Molecular genetics and metabolism最新文献

{"title":"A prospective, longitudinal, natural history study of neurological disease trajectory in children with late-infantile or juvenile-onset GM1 gangliosidosis or GM2 gangliosidoses: the PRONTO study.","authors":"Laura López de Frutos, Andreas Hahn, Radhika Dhamija, Bénédicte Héron, Alexander Fay, Susanne A Schneider, Aurélie Bourchany, Lara Cirnigliaro, Célia Hoebeke, Daniel Almeida do Valle, Anna Ardissone, Spyros Batzios, Maurizio Scarpa, Christian Freitag, Roberto Giugliani","doi":"10.1016/j.ymgme.2026.110291","DOIUrl":"https://doi.org/10.1016/j.ymgme.2026.110291","url":null,"abstract":"<p><strong>Background: </strong>Gangliosidoses are rare, autosomal recessive lysosomal diseases characterized by ganglioside accumulation, causing progressive neurodegeneration. Prospective natural history data are limited, particularly for late-infantile and juvenile-onset forms.</p><p><strong>Methods: </strong>PRONTO was a prospective, longitudinal natural history study conducted at 13 sites in six countries (February 2022 to September 2025). Participants were aged 2-20 years and had genetically confirmed GM1 gangliosidosis or GM2 gangliosidoses and neurological symptom onset at ≥12 months of age. Assessments were conducted at baseline and every 6 months up to 24 months. Changes from baseline were assessed using Scale for the Assessment and Rating of Ataxia (SARA), functional SARA (fSARA), Inventory of Non-Ataxia Signs (INAS), swallowing function, Vineland Adaptive Behavior Scales, Third Edition (VABS-3), and Burden Scale for Family Caregivers-short version (BSFC-s).</p><p><strong>Results: </strong>Thirty-one participants were enrolled. Analyses included those with data at baseline and at 24 months. SARA, fSARA, and INAS scores worsened during follow-up; at 24 months, mean changes from baseline were +2.6 (n = 27), +1.8 (n = 28), and +1.1 (n = 22) points, respectively. Enteral feeding use rate increased from 13.8% (4/29) of participants at baseline to 32.1% (9/28) at 24 months. Mean change from baseline in VABS-3 Adaptive Behavior Composite was -5.4 points (n = 14) at 24 months; BSFC-s scores showed modest changes over time. Disease progression was greater in GM2 gangliosidoses than in GM1 gangliosidosis.</p><p><strong>Conclusions: </strong>PRONTO highlights the substantial neurological, functional, and caregiver burdens of late-infantile and juvenile-onset GM1 gangliosidosis and GM2 gangliosidoses over 2 years.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 3","pages":"110291"},"PeriodicalIF":4.0,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug repurposing of glycerol phenylbutyrate for children with SLC6A1-related neurodevelopmental disorder: A prospective open-label case series","authors":"E.S. van Walree,&nbsp;D.Z. Dekker,&nbsp;J.J. Sprengers,&nbsp;I. Boussaad,&nbsp;M.M. van Muilekom,&nbsp;M.J. Smits,&nbsp;M.A. Alders,&nbsp;M.M. van Haelst,&nbsp;A. Altinbas,&nbsp;W.B. Gunning,&nbsp;C.A. Haaxma,&nbsp;J.P.M. van der Vegt,&nbsp;J.S. Verhoeven,&nbsp;Z.M. Grinspan,&nbsp;J.H. Schieving,&nbsp;A.R. Müller,&nbsp;C.D. van Karnebeek","doi":"10.1016/j.ymgme.2026.110256","DOIUrl":"10.1016/j.ymgme.2026.110256","url":null,"abstract":"<div><h3>Background</h3><div><em>SLC6A1-</em>related neurodevelopmental disorder (<em>SLC6A1</em>-NDD) is characterized by intellectual disability, epilepsy, and behavioral difficulties. It is caused by pathogenic variants in <em>SLC6A1</em>, encoding the GABA transporter protein 1 (GAT1). Glycerol phenylbutyrate increases GAT1 expression in preclinical models and has shown promising effects on seizure control in a clinical study.</div></div><div><h3>Methods</h3><div>We conducted a prospective open-label observational study of glycerol phenylbutyrate (target dose 11.2 ml/m²/day) in pediatric patients with NDD and/or epilepsy and rare <em>SLC6A1</em> variants (including (likely) pathogenic variants and variants of uncertain significance (VUS)). Primary outcomes were personalized goals. Secondary outcomes included seizure burden, development, irritability, quality of life, and tolerability.