Pub Date : 2025-09-01DOI: 10.1016/j.ymgme.2025.109238
Rui-Lan Cheng , Jian-Wu Qiu , Qin Zhou , Joseph Hong Saberon , Jian Shi , Mei Deng , Li Guo , Feng-Ping Chen , Wei-Xia Lin , Yuan-Zong Song
Objective
Citrin deficiency (CD), caused by biallelic pathogenic variants in SLC25A13, remains underdiagnosed due to allelic heterogeneity, variants of uncertain significance (VUS), and technical limitations. This study aimed to improve the diagnosis of CD by identifying novel pathogenic SLC25A13 variants and characterizing the variant spectrum and geographic distribution in a large Chinese pediatric cohort.
Methods
Polymerase chain reaction (PCR)-based methods and Sanger sequencing were performed to identify pathogenic SLC25A13 variants in 220 pediatric patients with clinically suspected CD and their parents from 2016 to 2024. We functionally validated novel missense and splice-site variants using agc1-knockout yeast modeling and minigene assays, respectively. Data from these 191 newly diagnosed CD patients (2016–2024) were combined with data from 274 previously reported CD cases (2005–2016) and from 186 additional CD patients diagnosed via next-generation sequencing since 2016. The SLC25A13 variant spectrum and geographic distribution were then analyzed in this combined cohort. Statistical analyses were performed using Chi-square/Fisher's exact tests and one-way analysis of variance, as appropriate.
Results
A large cohort of 651 CD patients was assembled, and 13 novel pathogenic SLC25A13 variants were identified, including c.177_189del, c.188del, c.212 + 3 A > G, c.889G > T, c.1193 T > A, c.1210G > T, c.1352 T > A, c.1620del, c.1722del, c.1799_1800insAAA, c.1853_1855dup, c.1603_1609dup, and c.819-16 T > A. The most frequent variants were c.852_855del (57.56 %), c.1751-5_1751–4ins(2684) (10.06 %), c.1638_1660dup (8.42 %), and c.615 + 5G > A (7.93 %). The variant c.329-3_329-2ins(6072) ranked fifth at 2.13 %. In the Chinese mainland, the variant c.852_855del was most prevalent in southern and southwestern provinces, c.1638_1660dup was enriched in eastern coastal regions, and c.1751-5_1751–4ins(2684) reached its highest frequency in Sichuan Province (29.7 %).
Conclusions
The study established the largest CD cohort to date, expanded the SLC25A13 variant spectrum, and delineated the distinct geographic distribution of these variants. These findings refined diagnostic protocols and emphasized the necessity for population-tailored genetic screening to optimize early diagnosis of CD.
目的：由于等位基因异质性、不确定意义变异（VUS）和技术限制，SLC25A13双等位基因致病变异引起的卵黄素缺乏症（CD）仍未得到充分诊断。本研究旨在通过鉴定新的致病SLC25A13变异，并在中国大型儿科队列中描述变异谱和地理分布，以提高CD的诊断水平。方法采用聚合酶链反应（PCR）方法和Sanger测序对2016 - 2024年220例临床疑似CD患儿及其父母的SLC25A13致病变异进行鉴定。我们分别使用agc1敲除酵母模型和迷你基因分析对新的错义和剪接位点变异进行了功能验证。来自这191名新诊断的CD患者（2016 - 2024）的数据与先前报告的274例CD病例（2005-2016）的数据以及自2016年以来通过下一代测序诊断的额外186例CD患者的数据相结合。然后在这个联合队列中分析SLC25A13变异谱和地理分布。采用卡方/费雪精确检验和单因素方差分析进行统计分析。结果对651例CD患者进行了大队列分析，鉴定出13种新的SLC25A13致病变异，包括c.177_189del、c.188del、c.212 + 3 A > G、c.889G > T、c.1193T >； A, c.1210G >； T, c.1352T > A、c.1620del、c.1722del、c.1799_1800insAAA、c.1853_1855dup、c.1603_1609dup和c.819-16 T >； A最常见的变异是c.852_855del（57.56%）、c.1751-5_1751-4ins(2684)（10.06%）、c.1638_1660dup（8.42%）和c.615 + 5G >； A（7.93%）。改型c.329-3_329-2ins（6072）排在第5位，为2.13%。在中国大陆，c.852_855del变异在南部和西南省份最为普遍，c.1638_1660dup富集于东部沿海地区，c.1751-5_1751-4ins（2684）在四川省出现频率最高（29.7%）。该研究建立了迄今为止最大的CD队列，扩展了SLC25A13变异谱，并描绘了这些变异的独特地理分布。这些发现完善了诊断方案，并强调了针对人群进行遗传筛查以优化乳糜泻早期诊断的必要性。
{"title":"Identification of 13 novel pathogenic SLC25A13 variants and comparison of the genetic spectrum among different geographic regions: Molecular characterization of a large cohort of citrin deficiency in China","authors":"Rui-Lan Cheng , Jian-Wu Qiu , Qin Zhou , Joseph Hong Saberon , Jian Shi , Mei Deng , Li Guo , Feng-Ping Chen , Wei-Xia Lin , Yuan-Zong Song","doi":"10.1016/j.ymgme.2025.109238","DOIUrl":"10.1016/j.ymgme.2025.109238","url":null,"abstract":"<div><h3>Objective</h3><div>Citrin deficiency (CD), caused by biallelic pathogenic variants in <em>SLC25A13</em>, remains underdiagnosed due to allelic heterogeneity, variants of uncertain significance (VUS), and technical limitations. This study aimed to improve the diagnosis of CD by identifying novel pathogenic <em>SLC25A13</em> variants and characterizing the variant spectrum and geographic distribution in a large Chinese pediatric cohort.