Biol. Neonate 26: 102-108 (1975)
Serum Amino Acid Concentrations during Pregnancy of Women Heterozygous for Phenylketonuria1 H elen K. Berry, I nna B.P oncet, Betty S. Sutherland and R obert Burkett Children’s Hospital Research Foundation Institute for Developmental Research and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
Key Words. Phenylketonuria • Heterozygote • Pregnancy ■Serum phenylalanine Abstract. Increased concentrations of phenylalanine were found in blood specimens from pregnant women who were heterozygous for phenylketonuria, but the concentration differences between normal controls, nonpregnant heterozygous, and pregnant hetero zygous, and pregnant heterozygous women were small. Phenylalanine concentrations in cord blood were in the same range as in maternal blood at time of delivery. Phenylalanine concentrations in the carrier do not rise sufficiently during pregnancy to harm the infant in utero.
K ang and P aine [6] reported higher levels of phenylalanine in blood of
pregnant heterozygous mothers of phenylketonuric children than in normal pregnant controls or nonpregnant heterozygotes. Recently we had the opportunity to follow serum amino acid levels in a pregnant heterozygous mother during the last trimester of pregnancy. Three additional mothers were studied for shorter periods or at delivery; one of these had two preg nancies. We report here the results of analyses of serum amino acids in four women heterozygous for phenylketonuria during five pregnancies.
Methods
1 This work was supported in part by grants HD00324, HD05221, and HD06018 from the National Institutes of Health and Project Grant 427, Maternal and Child Health Services, Health Services and Mental Health Administration.
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The women ranged in age from 24 to 42 years. Each had one or more children with classic phenylketonuria (serum phenylalanine concentration over 30 mg/100 ml). One
Berry/P oncet/S utherland/B urkett
103
mother had two pregnancies approximately a year apart. Duration of pregnancy was approximately 39 weeks in all instances. Deliveries were normal and uncomplicated. Blood from mother G was obtained at intervals from the 26th week of pregnancy. Blood was drawn approximately 3-4 h after a meal. The last specimen was obtained immediately before delivery. Blood was obtained from mother C 1 month prior to delivery, at time of delivery, and 6 months postpartum. Specimens were obtained from mothers B and F at time of delivery only. Cord blood was obtained from all five infants. None of the infants had phenylketonuria as shown by subsequent testing. Scrum was deproteinized with an equal volume of 20% sulfosalicylic acid. Supernatants were stored overnight in the cold to remove traces of protein. All analyses were carried cut on a Beckman Spinco Model 120C Amino Acid Analyzer. Some specimens were too small for complete analyses and determinations were made of amino acids on the long column only.
Results of amino acid analyses from mothers G and C and their infants are shown in table I. In mother G concentration of phenylalanine ranged from a low value of 0.042 pmol/ml at 26 weeks to a high of 0.145 ¡zmol/ml 3 weeks prior to delivery. During this period, total amino acids increased to a peak at 36 weeks gestation and declined between 36 and 39 weeks. The increase in phenylalanine was relative as well as absolute. Phenylalanine concentration as percent of total amino acids increased from 2.2 to 3.4% from 26 to 36 weeks and declined to 2.4% by time of delivery. Normally phenylalanine accounts for about 2.0% of total free amino acids in serum. There was an overall increase in