The Diagnostic and Therapeutic Challenges of Fabry Nephropathy—A Review of the Literature, Illustrated by a Clinical Case

Fabry Disease (FD) is a rare lysosomal storage disorder characterized by α-galactosidase A (α-Gal A) enzyme deficiency, resulting in glycosphingolipid accumulation. Its clinical spectrum ranges from severe classical to milder nonclassical or late-onset phenotypes. Renal involvement, termed Fabry Nephropathy (FN), can vary from mild proteinuria to kidney failure. FN diagnosis, especially in nonclassical cases with a genetic Variant of Unknown Significance (VUS) in the GLA gene, poses challenges. Measurement of plasma lyso-Gb3 levels is gaining importance in FN diagnosis, while renal biopsy with electron microscopy remains the gold standard in equivocal cases. Treatment options include Enzyme Replacement Therapy (ERT) and chaperone therapy, demanding careful candidate selection due to high treatment costs. Research has predominantly focused on classical FD, revealing modest treatment benefits. However, evidence for treating patients, especially females, with milder nonclassical or late-onset phenotypes is scarce, emphasizing the necessity for placebo-controlled clinical trials in these subgroups. Meanwhile, participation in global FD registries can improve our understanding of disease management. Case Presentation: A woman in her late sixties presented with moderate chronic kidney disease, mild proteinuria, and microscopic hematuria. Her family history included a prevalence of renal, cardiac and cerebrovascular diseases. Kidney biopsy revealed characteristic myelin figures and zebra bodies in podocytes, strongly suggestive of FN. Genetic analysis identified a VUS in the GLA gene (c.655A > C, p.Ile219Leu), introducing diagnostic uncertainty. Further investigations revealed severe cardiac involvement. Considering the recurring difficulty presented by the finding of a VUS in the GLA gene during FN assessments, along with the uncertainty regarding the need for treatment in nonclassical or late-onset FD phenotypes, especially in women, this case becomes a central focus for a thorough review of the literature. This review aims to propose a practical algorithm that integrates clinical, biochemical, and genetic markers for FN screening and diagnosis. Additionally, it explores treatment benefits in nonclassical or late-onset FD phenotypes, with a focus on female patients.

Globoside accelerates the differentiation of dental epithelial cells into ameloblasts

Tooth crown morphogenesis is tightly regulated by the proliferation and differentiation of dental epithelial cells. Globoside （Gb4）, a globo-series glycosphingolipid, is highly expressed during embryogenesis as well as organogenesis, including tooth development. We previously reported that Gb4 is dominantly expressed in the neutral lipid fraction of dental epithelial cells. However, because its functional role in tooth development remains unknown, we investigated the involvement of Gb4 in dental epithelial cell differentiation. The expression of Gb4 was detected in ameloblasts of postnatal mouse molars and incisors. A cell culture analysis using HAT-7 cells, a rat-derived dental epithelial cell line, revealed that Gb4 did not promote dental epithelial cell proliferation. Interestingly, exogenous administration of Gb4 enhanced the gene expression of enamel extracellular matrix proteins such as ameloblastin, amelogenin, and enamelin in dental epithelial cells as well as in developing tooth germs. Gb4 also induced the expression of TrkB, one of the key receptors required for ameloblast induction in dental epithelial cells. In contrast, Gb4 downregulated the expression of p75, a receptor for neurotrophins （including neurotrophin-4） and a marker of undifferentiated dental epithelial cells. In addition, we found that exogenous administration of Gb4 to dental epithelial cells stimulated the extracellular signal-regulated kinase and p38 mitogen-activated protein kinase signalling pathways. Furthermore, Gb4 induced the expression of epiprofin and Runx2, the positive regulators for ameloblastin gene transcription. Thus, our results suggest that Gb4 contributes to promoting the differentiation of dental epithelial cells into ameloblasts.