</div></div><div><h3>Methods</h3><div>Polymerase chain reaction (PCR)-based methods and Sanger sequencing were performed to identify pathogenic <em>SLC25A13</em> variants in 220 pediatric patients with clinically suspected CD and their parents from 2016 to 2024. We functionally validated novel missense and splice-site variants using agc1-knockout yeast modeling and minigene assays, respectively. Data from these 191 newly diagnosed CD patients (2016–2024) were combined with data from 274 previously reported CD cases (2005–2016) and from 186 additional CD patients diagnosed via next-generation sequencing since 2016. The <em>SLC25A13</em> variant spectrum and geographic distribution were then analyzed in this combined cohort. Statistical analyses were performed using Chi-square/Fisher's exact tests and one-way analysis of variance, as appropriate.</div></div><div><h3>Results</h3><div>A large cohort of 651 CD patients was assembled, and 13 novel pathogenic <em>SLC25A13</em> variants were identified, including c.177_189del, c.188del, c.212 + 3 A > G, c.889G > T, c.1193 T > A, c.1210G > T, c.1352 T > A, c.1620del, c.1722del, c.1799_1800insAAA, c.1853_1855dup, c.1603_1609dup, and c.819-16 T > A. The most frequent variants were c.852_855del (57.56 %), c.1751-5_1751–4ins(2684) (10.06 %), c.1638_1660dup (8.42 %), and c.615 + 5G > A (7.93 %). The variant c.329-3_329-2ins(6072) ranked fifth at 2.13 %. In the Chinese mainland, the variant c.852_855del was most prevalent in southern and southwestern provinces, c.1638_1660dup was enriched in eastern coastal regions, and c.1751-5_1751–4ins(2684) reached its highest frequency in Sichuan Province (29.7 %).</div></div><div><h3>Conclusions</h3><div>The study established the largest CD cohort to date, expanded the <em>SLC25A13</em> variant spectrum, and delineated the distinct geographic distribution of these variants. These findings refined diagnostic protocols and emphasized the necessity for population-tailored genetic screening to optimize early diagnosis of CD.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109238"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117813","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}
Pub Date : 2025-09-01DOI: 10.1016/j.ymgme.2025.109227
Aaron Williams , Monika Weisz-Hubshman , Vittoria Rossi , Emily Bland , Elizabeth Mizerik , Xi Luo , Paul R. Hillman , Kathleen Shields , Fernando Scaglia
Triosephosphate isomerase (TPI) is a ubiquitously expressed enzyme encoded by the TPI1 gene. It catalyzes the interconversion of the triose phosphate isomers dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in the fifth step of glycolysis. TPI deficiency (TPI Df; MIM# 615512) is an autosomal recessive disorder due to biallelic pathogenic variants in TPI1. In keeping with other glycolytic enzymopathies, severe hemolytic anemia is a common finding. Additionally, many individuals with TPI Df develop neuromuscular symptoms, which is unusual for a glycolytic enzymopathy. There appears to be a genotype-phenotype correlation between a TPI1 p.Glu105Asp/null genotype and a severe life-limiting neuromuscular phenotype. Tpi1-deficient mice with a p.Glu105Asp/null genotype recapitulate the life-limiting neuromuscular phenotype seen in humans, but the exact pathomechanism remains unclear. Here we describe a 2-month-old male proband who presented with failure to thrive, respiratory failure, seizures, and severe hemolytic anemia, who passed away at 3 months of age. Trio whole genome sequencing showed compound heterozygous variants with the common p.Glu105Asp variant in trans to a newly described likely pathogenic splice site c.324 + 1G > C variant, predicted to cause nonsense mediated decay. Here we review our case as well as the literature to hypothesize a mechanism by which TPI Df due to a p.Glu105Asp/null genotype causes severe disease. Given the overall fatal nature of this condition, novel therapeutic approaches are urgently needed. Currently, treatments are experimental. Ketogenic diet and triheptanoin were effective in treating seizures in a TPI mutant Drosophila, known as TPIsugarkill, although clinical data in humans is lacking. Additionally, bone marrow transplant has been shown to improve the hematologic phenotype in mice and has been done in an isolated number of patients. While there are no proven therapies available at this time, we hope this review will lead the discussion to consider future therapeutic options.
