Abstract
We describe a childhood mitochondrial disorder in which the clinical symptoms began and remained confined to the gastrointestinal (GI) system during the first 4 y. Seizures heralded the onset of progressive encephalopathy at age 7. Peripheral neuropathy, retinitis pigmentosa, and neural deafness developed subsequently. Laboratory investigations disclosed elevated levels of plasma lactate, and a muscle biopsy revealed ragged red fibers lacking cytochrome c oxidase activity and diminished levels of respiratory chain enzyme complexes. Molecular genetic tests failed to show any of the previously reported pathogenic mitochondrial DNA (mtDNA) mutations. We therefore screened the whole mitochondrial genome by coupling restriction digestions with single-strand conformational polymorphism (SSCP) patterns. We identified a unique SSCP in the segment that encompassed the tRNALys gene, and direct sequencing of this segment revealed a G → A transition at an evolutionarily conserved nucleotide at mtDNA position 8313. This G8313A transition was heteroplasmic in muscle and fibroblasts of the patient, but was absent in the white blood cells and platelets from his maternal relatives. This report illustrates how GI symptoms can be the initial manifestation in a mitochondrial disorder and suggests that mitochondrial dysfunction should be considered in differentials of unexplained chronic GI symptoms, especially when lactic acidosis or other unrelated clinical signs or symptoms are present.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- mtDNA:
-
mitochondrial DNA
- nDNA:
-
nuclear DNA
- GI:
-
gastrointestinal
- RRF:
-
ragged red fiber
- COX:
-
cytochrome oxidase
- SSCP:
-
single-strand conformational polymorphism
- MNGIE:
-
mitochondrial neurogastrointestinal encephalomyopathy
- MERRF:
-
myoclonic epilepsy with RRF
- CIP:
-
chronic intestinal pseudoobstruction
- RFLP:
-
restriction fragment length polymorphism
References
DiMauro S 1993 Mitochondrial encephalomyopathies. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL, Kunkel LM (eds) The Metabolic and Genetic Basis of Neurological Disease. Butterworth-Heinemann, Boston, pp 665–694.
DiMauro S, Moraes CT 1993 Mitochondrial encephalomyopathies. Arch Neurol 50: 1197–1208.
Rotig 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.
Moraes CT, Shanske S, Tritschler HJ, Aprille JR, Andreeta F, Bonilla E, Schon EA, DiMauro S 1991 mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. Am J Hum Genet 48: 492–501.
Rotig A, Bessis JL, Romero N, Cormier V, Saudubray J, Narcy P, Lenoir G, Rustin P, Munnich A 1992 Maternally inherited duplication of the mitochondrial genome in a syndrome of proximal tubulopathy, diabetes mellitus and cerebellar ataxia. Am J Hum Genet 50: 364–370.
Ballinger SW, Shoffner JM, Hedaya EV, Trounce I, Polak MA, Koontz DA, Wallace DC 1992 Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nat Genet 1: 11–15.
Ozawa T, Tanaka M, Sugiyama S, Hattori K, Ito I, Ohno K, Takahashi A, Sato W, Takada G, Mayumi B, Yamato K, Adachi K, Koga Y, Toshima H 1990 Multiple mitochondrial DNA deletions exist in cardiomyocytes of patients with hypertrophic or dilated cardiomyopathy. Biochem Biophys Res Commun 170: 830–836.
Hattori K, Ogawa T, Kondo T, Mochizuki M, Tanaka M, Sugiyama S, Ito T, Satake T, Ozawa T 1991 Cardiomyopathy with mitochondrial DNA mutations. Am Heart J 122: 866–869.
Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda AF, Nakase H, Bonilla E, Werneck LC, Servidei S, Nonaka I, Koga Y, Spiro AJ, Brownelik W, Schmidt B, Schotland L, Zupac M, DeVivo DC, Schon EA, Rowland LP 1989 Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 320: 1293–1299.
Lertrit P, Noer AS, Byrne E, Marzuki S 1992 Tissue segregation of a heteroplasmic mtDNA mutation in MERRF (myoclonic epilepsy with ragged red fibers) encephalomyopathy. Hum Genet 90: 251–254.
Okamura K, Santa T, Nagae K, Omae T 1976 Congenital oculoskeletal myopathy with abnormal muscle and liver mitochondria. J Neurol Sci 27: 79–91.
Bardosi A, Creutzfeldt W, DiMauro S, Felgenhauer K, Friede RL, Goebel HH, Kohlschutter A, Mayer G, Rahlf G, Servidei S, VanLessen G, Wetterling T 1987 Myo-, neuro-, gastrointestinal encephalopathy (MNGIE syndrome) due to partial deficiency of cytochrome-c-oxidase. A new mitochondrial multisystem disorder. Acta Neuropathol 74: 248–258.
