Journal of Inherited Metabolic Disease最新文献

{"title":"Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects","authors":"Eva M. M. Hoytema van Konijnenburg,&nbsp;Joline Rohof,&nbsp;Gautam Kok,&nbsp;Peter M. van Hasselt,&nbsp;Clara D. van Karnebeek,&nbsp;Irena J. J. Muffels,&nbsp;Sabine A. Fuchs","doi":"10.1002/jimd.70017","DOIUrl":"https://doi.org/10.1002/jimd.70017","url":null,"abstract":"<p>Aminoacyl-transfer RNA (tRNA) synthetases (ARSs) are key enzymes for protein translation. The number of identified patients with recessive ARS1 deficiencies is rapidly increasing. Initially, only supportive care was available, but in recent years beneficial effects of targeted amino acid supplementation have been described. To allow early treatment and prevention of symptoms, rapid recognition is necessary, as well as insight into the natural history to evaluate treatment effects. We performed a scoping literature search for clinical characteristics and treatment effects of patients with ARS1 deficiencies. Symptoms were matched to Human Phenotype Ontology terms. We identified 438 patients with 20 different ARS1 deficiencies. Overall mortality was 22%. Neurological symptoms were most prevalent across all ARS1 deficiencies (in 87% of patients), including neurodevelopmental disorder (79%), microcephaly (50%) and seizures (46%). Growth issues and ophthalmological symptoms were also prevalent in many ARS1 deficiencies. Two distinct phenotypical clusters were seen: one with multisystemic disease including liver- and lung disease and another with a predominantly neurological phenotype. Supplementation with cognate amino acids was described in 21 patients, with beneficial effects (e.g., improvements in growth, development, liver and lung disease) in the majority. Treatment did not alleviate the most severe phenotypes. Specific symptoms relate to (a cluster of) specific ARS1 deficiencies; the mechanism is not yet understood. Multi-organ involvement should trigger inclusion of ARS1 genes in the diagnostic work-up. Treatment with cognate amino acids is promising, but it remains challenging to distinguish treatment effects from natural history. Synopsis: Treatment with cognate amino acids in ARS1 deficiencies is promising, but it remains challenging to distinguish treatment effects from natural history.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554717","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":"Normothermic Machine Perfusion of Explanted Human Metabolic Livers: A Proof of Concept for Studying Inborn Errors of Metabolism","authors":"Samira Safarikia,&nbsp;Riccardo Cirelli,&nbsp;Gionata Spagnoletti,&nbsp;Diego Martinelli,&nbsp;Giulia Bravetti,&nbsp;Paola Francalanci,&nbsp;Annamaria D'Alessandro,&nbsp;Giovina Di Felice,&nbsp;Marta Maistri,&nbsp;Elena Baldissone,&nbsp;Alberto M. Fratti,&nbsp;Raffaele Simeoli,&nbsp;Elisa Sacchetti,&nbsp;Sara Cairoli,&nbsp;Cristiano Rizzo,&nbsp;Rosanna Pariante,&nbsp;Michele Vacca,&nbsp;Andrea Cappoli,&nbsp;Christian Albano,&nbsp;Andrea Pietrobattista,&nbsp;Marco Spada,&nbsp;Carlo Dionisi Vici","doi":"10.1002/jimd.70010","DOIUrl":"https://doi.org/10.1002/jimd.70010","url":null,"abstract":"<p>The human liver plays a central metabolic role; however, its physiology may become imbalanced in inborn errors of metabolism (IEM), a broad category of monogenic disorders. Liver transplantation has been increasingly used to improve patient metabolic control, especially in diseases related to amino acid metabolism, such as urea cycle disorders and organic acidurias, to provide enzyme replacement. Ex vivo liver normothermic machine perfusion (NMP) techniques have recently been developed to increase the number of transplantable grafts and improve transplantation outcomes. This study used seven NMP of explanted livers from patients with IEM undergoing transplantation as models to investigate disease-related liver metabolism and function. The perfused livers demonstrated positive viability indicators and disease-specific targeted metabolomics providing the proof-of-principle that our ex vivo model expresses the biochemical disease characteristics and responds to therapeutical intervention in a unique “physiological” milieu, offering an ideal tool to study novel treatments, in a setting closely mirroring human disease.