Pub Date : 2026-03-01Epub Date: 2026-01-19DOI: 10.1016/j.ymgme.2026.109737
Karen Driesen , Veronika Holubová , Pedro Magalhães , Shauni Loopmans , Mainak Guharoy , Isabelle Meyts , Eva Morava , Bart Ghesquière , Peter Witters
Glycosylation is one of the most important posttranslational modifications. When the glycosylation machinery is affected, this leads to a congenital disorder of glycosylation (CDG). CDG are a class of rare multisystemic diseases that often affect the endoplasmic reticulum (ER). Although vascular complications have been reported in CDG, the contribution of endothelial dysfunction to these phenotypes remains incompletely understood. Here, we evaluated the effect of glycosylation deficiency on endothelial dysfunction by generating two endothelial cell models using pharmacological inhibitors: tunicamycin (a well-known glycosylation inhibitor at the level of DPAGT1), and 2-deoxy-2-fluoro-D-mannose (FMan). This is a novel inhibitor that inhibits mannose and related sugar-phosphate metabolism. These cell models were subjected to transcriptomics, proteomics, and tracer metabolomics to pinpoint the pathways that are most affected across these different levels. Both transcriptomics and proteomics revealed ER stress as the top upregulated feature. This was functionally characterized by decreased cell growth, induced apoptosis, decreased cell migration, and induced an immune response. The barrier function of the cells was not affected. Here, we demonstrate that N-glycosylation deficiency triggers an ER stress response, contributing to endothelial dysfunction, and investigated ER stress mitigation as a potential therapeutic strategy for CDG.
{"title":"Multi-omics analysis reveals ER stress as a main feature in two endothelial cell models of N-linked congenital disorders of glycosylation","authors":"Karen Driesen , Veronika Holubová , Pedro Magalhães , Shauni Loopmans , Mainak Guharoy , Isabelle Meyts , Eva Morava , Bart Ghesquière , Peter Witters","doi":"10.1016/j.ymgme.2026.109737","DOIUrl":"10.1016/j.ymgme.2026.109737","url":null,"abstract":"<div><div>Glycosylation is one of the most important posttranslational modifications. When the glycosylation machinery is affected, this leads to a congenital disorder of glycosylation (CDG). CDG are a class of rare multisystemic diseases that often affect the endoplasmic reticulum (ER). Although vascular complications have been reported in CDG, the contribution of endothelial dysfunction to these phenotypes remains incompletely understood. Here, we evaluated the effect of glycosylation deficiency on endothelial dysfunction by generating two endothelial cell models using pharmacological inhibitors: tunicamycin (a well-known glycosylation inhibitor at the level of DPAGT1), and 2-deoxy-2-fluoro-D-mannose (FMan). This is a novel inhibitor that inhibits mannose and related sugar-phosphate metabolism. These cell models were subjected to transcriptomics, proteomics, and tracer metabolomics to pinpoint the pathways that are most affected across these different levels. Both transcriptomics and proteomics revealed ER stress as the top upregulated feature. This was functionally characterized by decreased cell growth, induced apoptosis, decreased cell migration, and induced an immune response. The barrier function of the cells was not affected. Here, we demonstrate that N-glycosylation deficiency triggers an ER stress response, contributing to endothelial dysfunction, and investigated ER stress mitigation as a potential therapeutic strategy for CDG.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109737"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030450","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 : 2026-03-01Epub Date: 2026-01-08DOI: 10.1016/j.ymgme.2026.109727
Rodrigo T. Starosta , Miao He , Sara Gracie , Janell Kierstein , Christian Thiel , Nastassja Himmelreich , Yupeng Liu , Wenyue Zhang , Andrew C. Edmondson , Naomi Meeks , Austin Larson , Johan L.K. Van Hove , Aaina Kochhar
Fucosylation disorders are rare types of congenital disorders of glycosylation (CDG), the most common being SLC35C1-CDG, which is classically described as a leukocyte adhesion deficiency (hence the previous name of “leukocyte adhesion deficiency type II”) with dysmorphic features, short stature, and moderate-to-severe developmental and intellectual disabilities. In more recent years, several cases have been described of individuals with bi-allelic SLC35C1 variants and biochemical proof of hypofucosylation who had short stature, dysmorphic features, and intellectual disability, but no hematological abnormalities. In this article, we report a patient with growth faltering, neuroirritability, nystagmus, developmental delays, microcephaly, dysmorphic features, and hypogammaglobulinemia G. Biochemical investigations including serum N-glycan profiling, fucosylation-focused whole serum glycoprotein profiling, and serum lectin blots, all of which showed significant global hypofucosylation. Exome sequencing revealed a single likely pathogenic variant, SLC35C1 (NM_018389.4):c.503_505delTCT, p.(Phe168del), which was inherited from an unaffected mother. Whole genome sequencing with manual review of raw data did not reveal any second pathogenic variants; SLC35C1 mRNA sequencing was negative for changes in the second allele or allelic imbalance. The patient was started on L-fucose supplementation, with subsequent improvements in weight and head circumference, normalization of IgG levels, and remarkable developmental catch-up. Biochemically, there was an increase in abundance of previously decreased fucosylated glycan species in serum, especially Fuc1GlcNAc2Man3 (a glycan that is known to be enriched in neutrophils). In summary, we present here further evidence for the role of L-fucose supplementation in treating hypofucosylation disorders and suggest that IgG and fucosylated glycan species may be useful as biomarkers in this scenario, although further research is needed to validate them as such. It is likely that the early introduction of L-fucose in this patient may have led to the excellent developmental outcomes observed.
