Fabry disease is the most frequently occurring form of lysosomal disease in Japan, and is characterized by a wide variety of conditions. Primarily, the three major types of concerns associated with Fabry disease observed during adulthood that must be prevented are central nervous system, renal, and cardiac complications. Cardiac complications, such as cardiomyopathy, cardiac muscle fibrosis, and severe arrhythmia, are the most common mortality causes in patients with Fabry disease. To predict cardiac complications of Fabry disease, we extracted RNA from the venous blood of patients for cap analysis of gene expression (CAGE), performed likelihood ratio tests for each RNA expression dataset obtained from individuals with and without cardiac complications, and analyzed the correlation between cardiac functional factors observed using magnetic resonance imaging data extracted using artificial intelligence algorithms and RNA expression. Our findings showed that CHN1 expression was significantly higher in male Fabry disease patients with cardiac complications and that it could be associated with many cardiac functional factors. CHN1 encodes a GTPase-activating protein, chimerin 1, which is specific to the GTP-binding protein Rac (involved in oxidative stress generation and the promotion of myocardial fibrosis). Thus, CHN1 is a potential predictive biomarker of cardiac complications in Fabry disease; however, further studies are required to confirm this observation.
{"title":"Using artificial intelligence and promoter-level transcriptome analysis to identify a biomarker as a possible prognostic predictor of cardiac complications in male patients with Fabry disease","authors":"Hiroshi Kobayashi , Norio Nakata , Sayoko Izuka , Kenichi Hongo , Masako Nishikawa","doi":"10.1016/j.ymgmr.2024.101152","DOIUrl":"10.1016/j.ymgmr.2024.101152","url":null,"abstract":"<div><div>Fabry disease is the most frequently occurring form of lysosomal disease in Japan, and is characterized by a wide variety of conditions. Primarily, the three major types of concerns associated with Fabry disease observed during adulthood that must be prevented are central nervous system, renal, and cardiac complications. Cardiac complications, such as cardiomyopathy, cardiac muscle fibrosis, and severe arrhythmia, are the most common mortality causes in patients with Fabry disease. To predict cardiac complications of Fabry disease, we extracted RNA from the venous blood of patients for cap analysis of gene expression (CAGE), performed likelihood ratio tests for each RNA expression dataset obtained from individuals with and without cardiac complications, and analyzed the correlation between cardiac functional factors observed using magnetic resonance imaging data extracted using artificial intelligence algorithms and RNA expression. Our findings showed that CHN1 expression was significantly higher in male Fabry disease patients with cardiac complications and that it could be associated with many cardiac functional factors. <em>CHN1</em> encodes a GTPase-activating protein, chimerin 1, which is specific to the GTP-binding protein Rac (involved in oxidative stress generation and the promotion of myocardial fibrosis). Thus, CHN1 is a potential predictive biomarker of cardiac complications in Fabry disease; however, further studies are required to confirm this observation.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101152"},"PeriodicalIF":1.8,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142433110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Many adults with phenylketonuria (PKU) were discharged from clinics before lifelong treatment guidelines and new therapies. As part of the PKU lost to clinical care study, moderated focus groups were conducted to understand why individuals become lost to care and how to maintain patient engagement. Focus groups involved active clinic patients and those lost to PKU care. Discussions revealed desire for enhanced communication, improved support and access, and community connections.
