Pathogenic variants in several genes encoding components of the mitochondrial respiratory chain have been linked to various clinical phenotypes such as progressive cavitating leukoencephalopathy (PCL). The association between PCL, previously linked to numerous gene mutations in the literature, and the NDUFV2 gene mutations has emerged as a recent and noteworthy discovery. PCL is generally diagnosed in symptomatic patients during the early years of life, mostly in infancy. In a previously healthy 12-year-old Turkish girl, a computed tomography scan taken for minor head trauma incidentally revealed suspicious hypodense areas in the periventricular white matter. Subsequently, a magnetic resonance imaging evaluation was performed. There was no history of motor regression, irritability, or seizures up to the age of 12. The case exhibited normal neurological and cranial nerve examinations. Magnetic resonance imaging detected bilateral periventricular T2/FLAIR hyperintensities with cystic areas suggestive of PCL. Whole-exome sequencing revealed the presence of a homozygous p.R222C missense variant in the NDUFV2 gene. Over a 6-year follow-up period, the patient remained asymptomatic, and there were no discernible changes in the magnetic resonance imaging findings. This case underscores the association between a potentially causal variant at the NDUFV2 locus and PCL. It is worth noting that this novel variation in PCL can not only manifest with symptoms in the infantile period but also remain asymptomatic into adolescence.

Pathogenic variants in the NDUFV1 gene, which codes for complex I of the mitochondrial respiratory chain, have been associated with a variety of clinical phenotypes, including a progressive cavitating leukoencephalopathy. The neuropathology of NDUFV1-associated leukoencephalopathy is not well-described. We present a report of a 24-year-old female with two pathogenic variants in the NDUFV1 gene, together with antemortem skeletal muscle biopsy and postmortem neuropathologic examination. Autopsy neuropathology showed a cavitating leukoencephalopathy with extensive white matter involvement, regions of active demyelination, and sparing of the subcortical U-fibers. Muscle biopsy showed subtle but distinct histologic abnormalities by light microscopy, and ultrastructural analysis demonstrated mitochondrial abnormalities including abnormal subsarcolemmal mitochondrial accumulation, electron-dense inclusions, and enlarged mitochondria with abnormal cristae. Our report is the first comprehensive description of the neuropathology in a patient with compound heterozygous variants in the NDUFV1 gene and progressive cavitating leukoencephalopathy. This case is evidence of pathogenicity of one NDUFV1 variant (c.565 T > C, p.S189P), which has not been previously described as pathogenic. These findings, in combination with the ultrastructural abnormalities in the mitochondria by electron microscopy, support the mitochondrial nature of the pathology. Together, this case highlights the link between mitochondrial abnormalities and demyelinating processes in the central nervous system (CNS).

Progressive cavitating leukoencephalopathy (PCL) is thought to result from mutations in nuclear genes affecting mitochondrial function and energy metabolism. To date, mutations in two subunits of complex I, NDUFS1 and NDUFV1, have been reported to be related to PCL. Patients underwent clinical examinations, brain MRI, skin biopsy and muscle biopsy. Whole-genome or whole-exome sequencing was performed on the index patients from two unrelated families with PCL. The effects of the mutations were examined through complementation of the NDUFV2 mutation by cDNA expression. The common clinical features of the patients in this study were recurring episodes of acute or subacute developmental regression that appeared in the first years of life, followed by gradual remissions and prolonged periods of stability. MRI showed leukoencephalopathy with multiple cavities. Three novel NDUFV2 missense mutations were identified in these families. Complex I deficiency was confirmed in affected individuals' fibroblasts and a muscle biopsy. Functional and structural analyses revealed that these mutations affect the structural stability and function of the NDUFV2 protein, indicating that defective NDUFV2 function is responsible for the phenotypes in these individuals. Here, we report the clinical presentations, neuroimaging and molecular and functional analyses of novel mutations in NDUFV2 in two sibling pairs of two Chinese families presenting with PCL. We hereby expand the knowledge on the clinical phenotypes associated with mutations in NDUFV2 and the genotypes causative for PCL.

