Pub Date : 2025-02-01Epub Date: 2024-11-14DOI: 10.1016/j.ymgme.2024.108611
William L Simpson, Jaya Ganesh
{"title":"Imaging improvement in acid sphingomyelinase deficiency on enzyme replacement therapy.","authors":"William L Simpson, Jaya Ganesh","doi":"10.1016/j.ymgme.2024.108611","DOIUrl":"10.1016/j.ymgme.2024.108611","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":" ","pages":"108611"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687522","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 : 2025-02-01Epub Date: 2025-01-03DOI: 10.1016/j.ymgme.2025.109010
Rodrigo T Starosta, Lethicia Campos Ferraro, Gabriela Ponte de Mattos, Lucas Ferreira Teixeira, Fabiano de Oliveira Poswar, Matheus Michalczuk, Mário Reis Álvares-da-Silva, Ida Vanessa Doederlein Schwartz
Gaucher disease (GD) is a rare genetic disorder with multi-system involvement. Liver fibrosis is a long-term complication of GD, potentially leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. There are currently no validated clinical tools for the monitoring of liver fibrosis in patients with GD. In this study, we aim at assessing the validity of common fibrosis-predicting scores, developed for other diseases, for the use in GD, using transient elastography as a gold-standard, as well as developing the first GD-specific liver fibrosis predicting score. We enrolled 19 adult patients with GD who had been on treatment for a minimum of 1 year on enzyme replacement therapy or substrate reduction therapy and who had no evidence of any other liver disease except GD or metabolic-associated steatotic liver disease (MASLD), which is a common comorbidity of GD. We analyzed the correlation between liver stiffness and genotype, treatment modality (imiglucerase or other therapies), clinical severity, and clinical laboratory tests. We found that the common liver fibrosis scores APRI, FIB-4, and NFS did not accurately predict liver fibrosis in people with GD. We also found that male sex, the DS3 score, AST, and GGT levels significantly correlated with liver stiffness, and used these to create a simple but accurate fibrosis-predicting score specifically for GD (the "Gaucher liver fibrosis score", or GLFS), with high accuracy (AUC = 0.8571, p = 0.0206). We believe that our new GLFS may be used in clinical practice to help prioritize GD patients for closer monitoring of liver fibrosis.
戈谢病是一种罕见的多系统累及的遗传性疾病。肝纤维化是GD的长期并发症,可能导致肝硬化、终末期肝病和肝细胞癌。目前还没有有效的临床工具来监测GD患者的肝纤维化。在这项研究中,我们的目标是评估用于其他疾病的常见纤维化预测评分的有效性,使用瞬变弹性成像作为金标准,以及开发第一个GD特异性肝纤维化预测评分。我们招募了19名患有GD的成年患者,他们接受了至少1年的酶替代治疗或底物减少治疗,除了GD或代谢相关脂肪变性肝病(MASLD)外,没有任何其他肝脏疾病的证据,这是GD的常见合并症。我们分析了肝僵硬与基因型、治疗方式(依米格鲁糖酶或其他治疗)、临床严重程度和临床实验室检查之间的相关性。我们发现常见肝纤维化评分APRI、FIB-4和NFS不能准确预测GD患者的肝纤维化。我们还发现,男性、DS3评分、AST和GGT水平与肝脏硬度显著相关,并利用这些数据创建了一个简单但准确的GD纤维化预测评分(“高雪肝纤维化评分”,或GLFS),准确度很高(AUC = 0.8571, p = 0.0206)。我们相信我们的新GLFS可用于临床实践,以帮助优先考虑GD患者,以便更密切地监测肝纤维化。
{"title":"Predicting liver fibrosis in Gaucher disease: Investigation of contributors and development of a clinically applicable Gaucher liver fibrosis score.","authors":"Rodrigo T Starosta, Lethicia Campos Ferraro, Gabriela Ponte de Mattos, Lucas Ferreira Teixeira, Fabiano de Oliveira Poswar, Matheus Michalczuk, Mário Reis Álvares-da-Silva, Ida Vanessa Doederlein Schwartz","doi":"10.1016/j.ymgme.2025.109010","DOIUrl":"10.1016/j.ymgme.2025.109010","url":null,"abstract":"<p><p>Gaucher disease (GD) is a rare genetic disorder with multi-system involvement. Liver fibrosis is a long-term complication of GD, potentially leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. There