Background:Nucleotide repeat expansion disorders constitute a group of clinically and genetically heterogeneous diseases, pathologically characterized by the misfolding, aggregation, and accumulation of proteins. The expanded GGC repeats in the 5' untranslated region (5'UTR) of the NOTCH2NLC gene translate into uN2CpolyG, a toxic polyglycine protein that leads to neuronal intranuclear inclusion disease (NIID). However, the precise composition of uN2CpolyG and its pathogenic mechanisms remain fully unclear. Objectives:We aimed to investigate the proteomic profile of uN2CpolyG and explore the novel neuropathology in NIID patients, which may underlie the disease pathogenesis. Methods:Mass spectrometry analysis was performed on purified intranuclear inclusions to investigate the proteomic profile. Three patients with genetically confirmed NIID were enrolled; two participants underwent skin biopsy, and one underwent brain autopsy. Skin and brain tissues derived from these patients were used to examine NOTCH2NLC-related pathological changes. Results:A group of enriched proteins interacting with uN2CpolyG were identified, characterized by significant intrinsically disordered regions (IDRs). Among these, we detected the co-localization of uN2CpolyG with PML and FUS in notably distinct patterns, causing significant DNA damage and impaired stress response. Furthermore, FUS- and PML-positive inclusions were confirmed in NIID patients' tissues. Conclusion:Our findings provide novel insights into the proteomic profile and neuropathology of NIID, potentially enlightening the pathogenesis and therapeutic strategies for protein aggregation-related neurodegenerative diseases.

Intranuclear inclusions are defining features of many neurodegenerative diseases, yet their assembly mechanisms and pathological roles remain poorly understood. Here, we investigate polyglycine (polyG) inclusions in neuronal intranuclear inclusion disease (NIID) and show that they recruit intrinsically disordered proteins to form stratified, immobile condensates that disrupt nuclear protein quality control and DNA damage repair. Leveraging their ordered and stepwise assembly, we identify promyelocytic leukaemia protein (PML) as a key factor that actively recognizes and eliminates polyG inclusions through chaperone-mediated disaggregation and proteasome-dependent degradation. Engineered PML variants selectively clear both nuclear and cytoplasmic aggregates, including polyG, polyGA, polyQ, TDP-43 and SOD1. Systemic PML delivery alleviates cognitive and motor deficits in mouse models of NIID and TDP-43 proteinopathy. These findings uncover a conserved spatial organization of nuclear inclusions and establish PML as a therapeutic effector for neurodegenerative diseases linked to protein aggregation.

Objective To report 2 cases of Charcot-Marie-Tooth disease type 4H (CMT4H) caused by FGD4 gene variation and review the relevant literatures, summarizing the clinical and gene mutation characteristics of CMT4H. Methods and Results Two families with CMT4H diagnosed by genetic test in Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine from May 2020 to July 2022 were included. The probands in 2 families were both sporadic patients with onset in early adolescence, manifesting as progressive postural gait abnormalities, difficulty walking, and foot deformities. Nerve electrophysiological examination showed multiple demyelinating damages to sensory and motor nerves. Sural nerve biopsy in proband of family 1 disclosed a decreased density of myelin fibers and demyelinating neuropathy with thickened and excessively folded myelin sheath. Whole exome sequencing (WES) revealed that both probands had compound heterozygous mutations in the FGD4 gene, all of which were novel, and cosegregated with the family members. Conclusions CMT4H is a peripheral neuropathy mainly caused by autosomal recessive demyelination, and case report from 2 families further expand the spectrum of FGD4 gene mutations.

