Charcot-Marie-Tooth Disease Type 2P (CMT2P) is an inherited axonal neuropathy caused by dominant mutations in the RING domain of LRSAM1. The precise cellular consequences of these mutations remain unclear. Here, we investigated the subcellular localization of wild-type and RING mutant LRSAM1 in multiple cell models, including patient-derived fibroblasts and neuronal cell lines. Using immunocytochemistry, membrane and lipid droplet fractionation, and colocalization with organelle markers, we found that RING mutant LRSAM1 consistently mislocalized, deviating from its typical diffuse cytosolic pattern to form large perinuclear aggregates. This mislocalization also caused abnormal clustering of the LRSAM1 target protein TSG101 that coaggregated with mutant LRSAM1. Wild-type LRSAM1 predominantly localized to the cytosolic fraction, whereas the mutant protein shifted toward the membranous fraction. Wild-type LRSAM1 was also observed in the lipid droplet fraction, whereas mutant LRSAM1 was absent. Our findings demonstrate that pathogenic RING mutations in LRSAM1 disrupt its subcellular localization and that of its targets. These results highlight protein mislocalization as a pathogenic mechanism in CMT2P, providing new insight into disease etiology.

Objective: To compare serum neurofilament light chain (NfL) concentrations between individuals with type 2 diabetes mellitus (T2DM) with and without diabetic polyneuropathy (DPN), and to examine associations with neuropathy burden, balance impairment, fear of falling, and fall history. Methods: This analytical cross-sectional study included 88 participants with T2DM (44 with DPN and 44 without DPN). Serum NfL was measured by enzyme-linked immunosorbent assay (ELISA); neuropathy burden was assessed with the Michigan Neuropathy Screening Instrument (MNSI), balance with the Berg Balance Scale (BBS), and fear of falling with the Falls Efficacy Scale-International (FES-I). Results: Serum NfL was higher in DPN than non-DPN participants [3.47 (2.68-4.77) vs. 2.47 (1.48-3.07) pg/mL; p < 0.001]. NfL correlated with MNSI-A (ρ = 0.562), MNSI-B (ρ = 0.550), FES-I (ρ = 0.431), falls (ρ = 0.344), and BBS (ρ = -0.450) (all p ≤ 0.001). In the comprehensively adjusted model, the NfL association was attenuated (adjusted odds ratio [aOR] = 1.352; 95% confidence interval [CI], 0.991-1.844; p = 0.057). NfL showed moderate discrimination (area under the receiver operating characteristic curve [AUC] = 0.716; 95% CI, 0.607-0.825); the internally derived Youden threshold was ≥2.823 pg/mL (sensitivity 72.7%, specificity 65.9%). Conclusions: NfL may be a complementary marker of DPN-related neuropathy and functional burden, but the adjusted association was attenuated and the study-specific threshold requires external validation. Study Registration: ClinicalTrials.gov identifier NCT07480330. The study was prospectively registered; the initial registry release occurred on 14 March 2026, before study initiation on 25 March 2026.

A 70-year-old man presented with biopsy-proven phospholipase A2 receptor--negative membranous nephropathy (MN). Shortly thereafter, he presented with progressive sensorimotor polyneuropathy, initially consistent with an inflammatory demyelinating polyneuropathy. Laboratory testing revealed strongly positive anti-contactin-1 (CNTN1) autoantibodies, a rare antigen target recently implicated in a subset of MN patients with concurrent inflammatory demyelinating polyneuropathy, reclassifying it as an autoimmune nodopathy. Intensive immunosuppressive treatment including methylprednisolone, cyclophosphamide, plasmapheresis, intravenous immunoglobulins, and rituximab led to significant neurological improvement and seronegativity for anti-CNTN1 antibodies. Nephrotic syndrome improved gradually with partial remission observed 2 years after treatment initiation. This case highlights the autoimmune overlap of MN and autoimmune nodopathy mediated by anti-CNTN1 antibodies, targeting shared epitopes in podocytes and the paranodal region of myelinated peripheral nerves. It underscores the clinical importance of screening for novel antibodies in phospholipase A2 receptor--negative MN patients, particularly anti-CNTN1 when neurological symptoms develop. This report supports aggressive immunosuppression tailored to antibody-mediated disease and suggests anti-CNTN1 titers as a biomarker for monitoring therapeutic response.

