Pub Date : 2025-03-01DOI: 10.1016/j.ymgme.2025.109073
Clara D.M. van Karnebeek , Annelieke R. Müller , Laura Benkemoun , Ibrahim Boussaad , Martina C. Cornel , Joanna IntHout , Martin de Kort , Sofia de Oliveira Martins , Alessandro Prigione , Tessel Rigter , Kit C.B. Roes , Anna Sanchez , Raymond Schipper , Mark D. Wilkinson , Peter A.C. ’t Hoen
Rare diseases affect over 400 million people worldwide, with approved treatment available for less than 6 % of these diseases. Drug repurposing is a key strategy in the development of therapies for rare disease patients with large unmet medical needs. The process of repurposing drugs compared to novel drug development is a time-saving and cost-efficient method potentially resulting in higher success rates. To accelerate and ensure sustainability in therapy development for rare neurometabolic, neurological, and neuromuscular diseases, an international consortium SIMilarities in clinical and molecular PATHology (SIMPATHIC) has been established where we move away from the one drug one disease concept and move towards one drug targeting a pathomechanism shared between diseases, by applying parallel preclinical and clinical drug development. Here the consortium describes accelerators of drug repurposing pursued by the consortium, including 1) co-creation, 2) patient empowerment, 3) use of standardized induced pluripotent stem cell (iPSC)-derived disease models and cellular and molecular profiling, 4) high-throughput drug screening in neurons, 5) innovative clinical trial design, and 6) selection of appropriate exploitation and patient access models. In this way, a fast and effective drug repurposing pathway for several rare diseases will be established to reduce time from discovery to patient access.
{"title":"SIMPATHIC: Accelerating drug repurposing for rare diseases by exploiting SIMilarities in clinical and molecular PATHology","authors":"Clara D.M. van Karnebeek , Annelieke R. Müller , Laura Benkemoun , Ibrahim Boussaad , Martina C. Cornel , Joanna IntHout , Martin de Kort , Sofia de Oliveira Martins , Alessandro Prigione , Tessel Rigter , Kit C.B. Roes , Anna Sanchez , Raymond Schipper , Mark D. Wilkinson , Peter A.C. ’t Hoen","doi":"10.1016/j.ymgme.2025.109073","DOIUrl":"10.1016/j.ymgme.2025.109073","url":null,"abstract":"<div><div>Rare diseases affect over 400 million people worldwide, with approved treatment available for less than 6 % of these diseases. Drug repurposing is a key strategy in the development of therapies for rare disease patients with large unmet medical needs. The process of repurposing drugs compared to novel drug development is a time-saving and cost-efficient method potentially resulting in higher success rates. To accelerate and ensure sustainability in therapy development for rare neurometabolic, neurological, and neuromuscular diseases, an international consortium <em>SIMilarities in clinical and molecular PATHology</em> (SIMPATHIC) has been established where we move away from the one drug one disease concept and move towards one drug targeting a pathomechanism shared between diseases, by applying parallel preclinical and clinical drug development. Here the consortium describes accelerators of drug repurposing pursued by the consortium, including 1) co-creation, 2) patient empowerment, 3) use of standardized induced pluripotent stem cell (iPSC)-derived disease models and cellular and molecular profiling, 4) high-throughput drug screening in neurons, 5) innovative clinical trial design, and 6) selection of appropriate exploitation and patient access models. In this way, a fast and effective drug repurposing pathway for several rare diseases will be established to reduce time from discovery to patient access.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 4","pages":"Article 109073"},"PeriodicalIF":3.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609885","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}
In mucopolysaccharidosis (MPS) disease, glycosaminoglycan (GAG) accumulates in the cardiovascular system and creates clinical conditions. Our aim in the study is to analyze the cardiac functions of MPS patients and reveal their characteristics.
Methods
All patients underwent transthoracic echocardiographic evaluation. Left ventricular wall thickness and diameter were measured. Analyses were performed by dividing MPS patients into subgroups: those receiving or not receiving enzyme replacement therapy (ERT), and those receiving ERT for ≤5 years and > 5 years. The left ventricular wall thickness, ventricular function parameters, ventricular tissue Doppler velocities, valve thicknesses, and functions were evaluated. Annular plane systolic excursion (APSE) and APSE-z scores were evaluated for ventricular systolic function.