Background and Purpose X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is char-acterized by peripheral neuropathy with or without episodic neurological dysfunction. We performed clinical, neuropathological, and genetic investigations of a series of patients with mutations of the gap-junction beta-1 gene (GJB1) to extend the phenotypic and genetic de-scription of CMTX1. Methods Detailed clinical evaluations, sural nerve biopsy, and genetic analysis were applied to patients with CMTX1. Results We collected 27 patients with CMTX1 with GJB1 mutations from 14 unrelated fami-lies. The age at onset (AAO) was 20.9 +/- 12.2 years (mean +/- standard deviation; range, 2-45 years). Walking difficulties, weakness in the legs, and pes cavus were common initial symp-toms. Compared with female patients, males tended to have a younger AAO (males vs. fe-males=15.4 +/- 9.6 vs. 32.0 +/- 8.8 years, p=0.002), a longer disease course (16.8 +/- 16.1 vs. 5.5 +/- 3.8 years, p=0.034), and more-severe electrophysiological results. Besides peripheral neuropathy, six of the patients had special episodic central nervous system (CNS) evidence from symp-toms, signs, and/or reversible white-matter lesions. Neuropathology revealed the loss of large myelinated fibers, increased number of regenerated axon clusters with abnormally thin my-elin sheaths, and excessively folded myelin. Genetic analysis identified 14 GJB1 variants, 6 of which were novel. Conclusions These findings expand the phenotypic and genetic spectrum of CMTX1. Al-though CMTX1 was found to have high phenotypic and CNS involvement variabilities, detailed neurological examinations and nerve conduction studies will provide critical clues for accurate diagnoses. Further exploration of the underlying mechanisms of connexin 32 involvement in neuropathy or CNS dysfunction is warranted to develop promising therapies.

Background: Colony-stimulating factor 1 receptor (CSF1R)-related disorder (CRD) is a rare autosomal dominant disease. The clinical and genetic characteristics of Chinese patients have not been elucidated. Objective: The objective of the study is to clarify the core features and influence factors of CRD patients in China. Methods: Clinical and genetic-related data of CRD patients in China were collected. Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Sundal MRI Severity Score were evaluated. Whole exome sequencing was used to analyze the CSF1R mutation status. Patients were compared between different sexes, mutation types, or mutation locations. Results: A total of 103 patients were included, with a male-to-female ratio of 1:1.51. The average age of onset was (40.75 +/- 8.58). Cognitive impairment (85.1%, 86/101) and parkinsonism (76.2%, 77/101) were the main clinical symptoms. The most common imaging feature was bilateral asymmetric white matter changes (100.0%). A total of 66 CSF1R gene mutants (22 novel mutations) were found, and 15 of 92 probands carried c.2381 T > C/p.I794T (16.30%). The MMSE and MoCA scores (17.0 [9.0], 11.90 +/- 7.16) of female patients were significantly lower than those of male patients (23.0 [10.0], 16.36 +/- 7.89), and the white matter severity score (20.19 +/- 8.47) of female patients was significantly higher than that of male patients (16.00 +/- 7.62). There is no statistical difference in age of onset between male and female patients. Conclusions: The core manifestations of Chinese CRD patients are progressive cognitive decline, parkinsonism, and bilateral asymmetric white matter changes. Compared to men, women have more severe cognitive impairment and imaging changes. c.2381 T > C/p.I794T is a hotspot mutation in Chinese patients. (c) 2024 International Parkinson and Movement Disorder Society.

Objective To report 5 patients with adrenomyeloneuropathy (AMN), and to summarize the clinical phenotype and gene mutation characteristics in combination with literature and mutation database. Methods and Results Five patients with AMN who were treated in the Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University and Shanghai Fengxian District Central Hospital from May 2008 to December 2021 were selected. Spastic paraplegia was the main manifestation in all the 5 patients. Laboratory test showed that Case 2 had abnormal levels of very long⁃chain fatty acids (VLCFA), and Case 5 had higher level of adrenocorticotropic hormone (ACTH). Cranial MRI showed multiple ischemic foci in the right frontal parietal lobe, brainstem and cerebellum in Case 5. Three patients (Case 2, Case 3, Case 5) underwent spinal MRI and showed protrusion of intervertebral disc or degenerative change of vertebral body. Gene detection showed that all 5 patients had pathogenic mutation located in exon 1 of ABCD1 gene, Case 1 was c.421G＞A (p.Ala141Thr) hemizygous mutation, Case 2 was c.454C＞G (p.Arg152Gly) hemizygous mutation, Case 3 was c.521A＞G (p.Tyr174Cys) hemizygous mutation, Case 4 and Case 5 from the same family, all of them were c.293C＞T (p.Ser98Leu) hemizygous mutation, which were "pathogenic" mutations, and the c.454C＞G mutation was first reported in this study. This study summarized the genetic variation of ABCD1 gene in the adrenoleukodystrophy (ALD) mutation database. The ALD mutation database contained 1255 genetic variations, which were distributed in exons, introns and 5' untranslated region (5'UTR) regions, of which exon 1 (43.12%, 370/858) and exon 6 (10.02%, 86/858) were the most common. Conclusions The diagnosis of ALD with spastic paraplegia as its main manifestation needs to be combined with clinical manifestations and imaging examinations. ABCD1 gene detection is important for diagnosis. Exon 1 and 6 are hotspot exons of ABCD1 gene.

