Skip to main content
Log in

Novel mutations in IBA57 are associated with leukodystrophy and variable clinical phenotypes

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Defects of the Fe/S cluster biosynthesis represent a subgroup of diseases affecting the mitochondrial energy metabolism. In the last years, mutations in four genes (NFU1, BOLA3, ISCA2 and IBA57) have been related to a new group of multiple mitochondrial dysfunction syndromes characterized by lactic acidosis, hyperglycinemia, multiple defects of the respiratory chain complexes, and impairment of four lipoic acid-dependent enzymes: α-ketoglutarate dehydrogenase complex, pyruvic dehydrogenase, branched-chain α-keto acid dehydrogenase complex and the H protein of the glycine cleavage system. Few patients have been reported with mutations in IBA57 and with variable clinical phenotype. Herein, we describe four unrelated patients carrying novel mutations in IBA57. All patients presented with combined or isolated defect of complex I and II. Clinical features varied widely, ranging from fatal infantile onset of the disease to acute and severe psychomotor regression after the first year of life. Brain MRI was characterized by cavitating leukodystrophy. The identified mutations were never reported previously and all had a dramatic effect on IBA57 stability. Our study contributes to expand the array of the genotypic variation of IBA57 and delineates the leukodystrophic pattern of IBA57 deficient patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Vanderver A, Prust M, Tonduti D et al (2015) Case definition and classification of leukodystrophies and leukoencephalopathies. Mol Genet Metab 114:494–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Morató L, Bertini E, Verrigni D et al (2014) Mitochondrial dysfunction in central nervous system white matter disorders. Glia 62:1878–1894

    Article  PubMed  Google Scholar 

  3. Dallabona C, Abbink TE, Carrozzo R et al (2016) LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance. Brain 139:782–794

    Article  PubMed  Google Scholar 

  4. Taft RJ, Vanderver A, Leventer RJ et al (2013) Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity. Am J Hum Genet 92:774–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dallabona C, Diodato D, Kevelam SH et al (2014) Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology 82:2063–2071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Steenweg ME, Ghezzi D, Haack T et al (2012) Leukoencephalopathy with thalamus and brainstem involvement and high lactate ‘LTBL’ caused by EARS2 mutations. Brain 135:1387–1394

    Article  PubMed  Google Scholar 

  7. van Berge L, Hamilton EM, Linnankivi T et al (2014) Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy. Brain 137:1019–1029

    Article  PubMed  Google Scholar 

  8. Cameron JM, Janer A, Levandovskiy V et al (2011) Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes. Am J Hum Genet 89:486–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Navarro-Sastre A, Tort F, Stehling O et al (2011) A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins. Am J Hum Genet 89:656–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Baker PR, Friederich MW, Swanson MA et al (2014) Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain 137:366–379

    Article  PubMed  Google Scholar 

  11. Ajit Bolar N, Vanlander AV, Wilbrecht C et al (2013) Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy. Hum Mol Gene 22:2590–2602

    Article  CAS  Google Scholar 

  12. Al-Hassnan ZN, Al-Dosary M, Alfadhel M et al (2015) ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder. J Med Genet 52:186–194

    Article  CAS  PubMed  Google Scholar 

  13. Stehling O, Wilbrecht C, Lill R (2014) Mitochondrial iron-sulfur protein biogenesis and human disease. Biochimie 100:61–77

    Article  CAS  PubMed  Google Scholar 

  14. Bugiani M, Invernizzi F, Alberio S et al (2004) Clinical and molecular findings in children with complex I deficiency. Biochim Biophys Acta 1659:136–147

    Article  CAS  PubMed  Google Scholar 

  15. Rizza T, Vazquez-Memije ME, Meschini MC et al (2009) Assaying ATP synthesis in cultured cells: a valuable tool for the diagnosis of patients with mitochondrial disorders. Biochem Biophys Res Commun 383:58–62

    Article  CAS  PubMed  Google Scholar 

  16. Munujos P, Coll-Cantí J, Beleta J, González-Sastre F, Gella FJ (1996) Brain pyruvate oxidation in experimental thiamin-deficiency encephalopathy. Clin Chim Acta 255:13–25

    Article  CAS  PubMed  Google Scholar 

  17. Nakai N, Kobayashi R, Popov KM, Harris RA, Shimomura Y (2000) Determination of branched-chain alpha-keto acid dehydrogenase activity state and branched-chain alpha-keto acid dehydrogenase kinase activity and protein in mammalian tissues. Methods Enzymol 324:48–62