Results
The left ventricular wall thickness and mass were significantly higher in the MPS group.Although the EF values were similar between the groups, the MAPSE and MAPSE z-scores were significantly lower in patients with MPS. The Left ventricular diastolic filling velocity and tissue velocity were significantly lower in the MPS group. The TAPSE, z-score, and right ventricular tissue velocities were significantly lower in the MPS group.Although ventricular functions and remodeling were similar in patients with MPS receiving ERT, valve pathologies were significantly higher in patients with MPS receiving ERT.
Conclusion
Patients with MPS have both systolic and diastolic dysfunction in the early stages. Annular plane systolic excursion (APSE) can be routinely evaluated for ventricular systolic function in patients with MPS because it shows systolic dysfunction and is easy to apply. The left ventricular diameter and mass index increased in patients with MPS. Although ERT has positive effects on cardiac function in patients with MPS, it does not appear to affect valve pathologies.
{"title":"Evaluation of cardiac function in pediatric patients diagnosed with mucopolysaccharidosis (MPS) and use of annular plane systolic excursion (APSE) to evaluate systolic function","authors":"Kerem Ertaş , Özlem Gül , Ayşe Ergül Bozacı , Hüseyin Bilgin","doi":"10.1016/j.ymgme.2025.109069","DOIUrl":"10.1016/j.ymgme.2025.109069","url":null,"abstract":"<div><h3>Aim</h3><div>In mucopolysaccharidosis (MPS) disease, glycosaminoglycan (GAG) accumulates in the cardiovascular system and creates clinical conditions. Our aim in the study is to analyze the cardiac functions of MPS patients and reveal their characteristics.</div></div><div><h3>Methods</h3><div>All patients underwent transthoracic echocardiographic evaluation. Left ventricular wall thickness and diameter were measured. Analyses were performed by dividing MPS patients into subgroups: those receiving or not receiving enzyme replacement therapy (ERT), and those receiving ERT for ≤5 years and > 5 years. The left ventricular wall thickness, ventricular function parameters, ventricular tissue Doppler velocities, valve thicknesses, and functions were evaluated. Annular plane systolic excursion (APSE) and APSE-z scores were evaluated for ventricular systolic function.</div></div><div><h3>Results</h3><div>The left ventricular wall thickness and mass were significantly higher in the MPS group.Although the EF values were similar between the groups, the MAPSE and MAPSE z-scores were significantly lower in patients with MPS. The Left ventricular diastolic filling velocity and tissue velocity were significantly lower in the MPS group. The TAPSE, z-score, and right ventricular tissue velocities were significantly lower in the MPS group.Although ventricular functions and remodeling were similar in patients with MPS receiving ERT, valve pathologies were significantly higher in patients with MPS receiving ERT.</div></div><div><h3>Conclusion</h3><div>Patients with MPS have both systolic and diastolic dysfunction in the early stages. Annular plane systolic excursion (APSE) can be routinely evaluated for ventricular systolic function in patients with MPS because it shows systolic dysfunction and is easy to apply. The left ventricular diameter and mass index increased in patients with MPS. Although ERT has positive effects on cardiac function in patients with MPS, it does not appear to affect valve pathologies.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 4","pages":"Article 109069"},"PeriodicalIF":3.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143550049","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 : 2025-02-25DOI: 10.1016/j.ymgme.2025.109070
Ashley N. Gregor , Philippe Delerive , Bernard Cuenoud , Irina Monnard , Karine Redeuil , Cary O. Harding , Melanie B. Gillingham
