Molecular genetics and metabolism最新文献

{"title":"Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations","authors":"Graeme Preston ,&nbsp;Neil Jacob ,&nbsp;Ibrahim Elsharkawi ,&nbsp;Eva Morava ,&nbsp;Tamas Kozicz","doi":"10.1016/j.ymgme.2025.109197","DOIUrl":"10.1016/j.ymgme.2025.109197","url":null,"abstract":"<div><div>Primary mitochondrial diseases are a heterogeneous group of disorders caused by impaired mitochondrial respiratory chain function due to pathogenic variants in nuclear or mitochondrial DNA. These variants disrupt enzyme activity, membrane integrity, or mitochondrial genome maintenance. Phosphodiesterase type 5 (PDE5) inhibitors have recently emerged as potential modulators of mitochondrial function. Prompted by self-reported symptom improvement in an individual with mitochondrial disease taking tadalafil, we investigated the effects of PDE5 inhibitors in this context. Using high-resolution respirometry, we analyzed mitochondrial function in fibroblasts from six individuals with primary mitochondrial disease following treatment with sildenafil or tadalafil. We hypothesized that PDE5 inhibition would improve mitochondrial respiratory function and alleviate clinical symptoms. Clinical outcomes were also assessed in three individuals receiving off-label tadalafil therapy. Patient-derived fibroblasts showed elevated basal and non-mitochondrial respiration, along with increased glycolytic flux. Treatment with PDE5 inhibitors reduced proton leak-associated OCR, improved coupling efficiency, and normalized metabolic profiles. Off-label tadalafil use was associated with acute, dose-dependent, and sustained symptom improvements in all three individuals, with no adverse effects reported. In MELAS fibroblasts responses varied with m.3243 A &gt; G heteroplasmy levels. These findings suggest PDE5 inhibitors may offer safe, accessible, and personalized therapeutic options for mitochondrial diseases, particularly those involving mitochondrial DNA pathogenic variants.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109197"},"PeriodicalIF":3.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714243","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":"Progression of left ventricular mass is associated with clinical events in key subgroups of Fabry disease: Analyses from the Fabry Registry","authors":"James C. Moon ,&nbsp;Gavin Y. Oudit ,&nbsp;Julie L. Batista ,&nbsp;Kathryn M. Wilson ,&nbsp;Pronabesh DasMahapatra ,&nbsp;Derralynn Hughes ,&nbsp;Aleš Linhart","doi":"10.1016/j.ymgme.2025.109200","DOIUrl":"10.1016/j.ymgme.2025.109200","url":null,"abstract":"<div><h3>Introduction</h3><div>Cardiovascular complications are the primary cause of morbidity and mortality in Fabry disease. Despite disease-specific and adjuvant treatments, gaps in care exist. Cardiac imaging facilitates the understanding of disease progression, however data on the clinical relevance of imaging endpoints in Fabry disease are scant. Therefore, we evaluated the association between left ventricular mass index (LVMi) measured via echocardiography and risk of subsequent clinical events.</div></div><div><h3>Methods</h3><div>Adult patients from the Fabry Registry treated with enzyme replacement therapy, with echocardiography measurements and no prior kidney events were analyzed. Composite clinical events included cardiac, cerebrovascular, and kidney events, or death. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for the association between (1) baseline LVMi and (2) LVMi progression (i.e., slopes) with the risk of subsequent clinical events.</div></div><div><h3>Results</h3><div>Baseline LVMi analysis included 809 patients (53.1 % females) with median age at diagnosis [25^th, 75^th percentile]: 39.5 years [26.7, 52.2]) who had 248 clinical events, including 170 cardiac events, over 4752 and 5128 person-years, respectively. Higher baseline LVMi was associated with greater risk of composite clinical and cardiac events (adjusted HR per 10 % higher baseline LVMi: 1.09 [95 % CI: 1.04–1.13; <em>p</em> &lt; 0.001] and 1.11 [95 % CI: 1.06–1.17; <em>p</em> &lt; 0.0001], respectively). LVMi slope analysis included 377 patients with median 3-year LVMi slope [25^th, 75^th percentile] of −0.5 g/m²/year [−7.8, 7.2]; and evaluated 86 composite clinical events and 57 cardiac events, over 1899 and 2028 person-years, respectively. Increasing LVMi slope was associated with higher incidence of clinical events in key subgroups including in those with the classic Fabry phenotype, those with left ventricular hypertrophy (LVH) at baseline, those with pre-baseline clinical events and in patients with history of hypertension; adjusted HR per 10 g/m²/year increase in LVMi slope ranged from 1.16 to 1.64 (<em>p</em> &lt; 0.05).