Search Results (47)

Light-chain (AL) amyloidosis is a rare clonal plasma cell disorder that, if left untreated, carries a high risk of organ damage and mortality. Due to the rarity of the disease and the vulnerability of affected organ systems, treatment requires significant caution and nuance. As a plasma cell dyscrasia, AL amyloidosis treatment regimens are often adapted from those used for related disorders, particularly multiple myeloma. Despite substantial progress in research and drug development, optimal treatment strategies for relapsed/refractory (RR) AL amyloidosis remain unclear, and no FDA-approved therapies currently exist for this setting. B-cell maturation antigen (BCMA) has emerged as a promising immunotherapy target, with associated drug classes including antibody–drug conjugates, bispecific antibodies, and CAR-T cell therapies. These therapies have been extensively studied in relapsed/refractory multiple myeloma (RRMM) and are now being explored in the context of RR AL amyloidosis. This review summarizes the current literature on the efficacy and tolerability of BCMA-directed therapies in AL amyloidosis, with a particular emphasis on CAR-T cell therapy and offers comparisons to outcomes observed in RRMM. Full article

Rare plasma cell disorders—including IgD, IgE, and IgM multiple myeloma, non-secretory myeloma (NSMM), plasma cell leukemia (PCL), and heavy chain disease (HCD)—are biologically heterogeneous and often present with atypical features and aggressive behavior. This review synthesizes current evidence on their epidemiology, pathophysiology, diagnosis, and treatment. Advances in proteasome inhibitors, immunomodulatory agents, and autologous transplantation have improved outcomes in select subtypes. However, challenges persist in distinguishing IgM myeloma from Waldenström macroglobulinemia, monitoring non-secretory disease, and treating highly aggressive forms such as IgE myeloma and PCL. Standardized diagnostic criteria and prospective trials are essential to guide future management. Full article

Cryoglobulinemia is a rare disorder characterized by the presence of abnormal proteins (cryoglobulins) in the blood that precipitate at low temperatures. It presents with a wide clinical spectrum, from mild symptoms to severe, life-threatening disease. In mixed cryoglobulinemia (MC), vascular damage results from immune complexes—typically monoclonal IgM with rheumatoid factor activity and polyclonal IgG (Type II), or polyclonal/oligoclonal IgM and IgG (Type III). These complexes can obstruct small blood vessels, leading to ischemia and leukocytoclastic vasculitis. Renal involvement occurs in about 30% of MC patients and it is a manifestation with poor prognosis. Nowadays, types II and III MC are the most common forms, often linked to autoimmune diseases like Sjögren’s syndrome and systemic lupus erythematosus, or to viral infections such as hepatitis B or persisting despite hepatitis C eradication. This review explores renal involvement in MC, offering a comprehensive perspective on current knowledge, including recent advances in pathophysiological understanding, evolving diagnostic strategies, and novel therapeutic approaches. In this context, “perspectives” refers to the growing recognition of the shifting epidemiology of MC—particularly the changing etiological landscape following hepatitis C virus eradication—as well as the integration of emerging clinical and pathological entities such as cryofibrinogenemia and monoclonal gammopathy of renal significance into diagnostic and management frameworks. Furthermore, the review highlights current therapeutic strategies recognized as most effective, emphasizing the importance of a multidisciplinary and multimodal approach that combines etiological treatment, B-cell–targeted therapy (notably rituximab), plasma exchange in selected cases, and comprehensive supportive care for renal and systemic complications. Moreover, the landscape of management could be enriched in future years, since clinical trials are ongoing to explore novel therapies for refractory or relapsing cases of MC with renal involvement. Full article

