高鸟氨酸血症-高氨血症-高同型瓜氨酸尿症综合征三例诊疗研究

Clinical diagnosis and treatment of three cases with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

目的探讨高鸟氨酸血症-高氨血症-高同型瓜氨酸尿症（HHH）综合征的临床特点、诊断及治疗经验。方法对2011年7月至2016年8月北京大学第一医院儿科确诊的3例HHH综合征患儿的临床经过、生化异常、头颅核磁特点及基因突变进行研究。结果3例男性患儿于3月龄至7岁发病，于3岁10月龄至9岁10月龄确诊，均自幼厌食高蛋白食物、运动发育落后及姿势异常，其中例1、2伴有智力落后表现。血氨（μmol／L）25～276（正常值〈60），血谷氨酸转氨酶（IU／L）20～139（正常值9～50），鸟氨酸（μmol／L）29．12～99．44（正常值15．00-100．00），尿乳清酸（mmol／mol肌酐）1．49～29．75（正常值0～7．00），尿嘧啶（mmol／mol肌酐）6．09～103．97（正常值0～1．50）。头颅磁共振提示基底节区、脑白质信号异常、脱髓鞘病变及脑萎缩。3例均为SLC25A15基因缺陷，例1为c．416A〉G（P．E139G）纯合错义突变，尚无该基因特定位点的突变的文献报道。例2、例3为13．535C〉T（P．R179X）纯合无义突变，为已报道的致病突变。例1于6岁时接受活体肝移植，术后饮食习惯、智力、运动及生化指标均得到显著改善。例2运动及发育情况缓慢进步。例3经低蛋白饮食、口服精氨酸及左卡尼汀后，痉挛性截瘫无缓解，建议肝移植。结论HHH综合征患儿常见的临床表现为厌食蛋白、反复呕吐及进行性的神经系统损害，临床表现缺乏特异性，生化表型常不完整，SLC25A15基因分析是关键方法。根据个体情况，可采用饮食、药物及肝移植治疗。

Objective To study the clinical characteristics, methods of diagnosis and treatment of hyperornithinemia-hyperammonemia- homocitrullinuria （ HHH ） syndrome. Method From July 2011 to August 2016, 3 Chinese patients with HHH syndrome were enrolled in this study. The clinical course, biochemical features, brain MRI findings, and gene mutations were analyzed. Result The three patients＇ age at onset of symptoms was 3 months to 7 years, and the age of diagonosis was 3 years and 10 months to 9 years and 10 months. All of them presented with intolerance to protein-rich foods from the infant period, development retardation and abnormal posture. Case 1 and 2 had moderate mental retardation. Serum ammonia 25 -276 μmol/L （reference range 〈 60 p.mol/L） , alanine aminotransferase （ALT） 20 - 139 IU/L （reference range 9 - 50 IU/L） , ornithiue 29. 12 - 99.44 p.mol/L（ reference range 15 - 100 μmol/L） , urinary orotic acid 1.49 - 29.75 mmol/mol Cr （ reference range 0 - 7 mmol/mol Cr） , uracil 6.09 - 103.97 mmoL/mol Cr （reference range 0 - 1.5 mmol/mol Cr ）. The cranial MRI revealed lesions in the basal ganglia, abnormal white matter signal, progressive demyelination and cerebral atrophy. On their SLC25A15 gene, a novel homozygous missense mutation c. 416A 〉 G （p. E139G） was identified in case 1, a known pathogenic homozygous nonsense mutation c. 535C 〉 T was found in case 2 and 3. Liver transplantation had been performed when case 1 was 6 years old. Significant improvements were observed in dietary habit, mental and motor functions, and biochemical parameters. After the dietary intervention with the supplements of arginine, L-carnitine, case 2 was improved, spastic paraplegia of case 3 had no mitigation. Liver transplant was recommended. Conclusion HHH syndrome has an aversion to protein-rich food, and the patients have recurrent vomiting and progressive neurological dysfunction. Clinical diagnosis of HHH syndrome is difficult and patients may present with incomplete biochemical phenotype. The genetic analysis is key for the diagnosis. Depending on their condition, individuals with HHH syndrome can be treated with a low-protein diet, drugs and liver transplantation.