Our present study described two cases with a genetically confirmed diagnosis of MMDS3. Both two individuals displayed acute and progressive psychomotor regression with a brain MRI profile of diffuse vacuolar leukoencephalopathy. MMDS is a rare mitochondrial disorder which has a broad phenotypic spectrum with a heterogeneous course, ranging from fatal early-onset to acute and severe psychomotor regression after the first year of life, followed by recovery of symptom control and longer survival (Debray et al. 2015; Hamanaka et al. 2018; Torraco et al. 2017). Prenatal ultrasound had found intra-uterine dysplasia in two siblings with homozygous IBA57 mutation (Ajit Bolar et al. 2013). In infantile cases, the average onset age was 8 months (4–18 months), with initial symptoms of motor regression or feeding difficulties. Encephalopathy, myopathy, vision impairment, seizures, and respiratory failure can be presented as disease progressed. Symptomatic fluctuation with transient stability or turn to severe phenotypes which are usually associated with early fatal or debilitating conditions have been described (Alfadhel 2019; Ishiyama et al. 2017; Liu et al. 2018; Uzunhan et al. 2020). In line with the previous report, the patient 2 in our study suffered from a recurrent preceding infection which may induce or aggravate the symptoms, this may be associated with the increased level of lactate (Liu et al. 2018). The milder phenotype which is presented with slowly progressive neurological symptoms characterized by spastic paraparesis, optic atrophy, and peripheral neuropathy is more common in childhood or more older cases (Lossos et al. 2015). MMDS often show the similar biochemical features with lactic acidosis in serum and cerebrospinal fluid, and hyperglycinemia (Ajit Bolar et al. 2013; Nizon et al. 2014; Toldo et al. 2018). Moreover, deficient activity and expression of the respiratory chain complexes I and II, and a decrease in mitochondrial protein lipoylation can be detected in the affected patients (Ishiyama et al. 2017; Lill and Freibert 2020). Brain MRI showed diffuse leukoencephalopathy that completely implicated in the white matter around the lateral ventricle, splenium of the corpus callosum, and posterior limb of the internal capsule. An extension or progression of infratentorial white matter involvement in the cerebellum, brainstem, or cervical spinal cord were frequently found in late MRI. In both the peak and recovery stages, cavitating lesions could be observed (Al-Hassnan et al. 2015; Ishiyama et al. 2017; Liu et al. 2018; Torraco et al. 2017). Cavitating leukoencephalopathies was described as irregular, asymmetric, patchy areas of white matter abnormalities that evolve to develop cystic degeneration, which indicates a high clinical diagnostic significance in patients with mitochondrial defects (Naidu et al. 2005). What’s more, a variable degree of cerebral atrophy was also found (Ajit Bolar et al. 2013; Vögtle et al. 2018).
So far, based on different genotypes, mutations in NFU1, BOLA3, IBA57, ISCA2, ISCA1 and PMPCB have been identified lead to MMDS types 1 to 6, respectively. All the first five genes play a vital role in the biogenesis of mitochondrial (4Fe–4S) cluster-binding proteins (Lill and Freibert 2020). Located in mitochondria, cytosol, endoplasmic reticulum and nucleus, ISCs contribute to respiration, iron homeostasis, heme biosynthesis, oxidative phosphorylation, citric acid cycle, and DNA repair, among regulation of other pathways (Lill 2009; Maio and Rouault 2020). Assembly of ISCs usually begins in mitochondria, where ISCs work as essential protein cofactors of numerous key mitochondrial enzymes, including respiratory chain complexes I and II, mitochondrial aconitase and lipoic acid synthase (Lill and Freibert 2020; Stehling and Lill 2013). At present, there are approximately 20 different proteins involved in the mitochondrial ISC assembly machinery, which is mainly composed of three consecutive steps: firstly, the de novo synthesis of a (2Fe-2S) cluster on the scaffold protein; secondly, chaperone assisted release of the Fe-S cluster and mitochondrial trafficking; finally, the conversion of (2Fe-2S) cluster into a (4Fe-4S) type by proteins ISCA1, ISCA2, and IBA57, then followed by transfer and insertion into target recipient apoproteins either directly or through some specific proteins, like NFU1, NUBPL, and BOLA3 (Alfadhel et al. 2017). Therefore, the proteins ISCA1, ISCA2, IBA57, NFU1, IND1, and BOLA are crucial late-acting ISC factors required for (4Fe-4S) protein maturation and dedicated insertion (Lill and Freibert 2020). Mutations in late-acting ISC genes are usually associated with neurological impairments, respiratory deficiencies, and metabolism disturbance. However, the severity of functional defects caused by different mutations within MMDS1-5 genes differs dramatically, which may have great relevance with the extent of biochemical alterations (Lebigot et al. 2017). Mutations in PMPCB, which encoding the catalytic subunit of the essential mitochondrial processing protease, have been found in patients presented with leigh-like neurodegeneration in childhood with prominent cerebellar atrophy. Functional study showed that biallelic PMPCB mutations cause defects in mitochondrial processing protease proteolytic activity accompanied by dysregulation of ISC biogenesis (Vögtle et al. 2018).
