Orphanet Journal of Rare Diseases最新文献

{"title":"Generalized pustular psoriasis: a multicentric study on patient characteristics and clinical burden.","authors":"Cristina Bulai Livideanu, Jérémy Gottlieb, Denis Jullien, Thierry Passeron, Sophie Vildy, Emmanuel Delaporte, Carle Paul, Julien Chollet, Marie Najean, Denis San, Charles Taieb, Bénédicte Charles, Emmanuel Mahe, Pierre-André Becherel, Laurent Misery","doi":"10.1186/s13023-025-03559-w","DOIUrl":"10.1186/s13023-025-03559-w","url":null,"abstract":"<p><p>The objective of this study was to assess the demographic characteristics and impact on quality of life (QoL) of patients with PPG in France through a multicentre study. The results of the study are as follows: The PRO [PUSH-D, PHQ-9 et GAD-7] revealed that more than half of the patients exhibited a significant impact on their quality of life. High scores for fatigue, stress, skin and joint pain were reported, with 65% of patients at risk of mild to severe depression. The clinical burden was also assessed. A total of 48.8% of patients were hospitalised, while 39% took sick leave. This study is the first to assess the PUSH-D, PHQ-9 and GAD-7 scores in patients with PPG, which highlighted a significant clinical burden and negative impact on their daily lives.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"61"},"PeriodicalIF":3.4,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374531","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":"Impaired cognitive function and decreased monoamine neurotransmitters in the DNAJC12 gene knockout mouse model.","authors":"Shunan Wang, Ming Shen, Bo Pang, Bo Zhou, Yuan Yuan, Mei Lu, Xiangling Deng, Min Yang, Shufang Liu, Qiong Wang, Mei Xue, Qisheng Xia, Zhixin Zhang","doi":"10.1186/s13023-025-03580-z","DOIUrl":"10.1186/s13023-025-03580-z","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Hyperphenylalaninemia, a prevalent amino acid metabolism disorder, often results in cognitive impairment. Recent studies have identified a rare variant of this disorder caused by mutations in the DNAJC12 gene. The specific mechanisms by which DNAJC12 mutations lead to hyperphenylalaninemia and the lack of an animal model for study remain significant gaps in understanding.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;This study aims to elucidate the role of DNAJC12 in intellectual disability and explore the mechanisms by which DNAJC12 deficiency leads to hyperphenylalaninemia through developing a DNAJC12 gene knockout mouse model.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We thoroughly examined the clinical features and genetic mutations evident in two patients with biallelic mutations in the DNAJC12 gene. Based on the patient's mutation locations, we determined the target site for the knockout utilizing CRISPR/Cas9 technology. To assess the impact of these mutations on DNAJC12 expression, we used quantitative real-time PCR and Western blotting techniques to measure mRNA and protein levels, respectively. The Morris water maze test was administered to evaluate the cognitive functions of the mice. Additionally, we utilized High-Performance Liquid Chromatography (HPLC) to measure serum aromatic amino acids and brain monoamines, facilitating an investigation into the metabolism of phenylalanine and tyrosine.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We reported two patients with mutations in the DNAJC12 gene. Case 1 carried the mutations c.158-1G &gt; A and c.262 C &gt; T in the DNAJC12 gene. He presented with nocturnal eye closure, crying, and arching back in reverse tension before treatment, suggesting a neurotransmitter metabolism disorder. Case 2 carried the mutations c.473 C &gt; G, and c.102 deletion in the DNAJC12 gene. He showed elevated blood phenylalanine levels, although further clinical details were not available. Based on the patients' mutation locations, exons 2-4 of the DNAJC12 gene were targeted and eliminated. In our animal model experiments, DNAJC12 gene knockout mice exhibited a complete absence of DNAJC12 expression at both mRNA and protein levels. These knockout mice showed significant deficits in learning and memory performance as assessed by the Morris water maze test. Quantitative real-time PCR analysis indicated no significant differences in the levels of aromatic amino hydroxylases between knockout and wild-type mice. However, Western blot analysis revealed a substantial reduction in phenylalanine hydroxylase (PAH) protein levels in the liver of knockout mice, while tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2) expression remained unchanged. HPLC analysis demonstrated increased serum Phe concentrations and decreased levels of brain neurotransmitters in the knockout group.