Pub Date : 2025-09-18DOI: 10.1016/j.ymgme.2025.109237
Neelam Makhijani , Myriam Boueri , Bijan Abar , Tracy Boggs , Laura E. Case , Natalia L. Gonzalez , Lisa D. Hobson-Webb , Sarah P. Young , Priya S. Kishnani
Background
Infantile-onset Pompe disease (IOPD) is caused by a deficiency of the enzyme acid alfa glucosidase, resulting in glycogen accumulation in muscles and other tissues. Without treatment, affected infants typically die within two years. Enzyme replacement therapy (ERT) has significantly improved survival and functional outcomes, especially with early initiation, higher dosing, immune modulation, and newer therapeutic options. However, effective noninvasive tools to monitor disease progression and treatment response are still needed. Quantitative muscle ultrasound (QMUS) may serve as a useful alternative.
Objective
To evaluate the effectiveness and feasibility of QMUS for monitoring muscle involvement in IOPD.
Methods
This study assessed echo intensity (EI) measurements from QMUS in eight patients with IOPD receiving long-term ERT. EI was recorded annually in seven muscle groups. EI >50 units was considered abnormal, and a composite EI Sum Score was calculated. These values were compared with Gross Motor Function Measure (GMFM) scores using univariable regression.
Results
Patients began ERT at a median age of 7 weeks. QMUS assessments were performed, with ages ranging from 7 months to 21 years (median age of 9.5 years) at first evaluation. All patients had at least one muscle group with abnormal EI. Upper extremity EI was significantly lower (mean 47.3) than lower extremity muscle groups (mean 64.1, p = 0.002). Higher EI scores correlated with more severe myopathy and wheelchair use, while lower scores reflected better motor outcomes.
Conclusions
QMUS is a promising noninvasive tool for monitoring muscle health in patients with IOPD receiving ERT. It may aid in assessing disease progression and treatment efficacy.
背景：早发性庞贝病（IOPD）是由酸性α葡萄糖苷酶缺乏引起的，导致糖原在肌肉和其他组织中积累。如果不进行治疗，受感染的婴儿通常会在两年内死亡。酶替代疗法（ERT）显著提高了生存率和功能预后，特别是早期开始、高剂量、免疫调节和更新的治疗选择。然而，仍然需要有效的非侵入性工具来监测疾病进展和治疗反应。定量肌肉超声（QMUS）可以作为一种有用的替代方法。目的评价QMUS监测IOPD肌肉受累的有效性和可行性。方法本研究评估了8例接受长期ERT治疗的IOPD患者QMUS的回声强度（EI）测量结果。每年在7个肌肉群中记录EI。EI >；50为异常，计算综合EI Sum Score。使用单变量回归将这些值与大肌肉运动功能测量（GMFM）评分进行比较。结果患者开始ERT治疗的中位年龄为7周。进行QMUS评估，首次评估时年龄范围为7个月至21岁（中位年龄9.5岁）。所有患者至少有一个肌群出现EI异常。上肢EI（平均47.3）明显低于下肢肌群（平均64.1,p = 0.002）。较高的EI分数与更严重的肌病和轮椅使用相关，而较低的分数反映了更好的运动结果。结论sqmus是一种很有前途的无创工具，可用于监测接受ERT治疗的IOPD患者的肌肉健康状况。它可能有助于评估疾病进展和治疗效果。
{"title":"Quantitative muscle ultrasound as a window into disease progression in infantile-onset Pompe disease","authors":"Neelam Makhijani , Myriam Boueri , Bijan Abar , Tracy Boggs , Laura E. Case , Natalia L. Gonzalez , Lisa D. Hobson-Webb , Sarah P. Young , Priya S. Kishnani","doi":"10.1016/j.ymgme.2025.109237","DOIUrl":"10.1016/j.ymgme.2025.109237","url":null,"abstract":"<div><h3>Background</h3><div>Infantile-onset Pompe disease (IOPD) is caused by a deficiency of the enzyme acid alfa glucosidase, resulting in glycogen accumulation in muscles and other tissues. Without treatment, affected infants typically die within two years. Enzyme replacement therapy (ERT) has significantly improved survival and functional outcomes, especially with early initiation, higher dosing, immune modulation, and newer therapeutic options. However, effective noninvasive tools to monitor disease progression and treatment response are still needed. Quantitative muscle ultrasound (QMUS) may serve as a useful alternative.