g(m2)-ganglioside and Demyelinating-Diseases

We found that a monoclonal human IgM anti-GM2 was fixed in rat sciatic axons and Schwann cells and was able to activate human complement. The passive transfer of IgM and complement in sciatic nerves can induce an acute alteration in nerve conduction. When the transfer of IgM plus complement was repeated for 10 days, the compound action motor potential amplitude was very low and the morphological study showed axons and myelin damage. Without human complement, IgM can only slightly disorganize the myelin by separating some layers, probably by interfering with the functional role of gangliosides in the myelin package.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Autoantibodies; Chronic Disease; Demyelinating Diseases; G(M2) Ganglioside; Humans; Immunoglobulin M; Male; Neuroimmunomodulation; Rats; Rats, Sprague-Dawley; Sciatic Nerve

Several polyneuropathy syndromes have been described with polyclonal serum immunoglobulin G (IgG) or immunoglobulin M (IgM) binding to gangliosides GM2 and GalNAc-GD1a that contain the terminal trisaccharide moiety GalNAc(beta1-4)Gal(alpha2-3)NeuAc. We describe the clinical and electrodiagnostic features in two patients with serum IgM monoclonal anti-GM2 and anti-GalNAc-GD1a antibodies. These patients had slowly progressive, panmodal sensory loss with severe sensory ataxia. Electrodiagnostic testing showed demyelinating features. Prominent improvement in gait ataxia occurred after treatment with human immune globulin but not after other immunomodulating therapies. Enzyme-linked immunoabsorbent assay and thin-layer chromatography demonstrate that the patient's serum monoclonal IgM bound to gangliosides GM2 and GalNac-GD1a but not to gangliosides without the GalNAc(beta1-4)Gal(alpha2-3)NeuAc moiety. This neuropathy differs from previously reported neuropathy syndromes associated with polyclonal GM2 and GalNAc-GD1a antibodies and from other chronic demyelinating polyneuropathies. We conclude that a distinct syndrome of chronic demyelinating neuropathy with sensory ataxia, unresponsive to corticosteroids, is associated with monoclonal IgM binding to gangliosides with a terminal GalNAc(beta1-4)Gal(alpha2-3)NeuAc trisaccharide moiety. Diagnosis of this syndrome is important to direct appropriate treatment.

Topics: Ataxia; Chromatography, Thin Layer; Chronic Disease; Demyelinating Diseases; Electrodiagnosis; Enzyme-Linked Immunosorbent Assay; G(M2) Ganglioside; Gait Disorders, Neurologic; Gangliosides; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Male; Middle Aged; Polyneuropathies

We analyzed the characteristics of 29 Guillain-Barré syndrome (GBS) patients with IgM anti-GalNAc-GD1a antibodies. Fourteen of them had had an antecedent cytomegalovirus infection (CMV group) and 12 gastrointestinal infection (G-I group). Most of the G-I group patients (nine of 12) were subsequent to Campylobacter jejuni infection. Electrophysiological results in both groups patients predominantly indicated demyelinating neuropathy. The CMV group patients were characterized by slow progression and frequent facial and sensory deficits. IgM antibodies in their sera recognized an epitope shared by GalNAc-GD1a and GM2. The G-I group patients frequently showed motor type of GBS with cranial nerves spared. IgM antibodies specific to GalNAc-GD1a were present in their sera.

Topics: Adult; Antibodies; Campylobacter Infections; Campylobacter jejuni; Cytomegalovirus Infections; Demyelinating Diseases; Electrophysiology; Female; G(M2) Ganglioside; Gangliosides; Gastrointestinal Diseases; Guillain-Barre Syndrome; Humans; Immunoglobulin M; Infections; Male; Middle Aged; Neural Conduction; Prognosis

We describe a patient with a pure motor chronic demyelinating polyneuropathy with an IgM monoclonal component showing anti-GM2, GalNAc-GD1a and GalNAc-GM1b reactivity whose common epitope appears to be -[GalNAcbeta1-4Gal(3-2alphaNeuAc)beta1]. We used intracellular recording to study how IgM from this patient affected neurotransmitter release in the mouse diaphragm in vitro. Adding serum (and specifically, the purified monoclonal IgM component) blocked the nerve-evoked response in both quantal content and evoked endplate potential (EPP) amplitude in a complement-independent and reversible manner. The IgM increased the frequency of spontaneous miniature endplate potentials (MEPPs) in a complement-dependent and reversible manner but had no effect on MEPP amplitude.

