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Management of three preterm infants with phenylketonuria
Journal Pre-proof
Management of three Preterm Infants with Phenylketonuria Katharina Weiss , Amelie Lotz-Havla , Katharina Dokoupil , Esther M. Maier PII: DOI: Reference:
S0899-9007(19)30202-3 https://doi.org/10.1016/j.nut.2019.110619 NUT 110619
To appear in:
Nutrition
Received date: Revised date: Accepted date:
20 February 2019 5 October 2019 6 October 2019
Please cite this article as: Katharina Weiss , Amelie Lotz-Havla , Katharina Dokoupil , Esther M. Maier , Management of three Preterm Infants with Phenylketonuria, Nutrition (2019), doi: https://doi.org/10.1016/j.nut.2019.110619
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Management of three Preterm Infants with Phenylketonuria
Katharina Weiss, Amelie Lotz-Havla, Katharina Dokoupil, and Esther M. Maier
Dr. von Hauner Children’s Hospital, Department of Inborn Errors of Metabolism, LudwigMaximilians-University, Lindwurmstr. 4, 80337 Munich, Germany
Corresponding Author: Esther M. Maier Department of Inborn Errors of Metabolism, Dr. von Hauner Children’s Hospital Lindwurmstr. 4, 80337 Munich, Germany Phone +49 89 440052746, fax +49 89 440057722; [email protected]
Declaration of interest: The authors report non-financial support from different companies, outside the submitted work (see detailed disclosures in Conflict of Interest forms).
This research did not receive any specific grant from funding agencies in the public commercial, or not-for-profit sectors.
1
Highlights
Providing adequate amounts of protein in preterm infants is mandatory Dietary treatment of phenylketonuria (PKU) requires strict restriction of natural protein intake Three preterm infants with PKU were treated meeting the high protein demands of prematurity PKU preterm infants tolerated amounts of phenylalanine as high as healthy preterm infants The availability of a phenylalanine-free parenteral amino acid mixture was not required
Abstract Providing adequate amounts of protein in preterm infants suffering from a metabolic disease that requires a reduced intake of natural protein is challenging. Phenylketonuria (PKU) is an inborn error of metabolism affecting the enzymatic conversion of phenylalanine to tyrosine. The dietary treatment of PKU aims to lower phenylalanine concentrations in blood by implementing a low-phenylalanine diet, restrictive in natural protein We describe the nutritional management of three preterm infants, two of them very low birth weight infants, with PKU detected by newborn screening. All three infants tolerated high amounts of phenylalanine, two were breastfed unrestrictedly during late prematurity. We show that nutrition of preterm infants with PKU according to recommendations of early and intensive nutrition with a high intake of protein is feasible even in infants with impaired enteral feeding. Due to a high phenylalanine tolerance of PKU infants during prematurity, there is no need for a phenylalanine-free parenteral amino acid mixture. During the catabolic state of
2
prematurity preterm infants with PKU have phenylalanine requirements comparable to healthy preterm infants.
Introduction Phenylketonuria (PKU), an autosomal recessively inherited inborn error of metabolism, results from a deficiency of the enzyme phenylalanine hydroxylase (PAH) converting phenylalanine to tyrosine. Untreated, PKU leads to severe intellectual disability, microcephaly, and seizures.1 Treated in time, individuals with PKU show a largely normal development. This favorable prognosis prompted the invention of newborn screening programs for PKU some 50 years ago.1 Ever since, PKU has been the condition most babies worldwide have been screened for and, at the same time, has been the metabolic condition most frequently diagnosed by newborn screening. Treatment of PKU aims to lower phenylalanine concentrations in blood. It consists of a low-phenylalanine diet, restrictive in natural protein and complemented by phenylalanine-free amino acid supplements. Some PKU patients respond to tetrahydrobiopterin (BH4), the natural cofactor of PAH acting as a pharmacological chaperone and thereby augmenting residual PAH activity and allowing higher phenylalanine intake.2 At the time of diagnosis, phenylalanine concentrations in affected newborns are considerably elevated and usually require a temporary stop of natural protein intake (mostly breast milk) to ensure a rapid decline of phenylalanine concentrations. As soon as phenylalanine concentrations have decreased into the target range, natural protein gradually is reintroduced. Early and intensive nutrition is a crucial element in the medical care for preterm infants. It aims to accomplish growth similar to intrauterine growth and normal neurodevelopmental
3
outcome. Protein is the main driving force of growth and brain development and should be provided in sufficient quantities from the first day of life.3, 4 Since enteral feeding is often hindered in small preterm infants, nutrition often needs to be administered parenterally. Only few case reports of premature infants with PKU have been described in the literature. In the absence of a phenylalanine-free parenteral amino acid mixture, parenteral amino acids have been applied very reluctantly.5, 6 We report three premature infants with PKU, two of them very low birth weight (VLBW) infants, describing their nutritional management in the light of high protein demands of prematurity.