{"title":"Patient voices on PKU care: Insights from focus groups with current and former patients","authors":"Emily Zhu , Suzanne Hollander , Stephanie Sacharow","doi":"10.1016/j.ymgmr.2024.101148","DOIUrl":"10.1016/j.ymgmr.2024.101148","url":null,"abstract":"<div><div>Many adults with phenylketonuria (PKU) were discharged from clinics before lifelong treatment guidelines and new therapies. As part of the PKU lost to clinical care study, moderated focus groups were conducted to understand why individuals become lost to care and how to maintain patient engagement. Focus groups involved active clinic patients and those lost to PKU care. Discussions revealed desire for enhanced communication, improved support and access, and community connections.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101148"},"PeriodicalIF":1.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142421596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-07DOI: 10.1016/j.ymgmr.2024.101149
Viridiana Berstein , Eduardo M. Pirotzky , Hernán D. Taconelli , M. Gabriela Gobbi , Lara Beider , Natali D. Salgueiro , Laila Dome , Roberto A. Diez , Hugo Sotelo , Sabrina Coppola
Fabry disease is a rare X-linked lysosomal condition that leads to the accumulation of glycosphingolipids in various tissues, causing cellular dysfunction, tissue remodeling, progressive fibrosis, and organ failure. The disease results from a deficiency in the human α-galactosidase A enzyme, responsible for breaking down glycosphingolipids like globotriaosylceramide (GL-3 or Gb3) into galactose and dihexose ceramides. In individuals diagnosed with Fabry disease, treatment from 2 years of age onwards typically involves agalsidase beta, the normal recombinant form of the defective enzyme. Agalsidase beta from Biosidus has been developed as a biosimilar to Sanofi-Genzyme's Fabrazyme®. In the molecule's clinical journey, a phase I trial was designed to establish its similarity in terms of pharmacokinetics, pharmacodynamics, and immunogenicity compared to the reference medication. The study was conducted on 24 healthy male volunteers, aged between 18 and 40 years. All volunteers received a single 1 mg/kg bw dose of Fabrazyme® or Biosidus Agalsidase beta by continuous intravenous (IV) infusion over 5 h. The 90 % confidence interval (CI) of the maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to 12 h (AUC0-12 h) and area under the plasma concentration-time curve extrapolated from time 0 to infinity (AUC0-∞) ratios fell within the accepted range of 80–125 %. No differences were detected in adverse effects or antibody induction. This indicates that Biosidus agalsidase beta meets the criteria for being considered similar to the reference formulation Sanofi Genzyme's Fabrazyme®.
{"title":"Comparative pharmacokinetics and pharmacodynamics of two formulations of agalsidase beta (agalsidase Biosidus) and Fabrazyme® by intravenous infusion in healthy male volunteers","authors":"Viridiana Berstein , Eduardo M. Pirotzky , Hernán D. Taconelli , M. Gabriela Gobbi , Lara Beider , Natali D. Salgueiro , Laila Dome , Roberto A. Diez , Hugo Sotelo , Sabrina Coppola","doi":"10.1016/j.ymgmr.2024.101149","DOIUrl":"10.1016/j.ymgmr.2024.101149","url":null,"abstract":"<div><div>Fabry disease is a rare X-linked lysosomal condition that leads to the accumulation of glycosphingolipids in various tissues, causing cellular dysfunction, tissue remodeling, progressive fibrosis, and organ failure. The disease results from a deficiency in the human α-galactosidase A enzyme, responsible for breaking down glycosphingolipids like globotriaosylceramide (GL-3 or Gb3) into galactose and dihexose ceramides. In individuals diagnosed with Fabry disease, treatment from 2 years of age onwards typically involves agalsidase beta, the normal recombinant form of the defective enzyme. Agalsidase beta from Biosidus has been developed as a biosimilar to Sanofi-Genzyme's Fabrazyme®. In the molecule's clinical journey, a phase I trial was designed to establish its similarity in terms of pharmacokinetics, pharmacodynamics, and immunogenicity compared to the reference medication. The study was conducted on 24 healthy male volunteers, aged between 18 and 40 years. All volunteers received a single 1 mg/kg bw dose of Fabrazyme® or Biosidus Agalsidase beta by continuous intravenous (IV) infusion over 5 h. The 90 % confidence interval (CI) of the maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to 12 h (AUC0-12 h) and area under the plasma concentration-time curve extrapolated from time 0 to infinity (AUC0-∞) ratios fell within the accepted range of 80–125 %. No differences were detected in adverse effects or antibody induction. This indicates that Biosidus agalsidase beta meets the criteria for being considered similar to the reference formulation Sanofi Genzyme's Fabrazyme®.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101149"},"PeriodicalIF":1.8,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142421594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.ymgmr.2024.101145
Kimberly M. Ezell , Yutaka Furuta , Devin Oglesbee , Eniko K. Pivnick , David Rinker , Jonathan H. Sheehan , Rory J. Tinker , Rizwan Hamid , Joy D. Cogan , Lynette Rives , Serena Neumann , Brian Corner , Mary Koziura , John A. Phillips III , the Undiagnosed Diseases Network
Autosomal dominant congenital disorder of glycosylation (CDG) type Iw (OMIM# 619714) is caused by a heterozygous mutation in the STT3A gene. Most CDGs have an autosomal recessive (AR) mode of inheritance, but several cases with an autosomal dominant (AD) form of an AR CDG have been recently identified. This report describes a 17-year-old male who was referred to the Undiagnosed Diseases Network (UDN) with a history of macrocephaly, failure to thrive, short stature, epilepsy, autism, attention-deficit/hyperactivity disorder, mild developmental delay, intermittent hypotonia, dysmorphic features, and mildly enlarged aortic root. Trio exome sequencing was negative. His biochemical workup included normal plasma amino acids, ammonia, acylcarnitine profile and urine organic and amino acids. His UDN genome sequencing (GS) identified a previously unreported de novo STT3A variant (c.1631A > G: p.Asn544Ser). This variant removes a glycosylation site and was predicted to be destabilizing by structural biology modeling. The patient was formally diagnosed by the UDN Metabolomics Core as having an abnormal transferrin profile indicative of CDG type Iw through metabolomic profiling. We report here an affected male with phenotypic, molecular, and metabolic findings consistent with CDG type Iw due to a heterozygous STT3A variant. This case highlights the importance of further testing of individuals with the phenotypic and metabolic findings of an AR disorder who are heterozygous for a single disease-causing allele and can be shown to have a new AD form of the disorder that represents clinical heterogeneity.
