i(3)so3-galactosylceramide and Peripheral-Nervous-System-Diseases

Topics: Autoantibodies; Demyelinating Diseases; Diagnosis, Differential; Glycosphingolipids; Humans; Peripheral Nervous System Diseases; Prognosis; Sulfoglycosphingolipids

Approximately 10% of patients with peripheral neuropathy of otherwise unknown etiology have an associated monoclonal gammopathy. Both the neuropathies and the monoclonal gammopathies in these patients are heterogeneous, but several distinct clinical syndromes that may respond to specific therapies can be recognized. It is important to recognize these syndromes because monoclonal gammopathies also occur in 1% of the normal adult population, and in some cases, monoclonal gammopathies are coincidental and unrelated to the neuropathy. In patients with IgM monoclonal gammopathies, IgM M proteins frequently have autoantibody activity and are implicated in the pathogenesis of the neuropathy. IgM M proteins that bind to myelin-associated glycoprotein (MAG) have been shown to cause demyelinating peripheral neuropathy; anti-GM1 antibody activity is associated with predominantly motor neuropathy, and anti-sulfatide or chondroitin sulfate antibodies are associated with sensory neuropathy. The IgM monoclonal gammopathies may be malignant or nonmalignant, and polyclonal antibodies with the same specificities are associated with similar clinical presentations in the absence of monoclonal gammopathy. IgG or IgA monoclonal gammopathies are associated with neuropathy in patients with osteosclerotic myeloma or the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy myeloma, and skin changes). Amyloidosis or cryoglobulinemic neuropathies can occur with either IgM or IgG and IgA monoclonal gammopathies. Therapeutic intervention depends on the specific clinical syndrome but is generally directed at removing the autoantibodies, reducing the number of monoclonal B cells, and interfering with the effector mechanisms.

Topics: Adult; Aged; Amyloidosis; Antibody Specificity; Antineoplastic Agents; Autoantibodies; Autoantigens; Autoimmune Diseases; Chondroitin Sulfates; Gangliosides; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins, Intravenous; Middle Aged; Myelin-Associated Glycoprotein; Paraneoplastic Syndromes; Paraproteinemias; Paraproteins; Peripheral Nervous System Diseases; Plasmapheresis; Sulfoglycosphingolipids

To assess whether pegylated interferon alpha (PEG-IFNalpha) may induce peripheral neuropathy or antibodies to peripheral nerve antigens in patients with hepatitis C virus (HCV) infection.. We studied 52 patients with HCV (38 men, 14 women; mean age 44.6 +/- 10.6 years) treated with IFNalpha. Before therapy (T(0)), patients underwent quantitative viral RNA determination, HCV genotype analysis, and neurologic and electrophysiologic evaluation. At the end (T(1)) and after therapy (T(2)), patients were neurologically and electrophysiologically re-evaluated. Antibodies to gangliosides and sulfatides were assayed by ELISA at T(0) and T(1). Twenty-three patients with HCV with comparable age, viral load, and genotype, not treated with IFNalpha, were studied as controls.. Seven patients (six in IFNalpha, one control) had peripheral neuropathy at recruitment. No significant differences in the electrophysiologic measures were detected between T(0) and T(1) (repeated-measures analysis of variance [ANOVA]) in any of the 52 patients or in those with neuropathy at T(0). No changes were found at T(2), independent of the viral response to treatment. Two patients, one with neuropathy, had antiganglioside antibodies at recruitment. Two patients, one not treated with IFNalpha, developed low antibody titers during follow-up, without symptoms or signs of neuropathy.. Pegylated interferon alpha therapy was not associated with the occurrence (or worsening) of peripheral neuropathy or antibodies to peripheral nerve antigens in patients with hepatitis C virus.

Topics: Adolescent; Adult; Aged; Antibodies; Antiviral Agents; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Gangliosides; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Neural Conduction; Neurologic Examination; Peripheral Nervous System Diseases; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Retrospective Studies; Ribavirin; RNA, Viral; Statistics, Nonparametric; Sulfoglycosphingolipids; Time Factors