</div></div><div><h3>Objective</h3><div>To evaluate the effectiveness and feasibility of QMUS for monitoring muscle involvement in IOPD.</div></div><div><h3>Methods</h3><div>This study assessed echo intensity (EI) measurements from QMUS in eight patients with IOPD receiving long-term ERT. EI was recorded annually in seven muscle groups. EI >50 units was considered abnormal, and a composite EI Sum Score was calculated. These values were compared with Gross Motor Function Measure (GMFM) scores using univariable regression.</div></div><div><h3>Results</h3><div>Patients began ERT at a median age of 7 weeks. QMUS assessments were performed, with ages ranging from 7 months to 21 years (median age of 9.5 years) at first evaluation. All patients had at least one muscle group with abnormal EI. Upper extremity EI was significantly lower (mean 47.3) than lower extremity muscle groups (mean 64.1, <em>p</em> = 0.002). Higher EI scores correlated with more severe myopathy and wheelchair use, while lower scores reflected better motor outcomes.</div></div><div><h3>Conclusions</h3><div>QMUS is a promising noninvasive tool for monitoring muscle health in patients with IOPD receiving ERT. It may aid in assessing disease progression and treatment efficacy.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109237"},"PeriodicalIF":3.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145157142","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 : 2025-09-18DOI: 10.1016/j.ymgme.2025.109234
Chloé J. Geerts , Fernando Alvarez , Brian M. Gilfix , Matthew J. Schultz , Philippe M. Campeau
CCDC115-CDG is a recently described combined N- and O-linked congenital disorder of glycosylation affecting Golgi apparatus homeostasis. To date, only thirteen patients have been reported with this condition. The clinical presentation is characterized by hepatosplenomegaly, elevated serum aminotransferases and alkaline phosphatase, often accompanied by psychomotor delay and hypotonia, hypercholesterolemia and copper metabolism anomalies, features that can mimic Wilson disease. Serum transferrin capillary electrophoresis shows a pattern compatible with abnormal Golgi N-glycosylation. We gathered phenotype descriptions and molecular data from all reported patients to better characterize this condition and explore potential genotype-phenotype correlation. Notably, we observed that homozygosity for the p.Leu31Ser variant is associated with higher serum transaminase levels. We also report the natural history of a patient, as clinical narratives are lacking in the literature for this condition. In summary, our report provides new insights into the natural history and genotype-phenotype correlation of CCDC115-CDG, key elements to focus on in ultra-rare conditions.