other essential amino acids but their con centration in relation to the total remained relatively constant. For example, leucine accounted for 3.5% of total amino acids at 26 weeks, for 3.8% at 36 weeks; threonine accounted for 8.0% of total amino acids at 26 weeks, 7,9% at 36 weeks. Tyrosine concentration and phenylalanine/tyrosine ratios (P/T) were variable, ranging from 0.033 pmol/ml and a P/T of 1.3 at 26 weeks to 0.096 ¡jtmol/ml and P/T of 1.5 at 36 weeks. Amino acid levels in serum from mother C taken approximately 4 weeks prior to delivery were low, and the aminoacidemia noted in mother G at the same stage of pregnancy was not seen. Phenylalanine accounted for 3.5% of total amino acids, similar to mother G at a comparable time. Serum amino acids remained low in the specimen from mother C at delivery and were even lower in a specimen obtained 6 months postpartum. Specimens obtained from mother B at the time of deliveries approximately a year apart showed remarkably similar concentrations of amino acids. There was a generalized elevation of amino acids including phenylalanine in both
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Results and Discussion
104
B erry/P oncet/S utherland/B urkett
Table la. Serum amino acids in mother G and baby at different weeks of gestation, (¿mol/ml Mother G Baby G 26 30 32 35 36 38 39 39 cord age, 10 weeks weeks weeks weeks weeks weeks weeks weeks blood days (delivery) 1-14 2-11 2-25 3-18 3-25 4-8 4-15 4-16 4-16 0.233 0.013 0.062 0.017 0.028 0.031 0.031 0.415 0.112 0.068 0.040 0.073 0.124 0.013 0.040 0.042 0.067 0.100 0.149 0.037 0.033 0.142
0.445 0.018 0.050 0.038 0.038 0.017 0.084 0.434 0.192 0.106 0.047 0.074 0.148 0.020 0.077 0.060 0.101 0.146 0.238 0.068 0.041 0.150
0.493 0.023 0.101 0.020 0.078 0.028 0.099 0.518 0.309 0.140 0.063 0.104 0.390 0.033 0.147 0.086 0.134 0.211 0.345 0.108 0.060 0.228
Total
1.868 3.051 3.637 3.525 4.321 3.162 3.117 2.588
3.718
0.503 0.013 0.092 0.031 0.026 0.020 0.082 0.543 0.216 0.080 0.059 0.115 0.147 0.028 0.053 0.084 0.180 0.196 0.255 0.043 0.068 0.219
0.535 0.021 0.073 0.071 0.041 0.040 0.113 0.571 0.230 0.133 0.084 0.159 0.211 0.031 0.090 0.108 0.174 0.210 0.296 0.068 0.092 0.289
0.554 0.018 0.046 0.063 0.046 0.018 0.274 0.481 0.282 0.109 0.064 0.125 0.176 0.029 0.122 0.113 0.159 0.203 0.267 0.027 0.063 0.237
0.623 0.022 0.054 0.092 0.041 0.030 0.254 0.539 0.314 0.154 0.078 0.166 0.268 0.040 0.184 0.140 0.230 0.253 0.341 0.080 0.096 0.322
0.422 0.020 0.045 0.076 0.032 0.026 0.279 0.414 0.262 0.132 0.066 0.141 0.160 0.023 0.125 0.096 0.137 0.225 0.232 0.037 0.053 0.203
0.417 0.016 0.035 0.077 0.033 0.021 0.228 0.393 0.233 0.113 0.065 0.130 0.170 0.021 0.154 0.088 0.161 0.210 0.244 0.050 0.064 0.194
Alanine a-Aminobutyric Arginine Aspartic Citrulline Cystine Glutamic Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Ornithine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine
0.515 * 0.017 0.481 0.238 0.465 * 0.056 0.124 ★ 0.016 * 0.064 0.248 0.396 0.143 * 0.069 0.186
specimens. Amino acids in serum from mother F at time of delivery were normal except for a mild elevation of phenylalanine. Mean values for serum amino acids in mothers’ bloods at delivery and in cord bloods from their infants are summarized in table II. Concentrations of lysine, ornithine, and tryptophan were higher in cord blood than maternal blood with cord: maternal (C/M) ratios of 2.3-1.7. Methionine, proline, threonine, glycine, and tyrosine showed slightly higher concentrations in cord blood than in maternal blood with C/M values of 1.3-1.4. Other amino
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—= Below minimum amount detectable; *= n o t determined.
