Molecular genetics and metabolism最新文献

{"title":"Clinical, biochemical, and molecular findings in adults with hyperammonemia: A French bi-centric retrospective study","authors":"Julien Maquet ,&nbsp;Clément Pontoizeau ,&nbsp;Apolline Imbard ,&nbsp;Stéphanie Gobin-Limballe ,&nbsp;Jean-Baptiste Arnoux ,&nbsp;Édouard Le Guillou ,&nbsp;Patricia Dubot ,&nbsp;Anaïs Brassier ,&nbsp;Claire-Marine Bérat ,&nbsp;Lucile Altenburger ,&nbsp;Juliette Bouchereau ,&nbsp;Aude Servais ,&nbsp;Myriam Dao ,&nbsp;Jean-Paul Bonnefont ,&nbsp;Chris Ottolenghi ,&nbsp;Jean-François Benoist ,&nbsp;Pascale de Lonlay ,&nbsp;Manuel Schiff","doi":"10.1016/j.ymgme.2025.109223","DOIUrl":"10.1016/j.ymgme.2025.109223","url":null,"abstract":"<div><h3>Introduction</h3><div>Regardless of its mechanism, hyperammonemia can cause coma and death, and requires urgent management. This study aims at describing the landscape of causes of hyperammonemia in adults and at evaluating the performance of targeted next-generation sequencing (NGS) in this setting.</div></div><div><h3>Methods</h3><div>We analyzed two cohorts. The first included patients aged ≥15 years presenting with hyperammonemia ≥100 μmol/L at <em>Necker</em>-<em>Enfants Malades</em> (NEM) University Hospital for 10 years and at Toulouse University Hospital for 1.5 years. The second cohort included patients who underwent genetic testing for inherited metabolic disease (IMD) <em>via</em> targeted NGS at NEM hospital over a 5 year-period, regardless of their inclusion in the first cohort, all with hyperammonemia ≥100 μmol/L after age 15.</div></div><div><h3>Results</h3><div>We included 184 patients in the first cohort, with a median peak ammonia concentration of 155 μmol/L. Among them, 61 patients (33 %) presented with coma. Non-genetic liver failure or portosystemic shunt was present in 133 patients. Twenty-three patients had received asparaginase treatment (none with coma despite a median ammonia level of 257 μmol/L), 7 had received valproic acid, 3 had undergone surgical ureterorectal anastomosis, 2 had multiple myeloma, 1 was receiving 5-Fluorouracil (5FU) for metastatic gastrointestinal cancer, 1 had disseminated atypical mycobacteriosis with <em>Mycobacterium genavense</em> (urease-producing bacteria) in a renal transplant setting and 13 had a genetically confirmed IMD diagnosed in adulthood.</div><div>In the second cohort of 17 patients, genetic testing was positive in 5 of 6 patients with IMD-suggestive biochemical profiles (2 CPS1 deficiencies, 1 OTC deficiency, 1 multiple acyl-coA dehydrogenase deficiency, and 1 lysinuric protein intolerance), and negative in patients without biochemical profile suggesting an IMD. Among them, four patients suffered from protein malnutrition related to various severe conditions (gastric bypass, metastatic colorectal adenocarcinoma, Duchenne muscular dystrophy, and short bowel syndrome).</div></div><div><h3>Conclusion</h3><div>The causes of hyperammonemia in adults are varied. In cases of acute episodes without unequivocal metabolic profiles (when unwell) and with an acquired identified cause of hyperammonemia, genetic investigations had a low yield.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109223"},"PeriodicalIF":3.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144867073","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":"Fabry disease and evolving story of I198T and A143T: Variants of varying clinical consequence (VVCC)","authors":"Nishitha R. Pillai ,&nbsp;Sofia Shrestha ,&nbsp;Alia Ahmed ,&nbsp;Grace Bronken McCarthy ,&nbsp;Chester B. Whitley ,&nbsp;Jeanine Jarnes","doi":"10.1016/j.ymgme.2025.109222","DOIUrl":"10.1016/j.ymgme.2025.109222","url":null,"abstract":"<div><div>Fabry disease is an X-linked condition that historically was thought to only affect males, but it is well known that females can also be equally affected. With the advent of newborn screening, understanding genotype-phenotype correlations, especially among variants of uncertain significance, has become essential. Two such <em>GLA</em> variants, p.Ile198Thr (I198T) and p.Ala143Thr (A143T) are associated with later-onset disease, though their pathogenicity remains debated. A cohort of 21 individuals (4 males, 17 females; ages 8–79 years) with these two genotypes from the University of Minnesota is presented here with their phenotypic characterization. In the I198T subgroup, males exhibited higher Lyso-GL3 levels and lower enzymatic activity than females, consistent with X-linked inheritance. A mild cardiac phenotype was observed on imaging in three out of four females over the age of 60, suggesting a potential association between this genotype and a later-onset cardiac risk. The predominant early presenting symptoms and signs included numbness and tingling suggestive of small fiber neuropathy and angiokeratomas, respectively. None of the males in this cohort had any evidence of end-organ damage. Our cohort of p.A143T exhibited no signs of end organ damage, except for one female who presented with concentric left ventricular hypertrophy at a young age. Gastrointestinal symptoms and recurrent headaches were common presenting features. The limited number of males in both cohorts restricts generalizability and underscores the need for larger studies. Given their uncertain pathogenicity and diverse clinical presentations, we propose classifying p.I198T and p.A143T as <em>Variants of Varying Clinical Consequence</em> (VVCC).