Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. Although the classical presentation is dominated by hyperammonemia-related neurological manifestations, some patients may present with atypical liver-predominant phenotypes, which can delay early diagnosis. Here, we identified a 3-year-6-month-old female patient who presented primarily with liver dysfunction, characterized by elevated transaminases, mild coagulation abnormalities, and increased hepatic parenchymal echogenicity, without overt jaundice or typical neurological symptoms. Metabolic mass spectrometry screening revealed elevated urinary uracil, whereas amino acid and acylcarnitine profiles were unremarkable. Trio whole-exome sequencing followed by Sanger validation identified a novel de novo heterozygous missense sequence variant in exon 6 of OTC, c.541G > A (p.Glu181Lys), which was absent in both parents. According to OTC/UCD-specific curation recommendations, this sequence variant was classified as pathogenic. Structural modeling and mature-trimer molecular dynamics simulations suggested that the p.Glu181Lys substitution may modestly alter OTC conformational dynamics, including local flexibility around residues 120-150 and the variant site. Together with the liver-predominant clinical presentation and supportive metabolic screening findings, these results indicate that OTC c.541G > A (p.Glu181Lys) is the most likely genetic basis of disease in this patient. This study expands the variant spectrum of OTC and highlights the importance of considering OTCD in children with otherwise unexplained liver dysfunction, even in the absence of classical hyperammonemic encephalopathy.

BACKGROUND:We investigated the association between food-derived dietary magnesium intake and all-cause mortality among adults with chronic kidney disease. METHODS:We analysed data from adults aged ≥20 years with CKD who participated in the National Health and Nutrition Examination Survey between 1999 and 2018. Mortality status was ascertained through linkage to the National Death Index through 31 December 2019. Multivariable Cox proportional hazards models were used to evaluate the association between dietary magnesium intake and all-cause mortality. Restricted cubic spline analysis, Kaplan-Meier survival analysis, subgroup analyses, and sensitivity analyses were also performed. RESULTS:A total of 8,104 CKD patients were included in this cohort study with a median follow-up of 85 months, during which 3,134 (38.7%) died from all causes. In the fully adjusted Cox model, each 100 mg/day increase in dietary magnesium intake was associated with a 7.5% lower risk of all-cause mortality (HR = 0.925, 95% CI 0.881-0.971; P = 0.002). Compared with the lowest quartile, adjusted hazard ratios were 0.978 (95% CI 0.883-1.083) for Q2, 0.904 (95% CI 0.804-1.016) for Q3, and 0.866 (95% CI 0.744-1.007) for Q4, with a significant trend across quartiles (P for trend = 0.036). RCS analysis demonstrated a significant overall association with no evidence of nonlinearity (P for overall association = 0.009; P for nonlinearity = 0.472). Kaplan-Meier analysis showed higher survival probabilities among participants with higher dietary magnesium intake. CONCLUSIONS:Higher dietary magnesium intake was independently associated with a lower risk of all-cause mortality among adults with CKD. These findings suggest that adequate dietary magnesium intake may represent an important nutritional factor associated with prognosis in CKD. Further prospective studies and randomised clinical trials are warranted to determine whether increasing dietary magnesium intake can improve clinical outcomes. SUMMARY STATEMENT:Higher dietary magnesium intake was independently associated with lower all-cause mortality among patients with chronic kidney disease in NHANES 1999-2018. These findings highlight the potential protective role of adequate magnesium intake in improving long-term survival in this population.