{"title":"L-fucose supplementation in a patient with global hypofucosylation and a mono-allelic variant in SLC35C1: Clinical improvement and assessment of biomarkers","authors":"Rodrigo T. Starosta , Miao He , Sara Gracie , Janell Kierstein , Christian Thiel , Nastassja Himmelreich , Yupeng Liu , Wenyue Zhang , Andrew C. Edmondson , Naomi Meeks , Austin Larson , Johan L.K. Van Hove , Aaina Kochhar","doi":"10.1016/j.ymgme.2026.109727","DOIUrl":"10.1016/j.ymgme.2026.109727","url":null,"abstract":"<div><div>Fucosylation disorders are rare types of congenital disorders of glycosylation (CDG), the most common being SLC35C1-CDG, which is classically described as a leukocyte adhesion deficiency (hence the previous name of “leukocyte adhesion deficiency type II”) with dysmorphic features, short stature, and moderate-to-severe developmental and intellectual disabilities. In more recent years, several cases have been described of individuals with bi-allelic <em>SLC35C1</em> variants and biochemical proof of hypofucosylation who had short stature, dysmorphic features, and intellectual disability, but no hematological abnormalities. In this article, we report a patient with growth faltering, neuroirritability, nystagmus, developmental delays, microcephaly, dysmorphic features, and hypogammaglobulinemia G. Biochemical investigations including serum N-glycan profiling, fucosylation-focused whole serum glycoprotein profiling, and serum lectin blots, all of which showed significant global hypofucosylation. Exome sequencing revealed a single likely pathogenic variant, <em>SLC35C1</em> (NM_018389.4):c.503_505delTCT, p.(Phe168del), which was inherited from an unaffected mother. Whole genome sequencing with manual review of raw data did not reveal any second pathogenic variants; <em>SLC35C1</em> mRNA sequencing was negative for changes in the second allele or allelic imbalance. The patient was started on L-fucose supplementation, with subsequent improvements in weight and head circumference, normalization of IgG levels, and remarkable developmental catch-up. Biochemically, there was an increase in abundance of previously decreased fucosylated glycan species in serum, especially Fuc<sub>1</sub>GlcNAc<sub>2</sub>Man<sub>3</sub> (a glycan that is known to be enriched in neutrophils). In summary, we present here further evidence for the role of L-fucose supplementation in treating hypofucosylation disorders and suggest that IgG and fucosylated glycan species may be useful as biomarkers in this scenario, although further research is needed to validate them as such. It is likely that the early introduction of L-fucose in this patient may have led to the excellent developmental outcomes observed.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109727"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966421","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 : 2026-03-01Epub Date: 2025-12-29DOI: 10.1016/j.ymgme.2025.109716
Neena Agrawal , Simona Bianconi , Rebecca Jaeger , Nicole Y. Farhat , Derek M. Alexander , Ninet Sinaii , Colleen Hadigan , Elizabeth Berry-Kravis , Forbes D. Porter
Purpose
Niemann-Pick Disease, Type C1 (NPC1) is a neurodegenerative lysosomal disease in which the first manifestation is often cholestatic liver disease at birth. The neurodegenerative symptoms typically manifest later. The aim of this study was to see if the presence and severity of liver disease at birth predicted whether a participant would develop liver disease later and if there was any correlation with the age of onset of neurological symptoms.
Methods
Liver disease was characterized in 93 individuals with NPC1 using FibroScan, abdominal ultrasound, and plasma liver function tests at baseline and longitudinally over up to a four-year period. This information was correlated with the presence or absence of liver disease noted at birth.
