Molecular genetics and metabolism最新文献

{"title":"The origin of abnormal organic acids in HMG-CoA synthase deficiency","authors":"F.-G. Debray , E. Van Schaftingen","doi":"10.1016/j.ymgme.2025.109177","DOIUrl":"10.1016/j.ymgme.2025.109177","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109177"},"PeriodicalIF":3.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144306275","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":"Colonic xanthomas in an adult with skeletal anomalies and dyslipidemia: Colonoscopic findings of NSDHL-related CHILD syndrome due to NSDHL haploinsufficiency","authors":"Bukola A. Olarewaju , Judy B. Tejon , Misha B. Asif , Mayowa A. Osundiji","doi":"10.1016/j.ymgme.2025.109174","DOIUrl":"10.1016/j.ymgme.2025.109174","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109174"},"PeriodicalIF":3.7,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288700","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":"Clinical and genetic features of Classic Galactosemia in the south of Brazil","authors":"Leonardo Simão Medeiros ,&nbsp;Lucas Ferreira Teixeira ,&nbsp;Alexandra Gomes ,&nbsp;Isabel Rivera ,&nbsp;Cláudia Fernandes Lorea ,&nbsp;Lilia Farret ,&nbsp;Kristiane Michelin Tirelli ,&nbsp;Fernanda Medeiros Sebastião ,&nbsp;Fernanda Bender Pasetto ,&nbsp;Carolina Fischinger Moura de Souza ,&nbsp;Fabiano de Oliveira Poswar ,&nbsp;Raquel Borges Pinto ,&nbsp;Mariana Marcano-Ruiz ,&nbsp;Fernanda Sperb-Ludwig ,&nbsp;Sandra Maria Vieira ,&nbsp;Lavínia Schuler-Faccini ,&nbsp;Ida Vanessa Doederlein Schwartz","doi":"10.1016/j.ymgme.2025.109173","DOIUrl":"10.1016/j.ymgme.2025.109173","url":null,"abstract":"<div><h3>Introduction</h3><div>Classic Galactosemia (CG) is a rare metabolic disorder that leads to acute neonatal hepatic dysfunction, with striking improvement after diet treatment. However, long-term complications, such as intellectual deficits, often persist.</div></div><div><h3>Aim</h3><div>To describe the demographic, clinical, and genetic features of CG in a cohort of patients from South Brazil.</div></div><div><h3>Methods</h3><div>Data were retrieved through medical charts review of CG patients followed in Rio Grande do Sul, Brazil.</div></div><div><h3>Results</h3><div>Thirty-one patients were included (families = 29; ethnicity: white = 20, indigenous Kaingang = 9, black = 2; female = 14). Five patients were diagnosed through private NBS and began treatment at a median age of 17 days (15–30), while others presented symptoms at 5 days (1–19) starting treatment at 27 days (5–4680). Eight patients presented Cerebral Palsy, Microcephaly, and/or Epilepsy, and two had died. Notable clinical findings were the “double cap sign” in Brain MRI (<em>n</em> = 1), pseudohyperglycemia (<em>n</em> = 3), and elevated chitotriosidase activity (n = 3). <em>GALT</em> sequencing was performed in 25/31 patients, and the most frequent causal variant found was c.563 A &gt; G (p.Gln188Arg). Two novel variants were detected: c.164G &gt; T (p.Gly55Val), associated with clinical variant galactosemia; and a novel haplotype c.[90dup; 529 A &gt; G] (p.[His31Alafs*9;Met177Val]) detected in Kaingang patients. The minimal prevalence of CG in this Indigenous population was estimated in at least 1:900 live births.</div></div><div><h3>Conclusion</h3><div>This data improves the characterization of CG in symptomatic diagnosed patients and identifies a high incidence of CG in the Kaingang people due to a founder effect.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109173"},"PeriodicalIF":3.