Patients with long-chain fatty acid oxidation disorders (LC-FAOD) have impaired endogenous ketone production due to defects in the beta-oxidation pathway. We explored supplementation of exogenous D-beta-hydroxybutyrate (D-BHB) as an alternative source of energy in a randomized, double-blinded crossover pilot study. Participants ≥18 years of age with a diagnosis of LC-FAOD completed two moderate-intensity treadmill exercises following an oral supplementation of D-BHB salts or an isocaloric maltodextrin beverage. Five subjects (1 VLCADD, 2 CPT2D, 2 LCHADD), 60 % male, mean age = 33 years were enrolled. Mild to moderate GI symptoms were related to ingestion of D-BHB. Plasma D-BHB was increased after oral D-BHB compared to maltodextrin (p < .001) with an average concentration of 0.43 mM in the post-exercise period. During exercise, free fatty acids (p = .01), fold change in long-chain acylcarnitine species (LC-AC) (p ≤ .03) and systolic BP (p = .02) were lower after D-BHB compared to the maltodextrin beverage. D-BHB suppresses lipolysis and selectively blunts exercise-induced long-chain acylcarnitines. There were no differences between beverages in acetylcarnitine, blood glucose, creatine kinase, VO2, HR, RPE or respiratory exchange ratio. Consumption of the D-BHB beverage was safe and well-tolerated. Plasma D-BHB levels achieved mild ketosis and suppressed lipolysis and the associated rise in LC-AC, but fell short of stimulating the energetic effects that might have resulted in altered exercise parameters such as RER, or HR. In conclusion, our results provide a strong rationale for future studies aimed toward defining the optimal multiple-dose regimen of D-BHB per day that might improve exercise tolerance and understanding the long-term impact of treatment in LC-FAOD subjects.
{"title":"D-BHB supplementation before moderate-intensity exercise suppresses lipolysis and selectively blunts exercise-induced long-chain acylcarnitine increase in pilot study of patients with long-chain fatty acid oxidation disorders","authors":"Ashley N. Gregor , Philippe Delerive , Bernard Cuenoud , Irina Monnard , Karine Redeuil , Cary O. Harding , Melanie B. Gillingham","doi":"10.1016/j.ymgme.2025.109070","DOIUrl":"10.1016/j.ymgme.2025.109070","url":null,"abstract":"<div><div>Patients with long-chain fatty acid oxidation disorders (LC-FAOD) have impaired endogenous ketone production due to defects in the beta-oxidation pathway. We explored supplementation of exogenous D-beta-hydroxybutyrate (D-BHB) as an alternative source of energy in a randomized, double-blinded crossover pilot study. Participants ≥18 years of age with a diagnosis of LC-FAOD completed two moderate-intensity treadmill exercises following an oral supplementation of D-BHB salts or an isocaloric maltodextrin beverage. Five subjects (1 VLCADD, 2 CPT2D, 2 LCHADD), 60 % male, mean age = 33 years were enrolled. Mild to moderate GI symptoms were related to ingestion of D-BHB. Plasma D-BHB was increased after oral D-BHB compared to maltodextrin (<em>p</em> < .001) with an average concentration of 0.43 mM in the post-exercise period. During exercise, free fatty acids (<em>p</em> = .01), fold change in long-chain acylcarnitine species (LC-AC) (<em>p</em> ≤ .03) and systolic BP (<em>p</em> = .02) were lower after D-BHB compared to the maltodextrin beverage. D-BHB suppresses lipolysis and selectively blunts exercise-induced long-chain acylcarnitines. There were no differences between beverages in acetylcarnitine, blood glucose, creatine kinase, VO2, HR, RPE or respiratory exchange ratio. Consumption of the D-BHB beverage was safe and well-tolerated. Plasma D-BHB levels achieved mild ketosis and suppressed lipolysis and the associated rise in LC-AC, but fell short of stimulating the energetic effects that might have resulted in altered exercise parameters such as RER, or HR. In conclusion, our results provide a strong rationale for future studies aimed toward defining the optimal multiple-dose regimen of D-BHB per day that might improve exercise tolerance and understanding the long-term impact of treatment in LC-FAOD subjects.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 4","pages":"Article 109070"},"PeriodicalIF":3.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143550702","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 : 2025-02-23DOI: 10.1016/j.ymgme.2025.109068
Catarina Rodrigues , Catarina Sousa Barbosa , Manuela Ferreira de Almeida , Anabela Bandeira , Esmeralda Martins , Sara Rocha , Arlindo Guimas , Rosa Ribeiro , António Soares , André Moreira-Rosário , Cláudia Camila Dias , Anita MacDonald , Nuno Borges , Júlio César Rocha
Background
Overweight has been identified as a comorbidity associated with phenylketonuria (PKU). A systematic review with meta-analysis found that although patients with PKU had a similar body mass index (BMI) when compared to non-PKU controls, there was a significantly higher BMI when measured in patients described as having classical PKU.