{"title":"Review and metabolomic profiling of unsolved case reveals newly reported autosomal dominant congenital disorder of glycosylation, type Iw formerly thought to only be an autosomal recessive condition","authors":"Kimberly M. Ezell , Yutaka Furuta , Devin Oglesbee , Eniko K. Pivnick , David Rinker , Jonathan H. Sheehan , Rory J. Tinker , Rizwan Hamid , Joy D. Cogan , Lynette Rives , Serena Neumann , Brian Corner , Mary Koziura , John A. Phillips III , the Undiagnosed Diseases Network","doi":"10.1016/j.ymgmr.2024.101145","DOIUrl":"10.1016/j.ymgmr.2024.101145","url":null,"abstract":"<div><div>Autosomal dominant congenital disorder of glycosylation (CDG) type Iw (OMIM# <span><span>619714</span><svg><path></path></svg></span>) is caused by a heterozygous mutation in the <em>STT3A</em> gene. Most CDGs have an autosomal recessive (AR) mode of inheritance, but several cases with an autosomal dominant (AD) form of an AR CDG have been recently identified. This report describes a 17-year-old male who was referred to the Undiagnosed Diseases Network (UDN) with a history of macrocephaly, failure to thrive, short stature, epilepsy, autism, attention-deficit/hyperactivity disorder, mild developmental delay, intermittent hypotonia, dysmorphic features, and mildly enlarged aortic root. Trio exome sequencing was negative. His biochemical workup included normal plasma amino acids, ammonia, acylcarnitine profile and urine organic and amino acids. His UDN genome sequencing (GS) identified a previously unreported <em>de novo STT3A</em> variant (c.1631A > G: p.Asn544Ser). This variant removes a glycosylation site and was predicted to be destabilizing by structural biology modeling. The patient was formally diagnosed by the UDN Metabolomics Core as having an abnormal transferrin profile indicative of CDG type Iw through metabolomic profiling. We report here an affected male with phenotypic, molecular, and metabolic findings consistent with CDG type Iw due to a heterozygous <em>STT3A</em> variant. This case highlights the importance of further testing of individuals with the phenotypic and metabolic findings of an AR disorder who are heterozygous for a single disease-causing allele and can be shown to have a new AD form of the disorder that represents clinical heterogeneity.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101145"},"PeriodicalIF":1.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142421593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.ymgmr.2024.101151
Chih-Hsuan Lu , Chia-Feng Yang , Yun-Ru Chen , Yann-Jang Chen , Yung-Hsiu Lu , Dau-Ming Niu
Recurrent rhabdomyolysis, marked by skeletal muscle breakdown, can stem from various causes, including genetic disorders. We detail a patient of a 22-year-old male with carnitine palmitoyltransferase II (CPT-2) deficiency manifesting recurrent rhabdomyolysis despite normal acylcarnitine profiles. Whole-genome sequencing identified two CPT2 gene variants: c.338C > T and c.482G > A, confirming the diagnosis. We conducted a case report and a comprehensive literature review encompassing 262 articles related to CPT-2 deficiency available on PubMed. The review detailed 245 cases across various forms, including lethal neonatal, severe infantile hepatocardiomuscular, and myopathic forms. The study highlighted the variability and complexity of CPT-2 deficiency phenotypes, emphasizing correlations between variants and phenotypes as well as gender distribution. Although the CPT-2 deficiency genotype does not entirely predict phenotype severity, it remains informative for most patients, assisting in assessing the severity linked to each genetic variant. The results of our study offer crucial insights into evaluating the severity associated with individual genetic variants. Notably, our patient displayed normal acylcarnitine profiles between illness episodes, indicating possible profile abnormalities only during active disease states.