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271537","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":"Differentiation of neonatal and infantile onset ECHS1 deficiency using SCEH enzyme activity and plasma acylcarnitine analysis","authors":"Olivia D'Annibale ,&nbsp;Whitney Phinney ,&nbsp;Molly Crenshaw ,&nbsp;Mary Kate LoPiccolo ,&nbsp;Ibrahim Elsharkawi ,&nbsp;Emily Shelkowitz ,&nbsp;Daniel Pique ,&nbsp;Rodrigo T. Starosta ,&nbsp;Austin Larson ,&nbsp;Johan L.K. Van Hove ,&nbsp;Tim Wood ,&nbsp;Aaina Kochhar","doi":"10.1016/j.ymgme.2025.109156","DOIUrl":"10.1016/j.ymgme.2025.109156","url":null,"abstract":"<div><div>Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is an autosomal recessive disorder that presents in the neonatal or infantile period with encephalopathy and lactic acidosis. Biomarkers are variable, with many ECHS1D patients having elevated plasma C4-carnitine and urine 2-methyl-2,3-dihydroxybutyric acid while others have none. Neonates often succumb prior to molecular sequencing results being returned. ECHS1D diagnosis may be faster if biomarkers are used in plasma and urine along with enzyme activity measurement. Short-chain enoyl-CoA hydratase activity was performed in six ECHS1D fibroblasts with neonatal or infantile onset. DBS cards were obtained from two patients and one carrier. Control fibroblasts (<em>n</em> = 11) activity was 229.62 ± 68.52 nmol/min/mg. Neonatal ECHS1D fibroblasts activity was 3.92 ± 0.62 nmol/min/mg. Infantile onset ECHS1D fibroblasts activity was 17.27 ± 2.14 nmol/min/mg. Control DBS SCEH activity was 141.18 ± 34.00 nmol/min/mg (<em>n</em> = 10) and one neonatal and infantile patient sample showed approximately 2 % and 27 % activity, respectively. One carrier had 45 % activity. We described five new cases of ECHS1D and analyzed seven total cases. We determined SCEH activity reference ranges in neonatal and infantile onset ECHS1D fibroblasts. For the first time, we demonstrated SCEH activity in DBS with separation between ECHS1D and controls. SCEH activity in DBS could allow for newborn screening for ECHS1D as new treatments are developed.</div></div><div><h3>Synopsis</h3><div>Neonatal and infantile onset ECHS1D can be differentiated via fibroblast and dried blood spot short-chain enoyl-CoA hydratase activity and detection of plasma S-(2-carboxypropyl)cysteine carnitine species to allow for faster diagnosis and prompt treatment.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109156"},"PeriodicalIF":3.7,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279157","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":"Treatment preferences of adult patients with hereditary fructose intolerance: A discrete choice experiment","authors":"Lise E.F. Janssen ,&nbsp;Mickaël Hiligsmann ,&nbsp;Corrie Timmer ,&nbsp;Liesbeth M.C. van der Ploeg ,&nbsp;Kristel Vande Kerckhove ,&nbsp;Timothy Cox ,&nbsp;Javier de las Heras ,&nbsp;David Cassiman ,&nbsp;Martijn C.G.J. Brouwers","doi":"10.1016/j.ymgme.2025.109169","DOIUrl":"10.1016/j.ymgme.2025.109169","url":null,"abstract":"<div><h3>Background</h3><div>Patients with hereditary fructose intolerance (HFI) follow a fructose-restricted diet to avoid life-threatening complications. The aim of this study was to investigate whether patients with HFI have a preference for a pharmacological therapy as an add-on or replacement of their current diet.</div></div><div><h3>Methods</h3><div>Adult patients with HFI recruited from metabolic clinics and through social media (<em>n</em> = 90) were asked to complete a labelled discrete choice experiment (DCE). The DCE was composed after personal interviews with patients (<em>n</em> = 3) and health care providers (<em>n</em> = 6), and contained 12 choice sets. In each choice set, patients were asked to choose between their current fructose-restricted diet or pharmacological therapy, which consisted of four attributes: side effects, costs, mode of administration and effect on fructose restriction.</div></div><div><h3>Results</h3><div>Although the random parameter model showed that patients on average preferred their current diet over a putative pharmacological therapy, 86 % of the patients opted for pharmacological therapy in at least one of the choice tasks. One tablet daily on special occasions without any fructose restriction, no side effects and no additional costs were significantly associated with a preference for pharmacological therapy. Younger age, more daily impact of the disease and more daily impact of the dietary restriction were associated with a preference for pharmacological therapy.