    Article  CAS  PubMed  Google Scholar 

  18. Nijtmans LG, Henderson NS, Holt IJ (2002) Blue native electrophoresis to study mitochondrial and other protein complexes. Methods 26:327–334

    Article  CAS  PubMed  Google Scholar 

  19. Zerbetto E, Vergani L, Dabbeni-Sala F (1997) Quantification of muscle mitochondrial oxidative phosphorylation enzymes via histochemical staining of blue native polyacrylamide gels. Electrophoresis 18:2059–2064

    Article  CAS  PubMed  Google Scholar 

  20. Calvo SE, Compton AG, Hershman SG et al (2012) Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med 4:118

    Article  Google Scholar 

  21. Debray FG, Stümpfig C, Vanlander AV et al (2015) Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy. J Inherit Metab Dis 38:1147–1153

    Article  CAS  PubMed  Google Scholar 

  22. Bugiani M, Lamantea E, Invernizzi F et al (2006) Effects of riboflavin in children with complex II deficiency. Brain Dev 28:576–581

    Article  PubMed  Google Scholar 

  23. Gelling C, Dawes IW, Richhardt N, Lill R, Mühlenhoff U (2008) Mitochondrial Iba57p is required for Fe/S cluster formation on aconitase and activation of radical SAM enzymes. Mol Cell Biol 28:1851–1861

    Article  CAS  PubMed  Google Scholar 

  24. Sheftel AD, Wilbrecht C, Stehling O et al (2012) The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation. Mol Biol Cell 23:1157–1166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lossos A, Stümpfig C, Stevanin G et al (2015) Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia. Neurology 84:659–667

    Article  CAS  PubMed  Google Scholar 

  26. Invernizzi F, Ardissone A, Lamantea E et al (2014) Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations. Front Genet 5:412

    Article  PubMed  PubMed Central  Google Scholar 

  27. Nizon M, Boutron A, Boddaert N et al (2014) Leukoencephalopathy with cysts and hyperglycinemia may result from NFU1 deficiency. Mitochondrion 15:59–64

    Article  CAS  PubMed  Google Scholar 

  28. Carrozzo R, Torraco A, Fiermonte G et al (2014) Riboflavin responsive mitochondrial myopathy is a new phenotype of dihydrolipoamide dehydrogenase deficiency. The chaperon-like effect of vitamin B2. Mitochondrion 18:49–57

    Article  CAS  PubMed  Google Scholar 

  29. Uzarska MA, Nasta V, Weiler BD et al (2016) Mitochondrial Bol1 and Bol3 function as assembly factors for specific iron-sulfur proteins. Elife. doi:10.7554/eLife.16673

    PubMed  PubMed Central  Google Scholar 

  30. Ahting U, Mayr JA, Vanlander AV et al (2015) Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency. Front Genet 6:123

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work received financial support from the Telethon Grant GGP11011, the Italian Ministry of Health (GR2010–2316392), and the Italian Association of Mitochondrial Disease Patients and Families (Mitocon).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rosalba Carrozzo.

Ethics declarations

Conflicts of interest

The authors declare that there is no conflict of interest.

Additional information

E. Bertini, D. Ghezzi and R. Carrozzo contributed equally to this work as senior authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 38 kb)

415_2016_8312_MOESM2_ESM.tif

Supplementary Fig. 1a Electropherograms showing the variants in Pt.1 (c.686C>T [p.P229L]; c.586T>G [p.W196G]); b in Pt.2 (c.87_insGCCCAAGGTGC [p.R30Afs*46]; c.313C>T [p.R105W]); c in Pt.3 (c.706C>T [p.P236S]); d in Pt.4 (c.316G>A [p.T106A]; c.757G>C [p.V253L]). (TIFF 3,299 kb)

415_2016_8312_MOESM3_ESM.tif

Supplementary Fig. 2 Alignment of IBA57 proteins showing the conservation degree of the variants found amongst the species. (TIFF 3215 kb)

Supplementary material 4 (DOCX 18 kb)

Supplementary material 5 (DOCX 14 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Torraco, A., Ardissone, A., Invernizzi, F. et al. Novel mutations in IBA57 are associated with leukodystrophy and variable clinical phenotypes. J Neurol 264, 102–111 (2017). https://doi.org/10.1007/s00415-016-8312-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-016-8312-z

Keywords

Navigation