We propose the collection of additional blood samples for acylcarnitine analysis during episodes of rhabdomyolysis without delay in all patients presenting with rhabdomyolysis of unknown cause as a crucial diagnostic strategy. This approach may unveil unexpected underlying diseases, enabling early and accurate diagnoses.
{"title":"Recurrent rhabdomyolysis caused by palmitoyltransferase II (CPT-2) deficiency but complete normal acylcarnitine profile: A patient presentation and review of the literature","authors":"Chih-Hsuan Lu , Chia-Feng Yang , Yun-Ru Chen , Yann-Jang Chen , Yung-Hsiu Lu , Dau-Ming Niu","doi":"10.1016/j.ymgmr.2024.101151","DOIUrl":"10.1016/j.ymgmr.2024.101151","url":null,"abstract":"<div><div>Recurrent rhabdomyolysis, marked by skeletal muscle breakdown, can stem from various causes, including genetic disorders. We detail a patient of a 22-year-old male with carnitine palmitoyltransferase II (CPT-2) deficiency manifesting recurrent rhabdomyolysis despite normal acylcarnitine profiles. Whole-genome sequencing identified two <em>CPT2</em> gene variants: c.338C > T and c.482G > A, confirming the diagnosis. We conducted a case report and a comprehensive literature review encompassing 262 articles related to CPT-2 deficiency available on PubMed. The review detailed 245 cases across various forms, including lethal neonatal, severe infantile hepatocardiomuscular, and myopathic forms. The study highlighted the variability and complexity of CPT-2 deficiency phenotypes, emphasizing correlations between variants and phenotypes as well as gender distribution. Although the CPT-2 deficiency genotype does not entirely predict phenotype severity, it remains informative for most patients, assisting in assessing the severity linked to each genetic variant. The results of our study offer crucial insights into evaluating the severity associated with individual genetic variants. Notably, our patient displayed normal acylcarnitine profiles between illness episodes, indicating possible profile abnormalities only during active disease states.</div><div>We propose the collection of additional blood samples for acylcarnitine analysis during episodes of rhabdomyolysis without delay in all patients presenting with rhabdomyolysis of unknown cause as a crucial diagnostic strategy. This approach may unveil unexpected underlying diseases, enabling early and accurate diagnoses.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101151"},"PeriodicalIF":1.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142421595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-29DOI: 10.1016/j.ymgmr.2024.101147
Krista Viau , Sommer Gaughan , Jessica Kopesky , Beth Ogata , Heather Saavedra , Mary Sowa , Erin MacLeod
Background
Genetic Metabolic Dietitians International (GMDI) conducted a professional status survey of metabolic dietitians working in the United States to describe job satisfaction and establish salary and compensation benchmarks specific to metabolic dietitians.
Methods
The survey was anonymously administered in a web-based format via REDCap between October and November 2023. Registered dietitians working with inborn errors of metabolism (IEM) were eligible to participate.
Results
A total of 178 surveys were received and 147 were included in the final analysis. Most respondents were female (96 %), worked in a clinical setting (83 %), and held a graduate degree (75 %), while 30 % had one or more board certifications and 8 % were faculty. Respondents specialized in genetic metabolic nutrition for a median of 6 years (IQR 2–15). Overall satisfaction with one's professional focus in IEM was high among respondents (87 %), though 40 % reported dissatisfaction with earnings potential in their current position.
The median annual, full-time salary for US-based metabolic dietitians in all work settings was $80,400 (IQR $67,100-96,000). After excluding dietitians working in the pharmaceutical and/or nutrition industry (n = 14), the median annual salary decreased to $76,200 (IQR $66,700-91,000). Increased years' experience, responsibility (e.g., supervisor), expertise (i.e., board certification), and categorization as a Level II dietitian or higher were associated with higher annual salary.