are currently no validated clinical tools for the monitoring of liver fibrosis in patients with GD. In this study, we aim at assessing the validity of common fibrosis-predicting scores, developed for other diseases, for the use in GD, using transient elastography as a gold-standard, as well as developing the first GD-specific liver fibrosis predicting score. We enrolled 19 adult patients with GD who had been on treatment for a minimum of 1 year on enzyme replacement therapy or substrate reduction therapy and who had no evidence of any other liver disease except GD or metabolic-associated steatotic liver disease (MASLD), which is a common comorbidity of GD. We analyzed the correlation between liver stiffness and genotype, treatment modality (imiglucerase or other therapies), clinical severity, and clinical laboratory tests. We found that the common liver fibrosis scores APRI, FIB-4, and NFS did not accurately predict liver fibrosis in people with GD. We also found that male sex, the DS3 score, AST, and GGT levels significantly correlated with liver stiffness, and used these to create a simple but accurate fibrosis-predicting score specifically for GD (the \"Gaucher liver fibrosis score\", or GLFS), with high accuracy (AUC = 0.8571, p = 0.0206). We believe that our new GLFS may be used in clinical practice to help prioritize GD patients for closer monitoring of liver fibrosis.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":" ","pages":"109010"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951474","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 : 2025-02-01Epub Date: 2024-11-18DOI: 10.1016/j.ymgme.2024.108612
Zackary M Herbst, Francyne Kubaski, Laura Pollard, Khaja Basheeruddin, Barbara Burton, Joseph Orsini, Matthew Henderson, Pranesh Chakraborty, Michael H Gelb
Measurement of enzymatic activity in newborn dried blood spots (DBS) is the preferred first-tier method in newborn screening (NBS) for mucopolysaccharidosis (MPS) disorders. However, false positives are observed due mainly to the presence of pseudodeficiencies. Our previous publications on glycosaminoglycan (GAG) biomarker levels in dried blood spots (DBS) for mucopolysaccharidoses demonstrated that second-tier GAG biomarker analysis can dramatically reduce the false positive rate in NBS. In the present study, we extend this approach to the analysis of a large number of false positives for MPS-I obtained from the Illinois, New York, and Tennessee NBS programs and from Greenwood Genetics Center. Results show that GAG levels measured by the Endogenous-Non-Reducing End method (Endogenous-NRE) are in the normal reference range for all samples. In a second study, we analyzed 166 samples that showed below-cutoff MPS-I enzymatic activity level after testing 384,144 newborns in the Ontario, Canada NBS program. Both genotype and Endogenous-NRE GAG levels were determined for all 166 samples. Newborns at high risk for MPS-I based on genotype also showed elevated GAG levels and were clinically confirmed to be symptomatic for MPS-I. All newborns with pseudodeficiency or carrier status by genotyping all showed normal levels of the appropriate GAG biomarker. Samples found to be inconclusive based on one or more variants of unknown significance (VUS) all showed normal GAG biomarker levels and were found to be clinically normal during follow-up. These studies show that the Endogenous-NRE GAG second-tier NBS method is preferred over second-tier DNA analysis for the NBS of MPS-I with minimal false positives.
