Mitochondrial DNA Depletion in Alpers Syndrome

M. Tesarova; J. A. Mayr; L. Wenchich; H. Hansikova; M. Elleder; K. Blahova; W. Sperl; J. Zeman

doi:10.1055/s-2004-821081

Neuropediatrics, Table of Contents

Neuropediatrics 2004; 35(4): 217-223
DOI: 10.1055/s-2004-821081

Original Article

Georg Thieme Verlag KG Stuttgart · New York

Mitochondrial DNA Depletion in Alpers Syndrome

M. Tesarova¹ , J. A. Mayr² , L. Wenchich¹ , H. Hansikova¹ , M. Elleder¹ , K. Blahova¹ , W. Sperl² , J. Zeman¹

¹Department of Paediatrics and Center for Integrated Genomics, Faculty of Medicine, Charles University, Prague, Czech Republic
²Department of Paediatrics, Paracelsus Private Medical University, Salzburg, Austria

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

Full Text

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

Prof. M. D., PhD Jiri Zeman

Department of Paediatrics
Faculty of Medicine
Charles University

Ke Karlovu 2

12808 Prague 2

Czech Republic

Email: jzem@lf1.cuni.cz