BACKGROUND:Sitosterolemia (STSL) is a rare autosomal recessive disorder caused by biallelic mutations in ABCG5 or ABCG8, which encode sterolin efflux transporters. Defective transport leads to intestinal hyperabsorption and reduced biliary excretion of plant sterols and cholesterol, causing their accumulation and heterogeneous phenotypes often misdiagnosed as familial hypercholesterolemia. METHODS:Whole-exome sequencing was performed in a 3-year-old child with early-onset hypercholesterolemia. Candidate variants were validated by Sanger sequencing of family members, followed by genotype-phenotype analysis. Plasma plant sterols were quantified by gas chromatography-mass spectrometry, and structural modeling was used to predict the impact of variants. RESULTS:The proband developed multiple xanthomas over the knees, elbows, ankles, finger joints and skin folds at 2 years of age. Her father and grandfather had obesity and hypercholesterolemia with fatty liver but no xanthomas. Genetic analysis identified a novel compound heterozygous ABCG5 mutation: c.1337G > A (p.Arg446Gln), inherited from the father and classified as likely pathogenic, and c.1396G > C (p.Ala466Pro), inherited from the mother and classified as a variant of uncertain significance according to ACMG guidelines. Segregation supported the genotype-phenotype correlation. Plasma sterol profiling showed elevated cholestanol, desmosterol, campesterol, stigmasterol and sitosterol with normal squalene and lathosterol. Ezetimibe plus a low-plant-sterol diet improved xanthomas and biochemical parameters. Structural modeling demonstrated conformational changes and reduced hydrogen bonding for both variants, suggesting impaired protein stability. CONCLUSION:The missense variants c.1337G > A (p.Arg446Gln) and c.1396G > C (p.Ala466Pro) in exon 10 of ABCG5 likely represent the molecular genetic basis of STSL in this family.

Lung adenocarcinoma (LUAD) is a highly lethal malignancy in which the tumor microenvironment (TME) plays an important role in disease progression and therapeutic resistance. However, the spatial organization and molecular basis of stromal–immune interactions in LUAD remain incompletely understood. We integrated bulk RNA sequencing, single-cell RNA sequencing, spatial transcriptomics, multiplex immunofluorescence, and in vitro functional assays to characterize TME heterogeneity and investigate mechanisms associated with stromal barrier formation and immune exclusion in LUAD. POSTN⁺ cancer-associated fibroblasts (CAFs) and SPP1⁺ macrophages were enriched in LUAD, showed marked spatial colocalization, and were associated with an immune-excluded spatial pattern characterized by limited effector T-cell infiltration. Cell–cell communication analysis identified SPP1-centered signaling from SPP1⁺ macrophages to POSTN⁺ CAFs, with CD44 emerging as a prominent receptor candidate and integrin-related receptor pairs suggested as additional candidate branches. In vitro experiments showed that TAM-like macrophage-conditioned medium activated CAF-like HFL-1 cells, increased POSTN, FN1, and COL1A1 expression, enhanced fibroblast adhesion and collagen gel contraction, and restricted primary CD8⁺ T-cell migration across CAF-like stromal barriers. These effects were attenuated by SPP1 neutralization or CD44 knockdown. In addition, CAF-derived C3 was implicated in a feedback loop that may reinforce the SPP1⁺/CD206⁺ macrophage-like phenotype. Pan-cancer analyses further showed that this stromal–myeloid program was conserved across multiple solid tumor types and was associated with poor overall survival, while exploratory cross-cancer immunotherapy analysis suggested a potential association with reduced response to immune checkpoint blockade. These findings further define a spatially organized POSTN⁺ CAF–SPP1⁺ macrophage niche that may contribute to stromal remodeling, CD8⁺ T-cell exclusion, and potentially reduced immunotherapy benefit in LUAD. The TAM-derived SPP1–CD44 axis and CAF-derived C3 feedback loop may provide a framework for biomarker development and therapeutic targeting in immune-excluded solid tumors.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial hyperplasia, inflammatory cell infiltration, and joint destruction. This study investigates the inhibitory effects and metabolic mechanisms of Eucalrobusone C (EC), a novel formyl-phloroglucinol meroterpenoid derivative isolated from Eucalyptus robusta, on Tumour Necrosis Factor-α (TNF-α)-induced rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs). EC was extracted and purified, with purity confirmed using 1H Nuclear Magnetic Resonance Spectrum (NMR) at 400 MHz. RA-FLSs were exposed to varying concentrations of EC, followed by comprehensive assessment including CCK8 assay for cell proliferation, flow cytometry for cell death, and Transwell assay for migration and invasion capacity. Metabolomic profiling employed Ultra-High Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (UHPLC-Q-TOF MS), integrated with multivariate statistical analysis and bioinformatics tools to identify metabolic alterations. Results indicated that EC suppressed RA-FLS proliferation in a time- and concentration-dependent manner, significantly enhanced apoptosis, and inhibited cell migration and invasion. Metabolomics analysis detected 898 metabolites, with 112 upregulated and 67 downregulated in EC-treated groups compared to TNF-α-induced controls. Key differentially expressed metabolites were enriched in pathways including ABC transporters, neuroactive ligand-receptor interactions, protein digestion and absorption, and cAMP signalling. These findings suggest that EC exerts anti-rheumatic effects by modulating these metabolic pathways, offering potential as a therapeutic agent for RA management.

