Martinez-Aracil Adriano, Ruiz-Onandi Rebeca, Perez-Rodriguez Alvaro, Sagasta Amaia, Llano-Rivas Isabel, Perez de Nanclares Guiomar
Pathology Service, Bioaraba Research Health Institute, Araba University Hospital, C/Jose Atxotegi s/n, Vitoria-Gasteiz, Alava, Spain.
Service of Genetics, BioCruces Bizkaia Reseach Health Institute, Cruces University Hospital, Plaza de Cruces s/n, Barakaldo, Bizkaia, Spain.
Birth Defects Res. 2020 Nov;112(19):1738-1749. doi: 10.1002/bdr2.1805. Epub 2020 Sep 22.
Glutaric aciduria type 2 is a rare, lethal disorder that affects metabolism of fatty acids caused by genetic defects in electron transfer (ETF) or in electron transfer flavoprotein dehydrogenase (ETFDH). We aimed to describe the pathological findings of 15 week old foetus, born from a consanguineous couple with 3 previous perinatal deaths. The last son died at 4 days of life and genetic analyses revealed a novel probably pathogenic variant at ETFDH (c.706dupG + c.706dupG) that codifies for a truncated protein (p.Glu236Glyfs5 + p.Glu236Glyfs5).
During the gestation, due to the medical familial history, prenatal echography and a chorial biopsy for ETFDH-associated glutaric aciduria analysis were carried out. Sanger sequencing confirmed the presence of the homozygous familial variant in the ETFDH gene. The gestation was terminated and the foetal autopsy performed. Autopsy revealed prominent forehead, flat nasal bridge, malformed ears, intrauterine growth retardation, polycystic kidneys and steatosis in the liver, consistent with the diagnosis of glutaric aciduria type II. The comparison of present cases with the previously reported in the literature confirmed the presence of classical criteria, but also revealed the association with urogenital deformities, not previously stated.
Clinical and foetal findings allowed the characterisation of the novel variant (c.706dupG at ETDFH) as pathogenic. Genotype-phenotype relationship is important when studying rare genetic disorders such as glutaric aciduria type II, as variants are usually family-specific, leading to a difficulty in the characterisation of their pathogenicity.
2型戊二酸尿症是一种罕见的致死性疾病，由电子传递黄素蛋白（ETF）或电子传递黄素蛋白脱氢酶（ETFDH）的基因缺陷导致脂肪酸代谢异常。我们旨在描述一名15周龄胎儿的病理检查结果，该胎儿出生于一对近亲结婚夫妇，此前已有3次围产期死亡。他们的上一个儿子出生后4天死亡，基因分析显示ETFDH基因存在一个新的可能致病变异（c.706dupG + c.706dupG），该变异编码截短蛋白（p.Glu236Glyfs5 + p.Glu236Glyfs5）。
孕期因家族病史，进行了产前超声检查及绒毛膜活检以分析与ETFDH相关的戊二酸尿症。桑格测序证实ETFDH基因存在纯合家族变异。终止妊娠并进行了胎儿尸检。尸检发现前额突出、鼻梁扁平、耳部畸形、宫内生长受限、多囊肾及肝脏脂肪变性，符合2型戊二酸尿症诊断。将本病例与文献报道病例对比，不仅证实了经典标准的存在，还发现了与泌尿生殖系统畸形的关联，此前未见相关报道。
临床及胎儿检查结果表明新变异（ETDFH基因c.706dupG）具有致病性。在研究如2型戊二酸尿症这类罕见遗传病时，基因型 - 表型关系很重要，因为变异通常具有家族特异性，导致其致病性难以确定。
