Neuropediatrics 2014; 45(06): 346-353
DOI: 10.1055/s-0034-1383823
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Long Survival in Leigh Syndrome: New Cases and Review of Literature

Wiebke Aulbert
1   Department of Neuropediatrics, University Children's Hospital, Ruhr University, Bochum, Germany
2   Department of Pediatrics, University Medical Centre Hamburg-Eppendorf, Germany
*   The authors, W.A. and K.W.-U., have contributed equally.
,
Katharina Weigt-Usinger
1   Department of Neuropediatrics, University Children's Hospital, Ruhr University, Bochum, Germany
*   The authors, W.A. and K.W.-U., have contributed equally.
,
Charlotte Thiels
1   Department of Neuropediatrics, University Children's Hospital, Ruhr University, Bochum, Germany
,
Cornelia Köhler
1   Department of Neuropediatrics, University Children's Hospital, Ruhr University, Bochum, Germany
,
Matthias Vorgerd
3   Department of Neurology, University Hospital Bergmannsheil, Ruhr University, Bochum, Germany
,
Anja Schreiner
3   Department of Neurology, University Hospital Bergmannsheil, Ruhr University, Bochum, Germany
,
Sabine Hoffjan
5   Department of Human Genetics, Ruhr University, Bochum, Germany
,
Tobias Rothoeft
6   Department of Pediatric Pneumology and Immunology, University Children's Hospital, Ruhr University, Bochum, Germany
,
Saskia Brigitte Wortmann
7   Nijmegen Centre for Mitochondrial Disorders (NCMD) at the Department of Pediatrics and the Institute for Genetic and Metabolic Disease (IGMD), Radboud University Medical Centre, Nijmegen, The Netherlands
,
Christoph Malte Heyer
8   Institute of Diagnostic Radiology, Interventional Radiology and Nuclear Medicine, University Hospital Bergmannsheil, Ruhr University, Bochum, Germany
,
Teodor Podskarbi
4   Laboratory for Molecular Genetics and Metabolic Diseases, Munich, Germany
,
Thomas Lücke
1   Department of Neuropediatrics, University Children's Hospital, Ruhr University, Bochum, Germany
› Author Affiliations
Further Information

Publication History

30 October 2013

01 May 2014

Publication Date:
11 August 2014 (online)

Abstract

Leigh syndrome (MIM 25600), also known as infantile subacute necrotizing encephalomyelopathy, is a neurodegenerative disorder with characteristic bilateral symmetric lesions in basal ganglia and subcortical brain regions. It is commonly associated with systemic cytochrome c oxidase (COX) deficiency and mutations in the SURF1 gene (MIM 185620), encoding a putative assembly or maintenance factor of COX. The clinical course is dominated by neurodevelopmental regression, brain stem, and basal ganglia involvement (e.g., dystonia, apnea) with death often occurring before the age of 10 years. Herein, we present three sisters carrying a previously reported homozygous SURF1 mutation (c.868_869insT) that is predicted to result in a truncated protein with loss of function. Our patients show heterogeneous clinical findings with different distribution patterns of metabolic lesions in brain magnetic resonance imaging (MRI) as well as a Chiari malformation with hydrocephalus in one patient. However, all three siblings show an unusual long survival (12 years and > 16 years). COX activity was not detectable in one patient and strongly reduced in the other two. We discuss these findings with respect to a review of the literature. A total of 15 additional patients with survival > 14 years have been reported so far. Overall, no clear genotype–phenotype correlations are detectable among these patients.

