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In Memoriam Douglas S. Kerr 纪念道格拉斯·s·科尔
IF 3.8 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-08-22 DOI: 10.1002/jimd.70082
Suzanne D. DeBrosse, Jirair K. Bedoyan
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引用次数: 0
Treatment of Inborn Errors by Product Replacement: The Example of Inborn Errors of Bile Acid Synthesis 通过产品替代治疗先天性错误:胆汁酸合成先天性错误的例子
IF 3.8 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-08-22 DOI: 10.1002/jimd.70081
Peter T. Clayton, Rohit Hirachan, Elaine Murphy

Many inborn errors of metabolism affect pathways involved in the synthesis of a metabolite that has an important biochemical or physiological function, and adverse effects of the disorder can be attributed to the lack of this metabolite. Thus, there is the opportunity for treatment by ‘product replacement’. One of the disorders in the pathways for the synthesis of bile acids from cholesterol, 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency, causes cholestatic liver disease in infancy that can be treated very effectively with chenodeoxycholic acid (CDCA) and/or cholic acid (CA). There are several other enzyme deficiencies that can cause liver disease in infancy that improve with CDCA or CA or both (alongside a reduction of abnormal bile acids or alcohols); however, individuals with the same gene variant(s) may remain asymptomatic or have transient liver dysfunction that resolves spontaneously. In some disorders, the more usual presentation is with neurological disease later in childhood or in adolescence or adult life, for example, cerebrotendinous xanthomatosis (CTX), α-methylacyl-CoA racemase deficiency, and oxysterol 7α-hydroxylase deficiency. Treatment with CDCA has been dramatically effective in the neurological disease of CTX. In the disorders of peroxisome biogenesis, liver disease is a part of the clinical picture although neurological symptoms tend to be predominant. Treatment with CDCA and CA (or CA alone) leads to a reduction in the levels of C27 bile acids. Some trials suggest this treatment leads to significant improvement in clinical status and liver function tests; others do not. Defects in individual peroxisomal enzymes and transporters vary in their clinical presentations. Treatment of acyl-CoA oxidase 2 deficiency with ursodeoxycholic acid is discussed.

许多天生的代谢错误会影响一种具有重要生化或生理功能的代谢物的合成途径,这种疾病的不良影响可归因于缺乏这种代谢物。因此,有机会通过“产品更换”进行治疗。3β-羟基-Δ5-C27-steroid脱氢酶缺乏症是由胆固醇合成胆汁酸的途径中的一种疾病,可导致婴儿期胆汁淤积性肝病,这种疾病可以用鹅脱氧胆酸(CDCA)和/或胆酸(CA)非常有效地治疗。还有其他几种酶缺乏可导致婴儿期肝脏疾病,CDCA或CA或两者均可改善(同时减少异常胆汁酸或酒精);然而,具有相同基因变异的个体可能仍然无症状或有一过性肝功能障碍,并自行消退。在某些疾病中,更常见的表现是在儿童后期或青少年或成年时出现神经系统疾病,例如,脑腱黄瘤病(CTX)、α-甲基酰基辅酶a消旋酶缺乏和羟化酶缺乏。CDCA治疗CTX的神经系统疾病非常有效。在过氧化物酶体生物发生障碍中,肝脏疾病是临床表现的一部分,尽管神经症状往往占主导地位。CDCA和CA(或单独CA)治疗可导致C27胆汁酸水平的降低。一些试验表明,这种治疗可以显著改善临床状况和肝功能检查;其他人则不然。个别过氧化物酶体和转运体的缺陷在临床表现上各不相同。讨论了熊去氧胆酸治疗酰基辅酶a氧化酶2缺乏症。
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引用次数: 0
Delivering the Message: Translating mRNA Therapy for Liver Inherited Metabolic Diseases 传递信息:翻译mRNA治疗肝脏遗传性代谢疾病
IF 3.8 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-08-18 DOI: 10.1002/jimd.70078
Sonam Gurung, Dany Perocheau, Roopkatha Ghosh, Stephen L. Hart, Julien Baruteau

