Metachromatic leukodystrophy (MLD) is a rare genetic disorder often regarded as a lysosomal storage disorder. It mainly affects myelination in the central nervous systems (CNS) and peripheral nervous systems (PNS) and is characterized by progressive deterioration of the protective myelin sheath covering the neurons. Demyelination of the CNS and PNS. This erosion of myelin cushion is biochemically linked to the deficiency/inability of the enzyme arylsulfatase A (ASA) to hydrolyze its substrates. This enzymatic defect leads to the pathological accumulation of sulfatides, resulting in widespread irreversible damage to the white matter. The goal of this review is to present a thorough, in-depth summary of the underlying biochemical alterations, existing treatments, and the genetic foundation of MLD. Clinically, MLD presents with a spectrum of severe neurological symptoms, often culminating in profound disability and premature death. The disease is typically classified based on the age of onset into late-infantile, juvenile, and adult forms. The clinical diagnosis is achieved through measuring ASA enzymatic activity, quantifying sulfatides levels and performing genetic tests using conventional and next-generation sequencing (NGS) approaches to establish causality. Currently, hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy are established therapeutic options for MLD patients. However, given the widespread systemic involvement and neuronal damage in the brain, identifying novel biomarkers and treatment regimens is an unmet need to timely reverse the neuronal impairment before unrepairable damage. A deeper understanding of MLD pathogenesis is essential to achieve these advances. There view aims to present a thorough, in-depth summary of the underlying biochemical alterations, existing treatments, and the genetic foundation of MLD.
Pheochromocytomas and paragangliomas (PPGLs) are highly heritable neuroendocrine tumors frequently associated with germline pathogenic variants in SDHB. Although large SDHB deletions are rare worldwide, a recurrent 15,678 bp deletion encompassing the promoter region and exon 1 has been described in the Iberian Peninsula and Latin America, suggesting a founder effect. We report three apparently unrelated Brazilian patients with paragangliomas carrying the same heterozygous germline SDHB exon 1 deletion (NM_003000.3: c.1-10413_73-3866del; g.17043962_17059585del). Clinical presentation was heterogeneous, including early-onset secretory paragangliomas and one patient with the 3P association (pheochromocytoma, paraganglioma, and pituitary adenoma). All tumors were surgically treated, and long-term follow-up showed favorable outcomes without metastatic disease. Breakpoint and haplotype analyses confirmed identity with the previously reported Iberian founder variant, supporting a shared ancestral origin. These findings reinforce the high prevalence of this deletion in Brazil and its relevance for targeted genetic testing, family screening, and long-term surveillance strategies.
Esthesioneuroblastoma (ENB) is a rare and clinically heterogeneous neuroectodermal malignancy arising from the sinonasal tract. Despite its recognition for over a century, the precise cellular origin and the molecular drivers of its diverse clinical behaviour, ranging from indolent growth to aggressive intracranial invasion, have remained poorly defined. The olfactory epithelium (OE), characterized by its unique capacity for lifelong neurogenesis through a structured lineage of basal stem cells, seems to provide the physiological blueprint from which ENB is thought to emerge. Recent advancements in single-cell transcriptomics (scRNA-seq) have revolutionized the understanding of this relationship by enabling the high-resolution deconvolution of the olfactory niche. This review synthesizes current knowledge on the transcriptomic landscape of normal olfactory neurogenesis and its subversion in ENB. The discussion explores how ENB cells hijack the globose basal cell (GBC) progenitor state, which may result in a maturation arrest governed by the dysregulation of key neurogenic transcription factors such as ASCL1 and NEUROD1, the regulatory balance of which varies distinctly across different histological grades. Furthermore, an examination of single-cell data reveals previously hidden intratumoral heterogeneity, hybrid epithelial-mesenchymal states driving invasion, and an immunosuppressive microenvironment that facilitates tumor progression. By bridging the gap between developmental neurobiology and oncology, this analysis highlights the potential for single-cell atlases to redefine ENB grading, identify novel biomarkers, and inform the development of differentiation-based therapies that force malignant progenitors toward terminal, non-proliferative states.