Topics: Adult; Animals; Antibodies, Monoclonal; Antibody Specificity; Blood Physiological Phenomena; Chronic Disease; Demyelinating Diseases; Diaphragm; Electrophysiology; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosides; Humans; Immunoglobulin M; Male; Mice; Motor Endplate; Neuromuscular Junction; Neurotransmitter Agents; Peripheral Nervous System Diseases; Reference Values

Although gangliosides are abundant molecular determinants on all vertebrate nerve cells (comprising approximately 1.5% of brain dry weight) their functions have remained obscure. We report that mice engineered to lack a key enzyme in complex ganglioside biosynthesis (GM2/GD2 synthase), and which express only the simple ganglioside molecular species GM3 and GD3, develop significant and progressive behavioral neuropathies, including deficits in reflexes, strength, coordination, and balance. Quantitative indices of motor abilities, applied at 8 and 12 months of age, also revealed progressive gait disorders in complex ganglioside knockout mice compared to controls, including reduced stride length, stride width, and increased hindpaw print length as well as a marked reduction in rearing. Compared to controls, null mutant mice tended to walk in small labored movements. Twelve-month-old complex ganglioside knockout mice also displayed significant incidence of tremor and catalepsy. These comprehensive neurobehavioral studies establish an essential role for complex gangliosides in the maintenance of normal neural physiology in mice, consistent with a role in maintaining axons and myelin (Sheikh, K. A. , J. Sun, Y. Liu, H. Kawai, T. O. Crawford, R. L. Proia, J. W. Griffin, and R. L. Schnaar. 1999. Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Proc. Natl. Acad. Sci. USA 96: 7532-7537), and may provide insights into the mechanisms underlying certain neural degenerative diseases.

Topics: Animals; Ataxia; Axons; Behavior, Animal; Catalepsy; Demyelinating Diseases; Disease Models, Animal; Exploratory Behavior; G(M2) Ganglioside; G(M3) Ganglioside; Gait; Male; Mice; Mice, Knockout; Mice, Neurologic Mutants; Muscle Contraction; N-Acetylgalactosaminyltransferases; Polypeptide N-acetylgalactosaminyltransferase; Postural Balance; Reflex, Abnormal; Tremor; Walking; Wallerian Degeneration

After treatment of melanomas with anti-GD2 monoclonal antibody (MAb) (14G2a), some patients develop sensorimotor demyelinating polyneuropathy with and without the syndrome of inappropriate antidiuretic hormone (SIADH). To clarify what causes the neurotoxicity of anti-GD2 MAb, we investigated the immunohistochemical localization of GD2 in the human nervous system. Anti-GD2 MAb (14G2a) reacted with the myelin sheaths in the peripheral nerves as well as with the pituicyte cytoplasm in the posterior lobe of the pituitary gland. We assume that the binding of anti-GD2 MAb to peripheral nerve myelin and the pituicytes in the posterior pituitary causes sensorimotor demyelinating neuropathy and SIADH.

Topics: Animals; Antibodies, Monoclonal; Biopsy; Central Nervous System; Demyelinating Diseases; G(M2) Ganglioside; Humans; Inappropriate ADH Syndrome; Melanoma; Mice; Myelin Sheath; Neurotoxins; Oculomotor Nerve; Peripheral Nervous System Diseases; Pituitary Gland; Sural Nerve; Tibial Nerve; Trochlear Nerve

Acute symmetric demyelinating polyneuropathy of the Guillain-Barré type is known in systemic lupus erythematosus (SLE). Chronic idiopathic demyelinating polyneuropathy (CIDP) has been reported rarely with SLE. A case is reported of CIDP accompanying SLE with autoantibodies against GM1- and GM3-gangliosides. There was no historical evidence to suggest SLE, and CIDP was the first manifestation of SLE. The 38-year-old patient had elevated CSF-protein, slow nerve conduction velocities, sural nerve biopsy revealed mixed axon loss with demyelination and CIDP white matter lesions were observed in magnetic resonance imaging, the GM1- and GM3-autoantibodies may play a role in the pathogenesis of CIDP in SLE.

Topics: Adult; Autoantibodies; Chronic Disease; Demyelinating Diseases; G(M1) Ganglioside; G(M2) Ganglioside; Humans; Lupus Erythematosus, Systemic; Male; Neurologic Examination; Polyradiculoneuropathy