Results
Higher liver stiffness measurement scores, suggesting increased risk for liver fibrosis, were associated with a history of significant liver disease in infancy (p = 0.001). A history of absent or mild/moderate liver disease at birth had no correlation with differences in liver stiffness measurements The presence of any degree of liver disease at birth corresponded to earlier onset of neurological symptoms compared to having no liver disease at birth (p = 0.002). Those with no history of neonatal liver disease had an average age of 10.3 years at time of neurological symptoms, compared to 5.9 years for those with mild/moderate disease and 3.6 years for those with severe disease (p = 0.002).
Conclusions
The presence of liver disease at birth can provide prognostic information on when individuals with NPC1 may manifest neurologic symptoms. In addition, individuals who had severe liver disease at birth are at higher risk for developing clinically significant liver disease after the neonatal period. Given multiple reports of hepatocellular carcinoma in individuals with NPC1, those with a history of severe liver disease should be closely monitored.
{"title":"Characterization of liver disease in a cohort of individuals with Niemann-Pick Disease, Type C1","authors":"Neena Agrawal , Simona Bianconi , Rebecca Jaeger , Nicole Y. Farhat , Derek M. Alexander , Ninet Sinaii , Colleen Hadigan , Elizabeth Berry-Kravis , Forbes D. Porter","doi":"10.1016/j.ymgme.2025.109716","DOIUrl":"10.1016/j.ymgme.2025.109716","url":null,"abstract":"<div><h3>Purpose</h3><div>Niemann-Pick Disease, Type C1 (NPC1) is a neurodegenerative lysosomal disease in which the first manifestation is often cholestatic liver disease at birth. The neurodegenerative symptoms typically manifest later. The aim of this study was to see if the presence and severity of liver disease at birth predicted whether a participant would develop liver disease later and if there was any correlation with the age of onset of neurological symptoms.</div></div><div><h3>Methods</h3><div>Liver disease was characterized in 93 individuals with NPC1 using FibroScan, abdominal ultrasound, and plasma liver function tests at baseline and longitudinally over up to a four-year period. This information was correlated with the presence or absence of liver disease noted at birth.</div></div><div><h3>Results</h3><div>Higher liver stiffness measurement scores, suggesting increased risk for liver fibrosis, were associated with a history of significant liver disease in infancy (<em>p</em> = 0.001). A history of absent or mild/moderate liver disease at birth had no correlation with differences in liver stiffness measurements The presence of any degree of liver disease at birth corresponded to earlier onset of neurological symptoms compared to having no liver disease at birth (<em>p</em> = 0.002). Those with no history of neonatal liver disease had an average age of 10.3 years at time of neurological symptoms, compared to 5.9 years for those with mild/moderate disease and 3.6 years for those with severe disease (<em>p</em> = 0.002).</div></div><div><h3>Conclusions</h3><div>The presence of liver disease at birth can provide prognostic information on when individuals with NPC1 may manifest neurologic symptoms. In addition, individuals who had severe liver disease at birth are at higher risk for developing clinically significant liver disease after the neonatal period. Given multiple reports of hepatocellular carcinoma in individuals with NPC1, those with a history of severe liver disease should be closely monitored.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109716"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966447","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 : 2026-03-01Epub Date: 2026-01-07DOI: 10.1016/j.ymgme.2026.109731
Steven H. Lang , Naiga Cottingham , Colleen Donnelly , Sarah Risen , Rossana Malatesta Muncher , Eileen D. Brewer , Jeffery M. Saland , Corrine Benchimol , Fernando Scaglia , Jaya Ganesh
Single large-scale mitochondrial DNA deletion syndromes (SLSMDS) are a clinical continuum of three classic discrete clinical syndromes: Pearson marrow-pancreas syndrome, Kearns-Sayre syndrome, and chronic progressive ophthalmoplegia. Kidney manifestations, including chronic kidney disease with progression kidney failure has emerged as significant cause of morbidity and mortality in SLSMDS. Despite this recognition, reports of kidney transplantation in this population are limited. Here, we describe outcomes of kidney transplantation in three patients with SLSMDS and kidney failure over a 1–2.5-year follow-up period. All three patients had multisystem involvement at the time of transplantation. In all three patients, surgery was uncomplicated without evidence of acute metabolic decompensation in the perioperative period and standard immunosuppressive protocols were well tolerated. One patient developed post-transplant lymphoproliferative disease at 9 months status-post transplant which was ultimately fatal. The two surviving patients remain with stable graft function and functional quality of life at 1- and 3.5-years post-transplant.