{"title":"High precision newborn screening for mucopolysaccharidosis type I by enzymatic activity followed by endogenous, non-reducing end glycosaminoglycan analysis.","authors":"Zackary M Herbst, Francyne Kubaski, Laura Pollard, Khaja Basheeruddin, Barbara Burton, Joseph Orsini, Matthew Henderson, Pranesh Chakraborty, Michael H Gelb","doi":"10.1016/j.ymgme.2024.108612","DOIUrl":"10.1016/j.ymgme.2024.108612","url":null,"abstract":"<p><p>Measurement of enzymatic activity in newborn dried blood spots (DBS) is the preferred first-tier method in newborn screening (NBS) for mucopolysaccharidosis (MPS) disorders. However, false positives are observed due mainly to the presence of pseudodeficiencies. Our previous publications on glycosaminoglycan (GAG) biomarker levels in dried blood spots (DBS) for mucopolysaccharidoses demonstrated that second-tier GAG biomarker analysis can dramatically reduce the false positive rate in NBS. In the present study, we extend this approach to the analysis of a large number of false positives for MPS-I obtained from the Illinois, New York, and Tennessee NBS programs and from Greenwood Genetics Center. Results show that GAG levels measured by the Endogenous-Non-Reducing End method (Endogenous-NRE) are in the normal reference range for all samples. In a second study, we analyzed 166 samples that showed below-cutoff MPS-I enzymatic activity level after testing 384,144 newborns in the Ontario, Canada NBS program. Both genotype and Endogenous-NRE GAG levels were determined for all 166 samples. Newborns at high risk for MPS-I based on genotype also showed elevated GAG levels and were clinically confirmed to be symptomatic for MPS-I. All newborns with pseudodeficiency or carrier status by genotyping all showed normal levels of the appropriate GAG biomarker. Samples found to be inconclusive based on one or more variants of unknown significance (VUS) all showed normal GAG biomarker levels and were found to be clinically normal during follow-up. These studies show that the Endogenous-NRE GAG second-tier NBS method is preferred over second-tier DNA analysis for the NBS of MPS-I with minimal false positives.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":" ","pages":"108612"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792094","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 : 2025-02-01Epub Date: 2024-12-31DOI: 10.1016/j.ymgme.2024.109008
Melania Scarcella, Simona Fecarotta, Marianna Alagia, Ferdinando Barretta, Fabiana Uomo, Valeria De Pasquale, Hari S Patel, Pietro Strisciuglio, Giancarlo Parenti, Giulia Frisso, Luigi Michele Pavone, Margherita Ruoppolo
Background: Newborn screening (NBS) is a simple, non-invasive test that allows for the early identification of genetic diseases within the first days of a newborn's life. The aim of NBS is to detect potentially fatal or disabling conditions in newborns as early as possible, before the onset of disease symptoms. Early diagnosis enables timely treatments and improves the quality of life for affected patients.
Results: A pilot project for dried blood spot (DBS) NBS of lysosomal storage diseases (LSDs), including Mucopolysaccharidosis I (MPSI, IDUA α-L-iduronidase deficiency), Pompe disease (GAA α-glucosidase acid deficiency), Gaucher disease (GBA β-glucosidase deficiency) and Fabry disease (GLA α-galactosidase deficiency), was conducted using the digital microfluidic (DMF) technique. DBS were analyzed in a multiplexed assays for the enzymatic activities of four lysosomal enzymes (IDUA, GAA, GBA, GLA), and subjects identified as deficient in any of these enzymes were referred to the clinical reference center for diagnosis confirmation. From June 6th, 2022, to May 12th, 2023, a total of 7650 newborns were analyzed and 1 subject affected by Pompe disease was identified together with two additional subjects, suspected of Pompe and Fabry disease respectively, for whom continued follow-up is mandatory to determine the phenotype.
Conclusions: The pilot project for DBS NBS of four LSDs in Campania Region validated the effectiveness of DMF method, established enzymatic activity cut-offs, and identified newborns referred to the clinical center for integrated diagnostics, including genetic analyses. The results suggest that this technique can effectively detect potentially affected newborns, who will require further diagnostic confirmation and clinical follow-up. This diagnostic flow chart provides the opportunity to initiate early treatments and improve LSD patients' life span.