To investigate the clinical and electrophysiologic characteristics of the neuropathy associated with elevated serum antisulfatide antibodies.. Clinical, electrophysiologic, morphologic, and laboratory data of 25 patients with significantly elevated (>25,600) antisulfatide antibodies were reviewed.. Four groups were distinguished based on clinical and electrophysiologic data: Group 1, eight patients with predominantly small fiber sensory neuropathy (32%); Group 2, five patients with mixed large and small fiber sensory neuropathy (20%); Group 3, seven patients with axonal sensorimotor neuropathy (28%); and Group 4, three patients with demyelinating sensorimotor neuropathy (12%). One additional patient had mononeuritis multiplex and one had ALS. An immunoglobulin M (IgM) monoclonal gammopathy was found in 30% of the patients tested, but not in any of the Group 1 patients with small fiber sensory neuropathy. Serum IgM level was elevated in 12 patients, of whom six had a concomitant monoclonal gammopathy. Morphologic studies in five patients showed predominantly axonal degeneration, with three of the patients also exhibiting additional features of demyelination.. Antisulfatide antibodies are associated with several subtypes of peripheral neuropathy. Predominantly sensory or sensorimotor axonal neuropathies are most common in this series, with the sensory component either small fiber or mixed fiber type. A smaller demyelinating group indistinguishable from patients with chronic inflammatory demyelinating polyradiculopathy was also seen. One third of patients had a concomitant IgM monoclonal gammopathy, and approximately one half had elevated serum IgM.

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Axons; Electromyography; Female; Humans; Male; Middle Aged; Neural Conduction; Pain; Peripheral Nervous System Diseases; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Psychomotor Performance; Sulfoglycosphingolipids; Sural Nerve

Anti-sulfatide antibodies have been observed in heterogeneous neuropathies and their clinical relevance is still controversial. Whether the combination of sulfatide with galactocerebroside would increase sensitivity or specificity of enzyme-linked immunosorbent assay testing compared to sulfatide alone was assessed.. Immunoglobulin M (IgM) antibodies to sulfatides, galactocerebroside and combined sulfatide and galactocerebroside (Sulf/GalC) were measured in 229 neuropathy patients, including 73 with IgM paraproteinemic neuropathy [62 with anti-myelin-associated glycoprotein (anti-MAG) antibody] and 156 with other neuropathies. Results from 27 patients with IgM monoclonal gammopathy without neuropathy and 28 healthy subjects served as control.. Thirty-three patients showed increased titers of anti-sulfatide antibodies, 28 of whom had an IgM paraproteinemic neuropathy (P < 0.0001). When evaluating the reactivity for the combination Sulf/GalC, 57/229 patients were found to be positive, including 36/73 (49%) with IgM paraproteinemic neuropathy (P < 0.0001). Patients with known anti-sulfatide antibodies also showed anti-Sulf/GalC reactivity, with increased titers in 48.5% of the cases. Testing for anti-Sulf/GalC antibodies allowed 24 additional patients to be detected (eight with IgM paraproteinemic neuropathies), who had no reactivity to the individual glycolipids. Amongst the 11 subjects with IgM paraproteinemic neuropathy who were negative for anti-MAG antibodies, only two were reactive to sulfatide, whilst six (55%) were found to be positive when tested against the combination of sulfatide and galactocerebroside.. Testing for both sulfatide and galactocerebroside in IgM paraproteinemic neuropathies seems to increase the sensitivity compared to anti-sulfatide antibodies alone (49% and 39%, respectively, with a slightly reduced specificity, from 97% to 87%), helping the characterization of otherwise undefined neuropathy that could benefit from immunomodulatory therapy.

Topics: Adult; Aged; Autoantibodies; Female; Galactosylceramides; Humans; Immunoglobulin M; Male; Middle Aged; Myelin-Associated Glycoprotein; Peripheral Nervous System Diseases; Sulfoglycosphingolipids; Young Adult

Anti-sulfatide immunoglobulin M (IgM) antibodies have been associated with different forms of neuropathies but their diagnostic role in neuropathy remains unclear.. The clinical association of increased titers of anti-sulfatide IgM antibodies in 570 patients with neuropathy and related disorders examined in our laboratory since 2004 was reviewed. Sera were tested by enzyme-linked immunosorbent assay at the initial serum dilution of 1:32,000 and titrated by serial two-fold dilution. In all positive patients IgM antibodies to myelin-associated glycoprotein (MAG) were also measured by western blot.. High titers of anti-sulfatide antibodies were found in 39 patients including 33 (85%) who also had anti-MAG IgM. Six patients did not have anti-MAG IgM including five in whom moderately increased anti-sulfatide titers were associated with different forms of neuropathy. One patient with a demyelinating neuropathy and IgM monoclonal gammopathy had markedly increased anti-sulfatide titers (1:256,000).. Increased titers of anti-sulfatide IgM antibodies are not infrequent in patients with neuropathy where they are often associated with a concomitant reactivity to MAG. A selective reactivity to sulfatide, however, is rarely found and is associated with different forms of neuropathy limiting its usefulness in the diagnosis of neuropathy.

