更新于：2024-11-01

Malonic Aciduria

丙二酸尿症

更新于：2024-11-01

基本信息

别名

Deficiency of malonyl-CoA decarboxylase、Deficiency of malonyl-coenzyme A decarboxylase、Deficiency of malonyl-coenzyme A decarboxylase (disorder)

+ [9]

简介

A rare metabolic disorder caused by deficiency of malonyl-CoA decarboxylase (MCD). This condition usually presents in early childhood and the manifestations are variable. The disease is caused by mutations in the malonyl-CoA decarboxylase gene (MLYCD, chromosome 16q24) and is inherited as an autosomal recessive trait. The MCD enzyme is involved in the degradation of malonyl-CoA and it appears that inhibition of fatty acid synthesis as a result of malonyl-CoA accumulation is responsible for at least some of the clinical manifestations of the disorder.

关联

项与丙二酸尿症相关的药物

VB-1197

靶点-

作用机制-

在研机构

Comet Therapeutics, Inc.初创企业

原研机构

Comet Therapeutics, Inc.初创企业

在研适应症

甲基丙二酸血症

非在研适应症

有机酸血症 [+2]

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

项与丙二酸尿症相关的临床试验

NCT05910151 / RecruitingN/AIIT

Introduction of Tandem Mass Spectrometry (MS/MS) Technology in the Program of Selective Screening of Hereditary Metabolic Diseases in Kazakhstan

Inborn errors of metabolism (IEM) are not have specific clinical signs, they masquerade as other diseases, and are difficult to diagnose using only clinical manifestations or routine laboratory tests. IEM most commonly manifest in early infancy and childhood. Despite the fact that most IEM are rare in the population, they occupy one of the first places in the structure of childhood pathology, early infant mortality and disability. IEM often remains undiagnosed, while timely diagnosis and timely treatment started can prevent severe systemic damage leading to death and disability. The appointment of a special treatment (diet therapy, cofactors, enzyme replacement therapy) prevents or significantly inhibits the development of the pathological process, especially if the diagnosis is made in the early stages of the disease. To start pathogenetic treatment as early as possible, it is necessary to diagnose IEM as accurately and as early as possible.
Among the diseases included in mass screening programs IEM are especially important due to the development of disability and early mortality in the absence of timely diagnosis and treatment, as well as a high risk of recurrence in burdened families. In this connection, the main goals of mass screening - the prevention of disability in children and the reduction of early infant mortality - dictate the need to introduce modern technologies for preclinical diagnosis of IEM.
Based on the results of the study, it is planned to scientifically substantiate the need for the introduction of selective screening of children for hereditary metabolic diseases using the technology of tandem mass spectrometry in the Republic of Kazakhstan for timely diagnosis, therapy of IEM and prevention of disability. The introduction of a selective newborn screening program for IEM should always be preceded by a study aimed at studying the prevalence of the disease in a certain region, determining regional reference values of the studied metabolites. Local incidence and outcome data can be used to persuade health officials to prioritize screening in health care spending.
The main scientific question and hypothesis of the project is whether it is necessary to introduce tandem mass spectrometry technology in the neonatal screening program for IEM.

开始日期2022-10-03

申办/合作机构-

NCT05687474 / RecruitingN/AIIT

Universal Genomic Newborn Screening in the Wallonia-Brussels Federation: Baby Detect

Newborn screening (NBS) is a global initiative of systematic testing at birth to identify babies with pre-defined severe but treatable conditions. With a simple blood test, rare genetic conditions can be easily detected, and the early start of transformative treatment will help avoid severe disabilities and increase the quality of life.
Baby Detect Project is an innovative NBS program using a panel of target sequencing that aims to identify 126 treatable severe early onset genetic diseases at birth caused by 361 genes. The list of diseases has been established in close collaboration with the Paediatricians of the University Hospital in Liege. The investigators use dedicated dried blood spots collected between the first day and 28 days of life of babies, after a consent sign by parents.