{"title":"TPI deficiency: A case report and review of the literature","authors":"Aaron Williams , Monika Weisz-Hubshman , Vittoria Rossi , Emily Bland , Elizabeth Mizerik , Xi Luo , Paul R. Hillman , Kathleen Shields , Fernando Scaglia","doi":"10.1016/j.ymgme.2025.109227","DOIUrl":"10.1016/j.ymgme.2025.109227","url":null,"abstract":"<div><div>Triosephosphate isomerase (TPI) is a ubiquitously expressed enzyme encoded by the <em>TPI1</em> gene. It catalyzes the interconversion of the triose phosphate isomers dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in the fifth step of glycolysis. TPI deficiency (TPI Df; MIM# <span><span>615512</span><svg><path></path></svg></span>) is an autosomal recessive disorder due to biallelic pathogenic variants in <em>TPI1</em>. In keeping with other glycolytic enzymopathies, severe hemolytic anemia is a common finding. Additionally, many individuals with TPI Df develop neuromuscular symptoms, which is unusual for a glycolytic enzymopathy. There appears to be a genotype-phenotype correlation between a <em>TPI1</em> p.Glu105Asp/null genotype and a severe life-limiting neuromuscular phenotype. <em>Tpi1</em>-deficient mice with a p.Glu105Asp/null genotype recapitulate the life-limiting neuromuscular phenotype seen in humans, but the exact pathomechanism remains unclear. Here we describe a 2-month-old male proband who presented with failure to thrive, respiratory failure, seizures, and severe hemolytic anemia, who passed away at 3 months of age. Trio whole genome sequencing showed compound heterozygous variants with the common p.Glu105Asp variant <em>in trans</em> to a newly described likely pathogenic splice site c.324 + 1G > C variant, predicted to cause nonsense mediated decay. Here we review our case as well as the literature to hypothesize a mechanism by which TPI Df due to a p.Glu105Asp/null genotype causes severe disease. Given the overall fatal nature of this condition, novel therapeutic approaches are urgently needed. Currently, treatments are experimental. Ketogenic diet and triheptanoin were effective in treating seizures in a TPI mutant <em>Drosophila,</em> known as <em>TPI</em><sup><em>sugarkill</em></sup><em>,</em> although clinical data in humans is lacking. Additionally, bone marrow transplant has been shown to improve the hematologic phenotype in mice and has been done in an isolated number of patients. While there are no proven therapies available at this time, we hope this review will lead the discussion to consider future therapeutic options.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109227"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923004","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}
Pub Date : 2025-09-01Epub Date: 2025-07-29DOI: 10.1016/j.ymgme.2025.109215
Mildrid Yeo, Jeannette Lay Kuan Goh, Ai Ling Koh, Nikki Fong, Ee Shien Tan, Saumya Jamuar, Chew Yin Jasmine Goh, Eunice Lim, Sherry Poh, Soon Chuan James Lim, Sylvia Kam, Breana Cham, Jiin Ying Lim, Kong Boo Phua, Fang Kuan Chiou, Veena Logarajah, Christopher Wen Wei Ho, Lay Queen Ng, Sarah Ailyne Wong, Lynette Goh, Christine Ong, Grace Quek, Chengsi Ong, Kar Yin Phuah, Teck Wah Ting
Background: Citrin deficiency (CD) is a pan-ethnic autosomal recessive inborn error of metabolism due to-pathogenic variants in the SLC25A13 gene which results in disruptions of multiple metabolic pathways including glycolysis, gluconeogenesis, lipogenesis, the urea cycle, and tricarboxylic cycle.
Methods: A retrospective observational study of CD patients managed according to standard clinical practice at a single centre in Singapore (KK Women's and Children's Hospital, KKH) was undertaken from August 2016-August 2024. We present the largest cohort of patients reported in Southeast Asia focusing on clinical, biochemical and imaging findings at diagnosis, and long-term outcomes/management (including drug therapy, food preferences/adherence, hospital admissions, growth, neurodevelopmental, biochemical, and imaging outcomes). We also explore the utility of newborn screening (NBS) as a means for early detection of CD.
