Journal of Inherited Metabolic Disease最新文献

{"title":"Results From a Phase 2, Open-Label Study Evaluating the Safety, Tolerability, and Effect on Ataxia of GLM101 in Three Adult Patients With PMM2-CDG","authors":"Mercedes Serrano,&nbsp;Florencia Epifani,&nbsp;Rose Marino,&nbsp;Peter McWilliams","doi":"10.1002/jimd.70240","DOIUrl":"10.1002/jimd.70240","url":null,"abstract":"<p>Phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG) is a rare, autosomal recessive disease caused by PMM2 deficiency, which impairs conversion of mannose-6-phosphate into mannose-1-phosphate (M1P) and disrupts N-linked glycosylation. It typically results in a multisystem disorder in which a prominent cerebellar syndrome, characterized by ataxia among other clinical manifestations, can be assessed using the International Cooperative Ataxia Rating Scale (ICARS). GLM101 is a liposomal M1P substrate replacement therapy in clinical development. We present results conducted both within and outside the protocol-defined schedule from three adult patients enrolled in a Phase 2 study evaluating the efficacy, safety, and tolerability of GLM101 (NCT05549219). PMM2-CDG patients received weekly infusions of 30 mg/kg GLM101 for 24 weeks. Ataxia was measured by ICARS as standard of care. Absolute and percent change from baseline were calculated. Additional results reported include global impression of change scales (caregiver and clinician) and safety. Three adult patients (1 M, 2 F) completed 24 weeks of treatment. The mean (SD) baseline ICARS was 50.7 (19.0) and mean (SD) change from baseline was −14.0 (7.2) and −17.7 (3.1) at Weeks 12 and 24, respectively. Improvements were seen across all ICARS subdomains. All patients and clinicians reported global clinical improvement. GLM101 was well tolerated with no serious adverse events. Infusion-associated reactions were reported in one patient, with no need to interrupt the therapy. Safety findings showed no adverse trends. In conclusion, GLM101 was well tolerated and demonstrated potential for meaningful clinical benefit. These findings support continued evaluation of GLM101 in patients with PMM2-CDG.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900690","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":"Mitochondrial CLPP in Health and Disease: Mechanisms, Therapeutic Duality and Emerging Opportunities","authors":"Lea Isermann,&nbsp;Aleksandra Trifunovic","doi":"10.1002/jimd.70247","DOIUrl":"10.1002/jimd.70247","url":null,"abstract":"<p>Mitochondrial CLPP has emerged as an unusual therapeutic target because both increasing and decreasing its proteolytic activity can be beneficial, depending on the cellular and disease context. Pharmacological CLPP hyperactivation drives broad degradation of mitochondrial proteins and can selectively collapse mitochondrial fitness in susceptible tumor cells, an approach now clinically validated by the approval of dordaviprone for mutant diffuse midline glioma. Conversely, reduced CLPP activity can preserve respiratory-chain components and promote adaptive metabolic and redox remodelling in selected models of mitochondrial disease, neurodegeneration and metabolic dysfunction, with emerging potential in ischaemia-reperfusion injury. These opposing outcomes reflect the broader role of CLPXP in controlling mitochondrial translation, respiratory-chain integrity and metabolism rather than acting simply as a general protein quality-control system. In this review, we discuss the physiological functions and substrate selectivity of CLPXP, the mechanistic basis and clinical development of CLPP inhibitors and activators, and the growing evidence that therapeutic responses depend strongly on tissue identity, metabolic state and the nature of the underlying mitochondrial defect. Together, these findings position CLPP as a context-dependent therapeutic switch whose activity may need to be tuned in opposite directions to either preserve mitochondrial resilience or selectively dismantle mitochondrial fitness.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880864","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":"Sarcopenia in Pediatric Intoxication Type Inborn Errors of Metabolism: A Frequent and Underrecognized Condition.","authors":"Silvio Veraldi, Maria Sole Basso, Giovanna Soglia, Riccardo Cirelli, Gionata Spagnoletti, Silvia Maria Bernabei, Alessia Esposito, Cristiano Rizzo, Sara Cairoli, Diego Martinelli, Lidia Monti, Marco Spada, Andrea Pietrobattista, Carlo Dionisi-Vici","doi":"10.1002/jimd.70250","DOIUrl":"10.1002/jimd.70250","url":null,"abstract":"<p><p>Sarcopenia is increasingly recognized in pediatric chronic diseases, yet its prevalence and determinants in children with intoxication-type inborn errors of metabolism (IEM) have never been investigated. This study