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;We report two patients with four novel DNAJC12 mutations (c.158-1G &gt; A, c.262 C &gt; T, c.473 C &gt; G, c.102delT), expa","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"60"},"PeriodicalIF":3.4,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374534","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":"Clinically meaningful improvements after gene therapy for aromatic L-amino acid decarboxylase deficiency (AADCd) in the Peabody Developmental Motor Scale, Second Edition (PDMS-2) and correlation with Bayley-III scores and motor milestones.","authors":"Wuh-Liang Hwu, Hui-Min Lee, John Devin Peipert, Rongrong Zhang, Christian Werner, J Rafael Sierra, Thomas O'Connell, Jonathan J Woolley, Marjorie Crowell, Antonia Wang, Ioannis Tomazos","doi":"10.1186/s13023-025-03584-9","DOIUrl":"10.1186/s13023-025-03584-9","url":null,"abstract":"<p><strong>Background: </strong>Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare genetic disorder characterized by movement disorders, motor and autonomic dysfunction, and developmental delays. The gene therapy eladocagene exuparvovec has become available in some regions; pooled clinical trial results demonstrate continuous long-term improvement in motor development and cognitive function. We sought to characterize clinically meaningful change in motor function, as measured by Total Peabody Developmental Motor Scales-Second Edition (PDMS-2) score, and assess correlations with cognition and language domains of the Bayley-III and motor milestone (MM) achievement.</p><p><strong>Methods: </strong>Data from N = 30 patients from three single-arm clinical studies of eladocagene exuparvovec were analyzed. Anchor-based estimation of the meaningful score difference (MSD) of Total PDMS-2 score was conducted using mean-difference and receiver operating characteristic curve (ROC) approaches. MM achievement served as the anchor defining meaningful change.</p><p><strong>Results: </strong>An MSD of 40 points for Total PDMS-2 score was selected for analysis as it yielded specificity > 0.95 using the ROC approach, and generally aligned with the mean-difference approach. Cumulative incidence analysis reflected that 50% of patients treated with eladocagene exuparvovec may achieve the MSD of 40-point change in Total PDMS-2 score at 6 months, and 86% at 18 months. Correlations between measures were of large magnitude and improved over time (Month 6: r = 0.599 [p = 0.0032]; Month 18: r = 0.796 [p = 0.0002]; Month 60: r = 0.861 [p = 0.0007]).</p><p><strong>Conclusions: </strong>The MSD of 40 points for Total PDMS-2 score enables the interpretation of changes observed in patients with AADCd, and suggests that treatment with eladocagene exuparvovec leads to significant improvements in motor and cognitive function.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"58"},"PeriodicalIF":3.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370911","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":"Deciphering TCOF1 mutations in Chinese Treacher Collins syndrome patients: insights into pathogenesis and transcriptional disruption.","authors":"Zhuoyuan Jiang, Ke Mao, Bingqing Wang, Hao Zhu, Jiqiang Liu, Ruirui Lang, Baichuan Xiao, Hailin Shan, Qi Chen, Ying Li, Shouqin Zhao, Qingguo Zhang, Huisheng Liu, Yong-Biao Zhang","doi":"10.1186/s13023-024-03508-z","DOIUrl":"10.1186/s13023-024-03508-z","url":null,"abstract":"<p><strong>Background: </strong>Treacher Collins syndrome (TCS, MIM #154500), a severe congenital disorder, predominantly involves dysplasia of craniofacial bones and is characterized by features such as downslanting palpebral fissures, lower eyelid colobomas, microtia, and other craniofacial anomalies. Despite its clinical importance, the underlying pathogenic mutations in TCS remain largely uncharacterized, representing a critical knowledge gap for researchers in the field.