Search Results (3,340)

Background/Objectives: Fatigue is a highly prevalent and burdensome symptom among individuals with Marfan syndrome (MFS), yet its heterogeneity and underlying psychosocial and clinical correlates remain underexplored. This study aimed to identify and characterize distinct fatigue-related profiles in MFS patients using a data-driven cluster analysis approach. Methods: A cross-sectional study was conducted involving 127 patients with MFS from a specialized connective tissue disorder center in Italy. Participants completed self-reported measures of fatigue severity (Fatigue Severity Scale, FSS), depressive symptoms (Patient Health Questionnaire-9, PHQ-9), and insomnia (Insomnia Severity Index, ISI). The body mass index (BMI) and clinical data were also collected. A t-distributed stochastic neighbor embedding (t-SNE) analysis was performed to reduce dimensionality, followed by hierarchical clustering (Ward’s method), exploring solutions from k = 2 to k = 10. The optimal cluster solution was identified based on silhouette scores and clinical interpretability. Results: Three distinct clusters emerged: (1) a cluster characterized by low fatigue with minimal psychological and sleep-related symptoms (younger patients, lower PHQ-9 and ISI scores), (2) a cluster characterized by moderate fatigue with moderate psychological and sleep-related symptoms (intermediate age, moderate PHQ-9 and ISI scores), and (3) a cluster characterized by high fatigue with elevated psychological and sleep-related symptoms (older patients, higher PHQ-9, ISI, and FSS scores). Significant differences were observed across clusters in age, BMI, depressive symptoms, insomnia severity, and fatigue levels (all p < 0.05). Conclusions: Our findings highlight the heterogeneity of fatigue experiences in MFS and suggest the importance of profiling patients to guide personalized interventions. This approach may inform precision medicine strategies and enhance the quality of life for individuals with this rare disease. Full article

Hypersomnia may be classified as primary or secondary, with secondary hypersomnia arising from a variety of underlying causes. Thus, according to ICSD3-TR classification, the diagnosis of idiopathic hypersomnia (IH) is established based on (1) excessive daytime sleepiness (EDS); (2) electrophysiological findings including either a mean sleep latency of less than 8 min on the Multiple Sleep Latency Test (MSLT) or increased total sleep (≥11 h) on 24 h polysomnography; and (3) systematic elimination of other potential etiologies, including sleep deprivation, substances, and medical, psychiatric (notably mood disorders), or sleep disorders. Nevertheless, the clinical heterogeneity observed in IH fuels an ongoing debate, reflecting the limited understanding of its underlying pathophysiological mechanisms. This report describes the case of a patient presenting with a clinical and polysomnographic phenotype of IH (MSLT < 8 min). A comprehensive psychopathological evaluation was performed to explore the possibility of secondary hypersomnia, which revealed features consistent with complex post-traumatic stress disorder (c-PTSD). Psychotherapy focused on c-PTSD was administered with positive and objective results in hypersomnolence/EDS. This clinical improvement suggests a potential relationship between psychological trauma and hypersomnia, a connection that is rarely described in the literature and warrants further investigation. This case highlights the need for a comprehensive assessment of secondary factors, particularly complex trauma, even in the presence of a clinical and polysomnographic phenotype consistent with IH. Full article

Fatty-acid-hydroxylase-associated neurodegeneration (FAHN) is a rare neurodegenerative disorder caused by loss-of-function mutations in the FA2H gene, leading to impaired enzymatic activity and resulting in myelin sheath instability, demyelination, and axonal degeneration. In this study, we established a human in vitro model using neurons and oligodendrocytes derived from induced pluripotent stem cells (hiPSCs) of a FAHN patient. This coculture system enabled the investigation of myelination processes and myelin integrity in a disease-relevant context. Analyses using immunofluorescence and Western blot revealed impaired expression and localisation of key myelin proteins in oligodendrocytes and cocultures. FA2H-deficient cells showed reduced myelination, shortened internodes, and disrupted formation of the nodes of Ranvier. Additionally, we identified autophagy defects—a hallmark of many neurodegenerative diseases—including reduced p62 expression, elevated LC3B levels, and impaired fusion of autophagosomes with lysosomes. This study presents a robust hiPSC-based model to study FAHN, offering new insights into the molecular pathology of the disease. Our findings suggest that FA2H mutations compromise both the structural integrity of myelin and the efficiency of the autophagic machinery, highlighting potential targets for future therapeutic interventions. Full article

