Journal of Inherited Metabolic Disease最新文献

{"title":"Metabolism Controls the Timing of Human Brain Development and Maturation","authors":"Valentina Rava,&nbsp;Erica Cannone,&nbsp;Maura Francolini,&nbsp;Elena Taverna","doi":"10.1002/jimd.70180","DOIUrl":"10.1002/jimd.70180","url":null,"abstract":"<p>Among primates the human brain is the largest in size, exhibiting a higher neuronal density and connectivity. The prolonged expansion and subsequent connectome reorganization of the human brain have been suggested to promote higher cognitive and behavioral abilities. The notable variations in cognitive functions between human and nonhuman primates do not exclusively reside in neuronal abundance and connectivity but are also linked to a higher complexity in glial cells' morphology and functions at earlier time points, during embryonic brain development. Here we discuss two features of the human brain and their reciprocal connection. One feature is the high metabolic need of the developing and adult human brain. The other is its prolonged maturation, also known as neoteny. Even though the human brain occupies only a small percentage of the body mass, it is the highest consumer of glucose and oxygen. Among all brain cells, neurons have a great energy demand. Comparative studies suggest that increased glucose consumption and energy metabolism are positively correlated with higher cognitive abilities in humans. In line with the essential role of metabolism as a regulator of brain functions, recent breakthrough works have uncovered the correlation between metabolism and the timing of brain and neuron maturation during evolution. In this review, we specifically focus on the role of time in the evolution of the human brain and its synapses, focusing on the involvement of tissue, cellular, and subcellular metabolism.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13033476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147574336","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":"Heritability of Long-Term Complications in Classic Galactosemia","authors":"Olivia S. Garrett,&nbsp;Nicole H. Smith,&nbsp;David J. Cutler,&nbsp;Yuhan Wu,&nbsp;Ina Knerr,&nbsp;Doireann Pereira,&nbsp;M. Estela Rubio-Gozalbo,&nbsp;E. Naomi Vos,&nbsp;Megan Harrison,&nbsp;Kara Pappas,&nbsp;David Coman,&nbsp;Karolina M. Stepien,&nbsp;Daniela Karall,&nbsp;Julian Margreitter,&nbsp;Sabine Scholl-Bürgi,&nbsp;Madison A. Heisler,&nbsp;Christina Lam,&nbsp;Maria R. Mills,&nbsp;Emilia Bélanger,&nbsp;Andrea C. Yu,&nbsp;Judith L. Fridovich-Keil","doi":"10.1002/jimd.70181","DOIUrl":"10.1002/jimd.70181","url":null,"abstract":"<div>\u0000 \u0000 <p>As a group, patients with classic galactosemia (CG) demonstrate a high prevalence of long-term complications despite early detection and life-long dietary restriction of galactose, which is the current standard of care. Individual outcomes, however, vary widely. For decades, research teams have sought to identify potential environmental, metabolic, and/or galactose-1-phosphate uridylyltransferase (<i>GALT</i>) allelic differences that might explain this variability—with limited success. Among large cohorts, only severe brain-related disease in infancy has been associated with increased prevalence of complications, and only the presence of predicted or detected residual GALT activity has been associated with decreased prevalence. While significant, these factors fail to account for the majority of long-term outcome variability in CG. Here, we tested whether genetic factors, both inside and outside the <i>GALT</i> locus, might contribute to variability in speech/voice/language, cognitive, and/or motor outcomes among patients. Specifically, we compared outcomes among 66 sets of affected siblings who share both <i>GALT</i> genotype and genetic background, 54 unrelated CG patients who share <i>GALT</i> genotype (p.Gln188Arg/p.Gln188Arg) but not genetic background, and 52 unrelated CG patients who share neither <i>GALT</i> genotype nor genetic background. Heritability estimates for all three complications demonstrate substantial genetic contributions, with point estimates of 100% heritability for all three. Less than 8% of this heritability appears due to residual GALT activity from hypomorphic <i>GALT</i> alleles. Combined with prior data demonstrating clustering of all three outcomes, these results offer compelling evidence for the existence of genetic modifiers of developmental outcomes in CG beyond the <i>GALT</i> locus.