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首页> 外文期刊>Molecular Genetics and Metabolism Reports >Mildly elevated succinylacetone and normal liver function in compound heterozygotes with pathogenic and pseudodeficient FAH alleles
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Mildly elevated succinylacetone and normal liver function in compound heterozygotes with pathogenic and pseudodeficient FAH alleles

机译：具有致病性和假缺陷性FAH等位基因的复合杂合子中丁二酰丙酮的轻度升高和肝功能正常

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Background 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 FAH 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 Observations 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 trans with a prevalent “pseudodeficient” FAH 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. Conclusion 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.
机译：背景技术血液中的琥珀酰丙酮（SA）含量高是筛查和诊断肝肾酪氨酸血症（HT1，MIM 276700）的敏感，特异性标志物。 HT1是由FAH基因突变引起的，导致富马酰乙酰乙酸水解酶的缺乏。 HT1新生儿通常在临床上无症状，但凝血功能异常，显示肝脏功能障碍。尼替尼酮（NTBC）加上饮食限制的酪氨酸和苯丙氨酸治疗可预防HT1并发症。观察结果两个新生儿筛查出SA阳性，但凝血功能正常。血浆和尿液SA水平比参考范围高3-5倍，但明显低于典型的HT1。没有人接受过尼替尼酮或饮食疗法。他们在临床上保持正常，目前年龄分别为9岁和15岁。每个都是复合杂合子，在反式中具有剪接变体，并带有一个普遍的“伪缺陷” FAH等位基因，c.1021C> T（p.Arg341Trp），赋予部分FAH活性。在魁北克，所有被确认患有轻度高琥珀酰丙酮血症的新生儿均具有酪氨酸降解的遗传缺陷：FAH之前缺乏酶，马来酰乙酰乙酸异构酶或FAH本身部分缺乏。结论c.1021C> T（p.Arg341Trp）的复合杂合子和严重缺陷的FAH等位基因具有轻度的高琥珀酰丙酮酸血症，迄今为止，它们未经治疗仍无症状。确定此类个体的长期结果非常重要。

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