mRNA encapsulated in lipid nanoparticles (LNPs) provides a dual revolution in the field of gene therapy. mRNA brings fleeting efficacy and the possibility to adjust the therapy to clinical needs. LNP, as a non-viral vehicle with flexible organ-targeting, overcomes most immune complications of viral gene therapy. mRNA-LNP has rapidly progressed from preventive medicine and vaccine applications to therapeutic use, especially in inherited metabolic diseases (IMDs). Given their natural tropism for liver uptake, this platform has been utilised successfully in numerous preclinical programmes. Early phase clinical trials are recruiting to assess safety and efficacy in liver IMDs. Here, we provide the latest update on mRNA and LNP technologies, preclinical studies and clinical trials targeting IMDs, safety considerations with a spotlight on infusion-related reactions and safety modelling. We discuss the future directions of therapeutic mRNA-LNP in IMDs and the right clinical use of this adjustable therapy, still to be defined. The versatility of this technology is appealing, with multiple clinical applications as bridge, long-term cure, rescue, or adjuvant therapy. mRNA-LNP for gene editing/insertion is an alternative approach for one-off cure. Translating various successful preclinical programmes in patients remains an unsolved limitation. mRNA-LNP can be tuned according to the patient's needs and is the next step in personalised medicine and individualised gene therapy.

脂质纳米颗粒(LNPs)包裹的mRNA在基因治疗领域提供了双重革命。mRNA带来了短暂的疗效和根据临床需要调整治疗的可能性。LNP作为一种具有灵活器官靶向性的非病毒载体,克服了病毒基因治疗的大多数免疫并发症。mRNA-LNP已从预防医学和疫苗应用迅速发展到治疗应用,特别是在遗传性代谢疾病(IMDs)方面。鉴于其天然的肝脏摄取倾向,该平台已成功地用于许多临床前项目。正在招募早期临床试验来评估肝脏imd的安全性和有效性。在这里,我们提供mRNA和LNP技术的最新进展,针对imd的临床前研究和临床试验,安全考虑,重点关注输注相关反应和安全建模。我们讨论了治疗mRNA-LNP在IMDs中的未来方向,以及这种可调节疗法的正确临床应用,这些仍有待确定。该技术的多功能性是吸引人的,具有多种临床应用,作为桥梁,长期治愈,救援,或辅助治疗。用于基因编辑/插入的mRNA-LNP是一种一次性治疗的替代方法。将各种成功的临床前程序翻译给患者仍然是一个未解决的限制。mRNA-LNP可以根据患者的需要进行调整,是个体化医疗和个体化基因治疗的下一步。
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引用次数: 0
Biomarker Validation in NPC1: Foundations for Clinical Trials and Regulatory Alignment NPC1的生物标志物验证:临床试验和法规一致性的基础
IF 3.8 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-08-15 DOI: 10.1002/jimd.70075
Krista Casazza, Stephanie M. Cologna, Elizabeth Berry-Kravis, Jeanine Jarnes, Forbes D. Porter

Niemann–Pick Type C1 (NPC1) disease is a rare, autosomal recessive, neurovisceral lysosomal storage disorder caused by mutations in the NPC1. This condition leads to defective intracellular cholesterol and lipid trafficking, resulting in the accumulation of unesterified cholesterol and glycosphingolipids in late endosomes and lysosomes. Clinically, NPC1 manifests with a heterogeneous spectrum of progressive neurological symptoms, including ataxia, vertical supranuclear gaze palsy, dysarthria, cognitive decline, and dystonia, often accompanied by systemic signs such as hepatosplenomegaly and neonatal cholestasis. The age of neurological symptom onset, rather than age at diagnosis, better reflects disease severity and progression, as delays in diagnosis are common due to phenotypic variability and lack of awareness. Therapeutic development for NPC1 has been historically limited, with miglustat approved in some regions for off-label use and 2-hydroxypropyl-β-cyclodextrin currently under clinical investigation. Recent advances in disease understanding have prompted the development of pharmacodynamic, diagnostic, and prognostic biomarkers to support earlier diagnosis and monitor therapeutic efficacy. Dysregulation of cholesterol homeostasis, neuroinflammation, and neuronal loss have guided biomarker discovery, with promising candidates including 24(S)-hydroxycholesterol, neurofilament light chain, and bile acid derivatives such as 3β,5α,6β-trihydroxycholanic acid. Novel lipid biomarkers including N-palmitoyl-O-phosphocholine-serine and oxysterols such as 7-ketocholesterol and cholestane-3β,5α,6β-triol also show diagnostic value. Despite growing mechanistic insight and a robust pipeline of candidate biomarkers and therapies, NPC1 remains a life-limiting disease with significant diagnostic and therapeutic gaps. Ongoing clinical trials and translational research are essential to accelerate biomarker qualification and regulatory approval of disease-modifying treatments. A comprehensive, mechanistically driven approach that integrates molecular, biochemical, and clinical endpoints is key to advancing precision medicine for NPC1.

