Journal of Inherited Metabolic Disease最新文献

{"title":"Adults With Acid Sphingomyelinase Deficiency Have Sustained Improvements in Clinical Outcomes With up to 5 Years of Olipudase Alfa Enzyme Replacement Therapy: ASCEND Trial Final Results.","authors":"Melissa P Wasserstein, Carla E Hollak, Antonio Barbato, Renata C Gallagher, Roberto Giugliani, Norberto Bernardo Guelbert, Julia B Hennermann, Takayuki Ikezoe, Robin Lachmann, Olivier Lidove, Paulina Mabe, Eugen Mengel, Maurizio Scarpa, Ebubekir Senates, Michel Tchan, Beth L Thurberg, Jesus Villarrubia, Nicole M Armstrong, Shashi Bhushan, Yong Kim, Monica Kumar","doi":"10.1002/jimd.70192","DOIUrl":"https://doi.org/10.1002/jimd.70192","url":null,"abstract":"<p><p>Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal storage disease resulting in multisystemic disease manifestations, significant disease burden, and early mortality for some individuals. Enzyme replacement therapy (ERT) with olipudase alfa (Xenpozyme) is the first disease-specific treatment indicated for noncentral nervous system manifestations of ASMD in children and adults. During the 1-year primary analysis of the ASCEND placebo-controlled trial in 36 adults with ASMD, olipudase alfa treatment reduced sphingomyelin storage and was associated with clinically significant improvements relative to placebo in multiple endpoints. An open-label extension of the ASCEND trial followed 35 of 36 adults during olipudase alfa treatment for up to 5 years. Mean time on olipudase alfa was 4.2 ± 1.0 years; mean compliance was 90% ± 13%. During long-term olipudase alfa treatment, percent predicted diffusing capacity for carbon monoxide (DL_CO) increased (mean 50.1% ± 10.8% at baseline vs. 66.5% ± 13.3% at final assessment; mean change from baseline of 35.9% ± 27.5% (p < 0.0001). Mean baseline spleen volume of 11.5 ± 4.6 multiples of normal (MN) decreased to 4.8 ± 2.1 MN at final assessment, mean change from baseline -57.5% ± 10.1% (p < 0.0001) and mean baseline liver volume (1.5 ± 0.4 MN) decreased to 0.95 ± 0.23 MN at final assessment, (mean change from baseline -36.8% ± 11.5%, p < 0.0001). Plasma lyso-sphingomyelin levels decreased by 72% from baseline to final assessment. Overall, improvements in clinical parameters occurred regardless of baseline severity. No new safety issues emerged during the trial extension and 98% of treatment emergent adverse events were mild/moderate. Improvements in visceral ASMD disease with olipudase alfa treatment will significantly impact the disease burden for those with this progressive multiorgan disorder.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70192"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver Gene Therapy in Fabry Disease Mice With Low Doses of rAAV2/8 Expressing a Codon-Optimized hGLA cDNA Results in Long-Term Disease Correction.","authors":"Himanshi Saxena, Rossana Domenis, Giulia Romano, Jessica Biasizzo, Martina Ferro, Dania Ferino, Antonio Vicidomini, Alessandra Iaconcig, Giulia Bortolussi, Lorena Zentilin, Andrea Dardis, Andrés F Muro","doi":"10.1002/jimd.70188","DOIUrl":"https://doi.org/10.1002/jimd.70188","url":null,"abstract":"<p><p>Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene, which encodes for Alpha Galactosidase-A (α-Gal A). α-Gal A deficiency leads to glycosphingolipid accumulation, like globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (lyso-Gb3), resulting in systemic symptoms and reduced lifespan. Current treatments such as enzyme replacement therapy (ERT) and chaperone therapy are noncurative and have limitations. Gene therapy is an interesting alternative approach that may overcome most of these limitations, and different approaches are currently being tested. Here, we developed a gene therapy approach using rAAV2/8 vectors, delivered intravenously, that target the liver to produce and secrete functional α-Gal A into circulation. This enzyme is then captured by organs expressing mannose-6-phosphate receptors, reducing glycosphingolipid accumulation in affected tissues. We generated a codon-optimized GLA cDNA with enhanced