</div></div><div><h3>Conclusions</h3><div>Our study quantifies the biologically plausible association between LVMi and its progression with composite clinical events, including in key subgroups of Fabry patients.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109200"},"PeriodicalIF":3.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144827519","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 PKU Patient Registry: Development of a patient-driven registry and initial outcomes","authors":"Lauren Youngborg ,&nbsp;Christine S. Brown ,&nbsp;Eileen M. Blakely ,&nbsp;Olaf Bodamer ,&nbsp;Rhonda Connolly ,&nbsp;Kathryn D. Moseley ,&nbsp;Elaina Jurecki ,&nbsp;Kelsey McQueen ,&nbsp;Susan A. Berry","doi":"10.1016/j.ymgme.2025.109199","DOIUrl":"10.1016/j.ymgme.2025.109199","url":null,"abstract":"<div><div>A patient registry facilitates collection of data on a group of patients with similar conditions. While some registries collect clinician-input data, patient-entered registries prioritize the perspective of patients and families. To better support research for phenylketonuria (PKU), National PKU Alliance (NPKUA) launched the PKU Patient Registry in 2017 to collect patient-entered lived experience and natural history data. It gathers medical information and queries the lived experience of PKU through the completion of surveys, developed by a group of key stakeholders, individuals with PKU, and healthcare providers which includes validated tools and patient surveys. The data collected provide insights about the needs of the community and assist in recruitment for external research studies. This Registry uses the National Organization for Rare Disorders' IAMRARE® platform, as it is a secure, user-friendly system compliant with federal and state information privacy laws. The Registry and participant data are owned by NPKUA on behalf of the PKU community and are governed by NPKUA and the Registry Advisory Committee. As of November 2024, there are 1125 consented participants representing 46 states plus the District of Columbia and 36 different countries with the completion of 123,044 surveys over the past seven years. Since the Registry's inception, it has supported recruitment for over 35 external research studies and shared anonymized data through industrial and federal collaborations. The PKU Patient Registry collects longitudinal patient-entered data and allows for collaboration with other PKU datasets, permitting an improved understanding of the natural history of this condition.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109199"},"PeriodicalIF":3.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144814009","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":"Hearing rehabilitation in SERAC1 related MEGD(H)EL syndrome – implications from a multi-center retrospective cohort study","authors":"Sebastian Roesch ,&nbsp;Anna O'Sullivan ,&nbsp;Stefan Tschani ,&nbsp;Anna Baghdasaryan ,&nbsp;Shanti Balasubramaniam ,&nbsp;Ivo Barić ,&nbsp;Lonneke de Boer ,&nbsp;Sarah C. Grünert ,&nbsp;Anna Guzek ,&nbsp;Mirian Janssen ,&nbsp;Zita Krumina ,&nbsp;Mary Kay Koenig ,&nbsp;Ashleigh M. Lewkowitz ,&nbsp;Fanny Mochel ,&nbsp;Arianne Monge Naldi ,&nbsp;Barbara Plecko ,&nbsp;Kerem Öztürk ,&nbsp;Lauren O'Grady ,&nbsp;Gillian Riordan ,&nbsp;Daisy Rymen ,&nbsp;Katarzyna Iwanicka-Pronicka","doi":"10.1016/j.ymgme.2025.109193","DOIUrl":"10.1016/j.ymgme.2025.109193","url":null,"abstract":"<div><h3>Objective</h3><div>3-methylglutaconic aciduria (MEG), dystonia-deafness (D), (hepatopathy (H)), encephalopathy (E), and Leigh-like-syndrome (L) (MEGD(<em>H</em>)EL) syndrome is a rare, severely disabling progressive mitochondrial disease associated with biallelic pathogenic variants in <em>SERAC1</em>. Knowledge about hearing loss (HL) and hearing rehabilitation is scarce but highly sought after for best possible care in the absence of causative treatment.</div></div><div><h3>Methods</h3><div>Retrospective cross-sectional study.