- Email: [email protected]
Transient phenylketonuria in premature infants
Accepted Manuscript
TRANSIENT PHENYLKETONURIA IN THE PREMATURE Beatriz Salamanca-Zarzuela , Mar´ıa Elena Infante Lopez , ´ Carlos Alcalde Mart´ın PII: DOI: Reference:
S0899-9007(18)30919-5 https://doi.org/10.1016/j.nut.2018.08.013 NUT 10310
To appear in:
The End-to-end Journal
Received date: Accepted date:
21 March 2018 11 August 2018
Please cite this article as: Beatriz Salamanca-Zarzuela , Mar´ıa Elena Infante Lopez , ´ Carlos Alcalde Mart´ın , TRANSIENT PHENYLKETONURIA IN THE PREMATURE, The End-toend Journal (2018), doi: https://doi.org/10.1016/j.nut.2018.08.013
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
ACCEPTED MANUSCRIPT
A CASE REPORT TITLE: TRANSIENT PHENYLKETONURIA IN THE PREMATURE Authors:
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Dr. Beatriz Salamanca-Zarzuela. Pediatrician. Hospital Universitario Rio Hortega de Valladolid. (Spain) Ms. María Elena Infante López. Neonathology. Hospital Universitario Rio Hortega de Valladolid. (Spain) Mr. Carlos Alcalde Martín. Pediatrician. Hospital Universitario Rio Hortega de Valladolid. (Spain)
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Contact: [email protected]
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ACCEPTED MANUSCRIPT ARTICLE:
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Phenylketonuria (PKU) is the most frequent hereditary metabolic disorder in our environment. Its frequency ranges between 1 / 4000-40,000 live births. PKU is an autosomal recessive inborn error of phenylalanine (phe) metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine , together with its cofactor tetrahydrobiopterin (BH4), into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. These disorders can be prevented if a diet poor in phe is introduced. To be useful, this dietary treatment must begin in the first days of life and before the clinical symptoms appear. The screening programs in the newborn and the early dietary treatment have drastically modified their prognosis. 1 2 For neonatal screening, a capillary blood sample obtained by puncturing the heel of the newborn is usually obtained by impregnating an absorbent paper with a standardized volume. The Commission of Congenital Metabolic Errors of the Society of Clinical Biochemistry and Molecular Pathology recommends that, as a general rule, the extraction of blood from the heel should be carried out as soon as possible after 48 hours of life, with protein feed established, either by enteral or parenteral nutrition. 1
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Complete enzyme deficiency results in classic PKU, in which serum phe concentration exceeds 20 mg/dL (1200 micromol/L). Residual enzyme activity causes moderate PKU (phe concentrations 900 to 1200 micromol/L), mild PKU (phe concentrations 600 to 900 micromol/L), mild hyperphenylalaninemia (phe concentrations 360 to 600 micromol/L), and benign mild HPA not requiring treatment (phe concentrations 120 to 360 micromol/L)3 4
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We present the case of a preterm newborn (29 + 4 weeks of gestational age) with adequate weight for his gestational age (1,290 grams). Immediate neonatal period with distress that requires NIMV mode CPAP for 11 days, without other complications. No family history of pku His parents, were foreign, had not received metabolic neonatal screening. He had a healthy sister too. A blood sample is taken on blotting paper for screening of metabolic . Enteral feeding is initiated with fortified breastfeeding, which implies a protein intake of 3.5 g / kg / day. A new blood sample was taken on blotting paper at 16 days of age with a weight of 1430gr: phe 420 micromol/L, compatible with mild PKU. Started mixed feeding with formula free of phe (X-Phe) and breastfeeding fortified with a contribution of 3.5 gr / Kg / day of free proteins (2.5 g X-Phe and 1 g of high-value proteins biological), assuring also, the necessary caloric and volumetric contribution, for a preterm of its age and weight. The next levels of amino acids in blood and urine were normal, and the progenitors study for pku, was negative. Normal feeding was reintroduced with normal neurological and metabolic later evolution. The disorders of the metabolism of phe, in most cases, are due to a genetic condition, with autosomal recessive inheritance, by mutations in a gene located on chromosome 12 (12q24.1), which encodes the enzyme phenylalanine hydroxylase. 1 2 However, there are infrequent cases of transient hyperphenylalaninemia secondary to delayed maturation of the hydroxylation enzyme system. In these cases, serum phe levels are higher than the upper limit of normal, but lower than those of classical pku. The levels decreasing with time and without causing symptoms. 5 Our patient presented especially high levels of phe for this type of pku. These cases appear in patients heterozygous for the mutation, or in the context of generalized inflammatory processes, secondary to drugs or renal failure. They are especially significant in the neonatal period, especially in prematures, due to
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the functional immaturity of the enzymatic system of oxidation of the aromatic amino acids phe. 6 Although these forms have not been shown to cause sequelae, in view of high levels of phe in the blood, consumption of phenylalanine must be restricted. Phe, ensuring an adequate total protein intake, until ruling out a classic form of PKU, since there is a risk of neurological involvement, especially in patients of such a young age.
