title: Mitochondrial DNA G8363A mutation in the tRNA Lys gene: clinical, biochemical and pathological study.
abstract: The G8363A is a very rare mtDNA tRNA(Lys) gene mutation that has been associated to MERRF-like syndrome, cardiomyopathy or Leigh syndrome. Here, we describe the clinical and molecular features of a new large multigenerational family and we review the literature of cases with this mutation. In our family seven members presented a heterogeneous mitochondrial disease phenotype, from MERRF-like syndrome to isolated psychiatric disorder, associated with the G8363A mutation. The two probands are dizygotic twin sisters affected by mental retardation, neural deafness, myopathy, myoclonic epilepsy and ataxia. Twins' muscle biopsies showed a severe cytochrome c oxidase (COX) deficiency and ragged-red fibers. Their mitochondrial respiratory chain was defective in complexes I and IV in muscle. A severe reduction in complex IV activity was also observed in fibroblasts and myoblasts. Molecular analysis showed a G8363A transition in the mtDNA tRNA(Lys) gene. The mutation was almost homoplasmic (>90%) in muscle and blood of the twins and heteroplasmic (55+/-8%) in blood sample from affected maternal relatives. Based on our family data and the meta-analysis of the literature, we confirm that mutational load directly correlates with severity of the disease (severe vs mild/moderate phenotype; P=0.00168) and with disease onset (P<0.00001). However the presence of several exceptions and overlaps among patients with different clinical severity limits the clinical usefulness of this observation. Although the pathogenicity of the G8363A mutation is well established, counselling is a difficult task for clinicians because of the large phenotypical variability. Our study contributes further data on the clinical spectrum and its relation with the level of G8363A tRNA(Lys) mtDNA mutation.
authors.affiliation: Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Virgilio
authors.forename: Dario
authors.initials: D
authors.lastname: Ronchi
authors.forename: Andreina
authors.initials: A
authors.lastname: Bordoni
authors.forename: Elisa
authors.initials: E
authors.lastname: Fassone
authors.forename: Sara
authors.initials: S
authors.lastname: Bonato
authors.forename: Chiara
authors.initials: C
authors.lastname: Donadoni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Torgano
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics*; D004579:Electron Transport; D005190:Family; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D017243:MERRF Syndrome / Q000235:genetics; D001523:Mental Disorders / Q000235:genetics; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000235:genetics*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D020125:Mutation, Missense; D032446:Myoblasts / Q000201:enzymology; D010375:Pedigree; D010641:Phenotype; D012357:RNA, Transfer, Lys / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D012357:RNA, Transfer, Lys