Background

Aromatic L-amino acid decarboxylase (AADC) deficiency and tyrosine hydroxylase (TH) deficiency are rare inherited disorders of monoamine neurotransmitter synthesis which are typically diagnosed using cerebrospinal fluid examination of monoamine neurotransmitter metabolites. Until now, it has not been systematically studied whether analysis of monamine neurotransmitter metabolites in blood or urine has diagnostic value as compared to cerebrospinal fluid examination, or whether monoamine neurotransmitter metabolites in these peripheral body fluids is useful to monitor treatment efficacy.

Methods

Assessment, both by literature review and retrospective analysis of our local university hospital database, of monoamine neurotransmitter metabolites in urine, blood and cerebrospinal fluid, and serum prolactin levels, before and during treatment in patients with AADC and TH deficiency.

Results

In AADC deficiency, 3-O-methyldopa in serum or dried blood spots was reported in 34 patients and found to be (strongly) increased in all, serotonin in serum was decreased in 7/7 patients. Serum prolactin was increased in 34/37 and normal in 3 untreated patients. In urine, dopamine was normal or increased in 21/24 patients, 5-hydroxyindoleacetic acid was decreased in 9/10 patients, and vanillactic acid was increased in 19/20 patients. No significant changes were seen in monoamine neurotransmitter metabolites after medical treatment, except for an increase of homovanillic acid in urine and cerebrospinal fluid after levodopa therapy, sometimes even in absence of a clinical response. After gene therapy, cerebrospinal fluid homovanillic acid increased in most patients (8/12), but 5-hydroxyindoleacetic acid remained unchanged in 9/12 patients.

In TH deficiency, serum prolactin was increased in 12/14 and normal in the remaining untreated patients. Urinary dopamine was decreased in 2/8 patients and normal in 6. Homovanillic acid concentrations in cerebrospinal fluid increased upon levodopa treatment, even in the absence of a clear treatment response.

Conclusions

This study confirms that cerebrospinal fluid is the most informative body fluid to measure monoamine neurotransmitter metabolites when AADC or TH deficiency is suspected, and that routine follow-up of cerebrospinal fluid measurements to estimate treatment response is not needed. 3-O-methyldopa in dried blood spots and vanillactic acid in urine are promising peripheral biomarkers for diagnosis of AADC deficiency. However, in many patients with TH or AADC deficiency dopamine in urine is normal or increased thereby not reflecting the metabolic block. The value of serum prolactin for follow-up of AADC and TH deficiency should be further studied.

中文翻译：

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TH和AADC缺乏症的血、尿、脑脊液分析及治疗效果

背景

芳香族 L-氨基酸脱羧酶 (AADC) 缺乏症和酪氨酸羟化酶 (TH) 缺乏症是单胺类神经递质合成的罕见遗传性疾病，通常使用单胺类神经递质代谢物的脑脊液检查来诊断。到目前为止，尚未系统地研究血液或尿液中单胺神经递质代谢物的分析与脑脊液检查相比是否具有诊断价值，或者这些外周体液中的单胺神经递质代谢物是否有助于监测治疗效果。

方法

通过文献回顾和对我们当地大学医院数据库的回顾性分析，评估 AADC 和 TH 缺乏症患者治疗前和治疗期间尿液、血液和脑脊液中的单胺神经递质代谢物以及血清催乳素水平。

结果

在 AADC 缺乏时，3- O在 34 名患者中报告了血清或干血斑中的甲基多巴，并且发现所有患者（强烈）增加，7/7 患者血清中的血清素降低。34/37 的血清催乳素升高，3 名未经治疗的患者正常。尿液中，21/24 例患者多巴胺正常或升高，9/10 例患者 5-羟基吲哚乙酸降低，19/20 例患者香草酸升高。药物治疗后单胺类神经递质代谢物没有明显变化，除了左旋多巴治疗后尿液和脑脊液中的高香草酸增加，有时甚至没有临床反应。基因治疗后，大多数患者（8/12）的脑脊液高香草酸增加，但 9/12 患者的 5-羟基吲哚乙酸保持不变。

在 TH 缺乏症中，12/14 的血清催乳素升高，其余未治疗患者的血清催乳素正常。2/8 患者的尿多巴胺减少，6 人正常。左旋多巴治疗后脑脊液中的高香草酸浓度增加，即使没有明确的治疗反应。

结论

本研究证实，当怀疑 AADC 或 TH 缺乏时，脑脊液是测量单胺神经递质代谢物信息最丰富的体液，不需要常规随访脑脊液测量以估计治疗反应。干血斑中的3 - O-甲基多巴和尿液中的香草酸是用于诊断 AADC 缺乏的有希望的外周生物标志物。然而，在许多 TH 或 AADC 缺乏的患者中，尿液中的多巴胺正常或增加，因此不能反映代谢阻滞。血清催乳素对 AADC 和 TH 缺乏症的随访价值有待进一步研究。