Patient 1 Patient 1, a boy, was born after 26 weeks and 3 days of gestation by Cesarean section due to a prolapse of the membranes and the umbilical cord. His birth weight was 1030 g, birth length 34 cm, head circumference 26 cm, APGAR 5/6/8 (Table). He required respiratory support by continuous positive airway pressure (CPAP) and received antibiotic therapy for 4 days. Enteral feeding was confined to few milliliters of breast milk due to vomiting, and parenteral nutrition was established. Newborn screening performed on day 3 revealed an elevated phenylalanine concentration of 612 µmol/l (<120 µmol/l). Hence, patient 1 was transferred to our hospital for further treatment on day 7. At that time, plasma concentration of phenylalanine had risen to 1636 µmol/l. His nutrition consisted of 104 kcal/kg, 4.3 g/kg protein (0.4 g/kg from breast milk), and 161 mg/kg phenylalanine (Table and Figure).
4
Since enteral feeding was poorly tolerated and no phenylalanine-free parenteral amino acid mixture is available, phenylalanine intake was not suspended in order to provide a protein intake recommended for VLBW infants. To reduce phenylalanine intake the standard parenteral amino acid mixture Aminopaed® 10% (3.1 g/l phenylalanine) was substituted by Aminosteril® Hepa 8% (0.88 g/l phenylalanine), the mixture containing the least amount of phenylalanine available. Feeding of breast milk was continued to prevent necrotizing enterocolitis but was combined with a phenylalanine-free infant formula. By these means, phenylalanine intake was reduced to 37 mg/kg still providing a protein intake of 3.1 g/kg and an energy intake of 99 kcal/kg. The phenylalanine concentration in blood decreased rapidly and was normal at day 13. Tolerance of enteral feeding improved day by day. At day 17 parenteral nutrition was terminated, a breast milk fortifier, preterm formula, and phenylalanine-free amino acid supplements were introduced. To achieve an adequate gain of weight nutritional intake was increased to a maximum of 140 kcal/kg, 5.4 g/kg protein (168 mg/kg phenylalanine), phenylalanine concentrations still within the target range (<240 µmol/l). With increasing weight, preterm formula and breast milk fortifier were decreased. At the time of his expected date of delivery, patient 1 had an energy intake of 115 kcal/kg and protein intake of 2.5 g/kg protein (62 mg/kg phenylalanine) from fortified breast milk, infant formula, and phenylalanine-free amino acid supplements (Figure). At the age of 2 months corrected for prematurity, his intake was 93 kcal/kg, and 1.9 g/kg protein (48 mg/kg phenylalanine). Diagnosis of PKU was confirmed by mutational analysis of the PAH gene revealing two compound heterozygous mutations, c.165delT (p.Phe55Leufs*6) and c.284-286delTCA (p.Ile95_Lys96delinsLys) (Table). No information on BH4-responsiveness of this rare genotype was available. Thus, at the age of 17 months, a treatment trial with BH4 (20
5
mg/kg per day orally) was initiated. Patient 1 responded well with a significant decrease of phenylalanine concentrations in blood and the intake of natural protein was steadily increased. Treated with BH4, no protein restriction is required to date. At the age of 2 years now, the neurocognitive development of patient 1 is normal.
Patient 2 Patient 2, a boy, was born after 29 weeks and 3 days of gestation by Cesarean section due to broken membranes and preterm labor. His birth weight was 1330 g, birth length 35 cm, head circumference 28 cm, APGAR 9/9/10 (Table). He required antibiotic therapy for few days. Enteral feeding was tolerated, but complemented by parenteral nutrition. Newborn screening was performed on day 3 and showed an elevated concentration of phenylalanine (1635 µmol/l; Ref. <120 µmol/l). Patient 2 was transferred to our hospital for further treatment on day 7. At that time, he was fed breast milk (89 kcal/kg; 1.5 g/kg protein), complemented by parenteral nutrition (45 kcal/kg; 1.5 g/kg protein), the concentration of phenylalanine in blood was 2148 µmol/l (Table). Phenylalanine intake was suspended by replacing breast milk with phenylalanine-free infant formula enhanced by phenylalanine-free amino acid supplement to make up for the parenteral protein intake. Parenteral nutrition was continued for 2 more days, limited to carbohydrates and lipids. With phenylalanine concentrations declining into the normal range, breast milk was reintroduced after 3 days. The intake of natural protein from breast milk was steadily increased, a breast milk fortifier was used to provide a high protein intake recommended for VLBW infants. No phenylalanine-free infant formula and only a small amounts of phenylalanine-free amino acid supplement were required. Patient 2 received up to 4.7 g/kg protein (140 mg/kg phenylalanine) showing phenylalanine concentrations within the target
6
range (<240 µmol/l). With adequate weight gain, breast milk fortifiers and amino acid supplements were decreased and finally stopped at 38 weeks of gestation. Patient 2 was given breast milk ad libitum until his discharge from hospital (Table). Breast milk was then confined to 130 ml/kg (1.6 g/kg protein, 65 mg/kg phenylalanine) due to increasing concentrations of phenylalanine in blood. PKU was confirmed by identifying the homozygous mutation c.1222C>T (p.R408W) in the PAH gene (Table). This common genotype is known to be associated with a severe (“classic”)
phenotype
and
to
lack
BH4-responsiveness
(BIOPKU
database;
www.biopku.org). Aged 13 years now, patient 2 shows an average non-verbal intelligence. His speech development is affected due to cochlea implants and a bilingual education.
