A Novel 7301-bp Deletion in Mitochondrial DNA in a Patient with Kearns-Sayre Syndrome, Diabetes Mellitus, and Primary Amenorrhoea

Abstract

We report a 27-year-old woman with a form of mitochondrial myopathy including chronic progressive external opthalmoplegia, retinal pigmentary dystrophy, cerebellar ataxia, and cardiac conduction block (Kearns-Sayre syndrome). At age 13 years a cardiac pacemaker was implanted. She also had sensineural hearing loss, delayed puberty, and primary amenorrhoea. She was weelchair-bound since the age of 20 years. At age 27, insulin-dependent diabetes mellitus and osteoporosis were diagnosed. Insulin treatment was started and associated endocrinopathies were investigated. DNA analysis identified a novel 7301-bp deletion in mitochondrial DNA, ranging from position 6530 to 13 831 corroborating the diagnosis of Kearns-Sayre syndrome.

Key words

Kearns-Sayre syndrome - mitochondrial DNA mutations - diabetes mellitus

References

• 1 Abramowicz M J, Cochaux P, Cohen L HF, Vamos E. Pernicious anaemia and hypoparathyroidism in a patient with Kearns-Sayre syndrome with mitochondrial DNA duplication.  J Inherit Metab Dis. 1996;  19 101-111
• 2 Ballinger S W, Shoffner J M, Hedaya E V, Trounce I, Polak M A, Koontz D A, Wallace D C. Maternally transmitted diabetes and deafness associated with a 10. 4 kb mitochondrial DNA deletion.  Nat Genet. 1992;  1 11-15
• 3 Berenberg R A, Pellock J M, DiMauro S, Schotland D L, Bonilla E, Eastwood A, Hays A, Vicale C T, Behrens M, Chutorian A, Rowland L P. Lumping or splitting? “Ophthalmoplegia-plus or Kearns-Sayre syndrome”?.  Ann Neurol. 1977;  1 37-54
• 4 Burns E C, Preece M A, Cameron N, Tanner J M. Growth hormone deficiency in mitochondrial cytopathy.  Acta Paediatr Scand. 1982;  71 693-697
• 5 Coulter D, Allen R J. Abrupt neurological deterioration in children with Kearns-Sayre syndrome.  Arch Neurol. 1981;  38 247-250
• 6 Egger J, Lake B D, Wilson J. Mitochondrial cytopathy. A multisystem disorder with ragged red fibres on muscle biopsy.  Arch Disease in Childhood. 1981;  56 741-752
• 7 Harvey J N, Barnett D. Endocrine dysfunction in Kearns-Sayre syndrome.  Clin Endocrinol (Oxford). 1992;  37 97-103
• 8 Kadowaki T, Kadowaki H, Mori Y, Tobe K, Sakuta R, Suzuki Y, Tanabe Y, Sakura H, Awata T, Goto Y, Hayakawa T, Matsuoka K, Kawamori R, Kamada T, Horai S, Nonaka I, Hagura R, Akanuma Y, Yakazi Y. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA.  N Engl J Med. 1994;  330 962-968
• 9 Karpati G, Carpenter S, Larbrisseau A, Lafontaine R. The Kearns-Shy syndrome. A multisystem disease with mitochondrial abnormality demonstrated in skeletal muscle and skin.  J Neurol Sci. 1973;  19 133-151
• 10 Kearns T P, Sayre G P. Retinitis pigmentosa, external ophthalmoplegia and complete heart block.  Arch Ophthalmology. 1958;  60 280-289
• 11 Kishimoto M, Hashiramoto M, Araki S, Ishida Y, Kazumi T, Kanda F, Kasuga M. Diabetes mellitus carrying a mutation in the mitochondrial tRNA^Leu(UUR) gene.  Diabetologia. 1995;  38 193-200
• 12 Kuriyama M, Suehara M, Marume N, Osame M, Igata A. High CSF lactate and pyruvate content in Kearns-Sayre syndrome.  Neurology. 1984;  34 253-255
• 13 Maassen J A. Mitochondrial diabetes, pathophysiology, clinical presentation and genetic analysis.  Am J Med Genet. 2002;  115 66-70
• 14 Mandrup-Poulsen T, Helqvist S, Wogensen L D, Movig J, Pociot F, Johannesen J, Nerup J. Cytokines and free radicals as effector molecules in the destruction of pancreatic β-cells.  Curr Top Microbiol Immunol. 1990;  164 169-193