开始日期2022-09-01

申办/合作机构

Centre Hospitalier Universitaire de Liege

[+5]

ChiCTR2100047701 / CompletedN/AIIT

A retrospective study on the clinical features and gene mutations of neonatal malonic aciduria

开始日期2021-07-01

申办/合作机构-

100 项与丙二酸尿症相关的临床结果

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100 项与丙二酸尿症相关的转化医学

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0 项与丙二酸尿症相关的专利（医药）

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项与丙二酸尿症相关的文献（医药）

2024-10-01·Brain and Development

Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency

Article

作者: Hao, L L ; Yang, S H ; Chen, T ; Zhang, H W ; Liu, F ; Zhang, J M ; Ji, W J ; Qiu, W J ; Zhang, Y ; Gu, X F ; Han, L S

BACKGROUNDMalonyl-CoA decarboxylase (MLYCD) deficiency, also known as malonic aciduria (MAD), is a rare autosomal recessive inherited metabolic defect. In this study, we aimed to investigate the clinical and molecular features of five patients with MAD in order to increase clinicians' awareness of the disease.METHODSSanger sequencing was used to detect and genetically analyze the MLYCD variations in the preexisting patients and their parents.RESULTSFive patients with MAD (5 months to 9.6 years old; two males and three females) rarely exhibited metabolic decompensation episodes or seizures. All patients exhibited varying degrees of developmental delay and hypotonia. Our study expands the spectrum of variants of the MLYCD gene. MLYCD gene variations were detected in all five patients, and five new variants were identified: c.60delG (p.Arg21Glyfs*52), c.928C > T (p.Arg310*), c.1293G > T (p.Trp431Cys), c.721T > C (p.Ser241Pro), and Exons 4-5 deletion. Additionally, there is no correlation between various genotypes and phenotypes.CONCLUSIONA high-medium-chain triglyceride and low-long-chain triglyceride diet supplemented with L-carnitine was effective in most patients and may improve cardiomyopathy and muscle weakness. Newborn screening may aid in the early diagnosis, treatment, and prognosis of this rare disorder.

2023-12-01·European Journal of Medical Genetics

Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review

Review

作者: Mohiddin, Saidi ; Ferdinandusse, Sacha ; Syrris, Petros ; Elliott, Perry Mark ; Bakalakos, Athanasios ; Murphy, Elaine ; Monda, Emanuele

BACKGROUNDMalonyl-CoA decarboxylase deficiency (MLYCDD) is an ultra-rare inherited metabolic disorder, characterized by multi-organ involvement manifesting during the first few months of life. Our aim was to describe the clinical, biochemical, and genetic characteristics of patients with later-onset MLYCDD.METHODSClinical and biochemical characteristics of two patients aged 48 and 29 years with a confirmed molecular diagnosis of MLYCDD were examined. A systematic review of published studies describing the characteristics of cardiovascular involvement of patients with MLYCDD was performed.RESULTSTwo patients diagnosed with MLYCDD during adulthood were identified. The first presented with hypertrophic cardiomyopathy and ventricular pre-excitation and the second with dilated cardiomyopathy (DCM) and mild-to-moderate left ventricular (LV) systolic dysfunction. No other clinical manifestation typical of MLYCDD was observed. Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity. During follow-up, no deterioration of LV systolic function was observed. The systematic review identified 33 individuals with a genetic diagnosis of MLYCDD (median age 6 months [IQR 1-12], 22 males [67%]). Cardiovascular involvement was observed in 64% of cases, with DCM the most common phenotype. A modified diet combined with levocarnitine supplementation resulted in the improvement of LV systolic function in most cases. After a median follow-up of 8 months, 3 patients died (two heart failure-related and one arrhythmic death).CONCLUSIONSFor the first time this study describes a later-onset phenotype of MLYCDD patients, characterized by single-organ involvement, mildly reduced enzyme activity, and a benign clinical course.

2023-11-01·Journal of Inherited Metabolic Disease

Collaborative evaluation study on 18 candidate diseases for newborn screening in 1.77 million samples

Article

作者: Odenwald, Birgit ; Janzen, Nils ; Hennermann, Julia B ; Lotz-Havla, Amelie S ; Grünert, Sarah C ; Krämer, Johannes ; Freisinger, Peter ; Weiss, Katharina J ; Thimm, Eva ; Okun, Jürgen G ; Garbade, Sven F ; Mütze, Ulrike ; Hoffmann, Georg F ; Hammersen, Johanna ; Kölker, Stefan ; Gramer, Gwendolyn ; Das, Anibh M ; Steuerwald, Ulrike ; Nennstiel, Uta ; Fang-Hoffmann, Junmin ; Röschinger, Wulf ; Schuhmann, Elfriede ; Weigel, Corina ; Illsinger, Sabine ; Maier, Esther M