背景:新生儿筛查(NBS)是一种简单、无创的检测方法,可在新生儿出生后几天内早期发现遗传疾病。国家统计局的目标是在新生儿出现疾病症状之前尽早发现可能致命或致残的病症。早期诊断能够及时治疗并改善受影响患者的生活质量。结果:采用数字微流控(DMF)技术对溶酶体贮积病(包括粘多糖病I型(MPSI, IDUA α- l -伊杜糖苷酶缺乏症)、Pompe病(GAA α-葡萄糖苷酶缺乏症)、戈谢病(GBA β-葡萄糖苷酶缺乏症)和Fabry病(GLA α-半乳糖糖苷酶缺乏症)的干血斑(DBS) NBS进行了中试研究。对DBS患者进行四种溶酶体酶(IDUA、GAA、GBA、GLA)活性的多重检测,发现其中任何一种酶缺乏的受试者将被转至临床参考中心进行诊断确认。从2022年6月6日至2023年5月12日,共分析7650例新生儿,发现1例Pompe病患者,另外2例疑似Pompe病和Fabry病患者,需继续随访以确定表型。结论:Campania地区4个lsd的DBS NBS试点项目验证了DMF方法的有效性,建立了酶活性截止点,并确定了新生儿转介到临床中心进行综合诊断,包括遗传分析。结果表明,该技术可以有效地发现潜在的受影响的新生儿,需要进一步的诊断确认和临床随访。该诊断流程图提供了早期治疗和改善LSD患者寿命的机会。
{"title":"Digital microfluidic platform for dried blood spot newborn screening of lysosomal storage diseases in Campania region (Italy): Findings from the first year pilot project.","authors":"Melania Scarcella, Simona Fecarotta, Marianna Alagia, Ferdinando Barretta, Fabiana Uomo, Valeria De Pasquale, Hari S Patel, Pietro Strisciuglio, Giancarlo Parenti, Giulia Frisso, Luigi Michele Pavone, Margherita Ruoppolo","doi":"10.1016/j.ymgme.2024.109008","DOIUrl":"10.1016/j.ymgme.2024.109008","url":null,"abstract":"<p><strong>Background: </strong>Newborn screening (NBS) is a simple, non-invasive test that allows for the early identification of genetic diseases within the first days of a newborn's life. The aim of NBS is to detect potentially fatal or disabling conditions in newborns as early as possible, before the onset of disease symptoms. Early diagnosis enables timely treatments and improves the quality of life for affected patients.</p><p><strong>Results: </strong>A pilot project for dried blood spot (DBS) NBS of lysosomal storage diseases (LSDs), including Mucopolysaccharidosis I (MPSI, IDUA α-L-iduronidase deficiency), Pompe disease (GAA α-glucosidase acid deficiency), Gaucher disease (GBA β-glucosidase deficiency) and Fabry disease (GLA α-galactosidase deficiency), was conducted using the digital microfluidic (DMF) technique. DBS were analyzed in a multiplexed assays for the enzymatic activities of four lysosomal enzymes (IDUA, GAA, GBA, GLA), and subjects identified as deficient in any of these enzymes were referred to the clinical reference center for diagnosis confirmation. From June 6th, 2022, to May 12th, 2023, a total of 7650 newborns were analyzed and 1 subject affected by Pompe disease was identified together with two additional subjects, suspected of Pompe and Fabry disease respectively, for whom continued follow-up is mandatory to determine the phenotype.</p><p><strong>Conclusions: </strong>The pilot project for DBS NBS of four LSDs in Campania Region validated the effectiveness of DMF method, established enzymatic activity cut-offs, and identified newborns referred to the clinical center for integrated diagnostics, including genetic analyses. The results suggest that this technique can effectively detect potentially affected newborns, who will require further diagnostic confirmation and clinical follow-up. This diagnostic flow chart provides the opportunity to initiate early treatments and improve LSD patients' life span.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":" ","pages":"109008"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952004","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 : 2025-01-22DOI: 10.1016/j.ymgme.2025.109041
Jennifer Hanson, Penelope E Bonnen
Cerebrotendinous Xanthomatosis (CTX) is a treatable, inborn error of bile acids metabolism caused by pathogenic variants in CYP27A1. CTX is a multi-organ system disorder that progresses over decades. Clinical features include cerebellar dysfunction, pyramidal tract dysfunction, cognitive deficits and decline, peripheral neuropathy, chronic diarrhea, bilateral cataracts, and tendon xanthomas. Treatment is effective when started early, but diagnostic delays often result in individuals not being diagnosed until after the window of highest treatment efficacy. CTX is documented to occur in most global populations, however, no CTX-causing genetic variants have been reported in Ashkenazi Jews. We conducted a systematic review of every case of CTX reported in a person identified as Jewish and the specific CYP27A1 variants present. We also leveraged the Israeli Medical Genetics Database and the population genetics data resource gnomAD to identify CTX-causing alleles in Ashkenazi Jews. We found that there are three pathogenic CYP27A1 variants in the Ashkenazi Jewish population segregating at an appreciable frequency, with a gene carrier rate of 0.002 based on the gnomAD Ashkenazi Jewish data. One pathogenic variant appears only in the Ashkenazi Jewish group in gnomAD, which contains genetic data from across the globe. We compared the carrier frequency for CTX to the carrier frequencies for diseases that are commonly included in carrier screening for Ashkenazi Jews. These results show that CTX occurs in Ashkenazi Jews, and that both Sephardi and Ashkenazi Jews may benefit from newborn and carrier screening for CTX.