Topics: Aged; Antibodies; Female; Humans; Immunoglobulin M; Male; Middle Aged; Myelin-Associated Glycoprotein; Peripheral Nervous System Diseases; Sulfoglycosphingolipids

One of the fundamental goals of lipidomics research is to identify the linkage of an individual gene with a given lipidome, thereby revealing the role of that gene in lipid metabolism, transport, and homeostasis. In this study, we have identified four apolipoprotein E (apoE)-induced alterations in the lipidome of mouse dorsal root ganglia (DRG) through utilizing the technology of shotgun lipidomics. First, apoE mediates sulfatide mass content in mouse DRG, which is comparable to its role in the CNS. Second, apoE contributes to galactosylceramide and ceramide homeostasis in mouse DRG. Third, apoE significantly modulates cholesterol levels in mouse DRG. The latter two functions of apoE are distinct from those in the CNS. Finally, mice null for apoE have dramatically less triacylglycerol mass content in DRG which are opposite to the effects observed in the peripheral organs and vascular system. Collectively, this study identifies the specific alterations in the DRG lipidome induced by apoE knockout and suggests the potential roles of apoE in lipid transport and homeostasis in a tissue specific manner, thereby providing insights into the biochemical mechanisms underlying the functions of apoE in the PNS.

Topics: Animals; Apolipoproteins E; Cells, Cultured; Ceramides; Cholesterol; Galactosylceramides; Ganglia, Spinal; Homeostasis; Lipid Metabolism; Lipids; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mice, Knockout; Neck; Neurons, Afferent; Peripheral Nervous System Diseases; Sulfoglycosphingolipids; Triglycerides

Galactocerebroside and sulfatide are two major glycolipids in myelin; however, their independent functions are not fully understood. The absence of these glycolipids causes disruption of paranodal junctions, which separate voltage-gated Na(+) and Shaker-type K(+) channels in the node and juxtaparanode, respectively. In contrast to glial cells in the central nervous system (CNS), myelinating Schwann cells in the peripheral nervous system (PNS) possess characteristic structures, including microvilli and Schmidt-Lanterman incisures, in addition to paranodal loops. All of these regions are involved in axo-glial interactions. In the present study, we examined cerebroside sulfotransferase-deficient mice to determine whether sulfatide is essential for axo-glial interactions in these PNS regions. Interestingly, marked axonal protrusions were observed in some of the nodal segments, which often contained abnormally enlarged vesicles, like degenerated mitochondria. Moreover, many transversely cut ends of microvilli surrounded the mutant nodes, suggesting that alignments of the microvilli were disordered. The mutant PNS showed mild elongation of nodal Na(+) channel clusters. Even though Caspr and NF155 were completely absent in half of the paranodes, short clusters of these molecules remained in the rest of the paranodal regions. Ultrastructural analysis indicated the presence of transverse bands in some paranodal regions and detachment of the outermost several loops. Furthermore, the numbers of incisures were remarkably increased in the mutant internode. Therefore, these results indicate that sulfatide may play an important role in the PNS, especially in the regions where myelin-axon interactions occur.

Topics: Action Potentials; Animals; Axons; Cell Communication; Cell Membrane; Cytoskeletal Proteins; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Microvilli; Neural Conduction; Peripheral Nerves; Peripheral Nervous System Diseases; Potassium Channels, Voltage-Gated; Ranvier's Nodes; Schwann Cells; Sodium Channels; Sulfoglycosphingolipids; Sulfotransferases

We used ELISA to estimate the prevalence of anti-sulfatide antibodies in HIV-infected individuals with distal sensory neuropathy (DSP) and compared the results with the prevalence in HIV-infected individuals without DSP and in individuals with neuropathy who are not infected with HIV. We found that 36% of HIV+/DSP+ individuals had immunoglobulin (Ig) G anti-sulfatide antibody titers greater than 1,500, whereas IgG anti-sulfatide antibodies were rarely found in HIV+/DSP- or HIV-/DSP+ patients.

Topics: Autoantibodies; Enzyme-Linked Immunosorbent Assay; HIV Infections; Humans; Immunoglobulin G; Neuralgia; Paresthesia; Peripheral Nervous System Diseases; Predictive Value of Tests; Sulfoglycosphingolipids