Rafiq syndrome (RAFQS) is a rare autosomal recessive disorder that is classified as a type II congenital disorder of glycosylation (CDG-II), and caused by MAN1B1 gene mutation. To date, 24 pathogenic MAN1B1 mutations have been reported in association with MAN1B1-CDG. However, the underlying pathogenic mechanisms remain poorly understood. In this study, we recruited a consanguineous family from Pakistan with multiple affected individuals exhibiting mild facial dysmorphism, developmental delay, and intellectual disability. Utilizing exome sequencing and homozygosity mapping, we identified a novel MAN1B1 mutation (c.772_775del) that co-segregated with RAFQS in this family. Analysis of public single-cell transcriptomic data revealed that MAN1B1 is predominantly expressed in dorsal progenitors and intermediate excitatory neurons during human brain development. Knockdown of Man1b1 in primarily cultured mouse excitatory neurons disrupted axon growth, dendrite formation, and spine maturation, and could not be rescued by truncated variants identified in the family. Furthermore, in utero, electroporation experiments revealed that Man1b1 knockdown in the murine cortex impaired neural stem cells’ proliferation and differentiation, as well as cortical neuron migration. Collectively, these findings elucidate a critical role for MAN1B1 in the etiology of RAFQS and demonstrate that loss-of-function mutation in MAN1B1 disrupt neuro-developmental processes, providing mechanistic insights into the pathogenesis of this disorder. Full article

The etiology of obsessive–compulsive disorder (OCD) remains incompletely understood, but it is widely recognized as the result of a complex interplay among multiple contributing mechanisms, often emerging during childhood. This narrative review synthesizes current evidence on the etiology of childhood-onset OCD, with particular focus on whether GM alterations are involved in the pathophysiological mechanisms underlying the disorder. Specifically, the review first examines both biological and psychosocial determinants of OCD, and then explores the role of the gut microbiome (GM), including the potential of psychobiotics as a novel therapeutic approach. OCD has a strong hereditary component, involving both common polygenic variants and rare mutations. Epigenetic mechanisms such as DNA methylation and microRNA play a role in mediating gene–environment interactions and influencing OCD risk. Dysfunction and hyperactivity within cortico-striato-thalamo-cortical circuits underlie one of the neurobiological bases of OCD. Infections and autoimmune reactions can trigger or exacerbate OCD, particularly in pediatric populations. A range of psychosocial factors have been implicated in the onset of OCD, often in interaction with underlying neurobiological vulnerabilities. Current evidence indicates that GM alterations may also contribute to OCD pathophysiology through immune-mediated neuroinflammation, disrupted gut–brain signaling, and neurotransmitter imbalance. Individuals with OCD present reduced microbial diversity and lower abundance of butyrate-producing taxa, as well as altered IgA levels and increased infection susceptibility. These shifts may affect dopaminergic, glutamatergic, and serotonergic pathways, particularly via tryptophan metabolism and compromised gut integrity. Thus, the GM plays a pivotal role in OCD, constituting a promising approach for understanding its etiology and highlighting the significant clinical potential of microbial-based treatments such as psychobiotics. Nevertheless, despite progress, gaps remain in understanding childhood-onset OCD determinants, including limited longitudinal studies, incomplete characterization of the GM, scarce psychobiotic trials, and a need for integrated multidisciplinary approaches. Moreover, epidemiological evidence is compromised by reliance on lay diagnoses, questionable assessment validity, and insufficient distinction from related disorders. Full article

Introduction: Downbeat nystagmus (DBN) is an ocular motor disorder characterized by persistent to-and-fro eye movements with a slow phase directed upwards and a corrective fast phase downwards. DBN in the context of myelin oligodendrocyte glycoprotein-associated disorder (MOGAD) represents a rare clinical presentation. Case Presentation: A 24-year-old male with MOGAD presented with DBN, status epilepticus, and longitudinally extensive transverse myelitis (LETM). Intervention: The clinical course, diagnostic findings, and management approach are described in detail within the full report. Outcomes: The patient at follow-up was able to ambulate independently, and his nystagmus had improved. He continued to demonstrate transient DBN on supine positioning and head-shaking test. Conclusions: This case report contributes to the understanding of DBN as a manifestation of MOGAD. The accompanying literature review examines the neuroanatomy, pathophysiology, and emerging therapeutic approaches for DBN, providing context for this unusual presentation. Full article