translatability that was expressed under a strong liver-specific promoter. In a dose escalation study in juvenile Gla knock-out (ko) mice, the lowest dose (3.0E11vg/kg) resulted in 85%-95% clearance of lyso-Gb3 in plasma and tissues, while doses of 3.0E12 vg/kg and higher showed 98%-100% clearance of the glycosphingolipid. All AAV doses were more effective than systemic α-Gal A administration (ERT). Long-term treatment showed normal levels of lyso-Gb3 in plasma and tissues, and corrected neuropathic involvement, as shown in the hot plate test. This study provides a proof-of-concept showing that the tested liver-specific gene therapy vector is capable of preventing disease progression in juvenile Fabry mice at relatively low doses and shows potential in treating both early- and late-onset FD in patients.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70188"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13112331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Analysis of Dietary Patterns in Children With Phenylketonuria Phenotypes and Controls: Implications for Nutritional Status.","authors":"Dolores Garcia-Arenas, Aida Ormazabal, Paula Isern, Blanca Barrau-Martinez, Arnau Gonzalez-Rodriguez, Alba Tor-Roca, Rafael Llorach, Jaume Campistol-Plana, Mireia Urpi-Sarda","doi":"10.1002/jimd.70196","DOIUrl":"10.1002/jimd.70196","url":null,"abstract":"<p><p>Individuals with phenylketonuria (PKU), caused by different variants of the phenylalanine hydroxylase gene, need to restrict their intake of phenylalanine. This study evaluated dietary patterns and physical activity levels in children with different PKU phenotypes compared to healthy controls. Eighty-two children were recruited (22 classic PKU [cPKU], 21 BH₄-responsive PKU, 19 hyperphenylalaninemia, and 20 controls). Anthropometric data, dietary intake, biochemical markers, and physical activity were assessed. Classic PKU (cPKU) subjects exhibited higher carbohydrate and sugar intake than other PKU phenotypes and controls. Notably, 42% of carbohydrate and 17% of sugar intake was from special low-protein foods, and 20% of carbohydrate and 29% of sugar intake was from protein substitutes. Compared to controls, the cPKU group was less physically active and reported a higher frequency of sweet consumption. Ninety percent of PKU had good metabolic control and carbohydrate intake was significantly correlated with HOMA-IR; however, after adjusting for age, only a trend remained (p = 0.08). Participants in the PKU group following a low natural protein diet consumed more carbohydrate and sugars than those on a normal-protein diet. Multivariate regression analysis showed that the low natural protein diet group was significantly associated with higher levels of vitamin B₁₂, linoleic acid, α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid, and with lower levels of total cholesterol and HDL-C compared to the normal-protein diet group. In conclusion, children with PKU, particularly those with classical PKU following low-protein diets, showed higher carbohydrate intake and distinct micronutrient and lipid profiles compared with healthy controls.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70196"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disease Burden and Pharmacological Treatment Patterns in Children and Adults With Phenylketonuria: A Real-World Matched Cohort Study.","authors":"Nicola Longo, Barbara K Burton, Shailja Vaghela, Fan Mu, Aolin Wang, Jess Smith, Emily Reichert, Ryan B Simpson, Vanja Sikirica, Sue Perera","doi":"10.1002/jimd.70194","DOIUrl":"https://doi.org/10.1002/jimd.70194","url":null,"abstract":"<p><p>Phenylketonuria (PKU) is caused by defective catabolism of phenylalanine (Phe), resulting in Phe accumulation and subsequent neurocognitive impairment. This retrospective study used a large United States claims database linked to laboratory records (6/2018-05/2023) to compare comorbidities, healthcare resource utilization, and healthcare costs between individuals with PKU and matched controls, stratified by age and Phe level, as well as describe