新生儿酪氨酸血症筛查及基因谱分析

目的: 探讨酪氨酸血症（HT）在中国南方人群中的流行、分布、基因谱特征和预后。方法: 回顾性分析2013年11月至2018年11月以酪氨酸/琥珀酰丙酮增高为关键指标，经串联质谱筛查检出并结合基因检测诊断为HT的新生儿的资料。结果: 共2 188 784名新生儿接受筛查，酪氨酸、琥珀酰丙酮正常范围（0.5%~95.5%）分别为34.5~280.0 μmol/L、0.16~2.58 μmol/L。诊断HT 3例，患病率为1:729 595。其中HTⅠ型（FAH基因c.455G>A纯合变异）、Ⅱ型（TAT基因c.890G>T及c.408+1G>A复合杂合变异）、Ⅲ型（HPD基因c.257T>C纯合变异）各1例，后两者为新发突变。HT筛查阳性预测值为3.4%。Ⅰ型患儿初筛酪氨酸666.9 μmol/L，琥珀酰丙酮3.87 μmol/L，伴胆汁淤积，肝酶、乳酸轻度增高，虽经特殊奶粉（去除酪氨酸、苯丙氨酸）治疗，2月龄时仍死于家中；Ⅱ型患儿初筛酪氨酸625.6 μmol/L，琥珀酰丙酮正常，经特殊奶粉治疗，酪氨酸控制在正常范围，随访至7个月，体格、行为发育正常，未见眼、皮肤病变；Ⅲ型患儿初筛酪氨酸1035.3 μmol/L，琥珀酰丙酮正常，不规则应用特殊奶粉治疗，随访至29个月，酪氨酸在532.1~1060.3 μmol/L波动，体格发育、智力发育正常。结论: HT在中国南方人群中罕见，三型在人群中均有分布，基因谱分散。Ⅰ型患儿建议早期联合尼替西农治疗，否则预后可能不良；Ⅱ型患儿如早期采取特殊饮食治疗，一般预后良好；Ⅲ型患儿的预后有待进一步积累资料后确定。

Screening for hereditary tyrosinemia and genotype analysis in newborns

Objective: To analyze the results of screening for hereditary tyrosinemia (HT) in newborns and its clinical features and genotype. Methods: The HT screening was conducted among 2 188 784 newborns from November 2013 to November 2018. The tyrosine (TYR)/ succinylacetone (SA) levels were detected by tandem mass spectrometry (MS-MS). The clinical characteristics, genetic results and following up data of identified patients were analyzed. Results: The normal ranges (0.5%-95.5%) of TYR and SA were 34.5-280.0 μmol/L and 0.16-2.58 μmol/L, respectively. Three HT cases were confirmed with a detection rate of 1:729 595. There was 1 case of tyrosinemia type Ⅰ (HTⅠ) (homozygous variations of c.455G>A in FAH gene), 1 case of tyrosinemia type Ⅱ(HTⅡ) (heterozygous variations of c.890G>T and c.408+1G>A in TAT gene), and 1 case of tyrosinemia type Ⅲ (HT Ⅲ) (homozygous variations of c.257T>C in HPD gene). The variations of c.890G>T, c.4081G>A of TAT and c.257T>C of HPD were novel. The positive predictive value of the screening was 3.4%. Case 1 (HTⅠ) with TYR and SA values of 666.9 μmol/L and 3.87 μmol/L respectively, presented cholestasis, mild elevated of liver enzyme and lactic acid, who were although fed with TYR and phenylalanine free milk, but died at 2 months of age. Case 2 (HTⅡ) with higher TYR (625.6 μmol/L) and normal SA at screening, received medical milk treatment; during the 7 months of follow-up the baby showed normal score of Bayley assessment and normal TYR without eye and skin symptoms. Case 3 (HT Ⅲ) with TYR of 1035.3 μmol/L and normal SA at screening; during the 29 months of follow-up the value of TYR fluctuated from 532.1 μmol/L to 1060.3 μmol/L due to irregular medical milk treatment, while the score of Bayley assessment was normal. Conclusions: HT is rare in the southern Chinese population, and the gene spectrum is scattered. Early treatment with nitisinone is recommended in children with HTⅠ, otherwise the prognosis is poor; the prognosis of children with HTⅡ is good when early treated with special diet; the prognosis of children with HTⅢ needs to be determined with more data.