Isolated gastric varices type I (IGV1) is a rare but severe manifestation of splenic vein thrombosis. While thrombophilia is a recognized cause, the underlying genetic determinants are often elusive. This study investigates the case of a proband presenting with IGV1, deep vein thrombosis (DVT), and Long QT syndrome Type 2 (LQT2), aiming to elucidate the genetic basis and functional impact of the identified SERPIND1 variants. Whole-exome sequencing identified candidate variants in the proband, which were validated by Sanger sequencing. Functional assessment included quantifying SERPIND1 and KCNH2 mRNA in proband and control blood, analyzing heparin cofactor Ⅱ (HCⅡ) protein expression and localization in transfected 293T cells, and predicting the potential structural consequences of the variants using bioinformatic tools. The proband, a 31-year-old female, presented with isolated gastric fundal varices and a history of deep venous thrombosis (DVT), along with long QT syndrome type 2 (LQT2). Whole-exome sequencing (WES) identified two heterozygous variants, both confirmed by Sanger sequencing: a de novo SERPIND1 c.940 C > T (p.Arg314Trp) variant, classified as Pathogenic according to ACMG guidelines (PS2, PS3, PM2_Supporting, PP3), and a KCNH2 c.1707 C > A (p.Tyr569*) variant, also classified as Pathogenic (PVS1, PP1, PM2_Supporting) and showing familial co-segregation. The SERPIND1 variant was associated with reduced HCⅡ antigen levels and activity in plasma. In vitro assays revealed that both variants led to significantly reduced SERPIND1 and KCNH2 mRNA expression. In transfected cells, the SERPIND1 p.Arg314Trp variant markedly decreased HCⅡ protein levels and possibly induced aberrant nuclear mislocalization. Structural modeling suggested that the Arg314Trp substitution disrupts a key hydrogen bond within HCⅡ, while the KCNH2 p.Tyr569* nonsense variant is predicted to generate a truncated protein. The SERPIND1 c.940 C > T (p.Arg314Trp) variant is associated with reduced HCⅡ expression and functional impairment, which may contribute to a prothrombotic tendency in this patient. This study provides a hypothesis-generating observation supporting a potential role of HCⅡ deficiency in venous thrombosis and IGV1. The KCNH2 variant was accounted for the coexisting LQT2 phenotype.

This study identifies two pedigrees with autosomal dominant polycystic kidney disease (ADPKD) caused by de novo PKD1 variants. Proband A carried a heterozygous splicing variant (c.9202-16G > A), presenting with bilateral renal cysts. The miniGENE assay confirmed this variant causes aberrant splicing with a 60-base excision, leading to a frameshift and a predicted truncated protein. Proband B carried a missense variant (c.2180 T > C; p. Leu727Pro), presenting with polycystic kidney and liver disease. Structural modeling revealed this variant severely disrupts local secondary structure and a critical spatial interaction, compromising protein stability. Functional analyses demonstrate that both de novo variants are pathogenic through distinct mechanisms, implicating aberrant splicing and structural disruption in ADPKD etiology.

