Molecular genetics and metabolism最新文献

{"title":"Cover 2 / Ed. Board","authors":"","doi":"10.1016/S1096-7192(24)00384-6","DOIUrl":"https://doi.org/10.1016/S1096-7192(24)00384-6","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 2","pages":"Article 108500"},"PeriodicalIF":3.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224003846/pdfft?md5=d30d76f5a6723e4330c1f643d5da5793&pid=1-s2.0-S1096719224003846-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141244352","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":"Dysarthria and dysphagia in patients with mitochondrial diseases","authors":"R.E.M. Kuin ,&nbsp;J.T. Groothuis ,&nbsp;P. Buit ,&nbsp;M.C.H. Janssen ,&nbsp;S. Knuijt","doi":"10.1016/j.ymgme.2024.108510","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108510","url":null,"abstract":"<div><h3>Background</h3><p>Information about dysarthria and dysphagia in mitochondrial diseases (MD) is scarce. However, this knowledge is needed to identify speech and swallowing problems early, to monitor the disease course, and to develop and offer optimal treatment and support. This study therefore aims to examine the prevalence and severity of dysarthria and dysphagia in patients with MD and its relation to clinical phenotype and disease severity. Secondary aim is to determine clinically relevant outcome measures for natural history studies and clinical trials.</p></div><div><h3>Methods</h3><p>This retrospective cross-sectional medical record study includes adults (age ≥ 18 years) diagnosed with genetically confirmed MD who participated in a multidisciplinary admission within the Radboud center for mitochondrial medicine between January 2015 and April 2023. Dysarthria and dysphagia were examined by administering the Radboud dysarthria assessment, swallowing speed, dysphagia limit, test of mastication and swallowing solids (TOMASS), and 6-min mastication test (6MMT). The disease severity was assessed using the Newcastle mitochondrial disease scale for adults (NMDAS).</p></div><div><h3>Results</h3><p>The study included 224 patients with MD with a median age of 42 years of whom 37.5% were male. The pooled prevalence of dysarthria was 33.8% and of dysphagia 35%. Patients with MD showed a negative deviation from the norm on swallowing speed, TOMASS (total time) and the 6MMT. Furthermore, a significant moderate relation was found between the presence of dysarthria and the clinical phenotypes. There was a statistically significant difference in total time on the TOMASS between the clinical phenotypes. Finally, disease severity showed a significant moderate relation with the severity of dysarthria and a significant weak relation with the severity of dysphagia.</p></div><div><h3>Conclusion</h3><p>Dysarthria and dysphagia occur in about one-third of patients with MD. It is important for treating physicians to pay attention to this subject because of the influence of both disorders on social participation and wellbeing. Referral to a speech and language therapist should therefore be considered, especially in patients with a more severe clinical phenotype. The swallowing speed, TOMASS and 6MMT are the most clinically relevant tests to administer.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 3","pages":"Article 108510"},"PeriodicalIF":3.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224003949/pdfft?md5=e94ba209772d5f677f08e0849748698c&pid=1-s2.0-S1096719224003949-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141250092","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":"Further delineation of short-chain enoyl-CoA hydratase deficiency in the Pacific population","authors":"Isaac Bernhardt ,&nbsp;Leah E. Frajman ,&nbsp;Bryony Ryder ,&nbsp;Erik Andersen ,&nbsp;Callum Wilson ,&nbsp;Colina McKeown ,&nbsp;Tim Anderson ,&nbsp;David Coman ,&nbsp;Andrea L. Vincent ,&nbsp;Christina Buchanan ,&nbsp;Richard Roxburgh ,&nbsp;James Pitt ,&nbsp;Mark De Hora ,&nbsp;John Christodoulou ,&nbsp;David R. Thorburn ,&nbsp;Francessa Wilson ,&nbsp;Kylie M. Drake ,&nbsp;Megan Leask ,&nbsp;Anne-Marie Yardley ,&nbsp;Tony Merriman ,&nbsp;Emma Glamuzina","doi":"10.1016/j.ymgme.2024.108508","DOIUrl":"10.1016/j.ymgme.2024.108508","url":null,"abstract":"<div><p>Short-chain enoyl-coA hydratase (SCEH) deficiency due to biallelic pathogenic <em>ECHS1</em> variants was