Conclusion
The results of the 2023 GMDI Professional Status Survey provide insight into the current compensation and benefits of metabolic dietitians practicing in the US. These data can be used to support individual efforts to secure equitable compensation for the metabolic dietitian's critical role in the medical nutrition therapy for individuals with IEM.
{"title":"Compensation for metabolic dietitians practicing in the United States: 2023 genetic metabolic dietitians international professional status survey","authors":"Krista Viau , Sommer Gaughan , Jessica Kopesky , Beth Ogata , Heather Saavedra , Mary Sowa , Erin MacLeod","doi":"10.1016/j.ymgmr.2024.101147","DOIUrl":"10.1016/j.ymgmr.2024.101147","url":null,"abstract":"<div><h3>Background</h3><div>Genetic Metabolic Dietitians International (GMDI) conducted a professional status survey of metabolic dietitians working in the United States to describe job satisfaction and establish salary and compensation benchmarks specific to metabolic dietitians.</div></div><div><h3>Methods</h3><div>The survey was anonymously administered in a web-based format via REDCap between October and November 2023. Registered dietitians working with inborn errors of metabolism (IEM) were eligible to participate.</div></div><div><h3>Results</h3><div>A total of 178 surveys were received and 147 were included in the final analysis. Most respondents were female (96 %), worked in a clinical setting (83 %), and held a graduate degree (75 %), while 30 % had one or more board certifications and 8 % were faculty. Respondents specialized in genetic metabolic nutrition for a median of 6 years (IQR 2–15). Overall satisfaction with one's professional focus in IEM was high among respondents (87 %), though 40 % reported dissatisfaction with earnings potential in their current position.</div><div>The median annual, full-time salary for US-based metabolic dietitians in all work settings was $80,400 (IQR $67,100-96,000). After excluding dietitians working in the pharmaceutical and/or nutrition industry (<em>n</em> = 14), the median annual salary decreased to $76,200 (IQR $66,700-91,000). Increased years' experience, responsibility (e.g., supervisor), expertise (i.e., board certification), and categorization as a Level II dietitian or higher were associated with higher annual salary.</div></div><div><h3>Conclusion</h3><div>The results of the 2023 GMDI Professional Status Survey provide insight into the current compensation and benefits of metabolic dietitians practicing in the US. These data can be used to support individual efforts to secure equitable compensation for the metabolic dietitian's critical role in the medical nutrition therapy for individuals with IEM.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101147"},"PeriodicalIF":1.8,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142357434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-28DOI: 10.1016/j.ymgmr.2024.101144
Amber Van Baelen , Stijn Verhulst , François Eyskens
Acid Sphingomyelinase Deficiency (ASMD) is a lysosomal storage disorder that can lead to severe complications if not promptly treated. This case aims to highlight the critical importance of early awareness of ASMD and to introduce, for the first time in the literature, a new and highly effective treatment option for children.
{"title":"Unexplained splenomegaly as a diagnostic marker for a rare but severe disease with an innovative and highly effective new treatment option: A case report","authors":"Amber Van Baelen , Stijn Verhulst , François Eyskens","doi":"10.1016/j.ymgmr.2024.101144","DOIUrl":"10.1016/j.ymgmr.2024.101144","url":null,"abstract":"<div><div>Acid Sphingomyelinase Deficiency (ASMD) is a lysosomal storage disorder that can lead to severe complications if not promptly treated. This case aims to highlight the critical importance of early awareness of ASMD and to introduce, for the first time in the literature, a new and highly effective treatment option for children.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101144"},"PeriodicalIF":1.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder. It may occur due to various changes to the OTC gene located on the X chromosome. Many sequence variants in the OTC gene result in different severity and require different types of molecular testing. We present a familial case of hyperammonemia possibly caused by the small CNV (duplication) within exon 2 of the OTC gene that was not detected by standard sequencing methods. In this case, the knowledge of the underlying molecular changes to the gene results in an appropriate approach to future sibling screening. Collecting more data, especially regarding rare variants of genetic disorders, is essential as it will help to create the best diagnostic-therapeutic path in prenatal and neonatal care in the future. Early diagnosis and treatment can lead to a better prognosis, and this case emphasizes the importance of understanding genetic changes in OTC deficiency.