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147574371","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":"Dietary Protein Modulation, Gut Microbiota, and Metabolic Control in Methylmalonic Acidemia: A Prospective Longitudinal Study","authors":"Engin Köse,&nbsp;Berkay Yekta Ekren,&nbsp;Neslihan Doğulu,&nbsp;Furkan Yolcu,&nbsp;Cemil Can Eylem,&nbsp;Emirhan Nemutlu,&nbsp;Uğur Sezerman,&nbsp;Fatma Tuba Eminoğlu","doi":"10.1002/jimd.70172","DOIUrl":"10.1002/jimd.70172","url":null,"abstract":"<div>\u0000 \u0000 <p>Methylmalonic acidemia (MMA) is a rare inherited metabolic disorder caused by defective conversion of methylmalonyl-CoA to succinyl-CoA. Emerging evidence suggests that both dietary protein composition and intestinal microbiota influence metabolic stability and clinical outcomes. This study aimed to evaluate the effects of stepwise dietary modification and short-term metronidazole therapy on systemic and gut-derived metabolic profiles in MMA. In this prospective, longitudinal, single-center study, eight genetically confirmed MMA patients underwent four sequential phases: baseline mixed-protein diet (50% intact protein/50% medical formula), protein restriction, intact protein enrichment (80% intact protein/20% medical formula), and adjunctive metronidazole therapy (20 mg/kg/day, 10 days/month for 3 months). Plasma amino acids, urinary metabolites, stool microbiota (16S rRNA long-read sequencing), and untargeted/tandem metabolomic profiles were analyzed at each phase. Transition to an intact protein-enriched diet significantly reduced plasma leucine levels (<i>p</i> = 0.008) without affecting isoleucine or valine. Urinary methylmalonic acid, 3-hydroxypropionate, lactate, and pyruvate decreased, indicating improved propionyl-CoA clearance. Microbiota diversity progressively declined, accompanied by reductions in butyrate-producing genera (Novisyntrophococcus, Lacrimispora, Hespellia). Metronidazole further lowered urinary methylmalonic acid and 3-hydroxypropionate (<i>p</i> = 0.017 and <i>p</i> = 0.028), with parallel decreases in fecal 3-indolelactic acid and phytosphingosine, suggesting suppression of gut-derived propionate and tryptophan metabolism. Despite antibiotic-induced dysbiosis with expansion of Trabulsiella (Proteobacteria), systemic propiogenic burden decreased. A phased dietary regimen emphasizing intact protein, combined with intermittent metronidazole therapy, favorably modulated biochemical and microbial parameters in MMA. These findings support microbiome-informed dietary strategies and selective gut-targeted interventions to optimize metabolic control in organic acidemias.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 2","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147433242","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":"Advances in Therapeutics—Enzyme Replacement Therapy: Long-Term Evaluation and New Approaches","authors":"Robin Lachmann","doi":"10.1002/jimd.70166","DOIUrl":"10.1002/jimd.70166","url":null,"abstract":"<div>\u0000 \u0000 <p>The first enzyme replacement therapy (ERT) for a lysosomal storage disorder was marketed more than 30 years ago. We now have licensed products for 12 different conditions, and for a number of conditions, up to three different preparations are commercially available. These products were licensed on the basis of their ability to achieve pre-defined endpoints in clinical trials, but many have now been in clinical use for decades, and large amounts of real-world evidence have been generated. This has shown that not all treatments are equally effective and that there is still much unmet need, even for patients who have been treated for many years. Second-generation enzyme therapies are now being designed that will hopefully lead to improved clearance from currently hard-to-access cells and tissues, hence improving long-term clinical outcomes.