尼曼-匹克C1型(NPC1)疾病是一种罕见的常染色体隐性遗传,由NPC1突变引起的神经内脏溶酶体贮积症。这种情况导致细胞内胆固醇和脂质运输缺陷,导致未酯化胆固醇和鞘糖脂在晚期内体和溶酶体中积累。临床上,NPC1表现为异质性进行性神经系统症状,包括共济失调、垂直核上凝视性麻痹、构音障碍、认知能力下降和张力障碍,常伴有肝脾肿大和新生儿胆汁淤积等全身性体征。神经症状出现的年龄,而不是诊断时的年龄,更能反映疾病的严重程度和进展,因为由于表型变异和缺乏认识,诊断延误很常见。NPC1的治疗发展一直受到限制,米卢司他在一些地区被批准用于标签外使用,2-羟丙基-β-环糊精目前正在临床研究中。疾病认识的最新进展促进了药效学、诊断和预后生物标志物的发展,以支持早期诊断和监测治疗效果。胆固醇稳态失调、神经炎症和神经元丢失引导了生物标志物的发现,有希望的候选者包括24(S)-羟基胆固醇、神经丝轻链和胆汁酸衍生物,如3β、5α、6β-三羟基胆酸。新的脂质生物标志物包括n -棕榈酰- o -磷脂-丝氨酸和7-酮胆固醇和胆固醇-3β,5α,6β-三醇等氧甾醇也显示出诊断价值。尽管对NPC1的机制越来越了解,候选生物标志物和治疗方法也越来越多,但NPC1仍然是一种具有重大诊断和治疗空白的限制性疾病。正在进行的临床试验和转化研究对于加快生物标志物的鉴定和改善疾病治疗的监管批准至关重要。整合分子、生化和临床终点的全面、机械驱动的方法是推进NPC1精准医疗的关键。
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引用次数: 0
Personalized Genome-Scale Modeling Reveals Metabolic Perturbations in Fibroblasts of Methylmalonic Aciduria Patients 个性化基因组尺度模型揭示甲基丙二酸尿患者成纤维细胞代谢紊乱
IF 3.8 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-08-11 DOI: 10.1002/jimd.70077
Almut Heinken, Hussein Awada, Vito R. T. Zanotelli, D. Sean Froese, Rosa-Maria Guéant-Rodriguez, Jean-Louis Guéant

Cobalamin (vitamin B12) is an essential cofactor for two human enzymes, methionine synthase and methylmalonyl-CoA mutase. Inborn errors of cobalamin metabolism (IECMs) are inherited genetic defects resulting in improper transport, modification, or utilization of cobalamin and include inherited methylmalonic acidurias, a group of IECMs most frequently caused by a defect in the methylmalonyl-CoA mutase enzyme. Here, we performed genome-scale modeling of IECMs to gain insight into their metabolic perturbations. First, we simulated deficiencies in 11 IECM-related genes and demonstrated that they cluster based on impaired metabolic pathways. Next, we leveraged RNA sequencing data from fibroblasts of 202 individuals with methylmalonic aciduria and 19 unaffected controls to construct and interrogate personalized metabolic models. Finally, we analyzed fluxes differing between patients depending on reported symptom presentation. Our findings reveal that (i) metabolic pathways including fatty acid metabolism and heme biosynthesis have reduced flux in IECMs, (ii) in personalized simulations, succinate and fumarate production and heme biosynthesis are impaired, especially in methylmalonyl-CoA mutase deficiency, (iii) one-carbon metabolism reactions such as serine hydroxymethyltransferase and folylglutamate synthase have reduced flux in all individuals with methylmalonic aciduria, and (iv) specific metabolic pathways are up- or down-regulated according to symptoms, including failure to thrive and hematological abnormalities, and treatments, such as antibiotics and protein restriction. Overall, our study delineates metabolic pathways perturbed in IECMs. In future applications, our modeling framework could be applied to other rare genetic diseases or used to predict personalized therapeutic or dietary interventions.

