DGUOK gene mutation causes hepato-encephalopathy form of mitochondrial DNA depletion syndrome: clinical diagnosis and treatment and prenatal diagnosis

doi:10.3877/cma.j.issn.1673-5250.2020.04.013

Objective

To investigate clinical characteristics and prenatal diagnostic value of hepato-encephalopathy form of mitochondrial DNA depletion syndrome (MDS) caused by missense mutation variant in DGUOK gene.

Methods

A infant with hepato-encephalopathy form of MDS who was diagnosed and hospitalized in People′s Hospital of Xinjiang Uygur Autonomous Region in January 2018 due to " persistent jaundice for 4 months + 19 days and abnormal liver function for 1 months+ 19 days" , was selected as research subject. The clinical data of this case of infant were retrospectively analyzed, including clinical diagnosis and treatment process, gene mutation characteristics, etc..The procedure followed in this study was consistent with World Medical Association Declaration of Helsinki revised in 2013. For the treatment and genetic testing of the child, the informed consent of guardians was given and signed.

Results

① Collection of medical history: this case of infant was a girl, G₅P₃, hospitalized in hospital at age of 4 months+ 20 days old. She developed jaundice on the second day after birth and lasted until 4 months+ 19 days old, accompanied with nystagmus and abnormal liver function. Her family history referred to 2 neonates with jaundice and unexplainable neonatal death. At the age of 4 months, this case of infant developed bronchopneumonia, hypoproteinemia and systemic edema. At the age of 5 months, she died of respiratory, circulatory, liver and other multiple organ failure. ②Genetic testing results: mitochondrial nuclear gene screening results of peripheral blood sample showed that she had homozygous mutation variant of exon 1: c. 130G>A (p. Glu44Lys) in DGUOK gene, which was known as missense mutation and a reported pathogenicity mutation variant. ③ Prenatal diagnosis results: mother of this case of hepato-encephalopathy form of MDS infant was pregnant again at 30 years old. Sanger sequencing of amniotic fluid cast off cells at 20 weeks of the pregnant woman showed exon 1: c. 130G>A (p.glu44lys) heterozygous mutation variant in DGUOK gene, and the fetus was free of MDS.

Conclusions

For children with unexplained liver disease, especially when multiple organs were involved or tyrosinemia was suspected, attention should be paid to the possibility of hepato-encephalopathy form of MDS, which can be clearly diagnosed through gene analysis. Prenatal diagnosis of fetus MDS could be made by gene analysis of amniotic fluid cast off cells of fetus.

Key words: Mitochondrial diseases, Deoxyguanosine kinase deficiency, DGUOK gene, Prenatal diagnosis, DNA, mitochondrial, Genetic testing, Infant

表1 本例患儿生后不同时间点的血清生化检查结果比较

检查项目	出生时	生后10 d	生后75 d	生后90 d	生后140 d	正常参考值
总胆红素(μmol/L)^a	210.9	257.0	65.0	71.8	111.4	5.1～19.0
直接胆红素(μmol/L)^a	18.4	35.0	44.0	53.0	73.0	1.7～6.8
间接胆红素(μmol/L)^a	192.5	222.0	20.0	26.0	37.0	0～12.0
丙氨酸转氨酶(IU/L)^a	45	38	32	56	33	0～40
天冬氨酸氨基转移梅(IU/L)^a	81	42	80	131	108	0～45
白蛋白(g/L)	19	24	28	23	40	38～54
甲胎蛋白(μg/L)^b	17.56	17.32	15.21	>20.00	>20.00	<20.00
尿素氮(μmol/L)	7.9	7.3	6.2	5.1	2.3	1.7～8.3
肌酐(μmol/L)	14	53	68	56	35	59～104
尿酸(μmol/L)	96	186	216	211	236	202～416
血糖(mmol/L)^b	2.35	4.00	2.70	3.63	1.54	4.11～6.05
血清Ca^2＋(mmol/L)	2.13	2.63	2.17	2.51	2.39	2.25～2.75
血清K^＋(mmol/L)	3.9	4.2	3.6	5.2	4.6	3.5～5.0
血清Na^＋(mmol/L)	139.0	142.5	138.6	142.0	136.0	136.0～145.0
血清Cl^-(mmol/L)	107.3	111.0	103.2	102.0	100.2	98.0～110.0
血氨(μmol/L)^a	89.3	87.0	93.2	84.0	95.0	18.0～72.0
乳酸(mmol/L)^a	4.95	5.75	5.90	4.90	4.50	0.50～2.20
丙酮酸(μmol/L)^a	138	142	135	152	143	30～100

表1 本例患儿生后不同时间点的血清生化检查结果比较

检查项目	出生时	生后10 d	生后75 d	生后90 d	生后140 d	正常参考值
总胆红素(μmol/L)^a	210.9	257.0	65.0	71.8	111.4	5.1～19.0
直接胆红素(μmol/L)^a	18.4	35.0	44.0	53.0	73.0	1.7～6.8
间接胆红素(μmol/L)^a	192.5	222.0	20.0	26.0	37.0	0～12.0
丙氨酸转氨酶(IU/L)^a	45	38	32	56	33	0～40
天冬氨酸氨基转移梅(IU/L)^a	81	42	80	131	108	0～45
白蛋白(g/L)	19	24	28	23	40	38～54
甲胎蛋白(μg/L)^b	17.56	17.32	15.21	>20.00	>20.00	<20.00
尿素氮(μmol/L)	7.9	7.3	6.2	5.1	2.3	1.7～8.3
肌酐(μmol/L)	14	53	68	56	35	59～104
尿酸(μmol/L)	96	186	216	211	236	202～416
血糖(mmol/L)^b	2.35	4.00	2.70	3.63	1.54	4.11～6.05
血清Ca^2＋(mmol/L)	2.13	2.63	2.17	2.51	2.39	2.25～2.75
血清K^＋(mmol/L)	3.9	4.2	3.6	5.2	4.6	3.5～5.0
血清Na^＋(mmol/L)	139.0	142.5	138.6	142.0	136.0	136.0～145.0
血清Cl^-(mmol/L)	107.3	111.0	103.2	102.0	100.2	98.0～110.0
血氨(μmol/L)^a	89.3	87.0	93.2	84.0	95.0	18.0～72.0
乳酸(mmol/L)^a	4.95	5.75	5.90	4.90	4.50	0.50～2.20
丙酮酸(μmol/L)^a	138	142	135	152	143	30～100

图1 本例脑肝型线粒体DNA耗竭综合征患儿(女性，4^＋个月龄)的外周血外显子捕获测序结果图[患儿DGUOK基因第1外显子c.130G>A(p.Glu44Lys)纯合突变]

图2 本例患儿母亲及其再次妊娠胎儿的DGUOK基因Sanger法测序图[红色箭头所示为母亲、胎儿均存在第1外显子c.130G>A(p.Glu44Lys)杂合突变]

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