Progressive cavitating leukoencephalopathy is a childhood neurodegenerative syndrome characterized by brain MR imaging findings of patchy leukoencephalopathy with cavities and vascular permeability, initially affecting the corpus callosum and centrum semiovale, and eventually coalescing into large cystic regions of white matter. We report a case of progressive cavitating leukoencephalopathy in a 2-year-old female patient presenting as intermittent motor deficits which partially resolved over several months. Whole exome sequencing revealed a homozygous c.264C>G (p.F88L) POLG variant of uncertain pathogenicity which was potentially related to this presentation. Further testing and information are needed to prove the pathogenicity of this variant, but considering other studies which report similar genotypes in association with differing phenotypes, the current case report supports a possible pathogenicity. This case could therefore represent the first reported instance of progressive cavitating leukoencephalopathy in the presence of a POLG mutation.

Objective: To summarize the clinical and genetic characteristics of children with mitochondrial epilepsy. Methods: Clinical data of 62 children who were clinically and genetically diagnosed with mitochondrial epilepsy by the Department of Neurology, Beijing Children's Hospital from October 2011 to December 2018 were analyzed retrospectively, and the control of epilepsy was followed up. T test or χ(2) test were used to analyze the related factors affecting the prognosis of epilepsy between the effective group and the ineffective group. Results: Of the 62 patients, 33 were male and 29 were female. The age of onset was 3.38 (0-12.00) years; for the type of seizures, 68% (42/62) of the patients had focal seizures, generalized or secondary generalized tonic-clonic seizures were seen in 32% (20/62), myoclonic seizures in 23% (14/62), spastic seizures in 7 cases, tonic seizures in 4 cases, absence seizure, atonic seizure and clonic seizure in 1 case each; 16 cases (26%) had status epilepticus, of whom 6 cases had epilepsia partialis continua; 52% (32/62) had 2 or more types of seizures. The clinical phenotypes were mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) in 29 cases, Leigh syndrome (LS) in 11 cases, combined oxidative phosphorylation deficiency in 6 cases, myoclonus epilepsy with ragged-red fibers in 5 cases, Alpers syndrome in 4 cases, pontocerebellar hypoplasia type 6 and mitochondrial DNA depletion syndrome 9 in 2 cases each, mitochondrial complex Ⅰ deficiency nuclear type 20, progressive cavitating leukoencephalopathy, and biotinidase deficiency in 1 case each. Of the 62 cases, 40 cases (65%) had mitochondrial DNA (mtDNA) variations, of which 26 cases had m.3243A>G variants, 6 cases had m.8344A>G variants, and 3 cases had m.8993T>G/C variants, m.3271T>C, m.3481G>A, m.3946G>A, m.13094T>C, m.14487T>C variant was in 1 case each; nuclear DNA (nDNA) variations were identified in 22 cases (35%), of which 7 cases carrying