Mitochondrial DNA Depletion in Alpers Syndrome

Abstract

Mitochondrial dysfunction of the energy generating system was suggested in two infants with progressive infantile poliodystrophy characterised by hypotonia, refractory epilepsy, visual impairment, psychomotor retardation, profound brain atrophy, hepatopathy, and increased levels of lactate in blood and cerebrospinal fluid. Histochemical and electron microscopic analyses of liver biopsies revealed cytochrome c oxidase deficiency, microvesicular steatosis, and enormous multiplication of mitochondria of various sizes. In the first patient, the quantitative Southern blot analyses in tissues obtained at autopsy demonstrated reduced content of mtDNA in the liver, brain, and fibroblasts (11 %, 15 %, and 25 % of the mean values in controls) while a normal content of mtDNA was found in muscle and heart. In the second patient, a reduced content of mtDNA was found in the muscle, liver, and brain (15 %, 10 %, and 30 %, respectively, of the mean values in controls). Biochemical studies in the first patient revealed decreased activities of all respiratory chain complexes except complex II in isolated liver mitochondria and decreased amounts of respiratory chain complexes I, III, IV and ATP synthase in liver and frontal cortex, but not in muscle, heart, and fibroblasts. In conclusions, mtDNA depletion associated with Alpers syndrome may be tissue specific.

