更新于：2024-11-01

Multiple Mitochondrial Dysfunctions Syndrome

多发性线粒体功能障碍综合征

更新于：2024-11-01

基本信息

别名

MMDS - multiple mitochondrial dysfunctions syndrome、Multiple Mitochondrial Dysfunctions Syndrome、Multiple mitochondrial dysfunctions syndrome

+ [2]

简介

Syndrome caused by impairment of mitochondria. Whilst mitochondrial disorders may be caused by impairment of a single stage of energy production, individuals with multiple mitochondrial dysfunctions syndrome have reduced function of more than one stage. Symptoms begin in early life and affected individuals usually do not live past infancy. Symptoms include encephalopathy, hypotonia, seizures and psychomotor delay. Most affected babies have lactic acidosis that can be life threatening.

关联

项与多发性线粒体功能障碍综合征相关的药物

MiD49

靶点

DNM1L

作用机制

DNM1L抑制剂

在研机构

Mitobridge, Inc.

原研机构

Mitobridge, Inc.

在研适应症

多发性线粒体功能障碍综合征

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与多发性线粒体功能障碍综合征相关的临床试验

NCT06080581 / RecruitingN/AIIT

Mitochondrial Derangements Driving Muscle Insulin Resistance in Humans

The overarching aim of this observational study is to characterize muscle mitochondrial defects in individuals harboring pathogenic mitochondrial DNA (mtDNA) mutations associated with an insulin-resistant phenotype.
In a case-control design, individuals with pathogenic mtDNA mutations will be compared to controls matched for sex, age, and physical activity level. Participants will attend a screening visit and two experimental trials including:
An oral glucose tolerance test
A hyperinsulinemic-euglycemic clamp combined with measurements of femoral artery blood flow and arteriovenous difference of glucose
Muscle biopsy samples

开始日期2023-10-20

申办/合作机构

Rigshospitalet

[+1]

NCT01439854 / CompletedN/AIIT

Regulation of Hepatic and Peripheral Glucose Metabolism: Protocol IVA. Effect of Plasma Glucose Reduction by Selective SLGT2 Inhibition on Mitochondrial Dysfunction and Impaired Insulin Signaling/Sensitivity in T2DM

The purpose of this study is to examine the effect of the chronic treatment of type 2 diabetes (T2DM) with dapagliflozin on: (1) mitochondrial gene function/expression and insulin signaling/action and (2) oral glucose tolerance and beta cell function. Dapagliflozin is a potent, highly specific inhibitor of renal glucose transport [SGLT2].

开始日期2011-03-01

申办/合作机构

University of Texas Health Science Center At San Antonio

[+1]

100 项与多发性线粒体功能障碍综合征相关的临床结果

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100 项与多发性线粒体功能障碍综合征相关的转化医学

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0 项与多发性线粒体功能障碍综合征相关的专利（医药）

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103

项与多发性线粒体功能障碍综合征相关的文献（医药）

2024-09-01·European Journal of Pharmacology

Liraglutide alleviated alpha-pyrrolidinovalerophenone (α-PVP) induced cognitive deficits in rats by modifying brain mitochondrial impairment

Article

作者: Behmadi, Homayoon ; Ghahremani, Mohammad Hossein ; Sabzevari, Omid ; Sharifzadeh, Mohammad ; Baeeri, Maryam ; Gholami, Mahdi ; Ghahremanian, Amirhosein ; Hassani, Shokoufeh ; Foroumadi, Alireza ; Seyfi, Soheila ; Noruzi, Marzieh ; Taghizadeh, Ghorban ; Pourahmad, Jalal