AbstractAnalytical and therapeutic innovations led to a continuous but variable extension of newborn screening (NBS) programmes worldwide. Every extension requires a careful evaluation of feasibility, diagnostic (process) quality and possible health benefits to balance benefits and limitations. The aim of this study was to evaluate the suitability of 18 candidate diseases for inclusion in NBS programmes. Utilising tandem mass spectrometry as well as establishing specific diagnostic pathways with second‐tier analyses, three German NBS centres designed and conducted an evaluation study for 18 candidate diseases, all of them inherited metabolic diseases. In total, 1 777 264 NBS samples were analysed. Overall, 441 positive NBS results were reported resulting in 68 confirmed diagnoses, 373 false‐positive cases and an estimated cumulative prevalence of approximately 1 in 26 000 newborns. The positive predictive value ranged from 0.07 (carnitine transporter defect) to 0.67 (HMG‐CoA lyase deficiency). Three individuals were missed and 14 individuals (21%) developed symptoms before the positive NBS results were reported. The majority of tested candidate diseases were found to be suitable for inclusion in NBS programmes, while multiple acyl‐CoA dehydrogenase deficiency, isolated methylmalonic acidurias, propionic acidemia and malonyl‐CoA decarboxylase deficiency showed some and carnitine transporter defect significant limitations. Evaluation studies are an important tool to assess the potential benefits and limitations of expanding NBS programmes to new diseases.