Patient 3 Patient 3, a boy, was delivered by Cesarean section after 34 weeks and 1 day of gestation due to placenta praevia and vaginal bleeding. His birth weight was 2000 g, birth length 45 cm, head circumference 30 cm, APGAR 8/9/9 (Table). He received non-invasive breathing support and antibiotic therapy for two days. Enteral feeding was well tolerated. Newborn screening was performed on day 2 and showed an elevated concentration of phenylalanine (272 µmol/l; Ref. <120 µmol/l). Patient 3 was transferred to our hospital for further treatment on day 8. Upon arrival, his plasma phenylalanine concentration was 1417 µmol/l. He was fed breast milk 160 ml/kg (98 kcal/kg; 1.8 g/kg protein) (Table). Phenylalanine intake was suspended by substituting phenylalanine-free infant formula for breast milk. After 5 days, when phenylalanine concentrations in blood had dropped into the reference range, breast milk was gradually reintroduced. Despite increasing amounts of
7
breast milk phenylalanine concentrations remained within the normal range (<120 µmol/l), and patient 3 was given breast milk ad libitum until his expected date of delivery (protein intake approximately 2.4 g/kg, 99 mg/kg phenylalanine) (Table). Thereafter, his phenylalanine intake had progressively to be restricted. At 3 months of age, his phenylalanine tolerance was 40 mg/kg (250 mg per day). PKU was confirmed by identifying two compound heterozygous mutations in the PAH gene, c.1066-11G>A (IVS10-11G>A) and c.1222C>T (p.R408W) (Table), a genotype known to be associated with a severe (“classic”) phenotype and to lack BH4-responsiveness (BIOPKU database; www.biopku.org). Aged 4 years now, patient 3 shows a normal neurocognitive development.
Discussion Appropriate nutrition is essential for the growth and development of preterm infants.3 Based on current literature, protein intake should be started from the first day of life to achieve an anabolic state.4 Treatment of PKU, however, consists of a diet restrictive in natural protein.1 Previous case reports have described challenges in the management of PKU preterm infants arising from the non-availability of a phenylananine-free parental amino acid mixture.5, 6 We report the management of three preterm infants, two of them VLBW infants, affected with PKU. All three infants presented with considerably elevated concentrations of phenylalanine consistent with “classic” PKU (>1200 µmol/l).1 Due to sufficient enteral feeding, in patient 2 and patient 3 the intake of natural protein i.e. breast milk, and parental amino acids could be suspended and replaced by phenylalanine-free formula and amino acid
8
supplements until phenylalanine concentrations in blood had normalized. Reintroducing natural protein from breast milk, both infants tolerated surprisingly high amounts of natural protein and phenylalanine, respectively. In fact, they were fed breast milk unrestrictedly during late prematurity showing phenylalanine concentrations within the target range (<240 µmol/l).7 In comparison, breast fed term infants with PKU tolerate approximately 35 mg/kg phenylalanine comprising half of the required intake of natural protein during neonatal age.8 Having attained term, patient 2 and patient 3 required gradual restriction of phenylalanine intake consistent with phenylalanine intake of PKU infants during neonatal age. Patient 1 did not tolerate relevant amounts of enteral feeding at the time of diagnosis. According to nutrition recommendations for VLBW infants he received 3.9 g/kg parenteral amino acids.4 Since protein supply is a mainstay of preterm infants’ care, we decided against a stop of parenteral amino acids but to reduce the parenteral phenylalanine intake to a minimum by replacing the standard amino acid mixture high in phenylalanine by the mixture containing the least amount of phenylalanine available. The small amount of breast milk enterally tolerated was continued to prevent necrotizing enterocolitis. By these means, a sufficient anabolic state was achieved and phenylalanine concentrations in blood decreased into the normal range within 5 days. In contrast, Ballhausen et al. stopped parenteral amino acid supply for 5 days in a VLBW infant and described a very slow decline of phenylalanine concentration unless parenteral amino acids were reintroduced.5 Cole et al. also stopped parenteral amino acid mixture in a preterm infant and achieved a slow decline of phenylalanine concentrations in blood within 9 days on an enteral supply of only 50 kcal/kg. 6 Patient 1 and patient 2 were VLBW infants requiring protein intakes as high as 3.5 to 4.0 g/kg.3 Both patients tolerated high intakes of protein with only small amounts of phenylalanine-free amino acid supplements. Their phenylalanine intake exceeded 100 mg/kg
9
with maximum intakes of 140 mg/kg and 168 mg/kg, respectively. These intakes are consistent with phenylalanine requirements of healthy preterm neonates. 9 During late prematurity phenylalanine tolerance decreased, but all three infants still had a phenylalanine intake comparable to healthy term neonates.9 The high phenylalanine intakes of our patients reflect the higher nutritional needs of preterm infants. Compared to term infants, protein needs of preterm infants to promote anabolism and growth are higher, and fortification with proteins has been found to result in an increase in weight gain, linear growth, and head circumference in preterm infants.10 In preterm infants with PKU, phenylalanine intakes comparable to healthy preterm infants seem to be needed to promote protein synthesis and achieve growth. Similar phenylalanine requirements in preterm infants with PKU have been reported.5, 11, 12 We conclude that nutrition of preterm infants with PKU according to recommendations of early and intensive nutrition with a high intake of protein is feasible even in infants with impaired enteral feeding. Due to a high phenylalanine tolerance of PKU infants during prematurity, there is no need for a phenylalanine-free parenteral amino acid mixture. During prematurity, we expect that preterm infants with PKU have phenylalanine requirements comparable to healthy preterm infants.
