Molecular genetics and metabolism最新文献

{"title":"Letter to the editor: SSR4-CDG, an ultra-rare X-linked congenital disorder of glycosylation affecting the TRAP complex: Review of 22 affected individuals including the first adult patient","authors":"Ileana Trujillo , Maria E. Aguirre-Flores , Patrick Sarkis , Mayowa A. Osundiji","doi":"10.1016/j.ymgme.2025.109106","DOIUrl":"10.1016/j.ymgme.2025.109106","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109106"},"PeriodicalIF":3.7,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143825542","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":"RNA sequencing driven diagnosis expands the phenotypic spectrum of NBAS deficiency","authors":"Sarah Silverstein ,&nbsp;Thomas Cassini ,&nbsp;Jiayu Fu ,&nbsp;Barbara Pusey ,&nbsp;Ellen Macnamara ,&nbsp;F. Graeme Frost ,&nbsp;Charlotte Williams ,&nbsp;Yan Huang ,&nbsp;Cynthia J. Tifft ,&nbsp;Undiagnosed Diseases Network,&nbsp;William Gahl ,&nbsp;May-Christine Malicdan ,&nbsp;David R. Adams","doi":"10.1016/j.ymgme.2025.109105","DOIUrl":"10.1016/j.ymgme.2025.109105","url":null,"abstract":"<div><div>One in 10 individuals has a rare disease, with exome and genome sequencing yielding an overall diagnostic rate of approximately 30 %. RNA sequencing can augment genome analysis and improve diagnosis. We present a young woman with global developmental delay, poor growth, distinctive facial features, osteopenia, premature ovarian insufficiency, and ocular abnormalities who had non-diagnostic genome sequencing. RNAseq performed on her skin fibroblasts showed that <em>NBAS</em> gene expression was significantly reduced compared with controls. Manual inspection of the binary alignment map (BAM) files revealed compound heterozygous variants in <em>NBAS</em>: a rare deep intronic variant NM_015909.4:c.2423 + 403G &gt; C which creates a hypomorphic pseudoexon not seen in control samples (gnomad allele frequency (AF) 0.000006572); and a rare premature termination codon (PTC) NM_015909.4:c.4753C &gt; T; p.Arg1585Ter (gnomad AF 0.000006572). Both variants are predicted to cause nonsense mediated decay of transcripts, as the pseudoexon contains a PTC. Biallelic variants in <em>NBAS</em> are associated with two major phenotypes, i.e., infantile liver failure syndrome 2 (MIM # <span><span>616483</span><svg><path></path></svg></span>) and short stature, optic nerve atrophy, and Pelger-Huet anomaly (MIM # <span><span>614800</span><svg><path></path></svg></span>). Our patient, the first reported with one loss of function and one splice variant resulting in an out of frame transcript in <em>NBAS</em>, manifested a severe phenotype compared with previously reported individuals. This case demonstrates the utility of incorporating RNAseq to generate diagnostic candidates and expands the phenotypic spectrum of <em>NBAS</em> deficiency.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109105"},"PeriodicalIF":3.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816541","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":"Newborn screening follow-up for very long-chain acyl-CoA dehydrogenase deficiency in Colorado: Working towards a standardized protocol","authors":"M.M. Crenshaw ,&nbsp;O.M. D'Annibale ,&nbsp;A. Schechter ,&nbsp;M. Sethuraman ,&nbsp;C. Porter ,&nbsp;G. Bonn ,&nbsp;E. Wright ,&nbsp;T. Wood ,&nbsp;J. Vockley ,&nbsp;P.L. Hall ,&nbsp;McCandless SE","doi":"10.1016/j.ymgme.2025.109104","DOIUrl":"10.1016/j.ymgme.2025.109104","url":null,"abstract":"<div><div>Very long chain acyl-CoA dehydrogenase deficiency (VLCADD) is an autosomal recessive fatty acid β-oxidation disorder that has been identified by newborn screening (NBS) in most states since the early 2000s. Despite over 20 years of experience, there are aspects of VLCADD NBS that remain challenging. We conducted a retrospective chart review of abnormal NBS for VLCADD in Colorado between 2017 and 2023. We analyzed confirmatory plasma acylcarnitine profiles (P-ACP), genetic sequencing of <em>ACADVL</em>, Collaborative Laboratory Integrated Reports (CLIR) scores, patient enzyme analysis of VLCAD, and cell-based variant expression analysis. A real-world “Clinical Designation” was then compared to a variety of algorithms trialed on the data. Of the 67 infants with abnormal screens during this timeframe, 5 (7 %) had a Clinical Designation of affected, 4 (6 %) remained unclassified, and 58 (87 %) were