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Journal of the American College of Nutrition, Vol. 18, No. 2, 102-107 (1999)
Published by the American College of Nutrition

Protein Status of Infants with Phenylketonuria Undergoing Nutrition Management

P.B. Acosta, Dr PH1, S. Yannicelli, MMSc1, B. Marriage, MS, RD2, R. Steiner, MD3, B. Gaffield, MS, RD4, G. Arnold, MD5, V. Lewis, PhD, RD6, S. Cho, MD7, L. Berstein, MS, RD8, P. Parton, MD9, N. Leslie, MD10 and M. Korson, MD11

Medical Department, Ross Products Division/Abbott Laboratories, Columbus, Ohio (P.B.A., S.Y.)
Edmonton Genetics Clinic, University of Alberta Hospital, Edmonton, Alberta, Canada (B.M.)
Department of Pediatrics, Children’s Hospital, St. Louis, Missouri (R.S.)
Child Development Center, Children’s Hospital Medical Center, Oakland, California (B.G.)
Department of Pediatrics, Arkansas Children’s Hospital, Little Rock, Arkansas (G.A.)
Department of Pediatrics, Tulane University, New Orleans, Louisiana (V.L.)
Genetic Service, HCA Wesley Medical Center, Wichita, Kansas (S.C.)
Department of Pediatrics, The Children’s Hospital, Denver, Colorado (L.B.)
Department of Pediatrics, Stonybrook Medical Center, Stonybrook, New York (P.P.)
Department of Pediatrics, Children’s Hospital, Cincinnati, Ohio (N.L.)
Children’s Hospital, Boston, Massachusetts (M.K)

Address reprint requests to: P.B. Acosta, Dr PH, Medical Department, Ross Products Division, Abbott Laboratories, 625 Cleveland Ave., Columbus, OH 43215-1724


   ABSTRACT
TOP
 FOOTNOTES
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 CONCLUSIONS
 REFERENCES
 
Objectives: The objectives of this study were to determine if Phenex-1, amino-acid modified medical food with iron maintained normal indices of protein status in infants with phenylketonuria (PKU) and to investigate factors that influence plasma amino acid concentrations.

Methods: A study was conducted for six months in 35 infants with classical PKU diagnosed in the neonatal period. Diet diaries and plasma amino acid concentrations were obtained monthly. Blood for analysis of plasma albumin, blood urea nitrogen (BUN), retinol binding protein (RBP) and transthyretin was obtained at one, three and six months of study.

Results: Mean (±SEM) total daily intake of medical food and nutrients was 79 ± 4 g; 17.3 ± 0.6 g protein, 660 ± 18 kcal, 255 ± 10 mg phenylalanine (Phe), and 1423 ± 56 mg tyrosine (Tyr). Mean concentrations of plasma amino acids, except cystine (during entire study), glycine (first month) and Phe were in the normal range. Mean concentrations of plasma Phe were in the treatment range (120 to 360 µmol/L). Plasma concentrations of arginine, methionine, Phe, tryptophan, Tyr, and valine were positively correlated with intakes at various months of study. Concentrations of aspartic and glutamic acids, Phe, and Tyr were positively correlated and 17 amino acids were negatively correlated with the interval between feeding and blood draw. At six months of study, concentration of plasma albumin was 4.1 ± 0.1 g/dL, RBP was 3.74 ± 0.2 mg/dL, transthyretin was 17.9 ± 0.9 mg/dL, and urea nitrogen was 11.9 ± 0.5 mg/dL.

Conclusion: During study, all mean plasma indices of protein status were in normal reference ranges. Phenex-1 supports normal mean plasma amino acid, albumin, RBP, transthyretin, and BUN concentrations when fed in adequate amounts.

Key words: nutrient intake, phenylketonuria, plasma amino acids, albumin, retinol binding protein, transthyretin


   INTRODUCTION
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 CONCLUSIONS
 REFERENCES
 
PKU is an inherited disorder of Phe metabolism characterized by an inability to normally metabolize Phe to Tyr. Without restriction of dietary Phe intake, Phe and its metabolites accumulate in blood and tissues and Tyr becomes deficient. These metabolic changes result in mental retardation, seizures and hyperactivity. Therapy consists of restricting dietary Phe to an amount that results in near normal plasma Phe concentration. Tyr is supplemented in an effort to maintain normal plasma Tyr concentration. Nutrition management is accomplished through use of Phe-free elemental medical foods combined with intact protein to supply prescribed Phe.

