Orphanet Journal of Rare Diseases最新文献

{"title":"A micro-costing study of mass-spectrometry based quantitative proteomics testing applied to the diagnostic pipeline of mitochondrial and other rare disorders.","authors":"Francisco Santos Gonzalez, Daniella H Hock, David R Thorburn, Dylan Mordaunt, Nicholas A Williamson, Ching-Seng Ang, David A Stroud, John Christodoulou, Ilias Goranitis","doi":"10.1186/s13023-024-03462-w","DOIUrl":"https://doi.org/10.1186/s13023-024-03462-w","url":null,"abstract":"<p><strong>Background: </strong>Mass spectrometry-based quantitative proteomics has a demonstrated utility in increasing the diagnostic yield of mitochondrial disorders (MDs) and other rare diseases. However, for this technology to be widely adopted in routine clinical practice, it is crucial to accurately estimate delivery costs. Resource use and unit costs required to undertake a proteomics test were measured and categorized into consumables, equipment, and labor. Unit costs were aggregated to obtain a total cost per patient, reported in 2023 Australian dollars (AUD). Probabilistic and deterministic sensitivity analysis were conducted to evaluate parameter uncertainty and identify key cost drivers.</p><p><strong>Results: </strong>The mean cost of a proteomics test was $897 (US$ 607) per patient (95% CI: $734-$1,111). Labor comprised 53% of the total costs. At $342 (US$ 228) per patient, liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) was the most expensive non-salary component. An integrated analysis pipeline where all the standard analysis are performed automatically, as well as discounts or subsidized LC-MS/MS equipment or consumables can lower the cost per test.</p><p><strong>Conclusions: </strong>Proteomics testing provide a lower-cost option and wider application compared to respiratory chain enzymology for mitochondrial disorders and potentially other functional assays in Australia. Our analysis suggests that streamlining and automating workflows can reduce labor costs. Using PBMC samples may be a cheaper and more efficient alternative to generating fibroblasts, although their use has not been extensively tested yet. Use of fibroblasts could potentially lower costs when fibroblasts are already available by avoiding the expense of isolating PBMCs. A joint evaluation of the health and economic implications of proteomics is now needed to support its introduction to routine clinical care.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"443"},"PeriodicalIF":3.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751418","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":"Neurocognitive functioning in adults with neurofibromatosis type 1- a nationwide population-based study.","authors":"Karoline Doser, Jens Richardt Møllegaard Jepsen, Line Kenborg, Kamilla Woznica Miskowiak, Vanna Albieri, Susanne Oksbjerg Dalton, Anja Krøyer, Hanne Hove, John R Østergaard, Christoffer Johansen, Sven Asger Sørensen, John Mulvihill, Jeanette Falck Winther, Pernille Envold Bidstrup","doi":"10.1186/s13023-024-03454-w","DOIUrl":"https://doi.org/10.1186/s13023-024-03454-w","url":null,"abstract":"<p><strong>Background: </strong>Neurofibromatosis type 1 (NF1) is a genetic condition characterized by various somatic manifestations and cognitive impairments, but the latter are sparsely described in adults. This study aimed at characterizing potential impairments of neurocognitive functions using neuropsychological tests as well as a self-report questionnaire.</p><p><strong>Methods: </strong>In a nationwide, population-based study including 103 adults with NF1 and 38 age- and gender-matched NF1-free comparisons, we used a comprehensive neurocognitive test battery to assess intelligence and visual short-term memory, immediate visuospatial recall, reaction time, sustained attention, motor speed, planning, planning time, working memory as well as multitasking and a questionnaire to assess executive functions. Descriptive statistics, multivariate analysis of variance (MANOVA), and general linear models with repeated measure analysis of variance (ANOVA) were used.</p><p><strong>Results: </strong>We observed a statistically significant difference in overall performance-based cognitive functioning. Adults with NF1 showed significant, moderate-to-severe impairments in intelligence, visual short-term memory, immediate visuospatial recall, sustained attention (p < 0.0001-0.002), and some executive functions (p = 0.008 - 0.001), whereas other cognitive functions (multitasking, reaction time, motor speed, spatial working memory, planning time, and planning efficacy as well as some self-reported executive functions) were unimpaired.