Search Results (637)

Fabry disease is a rare X-linked lysosomal storage disorder characterized by progressive glycosphingolipid accumulation and multisystem organ involvement. Globotriaosylsphingosine (Lyso-Gb3) has emerged as a promising biomarker of disease burden; however, its relationship with validated clinical severity scoring systems remains incompletely understood. This study aimed to evaluate the associations between serum Lyso-Gb3 concentrations and the overall scores of three validated clinical severity assessment tools—the Mainz Severity Score Index (MSSI), Disease Severity Scoring System (DS3), and Fabry Stabilization Index (FASTEX)—in patients with Fabry disease. This retrospective observational study included 18 adult patients with genetically and/or enzymatically confirmed Fabry disease who were regularly followed at a tertiary referral center. Baseline and 12-month serum Lyso-Gb3 concentrations, MSSI scores, DS3 scores, and FASTEX values were evaluated. Correlations between Lyso-Gb3 concentrations and disease severity scores were assessed using Spearman correlation analysis. Exploratory sex-stratified analyses and univariable linear regression analyses were additionally performed to examine associations with disease severity; these analyses were considered hypothesis-generating because of the limited sample size. Median baseline Lyso-Gb3 concentration was 6.77 ng/mL (IQR: 3.94–50.10), median baseline MSSI score was 27.0 (IQR: 16.3–34.3), and median baseline DS3 score was 19.0 (IQR: 15.3–22.0). Significant reductions were observed in Lyso-Gb3 concentrations, MSSI scores, and DS3 scores after 12 months of follow-up (all p < 0.001). Baseline Lyso-Gb3 concentrations demonstrated strong positive correlations with baseline MSSI (ρ = 0.845, p < 0.001) and baseline DS3 scores (ρ = 0.854, p < 0.001), while no significant correlation was observed with FASTEX scores (ρ = −0.117, p = 0.644). Similar significant correlations were identified between 12-month Lyso-Gb3 concentrations and corresponding MSSI (ρ = 0.812, p < 0.001) and DS3 scores (ρ = 0.697, p = 0.001). In sex-stratified analyses, significant correlations between Lyso-Gb3 and disease severity scores were observed predominantly among male patients. In exploratory univariable linear regression analyses, baseline Lyso-Gb3 concentrations were strongly associated with baseline MSSI (R² = 0.758) and DS3 scores (R² = 0.579); however, these estimates should be interpreted cautiously because of the small sample size. Serum Lyso-Gb3 concentrations were strongly associated with MSSI and DS3 scores in this small retrospective cohort, whereas no statistically significant association was observed with FASTEX. The observed associations, particularly those derived from sex-stratified and regression analyses, should be considered exploratory and hypothesis-generating because of the limited sample size. Larger prospective multicenter studies are required to confirm the magnitude, independence, and clinical applicability of these relationships. Full article

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that is caused in most cases by pathogenic variants in MECP2, the gene encoding methyl-CpG-binding protein 2 (MeCP2). Despite substantial progress in the development of gene therapy, restoring MECP2 expression remains challenging because MeCP2 is highly dosage-sensitive. Both deficiency and excessive expression of this protein are associated with severe neurological abnormalities. This makes simple viral vector-mediated replacement of MECP2 potentially unsafe and underscores the need for multilayered systems that control transgene expression. This review discusses current and emerging strategies for regulating MeCP2 expression in RTT, with an emphasis on non-coding RNA-based and epigenetic mechanisms. Particular attention is given to the limitations of conventional AAV-mediated gene therapy, the use of cell-specific and endogenous promoters, miRNA-regulated elements, autoregulatory systems, and post-transcriptional control of MECP2 expression. Strategies for reactivating the inactive X chromosome are also discussed, including XIST-dependent regulation and epigenome editing. In addition, the review considers CRISPR-mediated regulation, selective epigenetic activation, and combined therapeutic platforms that integrate viral delivery, RNA-dependent post-transcriptional control, and endogenous gene regulation. Overall, clinically applicable gene therapy for RTT will likely need to move beyond simple MECP2 replacement and instead rely on precise cell- and dose-dependent regulation of its expression. Non-coding RNA and epigenetic mechanisms represent important layers of such control and may contribute to the development of safer gene therapy strategies for RTT. Full article

