GFM1突变所致儿童急性肝衰竭1例:质疑GFM1错义突变位置决定临床表型

Acute liver failure caused by GFM1 mutations in a child : the relationship between GFM1 missense mutation and the peripheral amino acid and the change of clinical phenotype

目的报告GFM1突变所致疾病的临床特征及验证基因型和临床表型关系。方法回顾性分析1例门诊就诊的GFM1基因突变儿童的临床及基因突变资料,结合文献归纳GFM1基因突变的临床特点,构建编码线粒体翻译因子G1(mt EFG1)空间结构图,检验GFM1基因错义突变位置与临床表型关系的假说。结果患儿,女,6个月28 d。生长发育迟缓,急性肝衰竭。体格检查:反应差,嗜睡,全身皮肤黏膜黄染,腹平软,肝脾肿大。辅助检查:总胆红素、直接胆红素、转氨酶、碱性磷酸酶、血清γ-谷氨酰转肽酶和血氨升高,白蛋白下降,凝血酶原时间延长,血糖下降,酸中毒,血乳酸升高,血浆氨基酸及酰基肉碱谱示血中多种氨基酸升高,尿有机酸检查提示酮尿,头颅MRI示双侧丘脑、大脑脚、基底节区、枕叶前内侧异常信号。GFM1基因的复合杂合突变,第5外显子c.688G>A点突变致蛋白质改变为p.Gly230Ser;第14外显子c.1686del G的移码突变致蛋白质改变为p.Asp563Thrfs*24。mt EFG1空间结构图显示,p.Gly230Ser处于蛋白周边位置,预测表现应该为脑型。结论 1例携带GFM1基因复合杂合突变(c.688G>A和c.1686del G)的中国儿童,其临床表现为急性肝衰竭,不支持以往GFM1基因错义突变导致蛋白周边位置的氨基酸改变时临床表现为脑型的假设。

Objective To summarize the clinical characteristics in children harboring GFM1 gene mutations. Methods Retrospective analysis about the clinical features was performed in a patient with biallelic GFM1 mutations. Mitochondrial translation factor G1（ mt EFG1） space structure was constructed to verify the hypothesis about the relation between GFM1 gene missense mutations and the results of clinical phenotypes. Results The patient was a girl aged six months and twenty-eight days. Growth retardation,abnormal liver function,jaundice,hepatomegaly and splenomegaly were presented with in poor response and lethargy. Serum biochemical tests demonstrated elevation in total bilirubin,direct bilirubin,aspartate transaminase,alkaline phosphatase,gammaglutamyltransferase,blood ammonia and blood lactic acid, as well as hypoalbumineamia, prolonged PT, acidosis, and hypoglycemia. Mass spectrometry of serum amino acids acyl carnitine and urine urine organic acids suggested elevation of many amino acids in serum and ketonuria. Abnormal signals were observed in bilateral thalamus,cerebral peduncle,basal ganglia,and medial anterior occipital lobes through cranial MRI. Sequencing of GFM1 revealed compound heterozygous mutations： a missense mutation c. 688 G A（ p. Gly230Ser） in exon 5 and a frameshift deletion c. 1686 del G（ p. Asp563 Thrfs ＊ 24） in exon 14.Gly230 Ser protein changed amino acid residue in the structure of peripheral mt EFG1 space,changes in which area resulted in encephalopathy. Conclusion A Chinese girl carrying compound heterozygous GFM1 gene mutations of c. 688 G A and c. 1686 del G was reported. Hepatic presentation of this case denied the assumption that missense mutations in GFM1 gene that changes the peripheral amino acids of the protein will cause phenotype of encephalopathy.