Molecular genetics and metabolism最新文献

{"title":"Genotype-phenotype correlations of GFAP variants in type I Alexander disease subtypes","authors":"Tiziana Bachetti ,&nbsp;Ylenia Vaia ,&nbsp;Alice Grossi ,&nbsp;Francesca Rosamilia ,&nbsp;Enrico Bertini ,&nbsp;Francesco Nicita ,&nbsp;Deianira Bellitto ,&nbsp;Florian Eichler ,&nbsp;Geneviève Bernard ,&nbsp;Amanda Nagy ,&nbsp;Ayelet Zerem ,&nbsp;Morteza Heidari ,&nbsp;Ali Reza Tavasoli ,&nbsp;Isabella Moroni ,&nbsp;Isabella Ceccherini ,&nbsp;Davide Tonduti ,&nbsp;AxD Type I Study Group","doi":"10.1016/j.ymgme.2025.109689","DOIUrl":"10.1016/j.ymgme.2025.109689","url":null,"abstract":"<div><h3>Introduction</h3><div>Alexander disease (AxD) is a rare and progressive leukodystrophy caused by variants in the Glial Fibrillary Acidic Protein (GFAP) gene. AxD presents as Type I and Type II, based on clinical and neuroradiological features. However, Type I patients variable disease progression has led to sub-classify them into subtypes Ia-Ib-Ic-Id. Our study investigated genotype-phenotype correlations in Type I AxD across these subtypes.</div></div><div><h3>Methods</h3><div>A cohort of 74 genetically confirmed Type I AxD patients was analysed, with variants classified according to the clinical subtypes Ia, Ib, Ic, and Id. Genotypic–phenotypic correlations were explored both across all subtype groups and in stratified analyses based on patients' ability to achieve independent ambulation versus those who never acquired this milestone. To investigate the functional consequences of a representative variant, in vitro assays were performed. Selected mutant GFAP protein was expressed and their ability to assemble into intermediate filament networks was assessed.</div></div><div><h3>Results</h3><div>The study revealed a progressive decrease in GFAP allelic heterogeneity across disease subtypes from Ia to Id. Additionally, <em>GFAP</em> pathogenic variants in exon 1 were more frequent in milder forms, whereas mutations in exon 4 were predominantly observed in severe phenotypes. In addition, changes at p.R239 and p.R79 residues showed an opposite trend, with variants affecting p.R239 never detected in Id subtype, while variants affecting p.R79 never detected in Ia. Specific aminoacidic changes at the p.R79 residue were able to stratify patients based on ability to acquire independent ambulation or not. Furthermore, the distribution of Combined Annotation Dependent Depletion (CADD) scores showed an inverse correlation with the acquisition of autonomous ambulation.</div></div><div><h3>Conclusions</h3><div>These results suggest that specific <em>GFAP</em> variants could be potential predictors for disease progression in Type I AxD, supporting patients' subclassification and underscoring the importance of considering both genetic and clinical factors in AxD management, particularly as therapeutic interventions are being developed.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 1","pages":"Article 109689"},"PeriodicalIF":3.5,"publicationDate":"2025-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683104","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":"Lysinuric protein intolerance: Allogeneic peripheral blood stem cell transplantation for an inborn error of metabolism and immunity","authors":"Natalia Zubarovskaya ,&nbsp;Johannes A. Mayr ,&nbsp;Elmar Aigner ,&nbsp;Georg Strebinger ,&nbsp;Sema Kalkan-Uçar ,&nbsp;Anita Lawitschka ,&nbsp;Saskia B. Wortmann","doi":"10.1016/j.ymgme.2025.109688","DOIUrl":"10.1016/j.ymgme.2025.109688","url":null,"abstract":"<div><div>Lysinuric protein intolerance (LPI) is not only an inborn metabolic disease with gastrointestinal, hepatic, renal and lung involvement but also an inborn error of immunity potentially leading to life-threatening autoimmune disorders (e.g. systemic lupus erythematosus (SLE), hemophagocytic lymphohistiocystosis (HLH)). Recently, one case of allogeneic hematopoietic stem cell transplantation (allo-HSCT) reversing SLE and HLH in a LPI patient was reported. We present 21 years of follow-up in a second LPI patient having undergone allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for HLH.