钴胺素(维生素B12)是两种人体酶必需的辅助因子,蛋氨酸合成酶和甲基丙二酰辅酶a变化酶。先天性钴胺素代谢错误(IECMs)是一种遗传性遗传缺陷,导致钴胺素运输、修饰或利用不当,包括遗传性甲基丙二酸尿症,这是一组最常见的由甲基丙二酰辅酶a变异酶缺陷引起的IECMs。在这里,我们对iecm进行了基因组尺度的建模,以深入了解它们的代谢扰动。首先,我们模拟了11个iecm相关基因的缺陷,并证明它们基于受损的代谢途径聚类。接下来,我们利用202名甲基丙二酸尿患者和19名未受影响的对照组的成纤维细胞的RNA测序数据来构建和询问个性化代谢模型。最后,我们根据所报告的症状表现分析了不同患者之间的通量差异。我们的研究结果显示:(1)代谢途径包括脂肪酸代谢和血红素生物合成降低了IECMs的通量,(2)在个性化模拟中,琥珀酸盐和富马酸盐的产生和血红素生物合成受损,特别是在甲基丙二酰辅酶a变化酶缺乏的情况下,(3)一碳代谢反应,如丝氨酸羟甲基转移酶和folylglutamate synthase,在所有甲基丙二酸尿症患者中减少了通量。(iv)特定的代谢途径根据症状上调或下调,包括发育不良和血液学异常,以及治疗,如抗生素和蛋白质限制。总的来说,我们的研究描述了iecm中紊乱的代谢途径。在未来的应用中,我们的建模框架可以应用于其他罕见的遗传疾病或用于预测个性化的治疗或饮食干预。
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引用次数: 0
Real-World Migalastat Use in Fabry Disease: Comparative Insights From the Pisani and Hughes Studies 现实世界中米加拉司他在法布里病中的应用:来自Pisani和Hughes研究的比较见解
IF 3.8 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-08-11 DOI: 10.1002/jimd.70080
Eleonora Riccio, Antonio Pisani
<p>Since its EU approval in 2016, the oral pharmacological chaperone migalastat has been available as a treatment option for Fabry disease (FD) patients with amenable GLA mutations; real-world data are crucial for better defining its effectiveness and its role in clinical practice.</p><p>Two recent studies published in the <i>Journal of Inherited Metabolic Disease</i>—by Hughes et al. [<span>1</span>] and Pisani et al. [<span>2</span>] offer contrasting insights into the effects of migalastat in a real-world setting. Notably, the study by Hughes et al. [<span>1</span>] was funded by Amicus Therapeutics, while the study by Pisani et al. [<span>2</span>] was supported by Sanofi.</p><p>Hughes et al. [<span>1</span>] analyzed 125 patients from the followME Pathfinder Registry (age at enrolment ≥ 12 years; median 58 years), ~75% of whom were treatment-naïve and ~25% had received ERT for ≤ 2 years. Only patients receiving ≥ 3 years of uninterrupted migalastat therapy were included. The reported annualized eGFR change was −0.9 mL/min/1.73 m<sup>2</sup>/year (95% confidence interval [CI]: −10.8, 9.9), with a low incidence of Fabry-associated clinical events (FACEs) (20.0%: 19.2% cardiac, 0.8% renal), suggesting favorable long-term outcomes. However, the broad CI and exclusion of patients treated for < 3 years may reflect a survivorship bias, potentially overestimating treatment benefit.</p><p>In contrast, Pisani et al. [<span>2</span>] evaluated 83 patients (median age at ERT initiation: 44 years; at switch to migalastat: 50 years) who switched from ≥ 1 year of agalsidase beta to migalastat for ≥ 6 months. The authors observed a mean eGFR decline of −1.96 mL/min/1.73 m<sup>2</sup>/year after the switch, with increasing lyso-Gb<sub>3</sub> levels, particularly in patients with the classic phenotype. Classic males experienced notable worsening in proteinuria and cardiac biomarkers.</p><p>Key differences in patient selection, baseline characteristics, and methodology are critical to interpreting these findings.</p><p>First, Hughes included predominantly treatment-naïve subjects with a median age of 58 years at treatment initiation, likely reflecting a milder disease course. In addition, patients treated with migalastat for ≤ 3 years were excluded, potentially overestimating effectiveness by excluding those who discontinued before 3 years due to inefficacy or intolerance. Conversely, Pisani's cohort comprised exclusively previously treated patients, with a median age of 50 years at switch to migalastat (and 44 years at first FD-treatment), and a higher proportion of classic males (38.6% vs. 6.7% in Hughes), a group known to have more severe manifestations. Moreover, Pisani analyzed a broader, more representative population, including both patients who successfully responded to migalastat and those who required to switch back to ERT. Again, variant amenability in Hughes may be overestimated, as some included mutations had high residual enzyme activity or u
自2016年获欧盟批准以来,口服药物伴侣米加拉司他(migalastat)一直可作为具有可调节GLA突变的Fabry病(FD)患者的治疗选择;真实世界的数据对于更好地定义其有效性及其在临床实践中的作用至关重要。最近发表在《遗传代谢性疾病杂志》上的两项研究(Hughes et al.[1]和Pisani et al.[1])对米加拉司他在现实环境中的作用提供了截然不同的见解。值得注意的是,Hughes等人[1]的研究是由Amicus Therapeutics资助的,而Pisani等人[1]的研究是由赛诺菲支持的。Hughes等人分析了来自以下me探路者注册的125例患者(入组时年龄≥12岁;中位58岁),其中~75%为treatment-naïve, ~25%接受ERT治疗≤2年。仅纳入接受≥3年不间断米伽司他治疗的患者。报告的年化eGFR变化为- 0.9 mL/min/1.73 m2/年(95%可信区间[CI]: - 10.8, 9.9), fabry相关临床事件(FACEs)发生率低(20.0%:19.2%心脏,0.8%肾脏),表明良好的长期预后。然而,广泛的CI和排除治疗3年的患者可能反映了生存偏倚,可能高估了治疗的益处。相比之下,Pisani等人评估了83例患者(ERT开始时的中位年龄:44岁;切换到米加司他:50岁),从≥1年的agalsidase - β切换到米加司他≥6个月。作者观察到,转换后eGFR平均下降- 1.96 mL/min/1.73 m2/年,溶素- gb3水平增加,特别是在经典表型患者中。典型男性的蛋白尿和心脏生物标志物明显恶化。患者选择、基线特征和方法学的关键差异是解释这些发现的关键。首先,Hughes主要纳入treatment-naïve受试者,治疗开始时的中位年龄为58岁,可能反映了较轻的病程。此外,排除了使用米加司他治疗≤3年的患者,排除了那些在3年之前因无效或不耐受而停药的患者,可能高估了疗效。相反,Pisani的队列只包括以前接受过治疗的患者,切换到migalastat时的中位年龄为50岁(首次fd治疗时的中位年龄为44岁),并且典型男性的比例更高(38.6%对6.7%),这一组已知有更严重的表现。此外,Pisani分析了更广泛、更有代表性的人群,包括对migalastat成功反应的患者和需要转回ERT的患者。同样,休斯的变异适应性可能被高估了,因为一些包括的突变具有高残留酶活性或不确定的致病性。相反,Pisani没有报道特异性GLA变异或基线α-Gal A活性,限制了对米加拉司他临床效果的解释。此外,两项研究均未考虑可能影响结果的支持性治疗(如ACE抑制剂、arb)。方法上的差异进一步限制了直接比较:Hughes采用了简单的线性回归,而Pisani采用了线性混合模型,更好地解释了患者内部的可变性和重复测量。此外,Hughes报告的平均eGFR年化率的95% CI宽(- 10.8至+9.9)强调了实质性的变异性,并质疑对“稳定”肾功能的解释。最后,基于注册表的限制,包括数据完整性和选择偏差,也适用于这两项研究。总之,Hughes提供了关于migalastat在选定的、稳定的长期应答者中的疗效的有用数据。然而,Pisani提供了一个更具异质性和临床相关性的视角,特别是对于更晚期或经典疾病的患者。这些发现强调了根据患者特征将真实世界数据置于环境中以指导个性化治疗决策的重要性。重要的是,基于这些比较数据,米加司他似乎不是典型表型男性患者的合适治疗选择,这些患者在开始治疗或切换治疗后始终表现出不利的结果。有最初的想法;急诊室写了论文;两位作者都对论文进行了修改,并批准了最终版本。Antonio Pisani曾担任法布里病研究性治疗临床试验的PI;获得研究经费、差旅经费;并曾担任赛诺菲-健赞(Sanofi-Genzyme)、Amicus、Chiesi-Protalix和武田的顾问委员会成员。
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引用次数: 0
Dietary Shift Leads to Venous Thrombosis-Induced Congestive Liver Failure in CBS-Deficient Mice 饮食改变导致cbs缺陷小鼠静脉血栓形成诱导的充血性肝衰竭
IF 3.8 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-08-05 DOI: 10.1002/jimd.70076
Hyung-Ok Lee, Cathy Q. Qai, Michael J. Slifker, Warren D. Kruger