Serum Amino Acids in Pregnant PKU Carriers
105
Table lb. Serum amino acid in mother C and baby G at different weeks of gestation, (xmol/ml Mother C 35 weeks
Baby C 39 weeks (delivery)
6 months postpartum
cord blood
Age, 4 weeks
0.551 -
Alanine a-Aminobutyric Arginine Aspartic Citrulline Glutamic Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Ornithine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine
0.341 0.012 0.090 0.014 0.059 0.220 0.117 0.048 0.049 0.086 0.207
0.286 *
0.217 0.008 *
*
0.275 *
0.090 0.153 0.139 0.204
0.026 0.066 0.342 0.231
*
*
0.052 0.189 0.115 0.366 *
0.029 0.018 0.123 0.252 0.180 *
0.029 0.077 *
0.028 0.050 *
0.044 0.077 *
0.084 0.147 *
0.011
0.008 *
0.006 *
0.010 *
0.025
0.057 0.175 0.142 0.106 *
0.046 0.109 0.117 0.087 *
0.081 0.243 0.179 0.148 ♦
0.075 0.149 0.169
0.028 0.110
0.032 0.103
0.041 0.124
0.092 0.246
Total
1.997
0.040 0.069 0.114 0.128 0.134 0.029 0.035 0.136
0.111
*
acids, including phenylalanine, were approximately the same or only slightly higher in cord blood than in maternal blood with C/M values of 1.0-1.2. A rm str o n g and Y ates [1] reported plasma amino acid levels of a normal woman from the 8th to 40th week of pregnancy and postpartum. There was relatively little change in most amino acids through the period; values were slightly higher from 28 to 40 weeks than at 8 to 20 weeks. Values obtained 19 weeks after delivery were in the same ranges as during the later part of the pregnancy. During pregnancy phenylalanine concentration increased from 0.062 at 8 weeks to 0.073 fxmol/ml at delivery while tyrosine concen tration decreased from 0.057 ¡xmol/ml at 8 weeks to 0.040 at delivery, and P/T ratio increased from 1.1 to 1.8.
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- = Below minimum amount detectable; * = not determined.
106
B erry/P oncet/S utherland/B urkett
Alanine a-Aminobutyric Arginine Aspartic Citrullinc Glutamic Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Ornithine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine
Mothers
Cord blood
Cord: maternal
0.528 0.015 0.099 0.088 0.031 0.089 0.470 0.386 0.119 0.059 0.124 0.193 0.024 0.097 0.107 0.191 0.225 0.204 0.055 0.054 0.182
0.611 0.016 0.092 0.049 0.037 0.098 0.513 0.430 0.138 0.061 0.112 0.442 0.033 0.195 0.105 0.233 0.221 0.259 0.093 0.065 0.203
1.2 1.2 1.1 0.6 1.1 1.1 1.1 1.3 1.2 1.1 1.0 2.3 1.4 2.0 1.1 1.3 1.1 1.3 1.7 1.3 1.1
Our mean values for maternal amino acids are higher than those reported by L indblad and Baldestin [7] and G hadimi and P ecora [3] and, with exception of phenylalanine, are in the range of nonpregnant controls. The decreasing concentration of plasma amino acids reported by these authors to take place during pregnancy was not seen either in our patient followed through the last trimester, nor in Armstrong’s subject [1]. Only one of the four mothers studied had serum amino acids below normal during pregnancy and delivery; this trend continued following pregnancy and levels at 6 months were lower than during pregnancy or at delivery in this individual. As a consequence of normal maternal amino acid concentrations in all but one mother, C/M ratios are lower than reported by other workers and show little evidence of concentration of phenylalanine by the infant. In table III are compared our data on concentrations of phenylalanine and tyrosine in cord blood of infants of mothers heterozygous for phenyl-
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Table II. Mean values for serum amino acids in maternal blood at delivery and infant cord blood
Serum Amino Acids in Pregnant PKU Carriers
107
Table III. Phenylalanine and tyrosine concentrations in cord blood of infants of women heterozygous for phenylketonuria and normal full-term infants, ¡¿mol/ml
n=5
L indblad and Baldestin [7] n = 10
G hadimi and Pécora [3, 4] n=8
0.105 0.065
0.067 0.061
0.056 0.064
This paper
Phenylalanine Tyrosine
Tyrosine concentrations are similar in all three groups, 0.061-0.065 [xmol/ml. Phenylalanine concentrations were higher in infants of women heterozygous for phenylketonuria than in normal infants. However, it should be pointed out that cord blood could not be used to determine carrier status of these infants. Although slightly elevated phenylalanine concentrations were noted in cord bloods, subsequent testing showed changes in both phenylalanine and tyrosine concentrations (table I). G riffin [5] and others reported that concentrations of plasma phenyl alanine and tyrosine in pregnant controls during the 8th to 21st weeks of gestation were lower than in nonpregnant controls. Pregnancy did not alter the fasting plasma phenylalanine level in normal controls in the study by K ang and P aine [6]. We do not report data on normal pregnant controls, but our values for pregnant heterozygous women are slightly increased compared to nonpregnant heterozygous women [2]. The increased concen tration noted here is substantially less than observed by K ang and P aine [6] and the differences between normal and heterozygous women are too small to be revealed except by highly sensitive procedures such as column chroma tography. One of our patients had a normal serum phenylalanine value at time of delivery, although it might be considered elevated when compared to the below normal concentrations of other amino acids. We conclude there is a great deal of individual variability in free amino acid concentrations in blood during pregnancy and that the heterozygous carrier could not be detected by routine testing of prenatal sera using usual screening procedures (inhibition assay or fluorimetric measurement of phenylalanine). Further, there is no evidence that phenylalanine levels in the heterozygous carrier might rise during pregnancy sufficiently to harm the infant in utero.
