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

 

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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.

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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 6 Leigh D. Subacute necrotizing encephalomyelopathy in an infant.  J Neurol Neurosurg Psychiatry. 1951;  14 216-221
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 8 Oldfors A, Sommerland H, Holme E, Tulinius M, Kristiansson B. Cytochrome c oxidase deficiency in infancy.  Acta Neuropathol. 1989;  77 267-275
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 17 Zeviani M, Bertagnolio B, Uziel G. Neurological presentations of mitochondrial diseases.  J Inherit Metab Dis. 1996;  19 504-520
  CrossrefPubMedGoogle Scholar

M. D. PhD Már Tulinius

Department of Pediatrics
The Queen Silvia Children's Hospital, Sahlgrenska University Hospital

41685 Göteborg

Sweden

Email: mar.tulinius@vgregion.se