Molecular genetics and metabolism最新文献

{"title":"Identification of genetic variants associated with Fabry nephropathy progression using whole-exome sequencing","authors":"Tina Levstek ,&nbsp;Bojan Vujkovac ,&nbsp;Albina Nowak ,&nbsp;João-Paulo Oliveira ,&nbsp;Gabriela Dostálová ,&nbsp;Aleš Linhart ,&nbsp;Markéta Šafaříková ,&nbsp;Gheona Altarescu ,&nbsp;Katarina Trebušak Podkrajšek","doi":"10.1016/j.ymgme.2025.109191","DOIUrl":"10.1016/j.ymgme.2025.109191","url":null,"abstract":"<div><div>Fabry nephropathy, a common complication of Fabry disease (FD), presents with a heterogeneous clinical phenotype. To date, genetic biomarkers associated with the progression of Fabry nephropathy have not been thoroughly investigated. The aim of our study was therefore to identify genetic variants associated with nephropathy progression in FD.</div><div>A total of 300 Caucasian patients were enrolled and stratified into two groups based on their estimated glomerular filtration rate (eGFR). Whole-exome sequencing was performed, and variants in a curated panel of 190 genes related to podocyte homeostasis were subjected to bioinformatic analysis.</div><div>We identified six genetic variants with a false discovery rate (FDR) below 0.05. Five of these variants were located in non-coding regions: the 3′ untranslated region (UTR) (<em>YRDC</em>: rs7686, <em>TPPP</em>: rs28364690), the 5’ UTR (<em>SNCA</em>: rs1372518), an upstream region (<em>COL4A2</em>: rs7320419), and a non-coding exon (<em>DLC1</em>: rs10888175). Each of these variants was associated with an odds ratio less than one, suggesting a potential protective effect against nephropathy progression. In contrast, the coding variant rs749735949 in the <em>FAT1</em> gene (FDR = 0.032) was associated with an odds ratio of 14.9, indicating a markedly increased risk of progressive nephropathy in carriers.</div><div>These findings suggest that rs749735949 in <em>FAT1</em> may serve as a predictive biomarker for accelerated eGFR decline, and could support the identification of biological targets for the prevention and improved management of Fabry nephropathy.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109191"},"PeriodicalIF":3.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144614728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term efficacy and safety of arimoclomol in Niemann-Pick disease type C: Final results of the phase 2/3 NPC-002 48-month open-label extension trial","authors":"Eugen Mengel ,&nbsp;Rosalia M. Da Riol ,&nbsp;Mireia Del Toro ,&nbsp;Federica Deodato ,&nbsp;Matthias Gautschi ,&nbsp;Stephanie Grunewald ,&nbsp;Sabine Weller Grønborg ,&nbsp;Paul Harmatz ,&nbsp;Julia B. Hennermann ,&nbsp;Bénédicte Héron ,&nbsp;Esther M. Maier ,&nbsp;Saikat Santra ,&nbsp;Reena Sharma ,&nbsp;Anna Tylki-Szymanska ,&nbsp;Malene Cording ,&nbsp;Louise Himmelstrup ,&nbsp;Sven Guenther ,&nbsp;Christine í Dali","doi":"10.1016/j.ymgme.2025.109189","DOIUrl":"10.1016/j.ymgme.2025.109189","url":null,"abstract":"<div><h3>Background</h3><div>This paper presents efficacy and safety outcomes from the 48-month open-label extension (OLE) of the phase 2/3 NPC-002 trial (<span><span>NCT02612129</span><svg><path></path></svg></span>) which evaluated arimoclomol treatment in patients with Niemann-Pick disease type C (NPC). Arimoclomol was recently approved by the US Food and Drug Administration for treatment of NPC in combination with miglustat.</div></div><div><h3>Methods</h3><div>Patients with NPC who completed the double-blind (DB) phase of the randomized controlled NPC-002 trial were eligible to continue in the OLE, during which all patients received arimoclomol in addition to routine clinical care. Primary efficacy outcomes were the 5-domain NPC Clinical Severity Scale (5DNPCCSS), and the rescored 4-domain NPCCSS (R4DNPCCSS), which was introduced <em>post-hoc</em>. Additional outcomes included NPC-specific measures (full scale NPCCSS, and NPC clinical database [NPC-cdb] score), and safety evaluations.</div></div><div><h3>Results</h3><div>Of the 50 patients who started the DB phase, 41 entered the OLE phase, with 29 completing 48 months. During the OLE, mean (SD) 5DNPCCS and R4DNPCCSS scores increased by 3.2 (4.8) and 2.7 (4.2) over 48 months, respectively. Among patients switching from placebo to arimoclomol after the DB phase, mean annual change in 5DNPCCSS decreased from 2.0 (on placebo) to 0.1 in the first year of receiving arimoclomol and mean annual change in R4DNPCCSS decreased from 1.9 to 0.2, indicating slowing of disease progression. Annual scores for both endpoints remained numerically smaller throughout the OLE than during the DB phase. The score pattern in the subset of patients who received miglustat as part of their standard care regime in addition to arimoclomol (<em>N</em> = 33) was similar to that seen in the total population. 