pharmacological treatment patterns among individuals with PKU. The study included 5729 and 2648 matched pairs aged ≥ 12 and < 12 years, respectively (mean age: 31 and 3 years; 60% and 47% female). Individuals aged ≥ 12 years with PKU had significantly higher prevalence of neuropsychiatric and cognitive comorbidities than controls, including intellectual or developmental disabilities (prevalence difference: 5.2%), fatigue and malaise (4.9%), and anxiety (4.2%; all p < 0.05), along with other comorbidities across multiple organ systems. Individuals aged ≥ 12 years with PKU also accessed the healthcare system more than controls (39% more hospitalizations, 18% more emergency room visits, and 25% more outpatient visits) and incurred higher medical and pharmacy costs ($2869 and $9075, respectively; p < 0.05). Individuals aged < 12 years similarly had higher burden than controls, but only for certain outcomes and at smaller magnitudes. Individuals with Phe ≥ 600 μmol/L showed a greater incremental burden for certain comorbidities, such as intellectual or developmental disabilities, compared to individuals with Phe < 600 μmol/L. These findings demonstrate the substantial burden of PKU across age and Phe level strata, notably in those aged ≥ 12 years, highlighting the need for improved treatments.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70194"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13112333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2025 Consensus Clinical Management Guidelines for Niemann-Pick Disease Type C.","authors":"Tarekegn Hiwot, Forbes D Porter, Tatiana Bremova-Ertl, Uma Ramaswami, Caroline Hastings, Bénédicte Héron, Justin Hopkin, Joella Melville, Hernan Amartino, Mireia Del Toro, Federica Deodato, Fatih Ezgü, Paul Gissen, James B Gibson, Can Ficicioglu, Roberto Giugliani, Orna Staretz-Chacham, Frances Platt, Nathalie Guffon, Kristina Julich, Nikola Kresojević, Anna Lehman, Yann Nadjar, Susanne A Schneider, Simon Jones, Eugen Mengel, Michel Tchan, Mark Walterfang, Ozlem Goker-Alpan, Charlotte Dawson, Sandra Cowie, Toni Mathieson, Elizabeth Berry-Kravis, Marc C Patterson","doi":"10.1002/jimd.70185","DOIUrl":"https://doi.org/10.1002/jimd.70185","url":null,"abstract":"<p><p>In 2018, the International Niemann-Pick Disease Alliance (INPDA) and the International Niemann-Pick Disease Registry (INPDR) developed and published comprehensive clinical management guidelines to support inclusive and standardized care pathways in Niemann-Pick disease type C (NPC)-an ultra-rare, autosomal recessive, neurovisceral lysosomal disorder. Since then, advances in diagnostics, care, and the approval of two novel disease-modifying agents have underscored the need to revise these guidelines to ensure safe, consistent, and high-quality care for those affected by NPC. In response, the INPDA and INPDR convened a multidisciplinary Guidelines Development Group (GDG) comprising individuals with NPC expertise from 14 countries across five continents, representing a broad range of specialties, as well as patients and families involved in NPC care. Informed by a comprehensive literature review and two meetings, the GDG systematically reviewed, revised, and updated the 2018 guideline statements, re-evaluating the level of evidence, strength of recommendations, and expert agreement for each. The resulting 2025 consensus clinical management guidelines constitute a timely, up-to-date, and internationally applicable resource for the diagnosis, treatment, and holistic management of individuals with NPC. These guidelines serve as a critical resource for specialist centers, hospital-based medical teams, staff involved in NPC patient care, family physicians and other primary caregivers, and, importantly, patients and their families.