10
References [1] Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376:1417-27. [2] Blau N, Erlandsen H. The metabolic and molecular bases of tetrahydrobiopterinresponsive phenylalanine hydroxylase deficiency. Mol Genet Metab. 2004;82:101-11. [3] Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2010;50:85-91. [4] van Goudoever JB, Carnielli V, Darmaun D, Sainz de Pipaon M, nutrition EEECwgopp. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Amino acids. Clin Nutr. 2018;37:2315-23. [5] Ballhausen D, Egli D, Bickle-Graz M, Bianchi N, Bonafe L. Born at 27 weeks of gestation with classical PKU: challenges of dietetic management in a very preterm infant. Pediatr Rep. 2011;3:e26. [6] Cole DE, Landry DA. Parenteral nutrition in a premature infant with phenylketonuria. JPEN J Parenter Enteral Nutr. 1984;8:42-4. [7] Burgard P, Bremer HJ, Buhrdel P, Clemens PC, Monch E, Przyrembel H, et al. Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997. Eur J Pediatr. 1999;158:46-54. [8] Cornejo V, Manriquez V, Colombo M, Mabe P, Jimenez M, De la Parra A, et al. [Phenylketonuria diagnosed during the neonatal period and breast feeding]. Rev Med Chil. 2003;131:1280-7. [9] Hogewind-Schoonenboom JE, Zhu L, Zhu L, Ackermans EC, Mulders R, Te Boekhorst B, et al. Phenylalanine requirements of enterally fed term and preterm neonates. Am J Clin Nutr. 2015;101:1155-62.
11
[10] Kumar RK, Singhal A, Vaidya U, Banerjee S, Anwar F, Rao S. Optimizing Nutrition in Preterm Low Birth Weight Infants-Consensus Summary. Front Nutr. 2017;4:20. [11] Randall R, Gick JA, Bird S, Champion MP. Increased phenylalanine requirements in a preterm infant with calssical phenylketonuria. J Inherit Metab Dis. 2000;23. [12] Shortland D, Smith I, Francis DE, Ersser R, Wolff OH. Amino acid and protein requirements in a preterm infant with classic phenylketonuria. Arch Dis Child. 1985;60:2635.
12
Figure Legend
Figure. Nutritional management of patient 1 during prematurity. The phenylalanine intake (mg/kg/d) is depicted as dashed line, the energy intake (kcal/kg/d) as solid line. The light gray area represents the total protein intake (g/kg/d), the dark grey area the phenylalanine-free protein intake (g/kg/d). Blood phenylalanine concentrations (mg/dl) are given as triangles.
13
Table. Clinical and nutritional data.
Gestational Age Birth Weight Genotype
BH4-sensitivity Phenylalanine concentration newborn screening (day of life) Phenylalanine concentration confirmation (day of life) Protein intake at time of diagnosis (phenylalanine intake) Calorie intake at time of diagnosis (enteral/parenteral) Parenteral amino acid intake at time of diagnosis Protein intake late prematurity (phenylalanine intake) Protein intake at 12 months of age (phenylalanine intake)
Patient 1 26 weeks and 3 days 1030 g c.165delT / c.284_286delTCA (p.Phe55Leufs*6 / p.Ile95_Lys96delinsLys) yes 612 µmol/l (3) 1636 µmol/l (7) 4.3 g/kg (161 mg/kg) 104 kcal/kg (22/82)
Patient 2 29 weeks and 2 days 1330 g c.1222C>T / c.1222C>T (p.R408W / p.R408W)
Patient 3 34 weeks and 1 day 2000 g c.1066-11 G>A / c.1222C>T (IVS10-11G>A / p.R408W)
no 1635 µmol/l (3) 2148 µmol/l (7) 3.0 g/kg (107 mg/kg) 127 kcal/kg (89/38)
no 272 µmol/l (2) 1417 µmol/l (8) 1.8 g/kg (72 mg/kg) 107 kcal/kg
3.9 g/kg 2.5 g/kg (62 mg/kg) 2.0 g/kg (40 mg/kg)
1.5 g/kg breast milk ad libitum 1.3 g/kg (22 mg/kg)
2.4 g/kg / (99 mg/kg) 2.0 g/kg (23 mg/kg)
14
Management of three Preterm Infants with Phenylketonuria Katharina Weiss , Amelie Lotz-Havla , Katharina Dokoupil , Esther M. Maier PII: DOI: Reference:
S0899-9007(19)30202-3 https://doi.org/10.1016/j.nut.2019.110619 NUT 110619
To appear in:
Nutrition
Received date: Revised date: Accepted date:
20 February 2019 5 October 2019 6 October 2019
Please cite this article as: Katharina Weiss , Amelie Lotz-Havla , Katharina Dokoupil , Esther M. Maier , Management of three Preterm Infants with Phenylketonuria, Nutrition (2019), doi: https://doi.org/10.1016/j.nut.2019.110619
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Management of three Preterm Infants with Phenylketonuria
Katharina Weiss, Amelie Lotz-Havla, Katharina Dokoupil, and Esther M. Maier
Dr. von Hauner Children’s Hospital, Department of Inborn Errors of Metabolism, LudwigMaximilians-University, Lindwurmstr. 4, 80337 Munich, Germany
Corresponding Author: Esther M. Maier Department of Inborn Errors of Metabolism, Dr. von Hauner Children’s Hospital Lindwurmstr. 4, 80337 Munich, Germany Phone +49 89 440052746, fax +49 89 440057722; [email protected]
Declaration of interest: The authors report non-financial support from different companies, outside the submitted work (see detailed disclosures in Conflict of Interest forms).