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 2","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147432963","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":"Organoids for Metabolic Disease Modeling","authors":"Arif Ibrahim Ardisasmita,&nbsp;Edward Eelco Salomon Nieuwenhuis,&nbsp;Sabine Annemijn Fuchs","doi":"10.1002/jimd.70164","DOIUrl":"10.1002/jimd.70164","url":null,"abstract":"<p>Inherited metabolic diseases (IMDs) are a diverse group of rare genetic disorders that disrupt metabolic pathways, leading to severe clinical manifestations. Disease models ranging from complex animal models to simple in vitro systems have provided insights into IMDs, but each has limitations. Organoids, three-dimensional in vitro models, bridge this gap by replicating key metabolic functions that are absent in most simple 2D cell models. While organoids do not fully mimic organ complexity, they effectively model disease-specific metabolic defects, as seen in methylmalonic acidemia, Wilson's disease, and cystic fibrosis. Recognizing that function is more critical than organ resemblance, we propose focusing on the specific function of interest rather than selecting a model solely based on its derivation from the most affected organ. Focusing on specific biological processes enables precise, disease-relevant studies that drive novel therapeutic strategies and personalized medicine.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 2","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12974558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147433278","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":"Signal Peptide Engineering and Codon Optimization to Enhance α-Gal A Activity for rAAV Gene Therapy of Fabry Disease","authors":"Siwu He,&nbsp;Li Yang,&nbsp;Ke Wan,&nbsp;Zhaoyue Zheng,&nbsp;Mi Leng,&nbsp;Chunmei Gan,&nbsp;Yu Liu,&nbsp;Lin Xiao,&nbsp;Jingya Ye,&nbsp;Zhian Chen,&nbsp;Jiao Zhou,&nbsp;C. Alexander Valencia,&nbsp;Aliah Abuammah,&nbsp;Hoi Yee Chow,&nbsp;Biao Dong,&nbsp;Yucheng Chen","doi":"10.1002/jimd.70168","DOIUrl":"10.1002/jimd.70168","url":null,"abstract":"<p>Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the <i>GLA</i> gene, leading to deficient α-galactosidase A (α-Gal A) activity and pathological accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3) in various organs. To enhance α-Gal A expression and secretion for recombinant adeno-associated viral (rAAV) gene therapy, the signal peptide was engineered in HepG2 cells. Among 22 heterogeneous signal peptides, sp21 was identified and validated for this purpose. The enzyme activity of <i>GLA</i> with sp21 in conditioned media was 2.3 times higher than that with the wild-type signal peptide. Furthermore, the human <i>GLA</i> gene was codon optimized (hGLAco), aiming to achieve increased hepatic expression and prevent gene silencing. The secreted α-Gal A activity of hGLAco increased approximately 4-fold in vitro. Finally, the hGLAco transgene with sp21 driven by a liver-specific promoter was packaged in rAAV8 vectors and injected into Fabry mice. Compared with the wild-type cDNA, the engineered <i>GLA</i> gene resulted in a 6.9-fold increase in secreted α-Gal A activity in Fabry mice, and toxic Lyso-Gb3 accumulation in plasma and key tissues was effectively cleared. These findings demonstrate a promising strategy to develop a more efficient rAAV gene therapy for Fabry disease.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 2","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12971190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147390318","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":"Safety and Effectiveness of Pharmacy Compounded Chenodeoxycholic Acid Capsules for Patients With Cerebrotendinous Xanthomatosis","authors":"Natalja Bouwhuis,&nbsp;Soumia Majait,&nbsp;Yasmin Polak,&nbsp;Aylene de Jong,&nbsp;Bart A. W. Jacobs,&nbsp;Frédéric M. Vaz,&nbsp;Willemijn G. Leen,&nbsp;E. Marleen Kemper,&nbsp;Eleonora L. Swart,&nbsp;Carla E. M. Hollak","doi":"10.1002/jimd.70170","DOIUrl":"10.1002/jimd.70170","url":null,"abstract":"<p>Chenodeoxycholic acid (CDCA) is an essential drug for patients with rare metabolic disease cerebrotendinous xanthomatosis (CTX). To ensure continuation of treatment, the Amsterdam UMC hospital pharmacy developed pharmacy compounded CDCA capsules when the authorized CDCA capsules were no longer available for Dutch patients. This study reports the safety of pharmacy compounded CDCA through pharmacovigilance monitoring and