AbstractObjectiveFlail arm syndrome (FAS) is one of the atypical subtypes of amyotrophic lateral sclerosis (ALS). Mutations in hnRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare genetic cause of ALS. Herein, marked clinical heterogeneity of FAS in a pedigree with a known hnRNPA1 variant was described to raise early awareness of the ALS variant. Furtherly, a literature review of the hnRNPA1‐related spectrum was made to summarize the clinical and genetic characteristics.MethodsDetailed clinical evaluation, muscle pathology, and whole‐exome sequencing were performed. The sequence and co‐segregation of the mutation among the family members were confirmed by Sanger sequencing.ResultsThe great clinical variability was found in a FAS pedigree. Muscle pathology revealed a cluster distribution of angulated or rounded atrophic fibers, accompanied by significant multi‐nucleus aggregation. Immunohistochemical staining showed that mutant hnRNPA1 proteins accumulated in muscle fiber cytoplasm. Exome sequencing identified a documented variant in hnRNPA1 gene c.1018C > T (p.P340S), which co‐segregated with disease in the family. Besides, highly phenotypic heterogeneity was also found in other hnRNPA1‐related diseases.InterpretationWe described a Chinese pedigree with hnRNPA1‐related FAS, which showed significant clinical variability among the intrafamilial members. FAS is a relatively milder variant of ALS, due to the highly heterogeneous clinical spectrum, early observation is of paramount importance. In addition, the highly phenotypic heterogeneity and molecular genetic mechanism of the hnRNPA1‐related spectrum are still beyond fully understood. Further, the detailed molecular mechanism underlying the clinical diversity is warranted to be explored.

目的 通过分析93例携带PRRT2基因c.649dupC突变的发作性运动诱发性运动障碍(paroxysmal kine-sigenic dyskinesia,PKD)患者的临床特点,总结该基因型的临床表型特征.方法 收集93例携带PRRT2基因热点突变(c.649dupC)的原发性PKD患者临床资料,采用自行设计的发作性运动诱发性运动障碍登记表记录并整理,就其临床表型进行总结分析,并比较男性与女性以及家族性与散发性患者的临床表型差异.结果 93例携带PRRT2基因热点突变的PKD患者男女比例为2.72:1,平均发病年龄为(9.93±3.52)岁,平均就诊年龄为(23.98±8.92)岁;单纯型54例(58.06％)、复杂型39例(41.94％);87例(93.55％)发作前有预感;发作形式包括肌张力障碍44例(47.31％),舞蹈样动作5例(5.38％),或混合发作(47.31％).散发性58例(62.37％)、家族性35例(37.63％),外显率为67.05％.62例(66.67％)服用抗癫药物患者中46例(74.19％)症状完全控制,14例(22.58％)发作频率下降但偶有发作,2例(3.23％)未见明显缓解.男性组面部累及比例低于女性组(P=0.017),家族性组面部累及比例低于散发性组(P=0.011).结论 PRRT2基因c.649dupC突变具有基因型-表型异质性,该基因型更容易表现为复杂型PKD,具有外显不全的遗传特点.

2例患者均幼年起病,主要临床表现为视觉障碍(如视觉闪光点)、偏侧肢体无力、麻木,症状持续约30 min后出现单侧搏动性头痛伴有恶心、呕吐,以上症状在休息后可缓解,不伴其他神经系统疾病.神经系统查体、头颅CT、磁共振成像、脑电图检查和遗传代谢疾病筛查均未见异常.根据《国际头痛疾病分类(第三版)》诊断标准,2例患者符合典型单纯偏瘫型偏头痛的诊断.ATP1A2基因检测显示,2例患者均存在ATP1A2基因突变.病例1为杂合突变c.G2284A/p.G762S,该突变此前报道为致病性突变;病例2为杂合突变c.C3022T/p.R1008W,查阅既往文献及数据库未见该位点单独致病的相关报道.根据美国医学遗传学和基因组学会指南,病例1的ATP1A2基因杂合突变c.G2284A/p.G762S评定为"可能致病",病例2的ATP1A2基因杂合突变c.C3022T/p.R1008W评定为"意义不明确".

