Molecular genetics and metabolism最新文献

{"title":"Cover 2 / Ed. Board","authors":"","doi":"10.1016/S1096-7192(25)00052-6","DOIUrl":"10.1016/S1096-7192(25)00052-6","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"Article 109061"},"PeriodicalIF":3.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511147","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}

{"title":"Improving acute care for Primary Mitochondrial Disease: Development of a publicly available clinical care pathway","authors":"Matthew M. Demczko ,&nbsp;Rebecca D. Ganetzky ,&nbsp;Cassandra Tormey ,&nbsp;Brandon C. Ku ,&nbsp;Bridget Blowey ,&nbsp;Jane Lavelle ,&nbsp;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}

{"title":"SGLT2 inhibitors for periodontitis in glycogen storage disease","authors":"M. Langeveld ,&nbsp;B.M. Balfoort ,&nbsp;S.B. Wortmann","doi":"10.1016/j.ymgme.2025.109057","DOIUrl":"10.1016/j.ymgme.2025.109057","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 4","pages":"Article 109057"},"PeriodicalIF":3.7,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143519060","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}

{"title":"Kidney involvement in glycogen storage disease type I: Current knowledge and key challenges","authors":"Anke Schumann ,&nbsp;Sven F. Garbade ,&nbsp;Skadi Beblo ,&nbsp;Matthias Gautschi ,&nbsp;Dorothea Haas ,&nbsp;Michel Hochuli ,&nbsp;Georg Hoffmann ,&nbsp;Petra May ,&nbsp;Martin Merkel ,&nbsp;Sabine Scholl-Bürgi ,&nbsp;Eva Thimm ,&nbsp;Natalie Weinhold ,&nbsp;Monika Williams ,&nbsp;Saskia Wortmann ,&nbsp;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}

{"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,&nbsp;Oeystein Roed Brekk,&nbsp;Scarlett Wang,&nbsp;Qihua Feng,&nbsp;Mariam Ahmed,&nbsp;Scott R.P. McDonnell ,&nbsp;Luying Pan,&nbsp;Tatiana Plavina,&nbsp;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}

{"title":"Genetic analysis and multimodal imaging confirm m.12148 T > C mitochondrial variant pathogenicity leading to multisystem dysfunction","authors":"Kinsley Belle ,&nbsp;Alexander Kreymerman ,&nbsp;Jill L. Young ,&nbsp;Nirmal Vadgama ,&nbsp;Marco H. Ji ,&nbsp;Sandeep Randhawa ,&nbsp;Juan Caicedo ,&nbsp;Megan Wong ,&nbsp;Stephanie P. Muscat ,&nbsp;Casey A. Gifford ,&nbsp;Richard T. Lee ,&nbsp;Jamal Nasir ,&nbsp;Gregory M. Enns ,&nbsp;Ioannis Karakikes ,&nbsp;Andrew M. Schaefer ,&nbsp;Robert W. Taylor ,&nbsp;Mark Mercola ,&nbsp;Dwight Koeberl ,&nbsp;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}