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530222","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":"Altered Fibroblast Glutamine Metabolism Is Linked to the Severity of Cardiac Dysfunction in DCMA, a Mitochondrial Cardiomyopathy","authors":"Melissa A. King,&nbsp;Katherine C. Heger,&nbsp;Marija Drikic,&nbsp;Ayush Mandwal,&nbsp;Aneal Khan,&nbsp;David S. Sinasac,&nbsp;Keir Pittman,&nbsp;Edward L. Huttlin,&nbsp;Steven C. Greenway,&nbsp;Ian A. Lewis","doi":"10.1002/jimd.70018","DOIUrl":"https://doi.org/10.1002/jimd.70018","url":null,"abstract":"<p>The dilated cardiomyopathy with ataxia (DCMA) syndrome is a rare mitochondrial disorder caused by mutations in the poorly understood <i>DNAJC19</i> gene. Cardiac involvement in DCMA ranges from mild conduction abnormalities to early severe myocardial dysfunction. Although evidence suggests that DCMA is linked to abnormalities in mitochondrial function, the molecular underpinnings of this condition are unclear, and there is no way to predict which patients will develop life-threatening disease. To address this, we developed a metabolic flux assay for assessing the metabolic function of mitochondria in fibroblasts derived from DCMA patients. Using this approach, we discovered that DCMA fibroblasts have elevated glutamine uptake, increased glutamate and ammonium secretion, and elevated lactate production. Moreover, we observed that these cellular perturbations were closely correlated with cardiac dysfunction in a blinded cohort of patient cell lines. These findings suggest that glutamine catabolism is abnormal in DCMA and may serve as a predictor of clinical progression.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143533556","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":"Spermidine Treatment Improves GRIN2B Loss-Of-Function, A Primary Disorder of Glutamatergic Neurotransmission","authors":"A. Santos-Gómez,&nbsp;N. Juliá-Palacios,&nbsp;A. Rejano-Bosch,&nbsp;R. Marí-Vico,&nbsp;F. Miguez-Cabello,&nbsp;M. Masana,&nbsp;D. Soto,&nbsp;M. Olivella,&nbsp;À. García-Cazorla,&nbsp;X. Altafaj","doi":"10.1002/jimd.70015","DOIUrl":"https://doi.org/10.1002/jimd.70015","url":null,"abstract":"<p>GRIN-related disorders (GRD) developmental and epileptic encephalopathies (DEEs) display a clinical spectrum including developmental delay, hypotonia, intellectual disability, epilepsy, and autistic traits. The presence of de novo pathogenic variants in the <i>GRIN</i> genes alters the <i>N</i>-methyl D-aspartate receptor (NMDAR) function, with a genotype-phenotype relationship. Despite recent advances to elucidate GRD pathophysiological mechanisms and to find treatments, to date, GRD therapeutic arms are still scarce and with limited efficacy. Herein, we investigated whether the natural polyamine spermine—positive allosteric modulators of GluN2B subunit-containing NMDARs—or its precursor spermidine might rescue NMDAR hypofunctionality. In heterologous cell systems, administration of spermine potentiated wild-type and loss-of-function (LoF) NMDAR-mediated currents and attenuated synaptic density deficits. Functionally, the putative therapeutic benefit of spermidine (spermine precursor) was assessed in constitutive <i>Grin2b</i>^+/− heterozygous mice, a GRIN2B-LoF genetic murine model recapitulating GRD-like synaptic, motor, and cognitive alterations. Chronic spermidine administration in young adult <i>Grin2b</i>^+/− mice partially rescued hippocampal long-term potentiation deficits in hippocampal slices of <i>Grin2b</i>^+/− mice, supporting the cognitive improvement observed in behavioral phenotyping. Based on these preclinical findings, a case study was conducted in two pediatric patients harboring mild GRIN2B-LoF variants. Importantly, in line with preclinical findings, 18 months of spermidine treatment resulted in the amelioration of adaptive behavior (notably in the younger treated patient), with the absence of noticeable side effects. Overall, our findings provide both preclinical and clinical data supporting the benefit of spermidine for the treatment of GRD in individuals harboring GRIN2B-LoF variants.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530056","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":"Phosphoinositide Metabolism: Biochemistry, Physiology and Genetic Disorders","authors":"Francis Rossignol,&nbsp;Foudil Lamari,&nbsp;Grant A. Mitchell","doi":"10.1002/jimd.70008","DOIUrl":"https://doi.org/10.1002/jimd.70008","url":null,"abstract":"<p>Phosphatidylinositol, a glycerophospholipid with a <i>myo</i>-inositol head group, can form seven different phosphoinositides (PItds) by phosphorylation at inositol carbons 3, 4 and/or 5. Over 50 kinases and phosphatases participate in PItd metabolism, creating an interconnected PItd network that allows for precise temporal and spatial regulation of PItd levels. We review paradigms of PItd action, including (1) the establishment of subcellular organelle identity by the acquisition of specific PItd signatures, permitting regulation of key processes of cell biology including trafficking (exocytosis, clathrin-dependent and -independent endocytosis, formation and function of membrane contact sites, cytoskeletal remodeling), (2) signaling through phospholipase C cleavage of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate and DAG, and (3) roles of PItds in molecular transport at membrane contact sites. To date, variants in 34 genes of PItd metabolism account for at least 41 distinguishable monogenic conditions. Clinical presentations