Cystathionine beta-synthase (CBS) deficiency is an inborn error of metabolism that results in a large increase in plasma total homocysteine (tHcy) and a significant risk of venous thrombosis. Although a mouse model of CBS deficiency (Tg-I278T Cbs−/−) has several phenotypes in common with human patients, it has not been shown to have elevated thrombosis risk. Here, we describe a novel phenotype in which 40% of Tg-I278T Cbs−/− mice die of liver failure due to hepatic vein thrombosis shortly after being shifted from a low methionine diet (LMD) to a regular diet (RD). Importantly, no deaths or thromboses occur if the mice are continuously maintained on RD or LMD for extended periods of time. RNAseq analysis of the livers of Tg-I278T Cbs−/− mice that were shifted to RD for 3 days after spending 1 week on LMD (RD3D) shows significant differences in many transcripts involved in coagulation and fibrinolysis, key processes involved in thrombosis. Interestingly, the liver gene expression profile and serum amino acid profiles of both Tg-I278T Cbs−/− and Tg-I278T Cbs+/− mice maintained continuously on RD are also significantly different from RD3D mice. Since the only difference between RD and RD3D mice is their previous exposure to an LMD diet, this shows that the liver transcriptional profile is affected not only by the current diet but also by the animals' previous dietary history. Overall, our findings indicate that there is a strong gene-diet interaction between the Cbs genotype and dietary methionine and that this interaction may help explain the thrombosis phenotype in human CBS deficient patients.