Adverse health effects of fungal bioaerosols on occupants of water-damaged homes and other buildings have been reported. Recently, it has been suggested that mold exposure causes neurological injury. The authors investigated neurological antibodies and neurophysiological abnormalities in patients exposed to molds at home who developed symptoms of peripheral neuropathy (i.e., numbness, tingling, tremors, and muscle weakness in the extremities). Serum samples were collected and analyzed with the enzyme-linked immunosorbent assay (ELISA) technique for antibodies to myelin basic protein, myelin-associated glycoprotein, ganglioside GM1, sulfatide, myelin oligodendrocyte glycoprotein, alpha-B-crystallin, chondroitin sulfate, tubulin, and neurofilament. Antibodies to molds and mycotoxins were also determined with ELISA, as reported previously. Neurophysiologic evaluations for latency, amplitude, and velocity were performed on 4 motor nerves (median, ulnar, peroneal, and tibial), and for latency and amplitude on 3 sensory nerves (median, ulnar, and sural). Patients with documented, measured exposure to molds had elevated titers of antibodies (immunoglobulin [Ig]A, IgM, and IgG) to neural-specific antigens. Nerve conduction studies revealed 4 patient groupings: (1) mixed sensory-motor polyneuropathy (n = 55, abnormal), (2) motor neuropathy (n = 17, abnormal), (3) sensory neuropathy (n = 27, abnormal), and (4) those with symptoms but no neurophysiological abnormalities (n = 20, normal controls). All groups showed significantly increased autoantibody titers for all isotypes (IgA, IgM, and IgG) of antibodies to neural antigens when compared with 500 healthy controls. Groups 1 through 3 also exhibited abnormal neurophysiologic findings. The authors concluded that exposure to molds in water-damaged buildings increased the risk for development of neural autoantibodies, peripheral neuropathy, and neurophysiologic abnormalities in exposed individuals.

Topics: Adult; Autoantibodies; Case-Control Studies; Chondroitin Sulfates; Environmental Exposure; Enzyme-Linked Immunosorbent Assay; Female; Fungi; G(M1) Ganglioside; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Mycotoxins; Myelin Proteins; Nerve Tissue Proteins; Neural Conduction; Neurofilament Proteins; Neuropsychological Tests; Peripheral Nervous System Diseases; Sick Building Syndrome; Sulfoglycosphingolipids; Surveys and Questionnaires; Tubulin; Water Microbiology

The common association between monoclonal gammopathy and peripheral neuropathy was studied in seven patients with demyelinating polyneuropathy and IgM paraproteinaemia. Plasma samples from these individuals were thoroughly tested for antiperipheral nerve myelin (PNM) antibodies and then screened for glycoprotein and glycolipid reactivity by western immunoblotting and thin-layer chromatography (TLC) immunostaining. Three of the seven samples showed strong IgM anti-PNM and antisulfatide (GalS) antibody reactivity. Two of these three plasma samples showed extraordinarily high antisulfatide IgM antibody titres, ranging from 1 x 104 to 1 x 106 arbitrary units/L. These same samples also showed intense myelin staining of sciatic nerve sections (paraffin and cryostat) and teased nerve fibres. No axonal immunoreactivity was observed. These results suggest that high titre IgM antisulfatide antibodies may play a pathogenetic role in the immune demyelination associated with IgM paraproteinaemia.

Topics: Adult; Aged; Antibodies; Blotting, Western; Chromatography, Thin Layer; Demyelinating Diseases; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Glycolipids; Humans; Immunoglobulin M; Male; Middle Aged; Myelin Sheath; Nerve Fibers; Paraproteinemias; Peripheral Nervous System Diseases; Sciatic Nerve; Sulfoglycosphingolipids

Anti-sulfatide IgM antibodies have been recently associated with neuropathy but the clinical and electrophysiological correlations of this reactivity remains unclear. We reviewed the clinical and electrophysiological features of patients with high anti-sulfatide titers detected in our laboratory from 1991 to 1998. Of the 564 patients with different neurological diagnosis tested by enzyme-linked immunosorbent assay (ELISA), 11 had high anti-sulfatide IgM titers (>1/8000), 26 had titers of 1/8000 while 78 had titers of 1/4000. All patients with high anti-sulfatide IgM titers had a chronic, dysimmune, mostly sensorimotor neuropathy that in seven was associated with IgM monoclonal gammopathy. In most of these patients electrophysiological and morphological studies were consistent with a predominantly demyelinating neuropathy frequently associated with prominent axonal loss. Antibody titers of 1/8000, though always associated with neuropathy, did not correlate with a particular form or cause of neuropathy, while lower titers were equally distributed in patients with different neurological disorders. Our study indicate that high anti-sulfatide IgM titers (>1/8000) are highly predictive for a chronic, dysimmune, mostly demyelinating neuropathy often associated with IgM monoclonal gammopathy, and may therefore have potential diagnostic relevance.

Topics: Aged; Female; Humans; Immunoglobulin M; Male; Middle Aged; Neural Conduction; Peripheral Nervous System Diseases; Sulfoglycosphingolipids

HIV-positive plasma samples from patients with and without neuropathy and with high titre anti-GalS antibodies showed strong binding to the myelin membrane of both fixed and unfixed human sciatic nerve specimens. This staining pattern was also seen with a plasma sample from a patient with IgM paraproteinaemic inflammatory demyelinating neuropathy with anti-GalS IgM antibody. Teased nerve fibres incubated with these anti-GalS antibodies from both HIV and non-HIV plasma samples showed immunofluorescence at the paranodal regions and Schmidt-Lanterman incisures. These data support a potential role for these antibodies in the aetiology of HIV-associated immune mediated neuropathies.