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ketonuria with values found by L indblad and Baldestin [7] and by G hadimi and P ecora [4] in cord blood from normal full-term infants.
108
Berry/P oncet/S utherland/B urkett
References 1 A rmstrong, M .D . and Y ates, K .N .: Amino acid excretions during pregnancy. Amer.
J. Obstet. Gynec. 88: 382-390 (1964). 2 Berry, H .K .; S utherland , B.S., and Poncet, I.: Phenylalanine concentrations in male and female phenylketonuric heterozygotes compared to normal and malnourished subjects. Unpublished data. 3 G hadimi, H. and P ecora, P .: Free amino acids of cord plasma as compared with maternal plasma during pregnancy. Pediatrics 33: 500-506 (1964). 4 G hadimi, H. and P ecora, P.: Plasma amino acids after birth. Pediatrics 34: 182-191 (1964). 5 G riffin , R .F .; H umienny, M .E .; H all, E .C., and E lsas, L .J.: Classic phenyl ketonuria: heterozygote detection during pregnancy. Amer. J. hum. Genet. 25: 646-654(1973).
H elen K. Berry, Division of Inborn Errors of Metabolism, Children’s Hospital Research Foundation, Elland and Bethesda Avenue, Cincinnati, OH 45229 (USA)
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6 K ang , E. and P aine, R. S.: Elevation of plasma phenylalanine levels during pregnancies of women heterozygous for phenylketonuria. J. Pediat. 63: 283-289 (1963). 7 L indblad, E.S. and Baldestin, A.: The normal venous plasma free amino acid levels of non-pregnant women and of mother and child during delivery. Acta pediat. scand. 56: 37-48 (1967).
Serum Amino Acid Concentrations during Pregnancy of Women Heterozygous for Phenylketonuria1 H elen K. Berry, I nna B.P oncet, Betty S. Sutherland and R obert Burkett Children’s Hospital Research Foundation Institute for Developmental Research and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
Key Words. Phenylketonuria • Heterozygote • Pregnancy ■Serum phenylalanine Abstract. Increased concentrations of phenylalanine were found in blood specimens from pregnant women who were heterozygous for phenylketonuria, but the concentration differences between normal controls, nonpregnant heterozygous, and pregnant hetero zygous, and pregnant heterozygous women were small. Phenylalanine concentrations in cord blood were in the same range as in maternal blood at time of delivery. Phenylalanine concentrations in the carrier do not rise sufficiently during pregnancy to harm the infant in utero.
K ang and P aine [6] reported higher levels of phenylalanine in blood of
pregnant heterozygous mothers of phenylketonuric children than in normal pregnant controls or nonpregnant heterozygotes. Recently we had the opportunity to follow serum amino acid levels in a pregnant heterozygous mother during the last trimester of pregnancy. Three additional mothers were studied for shorter periods or at delivery; one of these had two preg nancies. We report here the results of analyses of serum amino acids in four women heterozygous for phenylketonuria during five pregnancies.
Methods
1 This work was supported in part by grants HD00324, HD05221, and HD06018 from the National Institutes of Health and Project Grant 427, Maternal and Child Health Services, Health Services and Mental Health Administration.
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The women ranged in age from 24 to 42 years. Each had one or more children with classic phenylketonuria (serum phenylalanine concentration over 30 mg/100 ml). One
Berry/P oncet/S utherland/B urkett
103
mother had two pregnancies approximately a year apart. Duration of pregnancy was approximately 39 weeks in all instances. Deliveries were normal and uncomplicated. Blood from mother G was obtained at intervals from the 26th week of pregnancy. Blood was drawn approximately 3-4 h after a meal. The last specimen was obtained immediately before delivery. Blood was obtained from mother C 1 month prior to delivery, at time of delivery, and 6 months postpartum. Specimens were obtained from mothers B and F at time of delivery only. Cord blood was obtained from all five infants. None of the infants had phenylketonuria as shown by subsequent testing. Scrum was deproteinized with an equal volume of 20% sulfosalicylic acid. Supernatants were stored overnight in the cold to remove traces of protein. All analyses were carried cut on a Beckman Spinco Model 120C Amino Acid Analyzer. Some specimens were too small for complete analyses and determinations were made of amino acids on the long column only.
