Mu Heavy Chain Disease

Updated: Oct 13, 2017
  • Author: Jessica Katz, MD, PhD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Background

Heavy chain diseases (HCDs) are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains: alpha, gamma, or mu. The clinical manifestations vary with the heavy chain isotype and range from an asymptomatic presentation to aggressive lymphoma. [1]

HCDs characteristically involve production of a mutated immunoglobulin heavy chain that is incapable of either partnering with light chains to form a complete immunoglobulin molecule or incapable of being degraded by a proteasome. Their defining feature is the presence of an abnormal heavy chain in the urine and/or serum without an associated light chain. [2]

Normal immunoglobulin molecules are symmetrical and consist of 2 pairs of polypeptide chains, designated the light and heavy chains, which are interconnected by disulfide bonds. The heavy chains are the larger polypeptide subunits; they are specific and distinctive structures that distinguish the major classes of immunoglobulins.

B cell proliferative disorders that are characterized by an anomalous serum, and sometimes urinary, protein (from free light chain) that is immunochemically related to the Fc fragment of the immunoglobulin molecule are known as HCDs. The isotype of the mutated immunoglobulin heavy chain (α, γ, or µ) determines the nomenclature of HCD subtypes. When the anomalous protein structurally resembles the heavy chain fragment of the immunoglobulin M (IgM) molecule, it is designated as mu-HCD. Ballard and colleagues first described this entity in 1970. [3]

This article focuses on mu-HCD; however, other heavy chain diseases are described (eg, see Heavy Chain Disease, Gamma).

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Pathophysiology

The pathogenesis of mu-HCD is not completely understood. No viruses, chemical, physical, or genetic factors have been identified. [4] Most patients have a concurrent lymphoproliferative disorder resembling chronic lymphocytic leukemia/ small lymphocytic leukemia. There are also single reports of mu-HCD associated with myelodysplastic syndrome, amyloidosis, and diffuse large B cell lymphoma.

In mu-HCD the altered heavy chains contain deletions, insertions, and point mutations that are acquired during somatic hypermutation. These alterations typically result in loss of a large portion of the constant-1 (CH1) domain of the heavy chain, which is responsible for light chain binding. Additionally, this abnormal domain on the heavy chain is also unable to bind to the heat-shock protein 78 (hsp78), which would otherwise promote proteosomal degradation of the aberrant heavy chain. The heavy chain thus bypasses degradation and is instead secreted into the serum, where it can be detected. [2, 5, 6]

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Epidemiology

Frequency

United States

Mu-HCD is the least common of the HCDs. Fewer than 50 cases have been reported in the literature. [7] However, many cases likely have not been reported, especially in the past decade. Given the difficulty in diagnosing this disorder, most reports are from the United States, Western Europe, and Scandinavia.

Race-, Sex-, and Age-related Demographics

Mu-HCD is predominantly reported in white men in the 5th and 6th decades of life. However, reports also exist in black and Asian patients, with ages ranging from 15-80 years.

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Prognosis

The course of mu-HCD is variable. Survival ranges from a few months to several years, with a median survival of 24 months in well-studied cases

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