Journal of Inherited Metabolic Disease最新文献

{"title":"Characterizing Diagnostic Delays in Metachromatic Leukodystrophy: A Real-World Data Approach","authors":"Ali Mohajer,&nbsp;Anjana Sevagamoorthy,&nbsp;Karen Bean,&nbsp;Sylvia Mutua,&nbsp;Francis Pang,&nbsp;Laura Ann Adang","doi":"10.1002/jimd.70049","DOIUrl":"https://doi.org/10.1002/jimd.70049","url":null,"abstract":"<p>Neurodegeneration in metachromatic leukodystrophy (MLD) may be preceded by systemic complications. Characterization of these features is critical to define barriers to early diagnosis and treatment eligibility for gene therapy. We utilized medical billing (claims) datasets and a natural history study to capture pre-diagnosis MLD-related events. MLD-related events (ICD-10-CM codes) were aggregated into system-based diagnosis clusters, and time to MLD diagnosis (TTD) computed for each organ-system diagnosis cluster. Differences in TTD distribution, instantaneous diagnosis hazard, and survival to MLD diagnosis were compared by sex and payor type. TTD and regression from onset of first symptoms were described using median and inter-quartile range. The claims dataset identified 174 MLD cases (diagnosis ≤ 6 years old) with 14 diagnosed within the first year of life. General neurologic concerns (<i>n</i> = 138; median 257 days pre-diagnosis), gastrointestinal (<i>n</i> = 137; 231 days), seizures (<i>n</i> = 48; 236 days), ophthalmologic (<i>n</i> = 46; 362 days), and language-related events (<i>n</i> = 41; 267 days) were common. Time to MLD diagnosis from onset of prodromal clusters was longer for children with non-commercial insurance: most prominent with seizures (survival logrank <i>p</i> value &lt; 0.02) and non-degenerative neurological symptoms (survival logrank <i>p</i> value &lt; 0.04). Similar findings were noted in our analysis of a second claims dataset. The natural history cohort demonstrated a similar pattern of prodromal disease features and delayed diagnosis. This study defines barriers to MLD diagnosis and highlights prodromal periods of pre-regression symptomatology, further supporting the need for early screening in this fatal disorder of childhood.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197371","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-Directed Gene Therapy Mitigates Early Nephropathy in Murine Glycogen Storage Disease Type Ia","authors":"Cheol Lee,&nbsp;Kunal Pratap,&nbsp;Lisa Zhang,&nbsp;Hung Dar Chen,&nbsp;Irina Arnaoutova,&nbsp;Matthew F. Starost,&nbsp;Brian C. Mansfield,&nbsp;Janice Y. Chou","doi":"10.1002/jimd.70048","DOIUrl":"https://doi.org/10.1002/jimd.70048","url":null,"abstract":"<p>Nephropathy is a complication of glycogen storage disease type Ia (GSD-Ia), a metabolic disorder caused by pathogenic variants in glucose-6-phosphatase-α (G6Pase-α or G6PC1). While maintaining blood glucose homeostasis can delay the progression of renal disease in GSD-Ia, the benefits of liver-directed G6PC1 gene therapy on nephropathy remain unclear. This study evaluates the effects of low- and high-dose G6PC1 liver gene augmentation therapy on kidney function. The <i>G6pc</i>−/− mice, which lack G6Pase-α activity in both liver and kidney, were treated with G6PC1 gene therapy to restore either low or near-normal levels of liver G6Pase-α activity, and renal phenotype was examined at age 12 weeks. Both groups exhibited impaired renal glucose homeostasis, altered renal glucose reabsorption, acute kidney injury, and early signs of renal fibrosis. However, mice with near-normal liver G6Pase-α activity had better renal glucose reabsorption and homeostasis with lower serum levels of cystatin C and blood urea nitrogen, key markers of kidney function. These findings highlight the potential of liver-directed G6PC1 gene therapy to enhance metabolic control and mitigate early kidney disease in GSD-Ia.