半胱硫氨酸-合成酶(CBS)缺乏症是一种先天性代谢错误,可导致血浆总同型半胱氨酸(tHcy)大量增加,并具有静脉血栓形成的显著风险。尽管CBS缺陷小鼠模型(Tg-I278T CBS−/−)具有与人类患者共同的几种表型,但尚未显示其具有血栓形成风险升高。在这里,我们描述了一种新的表型,其中40%的Tg-I278T Cbs - / -小鼠在从低蛋氨酸饮食(LMD)转变为常规饮食(RD)后不久死于肝静脉血栓引起的肝功能衰竭。重要的是,如果小鼠持续使用RD或LMD较长时间,不会发生死亡或血栓形成。在使用LMD (RD3D)治疗1周后,转至RD治疗3天的Tg-I278T Cbs - / -小鼠肝脏的RNAseq分析显示,许多参与凝血和纤溶的转录本存在显著差异,这是血栓形成的关键过程。有趣的是,持续服用RD的Tg-I278T Cbs−/−和Tg-I278T Cbs+/−小鼠的肝脏基因表达谱和血清氨基酸谱也与RD3D小鼠有显著差异。由于RD和RD3D小鼠之间的唯一区别是它们以前暴露于LMD饮食,这表明肝脏转录谱不仅受到当前饮食的影响,还受到动物以前饮食史的影响。总的来说,我们的研究结果表明,Cbs基因型和膳食蛋氨酸之间存在很强的基因-饮食相互作用,这种相互作用可能有助于解释人类Cbs缺陷患者的血栓表型。
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引用次数: 0
Effectiveness of Pyridoxal-5′-Phosphate in PNPO Deficiency: A Systematic Review 吡哆醛-5′-磷酸治疗PNPO缺乏症的有效性:系统综述
IF 3.8 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-08-02 DOI: 10.1002/jimd.70074
Nina N. Stolwijk, Laura van Dussen, Niels D. Reijnhout, Marion M. M. G. Brands, Bregje Jaeger, Peter T. Clayton, Carla E. M. Hollak, Annet M. Bosch

Pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency is an ultrarare inherited neurometabolic disease, characterized by primarily neonatal-onset B6-responsive epileptic encephalopathies. Treatment often requires sustainable access to high-quality pyridoxal-5′-phosphate (PLP, i.e., active vitamin B6), although some patients (also) respond to pyridoxine (PN). While PN is authorized as a medicinal product, PLP is not, and this forces reliance on lesser-regulated food supplements, which risks dosing inaccuracies. This systematic review evaluates the effectiveness and safety of PLP in PNPO deficiency (PROSPERO, CRD42024542199). A systematic search was conducted in PubMed, Embase, and ClinicalTrials.gov, with risk of bias assessed and observational evidence summarized using a narrative synthesis approach. A total of 30 studies were included reporting on 49 patients treated with PLP. Clinical seizure responsiveness following PLP therapy was observed in the majority of patients (n = 38, 77.6%) and PLP treatment significantly improved survival (p < 0.001) compared with untreated siblings with a similar phenotype. The majority of PLP-responsive patients responded exclusively to PLP, with PN being attempted but ineffective in most of them (n = 30/33, 90.9%) Liver toxicity was the most frequently observed adverse event (n = 10, 20.4%) and although the underlying pathophysiological mechanism remains unclear, it may be associated with high-dose PLP. Therefore, regular liver disease screening is recommended during PLP therapy. This means that PLP remains the only effective therapy for achieving and maintaining seizure control in the majority of PNPO deficient patients, but the therapeutic window for optimal management is narrow. Thus, it is essential to ensure patient access to high-quality and appropriate forms of PLP.