</div></div><div><h3>Conclusions</h3><div>Under specific conditions, patients with HFI prefer a pharmacological therapy over their fructose-restricted diet. Therapy-related factors as well as patient-related factors play a role in this choice. These findings may guide the development and implementation of a pharmacologic therapy for patients with HFI.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109169"},"PeriodicalIF":3.7,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144254874","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":"Cover 2 / Ed. Board","authors":"","doi":"10.1016/S1096-7192(25)00153-2","DOIUrl":"10.1016/S1096-7192(25)00153-2","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109162"},"PeriodicalIF":3.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144230184","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":"Clinical, metabolic, and genetic characteristics of 42 children with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency in China","authors":"Yang Liu ,&nbsp;Danmin Shen ,&nbsp;Tianyu Song ,&nbsp;Chaolong Xu ,&nbsp;Xin Duan ,&nbsp;Minhan Song ,&nbsp;Tongyue Li ,&nbsp;Ying Zou ,&nbsp;Ruoyu Duan ,&nbsp;Zhimei Liu ,&nbsp;Suzhou Zhao ,&nbsp;Fang Fang","doi":"10.1016/j.ymgme.2025.109158","DOIUrl":"10.1016/j.ymgme.2025.109158","url":null,"abstract":"<div><h3>Objective</h3><div>To summarize clinical characteristics of the largest Chinese cohort of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D) and analyze the genotype-phenotype correlations.</div></div><div><h3>Methods</h3><div>This retrospective study enrolled 42 children with genetically diagnosed ECHS1D within the China Mitochondrial Disease Network. Patients were classified into severe infantile (SI), slowly progressive infantile (SPI), and late-onset phenotype (LP) based on onset age, disease progression rate, and gross motor impairment severity. Prognosis was assessed using the Modified Rankin Scale(mRS).</div></div><div><h3>Results</h3><div>Forty-two patients (25 male) were included, with a median onset age of 13.5 months (range 3–60). Paroxysmal dystonia (PD, 33.3 %) was the most common initial symptoms, followed by developmental delay(28.6 %) and regression(21.4 %). All patients had globus pallidus involvement and were diagnosed with Leigh syndrome (SI, <em>n</em> = 18; SPI, <em>n</em> = 13; LP, <em>n</em> = 11). SI cases all started with non-paroxysmal dystonia, and showed more frequent putamen (77.8 %) and caudate nucleus (72.2 %) involvement. In SPI and LP cases, PD was more common at onset, with milder symptoms and often isolated globus pallidus involvement. The proportions of elevated urinary metabolic markers 2,3-dihydroxy-2-methylbutyrate (2,3DH2MB) and S-(2-carboxypropyl) cysteamine (SCPCM) were 89.7 % and 93.1 % respectively, and the degree of their elevation was significantly correlated with phenotype severity. Regarding overall prognosis, 52.4 % of patients could walk independently (mRS &lt; 4), with three fatalities. SI cases had the worst prognosis, followed by SPI, while LP cases showed the best outcomes (<em>p</em> &lt; 0.05). In terms of genetics, all patients were compound heterozygous variants in the <em>ECHS1</em> gene, with 21 novel variants identified. The most common variant was the c.489G &gt; A (p.Pro163=) variant, which was found in 18 patients, accounting for as high as 42.8 % (allele frequency 0.214). And patients carrying this synonymous variant exhibited later onset age, longer diagnostic duration, milder phenotypes.</div></div><div><h3>Conclusions</h3><div>This study provides a comprehensive overview of ECHS1D, summarizing its clinical and genetic spectrum, and indicating that the c.489G &gt; A variant is a potential hotspot in the Chinese population. As findings from single-center studies may not be generalizable to a broader population, multi-center prospective studies are warranted.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109158"},"PeriodicalIF":3.