Alpha thalassemia/mental retardation X-linked (ATR-X) syndrome is a rare congenital disorder caused by mutations in the ATRX gene. It predominantly affects males and is characterized by a broad spectrum of clinical features including intellectual disability, distinctive craniofacial/skeletal anomalies, urogenital malformations, and alpha thalassemia. Dysglycemia and diabetes are not currently recognized as an endocrine-associated comorbidity of ATR-X syndrome. This case report presents a 14-year-old male with ATR-X syndrome who was admitted for pseudomonal tracheitis. Initial evaluation incidentally revealed marked hyperglycemia (random glucose 499 mg/dL), prompting further workup. Fasting glucose was 320 mg/dL, HbA1c was 10.2
HHIP-AS1 is a lncRNA located at the HHIP gene locus that has been previously implicated in cancer-related pathways. Nevertheless, the expression pattern and clinical relevance of HHIP-AS1 in AML remain unclear. The current study examined HHIP-AS1 expression status and its clinical significance in non-M3 AML patients. Quantitative reverse transcription–polymerase chain reaction was performed to evaluate HHIP-AS1 transcription profiles in 60 non-M3 AML patients compared with 49 control subjects. The correlation between HHIP-AS1 expression and clinicopathological parameters was then statistically examined. Analysis showed that non-M3 AML patients have lower HHIP-AS1 transcript levels than healthy volunteers (p < 0.001). Subsequently, patients were divided into HHIP-AS1 high-expressing (HHIP-AS1high) and low-expressing (HHIP-AS1low) groups based on the median HHIP-AS1 expression level. The HHIP-AS1low group tended to have a higher blast percentage and a higher peripheral white blood cell count and had notably shorter OS and RFS (p = 0.013 and 0.004, respectively). Moreover, patients with lower initial HHIP-AS1 expression had a refractory response to chemotherapies. Multivariate analysis confirmed the significant association between low HHIP-AS1 expression on both OS and RFS. Our study suggests that downregulation of HHIP-AS1 expression is an independent poor prognostic factor and a diagnostic biomarker in non-M3 AML patients.
Clinical and genetic characterization of a consanguineous family with cerebellar ataxia and tremors associated with a novel pathogenic variant in the KIF1C gene. We studied two generations of a family with cerebellar ataxia and tremor associated with a previously unreported variant in the KIF1C gene. We performed a clinical evaluation of all the available members and proceeded with genetic studies in patients with a positive clinical phenotype. A genetic analysis was also conducted, including KIF1C variant segregation analysis, runs of homozygosity analysis and haplotype analysis. Eleven individuals were identified, all exhibiting cerebellar tremors and ataxia with symptoms of onset around 45 years. Neuroimaging studies were unremarkable. Genetic testing revealed a homozygous KIF1C missense variant (NM_006612.6:c.941G > T, p.(Gly314Val)) in eight patients, and haplotype analysis confirmed a shared homozygous region surrounding KIF1C, consistent with a founder mutation. This represents the first report of this specific KIF1C variant, which is associated with late-onset symmetric tremor progressing to a pancerebellar syndrome. Unlike previously reported KIF1C-related cases (typically early-onset with prominent pyramidal signs), this cohort exhibits a later onset, rare pyramidal involvement, and no consistent neuroimaging abnormalities, thereby expanding the known clinical spectrum of KIF1C-associated disease.
Endometriosis is a gynecological disorder that affects a large number of women worldwide, with several complications including chronic pelvic pain, infertility, and reduced health. Considering the MAPK signaling pathway is involved in endometriosis, we examined the hsa-miR-199a-5p and its predicted target gene, MAP3K11, expression levels to investigate an association between their concurrent dysregulation and endometriosis and to assess their expression changes in peripheral blood mononuclear cells (PBMCs). The sequences of hsa-miR-199a-5p and its target gene, MAP3K11, were obtained by using TargetScan and miRDB databases. Blood samples were collected from 40 women diagnosed with endometriosis and 40 age-matched healthy controls. Quantitative real-time PCR was conducted to assess the expression levels of the genes, and GAPDH and U6 genes were used as internal control genes. We observed a notable increase in the expression levels of both hsa-miR-199a-5p and MAP3K11 genes, 6.6-times and 9.2-times, respectively, in the patient group compared with healthy controls. Despite increased expression levels of the studied genes, a weak, non-significant negative correlation was observed between them (r = − 0.15). These results indicate co-upregulation of both genes in PBMCs, suggesting that their interaction may involve an indirect or post-transcriptional relationship between hsa-miR-199a-5p and MAP3K11. Overall, the findings support that dysregulated circulating miRNAs and their target genes may be associated with endometriosis.