aimed to evaluate sarcopenia in this population and to investigate associated metabolic alterations. We conducted a retrospective single-center study including 45 pediatric patients (0-18 years) with maple syrup urine disease (MSUD, 11 pts.), organic acidurias (OA, 22 pts.), or urea cycle defects (UCD, 12 pts.) considered for liver transplantation. Sarcopenia was defined as total psoas muscle area z-score ≤ -2 on CT scan. Anthropometric, dietary, and laboratory parameters were analyzed. Forty percent of patients exhibited sarcopenia, most frequently among OA (54.5%) and UCD (33.3%), and only occasionally in MSUD (18.2%). Sarcopenic children showed lower weight, height, and were more likely to require enteral nutritional support. Plasma levels of essential amino acids, particularly branched-chain amino acids (leucine, isoleucine, valine), histidine, and glutamine, were significantly reduced in sarcopenic patients. Leucine emerged as an independent predictor of sarcopenia (p = 0.016). FGF21 levels were elevated in sarcopenic OA and UCD patients, whereas MSUD patients with higher branched-chain amino acids levels showed lower FGF21, suggesting a role beyond mitochondrial stress signaling. Sarcopenia is common in pediatric patients with severe intoxication-type IEM and is closely linked to essential amino acid deficiencies and altered FGF21 signaling. These monogenic diseases provide unique pathophysiological models for better understanding of sarcopenia. Our findings highlight the need for targeted nutritional and metabolic strategies to preserve muscle mass in these vulnerable patients.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":"e70250"},"PeriodicalIF":3.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13559199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148919301","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":"Longitudinal Assessment of Cognitive Development in 23 Patients With Mucopolysaccharidosis (MPS) Type II: Results of up to 14 Years of Follow-Up.","authors":"J Julia Holdorp, M E Michelle Kruijshaar, A A M Audrey Vollebregt, A B Andre Rietman, M R K Marianne Dijkstra, C Carina Klees, M Margreet Wagenmakers, A H P Annie Nguyen, E Esmee Oussoren, A T Ans van der Ploeg, J M P Hannerieke van den Hout","doi":"10.1002/jimd.70246","DOIUrl":"10.1002/jimd.70246","url":null,"abstract":"<p><p>This study investigated long-term cognitive development and genotype-phenotype relationships in patients with Mucopolysaccharidosis Type II (MPS II). A nationwide prospective cohort study was conducted in the Netherlands with cognitive follow-up since 2007. Patients were classified as neuronopathic or non-neuronopathic based on iduronate-2-sulphatase (IDS) genotype; novel variants based on age and intelligence quotient (IQ). IQ and Mental Age (MA) were analysed individually and, using linear mixed-effect models, at group level to compare trajectories by genotype and phenotype. Twenty-three male patients (22 children, 1 adult) underwent 136 cognitive assessments, beginning at a median age of 2.9 years with a median follow-up of 6.3 (range 0-13.5) years. IQ and MA trajectories significantly differed between neuronopathic and non-neuronopathic patients (p < 0.001). Non-neuronopathic patients (n = 5) showed normal or mildly impaired cognition. Neuronopathic patients (n = 18) initially developed normally, then stagnated, plateaued, and declined; IQ fell below 70 at a median age of 4 years. Patients with deletions (n = 3) experienced the earliest, most severe impairment (p < 0.001), while those with other IDS variants showed more variable trajectories. Neurocognitive patterns diverge early in MPS II, highlighting the importance of understanding genotype-specific developmental trajectories. This insight is essential for guiding timely brain-targeted interventions, ideally initiated before neurocognitive decline begins.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":"e70246"},"PeriodicalIF":3.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13562982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930022","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":"Revisiting Enzyme Replacement Therapy for Aspartylglucosaminuria: Truncated Phosphotransferase Enhances Mannose-6-Phosphorylation and Cellular Uptake of Aspartylglucosaminidase","authors":"Antje Banning,&nbsp;Lidia Reznikova,&nbsp;Adla Murad,&nbsp;Ritva Tikkanen","doi":"10.1002/jimd.70248","DOIUrl":"10.1002/jimd.70248","url":null,"abstract":"<p>Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by a deficiency of aspartylglucosaminidase (AGA), a hydrolase involved in the degradation of N-glycosylated proteins. Currently, no approved therapies are available for AGU. Development of enzyme replacement therapy (ERT) for AGU has been hampered by