Results: Eighteen CD patients (9 males; 2 sibling pairs) majority of Chinese ethnicity (n = 16) with a median duration of follow up 5 years 5 months, participated in this study. Median age at first presentation and at diagnosis was 50 days and 82 days, respectively. Fourteen patients presented with neonatal intrahepatic cholestasis caused by CD (NICCD), 2 asymptomatic from sibling screens, and two from abnormalities on NBS (one presenting with unconjugated hyperbilirubinaemia and the other with cholestasis and liver failure). Two patients had liver failure (one from NICCD group and another from NBS group). None required liver transplantation. All symptomatic patients had raised citrulline and threonine-serine ratios at presentation. None of the patients was prescribed any regular concomitant medications except for MCT oil. No genotype phenotype correlation was observed. At final assessment, all patients showed normalisation of liver parameter, galactose and plasma amino acids. Abnormalities in lipid profile in 9 patients (age 5-16 years) showed borderline high total cholesterol (median 5.4 mmol/L) and LDL (median 3.0 mmol/L) which was on the higher end of the normal range. Sixty-six percent of patients liver imaging findings were normal or showed stable changes. Food preferences (assessed in ≥1-year olds) did not reflect a clear bias towards high protein/fat diet. Adherence appeared to improve with a more prescriptive approach, it waned with age (more so in dietary aspects versus the use of MCT oil). Hospital admissions were few (median 1/patient) and unrelated to CD. Overall improvements were seen in weight, height and BMI for age z-scores, showing median weight/height/BMI for age z-scores to be -0.72, -0.83, 0.08, respectively. None had neurodevelopmental concerns.
Conclusion: CD remains challenging to diagnose biochemically at all ages. Current NBS strategies require further refining to increase pick up rates of CD. Cascade screening utilising g
{"title":"Deep phenotyping of patients with citrin deficiency in Singapore- single centre experience.","authors":"Mildrid Yeo, Jeannette Lay Kuan Goh, Ai Ling Koh, Nikki Fong, Ee Shien Tan, Saumya Jamuar, Chew Yin Jasmine Goh, Eunice Lim, Sherry Poh, Soon Chuan James Lim, Sylvia Kam, Breana Cham, Jiin Ying Lim, Kong Boo Phua, Fang Kuan Chiou, Veena Logarajah, Christopher Wen Wei Ho, Lay Queen Ng, Sarah Ailyne Wong, Lynette Goh, Christine Ong, Grace Quek, Chengsi Ong, Kar Yin Phuah, Teck Wah Ting","doi":"10.1016/j.ymgme.2025.109215","DOIUrl":"10.1016/j.ymgme.2025.109215","url":null,"abstract":"<p><strong>Background: </strong>Citrin deficiency (CD) is a pan-ethnic autosomal recessive inborn error of metabolism due to-pathogenic variants in the SLC25A13 gene which results in disruptions of multiple metabolic pathways including glycolysis, gluconeogenesis, lipogenesis, the urea cycle, and tricarboxylic cycle.</p><p><strong>Methods: </strong>A retrospective observational study of CD patients managed according to standard clinical practice at a single centre in Singapore (KK Women's and Children's Hospital, KKH) was undertaken from August 2016-August 2024. We present the largest cohort of patients reported in Southeast Asia focusing on clinical, biochemical and imaging findings at diagnosis, and long-term outcomes/management (including drug therapy, food preferences/adherence, hospital admissions, growth, neurodevelopmental, biochemical, and imaging outcomes). We also explore the utility of newborn screening (NBS) as a means for early detection of CD.</p><p><strong>Results: </strong>Eighteen CD patients (9 males; 2 sibling pairs) majority of Chinese ethnicity (n = 16) with a median duration of follow up 5 years 5 months, participated in this study. Median age at first presentation and at diagnosis was 50 days and 82 days, respectively. Fourteen patients presented with neonatal intrahepatic cholestasis caused by CD (NICCD), 2 asymptomatic from sibling screens, and two from abnormalities on NBS (one presenting with unconjugated hyperbilirubinaemia and the other with cholestasis and liver failure). Two patients had liver failure (one from NICCD group and another from NBS group). None required liver transplantation. All symptomatic patients had raised citrulline and threonine-serine ratios at presentation. None of the patients was prescribed any regular concomitant medications except for MCT oil. No genotype phenotype correlation was observed. At final assessment, all patients showed normalisation of liver parameter, galactose and plasma amino acids. Abnormalities in lipid profile in 9 patients (age 5-16 years) showed borderline high total cholesterol (median 5.4 mmol/L) and LDL (median 3.0 mmol/L) which was on the higher end of the normal range. Sixty-six percent of patients liver imaging findings were normal or showed stable changes. Food preferences (assessed in ≥1-year olds) did not reflect a clear bias towards high protein/fat diet. Adherence appeared to improve with a more prescriptive approach, it waned with age (more so in dietary aspects versus the use of MCT oil). Hospital admissions were few (median 1/patient) and unrelated to CD. Overall improvements were seen in weight, height and BMI for age z-scores, showing median weight/height/BMI for age z-scores to be -0.72, -0.83, 0.08, respectively. None had neurodevelopmental concerns.</p><p><strong>Conclusion: </strong>CD remains challenging to diagnose biochemically at all ages. Current NBS strategies require further refining to increase pick up rates of CD. Cascade screening utilising g","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1-2","pages":"109215"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804453","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}
Pub Date : 2025-09-01DOI: 10.1016/j.ymgme.2025.109233
Donna L. Bernstein , Inga Peter , Robert J. Desnick
Purpose
This study was designed to more accurately estimate the prevalence of severe, infantile onset, rapidly progressive lysosomal acid lipase deficiency (LALD), an autosomal recessive disorder caused by the homoallelic LIPA gene variant, c.260G>T; p.G87V in patients of Mizrahi Jewish ancestry. The previous estimates of LALD prevalence in Middle Eastern and Mizrahi Jewish populations, ranging from 1 in 12,100 to 1 in 4200, were based on historic, observational case reports and a population genetic screening of 165 Middle Eastern individuals and 162 Mizrahi Jews living in Southern California.