Hemophilia is an X-linked inherited bleeding disorder, classified as type A or type B. Therapeutic advances offer new treatment options that improve disease control and reduce associated complications, including inhibitor development and hemophilic arthropathy. This document aims to update the Mexican hemophilia consensus, reviewing current evidence on diagnosis and management, and addressing gaps in the treatment and follow-up of patients in Mexico, aligning local needs with international recommendations. A PubMed literature search covering the last five years (up to September 2025) was conducted, prioritizing consensus statements, guidelines, and systematic reviews. Using the Delphi methodology, a structured questionnaire was submitted electronically to forty-four experts. Aspects without initial agreement were discussed at an in-person meeting. Consensus was defined as at least 80% of votes in favor. Recommendations were issued across six domains: laboratory diagnosis, genetic testing, management of hemophilia A and B without and with inhibitors, adjuvant treatments, and gene therapy. The recommendations address prophylaxis with coagulation factor concentrates, non-factor therapies, immune tolerance induction, perioperative management, pain management, and eligibility criteria and follow-up protocols for gene therapy with adeno-associated viral vectors. This consensus provides updated, evidence-based recommendations adapted to the Mexican healthcare context, identifying priority areas, including timely access to non-factor therapies and gene therapy, development of a national referral network for complex cases, and inclusion of novel therapeutic agents in the institutional essential medicines list, with the aim of improving the quality of life of people with hemophilia in Mexico. Full article

Background: Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by renal resistance to arginine vasopressin, most commonly caused by pathogenic variants in the AVPR2 gene. While X-linked NDI classically affects males, heterozygous females may exhibit variable clinical expression. Certain AVPR2 variants are associated with partial NDI and milder phenotypes. Methods: We conducted a retrospective family study of a multigenerational Greek pedigree with suspected hereditary NDI. Clinical, biochemical, and pedigree data were collected through chart review and family interviews. Genetic analysis was performed using whole-exome sequencing, and variant interpretation followed ACMG/AMP guidelines. Results: Fourteen individuals across four generations were evaluated. Molecular analysis identified a familial AVPR2 (NM_000054.7):c.964C>T (p.Pro322Ser) missense variant in three males and three females, with obligate carrier status inferred in two deceased females, segregating in an X-linked pattern. Hemizygous males exhibited a broad phenotypic spectrum, ranging from partial NDI with later onset to severe early-onset disease with urinary tract complications. Heterozygous females showed variable expression, from asymptomatic carriers to mildly symptomatic individuals. The variant co-segregated with disease and, based on ACMG criteria, it was classified as pathogenic. Conclusions: In our family, the AVPR2 c.964C>T (p.Pro322Ser) variant was associated with a remarkably broad clinical spectrum, ranging from asymptomatic heterozygous females to severe early-onset disease with urinary tract complications in affected males. These observations emphasize the need for early molecular diagnosis, systematic evaluation of female carriers, and long-term surveillance to prevent disease-related complications and optimize genetic counselling. Full article

