Abstract
The male proband reported here was born with appropriate anthropometric parameters at term as the second child of healthy nonconsanguineous parents. His only clinical symptom was bilateral congenital cataracts with strabismus at birth, and both lenses were removed surgically at the age of 8 months. The perinatal and infantile period thereafter was clinically uneventful and his psychomotor development appeared almost normal. At the age of 6 years he was hospitalized for slight muscle weakness, minor ptosis, nystagmus and decreased physical activity. Soon after, his general condition worsened, gait ataxia presented, dysphagia and difficulty of speech followed by rapidly progressive generalized ataxia, and myopathy developed. Typical progressive gray matter degeneration with focal necrosis in the basal ganglia characteristic of the Leigh type of neuropathology could be detected by cranial MRI, the muscle histology showed ragged-red fibers. At the age of 7.5 years, unexpected left side hemiparesis with speech disability resembling that seen in MELAS syndrome developed, from which he recovered within 1.5 days. The mtDNA of the patient showed single 6.7 kb large-scale deletion harboring between 7817 and 14 536 bp. This case represents the first report of a verified mtDNA mutation associated with congenital cataracts as the first clinical sign of a later developing progressive neuromuscular disease presented with a combination of Leigh neuropathology, ragged-red fiber histopathology and stroke-like attack.
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
References
Cassidy L, Taylor D : Congenital cataract and multisystem disorders. Eye 1999; 13 (Part 3b): 464–473.
Francis PJ, Berry V, Moore AT, Bhattacharya S : Lens biology: development and human cataractogenesis. Trends Genet 1999; 15: 191–196.
McAvoy JW, Chamberlain CG, de Iongh RU, Hales AM, Lovicu FJ : Lens development. Eye 1999; 13 (Part 3b): 425–437.
He W, Li S : Congenital cataracts: gene mapping. Hum Genet 2000; 106: 1–13.
Gilbert C, Foster A : Childhood blindness in the context of VISION 2020–the right to sight. Bull World Health Organ 2001; 79: 227–232.
Kocur I, Resnikoff S : Visual impairment and blindness in Europe and their prevention. Br J Ophthalmol 2002; 86: 716–722.
Rahi JS, Botting B : Ascertainment of children with congenital cataract through the National Congenital Anomaly System in England and Wales. Br J Ophthalmol 2001; 85: 1049–1051.
Wirth MG, Russell-Eggitt IM, Craig JE, Elder JE, Mackey DA : Aetiology of congenital and paediatric cataract in an Australian population. Br J Ophthalmol 2002; 86: 782–786.
Rahi JS, Dezateaux C : Measuring and interpreting the incidence of congenital ocular anomalies: lessons from a national study of congenital cataract in the UK. Invest Ophthalmol Vis Sci 2001; 42: 1444–1448.
DiMauro S : Mitochondrial DNA: a genetic Pandora's box. Funct Neurol 2001; 16: 103–116.
DiMauro S, Andreu AL : Mutations in mtDNA: are we scraping the bottom of the barrel? Brain Pathol 2000; 10: 431–441.
DiMauro S : Lessons from mitochondrial DNA mutations. Semin Cell Dev Biol 2001; 12: 397–405.
Zeviani M, Klopstock T : Mitochondrial disorders. Curr Opin Neurol 2001; 14: 553–560.
Sligh JE, Levy SE, Waymire KG et al: Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice. Proc Natl Acad Sci USA 2000; 97: 14461–14466.
Sumegi B, Melegh B, Adamovich K, Trombitas K : Cytochrome oxidase deficiency affecting the structure of the myofibre and the shape of mitochondrial cristae membrane. Clin Chim Acta 1990; 192: 9–18.
Melegh B, Seress L, Bedekovics T et al: Muscle carnitine acetyl-transferase and carnitine deficiency in a case of mitochondrial encephalomyopathy. J Inherit Metab Dis 1999; 22: 827–838.