Methods
Carrier screening of 549 Mizrahi Jewish individuals for the c.260G>T; p.G87V LIPA variant and the common, c.894G>A; p.E8SJM-1LIPA variant, was carried out to determine their allele frequencies and expected prevalence of LALD in a larger Mizrahi population.
Results
This larger population screening study revealed a LIPA p.G87V Mizrahi founder variant allele frequency of 1 in 52.2, conferring a carrier frequency of 1 in 26.1. Therefore, the occurrence of infantile LALD was estimated to be one in 2724.8 Mizrahi Jewish conceptions in Southern California.
Conclusion
The present, larger study found the prevalence of rapidly progressive, infantile LALD disease was ∼35 % greater than the previous prevalence estimate in the major U.S. Mizrahi Jewish population.
{"title":"Rapidly progressive, infantile lysosomal acid lipase deficiency: Prevalence in the Mizrahi Jewish population","authors":"Donna L. Bernstein , Inga Peter , Robert J. Desnick","doi":"10.1016/j.ymgme.2025.109233","DOIUrl":"10.1016/j.ymgme.2025.109233","url":null,"abstract":"<div><h3>Purpose</h3><div>This study was designed to more accurately estimate the prevalence of severe, infantile onset, rapidly progressive lysosomal acid lipase deficiency (LALD), an autosomal recessive disorder caused by the homoallelic <em>LIPA</em> gene variant, c.260G>T; p.G87V in patients of Mizrahi Jewish ancestry. The previous estimates of LALD prevalence in Middle Eastern and Mizrahi Jewish populations, ranging from 1 in 12,100 to 1 in 4200, were based on historic, observational case reports and a population genetic screening of 165 Middle Eastern individuals and 162 Mizrahi Jews living in Southern California.</div></div><div><h3>Methods</h3><div>Carrier screening of 549 Mizrahi Jewish individuals for the c.260G>T; p.G87V <em>LIPA</em> variant and the common, c.894G>A; p.E8SJM<sup>-1</sup> <em>LIPA</em> variant, was carried out to determine their allele frequencies and expected prevalence of LALD in a larger Mizrahi population.</div></div><div><h3>Results</h3><div>This larger population screening study revealed a <em>LIPA</em> p.G87V Mizrahi founder variant allele frequency of 1 in 52.2, conferring a carrier frequency of 1 in 26.1. Therefore, the occurrence of infantile LALD was estimated to be one in 2724.8 Mizrahi Jewish conceptions in Southern California.</div></div><div><h3>Conclusion</h3><div>The present, larger study found the prevalence of rapidly progressive, infantile LALD disease was ∼35 % greater than the previous prevalence estimate in the major U.S. Mizrahi Jewish population.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109233"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154687","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}
Pub Date : 2025-09-01Epub Date: 2025-08-09DOI: 10.1016/j.ymgme.2025.109219
G Preston, N Jacob, I Elsharkawi, E Morava, T Kozicz
{"title":"Corrigendum to 'Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations' [Molecular Genetics and Metabolism Volume 146, Issues 1-2 (2025) Pages 109197].","authors":"G Preston, N Jacob, I Elsharkawi, E Morava, T Kozicz","doi":"10.1016/j.ymgme.2025.109219","DOIUrl":"10.1016/j.ymgme.2025.109219","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1-2","pages":"109219"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817180","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}
Pub Date : 2025-08-21DOI: 10.1016/j.ymgme.2025.109224
Andrea Parente , Luigi Borzacchiello , Marianna Giaccio , Martina Bamundo , Riccardo Rubino , Ludovica D'Auria , Antonio Monaco , Alessandro Fraldi
Neuroinflammation underlies neurodegenerative processes in neuronopathic mucopolysaccharidoses (MPS), with innate immunity known to have a dominating role. Here, by studying mouse models of neuronopathic MPS, we found that the neurotoxic reactive astrocytes A1 are present in the brain of MPS mice and progressively increase with age. Such A1 phenotype is associated to activated microglia and to microglia-mediated release of a subset of specific cytokines involved in the A1 phenotype. Additionally, in the mouse model of MPS-IIIA, one of the most severe neuronopathic MPS in humans, we also found that neuroinflammation proceeded concomitantly with the activation of transglutaminase 2, a multifunctional enzyme involved in a variety of cellular processes, mostly in the microglia. Moreover, amyloid deposition appears to be associated to the maintenance of these processes, indeed, inhibiting amyloid deposition in MPS-IIIA mice reduced TG2 expression, microglia activation and the relative amount of astrocyte A1 phenotype. Our results shed light on the microglia-astroglia crosstalk in neuronopathic MPS and on its implication in neuroinflammation and neurodegeneration in MPS, thus also suggesting new therapeutic targets for these diseases.