Brunner syndrome is a rare X-linked neurodevelopmental disorder caused by loss-of-function (LOF) variants in the monoamine oxidase A gene (MAOA), which encodes monoamine oxidase A, a key enzyme involved in the degradation of monoamine neurotransmitters such as serotonin, norepinephrine, and epinephrine. Impaired MAOA activity leads to abnormal monoamine accumulation and disruption of monoaminergic signalling, resulting in intellectual disability and behavioural dysregulation. Here, we systematically summarize the molecular landscape and report a genotype-driven diagnosis of MAOA deficiency in a patient presenting with intellectual disability and no reported family history. Clinical exome sequencing (cES) identified a novel splice-site variant in the MAOA gene that had not been detected by first-line diagnostic approaches. Functional analysis of patient-derived mRNA demonstrated intron 8 retention leading to a premature stop codon, consistent with a LOF mechanism. Based on the molecular diagnosis, the patient received treatment with serotonin antagonist and reuptake inhibitor (SARI) class medication, which was associated with improvement in social behaviour and sleep disturbances. Notably, to the best of our knowledge, this represents the first reported use of SARI therapy in MAOA deficiency. Although SARI therapy in this condition remains off-label, this observation provides preliminary evidence suggesting a potential therapeutic benefit. Our findings expand the mutational spectrum of the MAOA gene and highlight the importance of molecular diagnosis driving personalized management in rare neurogenetic disorders. Full article

Background and Objectives: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic GLA gene variants, leading to progressive multi-organ damage including end-stage renal disease. Although dialysis patients represent a high-risk population for undiagnosed FD, data from Türkiye using genetic analysis as the primary screening method remain limited. This study aimed to determine FD prevalence among hemodialysis patients across multiple centers in Türkiye and to perform cascade family screening of confirmed cases. Materials and Methods: This multicenter cross-sectional study screened 1359 adult hemodialysis patients across 8 centers in Ankara, Türkiye, using complete GLA gene sequencing. Variants were classified per American College of Medical Genetics and Genomics criteria. Patients with pathogenic variants underwent confirmatory biochemical testing (α-galactosidase A activity and plasma lyso-Gb3). Cascade screening was performed for confirmed index cases. Results: Among 1359 patients (mean age 62.3 ± 14.3 years; 38.5% female), GLA variants were identified in 12 (0.88%): 8 benign/likely benign (including 7 p.D313Y pseudodeficiency alleles), 2 unclassified variants, 1 variant of uncertain significance, and 1 confirmed classic FD (prevalence: 0.07%; 95% CI: 0.002–0.41%). Cascade screening of the index patient identified 6 carriers among 10 relatives tested (60% yield). Three of 7 carriers (43%) were initiated on enzyme replacement therapy. Conclusions: Among 1359 hemodialysis patients, GLA gene sequencing identified 12 variants (0.88%), yet only one was confirmed as a disease-causing mutation responsible for end-stage renal disease (prevalence: 0.07%). The remaining variants comprised polymorphisms, likely benign pseudodeficiency alleles and variants of uncertain significance; most of which would not have been detected by enzyme-based screening alone, as enzyme activity was normal in these carriers. Cascade screening of the single confirmed index case yielded 6 carriers among 10 relatives tested (60%), including one hemizygous male with classic FD on hemodialysis, and three carriers were initiated on enzyme replacement therapy. These findings demonstrate that GLA gene analysis is a valuable instrument for screening in dialysis populations, as it captures the full variant spectrum while enabling rigorous distinction between the overall GLA variant carrier rate and the true disease prevalence defined by variants causing end-stage renal disease. Future screening studies should report prevalence based exclusively on confirmed disease-causing variants rather than total variant counts, which have inflated prevalence estimates in prior literature. Full article

Colloidal processing provides a scalable non-vacuum route for fabricating CIGS and CZTSSe thin-film absorbers, but nanoparticle-derived films should be treated as constrained particulate green bodies rather than as simple chemically deposited semiconductor layers. This review reorganizes colloidal chalcogenide photovoltaics using ceramic-processing concepts: ink dispersion, green-body packing, capillary drying stress, ligand burnout, constrained shrinkage, reactive chalcogenization, transient liquid-assisted coarsening, secondary-phase control, defect chemistry, and interface reactions. The central argument is that film densification and grain growth are necessary but insufficient for high-performance CZTSSe devices. Residual carbon, Sn loss, Cu/Zn disorder, ZnSe or Cu_2−xSe secondary phases, excessive MoSe₂, and nonideal absorber/buffer band alignment can dominate open-circuit-voltage loss, fill factor, and carrier collection even when the absorber appears dense in cross-sectional microscopy. By linking ceramic-processing variables to photovoltaic loss mechanisms, this review identifies practical routes for improving colloidal chalcogenide solar cells: controlled ligand exchange and binder burnout, high-green-density precursor design, moderated chalcogen chemical potential, transient liquid management, depth-resolved phase analysis, and integrated front/back-interface engineering. Full article