first reported in 2014 in association with Leigh syndrome (LS) and increased S-(2-carboxypropyl)cysteine excretion. It is potentially treatable with a valine-restricted, high-energy diet and emergency regimen. Recently, Simon et al. described four Samoan children harbouring a hypomorphic allele (c.489G &gt; A, p.Pro163=) associated with reduced levels of normally-spliced mRNA. This synonymous variant, missed on standard genomic testing, is prevalent in the Samoan population (allele frequency 0.17). Patients with LS and one <em>ECHS1</em> variant were identified in NZ and Australian genomic and clinical databases<em>. ECHS1</em> sequence data were interrogated for the c.489G &gt; A variant and clinical data were reviewed. Thirteen patients from 10 families were identified; all had Pacific ancestry including Samoan, Māori, Cook Island Māori, and Tokelauan. All developed bilateral globus pallidi lesions, excluding one pre-symptomatic infant. Symptom onset was in early childhood, and was triggered by illness or starvation in 9/13. Four of 13 had exercise-induced dyskinesia, 9/13 optic atrophy and 6/13 nystagmus. Urine S-(2-carboxypropyl)cysteine-carnitine and other SCEH-related metabolites were normal or mildly increased. Functional studies demonstrated skipping of exon four and markedly reduced ECHS1 protein. These data provide further support for the pathogenicity of this <em>ECHS1</em> variant which is also prevalent in Māori, Cook Island Māori, and Tongan populations (allele frequency 0.14–0.24). It highlights the need to search for a second variant in apparent heterozygotes with an appropriate phenotype, and has implications for genetic counselling in family members who are heterozygous for the more severe <em>ECHS1</em> alleles.</p></div><div><h3>Synopsis</h3><p>Short-chain enoyl-CoA hydratase deficiency is a frequent cause of Leigh-like disease in Māori and wider-Pacific populations, due to the high carrier frequency of a hypomorphic <em>ECHS1</em> variant c.489G &gt; A, p.[Pro163=, Phe139Valfs*65] that may be overlooked by standard genomic testing.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 3","pages":"Article 108508"},"PeriodicalIF":3.8,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141184279","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":"Causes of death in mucopolysaccharidoses","authors":"Estera Rintz,&nbsp;Marcin Banacki,&nbsp;Maja Ziemian,&nbsp;Barbara Kobus,&nbsp;Grzegorz Wegrzyn","doi":"10.1016/j.ymgme.2024.108507","DOIUrl":"10.1016/j.ymgme.2024.108507","url":null,"abstract":"<div><p>Mucopolysaccharidoses are inherited metabolic diseases caused by mutations in genes encoding enzymes required for degradation of glycosaminoglycans. A lack or severe impairment of activity of these enzymes cause accumulation of GAGs which is the primary biochemical defect. Depending on the kind of the deficient enzyme, there are 12 types and subtypes of MPS distinguished. Despite the common primary metabolic deficit (inefficient GAG degradation), the course and symptoms of various MPS types can be different, though majority of the diseases from the group are characterized by severe symptoms and significantly shortened live span. Here, we analysed the frequency of specific, direct causes of death of patients with different MPS types, the subject which was not investigated comprehensively to date. We examined a total of 1317 cases of death among MPS patients, including 393 cases of MPS I, 418 cases of MPS II, 232 cases of MPS III, 45 cases of MPS IV, 208 cases of MPS VI, and 22 cases of MPS VII. Our analyses indicated that the most frequent causes of death differ significantly between MPS types, with cardiovascular and respiratory failures being predominant in MPS I, MPS II, and MPS VI, neurological deficits in MPS III, respiratory issues in MPS IV, and hydrops fetalis in MPS VII. Results of such studies suggest what specific clinical problems should be considered with the highest priority in specific MPS types, apart from attempts to correct the primary causes of the diseases, to improve the quality of life of patients and to prolong their lives.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 3","pages":"Article 108507"},"PeriodicalIF":3.