This research did not receive any specific grant from funding agencies in the public commercial, or not-for-profit sectors.
1
Highlights
Providing adequate amounts of protein in preterm infants is mandatory Dietary treatment of phenylketonuria (PKU) requires strict restriction of natural protein intake Three preterm infants with PKU were treated meeting the high protein demands of prematurity PKU preterm infants tolerated amounts of phenylalanine as high as healthy preterm infants The availability of a phenylalanine-free parenteral amino acid mixture was not required
Abstract Providing adequate amounts of protein in preterm infants suffering from a metabolic disease that requires a reduced intake of natural protein is challenging. Phenylketonuria (PKU) is an inborn error of metabolism affecting the enzymatic conversion of phenylalanine to tyrosine. The dietary treatment of PKU aims to lower phenylalanine concentrations in blood by implementing a low-phenylalanine diet, restrictive in natural protein We describe the nutritional management of three preterm infants, two of them very low birth weight infants, with PKU detected by newborn screening. All three infants tolerated high amounts of phenylalanine, two were breastfed unrestrictedly during late prematurity. We show that nutrition of preterm infants with PKU according to recommendations of early and intensive nutrition with a high intake of protein is feasible even in infants with impaired enteral feeding. Due to a high phenylalanine tolerance of PKU infants during prematurity, there is no need for a phenylalanine-free parenteral amino acid mixture. During the catabolic state of
2
prematurity preterm infants with PKU have phenylalanine requirements comparable to healthy preterm infants.
Introduction Phenylketonuria (PKU), an autosomal recessively inherited inborn error of metabolism, results from a deficiency of the enzyme phenylalanine hydroxylase (PAH) converting phenylalanine to tyrosine. Untreated, PKU leads to severe intellectual disability, microcephaly, and seizures.1 Treated in time, individuals with PKU show a largely normal development. This favorable prognosis prompted the invention of newborn screening programs for PKU some 50 years ago.1 Ever since, PKU has been the condition most babies worldwide have been screened for and, at the same time, has been the metabolic condition most frequently diagnosed by newborn screening. Treatment of PKU aims to lower phenylalanine concentrations in blood. It consists of a low-phenylalanine diet, restrictive in natural protein and complemented by phenylalanine-free amino acid supplements. Some PKU patients respond to tetrahydrobiopterin (BH4), the natural cofactor of PAH acting as a pharmacological chaperone and thereby augmenting residual PAH activity and allowing higher phenylalanine intake.2 At the time of diagnosis, phenylalanine concentrations in affected newborns are considerably elevated and usually require a temporary stop of natural protein intake (mostly breast milk) to ensure a rapid decline of phenylalanine concentrations. As soon as phenylalanine concentrations have decreased into the target range, natural protein gradually is reintroduced. Early and intensive nutrition is a crucial element in the medical care for preterm infants. It aims to accomplish growth similar to intrauterine growth and normal neurodevelopmental
3
outcome. Protein is the main driving force of growth and brain development and should be provided in sufficient quantities from the first day of life.3, 4 Since enteral feeding is often hindered in small preterm infants, nutrition often needs to be administered parenterally. Only few case reports of premature infants with PKU have been described in the literature. In the absence of a phenylalanine-free parenteral amino acid mixture, parenteral amino acids have been applied very reluctantly.5, 6 We report three premature infants with PKU, two of them very low birth weight (VLBW) infants, describing their nutritional management in the light of high protein demands of prematurity.