assesses its effectiveness by evaluating biochemical outcome measures, both in patients who were previously treated with authorized CDCA and subsequently switched to the compounded formulation and in new patients. Data were generated during routine patient care and collected retrospectively. Adverse events were reported by 45% of the patients; the most reported adverse events were diarrhea (16%), constipation (7%), and fatigue (7%). Biochemically, plasma cholestanol levels and urinary bile alcohol levels remained normalized before and after switching from the authorized product to pharmacy compounded capsules. It can be concluded that the pharmacy compounded CDCA capsules are well tolerated by patients with CTX and that the desired biochemical effect was maintained, supporting the use of a compounded formulation when the authorized product is unavailable.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 2","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12967102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147372747","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":"Long-Term Follow-Up of Patients With Transaldolase Deficiency.","authors":"M Scaglione, A Brassier, A Wiedemann, I Jankowska, J Pawłowska, T Lamireau, L Bridoux-Henno, C Douillard, T Casswall, U Cucinotta, M Gaschignard, P Socha, F Feillet, B Fischler, D Samara-Boustani, M C Schiaffino, M Schiff, P De Lonlay, F Lacaille","doi":"10.1002/jimd.70173","DOIUrl":"10.1002/jimd.70173","url":null,"abstract":"<p><p>Transaldolase (TALDO) deficiency has a well-characterized phenotype. However, there are few large cohort studies, and little is known about the long term, including the need for organ transplantation. Our aim was to share a long multicenter experience in managing these patients. We retrospectively collected data on 16 patients followed for up to 20 years. Liver involvement was present in all patients, with six presenting liver failure at birth. During long-term follow-up, 10 patients developed cirrhosis and four underwent liver transplantation (LTx). Two patients died from severe liver failure in the first months of life; persistent weight below 4 kg precluded LTx. A third patient died from posttransplant complications at 6 months of life. Five patients developed chronic kidney failure, and in two of them kidney transplantation was considered after the age of 20 years. Patent foramen ovale (PFO) was the most frequent cardiac finding; cardiomyopathy or ventricular dysfunction was diagnosed in five patients. Twelve patients developed chronic cytopenia, all presenting with thrombocytopenia. Hypergonadotropic hypogonadism was found in seven patients; two others developed secondary adrenal cortisol insufficiency and primary hypothyroidism requiring replacement therapy. Mild neurocognitive delay was observed only in a few cases. We described different patterns of liver disease progression. Transplantation should be early considered if indicated for liver insufficiency; in the most severe patients with neonatal onset, achieving sufficient weight for transplantation may be challenging. Our preliminary data suggest that, in older patients, kidney involvement may also warrant consideration of kidney transplantation, which was not previously described for this disease.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 2","pages":"e70173"},"PeriodicalIF":3.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12983187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147443853","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":"Tyrosine Hydroxylase Deficiency Impairs TH Axonal Transport, Brain Function, and Neuronal Plasticity.","authors":"Tie-Jun Sten Shi, Kunwar Jung-Kc, Gong-Wei Lyu, Liang Han, Ming Ying, Beat Thöny, Aurora Martinez","doi":"10.1002/jimd.70169","DOIUrl":"10.1002/jimd.70169","url":null,"abstract":"<p><p>Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder caused by biallelic pathogenic variants in the Th gene, leading to a deficiency in the rate-limiting enzyme for the synthesis of dopamine (DA) and other catecholamine neurotransmitters. THD is associated with dystonia and infantile parkinsonism with a broad and complex spectrum and variable response to l-Dopa therapy. TH1-p.R202H is a frequent THD variant that affects TH