{"title":"Cerebrotendinous Xanthomatosis occurs at high frequency in Ashkenazi Jews.","authors":"Jennifer Hanson, Penelope E Bonnen","doi":"10.1016/j.ymgme.2025.109041","DOIUrl":"https://doi.org/10.1016/j.ymgme.2025.109041","url":null,"abstract":"<p><p>Cerebrotendinous Xanthomatosis (CTX) is a treatable, inborn error of bile acids metabolism caused by pathogenic variants in CYP27A1. CTX is a multi-organ system disorder that progresses over decades. Clinical features include cerebellar dysfunction, pyramidal tract dysfunction, cognitive deficits and decline, peripheral neuropathy, chronic diarrhea, bilateral cataracts, and tendon xanthomas. Treatment is effective when started early, but diagnostic delays often result in individuals not being diagnosed until after the window of highest treatment efficacy. CTX is documented to occur in most global populations, however, no CTX-causing genetic variants have been reported in Ashkenazi Jews. We conducted a systematic review of every case of CTX reported in a person identified as Jewish and the specific CYP27A1 variants present. We also leveraged the Israeli Medical Genetics Database and the population genetics data resource gnomAD to identify CTX-causing alleles in Ashkenazi Jews. We found that there are three pathogenic CYP27A1 variants in the Ashkenazi Jewish population segregating at an appreciable frequency, with a gene carrier rate of 0.002 based on the gnomAD Ashkenazi Jewish data. One pathogenic variant appears only in the Ashkenazi Jewish group in gnomAD, which contains genetic data from across the globe. We compared the carrier frequency for CTX to the carrier frequencies for diseases that are commonly included in carrier screening for Ashkenazi Jews. These results show that CTX occurs in Ashkenazi Jews, and that both Sephardi and Ashkenazi Jews may benefit from newborn and carrier screening for CTX.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"109041"},"PeriodicalIF":3.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059763","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 : 2025-01-20DOI: 10.1016/j.ymgme.2025.109023
Paloma Martín-Jimenez, Laura Bermejo-Guerrero, María Navarro-Riquelme, Pablo Serrano-Lorenzo, Rocío Garrido-Moraga, Aurelio Hernández-Laín, Ana Hernández-Voth, David Lora, Montserrat Morales, Joaquín Arenas, Alberto Blázquez, Miguel Ángel Martín, Cristina Domínguez-González
Background and objectives: Mitochondrial diseases are caused by defects in oxidative phosphorylation, with primary mitochondrial myopathies (PMM) being a subset where muscle involvement is predominant. PMM presents symptoms ranging from exercise intolerance to progressive muscle weakness, often involving ocular muscles, leading to ptosis and progressive external ophthalmoplegia (PEO). PMM can be due to variants in mitochondrial or nuclear DNA. Growth differentiation factor 15 (GDF15) has been identified as an accurate biomarker for mitochondrial dysfunction. This study evaluates the utility of GDF15 as a biomarker for monitoring PMM.
Methods: This observational study involved 50 adult PMM patients. Clinical data were collected alongside functional motor outcomes measured by the Motor Research Council scale, 6-min walk test, North Star Ambulatory Assessment, and 100-m run test (100MRT). Biomarkers including serum lactate, creatine kinase (CK), creatinine, and plasma GDF15 were assessed.
