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.
Similar content being viewed by others
References
Vanderver A, Prust M, Tonduti D et al (2015) Case definition and classification of leukodystrophies and leukoencephalopathies. Mol Genet Metab 114:494–500
Morató L, Bertini E, Verrigni D et al (2014) Mitochondrial dysfunction in central nervous system white matter disorders. Glia 62:1878–1894
Dallabona C, Abbink TE, Carrozzo R et al (2016) LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance. Brain 139:782–794
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
Dallabona C, Diodato D, Kevelam SH et al (2014) Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology 82:2063–2071
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
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
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
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
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
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
Al-Hassnan ZN, Al-Dosary M, Alfadhel M et al (2015) ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder. J Med Genet 52:186–194
Stehling O, Wilbrecht C, Lill R (2014) Mitochondrial iron-sulfur protein biogenesis and human disease. Biochimie 100:61–77
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
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
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
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
Nijtmans LG, Henderson NS, Holt IJ (2002) Blue native electrophoresis to study mitochondrial and other protein complexes. Methods 26:327–334
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
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
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
Bugiani M, Lamantea E, Invernizzi F et al (2006) Effects of riboflavin in children with complex II deficiency. Brain Dev 28:576–581
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
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
Lossos A, Stümpfig C, Stevanin G et al (2015) Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia. Neurology 84:659–667
Invernizzi F, Ardissone A, Lamantea E et al (2014) Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations. Front Genet 5:412
Nizon M, Boutron A, Boddaert N et al (2014) Leukoencephalopathy with cysts and hyperglycinemia may result from NFU1 deficiency. Mitochondrion 15:59–64
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
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
Ahting U, Mayr JA, Vanlander AV et al (2015) Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency. Front Genet 6:123
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
Corresponding author
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.
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)
Rights and permissions
About this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-016-8312-z