Topics: Demyelinating Diseases; Fluorescent Antibody Technique; Glycolipids; HIV Antibodies; HIV Infections; Humans; Immunohistochemistry; Nerve Fibers; Paraffin Embedding; Peripheral Nervous System Diseases; Protein Binding; Sciatic Nerve; Sulfoglycosphingolipids

Increased titers of circulating antisulfatide antibodies are consistently associated with a variety of chronic axonal and demyelinating polyneuropathy syndromes. Previous studies have shown that the pattern of antisulfatide binding to neural tissues correlates with the type of neuropathy. This suggests a possible role for antisulfatide antibodies in inducing peripheral nerve dysfunction, although their exact contribution to the pathogenesis of neuropathy is still unknown. We examined sural nerve biopsy specimens from two patients with sensorimotor and small fiber sensory neuropathy associated with high titers of IgM monoclonal antibodies to sulfatide. Electrophysiological and pathological findings were consistent with predominant demyelination in the patient with sensorimotor involvement, whereas evidence of demyelination was obtained only by teased fiber examination in the other patient. The ultrastructural study disclosed in both cases the presence of myelinated fibers with widely spaced myelin, due to a separation of leaflets of the intraperiod lines. Immunocytochemistry, performed on frozen sections, demonstrated the presence of IgM and complement product C3d bound to myelin sheaths of almost all fibers. Few fibers were immunoreactive for complement components C1q and C5. In addition, the terminal complement complex neoantigen C5b-C9, not associated with S protein, was detected on some myelinated fibers. The results suggest that, at the least in some forms of demyelinating neuropathy associated with antisulfatide antibodies, pathological changes are complement mediated. Our data further confirm previous clinical and experimental observations that complement activation initiates separation of myelin intraperiod lines.

Topics: Aged; Antibodies; Complement System Proteins; Demyelinating Diseases; Electrophysiology; Female; Fluorescent Antibody Technique, Direct; Humans; Male; Myelin Sheath; Peripheral Nervous System Diseases; Sulfoglycosphingolipids

Previous studies of small numbers of patients have shown that antisulphatide autoantibodies are associated with polyneuropathies having a prominent sensory component. However, clinical and electrodiagnostic features are variable. The range of clinical and electrodiagnostic findings in 19 patients with polyneuropathies and high titre (> 4500) serum IgM antisulphatide antibodies is described, together with testing for serum monoclonal (M) proteins.. About 20000 serum samples that were referred to the clinical laboratory from 1990 to the end of 1994 were screened by enzyme linked immunosorbent assay (ELISA) for specific high titre antisulphatide antibodies. The clinical and electrodiagnostic data in 23 patients with positive results were reviewed. IgM binding to peripheral nerve structures was also evaluated in these patients.. Nineteen patients had predominantly distal, symmetric pansensory loss. Patients with IgM antisulphatide antibodies and no serum M protein usually had clinical syndromes that included: (1) neuropathic pain or dysaesthesiae, (2) no functionally significant weakness, and (3) an axonal neuropathy on electrodiagnostic testing. On immunocytochemical studies serum IgM from the patients without M proteins usually (nine of 10; 90%) bound to peripheral nerve axons, but never to myelin. Patients with antisulphatide antibodies and a serum M protein, usually IgM, were more likely than patients without a serum M protein, to have syndromes with: (1) no pain or dysaesthesiae, (2) motor abnormalities, and (3) a demyelinating polyneuropathy by electrodiagnostic criteria. In immunocytochemical studies serum IgM most often bound to either peripheral nerve myelin or endoneurial structures.. Patients with polyneuropathy and high titre serum IgM antisulphatide antibodies can be classified into subgroups according to the presence or absence of a serum M protein. Patients without an M protein are more likely to have pure sensory syndromes, pain, an axonal neuropathy, and serum IgM binding to axons. Patients with a serum M protein commonly had syndromes with prominent motor involvement, no pain, and a demyelinating neuropathy.

Topics: Adult; Aged; Autoantibodies; Binding Sites; Demyelinating Diseases; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin M; Immunohistochemistry; Male; Middle Aged; Peripheral Nervous System Diseases; Sulfoglycosphingolipids

Antibodies to sulfatide are associated with polyneuropathy. To investigate the role of anti-sulfatide antibodies in this neurological disorder, guinea-pigs were immunized with sulfatide, and their behavior, serology and pathology were compared with animals injected with simple Freund's adjuvant. Eleven of 13 guinea-pigs that developed raised serum anti-sulfatide antibodies after five injections of sulfatide showed definite motor weakness. Demyelination of peripheral nerves and immunoglobulin deposits at peripheral nerve myelin sheath were found in symptomatic animals only. Functional impairment of the animals was significantly correlated with serum anti-sulfatide IgG levels and pathological findings in nerve fiber studies. Control animals and animals that received 1-3 injections of sulfatide were behaviorally and pathologically normal.