{"title":"Progressive activation of the astrocyte A1 phenotype underlies microglia-astroglia crosstalk and contributes to neuroinflammation in neuronopathic MPS","authors":"Andrea Parente , Luigi Borzacchiello , Marianna Giaccio , Martina Bamundo , Riccardo Rubino , Ludovica D'Auria , Antonio Monaco , Alessandro Fraldi","doi":"10.1016/j.ymgme.2025.109224","DOIUrl":"10.1016/j.ymgme.2025.109224","url":null,"abstract":"<div><div>Neuroinflammation underlies neurodegenerative processes in neuronopathic mucopolysaccharidoses (MPS), with innate immunity known to have a dominating role. Here, by studying mouse models of neuronopathic MPS, we found that the neurotoxic reactive astrocytes A1 are present in the brain of MPS mice and progressively increase with age. Such A1 phenotype is associated to activated microglia and to microglia-mediated release of a subset of specific cytokines involved in the A1 phenotype. Additionally, in the mouse model of MPS-IIIA, one of the most severe neuronopathic MPS in humans, we also found that neuroinflammation proceeded concomitantly with the activation of transglutaminase 2, a multifunctional enzyme involved in a variety of cellular processes, mostly in the microglia. Moreover, amyloid deposition appears to be associated to the maintenance of these processes, indeed, inhibiting amyloid deposition in MPS-IIIA mice reduced TG2 expression, microglia activation and the relative amount of astrocyte A1 phenotype. Our results shed light on the microglia-astroglia crosstalk in neuronopathic MPS and on its implication in neuroinflammation and neurodegeneration in MPS, thus also suggesting new therapeutic targets for these diseases.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109224"},"PeriodicalIF":3.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144888931","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}
Pub Date : 2025-08-21DOI: 10.1016/j.ymgme.2025.109225
Lekha Chilakamarri , Matthew B. Neu , Rebekah Barrick , Suzette M. Huguenin , Jose E. Abdenur , Tina M. Cowan , Kristina P. Cusmano-Ozog , Christina G. Tise
This study evaluated the role of urine organic acid (UOA) analysis in eight infants initially flagged by California newborn screening and later diagnosed with Zellweger spectrum disorder (ZSD). Retrospective evaluation of UOA during workup of all patients with ZSD identified a consistent pattern of 2-hydroxysebacic acid, 3,6-epoxydeodecanedioic and 3,6-epoxytetracanedioic acids. These results highlight the value of UOA analysis in the evaluation of ZSD and provide images of clinically relevant peaks on UOA chromatograms.
{"title":"Urine organic acid analysis as a tool in evaluation for Zellweger Spectrum disorder: A retrospective study","authors":"Lekha Chilakamarri , Matthew B. Neu , Rebekah Barrick , Suzette M. Huguenin , Jose E. Abdenur , Tina M. Cowan , Kristina P. Cusmano-Ozog , Christina G. Tise","doi":"10.1016/j.ymgme.2025.109225","DOIUrl":"10.1016/j.ymgme.2025.109225","url":null,"abstract":"<div><div>This study evaluated the role of urine organic acid (UOA) analysis in eight infants initially flagged by California newborn screening and later diagnosed with Zellweger spectrum disorder (ZSD). Retrospective evaluation of UOA during workup of all patients with ZSD identified a consistent pattern of 2-hydroxysebacic acid, 3,6-epoxydeodecanedioic and 3,6-epoxytetracanedioic acids. These results highlight the value of UOA analysis in the evaluation of ZSD and provide images of clinically relevant peaks on UOA chromatograms.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109225"},"PeriodicalIF":3.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144908479","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}
Citrin deficiency is an autosomal recessive disorder caused by mutations in SLC25A13, encoding the inner mitochondrial membrane protein citrin. This disease manifests in age-dependent forms: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency, and adolescent and adult citrin deficiency (AACD). While NICCD often resolves with early treatment, AACD symptoms tend to persist or worsen over time. However, the long-term outcome in adult patients with citrin deficiency, particularly those affected by the symptoms of AACD, is not well understood. To address this gap, we conducted a new study from 2022 to 2024 that focused specifically on adult patients with citrin deficiency.
This retrospective study investigated the long-term outcomes in a total of 128 adult patients, categorized depending on their onset of disease into NICCD, Post-NICCD, and AACD groups. Significant differences in height were observed: NICCD patients had taller median heights than AACD patients (Males: 170.6 cm vs. 168.0 cm, P = 0.016; Females: 156.0 cm vs. 153.0 cm, P = 0.007). Former NICCD patients generally achieved favorable long-term outcomes with early intervention, while AACD patients often experienced persistent or worsening symptoms, including irreversible liver damage with impaired urea cycle function.