Objective
The aim of this retrospective longitudinal study was to identify the prevalence of overweight in patients with PKU, over 10 years, in a Portuguese Reference Centre, following a phenylalanine-restricted diet.
Methods
Inclusion criteria were diagnosis of PKU and completion of an annual nutritional status evaluation every 2 years. Information on anthropometry, dietary intake and blood phenylalanine levels was collected.
Results
The sample consisted of 94 patients (aged 14.0 ± 7.8y, 46 females). Over the study period, there was a non-statistically significant trend towards an increase in the prevalence of overweight (24.5 vs 33.0 %), as defined by age-appropriate BMI. When compared with normal-weight patients, overweight patients had significantly higher blood phenylalanine levels in the first and fifth biennium. Total and natural protein intake were significantly higher in normal-weight patients, at all timepoints, compared to overweight patients. Univariate analysis showed that a higher protein intake, particularly of natural protein, is a protective factor against the development of overweight. This result remained after adjusting total protein intake for age, gender, and metabolic control.
Conclusions
This study found a trend towards an increase in the prevalence of overweight in patients with PKU. Therefore, the nutritional status of patients with PKU should be regularly monitored, supported by preventive and attentive nutritional support.
{"title":"Protein intake and prevalence of overweight in patients with phenylketonuria: A 10-year longitudinal study","authors":"Catarina Rodrigues , Catarina Sousa Barbosa , Manuela Ferreira de Almeida , Anabela Bandeira , Esmeralda Martins , Sara Rocha , Arlindo Guimas , Rosa Ribeiro , António Soares , André Moreira-Rosário , Cláudia Camila Dias , Anita MacDonald , Nuno Borges , Júlio César Rocha","doi":"10.1016/j.ymgme.2025.109068","DOIUrl":"10.1016/j.ymgme.2025.109068","url":null,"abstract":"<div><h3>Background</h3><div>Overweight has been identified as a comorbidity associated with phenylketonuria (PKU). A systematic review with meta-analysis found that although patients with PKU had a similar body mass index (BMI) when compared to non-PKU controls, there was a significantly higher BMI when measured in patients described as having classical PKU.</div></div><div><h3>Objective</h3><div>The aim of this retrospective longitudinal study was to identify the prevalence of overweight in patients with PKU, over 10 years, in a Portuguese Reference Centre, following a phenylalanine-restricted diet.</div></div><div><h3>Methods</h3><div>Inclusion criteria were diagnosis of PKU and completion of an annual nutritional status evaluation every 2 years. Information on anthropometry, dietary intake and blood phenylalanine levels was collected.</div></div><div><h3>Results</h3><div>The sample consisted of 94 patients (aged 14.0 ± 7.8y, 46 females). Over the study period, there was a non-statistically significant trend towards an increase in the prevalence of overweight (24.5 vs 33.0 %), as defined by age-appropriate BMI. When compared with normal-weight patients, overweight patients had significantly higher blood phenylalanine levels in the first and fifth biennium. Total and natural protein intake were significantly higher in normal-weight patients, at all timepoints, compared to overweight patients. Univariate analysis showed that a higher protein intake, particularly of natural protein, is a protective factor against the development of overweight. This result remained after adjusting total protein intake for age, gender, and metabolic control.</div></div><div><h3>Conclusions</h3><div>This study found a trend towards an increase in the prevalence of overweight in patients with PKU. Therefore, the nutritional status of patients with PKU should be regularly monitored, supported by preventive and attentive nutritional support.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 4","pages":"Article 109068"},"PeriodicalIF":3.7,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143529829","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 : 2025-02-21DOI: 10.1016/j.ymgme.2025.109058
Matthew M. Demczko , Rebecca D. Ganetzky , Cassandra Tormey , Brandon C. Ku , Bridget Blowey , Jane Lavelle , Amy Goldstein
Primary mitochondrial diseases (PMD) are an increasingly recognized cause of multi-system organ dysfunction. Children frequently require acute care in an inpatient setting, though many hospitals do not have access to metabolic specialists. We developed a publicly available, evidenced-based clinical pathway utilizing expert consensus guidelines to guide the care of PMD patients during an emergency department visit and/or hospitalization. Utilization of the pathway may help improve triage time, clarify therapeutic options, and help initiate disease-specific screening.