We present here the first case report of Bamforth-Lazarus syndrome (BLS) in two siblings from Oman, with a novel mutation, p.Phe89Leu (F89L) in the FOXE1 gene. This study utilized an in-silico functional assessment strategy for use in extremely rare disorders such as BLS to assess the pathogenicity of novel variant. First, all previously reported germline pathogenic mutations in the FOXE1 gene were mapped. All previously-reported pathogenic missense mutations were located within the DNA-binding Forkhead domain critical to the transcription factor binding function of the FOXE1 protein. The F89L variant was also located in a highly conserved locus within the Forkhead domain. This was a strong indication that the novel mutation, F89L could likely be deleterious for protein function. Based on family segregation analysis, bioinformatic analyses and protein modelling, sufficient evidence was accrued to classify the novel F89L mutation as being pathogenic according to ACMG guidelines.
Familial hypertrophic cardiomyopathy (HCM) is an inherited genetic disorder that affects the heart muscle. Mutations in sarcomere protein genes are regarded as the primary defect that triggers cardiac remodeling and hypertrophy. MYH7 (Myosin Heavy Chain 7) gene mutations are reported as a frequent cause of familial HCM associated with a younger age at onset and poor prognosis, such as sudden cardiac death. Next-generation clinical exome sequencing in two HCM patients of South Asian ancestry revealed a missense ‘likely pathogenic’ variant c.2214 C > A, p.Ser738Arg, in the MYH7 gene, which was also validated by segregation analysis. This is the first report of the MYH7 c.2214 C > A variant from any population. Here, we present this variant’s clinical summary and segregation analysis from two HCM probands and their families.
Neurodevelopmental Disorder with or without anomalies of the Brain, Eye, or Heart (NEDBEH) is an ultra-rare autosomal dominant disorder caused by heterozygous pathogenic variants in RERE, a gene encoding a nuclear receptor coregulator essential for retinoic acid signaling and embryonic development. Fewer than 60 affected individuals have been reported to date, and the phenotypic spectrum remains incompletely defined. Two unrelated pediatric patients were evaluated clinically and by multidisciplinary investigations including echocardiography, brain MRI, renal ultrasound, and ophthalmologic and audiologic assessments. G-banded karyotyping was performed in both. Exome sequencing (CentoXome MOx) with NGS-based CNV assessment and uniparental disomy screening was followed by parental targeted testing. Variants were classified according to ACMG/AMP guidelines. Patient 1, a 6-year-old male born to non-consanguineous parents, harbored a novel de novo heterozygous nonsense variant (NM_001042681.1:c.3535C>T, p. (Arg1179*) and presented with a mild phenotype comprising congenital hypothyroidism, ventricular septal defect, pulmonary artery stenosis, and isolated speech delay. Patient 2, a 7-year-old female born to consanguineous parents, carried the recurrent de novo in-frame duplication (c.4313_4318dupTCCACC, p.(Leu1438_His1439dup) and presented with a severe multisystem phenotype including spastic quadriplegic cerebral palsy, complex congenital heart disease, unilateral renal agenesis, and profound global developmental delay. These two cases expand the clinical and molecular spectrum of RERE-related NEDBEH, illustrate the divergent outcomes associated with loss-of-function versus in-frame Atrophin-1 domain variants, and underscore the value of early exome sequencing in children with complex multisystem involvement.
Langerhans cell histiocytosis (LCH) is currently classified as a myeloid neoplasm that may occasionally coexist with other hematologic malignancies; however, its association with KMT2A-rearranged acute myeloid leukemia (AML) is extremely rare. We report a 76-year-old man with BRAF-mutant multisystem LCH involving the skin, lymph nodes, and spleen, who concurrently presented with AML characterized by t(9;11)(p21.3;q23.3) and an MLLT3–KMT2A fusion. Given his advanced age, significant comorbidities, and frailty, azacitidine was initiated as frontline therapy. After two treatment cycles, the patient achieved complete metabolic remission of LCH lesions and complete hematologic remission of AML, as confirmed by positron emission tomography/computed tomography and bone marrow evaluation. This case highlights a dual therapeutic response of concurrent LCH and KMT2A-rearranged AML to hypomethylating therapy. It also raises the possibility of a shared myeloid precursor with susceptibility to epigenetic modulation, although no direct molecular evidence of clonal relatedness was identified. Hypomethylating agents may represent a feasible treatment option in selected patients with concomitant LCH and myeloid neoplasms.