Phe-free sources of protein are essential to the management of patients with PKU. However, L-amino acids, which are the source of approximately 75% of the dietary protein equivalent consumed by these patients [1], have not been adequately studied in infants to determine their efficacy in supporting protein status. Hanley et al. [2] reported hypoproteinemia in five of 32 infants treated with Lofenalac (Mead Johnson Nutritionals, Evansville, Indiana), a casein hydrolysate. Many of the infants were not evaluated for protein status. Shenton et al. [3] reported that serum transthyretin (prealbumin) concentrations in 20 treated children with PKU, aged two to nine, were lower than in children from a normal group. Transthyretin concentrations have been reported in only a very small number of infants with PKU [4].

Plasma albumin concentrations fall only after significant protein depletion has occurred. RBP and transthyretin (half-lives of about twelve hours and two days, respectively) are sensitive indicators of visceral protein status and indicate possible problems in protein status long before plasma albumin concentration does [5]. The dearth of reported studies on the adequacy of L-amino acid mixtures to support indices of protein status in infants with PKU warranted evaluation of PhenexTM-1, an amino acid modified medical food with iron (Ross Products Division, Columbus, Ohio).

Phenex-1 is formulated from synthetic L-amino acids, carbohydrate, fat, minerals and vitamins. The amino acid profile, except for deleted Phe and increased Tyr, is based on a composite of human milk and whole chicken egg. The purposes of this report are to describe protein status of infants with PKU-fed Phenex-1 and to describe some factors that influenced plasma amino acid concentrations.


   MATERIALS AND METHODS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 CONCLUSIONS
 REFERENCES
 
Ethical Considerations
The investigators obtained approval of the consent form and the study design from the institutional review boards at the participating medical school clinics and hospitals. Parents of all subjects signed informed consent forms.

Study Design and Subject Selection Criteria
After diagnosis within the first month of life, protein status was evaluated during the ensuing six months in infants with classical PKU who met the following criteria: full-term and appropriate-for-gestational-age and free of major congenital anomalies, cardiac, liver, neurological, renal, or pulmonary disease. Parents agreed to follow the nutrition-support protocol prescribed by the physician/nutritionist team at each study site.

Diet Assessment
Nutrient intakes, based on monthly 3-day diaries of amounts of foods ingested prior to each blood test, were calculated by Amino Acid Analyzer© software (Ross Products Division). Since Phenex-1 contains L-amino acids, total nitrogen content x 6.25 is used to describe its protein content. Mean intakes of medical food, protein, energy and twelve amino acids were used to estimate mean and standard error of the mean (SEM) intakes monthly and overall during the study. The percentages of the 1980 Recommended Dietary Allowances (RDAs) [5] for protein and energy supplied by the diet were determined.

Blood Collection and Analysis
Blood samples were drawn by venipuncture approximately two to four hours after feeding. Plasma was immediately separated from the erythrocytes and stored at -70°C until analysis; amino acids were analyzed at Ross Products Division, Abbott Laboratories by methods previously described [7]. Means (±SEM) and the percentage of amino acid concentrations, except Phe, falling below or above mean values (±SD x 2.13) found for normal infants were calculated [7].

Plasma albumin and BUN concentrations were measured by automated procedures at each clinical site; transthyretin and RBP were analyzed by commercial enzyme immunoassay (Abbott Laboratories, North Chicago, Illinois). Means (±SEM) for the analytes were calculated and compared to reference ranges of 3.0 to 4.6 g/dL for albumin [8], 5 to 17 mg/dL for urea nitrogen [9], 6.7 to 21 mg/dL for transthyretin [10], and 1.0 to 7.6 mg/dL for RBP [10].

The decision was made to compare the data to normal reference data, given the small number of patients born yearly and the even smaller number of centers willing to cooperate in data collection. Many simple correlations were calculated post hoc using Pearson product moment correlations. Only those in which significant correlations (p < 0.05) were found are reported.


   RESULTS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
CONCLUSIONS
 REFERENCES
 
Subjects
Forty-two infants were enrolled, 31 in the in-depth study and 11 in a subgroup for whom only diet records, plasma amino acid concentrations and growth were evaluated. Four infants in the in-depth study and three in the subgroup were protocol failures and were not included in the data analyses. The remaining 35 infants (15 females and 20 males) were born at a mean gestational age of 38.7 (±0.3 SEM) weeks. Thirty-three subjects were Caucasian. Subjects entered the study at 13.7 (±1.9 SEM) days of age. Inadequate blood sample collection resulted in insufficient data for some infants at required times. Normal growth of these patients has been reported [11].