The use of NPS compounds is increasing, and impairment in spatial learning and memory is a growing concern. Alpha-pyrrolidinovalerophenone (α-PVP) consumption, as a commonly used NPS, can impair spatial learning and memory via the brain mitochondrial dysfunction mechanism. Liraglutide isone of the most well-known Glucagon-Like Peptide 1 (GLP-1) agonists that is used as an anti-diabetic and anti-obesity drug. According to current research, Liraglutide likely ameliorates cognitive impairment in neurodegenerative conditions and substance use disorders. Hence, the purpose of this study is examining the effect of Liraglutide on α-PVP-induced spatial learning and memory problems due to brain mitochondrial dysfunction. Wistar rats (8 in each group) received α-PVP (20 mg/kg/d for 10 consecutive days, intraperitoneally (I.P.)). Then, Liraglutide was administered at 47 and 94 μg/kg/d, I.P., for 4 weeks following the α-PVP administration. The Morris Water Maze (MWM) task evaluated spatial learning and memory 24 h after Liraglutide treatment. Bedside, brain mitochondrial activity parameters, including reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), cytochrome c release, mitochondrial outer membrane damage and swelling, and brain ADP/ATP ratio, were studied. Our results showed that Liraglutide ameliorated α-PVP-induced spatial learning and memory impairments through alleviating brain mitochondrial dysfunction (which is indicated by increasing ROS formation, collapsed MMP, mitochondrial outer membrane damage, cytochrome c release, mitochondrial swelling, and increased brain ADP/ATP ratio). This study could be used as a starting point for future studies about the possible role of Liraglutide in ameliorating mitochondrial dysfunction leading to substance use disorder- induced cognitive impairment.

2024-08-14·RETINAL Cases & Brief Reports

Long Term Follow Up of a Family with A3243G Mitochondrial Syndrome

Article

作者: Feo, Alessandro ; Voichanski, Shilo ; Abraham, Néda ; Fossataro, Claudia ; Lemon, Jack D. ; Sarraf, David

Purpose:To describe the clinical and multimodal imaging (MMI) features of a family (proband, sister and mother) with A3243G mitochondrial retinopathy and long-term follow up.Methods:Medical and imaging records were retrospectively evaluated. Multimodal imaging included ultra-widefield color fundus photography, fundus autofluorescence, and spectral-domain optical coherence tomography. Long-term MMI follow up ranged from 6 to 15 years and was available for each member.Results:The proband (Case 1) exhibited rapidly progressive bilateral macular atrophy, corneal endothelial polymegathism, and an A3243G mutation in the mitochondrial DNA. The proband also endorsed a history of early-onset myocardial infarction (MI) ten years prior at the age of 42. The proband’s sister (Case 2) only exhibited unilateral focal macular atrophy but admitted to a history of severe multiorgan systemic disease, including multiple sclerosis and major depression disorder. The proband’s mother (Case 3), the only one with diabetes mellitus and hearing loss, originally presented with branch retinal vein occlusion in the right eye and pattern dystrophy in the left eye which evolved to geographic atrophy, OD > OS, 15 years later.Conclusion:A3243G mitochondrial syndrome can exhibit heterogenous ocular and systemic features, even within members of the same family. The development of the characteristic maculopathy with early-onset MI warrants genetic testing. Early cardiac and systemic screening may be recommended in individuals with characteristic retinal findings and genetic confirmation.

2024-06-01·Molecular Genetics & Genomic Medicine

Clinical characteristics of a case of multiple mitochondrial dysfunction syndrome 3

Article

作者: Song, Qijun ; Ma, Kai ; Peng, Jiaxi ; Gao, Yuye ; Xu, Xiao ; Sun, Yan ; Xu, Hai ; Chen, Chaojin