</div></div><div><h3>Results</h3><div>This study analyzed the audiometric data of 36 MEGD(<em>H</em>)EL patients (14 unpublished). Bilateral HL was diagnosed in 31 individuals (86 %). Detailed audiometric data, available for 23 of 31 patients, did not allow for general statements on site and degree of HL. HL was mostly congenital (<em>n</em> = 14/31), pre-lingual in six and post-lingual in nine cases (median age 2 years, <em>n</em> = 15/31; age unknown in <em>n</em> = 2).</div><div>In four of the five patients without HL, the severity of the other clinical-neurological symptoms was milder and less progressive, and their onset was significantly later than in the patients with HL. Five of 36 patients acquired spoken language, these were 4 of the 5 individuals without and one with HL. Twenty-two individuals received hearing rehabilitation with conventional hearing aids, followed by cochlear implant (CI) surgery in six. One of these six individuals acquired spoken language, which lessened in clarity as disease progressed.</div></div><div><h3>Conclusions</h3><div>Congenital HL represents a ubiquitous symptom in severe types of MEGD(<em>H</em>)EL syndrome, being absent in late onset milder forms. Regularly, severely affected MEGD(<em>H</em>)EL patients do not achieve spoken language, even with CI. Hence, hearing rehabilitation with CIs needs to be discussed very critically.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109193"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711099","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":"Enzymatic synthesis of 3-hydroxyacyl-CoAs of branched-chain amino acid catabolism","authors":"Shupei Wang ,&nbsp;Karine Gilbert ,&nbsp;Hao Yang ,&nbsp;Youlin Wang ,&nbsp;Marie-Christine Tang ,&nbsp;Alexandra Furtos ,&nbsp;Grant A. Mitchell","doi":"10.1016/j.ymgme.2025.109192","DOIUrl":"10.1016/j.ymgme.2025.109192","url":null,"abstract":"<div><div>Acyl-coenzyme A (CoA) thioesters occupy key positions in normal metabolism and are directly related to many inborn errors of metabolism. The degradation pathways of the branched-chain amino acids (BCAAs) are rich in acyl-CoA intermediates, many of which give rise to diagnostically important organic acids and acylcarnitines. Because several such acyl-CoAs are not routinely commercially available, they cannot be identified and quantified in biological samples. This leaves a gap in the characterization of BCAA-related inborn errors of metabolism. We attempted the enzymatic synthesis of BCAA-related 3-hydroxyacyl-CoAs, starting with the corresponding 2,3-enoyl free acids. First the 2,3-enoyl free acid is linked to CoA by purified recombinant glutaconate coenzyme A-transferase (GctAB), a bacterial CoA transferase active toward short chain acids. Then, hydration of the resulting 2,3-enoyl-acyl-CoA is catalyzed by recombinant human short-chain enoyl-CoA hydratase (ECHS1, gene <em>ECHS1</em>), producing a 3-hydroxyacyl-CoA. In this fashion, we synthesized 3-hydroxyisovaleryl-CoA, 3-hydroxyisobutyryl-CoA, 2-methyl-3-hydroxybutyryl-CoA and 3-hydroxypropionyl-CoA. All of these are detectable in normal mouse liver. We also found an unexpected peak with the same mass/charge ratio as 2-methyl-3-hydroxybutyryl-CoA. This proved to be 3-hydroxyvaleryl-CoA, an intermediate of odd chain fatty acid oxidation. All 3-hydroxyacyl-CoA intermediates of BCAA degradation are either commercially available or can be synthesized by the methods described.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109192"},"PeriodicalIF":3.7,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711097","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":"Predicting disease-overarching therapeutic approaches for congenital disorders of glycosylation using multi-OMICS","authors":"I.J.J. Muffels ,&nbsp;R. Budhraja ,&nbsp;R. Shah ,&nbsp;S. Radenkovic ,&nbsp;E. Morava ,&nbsp;T. Kozicz","doi":"10.1016/j.ymgme.2025.109195","DOIUrl":"10.1016/j.ymgme.2025.109195","url":null,"abstract":"<div><h3>Background</h3><div>Congenital Disorders of Glycosylation (CDG) are a rapidly expanding group of inherited metabolic diseases caused by defects in glycosylation. Although over 190 genetic defects have been identified, effective treatments remain available for only a few. We hypothesized that integrative analysis of multi-omics datasets from individuals with various CDG could uncover common molecular signatures and highlight shared therapeutic targets.