Coelho Margarida Paiva, Correia Joana, Dias Aureliano, Nogueira Célia, Bandeira Anabela, Martins Esmeralda, Vilarinho Laura
Reference Center for Metabolic Disorders Centro Hospitalar Universitário do Porto Porto Portugal.
Newborn Screening, Metabolism and Genetics Unit, Human Genetics Department National Institute of Health Doutor Ricardo Jorge Lisboa Portugal.
JIMD Rep. 2019 Jul 24;49(1):11-16. doi: 10.1002/jmd2.12058. eCollection 2019 Sep.
In the era of genomics, the number of genes linked to mitochondrial disease has been quickly growing, producing massive knowledge on mitochondrial biochemistry. gene codifies for ISD11, a small protein (11 kDa) acting as an iron-sulfur cluster, that has been recently confirmed as a disease-causing gene for mitochondrial disorders. We present a 4-year-old girl patient, born from non-consanguineous healthy parents, with two episodes of cardiorespiratory arrest after respiratory viral illness with progressive decreased activity and lethargy, at the age of 2 and 3 years. She was asymptomatic between crisis with regular growth and normal development. During acute events of illness, she had hyperlactacidemia (maximum lactate 5.2 mmol/L) and urinary excretion of ketone bodies and 3-methylglutaconic acid, which are normalized after recovery. A Next Generation Sequence approach with a broad gene panel designed for mitochondrial disorders revealed a novel probably pathogenic variant in homozygosity in the gene [p.Tyr31Cys (c.92A>G)] with Mendelian segregation. Functional studies in the skeletal muscle confirmed a combined deficiency of the mitochondrial respiratory chain (I, II, and IV complexes). To our knowledge, this is the third case of deficiency worldwide and the first with 3-methylglutaconic aciduria, not reported in any Fe-S cluster deficiency. Remarkably, it appears to be no neurological involvement so far, only with life-threating acute crisis triggered by expectably benign autolimited illnesses. Respiratory chain cofactors and chaperones are a new field of knowledge and can play a remarkable effect in system homeostasis.
在基因组学时代，与线粒体疾病相关的基因数量迅速增加，产生了大量关于线粒体生物化学的知识。基因编码ISD11，一种作为铁硫簇的小蛋白（11 kDa），最近已被确认为线粒体疾病的致病基因。我们报告了一名4岁女童，其父母为非近亲健康人，在2岁和3岁时，因呼吸道病毒感染后出现两次心肺骤停，活动逐渐减少并伴有嗜睡。在两次发病间期，她无症状，生长正常，发育正常。在疾病急性发作期间，她出现高乳酸血症（最高乳酸水平5.2 mmol/L）以及酮体和3-甲基戊二酸的尿排泄，恢复后这些指标恢复正常。采用针对线粒体疾病设计的广泛基因panel的下一代测序方法，发现该基因存在一种新的纯合可能致病变异[p.Tyr31Cys (c.92A>G)]，符合孟德尔遗传模式。骨骼肌的功能研究证实线粒体呼吸链（复合体I、II和IV）存在联合缺陷。据我们所知，这是全球第三例该缺陷病例，也是首例伴有3-甲基戊二酸尿症的病例，在任何铁硫簇缺陷中均未报道。值得注意的是，到目前为止似乎没有神经受累情况，仅由预期为良性自限性疾病引发危及生命的急性危机。呼吸链辅因子和伴侣蛋白是一个新的知识领域，可能在系统稳态中发挥显著作用。