of these disorders produce a broad and often multisystemic spectrum of effects. The nervous system is often involved, and muscular, immunological, skeletal, renal, ophthalmologic and dermatologic features occur in several conditions. Some syndromes involving PItd metabolism can be distinguished clinically, but most diagnoses currently result from broad molecular diagnostic testing performed for the patient's presenting clinical complaint. Genetic disorders of PItd metabolism are a broad, expanding and challenging category of inborn errors. Challenges include improved documentation of the clinical spectra, development of broad biochemical diagnostic methods for these conditions and better understanding of the PItd networks in different cells and subcellular compartments necessary for the development of disease-specific therapies.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530057","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":"“Trafficking Disorders: Phenotypical Similarities and Differences With Other IMDs”","authors":"Ángeles García-Cazorla,&nbsp;Eva Morava,&nbsp;Jean-Marie Saudubray","doi":"10.1002/jimd.70004","DOIUrl":"https://doi.org/10.1002/jimd.70004","url":null,"abstract":"<div>\u0000 \u0000 <p>Cell trafficking disorders (CTD) are genetic defects in complex molecules and correspond to the largest category of IEM with mutations in more than 370 genes described. They are still poorly recognized as a global entity but rather seen as isolated rare diseases by non-metabolic specialists. Complex lipid metabolism (mostly phospholipids, sphingolipids, and non-mitochondrial fatty acids) is tightly associated with cell trafficking and interactions between organelles at the membrane contact sites. Accordingly, from a clinical point of view CTD presents with multisystem manifestations that may overlap and mimic mitochondrial and other complex molecule disorders such as peroxisomal, lysosomal defects, CDG, or autophagy disorders. The nervous system is especially vulnerable and neurological presentations are prominent, but CTD targets any organ at any age. Interestingly the involvement of the immune system is particularly characteristic of CTD and rarely (or at least little described so far) in other categories of IEM. Most CTD are progressive disorders, except for CDG. They may have “metabolic crises” mimicking disorders of intermediary and energy metabolism for which emergency protocols have been developed. They are generally diagnosed by exome sequencing. Relatively few biomarkers are available.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466293","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":"Effectiveness of Kidney Transplantation in Treating Alkaptonuric Skin Ochronosis","authors":"Aude Belbézier,&nbsp;Mathilde Tardieu,&nbsp;Nathalie Sturm,&nbsp;Julie Charles,&nbsp;Marie-Thérèse Leccia","doi":"10.1002/jimd.70012","DOIUrl":"https://doi.org/10.1002/jimd.70012","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455944","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":"Amino Acid Metabolism and Immune Dysfunction in Urea Cycle Disorders: T and B Cell Perspectives","authors":"Betul Gemici Karaaslan,&nbsp;Ayca Kiykim,&nbsp;Nihan Burtecene,&nbsp;Meltem Gokden,&nbsp;Mehmet Serif Cansever,&nbsp;Duhan Hopurcuoglu,&nbsp;Gökçe Nuran Cengiz,&nbsp;Birol Topcu,&nbsp;Tanyel Zubarioğlu,&nbsp;Ertugrul Kiykim,&nbsp;Haluk Cokuğras,&nbsp;Ayse Cigdem Aktuglu Zeybek","doi":"10.1002/jimd.70009","DOIUrl":"https://doi.org/10.1002/jimd.70009","url":null,"abstract":"<p>Urea cycle disorders (UCDs) are a group of genetic metabolic conditions characterized by enzyme deficiencies responsible for detoxifying ammonia. Hyperammonemia, the accumulation of intermediate metabolites, and a deficiency of essential amino acids—due to a protein-restrictive diet and the use of ammonia scavengers—can increase the risk of infections, particularly during metabolic crises. While the underlying mechanisms of immune suppression are still being fully elucidated, hyperammonemia may impair the function of immune cells, particularly T cells and macrophages, inhibiting the proliferation of T cells and cytokine production. Arginine, which is essential for T-cell activation and function, may also be limited in these patients, and its depletion can increase their vulnerability to infections. Twenty-four UCD patients and 31 healthy donors were recruited for the study. Peripheral lymphocyte subset analysis, intracellular protein and cytokine staining, and proliferation assays were performed by flow cytometry. Amino acid levels were measured using the HPLC method. The UCD patients exhibited low lymphocyte-proliferation capacity in both proximal and distal defects in response to phytohaemagglutinin (PHA) and anti-CD2, anti-CD3, and anti-CD28 (CD-mix), which was lower than healthy controls. Proximal-UCD patients exhibited a significantly higher response