{"title":"Retrospective review of urine organic acids data from patients with citrullinemia type I – Looking for the ‘cyclic derivative of citrulline’","authors":"Stephen A. Brose ,&nbsp;Judith A. Hobert","doi":"10.1016/j.ymgme.2025.109053","DOIUrl":"10.1016/j.ymgme.2025.109053","url":null,"abstract":"<div><div>European Research Network for evaluation and improvement of screening, Diagnosis, and treatment of Inherited disorders of Metabolism (ERNDIM) provides proficiency testing to clinical laboratories that offer biochemical testing, including urine organic acids analysis. Following an educational challenge, ERNDIM provided a mass spectrum of the ‘trimethylsilyl derivative of cyclic derivative of citrulline’ to participating laboratories. Though there is knowledge among some in the biochemical genetics' community, that the cyclic derivative of citrulline can be identified in urine of patients with citrullinemia type I, we could not find any published literature regarding this analyte in patient samples, nor were able to obtain any standard material. We did note two publications that proposed chemical structures for the cyclic derivative of citrulline, but neither suggested a clinical utility for this compound and the two proposed structures differed. Here, we used the mass spectrum provided by ERNDIM to retrospectively evaluate existing urine organic acids data from patients affected with conditions associated with elevated levels of plasma citrulline to learn more about this marker in urine and to correlate it with plasma citrulline data in diagnostic and follow-up samples. We document a positive correlation between the concentration of this compound in patient urine and the concentration of citrulline in concurrently collected plasma. We establish that this analyte is a good marker for citrullinemia type I but is not unique to this condition. Finally, we correlate the mass spectrum with the chemical structure originally proposed by Wilson et al. in 1978.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"Article 109053"},"PeriodicalIF":3.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396235","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}

{"title":"The neuropsychological profile of SSADH deficiency, a neurotransmitter disorder of GABA metabolism","authors":"Itay Tokatly Latzer ,&nbsp;Ellen Hanson ,&nbsp;Mariarita Bertoldi ,&nbsp;Melissa L. DiBacco ,&nbsp;Deniz Aygun ,&nbsp;Onur Afacan ,&nbsp;Àngeles García-Cazorla ,&nbsp;Natalia Juliá-Palacios ,&nbsp;Thomas Opladen ,&nbsp;Oya Kuseyri Hübschmann ,&nbsp;Kathrin Jeltsch ,&nbsp;Petra Aden ,&nbsp;Mari Oppebøen ,&nbsp;Alexander Rotenberg ,&nbsp;Melissa Tsuboyama ,&nbsp;Jean-Baptiste Roullet ,&nbsp;Phillip L. Pearl","doi":"10.1016/j.ymgme.2025.109051","DOIUrl":"10.1016/j.ymgme.2025.109051","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder resulting in hyper-physiologic concentrations of the neurotransmitter γ-aminobutyrate (GABA). This study aims to provide the most comprehensive description, to date, of the neuropsychological profile of individuals with SSADHD and assess whether neuroimaging, neurophysiologic, and biochemical indices of cortical inhibition correlate with those of standardized behavioral tests.</div></div><div><h3>Methods</h3><div>Participants enrolled in the SSADHD Natural History Study underwent medical and neurological examinations, magnetic resonance imaging (MRI) and spectroscopy (MRS), biochemical tests of GABA and its related metabolites, transcranial magnetic stimulation (TMS), and gene expression quantification, as well as complete neuropsychological assessment including standardized measures for cognition, adaptive skills, motor function, receptive and expressive language, autism spectrum disorder, and behavior problems.</div></div><div><h3>Results</h3><div>The neuropsychological profile of the study's 65 enrollees [54 % females, median (interquartile range) age 9.6 (5.4–14.7)] consisted almost universally of intellectual disability, delays in adaptive skills, and deficits in expressive more than receptive language. Autism Spectrum Disorder was noted in ∼50 %, and behavioral problems in ∼70 %, predominated by obsessive-compulsive behaviors and attention problems but also including affective problems, anxiety, and, rarely, aggression and possible psychosis. Correlation analyses showed that increased internalizing, externalizing, and overall psychiatric morbidity significantly correlated with increasing age (<em>R</em> = 0.391, <em>p</em> = 0.033), as well as age-independent indices representing decreased cortical inhibition such as lower MRS-derived GABA (<em>R</em> = −0.530, <em>p</em> = 0.029) and TMS-derived resting motor threshold (<em>R</em> = −0.418, <em>p</em> = 0.053).</div></div><div><h3>Discussion</h3><div>The natural history study of SSADHD indicates that intellectual disability, delayed adaptive skills, and expressive&gt;receptive language deficits are nearly universal, with behavior problems in the vast majority. Increased psychiatric morbidity in SSADHD with age-independent decreased cortical inhibition may serve as the basis for establishing disorder-specific biomarkers for behavioral and psychiatric outcomes in SSADHD and other non-syndromic psychiatric disorders.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"Article 109051"},"PeriodicalIF":3.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143318342","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}