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171615","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":"A Multiomic Network Approach to Uncover Disease Modifying Mechanisms of Inborn Errors of Metabolism","authors":"Aaron Bender,&nbsp;Pablo Ranea-Robles,&nbsp;Evan G. Williams,&nbsp;Mina Mirzaian,&nbsp;J. Alexander Heimel,&nbsp;Christiaan N. Levelt,&nbsp;Ronald J. Wanders,&nbsp;Johannes M. Aerts,&nbsp;Jun Zhu,&nbsp;Johan Auwerx,&nbsp;Sander M. Houten,&nbsp;Carmen A. Argmann","doi":"10.1002/jimd.70045","DOIUrl":"https://doi.org/10.1002/jimd.70045","url":null,"abstract":"<div>\u0000 \u0000 <p>For many inborn errors of metabolism (IEM) the understanding of disease mechanisms remains limited, in part explaining their unmet medical needs. The expressivity of IEM disease phenotypes is affected by disease-modifying factors, including rare and common polygenic variation. We hypothesize that we can identify these modulating pathways using molecular signatures of IEM in combination with multiomic data and gene regulatory networks generated from non-IEM animal and human populations. We tested this approach by identifying and subsequently validating glucocorticoid signaling as a candidate modifier of mitochondrial fatty acid oxidation disorders, and recapitulating complement signaling as a modifier of inflammation in Gaucher disease. Our work describes a novel approach that can overcome the rare disease–rare data dilemma and reveal new IEM pathophysiology and potential drug targets using multiomics data in seemingly healthy populations.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171633","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":"Audiovestibular Findings in Gaucher Disease Types I and III: Evidence of Vestibular Involvement in GD1","authors":"Elvan Onan,&nbsp;Fatma Derya Bulut,&nbsp;Deniz Kor,&nbsp;Muhammed Dagkiran,&nbsp;Caglar Eker,&nbsp;Ozgur Surmelioglu,&nbsp;Neslihan Önenli Mungan","doi":"10.1002/jimd.70046","DOIUrl":"https://doi.org/10.1002/jimd.70046","url":null,"abstract":"<p>Gaucher disease (GD), the most prevalent lysosomal storage disorder, is characterized by varying levels of systemic and neurological involvement. This study aims to investigate audiovestibular system involvement in patients with Gaucher disease type I (GD1) and type III (GD3) using audiometric and vestibular evaluations. We conducted a retrospective analysis of 42 patients diagnosed with GD who presented to the Department of Otorhinolaryngology at Çukurova University Faculty of Medicine between January 2001 and September 2023. The evaluations included pure tone audiometry (PTA), speech discrimination scores (SDS), acoustic impedance tests, and Video Head Impulse Test (vHIT) assessments. Of the 42 patients, 18 were diagnosed with GD1, and 24 with GD3. Audiovestibular anomalies were identified in 11 patients (26.2%). Sensorineural hearing loss (SNHL) was detected in 9 patients, including 4 GD1 and 5 GD3 patients, with bilateral involvement in 5 cases. The severity of hearing loss ranged from mild to moderately severe. Vestibular impairment, demonstrated by reduced vestibulo-ocular reflex (VOR) gain and catch-up saccades (CUS), was observed in 5 patients, predominantly among GD3 cases. Notably, concurrent audiovestibular dysfunction was observed in three patients, one with GD1 and two with GD3. This study is the first to describe the vestibular involvement in GD1. Audiovestibular abnormalities can manifest in both GD1 and GD3 patients, with distinct patterns of involvement. Regular auditory and vestibular assessments are essential to identify sensory deficits early, guide rehabilitation strategies, and enhance the quality of life for GD patients.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171632","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":"Regulatory News: Chenodiol for the Treatment of Cerebrotendinous Xanthomatosis: FDA Approval Summary","authors":"Theresa Bourne","doi":"10.1002/jimd.70051","DOIUrl":"https://doi.org/10.1002/jimd.70051","url":null,"abstract":"<p>Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by pathogenic variants in the <i>CYP27A1</i> gene which encodes the mitochondrial enzyme sterol 27-hydroxylase. This enzyme deficiency leads to abnormalities in bile acid synthesis, including deficient production of the primary bile acid chenodeoxycholic acid (CDCA) and loss of feedback inhibition on the enzyme 7α-hydroxylase, resulting in increased production of abnormal bile acids and bile alcohols, and accumulation of cholestanol, a toxic cholesterol metabolite, in various organs and tissues. Clinical manifestations of CTX include chronic diarrhea, juvenile-onset bilateral cataracts, tendon xanthomas, and progressive neurological dysfunction (pyramidal and cerebellar signs, seizures, dementia, and psychiatric disturbances).