Antibodies to L‐periaxin in sera of patients with peripheral neuropathy produce experimental sensory nerve conduction deficits

Abstract

L-Periaxin is a PDZ-domain protein localized to the plasma membrane of myelinating Schwann cells and plays a key role in the stabilization of mature myelin in peripheral nerves. Mutations in L-periaxin have recently been described in some patients with demyelinating peripheral neuropathy, suggesting that disruption of L-periaxin function may result in nerve injury. In this study, we report the presence of autoantibodies to L-periaxin in sera from two of 12 patients with diabetes mellitus (type 2)-associated neuropathy and three of 17 patients with IgG monoclonal gammopathy of undetermined significance (MGUS) neuropathy, an autoimmune peripheral nerve disorder. By comparison, anti-L-periaxin antibodies were not present in sera from nine patients with IgM MGUS neuropathy or in sera from 10 healthy control subjects. The effect of anti-L-periaxin serum antibody on peripheral nerve function was tested in vivo by intraneural injection. Sera containing anti-L-periaxin antibody, but not sera from age-matched control subjects, injected into the endoneurium of rat sciatic nerve significantly (p < 0.005, n ¼ 3) attenuated sensory-evoked compound muscle action potential (CMAP) amplitudes in the absence of temporal dispersion. In contrast, motor-evoked CMAP amplitudes and latencies were not affected by intraneural injection of sera containing anti-L-periaxin antibody. Light and electron microscopy of anti-L-periaxin serum-injected nerves showed morphologic evidence of demyelination and axon enlargement. Depleting sera of anti-L-periaxin antibodies neutralized the serum-mediated effects on nerve function and nerve morphology. Together, these data support anti-L-periaxin antibody as the pathologic agent in these serum samples. We suggest that anti-L-periaxin antibodies, when present in sera of patients with IgG MGUS-or diabetesassociated peripheral neuropathy, may elicit sensory nerve conduction deficits. Keywords: antibody, diabetes, MGUS, neuropathy, periaxin. Peripheral neuropathies are a heterogeneous group of nerve disorders often characterized by a mixture of sensory and motor disturbances (Adams et al. 1997). Although the etiology of the peripheral neuropathy is often obscure, some patients exhibit strong familial histories consistent with an autosomal dominance, autosomal recessive, or X-linked pattern of inheritance. In other patients, the peripheral neuropathy is acquired such as in monoclonal gammopathy of undetermined significance (MGUS) neuropathy (Kyle 1992) or is secondary to a metabolic disturbance such as diabetes mellitus.Serum autoantibodies have been implicated as potential pathogenic agents in several autoimmune-mediated peripheral nerve disorders (Ho et al. 1998;Quarles and Weiss 1999). In addition, a role of autoimmunity in peripheral nerve disorders associated with metabolic disturbances, such as diabetic neuropathy, has been entertained (Said et al. 1994;Krendel et al. 1995). However, the antigenic specificities Abbreviations used: CMAP, compound muscle action potential; D/P, distal (ankle) to...

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