Journal of Inherited Metabolic Disease最新文献

{"title":"Contribution of Brain Intrinsic Branched-Chain Amino Acid Metabolism in a Novel Mouse Model of Maple Syrup Urine Disease","authors":"Amanda C. Kuhs,&nbsp;Laura Ohl,&nbsp;Tegan Thurston,&nbsp;Jeet Singh,&nbsp;Sangeetha Bhuyan,&nbsp;Sarah Grandinette,&nbsp;Jing Xu,&nbsp;Sophie A. Siemsgluess,&nbsp;Youseff Jakher,&nbsp;Rebecca C. Ahrens-Nicklas","doi":"10.1002/jimd.70003","DOIUrl":"https://doi.org/10.1002/jimd.70003","url":null,"abstract":"<div>\u0000 \u0000 <p>Maple syrup urine disease (MSUD) results from loss of branched-chain ketoacid dehydrogenase (BCKDH) activity, the committed, rate-limiting step of branched-chain amino acid (BCAA) oxidation. Current treatments, including a low protein diet and liver transplantation, improve peripheral biochemistry and limit episodes of metabolic decompensation but do not fully prevent chronic neuropsychiatric symptoms. The mechanisms underlying chronic neurologic phenotypes remain poorly understood. Currently available MSUD mouse models do not survive long enough to evaluate chronic central nervous system (CNS) pathology. To investigate if loss of brain-intrinsic BCAA metabolism contributes to chronic neurologic disease, we developed a new brain-specific knockout mouse model of MSUD. First, we generated a mouse harboring a floxed <i>Dbt</i> allele (<i>Dbt</i>^flox/flox). Then we crossed this line with Cre recombinase driver lines to induce loss of <i>Dbt</i> expression in (1) all developing CNS cell populations (2) neurons alone or (3) astrocytes alone. We found that brain-specific KO mice have elevations in BCAA levels in cortex that are exacerbated by a high protein diet. They also have secondary changes in amino acids in brain that are important for neuronal function, including glutamine and glycine. These metabolic differences result in subtle functional deficits as measured by electroencephalogram and behavioral testing. Astrocyte and neuron-specific KO mice each also demonstrate mild biochemical features of MSUD in the cortex, suggesting that both cell populations may contribute to disease pathology. Collectively, these data suggest that therapies targeting the CNS directly, in addition to the periphery, may improve outcomes in MSUD.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111629","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":"Assessment of Long-Term Safety and Efficacy of Purple Sweet Potato Color (PSPC) and Myo-Inositol (MI) Treatment for Motor Related and Behavioral Phenotypes in a Mouse Model of Classic Galactosemia","authors":"Olivia Bellagamba,&nbsp;Aaron j Guo,&nbsp;Sandhya Senthilkumar,&nbsp;Synneva Hagen Lillevik,&nbsp;Davide De Biase,&nbsp;Kent Lai,&nbsp;Bijina Balakrishnan","doi":"10.1002/jimd.70002","DOIUrl":"10.1002/jimd.70002","url":null,"abstract":"<p>Classic galactosemia (CG) is a rare inherited metabolic disease caused by mutations in the <i>GALT</i> gene encoding the enzyme galactose-1 phosphate uridylyltransferase in galactose metabolism. The condition develops as a potentially fatal illness during the newborn period, but its acute clinical manifestations can be alleviated through a galactose restricted diet. Nonetheless, such dietary intervention is inadequate in preventing significant long-term consequences, including neurological impairments, growth restriction, cognitive delays, and, for most females, primary ovarian insufficiency. At present, no effective therapy exists to stop the progression of these complications, highlighting the urgent need for new treatment approaches to be developed. Supplements have been used in the treatment of other inborn errors of metabolism; however, they are not typically included in the clinical therapeutic regimen for CG. Recently, our research team has demonstrated that two generally recognized as safe supplements (purple weet potato color, PSPC and <i>myo</i>-inositol, MI) have been effective in partially restoring functions in the ovaries of our <i>GalT</i>-KO mouse model. However, the toxicological profile of both PSPC and MI has not been determined. In this study, we investigated the acute (30 days) and chronic (180 days) oral toxicities of PSPC and MI both in WT control and <i>GalT</i>-KO mice. Furthermore, our study aims to evaluate the effectiveness of oral feeding of PSPC and MI in correcting motor-related and behavioral phenotypes in <i>GalT</i>-KO mice. The long-term treatment of MI at a lower dose demonstrated promising improvements in motor deficit and anxiety driven hyperactivity in the mutant mice.