</p><p><strong>Conclusions: </strong>This is the first study with a population-based sample of persons with NF1 and the results show impairments of intelligence and other cognitive functions. The pattern of both significant cognitive impairments and non-significantly different cognitive functions suggests a cognitive profile of selective rather than generalized cognitive deficits in NF1.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"441"},"PeriodicalIF":3.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751423","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":"A therapeutic approach to pantothenate kinase associated neurodegeneration: a pilot study.","authors":"Alessandra Pereira, Carolina Fischinger Moura de Souza, Mónica Álvarez-Córdoba, Diana Reche-López, José Antonio Sánchez-Alcázar","doi":"10.1186/s13023-024-03453-x","DOIUrl":"https://doi.org/10.1186/s13023-024-03453-x","url":null,"abstract":"<p><strong>Background: </strong>Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic neurological disorders frequently associated with iron accumulation in the basal nuclei of the brain characterized by progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. Pantothenate kinase-associated neurodegeneration (PKAN) is one of the most widespread NBIA disorders. The diagnosis of PKAN is established with clinical features and the \"eye of the tiger\" sign identified on brain MRI and the identification of biallelic pantothenate kinase 2 (PANK2) pathogenic variants on molecular genetic testing. PANK2 catalyzes the first reaction of coenzyme A (CoA) biosynthesis, thus, altered PANK2 activity is expected to induce CoA deficiency as well as low levels of essential metabolic intermediates such as 4'-phosphopantetheine which is a necessary cofactor for critical proteins involved in cytosolic and mitochondrial pathways such as fatty acid biosynthesis, mitochondrial respiratory complex I assembly and lysine and tetrahydrofolate metabolism, among other metabolic processes.</p><p><strong>Methods: </strong>In this manuscript, we examined the effect of a multitarget complex supplements (pantothenate, pantethine, omega-3 and vitamin E) on in vitro patient-derived cellular models and the clinical outcome of the adjuvant supplements in combination with the baseline neurological medication in three PKAN patients.</p><p><strong>Results: </strong>Multitarget complex supplements significantly reduced iron accumulation and increased PANK2 and ACP expression levels in the cellular models derived from all three PKAN patients. In addition, the adjunct treatment to the standard neurological medication improved or stabilized the clinical symptoms of patients.</p><p><strong>Conclusions: </strong>Our results suggest that multitarget complex supplements can be clinically useful as augmentation therapy for PKAN patients harboring pathogenic variants with residual enzyme levels.</p><p><strong>Trial registration: </strong>CAAE: 58219522.6.0000.5330. Registered 25 May 2022-Retrospectively registered, https://plataformabrasil.saude.gov.br/visao/pesquisador/gerirPesquisa/gerirPesquisaAgrupador.jsf .</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"442"},"PeriodicalIF":3.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751422","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":"Two cases of type I sialidosis and a literature review.","authors":"Yuan Ding, Ming Cheng, Chunxiu Gong","doi":"10.1186/s13023-024-03431-3","DOIUrl":"https://doi.org/10.1186/s13023-024-03431-3","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to compare the clinical and electrophysiological characteristics of two cases of type I sialidosis in Chinese children with those reported in prior literature. The goal is to elucidate the clinical and genetic features of type I sialidosis.</p><p><strong>Methods: </strong>Clinical investigations and genetic analyses were conducted on an 11-year-old girl, primarily presenting with short stature, who was admitted in June 2020, and a 10-year-old boy, admitted in July 2023, exhibiting rapid weight gain and accompanying visual impairment as primary manifestations. A literature review was performed by summarizing data from 31 published articles encompassing 69 genetically confirmed cases of type I sialidosis up to 2023 for comparative analysis.