{"title":"Outcomes of kidney transplantation in three patients with single large-scale mitochondrial DNA deletion syndromes","authors":"Steven H. Lang , Naiga Cottingham , Colleen Donnelly , Sarah Risen , Rossana Malatesta Muncher , Eileen D. Brewer , Jeffery M. Saland , Corrine Benchimol , Fernando Scaglia , Jaya Ganesh","doi":"10.1016/j.ymgme.2026.109731","DOIUrl":"10.1016/j.ymgme.2026.109731","url":null,"abstract":"<div><div>Single large-scale mitochondrial DNA deletion syndromes (SLSMDS) are a clinical continuum of three classic discrete clinical syndromes: Pearson marrow-pancreas syndrome, Kearns-Sayre syndrome, and chronic progressive ophthalmoplegia. Kidney manifestations, including chronic kidney disease with progression kidney failure has emerged as significant cause of morbidity and mortality in SLSMDS. Despite this recognition, reports of kidney transplantation in this population are limited. Here, we describe outcomes of kidney transplantation in three patients with SLSMDS and kidney failure over a 1–2.5-year follow-up period. All three patients had multisystem involvement at the time of transplantation. In all three patients, surgery was uncomplicated without evidence of acute metabolic decompensation in the perioperative period and standard immunosuppressive protocols were well tolerated. One patient developed post-transplant lymphoproliferative disease at 9 months status-post transplant which was ultimately fatal. The two surviving patients remain with stable graft function and functional quality of life at 1- and 3.5-years post-transplant.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109731"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078683","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 : 2026-03-01Epub Date: 2026-02-10DOI: 10.1016/j.ymgme.2026.109761
Catherine Pilgrim-Grayson , Anna Choe , Naomi Knoble , Yan Wang , Kerry Jo Lee , Lea Ann Browning-McNee , Cartier Esham , Amel Karaa
{"title":"Corrigendum to “News: Primary mitochondrial diseases: A rare disease virtual workshop”[Molecular Genetics and Metabolism 147 (2026) 109707]","authors":"Catherine Pilgrim-Grayson , Anna Choe , Naomi Knoble , Yan Wang , Kerry Jo Lee , Lea Ann Browning-McNee , Cartier Esham , Amel Karaa","doi":"10.1016/j.ymgme.2026.109761","DOIUrl":"10.1016/j.ymgme.2026.109761","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109761"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147397345","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 : 2026-03-01Epub Date: 2026-02-08DOI: 10.1016/j.ymgme.2026.109765
Anjana Sevagamoorthy , Francesco Gavazzi , Zarrin Tashnim , Peter Hong , Ylenia Vaia , Min Ae Lee-Kirsch , Despina Eleftheriou , Shanice Beerepoot , Marie Hully , Elizabeth M. Berry Kravis , Pamela Ventola , Melissa Raspa , Anne Wheeler , Sara B. DeMauro , Allan M. Glanzman , Elise Townsend , Tina Duong , Stacy Cusack , Ann T. Harrington , Samuel Pierce , Adeline Vanderver
<div><h3>Introduction</h3><div>Aicardi-Goutières Syndrome (AGS) is a genetic type 1 interferonopathy that causes white matter abnormalities and intracranial calcifications, resulting in varying degrees of neurologic impairment and systemic manifestations. Novel disease-modifying therapies for AGS are forthcoming. The 2022 Food and Drug Administration guidance, “<em>Patient-Focused Drug Development</em>” (PFDD), emphasizes the importance of including patients' voices early in the design of clinical trials. This represents an urgent unmet need in rare disease research. In this study, we propose and pilot a new methodology to identify patient-centered Concepts of Interest (COIs) and suitable Clinical Outcome Assessments (COAs) for clinical trials.</div></div><div><h3>Methods</h3><div>The study was performed under the Myelin Disease Biorepository Project within the Global Leukodystrophy Initiative Clinical Trial Network. A sequential multicomponent approach, piloted in AGS, was designed to (i) identify COIs, (ii) select COAs capable of measuring the COIs through expert consensus, and (iii) assess the feasibility of COA application. Experts were identified based on relevant scientific publications and expertise in AGS (disease experts for COI) and/or their application of relevant COAs (outcome experts for COA). Expert consensus was achieved using the modified eDelphi approach for COIs, expertise-specific multi-panel focus group discussions, and pre-and post-surveys for COA selection. Consensus was defined as ≥70% agreement among the experts. This was followed by a virtual stakeholder discussion with patients and/or patient representatives to assess the feasibility of the COA application in the context of a clinical trial.</div></div><div><h3>Results</h3><div>Based on the health priorities identified by patient caregivers, the proposed approach revealed a set of fit-for-purpose COIs across the motor, adaptive behavior, and neurologic functional domains. All experts acknowledged the significance of each caregiver-identified priority but expressed differing opinions on the likelihood of observing changes in the functional domain within a 6- to 12-month timeframe. Following this, a consensus-building approach for COA selection for each identified COI resulted in a paired COI-COA panel applicable to future AGS clinical trials. Finally, the discussion on the feasibility of application of the selected COAs with the patients and/or patient representatives elicited critical information to design a patient-centered prospective COA protocol, applicable to clinical trials and natural history studies.</div></div><div><h3>Discussion</h3><div>The proposed approach marks the first step toward a patient-centered clinical trial design for rare diseases. It establishes a paired COI-COA panel, as well as informs the design of a patient-centered prospective COA protocol for upcoming AGS clinical trials and natural history studies. Additionally, the identified COA panel fa