Charcot-Marie-Tooth (CMT) is a group of inherited neuromuscular disorders with diverse clinical features such as muscle weakness and atrophy of the distal regions, foot deformities, sensory loss and decreased or absent reflexes. With the diverse inheritance patterns including dominant, recessive, and X-linked, it exhibits significant genetic heterogeneity often overlapping with other neurological disorders. Whole exome sequencing (WES) has emerged as favorable diagnostic tool for such challenging disease entities. We recruited five Pakistani families that consisted of 14 affected individuals exhibiting representative symptoms of CMT such as severe muscle weakness of the lower limbs, muscles atrophy, claw hands and feet deformities. WES data analysis revealed two novel and two already reported homozygous missense variants in GDAP1 (NM_018972) c.1A > G (p. Met1Val), c.683A > G (p. Glu228Gly), c.734C > T (p. Thr245Ile) and c.811G > A (p. Gly271Arg) in families A-D, respectively. While a novel homozygous SBF2 variant c.2746G > C, p. (Gly916Arg) was identified in family E. Sanger sequencing confirm the segregation of all candidate variants in their respective pedigrees. Moreover, molecular modeling supports the destabilizing effect of these variants on final protein product of both GDAP1 and SBF2 by inducing modifications in overall conformation of the protein. The present study expands the mutation spectrum of the GDAP1 and SBF2 genes, with possible implications for improved understanding of disease pathophysiology. Furthermore, the current study highlights the importance of NGS, particularly WES, in achieving rapid and precise molecular genetic diagnosis for clinical purposes, especially in neuromuscular disorders of heterogeneous nature.

We report an archival temporal bone case from the Otopathology Archives at Johns Hopkins of a man with progressive distal-predominant weakness, sensory loss, areflexia, and bilateral pes cavus, with clinicopathologic features suggestive of a chronic demyelinating peripheral neuropathy. Bilateral temporal bone histopathology demonstrated diffuse enlargement of the facial nerve throughout its intratemporal course, with additional enlargement of the glossopharyngeal and vagus nerves. This case suggests that marked cranial nerve hypertrophy may be clinically unapparent in some hereditary polyneuropathies and supports future correlation of temporal bone pathology with imaging and genotype in confirmed cases.

Castleman disease (CD) comprises a heterogenous group of rare nonmalignant lymphoproliferative disorders. CD is classified as unicentric (UCD) and multicentric CD (MCD) depending on the number of lymph node region involvement. Oligocentric CD (OligoCD) is a recently validated provisional subtype with intermediate clinical features and outcomes. MCD is further subcategorized by etiology into three distinct entities: (1) human herpesvirus 8 (HHV-8) associated (HHV-8+) MCD, (2) idiopathic MCD (iMCD), (3) polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins, and skin changes (POEMS)-associated MCD. Idiopathic MCD itself encompasses three clinical subtypes: iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly), idiopathic plasmacytic lymphadenopathy (iMCD-IPL), and iMCD-NOS (not otherwise specified). Recent advances suggest that CD comprises biologically distinct entities with unique genetic landscapes, cellular origins, and mechanisms underlying interleukin-6 production. MCD is thought to arise from multifactorial mechanisms, including autoimmune dysregulation, chronic inflammatory processes, and paraneoplastic phenomena. The diagnosis of CD remains challenging due to its overlapping features with a broad range of reactive and malignant disorders, as well as its potential coexistence with other underlying conditions. This review focuses on the cell origins and biological mechanisms underlying CD, with particular emphasis on distinguishing CD from conditions with overlapping features, thereby enhancing our understanding of its pathogenesis and disease biology.

Classic ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, frequent infections, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation. Non-classic forms of A-T have included adult-onset A-T and A-T with early-onset dystonia.