目的·研究周围髓鞘蛋白22(peripheral myelin protein-22,PMP22)基因相关性周围神经病患者的遗传学特点和临床特征,并探讨基因型和临床表型的相关性.方法·收集2006年-2022年就诊于上海交通大学医学院附属第六人民医院神经内科的162例周围神经病患者,应用多重连接依赖的探针扩增(multiplex ligation-dependent probe amplification,MLPA)、全外显子测序(whole exon sequencing,WES)和Sanger测序技术等分子诊断技术综合分析筛选出26例PMP22基因相关性周围神经病先证者及其33例家系成员患者的基因变异情况,包括重复突变、缺失突变及点突变.进一步分析26例PMP22基因相关性周围神经病患者的遗传学和临床特点,临床特点包括人口学数据、临床表现、神经电生理特点、病理学特点等.结果·PMP22基因相关性周围神经病患者共59例(男性37例,女性22例),其中46例为家系病例(来自13个家系),余13例为散发病例.所有患者发病年龄34.0(14.0,49.5)岁,首发症状为肢体无力或肢体麻木.51例为PMP22重复突变,临床表型为腓骨肌萎缩症1A型(Charcot-Marie-Tooth type-1 A,CMT1A);6例PMP22缺失突变,临床表型为遗传性压迫易感性神经病(hereditary neuropathy with liability to pressure palsies,HNPP);2 例 PMP22点突变(p.S72L 和 p.G 100V),表型为Dejerine-Sottas综合征(Dejerine-Sottas syndrome,DSS).16例PMP22基因相关性周围神经病患者进行神经电生理检测,12例PMP22重复突变患者的运动神经传导速度(motor nerve conduction velocity,MCV)、复合肌肉动作电位波幅(compound muscle action potential,CMAP)和感觉传导速度(sensory nerve conduction velocities,SCV)较 4 例PMP22缺失突变患者明显降低(均P＜0.05),2种突变类型均可出现传导阻滞现象.12例PMP22基因相关性周围神经病患者进行腓肠神经活检,包括8例PMP22重复突变、3例PMP22缺失突变和1例PMP22点突变,可见不同程度有髓神经纤维变薄、"洋葱球样"变及神经纤维密度减低等病理改变.结论·PMP22基因相关性周围神经病可表现为CMT1A、HNPP及DSS等表型,具有临床异质性.对于电生理检测和腓肠神经活检呈脱髓鞘表现的患者,排除获得性病因后,应予以PMP22基因重复、缺失和点突变的基因检测,有助于该病的优化诊断以及遗传咨询.

Mutations in HSPB1 are known to cause Charcot-Marie-Tooth disease type 2F (CMT2F) and distal hereditary motor neuropathy (dHMN). In this study, we presented three patients with mutation in HSPB1 who were diagnosed with dHMN. Proband 1 was a 14-year-old male with progressive bilateral lower limb weakness and walking difficulty for four years. Proband 2 was a 65-year-old male with chronic lower limb weakness and restless legs syndrome from the age of 51. Proband 3 was a 50-year-old female with progressive weakness, lower limbs atrophy from the age of 44. The nerve conduction studies (NCS) suggested axonal degeneration of the peripheral motor nerves and needle electromyography (EMG) revealed chronic neurogenic changes in probands. Open sural nerve biopsy for proband 2 and the mother of proband 1 showed mild to moderate loss of myelinated nerve fibers with some nerve fiber regeneration. A novel p.V97L in HSPB1 was identified in proband 3, the other two variants (p.P182A and p.R127W) in HSPB1 have been reported previously. The functional studies showed that expressing mutant p.V97L HSPB1 in SH-SY5Y cells displayed a decreased cell activity and increased apoptosis under stress condition. Our study expands the clinical phenotypic spectrum and etiological spectrum of HSPB1 mutation.

