Children and adolescents with phenylketonuria display fluctuations in their blood phenylalanine levels

Feldmann, Reinhold; Schallert, Michael; Nguyen, Thi Kim Anh; Och, Ulrike; Rutsch, Frank; Weglage, Josef

doi:10.1111/apa.14517

Cited by 12 publications

(16 citation statements)

References 15 publications

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“…A review of the literature suggests that it is the cumulative effect of day-to-day fluctuations over months and years that may affect cognition impacting on intelligence quotients [25,26]. A recent short study over 26 weeks by Feldmann concluded that Phe fluctuations were negatively correlated with IQ in children with mild PKU [27]. Although no study has definitively shown that fluctuation in Phe affects neurocognitive outcome, evidence suggests there is a correlation, and therefore the stabilization of Phe concentrations should be the aim of treatment.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Glycomacropeptide versus Amino Acids on Phenylalanine and Tyrosine Variability over 24 Hours in Children with PKU: A Randomized Controlled Trial

Daly¹,

Evans²,

Chahal³

et al. 2019

Nutrients

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Introduction: In phenylketonuria (PKU), evidence suggests that casein glycomacropeptide supplemented with rate-limiting amino acids (CGMP-AA) is associated with better protein utilisation and less blood phenylalanine (Phe) variability. Aim: To study the impact of CGMP-AA on blood Phe variability using 3 different dietary regimens in children with PKU. Methods: This was a 6-week randomised controlled cross-over study comparing CGMP-AA vs. Phe-free l-amino acids (l-AA) assessing blood Phe and tyrosine (Tyr) variability over 24 h in 19 children (7 boys) with PKU, with a median age of 10 years (6–16). Subjects were randomised to 3 dietary regimens: (1) R1, CGMP-AA and usual dietary Phe (CGMP + Phe); (2) R2, CGMP-AA − Phe content of CGMP-AA from usual diet (CGMP − Phe); and (3) R3, l-AA and usual dietary Phe. Each regimen was administered for 14 days. Over the last 48 h on days 13 and 14, blood spots were collected every 4 h at 08 h, 12 h, 16 h, 20 h, 24 h, and 04 h. Isocaloric intake and the same meal plan and protein substitute dosage at standardised times were maintained when blood spots were collected. Results: Eighteen children completed the study. Median Phe concentrations over 24 h for each group were (range) R1, 290 (30–580), R2, 220 (10–670), R3, 165 (10–640) μmol/L. R1 vs. R2 and R1 vs. R3 p < 0.0001; R2 vs. R3 p = 0.0009. There was a significant difference in median Phe at each time point between R1 vs. R2, p = 0.0027 and R1 vs. R3, p < 0.0001, but not between any time points for R2 vs. R3. Tyr was significantly higher in both R1 and R2 [70 (20–240 μmol/L] compared to R3 [60 (10–200) μmol/L]. In children < 12 years, blood Phe remained in the target range (120–360 μmol/L), over 24 h, for 75% of the time in R1, 72% in R2 and 64% in R3; for children aged ≥ 12 years, blood Phe was in target range (120–600 μmol/L) in R1 and R2 for 100% of the time, but 64% in R3. Conclusions: The residual Phe in CGMP-AA increased blood Phe concentration in children. CGMP-AA appears to give less blood Phe variability compared to l-AA, but this effect may be masked by the increased blood Phe concentrations associated with its Phe contribution. Reducing dietary Phe intake to compensate for CGMP-AA Phe content may help.

