eMedicine Specialties > Hematology > Plasma Cell Disorders
Heavy Chain Disease, Mu
Updated: Jan 2, 2010
Introduction
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.
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 1970.1
This article focuses on mu-HCD; however, other heavy chain diseases are described (eg, see Heavy Chain Disease, Gamma).
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.2 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.3
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
Most patients with mu-HCD reported in the literature were white, but at least 3 black patients and 1 Asian patient have also been reported.
Sex
No obvious sex predilection has been described; half the patients with mu-HCD are male.
Age
The age of reported patients varies from 15-80 years; mu-HCD does not have an obvious age predilection.
Clinical
History
- Initial reported cases had a clinical picture consistent with chronic lymphocytic leukemia (CLL); however, with better diagnostic procedures and a high index of suspicion, the defining protein abnormality has been noted in a broader range of clinical settings. Currently, only one third of patients with mu-HCD appear to have CLL. In 150 consecutive patients with CLL, thorough investigation of serum proteins failed to identify a single instance of mu-HCD, which suggests an incidence of less than 1% in this population.4
- Other clinical presentations vary, one of which may be essential monoclonal gammopathy with no clinical symptoms of B-cell lymphoma (20%). In 10% of cases, an intact IgM protein was simultaneously detected in the serum. Another 10% of cases were associated with clinical multiple myeloma or plasmacytoma. Mu-HCD is also reported to be associated with systemic amyloidosis in rare instances.5
- Patients usually present with evidence of systemic disease, such as weight loss, fever, anemia, and recurrent infection. Splenomegaly is detected in almost all cases, hepatomegaly is present in approximately 75% of cases, and peripheral lymphadenopathy is present in approximately 40% of patients.
- Bone involvement with osteolytic lesions and pathologic fractures has been noted in approximately 40% of patients. These patients usually present with bone pain, especially in the back.
- Renal complications seem infrequent, with cast nephropathy and renal failure reported in a single case. Two patients, including the first reported case, had amyloidosis with renal impairment.
- Some patients present with other pathologic conditions such as systemic lupus erythematosus, hepatic cirrhosis, and myelodysplastic syndrome.
Physical
- Physical examination findings are variable and depend on patient presentation.
- Pallor may be noted if significant anemia is present, which is usually observed only in advanced disease.
- Lymphadenopathy is noted in 40% of patients.
- Splenomegaly is almost universal, and hepatomegaly is noted in most cases.
Causes
The cause of mu-HCD is not known. No viruses, chemical, physical, or genetic factors have been identified.6
More on Heavy Chain Disease, Mu |
 Overview: Heavy Chain Disease, Mu |
| Differential Diagnoses & Workup: Heavy Chain Disease, Mu |
| Treatment & Medication: Heavy Chain Disease, Mu |
| Follow-up: Heavy Chain Disease, Mu |
| References |
| Further Reading |
| Next Page » |
References
Ballard HS, Hamilton LM, Marcus AJ, Illes CH. A new variant of heavy-chain disease (mu-chain disease). N Engl J Med. May 7 1970;282(19):1060-2. [Medline].
Bakhshi A, Guglielmi P, Coligan JE, et al. A pre-translational defect in a case of human mu heavy chain disease. Mol Immunol. Jul 1986;23(7):725-32. [Medline].
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. Aug 1990;27(8):771-6. [Medline].
Bonhomme J, Seligmann M, Mihaesco C, et al. MU-chain disease in an African patient. Blood. Apr 1974;43(4):485-92. [Medline].
Kinoshita K, Yamagata T, Nozaki Y, et al. Mu-heavy chain disease associated with systemic amyloidosis. Hematology. Apr 2004;9(2):135-7. [Medline].
Witzig TE, Wahner-Roedler DL. Heavy chain disease. Curr Treat Options Oncol. Jun 2002;3(3):247-54. [Medline].
Wahler-Roedler, DLKyle RA. Heavy hain Diseases. Best Practice & Research Clinical Hematology. 2005;18:729-46.
Lougaris V, Ferrari S, Cattalini M, Soresina A, Plebani A. Autosomal recessive agammaglobulinemia: novel insights from mutations in Ig-beta. Curr Allergy Asthma Rep. Sep 2008;8(5):404-8. [Medline].
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. Mar 2008;389(1-2):171-3. [Medline].
Yanai M, Maeda A, Watanabe N, et al. Successful treatment of mu-heavy chain disease with fludarabine monophosphate: a case report. Int J Hematol. Feb 2004;79(2):174-7. [Medline].
O'Connell TX, Horita TJ, Kasravi B. Understanding and interpreting serum protein electrophoresis. Am Fam Physician. Jan 1 2005;71(1):105-12. [Medline].
Buxbaum JN, Alexander A. Heavy Chain Diseases. In: Beutler B, Lichtman MA, Coller BS, Kipps TJ, and Seligsohn U, eds. Williams Hematology. 6th ed. New York, NY: McGraw-Hill; 2001:1327-36.
Fermand JP, Brouet JC. Heavy-chain diseases. Hematol Oncol Clin North Am. Dec 1999;13(6):1281-94. [Medline].
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. Oct 1997;66(3):359-65. [Medline].
Liapis H, Papadakis I, Nakopoulou L. Nodular glomerulosclerosis secondary to mu heavy chain deposits. Hum Pathol. Jan 2000;31(1):122-5. [Medline].
Preud'homme JL, Bauwens M, Dumont G, et al. Cast nephropathy in mu heavy chain disease. Clin Nephrol. Aug 1997;48(2):118-21. [Medline].
Wahner-Roedler DL, Kyle RA. Mu-heavy chain disease: presentation as a benign monoclonal gammopathy. Am J Hematol. May 1992;40(1):56-60. [Medline].
Further Reading
- O'Connell TX, Horita TJ, Kasravi B. Understanding and interpreting serum protein electrophoresis. Am Fam Physician. Jan 1 2005;71(1):105-12. [Medline]. 11
- IgA and IgG Subclass Deficiencies [in the Pediatrics: General Medicine section]
- Lymphoma, B-Cell
- Multiple Myeloma
- Panhypogammaglobulinemia [in the Allergy and Immunology section]
- Pure B-Cell Disorders
Keywords
mu-heavy chain disease, mu-HCD, heavy chain disease, HCD, B-cell proliferative disorder, immunoglobulin heavy chain, Ig heavy chain, plasma cell disorder, monoclonal gammopathy of unknown significance, gammopathies, chronic lymphocytic leukemia, CLL, multiple myeloma, plasmacytoma, splenomegaly, peripheral lymphadenopathy, hepatomegaly, osteolytic lesion, pathologic fractures, hypogammaglobulinemia