the complex proteolytic processing and activation of the AGA enzyme that involves dimerization and cleavage into two subunits. Targeting of AGA into lysosomes is mainly accomplished by a mannose-6-phosphate receptor-mediated pathway, and both AGA subunits contain phosphorylated N-glycans. In this study, we have developed an overexpression system for an optimized human AGA enzyme and a truncated GlcNAc-1-phosphotransferase, S1S3, that is required for the mannose-6-phosphorylation. We here show that the Man-6-phosphorylation and cellular uptake of AGA are enhanced by the coexpression of S1S3, and high amounts of affinity-tagged recombinant human AGA can be expressed in HEK293T cells and purified from the culture medium. Impairment of the N-glycosylation of AGA results in poor uptake into cells, indicating that the Man-6-dependent route is the main endocytic pathway of AGA. Furthermore, for optimal uptake, both subunits of AGA need to be glycosylated and Man-6-phosphorylated. The results of this study enhance the understanding of the lysosomal targeting mechanisms of AGA and pave the way for the development of ERT for AGU.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13531260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865370","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":"L-Carnitine Prevents Lipopolysaccharide-Induced Inflammatory Response, Microglia Activation and Neuronal Damage in Cerebral Cortex, as Well as Neuromotor Development Delay in Neonatal Glutaryl-CoA Dehydrogenase Deficient (Gcdh^-/-) Mice.","authors":"Ediandra Tissot Castro, Ângela Zanatta, Rafael Teixeira Ribeiro, Diorlon Nunes Machado, Andrey Vinicios Soares Carvalho, Ângela Beatris Zemniaçak, Sâmela de Azevedo Cunha, Tailine Quevedo Tavares, Manuela Bianchin Marcuzzo, Larissa Daniele Bobermin, Carlos Alexandre Netto, Alexandre Umpierrez Amaral, Carmen Regla Vargas, Guilhian Leipnitz, Moacir Wajner","doi":"10.1002/jimd.70253","DOIUrl":"10.1002/jimd.70253","url":null,"abstract":"<p><p>Patients with glutaric acidemia type I (GA I) frequently manifest with acute encephalopathy usually triggered by infections and by progressive neurological deterioration. Since the pathogenesis of the brain damage in GA I during inflammatory processes is poorly established, we investigated biomarkers of inflammatory response and neural damage in the cerebral cortex of wild type (WT) and glutaryl-CoA dehydrogenase (GCDH) deficient mice (Gcdh^-/-) receiving acute lysine and lipopolysaccharide (LPS) administration to induce inflammation. Neuromotor development reflexes and the neuroprotective effects of L-carnitine (Carn), whose potent anti-inflammatory properties have been recently described, were also evaluated. LPS increased the gene expression of most parameters of the inflammatory response, which were normalized or attenuated by Carn both in WT and Gcdh^-/- mice. Importantly, gene expression of TNF-α, IL-6, NFkB, IκBα, COX-2 and VEGF, and heme oxygenase-1 content were significantly increased in LPS-treated Gcdh^-/- relatively to the WT mice. Furthermore, the neuronal biomarker protein NeuN was reduced, whereas the number of vacuoles and neurodegenerative cells were increased in the LPS-treated Gcdh^-/- mice, indicating neuronal damage and loss in these animals. Furthermore, the righting and the gait reflexes were altered in the Gcdh^-/- mice, reflecting impairment of neuromotor development. Finally, Carn prevented LPS-induced inflammation, neuronal damage, vacuolation, increased neurodegenerative cells and the righting reflex. Our findings suggest that inflammation plays an important role in the pathogenesis of the neurological alterations following infectious/inflammatory processes in GA I patients and that higher doses of Carn should be considered during these episodes.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":"e70253"},"PeriodicalIF":3.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13590905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012477","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":"International Guideline on the Diagnosis, Treatment, and Monitoring of Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD).","authors":"Sarah C Grünert, Kaustuv Bhattacharya, Daniela Karall, Mirjam Langeveld, Fran Rohr, Gepke Visser, Jerry Vockley, Aileen Kenneson, Rani H Singh, Ute Spiekerkoetter","doi":"10.1002/jimd.70251","DOIUrl":"10.1002/jimd.70251","url":null,"abstract":"<p><p>Long-chain fatty acid oxidation disorders (LC-FAOD) are rare inherited defects of mitochondrial β-oxidation that impair energy generation during fasting or metabolic stress. Clinical manifestations range from neonatal hypoketotic hypoglycemia and cardiomyopathy to hepatopathy, recurrent rhabdomyolysis, and chronic myopathy. Although newborn