果糖-1,6-二磷酸酶缺乏症基因诊断1例

Genetic diagnosis of fructose-1,6-bisphosphatase deficiency: a case report

目的：报道1例基因诊断的果糖-1,6-二磷酸酶缺乏症,提高对此罕见病的认识。方法：对基因学诊断的1例果糖-1,6-二磷酸酶（fructose-1,6-bisphosphatase,FBPase）缺乏症患儿的临床表现、实验室检查及基因突变特点进行回顾性分析,并进行文献复习。结果：本例为1岁11个月的男性幼儿,断奶后7个月内反复5次发作腹泻、呕吐、拒食,2~3 d后出现精神差、软弱、嗜睡,并在最近的一次发作中出现抽搐,查体可见呼吸深快及肝轻度增大,体格及智力运动发育基本正常。患儿祖父母为姑表亲,父母为5代旁系血亲。患儿多次发作期血生化检查均提示严重低血糖、高乳酸血症、代谢性酸中毒伴阴离子间隙升高、酮症及高尿酸血症。经过葡萄糖输注、纠正酸中毒及抗感染治疗后病情可较快恢复。患儿尿代谢筛查示尿中乳酸、丙酮酸、甘油等糖异生底物显著增高,基因测序示肝FBPase编码区基因（FBP1）第7外显子961位点纯合突变,插入一个G碱基（c.960/961insG）,导致其所编码的蛋白在320位氨基酸处开始移码,并且在333位氨基酸处提前终止,该种突变为文献报道之最常见突变。出院后予患儿增加进食次数,避免摄入过多甜食,控制高蛋白及高脂食物,并辅助生玉米淀粉喂养,随诊9月余未见病情反复。结论：对于反复于感染及饥饿时出现严重低血糖、高乳酸血症,同时存在代谢性酸中毒及酮症的患儿,要考虑果糖-1,6-二磷酸酶缺乏症可能,早期基因学诊断、发作期及时正确治疗及长期饮食控制,可避免死亡,促进生长发育,提高患儿生活质量。

Objective：To report the first case of fructose-1,6-bisphosphatase（ FBPase） deficiency diagnosed by genetic sequencing in China,and to improve the cognition of this rare disease. Methods：The clinical and laboratory characteristics of FBPase deficiency were reviewed,and the findings of direct sequencing of genomic DNA described,and published literature on FBPase deficiency reviewed. Results：A 23-month-old boy was repeatedly admitted for 5 times with recurrent onset of lethargy and drowsiness every time after diarrhea and vomiting for 2- 3 days during the last 7 months after being weaned,and he had convulsion this time. On admission,his physical examination showed tachypnea,and mild hepatomegaly,and he had normal physical and mental development. His paternal-grandparents had cousinship,and his parents were collateral relatives in the fifth generation. The laboratory findings revealed severe hypoglycemia,lacticacidemia,metabolic acidosis,ketonemia and hyperuricacidemia. After intravenous infusion of glucose,bicarbonate and antibiotics,there was a dramatic clinical improvement in a short time.Urine organic acids analyses ever showed an elevation of gluconeogenetic substrates including lactic acid,ketone and glycerol. The molecular analysis of liver fructose-1,6-bisphosphatase（FBP1） gene showed a homozygous mutation with one G residue insertion at base 961 in exon 7（c. 960 /961insG）,resulting in a reading frame shift mutation of 320 th amino acid and premature termination at 333 th amino acid. This mutation had been reported to be the most common mutation among patients with FBPase deficiency. Frequent feeding by avoiding taking in too much sweet food,restriction of food with high protein and fat,and the use of uncooked starch had been taken after our patient was discharged from the hospital. There had been no attack in the last 9 months. Conclusion： Clinicians must consider the diagnosis of FBPase deficiency when confronted with the patient who has episodes of severe hypoglycemia and lacticacidemia,especially accompanied by metabolic acidosis and ketonemia,which are typically triggered by infection and fasting. Early diagnosis,urgent treatment of hypoglycemia and appropriate diet control can prevent death,improve growth and quality of life of these children.