</p><p><strong>Results: </strong>Patient 1 exhibited short stature, self-reported poor night vision, a history of occasional febrile seizures, mild scoliosis, bilateral cherry-red spots in the fundus, and prolonged P100 latency in both eyes as observed in visual evoked potentials (VEP). Genetic analysis revealed that she carried compound-heterozygous variants c.239 C > T (p.P80L) and c.880 C > T (p.R294C) in the NEU1 gene, inherited from her parents. Patient 2 presented with rapid weight gain and visual impairment, bilateral cherry-red spots in the fundus, abnormal neuroepithelial layer reflexes in both macular areas, approximately normal P100 latency but severely reduced amplitude in VEP after pupillary dilation, and severe bilateral optic nerve conduction block with relatively normal retinal cell function. Compound-heterozygous variants c.239 C > T (p.P80L) and c.803 A > G (p.T268C) were identified in the NEU1 gene of the Patient 2, inherited from his parents. By combining the cases reported in 31 literature articles with the 2 cases in our study, a total of 71 type I sialidosis patients were analyzed. The most common symptoms observed were muscle spasms (91.5%), followed by ataxia (75%) and seizures (63.6%). Intellectual impairment and abnormal electroencephalograms were more prevalent in Caucasian patients. Additionally, abnormal somatosensory evoked potentials, large cortical waves, and prolonged latency of VEP were more frequently observed in both Asian and Caucasian patients, serving as alternative indicators for early diagnosis.</p><p><strong>Conclusion: </strong>NEU1 gene analysis provides essential guidance for genetic counseling and prenatal diagnosis. The exon 2 variant c.239 C > T (p.P80L) in the NEU1 gene may represent a mutation hotspot among Chinese patients.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"440"},"PeriodicalIF":3.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740194","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":"Heparan sulfate in cerebrospinal fluid as a biomarker to assess disease severity and for treatment monitoring in patients with Mucopolysaccharidosis Type II: a position statement.","authors":"Roberto Giugliani, Ana Cecília Menezes de Siqueira, Emerson Santana Santos, Emília Katiane E A Leão, Gerson da Silva Carvalho, Mara Lúcia Schmitz Ferreira Santos, Salmo Raskin, Ana Maria Martins","doi":"10.1186/s13023-024-03463-9","DOIUrl":"https://doi.org/10.1186/s13023-024-03463-9","url":null,"abstract":"<p><p>Patients with mucopolysaccharidosis type II (MPS II) can present with a severe neuronopathic phenotype or an attenuated non-neuronopathic phenotype. In the light of the recent development of drugs that cross the blood-brain barrier for treatment of neurologic MPS II symptoms, it is critical to define biomarkers that objectively differentiate phenotypes and monitor therapeutic outcomes of advanced treatments. In December 2023, a panel of Brazilian experts discussed the potential of quantifying heparan sulfate (HS) in the cerebrospinal fluid (CSF) as a biomarker for assessing neurological impairment in patients with MPS II, as well as the potential of the molecule as an objective parameter for therapeutic monitoring. Based on scientific evidence, the experts concluded that HS in CSF is predominantly derived from the brain and reflects neurological impairment in patients with MPS II. CSF HS levels may help differentiate between neuronopathic and non-neuronopathic forms of MPS II, with preliminary observations suggesting a potential threshold around 4,000 ng/mL when HS quantification is performed using the same method described in clinical studies of pabinafusp alfa. According to the authors, monitoring HS levels in CSF can serve as an objective parameter for assessing the effectiveness of treatment with drugs that cross the blood-brain barrier. The recommended timing of HS evaluations in CSF of patients with the severe phenotype is: (i) before treatment; (ii) six months after starting treatment; and (iii) two years after starting treatment. The same monitoring scheme is recommended for patients with the attenuated MPS II phenotype, however, after two years of treatment, the physician may elect to perform regular neurocognitive evaluations instead of measuring HS in CSF. Lastly, the authors reinforced the importance of evaluating adherence to treatment, including interruptions, to provide a more meaningful assessment of the treatment's real-world impact and to determine the ideal timing of CSF collection for therapeutic monitoring.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"436"},"PeriodicalIF":3.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142731054","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":"α-mannosidosis diagnosis in Brazilian patients with MPS-like symptoms.","authors":"Maryana Marins, Marco Antonio Curiati, Caio Perez Gomes, Renan Paulo Martin, Priscila Nicolicht-Amorim, Joyce Umbelino da Silva Yamamoto, Vânia D'Almeida, Ana Maria Martins, João Bosco Pesquero","doi":"10.1186/s13023-024-03419-z","DOIUrl":"10.1186/s13023-024-03419-z","url":null,"abstract":"<p><strong>Background: </strong>α-mannosidosis is an inborn error of metabolism caused by the deficiency of the lysosomal enzyme α-mannosidase, which is encoded by the MAN2B1 gene and inherited in an autosomal recessive manner. The impairment of affected individuals is multisystemic and very similar to the observed in some mucopolysaccharidosis (MPS) patients. The aim of this study was to search for α-mannosidosis cases in individuals with clinical suspicion of MPS without a confirmed diagnosis. Biochemical and molecular analysis were standardized by our group for this study. Two hundred and fifty samples from patients with clinical suspicion of MPS, but with inconclusive MPS biochemical and/or molecular analysis, were screened for α-mannosidase activity. Subsequently the MAN2B1 gene was sequenced in samples from 53 patients by the Sanger method.