{"title":"OTC gene duplication as the possible cause of massive hyperammonaemia with a fatal prognosis","authors":"Borkowska Natalia , Kaluzny Lukasz , Rokicki Dariusz , Szmida Elzbieta , Kowalski Pawel , Dus-Zuchowska Monika , Skiba Pawel , Ciara Elzbieta , Biela Mateusz , Rydzanicz Malgorzata , Ploski Rafal , Smigiel Robert","doi":"10.1016/j.ymgmr.2024.101146","DOIUrl":"10.1016/j.ymgmr.2024.101146","url":null,"abstract":"<div><div>Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder. It may occur due to various changes to the <em>OTC</em> gene located on the X chromosome. Many sequence variants in the <em>OTC</em> gene result in different severity and require different types of molecular testing. We present a familial case of hyperammonemia possibly caused by the small CNV (duplication) within exon 2 of the <em>OTC</em> gene that was not detected by standard sequencing methods. In this case, the knowledge of the underlying molecular changes to the gene results in an appropriate approach to future sibling screening. Collecting more data, especially regarding rare variants of genetic disorders, is essential as it will help to create the best diagnostic-therapeutic path in prenatal and neonatal care in the future. Early diagnosis and treatment can lead to a better prognosis, and this case emphasizes the importance of understanding genetic changes in OTC deficiency.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101146"},"PeriodicalIF":1.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142357435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.ymgmr.2024.101143
Shami Pokhrel, Subha Sainju, Prasanna Lamsal, Uma Devi Chhetri
Fructose-1, 6- bisphosphatase deficiency is a rare autosomal recessive inborn error of fructose metabolism which mainly affects gluconeogenesis. It often presents with ketotic hypoglycemia and lactic acidosis, with hyperventilation. The disease has a high mortality rate when undiagnosed.
Here we report a case of this rare disorder, referred to our hospital in Western Nepal, diagnosed originally as pneumonia. The patient presented in respiratory distress with severe metabolic acidosis and dehydration. She also demonstrated hypoglycemia, hypernatremia, coagulation dysfunction and albuminuria, all of which gradually improved, though her lactate remained consistently elevated. This led to investigation of urinary ketones which were positive suggesting a defect in the metabolism of carbohydrates. Urine organic acid profile and whole exome sequencing finally confirmed the diagnosis of Fructose-1, 6- bisphosphatase deficiency. To our knowledge this is the first case report of this disease diagnosed in Nepal.
{"title":"A rare case of fructose-1, 6-bisphosphatase deficiency: Clinical features in a pediatric patient","authors":"Shami Pokhrel, Subha Sainju, Prasanna Lamsal, Uma Devi Chhetri","doi":"10.1016/j.ymgmr.2024.101143","DOIUrl":"10.1016/j.ymgmr.2024.101143","url":null,"abstract":"<div><div>Fructose-1, 6- bisphosphatase deficiency is a rare autosomal recessive inborn error of fructose metabolism which mainly affects gluconeogenesis. It often presents with ketotic hypoglycemia and lactic acidosis, with hyperventilation. The disease has a high mortality rate when undiagnosed.</div><div>Here we report a case of this rare disorder, referred to our hospital in Western Nepal, diagnosed originally as pneumonia. The patient presented in respiratory distress with severe metabolic acidosis and dehydration. She also demonstrated hypoglycemia, hypernatremia, coagulation dysfunction and albuminuria, all of which gradually improved, though her lactate remained consistently elevated. This led to investigation of urinary ketones which were positive suggesting a defect in the metabolism of carbohydrates. Urine organic acid profile and whole exome sequencing finally confirmed the diagnosis of Fructose-1, 6- bisphosphatase deficiency. To our knowledge this is the first case report of this disease diagnosed in Nepal.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101143"},"PeriodicalIF":1.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142318830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1016/j.ymgmr.2024.101142
Filippo Ingoglia , Mohsen Tanfous , Benjamin Ellezam , Katherine J. Anderson , Marzia Pasquali , Lorenzo D. Botto
