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: Nancy Leslie, Xinjian Wang, Yanyan Peng, C Alexander Valencia, Zaza Khuchua, Jessica Hata, David Witte, Taosheng Huang, Kevin E Bove
• Journal: Human pathology (Hum Pathol) Vol. 49 Pg. 27-32 (Mar 2016) ISSN: 1532-8392 [Electronic] United States
• PMID: 26826406 (Publication Type: Case Reports, Journal Article)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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