Noonan syndrome (NS) is a common autosomal dominant disorder with considerable clinical heterogeneity. Mutations in the PTPN11 gene, encoding the SHP2 protein, constitute the most prevalent genetic cause of NS. Genetic sequencing of a pedigree exhibiting typical facial dysmorphism and short stature identified the same heterozygous PTPN11 variant (NM_001330437.2: c.923 A > G, p.Asn308Ser) in all seven affected individuals, co-segregating with the phenotype. Using a multi-level approach that integrated experimental structural analysis, molecular dynamics simulations, protein-protein interaction network analysis, quantitative phosphoproteomics, and functional validation in cellular models, we systematically elucidated the pathogenic mechanism of the p.Asn308Ser mutation. This revealed that the mutation disrupts critical hydrogen bonds and remodels the interaction network. This change enhances conformational heterogeneity and shifts the protein into an activated "open" state. Consequently, the mutation strengthens interactions with hub proteins, such as GRB2 and SRC, resulting in sustained RAS/MAPK activation. Phosphoproteomic analysis showed that the mutation induces extensive phosphorylation events, with differentially phosphorylated proteins significantly enriched in the nucleus, particularly in pathways related to chromatin organization and ATP-dependent chromatin remodeling. Further functional validation indicated that aberrantly activated ERK may phosphorylate chromatin remodeling complexes such as SWI/SNF, thereby directly connecting cytoplasmic signaling to aberrant epigenetic regulation in the nucleus. This study delineates the complete pathogenic axis of the PTPN11 p.Asn308Ser mutation, spanning atomic conformational changes and sustained signaling activation to aberrant nuclear chromatin remodeling. These findings extend the understanding of NS pathophysiology to the epigenetic level and provide a theoretical foundation for future interventions targeting both signaling pathways and chromatin states.

RATIONALE:The opportunistic pathogen Corynebacterium striatum has been generating more clinical infections in recent years, but secondary infections at different parts caused by it have been reported more rarely. PATIENT CONCERNS:This case details a 52-year-old male patient who got an infection that advanced to multiple osteomyelitis and soft tissue abscess after block therapy for external humeral epicondylitis of the right arm. Unexpectedly, the chronic ulcerated region of the patient's neck was infested with Corynebacterium striatum due to inadequate treatment of the main infection, resulting in a secondary infection of the neck mass. DIAGNOSES:Microbiological cultures of the pus from the right elbow and neck indicated an infection with Corynebacterium striatum at both sites. INTERVENTIONS:We initiated antimicrobial therapy with linezolid (600 mg) in conjunction with Fosfomycin (4 g) every 12 hours. OUTCOMES:After 4 weeks of treatment, the infected lesion was resolved as evidenced by a repeat magnetic resonance imaging compared to the prior scan. LESSONS:This case not only demonstrates the significant pathogenicity of Corynebacterium striatum but also warns that traumatic locations, such as swellings resulting from chronic ulcers in the neck, may become prospective targets for this bacterium.

Type A insulin resistance syndrome (TAIRS) is a rare autosomal dominant disorder associated with variants in the Insulin Receptor (INSR) gene. It is characterized by insulin resistance, hyperandrogenism, and acanthosis nigricans. The severity of the condition may be influenced by homozygosity or heterozygosity, with some female patients being misdiagnosed with polycystic ovary syndrome (PCOS). A 13-year-old female proband from a family was identified with hyperinsulinemia, hyperandrogenism, acanthosis nigricans, hirsutism, acne, oligomenorrhea, and masculinization. Exome sequencing and Sanger sequencing confirmed that the proband was a carrier of the INSR (NM_000208.2): c.3734 T > A(p.V1245E) variant. This variant is not listed in the Human Gene Mutation Database (HGMD) or ClinVar. The novel variant was predicted to be deleterious by the bioinformatic tools SIFT, MutationTaster, and Condel. According to the American College of Medical Genetics and Genomics (ACMG) criteria, it was evaluated as PM6, PM2_Supporting, and PP3, and classified as uncertain significance. The variant was not detected in the proband's parents or other family members, all of whom lacked the associated clinical phenotypes. The p.V1245E variant was found to be a de novo variant. SWISS-MODEL analysis suggested that the p.V1245E variant induces structural changes in the three-dimensional configuration of the INSR protein, potentially impairing its normal function. RT-qPCR revealed a significant reduction in INSR mRNA expression in the proband. In a 293 T cell model transfected with lentivirus carrying the p.V1245E variant, both Western blotting and RT-qPCR demonstrated decreased INSR mRNA and protein expression, while immunofluorescence showed reduced INSR protein levels with altered localization. Therefore, the ACMG evaluation (PS2, PS3, PM2_Supporting, PP3) was further upgraded to pathogenic. In conclusion, this de novo variant represents the pathogenic variant responsible for TAIRS in this family, expanding the variant spectrum of the INSR gene.