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080255","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":"Obituary for Professor Ishwar Chander Verma","authors":"Sunita Bijarnia-Mahay,&nbsp;Ratna Dua Puri,&nbsp;Madhulika Kabra","doi":"10.1002/jimd.12825","DOIUrl":"10.1002/jimd.12825","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12825","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143033248","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 Recovers the Autophagy Defects Underlying the Pathophysiology of Cell Trafficking Disorders","authors":"Yaiza Díaz-Osorio,&nbsp;Helena Gimeno-Agud,&nbsp;Rosanna Mari-Vico,&nbsp;Sofía Illescas,&nbsp;Jose Miguel Ramos,&nbsp;Alejandra Darling,&nbsp;Àngels García-Cazorla,&nbsp;Alfonso Oyarzábal","doi":"10.1002/jimd.12841","DOIUrl":"10.1002/jimd.12841","url":null,"abstract":"<p>Cell trafficking alterations are a growing group of disorders and one of the largest categories of Inherited Metabolic Diseases. They have complex and variable clinical presentation. Regarding neurological manifestations they can present a wide repertoire of symptoms ranging from neurodevelopmental to neurodegnerative disorders. The study of monogenic cell trafficking diseases draws an scenario to understanding this complex group of disorders and to find new therapeutic avenues. Within their pathophysiology, alterations in autophagy outstand as a targetable mechanism of disease, ammended to be modulated through different strategies. In this work we have studied the pathophysiology of two cell trafficking disorders due to mutations in <i>SYNJ1</i> and <i>NBAS</i> genes. Specifically, we have assesed the autophagic flux in primary fibroblast cultures of the patients and gender/age-matched controls and whether it could be address with a therapeutic purpose. The results have shaped autophagy as one of the hallmarks of the disease. Moreover, we tested in vitro the effect of spermidine, a natural polyamine that acts as an autopagy inductor. Due to the positive results, its efficacy was evaluated later on the patients as well, in a series of n-of-1 clinical trials, achieving improvement in some clinical aspects related to motricity and cognition. Defining autophagy alterations as a common feature in the pathophysiology of cell trafficking disorders is a great step towards their treatment, as it represents a potential actionable target for the personalized treatement of these disorders.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11751594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006782","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":"Unifying biology of neurodegeneration in lysosomal storage diseases","authors":"Anna M. Ludlaim,&nbsp;Simon N. Waddington,&nbsp;Tristan R. McKay","doi":"10.1002/jimd.12833","DOIUrl":"10.1002/jimd.12833","url":null,"abstract":"<p>There are currently at least 70 characterised lysosomal storage diseases (LSD) resultant from inherited single-gene defects. Of these, at least 30 present with central nervous system (CNS) neurodegeneration and overlapping aetiology. Substrate accumulation and dysfunctional neuronal lysosomes are common denominator, but how variants in 30 different genes converge on this central cellular phenotype is unclear. Equally unresolved is how the accumulation of a diverse spectrum of substrates in the neuronal lysosomes results in remarkably similar neurodegenerative outcomes. Conversely, how is it that many other monogenic LSDs cause only visceral disease? Lysosomal substance accumulation in LSDs with CNS neurodegeneration (nLSD) includes lipofuscinoses, mucopolysaccharidoses, sphingolipidoses and glycoproteinoses. Here, we review the latest discoveries in the fundamental biology of four classes of nLSDs, comparing and contrasting new insights into disease mechanism with emerging evidence of unifying convergence.