17-domain NPCCSS (excluding hearing domains) and NPC-cdb results further supported sustained efficacy of arimoclomol. Arimoclomol was well-tolerated over 48 months, with no new safety concerns identified.</div></div><div><h3>Conclusion</h3><div>The OLE of the NPC-002 trial provides evidence for a sustained reduction in disease progression for at least 5 years in a heterogeneous population of NPC patients receiving arimoclomol in addition to routine clinical care, with no new safety concerns. These results align with the statistically significant and clinically meaningful reduction in disease progression observed over 12-months in the DB phase, further highlighting the potential of arimoclomol as an effective and well tolerated disease modifying treatment for NPC.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109189"},"PeriodicalIF":3.7,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144631124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The clinical utility of short-term protein substitute use during intercurrent illness in BH4-responsive phenylketonuria","authors":"Selin Akbulut ,&nbsp;Esma Uygur ,&nbsp;Tanyel Zubarioglu ,&nbsp;Mehmet Şerif Cansever ,&nbsp;Ertuğrul Kiykim ,&nbsp;Çiğdem Aktuğlu Zeybek","doi":"10.1016/j.ymgme.2025.109187","DOIUrl":"10.1016/j.ymgme.2025.109187","url":null,"abstract":"<div><h3>Objective</h3><div>Phenylketonuria (PKU) is a metabolic disorder that is primarily treated with dietary phenylalanine (Phe) restriction and/or tetrahydrobiopterin (BH4) therapy. Dietary liberalization is often possible in BH4-responsive PKU patients; however, metabolic control may be impaired during catabolic stress such as illness or fever. The aim of this study was to investigate the efficacy of temporary protein substitution (Phe-free amino acid mixture; PFAAM) during intercurrent illness in BH4-responsive PKU patients managed without dietary protein restriction.</div></div><div><h3>Methods</h3><div>This retrospective case series, descriptive study included ten BH4-responsive PKU patients treated with BH4 monotherapy. All patients received PFAAM supplementation exclusively during febrile or disease-related episodes. Clinical, biochemical and genetic data were obtained from medical records. Blood Phe levels were determined before and after PFAAM intake during illness episodes.</div></div><div><h3>Results</h3><div>All patients experienced a significant increase in blood Phe levels during febrile illnesses despite receiving maximum BH4 dose (20 mg/kg/day). PFAAM supplementation initiated at a median dose of 0.3–1.5 g/kg/day resulted in a rapid decrease in blood Phe levels, often within a few days. In most cases, PFAAM was gradually discontinued once metabolic control was restored, and no patient required long-term dietary Phe restriction. The intervention allowed restoration of metabolic control while maintaining a liberal dietary regimen.</div></div><div><h3>Conclusions</h3><div>Temporary PFAAM supplementation during intercurrent illness appears to be an effective adjunct to BH4 therapy to control transient elevations in blood Phe levels. This approach may support metabolic stability without the need for permanent dietary restriction in BH4-responsive PKU patients. Further prospective studies are needed to validate these results in larger cohorts.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109187"},"PeriodicalIF":3.7,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dolichol synthesis defects: a cautionary note on the use of statins","authors":"Matthew P. Wilson ,&nbsp;Eva Morava","doi":"10.1016/j.ymgme.2025.109186","DOIUrl":"10.1016/j.ymgme.2025.109186","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109186"},"PeriodicalIF":3.7,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144570163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The current social status in adult patients with urea cycle disorders in Japan","authors":"Jun Kido ,&nbsp;Johannes Häberle ,&nbsp;Keishin Sugawara ,&nbsp;Mitsuru Watanabe ,&nbsp;Koji Imoto ,&nbsp;Kazuhiro Yokota ,&nbsp;Minori Kodaira ,&nbsp;Nozomi Harai ,&nbsp;Ken Sato ,&nbsp;Keisuke Kakisaka ,&nbsp;Yusuke Hattori ,&nbsp;Kimitoshi