stability and activity. The Th knock-in (Th-ki) mice with the equivalent mutation (Th-p.R203H) present reduced TH and DA levels, biological and molecular alterations, different phosphorylation patterns and altered distribution of dopaminergic markers relative to wild-type mice. Th-ki mice displayed significantly reduced TH, especially in the striatum, but also in the cortex, olfactory bulb, cerebellum, substantia nigra, globus pallidus, and spinal cord, a decrease that is not associated with dopaminergic neuronal degeneration. No changes were observed in Th-mRNA expression, and the decreased level of TH in the concrete brain areas in Th-ki mice appears to be due to defective TH protein axonal transport. Moreover, we characterized the development of dopaminergic neurons in the substantia nigra and neuronal plasticity in various brain regions. Our results indicated that alterations in TH expression within specific striatal GABAergic interneurons due to TH deficiency may potentially disrupt the balance of inhibitory neurotransmission in the striatum. Overall, our findings demonstrate that TH deficiency disrupts striatal inhibitory circuitry and triggers compensatory neuronal plasticity, without causing neuronal degeneration.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 2","pages":"e70169"},"PeriodicalIF":3.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13008827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504227","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":"Acute Neurological Complications After Transplantation in Methylmalonic Acidemia: A 35-Patient French Cohort.","authors":"Adélaïde Vissac, Eugénie Sarda, Charles-Joris Roux, Manuel Schiff, Claire-Marine Bérat, Juliette Bouchereau, Jean-Baptiste Arnoux, Chloé de Puyraimond, Margaux Gaschignard, Tristan Mekdade, Ugo Cucinotta, Claire Mayer, Valérie Barbier, Jean François Benoist, Mehdi Oualha, Carmen Capito, Christophe Chardot, Myriam Dao, Aude Servais, Claire Francoz, Laurène Dehoux, Florence Lacaille, Isabelle Desguerre, Nathalie Boddaert, Pascale de Lonlay, Anaïs Brassier","doi":"10.1002/jimd.70165","DOIUrl":"10.1002/jimd.70165","url":null,"abstract":"<p><p>Transplantation is an effective therapeutic option to improve quality of life in patients with severe methylmalonic acidemia (MMA). However, data regarding neurological complications following transplantation remain limited. A retrospective, single-center study was conducted at Necker Hospital (France), including MMA patients who underwent kidney (KT), liver (LT), or liver-kidney transplantation (LKT) between 2007 and 2022. Our aim was to evaluate acute neurological complications occurring after transplantation, focusing on clinical features, laboratory parameters and neuroimaging. Sensorineural complications were also assessed. Thirty-five patients were included, 21 had undergone LKT, 10 LT and 4 KT. The median age at transplantation was 10.1 years, with a median follow-up of 5 years. Tacrolimus was used in 91% of patients. Acute neurological complications likely related to MMA occurred in 17% of patients. They include Leigh syndrome with identifiable triggers, observed in 4 patients (2 early and 2 late-post-transplantation), leading to one early- and one late-onset death. Stroke-like episodes occurred in 2 patients. Non-epileptic myoclonus, likely related to calcineurin inhibitor (CNI), were reported in 31% of patients. Pre-transplant brain MRI showed nonspecific abnormalities in 31% of patients and remained stable afterwards. Post-transplant ophthalmological data available for 17 patients showed 3 optic atrophies. No acute vision or hearing loss was reported. Although transplantation improves metabolic control in MMA, acute neurological complications can still occur following a triggering event, even years after transplantation. The risk may arise from sensitivity to CNI-induced neurotoxicity. Pre- and post-transplant neuroimaging, emergency metabolic protocols, and tailored immunosuppression are essential for long-term management.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 2","pages":"e70165"},"PeriodicalIF":3.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12984472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147443631","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}