screening (NBS) enables early detection, management remains inconsistent due to limited evidence, broadening phenotypic spectrum, and regional practice variation. An international multidisciplinary workgroup of 34 members, including clinicians, nurses, dietitians, and patient representatives, systematically reviewed the literature (1990-2022) using PubMed, Embase, and Web of Science. Evidence was graded using an adapted Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, and consensus was achieved through a modified Delphi-Nominal Group-Delphi methodology, with agreement defined as ≥ 75%. Especially when evidence was low, expert consensus was the basis for this guideline. Recommendations address diagnosis, dietary management, fasting tolerance, use of medium-chain fat sources, exercise and illness protocols, pregnancy care, and long-term monitoring. Evidence quality ranged from very low to moderate. Strong consensus was reached for critical clinical interventions. Standardized approaches for diagnostic work-up, management during metabolic stress, and follow-up monitoring were developed to promote uniform care across age groups, disease groups, and phenotypic severity. This international guideline integrates available evidence and expert consensus to provide standardized recommendations for diagnosis, treatment and lifelong management of LC-FAOD. They aim to harmonize clinical practice, improve patient outcomes, and support global implementation of evidence-based metabolic care.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":"e70251"},"PeriodicalIF":3.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030745","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":"Phase 3 Randomized Trial Results of DTX401 AAV Gene Therapy for the Treatment of GSDIa","authors":"John J. Mitchell,&nbsp;Jose E. Abdenur,&nbsp;Foekje de Boer,&nbsp;Monica Boyer,&nbsp;Margo Sheck Breilyn,&nbsp;María-Luz Couce,&nbsp;Diva D. De Leon,&nbsp;Terry G. Derks,&nbsp;Areeg El-Gharbawy,&nbsp;Andrea B. Haijer-Schreuder,&nbsp;Karen Loechner,&nbsp;Nicola Longo,&nbsp;Allan M. Lund,&nbsp;Miguel Angel Martinez Olmos,&nbsp;Shawn E. McCandless,&nbsp;Bibiana Mello de Oliveira,&nbsp;Malaya Mount,&nbsp;Nicole Muschol,&nbsp;Kristina Pytlak,&nbsp;Kadakkal Radhakrishnan,&nbsp;Rebecca Riba-Wolman,&nbsp;David F. Rodriguez-Buritica,&nbsp;Alessandro La Rosa,&nbsp;Alessandro Rossi,&nbsp;Heather Saavedra,&nbsp;René Santer,&nbsp;Brian Shayota,&nbsp;G. Peter A. Smit,&nbsp;Carolina F. Moura De Souza,&nbsp;Melanie M. van der Klauw,&nbsp;David A. Weinstein,&nbsp;Joseph I. Wolfsdorf,&nbsp;Anne Blake,&nbsp;Andrew A. Grimm,&nbsp;Deepali Mitragotri,&nbsp;Syeda Rahman,&nbsp;Diane M. Turner-Bowker,&nbsp;Richard Collis","doi":"10.1002/jimd.70241","DOIUrl":"10.1002/jimd.70241","url":null,"abstract":"<p>Glycogen storage disease type Ia (GSDIa) is a rare, life-threatening inherited carbohydrate metabolism disorder caused by biallelic pathogenic <i>G6PC</i> gene variants resulting in deficiency of glucose-6-phosphatase. DTX401 is an investigational AAV8 vector containing the human <i>G6PC</i> gene. DTX401-CL301 is a pivotal, phase 3, double-blind, randomized, placebo-controlled trial of DTX401 in patients ≥ 8 years with GSDIa. The primary endpoint was percent change from Baseline to Week 48 in daily cornstarch intake for the DTX401 versus placebo group. Participants were randomly assigned (1:1) to blinded DTX401 or placebo. After the 48-week Primary Efficacy Analysis Period (PEAP), participants crossed over in a blinded manner for an additional 48-week blinded Crossover Period. Following randomization: 21 participants received DTX401; 25 received placebo. At Week 48, DTX401 treatment resulted in a statistically significant least squares (LS) mean (SE) daily cornstarch intake reduction of 41% (4.6) versus 10% (4.1) for Placebo (<i>p</i> &lt; 0.0001). Clinical meaningfulness was evidenced by a mean desired percent reduction in daily cornstarch intake among those reporting in Baseline interviews (<i>n</i> = 33) of 45% (median = 41%). Greater and faster reductions in cornstarch were observed at Week 96 for the Crossover DTX401 group compared with the DTX401 group in the PEAP. The DTX401 safety profile was acceptable, and expected hepatic reactions consisting of transaminase elevations were managed with prophylactic corticosteroids. Treatment with DTX401 resulted in both a statistically significant and clinically meaningful reduction in cornstarch intake in the 48-week PEAP versus placebo, with greater cornstarch reductions in both groups at Week 96.