Center for Metabolic Diseases, Leuven University Hospitals, Leuven, Belgium.
Orphanet J Rare Dis. 2009 Dec 15;4:28. doi: 10.1186/1750-1172-4-28.
A male patient, born to unrelated Belgian parents, presented at 4 months with epistaxis, haematemesis and haematochezia. On physical examination he presented petechiae and haematomas, and a slightly enlarged liver. Serum transaminases were elevated to 5-10 times upper limit of normal, alkaline phosphatases were 1685 U/L (<720), total bilirubin was 2.53 mg/dl (<1.0), ammonaemia 69 microM (<32), prothrombin time less than 10%, thromboplastin time >180 s (<60) and alpha-fetoprotein 29723 microg/L (<186). Plasma tyrosine (651 microM) and methionine (1032 microM) were strongly increased. In urine, tyrosine metabolites and 4-oxo-6-hydroxyheptanoic acid were increased, but succinylacetone and succinylacetoacetate--pathognomonic for tyrosinemia type I--were repeatedly undetectable. Delta-aminolevulinic acid was normal, which is consistent with the absence of succinylacetone. Abdominal ultrasound and brain CT were normal.Fumarylacetoacetase (FAH) protein and activity in cultured fibroblasts and liver tissue were decreased but not absent. 4-hydroxyphenylpyruvate dioxygenase activity in liver was normal, which is atypical for tyrosinemia type I. A novel mutation was found in the FAH gene: c.103G>A (Ala35Thr). In vitro expression studies showed this mutation results in a strongly decreased FAH protein expression.Dietary treatment with phenylalanine and tyrosine restriction was initiated at 4 months, leading to complete clinical and biochemical normalisation. The patient, currently aged 12 years, shows a normal physical and psychomotor development.This is the first report of mild tyrosinemia type I disease caused by an Ala35Thr mutation in the FAH gene, presenting atypically without increase of the diagnostically important toxic metabolites succinylacetone and succinylacetoacetate.
一位男性患者，出生于无亲缘关系的比利时父母，4 个月时出现鼻出血、呕血和血便。体格检查发现有瘀点和血肿，肝脏略大。血清转氨酶升高至正常值上限的 5-10 倍，碱性磷酸酶为 1685U/L（<720），总胆红素为 2.53mg/dl（<1.0），血氨 69μM（<32），凝血酶原时间<10%，凝血活酶时间>180s（<60），甲胎蛋白 29723μg/L（<186）。血浆酪氨酸（651μM）和蛋氨酸（1032μM）明显升高。尿液中酪氨酸代谢物和 4-氧-6-羟基己酸增加，但反复检测不到特征性的 1 型酪氨酸血症的致病代谢物琥珀酰丙酮和琥珀酰乙酰乙酸。δ-氨基乙酰丙酸正常，这与无琥珀酰丙酮一致。腹部超声和脑 CT 正常。成纤维细胞和肝组织中 fumarylacetoacetase（FAH）蛋白和活性降低，但并未完全缺失。肝 4-羟苯基丙酮酸双加氧酶活性正常，这不符合 1 型酪氨酸血症的特征。在 FAH 基因中发现了一种新的突变：c.103G>A（Ala35Thr）。体外表达研究表明，该突变导致 FAH 蛋白表达明显减少。患者 4 个月时开始接受饮食治疗，限制苯丙氨酸和酪氨酸摄入，随后临床和生化完全正常化。目前该患者 12 岁，体格和精神运动发育正常。这是首例由 FAH 基因 c.103G>A（Ala35Thr）突变引起的轻度 1 型酪氨酸血症，其表现不典型，无诊断性重要毒性代谢物琥珀酰丙酮和琥珀酰乙酰乙酸增加。
