title: Neonatal multiorgan failure due to ACAD9 mutation and complex I deficiency with mitochondrial hyperplasia in liver, cardiac myocytes, skeletal muscle, and renal tubules.
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.
authors.affiliation: Divisions of Human Genetics, Gastroenterology, and Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Nancy
authors.initials: N
authors.lastname: Leslie
authors.affiliation: Divisions of Human Genetics, Gastroenterology, and Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Wang
authors.affiliation: Divisions of Human Genetics, Gastroenterology, and Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Divisions of Human Genetics, Gastroenterology, and Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: C Alexander
authors.initials: CA
authors.lastname: Valencia
authors.affiliation: Divisions of Human Genetics, Gastroenterology, and Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Zaza
authors.initials: Z
authors.lastname: Khuchua
authors.affiliation: Divisions of Human Genetics, Gastroenterology, and Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hata
authors.affiliation: Divisions of Human Genetics, Gastroenterology, and Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: David
authors.initials: D
authors.lastname: Witte
authors.affiliation: Divisions of Human Genetics, Gastroenterology, and Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
authors.affiliation: Divisions of Human Genetics, Gastroenterology, and Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. Electronic address: kevin.bove@uc.edu.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Bove
mesh_terms: D000138:Acidosis / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000140:Acidosis, Lactic / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D044944:Acyl-CoA Dehydrogenases / Q000172:deficiency / Q000235:genetics*; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D001344:Autopsy; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002423:Cause of Death; D002478:Cells, Cultured; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D003964:Diaphragm / Q000201:enzymology / Q000473:pathology*; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics; D017809:Fatal Outcome; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007684:Kidney Tubules / Q000201:enzymology / Q000473:pathology*; D007888:Leigh Disease / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008929:Mitochondria, Heart / Q000201:enzymology / Q000473:pathology*; D008930:Mitochondria, Liver / Q000201:enzymology / Q000473:pathology*; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000473:pathology*; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009102:Multiple Organ Failure / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018908:Muscle Weakness / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D014162:Transfection
chemical_list: D018389:Codon, Nonsense; D004272:DNA, Mitochondrial; D044944:Acyl-CoA Dehydrogenases; D042964:Acyl-CoA Dehydrogenase; C549517:ACAD9 protein, human; D042967:Electron Transport Complex I
keywords: ACAD9 defect; Complex I deficiency; Lethal neonatal lactic acidosis; Metabolic disease; Mitochondrial hyperplasia; Mitochondriopathy; Multiorgan failure; Whole-exome sequencing