discharged based on a designation of unaffected. A Kruskal-Wallis rank sum test showed the biomarker with the best discrimination between affected and unaffected individuals was C14:1/C12:1 [chi-squared 10.4 (<em>p</em> = 0.001)]. The highest performing algorithm was (Molecular testing + cell-based expression) + (P-ACP C14:1 OR P-ACP C14:1/C12:1). Excluding the missing data, this algorithm showed 96 % (46 of 48) agreement with the Clinical Designation. We conclude that there is not a single biomarker that can specifically discern affected from unaffected individuals who screen positive on NBS for VLCADD. Thus, we developed a standardized diagnostic approach to more accurately classify patients that starts with the molecular findings and requires at least one of the P-ACP C14:1 or P-ACP C14:1/C12:1 to agree with molecular findings. The algorithm needs to be trialed with a different data set, and will advance the conversation around maximizing benefits and minimizing harms for infants who screen positive for VLCADD.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109104"},"PeriodicalIF":3.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816540","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":"Mechanistic insights into arimoclomol mediated effects on lysosomal function in Niemann-pick type C disease","authors":"Hadeel Shammas ,&nbsp;Cathrine Kloster Fog ,&nbsp;Pontus Klein ,&nbsp;Anja Koustrup ,&nbsp;Marianne Terndrup Pedersen ,&nbsp;Anne Sigaard Bie ,&nbsp;Travis Mickle ,&nbsp;Nikolaj Havnsøe Torp Petersen ,&nbsp;Thomas Kirkegaard Jensen ,&nbsp;Sven Guenther","doi":"10.1016/j.ymgme.2025.109103","DOIUrl":"10.1016/j.ymgme.2025.109103","url":null,"abstract":"<div><div>Niemann-Pick disease type C (NPC) is an ultra-rare, fatal neurodegenerative disease. It is characterized by lysosomal dysfunction with cytotoxic accumulation of unesterified cholesterol and glycosphingolipids in lysosomes, which causes neurodegeneration and peripheral organ dysfunction. Arimoclomol, an orally available small molecule, is the first FDA-approved treatment for NPC when used in combination with miglustat. Here, we present the results of a series of in vitro studies performed to explore the pathways by which arimoclomol targets the fundamentals of NPC etiology. While the precise cellular interactions of arimoclomol remain unclear, the increased translocation of the transcription factors EB and E3 (TFEB and TFE3) from the cytosol to the nucleus is a key initial step for triggering a cascade of downstream events that can rescue cellular functions. Activation of TFEB and TFE3 raises the expression rates of coordinated lysosomal expression and regulation (CLEAR) genes including <em>NPC1</em> that are essential for the regulation of lysosomal function. The subsequent upregulation of CLEAR network proteins combined with increased unfolded protein response activation was shown to enlarge the pool of matured NPC1 capable of reaching the lysosome to reduce cholesterol accumulation. By also amplifying expression of CLEAR genes associated with autophagy, arimoclomol has the potential to act on different pathways and improve cell viability independent of NPC1 protein levels and functionality.</div><div>In summary, the findings presented illustrate how arimoclomol improves lysosomal function and potentially autophagy flux to decrease lipid burden in NPC patient fibroblasts.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109103"},"PeriodicalIF":3.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816542","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":"Safety and efficacy of migalastat in adolescent patients with Fabry disease: Results from ASPIRE, a phase 3b, open-label, single-arm, 12-month clinical trial, and its open-label extension","authors":"Uma Ramaswami ,&nbsp;Esperanza Font-Montgomery ,&nbsp;Ozlem Goker-Alpan ,&nbsp;Damara Ortiz ,&nbsp;Amarilis Sanchez-Valle ,&nbsp;Chester B. Whitley ,&nbsp;William R. Wilcox ,&nbsp;Hai Jiang ,&nbsp;Lee Ann Lawson ,&nbsp;Jennie Vosk ,&nbsp;Haichen Yang ,&nbsp;Robert J. Hopkin","doi":"10.1016/j.ymgme.2025.109102","DOIUrl":"10.1016/j.ymgme.2025.109102","url":null,"abstract":"<div><div>Fabry disease (FD) is a progressive, multisystemic, X-linked lysosomal disorder caused by reduced or absent α-galactosidase A activity due to galactosidase alpha (<em>GLA</em>) gene variants. Although clinical manifestations of