Bicuspid aortic valve (BAV) represents a prevalent form of congenital heart disease. The NOTCH1 gene is implicated in the pathogenesis of BAV, and congenital valve anomalies caused by variants in this gene are classified as Aortic Valve Disease 1 (AOVD1), which is inherited in an autosomal dominant pattern. Echocardiographic data and peripheral blood samples were collected from a Chinese family manifesting a clinical phenotype characterized by various cardiovascular abnormalities, including BAV. Exome sequencing target enrichment technology was performed to identify candidate genes and variants. This was followed by family segregation analysis using Sanger sequencing. A novel nonsense variant, c.2266G > T (p.Glu756Ter), was identified in the NOTCH1 gene (NM_017617.5) within this family. Individuals harboring the p.Glu756Ter pathogenic variant (III4, II7, II9, and I2) exhibited BAV – associated phenotypes. Conversely, the proband carrying p.Glu756Ter pathogenic variant (IV1) presented with distinct clinical phenotypes, including a persistent left superior vena cava (PLSVC) and a widened coronary sinus. Family members without the p.Glu756Ter pathogenic variant showed no cardiovascular abnormalities. This variant is located in exon 14 of the NOTCH1 gene, resulting in a premature stop codon. Bioinformatics analysis predicted that p.Glu756Ter induces nonsense-mediated mRNA decay or produces a truncated protein, impairing NOTCH1 receptor function. The NOTCH1 variant is a prevalent genetic factor in BAV etiology, exhibiting both interfamilial and intrafamilial phenotypic variability with incomplete penetrance. PLSVC and a widened coronary sinus represent common anatomical variations within the general population. Nevertheless, the potential role of NOTCH1 variants in the development of these vascular anomalies should be considered.

Hepatolenticular degeneration (HLD, MIM:277900) is an autosomal recessive disorder characterized by excessive copper accumulation in hepatocytes, leading to hepatic and neurological abnormalities, hepatocellular injury, neurodegeneration, and copper deposition in the cornea. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common genetic cause of hemolytic anemia, which can be triggered by chronic conditions, drugs, food, or infections, and exhibits highly variable severity. In some cases, multiple genetic factors may collectively influence disease presentation and progression. This study reports a proband who developed abnormal liver function at age 20. Four years later, she exhibited severe jaundice, liver dysfunction, serous effusions, anemia, and Kayser-Fleischer rings, leading to diagnoses including decompensated cirrhosis, splenomegaly, suspected HLD, hemolytic anemia, portal hypertension, hypoproteinemia, low T3 syndrome, primary peritonitis, and gallstones with cholecystitis. Genetic screening identified two pathogenic heterozygous variants in ATP7B (NM_000053.4): c.2128G > A (p.G710S) in exon 8 and c.525dupA (p.V176Sfs*28) in exon 2, together forming a compound heterozygous mutation. Additionally, a heterozygous mutation in G6PD (NM_001360016.2), c.1388G > A (p.R463H) in exon 12, was found. Family members carrying the G6PD variant showed recurrent benign jaundice or remained asymptomatic. A heterozygous missense variant of uncertain significance, c.205C > T (p.R69C), was also detected in exon 3 of STEAP3 (NM_182915.3), a gene linked to hypochromic microcytic anemia with iron overload type 2 (MIM#615234). This rare variant was predicted to be deleterious by in silico tools, suggesting possible genetic cosegregation. SWISS-MODEL analysis indicated that these variants may alter the three-dimensional structures of the copper-transporting ATPase and G6PD proteins, potentially impairing function-particularly the frameshift mutation p.V176Sfs*28. We hypothesize that the accumulation of multiple pathogenic genetic factors resulted in a "double-hit" effect, leading to the patient's severe phenotypes, including advanced liver cirrhosis and hemolytic anemia. Elucidating such multi-gene "double-hit" mechanisms may enhance the understanding of gene-gene interactions in complex diseases.