{"title":"Improving acute care for Primary Mitochondrial Disease: Development of a publicly available clinical care pathway","authors":"Matthew M. Demczko , Rebecca D. Ganetzky , Cassandra Tormey , Brandon C. Ku , Bridget Blowey , Jane Lavelle , Amy Goldstein","doi":"10.1016/j.ymgme.2025.109058","DOIUrl":"10.1016/j.ymgme.2025.109058","url":null,"abstract":"<div><div>Primary mitochondrial diseases (PMD) are an increasingly recognized cause of multi-system organ dysfunction. Children frequently require acute care in an inpatient setting, though many hospitals do not have access to metabolic specialists. We developed a publicly available, evidenced-based clinical pathway utilizing expert consensus guidelines to guide the care of PMD patients during an emergency department visit and/or hospitalization. Utilization of the pathway may help improve triage time, clarify therapeutic options, and help initiate disease-specific screening.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 4","pages":"Article 109058"},"PeriodicalIF":3.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143509196","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 : 2025-02-18DOI: 10.1016/j.ymgme.2025.109056
Tarun Kaniganti , Galit Gean-Akriv , Tal Keidar , Yael Levy-Shraga , Asaf Debby , Igor Grinberg , Sylvie Polak-Charcon , Yarden Haham Zarbib , Tal Yardeni , Ayelet Ollech , Ron Weiss , Lalitha Venkataraman , Stephen G. Kaler , Joshua Manor
Adaptor protein (AP) complexes play key roles in escorting transmembrane proteins to various intracellular destinations, including the trans-Golgi compartment, secretory vesicles, and the plasma membrane. The AP-1 complex is heterotetrametric, comprised of four individual subunits: β1, γ1, σ1, and μ1, and encoded by separate genes that interact selectively with distinct cargo proteins. When AP-1 complex assembly is impaired due to loss-of-function variants in any of its component genes, clinical consequences related to altered transmembrane protein trafficking may result. Biallelic pathogenic variants in the β1 subunit (AP1B1) are associated with a unique clinical phenotype including keratitis, ichthyosis, and deafness with autosomal recessive inheritance, the KIDAR syndrome. This disorder is further characterized by enteropathy, failure to thrive, neurodevelopmental delays, endocrinopathies, and abnormalities in copper (Cu) metabolism, the latter reflecting impact on intracellular trafficking of two transmembrane Cu-transporting ATPases, ATP7A and ATP7B. Ten individuals with KIDAR syndrome have been reported to date. Here we describe the clinical, biochemical, and cell biological effects associated with a novel homozygous AP1B1 variant, (NM_001127.4: c.667delC, p.Leu223Trp*fsTer38) in a previously unreported individual. Our findings expand the phenotypic spectrum of this rare inherited illness, provide new data related to its cell biological effects, and offer insights relevant to potential treatment.