FD often appear in childhood, approved treatments for the management of FD in children and adolescents are limited. ASPIRE (<span><span>NCT03500094</span><svg><path></path></svg></span>) was a phase 3b, two-stage, open-label, multicenter study evaluating the safety, pharmacokinetics, and efficacy of migalastat in adolescents 12 to &lt;18 years, ≥ 45 kg with FD and amenable <em>GLA</em> variants. Long-term outcomes were evaluated in the ongoing open-label extension (OLE) study (<span><span>NCT04049760</span><svg><path></path></svg></span>). Pharmacokinetic results (a primary objective of ASPIRE) were reported previously. Here, we report safety, efficacy, pharmacodynamic, and patient-reported outcome measures in adolescents treated with migalastat for up to 48 months across ASPIRE and the subsequent OLE. Outcome measures included treatment-emergent adverse events, estimated glomerular filtration rate, left ventricular mass index, plasma globotriaosylsphingosine (lyso-Gb3) levels, the Fabry-specific Pediatric Health and Pain Questionnaire (FPHPQ), and the Pediatric Quality of Life Inventory™. Overall, 21 patients (52.4 % female) received at least one dose of migalastat in ASPIRE, 11 of whom were enzyme replacement therapy experienced. Mean age at study entry was 14.7 years. Treatment with migalastat was well tolerated in this adolescent population with no new or unexpected safety findings observed. Renal and cardiac measures remained within the normal range for adolescent patients throughout ASPIRE and the OLE with no meaningful changes observed with migalastat treatment. Plasma lyso-Gb3 levels were stable. Pain related to heat or exertion (as measured by FPHPQ) improved with migalastat treatment, and other patient-reported measures of pain, gastrointestinal symptoms, and quality of life remained stable. These data show a benefit of long-term migalastat treatment in this adolescent patient population with amenable <em>GLA</em> variants.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109102"},"PeriodicalIF":3.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816543","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":"Recruitment through empathy and education: The role of the clinical experience on workforce development","authors":"Rishisree Achanta ,&nbsp;Ashley Cannon ,&nbsp;Shayla R. Goldberg ,&nbsp;Ryan Ha ,&nbsp;Andriae LaCour ,&nbsp;Christine Maccia ,&nbsp;Deepika Burkardt ,&nbsp;Jennifer Micham ,&nbsp;Debra S. Regier","doi":"10.1016/j.ymgme.2025.109101","DOIUrl":"10.1016/j.ymgme.2025.109101","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109101"},"PeriodicalIF":3.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143808704","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":"Efficacy and safety of Nitisinone for patients with alkaptonuria: A systematic review with metanalysis","authors":"Flávia Diniz Mayrink ,&nbsp;Gilson Dorneles ,&nbsp;Igor Martins da Silva ,&nbsp;Camila Alves Areda","doi":"10.1016/j.ymgme.2025.109099","DOIUrl":"10.1016/j.ymgme.2025.109099","url":null,"abstract":"<div><h3>Aim</h3><div>We conducted a systematic review to assess the efficacy and safety of nitisinone for the treatment of patients with alkaptonuria (AKU).</div></div><div><h3>Methods</h3><div>Randomized clinical trials that assessed the impact of nitisinone on urinary and serum homogentisic acid (HGA), quality of life, joint range of motion, and adverse events in AKU patients were retrieved from Pubmed and EMBASE up to May 2024. Risk of bias assessment was performed with RoB 2.0, and the GRADE approach assessed the certainty of evidence (CoE) of each main outcome.</div></div><div><h3>Results</h3><div>Four publications from three studies summarizing data of 218 patients with AKU were included in the review process. Nitisinone administration decreased the urinary HGA levels (mean difference [MD]: −38.98; 95 % confidence interval [95 %-CI]: −53.18 to −24.78; CoE: moderate) without changes in the range of motion of the worst hip joint (MD: -6.23; 95 %-CI: −13.91 to 1.44; CoE: High). On the other hand, large increases in tyrosine were observed associated with nitisinone treatment (MD: 708.77; 95 %-CI: 649.32 to 768.22; CoE: High). AKU patients treated with nitisinone presented increased general health perception (MD: 2.77; 95 %-CI: 0.62 to 4.91), mental health (MD: 1.03; 95 %-CI: 0.90 to 1.19) and mental role functioning (MD: 5.57; 95 %-CI: 0.47 to 10.66). No statistical increases in overall adverse events (Relative Risk [RR]: 1.03; 95 %-CI: 0.90 to 1.19; CoE: High) or serious adverse events (RR: 2.47; 95 %-CI: 0.24 to 25.91; CoE: low) were observed.