Leigh Syndrome with Cytochrome-c Oxidase Deficiency and a Single T Insertion nt 5537 in the Mitochondrial tRNA^Trp Gene

Abstract

We report a nine-year-old boy with the features of Leigh syndrome (LS) and a severe cytochrome-c oxidase (COX) deficiency with a single thymidine insertion at nucleotide position 5537 (T⁵⁵³⁷ⁱ) in the tRNA^Trp gene of mitochondrial DNA. During infancy the boy was irritable and hypotonus was noticed. Early motor development was delayed, although mental development seemed normal until eight months of age. Early neurological signs were nystagmus, hypertonus and optic atrophy. Severe seizures and mental retardation developed subsequently. Major findings on neuroradiological investigation were from the brainstem, thalami and white matter compatible with LS. Spectrophotometric analysis of skeletal muscle mitochondria showed a profound COX deficiency and a marked complex I deficiency. Enzyme-histochemical analysis showed reduced COX activity in the majority of the muscle fibres. There were no ragged red fibres. The T⁵⁵³⁷ⁱ mutation was found in a high proportion (> 95 %) in blood, liver and muscle tissue of the patient and in blood of the patient's mother (81 %). This mutation has previously been described in one family in which one child had a very high proportion of the T⁵⁵³⁷ⁱ mutation and clinical features of LS. We conclude that, although mtDNA mutations are considered to be rare in LS with COX deficiency, the T⁵⁵³⁷ⁱ mutation should be screened for in cases of LS with COX deficiency when SURF1 gene mutations have been excluded, especially when complex I activity is also decreased.

Key words

Leigh syndrome - cytochrome-c oxidase deficiency - point mutation - tRNA^Trp

References

• 1 Darin N, Oldfors A, Moslemi A-R, Holme E, Tulinius M. The incidence of mitochondrial encephalomyopathies in chlidhood: Clinical features and morphological, biochemical, and DNA abnormalities.  Ann Neurol. 2001;  49 377-383
• 2 DiMauro S, Bonilla E, De Vivo D C. Does the patient have a mitochondrial encephalomyopathy?.  J Child Neurol. 1999;  14 (Suppl 1) S23-35
• 3 Horvath R, Lochmuller H, Stucka R, Yao J, Shoubridge E A, Kim S H. et al . Characterization of human SCO1 and COX17 genes in mitochondrial cytochrome-c-oxidase deficiency.  Biochem Biophys Res Commun. 2000;  24 530-533
• 4 Houshmand M, Larsson N G, Holme E, Oldfors A, Tulinius M H, Andersen O. Automatic sequencing of mitochondrial tRNA genes in patients with mitochondrial encephalomyopathy.  Biochim Biophys Acta. 1994;  12 49-55
• 5 Jaksch M, Kleinle S, Scharfe C, Klopstock T, Pongratz D, Müller-Höcker J. et al . Frequency of mitochondrial transfer RNA mutations and deletions in 225 patients presenting with respiratory chain deficiencies.  J Med Genet. 2001;  38 665-673
• 6 Leigh D. Subacute necrotizing encephalomyelopathy in an infant.  J Neurol Neurosurg Psychiatry. 1951;  14 216-221
• 7 Nelson I, Hanna M G, Alsanjari N, Scaravilli F, Morgan-Hughes J A, Harding A E. A new mitochondrial DNA mutation associated with progressive dementia and chorea: A clinical, pathological, and molecular genetic study.  Ann Neurol. 1995;  37 400-403
• 8 Oldfors A, Sommerland H, Holme E, Tulinius M, Kristiansson B. Cytochrome c oxidase deficiency in infancy.  Acta Neuropathol. 1989;  77 267-275
• 9 Papadopoulou L C, Sue C M, Davidson M M, Tanji K, Nishino I, Sadlock J E. et al . Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene.  Nat Genet. 1999;  23 333-337
• 10 Rahman S, Blok R B, Dahl H H, Danks D M, Kirby D M, Chow C W. et al . Leigh syndrome: clinical features and biochemical and DNA abnormalities.  Ann Neurol. 1996;  39 343-351
• 11 Santorelli F M, Tanji K, Sano M, Shanske S, El-Shahawi M, Kranz-Eble P. et al . Maternally inherited encephalopathy associated with a single-base insertion in the mitochondrial tRNA^Trp gene.  Ann Neurol. 1997;  42 256-260
• 12 Silvestri G, Rana M, DiMuzio A, Uncini A, Tonali P, Servidei S. A late-onset mitochondrial myopathy is associated with a novel mitochondrial DNA (mtDNA) point mutation in the tRNA^Trp gene.  Neuromuscul Disord. 1998;  8 291-295
• 13 Silvestri G, Mongini T, Odoardi F, Modoni A, deRosa G, Doriguzzi C. et al . A new mtDNA mutation associated with a progressive encephalopathy and cytochrome c oxidase deficiency.  Neurology. 2000;  54 1693-1696
• 14 Tiranti V, Hoertnagel K, Carrozzo R, Galimberti C, Munaro M, Grantiero M. et al . Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency.  Am J Hum Genet. 1998;  63 1609-1621
• 15 Tulinius M H, Holme E, Kristiansson B, Larsson N-G, Oldfors A. Mitochondrial encephalomyopathies in childhood: I. Biochemical and morphologic investigations.  J Pediatr. 1991;  119 242-250
• 16 Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H. Neuroradiologic findings in children with mitochondrial disorders.  Am J Neuroradiol. 1998;  19 369-377
• 17 Zeviani M, Bertagnolio B, Uziel G. Neurological presentations of mitochondrial diseases.  J Inherit Metab Dis. 1996;  19 504-520