title: Hyperammonemia as a Presenting Feature in Two Siblings with FBXL4 Variants.
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.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Hunnewell 4, Boston, MA, 02115, USA.|Gene Discovery Core, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Sarah U
authors.initials: SU
authors.lastname: Morton
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Neilan
authors.affiliation: Department of Laboratory Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Roy W A
authors.initials: RWA
authors.lastname: Peake
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Pok Fu Lam, Hong Kong.
authors.forename: Jiahai
authors.initials: J
authors.lastname: Shi
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schmitz-Abe
authors.affiliation: Gene Discovery Core, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.|Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Towne
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Hunnewell 4, Boston, MA, 02115, USA.|Gene Discovery Core, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Kyriacos
authors.initials: K
authors.lastname: Markianos
authors.affiliation: Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Sanjay P
authors.initials: SP
authors.lastname: Prabhu
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Hunnewell 4, Boston, MA, 02115, USA. pagrawal@enders.tch.harvard.edu.|Gene Discovery Core, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. pagrawal@enders.tch.harvard.edu.|Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. pagrawal@enders.tch.harvard.edu.
authors.forename: Pankaj B
authors.initials: PB
authors.lastname: Agrawal
keywords: Anaplerosis; Aspartate; FBXL4; Hyperammonemia; Lactic acidosis; Mitochondrial encephalomyopathy