</p><p>Chenodiol is an orally administered exogenous CDCA that replaces the deficient bile acid in CTX. Chenodiol has been approved in the United States since 1983 for the treatment of radiolucent gallstones in adults and has been used off-label for the treatment of CTX for over 40 years. Although chenodiol is considered standard of care for the treatment of CTX worldwide, there have been no prospective, randomized, controlled trials to confirm the treatment benefit.</p><p>The FDA requires substantial evidence of effectiveness for drug approval, with benefits outweighing risks. Substantial evidence of effectiveness for chenodiol in patients with CTX was established using data from one adequate and well-controlled trial with confirmatory evidence. The recommended dosing regimen of 250 mg three times per day for adults was evaluated in a single trial in 14 patients aged 16 years and older with CTX. Chenodiol treatment resulted in lower levels of cholestanol compared to when treatment was withdrawn, which the review team considered clinically meaningful based on available literature supporting the role of cholestanol reduction and normalization in stabilizing or improving clinical symptoms for CTX patients. The confirmatory evidence providing strong mechanistic support includes the well-established etiology of the disease and the mechanism of action of chenodiol in replacing the deficient bile acid and restoring normal bile acid synthesis homeostasis. Since chenodiol treatment has been associated with hepatotoxicity, product labeling recommends monitoring liver transaminase and bilirubin levels and considering interrupting treatment if levels are significantly elevated. With all factors and limitations considered, the benefits of chenodiol were determined to outweigh the risks for adult patients with CTX.</p><p>The author declares no conflicts of interest.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171566","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":"Phosphoribosylformylglycinamidine Synthase (PFAS) Deficiency: Clinical, Genetic and Metabolic Characterisation of a Novel Defect in Purine de Novo Synthesis","authors":"Marie Zikanova,&nbsp;Vaclava Skopova,&nbsp;Kyra E. Stuurman,&nbsp;Veronika Baresova,&nbsp;Olga Souckova,&nbsp;Ales Hnizda,&nbsp;Matyas Krijt,&nbsp;Anthony J. Bleyer,&nbsp;Jiri Zeman,&nbsp;Stanislav Kmoch","doi":"10.1002/jimd.70041","DOIUrl":"https://doi.org/10.1002/jimd.70041","url":null,"abstract":"<p>Purine de novo purine synthesis involves 10 reactions catalysed by six enzymes, including phosphoribosylformyglycinamidine synthase (PFAS). To date, genetic defects of three of these enzymes, namely ATIC, ADSL and PAICS, have been characterised in humans. Here, we report for the first time two individuals with PFAS deficiency. Probands were identified through metabolic and genetic screening of neurologically impaired individuals. The pathogenicity of the variants was established by structural and functional studies. Probands C1 and C2 presented with prematurity, short stature, recurrent seizures and mild neurological impairment. C1 had elevated urinary levels of formylglycineamide riboside (FGAr) and bi-allelic PFAS variants encoding the NP_036525.1:p.Arg811Trp substitution and the NP_036525.1:p.Glu228_Ser230 in-frame deletion. C2 is a 20-year-old female with a homozygous NP_036525.1:p.Asn264Lys substitution. These amino acid changes are predicted to affect the structural stability of PFAS. Accordingly, C1 skin fibroblasts showed decreased PFAS content and activity, with impaired purinosome formation that was restored by transfection with pTagBFP_PFAS_wt. The enzymatic activities of the corresponding recombinant mutant PFAS proteins were also reduced, and none of them, after transfection, corrected the elevated FGAR/r levels in PFAS-deficient HeLa cells. While genetic defects in purine de novo synthesis are typically considered in patients with severe neurological impairment, these disorders, especially PFAS deficiency, should also be considered in milder phenotypes.