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224003913/pdfft?md5=4a17952c2bd8aa6267ca988d2056c3f0&pid=1-s2.0-S1096719224003913-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141135308","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":"AAV-mediated expression of mouse or human GLDC normalises metabolic biomarkers in a GLDC-deficient mouse model of Non-Ketotic Hyperglycinemia","authors":"Kit-Yi Leung ,&nbsp;Chloe Santos ,&nbsp;Sandra C.P. De Castro ,&nbsp;Diana Gold Diaz ,&nbsp;Andrew J. Copp ,&nbsp;Simon Waddington ,&nbsp;Nicholas D.E. Greene","doi":"10.1016/j.ymgme.2024.108496","DOIUrl":"10.1016/j.ymgme.2024.108496","url":null,"abstract":"<div><p>Non-Ketotic Hyperglycinemia (NKH) is a rare inborn error of metabolism caused by impaired function of the glycine cleavage system (GCS) and characterised by accumulation of glycine in body fluids and tissues. NKH is an autosomal recessive condition and the majority of affected individuals carry mutations in <em>GLDC</em> (glycine decarboxylase). Current treatments for NKH have limited effect and are not curative. As a monogenic condition with known genetic causation, NKH is potentially amenable to gene therapy. An AAV9-based expression vector was designed to target sites of GCS activity. Using a ubiquitous promoter to drive expression of a GFP reporter, transduction of liver and brain was confirmed following intra-venous and/or intra-cerebroventricular administration to neonatal mice. Using the same capsid and promoter with transgenes to express mouse or human GLDC, vectors were then tested in GLDC-deficient mice that provide a model of NKH. GLDC-deficient mice exhibited elevated plasma glycine concentration and accumulation of glycine in liver and brain tissues as previously observed. Moreover, the folate profile indicated suppression of folate one‑carbon metabolism (FOCM) in brain tissue, as found at embryonic stages, and reduced abundance of FOCM metabolites including betaine and choline. Neonatal administration of vector achieved reinstatement of <em>GLDC</em> mRNA and protein expression in GLDC<em>-</em>deficient mice. Treated GLDC<em>-</em>deficient mice showed significant lowering of plasma glycine, confirming functionality of vector expressed protein. AAV9-GLDC treatment also led to lowering of brain tissue glycine, and normalisation of the folate profile indicating restoration of glycine-derived one‑carbon supply. These findings support the hypothesis that AAV-mediated gene therapy may offer potential in treatment of NKH.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 3","pages":"Article 108496"},"PeriodicalIF":3.8,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224003809/pdfft?md5=33589d3a642c01ed6871d0e3cde2eb68&pid=1-s2.0-S1096719224003809-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958532","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":"Usefulness of antibody-drug conjugate as preconditioning for hematopoietic stem cell-targeted gene therapy in wild-type and Fabry disease mouse models","authors":"Jin Ogata ,&nbsp;Yohta Shimada ,&nbsp;Toya Ohashi ,&nbsp;Hiroshi Kobayashi","doi":"10.1016/j.ymgme.2024.108494","DOIUrl":"10.1016/j.ymgme.2024.108494","url":null,"abstract":"<div><h3>Background</h3><p>Fabry disease (FD) is characterized by deficient activity of α-galactosidase A (GLA). Consequently, globotriaosylceramide (Gb3) accumulates in various organs, causing cardiac, renal, and cerebrovascular damage. Gene therapies for FD have been investigated in humans. Strong conditioning is required for hematopoietic stem cell-targeted gene therapy (HSC-GT). However, strong conditioning leads to various side effects and should be avoided. In this study, we tested antibody-based conditioning for HSC-GT in wild-type and FD model mice.</p></div><div><h3>Methods</h3><p>After preconditioning with an antibody-drug conjugate, HSC-GT using a lentiviral vector was performed in wild-type and Fabry model mice. In the wild-type experiment, the <em>EGFP</em> gene was introduced into HSCs and transplanted into preconditioned mice, and donor chimerism and EGFP expression were analyzed. In the FD mouse model, the <em>GLA</em> gene was introduced into HSCs and transplanted into preconditioned Fabry mice. GLA activity and Gb3 accumulation in the organs were analyzed.