In conclusion, this study suggests that early intervention during infancy or childhood may improve long-term prognosis in citrin deficiency, particularly for NICCD patients. Conversely, outcome for AACD patients remains a concern, highlighting the need for improved management strategies in adulthood. This study emphasizes the importance of timely diagnosis and treatment to mitigate the progressive nature of citrin deficiency.
Citrin缺乏症是一种常染色体隐性遗传病，由编码线粒体内膜蛋白Citrin的SLC25A13突变引起。这种疾病表现为年龄依赖性形式：由柠檬素缺乏引起的新生儿肝内胆汁淤积症（NICCD），由柠檬素缺乏引起的发育不良和血脂异常，以及青少年和成人柠檬素缺乏（AACD）。虽然NICCD通常通过早期治疗得以解决，但AACD症状往往会持续存在或随着时间的推移而恶化。然而，成年柠檬素缺乏症患者的长期预后，特别是受AACD症状影响的患者，尚不清楚。为了解决这一差距，我们从2022年到2024年进行了一项新的研究，专门针对柑橘素缺乏症的成年患者。这项回顾性研究调查了128名成年患者的长期结果，根据他们的发病分为NICCD、NICCD后和AACD组。身高差异有统计学意义：NICCD患者的中位身高高于AACD患者（男性：170.6 cm比168.0 cm, P = 0.016；女性：156.0 cm比153.0 cm, P = 0.007）。前NICCD患者通常通过早期干预获得良好的长期预后，而AACD患者通常经历持续或恶化的症状，包括尿素循环功能受损的不可逆肝损伤。总之，本研究提示婴儿期或儿童期早期干预可能改善柠檬素缺乏症的长期预后，特别是NICCD患者。相反，AACD患者的预后仍然令人担忧，强调需要改善成年期的管理策略。本研究强调及时诊断和治疗的重要性，以减轻柠檬素缺乏症的进行性。
{"title":"The status of adult patients with citrin deficiency in Japan: A report from the nation-wide study","authors":"Jun Kido , Johannes Häberle , Keishin Sugawara , Masahide Yazaki , Ayano Inui , Chikahiko Numakura , Masaru Shimura , Keinosuke Ishido , Naomi Kuranobu , Kenyu Hashimoto , Kimitoshi Nakamura","doi":"10.1016/j.ymgme.2025.109221","DOIUrl":"10.1016/j.ymgme.2025.109221","url":null,"abstract":"<div><div>Citrin deficiency is an autosomal recessive disorder caused by mutations in <em>SLC25A13</em>, encoding the inner mitochondrial membrane protein citrin. This disease manifests in age-dependent forms: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency, and adolescent and adult citrin deficiency (AACD). While NICCD often resolves with early treatment, AACD symptoms tend to persist or worsen over time. However, the long-term outcome in adult patients with citrin deficiency, particularly those affected by the symptoms of AACD, is not well understood. To address this gap, we conducted a new study from 2022 to 2024 that focused specifically on adult patients with citrin deficiency.</div><div>This retrospective study investigated the long-term outcomes in a total of 128 adult patients, categorized depending on their onset of disease into NICCD, Post-NICCD, and AACD groups. Significant differences in height were observed: NICCD patients had taller median heights than AACD patients (Males: 170.6 cm vs. 168.0 cm, <em>P</em> = 0.016; Females: 156.0 cm vs. 153.0 cm, <em>P</em> = 0.007). Former NICCD patients generally achieved favorable long-term outcomes with early intervention, while AACD patients often experienced persistent or worsening symptoms, including irreversible liver damage with impaired urea cycle function.</div><div>In conclusion, this study suggests that early intervention during infancy or childhood may improve long-term prognosis in citrin deficiency, particularly for NICCD patients. Conversely, outcome for AACD patients remains a concern, highlighting the need for improved management strategies in adulthood. This study emphasizes the importance of timely diagnosis and treatment to mitigate the progressive nature of citrin deficiency.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109221"},"PeriodicalIF":3.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144867074","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}
Pub Date : 2025-08-13DOI: 10.1016/j.ymgme.2025.109223
Julien Maquet , Clément Pontoizeau , Apolline Imbard , Stéphanie Gobin-Limballe , Jean-Baptiste Arnoux , Édouard Le Guillou , Patricia Dubot , Anaïs Brassier , Claire-Marine Bérat , Lucile Altenburger , Juliette Bouchereau , Aude Servais , Myriam Dao , Jean-Paul Bonnefont , Chris Ottolenghi , Jean-François Benoist , Pascale de Lonlay , Manuel Schiff
Introduction
Regardless of its mechanism, hyperammonemia can cause coma and death, and requires urgent management. This study aims at describing the landscape of causes of hyperammonemia in adults and at evaluating the performance of targeted next-generation sequencing (NGS) in this setting.