</div></div><div><h3>Results</h3><div>We initiated treatment in six children; one was excluded due to lack of consent, leaving five for analysis. Three had (likely) pathogenic <em>SLC6A1</em> variants and constituted the main case series; two had a VUS and were analyzed separately. Mean treatment duration was 33.7 months (range 16–46). Side effects included mild gastrointestinal complaints (<em>n</em> = 2) and a honey-like body odor (<em>n</em> = 3). All three molecularly confirmed <em>SLC6A1</em>-NDD patients achieved or exceeded predefined personalized goals at 12 months, with improvements in goals associated with amelioration in behavior and development, even though standardized developmental assessments show a more nuanced picture. In a single patient with absence-like episodes without clear EEG correlate at baseline, a reduction in these events and in epileptiform activity on EEG was observed following treatment. Positive signals in quality of life (<em>n</em> = 1) and irritability (<em>n</em> = 2) questionnaires were observed.</div></div><div><h3>Conclusion</h3><div>Glycerol phenylbutyrate was associated with improvements in individualized outcomes in children with <em>SLC6A1</em>-NDD. However, personalized goal attainment measures are susceptible to expectation and observer bias in open-label study designs. Controlled studies are needed to determine efficacy and guide patient selection.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110256"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tividenofusp alfa-eknm (Avlayah) for the treatment of MPS II: FDA approval summary","authors":"Mehul Desai,&nbsp;Kathryn Hartka","doi":"10.1016/j.ymgme.2026.110250","DOIUrl":"10.1016/j.ymgme.2026.110250","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110250"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148935454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prescribing patterns of vitamin and cofactor therapies in genetically confirmed primary mitochondrial diseases","authors":"Merve Setenay Akyüzlüer Güneş,&nbsp;Merve Koç Yekedüz,&nbsp;Engin Köse,&nbsp;İlknur Sürücü Kara,&nbsp;Fatma Tuba Eminoğlu","doi":"10.1016/j.ymgme.2026.110247","DOIUrl":"10.1016/j.ymgme.2026.110247","url":null,"abstract":"<div><h3>Background</h3><div>Primary mitochondrial diseases (PMDs) comprise a genetically and clinically heterogeneous group of disorders for which evidence-based therapeutic options remain limited. Despite advances in molecular diagnosis and the identification of gene-specific therapeutic targets for selected conditions, vitamin and cofactor supplementation continues to be frequently prescribed. We aimed to evaluate prescribing patterns, dosing practices and the balance between PMDs with established genotype-directed metabolic therapy and PMDs managed with empirical supplementation in a genetically confirmed PMD cohort.</div></div><div><h3>Materials and methods</h3><div>We retrospectively reviewed 62 patients with genetically confirmed PMDs followed at a tertiary pediatric metabolism center between 2015 and 2025. Demographic, genetic and treatment-related data were collected, including vitamin and cofactor use and dosing regimens. Patients were categorized as PMDs with genotype-directed therapies and PMDs managed with empirical supplementation.</div></div><div><h3>Results</h3><div>Sixty-two patients were included (43.5% female; mean age 10.7 years). Oxidative phosphorylation (OXPHOS) complex defects were the most common genetic category (35.5%). Overall, 71% of patients received at least one vitamin or cofactor supplement. Coenzyme Q10 (62.9%), carnitine (53.2%), riboflavin (48.4%), biotin (37.1%) and thiamine (35.5%) were the most frequently prescribed agents. Thirteen patients (21%) had PMDs with established targeted therapies and received genotype-directed treatment. Among the remaining 49 patients, who lacked a defined genotype-directed therapeutic option and were therefore classified as being managed with empirical supplementation, 63.2% (31/49) received at least one vitamin or cofactor supplement.</div></div><div><h3>Conclusion</h3><div>Despite advances in molecular diagnosis, empirical vitamin and cofactor supplementation remains frequently used in patients with PMDs who lack established gene- or pathway-specific therapeutic options. These findings underscore the persistent gap between molecular diagnosis and evidence-based therapy and support the need for prospective multicenter studies to guide standardized treatment approaches in PMDs.