AbstractObjectiveTo further comprehend the phenotype of multiple mitochondrial dysfunction syndrome type 3 (MMDS3:OMIM#615330) caused by IBA57 mutation. We present a case involving a patient who experienced acute neurological regression, and the literature was reviewed.MethodsClinical data and laboratory test results were collected; early language and development progress were tested; and genetic testing was performed. Bioinformatics analysis was performed using Mutation Taster and PolyPhen‐2, and the literature in databases such as PubMed and CNKI was searched using MMDS3 and IBA57 as keywords.ResultsThe child, aged 1 year and 2 months, had motor decline, unable to sit alone, limited right arm movement, hypotonia, hyperreflexia of both knees, and Babinski sign positivity on the right side, accompanied by nystagmus. Blood lactate levels were elevated at 2.50 mmol/L. Brain MR indicated slight swelling in the bilateral frontoparietal and occipital white matter areas and the corpus callosum, with extensive abnormal signals on T1 and T2 images, along with the semioval center and occipital lobes bilaterally. The multiple abnormal signals in the brain suggested metabolic leukoencephalopathy. Whole‐exome sequencing analysis revealed that the child had two heterozygous mutations in the IBA57 gene, c.286T>C (p.Y96H) (likely pathogenic, LP) and c.992T>A (p.L331Q) (variant of uncertain significance, VUS). As of March 2023, a literature search showed that 56 cases of MMDS3 caused by IBA57 mutation had been reported worldwide, with 35 cases reported in China. Among the 35 IBA57 mutations listed in the HGMD database, there were 28 missense or nonsense mutations, 2 splicing mutations, 2 small deletions, and 3 small insertions.ConclusionMMDS3 predominantly manifests in infancy, with primary symptoms including feeding difficulties, neurological functional regression, muscle weakness, with severe cases potentially leading to mortality. Diagnosis is supported by elevated lactate levels, multisystem impairment (including auditory and visual systems), and distinctive MRI findings. Whole‐exome sequencing is crucial for diagnosis. Currently, cocktail therapy offers symptomatic relief.

