Expanding the phenotype of IBA57 mutations: related leukodystrophy can remain asymptomatic

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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.

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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.

Author contributions

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.

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Correspondence to Naomichi Matsumoto.

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