{"title":"A novel patient-Centered approach to clinical trial readiness in rare diseases: Application in Aicardi-Goutières Syndrome (AGS)","authors":"Anjana Sevagamoorthy , Francesco Gavazzi , Zarrin Tashnim , Peter Hong , Ylenia Vaia , Min Ae Lee-Kirsch , Despina Eleftheriou , Shanice Beerepoot , Marie Hully , Elizabeth M. Berry Kravis , Pamela Ventola , Melissa Raspa , Anne Wheeler , Sara B. DeMauro , Allan M. Glanzman , Elise Townsend , Tina Duong , Stacy Cusack , Ann T. Harrington , Samuel Pierce , Adeline Vanderver","doi":"10.1016/j.ymgme.2026.109765","DOIUrl":"10.1016/j.ymgme.2026.109765","url":null,"abstract":"<div><h3>Introduction</h3><div>Aicardi-Goutières Syndrome (AGS) is a genetic type 1 interferonopathy that causes white matter abnormalities and intracranial calcifications, resulting in varying degrees of neurologic impairment and systemic manifestations. Novel disease-modifying therapies for AGS are forthcoming. The 2022 Food and Drug Administration guidance, “<em>Patient-Focused Drug Development</em>” (PFDD), emphasizes the importance of including patients' voices early in the design of clinical trials. This represents an urgent unmet need in rare disease research. In this study, we propose and pilot a new methodology to identify patient-centered Concepts of Interest (COIs) and suitable Clinical Outcome Assessments (COAs) for clinical trials.</div></div><div><h3>Methods</h3><div>The study was performed under the Myelin Disease Biorepository Project within the Global Leukodystrophy Initiative Clinical Trial Network. A sequential multicomponent approach, piloted in AGS, was designed to (i) identify COIs, (ii) select COAs capable of measuring the COIs through expert consensus, and (iii) assess the feasibility of COA application. Experts were identified based on relevant scientific publications and expertise in AGS (disease experts for COI) and/or their application of relevant COAs (outcome experts for COA). Expert consensus was achieved using the modified eDelphi approach for COIs, expertise-specific multi-panel focus group discussions, and pre-and post-surveys for COA selection. Consensus was defined as ≥70% agreement among the experts. This was followed by a virtual stakeholder discussion with patients and/or patient representatives to assess the feasibility of the COA application in the context of a clinical trial.</div></div><div><h3>Results</h3><div>Based on the health priorities identified by patient caregivers, the proposed approach revealed a set of fit-for-purpose COIs across the motor, adaptive behavior, and neurologic functional domains. All experts acknowledged the significance of each caregiver-identified priority but expressed differing opinions on the likelihood of observing changes in the functional domain within a 6- to 12-month timeframe. Following this, a consensus-building approach for COA selection for each identified COI resulted in a paired COI-COA panel applicable to future AGS clinical trials. Finally, the discussion on the feasibility of application of the selected COAs with the patients and/or patient representatives elicited critical information to design a patient-centered prospective COA protocol, applicable to clinical trials and natural history studies.</div></div><div><h3>Discussion</h3><div>The proposed approach marks the first step toward a patient-centered clinical trial design for rare diseases. It establishes a paired COI-COA panel, as well as informs the design of a patient-centered prospective COA protocol for upcoming AGS clinical trials and natural history studies. Additionally, the identified COA panel fa","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109765"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166042","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 : 2026-03-01Epub Date: 2025-12-29DOI: 10.1016/j.ymgme.2025.109714
Kendall Plant , Caoimhe Howard , Philippe Bourdon , Raffaele J. Massarotto , Daniel Gamu , William T. Gibson , Sylvia Stockler , Catherine Brunel-Guitton , Rajavel Elango
Background
Metabolic myopathies (MM) are a diverse group of genetic disorders that impair cellular energy metabolism, resulting in exercise intolerance and fatigue. Previous studies have reported benefits of physiotherapy in patients with MM, however, objective assessments of their efficacy remain limited. The 13C glucose breath test (13C-GBT) is a non-invasive measure of glucose metabolism through the detection of 13CO2 expelled from the tricarboxylic acid cycle. This study utilizes the in vivo13C-GBT assessment pre- and post-therapeutic intervention to evaluate the impact of a supervised 12 wk. at-home resistance training program on patients with MM.