Mutations in PRRT2 and 16p11.2 microdeletion including PRRT2 have been identified as the pathogenic cause of paroxysmal kinesigenic dyskinesia (PKD). The objective was to investigate the clinical and genetic features of PKD and to analyze the genotype–phenotype correlation. We recruited PKD patients, recorded clinical manifestations, and performed PRRT2 screening in 150 PKD patients by unified PKD registration forms. Genotype–phenotype correlation analyses were conducted in probands. High-knee-exercise (HKE) tests were applied in one hundred and six patients. Eight PRRT2 mutations were detected, accounting for 22.76% of the probands. Three mutations (c.649dupC, c.649delC, and c.510_513delTCTG) were already reported, while four mutations (c.252_264delCACAGACCTCAGC, c.503_504delCT, c.679C > T, and c.804C > A) were first reported. One heterozygous microdeletion of 606 kb in 16p11.2 was detected in one patient. Compared with non-PRRT2 mutation carriers, the PRRT2 mutation carriers were younger at onset, experienced longer attacks, and tended to present with complicated PKD, combined phenotypes of dystonia and chorea. 57.01% of patients could effectively induce movement disorders through the HKE test. A good response was shown in 81.93% of the patients prescribed with antiepileptic drugs. 13.54% (13/96) had abnormal EEG results. PRRT2 mutations are common in patients with PKD and are significantly associated with an earlier age at onset, longer duration of attacks, a complicated form of PKD, combined phenotypes of dystonia and chorea. Patients with microdeletion of 16p11.2 may have more severe manifestations. The HKE test could contribute to the diagnosis of PKD. Carbamazepine is still the first choice for PKD patients, but individualized treatment should be formulated.

ABSTRACT Background Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one‐third of PKD patients are attributed to proline‐rich transmembrane protein 2 ( PRRT2 ) mutations. Objective We aimed to explore the potential causative gene for PKD. Methods A cohort of 196 PRRT2 ‐negative PKD probands were enrolled for whole‐exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case–control analysis, was applied to identify the candidate genes. Another 325 PRRT2 ‐negative PKD probands were subsequently screened with Sanger sequencing. Results Transmembrane Protein 151 ( TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A ‐related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A ‐positive and PRRT2 ‐positive groups. Conclusions We consolidated mutations in TMEM151A causing PKD with the aid of case–control analysis of a large‐scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A ‐related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A ‐related PKD. © 2021 International Parkinson and Movement Disorder Society

Startle, a basic alerting reaction common to all mammals, is described as a sudden involuntary movement of the body evoked by all kinds of sudden and unexpected stimulus. Startle syndromes are heterogeneous groups of disorders with abnormal and exaggerated responses to startling events, including hyperekplexia, stimulus-induced disorders, and neuropsychiatric startle syndromes. Hyperekplexia can be attributed to a genetic, idiopathic, or symptomatic cause. Excluding secondary factors, hereditary hyperekplexia, a rare neurogenetic disorder with highly genetic heterogeneity, is characterized by neonatal hypertonia, exaggerated startle response provoked by the sudden external stimuli, and followed by a short period of general stiffness. It mainly arises from defects of inhibitory glycinergic neurotransmission. GLRA1 is the major pathogenic gene of hereditary hyperekplexia, along with many other genes involved in the function of glycinergic inhibitory synapses. While about 40% of patients remain negative genetic findings. Clonazepam, which can specifically upgrade the GABARA1 chloride channels, is the main and most effective administration for hereditary hyperekplexia patients. In this review, with the aim at enhancing the recognition and prompting potential treatment for hyperekplexia, we focused on discussing the advances in hereditary hyperekplexia genetics and the expound progress in pathogenic mechanisms of the glycinergic-synapse-related pathway and then followed by a brief overview of other common startle syndromes.

In clinical practice, cerebral small vessel disease (CSVD) and sleep disorders are two common diseases in the elderly, the correlation between the two is not clear yet. Studies have found that different types of sleep disorders have different mechanisms for the occurrence and development of CSVD. Sleep⁃disordered breathing is a vital risk factor for CSVD. However, non⁃breathing⁃related sleep disorders may not only increase the risk of CSVD, but also be an important clinical manifestation of the disease. Based on whether sleep disorders are related to breathing or not, this article reviews the correlation between CSVD and sleep⁃disordered breathing, CSVD and non⁃breathing⁃related sleep disorders, respectively, to improve the understanding of the correlation between the two diseases, and to promote the comprehensive management and intervention research of CSVD.