</div></div><div><h3>Methods</h3><div>We compiled all publicly available RNA sequencing, proteomics and glycoproteomics datasets from patients with PMM2-CDG, ALG1-CDG, SRD5A3-CDG, NGLY1-CDDG, ALG13-CDG and PGM1-CDG, spanning different tissues, including induced cardiomyocytes, human cortical organoids, fibroblasts, and lymphoblasts. Differential expression and glycosylation analyses were performed, followed by Gene Set Enrichment Analysis (GSEA) to identify commonly dysregulated pathways. We then applied the EMUDRA drug prediction algorithm to prioritize candidate compounds capable of reversing these shared molecular signatures.</div></div><div><h3>Results</h3><div>We identified four glycoproteins with consistent differential glycosylation across all eight glycoproteomics datasets. Six glycosylation sites and glycan structures were recurrently altered across CDG and showed partial correction with treatment. Pathway analysis revealed shared disruptions in autophagy, vesicle trafficking, and mitochondrial function. EMUDRA predicted several repurposable drug classes, including muscle relaxants, antioxidants, beta-adrenergic agonists, antibiotics, and NSAIDs, that could reverse key pathway abnormalities, particularly those involving autophagy and N-glycosylation.</div></div><div><h3>Conclusion</h3><div>Most dysregulated pathways were shared across CDG, suggesting the potential for common therapeutic strategies. Several candidate drugs targeting these shared abnormalities emerged from integrative analysis and warrant validation in future <em>in vitro</em> studies.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109195"},"PeriodicalIF":3.5,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724815","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":"Two new cases of KYNU deficiency: Further delineation of the phenotypic and biochemical spectrum and exploration of treatment options","authors":"Susanna M.I. Goorden ,&nbsp;Désirée Y. van Haaften-Visser ,&nbsp;Maria M. Trętowicz ,&nbsp;Ramon Bonte ,&nbsp;Elly Bogaerts ,&nbsp;Youssra Jamal ,&nbsp;Sandrien Vrieswijk ,&nbsp;Erika Huijser ,&nbsp;Regina Bökenkamp ,&nbsp;Roel L.F. van der Palen ,&nbsp;Mariette J.V. Hoffer ,&nbsp;Riekelt H. Houtkooper ,&nbsp;Frédéric M. Vaz ,&nbsp;Gijs W.E. Santen ,&nbsp;Jörgen Bierau ,&nbsp;Esmeralda Oussoren","doi":"10.1016/j.ymgme.2025.109194","DOIUrl":"10.1016/j.ymgme.2025.109194","url":null,"abstract":"<div><div>Congenital NAD⁺ deficiency disorders (CNDD) represent a novel category of hereditary diseases that affect NAD⁺ biosynthesis from tryptophan. CNDD include kynureninase (KYNU) deficiency with only ten documented patients to date. Here, we report two new cases. In addition to the previously described clinical phenotype of congenital heart defects, skeletal abnormalities, hearing loss and airway malacia, our patients also had hypothyroidism, recurrent infections, and necrotizing enterocolitis. The first patient's exome analysis identified compound heterozygosity for two novel <em>KYNU</em> variants, pathogenicity being supported by extensive metabolic profiling. The second patient was homozygous for a known <em>KYNU</em> missense variant. For the first time we describe a potential treatment of KYNU deficiency as both patients were treated with oral nicotinamide (a B3 vitamer and NAD⁺ precursor) and pyridoxine (a vitamin B6, cofactor of KYNU) from young age, which improved biochemistry without evident short-term adverse effects. Furthermore, we show that maternal supplementation with nicotinamide riboside (another B3 vitamer and NAD⁺ precursor) during pregnancy appears to be safe. In conclusion, KYNU deficiency is an extremely rare disorder associated with severe congenital defects, demonstrating the indispensable role of <em>de novo</em> NAD⁺ biosynthesis in foetal development. Metabolomic profiling is a valuable tool in the analysis of new genetic variants. NAD⁺ precursor supplementation in the form of nicotinamide, combined with pyridoxine, may be a novel therapeutic approach.