</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109222"},"PeriodicalIF":3.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144867075","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":"Elamipretide in the Management of Barth Syndrome: Current Evidence and a Case Report","authors":"Neil Jacob ,&nbsp;Daniel Schecter ,&nbsp;Molly Marshall ,&nbsp;Neha Bansal ,&nbsp;Jacqueline Lamour ,&nbsp;Hilary Vernon ,&nbsp;Eva Morava ,&nbsp;Ibrahim Elsharkawi","doi":"10.1016/j.ymgme.2025.109220","DOIUrl":"10.1016/j.ymgme.2025.109220","url":null,"abstract":"<div><div>Barth syndrome is an exceedingly rare and potentially fatal X-linked mitochondrial disease arising from pathogenic variants in <em>TAFAZZIN</em> (<em>TAZ)</em>, leading to defects in mature cardiolipin synthesis and its integration into the mitochondrial inner mitochondrial membrane. Clinical features that may be severe include cardiomyopathy, cyclic neutropenia, skeletal myopathy, and growth delay. Currently, no FDA-approved therapies exist. Elamipretide (ELAM) has been shown to stabilize cardiolipin and improve mitochondrial bioenergetics in pre-clinical and clinical studies in older individuals with Barth syndrome. Here we describe a case of prenatally identified Barth syndrome-related severe left ventricle (LV) non-compaction cardiomyopathy, where ELAM was initiated shortly after birth for clinical heart failure and was associated with significant and sustained clinical improvement leading to an inactive status on the heart transplant list with eventual anticipated delisting. We provide a review of the current literature including the pathophysiology of Barth syndrome, the mechanism of action of ELAM, and its clinical applications.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109220"},"PeriodicalIF":3.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144841738","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":"Corrigendum to “SIMD Concerns Over Federal Support Changes affecting Newborn Screening” [Molecular Genetics and Metabolism Volume 145, Issue 4, August 2025, 109190].","authors":"Susan Berry ,&nbsp;Shibani Kanungo ,&nbsp;Erin Cooney","doi":"10.1016/j.ymgme.2025.109218","DOIUrl":"10.1016/j.ymgme.2025.109218","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109218"},"PeriodicalIF":3.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144810293","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":"In memoriam: Stephen G. Kahler, MD","authors":"Johan L.K. Van Hove ,&nbsp;Priya S. Kishnani ,&nbsp;David S. Millington ,&nbsp;Dietrich Matern ,&nbsp;Ayesha Ahmad","doi":"10.1016/j.ymgme.2025.109216","DOIUrl":"10.1016/j.ymgme.2025.109216","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109216"},"PeriodicalIF":3.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144770708","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":"Institutional readiness for novel therapeutics: A framework for multidisciplinary integration","authors":"Elizabeth G. Ames ,&nbsp;Nicholas A. Borja ,&nbsp;Russell J. Butterfield ,&nbsp;Dustin R. Donald ,&nbsp;Jeanine R. Jarnes ,&nbsp;Julie M. Porter ,&nbsp;Katie L. Sapp ,&nbsp;Ching-Sui Ueng ,&nbsp;Tao Wang ,&nbsp;Jennifer L. Cohen","doi":"10.1016/j.ymgme.2025.109214","DOIUrl":"10.1016/j.ymgme.2025.109214","url":null,"abstract":"<div><div>The landscape of therapeutic options for rare diseases is rapidly expanding, including a range of novel treatments such as antisense oligonucleotides, enzyme replacement therapies, targeted small molecules, mRNA, and gene replacement therapies. The integration of these high-cost, advanced therapeutics into clinical practice presents significant challenges. This focused review aims to outline the practical aspects of implementing non-gene therapy therapeutics that have been recently approved for rare diseases in a clinical setting, focusing on the multidisciplinary efforts required for successful integration, the coordination with various healthcare specialists, and the management of institutional and insurance-related barriers. Effective implementation necessitates strong institutional support and comprehensive infrastructure, including specialized clinics and dedicated pharmacy services. Key strategies involve developing new treatment protocols, ensuring robust payor support, and coordinating with pharmaceutical companies. The successful deployment of these new to market therapeutics hinges on a well-coordinated, institution-wide approach that addresses both clinical and logistical challenges. Emphasizing multi-disciplinary collaboration and patient-centric care, institutions can navigate the complexities of recently approved rare disease treatments, improving outcomes and access for this vulnerable patient population.