项与丙二酸尿症相关的新闻（医药）

2023-05-18

·生物制品圈

基于 mRNA 的药物的生物学作用

疫苗疫苗是公共卫生不可或缺的工具，可防止许多人丧生，并在医学中占有重要地位。然而，它们的功效和安全性要求非常严格，因为它们通常用于大量健康人群。早期使用减毒或灭活微生物的方法非常有效，但安全性问题存在争议，生产、纯化和质量控制既麻烦又昂贵。蛋白质疫苗缺点较少，但需要免疫佐剂，这可能涉及唤醒休眠的自身免疫过程。相比之下，基于 DNA 的疫苗受到细胞和核进入无效以及需要额外设备来支持这一过程的困扰。最近通过将DNA 包装到无害病毒中解决了这一挑战，但它仍然可以引起相关的不利影响。无论如何，几乎所有这些方法都需要活的或结构完整的有机体来生产，这使得开发速度更慢、成本更高。在这种背景下，使用 mRNA 的概念似乎是疫苗开发中的“圣杯”（图 4A）。只需在对微生物遗传物质进行测序后，通过简单地模拟受体结合域 (RBD) 的核苷酸序列，然后在机器人工厂中合成生产它们，就可以在几天内设计出 mRNA 疫苗。因此，从微生物发现到临床级候选疫苗的时间跨度极短。整个过程的简单性和速度还允许对初始疫苗进行快速反应和轻松调整，以应对微生物的遗传漂移和变异株的形成。也没有异源材料污染的风险，这让公众放心。这些特征似乎有利于 mRNA 作为理想的疫苗解决方案。图 4 由于引入了基于 mRNA 的技术，医学和科学领域最近取得了大量新进展。当 COVID-19 大流行出现时，mRNA 疫苗已经针对先前的威胁进行了尝试。第一批 mRNA 疫苗在肿瘤治疗领域初具规模。几年后，它们开始用于治疗传染病，尤其是流感。然后，mRNA 疫苗的临床前疗效被证明可以抵抗狂犬病。随后，单剂 mRNA 疫苗足以诱导小鼠和猴子产生针对寨卡病毒的持久保护。然而，这种病毒从未走向全球并成为大流行病，因此进一步开发疫苗的工作并没有实现。它还被证明在另一个潜在全球威胁的豚鼠模型中有效：埃博拉病毒。甚至在新冠病毒大流行之前，就提出了用 mRNA 疫苗来对抗疫情。mRNA 疫苗的其它临床前目标包括巨细胞病毒、蜱传播黄病毒、人类免疫缺陷病毒 (HIV)、登革热病毒、克里米亚-刚果出血热病毒 (CCHFV)、单纯疱疹病毒 2 (HSV-2)、尼帕病毒和呼吸道合胞病毒 (RSV)。mRNA 疫苗卓越的安全性甚至促使科学界提出将其用于治疗过敏症。因此，针对新型SARS-CoV-2设计 mRNA 疫苗也就不足为奇了。在小鼠中，用核苷修饰的 mRNA 疫苗进行单次免疫可引发针对 SARS-CoV-2的强烈细胞和体液免疫反应。由于上述优点，已发现 mRNA 疫苗不仅有效，而且开发速度最快并首先获得紧急使用授权。它们是真正的明星，它们对在许多地区“驯服” COVID-19 大流行产生了巨大影响。蛋白质补充由于蛋白质是所有生物体细胞内和细胞外区室的关键分子，它们的丢失或异常通常会导致病理后果。因此，补充蛋白质是一种有效的治疗方法。尽管有多种方法来递送蛋白质，例如基于病毒的基因替代或直接蛋白质递送，但行业对使用 mRNA 来实现这一目标的兴趣也越来越大（图 4B）。这种方法有一个特定的优势。与 DNA 不同，mRNA 不与基因组整合，避免了许多安全问题。在物理化学上，所有的 mRNA 分子都相对相似，因此相同的配方可能服务于许多基因。然而，蛋白质特性的巨大差异导致每种蛋白质的配方和递送都需要单独开发。早在近 30 年前，基于 mRNA 的蛋白质递送在动物模型中的治疗效果就已经得到证实。与疫苗相比，制备用于补充蛋白质的 mRNA 要求更高。尽管在疫苗应用中，诱导宿主免疫反应是受欢迎的，但最重要的是防止为蛋白质补充而递送的 mRNA 的免疫原性，特别是因为蛋白质补充可能会在整个生命周期内给药，而免疫原性材料可能会导致慢性炎症。肺部疾病特别引人注目，因为 mRNA 有可能通过吸入轻松地局部给药。沿着这条线，已经在哮喘小鼠模型中证明，吸入Foxp3 的 mRNA 可通过增加肺中的调节性 T (Treg) 细胞，降低肺部炎症。Foxp3 mRNA 的局部递送可以避免 Treg 细胞的全身激活。肺毛细血管中的无孔内皮细胞是将 mRNA系统性递送到肺部时的另一个障碍。mRNA 介导的 Toll 样受体基因补充是在哮喘小鼠模型中研究的另一种策略。CFTR 基因的 mRNA 吸入在单基因肺部疾病的小动物模型中证明是有效的，如囊性纤维化。Translate Bio（最近被赛诺菲收购）目前正在进行临床试验，用含有CFTR基因的mRNA组成的药物治疗囊性纤维化。最近还证实了基于 mRNA 的治疗药物在另一种单基因疾病（α1-抗胰蛋白酶缺乏症）的动物模型中的积极作用。代谢疾病是另一组可能通过编码缺失或异常酶的 mRNA 治愈的疾病。甲基丙二酸尿症可由编码甲基丙二酰辅酶 A (CoA) 变位酶的 mRNA 解决。mRNA 也已被尝试作为再生医学中的药物，以改善心脏和皮肤的血管再生以及肿瘤免疫治疗。基于mRNA的细胞工程干细胞和免疫细胞疗法正在成为医学研究的一个重要领域。细胞工程经常用于提高治疗潜力。通过施用 mRNA 可以实现多种细胞功能。该技术对于瞬时细胞修饰至关重要（图 4C）。基于 mRNA 的工程可以很好地解决细胞运输和迁移问题。