Biallelic mutations in IBA57 cause a mitochondrial disorder with a broad phenotypic spectrum that ranges from severe intellectual disability to adolescent-onset spastic paraplegia. Only 21 IBA57 mutations have been reported, therefore the phenotypic spectrum of IBA57-related mitochondrial disease has not yet been fully elucidated. In this study, we performed whole-exome sequencing on a Sepharadi Jewish and Japanese family with leukodystrophy. We identified four novel biallelic variants in IBA57 in the two families: one frameshift insertion and three missense variants. The three missense variants were predicted to be disease-causing by multiple in silico tools. The 29-year-old Sepharadi Jewish male had infantile-onset optic atrophy with clinically asymptomatic leukodystrophy involving periventricular white matter. The 19-year-old younger brother, with the same compound heterozygous IBA57 variants, had a similar clinical course until 7 years of age. However, he then developed a rapidly progressive spastic paraparesis following a febrile illness. A 7-year-old Japanese girl had developmental regression, spastic quadriplegia, and abnormal periventricular white matter signal on brain magnetic resonance imaging performed at 8 months of age. She had febrile convulsions at the age of 18 months and later developed epilepsy. In summary, we have identified four novel IBA57 mutations in two unrelated families. Consequently, we describe a patient with infantile-onset optic atrophy and asymptomatic white matter involvement, thus broadening the phenotypic spectrum of biallelic IBA57 mutations.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $37.50 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Sheftel AD, Wilbrecht C, Stehling O, Niggemeyer B, Elsasser HP, Muhlenhoff U, et al. The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation. Mol Biol Cell. 2012;23:1157–66.
Tort F, Ferrer-Cortes X, Ribes A. Differential diagnosis of lipoic acid synthesis defects. J Inherit Metab Dis. 2016;39:781–93.
Al-Hassnan ZN, Al-Dosary M, Alfadhel M, Faqeih EA, Alsagob M, Kenana R, et al. ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder. J Med Genet. 2015;52:186–94.
Ajit Bolar N, Vanlander AV, Wilbrecht C, Van der Aa N, Smet J, De Paepe B, et al. Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy. Hum Mol Genet. 2013;22:2590–602.
Navarro-Sastre A, Tort F, Stehling O, Uzarska MA, Arranz JA, Del Toro M, et al. 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. 2011;89:656–67.
Cameron JM, Janer A, Levandovskiy V, Mackay N, Rouault TA, Tong WH, et al. 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. 2011;89:486–95.
Shukla A, Hebbar M, Srivastava A, Kadavigere R, Upadhyai P, Kanthi A, et al. Homozygous p.(Glu87Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome. J Hum Genet. 2017;62:723–7.
Torraco A, Ardissone A, Invernizzi F, Rizza T, Fiermonte G, Niceta M, et al. Novel mutations in IBA57 are associated with leukodystrophy and variable clinical phenotypes. J Neurol. 2017;264:102–11.
Lossos A, Stumpfig C, Stevanin G, Gaussen M, Zimmerman BE, Mundwiller E, et al. Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia. Neurology. 2015;84:659–67.
Liu M, Zhang J, Zhang Z, Zhou L, Jiang Y, Wang J, et al. Phenotypic spectrum of mutations inIBA57, a candidate gene for cavitating leukoencephalopathy. Clin Genet. 2017;93:235–41.
Ishiyama A, Sakai C, Matsushima Y, Noguchi S, Mitsuhashi S, Endo Y, et al. IBA57 mutations abrogate iron-sulfur cluster assembly leading to cavitating leukoencephalopathy. Neurol Genet. 2017;3:e184.
Debray FG, Stumpfig C, Vanlander AV, Dideberg V, Josse C, Caberg JH, et al. Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy. J Inherit Metab Dis. 2015;38:1147–53.
Fujita A, Isidor B, Piloquet H, Corre P, Okamoto N, Nakashima M, et al. De novo MEIS2 mutation causes syndromic developmental delay with persistent gastro-esophageal reflux. J Hum Genet. 2016;61:835–8.
Vinkler C, Lev D, Kalish H, Watemberg N, Yanoov-Sharav M, Leshinsky-Silver E, et al. Familial optic atrophy with white matter changes. Am J Med Genet A. 2003;121a:263–5.