Faber J, Fich A, Steinberg A, Steiner I, Granot E, Alon I, Rachmilevitz D, Freier S, Gilai A 1987 Familial intestinal pseudoobstruction dominated by a progressive neurologic disease at a young age. Gastroenterology 92: 786–790.
Simon LT, Horoupian DS, Dorfman LJ, Marks M, Herrick MK, Wasserstein P, Smith ME 1990 Polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction: POLIP syndrome. Ann Neurol 28: 349–360.
Cave DR, Compton CC 1990 Case records of the Massachusetts General Hospital: case 12-1990. N Engl J Med 322: 829–841.
Blake D, Lombes A, Minetti C, Bonilla E, Hays AP, Lovelace AE, Butler I, DiMauro S 1990 MNGIE syndrome: report of two new patients. Neurology 40( suppl 1): 294.
Uncini A, Servidei S, Silvestri G, Manfredi G, Sabatelli A, DiMuzio A, Ricci E, Mirabella M, DiMauro S, Tonali P 1994 Ophthalmoplegia, demyelinating neuropathy, myopathy, and gastrointestinal dysfunction with multiple deletions of mitochondrial DNA: a mitochondrial multisystem disorder in search of a name. Muscle Nerve 17: 667–674.
Cormier-Daire V, Bonnefont JP, Rustin P, Maurage C, Ogier H, Schmitz J, Ricour C, Saundubray JM, Munnich A, Rotig A 1994 Mitochondrial DNA rearrangements with onset as chronic diarrhea with villous atrophy. J Pediatr 124: 63–70.
Sabatelli M, Servidei S, Ricci E, Manfredi C, Mirabella M, Tonali P, Uncini A, DiMuzio A, Gambi D, Silvestri G, DiMauro S 1992 Myo-neuro-gastro-intestinal disease and encephalopathy (MNGIE syndrome): a patient with multiple deletions of mitochondrial DNA. Neurology 42( suppl 3): 414.
Threlkeld AB, Miller NR, Golnik KC, Griffin GW, Kuncl RW, Johns DR, Lehar M, Hurko O 1992 Ophthalmic involvement in myo-neuro-gastro-intestinal encephalopathy syndrome. Am J Ophthalmol 114: 322–328.
Li V, Hostein J, Romero NB, Marsac C, Mezin P, Bost R, Degoul F, Fardeau M, Fournet J 1992 Chronic intestinal pseudoobstruction with myopathy and ophthalmoplegia: a muscular biochemistry study of a mitochondrial disorder. Dig Dis Sci 37: 456–463.
Cervera R, Bruix J, Bayes A, Blesa R, Illa I, Coll J, Garcia-Puges AM 1988 Chronic intestinal pseudoobstruction and ophthalmoplegia in a patient with mitochondrial myopathy. Gut 29: 544–547.
Ionasescu VV, Thompson SH, Ionasescu R, Searby CH, Anura S, Christensen J, Miros F, Heart M, Bosch P 1983 Inherited ophthalmoplegia with intestinal pseudoobstruction. J Neurol Sci 59: 215–228.
Ionasescu V, Thompson SH, Aschenbrener C, Anuras S, Risk WS 1984 Letter to the editor: late-onset oculogastrointestinal dystrophy. Am J Med Genet 18: 781–788.
Hirano M, Silvestri G, Blake DM, Lombes A, Minetti C, Bonilla E, Hays AP, Lovelace RE, Butler I, Bertorini TE, Trelkeld AB, Mitsumoto H, Salberg LM, Rowland LP, DiMauro S 1994 Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology 44: 721–727.
DiMauro S, Bonilla E 1997 Mitochondrial encephalomyopathies. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL (eds) The molecular and genetic bases of neurological diseases. Butterworth-Heinemann, Boston.
Bonilla E, Sciacco M, Tanzi K, Sparaco M, Petruzella V, Moraes CT 1992 New morphological approaches to the study of mitochondrial encephalomyopathies. Brain Pathol 2: 113–119.
DiMauro S, Servidei S, Zeviani M, DiRocco M, DeVivo DC, DiDonato S, Uziel G, Berry K, Hoganson G, Johnson SD, Johnson PC 1987 Cytochrome c oxidase deficiency in Leigh syndrome. Ann Neurol 22: 498–506.
Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, Rowland LP 1988 Deletions of mitochondrial DNA in Kearns-Syare syndrome. Neurology 38: 1339–1346.
Silvestri G, Moraes CT, Shanske S, Oh SJ, DiMauro S 1992 A new mtDNA mutation in the tRNALys gene associated with myoclonic epilepsy and ragged red fibers (MERRF). Am J Hum Genet 51: 1213–1217.
