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Nutrition Therapy of Inborn Errors of Metabolism
Published in Fima Lifshitz, Childhood Nutrition, 2020
Kimberlee Michals-Matalon, Reuben Matalon
The disease is a clinical spectrum. There can be a wide variation in initial blood phenylalanine levels in part due to clinical variation but also due to the type of formula consumed and the length of time before the diagnosis is confirmed. Patients that have blood phenylalanine levels greater than 2 mg/dl but below 6 mg/dl on normal dietary intake may have benign hyperphenylalaninemia. Benign hyperphenylalaninemia occurs in about 10% of patients with elevated phenylalanine levels. Patients with this condition will not require dietary therapy although occasional monitoring of blood phenylalanine levels is necessary. Blood phenylalanine levels greater than 6 mg/dl require dietary manipulation.
Genetic Disorders of the Autonomic Nervous System
Published in David Robertson, Italo Biaggioni, Disorders of the Autonomic Nervous System, 2019
About 2% of patients with persistent hyperphenylalaninemia have deficient tetrahydrobiopterin, the cofactor of tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase. This may result from inadequate biopterin synthesis or decreased regeneration by dihydropteridine reductase (Kaufman et al., 1975,1978). The resulting impaired hydroxylation of tyrosine and tryptophan may account for the marked developmental delay and seizures in these infants. Plasma dopamine, noradrenaline and adrenaline are low.
Screening for phenylketonuria and congenital hypothyroidism
Published in Micha de Winter, Mariëlle Balledux, José de Mare, Ruud Burgmeijer, Screening in Child Health Care, 2018
Micha de Winter, Mariëlle Balledux, José de Mare, Ruud Burgmeijer
PKU is an autosomal recessive hereditary metabolic disorder that is caused by the virtual inactivity of the enzyme phenylalanine hydroxylase. This enzyme is the catalyst for the metabolism of the amino acid phenylalanine into tyrosine. The result is an excess of phenylalanine and its by-products in the body. This raised concentration causes irreversible damage to the central nervous system. Newborn children with PKU are clinically normal. The mental retardation and developmental retardation caused by untreated PKU may become visible after approximately 6 months, and will be obvious at the end of the first year. Therefore, PKU can only be diagnosed on the basis of symptoms or clinical findings when the irreversible neurological damage is already extensive (Avery & First 1989). A related (autosomal recessive hereditary) disease is hyperphenylalaninemia (HPA). ‘In children with HPA there is still a slight to considerable residual activity of the enzyme phenylalanine. It is unknown whether HPA leads to clinical symptoms’ (Verkerk et al. 1990). The number of children with HPA that has been treated is very small. Two other fairly rare variants (both called malignant HPA) are characterized by the lack of the co-factor tetra hydrobiopterin. This cofactor is essential for the action of the enzyme phenylalanine hydroxylase so that, also in these forms, the phenylalanine is not converted into tyrosine. ‘The prevalence of PKU, treated HPA and malignant HPA among the neonates in the Netherlands was 1:18,000, 1:132,000 and 1:130,000, respectively; taken together this is 1:16,000’ (Verkerk et al. 1990).
Phenylketonuria in the adult patient
Published in Expert Opinion on Orphan Drugs, 2019
Leticia Ceberio, Álvaro Hermida, Eva Venegas, Francisco Arrieta, Montserrat Morales, Maria Forga, Montserrat Gonzalo
In most cases, the partial or total deficiency of the PAH enzyme and thereby the phenotype of hyperphenylalaninemia is determined by the position and nature of the mutation in the PAH gene. The classification of the different types of hyperphenylalaninemia can be made on the basis of the blood Phe concentrations at time of diagnosis and the tolerance for dietary Phe [1]. A mild hyperphenylalaninemia (HPA) is defined when individuals have blood Phe concentrations between 120 and 360 µmol/L [2]. When the concentrations are higher than 360 µmol/L, it is denoted as phenylketonuria and the individuals must be treated to avoid neurological damage. In the concentration range of 360–1200 µmol/L, the individuals are classified as having mild phenylketonuria and they might have higher tolerance for natural proteins. Classical phenylketonuria is distinguished when the Phe concentrations are >1200 µmol/L and the tolerance for natural proteins is very low. The enzyme PAH requires the cofactor tetrahydrobiopterin (BH4) [2]. In the PKU cases where the processes of biosynthesis or regeneration of BH4 are impaired, the treatment with BH4 facilitates the maintenance of Phe levels in a target range. Mild PKU patients with partial enzymatic activity are more likely to respond to BH4 treatment. Nowadays, another classification of PKU based on the treatment is commonly used. In the European guidelines on PKU, a simplified classification is described: patients not requiring treatment, patients requiring diet, BH4 or both [4].
Treatment options and dietary supplements for patients with phenylketonuria
Published in Expert Opinion on Orphan Drugs, 2018
Júlio César Rocha, Anita MacDonald
Sapropterin dihydrochloride (sapropterin, Kuvan®, BioMarin, Novato, CA, USA) is a synthetic formulation of BH4 [96]. The BH4, acting as a chaperone, helps correct the PAH protein tendency to misfold and loose its function [97]. The first report of using BH4 in PAH-deficient PKU patients was in 1999 [24]. It demonstrated that 4 patients with hyperphenylalaninemia were able to reduce blood Phe concentration after BH4 supplementation. Some years later, Muntau and co-workers showed that 87% of a sample of 31 patients with mild hyperphenylalaninemia or mild PKU significantly reduced blood Phe levels with BH4 supplementation; using in vivo rates of [13C] Phe oxidation, they showed a significantly increased Phe oxidation in 23 of these 31 patients (74%) [30].
Benchmark Examination of Blood Amino Acids Patterns in Phenylketonuria Neonates and Young Children on Phenylalanine-Restricted Dietary Treatment
Published in Fetal and Pediatric Pathology, 2022
Zhihui Wan, Eric R. Rosenbaum, Wei Liu, Boyan Song, Xiaofei Yue, Yunayuan Kong, Tianhe Li, Yanhong Zhai, Zhijun Ma, Zheng Cao
The aim of dietary treatment is to prevent toxic hyperphenylalaninemia, usually achieved by combining strict control of natural protein intake with administration of a Phe-free or low-Phe protein diet. Efficacy of the diet is monitored with regular laboratory measurements of blood Phe concentration. European guidelines for blood Phe concentration as established by van Spronsen et al. [11] are 120–360 μmol/L for those 0–12 years or pregnant and 120–600 μmol/L for those >12 years. U.S. guidelines, as set forth by the American College of Medical Genetics and the Genomics Therapeutics Committee, establish target Phe concentration in the range of 120–360 μmol/L for all patients, regardless of age and pregnancy status [12].