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006784","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":"Speech, Language and Non-verbal Communication in CLN2 and CLN3 Batten Disease","authors":"Lottie D. Morison,&nbsp;Ineka T. Whiteman,&nbsp;Adam P. Vogel,&nbsp;Lisa Tilbrook,&nbsp;Michael C. Fahey,&nbsp;Ruth Braden,&nbsp;Joanna Bredebusch,&nbsp;Michael S. Hildebrand,&nbsp;Ingrid E. Scheffer,&nbsp;Angela T. Morgan","doi":"10.1002/jimd.12838","DOIUrl":"10.1002/jimd.12838","url":null,"abstract":"<p>CLN2 and CLN3 diseases, the most common types of Batten disease (also known as neuronal ceroid lipofuscinosis), are childhood dementias associated with progressive loss of speech, language and feeding skills. Here we delineate speech, language, non-verbal communication and feeding phenotypes in 33 individuals (19 females) with a median age of 9.5 years (range 3–28 years); 16 had CLN2 and 17 CLN3 disease; 8/15 (53%) participants with CLN2 and 8/17 (47%) participants with CLN3 disease had speech and language impairments prior to genetic diagnosis. At the time of study all participants, bar one, had language impairments. The remaining participant with typical language was tested at age 3 years, following pre-symptomatic enzyme replacement therapy (ERT) from age 9 months. CLN2 and CLN3 disease had different profiles. For CLN2 disease, all affected individuals showed language impairment with dysarthria; older individuals with classical disease progressively became non-verbal. For CLN3 disease, the presentation was more heterogeneous. Speech impairment was evident early in the disease course, with dysarthria (13/15, 87%), often manifesting as neurogenic stuttering (5/15, 33%). Participants with CLN2 disease had comparable expressive and receptive language skills (<i>p</i> &gt; 0.99), yet participants with CLN3 disease had stronger expressive language than receptive language skills (<i>p</i> = 0.004). Speech, cognitive and language impairment and adaptive behaviour showed progressive decline in both diseases. Individuals with pre-symptomatic ERT or atypical CLN2 disease were less impaired. Challenging behaviours were common in CLN3 (11/17, 65%), but less frequent in CLN2 (4/16, 25%) disease. Individuals with Batten disease require tailored speech therapy incorporating communication partner training utilising environment adaptations and informal communication behaviours.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006780","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":"Response to Downie et al.","authors":"Isabel R. Betzler,&nbsp;Maja Hempel,&nbsp;Ulrike Mütze,&nbsp;Stefan Kölker,&nbsp;Eva Winkler,&nbsp;Nicola Dikow,&nbsp;Sven F. Garbade,&nbsp;Christian P. Schaaf,&nbsp;Heiko Brennenstuhl","doi":"10.1002/jimd.12837","DOIUrl":"10.1002/jimd.12837","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983812","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":"Cystathionine β-Synthase Deficiency in the E-HOD Registry—Part II: Dietary and Pharmacological Treatment","authors":"Andrew A. M. Morris,&nbsp;Jitka Sokolová,&nbsp;Markéta Pavlíková,&nbsp;Florian Gleich,&nbsp;Stefan Kölker,&nbsp;Carlo Dionisi-Vici,&nbsp;Matthias R. Baumgartner,&nbsp;Luciana Hannibal,&nbsp;Henk J. Blom,&nbsp;Martina Huemer,&nbsp;Viktor Kožich,&nbsp;E-HOD Consortium","doi":"10.1002/jimd.12844","DOIUrl":"https://doi.org/10.1002/jimd.12844","url":null,"abstract":"<p>Cystathionine β-synthase (CBS) deficiency (classical homocystinuria) has a wide range of severity. Mildly affected patients typically present as adults with thromboembolism and respond to treatment with pyridoxine. Severely affected patients usually present during childhood with learning difficulties, ectopia lentis and skeletal abnormalities; they are pyridoxine non-responders (NR) or partial responders (PR) and require treatment with a low-methionine diet and/or betaine. The European network and registry for Homocystinurias and methylation Defects (E-HOD) has published management guidelines for CBS deficiency and recommended keeping