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13529436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865437","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":"Treating a Disorder Caused by an Overactive Enzyme: BCKD-Kinase Deficiency","authors":"Juliana Ribeiro-Constante,&nbsp;Trine Tangeraas,&nbsp;Angeles García-Cazorla","doi":"10.1002/jimd.70242","DOIUrl":"10.1002/jimd.70242","url":null,"abstract":"<div>\u0000 \u0000 <p>Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency is a rare autosomal recessive disorder. Loss of this kinase leaves the branched-chain α-ketoacid dehydrogenase complex constitutively active, leading to depletion of branched-chain amino acids (BCAAs) rather than their accumulation. To date, 31 patients from 20 families have been reported. In the largest systematic series, global developmental delay and intellectual disability are universal, autism spectrum disorder occurs in 71%, epilepsy in 43%, and progressive postnatal microcephaly. Mean age at diagnosis is close to 6 years, partly because the clinical picture resembles many forms of idiopathic neurodevelopmental disability. Treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100–250 mg/kg/day) can normalize plasma BCAA levels and appears to stabilize motor function and head circumference. In the limited data available, three patients who started treatment before age 2 did not develop autism, and the earliest-treated patient (8 months) was developing normally at 3 years of follow-up. However, current therapy has clear limitations. Tracer studies in Bckdk knockout mice show reduced incorporation of BCAA-derived nitrogen into brain glutamate even with dietary intervention, pointing to a gap between peripheral biochemical correction and what the brain actually receives. Emerging strategies include partial pharmacological suppression of BCKDH activity, stabilization of residual mutant BCKDK protein, and gene therapy. Newborn screening, feasible with existing technology, deserves consideration given the contrast in outcomes between early and late treatment. This review examines what current treatment achieves, where it falls short, and what additional strategies may be needed.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840408","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":"Cobalamin-Related Remethylation Disorders: Pregnancy Outcomes and Prenatal Treatment-New Cases and a Literature Study","authors":"Karolina M. Stepien,&nbsp;Jolanta Sykut-Cegielska,&nbsp;Jennifer Sloan,&nbsp;Flavia Piazzon,&nbsp;Sarah Bick,&nbsp;Juliette Bouchereau,&nbsp;Edwin C. Ferren,&nbsp;Nina Gold,&nbsp;Apolline Imbard,&nbsp;Mirian C. H. Janssen,&nbsp;Pavel Jesina,&nbsp;Lisa A. Joseph,&nbsp;Amanda Krzywdzińska-Rogowska,&nbsp;Louise Lapagesse,&nbsp;Fanny Mochel,&nbsp;Carol Van Ryzin,&nbsp;Manuel Schiff,&nbsp;Ida Vanessa Schwartz,&nbsp;Audrey Thurm,&nbsp;Wadih M. Zein,&nbsp;Charles P. Venditti,&nbsp;Martina Huemer,&nbsp;Irini Manoli","doi":"10.1002/jimd.70243","DOIUrl":"10.1002/jimd.70243","url":null,"abstract":"<div>\u0000 \u0000 <p>Cobalamin-related remethylation disorders (cbl-RD) are rare, heterogenous conditions with a wide phenotypic spectrum, including prenatal and early infantile manifestations. Data on pregnancy outcomes in affected women and the efficacy and safety of prenatal treatment of affected fetuses remain limited. Here we report (1) five women with cbl-RDs (3 cblC/epi-cblC, 1 cblD, 1 cblE) who had in total nine pregnancies and (2) eight fetuses with cbl-RD (7 cblC, 1 cblF) diagnosed and treated prenatally. All affected mothers were treated with hydroxocobalamin (OHCbl) during pregnancy and two also received betaine and carnitine. Complications included three preterm deliveries and nephrotic-range proteinuria in one previously undiagnosed mother with cblE. All offspring had favourable outcomes. In pregnancies with affected fetuses, OHCbl was administered to the mother between gestational weeks 5 and 32 at varying doses. Prenatally treated cblC cases exhibited attenuated phenotypes without microcephaly, epilepsy, or severe multisystemic disease. Notably, three of five infants harbouring severe <i>MMACHC</i> variants, who received high-dose pre- and postnatal OHCbl, exhibited normal neurodevelopment and no maculopathy up to age 2–3 years, though variability in genotype, treatment regimens, and duration of follow-up limit generalizability. A literature review identified nine additional pregnancies in women with cbl-RD and seven prenatally treated fetuses, with follow-up available for three. Collectively, our main findings support the safety of maternal and fetal OHCbl treatment during pregnancy. We recommend that when combined with preconception counselling, early standardized diagnosis, optimal monitoring and postnatal care, prenatal OHCbl therapy can improve pregnancy outcomes and mitigate neurodevelopmental and ophthalmic complications in cbl-RD.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818653","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}