Iron-sulfur cluster ISD11 deficiency ( gene) presenting as cardiorespiratory arrest and 3-methylglutaconic aciduria.

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.