铁硫簇(FeS)是多种酶在多种途径中使用的最原始和普遍的辅因子之一。FeS的生物合成是一个复杂的多步骤过程,受到严格调控,需要多种机器。IBA57与ISCA1和ISCA2一起在[4Fe-4S]簇的成熟中起作用,这些簇是包括线粒体复合物I在内的多种线粒体酶所必需的。复杂II,硫辛酸合成酶,和乌头酸酶.IBA57的致病变异与多种线粒体功能障碍综合征3(MMDS3)有关,其特征是婴儿至儿童早期发作的精神运动消退,视神经萎缩和非特异性畸形。在这里,我们报告了一名女性先证者,其在先前病毒感染的情况下,在5周龄时发生了包括IUGR和小头畸形在内的产前受累,并出现了亚急性精神运动消退。脑成像显示皮质畸形伴多微陀螺,脑干和脊髓信号异常改变。生化分析显示血浆甘氨酸增加和尿液中多种有机酸的过度排泄,引起对硫辛酸生物合成缺陷和线粒体FeS组装缺陷的关注。分子分析随后在IBA57中检测到复合杂合变体,证实MMDS3的诊断。尽管MMDS3患者的数量有限,已观察到一定程度的基因型-表型相关性。先证者中异常的脑成像强调需要将线粒体疾病作为结构性脑异常的鉴别诊断。最后,除了先前已知的生物标志物,包括高血乳酸和血浆甘氨酸水平,尿有机酸分析中2-羟基己二酸和2-酮己二酸的增加,在适当的临床背景下,应提示对硫辛酸生物合成缺陷和线粒体FeS组装缺陷的评估。
Iron‑sulfur clusters (FeS) are one of the most primitive and ubiquitous cofactors used by various enzymes in multiple pathways. Biosynthesis of FeS is a complex multi-step process that is tightly regulated and requires multiple machineries.
IBA57, along with ISCA1 and ISCA2, play a role in maturation of [4Fe-4S] clusters which are required for multiple mitochondrial enzymes including mitochondrial Complex I, Complex II, lipoic acid synthase, and aconitase. Pathogenic variants in
IBA57 have been associated with multiple mitochondrial dysfunctions syndrome 3 (MMDS3) characterized by infantile to early childhood-onset psychomotor regression, optic atrophy and nonspecific dysmorphism. Here we report a female proband who had prenatal involvement including IUGR and microcephaly and developed subacute psychomotor regression at the age of 5 weeks in the setting of preceding viral infection. Brain imaging revealed cortical malformation with polymicrogyria and abnormal signal alteration in brainstem and spinal cord. Biochemical analysis revealed increased plasma glycine and hyperexcretion of multiple organic acids in urine, raising the concern for lipoic acid biosynthesis defects and mitochondrial FeS assembly defects. Molecular analysis subsequently detected compound heterozygous variants in
IBA57, confirming the diagnosis of MMDS3. Although the number of MMDS3 patients are limited, certain degree of genotype-phenotype correlation has been observed. Unusual brain imaging in the proband highlights the need to include mitochondrial disorders as differential diagnoses of structural brain abnormalities. Lastly, in addition to previously known biomarkers including high blood lactate and plasma glycine levels, the increase of 2-hydroxyadipic and 2-ketoadipic acids in urine organic acid analysis, in the appropriate clinical context, should prompt an evaluation for the lipoic acid biosynthesis defects and mitochondrial FeS assembly defects.