variations in mitochondrial ammonia acyl tRNA synthetase coding gene, mutations in POLG and the gene encoding complex Ⅰ were in 4 cases each, variations in SUCLG1 and SDHA genes were in 2 cases each, and variations in PDHA1, BTD and TRIT1 genes were in 1 case each. Forty-three patients were followed up, and the follow-up time was 20 (3-84) months. According to the follow-up results, the anti-epilepsy treatment was effective in 19 cases (44%) and ineffective in other 24 cases (56%). The onset age of the effective group was 3.42 (0-11.50) years and that of the ineffective group was 0.92 (0-9.50) years. The onset duration of the effective group was 0 (0-7.00) years and that of the ineffective group was 0 (0-4.83) years. There was no significant difference between the effective group and the ineffective group (t=1.662, 0.860; P=0.104, 0.395). In the effective group and the ineffective group, 12 cases and 9 cases used less than 2 kinds of antiepileptic drugs, 7 cases and 15 cases used more than or equal to 2 kinds of antiepileptic drugs, 13 and 15 cases had first epilepsy, 6 and 9 cases had non-first epilepsy, 14 and 11 cases had mtDNA variation, 5 and 13 cases had nDNA variation, respectively. There was no significant difference between the two groups (χ(2)=2.794, 0.164, 3.380; P=0.095, 0.686, 0.066). Conclusions: The types of seizures with mitochondrial epilepsy in children varied, with focal motor seizures being the most common, followed by generalized or secondary generalized tonic-clonic seizures. Most children have more than two types of seizures. MELAS is the most common clinical phenotype, followed by LS; mtDNA variation is the dominant gene variation, of which m.3243A>G variation is the most common hotspot variation, followed by gene variation encoding mitochondrial aminoacyl tRNA synthase. 目的： 总结儿童线粒体疾病相关癫痫的临床特点和遗传特征。 方法： 对2011年10月至2018年12月在北京儿童医院神经内科就诊，基因确诊的62例线粒体疾病相关癫痫患儿的临床资料进行回顾性总结，对癫痫控制情况进行随访，按治疗结果分为有效组和无效组，应用t检验或χ(2)检验进行组间比较。 结果： 62例中男33例、女29例，发病年龄为3.38（0~12.00）岁；癫痫发作类型以局灶性运动发作最多（68%，42例），其余依次为全面性或继发性全面性强直阵挛发作（32%，20例），肌阵挛发作（23%，14例），痉挛发作（7例），强直发作（4例），失神、失张力、阵挛发作各1例；癫痫持续状态16例（26%），其中持续性部分性癫痫6例；52%（32例）的患儿有2种或2种以上发作类型。线粒体脑肌病伴高乳酸血症和卒中样发作（MELAS）29例，Leigh综合征（LS）11例，联合氧化磷酸化缺乏症6例，肌阵挛癫痫伴破碎红纤维5例，Alpers综合征4例，脑桥小脑发育不良6型、线粒体缺失综合征9型各2例，ACAD9基因缺陷致线粒体复合物Ⅰ缺乏症、进行性空泡脑白质病、生物素酶缺乏症各1例。线粒体DNA（mtDNA）变异40例（65%)，其中26例为m.3243A>G变异，6例为m.8344A>G变异，3例为m.8993T>G/C变异，m.3271T>C、m.3481G>A、m.3946G>A、m.13094T>C、m.14487T>C变异各1例；核DNA(nDNA)变异22例（35%)，其中编码线粒体氨酰tRNA合成酶的基因7例，POLG基因和编码复合物Ⅰ的基因各4例，SUCLG1、SDHA基因各2例，PDHA1、BTD、TRIT1基因各1例。随访43例，随访时间为20（3~84）个月，其中癫痫治疗有效组19例（44%），无效组24例（56%）。癫痫治疗有效组与无效组起病年龄、发作时病程差异无统计学意义[3.42（0~11.50）岁比0.92（0~9.50）岁，0（0~7.00）年比0（0~4.83）年，t=1.662、0.860，P=0.104、0.395]。有效组与无效组使用抗癫痫药数量<2种的例数分别为12例和9例，≥2种分别为7例和15例、癫痫首发例数分别为13例和15例、非首发分别为6例和9例、mtDNA变异例数分别为14例和11例，nDNA变异例数分别为5例和13例，差异均无统计学意义（χ(2)=2.794、0.164、3.380，P=0.095、0.686、0.066）。 结论： 儿童线粒体疾病相关癫痫发作类型多样，以局灶性运动发作最常见，其次为全面性或继发性全面性强直阵挛发作，多数患儿存在2种以上发作类型。MELAS是最常见的临床表型，其次为LS；基因变异以mtDNA变异为主，其中m.3243A>G变异是最常见的热点变异，其次为编码线粒体氨酰tRNA合成酶的基因变异。.