Verma A, Moraes CT 1996 A simple endonuclease/single-strand conformational polymorphism technique to search for pathogenic mutations in human mitochondrial genome. Neurology 46( suppl 2): A228( abstr 1700).
Hao H, Bonilla E, Manfredi G, DiMauro S, Moraes CT 1995 Segregation pattern of a novel mutation in the mitochondrial tRNA glutamic acid gene associated with myopathy and diabetes mellitus. Am J Hum Genet 56: 1017–1025.
Anderson S, Bankier AT, Barrell BG, deBruijn MHL, Coulson AR, Drouin J, Eperon 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.
Moraes CT, Ricci E, Bonilla E, DiMauro S, Schon EA 1992 The mitochondrial tRNALeu(UUR) mutation in MELAS: genetic, biochemical, and morphological correlation in skeletal muscle. Am J Hum Genet 50: 934–949.
Shoffner JM, Lott MT, Lezza AMS, Seibel P, Ballinger SW, Wallace DC 1990 Myoclonic epilepsy and ragged red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell 61: 931–937.
Verma A, Moraes CT, Shebert RT, Bradley WG 1996 A MERRF/PEO overlap syndrome associated with the mitochondrial DNA 3243 mutation. Neurology 46: 1334–1336.
Silvestri G, Ciafaloni E, Santorelli F, Shanske S, Servidei S, Graf WD, Sumi M, DiMauro S 1993 Clinical features associated with the A → G transition at nucleotide 8344 of mtDNA ('MERRF' mutation). Neurology 43: 1200–1206.
Pavlakis SG, Rowland LP, De Vivo DC, Bonilla E, DiMauro S 1988 Mitochondrial myopathies and encephalomyopathies. In: Plum F (ed) Advances in Contemporary Neurology. FA Davis, Philadelphia, pp 95–133.
Holt IJ, Harding AE, Morgan-Hughes JA 1990 A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 46: 428–433.
Furnes JB, Costa M 1987 The Enteric Nervous System. Churchill Livingstone, New York
Goyal RK, Hirano I 1996 The enteric nervous system. N Engl J Med 334: 1106–1115.
Ikeda SI, Makishita H, Oguchi K, Yanagisawa N, Nagata T 1982 Gastrointestinal amyloid deposition in familial amyloid polyneuropathy. Neurology 32: 1364–1368.
Krishnamurthy S, Schuffler MD 1987 Pathology of neuromuscular disorders of the small intestine and colon. Gatroenterology 93: 610–639.
Cockel R, Hill EE, Ruston DI, Smith B, Howkins CF 1973 Familial steatorrhea with calcification of the basal ganglia and mental retardation. Q J Med 42: 771–783.
Engel AG, Yamamoto M, Fischbeck KH 1994 Dystrophinopathies. In: Engel AG, Franzini-Armstrong C (eds) Myology, 2nd Ed. McGraw-Hill, New York, p 1144
Yoshida MM, Krishnamurthy S, Wattchow DA, Furness JB, Schuffler MD 1988 Megacolon in myotonic dystrophy caused by a degenerative neuropathy of the myenteric plexus. Gastroenterology 95: 820–827.
Schuffner MD, Baird HW, Fleming CR, Bell CE, Bouldin TW, Malagelada JR, McGill DB, LeBauer SM, Abrams M, Love J 1983 Intestinal pseudoobstruction as a presenting manifestation of small-cell carcinoma of the lung. Ann Intern Med 98: 129–134.
May RJ, Goyal RK 1994 Effects of diabetes mellitus on the digestive system. In: Kahn CR, Weir GC (eds) Joslin's Diabetes Mellitus, 13th Ed. Lea & Febiger, Philadelphia, pp 921–954.
Author information
Authors and Affiliations
Additional information
Supported by the Muscular Dystrophy Association. A.V. holds a VA Fellowship in Neurosciences and Neurotrauma. C.T.M. is a Pew Scholar in the Biomedical Sciences.
Rights and permissions
About this article
Cite this article
Verma, A., Piccoli, D., Bonilla, E. et al. A Novel Mitochondrial G8313A Mutation Associated with Prominent Initial Gastrointestinal Symptoms and Progressive Encephaloneuropathy. Pediatr Res 42, 448–454 (1997). https://doi.org/10.1203/00006450-199710000-00005
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-199710000-00005
This article is cited by
-
Gastrointestinal and hepatic manifestations of mitochondrial disorders
Journal of Inherited Metabolic Disease (2013)
-
Multisystem manifestations of mitochondrial disorders
Journal of Neurology (2009)
-
Heteroplasmic mutation in the anticodon-stem of mitochondrial tRNAVal causing MNGIE-like gastrointestinal dysmotility and cachexia
Journal of Neurology (2009)
-
Motility disorders of the gastrointestinal tract
The Indian Journal of Pediatrics (2006)