 
  • References

  • 1 Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 1951; 14 (3) 216-221
  • 2 Medina L, Chi TL, DeVivo DC, Hilal SK. MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): correlation with biochemical defect. AJR Am J Roentgenol 1990; 154 (6) 1269-1274
  • 3 Péquignot MO, Dey R, Zeviani M , et al. Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome C oxidase deficiency. Hum Mutat 2001; 17 (5) 374-381
  • 4 Shoubridge EA. Cytochrome c oxidase deficiency. Am J Med Genet 2001; 106 (1) 46-52
  • 5 Yon J, Jones T, Garson K, Sheer D, Fried M. The organization and conservation of the human Surfeit gene cluster and its localization telomeric to the c-abl and can proto-oncogenes at chromosome band 9q34.1. Hum Mol Genet 1993; 2 (3) 237-240
  • 6 Williams SL, Valnot I, Rustin P, Taanman JW. Cytochrome c oxidase subassemblies in fibroblast cultures from patients carrying mutations in COX10, SCO1, or SURF1. J Biol Chem 2004; 279 (9) 7462-7469
  • 7 Böhm M, Pronicka E, Karczmarewicz E , et al. Retrospective, multicentric study of 180 children with cytochrome C oxidase deficiency. Pediatr Res 2006; 59 (1) 21-26
  • 8 Piekutowska-Abramczuk D, Magner M, Popowska E , et al. SURF1 missense mutations promote a mild Leigh phenotype. Clin Genet 2009; 76 (2) 195-204
  • 9 Lee IC, El-Hattab AW, Wang J , et al. SURF1-associated Leigh syndrome: a case series and novel mutations. Hum Mutat 2012; 33 (8) 1192-1200
  • 10 Wedatilake Y, Brown R, McFarland R , et al. SURF1 deficiency: a multi-centre natural history study. Orphanet J Rare Dis 2013; 8 (1) 96
  • 11 Teraoka M, Yokoyama Y, Ninomiya S, Inoue C, Yamashita S, Seino Y. Two novel mutations of SURF1 in Leigh syndrome with cytochrome c oxidase deficiency. Hum Genet 1999; 105 (6) 560-563
  • 12 Capková M, Hansíková H, Godinot C, Houst'ková H, Houstĕk J, Zeman J. [A new missense mutation of 574C>T in the SURF1 gene—biochemical and molecular genetic study in seven children with Leigh syndrome]. Cas Lek Cesk 2002; 141 (20) 636-641
  • 13 Tiranti V, Jaksch M, Hofmann S , et al. Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency. Ann Neurol 1999; 46 (2) 161-166
  • 14 Van Riesen A, Antonicka H, Kraemer E , et al. Long-surviving Leigh syndrome patients with COX deficiency and SURF1 mutations. (6th European Meeting on Mitochondrial Pathology, Nijmegen, The Netherlands) Biochim Biophys Acta 2004: 27
  • 15 Pequignot MO, Desguerre I, Dey R , et al. New splicing-site mutations in the SURF1 gene in Leigh syndrome patients. J Biol Chem 2001; 276 (18) 15326-15329
  • 16 Tiranti V, Hoertnagel K, Carrozzo R , et al. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet 1998; 63 (6) 1609-1621
  • 17 Trounce IA, Kim YL, Jun AS, Wallace DC. Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts, and transmitochondrial cell lines. Methods Enzymol 1996; 264: 484-509
  • 18 Zhu Z, Yao J, Johns T , et al. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 1998; 20 (4) 337-343
  • 19 Piekutowska-Abramczuk D, Popowska E, Pronicki M , et al. High prevalence of SURF1 c.845_846delCT mutation in Polish Leigh patients. Eur J Paediatr Neurol 2009; 13 (2) 146-153
  • 20 Xie S, Xiao JX, Qi ZY, Yang YL, Jiang XX. Heterogeneity of magnetic resonance imaging in Leigh syndrome with SURF1 gene 604G—>C mutation. Clin Imaging 2009; 33 (1) 1-6
  • 21 Speer MC, George TM, Enterline DS, Franklin A, Wolpert CM, Milhorat TH. A genetic hypothesis for Chiari I malformation with or without syringomyelia. Neurosurg Focus 2000; 8 (3) E12
  • 22 Boyles AL, Enterline DS, Hammock PH , et al. Phenotypic definition of Chiari type I malformation coupled with high-density SNP genome screen shows significant evidence for linkage to regions on chromosomes 9 and 15. Am J Med Genet A 2006; 140 (24) 2776-2785
  • 23 Steller J, Gargus JJ, Gibbs LH, Hasso AN, Kimonis VE. Mild phenotype in a male with pyruvate dehydrogenase complex deficiency associated with novel hemizygous in-frame duplication of the E1α subunit gene (PDHA1). Neuropediatrics 2014; 45 (1) 56-60
  • 24 Yüksel A, Seven M, Cetincelik U, Yeşil G, Köksal V. Facial dysmorphism in Leigh syndrome with SURF-1 mutation and COX deficiency. Pediatr Neurol 2006; 34 (6) 486-489
    • 25 Echaniz-Laguna A, Ghezzi D, Chassagne M , et al. SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease. Neurology 2013; 81 (17) 1523-1530
    • 26 Yao J, Shoubridge EA. Expression and functional analysis of SURF1 in Leigh syndrome patients with cytochrome c oxidase deficiency. Hum Mol Genet 1999; 8 (13) 2541-2549
    • 27 Sue CM, Karadimas C, Checcarelli N , et al. Differential features of patients with mutations in two COX assembly genes, SURF-1 and SCO2. Ann Neurol 2000; 47 (5) 589-595
    • 28 Moslemi AR, Tulinius M, Darin N, Aman P, Holme E, Oldfors A. SURF1 gene mutations in three cases with Leigh syndrome and cytochrome c oxidase deficiency. Neurology 2003; 61 (7) 991-993
    • 29 Mashkevich G, Repetto B, Glerum DM, Jin C, Tzagoloff A. SHY1, the yeast homolog of the mammalian SURF-1 gene, encodes a mitochondrial protein required for respiration. J Biol Chem 1997; 272 (22) 14356-14364
    • 30 Barrientos A, Korr D, Tzagoloff A. Shy1p is necessary for full expression of mitochondrial COX1 in the yeast model of Leigh's syndrome. EMBO J 2002; 21 (1-2) 43-52