“…This method, for example, can readily distinguish between normal subjects and obligate heterozygotes (i.e., parents of PKU patients) presumed to have 50% or less of the normal level of enzyme (8)(9)(10).…”

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confidence: 99%

A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients

Kaufman

1999

Proc. Natl. Acad. Sci. U.S.A.

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The derivation of a quantitative model of phenylalanine metabolism in humans is described. The model is based on the kinetic properties of pure recombinant human phenylalanine hydroxylase and on estimates of the in vivo rates of phenylalanine transamination and protein degradation. Calculated values for the steady-state concentration of blood phenylalanine, rate of clearance of phenylalanine from the blood after an oral load of the amino acid, and dietary tolerance of phenylalanine all agree well with data from normal as well as from phenylketonuric patients and obligate heterozygotes. These calculated values may help in the decision about the degree of restriction of phenylalanine intake that is necessary to achieve a satisfactory clinical outcome in classical patients and in those with milder forms of the disease.The initial and rate-limiting step in the complete catabolism of phenylalanine to CO 2 and water is its hydroxylation to tyrosine, a reaction catalyzed by the phenylalanine hydroxylating system. The system is complex, consisting of phenylalanine hydroxylase (PAH), the pterin coenzyme tetrahydrobiopterin (BH 4 ), and several enzymes that serve to regenerate BH 4 , i.e., dihydropteridine reductase and pterin 4␣-carbinolamine dehydratase (1, 2).Although the benzene ring of phenylalanine cannot be ruptured without first being hydroxylated in the para position, the alanine side-chain of the amino acid can be metabolized even in the absence of the ring-hydroxylation step. This alternate pathway is initiated by transamination of phenylalanine to phenylpyruvate followed by conversion of the latter compound to metabolites such as phenyllactate, phenylacetate, and o-hydroxyphenylacetate.

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“…Hsia et al (1956) first demonstrated a decreased ability to metabolise an ! oral load of t-phenylalanine in heterozygotes for PKU.…”

Section: Discriminants Based On Phenylalanine Loadingmentioning

confidence: 99%

“…Hsia et al, 1956;Hsia, 1958;Knox and Messinger, 1958;Wang et al, 1961;Perry et al, 1967;Woolf et al, 1967;Rosenblatt and Scriver, 1968;Rampini et al, 1969;Jackson et al, 1971;Kaariainen and Karlsson, 1973;Griffin and Elsas, 1975). Fasting values of phenylalanine or the ratio of phenylalanine to tyrosine have been compared with the discriminatory power of intravenous or oral phenylalanine loading test.…”

Section: Phenotypic Combination Of Parents Related To the Phenotype Omentioning

confidence: 99%

Different Phenotypes for Phenylalanine Hydroxylase Deficiency

Güttler¹,

Hansen²

1977

Ann Clin Biochem

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Abnormalities related to the hydroxylation of phenylalanine to tyrosine are classified into three phenotypes based on the amount of dietary phenylalanine tolerated to keep serum phenylalanine within therapeutic levels,i.e., 180-425p.mol/l (3-7 mg/IOO ml): (I) Classical phenylketonuria (PKU) tolerating approximately 17% of a normal intake of phenylalanine or approximately 0.12 mmol per kg body weight; (2) mild PKU with a tolerance some 50% higher; and (3) persistent hyperphenylalaninaemia(HPA) with serum phenylalanine valueswithin therapeutic levelson a daily intake of ;;'0.7 mmol phenylalanine per kg body weight.Oral phenylalanine loading was performed on 100 heterozygotes for these abnormalities and 33 normal homozygotes. The slope of the rise in serum tyrosine multiplied by the maximum serum tyrosine concentration over the maximum phenylalanine concentration was the most powerful discriminant (Dis, 3.54; overlapping 2.4%). Three heterozygous phenotypes were distinguished by this discriminant, and a significant correlation was observed between the phenotypic combination of the parents and the phenotype of their affected child. In particular, parents of children with classical PKU were clearly distinguished from heterozygotes for the other two abnormalities.Abnormalities related to the hydroxylation of phenylalanine to tyrosine may be classified into at least three forms (Scriver, 1967;Cohen, 1973): (I) Classical phenylketonuria (PKU); (2) Variant hyperphenylalaninaemias, a mixed group including "mild" and "transient" PKU, where the decision and classification soon after birth may be difficult (Hsia, 1970;Blaskovics et al., 1974;Rosenberg and Scriver, 1974); (3) Persistent hyperphenylalaninaemia (HPA). The three forms of abnormalities have in common that a loading dose of phenylalanine fails to produce a significant rise in serum tyrosine (Guttler and Warn berg, 1972).Several investigations have established that early detection and treatment of infants with elevated blood phenylalanine is beneficial to intellectual development if the child suffers from PKU (cf. Wamberg, 1973;Rosenberg and Scriver, 1974). Early treatment implies, however, that classical clinical features will not be observed. Thus, the correct diagnosis must be based on other criteria. The present investigation shows that children with PKU may be classified into two forms according to their dietary tolerance of phenylalanine: (I) Classical PKU, tolerating approximately 17% of a normal dietary intake of phenylalanine, and (2) mild PKU, tolerating an intake of phenylalanine 50 % larger than that of the classical form. The course of serum phenylalanine after a phenylalanine loading test dose also differs in these two forms. The various forms of PKU may be distinguished from HPA, the latter condition being defined as showing (a) serum phenylalanine within generally accepted therapeutic levels, i.e., 180-425 fLmol/1 (3-7 mg/IOO ml) on a normal dietary intake of phenylalanine (Guttier and Correspondence to Dr. F. Guttier. John F. Kennedy Institute. G...

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Detection by Phenylalanine Tolerance Tests of Heterozygous Carriers of Phenylketonuria

Cited by 133 publications

References 1 publication

Studies of Red-Cell Stromal Lipids in Tay-Sachs Disease and Other Lipidoses*

Studies of Red-Cell Stromal Lipids in Tay-Sachs Disease and Other Lipidoses*

A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients

Different Phenotypes for Phenylalanine Hydroxylase Deficiency

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