Background/Objectives: Hardikar syndrome (HDKR) is an X-linked dominant disorder caused by pathogenic variants in the Mediator complex subunit 12 (MED12) gene, predominantly affecting females. It is characterized by multisystem congenital anomalies involving the foregut, biliary tract, craniofacial structures, eyes, skeleton, and genitourinary system, with generally preserved neurodevelopment. Only 34 cases have been reported to date, and most exhibit multiple congenital anomalies. We describe a female infant who presented with progressive cholestatic liver disease and complex hepatobiliary malformations, including an absent gallbladder and paucity of bile ducts, with unremarkable prenatal imaging. The clinical course was notable for hepatosplenomegaly, markedly elevated total bile acids, portal hypertension with esophageal varices, and eventual liver failure. Methods: Whole-exome sequencing (WES) was performed to investigate the underlying genetic etiology, followed by parental segregation analysis using Sanger sequencing to confirm and characterize the identified variant. Results: WES identified a novel de novo intronic heterozygous variant in MED12 (c.3868-5C>G). Unlike most previously reported cases, the predominant and early manifestation in our case was severe hepatobiliary disease with limited additional anomalies, suggesting possible phenotypic variability within the MED12-related Hardikar syndrome spectrum. The identified MED12 variant is classified as a variant of uncertain significance (VUS). Conclusions: This case underscores the diagnostic utility of WES in infants with unexplained cholestasis, highlights the importance of considering noncoding variants, and illustrates the value of reporting well-characterized patients carrying novel VUS, thereby contributing to the growing body of clinical and molecular evidence on MED12-related Hardikar syndrome. Full article

Major depressive disorder (MDD) remains a leading cause of disability; however, monoaminergic models do not fully explain delayed treatment onset, incomplete remission, or rapid responses to glutamatergic interventions. In this study, we proposed a system-level ionic homeostasis framework for MDD. In this model, genetic susceptibility, chronic stress, metabolic burden, and neuroinflammation converge in neuronal and glial ion-channel systems, disrupting calcium, potassium, chloride, and purinergic homeostasis. These disturbances alter intrinsic excitability, synaptic integration, inhibitory tone, glial buffering, and neuron–glia signaling, thereby promoting excitation–inhibition imbalance, impaired plasticity, and corticolimbic network instability. We reviewed the evidence implicating the CACNA1C/Cav1.2, TREK-1, KCNQ, NKCC1/KCC2, HCN, transient receptor potential/acid-sensing ion channels, and glial mediators, including P2X7R, Kir4.1, and AQP4. We also discuss how ketamine-related mechanisms, chloride-restoring strategies, anti-inflammatory ion channel targeting, neuromodulation, EEG biomarkers, and AI/multiomics approaches support mechanism-informed precision therapeutics. MDD could be conceptualized as a distributed failure of ionic homeostasis that links neuroinflammation, E/I imbalance, network instability, and impaired adaptive plasticity. Full article