Background: GM3 Synthase Deficiency (GM3SD) is a rare autosomal recessive neurodevelopmental disease characterized by recurrent seizures and neurological deficits. The disorder stems from mutations in the ST3GAL5 gene, encoding GM3 synthase (GM3S), a key enzyme in ganglioside biosynthesis. While enzyme deficiencies affecting ganglioside catabolism are well-documented, the consequences of impaired ganglioside biosynthesis remain less explored. Methods: To investigate GM3SD, we used a Human Embryonic Kidney 293-T (HEK293-T) knockout (KO) cell model generated via CRISPR/Cas9 technology. Lipid composition was assessed via high-performance thin-layer chromatography (HPTLC); glycohydrolase activity in lysosomal and plasma membrane (PM) fractions was enzymatically analyzed. Lysosomal homeostasis was evaluated through protein content analysis and immunofluorescence, and cellular bioenergetics was measured using a luminescence-based assay. Results: Lipidome profiling revealed a significant accumulation of lactosylceramide (LacCer), the substrate of GM3S, along with increased levels of monosialyl-globoside Gb5 (MSGb5), indicating a metabolic shift in glycosphingolipid biosynthesis. Lipid raft analysis revealed elevated cholesterol levels, which may impair microdomain fluidity and signal transduction. Furthermore, altered activity of lysosomal and plasma membrane (PM)-associated glycohydrolases suggests secondary deregulation of glycosphingolipid metabolism, potentially contributing to abnormal lipid patterns. In addition, we observed increased lysosomal mass, indicating potential lysosomal homeostasis dysregulation. Finally, decreased adenosine triphosphate (ATP) levels point to impaired cellular bioenergetics, emphasizing the metabolic consequences of GM3SD. Conclusions: Together, these findings provide novel insights into the molecular alterations associated with GM3SD and establish the HEK293-T KO model as a promising platform for evaluating potential therapeutic strategies. Full article

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene, resulting in the accumulation of globotriaosylceramide (Gb3) and its deacetylated form, globotriaosylsphingosine (Lyso-Gb3) in various tissues and fluids throughout the body. This pathological accumulation triggers a cascade of processes involving immune dysregulation and complement system activation. Elevated levels of complement 3a (C3a), C5a, and their precursor C3 are observed in the plasma, serum, and tissues of patients with Fabry disease, correlating with significant endothelial cell abnormalities and vascular dysfunction. This review elucidates how the complement system, particularly through the activation of C3a and C5a, exacerbates disease pathology. The activation of these pathways leads to the upregulation of adhesion molecules, including vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), platelet and endothelial cell adhesion molecule 1 (PECAM1), and complement receptor 3 (CR3) on leukocytes and endothelial cells. This upregulation promotes the excessive recruitment of leukocytes, which in turn exacerbates disease pathology. Targeting complement components C3a, C5a, or their respective receptors, C3aR (C3a receptor) and C5aR1 (C5a receptor 1), could potentially reduce inflammation, mitigate tissue damage, and improve clinical outcomes for individuals with Fabry disease. Full article

Dent disease type 1 is a rare X-linked recessive inherited renal disorder affecting mainly young males, generally leading to end-stage renal failure and for which there is no cure. It is caused by inactivating mutations in the gene encoding ClC-5, a 2Cl⁻/H⁺ exchanger found on endosomes in the renal proximal tubule. This transporter participates in reabsorbing all filtered plasma proteins, which justifies why proteinuria is commonly observed when ClC-5 is defective. In the context of Dent disease type 1, a proximal tubule dedifferentiation was shown to be accompanied by a dysfunctional cell metabolism. However, the exact mechanisms linking such alterations to chronic kidney disease are still unclear. In this review, we gather knowledge from several Dent disease type 1 models to summarize the current hypotheses generated to understand the progression of this disorder. We also highlight some urinary biomarkers for Dent disease type 1 suggested in different studies. Full article

Lowe Syndrome (LS) is a rare X-linked disorder characterized by renal dysfunction, cataracts, and several central nervous system (CNS) anomalies. The mechanisms underlying the neurological dysfunction in LS remain unclear, albeit they share some phenotypic characteristics similar to the deficiency or dysfunction of the Reelin signaling, a relevant pathway with roles in CNS development and neuronal functions. In this study, we investigated the role of OCRL1, an inositol polyphosphate 5-phosphatase encoded by the OCRL gene, mutated in LS, focusing on its impact on endosomal trafficking and receptor recycling in human neuronal cells. Specifically, we tested the effects of OCRL1 deficiency in the trafficking and signaling of ApoER2/LRP8, a receptor for the ligand Reelin. We found that loss of OCRL1 impairs ApoER2 intracellular trafficking, leading to reduced receptor expression and decreased levels at the plasma membrane. Additionally, human neurons deficient in OCRL1 showed impairments in ApoER2/Reelin-induced responses. Our findings highlight the critical role of OCRL1 in regulating ApoER2 endosomal recycling and its impact on the ApoER2/Reelin signaling pathway, providing insights into potential mechanisms underlying the neurological manifestations of LS. Full article