Congenital disorders of glycosylation (CDG) are a group of rare, multisystemic genetic diseases caused by defects in glycan biosynthesis and protein glycosylation. Their broad clinical and genetic heterogeneity often require advanced diagnostic strategies. Clinical glycomics and glycoproteomics have emerged as powerful tools for understanding and diagnosing CDG by enabling high-resolution analysis of glycan structures and glycoproteins. Advancements in high-throughput mass spectrometry (MS) and site-specific glycoproteomics have led to the identification of disease-relevant biomarkers, providing insight into underlying glycosylation defects. These technologies enable detailed analysis of glycan structures and glycoproteins, improving early diagnosis, supporting biomarker discovery, and facilitating therapy monitoring. Integration with genomic and clinical data, including the use of dried blood spot testing and isotopic tracing, further enhances diagnostic precision and reveals the functional consequences of pathogenic variants. While challenges remain in standardizing methods, ensuring accessibility, and implementing bioinformatics tools, global collaborations and harmonized guidelines are beginning to address these gaps. Future directions include the use of artificial intelligence in data analysis, the development of comprehensive diagnostic frameworks, and international efforts to standardize glycomic methods. Collectively, these advances reinforce the growing clinical value of glycomics and glycoproteomics in the diagnosis and management of CDG. Full article

Background: The etiology of liver disease remains unidentified in approximately 30% of patients, presenting a persistent diagnostic challenge. While whole-exome sequencing (WES) is well established for identifying rare genetic conditions in pediatric populations, its utility in adult hepatology is less defined. This study aimed to evaluate the diagnostic value of WES in adults with unexplained liver disorder. Methods: Fifty-three Turkish adult patients with idiopathic liver disease underwent a comprehensive clinical evaluation and WES at Gazi University Ankara in 2024–2025. The cohort included individuals with idiopathic cholestasis (6/53, 11%), hepatic steatosis (28/53, 53%), unexplained elevated liver enzymes (12/53, 23%), and cryptogenic cirrhosis (7/53, 13%). All patients had inconclusive results from prior standard investigations. Results: ES yielded a definitive molecular diagnosis in 11% (6/53) of cases. Definitive diagnoses were distributed across the following disease categories: idiopathic cholestasis (n = 1), hepatic steatosis (n = 1), elevated liver enzymes (n = 2), and cryptogenic cirrhosis (n = 2). Pathogenic variants were detected in the ABCB4, AGL, APOB, CP, and MTTP genes. One patient was identified with mosaic Turner syndrome. Conclusions: This study highlights the role of rare genetic variants in the etiology of unexplained liver disease in adults. Integrating whole-exome sequencing into hepatology practice can uncover novel disease mechanisms and improve diagnostic yield, informing more precise patient care. Full article

Background and Clinical Significance: Retroperitoneal fibrosis (RPF), a rare fibroinflammatory disorder, is classified into idiopathic (iRPF) and secondary (sRPF) forms, with the latter posing significant diagnostic challenges in routine clinical pathway due to atypical presentations, especially in malignancy-associated (maRPF) cases. Case Presentation: Here, we report a 38-year-old female with congenital pancreatic hypoplasia presenting with elusive hypometabolic retroperitoneal masses, initially suggestive of iRPF. Persistent CA19-9 elevation prompted histopathological evaluation, revealing poorly differentiated adenocarcinoma of indeterminate origin. Timely integrated molecular profiling identified maRPF secondary to metastatic pancreatic adenocarcinoma, revealing rare genomic alterations, including a truncating ARID1A mutation NM_006015:c.4336C>T (p. R1446*) and CCND1/FGF3/FGF4/FGF19 (11q13) co-amplification, which resolved diagnostic ambiguity and delineated disease biology. Despite identifying these molecular features, poor prognosis was predicted, and no clinically actionable targets were detected, underscoring the need for future therapeutic development. Conclusions: This paradigm highlights molecular profiling as a critical adjunct to conventional diagnostics in maRPF, bridging the gap between histopathological ambiguity and biologically grounded clinical decision-making. Full article