Patient 1 Patient 1, a boy, was born after 26 weeks and 3 days of gestation by Cesarean section due to a prolapse of the membranes and the umbilical cord. His birth weight was 1030 g, birth length 34 cm, head circumference 26 cm, APGAR 5/6/8 (Table). He required respiratory support by continuous positive airway pressure (CPAP) and received antibiotic therapy for 4 days. Enteral feeding was confined to few milliliters of breast milk due to vomiting, and parenteral nutrition was established. Newborn screening performed on day 3 revealed an elevated phenylalanine concentration of 612 µmol/l (<120 µmol/l). Hence, patient 1 was transferred to our hospital for further treatment on day 7. At that time, plasma concentration of phenylalanine had risen to 1636 µmol/l. His nutrition consisted of 104 kcal/kg, 4.3 g/kg protein (0.4 g/kg from breast milk), and 161 mg/kg phenylalanine (Table and Figure).
4
Since enteral feeding was poorly tolerated and no phenylalanine-free parenteral amino acid mixture is available, phenylalanine intake was not suspended in order to provide a protein intake recommended for VLBW infants. To reduce phenylalanine intake the standard parenteral amino acid mixture Aminopaed® 10% (3.1 g/l phenylalanine) was substituted by Aminosteril® Hepa 8% (0.88 g/l phenylalanine), the mixture containing the least amount of phenylalanine available. Feeding of breast milk was continued to prevent necrotizing enterocolitis but was combined with a phenylalanine-free infant formula. By these means, phenylalanine intake was reduced to 37 mg/kg still providing a protein intake of 3.1 g/kg and an energy intake of 99 kcal/kg. The phenylalanine concentration in blood decreased rapidly and was normal at day 13. Tolerance of enteral feeding improved day by day. At day 17 parenteral nutrition was terminated, a breast milk fortifier, preterm formula, and phenylalanine-free amino acid supplements were introduced. To achieve an adequate gain of weight nutritional intake was increased to a maximum of 140 kcal/kg, 5.4 g/kg protein (168 mg/kg phenylalanine), phenylalanine concentrations still within the target range (<240 µmol/l). With increasing weight, preterm formula and breast milk fortifier were decreased. At the time of his expected date of delivery, patient 1 had an energy intake of 115 kcal/kg and protein intake of 2.5 g/kg protein (62 mg/kg phenylalanine) from fortified breast milk, infant formula, and phenylalanine-free amino acid supplements (Figure). At the age of 2 months corrected for prematurity, his intake was 93 kcal/kg, and 1.9 g/kg protein (48 mg/kg phenylalanine). Diagnosis of PKU was confirmed by mutational analysis of the PAH gene revealing two compound heterozygous mutations, c.165delT (p.Phe55Leufs*6) and c.284-286delTCA (p.Ile95_Lys96delinsLys) (Table). No information on BH4-responsiveness of this rare genotype was available. Thus, at the age of 17 months, a treatment trial with BH4 (20
5
mg/kg per day orally) was initiated. Patient 1 responded well with a significant decrease of phenylalanine concentrations in blood and the intake of natural protein was steadily increased. Treated with BH4, no protein restriction is required to date. At the age of 2 years now, the neurocognitive development of patient 1 is normal.
Patient 2 Patient 2, a boy, was born after 29 weeks and 3 days of gestation by Cesarean section due to broken membranes and preterm labor. His birth weight was 1330 g, birth length 35 cm, head circumference 28 cm, APGAR 9/9/10 (Table). He required antibiotic therapy for few days. Enteral feeding was tolerated, but complemented by parenteral nutrition. Newborn screening was performed on day 3 and showed an elevated concentration of phenylalanine (1635 µmol/l; Ref. <120 µmol/l). Patient 2 was transferred to our hospital for further treatment on day 7. At that time, he was fed breast milk (89 kcal/kg; 1.5 g/kg protein), complemented by parenteral nutrition (45 kcal/kg; 1.5 g/kg protein), the concentration of phenylalanine in blood was 2148 µmol/l (Table). Phenylalanine intake was suspended by replacing breast milk with phenylalanine-free infant formula enhanced by phenylalanine-free amino acid supplement to make up for the parenteral protein intake. Parenteral nutrition was continued for 2 more days, limited to carbohydrates and lipids. With phenylalanine concentrations declining into the normal range, breast milk was reintroduced after 3 days. The intake of natural protein from breast milk was steadily increased, a breast milk fortifier was used to provide a high protein intake recommended for VLBW infants. No phenylalanine-free infant formula and only a small amounts of phenylalanine-free amino acid supplement were required. Patient 2 received up to 4.7 g/kg protein (140 mg/kg phenylalanine) showing phenylalanine concentrations within the target
6
range (<240 µmol/l). With adequate weight gain, breast milk fortifiers and amino acid supplements were decreased and finally stopped at 38 weeks of gestation. Patient 2 was given breast milk ad libitum until his discharge from hospital (Table). Breast milk was then confined to 130 ml/kg (1.6 g/kg protein, 65 mg/kg phenylalanine) due to increasing concentrations of phenylalanine in blood. PKU was confirmed by identifying the homozygous mutation c.1222C>T (p.R408W) in the PAH gene (Table). This common genotype is known to be associated with a severe (“classic”)
phenotype
and
to
lack
BH4-responsiveness
(BIOPKU
database;
www.biopku.org). Aged 13 years now, patient 2 shows an average non-verbal intelligence. His speech development is affected due to cochlea implants and a bilingual education.
