果糖-1,6-二磷酸酶缺乏症基因型-表型相关性研究：一例报告及文献复习

doi:10.12280/gjszjk.20250082

摘要/Abstract

摘要：

果糖-1,6-二磷酸酶缺乏症（fructose-1,6-bisphosphatase deficiency，FBP1D）是一种罕见的遗传性糖异生障碍性疾病，若未得到及时有效的治疗，可能导致严重的神经系统后遗症。本研究通过家系外显子组测序（trio-whole exome sequencing，trio-WES）确诊了1例FBP1D患者，该患者携带的NM_000507.4(FBP1) c.977T>C变异在我国尚未见报道。此外，对31例中国FBP1D患者的基因型和表型特征进行了总结与分析发现，其典型临床表现包括低血糖、代谢性酸中毒、胃肠道症状及意识障碍，感染是最常见的发病诱因。基因分析显示，FBP1基因c.960dup变异是我国患者中最常见的突变类型。提高临床医生对FBP1D的认识有助于实现对该病的早期诊断和积极干预，从而显著改善患者预后。

关键词: 果糖-1,6-二磷酸酶缺乏, 低血糖症, 酸中毒, 全外显子组测序, FBP1基因

Abstract:

Fructose-1,6-bisphosphatase deficiency (FBP1D), a rare inherited metabolic disorder, may lead to severe neurological sequelae if not treated promptly and effectively. We report a case of FBP1D diagnosed through trio-whole exome sequencing (trio-WES). The NM_000507.4(FBP1) c.977T>C variant in this patient has not been reported in China. We summarized and analyzed the genotypic and phenotypic characteristics of 31 Chinese FBP1D patients from literature. The typical clinical manifestations included hypoglycemia, metabolic acidosis, gastrointestinal symptoms, and impaired consciousness, with the infection being the most common triggering factor. Genetic analysis revealed that the c.960dup variant in the FBP1 gene is the most prevalent variant among Chinese patients. Enhancing clinicians′ awareness of FBP1D can facilitate early diagnosis and active intervention, thereby significantly improve patient prognosis.

Key words: Fructose-1,6-diphosphatase deficiency, Hypoglycemia, Acidosis, Whole exome sequencing, FBP1 gene

王华, 薛峰, 熊复, 聂小成, 罗泽民, 朱书瑶, 曾兰, 皮光环. 果糖-1,6-二磷酸酶缺乏症基因型-表型相关性研究：一例报告及文献复习[J]. 国际生殖健康/计划生育杂志, 2025, 44(5): 377-382.

WANG Hua, XUE Feng, XIONG Fu, NIE Xiao-cheng, LUO Ze-min, ZHU Shu-yao, ZENG Lan, PI Guang-huan. Association Analysis of Genotype and Phenotype in Fructose-1,6-Bisphosphatase Deficiency: A Case Report and Literature Review[J]. Journal of International Reproductive Health/Family Planning, 2025, 44(5): 377-382.