项与多发性线粒体功能障碍综合征相关的新闻（医药）

2022-01-25

·药明康德

改善肌肉健康、抗疲劳！临床试验发现这种补充剂的抗衰老潜力

目前全球≥60岁的人口已超过10亿，随着老龄化进程加速，预计2050年全球将有1/4成人超过60岁。寻找抗衰老疗法、促进老龄健康正在逐渐成为医学科学的研究热点。延缓与衰老相关的机体功能减弱便是目标之一。衰老与肌肉质量和力量的逐渐衰退有关，进而导致躯体功能下降。近日，《美国医学会杂志》子刊JAMA Network Open发表一项随机临床试验显示，对于老年人或因病活动困难的人群，尿石素A（Urolithin A）补充剂可能有助于改善肌肉健康状况，进行所需锻炼。试验数据表明，补充尿石素A在研究人群中安全且耐受性良好，尽管对6分钟步行距离和手部肌肉最大ATP产量的改善不显著，但连续4个月补充尿石素A对肌肉耐力和细胞健康的生物标志物有益。截图来源：JAMA Network Open 研究主要作者，华盛顿大学医学院David Marcinek教授表示，“对于慢性病患者，以及希望在将来保持身体活跃的人群，这一发现都有潜在影响。只要让他们达到可以锻炼的程度，无论是在街区散步，还是爬楼梯，都可能会帮助一个人改善健康。” 1、线粒体功能与尿石素A 线粒体是为细胞功能提供能量的“发电厂”。在健康人体中，通过选择性自噬过程，细胞可以消除其中功能失调的线粒体，但随着年龄的增长，这种能力逐渐下降，导致线粒体质量下降。有研究证据表明，线粒体功能障碍在年龄相关疾病中起到重要作用。比如，在骨骼肌中，线粒体效率和线粒体产生能量“通货”ATP（三磷酸腺苷）的能力下降，与身体机能下降和疲劳增加有关。因此，恢复线粒体自噬水平，被视为改善线粒体功能、改善肌肉健康的潜在途径。尿石素A补充剂就是这样一种有潜力的在研疗法。事实上，尿石素A原本就是人体对饮食的代谢产物，富含多酚的天然食物（如石榴、浆果和坚果等）经肠道微生物组代谢后就会产生，但由于饮食、年龄、遗传和疾病会影响肠道微生物组的组成，不同人体内代谢产生尿石素A的水平也各有不同。尿石素A已在动物实验中被证明可刺激老年动物的线粒体自噬、改善肌肉功能，在初步的人体临床试验中也显示出在老年人中安全、生物可利用并能够诱导线粒体基因表达。在此基础上，这项研究旨在进一步验证长期补充尿石素A是否能够改善老年人线粒体功能和肌肉功能。 2、随机对照试验：部分指标确有改善具体而言，这是一项双盲、安慰剂对照随机临床试验，共招募了66名65-90岁成人。这些参与者平均71.7岁，主要是女性（75.8%）。加入研究前，他们都被证实线粒体的ATP生产能力均处于平均水平或低于标准。参与者随机分组接受安慰剂或尿石素A，每日补充1000 mg，为期4个月。研究团队评估口服尿石素A是否改善了6分钟步行距离（主要结局）、手和腿部的肌肉耐力，以及与线粒体和细胞健康相关的生物标志物。在研究基线、2个月和4个月时分别进行相关评估。 ▲在试验中，参与者被建议反复抬起脚趾来抵抗阻力，以锻炼胫骨前肌。（图片来源：华盛顿大学医学院David Marcinek教授）结果显示，无论是肌肉功能还是代谢相关的生物标志物，尿石素A补充剂确实改善了部分指标。从肌肉功能来看，与安慰剂组相比，尿石素A组的手部和腿部的两处肌肉耐力指标得到改善。这体现在治疗2个月时，特定部位肌肉在达到疲劳前肌肉收缩次数的增加：尿石素A组：手部第一背侧骨间肌（FDI，拇指和食指之间）收缩增加95.3次；腿部胫骨前肌（TA）收缩增加41.4次；安慰剂组：手部FDI收缩增加11.6次，腿部TA收缩增加5.7次。在4个月时，尿石素A组的耐力持续改善，但安慰剂组也有所增加，两组间差异不显著。 4个月期间，两组的6分钟步行距离都显著改善，但尿石素A组（增加60.8米）和安慰剂组（增加42.5米）相比没有显著差异。 ▲尿石素A补充剂对6分钟步行距离（A-B）、手部肌肉ATP最大产量（C）和肌肉耐力（D-I）的影响。（图片来源：参考资料[1]）从生物标志物来看，与安慰剂相比，尿石素A在4个月时降低了酰基肉碱、神经酰胺（反映线粒体健康）和C反应蛋白（CRP，反映炎症水平）的血浆水平。论文指出：酰基肉碱的降低，提示线粒体代谢效率有所提高。神经酰胺水平与炎症状态、年龄相关疾病（比如阿尔茨海默病和糖尿病）的风险有关。 CRP水平降低则提示炎症减少。不过，在任何一组中，4个月期间手部（FDI）和腿部（TA）肌肉的ATP最大产量（通过磁共振波谱法测定）都没有显著变化。两组之间的不良事件无统计学差异。 3、初步发现“令人兴奋” “即使我们没有观察到补充剂对全身功能的显著影响，比如对6分钟步行测试和 ATP 产生的大幅改善，这些结果仍然令人兴奋。”Marcinek教授表示，“因为即使是短期服用补充剂，就确实提高肌肉耐力，改善了整体新陈代谢。在没有运动的情况下，参与者的抗疲劳能力会更好。” 论文总结指出，这些数据提示，尿石素A有潜力缓解与年龄相关的肌肉衰退，需要进一步研究来证实这些发现。参考资料 [1] Liu S, D’Amico D, Shankland E, et al., (2022). Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial. JAMA Netw Open, doi:10.1001/jamanetworkopen.2021.44279 [2] Supplement appears to boost muscle, mitochondria health. Retrieved January 24, 2022 from https://medicalxpress.com/news/2022-01-supplement-boost-muscle-mitochondria-health.html 内容来源于网络，如有侵权，请联系删除，谢谢。