Results: Patients exhibited diverse phenotypes, including exercise intolerance (8 %), progressive myopathy (22 %), isolated PEO (24 %), and PEO plus (42 %). Significant correlations were found among motor function tests, with 100MRT being particularly sensitive. Biomarker analysis showed elevated lactate in 32 %, elevated CK in 54 %, reduced creatinine in 76 %, and elevated GDF15 in 86 % of cases. GDF15 levels correlated with motor performance, lactate levels, and mtDNA mutation load in muscle. Creatinine levels were strongly linked to disease severity.
Discussion: This study underscores the heterogeneity of PMM and the importance of reliable biomarkers. GDF15 was consistently elevated across all PMM phenotypes and genotypes, correlating well with disease severity. Reduced creatinine also emerged as a potential prognostic marker.
{"title":"Comprehensive analysis of GDF15 as a biomarker in primary mitochondrial myopathies.","authors":"Paloma Martín-Jimenez, Laura Bermejo-Guerrero, María Navarro-Riquelme, Pablo Serrano-Lorenzo, Rocío Garrido-Moraga, Aurelio Hernández-Laín, Ana Hernández-Voth, David Lora, Montserrat Morales, Joaquín Arenas, Alberto Blázquez, Miguel Ángel Martín, Cristina Domínguez-González","doi":"10.1016/j.ymgme.2025.109023","DOIUrl":"https://doi.org/10.1016/j.ymgme.2025.109023","url":null,"abstract":"<p><strong>Background and objectives: </strong>Mitochondrial diseases are caused by defects in oxidative phosphorylation, with primary mitochondrial myopathies (PMM) being a subset where muscle involvement is predominant. PMM presents symptoms ranging from exercise intolerance to progressive muscle weakness, often involving ocular muscles, leading to ptosis and progressive external ophthalmoplegia (PEO). PMM can be due to variants in mitochondrial or nuclear DNA. Growth differentiation factor 15 (GDF15) has been identified as an accurate biomarker for mitochondrial dysfunction. This study evaluates the utility of GDF15 as a biomarker for monitoring PMM.</p><p><strong>Methods: </strong>This observational study involved 50 adult PMM patients. Clinical data were collected alongside functional motor outcomes measured by the Motor Research Council scale, 6-min walk test, North Star Ambulatory Assessment, and 100-m run test (100MRT). Biomarkers including serum lactate, creatine kinase (CK), creatinine, and plasma GDF15 were assessed.</p><p><strong>Results: </strong>Patients exhibited diverse phenotypes, including exercise intolerance (8 %), progressive myopathy (22 %), isolated PEO (24 %), and PEO plus (42 %). Significant correlations were found among motor function tests, with 100MRT being particularly sensitive. Biomarker analysis showed elevated lactate in 32 %, elevated CK in 54 %, reduced creatinine in 76 %, and elevated GDF15 in 86 % of cases. GDF15 levels correlated with motor performance, lactate levels, and mtDNA mutation load in muscle. Creatinine levels were strongly linked to disease severity.</p><p><strong>Discussion: </strong>This study underscores the heterogeneity of PMM and the importance of reliable biomarkers. GDF15 was consistently elevated across all PMM phenotypes and genotypes, correlating well with disease severity. Reduced creatinine also emerged as a potential prognostic marker.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"109023"},"PeriodicalIF":3.7,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143039274","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 : 2025-01-19DOI: 10.1016/j.ymgme.2025.109025
Josephine Kolstad, Christopher Zoppo, Jean M Johnston, Precilla D'Souza, Anna Luisa Kühn, Zeynep Vardar, Ahmet Peker, Asma Hader, Hakki Celik, Connor J Lewis, Clifford Lindsay, Zubir S Rentiya, Catherine Lebel, Srinivasan Vedantham, Behroze Vachha, Heather L Gray-Edwards, Maria T Acosta, Cynthia J Tifft, Mohammed Salman Shazeeb
Objective: GM1 gangliosidosis is a rare lysosomal storage disorder characterized by the accumulation of GM1 gangliosides in neuronal cells, resulting in severe neurodegeneration. Currently, limited data exists on the brain volumetric changes associated with this disease. This study focuses on the late-infantile and juvenile subtypes of type II GM1 gangliosidosis, aiming to quantify brain volumetric characteristics to track disease progression.