图/表 4

参考文献 30

[1]	Lebigot E, Brassier A, Zater M, et al. Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic features in French patients[J]. J Inherit Metab Dis, 2015, 38(5):881-887. doi: 10.1007/s10545-014-9804-6. pmid: 25601412
[2]	Santer R, du Moulin M, Shahinyan T, et al. A summary of molecular genetic findings in fructose-1,6-bisphosphatase deficiency with a focus on a common long-range deletion and the role of MLPA analysis[J]. Orphanet J Rare Dis, 2016,11:44. doi: 10.1186/s13023-016-0415-1.
[3]	Ni Q, Tang M, Chen X, et al. Fructose-1, 6-bisphosphatase deficiency: estimation of prevalence in the Chinese population and analysis of genotype-phenotype association[J]. Front Genet, 2024,15:1296797. doi: 10.3389/fgene.2024.1296797.
[4]	张赟健, 路通, 王艺. FBP1基因突变致果糖1,6二磷酸酶缺乏的癫痫持续状态1例并文献复习[J]. 中国循证儿科杂志, 2018, 13(3):219-223. doi: 10.3969/j.issn.1673-5501.2018.03.013.
[5]	Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5):405-424. doi: 10.1038/gim.2015.30. pmid: 25741868
[6]	Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews[J]. BMJ, 2021,372:n71. doi: 10.1136/bmj.n71.
[7]	徐可, 刘雪芹, 张春雨, 等. 果糖-1,6-二磷酸酶缺乏症基因诊断1例[J]. 北京大学学报(医学版), 2014, 46(5):681-685. doi: 10.3969/j.issn.1671-167X.2014.05.003.
[8]	Li N, Chang G, Xu Y, et al. Clinical and Molecular Characterization of Patients with Fructose 1,6-Bisphosphatase Deficiency[J]. Int J Mol Sci, 2017, 18(4):857. doi: 10.3390/ijms18040857.
[9]	逯静茹, 郎艳华, 王翠, 等. 一例成人果糖-1,6-二磷酸酶缺乏症家系突变基因分析[J]. 中华内分泌代谢杂志, 2017, 33(9):752-754. doi: 10.3760/cma.j.issn.1000-6699.2017.09.009.
[10]	赵银霞, 梁娟, 刘静, 等. 果糖1,6二磷酸酶缺乏症的遗传学诊断及突变位点分析[J]. 临床儿科杂志, 2017, 35(12):881-884. doi: 10.3969/j.issn.1000-3606.2017.12.001.
[11]	董慧, 李东晓, 丁圆, 等. 果糖-1,6-二磷酸酶缺乏症导致的低血糖脑病1例及其FBP1基因新突变[J]. 中华实用儿科临床杂志, 2017,32(20):1587-1589. doi: 10.3760/cma.j.issn.2095-428X.2017.20.017.
[12]	毋盛楠, 陈琼, 刘芳, 等. 一例果糖-1,6二磷酸酶缺乏症患儿的临床及基因变异分析[J]. 中华医学遗传学杂志, 2019, 36(3):246-248. doi: 10.3760/cma.j.issn.1003-9406.2019.03.013.
[13]	吕楠, 尚清, 马彩云, 等. FBP1突变致果糖-1,6-二磷酸酶缺乏症2例临床及基因研究[J]. 中国实用儿科杂志, 2019, 34(10):854-858. doi: 10.19538/j.ek2019100614.
[14]	Wang H, Lu Y, Dong X, et al. Optimized trio genome sequencing (OTGS) as a first-tier genetic test in critically ill infants: practice in China[J]. Hum Genet, 2020, 139(4):473-482. doi: 10.1007/s00439-019-02103-8. pmid: 31965297
[15]	孟华夏, 张国强, 赵华锋, 等. FBP1基因新突变致果糖-1,6-二磷酸酶缺乏症一例并文献复习[J]. 国际儿科学杂志, 2020, 47(7):514-516. doi: 10.3760/cma.j.issn.1673-4408.2020.07.018.
[16]	杨凤华, 刘雪雁, 王华. 儿童果糖-1,6-二磷酸酶缺乏症一例临床特点及基因突变分析[J]. 中国小儿急救医学, 2020, 27(11):865-867. doi: 10.3760/cma.j.issn.1673-4912.2020.11.016.