事实上，已经表明，在给予编码mRNA 后，粘附分子整合素 α4 (ITGA4) 可以在间充质干细胞 (MSC) 的表面上表达，在体外获得它们的功能，而在体内的渗出过程是独立的。通过施用编码 CXCR4.127 的 mRNA 在体外也增加了 MSC 迁移。同样的策略也能够增强自然杀伤细胞的归巢。活性免疫分子的表达是基于 mRNA 的细胞工程的另一大领域。将嵌合抗原受体 (CAR) 或 T 细胞受体 (TCR) 的 mRNA施用于淋巴细胞可产生有效的免疫细胞。短暂的性质可以通过多次输注来克服，而短期表达可以防止由于免疫细胞自身攻击而导致的严重并发症。基于 mRNA 的树突细胞编程为淋巴细胞提供相关指令是进入临床试验的另一种有吸引力的治疗策略。基于 mRNA 的技术也非常适合基因组编辑。编码基因组整合酶转座酶的 mRNA 可以与转座子共同注射以递送DNA 有效载荷。最近通过 CRISPR 技术为转座酶增加了位点特异性，最终允许使用大量 DNA 有效载荷精确有效地编辑基因组。Cas9 酶也可以与相关的向导 RNA (gRNA) 序列一起以 mRNA 的形式递送给细胞。mRNA 也是在体细胞中诱导多能性的可行策略。mRNA包装和递送mRNA是一种脆弱的带负电荷的分子；因此，适当的包装和递送系统对于充分发挥其潜力至关重要。有许多方法可以完成这项任务。聚乙二醇化脂质纳米颗粒 (LNP) 目前是 mRNA 包封的主流，主要是因为它们成功地提供了 COVID-19 疫苗。然而，除了 LNP，还有许多其它方式来递送 mRNA，例如聚合物、无机结构、蛋白质、水凝胶等。基于脂质的载体具有很长的历史。脂质体已用于递送多种治疗性化合物。因此，它们是核酸递送的首选。然而，它们最终在体内小干扰 RNA (siRNA) 递送中失败，成为了进一步开发其它载体的动力，从而产生了 LNP。因此，mRNA 治疗药物的后起之秀立即拥有了强大的载体，能够有效地体内递送有效载荷而发挥作用。磷灰石等无机成分已被证明可以提高 mRNA 的功效。硅纳米颗粒是促进核酸递送的另一种选择，被认为是 COVID-19的新兴疫苗递送系统。硅是一种相对低成本且易于规模放大的安全mRNA递送解决方案，享有广泛的功能化产品组合以及非常令人鼓舞的储存特性。最近，具有小尺寸和大孔的树枝状介孔二氧化硅纳米颗粒的室温合成增强了 mRNA 递送性能。聚合物是一大类天然和合成化合物。它们的特点是在核酸结合和释放以及相对稳定性方面的高度通用性。聚乙烯亚胺-硬脂酸 (PSA) 等阳离子聚合物可以自组装和封装核酸。通过叔氨基醇的开环聚合合成的可电离氨基聚酯是另一组用于 mRNA 给药的令人兴奋的聚合物。它们不含强正电荷，因此对细胞来说更中性。两亲性多腙是另一种用于 mRNA 递送的聚合物候选物。由低分子量聚乙烯吡咯烷酮 (PVP) 组成的微针贴片 (RNApatch) 可以通过将 mRNA 功能在环境条件下保持长达 2 周的时间来解决 mRNA 稳定性极低的基本问题。脂质聚合物混合是另一种方法，利用脂质和聚合物的最佳特性。水凝胶在某种程度上与聚合物有关，聚合物是主要成分，尽管水凝胶作为载体具有不同的特性。水凝胶的典型特征是能够满足各种要求的高度可调结构。水凝胶的结构和可注射性允许将 mRNA 局部部署到体腔或其它相关位置。然而，水凝胶颗粒也可以用作任何其它核酸载体。这种颗粒的可调尺寸可以完全适合吸入途径。因此，水凝胶是一种用途广泛的载体。通常，mRNA 可以被困在水凝胶中，然后在相对较长的时间内缓慢释放。不同的释放速率是各种水凝胶系统的特性，混合多种水凝胶提供了发现最佳释放条件的机会。一个研究小组发现，壳聚糖-海藻酸盐杂化物可促进外源蛋白质在细胞中的局部和持续表达。氧化石墨烯和聚乙烯亚胺(PEI) 的水凝胶可以将 mRNA 输送到组织，并且这种mRNA 保持功能长达一个月。DNA 水凝胶是小干扰 RNA 生产的另一个概念，但它们也可能适用于 mRNA 生产。因为水凝胶可以相对快速地标记和成像，它们为程序提供了无缝的精确度。RNA病毒利用核蛋白包装mRNA的能力。已经表明，在某些情况下，跨膜蛋白可以相互作用并以病毒样颗粒的形式包装其它带有 mRNA 的 RNA 包装信号。还有其它内源性蛋白，它们选择性地结合其 mRNA 并保护它。其中一种蛋白质（polietylenoglikol 10，PEG10）已被设计为选择性地包裹和封装其它 mRNA。它是通过将目的基因与 PEG10 非翻译区连接起来来实现的。这种 mRNA-PEG10 复合物可以作为病毒样颗粒 (VLP) 在细胞之间穿梭。该平台地高度模块化特性适合各种 mRNA，而蛋白质的内源性特征可避免免疫激活，这些可能是推动采用这种方法被快速采用、以实现高效且无毒 mRNA 递送的优势。本文为以下文献内容简介，详细内容，请参考原文。本文旨在知识、信息分享，转载请注明出处和原文。原文：M.Janowski, A.Andrzejewska, The legacy of mRNA engineering: A lineup of pioneers for the Nobel Prize. CellPress, 2022, DOI:https://doi.org/10.1016/j.omtn.2022.07.003.

信使RNA疫苗寡核苷酸紧急使用授权