NDUFS6 related Leigh syndrome: a case report and review of the literature

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The genetic causes of Leigh syndrome are heterogeneous, with a poor genotype–phenotype correlation. To date, more than 50 nuclear genes cause nuclear gene-encoded Leigh syndrome. NDUFS6 encodes a 13 kiloDaltons subunit, which is part of the peripheral arm of complex I and is localized in the iron-sulfur fraction. Only a few patients were reported with proven NDUFS6 pathogenic variants and all presented with severe neonatal lactic acidemia and complex I deficiency, leading to death in the first days of life. Here, we present a patient harboring two NDUFS6 variants with a phenotype compatible with Leigh syndrome. Although most of previous reports suggested that NDUFS6 pathogenic variants invariably lead to early neonatal death, this report shows that the clinical spectrum could be larger. We found a severe decrease of NDUFS6 protein level in patient’s fibroblasts associated with a complex I assembly defect in patient’s muscle and fibroblasts. These data confirm the importance of NDUFS6 and the Zn-finger domain for a correct assembly of complex I.

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  1. 1.

    Brandt U. Energy converting NADH:quinone oxidoreductase (complex I). Annu Rev Biochem. 2006;75:69–92.

  2. 2.

    Guerrero-Castillo S, Baertling F, Kownatzki D, Wessels HJ, Arnold S, Brandt U, et al. The assembly pathway of mitochondrial respiratory chain complex I. Cell Metab. 2017;25:128–39.

  3. 3.

    Acin-Perez R, Enriquez JA. The function of the respiratory supercomplexes: the plasticity model. Biochim Biophys Acta. 2014;1837:444–50.

  4. 4.

    Acín-Pérez R, Fernández-Silva P, Peleato ML, Pérez-Martos A, Enriquez JA. Respiratory active mitochondrial supercomplexes. Mol Cell. 2008;32:529–39.

  5. 5.

    Loeffen JL, Smeitink JA, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC, et al. Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum Mutat. 2000;15:123–34.

  6. 6.

    Fassone E, Rahman S. Complex I deficiency: clinical features, biochemistry and molecular genetics. J Med Genet. 2012;49:578–90.

  7. 7.

    Rahman S, Thorburn D. Nuclear gene-encoded leigh syndrome overview. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, et al., éditeurs. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cité 24 févr 2019]. Disponible sur: http://www.ncbi.nlm.nih.gov/books/NBK320989/.

  8. 8.

    Ogawa E, Shimura M, Fushimi T, Tajika M, Ichimoto K, Matsunaga A, et al. Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients. J Inherit Metab Dis. 2017;40:685–93.

  9. 9.

    Rahman J, Rahman S. The utility of phenomics in diagnosis of inherited metabolic disorders. Clin Med (Lond). 2019;19:30–6.

  10. 10.

    Spiegel R, Shaag A, Mandel H, Reich D, Penyakov M, Hujeirat Y, et al. Mutated NDUFS6 is the cause of fatal neonatal lactic acidemia in Caucasus Jews. Eur J Hum Genet. 2009;17:1200–3.

  11. 11.

    Kirby DM, Salemi R, Sugiana C, Ohtake A, Parry L, Bell KM, et al. NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. J Clin Invest. 2004;114:837–45.

  12. 12.

    Haack TB, Madignier F, Herzer M, Lamantea E, Danhauser K, Invernizzi F, et al. Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9. J Med Genet. 2012;49:83–9.

  13. 13.

    Swalwell H, Kirby DM, Blakely EL, Mitchell A, Salemi R, Sugiana C, et al. Respiratory chain complex I deficiency caused by mitochondrial DNA mutations. Eur J Hum Genet. 2011;19:769–75.

  14. 14.

    Plutino M, Chaussenot A, Rouzier C, Ait-El-Mkadem S, Fragaki K, Paquis-Flucklinger V, et al. Targeted next generation sequencing with an extended gene panel does not impact variant detection in mitochondrial diseases. BMC Med Genet. 2018;19:57.

  15. 15.

    Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain août. 2014;137(Pt 8):2329–45.

  16. 16.

    Rustin P, Chretien D, Bourgeron T, Gérard B, Rötig A, Saudubray JM, et al. Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta. 1994;228:35–51.

  17. 17.

    Bradford M. A rapid and sensitive method for the quantitation of micrograms quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-54.

  18. 18.

    Pronicka E, Piekutowska-Abramczuk D, Ciara E, Trubicka J, Rokicki D, Karkucińska-Więckowska A, et al. New perspective in diagnostics of mitochondrial disorders: two years’ experience with whole-exome sequencing at a national paediatric centre. J Transl Med. 2016;14:174.

  19. 19.

    Rahman S, Blok RB, Dahl HH, Danks DM, Kirby DM, Chow CW, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol. 1996;39:343–51.

  20. 20.

    Kmita K, Wirth C, Warnau J, Guerrero-Castillo S, Hunte C, Hummer G, et al. Accessory NUMM (NDUFS6) subunit harbors a Zn-binding site and is essential for biogenesis of mitochondrial complex I. Proc Natl Acad Sci USA. 2015;112:5685–90.

  21. 21.

    Hoefs SJG, van Spronsen FJ, Lenssen EWH, Nijtmans LG, Rodenburg RJ, Smeitink JAM, et al. NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease. Eur J Hum Genet. 2011;19:270–4.

  22. 22.

    Ortigoza-Escobar JD, Oyarzabal A, Montero R, Artuch R, Jou C, Jiménez C, et al. Ndufs4 related Leigh syndrome: A case report and review of the literature. Mitochondrion. 2016;28:73–8.

  23. 23.

    Minoia F, Bertamino M, Picco P, Severino M, Rossi A, Fiorillo C, et al. Widening the Heterogeneity of Leigh Syndrome: Clinical, Biochemical, and Neuroradiologic Features in a Patient Harboring a NDUFA10 Mutation. JIMD Rep. 2017;37:37–43.

  24. 24.

    Angebault C, Charif M, Guegen N, Piro-Megy C, Mousson de Camaret B, Procaccio V, et al. Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability. Hum Mol Genet. 2015;24:3948–55.

  25. 25.

    Baertling F, Sánchez-Caballero L, van den Brand M a M, Fung C-W, Chan SH-S, Wong VC-N, et al. NDUFA9 point mutations cause a variable mitochondrial complex I assembly defect. Clin Genet. 2018;93:111–8.

  26. 26.

    Budde SM, van den Heuvel LP, Janssen AJ, Smeets RJ, Buskens CA, DeMeirleir L, et al. Combined enzymatic complex I and III deficiency associated with mutations in the nuclear encoded NDUFS4 gene. Biochem Biophys Res Commun. 2000;275:63–8.

  27. 27.

    Sofou K, De Coo IFM, Isohanni P, Ostergaard E, Naess K, De Meirleir L, et al. A multicenter study on Leigh syndrome: disease course and predictors of survival. Orphanet J Rare Dis. 2014;9:52.

  28. 28.

    Niyazov DM, Kahler SG, Frye RE. Primary mitochondrial disease and secondary mitochondrial dysfunction: importance of distinction for diagnosis and treatment. Mol Syndromol. 2016;7:122–37.

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We thank Gaëlle Auge, Mathieu Berthet, Christelle Camuso, Bernadette Chafino, Charlotte Cochaud, and Sandra Foustoul for technical help.

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Correspondence to Cécile Rouzier.

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Rouzier, C., Chaussenot, A., Fragaki, K. et al. NDUFS6 related Leigh syndrome: a case report and review of the literature. J Hum Genet 64, 637–645 (2019) doi:10.1038/s10038-019-0594-4

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