[17]	吴冰冰. FBP1基因突变致果糖1,6二磷酸酶缺乏症一例(附视频)[J]. 中国临床案例成果数据库, 2021, 3(1):E265. doi: 10.3760/cma.j.cmcr.2021.e00265.
[18]	杨蒙洁, 卢一丽, 吴慧平, 等. 一例延迟诊断7年的果糖-1,6二磷酸酶缺乏症报道及文献复习[J]. 中华内分泌代谢杂志, 2021, 37(5):457-461. doi: 10.3760/cma.j.cn311282-20200302-00122.
[19]	金颖, 李梦秋, 陈哲晖, 等. 感染诱发急性发病的果糖1,6-二磷酸酶缺乏症两兄妹[J]. 中国临床案例成果数据库, 2022, 4(1):E03277. doi: 10.3760/cma.j.cmcr.2022.e03277.
[20]	Cao J, Pan J. Fructose-1,6-bisphosphatase deficiency: A pediatric case report[J]. Pediatr Neonatol, 2022, 63(2):204-205. doi: 10.1016/j.pedneo.2021.08.016.
[21]	Yi C, Xie J. Fructose-1,6-bisphosphatase deficiency[J]. Endokrynol Pol, 2022, 73(5):911-912. doi: 10.5603/EP.a2022.0064. pmid: 35971930
[22]	古再丽阿依·艾萨, 热衣兰木·包尔汉, 米热古丽·买买提, 等. FBP1基因突变导致FBPase缺乏症1例[J]. 中国医学工程, 2023, 31(4):130-132. doi: 10.19338/j.issn.1672-2019.2023.04.028.
[23]	Liang X, Liu X, Li W, et al. A novel variant in the FBP1 gene causes fructose-1,6-bisphosphatase deficiency through increased ubiquitination[J]. Arch Biochem Biophys, 2023,742:109619. doi: 10.1016/j.abb.2023.109619.
[24]	余佳, 李佳, 邱世超, 等. FBP1基因新变异致果糖1,6二磷酸酶缺乏症1例[J]. 中国临床案例成果数据库, 2024, 6(1):E2645-E2645. doi: 10.3760/cma.j.cmcr20241028-02315.
[25]	Xin B, Chen H, Liu T, et al. Novel compound heterozygous mutations of the FBP1 gene in a patient with hypoglycemia and lactic acidosis: A case report[J]. Mol Genet Genomic Med, 2024, 12(1):e2339. doi: 10.1002/mgg3.2339.
[26]	Choe JY, Fromm HJ, Honzatko RB. Crystal structures of fructose 1, 6-bisphosphatase: mechanism of catalysis and allosteric inhibition revealed in product complexes[J]. Biochemistry, 2000, 39(29):8565-8574. doi: 10.1021/bi000574g. pmid: 10913263
[27]	Kaur R, Dahiya L, Kumar M. Fructose-1,6-bisphosphatase inhibitors: A new valid approach for management of type 2 diabetes mellitus[J]. Eur J Med Chem, 2017, 141:473-505. doi: 10.1016/j.ejmech.2017.09.029. pmid: 29055870
[28]	Sakuma I, Nagano H, Hashimoto N, et al. Identification of genotype-biochemical phenotype correlations associated with fructose 1,6-bisphosphatase deficiency[J]. Commun Biol, 2023, 6(1):787. doi: 10.1038/s42003-023-05160-y. pmid: 37507476
[29]	Bhai P, Bijarnia-Mahay S, Puri RD, et al. Clinical and molecular characterization of Indian patients with fructose-1, 6-bisphosphatase deficiency: Identification of a frequent variant (E281K)[J]. AnnHum Genet, 2018, 82(5):309-317. doi: 10.1111/ahg.12256.
[30]	Emecen Sanli M, Cengiz B, Kilic A, et al. Fructose 1,6 bisphosphatase deficiency: outcomes of patients in a single center in Turkey and identification of novel splice site and indel mutations in FBP1[J]. J Pediatr Endocrinol Metab, 2022, 35(4):497-503. doi: 10.1515/jpem-2021-0732. pmid: 35179010