{"title":"Defining the clinical spectrum and genotype-phenotype correlations for CCDC115-CDG: A patient report and review of the literature","authors":"Chloé J. Geerts , Fernando Alvarez , Brian M. Gilfix , Matthew J. Schultz , Philippe M. Campeau","doi":"10.1016/j.ymgme.2025.109234","DOIUrl":"10.1016/j.ymgme.2025.109234","url":null,"abstract":"<div><div>CCDC115-CDG is a recently described combined N- and O-linked congenital disorder of glycosylation affecting Golgi apparatus homeostasis. To date, only thirteen patients have been reported with this condition. The clinical presentation is characterized by hepatosplenomegaly, elevated serum aminotransferases and alkaline phosphatase, often accompanied by psychomotor delay and hypotonia, hypercholesterolemia and copper metabolism anomalies, features that can mimic Wilson disease. Serum transferrin capillary electrophoresis shows a pattern compatible with abnormal Golgi N-glycosylation. We gathered phenotype descriptions and molecular data from all reported patients to better characterize this condition and explore potential genotype-phenotype correlation. Notably, we observed that homozygosity for the p.Leu31Ser variant is associated with higher serum transaminase levels. We also report the natural history of a patient, as clinical narratives are lacking in the literature for this condition. In summary, our report provides new insights into the natural history and genotype-phenotype correlation of CCDC115-CDG, key elements to focus on in ultra-rare conditions.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109234"},"PeriodicalIF":3.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213266","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.2025.109229
Mary Kate LoPiccolo , Johan L.K. Van Hove
{"title":"Practical challenges and ethical considerations in treating early-onset MADD with exogenous ketones","authors":"Mary Kate LoPiccolo , Johan L.K. Van Hove","doi":"10.1016/j.ymgme.2025.109229","DOIUrl":"10.1016/j.ymgme.2025.109229","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109229"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925282","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.2025.109226
Eline Pieters , Jaak Jaeken , Matthew P. Wilson
The polyisoprenoid lipid dolichol is critical for eukaryotic glycosylation. It is used as the membrane anchor for mono- or oligosaccharides transferred during N-glycosylation, O/C-mannosylation and glycosylphosphatidylinositol anchor biosynthesis. Disorders affecting the synthesis or utilization of dolichol cause defective glycosylation and are therefore classified as Congenital Disorders of Glycosylation (CDG). CDG are a group of approximately 200 mostly autosomal recessive inherited metabolic disorders characterized by defective glycosylation of proteins and lipids. Through recently identified defects, we have gained new insights into dolichol synthesis, important to understand the pathological mechanisms in affected patients. This review provides an overview of dolichol synthesis and utilization and an update on CDG caused by disruption of these processes. Finally, we discuss the existing biomarkers for diagnosis of these disorders and the potential for effective therapies.
聚异戊二烯类脂质醇对真核生物的糖基化至关重要。在n -糖基化、O/ c -甘露糖基化和糖基磷脂酰肌醇锚定生物合成过程中，它被用作转移的单糖或寡糖的膜锚。影响酒精合成或利用的障碍会导致糖基化缺陷，因此被归类为先天性糖基化障碍（CDG）。CDG是一组约200种常染色体隐性遗传代谢疾病，其特征是蛋白质和脂质糖基化缺陷。通过最近发现的缺陷，我们对醇合成有了新的认识，这对理解受影响患者的病理机制很重要。本文综述了醇类化合物的合成和利用，并对这些过程的破坏引起的CDG的最新进展进行了综述。最后，我们讨论了诊断这些疾病的现有生物标志物和有效治疗的潜力。
{"title":"Genetic disorders of dolichol synthesis and utilization","authors":"Eline Pieters , Jaak Jaeken , Matthew P. Wilson","doi":"10.1016/j.ymgme.2025.109226","DOIUrl":"10.1016/j.ymgme.2025.109226","url":null,"abstract":"<div><div>The polyisoprenoid lipid dolichol is critical for eukaryotic glycosylation. It is used as the membrane anchor for mono- or oligosaccharides transferred during N-glycosylation, O/C-mannosylation and glycosylphosphatidylinositol anchor biosynthesis. Disorders affecting the synthesis or utilization of dolichol cause defective glycosylation and are therefore classified as Congenital Disorders of Glycosylation (CDG). CDG are a group of approximately 200 mostly autosomal recessive inherited metabolic disorders characterized by defective glycosylation of proteins and lipids. Through recently identified defects, we have gained new insights into dolichol synthesis, important to understand the pathological mechanisms in affected patients. This review provides an overview of dolichol synthesis and utilization and an update on CDG caused by disruption of these processes. Finally, we discuss the existing biomarkers for diagnosis of these disorders and the potential for effective therapies.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109226"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925283","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.2025.109232
Jeanna M. Blake , Andrew D. Miller , Jacqueline L. Marr , Kari J. Ekenstedt
Glycogen storage diseases (GSDs) are rare, typically inherited, disorders caused by various defects in glycogen metabolism enzymes, generally resulting in the accumulation of glycogen in several tissues. Recently, two young adult Basset Hound (BH) littermates were diagnosed with GSD via postmortem histopathology, with excess glycogen manifesting in both cardiac and smooth muscle. Using whole genome sequencing, a homozygous splice site donor variant was identified in exon 8 of RBCK1, a gene which encodes an E3 ubiquitin ligase, in both littermates, suggesting an autosomal recessive mode of inheritance. The presumptive loss of the splice site donor is predicted to result in premature termination in the mid-domain of the protein. Screening for the variant in related (n = 21) and unrelated (n = 124) BHs identified one additional affected littermate and nine familial heterozygous carriers. No variant alleles were present in the unrelated BH population, establishing the novelty of the identified mutation. RBCK1 variants have previously been associated with polyglucosan body myopathy type 1 (PGBM1), a type of GSD characterized by skeletal muscle myopathy, cardiomyopathy, and polyglucosan accumulation in humans. To date, no reported variants in RBCK1 have been identified in dogs or other large animals associated with GSD, making this the first naturally occurring large animal model of PGBM1 due to an RBCK1 defect.