BIBLIOGRAPHY
ACCEPTED MANUSCRIPT Matilde G, López C, Parrilla FJ, Martínez AL. Screening neonatal. Protocolos Diagnóstico Terapeúticos de la AEP: Neonatología. 2008. 423-433.
2.
Wegberg AMJ Van, Macdonald A, Ahring K, Blau N, Bosch AM, Burlina A. The complete European guidelines on phenylketonuria : diagnosis and treatment. Orphanet Journal of Rare Diseases. 2017.12:162.
3.
Viall S1, Ayyub O2, Rasberry M3, Lyons K2 AMN. “Mild” hyperphenylalaninemia? A case series of seven treated patients following newborn screening. Mol Genet Metab 2017 Dec;122(4)153-155.
4.
Camp KM et als. Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol Genet Metab. 2014 Jun;112(2):87-122
5.
Cristina P, Pinto G. Hiperfenilalaninemia transitória em recém-nascido prematuro : um relato de caso. HU Revista, v.36,n.3,2010:251-254.
6.
Mönch JBH/ AL/ AW/ E. Hyperphenylalaninemia in a premature infant with heterozygosity for phenylketonuria. J Perinat Med 2004;32(4)383-5.
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1.
TRANSIENT PHENYLKETONURIA IN THE PREMATURE Beatriz Salamanca-Zarzuela , Mar´ıa Elena Infante Lopez , ´ Carlos Alcalde Mart´ın PII: DOI: Reference:
S0899-9007(18)30919-5 https://doi.org/10.1016/j.nut.2018.08.013 NUT 10310
To appear in:
The End-to-end Journal
Received date: Accepted date:
21 March 2018 11 August 2018
Please cite this article as: Beatriz Salamanca-Zarzuela , Mar´ıa Elena Infante Lopez , ´ Carlos Alcalde Mart´ın , TRANSIENT PHENYLKETONURIA IN THE PREMATURE, The End-toend Journal (2018), doi: https://doi.org/10.1016/j.nut.2018.08.013
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
ACCEPTED MANUSCRIPT
A CASE REPORT TITLE: TRANSIENT PHENYLKETONURIA IN THE PREMATURE Authors:
-
Dr. Beatriz Salamanca-Zarzuela. Pediatrician. Hospital Universitario Rio Hortega de Valladolid. (Spain) Ms. María Elena Infante López. Neonathology. Hospital Universitario Rio Hortega de Valladolid. (Spain) Mr. Carlos Alcalde Martín. Pediatrician. Hospital Universitario Rio Hortega de Valladolid. (Spain)
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Contact: [email protected]
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ACCEPTED MANUSCRIPT ARTICLE:
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Phenylketonuria (PKU) is the most frequent hereditary metabolic disorder in our environment. Its frequency ranges between 1 / 4000-40,000 live births. PKU is an autosomal recessive inborn error of phenylalanine (phe) metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine , together with its cofactor tetrahydrobiopterin (BH4), into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. These disorders can be prevented if a diet poor in phe is introduced. To be useful, this dietary treatment must begin in the first days of life and before the clinical symptoms appear. The screening programs in the newborn and the early dietary treatment have drastically modified their prognosis. 1 2 For neonatal screening, a capillary blood sample obtained by puncturing the heel of the newborn is usually obtained by impregnating an absorbent paper with a standardized volume. The Commission of Congenital Metabolic Errors of the Society of Clinical Biochemistry and Molecular Pathology recommends that, as a general rule, the extraction of blood from the heel should be carried out as soon as possible after 48 hours of life, with protein feed established, either by enteral or parenteral nutrition. 1
AN US
Complete enzyme deficiency results in classic PKU, in which serum phe concentration exceeds 20 mg/dL (1200 micromol/L). Residual enzyme activity causes moderate PKU (phe concentrations 900 to 1200 micromol/L), mild PKU (phe concentrations 600 to 900 micromol/L), mild hyperphenylalaninemia (phe concentrations 360 to 600 micromol/L), and benign mild HPA not requiring treatment (phe concentrations 120 to 360 micromol/L)3 4