Objectives
The first experiment was to assess the repeatability of the in vivo13C-GBT through triplicate study days in healthy controls. The second experiment was to assess 13C-glucose metabolism in participants with MM pre- and post-therapeutic intervention.
Design
Six healthy adult controls (3 F: 3 M) aged 22–29 y, and three adolescent participants (1 F: 2 M) aged 10–18 y with diagnosed MM were recruited. Participants completed up to three study days pre- and post-intervention, consuming a 1.5 mg/kg body weight dose of [U-13C6] d-glucose, and 1.5 g/kg body weight Trutol® glucose beverage. Breath samples collected during the 4 h study day were analyzed for 13C enrichment with isotope ratio mass spectrometry, and used to calculate rate of glucose oxidation (mg/kg/min). Measured 13C enrichment was used to calculate the rate of glucose oxidation (mg/kg/min) and interpreted with Area Under the Curve analysis, and determination of maximum rate (Cmax).
Results
Repeatability of the 13C-GBT was confirmed in healthy participants, with average coefficients of variation (CV) being 8.9 % in males and 8.6 % in females at Cmax. Among MM participants, exercise intervention increased glucose oxidation 23.5 % in subject MM-01 (F, 14 y), and 9 % in MM-02 (M, 16 y); but decreased −11.7 % in MM-04 (M, 17 y). All subjects showed a marginal increase in lean body mass (2–4 %).
Conclusions
The non-invasive 4 h 13C-GBT protocol shows potential as a feasible tool for clinicians to monitor glucose utilization due to its low patient burden and good repeatability. Future work should validate the repeatability of the assay in a larger patient population to confirm its translational potential to guide the management of MM patients.
{"title":"Influence of a 12 week at-home resistance exercise program on 13C-glucose metabolism in patients with metabolic myopathies","authors":"Kendall Plant , Caoimhe Howard , Philippe Bourdon , Raffaele J. Massarotto , Daniel Gamu , William T. Gibson , Sylvia Stockler , Catherine Brunel-Guitton , Rajavel Elango","doi":"10.1016/j.ymgme.2025.109714","DOIUrl":"10.1016/j.ymgme.2025.109714","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic myopathies (MM) are a diverse group of genetic disorders that impair cellular energy metabolism, resulting in exercise intolerance and fatigue. Previous studies have reported benefits of physiotherapy in patients with MM, however, objective assessments of their efficacy remain limited. The <sup>13</sup>C glucose breath test (<sup>13</sup>C-GBT) is a non-invasive measure of glucose metabolism through the detection of <sup>13</sup>CO<sub>2</sub> expelled from the tricarboxylic acid cycle. This study utilizes the <em>in vivo</em> <sup>13</sup>C-GBT assessment pre- and post-therapeutic intervention to evaluate the impact of a supervised 12 wk. at-home resistance training program on patients with MM.</div></div><div><h3>Objectives</h3><div>The first experiment was to assess the repeatability of the <em>in vivo</em> <sup>13</sup>C-GBT through triplicate study days in healthy controls. The second experiment was to assess <sup>13</sup>C-glucose metabolism in participants with MM pre- and post-therapeutic intervention.</div></div><div><h3>Design</h3><div>Six healthy adult controls (3 F: 3 M) aged 22–29 y, and three adolescent participants (1 F: 2 M) aged 10–18 y with diagnosed MM were recruited. Participants completed up to three study days pre- and post-intervention, consuming a 1.5 mg/kg body weight dose of [U-<sup>13</sup>C<sub>6</sub>] <span>d</span>-glucose, and 1.5 g/kg body weight Trutol® glucose beverage. Breath samples collected during the 4 h study day were analyzed for <sup>13</sup>C enrichment with isotope ratio mass spectrometry, and used to calculate rate of glucose oxidation (mg/kg/min). Measured <sup>13</sup>C enrichment was used to calculate the rate of glucose oxidation (mg/kg/min) and interpreted with Area Under the Curve analysis, and determination of maximum rate (C<sub>max</sub>).</div></div><div><h3>Results</h3><div>Repeatability of the <sup>13</sup>C-GBT was confirmed in healthy participants, with average coefficients of variation (CV) being 8.9 % in males and 8.6 % in females at C<sub>max</sub>. Among MM participants, exercise intervention increased glucose oxidation 23.5 % in subject MM-01 (F, 14 y), and 9 % in MM-02 (M, 16 y); but decreased −11.7 % in MM-04 (M, 17 y). All subjects showed a marginal increase in lean body mass (2–4 %).</div></div><div><h3>Conclusions</h3><div>The non-invasive 4 h <sup>13</sup>C-GBT protocol shows potential as a feasible tool for clinicians to monitor glucose utilization due to its low patient burden and good repeatability. Future work should validate the repeatability of the assay in a larger patient population to confirm its translational potential to guide the management of MM patients.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109714"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911681","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 : 2026-03-01Epub Date: 2025-12-11DOI: 10.1016/j.ymgme.2025.109704