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 1","pages":"Article 109688"},"PeriodicalIF":3.5,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145645495","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":"Focused ultrasound delivery of enzyme replacement therapy to the brain of Gaa−/− Pompe disease mice","authors":"Paige Nowlin ,&nbsp;Yongzhi Zhang ,&nbsp;Amanda Chrisholm ,&nbsp;Haoyue Zhang ,&nbsp;Jian Dai ,&nbsp;Bernie Simone Owusu-Yaw ,&nbsp;Sarah P. Young ,&nbsp;Deeksha Bali ,&nbsp;Jaymin Upadhyay ,&nbsp;Nick Todd","doi":"10.1016/j.ymgme.2025.109294","DOIUrl":"10.1016/j.ymgme.2025.109294","url":null,"abstract":"<div><div>Clinically used enzyme replacements therapies (ERTs) have been successful in mitigating peripheral tissue pathology in patients with infantile onset (IOPD) and late onset (LOPD) Pompe disease (PD). However, none of the approved therapies are known to cross the blood brain barrier (BBB) and patients with PD have progressive central nervous system (CNS)-associated impairments due to lysosomal glycogen accumulation in the CNS. Here we investigate the use of focused ultrasound (FUS) to temporarily open the BBB as a treatment strategy for achieving delivery of intravenously administered recombinant human acid alpha glucosidase enzyme (rhGAA) into targeted regions of the mouse brain.</div><div>We investigated GAA delivery and glycogen accumulation in 5-month-old Gaa−/− knockout mice following administration of two clinically available rhGAA ERTS (alglucosidase alfa and avalglucosidase alfa) at different dosages with and without FUS-BBB opening over four biweekly treatment sessions. BBB opening was targeted specifically to the striatum and cortex bilaterally in the FUS groups. Diphenhydramine was administered intraperitoneally 10 min before ERT to avoid anaphylactic response. Mice were sacrificed 24 h after the last treatment session. One hemisphere was used for histological analysis based on periodic acid Schiff (PAS) and H&amp;E stained sections. The other hemisphere was used for biochemical assays to measure GAA enzyme activity and glycogen content.</div><div>Contrast MRI showed consistent BBB opening over all mice treated with FUS with no significant differences in extent of BBB opening between hemispheres or treatment session. We observed significant reductions in the level of PAS staining for FUS + ERT treated mice compared to No FUS + ERT treated mice, indicative of successful ERT delivery across the BBB resulting in glycogen clearance. Biochemical analysis supported these results, showing an increase in GAA enzyme activity and reduction in glycogen content for FUS + ERT treated mice compared to No FUS + ERT groups. Future work will determine if this promising treatment paradigm can rescue disease phenotypes that are downstream of glycogen accumulation and work towards clinical translation.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 1","pages":"Article 109294"},"PeriodicalIF":3.5,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683465","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":"Experimental insights into MMACHC variants using a novel minigene system","authors":"Yan Dong ,&nbsp;Xiaowei Xu ,&nbsp;Weiran Li ,&nbsp;Leyi Wang ,&nbsp;Bo Wu ,&nbsp;Ping Wang ,&nbsp;Dong Li ,&nbsp;Jianbo Shu ,&nbsp;Chunquan Cai","doi":"10.1016/j.ymgme.2025.109292","DOIUrl":"10.1016/j.ymgme.2025.109292","url":null,"abstract":"<div><h3>Background</h3><div>Methylmalonic aciduria and homocystinuria, cblC type, the most prevalent disorder of cobalamin (cbl) metabolism, results from genetic variants in the <em>MMACHC</em> gene. Although public databases document numerous splice variants of this gene, experimental evidence confirms pathogenicity for only a limited proportion.</div></div><div><h3>Methods</h3><div>We constructed a plasmid system encompassing the complete coding sequence of the <em>MMACHC</em> gene, enabling direct validation of protein expression following the evaluation of <em>MMACHC</em> splice variant effects. Using a minigene assay, we evaluated the impact of selected variants on the splicing and quantified their protein expression levels.</div></div><div><h3>Results</h3><div>26 variants, including a subset of missense variants that are usually underestimated but can also lead to aberrant splicing, were predicted by splicing prediction tools. Experimental testing proved that 14 candidate variants disrupted normal splicing of the <em>MMACHC</em> gene and induced diverse splicing events that encompass exon skipping, partial exon skipping, intron retention, and cryptic splicing. However, 10 variants had no effect on pre-mRNA splicing but significantly lowered the protein expression levels.</div></div><div><h3>Conclusion</h3><div>Our study elucidates the potential pathogenic mechanisms of some <em>MMACHC</em> variants and validates the utility of a novel plasmid system for the effective assessment of <em>MMACHC</em> variant pathogenicity. The application of this laboratory method for the analysis of patient-identified variants has the potential to be very valuable for the diagnosis of cblC disease at an early stage.