Topics: Animals; Antibodies, Monoclonal; Demyelinating Diseases; Female; Fluorescent Antibody Technique, Direct; Freund's Adjuvant; Guinea Pigs; Immunization; Male; Microscopy, Electron; Peripheral Nervous System Diseases; Sulfoglycosphingolipids

Gangliosides are a diverse class of glycolipids found in the plasma membrane of mammalian cells and are particularly abundant in cells of the nervous system. Serum antibodies to gangliosides have been detected in various neurological disorders with some evidence that they play a pathogenic role. In this study, we have investigated whether anti-ganglioside antibodies were elevated in a group of patients with rheumatoid arthritis (RA) who developed peripheral neuropathy (PN). An ELISA technique was used to test sera from 28 patients with RA and PN. 38 RA patients without PN and 20 normal controls for the presence of IgG and IgM anti-GM1 and sulphatide antibodies. The patients with RA and PN had higher pain scores (P < 0.005), more extra-articular features (P < 0.05), higher erosive scores (P < 0.0001), lower haemoglobin (P < 0.005), higher ESR (P < 0.001) and were more often on disease-modifying drugs (P < 0.05). Twelve RA patients with PN (43%), but only two RA controls (5%), had positive titres against one or more gangliosides (P < 0.001). The neurologic disability score (NDS) correlated with RA duration (P < 0.05), and with levels of IgM anti-GM1 (P < 0.001) and IgM anti-sulphatide (P < 0.05) antibodies. We conclude that PN is more common in patients with severe rheumatoid disease, and a significant proportion have elevated levels of anti-ganglioside antibodies.

Topics: Aged; Antibodies; Arthritis, Rheumatoid; Female; G(M1) Ganglioside; Humans; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Peripheral Nervous System Diseases; Severity of Illness Index; Sulfoglycosphingolipids

Peripheral nervous system involvement in the acquired immunodeficiency syndrome (AIDS) can take the form of an acute or chronic inflammatory demyelinating polyneuropathy, polyradiculopathy, mononeuropathy multiplex, or autonomic neuropathy. There is no widely held consensus on the etiology of PNS or other neurological complications associated with HIV infection. We report here that PNS disease in HIV-infected individuals is associated with intrathecal synthesis of an antibody directed against sulfatide, a major component of myelin. The anti-sulfatide antibody is also present nonspecifically in serum. The antibody requires the presence of the 3-O-sulfogalactosyl residue for binding and recognizes preferentially the hydroxy fatty acid-containing form of sulfatide. Anti-sulfatide antibodies are therefore one of the humoral factors responsible for demyelinating diseases in AIDS patients.

Topics: Acquired Immunodeficiency Syndrome; Animals; Cattle; HIV Seropositivity; Humans; Immunoglobulin G; Molecular Structure; Peripheral Nervous System Diseases; Structure-Activity Relationship; Sulfoglycosphingolipids

We report the presence of antisulfatide antibodies in a patient with type I Gaucher's disease and peripheral neuropathy. The association of Gaucher's disease with hypergammaglobulinemia and monoclonal gammopathy is well documented whereas its association with peripheral neuropathy is rare. We discuss whether antibodies directed against the sulfatide antigen are related to Gaucher's disease or are a coincidental association.

Topics: Antibodies; Female; Gaucher Disease; Humans; Middle Aged; Peripheral Nervous System Diseases; Sulfoglycosphingolipids

We present a patient with benign IgM-gamma anti-Sulfatide (SUL) whose neuropathy was transferred in newborn rabbits. The patient's clinico-pathological picture of anti-SUL-associated demyelinating neuropathy is reported. The monoclonal IgM antibodies prepared by Tatum's method, that retained their biological activity, were passively transferred to newborn rabbits. The passive transfer produced demyelinating nerve lesions very similar to the donor antibody neuropathy. In experimental lesions we observed the human IgM anti-SUL antibodies binding to Schmidt-Lanterman incisures and nodes of Ranvier. We postulate that the myelin-specific and complement-dependent lesions observed in the peripheral nerve support the potential demyelinating role of anti-SUL antibodies. Moreover, the pattern of the antibody binding to the perineuronal sheath of satellite cells in dorsal root ganglia strengthen the hypothesis that anti-SUL antibodies may have a pathogenetic role in this sensorimotor syndrome.