Melegh B, Bock I, Gati I, Mehes K : Multiple mitochondrial DNA deletions and persistent hyperthermia in a patient with Brachmann–de Lange phenotype. Am J Med Genet 1996; 65: 82–88.
Shoffner JM, Bialer MG, Pavlakis SG et al: Mitochondrial encephalomyopathy associated with a single nucleotide pair deletion in the mitochondrial tRNALeu(UUR) gene. Neurology 1995; 45: 286–292.
Melberg A, Arnell H, Dahl N et al: Anticipation of autosomal dominant progressive external ophthalmoplegia with hypo-gonadism. Muscle Nerve 1996; 19: 1561–1569.
Sengers RC, Trijbels JM, Willems JL, Daniels O, Stadhouders AM : Congenital cataract and mitochondrial myopathy of skeletal and heart muscle associated with lactic acidosis after exercise. J Pediatr 1975; 86: 873–880.
Valsson J, Laxdal T, Jonsson A, Jansson KK, Helgason H : Congenital cardiomyopathy and cataracts with lactic acidosis. Am J Cardiol 1988; 61: 193–194.
Rahman S, Blok RB, Dahl HH et al: Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 1996; 39: 343–351.
Arii J, Tanabe Y : Leigh syndrome: serial MR imaging and clinical follow-up. AJNR Am J Neuroradiol 2000; 21: 1502–1509.
Santorelli FM, Barmada MA, Pons R, Zhang LL, DiMauro S : Leigh-type neuropathology in Pearson syndrome associated with impaired ATP production and a novel mtDNA deletion. Neurology 1996; 47: 1320–1323.
Rotig A, Bourgeron T, Chretien D, Rustin P, Munnich A : Spectrum of mitochondrial DNA rearrangements in the Pearson marrow–pancreas syndrome. Hum Mol Genet 1995; 4: 1327–1330.
Lacbawan F, Tifft CJ, Luban NL et al: Clinical heterogeneity in mitochondrial DNA deletion disorders: a diagnostic challenge of Pearson syndrome. Am J Med Genet 2000; 95: 266–268.
Schroder R, Vielhaber S, Wiedemann FR et al: New insights into the metabolic consequences of large-scale mtDNA deletions: a quantitative analysis of biochemical, morphological, and genetic findings in human skeletal muscle. J Neuropathol Exp Neurol 2000; 59: 353–360.
Muraki K, Nishimura S, Goto Y, Nonaka I, Sakura N, Ueda K : The association between haematological manifestation and mtDNA deletions in Pearson syndrome. J Inherit Metab Dis 1997; 20: 697–703.
Muraki K, Goto Y, Nishino I et al: Severe lactic acidosis and neonatal death in Pearson syndrome. J Inherit Metab Dis 1997; 20: 43–48.
Isashiki Y, Nakagawa M, Ohba N et al: Retinal manifestations in mitochondrial diseases associated with mitochondrial DNA mutation. Acta Ophthalmol Scand 1998; 76: 6–13.
Oldfors A, Fyhr IM, Holme E, Larsson NG, Tulinius M : Neuropathology in Kearns–Sayre syndrome. Acta Neuropathol (Berlin) 1990; 80: 541–546.
Acknowledgements
This work was supported in part from grants of the Hungarian National Science Foundation OTKA T- T 032670, T-035026 and from a grant of the Ministry of Health (ETT 329/2000).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bene, J., Nádasi, E., Kosztolányi, G. et al. Congenital cataract as the first symptom of a neuromuscular disease caused by a novel single large-scale mitochondrial DNA deletion. Eur J Hum Genet 11, 375–379 (2003). https://doi.org/10.1038/sj.ejhg.5200975
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5200975
Keywords
This article is cited by
-
Maternally inherited deafness and unusual phenotypic manifestations associated with A3243G mitochondrial DNA mutation
Pathology & Oncology Research (2005)