Nutrient Intakes
Table 1 provides mean intakes (±SEM) of protein, energy, essential amino acids, arginine (Arg) and Cys. Seventeen percent of Phenex-fed infants had protein intakes below 100% of 1980 RDA; 80% of infants had energy intakes below 1980 RDA [3]. Mean intake of essential amino acids per kilogram of body weight were greater than recommended. Recommended Phe plus Tyr intake for normal infants is 141 mg/kg [3]. Overall mean (±SEM) Phe intake by infants in this study was 40 ± 1 mg/kg and Tyr intake was 219 ± 9 mg/kg [11].


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  		Table 1. Mean (±SEM) Medical Food, Protein, Energy and Selected Amino Acid Intakes by Infants by Month of Study and Overall During the Study

 
Plasma Amino Acid Concentrations and Protein Status
Mean concentrations of plasma amino acids are given in Table 2. Mean concentrations of all amino acids except Cys, glycine (Gly) and Phe were in the reference ranges. A small percentage of some amino acids were below the lower limit of the reference range. These were Arg (12%), Cys (71%), isoleucine (Ile) (12%), lysine (Lys) (14%) and threonine (Thr) (11%). In the Phenex-fed infants, dietary intakes of Arg (month 3, r = 0.36, p < 0.05), methionine (Met) (month 4, r = 0.43, p < 0.05), Phe (months 1, 2 and 5, r = 0.65, p < 0.01; r = 0.42, p < 0.05; r = 0.33, p < 0.07), tryptophan (Trp) (month 1, r = 0.51, p < 0.05), Tyr (month 4, r = 0.37, p < 0.05) and valine (Val) (month 3, r = 0.51, p < 0.01) were positively correlated with the respective plasma amino acid concentrations. At one or more times during the study, aspartic and glutamic acids, Phe, and Tyr concentrations were positively correlated with the interval between last meal and blood draw. Seventeen amino acid concentrations were negatively correlated with time from the last meal (Table 3).


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  		Table 2. Mean (±SEM) Plasma Amino Acid Concentrations (µmol/L) of Infants by Month of Study and Overall during the Study

 

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  		Table 3. Pearson’s Correlation Coefficients between Hours Postprandial Blood was Drawn and Plasma Amino Acid Concentrations

 
At baseline, one (4%) of the infants in the present study had a plasma albumin concentration <3.0 g/dL (Table 4). During the study, no subject had a plasma albumin concentration <3.0 g/dL. All transthyretin concentrations were within the reference range (6.7 to 21 mg/dL) for infants between birth and five years of age [7,8]. RBP concentrations were all >1.0 mg/dL and within the reference range (1.0 to 7.6 mg/dL) reported for one-to-five-year-old children [8]. During the study, no Phenex-fed infant had a low concentration of urea nitrogen.


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  		Table 4. Mean (±SEM) Indices of Protein Status of Infants by Month of Study and Overall

 

   DISCUSSION
 
Protein and Amino Acid Intakes
Analog-fed infants with PKU who weighed significantly less than infants in the present study [11,12] ingested, on average, 2.3 g/kg protein and 101 kcal/kg during the first six months of life [4], slightly lower than mean intakes of infants in this study. Infants, similar in mean weight to infants in the present study, fed Lofenalac®, ingested significantly more protein and somewhat more energy, 3.6 ± 0.7 g (mean ± SEM) protein/kg and 109 ± 20 kcal/kg [13], than present study infants. Analog-fed infants ingested a mean ± SEM of 34 ± 2 mg Phe and 208 ± 12 mg Tyr per kilogram of body weight per day [4], while Lofenalac-fed infants ingested 48 ± 2 mg/kg of Phe [9], in contrast to 40 ± 1 mg Phe and 219 ± 9 mg Tyr by present study infants [11]. Intakes of all essential amino acids were greater than recommended.

Plasma Amino Acid Concentrations and Protein Status
Plasma Cys concentrations were below the lower limit of the reference range in 71% of Phenex-fed and 94% of Analog-fed infants [4]. Low plasma Cys concentrations occurred in the present study despite intakes of Cys plus Met at more than two times the minimum intake recommended [3]. Binding of Cys in plasma that is not immediately deproteinized has been found in our laboratory and those of other investigators [14].

