简化干血斑中 3-O-甲基多巴的测定：前瞻性筛查芳香族 l-氨基酸脱羧酶缺陷。
Streamlined determination of 3-O-methyldopa in dried blood spots: Prospective screening for aromatic l-amino-acid decarboxylase deficiency.
机构信息
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatric, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan; Center for Precision Medicine, China Medical University Hospital, Taichung City, Taiwan.
出版信息
Mol Genet Metab. 2023 Sep-Oct;140(1-2):107687. doi: 10.1016/j.ymgme.2023.107687. Epub 2023 Aug 15.
BACKGROUND
Aromatic L-amino-acid decarboxylase (AADC) deficiency diagnosis is often delayed by low disease awareness and specific laboratory examinations. We demonstrated that an elevated concentration of L-dopa metabolite 3-O-methyldopa (3-OMD) in dried blood spots could be integrated into a newborn screening program to detect AADC deficiency.
METHODS
DBS samples for amino acid and acylcarnitine analysis using NeoBase™2 reagents were also analyzed for the 3-OMD concentration using C-phenylalanine as an internal standard. For samples exceeding the pre-defined cutoffs, an additional spot was punched from the original filter paper for second-tier 3-OMD measurement by high performance liquid chromatography (HPLC)-MS/MS assay. Newborns with a 3-OMD concentration exceeding 500 ng/mL were referred for confirmatory testing.
RESULTS
From Feb. 2020 to Dec. 2022, 157,371 newborns were screened for AADC deficiency. Eight newborns exhibited an elevated 3-OMD concentration (839-5170 ng/mL). Among them, six newborns were confirmed to carry two pathogenic DDC variants, indicating an incidence of AADC deficiency of ∼1:26,000 (95% confidence interval: 1 in 12,021 to 1 in 57,228). During the follow-up period, all six patients developed typical symptoms of AADC deficiency.
CONCLUSION
The screening for 3-OMD, a target for AADC deficiency, could be easily integrated into the existing newborn screening programs and facilitate the future application for early diagnosis and effective treatment.
背景
由于对疾病的认识不足和缺乏特异性的实验室检查，芳香族 L-氨基酸脱羧酶（AADC）缺乏症的诊断常常被延误。我们证明，在干血斑中升高的 L-多巴代谢物 3-O-甲基多巴（3-OMD）浓度可以整合到新生儿筛查程序中，以检测 AADC 缺乏症。
方法
使用 NeoBase™2 试剂对 DBS 样本进行氨基酸和酰基肉碱分析，同时也使用 C-苯丙氨酸作为内标分析 3-OMD 浓度。对于超过预定义截止值的样本，从原始滤纸上再打孔一个点，用于通过高效液相色谱-质谱联用（HPLC-MS/MS）测定法进行二级 3-OMD 测量。3-OMD 浓度超过 500ng/mL 的新生儿被转介进行确认性检测。
结果
从 2020 年 2 月至 2022 年 12 月，对 157371 名新生儿进行了 AADC 缺乏症筛查。有 8 名新生儿表现出升高的 3-OMD 浓度（839-5170ng/mL）。其中，有 6 名新生儿被证实携带两种致病性 DDC 变异体，表明 AADC 缺乏症的发病率约为 1:26000（95%置信区间：1 比 12021 到 1 比 57228）。在随访期间，所有 6 名患者均出现了典型的 AADC 缺乏症症状。
结论
AADC 缺乏症的 3-OMD （AADC 缺乏症的一个靶点）筛查可以很容易地整合到现有的新生儿筛查程序中，为早期诊断和有效治疗提供便利。
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