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70185"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimodal Noninvasive Biomarker Characterization of Structural and Functional Alterations in ADSS1-Deficient Myopathy.","authors":"Merve Koç Yekedüz, Raquel van Gool, Hanne van der Heijden, Buket Sonbas Cobb, Nehal Shah, Georgina Johnson, Cara A Timpani, Julie Shulman, Vanessa Rameh, Evan E Hsu, Courtney LeSon, Pui Y Lee, Adam P Vogel, Walla Al-Hertani, Hyung Jun Park, Emma Rybalka, Seward B Rutkove, Jaymin Upadhyay","doi":"10.1002/jimd.70193","DOIUrl":"https://doi.org/10.1002/jimd.70193","url":null,"abstract":"<p><p>Adenylosuccinate synthase 1 (ADSS1)-deficient myopathy is an ultra-rare disease characterized by progressive muscle dysfunction. The objective of this investigation was to employ a noninvasive biomarker approach to phenotype (fine-)motor skills, communication and cognition in adults with ADSS1-deficient myopathy. Five individuals with ADSS1-deficient myopathy and five age-sex-matched healthy controls (HCs) underwent a multimodal evaluation. Assessments included, (i) evaluation of motor performance, (ii) speech and voice production and cognitive test batteries, (iii) patient-reported outcomes, (iv) electrical impedance myography (EIM), (v) musculoskeletal magnetic resonance imaging (MRI), and (vi) plasma proteomics. ADSS1-deficient myopathy participants vs. HCs demonstrated reduced performance on the 9-Hole Peg and grip strength tests as well as lower self-reported mobility. Analysis of speech and voice performance revealed asthenia (vocal weakness) (p = 0.02), lower intelligibility (p = 0.008), and worse voice quality during the sustained vowel task (p = 0.03) in the ADSS1-deficient myopathy cohort. Cognitive functioning remained unaffected in patients with ADSS1-deficient myopathy. On EIM, ADSS1-deficient myopathy participants vs. HCs, demonstrated a pattern of higher resistance and lower reactance and phase across upper- and lower-extremity measurements, indicative of poorer muscle health, with large effect sizes (Cliff's δ = 0.5-0.9). MRI revealed intramuscular fat infiltration, particularly in posterior compartments of the upper leg (e.g., biceps femoris). Proteomics indicated reduced (p = 0.04) Neurotrophin-3 (NTF3; implicated in neuronal development, survival, and differentiation) levels in the ADSS1-deficient myopathy cohort relative to HCs. Lower NTF3 levels associated with poorer performance on hand-motor tasks as well as higher resistance and lower reactance and phase on EIM. This study highlighted the value of multimodal phenotyping for quantifying disease expression and advancing monitoring strategies in ADSS1-deficient myopathy. This multimodal investigation demonstrates that integrating electrical impedance myography with quantitative motor, speech, musculoskeletal imaging, and proteomic assessments provides a sensitive and noninvasive research framework for capturing neuromuscular dysfunction and functional disease burden in patients with ADSS1-deficient myopathy, thereby supporting the current biomarker strategy for refined phenotyping and longitudinal disease monitoring in this ultra-rare condition.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70193"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shifting Towards Empagliflozin First-Line Therapy in Glycogen Storage Disease Type Ib: A Nationwide Real-World Study.","authors":"Sema Kalkan Uçar, Neslihan Önenli Mungan, Gülden Fatma Gökçay, Ayşe Çiğdem Aktuğlu Zeybek, Sebile Kılavuz, Seda Güneş, Fatih Kardaş, Pelin Teke Kısa, Kısmet Çıkı, Aynur Küçükçongar Yavaş, Ayça Burcu Kahraman, Merve Yoldaş Çelik, Ebru Canda, Deniz Kor, Meryem Karaca, Tanyel Zübarioğlu, Emine Genç, Havva Yazıcı, Fatma Derya Bulut, Şebnem Kılıç, Hanım Aghakıshılı, Fehime Erdem Karapınar, Ezgi Burgaç, Ertuğrul Kıykım, Alperen Elek, Nihal Kardaş, Ekrem Ünal, Tuba Hilkay Karapınar, Meryem Albayrak, Canan Albayrak, Ayşegül Ünüvar, Saskia B Wortmann, Deniz Yılmaz Karapınar","doi":"10.1002/jimd.70198","DOIUrl":"10.1002/jimd.70198","url":null,"abstract":"<p><p>Neutrophil dysfunction and neutropenia are burdensome findings in glycogen storage disease type Ib (GSDIb). Treatment with granulocyte-colony stimulating factor (G-CSF) often corrects neutropenia but fails to improve clinical symptoms like inflammatory bowel disease (IBD). Recently, empagliflozin (EMPA) was