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Mu Heavy Chain Disease

  • Author: Ajeet Gajra, MD; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: Sep 10, 2015
 

Background

Heavy chain diseases (HCDs) are rare B-cell proliferative disorders characterized by the synthesis and secretion of incomplete immunoglobulin heavy chains. These disorders initially were recognized as gammopathies due to the presence of monoclonal proteins in the patient's serum or urine. The disorders were defined in terms of the production of structurally aberrant immunoglobulin molecules.[1]

Normal immunoglobulin molecules are symmetrical and are composed 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. Reductive cleavage of the immunoglobulin molecule by papain yields 2 Fab fragments (consisting of a light chain and an Fd fragment) and one Fc fragment (consisting of portions of the 2 heavy chains).

Plasma cell disorders characterized by an anomalous serum and urinary protein that is immunochemically related to the Fc fragment of the immunoglobulin molecule are known as HCDs. When the anomalous protein structurally resembles the heavy chain fragment of immunoglobulin M (IgM) molecule, it is designated as mu-HCD. Ballard and colleagues first described this entity in 1970.[2]

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

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Pathophysiology

Mu heavy chain disease was first described in 1969. The characteristic feature of HCD is the production of a monoclonal immunoglobulin molecule in which the heavy chain is truncated and the covalent attachment of light chains is absent. This may be due to lack of light chain production or the failure of heavy-light disulfide bond formation.

The mu heavy chains analyzed to date have an absent variable region and a shortened constant domain. The reasons a complete immunoglobulin fails to assemble are poorly understood. A defect at the level of immunoglobulin gene structure and assembly has been shown to be responsible for the synthesis of the truncated mu-HCD protein, caused by deletion of coding information and formation of an aberrant RNA molecule.[3] The available data do not allow for an accurate description of the molecular defects involved in mu-HCD proteins. Despite certain similarities, every case seems to have an individual pattern.[4, 5]

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Epidemiology

Frequency

United States

Mu heavy chain disease is rare, with 34 cases reported in the literature. 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.

International

True international incidence is difficult to ascertain for reasons stated above. A single case has been reported from Japan.

Mortality/Morbidity

Given its infrequent presentation, mu-HCD is not a major cause of morbidity or mortality. The disease course can be extremely variable, and the survival of patients in the literature reports varies from 1 month to 11 years. Reports of cures are also described.

Race-, Sex-, and Age-related Demographics

Most patients with mu-HCD reported in the literature were white, but at least three black patients and one Asian patient have also been reported. No obvious sex predilection has been described. Nor does mu-HCD have an obvious age predilection; the age of reported patients  has ranged from 15-80 years.

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Contributor Information and Disclosures
Author

Ajeet Gajra, MD Associate Professor of Medicine, Director of Hematology/Oncology Fellowship Program, State University of New York Upstate Medical University; Consulting Staff, Department of Internal Medicine, Division of Hematology and Oncology, Veterans Affairs Medical Center

Ajeet Gajra, MD is a member of the following medical societies: American Association for Cancer Research, American Medical Association, American Society of Hematology

Disclosure: Nothing to disclose.

Coauthor(s)

Sara J Grethlein, MD Associate Dean for Undergraduate Medical Education, Indiana University School of Medicine

Sara J Grethlein, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Neerja Vajpayee, MD Associate Professor, Department of Pathology, State University of New York Upstate Medical University

Neerja Vajpayee, MD is a member of the following medical societies: American Society of Hematology, College of American Pathologists, United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology

Disclosure: Nothing to disclose.

References
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  2. Ballard HS, Hamilton LM, Marcus AJ, Illes CH. A new variant of heavy-chain disease (mu-chain disease). N Engl J Med. 1970 May 7. 282(19):1060-2. [Medline].

  3. Bakhshi A, Guglielmi P, Coligan JE, et al. A pre-translational defect in a case of human mu heavy chain disease. Mol Immunol. 1986 Jul. 23(7):725-32. [Medline].

  4. Mihaesco C, Ferrara P, Guillemot JC, et al. A new extra sequence at the amino terminal of a mu heavy chain disease protein (DAG). Mol Immunol. 1990 Aug. 27(8):771-6. [Medline].

  5. Corcos D, Osborn MJ, Matheson LS. B-cell receptors and heavy chain diseases: guilty by association?. Blood. 2011 Jun 30. 117 (26):6991-8. [Medline].

  6. Bonhomme J, Seligmann M, Mihaesco C, et al. MU-chain disease in an African patient. Blood. 1974 Apr. 43(4):485-92. [Medline].

  7. Kinoshita K, Yamagata T, Nozaki Y, et al. Mu-heavy chain disease associated with systemic amyloidosis. Hematology. 2004 Apr. 9(2):135-7. [Medline].

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  9. Lougaris V, Ferrari S, Cattalini M, Soresina A, Plebani A. Autosomal recessive agammaglobulinemia: novel insights from mutations in Ig-beta. Curr Allergy Asthma Rep. 2008 Sep. 8(5):404-8. [Medline].

  10. Maisnar V, Tichy M, Stulik J, et al. Capillary immunotyping electrophoresis and high resolution two-dimensional electrophoresis for the detection of mu-heavy chain disease. Clin Chim Acta. 2008 Mar. 389(1-2):171-3. [Medline].

  11. Yanai M, Maeda A, Watanabe N, et al. Successful treatment of mu-heavy chain disease with fludarabine monophosphate: a case report. Int J Hematol. 2004 Feb. 79(2):174-7. [Medline].

  12. O'Connell TX, Horita TJ, Kasravi B. Understanding and interpreting serum protein electrophoresis. Am Fam Physician. 2005 Jan 1. 71(1):105-12. [Medline].

  13. Buxbaum JN, Alexander A. Heavy Chain Diseases. Beutler B, Lichtman MA, Coller BS, Kipps TJ, and Seligsohn U, eds. Williams Hematology. 6th ed. New York, NY: McGraw-Hill; 2001. 1327-36.

  14. Fermand JP, Brouet JC. Heavy-chain diseases. Hematol Oncol Clin North Am. 1999 Dec. 13(6):1281-94. [Medline].

  15. Iwasaki T, Hamano T, Kobayashi K, Kakishita E. A case of mu-heavy chain disease: combined features of mu-chain disease and macroglobulinemia. Int J Hematol. 1997 Oct. 66(3):359-65. [Medline].

  16. Liapis H, Papadakis I, Nakopoulou L. Nodular glomerulosclerosis secondary to mu heavy chain deposits. Hum Pathol. 2000 Jan. 31(1):122-5. [Medline].

  17. Preud'homme JL, Bauwens M, Dumont G, et al. Cast nephropathy in mu heavy chain disease. Clin Nephrol. 1997 Aug. 48(2):118-21. [Medline].

  18. Wahler-Roedler, DLKyle RA. Heavy chain Diseases. Best Practice & Research Clinical Hematology. 2005. 18:729-46.

  19. Wahner-Roedler DL, Kyle RA. Mu-heavy chain disease: presentation as a benign monoclonal gammopathy. Am J Hematol. 1992 May. 40(1):56-60. [Medline].

 
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