for IFN-γ compared to both distal-UCD patients and healthy controls. The different amino acids in the culture medium were changed significantly in the groups. This study highlights significant immune dysfunctions in UCD patients, particularly impaired T-cell proliferation and altered amino acid metabolism. Proximal UCD patients exhibited a higher IFN-γ response, indicating a potential for hyperinflammation. Despite this, infection rates did not significantly differ between proximal UCD and distal UCD patients, although distal UCD patients had higher hospitalization rates. Amino acid analysis revealed distinct metabolic disruptions, emphasizing the complex interplay between metabolism and immune function. These findings suggest that UCDs cause profound immune alterations, necessitating further research to develop targeted therapeutic strategies.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423728","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":"Emergency Management of Intoxication-Type Inherited Metabolic Disorders","authors":"J. Dexter Tarr,&nbsp;Andrew A. M. Morris","doi":"10.1002/jimd.70007","DOIUrl":"https://doi.org/10.1002/jimd.70007","url":null,"abstract":"<p>In many intoxication-type inherited metabolic disorders, the accumulation of the toxic chemical can cause acute life-threatening emergencies. Sometimes this is the inevitable consequence of a severe metabolic defect, but it is often triggered by catabolism. In this article, we consider the acute management when these conditions cause encephalopathy, seizures, stroke-like episodes, thromboses, liver failure, cardiac failure, arrhythmias and rhabdomyolysis. Treatment is available for most intoxication-type disorders, though it is seldom entirely satisfactory. The emergency management involves general measures for the immediate problem (such as liver failure, thrombosis or an arrhythmia) and specific treatment for the metabolic disorder. The latter usually aims to reduce the accumulation of the toxic small molecule. Often this involves preventing or reversing catabolism. Sometimes the formation of the toxic chemical can be reduced by removing dietary precursors, by diverting precursors to alternative pathways, or by inhibiting an earlier step in the affected pathway. Another strategy is to remove the toxic chemical by binding it to a drug or by extracorporeal blood purification. Occasionally, the block in the pathway can be ameliorated and some disorders, specific treatment may prevent the consequences of the accumulating chemical. Despite all these treatment strategies, outcomes are often disappointing, particularly if an intoxication disorder first presents as an emergency. Newborn screening has greatly improved the prognosis for some disorders. For others, outcomes can only be improved by earlier recognition and treatment.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423800","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":"Reshaping the Treatment Landscape of a Galactose Metabolism Disorder","authors":"M. Estela Rubio-Gozalbo,&nbsp;E. Naomi Vos,&nbsp;Isabel Rivera,&nbsp;Kent Lai,&nbsp;Gerard T. Berry","doi":"10.1002/jimd.70013","DOIUrl":"https://doi.org/10.1002/jimd.70013","url":null,"abstract":"<p>The Leloir pathway was elucidated decades ago, unraveling how galactose is metabolized in the body. Different inborn errors of metabolism in this pathway are known, the most frequent and well-studied being Classic Galactosemia (CG) (OMIM 230400) due to pathogenic variants in the <i>GALT</i> gene. Substrate reduction using dietary restriction of galactose is currently the only available treatment option. Although this burdensome diet resolves the life-threatening clinical picture in neonates, patients still face long-term complications, including cognitive and neurological deficits as well as primary ovarian insufficiency. Emerging therapies aim to address these challenges on multiple fronts: (1) restoration of GALT activity with nucleic acid therapies, pharmacological chaperones, or enzyme replacement; (2) influencing the pathological cascade of events to prevent accumulation of metabolites (Galactokinase 1 (GALK1) inhibitors, aldose reductase inhibitors), address myo-inositol deficiency, or alleviate cellular stress responses; (3) substrate reduction with synthetic biotics or galactose uptake inhibitors to eliminate the need for lifelong diet; and (4) novel approaches to mitigate existing symptoms, such as non-invasive brain stimulation and reproductive innovations. Early, personalized intervention remains critical for optimizing patient outcomes. We review the advances in the development of different treatment modalities for CG and reflect on the factors that need to be considered and addressed to reshape the landscape of treatment.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423971","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}