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mu-heavy chain disease (HCD) is very rare, with only 30 cases reported in the literature. We report a patient with mu-HCD associated with systemic amyloidosis. The diagnosis of mu-HCD was based on findings of mu-heavy chain fragments in the serum, Bence Jones proteinuria and vacuolated plasma cells in the bone marrow. To our knowledge, this is the third case in which systemic amyloidosis led to the patient's death.
The sequence of the amino-terminal 34 amino acids of gamma-heavy chain disease (gamma-HCD) protein Hi is homologous with the amino-terminal region of immunoglobulin heavy chains. gamma-heavy chain disease is smaller than a normal gamma-chain, but has the carboxy-terminal composition expected for gamma-chains and must, therefore, contain an internal deletion. Comparison of the Hi sequence with that of gamma-heavy chain disease Zu, which also has an internal deletion, indicates that the site of internal deletion is not a constant characteristic of gamma-heavy chain disease proteins. Heavy chains can be assigned to subgroups on the basis of variable region sequences. The variable regions of Hi and one other protein differ significantly from those determined for other heavy chains, and these two proteins are assigned to a new heavy chain variable region subgroup, V(HIV). It has been suggested that single immunoglobulin heavy chains are the products of two separate structural genes and that variable region genetic information is translocated and integrated into common region information. These multiple gene theories make no prediction as to whether DNA or RNA is translocated. gamma-heavy chain disease proteins provide unique information that indicates that if translocation is required for the production of immunoglobulin heavy chains, it is DNA, not RNA, that is translocated.
Human Ig heavy chain diseases of the alpha and gamma classes are characterized by the absence of light chain production as well as the disease-defining abnormalities in the heavy chain protein. Prior studies have suggested concomitant structural defects in productively rearranged L-chain genes as the reason for the absent L-chain proteins. We have found that the single rearranged lambda L-chain gene in the OMM heavy chain disease (HCD) cell line has a mutation in the splice donor site at the 3' end of the J exon, resulting in direct splicing of the 3' end of the leader to the acceptor site of the constant region. The cells contain an mRNA consisting of the leader-coding region joined directly to the constant region. The V-region exon is skipped and the shortened mRNA is translated into a truncated protein containing no V-region amino acids. We have also noted that, in contrast to most normal and neoplastic Ig-producing cells, the OMM cells produce an excess of heavy to light chain mRNA as well as protein. The excess is independent of the structural gene abnormality and is due to a low level of L-chain transcription, which can be increased by fusing the HCD cell to the murine myeloma cell line NS-1 or transfecting the defective OMM L-chain gene into a murine plasma cell. The latter data suggest that the OMM cells either lack a transcription factor present in mature plasma cells or have a functional repressor of L-chain transcription.
Heavy chain diseases (HCD) are monoclonal lymphoproliferative disorders of B-cells characterized by the synthesis of truncated heavy chains without associated light chains. In patients with mu-HCD, which is a very rare form of HCD, neoplastic cells produce immunoglobulin M heavy chain. The prognosis for patients with mu-HCD is poor, and there is no specific treatment for mu-HCD. In this report, we present a patient with mu-HCD accompanied by splenomegaly and thrombocytopenia. We treated this patient with the fludarabine monophosphate therapy we use for patients with B-cell chronic lymphocytic leukemia. After 5 courses of fludarabine monophosphate treatment, the splenomegaly and thrombocytopenia improved. Fludarabine monophosphate therapy may be a new strategy to improve the prognosis of patients with mu-HCD.
A gamma1 protein, designated CRA, found in heavy chain disease contains three inter-heavy disulfide bridges instead of the two normally found in gamma1 immunoglobulin heavy chains. Almost the entire Fd fragment is missing. The NH(2) terminal region is heterogeneous and contains carbohydrate; after 11 residues that do not resemble any of the known heavy-chain variable-region subclasses, normal synthesis seems to be resumed at the same amino acid residue as in another heavy-chain disease protein (ZUC). This finding raises the possibility that glutamic acid at position 216 represents the beginning of the Fe region, synthesized under the direction of another gene.
We have studied the structure of a crystallizable gamma 1 heavy-chain disease protein that lacks the entire VH and C gamma 1 domains. The protein starts within the hinge region at aspartic acid 221 (Eu numbering). The native protein is a disulphide-linked dimer with an apparent molecular weight of 52,000, consistent with the biochemical data obtained on the whole protein and its cyanogen bromide fragments. The carbohydrate content of this protein was 6.8%. As shown by biosynthesis experiments intracytoplasmic gamma chains synthesized by neoplastic cells had an apparent molecular weight similar to that of the serum heavy-chain disease protein. These data are compared with those obtained for other gamma 1 heavy-chain disease proteins beginning in the hinge region, and the mechanisms leading to those abnormal Ig products are discussed.
8 sera from patients with three types (gamma, alpha, mu) of heavy chain disease were tested by two-dimensional immunoelectrophoresis (Td. IEP) in order to assess the potential usefulness of such a technique as a routine diagnositc tool for heavy chain disease. Rocket immunoselection of the same sera was also performed by comparison. Characteristic, though not pathogomonic patterns were obtained by Td. IEP of the sera from patients with alpha chain disease. The main differential ciriteria by which heavy chain disease proteins could be differentiated from myeloma immunoglobulins were as follows: a) marked heterogeneity of the precipitin lines, ascribeable to the formation of polymers of different sizes; b) decreased sharpness, sometimes blurred delimitation, of the precipitin lines; c) frequent occurrence of spurs of the myeloma proteins over the deleted immunoglobulins in Kroll's tandeum variant, or between deleted immunoglobulins and small amounts of normal immunoglobulins present in the same serum. In our experience, rocket immunoselection does not show appreciable advantages as compared with Td. IEP.
