Abstract
Early-onset mitochondrial encephalomyopathy is a rare disorder that presents in the neonatal period with lactic acidosis, hypotonia, and developmental delay. Sequence variants in the nuclear-encoded gene FBXL4 have been previously demonstrated to be a cause of early-onset mitochondrial encephalomyopathy in several unrelated families. We have identified a pair of siblings with mutations in FBXL4 who each presented in the neonatal period with hyperammonemia, low plasma levels of aspartate, low urine levels of tricarboxylic acid cycle intermediates suggesting a defect in anaplerosis, and cerebellar hypoplasia in addition to lactic acidosis and other classic signs of mitochondrial encephalomyopathy. After initial clinical stabilization, both subjects continued to have episodic exacerbations characterized by lactic acidosis and hyperammonemia. Previously reported cases of FBXL4 mutations are reviewed and compared with these affected siblings. These two new cases add to the spectrum of disease caused by mutations in FBLX4 and suggest possible benefit from anaplerotic therapies.
Authors Sarah U. Morton and Edward G. Neilan equally contributed to the manuscript.
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Acknowledgments
The authors will like to thank the family for their support and enrollment. This work was made possible by grants from the following institutions: PBA was supported by 1R01AR068429-01 from the National Institute of Arthritis and Musculoskeletal and Skeletal Diseases (NIAMS) of National Institute of Health (NIH) and U19HD077671 from NICHD/NHGRI/NIH. SUM was supported by T32 HD7466-19 awarded to the Newborn Medicine Division at BCH. The Manton Center for Orphan Disease Research Gene Discovery Core, Boston Children’s Hospital, also supported the work. Sanger sequencing was performed by the Molecular Genetics Core Facility of the IDDRC at Boston Children’s Hospital, supported by National Institutes of Health grant P30 HD18655.
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Communicated by: John Christodoulou, MB BS PhD FRACP FRCPA
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Fig. 1
Representative gas chromatography-mass spectrometry (GC-MS) urine organic acid chromatogram of a healthy child in the first week of life. Peaks representing tricarboxylic acid cycle intermediates including fumarate, 2-ketoglutarate, aconitate, and citrate are often elevated in this age group and are among the most abundant peaks in the chromatogram. The Internal standards (IS) 2-ketocaproate (approximately 11 min) and pentadecanoate (approximately 20 min) are also shown for comparison of scale (TIFF 2467 kb)
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Synopsis
FBXL4 variants are associated with mitochondrial encephalopathy, and this report expands upon the known phenotype by describing a sibling pair with early-onset mitochondrial encephalopathy complicated by hyperammonemia associated with low-normal aspartate levels.
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Sarah Morton, Edward Neilan, Roy Peake, Jiahai Shi, Klaus Schmitz-Abe, Meghan Towne, Kyriacos Markianos, Sanjay Prabhu, and Pankaj Agrawal declare that they have no conflict of interest.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from the parents of the children included in the study.
Author Contributions: Drs. Morton, Neilan, and Agrawal had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Morton, Neilan, Agrawal. Acquisition of Data: Morton, Neilan, Towne, Agrawal. Analysis and interpretation of data: Morton, Neilan, Peake, Shi, Schmitz-Abe, Markianos, Agrawal. Drafting of the manuscript: Morton, Neilan, Agrawal. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Schmitz-Abe, Markianos. Obtained funding: Agrawal. Administrative, technical, or material support: Towne, Agrawal. Study supervision: Morton, Neilan, Agrawal.
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© 2016 Society for the Study of Inborn Errors of Metabolism (SSIEM)
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Morton, S.U. et al. (2016). Hyperammonemia as a Presenting Feature in Two Siblings with FBXL4 Variants. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 35. JIMD Reports, vol 35. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_17
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DOI: https://doi.org/10.1007/8904_2016_17
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