Objective:To summarize and analyze the clinical data of Chinese patients with colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy, and clarify the phenotypic and genetic characteristics of Chinese patients.Methods:Medical history of patients with CSF1R-related leukoencephalopathy diagnosed from April 1, 2018 to January 31, 2021 in the department of neurology of 22 hospitals in China was collected, and scores of Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment Scale (MoCA), magnetic resonance severity scale were evaluated. Group comparison was performed between male and female patients.Results:A total of 62 patients were included, and the male-female ratio was 1∶1.95. The age of onset was (40.35±8.42) years. Cognitive impairment (82.3%, 51/62) and motor symptoms (77.4%,48/62) were the most common symptoms. The MMSE and MoCA scores were 18.79±7.16 and 13.96±7.23, respectively, and the scores of two scales in male patients (22.06±5.31 and 18.08±5.60) were significantly higher than those in females (15.53±7.41 , t=2.954, P=0.006; 10.15±6.26, t=3.328 , P=0.003). The most common radiographic feature was bilateral asymmetric white matter changes (100.0%), and the magnetic resonance imaging severity scale score was 27.42±11.40, while the white matter lesion score of females (22.94±8.39) was significantly higher than that of males (17.62±8.74 , t=-2.221, P<0.05). A total of 36 CSF1R gene mutations were found in this study, among which c.2381T>C/p.I794T was the hotspot mutation that carried by 17.9% (10/56) of the probands. Conclusions:The core phenotypic characteristics of CSF1R-related leukoencephalopathy in China are progressive motor and cognitive impairment, with bilateral asymmetrical white matter changes. In addition, there exist gender differences clinically, with severer cognitive impairment and imaging changes in female patients. Thirty-six CSF1R gene mutations were found in this study, and c.2381T>C/p. I794T was the hotspot mutation.

CSF1R-related leukoencephalopathy is an adult-onset monogenic microgliopathy causing leukoencephalopathy with high mortality and disabiliity. Here, an human induced pluripotent stem cell (hiPSC) line was generated from peripheral blood mononuclear cells of a 46-year-old female patient carrying heterozygous c.2381 T>C/p.Ile794Thr mutation with episomal plasmids encoding hOCT4, hSOX2, hNANOG, hLIN28, hKLF4 and hMYC. With normal karyotype, pluripotent markers expression and the capability to differentiate into the three germ layers in vivo, the hiPSC line is a promising tool for further study the pathogenic mechanism and potential therapeutic targets of this disease.

Multiple mitochondrial dysfunction syndrome (MMDS) refers to a class of mitochondrial diseases caused by nuclear gene mutations, which usually begins in early infancy and is classically characterized by markedly impaired neurological development, generalized muscle weakness, lactic acidosis, and hyperglycinemia, cavitating leukoencephalopathy, respiratory failure, as well as early fatality resulted from dysfunction of energy metabolism in multiple systems. So far, six types of MMDS have been identified based on different genotypes, which are caused by mutations in NFU1, BOLA3, IBA57, ISCA2, ISCA1 and PMPCB, respectively. IBA57 encodes a protein involved in the mitochondrial Fe/S cluster assembly process, which plays a vital role in the activity of multiple mitochondrial enzymes. Herein, detailed clinical investigation of 2 Chinese patients from two unrelated families were described, both of them showed mildly delay in developmental milestone before disease onset, the initial symptoms were all presented with acute motor and mental retrogression, and brain MRI showed diffused leukoencephalopathy with cavities, dysplasia of corpus callosum and cerebral atrophy. Exome sequencing revealed three IBA57 variants, one shared variant (c.286T>C) has been previously reported, the remaining two (c.189delC and c.580 A>G) are novel. To enhance the understanding of this rare disease, we further made a literature review about the current progress in clinical, genetic and treatment of the disorder. Due to the rapid progress of MMDS, early awareness is crucial to prompt and proper administration, as well as genetic counseling.