Giguère Yves, Berthier Marie-Thérèse
Programme de dépistage néonatal sanguin, CHU de Québec - Université Laval, 10, rue de l'Espinay, Québec, QC, G1L 3L5, Canada.
Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec City, QC, Canada.
Adv Exp Med Biol. 2017;959:139-146. doi: 10.1007/978-3-319-55780-9_13.
Hereditary tyrosinemia type I (HTI) is a rare autosomal recessive disorder caused by a fumarylacetoacetate hydrolase (FAH) deficiency. If untreated, its acute form is characterized by hepatic failure, renal dysfunction and neurological crisis, and may lead to death. Due to a genetic founder effect in the French-Canadian population, the prevalence of HTI is increased in the province of Quebec (1/19 819), with the IVS12 + 5G>A (1062 + 5G>A) splice site mutation responsible for more than 90% of mutated alleles. Universal newborn screening for (HT1) was thus established in 1970, and close to four million infants have been tested so far, allowing to identify 185 of the 190 affected newborns. During the 1970-1997 period, 2,249,000 newborns were screened at 3-7 days of life on dried filter paper blood spots by tyrosine (Tyr) concentration followed by indirect colorimetric semi-quantitative and quantitative (Q) succinylacetone (SA) testing (red blood cells δ-aminolevulinate dehydratase inhibition), with immunoreactive FAH as the confirmatory test. This approach allowed to identify 118 of 123 affected newborns. In 1998, owing to earlier hospital discharge and increased rate of breastfeeding, four cases were missed within the same year as the discriminating power of blood Tyr became inadequate. Thus, the screening algorithm was modified: indirect semi-quantitative SA measurement became the first-tier test between 1998 and 2014, and direct SA measurement by tandem mass spectrometry (MS/MS) was implemented in 2014, followed by indirect quantitative SA measurement as second tier test. Confirmation is performed by plasmatic amino acid profile and molecular testing. During the 1998-2016 period, more than 1,5 million neonates have been tested (90% sampled between 24 and 48 h of life): 67 of the 67 HTI cases were identified. Both indirect and direct SA measurement as the initial HTI screening test proved to be highly sensitive and specific, with positive and negative predicting value of 79% and 100% respectively.
遗传性I型酪氨酸血症（HTI）是一种罕见的常染色体隐性疾病，由延胡索酰乙酰乙酸水解酶（FAH）缺乏引起。若不治疗，其急性形式的特征为肝功能衰竭、肾功能障碍和神经危机，并可能导致死亡。由于法裔加拿大人种群中的遗传奠基者效应，HTI在魁北克省的患病率有所增加（1/19819），IVS12 + 5G>A（1062 + 5G>A）剪接位点突变占突变等位基因的90%以上。因此，1970年建立了针对（HT1）的新生儿普遍筛查，迄今为止已对近400万婴儿进行了检测，得以识别出190名受影响新生儿中的185名。在1970 - 1997年期间，对224.9万名出生3 - 7天的新生儿，通过酪氨酸（Tyr）浓度检测干滤纸血斑，随后进行间接比色半定量和定量（Q）琥珀酰丙酮（SA）检测（红细胞δ-氨基乙酰丙酸脱水酶抑制），并以免疫反应性FAH作为确证试验。这种方法得以识别出123名受影响新生儿中的118名。1998年，由于医院出院时间提前和母乳喂养率上升，同年有4例漏诊，因为血Tyr的鉴别能力不足。因此，筛查算法进行了修改：1998年至2014年间，间接半定量SA测量成为一线检测，2014年实施串联质谱（MS/MS）直接测量SA，随后进行间接定量SA测量作为二线检测。通过血浆氨基酸谱和分子检测进行确证。在1998 - 2016年期间，对超过150万新生儿进行了检测（90%在出生24至48小时采样）：识别出了67例HTI病例中的67例。作为初始HTI筛查试验，间接和直接SA测量均被证明具有高度敏感性和特异性，阳性和阴性预测值分别为79%和100%。
