Abstract
We report a patient with a clinical picture consisting of small birth weight, connatal hypoplastic anaemia, vacuolised bone marrow precursors, failure to thrive, and, subsequently, by insulin-dependent diabetes, renal Fanconi syndrome, lactic acidosis, complex organic aciduria, and elevation of haemoglobin F and of adenosine deaminase activity. The clinical course was progressive and death occurred at age 19 months. A high proportion of mitochondrial (mt) DNA molecules with a deletion of nucleotides 9238 to 15575 were identified in several tissues; about half of the shortened mtDNA molecules were concatenated to form circular dimers. The clinical and laboratory findings support recent conclusions that Pearson syndrome is not confined to bone marrow and pancreas, as originally described, but is a multi-organ disorder associated with delctions in part of the mtDNA molecules. The tissue distribution and the relative proportions of the abnormal mtDNA molecules apparently determine the phenotype and clinical course.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- PCR:
-
polymerase chain reaction
References
Anderson S, Bankier AT, Barrell BG, Bruijn MHL de, Coulson AR, Drouin J, Eperson IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJH, Staden R, Young IG (1981) Sequence and organization of the human mitochondrial genome. Nature 290: 457–465
Baerlocher KE, Feldges A, Weissert M, Simonsz HJ, Rötig A (1992) Mitochondrial DNA deletion in an 8-year-old boy with Pearson syndrome. J Inherited Metab Dis (in press)
Blaw ME, Mize CE (1990) Juvenile Pearson syndrome. J Child Neurol 5: 186–189
Clayton DA (1982) Replication of animal mitochondrial DNA. Cell 28: 693–705
Clayton DA, Smith CA (1975) Complex mitochondrial DNA. Int Rev Exp Pathol 14: 1–67
Cormier V, Rötig A, Quartino AR, Forni GL, Cerone R, Maier M, Saudubray JM, Munnich A (1990) Widespread multitissue deletions of the mitochondrial genome in the Pearson marrow-pancreas syndrome. J Pediatr 117: 599–602
Demeocq F, Storme B, Schaison G, Bezou MJ, Bourges M, Chassagne J (1983) Anémie réfractaire sidéroblastique avec vacuolisation des précurseurs médullaires et déficit de la fonction exocrine du pancréas. Etude d'une nouvelle observation. Arch Fr Pediatr 40: 631–635
Glader BE, Backer K, Diamond LK (1983) Elevated erythrocyte adenosine deaminase activity in congenital hypoplastic anemia. N Engl J Med 309: 1486–1490
Grossman LI (1990) Invited editorial: Mitochondrial DNA in sickness and in health. Am J Hum Genet 46: 415–417
Holt IJ, Harding AE, Morgan-Hughes JA (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331: 717–719
Ihara Y, Namba R, Kuroda S, Sato T, Shirabe T (1989) Mitochondrial encephalomyopathy (MELAS): Pathological study and successful therapy with coenzyme Q10 and idebenone. J Neurol Sci 90: 263–271
Jakobs C, Danse P, Veerman AJP (1991) Organic aciduria in Pearson snydrome. Eur J Pediatr 150: 684
Larsson NG, Holme E, Kristinasson B, Oldfors A, Tulinius M (1990) Progressive increase of the mutated mitochondrial DnA fraction in Kearns-Sayre syndrome. Pediatr Res 28: 131–136
Majander A, Suomalainen A, Vettenranta K, Sariola H, Perkkio M, Holmberg C, Pihko H (1991) Congenital hypoplastic anemia, diabetes, and severe tubular dysfunction associated with a mitochondrial DNA deletion. Pediatr Res 30: 327–330
McShane MA, Hammans SR, Sweeney M, Holt IJ, Beattie TJ, Brett EM, Harding AE (1991) Pearson syndrome and mitochondrial encephalomyopathy in a patient with a deletion of mtDNA. Am J Hum Genet 48: 39–42
