Yang Hao, Rossignol Francis, Cyr Denis, Laframboise Rachel, Wang Shu Pei, Soucy Jean-François, Berthier Marie-Thérèse, Giguère Yves, Waters Paula J, Mitchell Grant A
Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.
Service de Génétique médicale, Département de Pédiatrie, Centre hospitalier universitaire de Sherbrooke (CHUS), Sherbrooke, Québec, Canada.
Mol Genet Metab Rep. 2017 Dec 27;14:55-58. doi: 10.1016/j.ymgmr.2017.12.002. eCollection 2018 Mar.
A high level of succinylacetone (SA) in blood is a sensitive, specific marker for the screening and diagnosis of hepatorenal tyrosinemia (HT1, MIM 276700). HT1 is caused by mutations in the gene, resulting in deficiency of fumarylacetoacetate hydrolase. HT1 newborns are usually clinically asymptomatic, but have coagulation abnormalities revealing liver dysfunction. Treatment with nitisinone (NTBC) plus dietary restriction of tyrosine and phenylalanine prevents the complications of HT1.
Two newborns screened positive for SA but had normal coagulation testing. Plasma and urine SA levels were 3-5 fold above the reference range but were markedly lower than in typical HT1. Neither individual received nitisinone or dietary therapy. They remain clinically normal, currently aged 9 and 15 years. Each was a compound heterozygote, having a splicing variant in with a prevalent "pseudodeficient" allele, c.1021C > T (p.Arg341Trp), which confers partial FAH activity. All newborns identified with mild hypersuccinylacetonemia in Québec have had genetic deficiencies of tyrosine degradation: either deficiency of the enzyme preceding FAH, maleylacetoacetate isomerase, or partial deficiency of FAH itself.
Compound heterozygotes for c.1021C > T (p.Arg341Trp) and a severely deficient FAH allele have mild hypersuccinylacetonemia and to date they have remained asymptomatic without treatment. It is important to determine the long term outcome of such individuals.
血液中高水平的琥珀酰丙酮（SA）是肝肾功能不全型酪氨酸血症（HT1，MIM 276700）筛查和诊断的敏感、特异性标志物。HT1由该基因突变引起，导致延胡索酰乙酰乙酸水解酶缺乏。HT1新生儿通常临床上无症状，但有凝血异常提示肝功能障碍。用尼替西农（NTBC）加酪氨酸和苯丙氨酸饮食限制治疗可预防HT1的并发症。
两名新生儿SA筛查呈阳性，但凝血检测正常。血浆和尿液SA水平比参考范围高3至5倍，但明显低于典型HT1。两人均未接受尼替西农或饮食治疗。他们目前临床正常，年龄分别为9岁和15岁。两人均为复合杂合子，在基因中有一个剪接变体，带有一个常见的“假缺陷”等位基因，c.1021C>T（p.Arg341Trp），该等位基因赋予部分FAH活性。在魁北克省所有被鉴定为轻度高琥珀酰丙酮血症的新生儿都有酪氨酸降解的基因缺陷：要么是FAH之前的酶马来酰乙酰乙酸异构酶缺乏，要么是FAH本身部分缺乏。
c.1021C>T（p.Arg341Trp）和严重缺陷的FAH等位基因的复合杂合子有轻度高琥珀酰丙酮血症，迄今为止未经治疗仍无症状。确定这些个体的长期预后很重要。