Turner syndrome (TS), a disorder caused by the complete or partial absence of an X chromosome, exhibits significant clinical variability that cannot be fully explained by chromosomal anomalies alone. This narrative review highlights the crucial role of epigenetic mechanisms, particularly X-chromosome inactivation (XCI), in shaping the TS phenotype. The haploinsufficiency of genes that normally escape XCI is a primary driver of TS features. The specific epigenetic consequences depend on the chromosomal anomaly. In complete monosomy (45,X), the absence of escape-mediated dosage compensation genes from a second X chromosome amplifies haploinsufficiency across X-linked escape genes. Isochromosome Xq (i(Xq)) variants involve the loss of the short arm (Xp) and duplication of the long arm (Xq), creating a dual dosage imbalance with extreme XCI skewing. Carriers of i(Xq) also have a heightened risk for autoimmune disorders compared to those with 45,X TS. For ring-X chromosomes (r(X)), which are mitotically unstable, the functional status of the XIST gene is critical. If the ring is XIST-negative, it remains transcriptionally active, resulting in functional disomy and a more severe phenotype with pronounced neurodevelopmental and craniofacial features. Ultimately, the clinical heterogeneity in TS arises from a complex interplay of the specific chromosomal structure, tissue-specific mosaicism, XIST function, and variable escape from XCI, defining TS as a disorder of epigenetic and gene-regulatory imbalance. However, future research requires a better understanding of the complex mechanism of X-chromosome inactivation. Full article

Background/Objectives: Duchenne muscular dystrophy (DMD) is a progressive X-linked neuromuscular disorder. This retrospective study evaluated the demographic, genetic, and clinical characteristics of children diagnosed with DMD before age three to understand early clinical presentation profiles. Methods: The cohort included 198 boys diagnosed with DMD before three years of age between January 2020 and July 2025. Medical records, serum creatine kinase (CK) levels, language milestones via Denver II criteria, and multi-exon deletion maps were retrospectively evaluated. Results: Regarding the diagnostic entry pathways, the initial clinical trigger that led to medical investigation was incidental hyperCKemia in 91.4% of cases. Regardless of the presentation trigger, a definitive, confirmed diagnosis was established in all 198 cases: 196 patients (99.0%) were securely confirmed via genetic testing (MLPA or sequencing), while 2 patients (1.0%) with negative genetic panels were confirmed via muscle biopsy demonstrating a complete absence of dystrophin expression. Genetic analysis revealed deletions in 77.8% of patients, predominantly multi-exon deletions clustered in the distal hotspot region. Independent ambulation occurred at a median age of 16 months, and 14.6% achieved walking after 18 months. Delayed language development was observed in 29.8% of patients. Conclusions: Our findings indicate that early childhood DMD is characterized not only by early muscle involvement but also by prominent neurodevelopmental features. These findings underscore the value of early CK screening in young boys and support integrating standardized neurodevelopmental surveillance into early DMD care. Full article

Autoimmune endocrine diseases constitute a group of disorders characterized by immune-mediated destruction or dysfunction of hormone-producing glands. The pathogenesis of these diseases reflects a breakdown of immune tolerance in which regulatory T cells (Tregs) play a key role. The transcription factor forkhead box P3 (FOXP3) is a master regulator of Treg differentiation and suppressive function. Also, it is central to maintaining self-tolerance. Genetic mutations in FOXP3, including those responsible for immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome, highlight the critical role of FOXP3 in endocrine immune tolerance. Emerging evidence suggests that autoimmune endocrine disorders may reflect organ-specific destabilization of FOXP3 expression rather than complete Treg deficiency. The reversibility or irreversible loss of FOXP3 gene expression represents a key determinant of Treg plasticity and the persistence of autoimmune inflammation. This review proposes an integrated genetic–epigenetic model of FOXP3 instability and examines how the endocrine microenvironment shapes Treg plasticity. Genetic or epigenetic alterations affecting FOXP3 expression can impair Treg activity and precipitate endocrine organ-specific autoimmunity. Epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNA-mediated regulation that modulate FOXP3 transcriptional activity are discussed. From a translational perspective, the potential of FOXP3 as a biomarker for endocrine disease susceptibility and progression was summarized. Furthermore, therapeutic strategies employed for expanding or engineering functional FOXP3⁺ Tregs using antigen-specific vaccines, chimeric antigen receptors (CAR)-Tregs, gene therapy, or low-dose interleukin-2 (IL-2) were described. Full article