Anderson-Fabry disease presenting with atrial fibrillation as earlier sign in a young patient:A case report

BACKGROUND Anderson-Fabry disease(AFD)is an X-linked lysosomal storage disorder that results from a deficiency ofα-galactosidase A enzyme activity in which glycosphingolipids gradually accumulate in multi-organ systems.Cardiac manifestations are the leading cause of mortality in patients with AFD.Among them,arrhythmias comprise a large portion of the heart disease cases in AFD,most of which are characterized by conduction disorders.However,atrial fibrillation as a presenting sign at the young age group diagnosed with AFD is uncommon.CASE SUMMARY We report a case of a 26-year-old man who was admitted with chest discomfort.Left ventricular hypertrophy was fulfilled in the criteria by the Sokolow-Lyon index and atrial fibrillation on the 12 Leads-electrocardiography(ECG)that was documented in the emergency room.After spontaneously restored to normal sinus rhythm,relationships between P and R waves,including a shorter PR interval on the ECG,were revealed.The echocardiographic findings showed thickened interventricular septal and left posterior ventricular walls.Based on the clues mentioned earlier,we realized the possibility of AFD.Additionally,we noticed the associated symptoms and signs,including bilateral mild hearing loss,neuropathic pain,anhidrosis,and angiokeratoma on the trunk and hands.He was finally diagnosed with classical AFD,which was confirmed by the gene mutation and abnormal enzyme activity ofα-galactosidase A.CONCLUSION This case is a rare case of AFD as a presentation with atrial fibrillation at a young age.Confirming the relationship between P and Q waves on the ECG through sinus rhythm conversion may help in differential diagnosis of the cause of atrial fibrillation and hypertrophic myocardium.

The Influences of Mifepristone, Norethisterone and Tamoxifen on the Glycosph

By using the Ladisch partitioning and microscale-analysis of HPTLC,the comparative quantitative and qualitative studies of gangliosides (Gg)and neutral glycosphingolipids(N-GSL)compositions from human chorionic villi tissues of normal early pregnant women and women treated with mifepristone, norethisterone(NET)and tamoxifen(TAM)were reported in this paper.The patterns of Gg and N-GSL in three treated groups were similar to those in normal pregnant group.The total values of Gg from the chorionic villi tissues reduced significantly in three treated groups(P<0.01).In all treated groups,the amounts of NeuNAC-Gal-Glc-cer(GM3),NeuNAC-NeuNAC-Gal-Glc-cer(GD3)and Gal-GalNAC-(NeuNAC)-Gal-Glc-cer(GM1)were decreased significantly compared with those in normal(P<0.01orP<0.05).In NET and TAM groups,Neu NAC-Gal-GalNAC-(NeuNAC-NeuNAC)-Gal-Glc-cer(GT1b) was markedly lower than that in normal(P<0.01).The total values of N-GSL extracted from the chorionic villi tissues were obviously higher in mifepristone and TAM groups than those in normal(P<0.01).The Gal-Glc-cer(LacCer)(CDH)and Gal-Gal-Glc-cer(Gal-LacCer)(CTH)were greatly increased in mifepristone group as compared with normal P<0.05).Paragloboside:Gal-GalNAC-Gal-Glc-cer(PG)in NETgroup was significantly higher than that in normal(P<0.01).

ACBD3 is required for FAPP2 transferring glucosylceramide through maintaining the Golgi integrity

Glycosphingolipid (GSL) metabolism is involved in various physiological processes, including all major cell signaling pathways, and its dysregulation is linked to some diseases. The four-phosphate adaptor protein FAPP2-mediated glucosylceramide (GlcCer) transport for complex GSL synthesis has been studied extensively. However, the molecular machinery of FAPP2 as a GlcCer-transferring protein remains poorly defined. Here, we identify a Golgi-resident protein, acyl-coenzyme A binding domain containing 3 (ACBD3), as an interacting partner of FAPP2. We find that ACBD3 knockdown leads to dramatic Golgi fragmentation, which subsequently causes FAPP2 dispersal throughout the cytoplasm and a decreased localization at trans-Golgi network. The further quantitative Upidomic analysis indicates that ACBD3 knockdown triggers abnormal sphingolipid metabolism. Interestingly, the expression of siRNA-resistant full-length ACBD3 can rescue these defects caused by ACBD3 knockdown. These data reveal critical roles for ACBD3 in maintaining the integrity of Golgi morphology and cellular sphingolipid homeostasis and establish the importance of the integrated Golgi complex for the transfer of GlcCer and complex GSL synthesis.

