Abstract
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.
Competing interests: None declared
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Communicated by: Shamima Rahman, FRCP, FRCPCH, PhD
One Sentence Summary
A homozygous frameshift mutation in FBXL4 was identified in a neonate with primary lactic acidosis, in whom cell-based mitochondrial phenotyping demonstrated severe global mitochondrial dysfunction.
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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, and Matthew A. Lines declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (2010) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients participating in the study. The research protocol was approved by the Children’s Hospital of Eastern Ontario Research Ethics Board.
Authors’ Contributions
All authors contributed to the conception and design of the study. ML, SR, JM, HJM, and JB acquired the clinical and genomic data. GA, SM, JV, and TN generated respirometry and cell-based data for mitochondrial phenotyping. Data were analyzed and interpreted by GA, SM, JV, TN, JM, MEH, and ML. The manuscript was drafted by GA, SM, MEH, and ML. Critical revisions were performed by all authors.
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Antoun, G. et al. (2015). Detailed Biochemical and Bioenergetic Characterization of FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 27. JIMD Reports, vol 27. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_491
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DOI: https://doi.org/10.1007/8904_2015_491
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