JIMD Reports, Volume 27

Antoun, Ghadi, McBride, Skye, Vanstone, Jason R, Naas, Turaya, Michaud, Jean, Redpath, Stephanie, McMillan, Hugh J, Brophy, Jason, Daoud, Hussein, Chakraborty, Pranesh, Dyment, David, Holcik, Martin, Harper, Mary-Ellen, Lines, Matthew A, Ghadi Antoun, Skye McBride, Jason R. Vanstone, Turaya Naas, Jean Michaud, Stephanie Redpath, Hugh J. McMillan, Jason Brophy, Hussein Daoud, Pranesh Chakraborty, David Dyment, Martin Holcik, Mary-Ellen Harper, Matthew A. Lines

Mutations of FBXL4, which encodes an orphan mitochondrial F-box protein, are a recently identified cause of encephalomyopathic mtDNA depletion. Here, we describe the detailed clinical and biochemical phenotype of a neonate presenting with hyperlactatemia, leukoencephalopathy, arrhythmias, pulmonary hypertension, dysmorphic features, and lymphopenia. Next-generation sequencing in the proband identified a homozygous frameshift, c.1641_1642delTG, in FBXL4, with a surrounding block of SNP marker homozygosity identified by microarray. Muscle biopsy showed a paucity of mitochondria with ultrastructural abnormalities, mitochondrial DNA depletion, and profound deficiency of all respiratory chain complexes. Cell-based mitochondrial phenotyping in fibroblasts showed mitochondrial fragmentation, decreased basal and maximal respiration, absence of ATP-linked respiratory and leak capacity, impaired survival under obligate aerobic respiration, and reduced mitochondrial inner membrane potential, with relative sparing of mitochondrial mass. Cultured fibroblasts from the patient exhibited a more oxidized glutathione ratio, consistent with altered cellular redox poise. High-resolution respirometry of permeabilized muscle fibers showed marked deficiency of oxidative phosphorylation using a variety of mitochondrial energy substrates and inhibitors. This constitutes the fourth and most detailed report of FBXL4 deficiency to date. In light of our patient's clinical findings and genotype (homozygous frameshift), this phenotype likely represents the severe end of the FBXL4 clinical spectrum.