Martina Messina , Rebecca Ganetzky , Carlos R. Ferreira , Nenad Blau , Shamima Rahman
Primary mitochondrial diseases (PMD) are a growing number of disorders caused by mitochondrial dysfunction. There is not yet a consensus on the precise definition of PMD. Therefore, this study presents an approach to developing a nosology for standardized, systematic classification of PMD, harmonized with ICIMD and IEMbase. A total of 452 PMD causative genes were included. The classification includes 18 categories: 1) Disorders of amino acid metabolism; 2) Disorders of peptide and amine metabolism; 3) Disorders of carbohydrate metabolism; 4) Disorders of fatty acid and ketone body metabolism; 5) Disorders of energy substrate metabolism; 6) Mitochondrial DNA-related disorders; 7) Nuclear-encoded disorders of oxidative phosphorylation; 8) Disorders of mitochondrial cofactor biosynthesis; 9) Disorders of mitochondrial DNA maintenance and replication; 10) Disorders of mitochondrial gene expression; 11) Other disorders of mitochondrial function; 12) Disorders of metabolite repair/proofreading; 13) Disorders of lipid metabolism; 14) Disorders of nucleobase, nucleotide and nucleic acid metabolism; 15) Disorders of tetrapyrrole metabolism; 16) Disorders of organelle biogenesis, dynamics and interaction; 17) Disorders of vitamin and cofactor metabolism and 18) Neurotransmitter disorders. We also describe the clinical involvement of 22 organs and systems and laboratory features. The most prevalent symptoms (per gene) were neurological (21.1%), ocular (10.3%), muscular (9.0%), gastrointestinal (8.3%), and cardiovascular (7.9%).
{"title":"Clinical and biochemical footprints of primary mitochondrial disorders: proposed nosology","authors":"Martina Messina , Rebecca Ganetzky , Carlos R. Ferreira , Nenad Blau , Shamima Rahman","doi":"10.1016/j.ymgme.2025.109704","DOIUrl":"10.1016/j.ymgme.2025.109704","url":null,"abstract":"<div><div>Primary mitochondrial diseases (PMD) are a growing number of disorders caused by mitochondrial dysfunction. There is not yet a consensus on the precise definition of PMD. Therefore, this study presents an approach to developing a nosology for standardized, systematic classification of PMD, harmonized with ICIMD and IEMbase. A total of 452 PMD causative genes were included. The classification includes 18 categories: 1) Disorders of amino acid metabolism; 2) Disorders of peptide and amine metabolism; 3) Disorders of carbohydrate metabolism; 4) Disorders of fatty acid and ketone body metabolism; 5) Disorders of energy substrate metabolism; 6) Mitochondrial DNA-related disorders; 7) Nuclear-encoded disorders of oxidative phosphorylation; 8) Disorders of mitochondrial cofactor biosynthesis; 9) Disorders of mitochondrial DNA maintenance and replication; 10) Disorders of mitochondrial gene expression; 11) Other disorders of mitochondrial function; 12) Disorders of metabolite repair/proofreading; 13) Disorders of lipid metabolism; 14) Disorders of nucleobase, nucleotide and nucleic acid metabolism; 15) Disorders of tetrapyrrole metabolism; 16) Disorders of organelle biogenesis, dynamics and interaction; 17) Disorders of vitamin and cofactor metabolism and 18) Neurotransmitter disorders. We also describe the clinical involvement of 22 organs and systems and laboratory features. The most prevalent symptoms (per gene) were neurological (21.1%), ocular (10.3%), muscular (9.0%), gastrointestinal (8.3%), and cardiovascular (7.9%).</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109704"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100550","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 : 2026-03-01Epub Date: 2026-01-22DOI: 10.1016/j.ymgme.2025.109707
Catherine Pilgrim-Grayson , Anna Choe , Naomi Knoble , Yan Wang , Kerry Jo Lee , Lea Ann Browning-McNee , Cartier Esham , Amel Karaa
The Reagan-Udall Foundation for the FDA (Foundation) in collaboration with the Food and Drug Administration (FDA) hosted a workshop titled “Primary Mitochondrial Diseases: A Rare Disease Virtual Workshop” on 22 May 2025, to explore opportunities to optimize therapeutic development for primary mitochondrial diseases (PMD). The event brought together a diverse group of experts including FDA regulators, regulated industries, health care professionals, scientists, patients and their families and caregivers, and patient organizations. The presentations and panels discussed existing challenges and proposed strategies to improve enrollment and optimize clinical trial design elements (e.g., outcome measures, endpoint and patient population selection, and statistical analysis) that may support clinical trial innovations for PMD therapeutics in alignment with regulatory standards.