shown to correct the neutrophil dysfunction and its clinical consequences. It is increasingly used as first-line monotherapy, but long-term, real-world data are lacking. This nation-wide retrospective study investigated 42 GSD1b patients (36 children) treated with EMPA as first-line monotherapy and compared them with those receiving combination therapy with G-CSF and treatment-naïve patients (I:EMPA first-line monotherapy [n = 9]; II:G-CSF monotherapy [n = 7]; III:EMPA plus G-CSF [n = 16]; and IV: neither EMPA nor GCSF [n = 10]). Pediatric (P) patients were evaluated separately. In pediatric patients receiving EMPA as first-line monotherapy (P-I) and those with EMPA plus G-CSF (P-III), the frequency of infections, hospital admissions, and IBD was significantly lower than in patients receiving GCSF-monotherapy (P-II) or no treatment (P-IV). Additionally, significantly improved weight gain was observed in P-I. While clinical improvement related to correction of neutrophil dysfunction was seen with EMPA first-line monotherapy (P-I), significant improvement in absolute neutrophil count (ANC) and hemoglobin levels was only seen in P-III with additional G-CSF treatment. In three cases, EMPA was safely paused and subsequently resumed, for example, during pregnancy or liver transplantation. First-line EMPA monotherapy effectively corrects clinical symptoms of neutrophil dysfunction in GSD Ib patients, even in the absence of a statistically significant increase in ANC.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70198"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147815443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Survival and Clinical Progression in Barth Syndrome: Insights From the Barth Syndrome Foundation's Database of 502 Affected Individuals.","authors":"Kexin Fu, Yonglin Huang, Valerie Bowen, Katherine McCurdy, Reina B Tan, Colin K L Phoon, Lindsay Marjoram, Alex Dahlen","doi":"10.1002/jimd.70189","DOIUrl":"10.1002/jimd.70189","url":null,"abstract":"<p><p>Barth syndrome (BTHS; OMIM 302060) is an ultra-rare, life-limiting genetic disorder characterized by cardiomyopathy, skeletal muscle myopathy, neutropenia, gastrointestinal issues, and fatigue. Formal analyses of survival and clinical progression remain limited. Barth Syndrome Foundation has maintained an intake database (n = 502), representing > 80% of the known global population, as well as a patient-inputted registry for a subset of individuals (n = 162) with up to 11 years of longitudinal outcome data. We estimate the survival curve, identify factors associated with mortality, characterize clinical manifestations over time, and evaluate causes of death. Death disproportionately affected young children, with a 59% transplant-free survival rate for those age < 5. The risk of death plateaued between ages 5-25 before rising again. Heart transplantation (HR = 0.316, 95% CI: 0.162-0.619, p < 0.001) and living in a developed country (HR = 0.109, 95% CI: 0.018-0.659, p < 0.05) were associated with reduced risk of death. Clinical manifestations increased with age, with musculoskeletal/fatigue (66%) being most frequent. Top causes of death were cardiac-related complications, with cardiomyopathy/heart failure (51.3%), mostly in young children < 5, and arrhythmia/cardiac arrest (15%). This is the most comprehensive longitudinal assessment of BTHS survival, mortality risk, and clinical manifestation progression. Early childhood is a period of high mortality risk, driven in large part by heart failure. Although risk of death and hospitalizations plateaued between ages 5-25, the clinical burden of BTHS increases throughout the lifespan. Our results may guide clinical care, identify time windows for optimal intervention, and help clinicians better recognize BTHS clinical features.