Background and aims Rapid diagnosis of mitochondrial disorder is difficult in newborn infants with metabolic crisis. We studied whether respiratory chain disorder can be assessed from circulating platelets.
Methods A full-term girl of consanguineous parents was born after uncomplicated pregnancy (2690 g, Apgar 10/10/10). On day one she was transferred to NICU with metabolic acidosis (pH 7.11, pCO2 2.8, BE -24, lactate 19 mmol/l). CSF/plasma lactate ratio (5.3/6.9) was increased. Cerebral MRI revealed diffuse changes in pyramidal tract and internal capsule. On day 4 she developed hepatic failure, conjugated hyperbilirubinemia and slight hyperammonemia. Urine metabolic analysis revealed increased 3-methylglutaconic acid (160 mmol/mol creatinine), and 4-hydroxyphenyllacetate suggestive of mitochondrial disorder. Respirometry (Oroboros Oxygraph, SUIT-protocol) was performed on blood cells. Isolated mitochondria from fibroblasts and liver were assessed with Blue Native-PAGE (BNGE) for respiratory chain complex assembly. Intensive care was withdrawn because of deterioration, and postmortem biopsies performed.
Results Respirometry on platelets showed a borderline oxygen consumption. Histology of muscle was normal, liver was cholestatic with iron accumulation. In fibroblasts, respiratory chain complex assembly was normal, but in liver levels of Complexes I, III and IV were decreased. Whole genome sequencing identified the candidate genes Sycp2, Clybl and Foxred1. The deficient complexes all possess mtDNA encoded subunits thus nuclear encoded translator mutation or other mtDNA related mutation might be causative.
Conclusions Respirometry from blood cells might suggest mitochondrial dysfunction that can be verified by structural analyses of respiratory chain complexes from the target organ. Causative mutation might be achieved with next generation sequencing.