Neonatal multiorgan failure due to ACAD9 mutation and complex I deficiency with mitochondrial hyperplasia in liver, cardiac myocytes, skeletal muscle, and renal tubules

Hum Pathol. 2016 Mar:49:27-32. doi: 10.1016/j.humpath.2015.09.039. Epub 2015 Oct 28.

Abstract

Complex I deficiency causes Leigh syndrome, fatal infant lactic acidosis, and neonatal cardiomyopathy. Mutations in more than 100 nuclear DNA and mitochondrial DNA genes miscode for complex I subunits or assembly factors. ACAD9 is an acyl-CoA dehydrogenase with a novel function in assembly of complex I; biallelic mutations cause progressive encephalomyopathy, recurrent Reye syndrome, and fatal cardiomyopathy. We describe the first autopsy in fatal neonatal lethal lactic acidosis due to mutations in ACAD9 that reduced complex I activity. We identified mitochondrial hyperplasia in cardiac myocytes, diaphragm muscle, and liver and renal tubules in formalin-fixed, paraffin-embedded tissue using immunohistochemistry for mitochondrial antigens. Whole-exome sequencing revealed compound heterozygous variants in the ACAD9 gene: c.187G>T (p.E63*) and c.941T>C (p.L314P). The nonsense mutation causes late infantile lethality; the missense variant is novel. Autopsy-derived fibroblasts had reduced complex I activity (53% of control) with normal activity in complexes II to IV, similar to reported cases of ACAD9 deficiency.

Keywords: ACAD9 defect; Complex I deficiency; Lethal neonatal lactic acidosis; Metabolic disease; Mitochondrial hyperplasia; Mitochondriopathy; Multiorgan failure; Whole-exome sequencing.

Publication types

  • Case Reports

MeSH terms

  • Acidosis / diagnosis*
  • Acidosis / enzymology
  • Acidosis / genetics
  • Acidosis / pathology
  • Acidosis, Lactic / diagnosis*
  • Acidosis, Lactic / enzymology
  • Acidosis, Lactic / genetics
  • Acidosis, Lactic / pathology
  • Acyl-CoA Dehydrogenase / deficiency*
  • Acyl-CoA Dehydrogenase / genetics
  • Acyl-CoA Dehydrogenases / deficiency
  • Acyl-CoA Dehydrogenases / genetics*
  • Amino Acid Metabolism, Inborn Errors / diagnosis*
  • Amino Acid Metabolism, Inborn Errors / enzymology
  • Amino Acid Metabolism, Inborn Errors / genetics
  • Amino Acid Metabolism, Inborn Errors / pathology
  • Autopsy
  • Cardiomyopathy, Hypertrophic / diagnosis*
  • Cardiomyopathy, Hypertrophic / enzymology
  • Cardiomyopathy, Hypertrophic / genetics
  • Cardiomyopathy, Hypertrophic / pathology
  • Cause of Death
  • Cells, Cultured
  • Codon, Nonsense*
  • DNA Mutational Analysis
  • DNA, Mitochondrial / genetics
  • Diaphragm / enzymology
  • Diaphragm / pathology*
  • Electron Transport Complex I / deficiency*
  • Electron Transport Complex I / genetics
  • Fatal Outcome
  • Fibroblasts / enzymology
  • Fibroblasts / pathology
  • Genetic Predisposition to Disease
  • Humans
  • Hyperplasia
  • Immunohistochemistry
  • Infant, Newborn
  • Kidney Tubules / enzymology
  • Kidney Tubules / pathology*
  • Leigh Disease / diagnosis*
  • Leigh Disease / enzymology
  • Leigh Disease / genetics
  • Leigh Disease / pathology
  • Male
  • Mitochondria, Heart / enzymology
  • Mitochondria, Heart / pathology*
  • Mitochondria, Liver / enzymology
  • Mitochondria, Liver / pathology*
  • Mitochondria, Muscle / enzymology
  • Mitochondria, Muscle / pathology*
  • Mitochondrial Diseases / diagnosis*
  • Mitochondrial Diseases / enzymology
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / pathology
  • Multiple Organ Failure / diagnosis*
  • Multiple Organ Failure / enzymology
  • Multiple Organ Failure / genetics
  • Multiple Organ Failure / pathology
  • Muscle Weakness / diagnosis*
  • Muscle Weakness / enzymology
  • Muscle Weakness / genetics
  • Muscle Weakness / pathology
  • Phenotype
  • Transfection

Substances

  • Codon, Nonsense
  • DNA, Mitochondrial
  • Acyl-CoA Dehydrogenases
  • Acyl-CoA Dehydrogenase
  • ACAD9 protein, human
  • Electron Transport Complex I

Supplementary concepts

  • Acyl-CoA Dehydrogenase Family, Member 9, Deficiency of
  • Lactic Acidosis, Fatal Infantile
  • Leigh Syndrome Due To Mitochondrial Complex I Deficiency