Crigler-Najjar syndrome (CNS) and Gilbert syndrome (GS; OMIM: 143500) are rare autosomal recessive diseases that cause unconjugated hyperbilirubinemia due to decreased UGT1A1 enzyme activity. Crigler-Najjar syndrome type 2 (CNS2; OMIM: 606785) increases the risk of gallbladder stone formation and cholecystitis, while GS seldom causes health issues. We found a 28-year-old male patient with recurring right upper abdomen pain who experienced persistent jaundice from birth. CNS2 with gallbladder stones and cholecystitis was diagnosed after genetic testing revealed rare double homozygous mutations A(TA)7TAA (rs3064744) and P229Q (rs35350960) in the UGT1A1 gene. After pedigree investigation, we found that the patient's parents with modestly increased bilirubin had compound heterozygous mutations A(TA)7TAA and P229Q, which were GS. Bioinformatics analysis showed that A(TA)7TAA is in the TATA-box region of the gene UGT1A1 promoter, affecting gene transcriptional initiation, whereas P229Q modifies protein three-dimensional structure and may be harmful. In this pedigree, double homozygous mutations have a more severe phenotype than compound heterozygous mutations. Inherited causes of hyperbilirubinemia should be suspected after ruling out biliary obstruction, and early bilirubin reduction (< 103 µmol/L (6 mg/dL)) may reduce the risk of complications like cholecystitis in CNS2 patients, though further studies with longer follow-up are needed to confirm this observation.

BACKGROUND:Tubulointerstitial nephritis and uveitis (TINU) syndrome is prevalent among adolescent females and less prevalent among the older people. Additionally, although both disorders are linked to immune modulation, clinical instances of simultaneous diagnosis of TINU syndrome and monoclonal gammopathies (MG) are exceedingly rare. In this case report, we present a rare concurrence of monoclonal gammopathies in an older adult with TINU syndrome. CASE PRESENTATION:A 74-year-old woman with chronic bilateral anterior uveitis and a non-oliguric acute kidney injury developed TINU syndrome. Unexpectedly, immunofixation electrophoresis testing confirmed MG in the patient. Her renal histology showed tubulointerstitial degeneration, confirming TINU syndrome with MG. The patient tended to have monoclonal gammopathy of undetermined significance because her renal vascular light chain Kappa immunofluorescence showed significant positivity but no glomerular or tubular damage from monoclonal immunoglobulin deposition. The patient's renal impairment was principally attributed to TINU syndrome, and after glucocorticoid treatment, ocular symptoms stabilized, renal impairment improved, and urine protein remained consistently negative. CONCLUSIONS:The high incidence of disease in the old population results in increased disease complexity. This report emphasizes that TINU syndrome might be complicated by various additional conditions, including the unusual occurrence of coupled MG. A renal tissue biopsy is crucial for a differential diagnosis in cases of severe kidney injury. Patients with TINU and MG present distinct clinical manifestations and renal damage pathologies. The diagnosis of these patients requires consideration of clinical data and renal pathological alterations to guide treatment planning.