Results of amino acid analyses from mothers G and C and their infants are shown in table I. In mother G concentration of phenylalanine ranged from a low value of 0.042 pmol/ml at 26 weeks to a high of 0.145 ¡zmol/ml 3 weeks prior to delivery. During this period, total amino acids increased to a peak at 36 weeks gestation and declined between 36 and 39 weeks. The increase in phenylalanine was relative as well as absolute. Phenylalanine concentration as percent of total amino acids increased from 2.2 to 3.4% from 26 to 36 weeks and declined to 2.4% by time of delivery. Normally phenylalanine accounts for about 2.0% of total free amino acids in serum. There was an overall increase in other essential amino acids but their con centration in relation to the total remained relatively constant. For example, leucine accounted for 3.5% of total amino acids at 26 weeks, for 3.8% at 36 weeks; threonine accounted for 8.0% of total amino acids at 26 weeks, 7,9% at 36 weeks. Tyrosine concentration and phenylalanine/tyrosine ratios (P/T) were variable, ranging from 0.033 pmol/ml and a P/T of 1.3 at 26 weeks to 0.096 ¡jtmol/ml and P/T of 1.5 at 36 weeks. Amino acid levels in serum from mother C taken approximately 4 weeks prior to delivery were low, and the aminoacidemia noted in mother G at the same stage of pregnancy was not seen. Phenylalanine accounted for 3.5% of total amino acids, similar to mother G at a comparable time. Serum amino acids remained low in the specimen from mother C at delivery and were even lower in a specimen obtained 6 months postpartum. Specimens obtained from mother B at the time of deliveries approximately a year apart showed remarkably similar concentrations of amino acids. There was a generalized elevation of amino acids including phenylalanine in both
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Results and Discussion
104
B erry/P oncet/S utherland/B urkett
Table la. Serum amino acids in mother G and baby at different weeks of gestation, (¿mol/ml Mother G Baby G 26 30 32 35 36 38 39 39 cord age, 10 weeks weeks weeks weeks weeks weeks weeks weeks blood days (delivery) 1-14 2-11 2-25 3-18 3-25 4-8 4-15 4-16 4-16 0.233 0.013 0.062 0.017 0.028 0.031 0.031 0.415 0.112 0.068 0.040 0.073 0.124 0.013 0.040 0.042 0.067 0.100 0.149 0.037 0.033 0.142
0.445 0.018 0.050 0.038 0.038 0.017 0.084 0.434 0.192 0.106 0.047 0.074 0.148 0.020 0.077 0.060 0.101 0.146 0.238 0.068 0.041 0.150
0.493 0.023 0.101 0.020 0.078 0.028 0.099 0.518 0.309 0.140 0.063 0.104 0.390 0.033 0.147 0.086 0.134 0.211 0.345 0.108 0.060 0.228
Total
1.868 3.051 3.637 3.525 4.321 3.162 3.117 2.588
3.718
0.503 0.013 0.092 0.031 0.026 0.020 0.082 0.543 0.216 0.080 0.059 0.115 0.147 0.028 0.053 0.084 0.180 0.196 0.255 0.043 0.068 0.219
0.535 0.021 0.073 0.071 0.041 0.040 0.113 0.571 0.230 0.133 0.084 0.159 0.211 0.031 0.090 0.108 0.174 0.210 0.296 0.068 0.092 0.289
0.554 0.018 0.046 0.063 0.046 0.018 0.274 0.481 0.282 0.109 0.064 0.125 0.176 0.029 0.122 0.113 0.159 0.203 0.267 0.027 0.063 0.237
0.623 0.022 0.054 0.092 0.041 0.030 0.254 0.539 0.314 0.154 0.078 0.166 0.268 0.040 0.184 0.140 0.230 0.253 0.341 0.080 0.096 0.322
0.422 0.020 0.045 0.076 0.032 0.026 0.279 0.414 0.262 0.132 0.066 0.141 0.160 0.023 0.125 0.096 0.137 0.225 0.232 0.037 0.053 0.203
0.417 0.016 0.035 0.077 0.033 0.021 0.228 0.393 0.233 0.113 0.065 0.130 0.170 0.021 0.154 0.088 0.161 0.210 0.244 0.050 0.064 0.194
Alanine a-Aminobutyric Arginine Aspartic Citrulline Cystine Glutamic Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Ornithine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine
0.515 * 0.017 0.481 0.238 0.465 * 0.056 0.124 ★ 0.016 * 0.064 0.248 0.396 0.143 * 0.069 0.186
specimens. Amino acids in serum from mother F at time of delivery were normal except for a mild elevation of phenylalanine. Mean values for serum amino acids in mothers’ bloods at delivery and in cord bloods from their infants are summarized in table II. Concentrations of lysine, ornithine, and tryptophan were higher in cord blood than maternal blood with cord: maternal (C/M) ratios of 2.3-1.7. Methionine, proline, threonine, glycine, and tyrosine showed slightly higher concentrations in cord blood than in maternal blood with C/M values of 1.3-1.4. Other amino
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—= Below minimum amount detectable; *= n o t determined.