The clinical presentation of ornithine transcarbamylase deficiency (OTCD) ranges from neonatal-onset hyperammonemia to milder, delayed symptoms, including impaired psychomotor development. We present the case of a male newborn from a dichorionic diamniotic twin pregnancy with no family history of metabolic disorders who developed desaturation, cyanosis and hypertonia in the early postnatal period, and was found to have severe hyperammonemia. Brain MRI revealed abnormalities in the white matter and basal ganglia, while elevated plasma glutamine and urine orotic acid confirmed the OTCD diagnosis. Due to the acute metabolic failure, continuous kidney replacement therapy was initiated to support metabolic clearance, alongside high-rate glucose, nitrogen scavengers, and urea cycle substrates. Despite intensive treatment the patient’s metabolic status continued to deteriorate, and he died a few days later. Genetic testing by Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) identified a novel, hemizygous 9,896-bp genomic deletion involving exon 3 of the OTC gene, which was inherited from the mother and was absent in the unaffected twin. This finding, confirmed by long-PCR to identify the deletion breakpoints, is likely to result in complete enzyme deficiency. This case demonstrates the significant phenotypic variability of OTCD, which is largely influenced by the underlying genetic variant. We also conducted a literature review on the genotype-phenotype correlation of this rare disease to further highlight the importance of genetic testing and counseling for patient and carrier management and reproductive planning.
Mucopolysaccharidosis type I (MPS1) is a rare multisystemic autosomal recessive disorder caused by the deficiency of alpha-L-iduronidase encoded by IDUA. Variants in IDUA lead to the production of malfunctioned enzyme, accumulation of glycosaminoglycans in different tissues, and abnormal clinical manifestations. This study was aimed at investigating IDUA variants underlying MPS1 to determine the spectrum of mutations in Pakistani patients. Ten patients from unrelated families were evaluated through clinical, biochemical, and molecular investigations for MPS1. All exons and exon-intron boundaries of IDUA were PCR amplified from genomic DNA of patients (and their parents, where available) and subjected to Sanger sequencing. The identified variants were evaluated through in silico prediction tools for structural and functional impact. Clinical and biochemical investigations in our patients were consistent with MPS1. Consanguinity was prevalent among parents of enrolled patients (80
Atrial Septal Defects (ASD) are second most common Congenital Heart Defects (CHD), characterized by abnormal communication between atria of the heart. Genetic analyses of familial and sporadic forms of ASD suggest a multigenic basis. Presented study summarizes findings from genome-wide genotyping analysis in ASD cases from Indian population. 12 non-syndromic ASD cases were confirmed by echocardiography (ECHO) and discharge summaries. DNA extracted from peripheral blood was subjected to genome-wide genotyping assay using Axiom™ Asia Precision Medicine Research Array with over 750,000 markers. Variant prioritization was performed using CADD scores along with location, allele frequency, functional impactand prediction scores. Clinical phenotypes were mapped to HPO terms for refined genotype-phenotype correlation. 16 genetic variants including 9 pathogenic, 5 likely pathogenic and 2 Variants of Unknown Significance (VUS) were observed. Heterozygous PKP2 variant rs762753884 (Chr12:32974457 G > A) was identified in all cases. TNNT2 variant rs397516469(Chr1:201332519 G > A) and MYBPC3 variant rs863224899 (Chr11:47359131 C > T) were found in 11 cases in heterozygous state. Additonal heterozygous pathogenic variants in DSP, ABCC9, TTN, MYH7, RBM20 and likely pathogenic variants in SCN5A, RERE, GATA4, TBX5 and MYBPC3 were observed in a subset of cases. This study highlights the polygenic basis of non-syndromic ASD in sporadic cases from the Indian population. Parental segregation analysis may further elucidate cumulative genetic risk and potential unrecognized familial predisposition.
To determine whether non‑coding variation in the CYP21A2 promoter contributes to congenital adrenal hyperplasia (CAH) and to test the functional impact of any enriched variant. Whole-genome data from the 100,000 Genomes Project (100k GP) were filtered to produce a case cohort of seven participants with recorded CAH diagnoses and a control cohort of 33,412 individuals. Bioinformatic screening of the 1 kb region upstream of CYP21A2 identified 3 promoter variants in the case cohort. Fisher’s exact testing showed significant enrichment of rs150223621 (NC_000006.12:g.32037495G > A) in confirmed cases versus controls (p = 2.6 × 10⁻⁵, odds ratio 30.4, 95
ATN1-related neurodevelopmental disorder (ATN1-NDD) is a rare genetic condition typically diagnosed in infancy, characterized by profound developmental delay and hypotonia due to heterozygous pathogenic variants in the highly conserved HX motif of the ATN1 gene. We present a unique case of a 29-year-old male with mild intellectual delay, autism spectrum disorder, and microcephaly, diagnosed in adulthood through reclassification of a heterozygous in-frame tandem duplication variant (c.3188_3193dupTGCACC) within the HX motif. This case represents one of the mildest and latest diagnosed presentations of ATN1-NDD, expanding the known phenotypic spectrum. Notably, the patient’s genotype parallels the only other known mild case, suggesting a possible genotype-phenotype correlation distinct from the severe phenotypes typically observed. This report underscores the importance of genetic re-evaluation in adults with unexplained neurodevelopmental disorders and contributes valuable insight into the variability and natural history of ATN1-NDD.