</p><p><strong>Results: </strong>The measurement of enzymatic activity detected fifty-three samples with abnormal results, suggesting α-mannosidosis. Molecular analysis confirmed three affected families, which presented the nonsense variant p.Ser899Ter. This variant generates a premature stop codon in exon 22, resulting in a truncated protein with no residual enzymatic activity.</p><p><strong>Conclusion: </strong>In conclusion, this work brings data for the beginning of a genetic characterization of α-mannosidosis in the Brazilian population. It also shows that α-mannosidosis cases may be underdiagnosed due to the clinical similarity to MPS and the lack of information about this ultra-rare disease. Based on our data, we strongly recommend to all screening centers to consider α-mannosidosis testing together with screening for MPS as a tool for diagnosis to MPS-like phenotype individuals, since the phenotype similarity between these diseases poses a significant challenge for clinicians worldwide and often leads to the failure of the correct clinical diagnosis and treatment.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"439"},"PeriodicalIF":3.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142731057","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":"Conjoint analysis of methylation, transcriptomic, and proteomic profiles in pemphigus vulgaris.","authors":"Xiaojia Luo, Jianting Ouyang, Fuqiong Jiang, Yaozhong Zhang, Yuan Wang, Yongzhuo Wu, Lingyu Hu","doi":"10.1186/s13023-024-03458-6","DOIUrl":"https://doi.org/10.1186/s13023-024-03458-6","url":null,"abstract":"<p><strong>Background: </strong>The underlying pathogenesis of pemphigus vulgaris, an autoimmune skin disorder, remains incompletely understood. An integrative analysis comprising DNA methylation, mRNA expression, and proteomic data in patients with pemphigus vulgaris was conducted to identify potential pathogenic contributors and explore the molecular mechanisms involved in its pathogenesis.</p><p><strong>Results: </strong>The analysis revealed differentially methylated regions (DMRs) in the promoter, exon, intron, and downstream regions in the peripheral blood DNA of patients with pemphigus vulgaris. Associations between methylation levels and both transcriptomic and proteomic profiles revealed that differentially expressed genes between patients with pemphigus vulgaris and healthy controls were primarily linked to biological functions such as platelet activation and coagulation, cellular adhesion, and immunoglobulin binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis highlighted notable pathway abnormalities, including those related to platelet activation, focal adhesions, tight junctions, and infectious inflammatory responses. Notably, genes such as FGA (fibrinogen alpha chain), VWF (von Willebrand factor), and ACTG1 (actin gamma 1) were dysregulated, with a prominent role in platelet activation.</p><p><strong>Conclusion: </strong>The dysregulation of genes such as FGA, VWF, and ACTG1 suggests that alterations in their transcription and expression may contribute to the pathogenesis of pemphigus vulgaris.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"437"},"PeriodicalIF":3.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142731049","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":"Current insights in ultra-rare adenylosuccinate synthetase 1 myopathy - meeting report on the First Clinical and Scientific Conference. 3 June 2024, National Centre for Advancing Translational Science, Rockville, Maryland, the United States of America.","authors":"Emma Rybalka, Hyung Jun Park, Atchayaram Nalini, Dipti Baskar, Kiran Polavarapu, Hacer Durmus, Yang Xia, Linlin Wan, Perry B Shieh, Behzad Moghadaszadeh, Alan H Beggs, David L Mack, Alec S T Smith, Wendy Hanna-Rose, Hyder A Jinnah, Cara A Timpani, Min Shen, Jaymin Upadhyay, Jeffrey J Brault, Matthew D Hall, Naveen Baweja, Priyanka Kakkar","doi":"10.1186/s13023-024-03429-x","DOIUrl":"https://doi.org/10.1186/s13023-024-03429-x","url":null,"abstract":"","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"438"},"PeriodicalIF":3.