plasma total homocysteine (tHcy) concentrations below 100 μmol/L. We have now analysed data from 311 patients in the registry to see how closely treatment follows the guidelines. Pyridoxine-responsive patients generally achieved tHcy concentrations below 50 μmol/L, but many NRs and PRs had a mean tHcy considerably above 100 μmol/L. Most NRs were managed with betaine and a special diet. This usually involved severe protein restriction and a methionine-free amino acid mixture, but some patients had a natural protein intake substantially above the WHO safe minimum. Work is needed on the methionine content of dietary protein as estimates vary widely. Contrary to the guidelines, most NRs were on pyridoxine, sometimes at dangerously high doses. tHcy concentrations were similar in groups prescribed high or low betaine doses and natural protein intakes. High tHcy levels were probably often due to poor compliance. Comparing time-to-event graphs for NR patients detected by newborn screening and those ascertained clinically showed that treatment could prevent thromboembolism (risk ratio 0.073) and lens dislocation (risk ratio 0.069).</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12844","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143114522","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":"Letter to the editor in response to Betzler et al.","authors":"Lilian Downie,&nbsp;Sebastian Lunke,&nbsp;Zornitza Stark","doi":"10.1002/jimd.12834","DOIUrl":"10.1002/jimd.12834","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971210","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":"The Metabolic Treatabolome and Inborn Errors of Metabolism Knowledgebase therapy tool: Do not miss the opportunity to treat!","authors":"Bibiche den Hollander,&nbsp;Eva M. M. Hoytema van Konijnenburg,&nbsp;Brittany Hewitson,&nbsp;Jan C. van der Meijden,&nbsp;Berith M. Balfoort,&nbsp;Brad Winter,&nbsp;Annelieke R. Müller,&nbsp;Wyeth W. Wasserman,&nbsp;Carlos R. Ferreira,&nbsp;Clara D. van Karnebeek","doi":"10.1002/jimd.12835","DOIUrl":"10.1002/jimd.12835","url":null,"abstract":"<p>Inborn errors of metabolism (IEMs) are rare genetic conditions with significant morbidity and mortality. Technological advances have increased therapeutic options, making it challenging to remain up to date. A centralized therapy knowledgebase is needed for early diagnosis and targeted treatment. This study aimed to identify all treatable IEMs through a scoping literature review, followed by data extraction and analysis according to the Treatabolome principles. Knowledge of treatable IEMs, therapeutic categories, efficacy, and evidence was integrated into the Inborn Errors of Metabolism Knowledgebase (IEMbase), an online database encompassing all IEMs. The study identified 275 treatable IEMs, 18% of all currently known 1564 IEMs, according to the International Classification of Inherited Metabolic Disorders. <i>Disorders of fatty acid and ketone body metabolism</i> had the highest treatability (67%), followed by <i>disorders of vitamin and cofactor metabolism</i> (60%), and <i>disorders of lipoprotein metabolism</i> (42%). The most common treatment strategies were pharmacological therapy (34%), nutritional therapy (34%), and vitamin and trace element supplementation (12%). Treatment effects were most commonly observed in nervous system abnormalities (34%), metabolism/homeostasis abnormalities (33%), and growth (7%). Predominant evidence sources included case reports with evidence levels 4 (48%) and 5 (12%), and individual cohort studies with evidence level 2b (12%). Our study generated the Metabolic Treatabolome 2024. IEMs are the largest group of monogenic disorders amenable to disease-modifying therapy. With drug repurposing efforts and advancements in gene therapies, this number will expand. IEMbase now provides up-to-date, comprehensive information on clinical and biochemical symptoms and therapeutic options, empowering patients, families, healthcare professionals, and researchers in improving patient outcomes.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950226","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}