{"title":"Identification of a novel RBCK1 splice site donor variant in Basset Hounds with glycogen storage disease myopathy","authors":"Jeanna M. Blake , Andrew D. Miller , Jacqueline L. Marr , Kari J. Ekenstedt","doi":"10.1016/j.ymgme.2025.109232","DOIUrl":"10.1016/j.ymgme.2025.109232","url":null,"abstract":"<div><div>Glycogen storage diseases (GSDs) are rare, typically inherited, disorders caused by various defects in glycogen metabolism enzymes, generally resulting in the accumulation of glycogen in several tissues. Recently, two young adult Basset Hound (BH) littermates were diagnosed with GSD via postmortem histopathology, with excess glycogen manifesting in both cardiac and smooth muscle. Using whole genome sequencing, a homozygous splice site donor variant was identified in exon 8 of <em>RBCK1</em>, a gene which encodes an E3 ubiquitin ligase, in both littermates, suggesting an autosomal recessive mode of inheritance. The presumptive loss of the splice site donor is predicted to result in premature termination in the mid-domain of the protein. Screening for the variant in related (<em>n</em> = 21) and unrelated (<em>n</em> = 124) BHs identified one additional affected littermate and nine familial heterozygous carriers. No variant alleles were present in the unrelated BH population, establishing the novelty of the identified mutation. <em>RBCK1</em> variants have previously been associated with polyglucosan body myopathy type 1 (PGBM1), a type of GSD characterized by skeletal muscle myopathy, cardiomyopathy, and polyglucosan accumulation in humans. To date, no reported variants in <em>RBCK1</em> have been identified in dogs or other large animals associated with GSD, making this the first naturally occurring large animal model of PGBM1 due to an <em>RBCK1</em> defect.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109232"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044510","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.2025.109231
Yuen T. Ngai , Clifford Young , Emma J. Parkinson-Lawrence , Sabine Wimmer-Kleikamp , Parul Mittal , Helen Beard , Matthew T. Briggs , Manuela Klingler-Hoffmann , Doug A. Brooks , Sandra Orgeig , Peter Hoffmann
Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disorder resulting from a deficiency in the lysosomal enzyme alpha-L-iduronidase, which degrades heparan sulfate and dermatan sulfate glycosaminoglycans (GAG) within endosome-lysosome compartments. MPS I patients demonstrate respiratory dysfunction with varying symptoms and severity during disease progression, which has been associated primarily with upper airway involvement and the thoracic cavity. However, the involvement of respiratory complications in patient morbidity and mortality suggests that we know relatively little about the pathogenic process in the lung. Using a proteomics approach, we analyzed lung tissues from a murine model of MPS I to identify proteins and molecular pathways contributing to respiratory pathology. A total of 7604 proteins were identified, of which 144 were significantly upregulated, 93 downregulated, and three proteins (GPNMB, SLC39A1, ABCC10) were uniquely detected in MPS I lung tissue compared to control lung tissue. Gene ontology analysis confirmed significant disruptions to lysosomal biogenesis, GAG degradation pathways, and extracellular matrix remodelling. Immunohistochemistry showed elevated LAMP I expression, which was consistent with the proteomic results and endosome-lysosome dysfunction being a key driver of disease pathogenesis in the MPS I lung. Our findings reveal novel proteomic alterations underlying distal lung pathology in MPS I and identify potential biomarkers that may have clinical utility for monitoring disease progression.