Background/Objectives: Interstitial lung disease (ILD) is a heterogenous group of disorders characterised by an association of inflammatory and fibrotic abnormalities of the lung. Acute respiratory failure (ARF) may represent the initial picture of the disease. This study aims to highlight the diagnosis of ILD in the intensive care unit (ICU) and to describe the epidemiological, prognostic, and imaging features of patients diagnosed for the first time with ILD in the ICU. Methods: We conducted a single-centre retrospective study. We screened all 2459 patients admitted to our ICU from October 2017 to February 2020. The inclusion criteria consisted of the ILD diagnosis criteria. For each patient, clinical data and lung computed tomography scan patterns were analysed. The selected cases were then reviewed by an expert team at the tertiary care teaching hospital of Marseille (Hôpital Nord, Marseille, France). Results: During the study period, 26 ICU patients were diagnosed with ILD and 20 cases were confirmed by the expert team. The most frequent diagnoses were idiopathic ILD (n = 7, 35%), auto-immune disease-related ILD (n = 7, 35%), exposure-related ILD (n = 3, 15%), and carcinomatous lymphangitis (n = 3, 15%). Fifteen patients were men (75%), with a mean age of 70 (62–72) years. The median SOFA score was 4 (3–7), and 16 (80%) patients received invasive mechanical ventilation. The mean ratio of the oxygen pressure to the fraction of inspired oxygen was 174 (148–198) mmHg. The ICU mortality rate of our cohort was significantly higher than the average ICU mortality (65% vs. 26%, p < 0.003). The mortality rate was lower among the subgroup of auto-immune disease-related ILD (57%). Conclusions: We conducted a single-centre cohort study of patients diagnosed with ILD in the ICU. This rare cause of ARF was associated with poor outcome in the ICU, but auto-immune disease-related ILD seemed to have a better prognosis. High-resolution lung CT and identification of lesion patterns are the cornerstones of the diagnosis. Improved knowledge of ILD and multidisciplinary discussion (MDD) involving radiologists, pneumologists, and intensivists may result in an earlier diagnosis and eventually improved treatments. Full article

Spinal muscular atrophy (SMA) is a rare, autosomal recessive neuromuscular disorder and a leading genetic cause of infant mortality. The past decade has witnessed a paradigm shift in SMA management with the advent of disease-modifying drugs (DMDs). This narrative review aims to (i) summarize pivotal randomized controlled trials (RCTs) that led to the approval of DMDs for SMA Types 1 and 2; (ii) synthesize real-world evidence on their safety and effectiveness; and (iii) explore emerging therapeutic frontiers, including gene modifiers, predictive biomarkers, prenatal interventions, and combination strategies. Pivotal RCTs and real-world studies demonstrate that onasemnogene abeparvovec (a single-dose gene therapy), nusinersen (an intrathecal antisense oligonucleotide), and risdiplam (an oral SMN2 splicing modifier) each significantly improve survival and motor function milestones compared to natural history in Type 1 and Type 2 SMA, with the majority of treated patients achieving independent sitting and prolonged ventilator-free survival, while safety profiles are generally manageable and distinct for each therapy. Similar outcomes have been demonstrated for presymptomatic patients with SMA. The introduction of DMDs has transformed the prognosis of SMA, particularly for early-onset forms, with robust evidence supporting their efficacy and safety. Continued real-world monitoring and exploration of adjunctive therapies are essential to optimize outcomes across the SMA setting and address unmet needs in non-responders and older patients. Full article

Background/Objectives: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder with a multifactorial pathogenesis and a well-established genetic component. While pathogenic variants in genes such as ABCB4 and ABCB11 are implicated in a subset of cases, many remain genetically unexplained. This study aimed to investigate the genetic background of ICP in a multi-generational family with recurrent hepatobiliary disease. Methods: Whole-exome sequencing was performed on the proband and five female relatives. Variant filtering prioritized rare, exonic or splice-site variants predicted to undergo damage by in silico tools and which were present in all affected family members. Identified variants were assessed using population databases and compared with a control group of 433 unrelated women with uncomplicated pregnancies. Variant confirmation was performed using Sanger sequencing and high-resolution melting analysis. Results: No pathogenic variants were identified in known ICP-associated genes. However, a rare heterozygous missense variant in ABCB5 (c.1610G>A; p.Arg537His; rs779950110) was found in all affected individuals and two younger female relatives. This variant is exceedingly rare in population databases, absent in controls, and predicted to be pathogenic by multiple algorithms. ABCB5, although not previously linked to ICP, is an ATP-binding cassette transporter expressed in various tissues, including liver compartments. Conclusions: This study reports a novel ABCB5 variant segregating with ICP and early-onset hepatobiliary disease in a family. These findings suggest ABCB5 as a potential new susceptibility gene in ICP, warranting further functional investigation. Full article

