European Journal of Pediatrics

, Volume 178, Issue 6, pp 903–911 | Cite as

Asymmetric dimethylarginine as a potential biomarker for management and follow-up of phenylketonuria

  • Fernando Andrade
  • Olatz Villate
  • María L. Couce
  • María A. Bueno
  • Carlos Alcalde
  • Javier de las Heras
  • Leticia Ceberio
  • Sergio Núñez-Marcos
  • Pablo Suárez Nambo
  • Luis Aldámiz-EchevarríaEmail author
Original Article


Phenylketonuria’s (PKU) treatment based on low-protein diet may affect other metabolic pathways, such as that of asymmetric dimethylarginine (ADMA). The aim of this study was to evaluate the reliability of ADMA as a biomarker of adequate metabolic control and possible nutritional risk in a long-term PKU patient population. One hundred and six dietary-treated PKU patients from four hospitals in Spain were enrolled in this cross-sectional study. Their lipid profile, total homocysteine, ADMA, and symmetric dimethylarginine (SDMA) concentrations were analyzed and compared with a control group. Sensitivity, specificity, and likelihood ratios of the proposed biomarker were calculated. PKU patients had statistically significant lower plasmatic ADMA, SDMA, and arginine concentrations as compared with the control group (p < 0.001). Significant correlations were found between ADMA, phenylalanine, and total homocysteine levels. The ADMA/creatinine ratio correlated with phenylalanine levels as metabolic control and nutritional risk in PKU patients. Its reliability as a management biomarker was studied with positive results. The ADMA/creatinine ratio might serve as an independent biomarker in the management of PKU patients, different from blood phenylalanine levels. It could be of particular usefulness to detect those who are following an unbalanced diet that could have long-term negative effects.

Conclusion: In this study, we have evaluated the reliability of ADMA as a potential biomarker of adequate metabolic control and possible nutritional risk in a long-term PKU patient population.

What is Known:

Although PKU individuals have lower values of ADMA even with blood Phe levels in the recommended range, little attention is payed to other metabolic pathways.

What is New:

ADMA could be used as new biomarker for PKU management and follow-up of the diet, after evaluating their reliability in a long-term PKU patient population.


Asymmetric dimethylarginine Biomarker Phenylketonuria 



Asymmetric dimethylarginine






Dimethylarginine dimethylamino hydrolase




Likelihood ratios


Nitric oxide


Nitric oxide synthase






Predictive values


Symmetric dimethylarginine


Total homocysteine



We thank all patients for kindly participating in the study. This work was supported in part by NUTRICIA S.L.R. (Madrid, Spain). Research in this paper was partially financed by Biocruces Bizkaia Health Research Institute and Carlos III Health Research Institute.

Authors’ contributions

LAE, MLC, MAB, CA, JH, and LC designed the study, conducted the research, and corrected the final version of the manuscript. FA, OV, SNM, and PSN analyzed samples and data and wrote the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

The study was approved by Clinical Research Ethics Committees at the hospitals involved and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

431_2019_3365_MOESM1_ESM.docx (27 kb)
ESM 1 (DOCX 27 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Fernando Andrade
    • 1
  • Olatz Villate
    • 1
  • María L. Couce
    • 2
  • María A. Bueno
    • 3
  • Carlos Alcalde
    • 4
  • Javier de las Heras
    • 1
    • 5
    • 6
  • Leticia Ceberio
    • 1
    • 7
  • Sergio Núñez-Marcos
    • 1
  • Pablo Suárez Nambo
    • 1
  • Luis Aldámiz-Echevarría
    • 1
    • 5
    • 6
    Email author
  1. 1.Group of MetabolismBiocruces Bizkaia Health Research InstituteBarakaldoSpain
  2. 2.Metabolic Disorders UnitSantiago de Compostela University HospitalSantiago de CompostelaSpain
  3. 3.Metabolic Disorders, Dietetics and Nutrition UnitVirgen del Rocío University HospitalSevillaSpain
  4. 4.Paediatrics UnitRío Hortega University HospitalValladolidSpain
  5. 5.Division of Pediatric MetabolismUniversity Cruces HospitalBarakaldoSpain
  6. 6.University of the Basque Country (UPV/EHU)BarakaldoSpain
  7. 7.Department of Internal MedicineUniversity Cruces HospitalBarakaldoSpain

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