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140828","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":"Novel Treatment Strategy for Patients With Urea Cycle Disorders: Pharmacological Chaperones Enhance Enzyme Stability and Activity in Patient-Derived Liver Disease Models","authors":"Adhuresa Ramosaj,&nbsp;Mariia Borsuk,&nbsp;Jarl Underhaug,&nbsp;Déborah Mathis,&nbsp;Shirou Matsumoto,&nbsp;Adrian Keogh,&nbsp;Vanessa Banz,&nbsp;Amit V. Pandey,&nbsp;Nadine Gougeard,&nbsp;Vicente Rubio,&nbsp;Aurora Martinez,&nbsp;Gabriella Allegri,&nbsp;Martin Poms,&nbsp;Beat Thöny,&nbsp;Johannes Häberle,&nbsp;Alexander Laemmle","doi":"10.1002/jimd.70043","DOIUrl":"https://doi.org/10.1002/jimd.70043","url":null,"abstract":"<p>Urea cycle disorders (UCDs) are inherited diseases causing recurrent life-threatening metabolic decompensations due to impaired hepatic ammonia detoxification and decreased ureagenesis. Ornithine transcarbamylase (OTC) deficiency (OTCD) is X-linked and the most common and often fatal UCD. In male hemizygous patients, disease severity primarily depends on the pathogenic sequence variant, while in heterozygous females, disease severity also depends on the X-chromosomal inactivation (XCI) pattern. Females with unfavorable XCI predominantly expressing the mutant OTC protein may be severely affected. Here, we investigated a novel treatment strategy for OTCD since there is an unmet need for better therapies. In the first step, we performed a high throughput screening (HTS) using a diversity library with 10 000 chemical compounds to identify pharmacological chaperone (PC) candidates that stabilize purified wild-type OTC. Stratification of our HTS results revealed five potential PCs, which were selected for further experimentation in cellular systems using primary human hepatocytes (PHHs) and human induced pluripotent stem cell (hiPSC)-derived hepatocytes (hiPSC-Heps) from healthy controls and OTCD patients. Two PCs—PC1 and PC4—increased OTC protein stability and activity in control hiPSC-Heps, while PC4 in addition increased OTC activity in patient-derived PHHs from a female OTCD patient with unfavorable XCI. Finally, PC1 and PC4 both significantly increased ureagenesis in patient-derived PHHs. To conclude, we identified two PCs that stabilized wild-type OTC and enhanced enzyme activity and ureagenesis. Our work suggests that PCs could provide a novel treatment strategy for OTCD specifically in females with unfavorable XCI.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140829","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":"Diagnosis of Inherited Metabolic Disease in Older Patients: A Systematic Literature Review","authors":"Maria-Rita Moio,&nbsp;Julia Cordeiro Milke,&nbsp;Yannick Moutapam-Ngamby-Adriaansen,&nbsp;Arthur Minas Alberti,&nbsp;Marie Gernay,&nbsp;Eduardo Schütz,&nbsp;Ida Vanessa Doederlein Schwartz,&nbsp;François Maillot","doi":"10.1002/jimd.70038","DOIUrl":"https://doi.org/10.1002/jimd.70038","url":null,"abstract":"<p>Inherited metabolic diseases (IMDs) are genetic disorders that disrupt biochemical processes in the human body, due to pathogenic variants in genes encoding enzymes or transporters. While IMDs are mostly diagnosed in infancy or childhood, there is an increasing number of diagnoses in adult patients. Delayed diagnosis, particularly in older patients, may reflect the diagnostic odyssey usually observed in rare diseases' patients and can result in complications and reduced quality of life for patients and their families. The aim of the study was to better characterize the diagnosis of IMDs in older patients (≥ 65 years). We conducted a systematic literature review (SLR) to examine the diagnosis and clinical presentation of IMDs in patients aged 65 and older. We searched databases like PubMed, Embase, and Lilacs for relevant studies from 1965 to 2023. A total of 260 articles were included, representing 293 patients with