Key words

MtDNA depletion - respiratory chain complexes - Alpers syndrome

References

• 1 Bakker H D, Scholte H R, Dingemans K P, Spelbrink J N, Wijburg F A, Van den Bogert C. Depletion of mitochondrial deoxyribonucleic acid in a family with fatal neonatal liver disease.  J Pediatr. 1996;  128 683-687
• 2 Barthelemy C, de Baulny H O, Lombes A. D-loop mutations in mitochondrial DNA: link with mitochondrial DNA depletion?.  Hum Genet. 2002;  110 479-487
• 3 Barthelemy C, Ogier de Baulny H, Diaz J, Cheval M A, Frachon P, Romero N. et al . Late-onset mitochondrial DNA depletion: DNA copy number, multiple deletions, and compensation.  Ann Neurol. 2001;  49 607-617
• 4 Berger A, Bruschek M, Grethen C, Sperl W, Kofler B. Poor storage and handling of tissue mimics mitochondrial DNA depletion.  Diagn Mol Pathol. 2001;  10 55-59
• 5 Bodnar A G, Cooper J M, Holt I J, Leonard J V, Schapira A H. Nuclear complementation restores mtDNA levels in cultured cells from a patient with mtDNA depletion.  Am J Hum Genet. 1993;  53 663-669
• 6 Castro-Gago M, Gonzalez-Conde V, Fernandez-Seara M J, Rodrigo-Saez E, Fernandez-Cebrian S, Alonso-Martin A. et al . Early mitochondrial encephalomyopathy due to complex IV deficiency consistent with Alpers-Huttenlocher syndrome: report of two cases.  Rev Neurol. 1999;  29 912-917
• 7 Clayton D A. Replication and transcription of vertebrate mitochondrial DNA.  Annu Rev Cell Biol. 1991;  7 453-478
• 8 Constantin-Teodosiu D, Cederblad G, Hultman E. A sensitive radioisotopic assay of pyruvate dehydrogenase complex in human muscle tissue.  Anal Biochem. 1991;  198 347-351
• 9 Farr C L, Matsushima Y, Lagina 3rd A T. Physiological and biochemical defects in functional interactions of mitochondrial DNA polymerase and DNA-binding mutants of single-stranded DNA-binding protein.  J Biol Chem. 2004;  279 17047-17053
• 10 Gabreels F J, Prick M J, Trijbels J M, Renier W O, Jaspar H H, Janssen A J. et al . Defects in citric acid cycle and the electron transport chain in progressive poliodystrophy.  Acta Neurol Scand. 1984;  70 145-154
• 11 Hargreaves P, Rahman S, Guthrie P, Taanman J W, Leonard J V, Land J M. et al . Diagnostic value of succinate ubiquinone reductase activity in the identification of patients with mitochondrial DNA depletion.  J Inherit Metab Dis. 2002;  25 7-16
• 12 Jullig M, Eriksson S. Mitochondrial and submitochondrial localization of human deoxyguanosine kinase.  Eur J Biochem. 2000;  267 5466-5472
• 13 Larsson N G, Oldfors A, Holme E, Clayton D A. Low levels of mitochondrial transcription factor A in mitochondrial DNA depletion.  Biochem Biophys Res Commun. 1994;  200 1374-1381
• 14 Lowry O H, Rosebrough N J, Farr A L, Randall R J. Protein measurement with the Folin phenol reagent.  J Biol Chem. 1951;  193 265-275
• 15 Macmillan C J, Shoubridge E A. Mitochondrial DNA depletion: prevalence in a pediatric population referred for neurologic evaluation.  Pediatr Neurol. 1996;  14 203-210
• 16 Makinen M W, Lee C P. Biochemical studies of skeletal muscle mitochondria. I. Microanalysis of cytochrome content, oxidative and phosphorylative activities of mammalian skeletal muscle mitochondria.  Arch Biochem Biophys. 1968;  126 75-82
• 17 Mancuso M, Salviati L, Sacconi S, Otaegui D, Camano P, Marina A. et al . Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.  Neurology. 2002;  59 1197-1202
• 18 Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A. et al . The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA.  Nat Genet. 2001;  29 337-341
• 19 Marin-Garcia J, Goldenthal M J. Mitochondrial biogenesis defects and neuromuscular disorders.  Pediatric Neurology. 2000;  22 122-129
• 20 Mariotti C, Uziel G, Carrara F, Mora M, Prelle A, Tiranti V. et al . Early-onset encephalomyopathy associated with tissue-specific mitochondrial DNA depletion: a morphological, biochemical and molecular-genetic study.  J Neurol. 1995;  242 547-556
• 21 Mazziotta M R, Ricci E, Bertini E, Vici C D, Servidei S, Burlina A B. et al . Fatal infantile liver failure associated with mitochondrial DNA depletion.  J Pediatr. 1992;  121 896-901
• 22 Montine T J, Powers J M, Vogel F S, Radtke R A. Alpers syndrome presenting with seizures and multiple stroke-like episodes in a 17-year-old male.  Clin Neuropathol. 1995;  14 322-326
• 23 Moraes C T, Shanske S, Tritschler H J, Aprille J R, Andreetta F, Bonilla E. et al . MtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases.  Am J Hum Genet. 1991;  48 492-501
• 24 Morris A A. Mitochondrial respiratory chain disorders and the liver.  Liver. 1999;  19 357-368
• 25 Naviaux R K, Nyhan W L, Barshop B A, Poulton J, Markusic D, Karpinski N C. et al . Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome.  Ann Neurol. 1999;  45 54-58
• 26 Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.  Science. 1999;  283 689-692
• 27 Poulton J, Morten K, Freeman-Emmerson C, Potter C, Sewry C, Dubowitz V. et al . Deficiency of the human mitochondrial transcription factor h-mtTFA in infantile mitochondrial myopathy is associated with mtDNA depletion.  Hum Mol Genet. 1994;  3 1763-1769
• 28 Prick M, Gabreels F, Renier W, Trijbels F, Jaspar H, Lamers K. et al . Pyruvate dehydrogenase deficiency restricted to brain.  Neurology. 1981;  31 398-404
• 29 Rahman S, Taanman J W, Harding B N, Moris A AM. Alpers syndrome with mitochondrial DNA depletion.  J Inherit Metab Dis. 2002;  25 85
• 30 Rampazzo C, Gallinaro L, Milanesi E, Frigimelica E, Reichard P, Bianchi V. A deoxyribonucleotidase in mitochondria: involvement in regulation of dNTP pools and possible link to genetic disease.  Proc Natl Acad Sci U S A. 2000;  97 8239-8244
• 31 Rustin P, Chretien D, Bourgeron T, Gerard B, Rotig A, Saudubray J M. et al . Biochemical and molecular investigations in respiratory chain deficiencies.  Clin Chim Acta. 1994;  228 35-51
• 32 Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, Elpeleg O. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.  Nat Genet. 2001;  29 342-344
• 33 Scaglia F, Sutton V R, Bodamer O A, Vogel H, Shapira S K, Naviaux R K. et al . Mitochondrial DNA depletion associated with partial complex II and IV deficiencies and 3-methylglutaconic aciduria.  J Child Neurol. 2001;  16 136-138
• 34 Shoffner J M, Wallace D C. Oxidative phosphorylation disease. Scriver CR, Beaudet AL, Sly WS, Valle D The Metabolic and Molecular Basis of Inherited Disease. New York; McGraw-Hill 1995: 1577
• 35 Schagger H, von Jagow G. Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form.  Anal Biochem. 1991;  199 223-231
• 36 Spelbrink J N, Van Galen M J, Zwart R, Bakker H D, Rovio A, Jacobs H T. et al . Familial mitochondrial DNA depletion in liver: haplotype analysis of candidate genes.  Hum Genet. 1998;  102 327-331
• 37 Suomalainen A, Kaukonen J. Diseases caused by nuclear genes affecting mtDNA stability.  Am J Med Genet. 2001;  106 53-61
• 38 Taanman J W, Bodnar A G, Cooper J M, Morris A A, Clayton P T, Leonard J V. et al . Molecular mechanisms in mitochondrial DNA depletion syndrome.  Hum Mol Genet. 1997;  6 935-942
• 39 Taanman J W, Kateeb I, Muntau A C, Jaksch M, Cohen N, Mandel H. A novel mutation in the deoxyguanosine kinase gene causing depletion of mitochondrial DNA.  Ann Neurol. 2002;  52 237-239
• 40 Van Goethem G, Dermaut B, Lofgren A, Martin J J, Van Broeckhoven C. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.  Nat Genet. 2001;  28 211-212
• 41 Zeviani M. Nucleus-driven mutations of human mitochondrial DNA.  J Inherit Metab Dis. 1992;  15 456-471