Background and Clinical Significance: Membranoproliferative glomerulonephritis (MPGN) is a rare and heterogeneous pattern of immune-mediated glomerular injury, often associated with infections, autoimmune disorders, or monoclonal gammopathies. Idiopathic cases remain a diagnostic challenge and frequently require empirical immunosuppressive treatment. There is increasing interest in environmental triggers that may activate the immune system in genetically or immunologically predisposed individuals. We report an unusual case of idiopathic immune complex-mediated MPGN with a relapsing course potentially associated with vaccine-induced immune reactivation. Case Presentation: A 35-year-old male with no significant medical history aside from untreated dyslipidemia and active smoking presented with a hypertensive emergency and acute kidney injury (AKI). Laboratory investigations revealed nephrotic-range proteinuria, microscopic hematuria, and reduced estimated glomerular filtration rate (eGFR). Kidney biopsy demonstrated type I immune complex-mediated MPGN with a diffuse endocapillary proliferative pattern and granular subendothelial deposits (IgG+++, C3+++, C1q++). An extensive work-up ruled out secondary causes, supporting a diagnosis of idiopathic MPGN. Immunosuppressive therapy with corticosteroids and mycophenolate mofetil led to a partial clinical response. However, after receiving multiple vaccinations, the patient experienced clinical deterioration. A second biopsy revealed persistent proliferative changes and new deposits of IgM++, C4d++, and both kappa and lambda light chains. This prompted a reintroduction of immunosuppressive therapy, which resulted in subsequent clinical improvement. Conclusions: This case supports the hypothesis that vaccine-induced immune reactivation may serve as a potential trigger for disease relapse in idiopathic MPGN. Clinicians should remain alert to environmental stimuli that may influence disease activity in immune-mediated glomerulopathies. Further research is needed to elucidate the underlying immunopathogenic mechanisms. Full article

Background: Langerhans Cell Histiocytosis (LCH) is a rare histiocytic hematological disorder that frequently involves the lungs. Due to a lack of data about sex-related differences in LCH, the aim of this study is to evaluate sex-related differences in pulmonary function in a cohort of patients with LCH. Methods: We retrospectively analyzed data from 79 adult patients diagnosed with LCH. Demographic, clinical, and spirometric data were collected and compared by sex. Continuous variables were analyzed using the Mann–Whitney test and categorical variables were analyzed with the Chi-square test. Results: Out of 79 patients, 47 (59.5%) were females and 32 (40.5%) were males. Women showed significantly lower diffusing capacity of the lungs for carbon monoxide (DLCO%) and lower diffusing capacity of the lungs for carbon monoxide per unit of alveolar volume (DLCO/VA%) compared to men. Females showed a trend toward lower small airway indices, including maximal expiratory flow at 25 (MEF₂₅%) and forced expiratory flow at 25–75% (FEF_25–75%), though this was not statistically significant, while the residual volume-to-total lung capacity (RV/TLC) ratio was significantly higher in women. Among the functional parameters, DLCO% showed the highest accuracy (AUC 0.70) in the identification of lung involvement after multivariate regression analysis. Conclusions: Our findings suggest that the combination of lower gas exchange efficiency and increased peripheral air trapping secondary to small airway involvement in female patients may reflect the presence of a distinct functional LCH phenotype in women characterized by early small airway involvement and altered ventilation–perfusion dynamics, which may influence the clinical management of these patients. Furthermore, the moderate predictive value of DLCO% for lung involvement at baseline in LCH women suggests that DLCO may contribute to the detection of LCH women with lung involvement, although it should not be considered a definitive diagnostic test without a prospective and independent external validation. Full article

Background: Double-valve infective endocarditis (DVIE) accounts for 15–20% of all endocarditis and represents a challenge due to the increased incidence of embolic events and congestive heart failure compared to infective endocarditis (IE) affecting one valve. This study aims to evaluate patients’ characteristics, surgical procedures, complications, and mortality associated with DVIE in our tertiary hospital in Italy. The Endocarditis Registry STEADY includes patients admitted with IE from January 2009 to March 2024 (n = 398). Sixty-three of them (16%) had DVIE. Methods: We conducted a retrospective single-center observational study, analyzing demographic, clinical, and microbiological data in DVIE patients, comparing those treated surgically (surgical group, SG) with those treated medically (non-surgical group, NSG). Results: The groups were homogeneous in age, microbiological yields, type of valve involved, and risk factors for infective endocarditis. The surgical group presented significantly more cancer history, intracardiac complications, and new-onset arrhythmias compared to the non-surgical group. Median hospital stay was similar in both groups. In SG, the most common postoperative complication was new rhythm disorders; other complications such as cardiac tamponade, pericardial effusion, and pneumothorax were rare. In-hospital mortality was similar between groups; however, one-year survival was higher in the surgical group (72% vs. 54%, p = 0.031). In our series, 16 patients were over 75 years old (25%), and 7 of them (44%) underwent cardiac surgery. One-year survival in the surgical group was also higher in this subgroup. Conclusions: Surgical treatment, when indicated, may improve the prognosis of patients with DVIE, including elderly patients. Full article