吡啶(am)线5′-磷酸氧化酶(PNPO)缺乏症是一种罕见的遗传性神经代谢疾病,主要以新生儿发作的b6反应性癫痫性脑病为特征。治疗通常需要持续获得高质量的吡哆醇-5 ' -磷酸(PLP,即活性维生素B6),尽管一些患者(也)对吡哆醇(PN)有反应。虽然PN被授权为药品,但PLP没有,这迫使人们依赖监管较少的食品补充剂,这有可能导致剂量不准确。本系统综述评估了PLP治疗PNPO缺乏症的有效性和安全性(PROSPERO, CRD42024542199)。在PubMed、Embase和ClinicalTrials.gov上进行了系统搜索,评估了偏倚风险,并使用叙述综合方法总结了观察性证据。共纳入了30项研究,报告了49例接受PLP治疗的患者。大多数患者(n = 38, 77.6%)在PLP治疗后观察到临床发作反应性,与未治疗的具有相似表型的兄弟姐妹相比,PLP治疗显著提高了生存率(p < 0.001)。大多数对PLP有反应的患者只对PLP有反应,其中大多数患者尝试过PN,但无效(n = 30/33, 90.9%)。肝毒性是最常见的不良事件(n = 10, 20.4%),尽管潜在的病理生理机制尚不清楚,但可能与高剂量PLP有关。因此,建议在PLP治疗期间定期进行肝脏疾病筛查。这意味着PLP仍然是大多数PNPO缺陷患者实现和维持癫痫控制的唯一有效治疗方法,但最佳管理的治疗窗口很窄。因此,确保患者获得高质量和适当形式的PLP至关重要。
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引用次数: 0
ARSA Variants Associated With Cognitive Decline and Long-Term Preservation of Motor Function in Metachromatic Leukodystrophy 异色性脑白质营养不良患者认知能力下降和运动功能长期保存相关的ARSA变异
IF 3.8 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-08-02 DOI: 10.1002/jimd.70072
Shanice Beerepoot, Daphne H. Schoenmakers, Francesca Fumagalli, Samuel Groeschel, Ludger Schöls, Raphael Schiffmann, Sheila Wong, Odile Boespflug-Tanguy, Caroline Sevin, Yann Nadjar, Annette Bley, Fanny Mochel, Morten A. Horn, Cristina Baldoli, Sara Locatelli, Holger Hengel, Lucia Laugwitz, Carla E. M. Hollak, Volkmar Gieselmann, Marjo S. van der Knaap, Nicole I. Wolf

Patients with metachromatic leukodystrophy (MLD) show variable motor and cognitive decline. The ARSA variants c.256C>T, p.(Arg86Trp), c.257G>A, p.(Arg86Gln) and c.542T>G, p.(Ile181Ser) are associated with predominantly cognitive decline. This multinational study analyzed MLD onset type, presenting signs/symptoms, cognitive function, gross motor function, central motor tract involvement, MRI severity score, peripheral neuropathy, and survival of 47 patients (three homozygous for c.256C>T and five, twelve and 27 compound heterozygous for c.256C>T, c.257G>A, or c.542T>G and another ARSA variant, respectively). Eleven underwent hematopoietic stem cell transplantation (HSCT). Onset was late-juvenile (46.8%) or adult (44.7%) with predominantly cognitive decline (n = 40/41 symptomatic patients). At diagnosis, untreated patients typically retained independent walking (100%), sparing of central motor tracts (87.5%), and absence of demyelinating neuropathy (95.5%), which persisted in follow-up for most (76.5%, 71.4%, and 64.7%, respectively). Early-juvenile onset and rapid motor decline occurred only in patients compound heterozygous for c.256C>T and a severe second variant (n = 4), showing central motor tract involvement at diagnosis. One untreated and one treated patient died of disease progression, and another from HSCT complications. All other treated patients retained independent walking, and four of five tested normal cognitive function. Median MRI severity score remained lower in treated (13) than untreated patients (25). The phenotype of c.256C>T carriers depends on the severity of the second ARSA variant. Patients harboring c.257G>A or c.542T>G show late-juvenile or adult onset with cognitive decline and preserved motor function, usually associated with sparing of central motor tracts. In these patients, cognitive function and MRI severity score should be preferred treatment outcomes.