Meeting purpose
Primary mitochondrial diseases (PMDs) are rare, often debilitating genetic disorders caused by variants in nuclear or mitochondrial DNA. There are approximately 70,000 PMD patients in the U.S. and 1 in 200 carry a pathogenic mtDNA variant.([1,2]) The multisystemic and heterogenous clinical presentations of PMDs present unique challenges for the development of targeted therapies.
There have been ongoing collaborations between the PMD community and FDA to discuss the challenges and align on solutions for successful PMD drug development. For example, in 2019 the FDA hosted a scientific symposium titled Developing Therapies for Primary Mitochondrial Diseases: Bridging the Gap, where multiple stakeholders discussed ways to integrate mitochondrial biology into drug development, the value of registries, the refinement of patient-focused outcomes, and additional regulatory and scientific considerations for clinical trial designs in PMD [3]. Building on the foundation laid, FDA and the PMD community continued to engage on approaches to clinical trial design and endpoint selection for PMD treatments and most recently, these discussions culminated in the 2025 “Primary Mitochondrial Diseases: A Rare Disease Virtual Workshop” [4]. This workshop focused on specific clinical development and design approaches, engagement with patients and other disease experts, analytic strategies for managing heterogeneity, and leveraging lessons learned for future success. PMD patients, families, advocates, academic clinical experts, FDA representatives, and others from the PMD community participated in the workshop.
This paper provides summaries of the presentations and reactor panels included in the workshop and concludes with key learnings and future directions for drug development for PMD identified during this meeting.
{"title":"Primary mitochondrial diseases: A rare disease virtual workshop","authors":"Catherine Pilgrim-Grayson , Anna Choe , Naomi Knoble , Yan Wang , Kerry Jo Lee , Lea Ann Browning-McNee , Cartier Esham , Amel Karaa","doi":"10.1016/j.ymgme.2025.109707","DOIUrl":"10.1016/j.ymgme.2025.109707","url":null,"abstract":"<div><div>The Reagan-Udall Foundation for the FDA (Foundation) in collaboration with the Food and Drug Administration (FDA) hosted a workshop titled “Primary Mitochondrial Diseases: A Rare Disease Virtual Workshop” on 22 May 2025, to explore opportunities to optimize therapeutic development for primary mitochondrial diseases (PMD). The event brought together a diverse group of experts including FDA regulators, regulated industries, health care professionals, scientists, patients and their families and caregivers, and patient organizations. The presentations and panels discussed existing challenges and proposed strategies to improve enrollment and optimize clinical trial design elements (<em>e.g.,</em> outcome measures, endpoint and patient population selection, and statistical analysis) that may support clinical trial innovations for PMD therapeutics in alignment with regulatory standards.</div></div><div><h3>Meeting purpose</h3><div>Primary mitochondrial diseases (PMDs) are rare, often debilitating genetic disorders caused by variants in nuclear or mitochondrial DNA. There are approximately 70,000 PMD patients in the U.S. and 1 in 200 carry a pathogenic mtDNA variant.([<span><span>1</span></span>,<span><span>2</span></span>]) The multisystemic and heterogenous clinical presentations of PMDs present unique challenges for the development of targeted therapies.</div><div>There have been ongoing collaborations between the PMD community and FDA to discuss the challenges and align on solutions for successful PMD drug development. For example, in 2019 the FDA hosted a scientific symposium titled <em>Developing Therapies for Primary Mitochondrial Diseases: Bridging the Gap</em>, where multiple stakeholders discussed ways to integrate mitochondrial biology into drug development, the value of registries, the refinement of patient-focused outcomes, and additional regulatory and scientific considerations for clinical trial designs in PMD [<span><span>3</span></span>]. Building on the foundation laid, FDA and the PMD community continued to engage on approaches to clinical trial design and endpoint selection for PMD treatments and most recently, these discussions culminated in the 2025 “Primary Mitochondrial Diseases: A Rare Disease Virtual Workshop” [<span><span>4</span></span>]. This workshop focused on specific clinical development and design approaches, engagement with patients and other disease experts, analytic strategies for managing heterogeneity, and leveraging lessons learned for future success. PMD patients, families, advocates, academic clinical experts, FDA representatives, and others from the PMD community participated in the workshop.</div><div>This paper provides summaries of the presentations and reactor panels included in the workshop and concludes with key learnings and future directions for drug development for PMD identified during this meeting.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109707"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035163","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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