a median age of 69 years at diagnosis. From this SLR, 67 different diagnoses have been reported. The most frequently reported diseases were Fabry disease, alkaptonuria, Gaucher disease, mitochondrial disorders, and glycogen storage disease type V. Median diagnostic delay was 14.5 years with a wide range of 1–91 years. Musculoskeletal symptoms were the most frequently reported, followed by neurological and cardiovascular symptoms. Our findings underscore the importance of recognizing IMDs in older patients and the need for awareness among healthcare providers to improve diagnosis and patient care. Future guidelines and teaching programs should incorporate metabolic investigations for older patients presenting with symptoms suggestive of IMDs.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118054","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":"Glut1 Deficiency Syndrome: Novel Pathomechanisms, Current Concepts, and Challenges","authors":"Joerg Klepper","doi":"10.1002/jimd.70044","DOIUrl":"https://doi.org/10.1002/jimd.70044","url":null,"abstract":"<p>Glut1 Deficiency Syndrome (Glut1DS) has emerged as a treatable, but complex entity. Increasing data on pathogenic mechanisms, phenotype, genotype, and ketogenic dietary therapies (KDT) are available, as summarized in this review. Many challenges remain: novel symptoms emerge and vary with age. In Glut1DS, KDT in pregnancy and the clinical features in neonates and adults are poorly understood. KDT are ineffective in some patients for reasons yet unknown. Research reaches beyond the concept of brain energy depletion by impaired GLUT1-mediated glucose transfer across the blood–brain barrier. Novel concepts investigate alternative substrates, transport mechanisms, and metabolic interactions of different brain cell types. Future, yet currently unavailable prospects are neonatal screening for Glut1DS, reliable biomarkers, predictors for outcome, and alternative therapies, along with and beyond KDT.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118094","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":"Adenosine Kinase: An Epigenetic Modulator and Drug Target","authors":"Uchenna Peter-Okaka,&nbsp;Detlev Boison","doi":"10.1002/jimd.70033","DOIUrl":"https://doi.org/10.1002/jimd.70033","url":null,"abstract":"<p>Adenosine kinase (ADK, EC: 2.7.1.20) is an evolutionarily ancient ribokinase, which acts as a metabolic regulator by transferring a phosphoryl group to adenosine to form AMP. The enzyme is of interest as a therapeutic target because its inhibition is one of the most effective means to raise the levels of adenosine and hence adenosine receptor activation. For these reasons, ADK has received significant attention in drug discovery efforts in the early 2000s for indications such as epilepsy, chronic pain, and inflammation; however, the report of adverse events regarding cardiovascular and hepatic function as well as instances of microhemorrhage in the brain of preclinical models prevented further development efforts. Recent findings emphasize the importance of compartmentalization of the adenosine system reflected by two distinct isoforms of the enzyme, ADK-S and ADK-L, expressed in the cytoplasm and the cell nucleus, respectively. Newly identified adenosine receptor independent functions of adenosine as a regulator of biochemical transmethylation reactions, which include DNA and histone methylation, identify ADK-L as a distinct therapeutic target for the regulation of the nuclear methylome. This newly recognized role of ADK-L as an epigenetic regulator points toward the potential disease-modifying properties of the next generation of ADK inhibitors. Continued efforts to develop therapeutic strategies to separate nuclear from extracellular functions of adenosine would enable the development of targeted therapeutics with reduced adverse event potential. This review will summarize recent advances in the discovery of novel ADK inhibitors and discuss their potential therapeutic use in conditions ranging from epilepsy to cancer.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100460","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}