Mature-onset diabetes of the young (MODY) is an autosomal dominant genetic disease that is typically diagnosed during childhood or early adolescence. The primary pathogenesis of MODY involves gene mutations that impair insulin synthesis and/or secretion by islet β cells, rendering the condition independent of insulin resistance. A family with the MODY-12 phenotype caused by an ATP-binding cassette subfamily C member 8 (ABCC8) gene mutation was investigated in the present study. Clinical data were collected from all family members, and second-generation gene sequencing and Sanger sequencing were performed. The suspected pathogenic mutation was validated by Sanger sequencing, and the three-dimensional structure of the pathogenic variant protein was predicted and simulated using the Swiss-Model platform. Five individuals with MODY-12, including the proband, were identified in this family. Second-generation gene sequencing confirmed that all family members carried the ABCC8 c.2500C>T (p.Arg834Cys) mutation. Structural modeling revealed that the replacement of arginine at position 834 in the wild-type protein with cysteine results in the formation of an additional hydrogen bond with the surrounding amino acids. In addition, the ABCC8 c.2500C>T carriers in this family experienced recurrent diabetic ketoacidosis and acute kidney involvement (AKI) phenotypes, and all patients had a history of sodium-glucose transporter 2 inhibitor (SGLT2i) use. We hypothesize that AKI in these patients may be pseudo-AKI associated with the use of SGLT2is. However, the proband exhibited symptoms indicative of rapidly progressing diabetic nephropathy. This study demonstrates that clinicians managing patients with MODY should be aware of the risk of acute and serious complications, particularly as SGLT2i may induce pseudo-AKI, which could ultimately compromise patients' long-term renal prognosis.

Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder, with spastic paraplegia type 56 (SPG56) being an exceptionally rare, autosomal recessive subtype caused by mutations in the CYP2U1 gene. This study reports a complex case of an adult female from a consanguineous family who presented with cognitive developmental delays, short stature, and progressive neurological symptoms. At age 39, she developed unilateral tremors, which progressed to generalized tremors and leg weakness with a tiptoe gait. The clinical findings included hypertonia in the upper limbs, exaggerated reflexes in the lower limbs, vague speech, and emotional disturbances. Brain MRI revealed corpus callosum thinning, “ears of the Lynx” sign, bilateral globus pallidus calcifications, and mild brain atrophy. Comprehensive genomic analysis, including whole exome sequencing (WES), copy number variation (CNV) assessment, mitochondrial DNA sequencing, variant filtering, and Sanger sequencing, identified a homozygous c.913 C > T (p.His305Tyr) mutation in CYP2U1 (NM_183075). The heterozygous carriers presented no symptoms. This case contributes to the phenotypic spectrum of SPG56, offering new insights into its diagnosis and genetic underpinnings.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the development of benign tumors and lesions in multiple organ systems. The syndrome arises from heterozygous mutations in either TSC1 or TSC2. In this study, we identified a family with a TSC1 c.363 + 668G > C mutation exhibiting diverse clinical phenotypes. The proband and affected family members exhibited multifocal nodular pneumocyte hyperplasia (MMPH), renal hamartomas, bone marrow hyperplasia, and pulmonary lymphangioleiomyomatosis (LAM), with genetic co-segregation analysis confirming the association between the mutation and the clinical phenotype. Genetic co-segregation analysis demonstrated that the TSC1 c.363 + 668G > C mutation was consistently associated with the observed clinical features in this family. Using first-generation Sanger sequencing, we identified a heterozygous splicing variation located in intron 5 of TSC1 (NM_000368.5). In vitro cell and family Minigene results show that TSC1 c.363 + 668G > C mutation can lead to abnormal retention of 92 bp intron sequence in different positions, which may be related to the alternative splicing phenomenon that the same gene produces different splicing variants in different tissues or development stages. The 3D protein structure analysis using Chimera revealed that the mutation site was located at the 363rd base, within the intron between the 121st and 122nd amino acids. This mutation resulted in the insertion of a 92-base sequence, causing a frameshift that led to premature termination of the TSC1 protein after the translation of 26 amino acids. Additionally, the 121st amino acid was altered from lysine to asparagine, significantly shortening the mutated TSC1 protein. These findings provide critical experimental evidence supporting the potential pathogenic mechanism of the TSC1 c.363 + 668G > C mutation. Future research should focus on validating this splicing abnormality in patient-derived cells or tissues and investigating its impact on protein expression and functional activity to better understand its role in disease progression.Clinical trial number: K2024-09-144.