{"title":"Defining lung pathogenesis in a murine model of mucopolysaccharidosis Type I by proteomic analysis","authors":"Yuen T. Ngai , Clifford Young , Emma J. Parkinson-Lawrence , Sabine Wimmer-Kleikamp , Parul Mittal , Helen Beard , Matthew T. Briggs , Manuela Klingler-Hoffmann , Doug A. Brooks , Sandra Orgeig , Peter Hoffmann","doi":"10.1016/j.ymgme.2025.109231","DOIUrl":"10.1016/j.ymgme.2025.109231","url":null,"abstract":"<div><div>Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disorder resulting from a deficiency in the lysosomal enzyme alpha-L-iduronidase, which degrades heparan sulfate and dermatan sulfate glycosaminoglycans (GAG) within endosome-lysosome compartments. MPS I patients demonstrate respiratory dysfunction with varying symptoms and severity during disease progression, which has been associated primarily with upper airway involvement and the thoracic cavity. However, the involvement of respiratory complications in patient morbidity and mortality suggests that we know relatively little about the pathogenic process in the lung. Using a proteomics approach, we analyzed lung tissues from a murine model of MPS I to identify proteins and molecular pathways contributing to respiratory pathology. A total of 7604 proteins were identified, of which 144 were significantly upregulated, 93 downregulated, and three proteins (GPNMB, SLC39A1, ABCC10) were uniquely detected in MPS I lung tissue compared to control lung tissue. Gene ontology analysis confirmed significant disruptions to lysosomal biogenesis, GAG degradation pathways, and extracellular matrix remodelling. Immunohistochemistry showed elevated LAMP I expression, which was consistent with the proteomic results and endosome-lysosome dysfunction being a key driver of disease pathogenesis in the MPS I lung. Our findings reveal novel proteomic alterations underlying distal lung pathology in MPS I and identify potential biomarkers that may have clinical utility for monitoring disease progression.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109231"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081128","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.2025.109228
Rebecca Sponberg , Rebekah Barrick , Kathryn Gasperian , Jose E. Abdenur
Newborn screening is one of the most successful public health programs that has improved outcomes for children with conditions that can cause long-term disability or even death if not treated quickly. With the introduction of expanded newborn screening (NBS) and the use of tandem mass spectrometry, the number of core and secondary conditions recommended on the United States national NBS guideline called the Recommended Uniform Screening Panel (RUSP), rapidly grew to help screen for inborn errors of metabolism (IEM) [1]. A few years after this initiation and as more newborns were screened, there were several case reports of mothers who were diagnosed with an IEM condition or vitamin deficiency that was causing their child's abnormal newborn screening results. We conducted a PubMed literature search and identified reports of 14 maternal conditions identified via NBS and provide a comprehensive review of their findings. We define a maternal condition as biochemical or genetic findings that confirm the mother has the condition and the child is unaffected or an obligate carrier. This review could be useful for countries that plan to initiate expanded newborn screening in the future as well as for metabolic providers, who are involved in the confirmatory testing process for newborn screening referrals.