Breast cancer remains a leading cause of cancer-related deaths among women. Despite advancements in treatment, drug resistance and tumor progression continue to present major challenges. CD39, an ecto-nucleotidase that regulates adenosine signaling, has been implicated in cancer progression and resistance to chemotherapy. This study investigates the role of CD39 in modulating the response of breast cancer cells to paclitaxel. Human breast cancer cell lines (MDA-MB-231, MDA-MB-468, and SKBR-3) were cultured, and CD39 expression was assessed. CD39 knockdown was achieved using siRNA transfection. The effects of CD39 inhibition on paclitaxel sensitivity were evaluated through MTT assays, apoptosis assays, cell cycle analysis, and wound healing assays. Gene expression was analyzed by quantitative PCR. CD39 expression was highest in MDA-MB-231 cells selected for further experiments. CD39 knockdown significantly increased paclitaxel sensitivity, lowering the IC50 from 0.52 µg/ml to 0.07 µg/ml. The combination of CD39 siRNA and paclitaxel treatment induced a substantial increase in apoptosis (63.78
Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically and phenotypically heterogeneous disorder characterized by impaired mucociliary clearance and recurrent respiratory infections. Although genotype–phenotype correlations are well established in PCD, intrafamilial phenotypic variability remains poorly understood. Here, we report monozygotic twins with biallelic variants in the HYDIN gene who exhibit markedly discordant clinical severity and ciliary function despite an identical genetic background. Transmission electron microscopy, high-speed video microscopy, immunofluorescence, and electron tomography were used to asses ciliary structure and function. Both patients were diagnosed with PCD with normal ciliary ultrastructure. Transmission electron microscopy revealed a significantly higher proportion of secondary ciliary ultrastructural defects in patient 1, who also demonstrated a higher clinical index and distinct ciliary beating patterns on high-speed video microscopy compared with patient 2. Genetic findings were confirmed by immunofluorescence and electron tomography in both patients. Despite sharing the same pathogenic HYDIN variants, patient 1 exhibited a significantly higher frequency of numerical axonemal defects, correlating with altered ciliary motility and more severe clinical manifestations. Monozygotic individuals with identical pathogenic HYDIN variants may show discordant clinical severity and ciliary function, highlighting intrafamiliar phenotypic variability in PCD.
Alzheimer’s disease (AD) is strongly influenced by genetic factors, with recent genome-wide association studies highlighting the MS4A gene cluster as a major locus beyond apolipoprotein E. This systematic review and bioinformatic analysis aimed to clarify the contribution of genes to AD pathogenesis. Twenty-nine studies (> 43,000 AD cases and > 66,000 controls) met the inclusion criteria. The most consistently associated variants were MS4A4A (rs1582763), MS4A6A (rs610932), MS4A4E (rs670139), and additional regulatory SNPs such as rs7232 and rs4938933. Most AD-associated variants in the MS4A region are intronic or intergenic regulatory SNPs acting as microglial expression quantitative trait loci, although coding variants (e.g., MS4A4A rs6591561, MS4A6A rs12453) also exist. Across multiple cohorts, MS4A4A and MS4A6A variants correlated with cerebrospinal fluid (CSF) soluble TREM2 (sTREM2), microglial activation, lipid handling, and neuroinflammatory states.Bioinformatic enrichment using ClusterProfiler (FDR < 0.05) revealed significant involvement of MS4A genes in cell-surface receptor signaling, plasma-membrane complexes, and the trans-Golgi network, supporting a mechanistic link to microglial immune regulation and amyloid precursor protein trafficking. The MS4A gene cluster—particularly MS4A4A and MS4A6A—emerges as a key modulator of microglial biology and sTREM2 levels in late-onset AD. These variants influence microglial inflammatory phenotypes and lipid metabolism and converge on an MS4A–TREM2 regulatory axis. Plasma or CSF MS4A4A/MS4A6A levels and sTREM2 show promise as biomarkers of AD progression, although no validated clinical assay is yet available. The MS4A4A–TREM2 pathway represents a potential therapeutic target for modulating neuroinflammation in AD.