Ahting U, Mayr JA, Vanlander AV, Hardy SA, Santra S, Makowski C, et al. Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency. Front Genet. 2015;6:123.
Baker PR 2nd, Friederich MW, Swanson MA, Shaikh T, Bhattacharya K, et al. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain. 2014;137 Pt 2:366–79.
Lerman-Sagie T, Leshinsky-Silver E, Watemberg N, Luckman Y, Lev D. White matter involvement in mitochondrial diseases. Mol Genet Metab. 2005;84:127–36.
Bargiela D, Chinnery PF. Mitochondria in neuroinflammation—multiple sclerosis (MS), leber hereditary optic neuropathy (LHON) and LHON-MS. Neurosci Lett. 2017. [Epub ahead of print]
Matthews L, Enzinger C, Fazekas F, Rovira A, Ciccarelli O, Dotti MT, et al. MRI in Leber’s hereditary optic neuropathy: the relationship to multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015;86:537–42.
Lev D, Yanoov-Sharav M, Watemberg N, Leshinsky-Silver E, Lerman-Sagie T. White matter abnormalities in Leber’s hereditary optic neuropathy due to the 3460 mitochondrial DNA mutation. European journal of paediatric neurology. Eur J Paediatr Neurol. 2002;6:121–3.
van der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter disease. Lancet Neurol. 2006;5:413–23.
Fogli A, Rodriguez D, Eymard-Pierre E, Bouhour F, Labauge P, Meaney BF, et al. Ovarian failure related to eukaryotic initiation factor 2B mutations. Am J Hum Genet. 2003;72:1544–50.
van der Knaap MS, Barth PG, Gabreels FJ, Franzoni E, Begeer JH, Stroink H, et al. A new leukoencephalopathy with vanishing white matter. Neurology. 1997;48:845–55.
Nizon M, Boutron A, Boddaert N, Slama A, Delpech H, Sardet C, et al. Leukoencephalopathy with cysts and hyperglycinemia may result from NFU1 deficiency. Mitochondrion. 2014;15:59–64.
Ferrer-Cortes X, Narbona J, Bujan N, Matalonga L, Del Toro M, Arranz JA, et al. A leaky splicing mutation in NFU1 is associated with a particular biochemical phenotype. Consequences for the diagnosis. Mitochondrion. 2016;26:72–80.
Tonduti D, Dorboz I, Imbard A, Slama A, Boutron A, Pichard S, et al. New spastic paraplegia phenotype associated to mutation of NFU1. Orphanet J Rare Dis. 2015;10:13.
Invernizzi F, Ardissone A, Lamantea E, Garavaglia B, Zeviani M, Farina L, et al. Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations. Front Genet. 2014;5:412.
We thank all the participants for their cooperation in this research. We also thank Ms. K. Takabe, Mr. T. Miyama, Ms. N. Watanabe, Ms. M. Sato, Mr. S. Nakamura, and Ms. S. Sugimoto at the Department of Human Genetics, Yokohama City University Graduate School of Medicine, for their technical assistance. This work was supported by grants from Research on Measures for Intractable Diseases (NMa), Comprehensive Research on Disability Health and Welfare (NMa), the Strategic Research Program for Brain Science (NMa), the Initiative on Rare and Undiagnosed Diseases in Pediatrics (NMa), the Initiative on Rare and Undiagnosed Diseases for Adults (NMa) from the Japanese Agency for Medical Research and Development, a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grants-in-Aid for Scientific Research [A (NMa), B (NMi, HS), and C (SMiy)], the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems (NMa) from the Japanese Science and Technology Agency, grants from the Ministry of Health, Labour and Welfare (NMa), the Takeda Science Foundation (NMi, HS, and NMa), and the Ichiro Kanehara Foundation for the Promotion of Medical Science & Medical Care (SMiy). We thank Rachel James, Ph.D., from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
KH: literature review, collection of data, and drafting the manuscript; AZS, LB, KY, AF, EI, KI, S.Mit, MN, TM, AT, NMi, HS: data collection; SMiy, DL, TL-S, MSvdK, and NMa: supervision of all aspects, including study design, data interpretation, and manuscript preparation.
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
About this article
Single-fiber electromyography-based diagnosis of CACNA1A mutation in children: A potential role of the electrodiagnosis in the era of whole exome sequencing
Brain and Development (2019)
MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: bioinformatics consideration
Human Molecular Genetics (2019)