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271536","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":"Doxecitine and doxribtimine treatment in an adult patient with thymidine kinase 2 deficiency","authors":"Elsbeth Chow ,&nbsp;Lindsey Miller ,&nbsp;Anna Clearman ,&nbsp;Patricia Arnold ,&nbsp;Mary Kay Koenig ,&nbsp;S. Nicholas Russo","doi":"10.1016/j.ymgme.2025.109159","DOIUrl":"10.1016/j.ymgme.2025.109159","url":null,"abstract":"<div><div>Thymidine kinase 2 (TK2) deficiency is an ultrarare mitochondrial depletion and deletion syndrome characterized by mutations in the nuclear <em>TK2</em> gene responsible for encoding the mitochondrial thymidine kinase 2 enzyme. TK2's role is to phosphorylate the nucleosides deoxycytidine (dC) and deoxythymidine (dT) required for mitochondrial DNA (mtDNA) replication; therefore, deficient TK2 enzymes result in dysfunctional replication of mtDNA. TK2 deficiency presents in children as progressive muscle weakness, respiratory difficulty, and mtDNA depletion. Fewer than 120 patients have been described in medical literature, and there are currently no FDA-approved treatments for TK2 deficiency. Provision of exogenous deoxynucleosides (dC/dT) allow for replication of mtDNA via cytosolic enzymes thymidine kinase 1 (TK1) and deoxycytidine kinase (dCK), as well as any residual TK2 activity. Here we describe a 26-year-old female with childhood-onset TK2 deficiency characterized by progressive myopathy, fatigue, weight loss, atrophy, bone fractures, dysphagia, neuropathy, and respiratory failure. With initiation of deoxynucleoside therapy and multiple therapy modalities (physical, occupational, and speech), her rate of decline slowed and she has shown steady improvement.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109159"},"PeriodicalIF":3.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271535","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":"C4OH-carnitine: an important marker of ketosis in patients with and without inborn errors of metabolism","authors":"Maria Laura Duque Lasio ,&nbsp;Maria Zaitsev ,&nbsp;Judith A. Hobert ,&nbsp;Irene De Biase ,&nbsp;Marzia Pasquali ,&nbsp;Tatiana Yuzyuk","doi":"10.1016/j.ymgme.2025.109160","DOIUrl":"10.1016/j.ymgme.2025.109160","url":null,"abstract":"<div><h3>Background</h3><div>Elevated C4OH (3-hydroxybutyryl−/3-hydroxyisobutyryl-) carnitine has been reported in physiologic ketosis, secondary to ketogenic diet, and is also observed in several Inborn Errors of Metabolism (IEMs). However, the reliability of plasma C4OH-carnitine as a marker of ketosis on routine acylcarnitine testing has not been extensively studied. The goal of this study was to correlate the plasma C4OH-carnitine levels with the measurements of plasma/serum β-hydroxybutyrate (BHB). We also investigated the prevalence of elevated C4OH-carnitine in different IEMs.</div></div><div><h3>Methods</h3><div>We conducted a retrospective analysis of &gt;75,000 samples sent to our laboratory for plasma acylcarnitine analysis. The concentrations of C4OH-carnitine and BHB were correlated in 559 samples with concurrent BHB and acylcarnitine profile (ACP). BHB was also directly measured in 151 samples submitted for acylcarnitine analysis. The range of C4OH-carnitine concentrations and the frequency of elevated C4OH-carnitine was evaluated in &gt;2000 samples from patients with known diagnosis of IEM.</div></div><div><h3>Results</h3><div>We observed a strong correlation between C4OH-carnitine and BHB concentration (Spearman coefficient <em>r</em> &gt; 0.80, <em>p</em> &lt; 0.0001). The overall concordance between C4OH-carnitine and BHB results in analyzed samples was 84 % with negative and positive predictive values of 74 % and 96 %, respectively. In the IEM cohort, isolated elevations of C4OH-carnitine were consistently present in a patient with L-3-hydroxyacyl-CoA dehydrogenase deficiency. A large number of samples from patients with beta-ketothiolase deficiency, methylmalonic acidemia (MMA) and propionic acidemia (PA) had high C4OH-carnitine (35 %, 21 % and 17 %, respectively) reflecting ketosis. Abnormal C4OH-carnitine was less commonly seen in multiple acyl-CoA dehydrogenase deficiency (7.7 %), very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, 5.8 %), glutaric acidemia type 1 (4.6 %), and medium-chain acyl-CoA dehydrogenase deficiency (0.4 %). Significantly higher concentrations of diagnostic acylcarnitine species were observed in MMA, PA and VLCADD samples with elevated C4OH-carnitine <em>vs</em> samples with normal C4OH-carnitine even after correcting for free carnitine.