title: Lifetime exercise intolerance with lactic acidosis as key manifestation of novel compound heterozygous ACAD9 mutations causing complex I deficiency.
abstract: We report a 36-year-old female having lifetime exercise intolerance and lactic acidosis with nausea associated with novel compound heterozygous Acyl-CoA dehydrogenase 9 gene (ACAD9) mutations (p.Ala390Thr and p.Arg518Cys). ACAD9 is an assembly factor for the mitochondrial respiratory chain complex I. ACAD9 mutations are recognized as frequent causes of complex I deficiency. Our patient presented with exercise intolerance, rapid fatigue, and nausea since early childhood. Mild physical workload provoked the occurrence of nausea and vomiting repeatedly. Her neurological examination, laboratory findings and muscle biopsy demonstrated no abnormalities. A bicycle spiroergometry provoked significant lactic acidosis during and following exercise pointing towards a mitochondrial disorder. Subsequently, the analysis of respiratory chain enzyme activities in muscle revealed severe isolated complex I deficiency. Candidate gene sequencing revealed two novel heterozygous ACAD9 mutations. This patient report expands the mutational and phenotypic spectrum of diseases associated with mutations in ACAD9.
authors.affiliation: Department of Neurology, DKD HELIOS Medical Center Wiesbaden, Wiesbaden, Germany.
authors.forename: Bertold
authors.initials: B
authors.lastname: Schrank
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, University Hospital of LMU Munich, Munich, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, University Hospital of LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, University Hospital of LMU Munich, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schneiderat
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.affiliation: MGZ, Medical Genetics Center, Munich, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Abicht
authors.affiliation: MGZ, Medical Genetics Center, Munich, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.affiliation: Department of Neurology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania. Electronic address: sarunas.augustis@gmail.com.
authors.forename: Sarunas
authors.initials: S
authors.lastname: Augustis
mesh_terms: D000140:Acidosis, Lactic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D044944:Acyl-CoA Dehydrogenases / Q000235:genetics*; D000328:Adult; D003937:Diagnosis, Differential; D042967:Electron Transport Complex I / Q000172:deficiency; D017079:Exercise Tolerance / Q000235:genetics* / Q000502:physiology; D005260:Female; D006579:Heterozygote; D006801:Humans; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D010641:Phenotype
chemical_list: D044944:Acyl-CoA Dehydrogenases; C549517:ACAD9 protein, human; D042967:Electron Transport Complex I
keywords: ACAD9 mutations; Complex I deficiency; Isolated myopathy; Life-long exercise intolerance