Blood Phenylalanine Fluctuation in Phenylketonuric Children Treated by BH4 or Low-phenylalanine Diet from Birth

Overview

Journal Sci Rep

Specialty Science

Date 2023 Jun 12

PMID 37308610

Authors

Maurane Theron

Elise Jeannesson

Marie Canton

Fares Namour

Abderrahim Oussalah

Francois Feillet

Arnaud Wiedemann

Affiliations

Soon will be listed here.

Abstract

The prognosis of phenylketonuria (PKU) is related to the quality of metabolic control all life-long. PKU treatment is based on a low-Phe diet, 6R-tetrahydrobiopterin (BH4) treatment for the BH4-responsive PKU patients or enzyme replacement therapy. Fluctuations in blood phenylalanine (Phe) concentrations may be an important determinant of intellectual outcome in patients with early and continuously treated phenylketonuria (PKU). The aim of this work is to study the fluctuation of Blood Phe in patients treated by BH4 from birth in comparison with patients treated by low-Phe diet. We conducted a retrospective study in a national reference center for PKU management. We compared mean phenylalanine blood concentration and its fluctuation in 10 BH4-responder patients (BH4R) and in 10 BH4 non-responder patients (BH4NR) treated from birth. The mean blood Phe concentration is similar between the two groups before 10 years of age (290 ± 135 (BH4R) vs. 329 ± 187 µmol/L, p = 0.066 (BH4NR)) while it is lower in the BH4R group after 10 years of age. (209 ± 69 vs. 579 ± 136 µmol/L, p = 0.0008). Blood Phe fluctuation is significantly lower in the BH4R group compared to the BH4NR group (70.2 ± 75.6 vs. 104.4 ± 111.6 µmol/L, p < 0.01) before 6 years of age. There are no significant differences observed on nutritional status, growth, and neuropsychological tests between the two groups. BH4 introduced in the neonatal period is associated with less blood Phe fluctuation before 6 years. Additional time and patients are required to determine if the decrease in Phe fluctuation would positively impact the long-term outcome of PKU patients.

References

Huijbregts S, de Sonneville L, Licht R, van Spronsen F, Verkerk P, Sergeant J . Sustained attention and inhibition of cognitive interference in treated phenylketonuria: associations with concurrent and lifetime phenylalanine concentrations. Neuropsychologia. 2001; 40(1):7-15. DOI: 10.1016/s0028-3932(01)00078-1. View

Burgard P, Rupp A, Konecki D, Trefz F, Schmidt H, Lichter-Konecki U . Phenylalanine hydroxylase genotypes, predicted residual enzyme activity and phenotypic parameters of diagnosis and treatment of phenylketonuria. Eur J Pediatr. 1996; 155 Suppl 1:S11-5. DOI: 10.1007/pl00014222. View

Salter A . The effects of meat consumption on global health. Rev Sci Tech. 2018; 37(1):47-55. DOI: 10.20506/rst.37.1.2739. View

Walter J, White F . Blood phenylalanine control in adolescents with phenylketonuria. Int J Adolesc Med Health. 2004; 16(1):41-5. DOI: 10.1515/ijamh.2004.16.1.41. View

Moats R, Moseley K, Koch R, Nelson Jr M . Brain phenylalanine concentrations in phenylketonuria: research and treatment of adults. Pediatrics. 2003; 112(6 Pt 2):1575-9. View

Vilaseca M, Lambruschini N, Gomez-Lopez L, Gutierrez A, Fuste E, Gassio R . Quality of dietary control in phenylketonuric patients and its relationship with general intelligence. Nutr Hosp. 2010; 25(1):60-6. View

Weglage J, Wiedermann D, Moller H, Ullrich K . Pathogenesis of different clinical outcomes in spite of identical genotypes and comparable blood phenylalanine concentrations in phenylketonurics. J Inherit Metab Dis. 1998; 21(2):181-2. DOI: 10.1023/a:1005328717095. View

Hood A, Grange D, Christ S, Steiner R, White D . Variability in phenylalanine control predicts IQ and executive abilities in children with phenylketonuria. Mol Genet Metab. 2014; 111(4):445-51. PMC: 4144445. DOI: 10.1016/j.ymgme.2014.01.012. View

Schlegel G, Scholz R, Ullrich K, Santer R, Rune G . Phenylketonuria: Direct and indirect effects of phenylalanine. Exp Neurol. 2016; 281:28-36. DOI: 10.1016/j.expneurol.2016.04.013. View

10.

Teissier R, Nowak E, Assoun M, Mention K, Cano A, Fouilhoux A . Maternal phenylketonuria: low phenylalaninemia might increase the risk of intra uterine growth retardation. J Inherit Metab Dis. 2012; 35(6):993-9. DOI: 10.1007/s10545-012-9491-0. View

11.

Blau N, van Spronsen F, Levy H . Phenylketonuria. Lancet. 2010; 376(9750):1417-27. DOI: 10.1016/S0140-6736(10)60961-0. View

12.

McCabe E, McCabe L, Mosher G, Allen R, BERMAN J . Newborn screening for phenylketonuria: predictive validity as a function of age. Pediatrics. 1983; 72(3):390-8. View

13.

Arnold G, Kramer B, Kirby R, Plumeau P, Blakely E, Sanger Cregan L . Factors affecting cognitive, motor, behavioral and executive functioning in children with phenylketonuria. Acta Paediatr. 1998; 87(5):565-70. DOI: 10.1080/08035259850158308. View

14.

Surtees R, Blau N . The neurochemistry of phenylketonuria. Eur J Pediatr. 2000; 159 Suppl 2:S109-13. DOI: 10.1007/pl00014370. View

15.

Guttler F, OLESEN E, WAMBERG E . Diurnal variations of serum phenylalanine in phenylketonuric children on low phenylalanine diet. Am J Clin Nutr. 1969; 22(12):1568-70. DOI: 10.1093/ajcn/22.12.1568. View

16.

Macdonald A . Diet and compliance in phenylketonuria. Eur J Pediatr. 2000; 159 Suppl 2:S136-41. DOI: 10.1007/pl00014375. View

17.

Viau K, Wengreen H, Ernst S, Cantor N, Furtado L, Longo N . Correlation of age-specific phenylalanine levels with intellectual outcome in patients with phenylketonuria. J Inherit Metab Dis. 2011; 34(4):963-71. DOI: 10.1007/s10545-011-9329-1. View

18.

Maillot F, Lilburn M, Baudin J, Morley D, Lee P . Factors influencing outcomes in the offspring of mothers with phenylketonuria during pregnancy: the importance of variation in maternal blood phenylalanine. Am J Clin Nutr. 2008; 88(3):700-5. DOI: 10.1093/ajcn/88.3.700. View

19.

Camp K, Parisi M, Acosta P, Berry G, Bilder D, Blau N . Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol Genet Metab. 2014; 112(2):87-122. DOI: 10.1016/j.ymgme.2014.02.013. View

20.

Pietz J, Kreis R, Boesch C, Penzien J, Rating D, HERSCHKOWITZ N . The dynamics of brain concentrations of phenylalanine and its clinical significance in patients with phenylketonuria determined by in vivo 1H magnetic resonance spectroscopy. Pediatr Res. 1995; 38(5):657-63. DOI: 10.1203/00006450-199511000-00005. View