广州地区新生儿遗传代谢病串联质谱法筛查结果及筛查性能评估

目的：了解广州地区新生儿遗传代谢病病种的分布特征、发病率及确诊患者的临床转归，优化筛查指标以提高串联质谱法遗传代谢病筛查效能。方法：采用串联质谱法对2015年1月至2020年12月在广州市出生的272?117名新生儿进行多种遗传代谢病筛查，以主要筛查指标2次超出阳性切值判断为筛查阳性，召回复查，对疑似母源性疾病连同母亲一并召回，复查仍阳性者进行生化及相关基因测序确诊。回顾性分析筛查结果、确诊病例的临床特点及转归，并进一步优化筛查指标。结果：在272?117名新生儿中，初筛阳性1808例，阳性率为0.66%；召回复查1738例，召回率为96.13%；临床诊断时间中位数为15?d，确诊新生儿遗传代谢病79例，包括氨基酸代谢病23例、有机酸代谢病17例及脂肪酸氧化障碍39例。共计21个病种，常见病种为原发性肉碱缺乏症（26.6%）、甲基丙二酸血症（12.7%）及苯丙氨酸羟化酶缺乏症（11.4%），发现假阴性病例4例，均为citrin蛋白缺乏症。272?117名新生儿遗传代谢病筛查总体发病率约为1/3444，阳性预测值为4.5%。确诊母亲患者32例，包括原发性肉碱缺乏症30例、异丁酰基辅酶A脱氢酶缺乏症及3-甲基巴豆酰辅酶A羧化酶缺乏症各1例。遗传代谢病筛查总体检出率为1/2451。所有确诊病例随访至今，5例重型患儿（枫糖尿症1例、单纯型甲基丙二酸血症2例、肉碱-酰基肉碱移位酶缺乏症2例）早期死亡，10例有机酸代谢病患儿出现轻度精神运动发育迟缓。优化各病种筛查指标后，初筛阳性数降至903例，阳性预测值提高至9.1%，未遗漏确诊病例。结论：广州地区新生儿脂肪酸氧化障碍发病率相对较高，串联质谱法能有效筛查多种遗传代谢病，优化筛查指标可提高筛查效能。

Screening for neonatal inherited metabolic disorders by tandem mass spectrometry in Guangzhou

Objective:To analyze the screening results for inherited metabolic disorders (IMD) in newborns by tandem mass spectrometry (MS/MS) in Guangzhou.Methods:A total of 272?117 newborns in Guangzhou from Jan 2015 to Dec 2020 were screened for IMD by MS/MS in Guangzhou Newborn Screening Center. When the primary screening was positive, the newborns and their mothers were recalled. For those with positive in re-examination, the biochemical and related genetic analysis were required for confirmation. The screening results, clinical characteristics and outcomes of the confirmed cases were retrospectively analyzed and the performance was optimized. Results:Among 272?117 neonates, 1808 (0.66%) cases were positive in primary screening, and 1738 cases (96.13%) were recalled for review. The median clinical diagnosis time was 15 d after birth. A total of 79 cases of IMD were diagnosed, including 23 with aminoacidopathy, 17 with disorder of organic acid metabolism and 39 with fatty acid oxidation disorders, involving 21 diseases. The incidence rate was 1/3444 in newborns, and the positive predictive value of 4.5%. Four false negative cases were found, all of them were citrin deficiency. The common diseases were primary carnitine deficiency (26.6%), methylmalonic aciduria (12.7%) and phenylalanine hydroxylase deficiency (11.4%). The mothers of 32 cases were confirmed, including 30 cases of primary carnitine deficiency, 1 case of isobutyl-coenzyme A dehydrogenase deficiency and 1 case of 3-methylcromaryl coenzyme A carboxylase deficiency. The detection rate was 1/2451 in total population. During the follow-up, most patients remain asymptomatic, except for 5 severe cases who died early (1 case of maple syrup urine disease, 2 cases of isolated methylmalonic acidurmia, and 2 cases of carnitine-acylcarnitine translocase deficiency); and 10 cases of organic acid metabolism disorders developed mild psychomotor developmental retardation. After optimizing the screening indicators, the number of initial screening positives dropped to 903, and the positive predictive value increased to 9.1%, and no confirmed cases were missed. Conclusion:The incidence rate of fatty acid oxidation disorders is high in Guangzhou. A variety of IMD can be effectively screened out by MS/MS, and the screening performance can be improved by optimizing screening indicators.