</p></div><div><h3>Results</h3><p>In the wild-type mouse experiment, when anti-CD45 antibody-drug conjugate was used, the percentage of donor cells at 6 months was 64.5%, and 69.6% of engrafted donor peripheral blood expressed EGFP. When anti-CD117 antibody-drug conjugate and ATG were used, the percentage of donor cells at 6 months was 80.7%, and 73.4% of engrafted donor peripheral blood expressed EGFP. Although large variations in GLA activity among mice were observed in the FD mouse experiment for both preconditioning regimens, Gb3 was significantly reduced in many organs.</p></div><div><h3>Conclusions</h3><p>Antibody-based preconditioning may be an alternative preconditioning strategy for HSC-GT for treating FD.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 3","pages":"Article 108494"},"PeriodicalIF":3.8,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141037183","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":"A multiomics approach reveals evidence for phenylbutyrate as a potential treatment for combined D,L-2- hydroxyglutaric aciduria","authors":"Yu Leng Phua ,&nbsp;Olivia M. D'Annibale ,&nbsp;Anuradha Karunanidhi ,&nbsp;Al-Walid Mohsen ,&nbsp;Brian Kirmse ,&nbsp;Steven F. Dobrowolski ,&nbsp;Jerry Vockley","doi":"10.1016/j.ymgme.2024.108495","DOIUrl":"10.1016/j.ymgme.2024.108495","url":null,"abstract":"<div><h3>Purpose</h3><p>To identify therapies for combined D, L-2-hydroxyglutaric aciduria (C-2HGA), a rare genetic disorder caused by recessive variants in the <em>SLC25A1</em> gene.</p></div><div><h3>Methods</h3><p>Patients C-2HGA were identified and diagnosed by whole exome sequencing and biochemical genetic testing. Patient derived fibroblasts were then treated with phenylbutyrate and the functional effects assessed by metabolomics and RNA-sequencing.</p></div><div><h3>Results</h3><p>In this study, we demonstrated that C-2HGA patient derived fibroblasts exhibited impaired cellular bioenergetics. Moreover, Fibroblasts form one patient exhibited worsened cellular bioenergetics when supplemented with citrate. We hypothesized that treating patient cells with phenylbutyrate (PB), an FDA approved pharmaceutical drug that conjugates glutamine for renal excretion, would reduce mitochondrial 2-ketoglutarate, thereby leading to improved cellular bioenergetics. Metabolomic and RNA-seq analyses of PB-treated fibroblasts demonstrated a significant decrease in intracellular 2-ketoglutarate, 2-hydroxyglutarate, and in levels of mRNA coding for citrate synthase and isocitrate dehydrogenase. Consistent with the known action of PB, an increased level of phenylacetylglutamine in patient cells was consistent with the drug acting as 2-ketoglutarate sink.</p></div><div><h3>Conclusion</h3><p>Our pre-clinical studies suggest that citrate supplementation has the possibility exacerbating energy metabolism in this condition. However, improvement in cellular bioenergetics suggests phenylbutyrate might have interventional utility for this rare disease.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 3","pages":"Article 108495"},"PeriodicalIF":3.8,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141046704","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":"Promyelinating drugs ameliorate oligodendrocyte pathologies in a mouse model of Krabbe disease","authors":"Naoko Inamura ,&nbsp;Taeko Kawai ,&nbsp;Takashi Watanabe ,&nbsp;Hiromasa Aoki ,&nbsp;Mineyoshi Aoyama ,&nbsp;Atsuo Nakayama ,&nbsp;Junko Matsuda ,&nbsp;Yasushi Enokido","doi":"10.1016/j.ymgme.2024.108497","DOIUrl":"10.1016/j.ymgme.2024.108497","url":null,"abstract":"<div><p>Krabbe disease (KD) is a rare inherited demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramide (GalCer) β-galactosidase. Most patients with KD exhibit fatal cerebral demyelination with apoptotic oligodendrocyte (OL) death and die before the age of 2–4 years. We have previously reported that primary OLs isolated from the brains of twitcher (twi) mice, an authentic mouse model of KD, have cell-autonomous developmental defects and undergo apoptotic death accompanied by abnormal accumulation of psychosine, an endogenous cytotoxic lyso-derivative of GalCer. In this study, we aimed to investigate the effects of the preclinical promyelinating drugs clemastine and Sob-AM2 on KD OL pathologies using primary OLs isolated from the brains of twi mice. Both agents specifically prevented the apoptotic death observed in twi OLs. However, while Sob-AM2 showed higher efficacy in restoring the impaired differentiation and maturation of twi OLs, clemastine more potently reduced the endogenous psychosine levels. These results present the first preclinical <em>in vitro</em> data, suggesting that clemastine and Sob-AM2 can act directly and distinctly on OLs in KD and ameliorate their cellular pathologies associated with myelin degeneration.