</p><p><strong>Results: </strong>To address this, we performed mutation screening on a familial TCS case (trio) and 11 sporadic cases from a Chinese population. We identified 11 mutations predominantly localized to the central repeat domain (CRD) and the C-terminal domain (CTD, including the nuclear localization sequence) of TCOF1. The de novo frameshift mutation identified in the trio led to TCOF1 truncation, disrupting the central repeat domain crucial for binding transcriptional factors. Immunoprecipitation assays revealed that this pathogenic mutation attenuates the interaction between TCOF1 and transcription-related proteins, such as Pol II. Furthermore, cellular luciferase assays demonstrated that the mutation compromises the nuclear localization capability of TCOF1.</p><p><strong>Conclusions: </strong>Our findings establish TCOF1 as the primary pathogenic gene in this Chinese TCS cohort, with mutations predominantly in the CRD and CTD, thereby expanding the known mutation spectrum of TCS and informing its prevention strategies.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"57"},"PeriodicalIF":3.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370988","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":"The distribution and spectrum of thalassemia variants in GUIYANG region, southern China.","authors":"Xuanyin Zhao, Zhiyu You, Yunyan Deng, Yi Zhou, Dongyang Deng, Jian Quan, Fang Chen, Zhimei Yan, Ya Qi, Leilei Chen, Fang Xiang, Weixian Zheng, Ruyi Zhang","doi":"10.1186/s13023-025-03569-8","DOIUrl":"10.1186/s13023-025-03569-8","url":null,"abstract":"<p><p>Thalassemia is one of southern China's most common inherited disorders. This retrospective study analyzed the results of thalassemia gene testing conducted on 20,478 individuals from January 1, 2019, to April 31, 2024 in the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine. The cohort consisted of 19,733 females and 745 males, with 1401 individuals testing positive for thalassemia. Among the positive cases, 942 had α thalassemia, 431 had β thalassemia, and 25 had variants in both α and β thalassemia genes. Interestingly, a subgroup of individuals with thalassemia variants not previously documented in medical literature was identified. The study highlighted the prevalence of thalassemia among different ethnic groups, with individuals of Han ethnicity being the most affected. Geographical analysis revealed a concentration of cases in Guizhou Province, particularly in Guiyang city, Bijie, and Qiannan Prefecture. These findings provide valuable insights into the epidemiology of thalassemia in the region and the distribution of affected individuals.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"56"},"PeriodicalIF":3.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370399","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":"Clinical and genetic analysis of methylmalonic aciduria in 60 patients from Southern China: a single center retrospective study.","authors":"Hiba Abid, Areeba Abid, Sarah Sohail, Sara Jawaid","doi":"10.1186/s13023-025-03585-8","DOIUrl":"10.1186/s13023-025-03585-8","url":null,"abstract":"<p><p>We read with interest the recent publication on methylmalonic aciduria (MMA) and commend the authors for their outstanding contribution. This letter aims to further build upon their work by emphasizing additional aspects to enhance clinical relevance and diagnostic precision. We highlight the variability in serum MMA levels due to dietary intake, renal function, and external factors, advocating for the integration of supplementary diagnostic tools, such as the 1-13 C-propionate oxidation breath test, alongside biomarkers like fibroblast growth factor 21, growth differentiation factor 15, and lipocalin-2, to improve diagnostic accuracy. Additionally, we discuss the limitations of first-tier newborn screening tests due to high false positive rates and recommend second-tier testing using liquid chromatography coupled with tandem mass spectrometry to increase specificity and reduce false positives. Moreover, we address the underestimation of liver dysfunction in MMA patients, noting the need for longitudinal follow-up to capture the progression of liver function abnormalities. This critique is intended to constructively expand the authors' findings and underscore the importance of a comprehensive diagnostic and management approach to MMA, ultimately improving patient outcomes.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"54"},"PeriodicalIF":3.