Methods: Brain volumetric analysis was conducted on 56 MRI scans from 24 type II GM1 patients (8 late-infantile and 16 juvenile) and 19 healthy controls over multiple time points. The analysis included the use of semi-automated segmentation of the whole brain, ventricles, cerebellum, corpus callosum, thalamus, caudate, and lentiform nucleus. A generalized linear model was used to compare the volumetric measurements between the patient groups and healthy controls, accounting for age as a confounding factor.
Results: Both late-infantile and juvenile GM1 patients exhibited significant whole-brain atrophy compared to healthy controls, even after adjusting for age. Notably, the late-infantile subtype displayed more pronounced atrophy in the cerebellum, thalamus, and corpus callosum compared to the juvenile subtype. Both late-infantile and juvenile subtypes showed significantly higher ventricular volumes and a significant reduction in all other structure volumes compared to the healthy controls. The volumetric measurements also correlated well with disease severity based on clinical metrics.
Conclusions: The findings underscore the distinct brain volumetrics of the late-infantile and juvenile subtypes of GM1 gangliosidosis compared to healthy controls. These quantifications can be used as reliable imaging biomarkers to track disease progression and evaluate responses to therapeutic interventions.
{"title":"Natural history progression of MRI brain volumetrics in type II late-infantile and juvenile GM1 gangliosidosis patients.","authors":"Josephine Kolstad, Christopher Zoppo, Jean M Johnston, Precilla D'Souza, Anna Luisa Kühn, Zeynep Vardar, Ahmet Peker, Asma Hader, Hakki Celik, Connor J Lewis, Clifford Lindsay, Zubir S Rentiya, Catherine Lebel, Srinivasan Vedantham, Behroze Vachha, Heather L Gray-Edwards, Maria T Acosta, Cynthia J Tifft, Mohammed Salman Shazeeb","doi":"10.1016/j.ymgme.2025.109025","DOIUrl":"https://doi.org/10.1016/j.ymgme.2025.109025","url":null,"abstract":"<p><strong>Objective: </strong>GM1 gangliosidosis is a rare lysosomal storage disorder characterized by the accumulation of GM1 gangliosides in neuronal cells, resulting in severe neurodegeneration. Currently, limited data exists on the brain volumetric changes associated with this disease. This study focuses on the late-infantile and juvenile subtypes of type II GM1 gangliosidosis, aiming to quantify brain volumetric characteristics to track disease progression.</p><p><strong>Methods: </strong>Brain volumetric analysis was conducted on 56 MRI scans from 24 type II GM1 patients (8 late-infantile and 16 juvenile) and 19 healthy controls over multiple time points. The analysis included the use of semi-automated segmentation of the whole brain, ventricles, cerebellum, corpus callosum, thalamus, caudate, and lentiform nucleus. A generalized linear model was used to compare the volumetric measurements between the patient groups and healthy controls, accounting for age as a confounding factor.</p><p><strong>Results: </strong>Both late-infantile and juvenile GM1 patients exhibited significant whole-brain atrophy compared to healthy controls, even after adjusting for age. Notably, the late-infantile subtype displayed more pronounced atrophy in the cerebellum, thalamus, and corpus callosum compared to the juvenile subtype. Both late-infantile and juvenile subtypes showed significantly higher ventricular volumes and a significant reduction in all other structure volumes compared to the healthy controls. The volumetric measurements also correlated well with disease severity based on clinical metrics.</p><p><strong>Conclusions: </strong>The findings underscore the distinct brain volumetrics of the late-infantile and juvenile subtypes of GM1 gangliosidosis compared to healthy controls. These quantifications can be used as reliable imaging biomarkers to track disease progression and evaluate responses to therapeutic interventions.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"109025"},"PeriodicalIF":3.7,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059766","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}