Soler-Alfonso Claudia, Pillai Nishita, Cooney Erin, Mysore Krupa R, Boyer Suzanne, Scaglia Fernando
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
Texas Children's Hospital, Houston, TX, United States.
Mol Genet Metab Rep. 2019 Jan 25;19:100453. doi: 10.1016/j.ymgmr.2019.100453. eCollection 2019 Jun.
Early recognition of rare mitochondrial respiratory chain defects has become readily available with the routine use of whole exome sequencing. Patients with oxidative phosphorylation defects present with a heterogenous phenotype, often rapidly progressive, and lethal. Clinicians aim for prompt identification of the specific molecular defect to provide timely management, decrease morbidity, and potentially improve survival rates. More recently, bi-allelic pathogenic variants in the gene responsible for encoding the mitochondrial tRNA-specific 2-thiouridylase were found in a syndrome characterized by infantile hepatopathy due to a mitochondrial translation defect (OMIM# 613070). This nuclear encoded enzyme catalyzes the addition of a sulfur-containing thiol group to the wobble position of mitochondrial specific tRNAs. TRMU deficiency is characterized by a combined respiratory chain deficiency without associated mitochondrial DNA depletion. This mitochondrial tRNA-modifying enzyme requires sulfur for its activity. Previous cellular models have suggested supplementation with cysteine, one of the sulfur containing amino acids, may play a role in increasing thiouridylation levels of mt-tRNAs by increasing sulfur availability for TRMU activity. Cysteine is considered a conditional essential amino acid due to limited availability in infants caused by immature cystathionine gamma-lyase (cystathionase) enzyme activity. The potential benefit of L-cysteine supplementation in TRMU deficiency has been previously proposed to ameliorate the severity and insidious course of the disease. Here we report the clinical, biochemical, and genetic findings of two siblings presenting with hepatopathy associated with hyperlactatemia due to bi-allelic pathogenic variants in . One patient died due to related complications. The other case was diagnosed prenatally allowing early implementation of L-cysteine supplementation, recovery of liver function, and avoidance of liver transplantation.
随着全外显子测序的常规使用，罕见线粒体呼吸链缺陷的早期识别已变得容易实现。氧化磷酸化缺陷患者表现出异质性表型，通常进展迅速且致命。临床医生旨在迅速识别特定的分子缺陷，以便及时进行管理，降低发病率，并有可能提高生存率。最近，在一种以线粒体翻译缺陷导致的婴儿肝病为特征的综合征（OMIM# 613070）中，发现了负责编码线粒体tRNA特异性2-硫尿苷酰化酶的基因中的双等位基因致病变异。这种由核基因编码的酶催化在特定线粒体tRNA的摆动位置添加含硫的巯基。TRMU缺乏症的特征是呼吸链联合缺陷，且无相关线粒体DNA耗竭。这种线粒体tRNA修饰酶的活性需要硫。先前的细胞模型表明，补充含硫氨基酸之一的半胱氨酸，可能通过增加TRMU活性的硫供应，在提高线粒体tRNA的硫尿苷酰化水平方面发挥作用。由于婴儿期胱硫醚γ-裂解酶（胱硫醚酶）活性不成熟导致半胱氨酸供应有限，半胱氨酸被认为是一种条件必需氨基酸。先前曾提出补充L-半胱氨酸对TRMU缺乏症可能有益，可改善疾病的严重程度和隐匿病程。在此，我们报告了两名因双等位基因致病变异而出现与高乳酸血症相关的肝病的兄弟姐妹的临床、生化和基因学发现。一名患者因相关并发症死亡。另一例在产前被诊断，从而得以早期实施L-半胱氨酸补充治疗，肝功能恢复，避免了肝移植。