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109194"},"PeriodicalIF":3.7,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703038","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":"Phenotypic and genotypic description of GMPPA-congenital disorder of glycosylation: A review of 26 cases","authors":"Ruqaiah Altassan ,&nbsp;Sarah K. Aldhahri ,&nbsp;Georgia Macdonald ,&nbsp;Rameen Shah ,&nbsp;Eva Morava","doi":"10.1016/j.ymgme.2025.109196","DOIUrl":"10.1016/j.ymgme.2025.109196","url":null,"abstract":"<div><div>GMPPA-Congenital Disorder of Glycosylation (CDG) is an ultra-rare autosomal recessive CDG caused by pathogenic variants in <em>GMPPA</em> that affects the N-linked glycosylation pathway. Affected individuals present with three major symptoms: achalasia, alacrima, and impaired intellectual development during infancy. Current management of GMPPA-CDG is targeted to address patients' symptoms. To date, 23 individuals have been reported with GMPPA-CDG.</div><div>This paper reviews the clinical, biochemical and genetic characteristics of the reported 23 patients and adds 3 patients with GMPPA-CDG. We also describe the effect of oral <em>N</em>-acetylglucosamine (GlcNAc) supplementation in 3 patients.</div><div>Besides alacrima, achalasia and developmental/ intellectual disability, we noted in these patients also variable growth impairment, facial dysmorphism, hyperkeratosis, hypohidrosis, anodontia, and hearing deficit. Under treatment with GlcNAc (4–6 g/day), we noted improved tear production in our 3 patients.</div><div>Given its effect on different developmental pathways, we emphasize the need for multidisciplinary care for this multisystem disorder. We did not find a genotype/phenotype correlation in our cohort of 26 patients.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109196"},"PeriodicalIF":3.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144686788","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":"Incidence and prevalence of phosphomannomutase 2-congenital disorder of glycosylation: Past, present, and future","authors":"Andrew C. Edmondson ,&nbsp;Tomáš Honzík ,&nbsp;Christina Lam ,&nbsp;Katrin Õunap ,&nbsp;Peter McWilliams ,&nbsp;Eva Morava","doi":"10.1016/j.ymgme.2025.109188","DOIUrl":"10.1016/j.ymgme.2025.109188","url":null,"abstract":"<div><div>Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) accounts for about 60 % of all CDGs and is caused by pathogenic variants of the gene encoding PMM2, which catalyzes an essential early step in N-linked glycosylation. Efforts to derive an accurate prevalence estimate for this often life-threatening disorder, for which there are currently no approved therapies, are hampered by the wide spectrum of clinical manifestations, the rarity of the disease, and the lack of a central global patient registry. Here, we calculated new estimates of PMM2-CDG incidence and prevalence in North America and Europe based on the frequency of disease-causing alleles using the Hardy–Weinberg equation. Allele frequencies were obtained from the Genome Aggregation Database (gnomAD v4.0) and the likelihood of specific allele combinations resulting in a live birth was adjusted based on the occurrence of genotypes in patient datasets and the expected consequences for protein function. New incidence and prevalence estimates were then calculated in the context of historical ethnicity and birth data from national statistical databases, combined with estimated patient mortality rates. The calculated new incidence estimate was 1 in 33,576 for North America and Europe combined (1 in 40,375 and 29,043, respectively), which predicts an average of 303 live births per year for both regions combined since 1980. The new prevalence estimate was 1 in 63,694 (1 in 76,183 and 57,022 in North America and Europe, respectively), which translates to a total of 14,154 patients living with PMM2-CDG in North America and Europe. Notably, this prevalence is more than 5-fold higher than the current estimate of 2447 diagnosed cases combined, and 10-fold higher than the worldwide prevalence most frequently quoted in the literature. These striking differences highlight the underdiagnosis of the disease and the critical need for improved diagnostic and therapeutic strategies for PMM2-CDG.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109188"},"PeriodicalIF":3.5,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723100","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":"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}