Topics: Aged; Animals; Antibodies, Monoclonal; Humans; Immunization, Passive; Immunoglobulin M; Male; Peripheral Nervous System Diseases; Rabbits; Sulfoglycosphingolipids

Antibodies directed against ganglioside GM1 or sulfatides are frequently associated with motor or sensorimotor neuropathies. To establish the prevalence of such anti-glycosphingolipid autoantibodies in autoimmune disorders and to determine whether they contribute to neurologic symptoms in those individuals, we measured these antibodies by enzyme-linked immunosorbent assay (ELISA) in serum samples from rheumatologic patients with and without peripheral neuropathies (PN). We tested 21 patients with systemic lupus erythematosus (9 with PN), 26 with Sjögren's syndrome (12 with PN), 34 with scleroderma (28 with PN), and 14 with rheumatoid arthritis (4 with PN). Samples from 32 normal individuals were also tested. Patients with systemic lupus erythematosus and rheumatoid arthritis had elevated concentrations of GM1 antibodies and scleroderma patients had lower levels of sulfatide antibodies compared to healthy individuals. The presence of ganglioside or sulfatide antibodies did not correlate with the development of peripheral neuropathy in these patients. These findings suggest that relatively low-titer glycosphingolipid antibodies may arise as part of a nonspecific polyclonal gammopathy in rheumatologic disorders but generally without clinical manifestation.

Topics: Adult; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; G(M2) Ganglioside; Glycosphingolipids; Humans; Male; Middle Aged; Peripheral Nervous System Diseases; Rheumatic Diseases; Sulfoglycosphingolipids

The clinical and electrophysiological features were prospectively studied of 75 patients (46 men and 29 women) with chronic polyneuropathy presenting in middle or old age in whom a diagnosis could not be made even after extensive evaluation and a follow up of six months. The mean age at the onset of symptoms was 56.5 years. The clinical features of chronic idiopathic polyneuropathy are heterogeneous. On clinical grounds 44 patients had a sensorimotor, 29 patients a sensory, and two patients a motor polyneuropathy. The overall clinical course in chronic idiopathic polyneuropathy was slowly progressive. None of the patients became severely disabled. Electrophysiological and nerve biopsy studies were compatible with an axonal polyneuropathy. Antibodies against myelin associated glycoprotein, gangliosides, and sulphatides were assessed in 70 patients and found to be negative.

Topics: Age of Onset; Autoantibodies; Chronic Disease; Electromyography; Female; G(M1) Ganglioside; Humans; Male; Middle Aged; Myelin Proteins; Myelin-Associated Glycoprotein; Neural Conduction; Peripheral Nerves; Peripheral Nervous System Diseases; Prospective Studies; Sulfoglycosphingolipids

A study was carried out on 135 patients with chronic idiopathic neuropathy (63), neuropathy associated with monoclonal gammopathy (51, including eight with anti-MAG antibody activity) and the Guillain-Barré syndrome (GBS) (21). Serum IgM, IgG and IgA anti-sulphatide antibody titres were compared with titres in 304 patients with other neurological or immunological diseases and in 50 normal subjects. Titres were presented a) as the highest serum dilution at which reactivity could be detected, and b) in the linear region of the optical density curve. A substantial number of patients with neurological or immunological diseases had higher titres than normal subjects. Compared with normal and disease controls, five patients with neuropathy associated with IgMk monoclonal gammopathy had raised titres of IgM anti-sulphatide antibodies and one patient with GBS had raised IgM, IgG and IgA anti-sulphatide antibodies in the acute phase of the disease. Two patients had a predominantly axonal sensory neuropathy with presenting symptoms of painful paresthesiae and minimal neurological deficit. Three patients had a predominantly demyelinating sensorimotor neuropathy associated with anti-MAG antibody activity. The patient with GBS had extensive sensory loss and antibody titres returned to normal within three weeks. Raised titres of anti-sulphatide antibodies occurred in several types of neuropathy, but all had some degree of sensory impairment and associated immunological abnormality.

Topics: Adult; Aged; Antibodies; Humans; Immunoglobulin A; Immunoglobulin M; Male; Middle Aged; Motor Activity; Paraproteinemias; Peripheral Nervous System Diseases; Polyradiculoneuropathy; Sensation; Sulfoglycosphingolipids

Sera from eight of 25 patients with chronic sensory neuropathy had high titers of antibodies to sulfatide and chondroitin sulfate C or both. Preclearing of patients' sera with either sulfatide or chondroitin sulfate C revealed that in four patients the antisulfatide antibodies crossreacted with chondroitin sulfate C. By indirect immunohistochemistry sera reactive to sulfatide only had a different staining pattern from those reactive to both sulfatide and chondroitin sulfate C. By direct immunohistochemistry we found immunoglobulins bound to nerve fibers only in patients with serum antibodies against both sulfatide and chondroitin sulfate C. Our study provides evidence that antibodies to sulfatide and to chondroitin sulfate C differ in their fine specificity and are present in 30% of patients with chronic sensory neuropathy.

