Mutations in the iron sulphur cluster assembly gene IBA57 cause a cavitating leukodystrophy associated with a variable phenotype

Objective: To describe two patients with a cavitating leukodsytrophy secondary to mutations in the iron cluster assembly gene IBA57. Methods: Two unrelated patients were referred to the Leeds Inherited White Matter disorders MDT for further investigation. No mutations were identified in any of the 94 genes in our white matter clinical exome. Therefore the whole exome was examined. Results: Patient 1 is a female born to consanguineous parents. She developed normally until 6 months after which she had rapid regression in motor and visual skills. At 11 months examination revealed irritability, evolving quadriparesis, poor vision and sluggish pupillary reactions. Magnetic resonance (MR) imaging demonstrated extensive bilateral leukoencephalopathy with involvement of the corpus callosum and middle cerebellar peduncles. Large cavitary areas were present in the deep white matter. Homozygous mutations in the IBA57 gene were identified. Patient 2 is a male born to non-consanguineous parents. There were developmental concerns from 6 months, particularly concerning vision. Examination at 17 months showed mild 4 limbed hypertonia, poor vision and optic atrophy. He made developmental progress and aged 7 has severe visual impairment, four limbed spasticity and epilepsy. MR at 17 months demonstrated diffuse leukoencephalopathy with large cavitated areas. Follow up at 6 yrs shows progression of cavitation, a small corpus callosum but some improvement in myelination. Molecular investigation demonstrated compound heterozygous mutations in IBA57. Conclusion: The IBA57 gene is involved in late iron sulphur cluster assembly and biosynthesis of essential cofactors for several key mitochondrial enzymes. The phenotype in previously reported cases varies widely from a rapidly progressive, fatal, neonatal onset disorder to a milder, later onset phenotype with spastic paraplegia, optic atrophy and peripheral neuropathy (Lossos 2015, Debray 2015, Torraco 2016). A cavitating leukoencephalopathy is characteristic and may not necessarily be associated with a severe phenotype as illustrated by our second patient.