Severe Combined Immunodeficiency (SCID), Spinal Muscular Atrophy (SMA), and X-Linked Agammaglobulinemia (XLA) are rare but life-threatening genetic disorders in infants that can lead to severe infections, progressive neuromuscular degeneration, or severe immune dysfunction associated with significant morbidity and mortality if not diagnosed early. Advances in newborn screening (NBS) technologies have enabled pre-symptomatic detection of these conditions, allowing early initiation of life-saving interventions such as hematopoietic stem cell transplantation, gene therapy, and immunoglobulin replacement therapy. However, the absence of a standardized national clinical pathway linking screening, confirmatory testing, and specialist referral in Malaysia continues to contribute to delayed diagnosis and suboptimal patient outcomes. This review examines and synthesizes current evidence on the clinical pathways for early diagnosis and management of SCID, SMA, and XLA, with particular emphasis on diagnostic workflows, screening technologies, and healthcare system challenges within the Malaysian context. The review examines disease epidemiology, consequences of delayed diagnosis, and the role of expanded NBS under the Screening for Health, Intervention, Nurturing of Every Child (SHINE) program in improving early diagnosis and management. In addition, the paper outlines the current NBS landscape, the use of multiplex real-time polymerase chain reaction (PCR) assays for simultaneous detection of T-cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and survival motor neuron 1 (SMN1) gene deletion of exon 7 from dried blood spot (DBS) samples. A structured diagnostic framework incorporating screening interpretation, confirmatory testing, and urgency-based referral pathways is also proposed. By addressing current operational barriers and coordinating laboratory referral systems, expanding NBS programs could significantly improve early diagnosis and long-term outcomes for infants affected by SCID, SMA, and XLA in Malaysia. Full article

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an adult-onset inflammatory disorder caused by acquired mutations in UBA1, the gene encoding the primary ubiquitin-activating enzyme. The recognition of VEXAS has transformed the current understanding of autoinflammatory disease by demonstrating that somatic alterations arising within hematopoietic stem cells can precipitate severe, multisystem inflammation in later life. While pathogenic UBA1 variants are essential to disease pathogenesis, many affected individuals also harbor additional somatic mutations associated with clonal hematopoiesis, most commonly involving DNMT3A and TET2. These concurrent mutations may contribute to clonal architecture; however, their independent impact on inflammatory phenotype and hematologic manifestations remains incompletely defined. Emerging evidence suggests that co-occurring clonal hematopoiesis mutations may be independently associated with poorer overall survival, though their causal role remains unestablished. This review examines the evolving genetic framework of VEXAS syndrome, emphasizing UBA1 as the obligate driver mutation while reviewing current evidence regarding non-Met41 UBA1 variants and co-occurring somatic mutations. Full article

Wilson–Turner syndrome (WTS) is an X-linked developmental disorder associated with variants in the LAS1L gene, which plays a role in ribosome biogenesis. We report a 6-year-and-5-month-old boy presenting with growth retardation, early developmental delay, and mild scoliosis. Exome sequencing analysis identified a novel hemizygous LAS1L frameshift variant, c.2082dup (p.Leu697ProfsTer59), inherited from his asymptomatic mother that was absent from population databases. Functional analysis in HEK-293T cells suggested reduced protein expression with a partial loss of function effect, while structural modeling indicated potential alteration of the C-terminal region. The patient lacked classical WTS features, including craniofacial dysmorphism, truncal obesity, hypogonadism, and neuromuscular involvement. This case expands the phenotypic spectrum of LAS1L-related disorders and highlights the consideration of LAS1L variants in children with unexplained growth failure, scoliosis, or developmental delay, even in the absence of classical WTS features. Full article