Novel mutations in IBA57 are associated with leukodystrophy and variable clinical phenotypes

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.

Phenotypic spectrum of mutations in IBA57, a candidate gene for cavitating leukoencephalopathy

“…IBA57 mutations in 11 patients MRI features in patients with IBA57 mutations MRI features varied among the different phenotypes. Lesions in thalamus and cervical spinal cord were described in a previously reported case 6. In the acute/subacute phase, lesions commonly involved the periventricular/central WM of the frontal and parieto-occipital lobes, the corpus callosum, and the temporal WM.…”

“…The lesion extent score was 6.7 (4)(5)(6)(7)(8)(9)(10)(11) in the peak phase and 8.3 (6)(7)(8)(9)(10) in the recovery phase (Z = −1.06, P = .35). The lesion extent score was 6.7 (4)(5)(6)(7)(8)(9)(10)(11) in the peak phase and 8.3 (6)(7)(8)(9)(10) in the recovery phase (Z = −1.06, P = .35).…”

“…[4][5][6][7] We identified 8 novel mutations in the present study. [4][5][6][7] We identified 8 novel mutations in the present study.…”

“…In a preliminary functional study, the pathogenesis of the IBA57 mutation was due to the decreased amount of IBA57 protein 4 and the reduced biosynthesis of mitochondrial [4Fe-4S] protein 6. 1 Consequently, a lack of IBA57 affects mitochondrial [4Fe-4S] protein assembly, whereas the generation of [2Fe-2S] proteins is preserved.…”

NMR as a Tool to Investigate the Processes of Mitochondrial and Cytosolic Iron-Sulfur Cluster Biosynthesis

“…A recent study using a mouse model suggested that only ISCA1 is required for the maturation of mitochondrial [4Fe-4S] clusters [ 43 ]. Defects in ISCA1, ISCA2 and IBA57 have been associated with numerous mitochondrial diseases now categorized as multiple mitochondrial dysfunctions syndromes MMDS3 (IBA57) [ 80 , 81 , 187 ], MMDS4 (ISCA2) [ 79 ], and MMDS5 (ISCA1) [ 77 , 78 ]. A common phenotype of these MMDS diseases is the deficiency in mitochondrial [4Fe-4S] proteins, such as lipoic acid synthase (LAS), a strong indication of their functions in mitochondrial [4Fe-4S] cluster maturation.…”