Department of Pediatrics, Peking University People's Hospital, Beijing, China.
Department of Pediatrics, Peking University First Hospital, Beijing, China.
PLoS One. 2022 Mar 31;17(3):e0265766. doi: 10.1371/journal.pone.0265766. eCollection 2022.
Methylmalonic aciduria (MMA), a rare inherited disorder, is the most common organic aciduria in China, and prenatal diagnosis has contributed to its prevention. However, the prenatal diagnosis of MMA using cultured amniocytes or chorionic villi to detect gene mutations is exclusively applicable to families with a definite genetic diagnosis. To evaluate the reliability of mass spectrometry assays for the prenatal diagnosis of MMA, we conducted a retrospective study of our 10 years' experience.
This retrospective compare study reviewed the medical records for maternal and fetuses data for 287 mothers with a family history of MMA from June 2010 to December 2020. Methylmalonate and propionylcarnitine in cell-free amniotic fluid were measured using a stable isotope dilution method (GC/MS) and MS/MS-based method (LC/MS/MS). Total homocysteine (tHcy) was measured by fluorescence polarization immunoassay. Depending on the presence of disease-causing gene mutations in probands, gene studies on amniocytes from 222 pregnant women were performed.
For 222 fetuses of the families with definite genetic diagnosis, gene analyses were performed using cultured amniocytes. 52 fetuses were affected by MMA, whereas 170 were "unaffected". For GC/MS and LC/MS/MS, the specificity was 96.5% and 95.9%, sensitivity was 71.2% and 84.6%, respectively. The positive and negative predictive values were 86.0% and 91.6% and 86.3% and 95.3%, respectively. Propionylcarnitine/butyrylcarnitine ratio showed the highest accuracy and could thus serve as a sensitive indicator to identify those at a risk for MMA. When GC/MS and LC/MS/MS were performed in parallel, the specificity was 92.5% and sensitivity was 95.6%. When evaluating tHcy, the positive and negative predictive values were 95.0% and 96.1%, respectively. In 65 fetuses without family genetic diagnosis, 11 were finally confirmed to have MMA and 54 were "unaffected" by amniotic fluid biochemical assays. The 54 children showed normal urine organic acids and healthy development after birth.
Amniotic fluid biochemical assays using GC/MS and LC/MS/MS in parallel increased the accuracy of prenatal diagnosis of MMA. Propionylcarnitine is a more reliable marker than methylmalonic acid in amniotic fluid. Further, tHcy is recommended for the prenatal diagnosis of combined MMA and homocysteinemia.
甲基丙二酸血症（MMA）是一种罕见的遗传性疾病，是中国最常见的有机酸血症，产前诊断有助于其预防。然而，使用培养的羊水细胞或绒毛膜来检测基因突变进行 MMA 的产前诊断仅适用于具有明确遗传诊断的家庭。为了评估质谱分析用于 MMA 产前诊断的可靠性，我们对 10 年来的经验进行了回顾性研究。
本回顾性比较研究回顾了 2010 年 6 月至 2020 年 12 月期间 287 名有 MMA 家族史的母亲的母婴数据。使用稳定同位素稀释法（GC/MS）和基于 MS/MS 的方法（LC/MS/MS）测量羊水细胞中的甲基丙二酸和丙酰肉碱。总同型半胱氨酸（tHcy）通过荧光偏振免疫测定法测量。根据先证者是否存在致病基因突变，对 222 名孕妇的羊水细胞进行了基因研究。
对于 222 名有明确遗传诊断家族的胎儿，使用培养的羊水细胞进行了基因分析。52 名胎儿患有 MMA，而 170 名胎儿“未受影响”。对于 GC/MS 和 LC/MS/MS，特异性分别为 96.5%和 95.9%，灵敏度分别为 71.2%和 84.6%。阳性和阴性预测值分别为 86.0%和 91.6%和 86.3%和 95.3%。丙酰肉碱/丁酰肉碱比值显示出最高的准确性，因此可以作为识别 MMA 风险的敏感指标。当 GC/MS 和 LC/MS/MS 并行进行时，特异性为 92.5%，灵敏度为 95.6%。当评估 tHcy 时，阳性和阴性预测值分别为 95.0%和 96.1%。在 65 名无家族遗传诊断的胎儿中，最终有 11 名被证实患有 MMA，54 名“未受影响”的胎儿通过羊水生化检测。54 名儿童的尿液有机酸正常，出生后发育正常。
GC/MS 和 LC/MS/MS 并行使用羊水生化分析提高了 MMA 产前诊断的准确性。羊水丙酰肉碱比甲基丙二酸更可靠的标志物。此外，建议在 MMA 和高同型半胱氨酸血症的产前诊断中使用 tHcy。