序号	文献	发表年份	患者性别	变异1	变异2	发病诱因			临床表现			发病年龄	酸中毒	神经发育障碍	血糖（mol/L）	患者诊断年龄
序号	文献	发表年份	患者性别	变异1	变异2	感染	水果	空腹	胃肠道	意识障碍	癫痫	发病年龄	酸中毒	神经发育障碍	血糖（mol/L）	患者诊断年龄
1	徐可等^[7]	2014	男	c.960dup	c.960dup	+	-	-	+	+	+	1岁 4个月	+	-	0.42	1岁 11个月
2	Li等^[8]	2017	女	c.960dup	c.704del	+	-	-	+	+	+	3 d	+	-	0.3	5岁 6个月
3	Li等^[8]	2017	女	c.960dup	c.825+1G>A	○	○	○	+	+	+	4岁	+	-	0.6	7岁 3个月
4	Li等^[8]	2017	男	c.720_729del	c.490G>A	○	○	○	+	-	+	1 d	+	+	0.6	10岁 8个月
5	逯静茹等^[9]	2017	女	c.960dup	c.960dup	-	+	-	+	+	+	<1岁	+	-	0.6	23岁
6	赵银霞等^[10]	2017	女	c.355G>A	c.355G>A	+	-	-	+	+	-	○	+	-	+	2岁
7	董慧等^[11]	2017	男	c.974T>A	c.755A>T	-	+	-	+	+	+	1岁 3个月	+	+	0.52	2岁 5个月
8	张赟健等^[4]	2018	男	c.704del	c.959dup	+	-	-	+	+	+	2 d	+	+	1.9	2岁 5个月
9	毋盛楠等^[12]	2019	男	c.826-2T>C	c.490G>A	-	-	-	+	-	-	3岁	+	-	0.5	3岁
10	吕楠等^[13]	2019	男	c.333+ 1_2delinsTC	c.490G>A	+	+	+	-	+	+	1岁 8个月	+	+	0.3	7岁
11	吕楠等^[13]	2019	男	c.333+ 1_2delinsTC	c.490G>A	-	+	+	-	-	+	3岁 6个月	-	-	4.5	5岁 8个月
12	Wang等^[14]	2020	男	c.333+2T>G	c.333+2T>G	+	-	-	-	-	+	7个月	+	-	+	9个月
13	孟华夏等^[15]	2020	女	c.960dup	c.500C>A	+	+	+	+	+	-	10个月	+	-	<0.3	2岁 3个月
14	杨凤华等^[16]	2020	男	c.960dup	c.960dup	+	-	-	+	+	-	3 d	+	+	1.6	2岁 6个月
15	吴冰冰^[17]	2021	男	c.704del	c.959dup	+	-	-	-	+	+	1岁 4个月	○	-	○	2岁
16	杨蒙洁等^[18]	2021	男	c.960dup	c.355G>A	+	-	-	+	+	+	6岁 3个月	+	-	2.1	13岁 5个月
17	金颖等^[19]	2022	男	c.861C>A	c.490G>A	+	-	-	+	-	-	3岁	+	-	2.67	7岁 2个月
18	金颖等^[19]	2022	女	c.861C>A	c.490G>A	+	-	-	+	+	-	1岁 5个月	+	-	1.28	1岁 8个月
19	Cao等^[20]	2022	女	c.355G>A	c.355G>A	○	○	○	+	+	+	8个月	+	-	2.0	6岁 4个月
20	Cao等^[20]	2022	男	c.490G>A	c.923C>G	-	-	+	-	+	-	1岁 6个月	+	-	1.3	2岁 6个月
21	Yi等^[21]	2022	女	c.761A>G	c.778G>A	-	-	-	-	+	+	4岁 1个月	+	-	0.48	4岁 1个月
22	古再丽阿依 ·艾萨等^[22]	2023	女	c.960dup	c.974T>A	+	-	-	+	+	-	1岁 1个月	+	-	0.2	1岁 5个月
23	Liang等^[23]	2023	男	c.962C>T	c.761A>G	○	○	○	-	+	+	3岁	+	+	0.02	12岁
24	余佳等^[24]	2024	男	c.974T>A	c.960dup	-	-	-	+	+	-	4岁	○	-	0.5	6岁 10个月
25	Xin等^[25]	2024	男	c.490G>A	c.861C>A	+	-	-	+	-	+	1岁 11个月	+	-	2.5	7岁
26	Ni等^[3]	2024	男	c.704del	c.959dup	○	○	○	+	-	-	新生儿	+	-	+	2岁
27	Ni等^[3]	2024	男	c.355G>A	c.960dup	+	-	+	+	+	+	1岁 8个月	+	○	+	2岁 6个月
28	Ni等^[3]	2024	男	c.841G>A	c.778G>A	+	-	-	+	+	+	11个月	+	-	+	1岁
29	Ni等^[3]	2024	男	c.355G>A	Exon1 deletion	-	-	-	-	-	+	新生儿	-	-	+	3岁
30	Ni等^[3]	2024	女	c.490G>A	c.490G>A	+	-	-	-	+	+	3岁	-	-	+	3岁
31	本病例	2025	女	c.778G>A	c.977T>C	+	+	-	+	+	-	2岁 1个月	+	-	3.4	3岁