We report a case of gamma heavy chain disease (GHCD) with several unique features: extensive osteolytic lesions simulating advanced multiple myeloma (MM), skin involvement, under the age of 40 yr, and the appearance of a series of pathological cells with indented or lobulated nuclei. The most remarkable feature is a previously unreported extensive bone destruction. Except for the presence of this bone disease, the clinical and pathological features of the patient resembled those of GHCD rather than those of MM. We have reviewed 3 previously reported cases of GHCD associated with skeletal involvement and compared these with our case.
Human alpha heavy chain disease is characterized by the production of abnormally short alpha IgH chains. In previously published cases it has been found that the malignant cells produce abnormal alpha mRNA, lacking VH and CH1 sequences and composed of a leader sequence peptide, sequences of variable length (69 to 84 bp) and of unknown origin, followed by normal CH2 and CH3 sequences. In this study we established the nucleotide sequence of alpha mRNA for six cases of alpha heavy chain disease. We observed that all six alpha mRNA lack the VH and CH1 sequences as do those previously described. They also contain in-frame inserts of unknown origin between the leader peptide and the normal CH2 and CH3 coding sequences. These inserts are of variable length (42 to 105 bp) and they are unrelated. These results suggest the existence of a common mechanism defect leading to deletions/insertions in alpha heavy chain disease rather than a specific interaction between alpha 1 IgH gene with a unique defined molecular species.
We have reported a case of gamma heavy-chain disease associated with hypercalcemia and reversible renal failure. After combined chemotherapy the patient remains well after 21 months of follow-up, and serum calcium levels remain in the normal range. This case supports the notion of Kyle et al that heavy-chain disease may present a diverse picture, and documents the first use of aggressive combination chemotherapy in the management of associated moderately severe hypercalcemia and hypercalcemic renal failure.
The urinary protein excreted in heavy-chain disease was separated by ion-exchange chromatography into two broad fractions designated Cra-1 and Cra-2. For a dimeric molecular weight of approx. 51000, Cra-1 contained 3-4 residues of 6-deoxy-l-galactose (l-fucose), 10 of d-mannose, 5-6 of d-galactose, 12 of 2-acetamido-2-deoxy-d-glucose (N-acetyl-d-glucosamine) and 4-5 of N-acetylneuraminic acid (sialic acid), whereas the corresponding values for Cra-2 were 2, 10, 7, 12 and 7. Cra-2 contained in addition 1 residue of 2-acetamido-2-deoxy-d-galactose (N-acetyl-d-galactosamine). Cra-1 contained an average of four oligosaccharide units, two of which contained 1 residue of 6-deoxy-l-galactose, 3 of d-mannose, 1 of d-galactose and 3 of 2-acetamido-2-deoxy-d-glucose, whereas the other two units contained the same proportions of 6-deoxy-l-galactose, d-mannose and 2-acetamido-2-deoxy-d-glucose but 2 residues of d-galactose and 2 of N-acetylneuraminic acid. Cra-2 also contained an average of four oligosaccharide units, but the range of glycopeptides was much wider, containing 0-1 residue of 6-deoxy-l-galactose, 2-3 of d-mannose, 2-3 of d-galactose, 2-3 of 2-acetamido-2-deoxy-d-glucose and 1-3 of N-acetylneuraminic acid. Possible reasons for this heterogeneity are discussed. Glycopeptides were also isolated from Cra-2 that contained 1 residue of d-mannose, 2 of d-galactose, 1 of 2-acetamido-2-deoxy-d-galactose and 0-3 of N-acetylneuraminic acid.
Erythematous, infiltrated plaques and extensive, heavy pleomorphic lymphoid cell infiltrates of the dermis were observed in a patient with gamma heavy-chain disease.
Heavy chain disease proteins (FOR) were isolated from human plasma. These proteins were also detected immunochemically in the urine of the patient. The proteins were disulphide-linked Fc-like dimers with molar mass 64.2 kg/mol and sedimentation rate S020,W = 0.356 ps (3.56 S). Similar amounts of aspartic acid and pyroglutamic acid were found at the N-terminus. After cyanogen bromide cleavage of the FOR proteins, three peptides were isolated and their amino acid composition and partial amino acid sequence was determined. We suggest that two Fc-like proteins of similar sizes are present in the plasma: (1) the first with N-terminal aspartic acid corresponding to position 221 of gamma 1 EU chain and (2) the second with N-terminal pyroglutamic acid. The first protein and small amounts of related low-molar mass fragments found also in the plasma could be degradation products of the second protein. Evidence is given on structural differences between the FOR proteins and the corresponding portion of the gamma 1 EU chain.
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We report a case of mu-heavy chain disease. A 56-year-old woman presented with anemia and hemorrhagic diathesis. The serum of the patient was found to have free mu-heavy chain. The patient also had a kappa type-Bence Jones protein in serum and urine. Immunoelectrophoresis showed an abnormal precipitin line in the alpha 2-globulin region which reacted with antiserum to mu-chain but not with antiserum for light chains. The molecular weight of the monomer of the patient's mu-heavy chain protein was approximately 67,000 daltons less than that of the normal mu-heavy chain protein.
The occurrence of alpha-heavy chain disease in an Italian adult, working in Libya, is reported, characterized by a spontaneous clinical and immunological recovery. It is suggested that the patient could have acquired the disease during his stay in an endemic area of alpha-heavy chain disease, and that the observed spontaneous remission could be related to the removal of environmental pathogenic factors, following his departure from Libya.