Davison A S, Norman B P, Smith E A, Devine J, Usher J, Hughes A T, Khedr M, Milan A M, Gallagher J A, Ranganath L R
Liverpool Clinical Laboratories, Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospitals Trust, Liverpool, UK.
Bone and Joint Research Group, Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
JIMD Rep. 2018;41:109-117. doi: 10.1007/8904_2018_109. Epub 2018 May 13.
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.
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.
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).
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.
黑尿症（AKU）是一种罕见的酪氨酸代谢途径遗传性疾病。我们的研究小组正在评估使用降尿黑酸药物尼替西农治疗AKU患者的效果。这种治疗的一个主要生化后果是高酪氨酸血症。在此，我们报告了尼替西农治疗前后36个月内20种血清氨基酸的浓度。
在基线（尼替西农治疗前）、3个月（每隔一天服用2mg尼替西农）、6个月、12个月、24个月和36个月（每天服用2mg尼替西农）时采集空腹血清样本。使用配备茚三酮检测的Biochrom 30高效液相色谱阳离子交换系统测量氨基酸。
纳入了50名患者[21名女性，平均年龄（±标准差）54.1（15.6）岁（范围25 - 75岁）；29名男性，平均年龄49.3（11.6）岁（范围22 - 70岁）]。治疗后，平均酪氨酸浓度增加了7至8倍（基线时为69.8μmol/L；3个月时为670.7μmol/L；6个月时为666.4μmol/L；12个月时为692.9μmol/L；24个月时为649.4μmol/L；36个月时为724.8μmol/L，与基线相比，所有随访时p均<0.001）。基线时，平均苯丙氨酸、天冬氨酸和精氨酸超出正常参考范围。治疗后，苯丙氨酸/酪氨酸、苯丙氨酸/大中性氨基酸、精氨酸/支链氨基酸和支链/芳香族氨基酸的比值降低（p<0.05），而酪氨酸/大中性氨基酸比值升高（p<0.0001）。
尼替西农治疗后观察到明显的高酪氨酸血症。尼替西农治疗后还观察到几种氨基酸比值的显著变化，这表明尼替西农治疗后神经递质生物合成和肝功能的氨基酸可用性可能会发生改变。