序号	文献	发表年份	患者性别	变异1	变异2	发病诱因			临床表现			发病年龄	酸中毒	神经发育障碍	血糖（mol/L）	患者诊断年龄
序号	文献	发表年份	患者性别	变异1	变异2	感染	水果	空腹	胃肠道	意识障碍	癫痫	发病年龄	酸中毒	神经发育障碍	血糖（mol/L）	患者诊断年龄
1	徐可等^[7]	2014	男	c.960dup	c.960dup	+	-	-	+	+	+	1岁 4个月	+	-	0.42	1岁 11个月
2	Li等^[8]	2017	女	c.960dup	c.704del	+	-	-	+	+	+	3 d	+	-	0.3	5岁 6个月
3	Li等^[8]	2017	女	c.960dup	c.825+1G>A	○	○	○	+	+	+	4岁	+	-	0.6	7岁 3个月
4	Li等^[8]	2017	男	c.720_729del	c.490G>A	○	○	○	+	-	+	1 d	+	+	0.6	10岁 8个月
5	逯静茹等^[9]	2017	女	c.960dup	c.960dup	-	+	-	+	+	+	<1岁	+	-	0.6	23岁
6	赵银霞等^[10]	2017	女	c.355G>A	c.355G>A	+	-	-	+	+	-	○	+	-	+	2岁
7	董慧等^[11]	2017	男	c.974T>A	c.755A>T	-	+	-	+	+	+	1岁 3个月	+	+	0.52	2岁 5个月
8	张赟健等^[4]	2018	男	c.704del	c.959dup	+	-	-	+	+	+	2 d	+	+	1.9	2岁 5个月
9	毋盛楠等^[12]	2019	男	c.826-2T>C	c.490G>A	-	-	-	+	-	-	3岁	+	-	0.5	3岁
10	吕楠等^[13]	2019	男	c.333+ 1_2delinsTC	c.490G>A	+	+	+	-	+	+	1岁 8个月	+	+	0.3	7岁
11	吕楠等^[13]	2019	男	c.333+ 1_2delinsTC	c.490G>A	-	+	+	-	-	+	3岁 6个月	-	-	4.5	5岁 8个月
12	Wang等^[14]	2020	男	c.333+2T>G	c.333+2T>G	+	-	-	-	-	+	7个月	+	-	+	9个月
13	孟华夏等^[15]	2020	女	c.960dup	c.500C>A	+	+	+	+	+	-	10个月	+	-	<0.3	2岁 3个月
14	杨凤华等^[16]	2020	男	c.960dup	c.960dup	+	-	-	+	+	-	3 d	+	+	1.6	2岁 6个月
15	吴冰冰^[17]	2021	男	c.704del	c.959dup	+	-	-	-	+	+	1岁 4个月	○	-	○	2岁
16	杨蒙洁等^[18]	2021	男	c.960dup	c.355G>A	+	-	-	+	+	+	6岁 3个月	+	-	2.1	13岁 5个月
17	金颖等^[19]	2022	男	c.861C>A	c.490G>A	+	-	-	+	-	-	3岁	+	-	2.67	7岁 2个月
18	金颖等^[19]	2022	女	c.861C>A	c.490G>A	+	-	-	+	+	-	1岁 5个月	+	-	1.28	1岁 8个月
19	Cao等^[20]	2022	女	c.355G>A	c.355G>A	○	○	○	+	+	+	8个月	+	-	2.0	6岁 4个月
20	Cao等^[20]	2022	男	c.490G>A	c.923C>G	-	-	+	-	+	-	1岁 6个月	+	-	1.3	2岁 6个月
21	Yi等^[21]	2022	女	c.761A>G	c.778G>A	-	-	-	-	+	+	4岁 1个月	+	-	0.48	4岁 1个月
22	古再丽阿依 ·艾萨等^[22]	2023	女	c.960dup	c.974T>A	+	-	-	+	+	-	1岁 1个月	+	-	0.2	1岁 5个月
23	Liang等^[23]	2023	男	c.962C>T	c.761A>G	○	○	○	-	+	+	3岁	+	+	0.02	12岁
24	余佳等^[24]	2024	男	c.974T>A	c.960dup	-	-	-	+	+	-	4岁	○	-	0.5	6岁 10个月
25	Xin等^[25]	2024	男	c.490G>A	c.861C>A	+	-	-	+	-	+	1岁 11个月	+	-	2.5	7岁
26	Ni等^[3]	2024	男	c.704del	c.959dup	○	○	○	+	-	-	新生儿	+	-	+	2岁
27	Ni等^[3]	2024	男	c.355G>A	c.960dup	+	-	+	+	+	+	1岁 8个月	+	○	+	2岁 6个月
28	Ni等^[3]	2024	男	c.841G>A	c.778G>A	+	-	-	+	+	+	11个月	+	-	+	1岁
29	Ni等^[3]	2024	男	c.355G>A	Exon1 deletion	-	-	-	-	-	+	新生儿	-	-	+	3岁
30	Ni等^[3]	2024	女	c.490G>A	c.490G>A	+	-	-	-	+	+	3岁	-	-	+	3岁
31	本病例	2025	女	c.778G>A	c.977T>C	+	+	-	+	+	-	2岁 1个月	+	-	3.4	3岁

组别	基因变异	氨基酸改变	患者序号
Ⅰ	c.704del；c.959dup	p.P235Qfs42；p.S321Vfs13	8，15，26
Ⅱ	c.960dup；HOM	p.S321Vfs*13	1，5，14
Ⅲ	c.355G>A；c.960dup	p.D119N；p.S321Vfs*13	16，27
Ⅳ	c.960dup；c.974T>A	p.S321Vfs*13；p.V325E	22，24
Ⅴ	c.490G>A；c.861C>A	p.G164S；p.Y287*	17，18，25
Ⅵ	c.355G>A；HOM	p.D119N	6，19

组别	基因变异	氨基酸改变	患者序号
Ⅰ	c.704del；c.959dup	p.P235Qfs42；p.S321Vfs13	8，15，26
Ⅱ	c.960dup；HOM	p.S321Vfs*13	1，5，14
Ⅲ	c.355G>A；c.960dup	p.D119N；p.S321Vfs*13	16，27
Ⅳ	c.960dup；c.974T>A	p.S321Vfs*13；p.V325E	22，24
Ⅴ	c.490G>A；c.861C>A	p.G164S；p.Y287*	17，18，25
Ⅵ	c.355G>A；HOM	p.D119N	6，19