Hereditary neuropathy with predisposition to pressure palsy
Nov. 09, 2023
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Autoantibodies against GD1b, a ganglioside abundant in the nervous system, have been implicated in neuropathy for over three decades. However, the exact pathomechanism of these antibodies and the full spectrum of the clinical phenotype associated with these antibodies are not well defined. These antibodies alone, or in combination with other ganglioside antibodies, have been found with acute postinfectious neuropathy as well as in chronic neuropathy and can be associated with paraproteinemia. Sensory deficit, areflexia, and ataxia are commonly noted in neuropathies associated with GD1b antibodies. Although some patients do respond to intravenous immunoglobulin, rituximab can also help a subset of patients.
• Anti-GD1b IgG antibodies are more frequently present in acute ataxic neuropathy syndrome, including a sensory ataxic variant of Guillain Barré syndrome
• Anti-GD1b IgM antibodies are common in chronic neuropathy or chronic ataxic neuropathies with anti-disialosyl ganglioside immunoglobulin M antibodies, and ataxia can be a prominent feature.
• In comparison to the chronic ataxic neuropathy with disialosyl antibodies (CANDA) nomenclature, chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies (CANOMAD) additionally highlights ophthalmoplegia and cold agglutinins, but these clinical and laboratory features are not universally present.
• Neuropathy associated with anti-GD1b antibody is usually responsive to immunoglobulin, but B cell depletion therapies, such as rituximab, can be helpful.
In the early 1980s, there was a growing interest in peripheral neuropathy syndromes associated with paraproteinemia, a condition also referred to as monoclonal gammopathy. This condition is characterized by the presence of heavy or light chains of monoclonal immunoglobulin, or its fragments, in blood secondary to clonal proliferation of plasma cells of B cell lineage (52; 14). These paraproteins were frequently directed to carbohydrate determinants present on different glycoproteins and glycolipids distributed in neural tissue, and antibodies against myelin-associated glycoprotein and structurally related glucuronic acid-containing acidic glycosphingolipids were the first to be identified (04).
Gangliosides are a class of complex glycolipids composed of a ceramide attached to one or more sugars (hexoses) and contain sialic acid (N-acetylneuraminic acid) linked to an oligosaccharide core. They are abundant in peripheral nerves and participate in the maintenance and repair of neuronal cells, modulation of cell growth, memory formation, and synaptic transmission (76; 08). The number of sialic acid residues attached to the inner sugar moiety determines the classification of a ganglioside (M for one [mono], D for two [di], T for 3 [tri] and Q for 4 [quadri]). The numbering of the gangliosides is based on the number (x) of the inner sugar moieties (glucose, galactose, or GalNAc) with a formula of 5−x. If there are four sugar moieties (x=4), the gangliosides are GM1, GD1, and GT1; if x = 3, then GM2, GD2, and GT2; and for x=2, they are GM3, GD3, and GT3 (76; 08). In 1985, a case of IgM paraproteinemic neuropathy in which the paraprotein reacted with NeuNAc(alpha2-8) configured disialylated gangliosides including GD1b, GD3, GD2, and GT1b was reported (25). Following this report, several other cases similarly characterized by chronic sensory ataxic neuropathy were reported in the early 1990s (01; 10; 45; 75; 78; 70; 19; 20). A series of 18 cases was reported in 2001 that better captured the clinical spectrum of the syndrome (69).
On the other hand, acute phase anti-GD1b IgG antibodies have been identified in isolated patients with acute sensory neuropathies, acute ataxic neuropathies, or both, without limb weakness, which is considered a forme fruste or regional variant of Guillain Barré syndrome (71; 77; 73). Some patients with Miller Fisher syndrome (MFS or Fisher syndrome) also have anti-GD1b antibodies by virtue of their cross-reactivity with anti-GQ1b/GT1a antibodies (06; 71; 60). Ataxia is more likely to be present in patients with highly specific IgG against GD1b (30).
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