Patient 3 Patient 3, a boy, was delivered by Cesarean section after 34 weeks and 1 day of gestation due to placenta praevia and vaginal bleeding. His birth weight was 2000 g, birth length 45 cm, head circumference 30 cm, APGAR 8/9/9 (Table). He received non-invasive breathing support and antibiotic therapy for two days. Enteral feeding was well tolerated. Newborn screening was performed on day 2 and showed an elevated concentration of phenylalanine (272 µmol/l; Ref. <120 µmol/l). Patient 3 was transferred to our hospital for further treatment on day 8. Upon arrival, his plasma phenylalanine concentration was 1417 µmol/l. He was fed breast milk 160 ml/kg (98 kcal/kg; 1.8 g/kg protein) (Table). Phenylalanine intake was suspended by substituting phenylalanine-free infant formula for breast milk. After 5 days, when phenylalanine concentrations in blood had dropped into the reference range, breast milk was gradually reintroduced. Despite increasing amounts of
7
breast milk phenylalanine concentrations remained within the normal range (<120 µmol/l), and patient 3 was given breast milk ad libitum until his expected date of delivery (protein intake approximately 2.4 g/kg, 99 mg/kg phenylalanine) (Table). Thereafter, his phenylalanine intake had progressively to be restricted. At 3 months of age, his phenylalanine tolerance was 40 mg/kg (250 mg per day). PKU was confirmed by identifying two compound heterozygous mutations in the PAH gene, c.1066-11G>A (IVS10-11G>A) and c.1222C>T (p.R408W) (Table), a genotype known to be associated with a severe (“classic”) phenotype and to lack BH4-responsiveness (BIOPKU database; www.biopku.org). Aged 4 years now, patient 3 shows a normal neurocognitive development.
Discussion Appropriate nutrition is essential for the growth and development of preterm infants.3 Based on current literature, protein intake should be started from the first day of life to achieve an anabolic state.4 Treatment of PKU, however, consists of a diet restrictive in natural protein.1 Previous case reports have described challenges in the management of PKU preterm infants arising from the non-availability of a phenylananine-free parental amino acid mixture.5, 6 We report the management of three preterm infants, two of them VLBW infants, affected with PKU. All three infants presented with considerably elevated concentrations of phenylalanine consistent with “classic” PKU (>1200 µmol/l).1 Due to sufficient enteral feeding, in patient 2 and patient 3 the intake of natural protein i.e. breast milk, and parental amino acids could be suspended and replaced by phenylalanine-free formula and amino acid
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supplements until phenylalanine concentrations in blood had normalized. Reintroducing natural protein from breast milk, both infants tolerated surprisingly high amounts of natural protein and phenylalanine, respectively. In fact, they were fed breast milk unrestrictedly during late prematurity showing phenylalanine concentrations within the target range (<240 µmol/l).7 In comparison, breast fed term infants with PKU tolerate approximately 35 mg/kg phenylalanine comprising half of the required intake of natural protein during neonatal age.8 Having attained term, patient 2 and patient 3 required gradual restriction of phenylalanine intake consistent with phenylalanine intake of PKU infants during neonatal age. Patient 1 did not tolerate relevant amounts of enteral feeding at the time of diagnosis. According to nutrition recommendations for VLBW infants he received 3.9 g/kg parenteral amino acids.4 Since protein supply is a mainstay of preterm infants’ care, we decided against a stop of parenteral amino acids but to reduce the parenteral phenylalanine intake to a minimum by replacing the standard amino acid mixture high in phenylalanine by the mixture containing the least amount of phenylalanine available. The small amount of breast milk enterally tolerated was continued to prevent necrotizing enterocolitis. By these means, a sufficient anabolic state was achieved and phenylalanine concentrations in blood decreased into the normal range within 5 days. In contrast, Ballhausen et al. stopped parenteral amino acid supply for 5 days in a VLBW infant and described a very slow decline of phenylalanine concentration unless parenteral amino acids were reintroduced.5 Cole et al. also stopped parenteral amino acid mixture in a preterm infant and achieved a slow decline of phenylalanine concentrations in blood within 9 days on an enteral supply of only 50 kcal/kg. 6 Patient 1 and patient 2 were VLBW infants requiring protein intakes as high as 3.5 to 4.0 g/kg.3 Both patients tolerated high intakes of protein with only small amounts of phenylalanine-free amino acid supplements. Their phenylalanine intake exceeded 100 mg/kg
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with maximum intakes of 140 mg/kg and 168 mg/kg, respectively. These intakes are consistent with phenylalanine requirements of healthy preterm neonates. 9 During late prematurity phenylalanine tolerance decreased, but all three infants still had a phenylalanine intake comparable to healthy term neonates.9 The high phenylalanine intakes of our patients reflect the higher nutritional needs of preterm infants. Compared to term infants, protein needs of preterm infants to promote anabolism and growth are higher, and fortification with proteins has been found to result in an increase in weight gain, linear growth, and head circumference in preterm infants.10 In preterm infants with PKU, phenylalanine intakes comparable to healthy preterm infants seem to be needed to promote protein synthesis and achieve growth. Similar phenylalanine requirements in preterm infants with PKU have been reported.5, 11, 12 We conclude that nutrition of preterm infants with PKU according to recommendations of early and intensive nutrition with a high intake of protein is feasible even in infants with impaired enteral feeding. Due to a high phenylalanine tolerance of PKU infants during prematurity, there is no need for a phenylalanine-free parenteral amino acid mixture. During prematurity, we expect that preterm infants with PKU have phenylalanine requirements comparable to healthy preterm infants.