Role of glycosylation in TGF-β signaling and epithelial-to-mesenchymal transition in cancer

Glycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions.Aberrant glycosylation can lead to uncontrolled cell proliferation,cell-matrix interactions,migration and differentiation,and has been shown to be involved in cancer and other diseases.The epithelial-to-mesenchymal transition is a key step in the metastatic process by which cancer cells gain the ability to invade tissues and extravasate into the bloodstream.This cellular transformation process,which is associated by morphological change,loss of epithelial traits and gain of mesenchymal markers,is triggered by the secreted cytokine transforming growth factor-β(TGF-β).TGF-βbioactivity is carefully regulated,and its effects on cells are mediated by its receptors on the cell surface.In this review,we first provide a brief overview of major types of glycans,namely,N-glycans,O-glycans,glycosphingolipids and glycosaminoglycans that are involved in cancer progression.Thereafter,we summarize studies on how the glycosylation of TGF-βsignaling components regulates TGF-βsecretion,bioavailability and TGF-βreceptor function.Then,we review glycosylation changes associated with TGF-β-induced epithelial-to-mesenchymal transition in cancer.Identifying and understanding the mechanisms by which glycosylation affects TGF-βsignaling and downstream biological responses will facilitate the identification of glycans as biomarkers and enable novel therapeutic approaches.

Neurological manifestations in Fabry disease

Fabry disease(FD)is a rare,progressive,multisystem and highly debilitating disease.FD is an X-linked lysosome storage disorder that results inα-galactosidase A deficiency.The subsequent accumulation of glycosphingolipids is more evident in vascular endothelium and smooth-muscle cells.The resulting effect of the deposition is generalized inflammation and vasculopathy,which can also affect the central and peripheral nervous system.FD progresses with kidney dysfunction,angiokeratoma of the skin,cardiomyopathy,cerebrovascular events and neurological disorders.In the present review,the neurological manifestations of FD are summarized with emphasis on cerebral vasculopathy,cochlear nerve dysfunction,psychiatric and cognitive symptoms,autonomic dysfunction and peripheral neuropathy.Enzyme replacement therapy is also discussed in the light of its more prominent effects when administered early in life,which make it essential to diagnose FD as soon as possible.

Characterization of Acidic Glycosphingolipid Changes in C6 Glioma Rats Treated With Temozolomide Using Ultra-High-Performance Liquid Chromatography Coupled With Quadrupole Time-of-Flight Mass Spectrometry

Ganglioside and sulfatide are primary components of acidic glycosphingolipids(AGSLs),which are abundant in the brain tissue.AGSLs are potential tumor markers.In this paper,we use ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry to generate a first-ever comprehensive profile of AGSLs in brain and plasma of C6 glioma rats treated with temozolomide(TMZ).The AGSLs detected consisted mainly of C18-/C20-sphingosine.12,20,19,14 and 12 species were identified in GM1,GD1a,GD1b,GM3 and GT1b ganglioside groups which were abundant in rat brain,respectively.These five groups accounted for 88-89%of total ganglioside content.However,no AGSLs were detected in rat plasma.Possible biomarkers for abnormal changes in the glioma model and the protective effect of TMZ were mainly found in these ganglioside groups and sulfatide.The main lipid component of central and peripheral nervous system myelin sheathes is sulfatide,which is upregulated in many tumors.Antitumor properties of TMZ are due to modulation of sulfatide levels in tumor tissues.