{"title":"Clinical, biochemical and cell biological characterization of KIDAR syndrome associated with a novel AP1B1 variant","authors":"Tarun Kaniganti , Galit Gean-Akriv , Tal Keidar , Yael Levy-Shraga , Asaf Debby , Igor Grinberg , Sylvie Polak-Charcon , Yarden Haham Zarbib , Tal Yardeni , Ayelet Ollech , Ron Weiss , Lalitha Venkataraman , Stephen G. Kaler , Joshua Manor","doi":"10.1016/j.ymgme.2025.109056","DOIUrl":"10.1016/j.ymgme.2025.109056","url":null,"abstract":"<div><div>Adaptor protein (AP) complexes play key roles in escorting transmembrane proteins to various intracellular destinations, including the <em>trans</em>-Golgi compartment, secretory vesicles, and the plasma membrane. The AP-1 complex is heterotetrametric, comprised of four individual subunits: β1, γ1, σ1, and μ1, and encoded by separate genes that interact selectively with distinct cargo proteins. When AP-1 complex assembly is impaired due to loss-of-function variants in any of its component genes, clinical consequences related to altered transmembrane protein trafficking may result. Biallelic pathogenic variants in the β1 subunit (<em>AP1B1</em>) are associated with a unique clinical phenotype including <u>k</u>eratitis, <u>i</u>chthyosis, and <u>d</u>eafness with <u>a</u>utosomal <u>r</u>ecessive inheritance, the KIDAR syndrome. This disorder is further characterized by enteropathy, failure to thrive, neurodevelopmental delays, endocrinopathies, and abnormalities in copper (Cu) metabolism, the latter reflecting impact on intracellular trafficking of two transmembrane Cu-transporting ATPases, ATP7A and ATP7B. Ten individuals with KIDAR syndrome have been reported to date. Here we describe the clinical, biochemical, and cell biological effects associated with a novel homozygous <em>AP1B1</em> variant, (NM_001127.4: c.667delC, p.Leu223Trp*fsTer38) in a previously unreported individual. Our findings expand the phenotypic spectrum of this rare inherited illness, provide new data related to its cell biological effects, and offer insights relevant to potential treatment.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 4","pages":"Article 109056"},"PeriodicalIF":3.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-11DOI: 10.1016/j.ymgme.2025.109054
Anke Schumann , Sven F. Garbade , Skadi Beblo , Matthias Gautschi , Dorothea Haas , Michel Hochuli , Georg Hoffmann , Petra May , Martin Merkel , Sabine Scholl-Bürgi , Eva Thimm , Natalie Weinhold , Monika Williams , Saskia Wortmann , Sarah C. Grünert
Glycogen storage disease (GSD) type Ia (glucose-6-phosphatase deficiency) and Ib (glucose-6-phosphate transporter deficiency) are both clinically characterized by fasting hypoglycaemia and hepatomegaly. Chronic kidney disease (CKD) with loss of glomerular filtration rate and albuminuria/proteinuria is a known long-term complication of GSD I that has become less frequent with improvement of therapy over the last decades.
We retrospectively investigated a cohort of 63 GSD I patients (51 GSD Ia, 12 GSD Ib, mostly adults) with a mean age of 27.8 ± 1.8 years. We performed a cross-sectional analysis of renal function, metabolic parameters, co-morbidities and medication at the time of last-follow-up. Our study shows that renal complications have become less common since standardized diet and renoprotective medications are available. CKD was only evident above the age of 25 years in our cohort and the decline in glomerular filtration rate was moderate. No patient required renal replacement therapy. Renal calcifications and kidney stones were no frequent complications. Insufficient metabolic control was a potential risk factor for proteinuria. Supportive therapy with angiotensin-converting enzyme inhibitors is not regularly used in patients suffering from (micro-) albuminuria.
This study reveals that with adherence to a standardized diet and renoprotective medication, renal complications in GSD I occur later and are less severe. However, renal involvement occurs at a similar frequency to GSD cohorts studied about 20 years earlier. Since micro-albuminuria in GSD increases the risk of progression of renal disease to kidney failure, a thorough characterization of larger GSD cohorts and a better understanding of underlying pathomechanisms are needed to minimize kidney involvement in GSD I.
