title: The mitochondrial 13513G>A mutation is associated with Leigh disease phenotypes independent of complex I deficiency in muscle.
abstract: The mitochondrial 13513G>A (D393N) mutation in the ND5 subunit of the respiratory chain complex I was initially described in association with MELAS syndrome. Recent observations have linked this mutation to Leigh disease. We screened for the 13513G>A mutation in a cohort of 265 patients with Leigh and Leigh-like disease. The mutation was found in a total of 5 patients. An additional patient who had clinical presentation consistent with a Leigh-like phenotype but with a normal brain MRI was added to the cohort. None of an additional 88 patients meeting MELAS disease criteria, nor 56 patients with respiratory chain deficiency screened for the 13513G>A were found positive for the mutation. The most frequent clinical manifestations in our patients were hypotonia, ocular and cerebellar involvement. Low mutation heteroplasmy in the range of 20-40% was observed in all 6 patients. This observation is consistent with the previously reported low heteroplasmy of this mutation in some patients with the 13513G>A mutation and complex I deficiency. However, normal complex I activity was observed in two patients in our cohort. As most patients with Leigh-like disease and the 13513G>A mutation have been described with complex I deficiency, this report adds to the previously reported subset of patients with normal respiratory complex function. We conclude that in any patient with Leigh or Leigh-like disease, testing for the 13513G>A mutation is clinically relevant and low mutant loads in blood or muscle may be considered pathogenic, in the presence of normal respiratory chain enzyme activities.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, TX 77030, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Brautbar
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, TX 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, CA, USA.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Abdenur
authors.affiliation: Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, CA, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Chang
authors.affiliation: Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, School of Medicine, Denver, CO, USA.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Thomas
authors.affiliation: Phoenix Genetics Program, St. Joseph's Hospital, Phoenix, AZ, USA.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Grebe
authors.affiliation: Phoenix Genetics Program, St. Joseph's Hospital, Phoenix, AZ, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lim
authors.affiliation: Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Shao-Wen
authors.initials: SW
authors.lastname: Weng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, TX 77030, USA.
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, TX 77030, USA.
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
mesh_terms: D000595:Amino Acid Sequence; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D008928:Mitochondria / Q000737:chemistry / Q000201:enzymology / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D008969:Molecular Sequence Data; D009132:Muscles / Q000737:chemistry / Q000201:enzymology*; D020125:Mutation, Missense; D010641:Phenotype; D017354:Point Mutation; D016415:Sequence Alignment
chemical_list: D024101:Mitochondrial Proteins; C481838:MT-ND5 protein, human; D042967:Electron Transport Complex I