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109292"},"PeriodicalIF":3.5,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145577245","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":"A proposed nosology of inherited disorders of the extracellular matrix (ECM): Insights from the IEMbase and dyadic classification","authors":"Cecilia Giunta ,&nbsp;Giulio Marcionelli ,&nbsp;Carlos R. Ferreira ,&nbsp;Nenad Blau ,&nbsp;Marianne Rohrbach","doi":"10.1016/j.ymgme.2025.109288","DOIUrl":"10.1016/j.ymgme.2025.109288","url":null,"abstract":"<div><div>We have identified 252 inherited disorders of the extracellular matrix (ECM) caused by 154 different gene defects and have proposed a classification system in 8 categories based on their mode of action: 1. Disorders of ECM glycoproteins, 2. Disorders of ECM proteoglycans, 3. Disorders of proteins in TGF-beta signaling pathway, 4. Disorders of fibrillar collagens, 5. Disorders of fibrillar collagen processing and maturation, 6. Disorders of non-fibrillar collagens, 7. Other disorders of connective tissue with bone fragility and 8. Other disorders of connective tissue. Additionally, using information from IEMbase, we have described the clinical involvement of 18 organs and systems, as well as essential laboratory investigations for each type of ECM disorder. Skeletal, ocular, neurological and dysmorphic manifestations were the most prevalent, occurring in 18 %, 12 %, 10 %, and 10 % of ECM disorders, respectively. This was followed by cardiovascular, dermatological, ear-related, muscular, digestive, endocrine, and hematological symptoms (3–7 %). Among the skeletal symptoms, those affecting joints, spine, upper limbs, lower limbs and mineralization were the most common with rates of 25.8 %, 18.0 %, 14.3 %, 14.1 % and 11.5 %, respectively. 27.4 % of the disorders display a single phenotype, with skeletal issues being the most common at 17.8 % and ocular abnormalities 12.2 %. Conversely, 72.6 % of disorders have multiple phenotypes, with LTBP4-related Cutis laxa (10 phenotypes) and SMAD4- related Myhre Syndrome (gain of function) at the end of the spectrum with up to 11 phenotypes. The information provided in this study, including our proposed dyadic classification system for ECM disorders, may be useful for healthcare providers caring for individuals with conditions associated with ECM problems.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 1","pages":"Article 109288"},"PeriodicalIF":3.5,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683147","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":"Evaluation and follow-up of newborns screening positive for mucopolysaccharidosis II: Results from an international modified Delphi consensus","authors":"Barbara K. Burton ,&nbsp;N. Matthew Ellinwood ,&nbsp;Katey K. Hoffman ,&nbsp;Joseph Muenzer","doi":"10.1016/j.ymgme.2025.109285","DOIUrl":"10.1016/j.ymgme.2025.109285","url":null,"abstract":"<div><div>Mucopolysaccharidosis II (MPS II; Hunter syndrome; OMIM <span><span>309900</span><svg><path></path></svg></span>) is a rare, X-linked lysosomal storage disease caused by deficient activity of the enzyme iduronate-2-sulfatase (I2S, EC 3.1.6.13), due to pathological variants of the I2S gene (IDS). Clinically, MPS II is a chronic progressive multisystem developmental and degenerative disorder, typically associated with manifestations in early childhood. Intravenous enzyme replacement therapy has been available since 2006, with improved outcomes seen with early initiation of therapy. Newborn screening for MPS II in a public health setting has been ongoing in Taiwan since 2015 and in some states of the USA since 2017. These developments prompted a successful nomination of MPS II to be included as a core screening condition on the US Federal Recommended Uniform Screening Panel (RUSP), which was approved by the US Secretary of Health and Human Services on August 2, 2022. With the promise of expanded public health screening for MPS II, there was a perceived need for a set of consensus recommendations on MPS II newborn screening, the clinical confirmation of screened positive cases, and their clinical management. To this end an international expert panel of 21 members from 8 countries was convened to conduct a modified Delphi consensus on the evaluation and follow-up of newborns who screened positive for MPS II, the results of which are presented.