{"title":"Kidney involvement in glycogen storage disease type I: Current knowledge and key challenges","authors":"Anke Schumann , Sven F. Garbade , Skadi Beblo , Matthias Gautschi , Dorothea Haas , Michel Hochuli , Georg Hoffmann , Petra May , Martin Merkel , Sabine Scholl-Bürgi , Eva Thimm , Natalie Weinhold , Monika Williams , Saskia Wortmann , Sarah C. Grünert","doi":"10.1016/j.ymgme.2025.109054","DOIUrl":"10.1016/j.ymgme.2025.109054","url":null,"abstract":"<div><div>Glycogen storage disease (GSD) type Ia (glucose-6-phosphatase deficiency) and Ib (glucose-6-phosphate transporter deficiency) are both clinically characterized by fasting hypoglycaemia and hepatomegaly. Chronic kidney disease (CKD) with loss of glomerular filtration rate and albuminuria/proteinuria is a known long-term complication of GSD I that has become less frequent with improvement of therapy over the last decades.</div><div>We retrospectively investigated a cohort of 63 GSD I patients (51 GSD Ia, 12 GSD Ib, mostly adults) with a mean age of 27.8 ± 1.8 years. We performed a cross-sectional analysis of renal function, metabolic parameters, co-morbidities and medication at the time of last-follow-up. Our study shows that renal complications have become less common since standardized diet and renoprotective medications are available. CKD was only evident above the age of 25 years in our cohort and the decline in glomerular filtration rate was moderate. No patient required renal replacement therapy. Renal calcifications and kidney stones were no frequent complications. Insufficient metabolic control was a potential risk factor for proteinuria. Supportive therapy with angiotensin-converting enzyme inhibitors is not regularly used in patients suffering from (micro-) albuminuria.</div><div>This study reveals that with adherence to a standardized diet and renoprotective medication, renal complications in GSD I occur later and are less severe. However, renal involvement occurs at a similar frequency to GSD cohorts studied about 20 years earlier. Since micro-albuminuria in GSD increases the risk of progression of renal disease to kidney failure, a thorough characterization of larger GSD cohorts and a better understanding of underlying pathomechanisms are needed to minimize kidney involvement in GSD I.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"Article 109054"},"PeriodicalIF":3.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143421300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-11DOI: 10.1016/j.ymgme.2025.109055
Christian Argueta, Oeystein Roed Brekk, Scarlett Wang, Qihua Feng, Mariam Ahmed, Scott R.P. McDonnell , Luying Pan, Tatiana Plavina, David A.H. Whiteman
Mucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, X-linked, recessive lysosomal storage disorder that impacts approximately 1:162000 live births. It is caused by deficiencies in the lysosomal enzyme iduronate-2-sulfatase (I2S), resulting in harmful accumulation of specific glycosaminoglycans in cells, tissues and organs throughout the body. Clinical manifestations are varied and include airway obstruction, impaired mobility and, in two-thirds of cases, neurocognitive impairment (neuronopathic MPS II). Intravenous idursulfase enzyme replacement therapy (elaprase), improves many physical symptoms and signs of the disease but has limited neurological efficacy due to impaired crossing of the blood–brain barrier. TAK-609 is an intrathecal formulation of idursulfase (idursulfase-IT) that is delivered directly to the cerebrospinal fluid (CSF) of patients with neuronopathic MPS II to attenuate the neurocognitive decline. This study investigated the relationship between clinical outcomes of patients treated with TAK-609 and levels of neurofilament light chain (NfL), a component of the neuronal cytoskeleton that accumulates under neurodegenerative conditions. We report an association between the severity of I2S gene (IDS) variants and baseline CSF NfL levels in patients with neuronopathic MPS II that corresponded to primary substrate burden as measured by heparan sulfate and total GAGs. Supraphysiological (high) NfL levels corresponded to a more rapid rate of cognitive decline than physiological (normal) baseline levels. Taken together, this study establishes a clear link between genetic status, accumulation of primary substrate and circulating CSF NfL levels, allowing for bioanalytical stratification of patient outcomes in MPS II.
Take-home message
Baseline cerebrospinal neurofilament light chain levels correspond to the severity of iduronate-2-sulfatase gene (IDS) genotype, the degree of primary substrate burden and subsequent clinical outcomes in patients with neuronopathic mucopolysaccharidosis II, and can complement clinical assessments of disease heterogeneity.
