Monoclonal Protein–Associated Neuropathies: Amyloid Neuropathy

IgM MGUS NEUROPATHY

Although most patients who present with chronic distal sensory or sensorimotor symptoms and signs have an axonal polyneuropathy unrelated to a paraprotein, rarely, patients with distal clinical features have electrodiagnostic evidence of demyelination and are found to have an IgM monoclonal protein. These patients are often referred to as distal acquired demyelinating symmetric (DADS) neuropathy. The majority of patients with a DADS neuropathy phenotype will have a MGUS, which is almost exclusively IgM kappa. The IgM MGUS neuropathy (e.g., DADS neuropathy) patient presents with sensory-predominant polyneuropathies of insidious onset, particularly in men older than 50 years. Because of profound sensory involvement, gait unsteadiness (sensory ataxia) is a common complaint. When motor signs are present, they are confined to the distal (toes, ankles, fingers, wrists) musculature. Tremor is also a frequent finding. These patients are often found to have associated myelin-associated glycoprotein (MAG) autoantibodies. Motor nerve conduction studies demonstrate widespread symmetric slowing. In many cases, distal latencies are dramatically prolonged, resulting in a short terminal latency index (TLI). This finding implies that the motor conduction velocity slowing is more pronounced in distal nerve segments and is considered an electrodiagnostic hallmark of anti-MAG neuropathy. In neuropathies felt to have a clear association with anti-MAG antibodies or with other monoclonal proteins in the absence of a more severe hematologic disorder, some immunomodulatory treatments (e.g., rituximab) have been tried with varying degrees of success. Sensory or sensorimotor polyneuropathies are often seen in patients with Waldenstrom macroglobulinemia, an IgM-associated cancer of B cells.

AMYLOID NEUROPATHY

Amyloidosis that causes neuropathy can be separated into primary amyloidosis (associated with a bone marrow disorder) and inherited forms. Amyloid is an amorphous material that can deposit in nerve, causing significant neuropathy, but can also deposit in many other tissues including fat, gastrointestinal tissue, kidney, and heart, leading to multisystem damage, and in some cases to death. Primary amyloidosis occurs in patients with a serum monoclonal protein, with free light-chain deposition into tissues. There are inherited forms of amyloidosis, the most common being associated with mutations in transthyretin (which is largely made by the liver), but there are other subtypes. Approximately 15% of patients with primary amyloidosis will develop neuropathy. These neuropathies are usually diffuse, but lower limb predominant, and symmetric. Classically, there is significant small greater than large nerve fiber involvement, with prominent features of pain, sensory loss, orthostasis, and sweat loss. Clinical suspicion should be elevated for this diagnosis in those circumstances, and especially when there are associated systemic symptoms or evidence of multiorgan dysfunction. Diagnosis can be challenging, and requires a high clinical suspicion. In cases of primary amyloidosis, the presence of a monoclonal protein in the blood should prompt further evaluation. If there is a strong family history of peripheral neuropathy, particularly with associated cardiomyopathy and early demise, this should be considered. Assessment of kappa and lambda light chains in the blood, as well as urine monoclonal protein study, can be helpful. Genetic testing for transthyretin abnormalities is also available. Tissue biopsy can be helpful if amyloid can be demonstrated, potential sites of biopsy include subcutaneous fat, rectum, and peripheral nerve. Other tissues suspected to be affected can be biopsied as well. Treatment depends on the type of amyloid demonstrated. Treatments for primary amyloidosis include melphalan and peripheral blood stem cell transplant. Because the primary source of transthyretin is in the liver, liver transplantation can be considered in patients with transthyretin amyloidosis. In transthyretin amyloidosis, some newer agents that prevent the folding conformational changes may prevent the formation of new amyloid deposits.

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