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109285"},"PeriodicalIF":3.5,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564757","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":"Measuring dietary intake among participants with a urea cycle disorder using standard diet records or a novel food photography app","authors":"Elaine Sim ,&nbsp;Ashley Gregor ,&nbsp;Erin MacLeod ,&nbsp;Rachel Moore ,&nbsp;Michele N. Ravelli ,&nbsp;Dale A. Schoeller ,&nbsp;Cary O. Harding ,&nbsp;Peter Jacobs ,&nbsp;Melanie B. Gillingham","doi":"10.1016/j.ymgme.2025.109291","DOIUrl":"10.1016/j.ymgme.2025.109291","url":null,"abstract":"<div><div>Nutrition management of urea cycle disorders (UCDs) focuses on limiting dietary protein and providing adequate energy to ensure appropriate growth and prevent catabolism. Dietary protein intakes are recommended to patients; however, assessment of actual protein intake is challenging as standard assessment methods are recognized to be inaccurate, time-consuming, and cumbersome. A new dietary collection method utilizes a smartphone camera; participants take photos of meals and snacks for remote analysis by a registered dietitian. This food photography method using the mFood app was compared to traditional 3-day diet records in individuals with UCDs and reported energy intake for both were validated against an objective gold-standard measurement of total energy expenditure (TEE) by doubly labeled water. In weight-stable adults, energy intake is approximately equal to TEE. Eight individuals ≥16 years old participated in a randomized crossover design study. In this cohort, protein intake was 13 % and 15 % of energy for 3-day diet records and mFood, respectively. There was no statistical difference in gram intake of the macronutrients between the two methods. Compared to TEE, participants reported 16 % lower total energy intake by 3-day diet records and 22 % lower energy intake by mFood, demonstrating limited benefit to using mFood. We highlight the importance of utilizing consistent nutrient analysis methods to compare dietary assessments within a population. mFood, although not superior to traditional dietary collection methods, was preferred by the majority of participants and offers a novel method for collecting nutrition information in individuals with UCD who frequently find this task cumbersome.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109291"},"PeriodicalIF":3.5,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145526809","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":"Survival, growth, and safety findings in patients with rapidly progressive, infantile-onset LAL-D: Results from the international LAL-D registry","authors":"Suresh Vijay ,&nbsp;Jennifer Evans ,&nbsp;Florence Lacaille ,&nbsp;Florian Abel ,&nbsp;Javier de las Heras","doi":"10.1016/j.ymgme.2025.109290","DOIUrl":"10.1016/j.ymgme.2025.109290","url":null,"abstract":"<div><div>In symptomatic infants, lysosomal acid lipase deficiency (LAL-D; historically Wolman disease) is characterized by a rapidly progressive disease course of hepatosplenomegaly and liver disease. This course includes liver failure, malabsorption and growth failure, and systemic inflammation, such as hemophagocytic lymphohistiocytosis, typically leading to death by 6 months of age if untreated. Sebelipase alfa (KANUMA®; Alexion, AstraZeneca Rare Disease, Boston, MA) is a recombinant human LAL (a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme) approved for the treatment of LAL-D in infants with rapidly progressive disease as well as in children and adults with LAL-D. Previous studies showed that enzyme replacement therapy (ERT) with sebelipase alfa led to survival with improved growth and development, hematologic parameters, and liver parameters and was well tolerated. We report long-term outcomes in 29 patients with rapidly progressive LAL-D who were symptomatic in infancy using patient data from the International LAL-D Registry, an ongoing observational, multicenter, international registry (<span><span>NCT01633489</span><svg><path></path></svg></span>) that collects data on patients with LAL-D. Among these 29 patients treated with sebelipase alfa, 41 % were male, and 28 % had participated in clinical trials with sebelipase alfa. Median age (Q1, Q3) was 2.3 months (1.8, 3.1) at the start of ERT. Patients received a starting ERT dose of ≤1 mg/kg or ≥3 mg/kg per week. In patients who had participated in clinical trials of sebelipase alfa, the starting dose was driven by the clinical trial protocol and was between 0.2 and 1.0 mg/kg per week. Overall, 27 of 29 (93 %) patients survived during the median observation time (Q1, Q3) of 6.2 years (3.5, 8.4). At baseline, 11 patients had abnormally low weight-for-age <em>z</em> scores (&lt;−2); for 5 of these patients, weight stabilized after 6 to 12 months of treatment (<em>z</em> scores between −2 and 2). Adverse events occurred in 23 (79 %) patients. Eleven (38 %) patients experienced adverse events potentially related to sebelipase alfa, which were generally not severe and most resolved. Four patients among 7 tested developed antidrug antibodies, and 3 had positive results for neutralizing antidrug antibodies. These results confirmed the dramatic survival and metabolic benefit associated with sebelipase alfa ERT in patients with symptomatic, rapidly progressive LAL-D.