Serum Amino Acid Profiling in Patients with Alkaptonuria Before and After Treatment with Nitisinone

  • A. S. DavisonEmail author
  • B. P. Norman
  • E. A. Smith
  • J. Devine
  • J. Usher
  • A. T. Hughes
  • M. Khedr
  • A. M. Milan
  • J. A. Gallagher
  • L. R. Ranganath
Research Report
Part of the JIMD Reports book series (JIMD, volume 41)


Background: Alkaptonuria (AKU) is a rare inherited disorder of the tyrosine metabolic pathway. Our group is evaluating the use of the homogentisic acid-lowering agent nitisinone in patients with AKU. A major biochemical consequence of this treatment is hypertyrosinaemia. Herein we report the concentration of 20 serum amino acids over a 36-month period pre- and post-treatment with nitisinone.

Methods: Fasting serum samples were collected at baseline (pre-nitisinone), 3 (2 mg nitisinone every other day), 6, 12, 24 and 36 (2 mg nitisinone daily) months. Amino acids were measured using the Biochrom 30 high-performance liquid chromatography cation exchange system with ninhydrin detection.

Results: Fifty patients [21 female, mean age (±standard deviation) 54.1 (15.6) years (range 25–75); 29 male, mean age 49.3 (11.6) years (range 22–70 years)] were included. Following treatment mean tyrosine concentrations increased seven- to eight-fold (baseline, 69.8 μmol/L; 3 months, 670.7 μmol/L; 6 months, 666.4 μmol/L; 12 months, 692.9 μmol/L; 24 months, 649.4 μmol/L; 36 months, 724.8 μmol/L, p = <0.001 for all visits compared to baseline).

At baseline mean phenylalanine, aspartic acid and arginine were outside the normal reference range. Following treatment the ratios of phenylalanine/tyrosine, phenylalanine/large neutral amino acids, arginine/branched chain amino acids and branched chain/aromatic amino acids decreased (p = <0.05), and the tyrosine/large neutral amino acid ratio increased (p = <0.0001).

Conclusions: Marked hypertyrosinaemia was observed following treatment with nitisinone. Noteworthy changes were also observed in the ratio of several amino acids following treatment with nitisinone suggesting that the availability of amino acids for neurotransmitter biosynthesis and liver function may be altered following treatment with nitisinone.


Alkaptonuria Amino acids Nitisinone 



Aromatic amino acids




Branched chain amino acids


Homogentisic acid




Hydroxyphenylpyruvic acid dioxygenase


Tyrosinaemia type 1


Large neutral amino acid transporter


Large neutral amino acids


National Alkaptonuria Centre

Supplementary material

472895_1_En_109_MOESM1_ESM.pptx (1.2 mb)
Fig. S1 Serum amino acid concentrations (mean ± standard deviation, μmol/L) in patients attending the National Alkaptonuria Centre over a 36-month period. All samples were collected in a fasted state (overnight fast >8 h). Baseline refers to pre-nitisinone therapy; at 3 months, patients received 2 mg nitisinone every other day; after 3 months, patients received 2 mg nitisinone daily. (a)–(f) amidic, (g)–(i) basic, (j)–(l) aromatic, (m)–(n) acidic, (o)–(p) hydroxylic, (q)–(r) sulphur containing and (s)–(t) aliphatic amino acids (PPTX 1245 kb)


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Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  • A. S. Davison
    • 1
    • 2
    Email author
  • B. P. Norman
    • 2
  • E. A. Smith
    • 3
  • J. Devine
    • 1
  • J. Usher
    • 1
  • A. T. Hughes
    • 1
    • 2
  • M. Khedr
    • 1
    • 2
  • A. M. Milan
    • 1
    • 2
  • J. A. Gallagher
    • 2
  • L. R. Ranganath
    • 1
    • 2
  1. 1.Liverpool Clinical Laboratories, Department of Clinical Biochemistry and Metabolic MedicineRoyal Liverpool University Hospitals TrustLiverpoolUK
  2. 2.Bone and Joint Research Group, Musculoskeletal BiologyUniversity of LiverpoolLiverpoolUK
  3. 3.Department of Clinical BiochemistryAlder Hey Children’s HospitalLiverpoolUK

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