Influence of Age on ortho-Hydroxyphenylacetic Acid Excretion in Phenylketonuria and Its Genetic Variants

Abstract

ExtractExcretion in urine of o-hydroxyphenylacetic acid (0-OH-PAA) was measured quantitatively during a 24-hr period in 43 children ranging from 2 weeks to 12 years of age who were affected by different types of hyperphenylalaninemia (20 typical phenylketonuria (PKU) 7 atypical PKU, and 16 mild forms according to the classification of Auerbach et 01.); 28 out of the 33 cases diagnosed at birth in the course of a screening program were examined before reaching 3 months of age. Phenylpyruvic acid (PPA) excretion was estimated at the same time semiquantitatively.I t was found ( I ) that ferric chloride tests were negative constantly and the daily excretion of o-OH-PAA was always inferior to 5 p~/ 2 4 hr in the younger group when the level of phenylalanine in plasma was below 1.5 pmol/ml; (2) that o-OH-PAA excretion increased significantly as the children got older : 1 1.0 f 3.8 before 3 months, 16.1 f 15.9 at 6 months, 75.0 f 48.5 at 1 year, and 122.1 i 84.7 p~/ 2 4 hr at 2 years of age for levels of phenylalanine in plasma which ranged from 1.5 to 2.1 pmol/ ml; (3) that the excretion thresholds for o-OH-PAA and PPA reached adult values (0.4-0.5 and 0.7-0.9 pmol/ml, respectively) only after 2 years.In 16 cases, using intravenous perfusion of 0.06 M L-phenylalanine, we have shown also that the PPA and o-OH-PAA excretion was identical whatever the type of (PKU) or mild forms) insofar as the levels of phenylalanine in plasma reached (1.5-3.0 pmol/ml) were equal in both types. Speculation This paper presents observations which demonstrate that only a minute amount of o-OH-PAA is excreted daily in the urine of both classic PKU and other forms of hyperphenylalaninemia during the first months of life. I t is suggested that this very low excretion is caused by a delayed maturation of phenylalanine transaminase; it is further proposed that the different types of hyperphenylalaninemia, with the exception of those caused by a deficiency of the tyrosine-oxidizing system, are all secondary to mutations affecting the phenylalanine hydrox>lase system.

Development of Metabolic Phenotype in Phenylketonuria: Evaluation of the Blaskovics Protein Loading Test at 5 Years of Age

“…Rey et al (1974) first described the influence of age on excretion of OHPAA in children with PKU and found adult threshold values only after 2 years. Accordingly, metabolic data of PKU children older than 2 years conform with respective findings in juvenile patients (Langenbeck et al 1980(Langenbeck et al , 1992, and phe tolerance at 10 years of age can be predicted reliably from the respective data at 2 years (van Spronsen et al 2009).…”

“…Whether delayed maturation of phe transaminase, as suggested by Rey et al (1974), and/or delayed maturation of the pAH transporter explains the data could be decided by knowledge of phe metabolite blood levels. However, we only know of three such observations: Partington and Vickery (1974), using the enol-borate method for quantifying PPA, found in a 3-week-old infant plasma PPA levels in the range seen in older children.…”

Non‐invasive and Sensitive Fluorescence Detection of Phenylpyruvic Acid via a Guanidinomethyl‐modified Calixarene

“…Many methods, including ferric chloride assay, electrochemical sensing, chemiluminescence detection, HPLC-MS, GC-MS, have been reported to detect PPA in urine. [10][11][12][13][14][15][16] However, although with high sensitivity and excellent specificity, these methods are suffered from the complicated and laborious procedures, cost and time consumption, which is not conducive to home-based diagnosis and can impose a huge financial burden on families requiring long-time monitoring. [17] Consequently, it is urgent to develop a low-cost, simple, rapid, and sensitive method for PPA detection.…”

“…Therefore, developing methods to quantificationally detect PPA in urine is an ideal option. Many methods, including ferric chloride assay, electrochemical sensing, chemiluminescence detection, HPLC–MS, GC–MS, have been reported to detect PPA in urine [10–16] . However, although with high sensitivity and excellent specificity, these methods are suffered from the complicated and laborious procedures, cost and time consumption, which is not conducive to home‐based diagnosis and can impose a huge financial burden on families requiring long‐time monitoring [17] .…”

Absence of a significant renal threshold for two aromatic acids in phenylketonuric children over two years of age

“…Earlier reports [3,15] claimed that in older children the metabolites ofphe are excreted only when phe levels in blood rise above a so-called "threshold" of 0.4-0.9 mM (7-15 mg/100 ml). Two recent papers provide evidence that not only untreated patients with PKU variants (phe < 1.20 mM) but also patients under the more stringent therapeutic standards (0.50mM phe) of Bickel [1] are exposed to abnormally elevated concentrations of the metabolites of phe.…”