Serum Amino Acids in Pregnant PKU Carriers
105
Table lb. Serum amino acid in mother C and baby G at different weeks of gestation, (xmol/ml Mother C 35 weeks
Baby C 39 weeks (delivery)
6 months postpartum
cord blood
Age, 4 weeks
0.551 -
Alanine a-Aminobutyric Arginine Aspartic Citrulline Glutamic Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Ornithine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine
0.341 0.012 0.090 0.014 0.059 0.220 0.117 0.048 0.049 0.086 0.207
0.286 *
0.217 0.008 *
*
0.275 *
0.090 0.153 0.139 0.204
0.026 0.066 0.342 0.231
*
*
0.052 0.189 0.115 0.366 *
0.029 0.018 0.123 0.252 0.180 *
0.029 0.077 *
0.028 0.050 *
0.044 0.077 *
0.084 0.147 *
0.011
0.008 *
0.006 *
0.010 *
0.025
0.057 0.175 0.142 0.106 *
0.046 0.109 0.117 0.087 *
0.081 0.243 0.179 0.148 ♦
0.075 0.149 0.169
0.028 0.110
0.032 0.103
0.041 0.124
0.092 0.246
Total
1.997
0.040 0.069 0.114 0.128 0.134 0.029 0.035 0.136
0.111
*
acids, including phenylalanine, were approximately the same or only slightly higher in cord blood than in maternal blood with C/M values of 1.0-1.2. A rm str o n g and Y ates [1] reported plasma amino acid levels of a normal woman from the 8th to 40th week of pregnancy and postpartum. There was relatively little change in most amino acids through the period; values were slightly higher from 28 to 40 weeks than at 8 to 20 weeks. Values obtained 19 weeks after delivery were in the same ranges as during the later part of the pregnancy. During pregnancy phenylalanine concentration increased from 0.062 at 8 weeks to 0.073 fxmol/ml at delivery while tyrosine concen tration decreased from 0.057 ¡xmol/ml at 8 weeks to 0.040 at delivery, and P/T ratio increased from 1.1 to 1.8.
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- = Below minimum amount detectable; * = not determined.