Methods
We analyzed two cohorts. The first included patients aged ≥15 years presenting with hyperammonemia ≥100 μmol/L at Necker-Enfants Malades (NEM) University Hospital for 10 years and at Toulouse University Hospital for 1.5 years. The second cohort included patients who underwent genetic testing for inherited metabolic disease (IMD) via targeted NGS at NEM hospital over a 5 year-period, regardless of their inclusion in the first cohort, all with hyperammonemia ≥100 μmol/L after age 15.
Results
We included 184 patients in the first cohort, with a median peak ammonia concentration of 155 μmol/L. Among them, 61 patients (33 %) presented with coma. Non-genetic liver failure or portosystemic shunt was present in 133 patients. Twenty-three patients had received asparaginase treatment (none with coma despite a median ammonia level of 257 μmol/L), 7 had received valproic acid, 3 had undergone surgical ureterorectal anastomosis, 2 had multiple myeloma, 1 was receiving 5-Fluorouracil (5FU) for metastatic gastrointestinal cancer, 1 had disseminated atypical mycobacteriosis with Mycobacterium genavense (urease-producing bacteria) in a renal transplant setting and 13 had a genetically confirmed IMD diagnosed in adulthood.
In the second cohort of 17 patients, genetic testing was positive in 5 of 6 patients with IMD-suggestive biochemical profiles (2 CPS1 deficiencies, 1 OTC deficiency, 1 multiple acyl-coA dehydrogenase deficiency, and 1 lysinuric protein intolerance), and negative in patients without biochemical profile suggesting an IMD. Among them, four patients suffered from protein malnutrition related to various severe conditions (gastric bypass, metastatic colorectal adenocarcinoma, Duchenne muscular dystrophy, and short bowel syndrome).
Conclusion
The causes of hyperammonemia in adults are varied. In cases of acute episodes without unequivocal metabolic profiles (when unwell) and with an acquired identified cause of hyperammonemia, genetic investigations had a low yield.
{"title":"Clinical, biochemical, and molecular findings in adults with hyperammonemia: A French bi-centric retrospective study","authors":"Julien Maquet , Clément Pontoizeau , Apolline Imbard , Stéphanie Gobin-Limballe , Jean-Baptiste Arnoux , Édouard Le Guillou , Patricia Dubot , Anaïs Brassier , Claire-Marine Bérat , Lucile Altenburger , Juliette Bouchereau , Aude Servais , Myriam Dao , Jean-Paul Bonnefont , Chris Ottolenghi , Jean-François Benoist , Pascale de Lonlay , Manuel Schiff","doi":"10.1016/j.ymgme.2025.109223","DOIUrl":"10.1016/j.ymgme.2025.109223","url":null,"abstract":"<div><h3>Introduction</h3><div>Regardless of its mechanism, hyperammonemia can cause coma and death, and requires urgent management. This study aims at describing the landscape of causes of hyperammonemia in adults and at evaluating the performance of targeted next-generation sequencing (NGS) in this setting.</div></div><div><h3>Methods</h3><div>We analyzed two cohorts. The first included patients aged ≥15 years presenting with hyperammonemia ≥100 μmol/L at <em>Necker</em>-<em>Enfants Malades</em> (NEM) University Hospital for 10 years and at Toulouse University Hospital for 1.5 years. The second cohort included patients who underwent genetic testing for inherited metabolic disease (IMD) <em>via</em> targeted NGS at NEM hospital over a 5 year-period, regardless of their inclusion in the first cohort, all with hyperammonemia ≥100 μmol/L after age 15.</div></div><div><h3>Results</h3><div>We included 184 patients in the first cohort, with a median peak ammonia concentration of 155 μmol/L. Among them, 61 patients (33 %) presented with coma. Non-genetic liver failure or portosystemic shunt was present in 133 patients. Twenty-three patients had received asparaginase treatment (none with coma despite a median ammonia level of 257 μmol/L), 7 had received valproic acid, 3 had undergone surgical ureterorectal anastomosis, 2 had multiple myeloma, 1 was receiving 5-Fluorouracil (5FU) for metastatic gastrointestinal cancer, 1 had disseminated atypical mycobacteriosis with <em>Mycobacterium genavense</em> (urease-producing bacteria) in a renal transplant setting and 13 had a genetically confirmed IMD diagnosed in adulthood.</div><div>In the second cohort of 17 patients, genetic testing was positive in 5 of 6 patients with IMD-suggestive biochemical profiles (2 CPS1 deficiencies, 1 OTC deficiency, 1 multiple acyl-coA dehydrogenase deficiency, and 1 lysinuric protein intolerance), and negative in patients without biochemical profile suggesting an IMD. Among them, four patients suffered from protein malnutrition related to various severe conditions (gastric bypass, metastatic colorectal adenocarcinoma, Duchenne muscular dystrophy, and short bowel syndrome).</div></div><div><h3>Conclusion</h3><div>The causes of hyperammonemia in adults are varied. In cases of acute episodes without unequivocal metabolic profiles (when unwell) and with an acquired identified cause of hyperammonemia, genetic investigations had a low yield.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109223"},"PeriodicalIF":3.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144867073","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}
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