</div></div><div><h3>Conclusion</h3><div>Plasma C4OH-carnitine concentration showed a strong positive correlation with plasma/serum concentrations of BHB, demonstrating that elevated C4OH-carnitine is a reliable marker of ketosis. Elevated C4OH-carnitine in individuals with IEMs could indicate catabolic state and should prompt additional metabolic and nutritional evaluations to prevent metabolic decompensation.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109160"},"PeriodicalIF":3.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223324","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":"Fabry disease - a risk factor for renal cell cancer? - case series","authors":"Subadra Wanninayake ,&nbsp;L. van Dussen ,&nbsp;Antonio Ochoa-Ferraro ,&nbsp;Rupesh I Bhatt ,&nbsp;Charlotte Dawson ,&nbsp;Mirjam Langeveld ,&nbsp;Tarekegn Geberhiwot","doi":"10.1016/j.ymgme.2025.109157","DOIUrl":"10.1016/j.ymgme.2025.109157","url":null,"abstract":"<div><h3>Introduction</h3><div>Fabry disease (FD) is an X-linked lysosomal storage disease characterised by glycosphingolipid globotriaosylceramide (Gb3) accumulation in the lysosomes of multiple organs including the kidneys. Anecdotally we observed a higher-than-expected incidence of renal cell carcinoma (RCC) in FD patients.</div></div><div><h3>Methods</h3><div>Retrospective, observational study at two specialist national centres for lysosomal storage disorders (LSD) in the UK and Netherlands looking after a total of 520 patients with FD, 289 with a classical phenotype and 231 with non-classical ‘cardiac variant’ phenotype.</div></div><div><h3>Results</h3><div>There were 11/520 (equivalent 70.5/100000/year) incidences in 10 patients with an additional diagnosis of RCC. The median (IQR) age at RCC diagnosis was 55 (39–59) years. 5/10 were identified incidentally. RCC affected 6/289 (2.1 %) patients with classical Fabry disease and 5/231 (2.2 %) with the non-classical phenotype. The median (range) plasma lyso-Gb3 concentration was 21.6 (2.9–95.6 nmol/L). 55 % of RCCs were diagnosed before starting disease modifying treatment, the remaining were diagnosed 5–18 years after the start of treatment. Commonest subtype was clear-cell-RCC (7/11 incidences with 7 patients having WHO/ISUP grade 2 or above tumours. 3 had papillary-RCC (1 had two episodes at age 27 and 39).</div></div><div><h3>Conclusion</h3><div>The annual incidence of RCC in patients with FD was higher than the peak global incidence (70.5 vs 4.6/100000/year) and occurred at a younger age. FD may be an independent risk factor for RCC. This suggests that routine screening for RCC may be beneficial in patients with FD.</div><div><strong>Key learning points:</strong> Fabry disease may be an independent risk factor for renal cell carcinoma.</div><div><strong>What was known:</strong> Renal involvement, primarily progressive chronic kidney disease (CKD) is a well-known manifestation of Fabry disease.</div><div><strong>This study adds:</strong> Our findings indicate a significant increase in RCC among patients with FD.</div><div><strong>Potential impact:</strong> Effective screening tool will be available for patient with this genetic condition and further research into the mechanisms by which GLA gene variants increase RCC risk may enhance our understanding of RCC pathophysiology and inform the development of new therapeutic approaches.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109157"},"PeriodicalIF":3.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144229647","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}