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References [1] Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376:1417-27. [2] Blau N, Erlandsen H. The metabolic and molecular bases of tetrahydrobiopterinresponsive phenylalanine hydroxylase deficiency. Mol Genet Metab. 2004;82:101-11. [3] Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2010;50:85-91. [4] van Goudoever JB, Carnielli V, Darmaun D, Sainz de Pipaon M, nutrition EEECwgopp. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Amino acids. Clin Nutr. 2018;37:2315-23. [5] Ballhausen D, Egli D, Bickle-Graz M, Bianchi N, Bonafe L. Born at 27 weeks of gestation with classical PKU: challenges of dietetic management in a very preterm infant. Pediatr Rep. 2011;3:e26. [6] Cole DE, Landry DA. Parenteral nutrition in a premature infant with phenylketonuria. JPEN J Parenter Enteral Nutr. 1984;8:42-4. [7] Burgard P, Bremer HJ, Buhrdel P, Clemens PC, Monch E, Przyrembel H, et al. Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997. Eur J Pediatr. 1999;158:46-54. [8] Cornejo V, Manriquez V, Colombo M, Mabe P, Jimenez M, De la Parra A, et al. [Phenylketonuria diagnosed during the neonatal period and breast feeding]. Rev Med Chil. 2003;131:1280-7. [9] Hogewind-Schoonenboom JE, Zhu L, Zhu L, Ackermans EC, Mulders R, Te Boekhorst B, et al. Phenylalanine requirements of enterally fed term and preterm neonates. Am J Clin Nutr. 2015;101:1155-62.
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[10] Kumar RK, Singhal A, Vaidya U, Banerjee S, Anwar F, Rao S. Optimizing Nutrition in Preterm Low Birth Weight Infants-Consensus Summary. Front Nutr. 2017;4:20. [11] Randall R, Gick JA, Bird S, Champion MP. Increased phenylalanine requirements in a preterm infant with calssical phenylketonuria. J Inherit Metab Dis. 2000;23. [12] Shortland D, Smith I, Francis DE, Ersser R, Wolff OH. Amino acid and protein requirements in a preterm infant with classic phenylketonuria. Arch Dis Child. 1985;60:2635.
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Figure Legend
Figure. Nutritional management of patient 1 during prematurity. The phenylalanine intake (mg/kg/d) is depicted as dashed line, the energy intake (kcal/kg/d) as solid line. The light gray area represents the total protein intake (g/kg/d), the dark grey area the phenylalanine-free protein intake (g/kg/d). Blood phenylalanine concentrations (mg/dl) are given as triangles.
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Table. Clinical and nutritional data.
Gestational Age Birth Weight Genotype
BH4-sensitivity Phenylalanine concentration newborn screening (day of life) Phenylalanine concentration confirmation (day of life) Protein intake at time of diagnosis (phenylalanine intake) Calorie intake at time of diagnosis (enteral/parenteral) Parenteral amino acid intake at time of diagnosis Protein intake late prematurity (phenylalanine intake) Protein intake at 12 months of age (phenylalanine intake)
Patient 1 26 weeks and 3 days 1030 g c.165delT / c.284_286delTCA (p.Phe55Leufs*6 / p.Ile95_Lys96delinsLys) yes 612 µmol/l (3) 1636 µmol/l (7) 4.3 g/kg (161 mg/kg) 104 kcal/kg (22/82)
Patient 2 29 weeks and 2 days 1330 g c.1222C>T / c.1222C>T (p.R408W / p.R408W)
Patient 3 34 weeks and 1 day 2000 g c.1066-11 G>A / c.1222C>T (IVS10-11G>A / p.R408W)
no 1635 µmol/l (3) 2148 µmol/l (7) 3.0 g/kg (107 mg/kg) 127 kcal/kg (89/38)
no 272 µmol/l (2) 1417 µmol/l (8) 1.8 g/kg (72 mg/kg) 107 kcal/kg
3.9 g/kg 2.5 g/kg (62 mg/kg) 2.0 g/kg (40 mg/kg)
1.5 g/kg breast milk ad libitum 1.3 g/kg (22 mg/kg)
2.4 g/kg / (99 mg/kg) 2.0 g/kg (23 mg/kg)
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