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a primary mitochondrial dysfunction affecting mitochondrial fatty acid and protein metabolism, caused by biallelic pathogenic variants in ETFA, ETFB, or ETFDH genes. The heterogeneous phenotypes associated with MADD have been classified into three groups: neonatal onset with congenital anomalies (type 1), neonatal onset without congenital anomalies (type 2), and attenuated and/or later onset (type 3). Here, we present two cases with biochemical profiles mimicking late-onset MADD but negative genetic testing, associated with the use of sertraline, a commonly used antidepressant. Case 1 is a 22 yo woman diagnosed with depression and profound fatigue who was referred to the metabolic clinic because of carnitine deficiency and a plasma acylcarnitine profile with a MADD-like pattern. Case 2 is a 61 yo woman with a history of chronic fatigue who was admitted to the emergency department with difficulty swallowing, metabolic acidosis, and mild rhabdomyolysis. Plasma acylcarnitine profile showed a MADD-like pattern. The muscle biopsy revealed lipid droplet accumulation and proliferation of mitochondria with abnormal osmiophilic inclusions, and a biochemical assay of the respiratory chain showed a deficit in complex II activity. In both cases, urine organic acid profile was normal, and genetic tests did not detect variants in the genes involved in MADD. Sertraline was on their list of medications and considering its association with inhibition of mitochondrial function and rhabdomyolysis, the team recommended the discontinuation under medical supervision. In Case 1 after discontinuation, the plasma acylcarnitine test normalized, only to return abnormal when the patient resumed sertraline. In Case 2, after sertraline was discontinued rhabdomyolysis resolved, and the muscle biopsy and biochemical assay of the respiratory chain normalized. Although sertraline is considered a safe drug, these two cases suggest that the use of sertraline may be associated with a potentially reversible form of mitochondrial dysfunction mimicking MADD. Further studies are needed to confirm and estimate the risk of MADD-like presentations with the use of sertraline, as well as identifying additional contributing factors, including genetic factors. Metabolic physicians should consider sertraline use in the differential diagnosis of MADD, particularly when genetic testing is negative.
{"title":"MADD-like pattern of acylcarnitines associated with sertraline use","authors":"Filippo Ingoglia , Mohsen Tanfous , Benjamin Ellezam , Katherine J. Anderson , Marzia Pasquali , Lorenzo D. Botto","doi":"10.1016/j.ymgmr.2024.101142","DOIUrl":"10.1016/j.ymgmr.2024.101142","url":null,"abstract":"<div><p>Multiple acyl-CoA dehydrogenase deficiency (MADD) is a primary mitochondrial dysfunction affecting mitochondrial fatty acid and protein metabolism, caused by biallelic pathogenic variants in ETFA, ETFB, or ETFDH genes. The heterogeneous phenotypes associated with MADD have been classified into three groups: neonatal onset with congenital anomalies (type 1), neonatal onset without congenital anomalies (type 2), and attenuated and/or later onset (type 3). Here, we present two cases with biochemical profiles mimicking late-onset MADD but negative genetic testing, associated with the use of sertraline, a commonly used antidepressant. Case 1 is a 22 yo woman diagnosed with depression and profound fatigue who was referred to the metabolic clinic because of carnitine deficiency and a plasma acylcarnitine profile with a MADD-like pattern. Case 2 is a 61 yo woman with a history of chronic fatigue who was admitted to the emergency department with difficulty swallowing, metabolic acidosis, and mild rhabdomyolysis. Plasma acylcarnitine profile showed a MADD-like pattern. The muscle biopsy revealed lipid droplet accumulation and proliferation of mitochondria with abnormal osmiophilic inclusions, and a biochemical assay of the respiratory chain showed a deficit in complex II activity. In both cases, urine organic acid profile was normal, and genetic tests did not detect variants in the genes involved in MADD. Sertraline was on their list of medications and considering its association with inhibition of mitochondrial function and rhabdomyolysis, the team recommended the discontinuation under medical supervision. In Case 1 after discontinuation, the plasma acylcarnitine test normalized, only to return abnormal when the patient resumed sertraline. In Case 2, after sertraline was discontinued rhabdomyolysis resolved, and the muscle biopsy and biochemical assay of the respiratory chain normalized. Although sertraline is considered a safe drug, these two cases suggest that the use of sertraline may be associated with a potentially reversible form of mitochondrial dysfunction mimicking MADD. Further studies are needed to confirm and estimate the risk of MADD-like presentations with the use of sertraline, as well as identifying additional contributing factors, including genetic factors. Metabolic physicians should consider sertraline use in the differential diagnosis of MADD, particularly when genetic testing is negative.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101142"},"PeriodicalIF":1.8,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000958/pdfft?md5=5fe038506b2728ec375355d46e97c8be&pid=1-s2.0-S2214426924000958-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号