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CE
PT
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M
We present the case of a preterm newborn (29 + 4 weeks of gestational age) with adequate weight for his gestational age (1,290 grams). Immediate neonatal period with distress that requires NIMV mode CPAP for 11 days, without other complications. No family history of pku His parents, were foreign, had not received metabolic neonatal screening. He had a healthy sister too. A blood sample is taken on blotting paper for screening of metabolic . Enteral feeding is initiated with fortified breastfeeding, which implies a protein intake of 3.5 g / kg / day. A new blood sample was taken on blotting paper at 16 days of age with a weight of 1430gr: phe 420 micromol/L, compatible with mild PKU. Started mixed feeding with formula free of phe (X-Phe) and breastfeeding fortified with a contribution of 3.5 gr / Kg / day of free proteins (2.5 g X-Phe and 1 g of high-value proteins biological), assuring also, the necessary caloric and volumetric contribution, for a preterm of its age and weight. The next levels of amino acids in blood and urine were normal, and the progenitors study for pku, was negative. Normal feeding was reintroduced with normal neurological and metabolic later evolution. The disorders of the metabolism of phe, in most cases, are due to a genetic condition, with autosomal recessive inheritance, by mutations in a gene located on chromosome 12 (12q24.1), which encodes the enzyme phenylalanine hydroxylase. 1 2 However, there are infrequent cases of transient hyperphenylalaninemia secondary to delayed maturation of the hydroxylation enzyme system. In these cases, serum phe levels are higher than the upper limit of normal, but lower than those of classical pku. The levels decreasing with time and without causing symptoms. 5 Our patient presented especially high levels of phe for this type of pku. These cases appear in patients heterozygous for the mutation, or in the context of generalized inflammatory processes, secondary to drugs or renal failure. They are especially significant in the neonatal period, especially in prematures, due to
ACCEPTED MANUSCRIPT
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PT
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M
AN US
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the functional immaturity of the enzymatic system of oxidation of the aromatic amino acids phe. 6 Although these forms have not been shown to cause sequelae, in view of high levels of phe in the blood, consumption of phenylalanine must be restricted. Phe, ensuring an adequate total protein intake, until ruling out a classic form of PKU, since there is a risk of neurological involvement, especially in patients of such a young age.
BIBLIOGRAPHY
ACCEPTED MANUSCRIPT Matilde G, López C, Parrilla FJ, Martínez AL. Screening neonatal. Protocolos Diagnóstico Terapeúticos de la AEP: Neonatología. 2008. 423-433.
2.
Wegberg AMJ Van, Macdonald A, Ahring K, Blau N, Bosch AM, Burlina A. The complete European guidelines on phenylketonuria : diagnosis and treatment. Orphanet Journal of Rare Diseases. 2017.12:162.
3.
Viall S1, Ayyub O2, Rasberry M3, Lyons K2 AMN. “Mild” hyperphenylalaninemia? A case series of seven treated patients following newborn screening. Mol Genet Metab 2017 Dec;122(4)153-155.
4.
Camp KM et als. Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol Genet Metab. 2014 Jun;112(2):87-122
5.
Cristina P, Pinto G. Hiperfenilalaninemia transitória em recém-nascido prematuro : um relato de caso. HU Revista, v.36,n.3,2010:251-254.
6.
Mönch JBH/ AL/ AW/ E. Hyperphenylalaninemia in a premature infant with heterozygosity for phenylketonuria. J Perinat Med 2004;32(4)383-5.
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1.