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 3","pages":"Article 108497"},"PeriodicalIF":3.8,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141061361","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, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals","authors":"Tanyel Zubarioglu ,&nbsp;Ertuğrul Kıykım ,&nbsp;Engin Köse ,&nbsp;Fatma Tuba Eminoğlu ,&nbsp;Pelin Teke Kısa ,&nbsp;Mehmet Cihan Balcı ,&nbsp;Işıl Özer ,&nbsp;Aslı İnci ,&nbsp;Kübra Çilesiz ,&nbsp;Ebru Canda ,&nbsp;Havva Yazıcı ,&nbsp;Burcu Öztürk-Hişmi ,&nbsp;Fatma Derya Bulut ,&nbsp;Sevil Dorum ,&nbsp;Abdurrahman Akgun ,&nbsp;Gül Yalçın-Çakmaklı ,&nbsp;Gonca Kılıç-Yıldırım ,&nbsp;Erdoğan Soyuçen ,&nbsp;Aylin Akçalı ,&nbsp;Dilek Güneş ,&nbsp;Çiğdem Aktuğlu-Zeybek","doi":"10.1016/j.ymgme.2024.108493","DOIUrl":"10.1016/j.ymgme.2024.108493","url":null,"abstract":"<div><h3>Objective</h3><p>Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey.</p></div><div><h3>Methods</h3><p>The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed.</p></div><div><h3>Results</h3><p>100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (<em>p</em> = 0.069), peripheral neuropathy (<em>p</em> = 0.234) and psychiatric manifestations (<em>p</em> = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the <em>CYP27A1</em> gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature.</p></div><div><h3>Conclusion</h3><p>Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 2","pages":"Article 108493"},"PeriodicalIF":3.8,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141040956","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":"D-mannose as a new therapy for fucokinase deficiency-related congenital disorder of glycosylation (FCSK-CDG)","authors":"Rodrigo Tzovenos Starosta ,&nbsp;Angela J. Lee ,&nbsp;Elizabeth R. Toolan ,&nbsp;Miao He ,&nbsp;Parith Wongkittichote ,&nbsp;Earnest James Paul Daniel ,&nbsp;Silvia Radenkovic ,&nbsp;Rohit Budhraja ,&nbsp;Akhilesh Pandey ,&nbsp;Jaiprakash Sharma ,&nbsp;Eva Morava ,&nbsp;Hoanh Nguyen ,&nbsp;Patricia I. Dickson","doi":"10.1016/j.ymgme.2024.108488","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108488","url":null,"abstract":"<div><h3>Introduction</h3><p>Fucokinase deficiency-related congenital disorder of glycosylation (FCSK-CDG) is a rare autosomal recessive inborn error of metabolism characterized by a decreased flux through the salvage pathway of GDP-fucose biosynthesis due to a block in the recycling of L-fucose that exits the lysosome. FCSK-CDG has been described in 5 individuals to date in the medical literature, with a phenotype comprising global developmental delays/intellectual disability, hypotonia, abnormal myelination, posterior ocular disease, growth and feeding failure, immune deficiency, and chronic diarrhea, without clear therapeutic recommendations.</p></div><div><h3>Patient and methods</h3><p>In a so far unreported FCSK-CDG patient, we studied proteomics and glycoproteomics <em>in vitro</em> in patient-derived fibroblasts and also performed <em>in vivo</em> glycomics, before and after treatment with either D-Mannose or L-Fucose.</p></div><div><h3>Results</h3><p>We observed a marked increase in fucosylation after D-mannose supplementation in fibroblasts compared to treatment with L-Fucose. The patient was then treated with D-mannose at 850 mg/kg/d, with resolution of the chronic diarrhea, resolution of oral aversion, improved weight gain, and observed developmental gains. Serum N-glycan profiles showed an improvement in the abundance of fucosylated glycans after treatment. No treatment-attributed adverse effects were observed.</p></div><div><h3>Conclusion</h3><p>D-mannose is a promising new treatment for FCSK-CDG.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 2","pages":"Article 108488"},"PeriodicalIF":3.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140910194","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}