</div></div><div><h3>Conclusion</h3><div>This systematic review identified significant potential for nitisinone to modify the natural history of AKU, considering the relevance of clinical changes induced by the treatment.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109099"},"PeriodicalIF":3.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724985","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 role of large language models in medical genetics","authors":"Rona Merdler-Rabinowicz ,&nbsp;Mahmud Omar ,&nbsp;Jaya Ganesh ,&nbsp;Eva Morava ,&nbsp;Girish N. Nadkarni ,&nbsp;Eyal Klang","doi":"10.1016/j.ymgme.2025.109098","DOIUrl":"10.1016/j.ymgme.2025.109098","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109098"},"PeriodicalIF":3.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704763","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":"Cover 2 / Ed. Board","authors":"","doi":"10.1016/S1096-7192(25)00082-4","DOIUrl":"10.1016/S1096-7192(25)00082-4","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 4","pages":"Article 109091"},"PeriodicalIF":3.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143683584","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":"Goal attainment in PMM2-CDG: A new approach measuring meaningful clinical outcomes","authors":"Sanne Verberkmoes ,&nbsp;Gina L. Mazza ,&nbsp;Andrew C. Edmondson ,&nbsp;Fernando Scaglia ,&nbsp;Seishu Horikoshi ,&nbsp;Bryce Kuschel ,&nbsp;Mirian C.H. Janssen ,&nbsp;Jehan Mousa ,&nbsp;Austin Larson ,&nbsp;Rameen Shah ,&nbsp;Georgia McDonald ,&nbsp;Kyriaki Sarafoglou ,&nbsp;Gerard Berry ,&nbsp;Tamas Kozicz ,&nbsp;Christina Lam ,&nbsp;Eva Morava","doi":"10.1016/j.ymgme.2025.109087","DOIUrl":"10.1016/j.ymgme.2025.109087","url":null,"abstract":"<div><div>Patient-centered outcomes, including patient-reported outcomes (PROs), are increasingly important in healthcare and research, though their use in rare diseases remains limited. In disorders with significant phenotypic variation, selecting appropriate outcome measures is crucial to ensuring the relevance of clinical trials for the patient population.</div><div>Phosphomannomutase 2-CDG (PMM2-CDG) involves a complex genotype-phenotype relationship, making it challenging to predict clinical outcomes and select reliable measures for clinical trials. Caused by biallelic pathogenic variants in the <em>PMM2</em>, PMM2-CDG displays highly variable clinical severity, underscoring the need for personalized outcome measures. One such so far unexplored, individualized approach is Goal Attainment Scaling (GAS), which allows patients to set and track personal goals over time.</div><div>We evaluated 93 PMM2-CDG patients enrolled in the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) Natural History study, classifying patient goals using the International Classification of Functioning, Disability, and Health (ICF) model, and assessing goal achievement prospectively. We also analyzed potential associations between GAS and factors such as age, sex, genetic background, and disease severity measured by the Nijmegen Progression CDG Rating Scale (NPCRS).</div><div>The most common goals set by patients were related to mobility (31.5 %) and communication (26.8 %), with additional goals focused on body function (22.8 %) and independence (18.8 %). Of the 68 patients with follow-up data, 23.5 % showed no improvement in their goals, while 20.6 % improved in all three personal goals. Patients with pathogenic variants affecting the PMM2 dimerization domain had lower GAS improvement scores (M = 1.3 [SD = 1.1]) compared to those without such variants (M = 2.2 [SD = 1.7], <em>p</em> = 0.03). There was no significant correlation between NPCRS score changes and GAS improvement (<em>r</em> = −0.18, <em>p</em> = 0.19).</div><div>GAS is a valuable additional outcome measure that ensures clinical improvements are meaningful for patients and their representatives, helping to assess individual goals and overall wellbeing.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109087"},"PeriodicalIF":3.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143684768","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}