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11804001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370907","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":"Genomic analysis of the SMN1 gene region in patients with clinically diagnosed spinal muscular atrophy: a retrospective observational study.","authors":"Tamaki Kato, Mamoru Yokomura, Yutaka Osawa, Kensuke Matsuo, Yuji Kubo, Taihei Homma, Kayoko Saito","doi":"10.1186/s13023-025-03568-9","DOIUrl":"10.1186/s13023-025-03568-9","url":null,"abstract":"<p><strong>Background: </strong>Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease. Most patients with SMA have a mutation in the survival motor neuron 1 (SMN1) gene on chromosome 5q. With current genetic testing, SMN1 copy number is determined; a diagnosis is reached when the copy number is zero. When the SMN1 copy number is 1, exons and intron/exon boundaries of the allele are examined for single-nucleotide variants (SNVs). Genetically undiagnosed cases of SMA exist when 2 copies of SMN1 exist or when a SNV is in the deep intron. Furthermore, SMN1 is highly homologous to SMN2; therefore, it is expected that many SNVs have not been elucidated.</p><p><strong>Methods: </strong>This retrospective observational study conducted in Japan used pre-collected DNA samples from patients with clinically diagnosed SMA. Enrollment period was January 28, 2020 to September 30, 2021. SNV analysis of SMN1 (exon 1-8 and intron 1-7) was conducted by long-range polymerase chain reaction and next-generation sequencing.</p><p><strong>Results: </strong>From 336 DNA samples collected from patients, 62 patient samples were included in the SNV analysis. Two patients have been genetically diagnosed (a heterozygous variant in intron 6 with 1 copy of SMN1; a homozygous missense mutation in exon 3 with 2 copies of SMN1). Three SNVs in intron 6, c.834+1506A>G (n = 9), c.834+1751G>A (n = 2), and c.835-367C>A (n = 5) were identified; all were numerically, and c.834+1506A>G and c.835-367C>A were significantly, more frequent in patients with 0 copies versus those with ≥ 1 copy of exon 7 in SMN1. We confirmed 3 hybrid SMN gene types in 5 patients that contained SMN2 gene sequence (aaTgg) flanked by upstream \"t\" and downstream \"G\" SMN1 sequence.</p><p><strong>Conclusions: </strong>In this study of patients with clinically diagnosed SMA, 2 cases with genetic SMN types were identified that would not have been identified through current genetic testing, which examines SMN1 deletions only. Furthermore, for 1 patient with a homozygous SMN1 missense mutation, SMA was not suspected by the current copy number screening method. This study demonstrated the importance of performing full-length sequencing for clinically diagnosed SMA to complement current screening methods.</p><p><strong>Trial registration: </strong>University Hospital Medical Information Network Clinical Trials Registry (Number: UMIN000040095).</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"55"},"PeriodicalIF":3.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370278","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":"Correction To: Uncovering a novel SERPING1 pathogenic variant: insights into the aggregation of C1-INH in hereditary angioedema.","authors":"Lingxi Jiang, Chao Dai, Suyang Duan, Tingting Wang, Chunbao Xie, Luhan Zhang, Zimeng Ye, Xiumei Ma, Yi Shi","doi":"10.1186/s13023-025-03572-z","DOIUrl":"10.1186/s13023-025-03572-z","url":null,"abstract":"","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"52"},"PeriodicalIF":3.4,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365359","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":"Clinical characteristics and prognosis of amyopathic dermatomyositis patients with interstitial lung disease: insights from a retrospective cohort.","authors":"Yanan Ying, Tingting Wu, Long Wang, Yun Zhang, Yiming Yu, Zaichun Deng, Qunli Ding","doi":"10.1186/s13023-025-03575-w","DOIUrl":"10.1186/s13023-025-03575-w","url":null,"abstract":"<p><strong>Introduction: </strong>The diagnosis of amyopathic dermatomyositis with interstitial lung disease (ADM-ILD) is challenging due to the lack of typical skin features and overlapping syndromes. We aimed to determine the characteristics and prognosis of patients with ADM-ILD to further guide their clinical management.</p><p><strong>Methods: </strong>A retrospective cohort study comprising 190 Chinese patients diagnosed with interstitial lung disease (ILD) was conducted. Patients were stratified into four groups using the Sontheimer criteria and predominant high-resolution computed tomography (HRCT) patterns. Demographic features, clinical presentation, laboratory parameters, duration of ILD, and follow-up data were analysed.