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109214"},"PeriodicalIF":3.5,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144771832","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":"Childhood POLG-related disorders: Focus on polyradiculoneuropathy","authors":"Claire-Marine Bérat ,&nbsp;Marie Hully ,&nbsp;Agnès Rötig ,&nbsp;Giulia Barcia ,&nbsp;Zahra Assouline ,&nbsp;Marie-Thérèse Abi-Warde ,&nbsp;Christine Barnerias ,&nbsp;Elise Payen ,&nbsp;Marianne Jaroussie ,&nbsp;Pauline Gaignard ,&nbsp;Elise Lebigot ,&nbsp;Agathe Roubertie ,&nbsp;Nathalie Boddaert ,&nbsp;Charles-Joris Roux ,&nbsp;Pascale de Lonlay ,&nbsp;Isabelle Desguerre ,&nbsp;Arnold Munnich ,&nbsp;Manuel Schiff ,&nbsp;Cyril Gitiaux","doi":"10.1016/j.ymgme.2025.109213","DOIUrl":"10.1016/j.ymgme.2025.109213","url":null,"abstract":"<div><div>Pathogenic variants in <em>POLG</em> are involved in a large spectrum of neurological, gastrointestinal and liver impairments. Children affected with POLG-related disorders rarely exhibit peripheral neuropathy, the latter being most often described in adults as axonal polyneuropathy. Our aim was to focus on electrophysiological findings in young children affected with POLG-related disorder.</div><div>We report herein 6 unrelated early-onset POLG patients presenting with an atypical and severe polyradiculoneuropathy mimicking Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). All these patients also exhibited severe intestinal dysmotility and liver disease. Different compound heterozygous pathogenic variants in <em>POLG</em> were found and 4/6 patients shared the same heterozygous R232H variation. POLG-related disorders should therefore be considered in the setting of atypical childhood onset CIDP with gastrointestinal and liver impairments.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109213"},"PeriodicalIF":3.5,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144827520","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":"Reframing primary mitochondrial disease as a sterile interferonopathy","authors":"Eva Morava ,&nbsp;Ibrahim Elsharkawi ,&nbsp;Tamas Kozicz","doi":"10.1016/j.ymgme.2025.109217","DOIUrl":"10.1016/j.ymgme.2025.109217","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109217"},"PeriodicalIF":3.5,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144771830","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)00194-5","DOIUrl":"10.1016/S1096-7192(25)00194-5","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109203"},"PeriodicalIF":3.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713194","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":"Meta-analysis of cognitive outcomes in children and adults with early treated phenylketonuria – Results across functions","authors":"Cristina Romani ,&nbsp;Stephan Huijbregts ,&nbsp;Francjan J. van Spronsen ,&nbsp;Anita MacDonald ,&nbsp;Annemiek M.J. van Wegberg ,&nbsp;Megan Staines ,&nbsp;Andrew Olson","doi":"10.1016/j.ymgme.2025.109210","DOIUrl":"10.1016/j.ymgme.2025.109210","url":null,"abstract":"<div><div>Meta-analyses were used to track cognitive outcomes in early treated people with phenylketonuria. We compared impairment sizes and possible modulations by blood Phe in young adults and children/early adolescents.</div><div>We identified results for 29 adult PKU groups and 21 child groups (N-participants = 904 and 460; mean age 27 and 11 years; mean current blood Phe: 1010; and 527; median 899 and 494; SD= =396 and 159) with 278 separate outcome measures available for adults and 175 for children.</div><div>Results demonstrated a similar overall level of impairment across ages, corresponding to approximately 0.5 of a standard deviation difference from controls. However, children showed more homogeneous impairments across functions compared to adults who showed a larger difference between the most and least impaired measures and a stronger difference of impairment between speed measures (impaired) and accuracy measures (preserved). In both age groups, blood Phe level modulated the effect size of the impairment in several conditions, but speed of processing appeared to be affected more by childhood levels than current adult levels consistent with previous results.</div><div>Results indicate that negative effects of PKU persist across the lifespan, but that adults with PKU may rely on relatively unaffected learning skills and on prioritization of resources to achieve good accuracy and good performance in tasks tapping crystallized intelligence, even if speed remains impaired. This has positive implications for educational and employment prospects, but it is unclear how positive trends generalize to the whole PKU population beyond groups engaged in research.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109210"},"PeriodicalIF":3.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144771836","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}