{"title":"Causes of mortality in the congenital disorders of glycosylation","authors":"Hana Alharbi ,&nbsp;Seishu Horikoshi ,&nbsp;Sabrina Malone Jenkins ,&nbsp;Fernando Scaglia ,&nbsp;Christina Lam ,&nbsp;Eva Morava ,&nbsp;Austin Larson ,&nbsp;Andrew C. Edmondson","doi":"10.1016/j.ymgme.2025.109052","DOIUrl":"10.1016/j.ymgme.2025.109052","url":null,"abstract":"<div><div>Congenital Disorders of Glycosylation (CDG) are a group of some 200 genetic disorders with PMM2-CDG being the most common disease. These disorders individually remain rare with poorly understood natural history (NH) and causes of mortality. We established a NH study for CDG and collected both prospective and retrospective data on CDG outcomes. In the current data set analysis on deceased patients, we describe the clinical phenotype and causes of death for thirty-seven individuals with various genetic causes of CDG. About a third of this cohort were affected with PMM2-CDG. All of the patients presented with multisystem features with involvement of the neurological system. The majority of patients involved in this study died during the first three years of life, and only four patients lived beyond ten years. The cause of death was unavailable for two patients, and about a third died secondary to cardiopulmonary failure. Progression of neurological involvement, sepsis and respiratory infection were also among the reported causes. Pericardial effusion was the primary cause of death for three infants affected with PMM2-CDG. This study emphasizes the importance of diagnosis and supportive care following the published monitoring and management guidelines for affected patients with CDG to optimize their health and development in the early stages of the disease.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"Article 109052"},"PeriodicalIF":3.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143351138","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}

{"title":"The ELOVL proteins: Very and ultra long-chain fatty acids at the crossroads between metabolic and neurodegenerative disorders","authors":"Enza Ferrero ,&nbsp;Frédéric M. Vaz ,&nbsp;David Cheillan ,&nbsp;Alfredo Brusco ,&nbsp;Cecilia Marelli","doi":"10.1016/j.ymgme.2025.109050","DOIUrl":"10.1016/j.ymgme.2025.109050","url":null,"abstract":"<div><div>In lipid metabolism, the fatty acid (FA) elongation system synthesises a wide array of FAs, crucial for various biological functions. The role of this system is to lengthen FA carbon chains to produce FAs with ≥C16, and notably, very long-chain FAs (VLCFAs, C24-C26) and ultra long-chain FAs (ULCFAs, C28 to ≥C36). Elongation occurs in the endoplasmic reticulum (ER) through the actions of a complex of four ER-embedded enzymes, which includes the ELOVL proteins. Together with desaturases that introduce double bonds, these processes significantly increase the variety of FAs. VLCFAs and ULCFAs are required for the biosynthesis of complex lipids, notably <em>glycero</em>(phospho)lipids, ether(phospho)lipids and sphingolipids. The FA elongation system is therefore fundamental for membrane biogenesis and lipid homeostasis, and also for signalling pathways associated with inflammation and cell proliferation. This review focuses on the elongase enzymes, encoded by the <em>ELOVL</em> genes, which catalyze the first and rate-limiting step of the FA elongation cycle. We summarize the physiological roles of the elongase system, with emphasis on the less-characterized ULCFAs, their biological functions, and the functional tools, biomarkers and lipidomic studies used to study them. Additionally, we discuss how ELOVL enzyme defects contribute to disorders at the intersection of metabolic and neurodegenerative conditions, driven by disrupted lipid metabolism and misfolded enzymes in the ER and Golgi.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"Article 109050"},"PeriodicalIF":3.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396234","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}