IBA57 located in 1q42.13, contains 3 exons and encodes the mitochondrial Fe-S protein assembly factor, which has a globular shape and consists of three tightly packed domains arranged in a rigid ring-like structure, and forms a heterodimeric complex with ISCA2 upon (2Fe-2S) cluster binding (Gourdoupis et al. 2018; Nasta et al. 2019). The clinical presentations of IBA57-mutated MMDS can range from severe early fatality to childhood or adolescent-onset spastic paraplegia, optic atrophy, neuropathy or asymptomatic cavitating leukoencephalopathy (Ajit Bolar et al. 2013; Hamanaka et al. 2018; Lossos et al. 2015). Moreover, the highly clinical variability even among siblings with identical genotypes, pointing to the possibility of significant interaction among genetic, epigenetic, and environmental factors (Hamanaka et al. 2018). Up to now, total 28 patients with IBA57-mutated MMDS from 25 different families (including the present cases) have been described, including16 females and 12 males, the average age of onset was 10 months (range from prenatal to 22 months). About 28 IBA57 mutations have been identified, including missense, nonsense, and frameshift variants (Ajit Bolar et al. 2013; Debray et al. 2015; Hamanaka et al. 2018; Ishiyama et al. 2017;Liu et al. 2018; Torraco et al. 2017) (Fig. 2B). It is noteworthy that including present study, almost all the Chinese patients carried the same mutation c.286T > C, which might show a founder mutation effect in Chinese sufferers (Liu et al. 2018). Cellular functional assays showed that mutation leads to substantial decreases in IBA57 protein expression, and partial functional impairment, which mainly resulted from its proteolytic degradation (Ajit Bolar et al. 2013). Moreover, IBA57 mutations resulted in defect of respiratory chain complexes, and deficiency of lipoic acid synthetase through aberrant NFU1 function (Debray et al. 2015; Ishiyama et al. 2017). All mutations in our study were highly conservative in the related species (Fig. 2A). The mutation c.189delC caused frame shift and a premature termination codon, resulting in abnormal truncated protein, and both c.189delC and c.580A > G were located in the helix structure, thus we speculated the novel mutations in the present study have an impaired function. Further functional assays are needed to confirm the influences.
Due to the highly heterogeneous clinical spectrum of mitochondrial diseases, when concurrence of neurodegeneration, optic atrophy, and leukoencephalopathy, many other diseases such as different types of MMDS, Leigh syndrome, Leber’s hereditary optic neuropathy, vanishing white matter disease, as well as Kearns–Sayre syndrome can also be considered (Ashrafi et al. 2020; Lerman-Sagie et al. 2005). Thus, it’s appropriate to perform the molecular genetic analysis for reliable diagnosis, and further make a MMDS genotype. The current overall administration of MMDS is symptomatic and supportive treatment, and exercise, nutrition and supplements, social care, and mental wellbeing were used as a framework to guide the disease management (Long et al. 2021; Parikh et al. 2017). Previous studies have suggested that cocktail therapy (a mix of supplements and vitamins) for mitochondrial diseases may has a certain effect (Tarnopolsky 2008). Since the rapidly progressive course and high mortality of the disease, earlier recognition and diagnosis with multidisciplinary collaboration is much more crucial to provide timely intervention and accurate genetic counseling.