Nakamura","doi":"10.1016/j.ymgme.2025.109185","DOIUrl":"10.1016/j.ymgme.2025.109185","url":null,"abstract":"<div><div>Urea cycle disorders (UCDs) are inherited metabolic conditions that lead to inadequate nitrogen detoxification due to defects in urea cycle enzymes or transporters. The severity of UCDs is classified into two types: neonatal onset (severe) and late onset (often milder). This cross-sectional study aimed to assess the levels of intelligence, developmental disabilities, and social functioning in adult patients with UCDs in Japan. A total of 116 adult patients with UCDs were enrolled in the study, including 10 with carbamoyl phosphate synthetase 1 deficiency, 69 with ornithine transcarbamylase deficiency (OTCD), 17 with argininosuccinate synthetase deficiency, 9 with argininosuccinate lyase deficiency, 4 with arginase 1 deficiency, and 7 with Hyperornithinemia-Hyperammonemia-Homocitrullinuria syndrome. Of these, 25 (21.6 %) developed symptoms during the neonatal period (within 28 days after birth), while 86 (74.1 %) presented with symptoms after 28 days of age. The age of onset was unknown in 5 patients. This study included 111 surviving patients and 5 deceased patients (3 with OTCD and 2 with CPS1D). Fifty-three patients (45.7 %) experienced intellectual disabilities, while 48 (41.4 %) had non-intellectual disabilities. Additionally, learning disorders and communication disorders were common among many of the study participants. Sixty patients (51.7 %) graduated from regular high school, and most patients with intellectual disabilities graduated from special education schools. Almost half of the patients (51, 44.0 %) were able to obtain jobs, including simple tasks in supported workplaces, and received compensation for their work. Notably, more patients with OTCD could demonstrate higher social performance including experience of higher education and marriage. However, even OTCD patients without intellectual disabilities often struggled with specific neurobehavioral issues. This study provides information on the social situation of adult UCD patients and underlines the importance for clinicians, as well as society and communities, to understand the ongoing challenges faced by patients with UCDs in order to provide better support.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109185"},"PeriodicalIF":3.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A review of disorders of cardiolipin metabolism: Pathophysiology, clinical presentation and future directions","authors":"Olivia Sniezek Carney ,&nbsp;Kodi Harris ,&nbsp;Madison Santizo ,&nbsp;Valeria Silva ,&nbsp;Jhanay Davis ,&nbsp;Kyuna Lee ,&nbsp;Sharada Vishwanath ,&nbsp;Anne Hamacher-Brady ,&nbsp;Hilary J. Vernon","doi":"10.1016/j.ymgme.2025.109184","DOIUrl":"10.1016/j.ymgme.2025.109184","url":null,"abstract":"<div><div>Cardiolipin is a mitochondria-specific phospholipid essential for maintaining mitochondrial membrane architecture, supporting respiratory chain function, and regulating apoptotic signaling. Its biosynthesis and remodeling are mediated by a coordinated set of enzymes, and disruptions in this pathway are increasingly recognized as causes of inherited mitochondrial diseases. This review provides a comprehensive overview of the genetic disorders associated with defects in cardiolipin metabolism, highlighting genetic and molecular characteristics, clinical manifestations, and available models with which to study these diseases. We examine the roles of key genes involved in cardiolipin biosynthesis (<em>PGS1</em>, <em>CRLS1</em>) and remodeling (<em>TAZ</em>, <em>AGK</em>, among others), and describe how pathogenic variants disrupt mitochondrial function. The prototypical disorder, Barth syndrome, is discussed in depth alongside recently identified conditions linked to defects in related enzymes.