Journal of Inherited Metabolic Disease

, Volume 34, Issue 1, pp 197–201

Acute liver failure with subsequent cirrhosis as the primary manifestation of TRMU mutations

  • Ulrike Schara
  • Jürgen-Christoph von Kleist-Retzow
  • Elke Lainka
  • Patrick Gerner
  • Angela Pyle
  • Paul M. Smith
  • Hanns Lochmüller
  • Birgit Czermin
  • Angela Abicht
  • Elke Holinski-Feder
  • Rita Horvath
Original Article

Abstract

Combined respiratory chain deficiency accounts for about 30% of mitochondrial respiratory chain deficiencies and is frequently associated with mtDNA depletion, deletions or point mutations. However combined respiratory chain deficiency may also be caused by mutations in nuclear genes affecting mitochondrial translation. Here we describe a 2-year-old girl, who developed an acute, isolated, severe liver failure with mitochondrial pathology and decreased respiratory chain enzyme activities both in liver and skeletal muscle at 4 months of age. Her liver function improved significantly within a month, liver function tests returned to normal. Liver cirrhosis remained without any further complications so far. Pathogenic compound heterozygous mutations were identified in the TRMU gene. This condition is one of the few mitochondrial disorders with a life-threatening onset showing recovery later in life, therefore a prompt diagnosis and treatment of these patients has great importance in clinical practice. We suggest that TRMU deficiency should be considered in infants with acute liver disease.

References

  1. Antonicka H, Sasarman F, Kennaway NG, Shoubridge EA (2006) The molecular basis for tissue specificity of the oxidative phosphorylation deficiencies in patients with mutations in the mitochondrial translation factor EFG1. Hum Mol Genet 15:1835–1846CrossRefPubMedGoogle Scholar
  2. Bykhovskaya Y, Casas K, Mengesha E, Inbal A, Fischel-Ghodsian N (2004) Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). Am J Hum Genet 74:1303–1308CrossRefPubMedGoogle Scholar
  3. Coenen MJ, Antonicka H, Ugalde C et al. (2004) Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. N Engl J Med 351:2080–2086CrossRefPubMedGoogle Scholar
  4. Fernandez-Vizarra E, Berardinelli A, Valente L, Tiranti V, Zeviani M (2007) Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA). J Med Genet 44:173–180CrossRefPubMedGoogle Scholar
  5. Guan MX, Yan Q, Li X et al. (2006) Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. Am J Hum Genet 79:291–302CrossRefPubMedGoogle Scholar
  6. Horvath R, Kemp JP, Tuppen HA et al. (2009) Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy. Brain 132:3165–3174CrossRefPubMedGoogle Scholar
  7. Jacobs HT, Turnbull DM (2005) Nuclear genes and mitochondrial translation: a new class of genetic disease. Trends Genet 21:312–314CrossRefPubMedGoogle Scholar
  8. Levinger L, Mörl M, Florentz C (2004) Mitochondrial tRNA 3′end metabolism and human disease. Nucl Acids Res 32:5430–5441CrossRefPubMedGoogle Scholar
  9. Miller C, Saada A, Shaul N et al. (2004) Defective mitochondrial translation caused by a ribosomal protein (MRPS16) mutation. Ann Neurol 56:734–738CrossRefPubMedGoogle Scholar
  10. Montero R, Sánchez-Alcázar JA, Briones P et al. (2009) Coenzyme Q10 deficiency associated with a mitochondrial DNA depletion syndrome: a case report. Clin Biochem 42:742–745CrossRefPubMedGoogle Scholar
  11. Riley LG, Cooper S, Hickey P et al. (2010) Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia–MLASA syndrome. Am J Hum Genet 87:52–59CrossRefPubMedGoogle Scholar
  12. Saada A, Shaag A, Arnon S et al. (2007) Antenatal mitochondrial disease caused by mitochondrial ribosomal protein (MRPS22) mutation. J Med Genet 44:784–786CrossRefPubMedGoogle Scholar
  13. Sacconi S, Trevisson E, Salviati L et al. (2010) Coenzyme Q10 is frequently reduced in muscle of patients with mitochondrial myopathy. Neuromuscul Disord 20:44–48CrossRefPubMedGoogle Scholar
  14. Sarzi E, Bourdon A, Chrétien D et al. (2007) Mitochondrial DNA depletion is a prevalent cause of multiple respiratory chain deficiency in childhood. J Pediatr 150:531–534CrossRefPubMedGoogle Scholar
  15. Smeitink JA, Elpeleg O, Antonicka H et al. (2006) Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs. Am J Hum Genet 79:869–877CrossRefPubMedGoogle Scholar
  16. Smits P, Mattijssen S, Morava E et al. (2010a) Functional consequences of mitochondrial tRNA Trp and tRNA Arg mutations causing combined OXPHOS defects. Eur J Hum Genet 18:324–329CrossRefPubMedGoogle Scholar
  17. Smits P, Smeitink J, van den Heuvel L (2010b) Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies. J Biomed Biotechnol 2010:737385PubMedGoogle Scholar
  18. Spinazzola A, Invernizzi F, Carrara F et al. (2009) Clinical and molecular features of mitochondrial DNA depletion syndromes. J Inherit Metab Dis 32:143–158CrossRefPubMedGoogle Scholar
  19. Tuppen HA, Blakely EL, Turnbull DM, Taylor RW (2010) Mitochondrial DNA mutations and human disease. Biochim Biophys Acta 1797:113–128PubMedGoogle Scholar
  20. Valente L, Tiranti V, Marsano RM et al. (2007) Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu. Am J Hum Genet 80:44–58CrossRefPubMedGoogle Scholar
  21. Yan Q, Bykhovskaya Y, Li R et al. (2006) Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations. Biochem Biophys Res Commun 342:1130–1136CrossRefPubMedGoogle Scholar
  22. Zeharia A, Shaag A, Pappo O et al. (2009) Acute infantile liver failure due to mutations in the TRMU gene. Am J Hum Genet 85:401–407CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  • Ulrike Schara
    • 1
  • Jürgen-Christoph von Kleist-Retzow
    • 2
    • 3
  • Elke Lainka
    • 4
  • Patrick Gerner
    • 4
  • Angela Pyle
    • 5
    • 6
  • Paul M. Smith
    • 5
  • Hanns Lochmüller
    • 6
  • Birgit Czermin
    • 7
  • Angela Abicht
    • 7
  • Elke Holinski-Feder
    • 7
  • Rita Horvath
    • 5
    • 6
    • 7
  1. 1.Pediatric NeurologyUniversity of EssenEssenGermany
  2. 2.Department of PediatricsUniversity of CologneCologneGermany
  3. 3.Center for Molecular Medicine CMMCUniversity of CologneCologneGermany
  4. 4.Pediatric GastroenterologyUniversity of EssenEssenGermany
  5. 5.Mitochondrial Research Group, Institute for Ageing and HealthNewcastle UniversityNewcastle upon TyneUK
  6. 6.Institute of Human GeneticsNewcastle UniversityNewcastle upon TyneUK
  7. 7.Medical Genetics CenterMunichGermany

Personalised recommendations