Plasma Phe concentrations of normal infants range from 19 to 78 µmol/L [7]. Such low concentrations of plasma Phe in patients with PKU result in malnutrition, poor growth and mental retardation [2]. The range of plasma Phe concentration suggested for management of patients with PKU is 120 to 360 µmol/L. Although mean plasma Phe concentrations were within the treatment range in the present study, some 6% of samples had concentrations <120 µmol/L and 37% had concentrations >360 µmol/L. Forty-four infants in the National PKU Collaborative Study [3], for whom the targeted plasma Phe concentration was 60 to 327 µmol/L, had a mean (±SEM) plasma Phe concentration of 326 ± 163 µmol/L during the first six months of life. Substantial difficulty occurred in maintaining plasma Phe concentration in the target range. Analog-fed infants had a mean plasma Phe concentration of 310 ± 81 µmol/L [4]. Inappropriate diet prescription, rapidly changing Phe requirement, illness of the subject or poor parental compliance may each have contributed to plasma Phe concentrations greater than 360 µmol/L.

Buist et al. [15] reported that, except for Gly, all mean fasting plasma amino acid concentrations of children who were fed Periflex® (Scientific Hospital Supplies, Ltd, Gaithersburg, Maryland) or Phenyl-Free® (Mead Johnson Nutritionals, Evansville, Indiana) were lower than those found in normal children. Low mean fasting concentrations of amino acids found by Buist et al. [15] contrast sharply with the normal mean concentrations found for most amino acids in the present study where blood was drawn two to four hours after feeding. Twenty-three percent of plasma Gly concentrations were elevated in infants in the present study, compared to 62% in Analog-fed infants [4]. Analog XP contains 69 mg Gly/g protein and Phenex-1 contains 67 mg Gly/g protein. Several groups of investigators [15–17] found elevated plasma Gly concentrations in patients with PKU who were undergoing therapy. Periflex fed by Buist, et al. [15] contains no Gly. According to Arroyave [18], elevated plasma Gly concentrations are indicative of protein malnutrition. Analog-fed infants ingested significantly less protein per day than Phenex-fed infants [4].

Our data strongly suggest that the timing of blood sampling had a greater effect on most plasma amino acid concentrations than the amounts of L-amino acids fed to infants. The time elapsed between meal and blood draw in the present study ranged from 2.40 to 3.03 hours. According to Gropper, et al. [19] plasma amino acid concentrations in normal adult males peaked at 30 minutes after a meal in which 75% of protein was derived from synthetic L-amino acids and 25% from intact protein, in contrast to the peak found at 150 minutes after a meal of intact protein [19].

Mean daily total Tyr intakes of infants fed Phenex were greater than intakes of infants fed Analog [4]. Analog-fed infants, however, had higher mean plasma Tyr concentrations. Reasons for lower, but normal mean plasma Tyr concentrations in infants fed Phenex are unclear, but may be related to competition between branched chain amino acids and Tyr for the same intestinal transport system [20], better growth by the Phenex-fed infants [11,12] and the time after feeding blood was drawn [19]. Van Spronsen et al. [21] reported large fluctuations in plasma Tyr concentrations of treated patients with PKU.

Shenton et al. [3] has previously reported lower than normal plasma transthyretin concentrations in children with PKU and suggested that the low values were indicative of marginal malnutrition. Trp, known to exert a key role in the polyribosomal aggregation required for liver protein synthesis [22], was adequate in the diets of infants in the present study, and all had normal plasma Trp concentrations. Although no correlation was found between transthyretin concentrations and energy, protein or amino acid intakes in this study, plasma concentrations of Met (r = 0.59; p < 0.01), serine (r = 0.57, p < 0.01) and Thr (r = 0.57, p < 0.01) were positively correlated with plasma transthyretin concentrations. In the present study, mean plasma concentrations of transthyretin were slightly greater than those found in 3.7 month old infants fed a soy protein isolate formula from birth [23].


   CONCLUSIONS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 CONCLUSIONS
REFERENCES
 
Phenex-1, as fed to infants in the study, maintained protein status indices in the reference ranges. This study supports the recommendation of the Medical Research Council Working Party on Phenylketonuria [24] for 3 g/kg/day of amino acids from medical food for infants.


   FOOTNOTES
TOP
 FOOTNOTES
ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 CONCLUSIONS
 REFERENCES
 
Present address, R. Steiner, MD, Department of Pediatrics, Oregon Health Sciences University, Portland, Oregon. Present address, G. Arnold, MD, Department of Pediatrics, University of Rochester, School of Medicine and Dentistry, Rochester, New York. Present address, V. Lewis, PhD, RD, Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, Maryland.

Received June 1, 1998. Accepted October 1, 1998.


   REFERENCES
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 CONCLUSIONS
 REFERENCES
 

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