Infantile Progressive Hepatoencephalomyopathy with Combined OXPHOS Deficiency due to Mutations in the Mitochondrial Translation Elongation Factor Gene GFM1

Abstract

Mitochondrial disorders are a heterogeneous group of often multisystemic and early fatal diseases caused by defects in the oxidative phosphorylation (OXPHOS) system. Given the complexity and intricacy of the OXPHOS system, it is not surprising that the underlying molecular defect remains unidentified in many patients with a mitochondrial disorder. Here, we report the clinical features and diagnostic workup leading to the elucidation of the genetic basis for a combined complex I and IV OXPHOS deficiency secondary to a mitochondrial translational defect in an infant who presented with rapidly progressive liver failure, encephalomyopathy, and severe refractory lactic acidemia. Sequencing of the GFM1 gene revealed two inherited novel, heterozygous mutations: a.539delG (p.Gly180AlafsX11) in exon 4 which resulted in a frameshift mutation, and a second c.688G > A (p.Gly230Ser) mutation in exon 5. This missense mutation is likely to be pathogenic since it affects an amino acid residue that is highly conserved across species and is absent from the dbSNP and 1,000 genomes databases. Review of literature and comparison were made with previously reported cases of this recently identified mitochondrial disorder encoded by a nuclear gene. Although limited in number, nuclear gene defects causing mitochondrial translation abnormalities represent a new, rapidly expanding field of mitochondrial medicine and should potentially be considered in the diagnostic investigation of infants with progressive hepatoencephalomyopathy and combined OXPHOS disorders.

Fig. 1

(a, b) MRI brain T1 and T2 weighted axial images showing global, cystic changes and hyperintensities in putamen and glubus pallidi. (c) MRI brain showing subcortical cystic changes and dilated lateral ventricles with ventricular septae

Fig. 2

Liver H&E X40: Liver tissue displaying moderate microvesicular steatosis and patchy macrovesicular steatosis with intrahepatic and intracanicular cholestasis. The portal tracts are expanded with accompanying portal fibrosis and portal to portal bridging fibrosis

Fig. 3

Liver MT X10: Lobular disarray of liver tissue is evident with the nodular pattern emphasized by Masson’s Trichrome stain