Quantitative proteomics of patient fibroblasts reveal biomarkers and diagnostic signatures of mitochondrial disease.

BACKGROUNDMitochondrial diseases belong to the group of inborn errors of metabolism (IEM), with a prevalence of 1 in 2,000-5,000 individuals. They are the most common form of IEM, but, despite advances in next-generation sequencing technologies, almost half of the patients are left genetically undiagnosed.METHODSWe investigated a cohort of 61 patients with defined mitochondrial disease to improve diagnostics, identify biomarkers, and correlate metabolic pathways to specific disease groups.

Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications.

PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly.

Severe congenital lactic acidosis and hypertrophic cardiomyopathy caused by an intronic variant in NDUFB7.

Mutations in structural subunits and assembly factors of complex I of the oxidative phosphorylation system constitute the most common cause of mitochondrial respiratory chain defects. Such mutations can present a wide range of clinical manifestations, varying from mild deficiencies to severe, lethal disorders. We describe a patient presenting intrauterine growth restriction and anemia, which displayed postpartum hypertrophic cardiomyopathy, lactic acidosis, encephalopathy, and a severe complex I defect with fatal outcome.