Prenatal onset of mitochondrial disease is associated with sideroflexin 4 deficiency.

Prenatal onset of mitochondrial disease has been described in two cases with recessive mutations in the sideroflexin 4 gene (SFXN4). We present a third case with complex I deficiency associated with novel mutations in SFXN4. Our patient presented with intrauterine growth retardation, neonatal lactic acidosis, and developed macrocytic anemia and optic nerve hypoplasia. Muscle mitochondrial investigations revealed ultrastructural abnormalities, severe deficiency of complex I enzyme activity, and loss of subunit proteins. Whole-exome sequencing revealed bi-allelic SFXN4 mutations: a 1-base deletion, c.969delG, leading to frameshift and a premature stop codon, p.(Gln323His fs *20), and a stop-loss mutation in the C-terminal region, c.1012 T > C; p.(*388Glnext2), resulting in elongation of the protein by two amino acids. Expression analysis of mRNA from muscle showed loss of SFXN4 transcripts. • Mutations in the sideroflexin 4 (SFXN4) gene cause a mitochondrial disorder with severe complex I deficiency • SFXN4 -associated disease is characterized by prenatal onset, macrocytic anemia and optic nerve hypoplasia • We present the third patient known to date with SFXN4 -associated disease and loss of complex I proteins in muscle [ABSTRACT FROM AUTHOR]