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109184"},"PeriodicalIF":3.7,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144580908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effective algorithm to differentiate NBS MCADD cases from carriers and non-carriers and an assessment of the utility of the second newborn screen for MCADD","authors":"Matthew T. Snyder ,&nbsp;Kristian Divin ,&nbsp;Ning Liu ,&nbsp;Qin Sun ,&nbsp;Yue Wang ,&nbsp;Xi Luo ,&nbsp;Yishay Ben-Moshe ,&nbsp;Lindsay C. Burrage ,&nbsp;V. Reid Sutton","doi":"10.1016/j.ymgme.2025.109183","DOIUrl":"10.1016/j.ymgme.2025.109183","url":null,"abstract":"<div><div>False positives are an inherent part of newborn screening that can increase both costs to the healthcare system and parental anxiety. Previous studies primarily examined presumptive positive rates for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in places conducting one newborn screen (NBS), with predominantly white, non-Hispanic subjects. Texas performs two NBSs and there is a majority Hispanic population in our region. This study aims to analyze biochemical and DNA data to more easily distinguish affected individuals from carriers or healthy non-carriers and identify benefits and challenges of a second NBS for MCADD. Biochemical and targeted DNA data from NBS dried blood spots (DBS) were analyzed, alongside diagnostic biochemical and DNA testing. A Kruskal Wallis Test with Dunn's post-test was performed to compare the groups. Significant differences in all analyte values were observed among MCADD, carrier and non-carrier groups, and between carriers and non-p.Lys329Glu homozygous MCADD cases. Many false positives were detected due to low DBS C8 cutoff and the second NBS. An analyte algorithm including DBS C8, plasma acylcarnitine C6, and plasma C8/C10 was identified and discriminated MCADD cases from carrier and non-carrier cases. All cases with MCADD were identified on the first NBS demonstrating limited utility of a second NBS for MCADD.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109183"},"PeriodicalIF":3.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The clinical utility of neurofilament light chain for early detection and prediction of disease burden and severity in neuronopathic Gaucher disease","authors":"Leah Svarny,&nbsp;Arooj Agha,&nbsp;Julia Dao,&nbsp;Bobby Sandhu,&nbsp;Margarita Ivanova,&nbsp;Ozlem Goker-Alpan","doi":"10.1016/j.ymgme.2025.109181","DOIUrl":"10.1016/j.ymgme.2025.109181","url":null,"abstract":"<div><div>Newborn screening, while enabling early diagnosis, poses challenges to correctly identifying and typing otherwise asymptomatic infants with neuropathic Gaucher disease (nGD). Glucosylsphingosine (Lyso-GL1) may be elevated at birth, but it does not help differentiate between nGD types. Neurofilament light chain (NfL), a neuronal cytoplasmic protein, is a marker for axonal damage and is associated with elevated levels in cerebrospinal fluid (CSF) and blood in lysosomal disorders characterized by neurodegeneration.</div><div>In a prospective study (<span><span>NCT02000310</span><svg><path></path></svg></span>, 13-CFCT-07), NfL and Lyso-GL1 levels were assessed along with other neurological indicators in 35 GD patients (ages 6 months to 72 years: 8 GD1, 7 GD2, 20 GD3). Eighteen patients with other LSDs—with or without neurodegeneration—served as controls. In GD2, Lyso-GL1 was markedly elevated (range: 105–457 ng/mL), and all GD2 patients with neurological manifestations had elevated NfL. In GD3, Lyso-GL1 levels were highly variable, reflecting the clinical heterogeneity. NfL was elevated in 4 of 20 GD3 patients, all of whom had clinically discernable neurological involvement. All GD1 patients had normal NfL levels (max: 0.9 (ref:&lt;1.63)) and near-normal Lyso-GL1 (maximum pretreatment: 10).</div><div>Clinically, an abnormal Auditory Brainstem Response (ABR) correlated with neurodegeneration. ABR was abnormal in all GD2 infants tested, while 65 % (13/20) of GD3 patients had normal auditory function. The combination of elevated NfL and Lyso-GL1 levels, along with abnormal ABR, can aid in the early identification of severe nGD—even in the absence of characteristic neurological symptoms—supporting the need for earlier diagnosis and timely clinical intervention.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109181"},"PeriodicalIF":3.7,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144472327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variable phenotypes and outcomes associated with the MMACHC c.1A>G variant in Chinese patients with combined methylmalonic acidemia and homocystinuria cblC type","authors":"Lili Hao ,&nbsp;Yuxin Deng ,&nbsp;Si Ding,&nbsp;Wenjuan Qiu,&nbsp;Huiwen Zhang,&nbsp;Lili Liang,&nbsp;Xia Zhan,&nbsp;Ting Chen,&nbsp;Xuefan Gu,&nbsp;Lianshu Han","doi":"10.1016/j.ymgme.2025.109182","DOIUrl":"10.1016/j.ymgme.2025.109182","url":null,"abstract":"<div><h3>Background</h3><div>Combined methylmalonic acidemia and homocystinuria cblC type (cblC) is a multisystemic disease with diverse clinical presentations and known genotype-phenotype correlations. This study aims to define and explain the phenotypes and outcomes associated with the <em>MMACHC</em> variant c.1A&gt;G (p.M1V), previously reported in several cases.