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110247"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover 2 / Ed. Board","authors":"","doi":"10.1016/S1096-7192(26)00550-0","DOIUrl":"10.1016/S1096-7192(26)00550-0","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110267"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149044134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Attitudes of people with lived experience of hypophosphatasia (HPP) toward in-utero enzyme replacement therapy (IU-ERT) for life-threatening HPP","authors":"Tanvi Kaushal,&nbsp;Angela Krutish,&nbsp;Rebekah Kukurudz-Gorowski,&nbsp;Emily Barker,&nbsp;Deborah Fowler,&nbsp;Jennifer Paulson Brand,&nbsp;Denise Goodbar,&nbsp;Cheryl Rockman-Greenberg","doi":"10.1016/j.ymgme.2026.110251","DOIUrl":"10.1016/j.ymgme.2026.110251","url":null,"abstract":"<div><h3>Purpose</h3><div>Hypophosphatasia (HPP) is a multi-system genetic disorder that affects mineralization of the skeleton and dentition. Despite the success of postnatal enzyme replacement therapy (ERT), children with life-threatening presentations (LT-HPP) experience significant morbidity, decreased quality of life, and risk of death. Recent evidence suggests that in-utero ERT (IU-ERT) may further improve outcomes; however, acceptability within the HPP community has not been assessed. This study aimed to explore patient and caregiver attitudes toward IU-ERT for LT-HPP.</div></div><div><h3>Methods</h3><div>We surveyed adults with lived experience with HPP. The survey was distributed through patient advocacy organizations.</div></div><div><h3>Results</h3><div>Ninety-two individuals completed the survey. Most participants supported availability of IU-ERT following prenatal detection of LT-HPP and further research in this area. Predominant concerns were potential risks for the baby or mother, long-term side effects, and uncertainty regarding treatment effectiveness. Frequent reasons cited for one to pursue IU-ERT were reduced disease severity, a potential cure, and reduced mortality. Potential barriers included perceived risks, uncertainty regarding safety or benefits, and financial burden.</div></div><div><h3>Conclusions</h3><div>Participants were supportive of further research and clinical trials for IU-ERT for LT-HPP. These results provide preliminary evidence that can be used to inform the development and implementation of IU-ERT for LT-HPP.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110251"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and biochemical footprints of inherited disorders of autophagy","authors":"Heinz Jungbluth,&nbsp;Hormos S. Dafsari,&nbsp;Carlos R. Ferreira,&nbsp;Nenad Blau","doi":"10.1016/j.ymgme.2026.110248","DOIUrl":"10.1016/j.ymgme.2026.110248","url":null,"abstract":"<div><div>Autophagy is an evolutionarily conserved lysosomal recycling system that integrates nutrient sensing, organelle quality control, proteostasis, cellular stress responses and metabolic adaptation. Autophagy is particularly relevant for post-mitotic tissue such as neurons, skin, and immune cells. Monogenic disorders disrupting autophagy or closely coupled endolysosomal trafficking pathways have recently emerged as a recognizable group of inherited metabolic diseases. These conditions are individually rare inborn errors of metabolism and collectively important because they bridge neurodevelopmental, neuromuscular and neurodegenerative disorders, including hereditary forms of Parkinson's disease, spastic paraplegias and neurodegeneration with brain iron accumulation. Multisystem involvement is common but variable. The prototypic disorder is <em>EPG5</em>-related Vici syndrome, in which defective autophagosome-lysosome fusion causes severe neurodevelopmental and multisystem disease. Other disorders may affect any step of the pathway, from phosphatidylinositol 3-phosphate effector biology and <em>ATG</em> conjugation/lipidation to autophagosome maturation, <em>ATG9</em> trafficking, HOPS/CORVET-related vesicle trafficking (including <em>VPS16</em> and <em>VPS33A</em>), autophagosome-lysosome fusion, autolysosome reformation and lysosome-mTOR signaling. Clinically, affected individuals commonly present with global developmental delay and/or intellectual disability, epilepsy, movement disorders including dystonia, parkinsonism, ataxia and spasticity, and both neuropathic and myopathic neuromuscular manifestations. A biphasic course with