</p><p><strong>Results: </strong>There were significant differences in the clinical parameters among the 190 patients with ILD in the amyopathic dermatomyositis (ADM, n = 69) and control (n = 121) groups. The ADM with nonspecific interstitial pneumonia (NSIP) group (n = 46) presented increased haemoglobin (125.93 ± 12.91 g/L, p = 0.005), creatine kinase-MB (15.19 ± 8.58 U/L, p < 0.001), and partial pressure of oxygen (93.08 ± 26.20 mmHg, p = 0.003) levels and decreased β2-microglobulin (2.61 ± 1.21 mg/L, p = 0.039) levels compared to the control-NSIP group (n = 92). The ADM with organizing pneumonia (OP) group (n = 23) had a greater percentage of females (7/16, p = 0.023) and higher alanine aminotransferase (30.30 ± 20.67 U/L, p = 0.039) and aspartate aminotransferase (53.35 ± 65.86 U/L, p = 0.003) levels than the control-OP group (n = 29). Both the ADM-NSIP and OP groups presented elevated lactate dehydrogenase (LDH) levels (290.61 ± 86.49 U/L, p = 0.009; 317.35 ± 181.32 U/L, p = 0.003, respectively) and increased anti-nuclear antibody (ANA) positivity rates (82.61%, p = 0.01; 73.91%, p < 0.001, respectively). Notably, 81.26% of patients with ADM-NSIP/OP had LDH levels above normal. The serum LDH levels could be used to distinguish patients with ADM-NSIP/OP (sensitivity: 73.91%, specificity: 82.64%). Survival was shorter among patients with ADM-OP than among control patients (p = 0.002). Cox multivariate analysis revealed that age (p = 0.002), smoking status (p = 0.011), anti-melanoma differentiation-associated gene 5 (MDA5) antibody (p = 0.017), and white blood cell count (p = 0.004) were independent predictors of shorter survival.</p><p><strong>Conclusions: </strong>Elevated serum LDH levels in patients predominantly presenting with NSIP or OP patterns may indicate the presence of ADM-ILD. The identified prognostic factors underscore the importance of early detection and personalized management strategies for optimizing outcomes in patients with ADM-ILD.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"53"},"PeriodicalIF":3.4,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11804100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365354","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":"The mutational landscape of ARMC5 in Primary Bilateral Macronodular Adrenal Hyperplasia: an update.","authors":"Lucas Bouys, Anna Vaczlavik, Isadora P Cavalcante, Florian Violon, Anne Jouinot, Annabel Berthon, Patricia Vaduva, Stéphanie Espiard, Karine Perlemoine, Peter Kamenicky, Marie-Christine Vantyghem, Antoine Tabarin, Gérald Raverot, Cristina L Ronchi, Ulrich Dischinger, Martin Reincke, Maria C Fragoso, Constantine A Stratakis, Albain Chansavang, Eric Pasmant, Bruno Ragazzon, Jérôme Bertherat","doi":"10.1186/s13023-025-03554-1","DOIUrl":"10.1186/s13023-025-03554-1","url":null,"abstract":"<p><strong>Background: </strong>Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a rare cause of Cushing's syndrome due to bilateral adrenocortical macronodules. Germline inactivating variants of the tumor suppressor gene ARMC5 are responsible for 20-25% of apparently sporadic PBMAH cases and 80% of familial presentations. ARMC5 screening is now routinely performed for PBMAH patients and families. Based on literature review and own observation, this study aims to give an overview of both published and unpublished ARMC5 genetic alterations and to compile the available evidence to discriminate pathogenic from benign variants.</p><p><strong>Results: </strong>146 different germline variants (110 previously published and 36 novel) are identified, including 46% missense substitutions, 45% truncating variants, 3% affecting splice sites, 4% in-frame variants and 2% large deletions. In addition to the germline events, somatic 16p loss-of-heterozygosity and 104 different somatic events are described. The pathogenicity of ARMC5 variants is established on the basis of their frequency in the general population, in silico predictions, familial segregation and tumor DNA sequencing.</p><p><strong>Conclusions: </strong>This is the first extensive review of ARMC5 pathogenic variants. It shows that they are spread on the whole coding sequence. This is a valuable resource for genetic investigations of PBMAH and will help the interpretation of new missense substitutions that are continuously identified.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"51"},"PeriodicalIF":3.4,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255280","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}