Light-chain (AL) amyloidosis is a rare plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains in target organs, leading to multi-organ dysfunction. Treatment approaches have historically mirrored but lagged behind those of multiple myeloma (MM). Recent advancements in MM immunotherapy are gradually being evaluated and adopted in AL amyloidosis. This review explores the current state of immunotherapeutic strategies in AL amyloidosis, including monoclonal antibodies, antibody–drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapy. We discuss the unique challenges and prospects of these therapies in AL amyloidosis, including the exposure of frail AL amyloidosis patients to immune-mediated toxicities such as cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS), as well as their efficacy in promoting rapid and deep hematologic responses. Furthermore, we highlight the need for international initiatives and compassionate programs to provide access to these promising therapies and address critical unmet needs in AL amyloidosis management. Finally, we discuss future directions, including optimizing treatment sequencing and mitigating toxicities, to improve outcomes for AL amyloidosis patients. Full article

Background: Parry–Romberg syndrome (PRS) is a rare craniofacial disorder. The aim of this study is to provide information on the immunological profile of this pathology. Since PRS can be included in a wider spectrum of sclerodermic diseases, we propose a case–control study comparing a patient affected by PRS with one with a diagnosis of scleroderma, herein used as control (CTR). Methods: B lymphocyte, T lymphocyte, and monocyte phenotypes and functions were assessed by flow cytometry in influenza (Flu)- or anti cluster differentiation (CD)3/CD28-stimulated peripheral blood mononuclear cells (PBMCs). Cytokine concentration was evaluated as well in PBMC supernatants, plasma, and saliva by Luminex assay. Results: T and B lymphocytes were similarly activated in unstimulated PRS and CTR cells but differed following antigen stimulation. T helper (Th)17 lymphocytes were expanded in PRS compared to CTR; this increase correlated with higher interleukin (IL)-17 concentration. Conclusions: Our case–control study is the first to compare the immunological profiles of PRS and scleroderma patients. The higher percentage of Th17 cells in PRS suggests the use of anti-IL17 receptor monoclonal antibody in this rare disease; however, further studies with larger numbers of patients are needed to confirm our findings. Full article

Immunoglobulin G4-related disease (IgG4-RD) is a novel fibroinflammatory disorder characterized by enlargement of the involved organs, elevated IgG4 levels, and abundant infiltration of IgG4-positive plasma cells. Indeed, primary colon cancers arising from IgG4-RD are rare. This case report describes a rare occurrence of simultaneous colorectal cancer and IgG4-RD in the same lesion in a 62-year-old male patient. The patient underwent a right hemicolectomy under the suspicion of primary colon cancer. The mass was grossly well-defined and yellowish tan, and the background colon was fibrotic. Microscopically, the tumor cells showed glandular differentiation characteristic of adenocarcinoma in a background of dense lymphoplasmacytic infiltration with fibrosis and obliterative phlebitis in the pericolic fat tissue. IgG4 immunohistochemical staining showed diffuse positivity in infiltrating plasma cells. The patient was administered adjuvant chemotherapy and prednisolone therapy. The patient’s serum IgG4 levels gradually decreased, and a follow-up positron emission tomography-computed tomography scan 1 year after surgery showed no evidence of local or distant recurrence of colorectal cancer. IgG4-RD occurring concurrently with primary colon adenocarcinoma has not been reported. Increased awareness of this rare coexistence can guide clinicians in navigating diagnostic complexities and selecting optimal therapeutic strategies. Full article

Plasmacytoma is a neoplastic disorder originating from plasma cells, with bone and soft tissue being common sites of manifestation. This report presents the clinical and radiological findings of a 65-year-old female patient who presented with an exophytic lesion in the upper right lateral incisor region. The lesion appeared as a unilocular radiotransparent area in imaging tests. Following an excisional biopsy, histological and immunohistochemical evaluations confirmed the presence of mature plasmacellular elements and small infiltrates of B and T lymphocytes. The patient did not exhibit systemic manifestations of multiple myeloma. Surgical intervention, in the form of enucleation of the lesion combined with root canal treatment and apicoectomy, was performed. This case underscores the rare occurrence of plasmacytoma in the jaw region and highlights the importance of surgical management in cases where structural damage or functional impairment is present. Further research on novel treatment approaches is also mentioned, including targeted therapies, immunomodulatory agents, and monoclonal antibodies. The patient is currently under the care of a hematologist for further investigation and the choice of the most appropriate therapy. Full article

