Background

Aromatic L-amino acid decarboxylase (AADC) deficiency is a primary neurotransmitter defect of the biosynthesis of catecholamines and serotonin. The phenotype consists of varying degrees of neurological impairment, including motor and non-motor symptoms. Treatment outcomes correlate with the time point of diagnosis and treatment initiation; therefore, reliable diagnostic markers are necessary. Increased vanillactic acid (VLA) concentrations in the analysis of organic acids in urine have been reported in AADC deficiency. However, this elevation is often subtle and easily missed. In this study, we evaluate the semi-quantitative determination of VLA and vanillylmandelic acid (VMA) concentrations and establish the ratio of a VLA/VMA as a novel diagnostic marker for AADC deficiency.

Methods

Urine samples obtained from 10,095 non-AADC deficient controls and 14 confirmed AADC deficient patients were used for organic acid analysis by liquid-liquid extraction of the acidified samples and gas chromatographic-mass spectrometric separation after trimethylsilylation. The semi-quantitative determination of VLA and VMA concentrations and the calculation of a VLA/VMA ratio were evaluated as a diagnostic marker for AADC deficiency.

Results

The mean VLA and VMA concentrations in 10,095 non-AADCD samples was 0.3 mmol/mol creatinine (SD = 1.18, range 0–57.79) and 5.59 mmol/mol creatinine (SD = 3.87, range 0.04–60.62), respectively. The mean concentration of VLA in 14 patient-derived samples was 10.24 mmol/mol creatinine, (SD = 11.58, range = 0.37–33.06) and 0.45 mmol/mol creatinine for VMA (SD = 0.29, range 0.11–1.27). The mean VLA/VMA ratio in non-AADC controls was 0.07 (SD = 0.37, range 0.0–23.24), whereas AADC deficient patients revealed a mean VLA/VMA ratio of 23.16 (SD = 22.83, range 0.97–74.1). The VLA/VMA ratio thus allows a reliable identification of patients with AADC deficiency, especially in the young age cohort as it decreases with age. To take this into account, age-adjusted thresholds have been developed. .

Conclusion

Determination of individual concentrations of VLA and VMA in urine does not allow a reliable diagnosis of AADC deficiency. In this study, we could demonstrate that a semi-quantitative analysis of organic acids in urine allows the formation of metabolite ratios and that the VLA/VMA ratio is a reliable, easy accessible, new parameter for the diagnosis of AADC deficiency.

中文翻译：

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半定量检测尿液中香草酸/香草醛酸比率是一种可靠的诊断指标，可用于诊断芳香族L-氨基酸脱羧酶缺乏症。

背景

芳香族L-氨基酸脱羧酶（AADC）缺陷是儿茶酚胺和5-羟色胺生物合成的主要神经递质缺陷。该表型由不同程度的神经系统损害组成，包括运动和非运动症状。治疗结果与诊断和治疗开始的时间点相关。因此，可靠的诊断标记是必要的。在AADC缺乏症中，尿中有机酸分析中的香草酸（VLA）浓度增加。但是，这种高度通常很微妙，很容易错过。在这项研究中，我们评估半定量测定VLA和香草醛酸（VMA）的浓度，并建立VLA / VMA之比作为AADC缺乏症的新型诊断标记。

方法

从10,095名非AADC缺陷对照和14名经确证的AADC缺陷患者获得的尿液样品通过酸化样品的液-液萃取和三甲基甲硅烷基化后的气相色谱-质谱分离法用于有机酸分析。VLA和VMA浓度的半定量测定以及VLA / VMA比的计算被评估为AADC缺乏症的诊断指标。

结果

在10,095个非AADCD样本中，VLA和VMA的平均浓度分别为0.3 mmol / mol肌酐（SD = 1.18，范围0–57.79）和5.59 mmol / mol肌酐（SD = 3.87，范围0.04–60.62）。14个患者来源样品中VLA的平均浓度为10.24 mmol / mol肌酐（SD = 11.58，范围= 0.37-33.06）和VMA的0.45 mmol / mol肌酐（SD = 0.29，范围0.11-1.27）。非AADC对照者的平均VLA / VMA比为0.07（SD = 0.37，范围为0.0-23.24），而AADC缺乏症患者的平均VLA / VMA比为23.16（SD = 22.83，范围为0.97-74.1）。因此，VLA / VMA比值可以可靠地识别出患有AADC缺乏症的患者，尤其是在年轻的队列中，随着年龄的增长而降低。考虑到这一点，已经制定了年龄调整的阈值。。

结论

确定尿液中VLA和VMA的单独浓度不能可靠地诊断AADC缺乏症。在这项研究中，我们可以证明尿液中有机酸的半定量分析可以形成代谢物比率，而VLA / VMA比率是诊断AADC缺乏症的可靠，容易获得的新参数。