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Section: Discussionmentioning

confidence: 99%

The Effect of Glycomacropeptide versus Amino Acids on Phenylalanine and Tyrosine Variability over 24 Hours in Children with PKU: A Randomized Controlled Trial

Daly¹,

Evans²,

Chahal³

et al. 2019

Nutrients

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“…However, some authors highlight the variability in Phe levels as a stronger predictor of cognitive performance in ETPKU patients than the yearly median of blood Phe levels [22,26]. This impact of Phe levels fluctuations could be even especially meaningful for m-PKU patients [27]. Finally, our sample size remained limited to 39 patients.…”

Section: Discussionmentioning

confidence: 99%

Determining factors of the cognitive outcome in early treated PKU: A study of 39 pediatric patients

Herenger

Maes

François

et al. 2019

Molecular Genetics and Metabolism Reports

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Phenylketonuria (PKU) is a disorder of phenylalanine metabolism, characterized by a neurotoxic phenylalanine (Phe) accumulation, and treatable with a life-long Phe-restricted diet. Though early and continuously treated PKU (ETPKU) patients exhibit normal IQ, their cognitive outcome remains suboptimal. In this longitudinal study, we aimed at assessing the determinants of IQ subscales and quality of metabolic control in ETPKU children. We collected blood Phe levels, numbers of blood samples for Phe determination, parents' socio-professional categories and school achievement data of 39 classical and moderate ETPKU patients who underwent two cognitive evaluations performed by the same neuropsychologist (at 6.5 and 10y of mean age). We then sought to evaluate the determinants of 1) the changes in their IQ between the two testings (delta IQ) and 2) the quality of metabolic control (evaluated by the median Phe levels during the year before the second test) with multivariate regression analysis. Though in the normal range, mean total IQ slightly decreased between the two evaluations, and we observed a better verbal than performance outcome. Modeling the determining factors of the delta IQ, we found a significant influence of the number of blood samples (β = 0.46, 95%CI = 0.13 to 0.79, p < 0.01) and the moderate type of PKU (β = 12.40, 95%CI = 3.69 to 21.11, p < 0.01) on verbal outcome. We failed to find any determining factors that would statistically influence metabolic control. In conclusion, ETPKU cognitive outcome is influenced by a network of metabolic and environmental factors, which is not reflected by the sole metabolic control.

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“…Feldman et al (2019) found that persons with early treated PAH deficiency developed an IQ within the normal range, but still had lower IQ scores than their unaffected counterparts. Feldman et al (2018) found in patients with mild PAH deficiency, that full scale IQ was negatively correlated with fluctuating Phe levels; for patients with classical PKU, the opposite was true.…”

Section: Neurocognitive Complicationsmentioning

confidence: 99%

Neurocognitive, neuropsychiatric, and neurological outcomes associated with phenylalanine hydroxylase deficiency: Assessment considerations for nurse practitioners

Lowe

DeLuca

Arnold

2020

Specialist Pediatric Nursing

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PurposeThe purpose of this article is to review literature for neurocognitive, neuropsychiatric, neurological complications associated with phenylalanine hydroxylase (PAH) deficiency. The goal is to familiarize nurse practitioners with treatment and monitoring guidelines for persons living with the disorder.ConclusionsAppropriate treatment can maximize neurocognitive and neuropsychiatric outcomes.Practice ImplicationsNurse practitioners can help persons with PAH deficiency through education and providing appropriate referrals and by supporting disease‐specific treatment.

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Children and adolescents with phenylketonuria display fluctuations in their blood phenylalanine levels

Abstract: The blood phenylalanine levels of patients with mild PKU showed minor interindividual differences, which may have allowed fluctuations to exert a negative effect on the FSIQ.

Cited by 12 publications

References 15 publications

The Effect of Glycomacropeptide versus Amino Acids on Phenylalanine and Tyrosine Variability over 24 Hours in Children with PKU: A Randomized Controlled Trial

The Effect of Glycomacropeptide versus Amino Acids on Phenylalanine and Tyrosine Variability over 24 Hours in Children with PKU: A Randomized Controlled Trial

Determining factors of the cognitive outcome in early treated PKU: A study of 39 pediatric patients

Neurocognitive, neuropsychiatric, and neurological outcomes associated with phenylalanine hydroxylase deficiency: Assessment considerations for nurse practitioners

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