Mita S, Schmidt B, Schon EA, DiMauro S, Bonilla E (1989) Detection of “deleted” mitochondrial genomes in cytochrome c-oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome. Proc Natl Acad Sci USA 86: 9509–9513
Mita S, Rizzuto R, Moraes CT, Shanske S, Arnaudo E, Fabrizi GM, Koga Y, DiMauro S, Schon EA (1990) Recombination via flanking direct repeats is a major cause of large-scale deletions of human mitochondrial DNA. Nucleic Acids Res 18: 561–567
Munnich A, Saudubray JM (1991) Les cytopathies mitochondriales. Arch Fr Pediatr 48: 163–166
Nakase H, Moraes CT, Rizzuto R, Lombes A, DiMauro S, Schon EA (1990) Transcription and translation of deleted mitochondrial genomes in Kearns-Sayre syndrome: Implications for pathogenesis. Am J Hum Genet 46: 418–427
Pearson HA, Lobel JS, Kocoshis SA, Naiman JL, Windmiller J, Lammi AT, Hoffman R, Marsh JC (1979) A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction. J Pediatr 95: 976–984
Poulton J, Deadman ME, Gardiner RM (1989) Duplications of mitochondrial DNA in mitochondrial myopathy. Lancet I: 236–240
Rötig A, Colonna M, Bonnefont JP, Blanche S, Fischer A, Saudubray JM, Munnich A (1989) Mitochondrial DNA deletion in Pearson's marrow/pancreas syndrome. Lancet I:902–903
Rötig A, Cormier V, Blanche S, Bonnefont JP, Ledeist F, Romero N, Schmitz J, Rustin P, Fischer A, Saudubray JM, Munnich A (1990) Pearson's marrow-pancreas syndrome. A multisystem mitochondrial disorder in infancy. J Clin Invest 86: 1601–1608
Rötig A, Cormier V, Knoll F, Mize CE, Saudubray JM, Veerman A, Pearson HA, Munnich A (1991) Site-specific deletions of the mitochondrial genome in the Pearson marrow-pancreas syndrome. Genomics 10: 502–504
Saiki RK (1989) The design and optimization of the PCR. In: Ehrlich HA (ed) PCR technology, Stockton Press, New York, pp 7–16
Segal S (1989) Disorders of galactose metabolism. In: Seriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease. 6th edn. McGraw-Hill, New York, pp 453–480
Shoffner JM, Lott MT, Voljavec AS, Soueidan SA, Costigan DA, Wallace DC (1989) Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc Natl Acad Sci USA 86: 7952–7956
Stoddard RA, McCurnin DC, Shultenover SJ, Wright JE, Lemos RA de (1981) Syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction presenting in the neonate. J Pediatr 99:259–261
Superti-Furga A, Duc G, Steinmann B, Gitzelmann R (1991) Maternal phenylketonuria syndrome in cousins caused by mild, unrecognized phenylketonuria in their mothers homozygous for the phenylalanine hydroxylase Arg-261-Gln mutation. Eur J Pediatr 150: 493–497
Superti-Furga A, Schoenle E, Tuchschmid P, Pezzoli V, Caduff R, Sabato, E, Manzionna M, Gitzelmann R, Steinmann B (1991) Pearson's bone marrow-pancreas syndrome with elevated HbF, lactic acidosis, renal Fanconi syndrome, and insulin-dependent diabetes mellitus caused by deletion-duplication of mitochondrial DNA (abstract). Eur J Pediatr 150: 295
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Superti-Furga, A., Schoenle, E., Tuchschmid, P. et al. Pearson bone marrow-pancreas syndrome with insulin-dependent diabetes, progressive renal tubulopathy, organic aciduria and elevated fetal haemoglobin caused by deletion and duplication of mitochondrial DNA. Eur J Pediatr 152, 44–50 (1993). https://doi.org/10.1007/BF02072515
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02072515