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142731052","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":"Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree.","authors":"Zhenglong Guo, Dawei Huo, Yingying Shao, Wenke Yang, Jinming Wang, Yuwei Zhang, Hai Xiao, Bingtao Hao, Shixiu Liao","doi":"10.1186/s13023-024-03465-7","DOIUrl":"10.1186/s13023-024-03465-7","url":null,"abstract":"<p><strong>Background: </strong>Cellular iron metabolism is essential for maintaining various biological processes in organisms, and this is influenced by the function of iron-responsive element-binding protein 2 (IRP2), encoded by the IREB2 gene. Since 2019, three cases of a genetic neurodegenerative syndrome resulting from compound heterozygous mutations in IREB2 have been documented, highlighting the crucial role of IRP2 in regulating iron metabolism homeostasis. This study aims to investigate the molecular basis in a single proband born to non-consanguineous healthy parents, presenting with severe psychomotor developmental abnormalities and microcytic anemia.</p><p><strong>Methods: </strong>Trio-whole exome sequencing (WES) was applied to identify the disease-causing gene in an 8-month-old male patient from China. In silico tools were used to predict the pathogenicity of the identified variants, and in vitro functional studies were performed to evaluate the molecular mechanism.</p><p><strong>Results: </strong>WES identified novel biallelic variants, c.1111 A > G (P.Ile371Val) and c.2477 A > T (P.Asp826Val), in the IREB2 gene, which encodes the iron metabolism-related protein, IRP2. Functional studies revealed that c.2477 A > T resulted in a significant degradation of IRP2, which led to the misregulation of intracellular ferric iron.</p><p><strong>Conclusions: </strong>We report the identification of the first functional domain associated with the degradation of IRP2. The biallelic variants that affect protein degradation likely underlie the pathogenesis of the IRP2-related neurodegenerative disorder. Moreover, the use of proteasome inhibitors can potentially restore the expression of IRP2, highlighting a promising therapeutic target for patients with IRP2deficiency.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"435"},"PeriodicalIF":3.4,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716556","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":"Spectrum of IDH-mutant tumors in Ollier-Maffucci disease: the triple interaction theory.","authors":"Emmanuel Mandonnet, Thomas Funck-Brentano, Jean-Philippe Hugnot, Mehdi Touat","doi":"10.1186/s13023-024-03457-7","DOIUrl":"10.1186/s13023-024-03457-7","url":null,"abstract":"<p><p>We propose to refine our understanding of the pathophysiology underlying the tumor spectrum observed in patients with Ollier disease (OD) and Maffucci syndrome (MS). On one hand, assuming that all IDH-mutated tumors (as well as enchondromas) observed in OD-MS patients derive from one IDH-mutant cell giving rise to different lineages, the observation of different tumors arising in organs deriving from the neuroectoderm, mesoderm and endoderm points towards a very early post-zygotic event for the IDH mutation. To explain then that the spectrum of IDH-mutated tumors is restricted to some types of tumors, we propose the following hypothesis: - First, we posit that not every mutated cell of the lineage will \"express\" the IDH mutant phenotype. This can be due i/ to the disappearance in some tissue of the IDH-mutated clone due to negative selection pressure later in embryo development ii/ to the lack of expression of the IDH1 protein in specific cell types iii/ to a functional cell state not leading to the accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) in that tissue/organ. - Second, generalizing the recent understanding of the gliomagenesis in the general population bearing the rs55705857 G-allele variant at 8q24.21, we postulate that OD-MS patients with an inheritable predisposing single nucleotide polymorphism (SNP) are more likely to develop a malignancy, with a specific SNP for each kind of tumor/organ. In summary, our theory provides a new understanding of IDH-mutated tumors in OD-MS patients, as arising from the triple interaction within the same cell of a developmental defect (the somatic mutation that occurs early during the embryogenesis), an organ-specific functional state \"expressing\" the IDH mutation and leading to an accumulation of D-2HG, and an inheritable predisposing factor (a risky SNP, also specific to each organ). We discuss how this theory could guide future research in OD-MS patients and, more generally, in patients harboring sporadic IDH-mutated tumors.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"434"},"PeriodicalIF":3.4,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716559","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}