Lebigot Elise, Brassier Anaïs, Zater Mokhtar, Imanci Dilek, Feillet François, Thérond Patrice, de Lonlay Pascale, Boutron Audrey
Service de Biochimie, CHU Bicêtre, AP-HP, Le Kremlin-Bicêtre, France.
J Inherit Metab Dis. 2015 Sep;38(5):881-7. doi: 10.1007/s10545-014-9804-6. Epub 2015 Jan 20.
Fructose-1,6-bisphosphatase (FBPase) deficiency is a very rare autosomal recessive disorder caused by a mutation of the fructose-1,6-bisphosphatase gene(FBP1). Disease is mainly revealed by hypoglycemia and lactic acidosis, both symptoms being characteristic for an enzymatic block in the last steps of the gluconeogenesis. Twelve patients with FBPase deficiency were diagnosed in France in the 2001-2013 period, using a diagnostic system based on a single blood sample which allows simultaneous enzyme activity measurement on mononuclear white blood cells and molecular analysis. Sequencing of exons and intron-exon junctions of FBP1 gene was completed in unsolved cases by a gene dosage assay developed for each exon. For most patients, first metabolic decompensation occurred before two years of age with a similar sequence: the triggering factors were fever, fasting, or decrease of food intake. However, diagnosis was made late at a mean age of 3 years, as mitochondrial defects or glycogen storage diseases were firstly suspected. Enzyme activity in leukocytes was dramatically decreased (<10%). Twelve different mutations were identified in 22 alleles among them seven were novels: one missense mutation c.472C > T, one point deletion c.48del, one point duplication c.865dupA, one deletion-insertion, and two splice mutations (c.427-1del and c.825 + 1G > A). We described the first intragenic deletion in FBP1 (g.97,364,754_97,382,011del) in homozygous state. Our report also confirms that this very rare disease is misdiagnosed, as other energetic defects are firstly suspected.
果糖-1,6-二磷酸酶（FBPase）缺乏症是一种非常罕见的常染色体隐性疾病，由果糖-1,6-二磷酸酶基因（FBP1）突变引起。该病主要表现为低血糖和乳酸性酸中毒，这两种症状是糖异生最后步骤中酶阻断的特征性表现。在2001年至2013年期间，法国使用一种基于单一血样的诊断系统诊断出12例FBPase缺乏症患者，该系统可同时对单核白细胞进行酶活性测定和分子分析。对于未确诊的病例，通过针对每个外显子开发的基因剂量测定法完成FBP1基因外显子和内含子-外显子连接区的测序。对于大多数患者，首次代谢失代偿发生在两岁之前，且过程相似：触发因素为发热、禁食或食物摄入量减少。然而，诊断时间较晚，平均年龄为3岁，因为最初怀疑是线粒体缺陷或糖原贮积病。白细胞中的酶活性显著降低（<10%）。在22个等位基因中鉴定出12种不同的突变，其中7种为新突变：一种错义突变c.472C>T，一种点缺失c.48del，一种点重复c.865dupA，一种缺失-插入突变，以及两种剪接突变（c.427-1del和c.825+1G>A）。我们描述了FBP1基因中首次发现的纯合状态的基因内缺失（g.97,364,754_97,382,011del）。我们的报告还证实，这种非常罕见的疾病常被误诊，因为最初怀疑是其他能量缺陷。