偏色差性脑白质营养不良(MLD)患者表现出不同程度的运动和认知能力下降。ARSA变体c.256C>;T, p.(Arg86Trp), c.257G>;A, p.(Arg86Gln)和c.542T>;G, p.(Ile181Ser)主要与认知能力下降有关。这项多国研究分析了47例MLD患者的发病类型、体征/症状、认知功能、大运动功能、中枢运动道受累、MRI严重程度评分、周围神经病变和生存率(c.256C>;T纯合子3例,c.256C>T、c.257G>;A或c.542T>;G和另一种ARSA变异体分别为5例、12例和27例复合杂合子)。11人接受了造血干细胞移植(HSCT)。起病者为青少年晚期(46.8%)或成人(44.7%),以认知能力下降为主(n = 40/41例有症状患者)。在诊断时,未经治疗的患者通常保持独立行走(100%),保留中枢运动束(87.5%),没有脱髓鞘神经病变(95.5%),大多数患者(分别为76.5%,71.4%和64.7%)在随访中持续存在。仅在c.256C>;T复合杂合的患者和严重的第二变体(n = 4)中发生了早期青少年发病和快速运动功能下降,在诊断时显示中枢运动道受累。一名未经治疗和一名接受治疗的患者死于疾病进展,另一名死于移植并发症。所有其他接受治疗的患者都保持了独立行走,其中四人的认知功能测试正常。治疗组(13)的MRI严重程度评分中位数仍低于未治疗组(25)。c.256C>;T携带者的表型取决于第二种ARSA变异的严重程度。携带c.257G>;A或c.542T>;G的患者表现为青少年晚期或成人发病,认知能力下降,运动功能保留,通常与中枢运动束保留有关。在这些患者中,认知功能和MRI严重程度评分应该是首选的治疗结果。
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引用次数: 0
Personalized Genotype-Based Approach for Treatment of Phenylketonuria 基于个性化基因型的治疗苯丙酮尿的方法
IF 3.8 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-07-29 DOI: 10.1002/jimd.70067
Polina Gundorova, Behnam Yousefi, Mathias Woidy, Malcolm Summer Rose-Heine, Robin Khatri, Viviane Kasten, Stefan Bonn, Ania Carolina Muntau, Soeren Waldemar Gersting

Extensive studies have examined the clinical manifestations, pathogenic mechanisms, and genetic variations of phenylketonuria (PKU) across different populations, resulting in a substantial collection of molecular genetic data on the phenylalanine hydroxylase (PAH) gene and its variants. However, many genotypes are associated with a range of clinical phenotypes, as well as variable responsiveness to sapropterin, presenting ongoing challenges for effective treatment. To address this, we enhanced the PAH activity landscapes method by incorporating high-throughput techniques, including automated pipetting, integrated data processing via Gaussian modeling of 3D surfaces, and bioinformatics analyses with robust quality control. Using PAH activity landscapes, we visualized PAH enzymatic function across 99 common PAH genotypes under varying metabolic and therapeutic conditions. This deep functional phenotyping approach enabled us to identify distinct genotype subpopulations by using consensus clustering, correlate them with clinical phenotypes, and propose subpopulation-specific treatment protocols. Our findings suggest that clinical phenotypes can be predicted and treatment regimens can be adjusted based on residual PAH function profiles. To further support personalized treatment strategies, we revised our publicly accessible PAH genotype & activity landscapes database to share the latest insights into PAH function and patient phenotypes—namely residual enzyme activity and responsiveness to sapropterin as conveyed by two alleles. This resource underscores the translational significance of functional research in PKU and offers a practical tool to support personalized treatment in clinical settings.

广泛的研究调查了不同人群中苯丙酮尿症(PKU)的临床表现、致病机制和遗传变异,从而收集了大量关于苯丙氨酸羟化酶(PAH)基因及其变异的分子遗传数据。然而,许多基因型与一系列临床表型以及对沙普霉素的可变反应有关,这对有效治疗提出了持续的挑战。为了解决这个问题,我们通过结合高通量技术来增强多环芳烃活性景观方法,包括自动移液,通过3D表面的高斯建模集成数据处理,以及具有强大质量控制的生物信息学分析。利用多环芳烃活性图谱,我们可视化了99种常见多环芳烃基因型在不同代谢和治疗条件下的酶促功能。这种深度功能表型方法使我们能够通过共识聚类识别不同的基因型亚群,将它们与临床表型相关联,并提出亚群特异性治疗方案。我们的研究结果表明,临床表型可以预测,治疗方案可以根据残留的PAH功能谱进行调整。为了进一步支持个性化治疗策略,我们修订了可公开获取的PAH基因型;活动景观数据库,分享PAH功能和患者表型的最新见解-即残留酶活性和对沙普霉素的反应性,由两个等位基因传递。该资源强调了PKU功能研究的转化意义,并提供了一个实用的工具来支持临床环境中的个性化治疗。
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引用次数: 0
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Journal of Inherited Metabolic Disease
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