106
B erry/P oncet/S utherland/B urkett
Alanine a-Aminobutyric Arginine Aspartic Citrullinc Glutamic Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Ornithine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine
Mothers
Cord blood
Cord: maternal
0.528 0.015 0.099 0.088 0.031 0.089 0.470 0.386 0.119 0.059 0.124 0.193 0.024 0.097 0.107 0.191 0.225 0.204 0.055 0.054 0.182
0.611 0.016 0.092 0.049 0.037 0.098 0.513 0.430 0.138 0.061 0.112 0.442 0.033 0.195 0.105 0.233 0.221 0.259 0.093 0.065 0.203
1.2 1.2 1.1 0.6 1.1 1.1 1.1 1.3 1.2 1.1 1.0 2.3 1.4 2.0 1.1 1.3 1.1 1.3 1.7 1.3 1.1
Our mean values for maternal amino acids are higher than those reported by L indblad and Baldestin [7] and G hadimi and P ecora [3] and, with exception of phenylalanine, are in the range of nonpregnant controls. The decreasing concentration of plasma amino acids reported by these authors to take place during pregnancy was not seen either in our patient followed through the last trimester, nor in Armstrong’s subject [1]. Only one of the four mothers studied had serum amino acids below normal during pregnancy and delivery; this trend continued following pregnancy and levels at 6 months were lower than during pregnancy or at delivery in this individual. As a consequence of normal maternal amino acid concentrations in all but one mother, C/M ratios are lower than reported by other workers and show little evidence of concentration of phenylalanine by the infant. In table III are compared our data on concentrations of phenylalanine and tyrosine in cord blood of infants of mothers heterozygous for phenyl-
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Table II. Mean values for serum amino acids in maternal blood at delivery and infant cord blood
Serum Amino Acids in Pregnant PKU Carriers
107
Table III. Phenylalanine and tyrosine concentrations in cord blood of infants of women heterozygous for phenylketonuria and normal full-term infants, ¡¿mol/ml
n=5
L indblad and Baldestin [7] n = 10
G hadimi and Pécora [3, 4] n=8
0.105 0.065
0.067 0.061
0.056 0.064
This paper
Phenylalanine Tyrosine
Tyrosine concentrations are similar in all three groups, 0.061-0.065 [xmol/ml. Phenylalanine concentrations were higher in infants of women heterozygous for phenylketonuria than in normal infants. However, it should be pointed out that cord blood could not be used to determine carrier status of these infants. Although slightly elevated phenylalanine concentrations were noted in cord bloods, subsequent testing showed changes in both phenylalanine and tyrosine concentrations (table I). G riffin [5] and others reported that concentrations of plasma phenyl alanine and tyrosine in pregnant controls during the 8th to 21st weeks of gestation were lower than in nonpregnant controls. Pregnancy did not alter the fasting plasma phenylalanine level in normal controls in the study by K ang and P aine [6]. We do not report data on normal pregnant controls, but our values for pregnant heterozygous women are slightly increased compared to nonpregnant heterozygous women [2]. The increased concen tration noted here is substantially less than observed by K ang and P aine [6] and the differences between normal and heterozygous women are too small to be revealed except by highly sensitive procedures such as column chroma tography. One of our patients had a normal serum phenylalanine value at time of delivery, although it might be considered elevated when compared to the below normal concentrations of other amino acids. We conclude there is a great deal of individual variability in free amino acid concentrations in blood during pregnancy and that the heterozygous carrier could not be detected by routine testing of prenatal sera using usual screening procedures (inhibition assay or fluorimetric measurement of phenylalanine). Further, there is no evidence that phenylalanine levels in the heterozygous carrier might rise during pregnancy sufficiently to harm the infant in utero.
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ketonuria with values found by L indblad and Baldestin [7] and by G hadimi and P ecora [4] in cord blood from normal full-term infants.
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Berry/P oncet/S utherland/B urkett
References 1 A rmstrong, M .D . and Y ates, K .N .: Amino acid excretions during pregnancy. Amer.
J. Obstet. Gynec. 88: 382-390 (1964). 2 Berry, H .K .; S utherland , B.S., and Poncet, I.: Phenylalanine concentrations in male and female phenylketonuric heterozygotes compared to normal and malnourished subjects. Unpublished data. 3 G hadimi, H. and P ecora, P .: Free amino acids of cord plasma as compared with maternal plasma during pregnancy. Pediatrics 33: 500-506 (1964). 4 G hadimi, H. and P ecora, P.: Plasma amino acids after birth. Pediatrics 34: 182-191 (1964). 5 G riffin , R .F .; H umienny, M .E .; H all, E .C., and E lsas, L .J.: Classic phenyl ketonuria: heterozygote detection during pregnancy. Amer. J. hum. Genet. 25: 646-654(1973).
H elen K. Berry, Division of Inborn Errors of Metabolism, Children’s Hospital Research Foundation, Elland and Bethesda Avenue, Cincinnati, OH 45229 (USA)
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6 K ang , E. and P aine, R. S.: Elevation of plasma phenylalanine levels during pregnancies of women heterozygous for phenylketonuria. J. Pediat. 63: 283-289 (1963). 7 L indblad, E.S. and Baldestin, A.: The normal venous plasma free amino acid levels of non-pregnant women and of mother and child during delivery. Acta pediat. scand. 56: 37-48 (1967).