Acquired isolated factor VII (FVII) deficiency is a rare but important discovery in patients with plasma cell disorders with significant therapeutic and prognostic implications. The present analysis and review of cases reported in the literature is intended to highlight disease-related characteristics associated with this rare clotting defect, clinical manifestations and outcome, and potential underlying mechanisms, and to provide guidance on how to manage these patients in terms of prophylactic and therapeutic measures. The discovery of acquired FVII deficiency in a patient with multiple myeloma (MM) or monoclonal gammopathy of uncertain significance (MGUS) should prompt an evaluation for AL amyloidosis, particularly for amyloid hepatosplenic involvement, whenever not previously documented. Acquired FVII deficiency in patients with MM and AL amyloidosis is frequently associated with severe bleeding diathesis, also related to a number of concomitant predisposing factors, adversely affecting the outcome. The prompt institution of a rapidly acting therapy is crucial to prevent severe bleeding complications and positively impact outcome. Recombinant activated factor VII (rVIIa) may represent a useful supportive care measure, both in treating active bleeding and in the peri-procedural setting. However, further clinical experience is needed to optimize the therapeutic management of this rare disorder. Full article

Multicentric Castleman disease (MCD) is a systemic lymphoproliferative disorder that can lead to mass lesions in various body parts, including the lungs, kidneys, and extranodal sites. Meanwhile, orbital Castleman disease is extremely rare. Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized fibroinflammatory disorder and is characterized by the formation of tumor-like lesions with lymphoplasmacytic infiltrates, which are enriched in IgG4-positive plasma cells and may present with a characteristic storiform pattern of fibrosis to variable degrees. In this study, we report a case of a 67-year-old Taiwanese man with a 7-year history of bilateral eyelid swelling and proptosis. Orbital magnetic resonance imaging revealed soft tissue lesions in the bilateral intraconal region, demonstrating strong enhancement in the lacrimal glands, and extension into the bilateral infraorbital foramen, suggesting an orbital lymphoproliferative disease. The histopathological results of the intraorbital tumor excision were suggestive of a plasma-cell-predominant mixed-cell variant of MCD. However, the patient also showed definitive signs of IgG4-RD, including lacrimal gland enlargement and histopathological results of plasmacytosis, fibrosis, and germinal centers, with an increased ratio of IgG4 cells and elevated serum IgG4 levels. This case suggests a potential interacting pathway between these two disease entities that needs further studies. Full article

Congenital glucose-galactose malabsorption is a rare autosomal recessive disorder caused by mutations in SLC5A1 encoding the apical sodium/glucose cotransporter SGLT1. We present clinical and molecular data from eleven affected individuals with congenital glucose-galactose malabsorption from four unrelated, consanguineous Turkish families. Early recognition and timely management by eliminating glucose and galactose from the diet are fundamental for affected individuals to survive and develop normally. We identified novel SLC5A1 missense variants, p.Gly43Arg and p.Ala92Val, which were linked to disease in two families. Stable expression in CaCo-2 cells showed that the p.Ala92Val variant did not reach the plasma membrane, but was retained in the endoplasmic reticulum. The p.Gly43Arg variant, however, displayed processing and plasma membrane localization comparable to wild-type SGLT1. Glycine-43 displays nearly invariant conservation in the relevant structural family of cotransporters and exchangers, and localizes to SGLT1 transmembrane domain TM0. p.Gly43Arg represents the first disease-associated variant in TM0; however, the role of TM0 in the SGLT1 function has not been established. In summary, we are expanding the mutational spectrum of this rare disorder. Full article

Neurovegetative and autonomic symptoms are common presentations of various diseases, ranging from psychosomatic to severe organic disorders. A 23-year-old man presented with a history of recurrent presyncope, dizziness, and tachycardia. Repeated diagnostic work-up in various clinical settings could not identify any definite cause for approximately eight years. However, the incidental detection of postprandial and exercise-induced hypoglycemia was suggestive of an insulin-related disorder. A 72 h plasma glucose fasting test revealed endogenous hyperinsulinism. Upon imaging studies, no tumor mass potentially indicating insulinoma could be detected. ⁶⁸Ga-DOTA-Exendin-4 PET/CT showed diffuse tracer enrichment throughout the whole pancreas. A subtotal pancreatectomy was performed, and the diagnosis of diffuse, adult-onset nesidioblastosis was established histopathologically. This corresponds to the clinical findings of a functional β-cell disorder, also known as non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS). After nine months, the symptoms recurred, making complete pancreatectomy necessary. Postoperative laboratory evaluation exhibited no residual endogenous C-peptide production. This case illustrates the diagnostic challenges in patients presenting with unspecific, neurovegetative and autonomic symptoms with a severe and rare underlying cause. Full article