Shi Congcong, Li Sitao, Gao Yu, Deng Zhirong, Hao Hu, Xiao Xin
Inborn Errors of Metabolism Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Front Pediatr. 2022 Feb 9;10:824399. doi: 10.3389/fped.2022.824399. eCollection 2022.
Methylmalonic acidaemia (MMA) and ornithine transcarbamylase deficiency (OTCD) are both intoxication-type inborn errors of metabolism (IEM). Presently, genetic testing is the primary method for prenatally diagnosing these diseases. However, some reports have demonstrated that mass spectrometry approaches can prenatally diagnose some forms of inborn errors of metabolism using amniotic fluid. Therefore, in this study, genetic and mass spectrometry approaches were used for prenatally diagnosing MMA and OTCD. We collected amniotic fluid samples from 19 foetuses referred, 15 cases were referred for MMA and 4 for OTCD. Of the 15 MMA cases, seven were affected, as determined by genetic testing and the metabolite levels; the characteristic metabolites propionylcarnitine (C3), C3/acetylcarnitine (C2) ratio, methylmalonic acid and methylcitrate levels were significantly higher than the reference range. Eight foetuses were unaffected, and the C3, C3/C2 ratio, methylmalonic acid and methylcitrate levels were within the reference range. The C3, C3/C2, methylmalonic acid, and methylcitrate levels in the amniotic fluid significantly differed between the affected and unaffected foetuses ( = 0.0014, = 0.0014, = 0.0003, = 0.0014, respectively). Moreover, the homocysteine level increased in the amniotic fluid of affected foetuses with gene mutations. Of the four OTCD cases, genetic testing confirmed that two foetuses were affected and two were unaffected. However, the characteristic metabolite levels were within the reference range for all foetuses, including citrulline, orotic acid, and uracil. The genetic testing results were confirmed to be correct through the abortion tissue of the foetus and the postnatal follow-up. Our results suggest that mass spectrometry approaches are convenient method for improving the prenatal diagnosis of MMA. The characteristic metabolites C3, C3/C2, methylmalonic acid, and methylcitrate levels in amniotic fluid were reliable biochemical markers for the prenatal diagnosis of MMA.
甲基丙二酸血症（MMA）和鸟氨酸转氨甲酰酶缺乏症（OTCD）均为中毒型先天性代谢缺陷病（IEM）。目前，基因检测是这些疾病产前诊断的主要方法。然而，一些报告表明，质谱分析法可利用羊水对某些形式的先天性代谢缺陷进行产前诊断。因此，在本研究中，采用基因检测和质谱分析法对MMA和OTCD进行产前诊断。我们收集了19例转诊胎儿的羊水样本，其中15例因MMA转诊，4例因OTCD转诊。在15例MMA病例中，经基因检测和代谢物水平测定，7例为患病胎儿；特征性代谢物丙酰肉碱（C3）、C3/乙酰肉碱（C2）比值、甲基丙二酸和甲基柠檬酸水平显著高于参考范围。8例胎儿未患病，其C3、C3/C2比值、甲基丙二酸和甲基柠檬酸水平在参考范围内。患病胎儿和未患病胎儿羊水的C3、C3/C2、甲基丙二酸和甲基柠檬酸水平存在显著差异（分别为P = 0.0014、P = 0.0014、P = 0.0003、P = 0.0014）。此外，携带MMUT基因突变的患病胎儿羊水中同型半胱氨酸水平升高。在4例OTCD病例中，基因检测证实2例胎儿患病，2例未患病。然而，所有胎儿的特征性代谢物水平均在参考范围内，包括瓜氨酸、乳清酸和尿嘧啶。通过胎儿流产组织和产后随访证实基因检测结果正确。我们的结果表明，质谱分析法是改善MMA产前诊断的便捷方法。羊水中的特征性代谢物C3、C3/C2、甲基丙二酸和甲基柠檬酸水平是MMA产前诊断的可靠生化标志物。
