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J Neurol Neurosurg Psychiatry. 1997 July; 63(1): 16–22.
PMCID: PMC2169628

Mitochondrial disease associated with the T8993G mutation of the mitochondrial ATPase 6 gene: a clinical, biochemical, and molecular study in six families


AIM—To contribute to the establishment of a rational clinical, neuroradiological, and molecular approach to neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) and maternally inherited Leigh's syndrome (MILS).
METHODS AND RESULTS—The T8993G mutation in the mitochondrial genome was found in several maternal members of six pedigrees, whose clinical status ranged from no symptoms to severe infantile subacute necrotising encephalomyelopathy (Leigh's disease). In one case a MELAS-like syndrome was documented both clinically and neuroradiologically. Relevant genetic features of the series were anticipation of symptoms through subsequent generations, and the presence of several cases in whom the mutation apparently occurred recently or was new. A uniform distribution of the mutation in many tissues was shown in one patient subjected to necropsy. In general, a good correlation was found between clinical severity and mutation heteroplasmy in readily accessible tissues, such as lymphocytes or fibroblasts. By contrast, a consistent reduction of the mitochondrial ATPase activity, to about half of the normal values, was found in most of the clinically affected cases, irrespective of the amount of mutant mitochondrial DNA.
CONCLUSIONS—Although the measurement of ATP hydrolysis in cultured fibroblasts was a reliable, and sometimes instrumental, means to identify T8993G positive patients, the relation between the mutation and the oxidative phosphorylation defect is probably very complex, and its understanding requires more complex biochemical analysis.

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Selected References

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  • Holt IJ, Harding AE, Petty RK, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet. 1990 Mar;46(3):428–433. [PubMed]
  • Tatuch Y, Christodoulou J, Feigenbaum A, Clarke JT, Wherret J, Smith C, Rudd N, Petrova-Benedict R, Robinson BH. Heteroplasmic mtDNA mutation (T----G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet. 1992 Apr;50(4):852–858. [PubMed]
  • Ciafaloni E, Santorelli FM, Shanske S, Deonna T, Roulet E, Janzer C, Pescia G, DiMauro S. Maternally inherited Leigh syndrome. J Pediatr. 1993 Mar;122(3):419–422. [PubMed]
  • Yoshinaga H, Ogino T, Ohtahara S, Sakuta R, Nonaka I, Horai S. A T-to-G mutation at nucleotide pair 8993 in mitochondrial DNA in a patient with Leigh's syndrome. J Child Neurol. 1993 Apr;8(2):129–133. [PubMed]
  • Santorelli FM, Shanske S, Macaya A, DeVivo DC, DiMauro S. The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome. Ann Neurol. 1993 Dec;34(6):827–834. [PubMed]
  • Tatuch Y, Robinson BH. The mitochondrial DNA mutation at 8993 associated with NARP slows the rate of ATP synthesis in isolated lymphoblast mitochondria. Biochem Biophys Res Commun. 1993 Apr 15;192(1):124–128. [PubMed]
  • Tatuch Y, Pagon RA, Vlcek B, Roberts R, Korson M, Robinson BH. The 8993 mtDNA mutation: heteroplasmy and clinical presentation in three families. Eur J Hum Genet. 1994;2(1):35–43. [PubMed]
  • de Vries DD, van Engelen BG, Gabreëls FJ, Ruitenbeek W, van Oost BA. A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome. Ann Neurol. 1993 Sep;34(3):410–412. [PubMed]
  • Santorelli FM, Shanske S, Jain KD, Tick D, Schon EA, DiMauro S. A T-->C mutation at nt 8993 of mitochondrial DNA in a child with Leigh syndrome. Neurology. 1994 May;44(5):972–974. [PubMed]
  • Cox GB, Fimmel AL, Gibson F, Hatch L. The mechanism of ATP synthase: a reassessment of the functions of the b and a subunits. Biochim Biophys Acta. 1986 Apr 2;849(1):62–69. [PubMed]
  • Zheng XX, Shoffner JM, Voljavec AS, Wallace DC. Evaluation of procedures for assaying oxidative phosphorylation enzyme activities in mitochondrial myopathy muscle biopsies. Biochim Biophys Acta. 1990 Aug 9;1019(1):1–10. [PubMed]
  • Yoshihara Y, Nagase H, Yamane T, Oka H, Tani I, Higuti T. H(+)-ATP synthase from rat liver mitochondria. A simple, rapid purification method of the functional complex and its characterization. Biochemistry. 1991 Jul 16;30(28):6854–6860. [PubMed]
  • Chretien D, Rustin P, Bourgeron T, Rötig A, Saudubray JM, Munnich A. Reference charts for respiratory chain activities in human tissues. Clin Chim Acta. 1994 Jul;228(1):53–70. [PubMed]
  • Tiranti V, Munaro M, Sandonà D, Lamantea E, Rimoldi M, DiDonato S, Bisson R, Zeviani M. Nuclear DNA origin of cytochrome c oxidase deficiency in Leigh's syndrome: genetic evidence based on patient's-derived rho degrees transformants. Hum Mol Genet. 1995 Nov;4(11):2017–2023. [PubMed]
  • Smith RJ, Berlin CI, Hejtmancik JF, Keats BJ, Kimberling WJ, Lewis RA, Möller CG, Pelias MZ, Tranebjaerg L. Clinical diagnosis of the Usher syndromes. Usher Syndrome Consortium. Am J Med Genet. 1994 Mar 1;50(1):32–38. [PubMed]
  • Harding AE, Sweeney MG, Miller DH, Mumford CJ, Kellar-Wood H, Menard D, McDonald WI, Compston DA. Occurrence of a multiple sclerosis-like illness in women who have a Leber's hereditary optic neuropathy mitochondrial DNA mutation. Brain. 1992 Aug;115(Pt 4):979–989. [PubMed]
  • Harding AE, Holt IJ, Sweeney MG, Brockington M, Davis MB. Prenatal diagnosis of mitochondrial DNA8993 T----G disease. Am J Hum Genet. 1992 Mar;50(3):629–633. [PubMed]
  • Hartzog PE, Cain BD. The aleu207-->arg mutation in F1F0-ATP synthase from Escherichia coli. A model for human mitochondrial disease. J Biol Chem. 1993 Jun 15;268(17):12250–12252. [PubMed]

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