progressive neurodegeneration and variable multisystem (including ocular, cardiac, immunological, cutaneous and growth) involvement are important clinical clues. Diagnosis relies on careful phenotyping, brain MRI, targeted metabolic exclusion of mimics, genomic sequencing and functional assays in patient-derived cells as required. Supportive multidisciplinary management is essential. No disease-modifying therapy is currently established in humans, but pathway-based cellular assays, model systems and small-molecule or gene-replacement strategies are creating a rational therapeutic pipeline. Importantly, IEMbase dyadic nomenclature with system-level clinical annotations provides a standardized framework for quantifying shared phenotypic signatures across these ultra-rare conditions. This review summarizes pathobiochemistry, genetics, clinical presentation, diagnosis and treatment prospects for inherited disorders of autophagy.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110248"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional characterization of 42 GAA missense variants using a validated in vitro cellular functional assay","authors":"Shelly Goomber,&nbsp;Erin Huggins,&nbsp;Catherine W. Rehder,&nbsp;Gregory E. Crawford,&nbsp;Seung-Hye Jung,&nbsp;Jessica Doxey,&nbsp;Apoorva K. Iyengar,&nbsp;Erica B. Nading,&nbsp;Priya S. Kishnani,&nbsp;Deeksha S. Bali","doi":"10.1016/j.ymgme.2026.110237","DOIUrl":"10.1016/j.ymgme.2026.110237","url":null,"abstract":"<div><div>The advent of newborn screening for Pompe disease has led to a massive increase in the number of missense variants of uncertain significance (VUS) reported in GAA. Molecular diagnostic testing may be inconclusive in the presence of one or more VUS, posing a significant challenge since most positive NBS occur in healthy infants with no apparent disease-related symptoms. It then becomes challenging to distinguish between pre-symptomatic infants with late-onset Pompe disease who require close monitoring and follow-up, and those who may just be carriers or have a partially functional pseudodeficiency variant. Missense variants are notoriously difficult to interpret in a clinical setting. Thus, there is a high demand for functional evidence to predict their impact in the absence of documented clinical evidence. To address this rapidly growing need, we have developed and validated a cell-based in vitro assay to test individual missense variants and their impacts on GAA enzyme activity and protein processing. Using this assay, we characterized 42 missense GAA VUS. We found that residual enzyme activity spanned the full GAA activity range, from complete loss of product to near wild type, with 66% of these variants falling below established cutoffs for a potentially deleterious effect. In addition, we provide case examples from individuals evaluated at the Duke Pediatric Medical Genetics clinic with GAA VUS and describe the utility of this functional assay in solving clinical conundrums. While variant classification cannot rely on a single line of evidence, our assay adds functional evidence to support classifications and clinical decision making, especially in the setting of novel variants not previously reported in patients with Pompe disease.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110237"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute and chronic neurological manifestations of acute porphyria","authors":"E. Pischik","doi":"10.1016/j.ymgme.2026.110258","DOIUrl":"10.1016/j.ymgme.2026.110258","url":null,"abstract":"<div><h3>Background</h3><div>The neurological manifestations of acute attacks and chronic symptoms were evaluated both prospectively and retrospectively in 90 patients with acute porphyria and integrated with data from previously published series.</div></div><div><h3>Results</h3><div>Most acute attacks presented with a combination of abdominal pain, mild cognitive and behavioral symptoms, and autonomic dysfunction, predominantly attributed to vagal insufficiency. Acute peripheral neuropathy and encephalopathy developed if an acute attack proceeded.