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70189"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review.","authors":"Bregje Jaeger, Nina N Stolwijk, Femke Aaldering, Charlotte A Ruys, Marije Smits, Nicole I Wolf, Carla E M Hollak, Annet M Bosch","doi":"10.1002/jimd.70190","DOIUrl":"https://doi.org/10.1002/jimd.70190","url":null,"abstract":"<p><p>Riboflavin (RF, vitamin B2) is an essential vitamin of which the co-factors are critical to numerous cellular processes. RF is used as a treatment for inherited metabolic diseases (IMDs), although its effectiveness in many disorders has not been established. We aim to summarize all available data on the efficacy and safety of RF in the management of IMDs. A systematic literature search was conducted for articles reporting the effectiveness of RF in IMDs. RF therapy was considered \"effective\" in an IMD if more than 75% of patients showed a positive response, \"uncertain\" in case of a positive response in fewer than 75% of patients, and \"not effective\" if patients deteriorated or died following RF therapy. RF therapy was reported in 381 articles addressing 33 separate IMDs. A positive effect was established in MADD type 3 (n=536, 93.1% responsive), RTD 2,3 (n = 94, 90.4% responsive), ACAD 9 (n = 29, 75.9% responsive), and FAD transporter deficiency (n = 5, 100% responsive). The effect was uncertain in complex I and II deficiency, ethylmalonic encephalopathy, FAD synthase deficiency, glutaric aciduria type 1, L2 hydroxyglutaric aciduria, and MADD type 2. RF was not effective in MADD type 1. Adverse effects were infrequent and mild. RF therapy in MADD type 3, RTD 2 and 3, ACAD9, and FAD transporter deficiency is safe and effective. Access to RF for these patients is crucial. For a substantial group of IMDs, the effect of RF remains uncertain. In these conditions, a trial of RF therapy with clearly defined outcome criteria might be considered.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70190"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-Term Oral Spermidine Supplementation Modifies Aspects of Neurodegenerative Disease in Flies and Mice With MPS III.","authors":"Helen Beard, Sonia Dayan, Karissa Barthelson, Laura Hewson, Louise V O'Keefe, Kim M Hemsley","doi":"10.1002/jimd.70195","DOIUrl":"10.1002/jimd.70195","url":null,"abstract":"<p><p>Mucopolysaccharidosis type III (MPS III) is a group of autosomal recessive neurodegenerative lysosomal storage disorders that causes progressive cognitive and physical impairment, predominantly in child/early adulthood. The median age of death is 17 years as there is no safe, effective treatment approved. Using faithful Drosophila and murine models of MPS III, we have characterised the MPS IIIA and MPS IIIC fly metabolome, explored the ability of oral spermidine supplementation to ameliorate clinical disease in the fly models and explored its mechanism of action in MPS IIIA mice. Spermidine is a polyamine naturally synthesised by the body. Its manufacture decreases with age. Supplementation has been reported to stimulate autophagy, reduce cell senescence and increase health/lifespan. The metabolomic evaluation confirmed that whole MPS IIIA and MPS IIIC flies exhibit a progressively deranged metabolome. Significantly up-regulated metabolites were those involved in nucleotide and purine metabolism. The most significantly down-regulated metabolites were those involved in ascorbate and aldarate metabolism. Further, spermidine levels decreased significantly in all fly genotypes with age. In short-term studies, food enriched with 5 mM spermidine improved overall fly activity and climbing ability. A 4-week study in pre-symptomatic MPS IIIA mice (3- or 6-mM spermidine, supplemented in drinking water) revealed no improvement in microgliosis or lysosomal compartment size; however, we observed a significant reduction in the astroglial response in the brain, which is believed to drive disease progression. Longer-term confirmatory studies in larger cohorts of MPS III animals are now warranted to determine whether spermidine supplementation is of benefit in preventing or slowing clinical disease in this and other childhood dementias.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70195"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13125739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}