{"title":"A link between baseline neurofilament light chain and primary substrate accumulation in cerebrospinal fluid, and clinical outcomes in patients with MPS II from a phase 2/3 clinical trial and extension study of intrathecal idursulfase","authors":"Christian Argueta, Oeystein Roed Brekk, Scarlett Wang, Qihua Feng, Mariam Ahmed, Scott R.P. McDonnell , Luying Pan, Tatiana Plavina, David A.H. Whiteman","doi":"10.1016/j.ymgme.2025.109055","DOIUrl":"10.1016/j.ymgme.2025.109055","url":null,"abstract":"<div><div>Mucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, X-linked, recessive lysosomal storage disorder that impacts approximately 1:162000 live births. It is caused by deficiencies in the lysosomal enzyme iduronate-2-sulfatase (I2S), resulting in harmful accumulation of specific glycosaminoglycans in cells, tissues and organs throughout the body. Clinical manifestations are varied and include airway obstruction, impaired mobility and, in two-thirds of cases, neurocognitive impairment (neuronopathic MPS II). Intravenous idursulfase enzyme replacement therapy (elaprase), improves many physical symptoms and signs of the disease but has limited neurological efficacy due to impaired crossing of the blood–brain barrier. TAK-609 is an intrathecal formulation of idursulfase (idursulfase-IT) that is delivered directly to the cerebrospinal fluid (CSF) of patients with neuronopathic MPS II to attenuate the neurocognitive decline. This study investigated the relationship between clinical outcomes of patients treated with TAK-609 and levels of neurofilament light chain (NfL), a component of the neuronal cytoskeleton that accumulates under neurodegenerative conditions. We report an association between the severity of I2S gene (<em>IDS</em>) variants and baseline CSF NfL levels in patients with neuronopathic MPS II that corresponded to primary substrate burden as measured by heparan sulfate and total GAGs. Supraphysiological (high) NfL levels corresponded to a more rapid rate of cognitive decline than physiological (normal) baseline levels. Taken together, this study establishes a clear link between genetic status, accumulation of primary substrate and circulating CSF NfL levels, allowing for bioanalytical stratification of patient outcomes in MPS II.</div></div><div><h3>Take-home message</h3><div>Baseline cerebrospinal neurofilament light chain levels correspond to the severity of iduronate-2-sulfatase gene (<em>IDS</em>) genotype, the degree of primary substrate burden and subsequent clinical outcomes in patients with neuronopathic mucopolysaccharidosis II, and can complement clinical assessments of disease heterogeneity.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"Article 109055"},"PeriodicalIF":3.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143444324","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 : 2025-02-07DOI: 10.1016/j.ymgme.2025.109049
Kinsley Belle , Alexander Kreymerman , Jill L. Young , Nirmal Vadgama , Marco H. Ji , Sandeep Randhawa , Juan Caicedo , Megan Wong , Stephanie P. Muscat , Casey A. Gifford , Richard T. Lee , Jamal Nasir , Gregory M. Enns , Ioannis Karakikes , Andrew M. Schaefer , Robert W. Taylor , Mark Mercola , Dwight Koeberl , Edward H. Wood
{"title":"Genetic analysis and multimodal imaging confirm m.12148 T > C mitochondrial variant pathogenicity leading to multisystem dysfunction","authors":"Kinsley Belle , Alexander Kreymerman , Jill L. Young , Nirmal Vadgama , Marco H. Ji , Sandeep Randhawa , Juan Caicedo , Megan Wong , Stephanie P. Muscat , Casey A. Gifford , Richard T. Lee , Jamal Nasir , Gregory M. Enns , Ioannis Karakikes , Andrew M. Schaefer , Robert W. Taylor , Mark Mercola , Dwight Koeberl , Edward H. Wood","doi":"10.1016/j.ymgme.2025.109049","DOIUrl":"10.1016/j.ymgme.2025.109049","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"Article 109049"},"PeriodicalIF":3.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454682","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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