Topics: Adult; Aged; Antibodies; Chondroitin Sulfates; Chronic Disease; Female; Humans; Immunohistochemistry; Male; Middle Aged; Neurons, Afferent; Peripheral Nervous System Diseases; Sulfoglycosphingolipids

We studied a series of 64 patients with sensory +/- motor peripheral neuropathies by comparing clinical and physiologic features to serum antibody reactivity against compounds containing sulfated carbohydrate moieties. We determined antibody reactivity by an enzyme-linked immunosorbent assay (ELISA) using purified glycolipids and glycoproteins as antigens, and we used high-performance thin-layer chromatography and Western blotting to test the specificity of results. Twelve patients with high titers of IgM antibodies directed against the myelin-associated glycoprotein (MAG) had sensory-motor polyneuropathies with physiologic evidence of demyelination. IgM antibody reactivity to MAG was associated with an IgM serum M protein in five patients. Eight other patients, most with sensory greater than motor polyneuropathies, had high titers of antibody reactivity to sulfatide but not of IgM to MAG. Two had an associated IgM paraprotein. None of the patients with selective serum antisulfatide activity had predominantly demyelinating features on physiologic testing. We conclude that (1) high ELISA titers of antibodies to MAG may be more common than previously suspected in patients with chronic demyelinating sensory-motor neuropathies, and (2) the presence of high titers of antisulfatide antibodies in serum may provide clues to the pathogenesis of otherwise idiopathic, axonal, predominantly sensory neuropathies.

Topics: Adult; Aged; Antibodies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Myelin Proteins; Myelin-Associated Glycoprotein; Peripheral Nervous System Diseases; Sensation; Sulfoglycosphingolipids; Syndrome

Adult rats given high orally administered doses of triethyltin (TET) sulfate lost weight, developed hind limb wasting, and became paraplegic or quadriplegic within three weeks of intoxication. A 33% reduction in the motor nerve conduction velocity (MNCV) of the sciatic nerve in the absence of significant demyelination was observed. There was observed, however, intramyelinic edema formation and an increased number of axonal neurofilaments and neurotubules; changes that paralleled the decrease in MNCV during the period of intoxication. Although the animals became asymptomatic and the MNCV normalized within two to three weeks of discontinuing the TET intoxication, the intramyelinic vacuoles and the increased numbers of neurofilaments and neurotubules persisted.

Topics: Animals; Cholesterol; Collagen; Electrophysiology; Evoked Potentials; Female; Male; Microscopy, Electron; Muscles; Nerve Tissue Proteins; Neural Conduction; Peripheral Nerves; Peripheral Nervous System Diseases; Rats; Sulfoglycosphingolipids; Trialkyltin Compounds; Triethyltin Compounds

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Animals, Newborn; Binding Sites; Carbon Radioisotopes; Cerebellum; Chick Embryo; Cholesterol; Culture Techniques; Demyelinating Diseases; Depression, Chemical; Dose-Response Relationship, Drug; Hexachlorophene; Lipids; Microscopy, Electron; Myelin Sheath; Nerve Tissue Proteins; Peripheral Nerves; Peripheral Nervous System Diseases; Rats; Rats, Inbred Strains; Sulfates; Sulfoglycosphingolipids; Sulfur Radioisotopes; Time Factors

Topics: Animals; Centrifugation, Density Gradient; Demyelinating Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Evoked Potentials; Hexachlorophene; Myelin Sheath; Neural Conduction; Peripheral Nervous System Diseases; Rats; Sciatic Nerve; Sulfoglycosphingolipids

In a clinically unremarkable 39 year old sister of a patient afflicted with late adult metachromatic leukodystrophy, metachromatic deposits in the epithelial cells of the urine sediment, a high sulphatide excretion in the urine, and a deficiency of arylsulphatase A in urine and leucocytes were found. The motor nerve conduction velocity of the peripheral nerves in upper and lower extremities was distinctly decreased. Cerebral disturbances were not evident. It is surmised that this patient is a case of late adult metachromatic leukodystrophy in an early stage of the disease without obvious clinical signs. The peripheral neuropathy found by neurophysiological examination is interpreted as an early symptom of the disease.

Topics: Adult; Cerebrosides; Diffuse Cerebral Sclerosis of Schilder; Electroencephalography; Female; Humans; Lipid Metabolism; Metabolic Diseases; Neural Conduction; Peripheral Nervous System Diseases; Sulfatases; Sulfoglycosphingolipids