</div><div>Acute peripheral neuropathy emerged 1–3 weeks after the onset of an attack and was predominantly motor in nature. It was consistently associated with preceding abdominal pain (100%) and dysautonomia (100%), and frequently accompanied by central nervous system involvement (50%) and mild hepatopathy (75%). Acute encephalopathy (AE), which was transient resolving within a few days, manifested 3–19 days after attack onset. AE was characterized by a triad of seizures, confusion, and/or blurred vision. PRES was identified on MRI in 42% of patients with AE during acute attacks; among these, 88% were hyponatremic and 94% had mild hepatopathy.</div><div>Of the patients with recurrent attacks, ∼40% experienced chronic symptoms. The most common clinical pattern consisted of chronic mild-to-moderate neuropathic pain, fatigue, and nausea, typically developing within the first year of cyclical attacks. All patients in this subgroup exhibited persistently elevated urinary porphobilinogen (PBG) excretion.</div><div>Most patients without recurrent attacks reported no chronic symptoms. Seven patients experienced chronic neuropathic pain, fatigue, and nausea despite the absence of recurrent attacks. Only three of them exhibited persistently elevated urinary PBG excretion. They had previously demonstrated cyclical attacks that had spontaneously subsided but subsequently evolved into chronic mild pain and fatigue, often exacerbated by stress or infections, without further overt attacks. The remaining four patients had a mild increase in urinary PBG levels, and their chronic symptoms developed 3–23 years after their last documented acute attack.</div></div><div><h3>Conclusion</h3><div>The pathogenesis of autonomic and peripheral neuropathy in acute porphyria is complex; delta-aminolevulinic acid is considered a potential initiator of neuronal injury. The mechanisms underlying AE remain incompletely understood, but current evidence suggests a multifactorial process involving abrupt hypertensive episodes, SIADH, and acute metabolic or inflammatory factors of hepatic origin. Chronic symptoms are common among patients with recurrent attacks. The most effective treatment should focus on preventing recurrent attacks.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110258"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma and urinary NMR metabolic profiling of the phenylalanine-tyrosine pathway in nitisinone-treated alkaptonuria: comparison of two dosing regimens and identification of a candidate pharmacodynamic biomarker","authors":"Daniela Grasso,&nbsp;Valentina Balloni,&nbsp;Elena Bianchi,&nbsp;Andrea Mazzon,&nbsp;Marco Bardelli,&nbsp;Gabriella Iacomelli,&nbsp;Luana Peruzzi,&nbsp;Bruno Frediani,&nbsp;Annalisa Santucci,&nbsp;Andrea Bernini","doi":"10.1016/j.ymgme.2026.110255","DOIUrl":"10.1016/j.ymgme.2026.110255","url":null,"abstract":"<div><div>Alkaptonuria is an ultra-rare autosomal recessive inborn error of metabolism caused by a deficiency of homogentisate 1,2-dioxygenase, leading to the systemic accumulation of homogentisate and progressive ochronotic deposition in connective tissues. Nitisinone, an inhibitor of 4-hydroxyphenylpyruvate dioxygenase, effectively reduces homogentisate production but causes secondary hyper-tyrosinaemia, posing a risk of ocular complications. This study employed ¹H NMR spectroscopy to characterise the metabolic profiles of plasma and urine samples collected from 12 patients with alkaptonuria before and after three months of nitisinone treatment. Quantification of key intermediates in the tyrosine catabolism pathway revealed a marked reduction in urinary homogentisate, confirming drug efficacy, alongside a substantial rise in plasma tyrosine levels. Urinary metabolites upstream of 4-hydroxyphenylpyruvate dioxygenase showed significant accumulation, consistent with an enzymatic block. Comparison of two dosage regimens (10 mg once daily vs 10 mg on every other day) identified 4-hydroxyphenylpyruvate as the only metabolite exhibiting a statistically significant inter-regimen difference, while plasma tyrosine remained elevated in both groups. These findings highlight the complementary diagnostic value of plasma and urinary NMR profiling and underscore the limitations of current dosage strategies in controlling nitisinone-induced hyper-tyrosinaemia. NMR metabolomics provides a non-invasive, simultaneous snapshot of pathway-wide metabolic changes and represents a powerful tool for personalised therapeutic monitoring in AKU.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110255"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}