</div></div><div><h3>Methods</h3><div>A retrospective review of 54 Chinese patients with cblC carrying the <em>MMACHC</em> c.1A&gt;G variant was conducted. Clinical features, including onset age, initial symptoms, biochemical index and prognosis were analyzed and compared with 100 cblC patients without this variant. The variant's pathogenicity was investigated by <em>in vitro</em> experiments.</div></div><div><h3>Results</h3><div>Twenty-nine (54 %) of 54 individuals with the c.1A&gt;G variant were diagnosed <em>via</em> newborn screening (NBS) and 23 (79 %) remained asymptomatic. Among 19 symptomatic patients, 12 (63 %) developed symptoms after 1 year of age, with cognitive decline being the most common initial symptom (55 %). Before treatment, all analyzed biochemical indexes except homocysteine showed reduced levels in the c.1A&gt;G group compared to the Control group. Post-treatment, the poor prognosis rate and some metabolite levels in the c.1A&gt;G group were significantly decreased compared to those in the Control group. Western blotting indicated that c.1A&gt;G significantly reduced MMACHC protein expression, and co-immunoprecipitation provided evidence for impaired interaction between the variant MMACHC and methionine synthase (MTR).</div></div><div><h3>Conclusions</h3><div>The c.1A&gt;G variant in <em>MMACHC</em> is associated with later-onset disease, milder phenotypes and improved clinical outcomes in cblC patients. Functional studies suggest that this variant reduces MMACHC translation efficiency and disrupts its interaction with MTR. Our findings underscore the utility of NBS for early diagnosis and better management in c.1A&gt;G-associated cblC.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109182"},"PeriodicalIF":3.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144330991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Secondary accumulation of lyso-platelet activating factors in lysosomal storage diseases","authors":"Pamela Kell ,&nbsp;Sonali Mishra ,&nbsp;Heather L. Gray-Edwards ,&nbsp;Douglas R. Martin ,&nbsp;Angel Gaudioso Guirado ,&nbsp;María Dolores Ledesma ,&nbsp;Ernesto R. Bongarzone ,&nbsp;Mark S. Sands ,&nbsp;Ellen Sidransky ,&nbsp;Daniel S. Ory ,&nbsp;Xuntian Jiang","doi":"10.1016/j.ymgme.2025.109180","DOIUrl":"10.1016/j.ymgme.2025.109180","url":null,"abstract":"<div><div>Lysosomal storage diseases (LSDs) are a group of inherited disorders caused by defects in genes that encode lysosomal enzymes, transmembrane proteins, or transport proteins. These defects typically lead to the accumulation of undegraded substrates or obstructed substances in lysosomes, serving as primary storage materials. However, in certain LSDs, secondary storage products—such as glycosphingolipids, phospholipids, and cholesterol—can also accumulate in tissues, independent of the primary enzyme or protein defect. In our recent studies, we identified lyso-platelet activating factors (lyso-PAFs) as secondary storage compounds in multiple LSDs, including Niemann-Pick disease type C1 (NPC1), GM2 activator deficiency, and GM1 gangliosidosis (GM1). Our ongoing work suggests that lyso-PAFs are also prevalent secondary storage products in Niemann-Pick disease type A (NPA), Sandhoff disease (SD), Tay-Sachs disease (TSD), and Krabbe disease (KD). We observed that elevated lyso-PAF levels were significantly correlated with the accumulation of primary storage substances in these disorders, indicating their potential as biomarkers for disease progression in these LSDs. Moreover, treatment with adeno-associated virus (AAV)-based gene therapies led to a reduction in lyso-PAF levels in the central nervous systems of TSD sheep and GM1 cats, further supporting their potential as biomarkers for therapeutic efficacy. While it remains unclear whether changes in lyso-PAFs contribute directly to disease pathology or simply reflect disease progression, further research into the enzymes involved in their synthesis and degradation is essential for uncovering their functional role in the cellular physiology and pathology of LSDs. Thus, further exploration of lyso-PAF in biofluids as prognostic and pharmacodynamic biomarkers is warranted.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109180"},"PeriodicalIF":3.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144330990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}