• 15 Manolagas S C. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis.  Endocrine Reviews. 2000;  21 115-137
• 16 McDonald W I. Neurological associations of pigmentary retinopathy.  Transactions of the Ophthalmological Society of the United Kingdom. 1972;  92 179-186
• 17 Moraes C T, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda A F, Nakase H, Bonilla E, Werneck L C, Servidei S. et al . Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.  N Engl J Med. 1989;  320 1293-1299
• 18 Oexle K, Oberle J, Finckh B, Kohlschutter A, Nagy M, Seibel P, Seissler J, Hubner C. Islet cell antibodies in diabetes mellitus associated with a mitochondrial tRNA (Leu (UUR)) gene mutation.  Exp Clin Endocrinol Diabetes. 1996;  104 212-217
• 19 Ohno K, Yamamoto M, Engel A G, Harper C M, Roberts L R, Tan G H, Fatourechi V. MELAS and Kearns-Sayre type co-mutation with myopathy and autoimmune polyendocrinopathy.  Ann Neurol. 1996;  39 761-766
• 20 Oka Y, Katagiri H, Yakazi Y, Murase Y, Kobayashi T. Mitochondrial gene mutation in islet-cell antibody-positive patients who were initially non-insulin-dependent diabetics.  Lancet. 1993;  342 527-528
• 21 Pellock J M, Behrens M, Lewis L, Holub D, Carter S, Rowland L P. Kearns-Sayre syndrome and hypoparathyroidism.  Ann Neurol. 1978;  3 455-458
• 22 Quade A, Zierz S, Klingmüller D. Endocrine abnormalities in mitochondrial myopathy with external ophthalmoplegia.  Clin Invest. 1992;  70 396-402
• 23 Reardon W, Ross R JM, Sweeney M G, Luxon L M, Pembrey M E, Harding A E, Trembath R C. Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA.  Lancet. 1992;  340 1376-1379
• 24 Shanske S, Moraes C T, Lombes A, Miranda A F, Bonilla E, Lewis P, Whelan M A, Ellsworth C A, DiMauro S. Widespread tissue distribution of mitochondrial DNA deletions in Kearns-Sayre syndrome.  Neurology. 1990;  40 24-28
• 25 Tengan C H, Kiyomoto B H, Rocha M S, Tavares V LS, Gabbai A A, Moraes C T. Mitochondrial encephalomyopathy and hypoparathyroidism associated with a duplication and a deletion of mitochondrial deoxyribonucleic acid.  J Clin Endocrinol Metab. 1998;  83 125-129
• 26 van de Corput M P, van den Ouweland J M, Dirks R W, Hart L M, Bruining G J, Maassen J A, Raap A K. Detection of mitochondrial DNA deletions in human skin fibroblasts of patients with Pearson's syndrome by two-color fluorescence in situ hybridization.  J Histochem Cytochem. 1997;  45 55-61
• 27 Van den Ouweland J M, de Klerk J B, van de Corput M P, Dirks R W, Raap A K, Scholte H R, Huijmans J G, Hart L M, Bruining G J, Maassen J A. Characterization of a novel mitochondrial DNA deletion in a patient with a variant of the Pearson marrow-pancreas syndrome.  Eur J Hum Genet. 2000;  8 195-203
• 28 Van den Ouweland J MW, Lemkes H HPJ, Ruitembeek W, Sandkuijl L A, De Vijlder M F, Struyvenberg P AA, Van De Kamp J JP, Maassen J A. Mutation in mitochondrial tRNA^Leu(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness.  Nat Genet. 1992;  1 368-371
• 29 Wallace D C, Shoffner J M, Trounce I, Brown M D, Ballinger S W, Corral-Debrinski M, Horton T, Jun A S, Lott M T. Mitochondrial DNA mutations in human degenerative diseases and aging.  Biochim Biophys Acta. 1995;  1271 141-151
• 30 Yoneda M, Chomyn A, Martinuzzi A, Hurko O, Attardi G. Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy.  Proc Natl Acad Sci USA. 1992;  89 11164-11168