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109290"},"PeriodicalIF":3.5,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573911","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":"Propionic acidemia and methylmalonic aciduria: A portrait of the first 3 years—Admissions and complications","authors":"Kimberly A. Chapman ,&nbsp;Nicholas Ah Mew ,&nbsp;Nina Mickle ,&nbsp;Danielle Starin ,&nbsp;Erin MacLeod","doi":"10.1016/j.ymgme.2025.109289","DOIUrl":"10.1016/j.ymgme.2025.109289","url":null,"abstract":"<div><h3>Background</h3><div>Propionic acidemia (PA) and methylmalonic acidemia (MMA) are organic acidurias that can present with metabolic acidosis and hyperammonemia, often leading to frequent hospital admission. While recent studies have provided guidelines for management and diagnosis of these conditions, there is a lack of research detailing the frequency and reasons for hospital admission in the first three years of life.</div></div><div><h3>Methods</h3><div>As part of a quality improvement project, data were extracted from medical records of all patients with PA and MMA (born between 2000 and 2024) who were seen at Children's National Hospital (CNH) during their first three years of life, time of data pull, or up to point of liver transplant. We collected data on the number of individuals with PA or MMA in our patient population, the age at which they first presented, and the reason for their hospital admission.</div></div><div><h3>Results</h3><div>Our cohort included 11 individuals with MMA, all of whom had <em>MMUT</em> mutations, representing a total of 12 different variants. Additionally, 15 individuals with PA were reported. Of these, 2 individuals with PA did not undergo genetic testing, 5 had 7 separate variants in <em>PCCA</em> gene, and 8 had 10 different variants in <em>PCCB</em> gene. The mean number of hospitalizations for metabolic decompensation was 4.45 ± 6.6 for the MMA cohort and 8.7 ± 6.7 for the PA cohort, with no statistically significant difference between the groups. The MMA cohort experienced a total of 49 admissions, 16 (33 %) of which occurred in the first year of life. In the PA cohort, there were 130 total admissions, with 56 (43 %) occurring in the first year. The most frequent reason for admission in both groups was vomiting.</div></div><div><h3>Discussion/Conclusions</h3><div>Individuals with PA and MMA are frequently hospitalized (accounting for 5–6 % of their first three years of life) which likely impacts development and overall health. Data such as those presented in this study are crucial for improving our understanding of disease progression in these rare conditions. This information can help guide future research, support the development of the clinical guidelines, and provide healthcare providers with valuable insights to better educate families on risks and expectations. Using these data, we have altered our counseling at the time of diagnosis to better prepare families for their child's course.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109289"},"PeriodicalIF":3.5,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513525","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":"MEHMO syndrome: Review and proposed classification as an eIF2-related neuroendocrinopathy","authors":"An N. Dang Do ,&nbsp;Fatemeh Navid ,&nbsp;Sara K. Young-Baird","doi":"10.1016/j.ymgme.2025.109287","DOIUrl":"10.1016/j.ymgme.2025.109287","url":null,"abstract":"<div><div>MEHMO syndrome (OMIM#<span><span>300148</span><svg><path></path></svg></span>) is a rare, X-linked, multisystemic condition that predominantly involves endocrinologic and neurologic dysfunctions. Initial naming of the syndrome emphasizes the presentation of <u>M</u>ental disability, <u>E</u>pileptic seizures, <u>H</u>ypogonadism/<u>H</u>ypogenitalism, <u>M</u>icrocephaly, and <u>O</u>besity. This review provides a synthesis of the genetics, genotypes, and phenotypes of publicly available information on <em>EIF2S3</em> and MEHMO syndrome. Identification and confirmation of variants in the gene <em>EIF2S3</em> as the genetic underpinning of the syndrome's pathophysiology and reports of additional cases suggest a consideration for a re-definition of the acronym and a re-classification of the condition along with others as eIF2-related neuroendocrinopathies. This would allow for more standardized and encompassing characterization of the group of eIF2-related disorders, that in turn would support and continue to spur further research progress in basic pathophysiology, disease diagnosis and monitoring, and biomarker and therapeutic discoveries.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109287"},"PeriodicalIF":3.5,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468314","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}