{"title":"Maternal metabolic conditions identified by newborn screening","authors":"Rebecca Sponberg , Rebekah Barrick , Kathryn Gasperian , Jose E. Abdenur","doi":"10.1016/j.ymgme.2025.109228","DOIUrl":"10.1016/j.ymgme.2025.109228","url":null,"abstract":"<div><div>Newborn screening is one of the most successful public health programs that has improved outcomes for children with conditions that can cause long-term disability or even death if not treated quickly. With the introduction of expanded newborn screening (NBS) and the use of tandem mass spectrometry, the number of core and secondary conditions recommended on the United States national NBS guideline called the Recommended Uniform Screening Panel (RUSP), rapidly grew to help screen for inborn errors of metabolism (IEM) [<span><span>1</span></span>]. A few years after this initiation and as more newborns were screened, there were several case reports of mothers who were diagnosed with an IEM condition or vitamin deficiency that was causing their child's abnormal newborn screening results. We conducted a PubMed literature search and identified reports of 14 maternal conditions identified via NBS and provide a comprehensive review of their findings. We define a maternal condition as biochemical or genetic findings that confirm the mother has the condition and the child is unaffected or an obligate carrier. This review could be useful for countries that plan to initiate expanded newborn screening in the future as well as for metabolic providers, who are involved in the confirmatory testing process for newborn screening referrals.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109228"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987933","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.2025.109230
Maxwell B. Colonna , Andrzej B. Poplawski , Marie N. Brzoska , Dionne Le , Natasha L. Rudy , Kameryn M. Butler , Wesley G. Patterson , Camerun C. Washington , Elliot Stolerman , Libin Xu , Gavin Arno , Richard Steet
Numerous genetic conditions are represented within the biochemical pathway for de novo cholesterol biosynthesis. Among the emerging disease-gene associations is CYP51A1, encoding a lanosterol demethylase enzyme. Biallelic variants in CYP51A1 have been associated with congenital cataracts and variable liver disease but an appreciation of genotype/phenotype correlation is lacking due to the limited number of patients described. Here we report a 21 month-old female with congenital cataracts harboring compound heterozygous variants of uncertain significance in CYP51A1. Functional studies were performed to resolve the impact of these variants, demonstrating effects at the both the transcript and protein level, and clear evidence of pathogenicity. Molecular analysis of primary lymphoblastoid cells from the proband revealed defects in transcript expression, reduced protein abundance, and a loss of enzymatic function resulting in lanosterol accumulation and increased sensitivity to ferroptosis. These data provide supporting evidence of the association between CYP51A1 defects and congenital cataract that will aid in further establishing a genotype/phenotype correlation.
{"title":"Expansion of genotype/phenotype correlation in an individual with compound heterozygous variants in CYP51A1 and congenital cataract","authors":"Maxwell B. Colonna , Andrzej B. Poplawski , Marie N. Brzoska , Dionne Le , Natasha L. Rudy , Kameryn M. Butler , Wesley G. Patterson , Camerun C. Washington , Elliot Stolerman , Libin Xu , Gavin Arno , Richard Steet","doi":"10.1016/j.ymgme.2025.109230","DOIUrl":"10.1016/j.ymgme.2025.109230","url":null,"abstract":"<div><div>Numerous genetic conditions are represented within the biochemical pathway for de novo cholesterol biosynthesis. Among the emerging disease-gene associations is <em>CYP51A1</em>, encoding a lanosterol demethylase enzyme. Biallelic variants in <em>CYP51A1</em> have been associated with congenital cataracts and variable liver disease but an appreciation of genotype/phenotype correlation is lacking due to the limited number of patients described. Here we report a 21 month-old female with congenital cataracts harboring compound heterozygous variants of uncertain significance in <em>CYP51A1</em>. Functional studies were performed to resolve the impact of these variants, demonstrating effects at the both the transcript and protein level, and clear evidence of pathogenicity. Molecular analysis of primary lymphoblastoid cells from the proband revealed defects in transcript expression, reduced protein abundance, and a loss of enzymatic function resulting in lanosterol accumulation and increased sensitivity to ferroptosis. These data provide supporting evidence of the association between <em>CYP51A1</em> defects and congenital cataract that will aid in further establishing a genotype/phenotype correlation.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109230"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987934","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.2025.109238
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}
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