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

Kohei Hamanaka, Satoko Miyatake, Ayelet Zerem, Dorit Lev, Luba Blumkin, Kenji Yokochi, Atsushi Fujita, Eri Imagawa, Kazuhiro Iwama, Mitsuko Nakashima, Satomi Mitsuhashi, Takeshi Mizuguchi, Atsushi Takata, Noriko Miyake, Hirotomo Saitsu, Marjo S. van der Knaap, Tally Lerman-Sagie, Naomichi Matsumoto*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1223-1229
Number of pages7
JournalJournal of Human Genetics
Issue number12
StatePublished - 1 Dec 2018


FundersFunder number
Takeda Science Foundation
Japan Agency for Medical Research and Development
Japan Society for the Promotion of Science17H01539, 17K10080, 17H06994, 16H06254, 17K15630
Ministry of Education, Culture, Sports, Science and Technology
Japan Science and Technology Agency
Ministry of Health, Labour and Welfare
Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care


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