A pair of epimer with an unprecedented 4/7/6 tricyclic skeleton sesquiterpene (1 and 2) and five novel sesquiterpene (3-7) were isolated from Callicarpa nudiflora Hook. et Arn. Their structures were established by extensive spectroscopic analyses, single crystal X-ray diffraction, experimental electronic circular dichroism (ECD) spectra comparison and DP4+ probability analysis. In addition, the plausible biosynthetic pathways of 1 and 2 were proposed. Biological tests indicated that sesquiterpenes derived from the caryophyllene skeleton displayed hemostasis activities in vivo and in vitro, also possessed certain anti-inflammatory ability simultaneously.

IntroductionAdult Polyglucosan Body Disease (APBD) is a rare, autosomal recessive neurodegenerative disorder that affects both the central and peripheral nervous systems. It is primarily caused by mutations in the Glycogen Branching Enzyme 1 (GBE1) gene. APBD is typically associated with Ashkenazi Jewish populations, though it can occur in other ethnic groups. This study aims to expand the phenotypic and genetic spectrum of APBD, particularly in non-Ashkenazi Jewish patients, and to identify atypical genetic alterations linked to the disease.MethodsA 57-year-old Chinese male (Ⅱ3) presented with a 4-year history of progressive bladder dysfunction, upper and lower motor neuron impairment, sensory loss, and lower limb weakness, leading to difficulty with gait. Genetic testing was performed to identify potential pathogenic variants in the GBE1 gene. A family assessment revealed a sister (Ⅱ5) with the same clinical features. Both patients underwent genetic analysis, which included sequencing and deletion analysis.ResultsGenetic testing revealed that both affected individuals (Ⅱ3 and Ⅱ5) carried compound heterozygous variants in the GBE1 gene: c.466C>T (p.R156C) in exon 4 and a large deletion of exons 3–7. The two pathogenic variants co-segregated in the family, confirming the diagnosis of APBD in these individuals.DiscussionThis case expands the phenotypic and genetic spectrum of APBD, particularly by documenting its occurrence in non-Ashkenazi Jewish patients. Additionally, the identification of atypical genetic alterations, such as the large deletion in GBE1, provides new insights into the genetic basis of the disease and may aid in understanding its broader clinical manifestations. These findings suggest the need for a broader genetic screening approach in APBD diagnosis, especially in diverse populations.

Hereditary spastic paraplegia (HSP) is a rare and genetically heterogeneous neurodegenerative disorder, primarily defined by progressive lower-limb spasticity and weakness. Among the numerous genes implicated, pathogenic variants in the spastic paraplegia 7 (SPG7) gene represent one of the most common causes of HSP, whereas mutations in SCN4A, a skeletal muscle ion channel gene, are typically associated with a diverse spectrum of phenotypes, including hyperkalemic and hypokalemic periodic paralysis, potassium-aggravated myotonia, and congenital paramyotonia. To date, however, the coexistence of pathogenic variants in SPG7 and SCN4A within the same pedigree, and their potential pathogenic interplay, has not been documented. In this study, we performed comprehensive genetic profiling, including whole-exome sequencing, mitochondrial genome analysis, dynamic mutation screening, copy number variation assessment, and Sanger sequencing. We identified a novel heterozygous SPG7 variant (c.578A>G; p.E193G) alongside a known pathogenic SCN4A missense mutation (c.2111C>T; p.T704M). Remarkably, individuals harboring both variants presented with highly complex phenotypes that combined classical HSP manifestations with ion channel dysfunctions, such as congenital paramyotonia and hypokalemic periodic paralysis. These findings provide the first evidence of a possible genetic interaction between SPG7 and SCN4A, expanding the recognized clinical and molecular spectrum of HSP. Our results underscore the diagnostic value of multi-gene testing in patients with atypical or overlapping neuromuscular symptoms and highlight the importance of considering potential polygenic contributions when interpreting the clinical heterogeneity of HSP.