Shigeo Mamiya

Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions

AbstractThe autosomal dominant macrothrombocytopenia with leukocyte inclusions, May-Hegglin anomaly (MHA), Sebastian syndrome (SBS), and Fechtner syndrome (FTNS), are rare platelet disorders characterized by a triad of giant platelets, thrombocytopenia, and characteristic Döhle body-like leukocyte inclusions. The locus for these disorders was previously mapped on chromosome 22q12.3–q13.2 and the disease gene was recently identified as MYH9, the gene encoding the nonmuscle myosin heavy chain-A. To elucidate the spectrum of MYH9 mutations responsible for the disorders and to investigate genotype–phenotype correlation, we examined MYH9 mutations in an additional 11 families and 3 sporadic patients with the disorders from Japan, Korea, and China. All 14 patients had heterozygous MYH9 mutations, including three known mutations and six novel mutations (three missense and three deletion mutations). Two cases had Alport manifestations including deafness, nephritis, and cataracts and had R1165C and E1841K mutations, respectively. However, taken together with three previous reports, including ours, the data do not show clear phenotype–genotype relationships. Thus, MHA, SBS, and FTNS appear to represent a class of allelic disorders with variable phenotypic diversity.

Acquired pure red cell aplasia in Japan

Abstract: We reviewed the clinical features of 150 patients with acquired pure red cell aplasia (PRCA) in Japan. There were 35 patients with acute type and 115 with chronic type PRCA. Of the acute PRCA patients, 17 had human parvovirus B19 infection. Drug‐induced PRCA was demonstrated in 7 patients. Of the 115 patients with chronic PRCA, 51 patients were classified as primary and 64 cases were associated with miscellaneous diseases such as thymoma, a variety of hematological disorders and collagen diseases. Among the hematological disorders, PRCA was most frequently seen in granular lymphocyte proliferative disorders (GLPD). The erythroid colony growth patterns from bone marrow were variable. The serum erythropoietin level was high in most patients. Various kinds of treatment were tried for the chronic PRCA cases. Cyclosporin A (CyA) was the most effective form of treatment and the response rate was 82% (31/38). Twenty‐three of 37 patients (62%) responded to bolus methylprednisolone therapy. The largest number of patients were treated with oral prednisolone, and the therapy was effective in 27 of the 55 (49%). The response rate to cyclophosphamide was only 29% (5/17), but in combination with prednisolone, half of the patients (7/14) responded to the therapy. CyA is recommended as the first‐line therapy for acquired chronic PRCA.

Diffuse large cell lymphoma occurring in a patient with waldenström's macroglobulinemia. Evidence for the two different clones in richter's syndrome

The authors report a 60‐year‐old man with Richters syndrome, or diffuse large cell lymphoma (DLCL) occurring in a patient with either chronic lymphocytic leukemia (CLL) or Waldenströms macroglobulinemia (WM). Surface marker analysis revealed that the WM showed μK surface immunoglobulin (Ig) chains, and that the DLCL showed μλ Ig chains. Flow cytometric DNA analysis demonstrated DNA content differences between WM and DLCL, the former diploid and the latter aneuploid. The current study suggests that Richters syndrome derives from two independent B‐cell malignancies.

Factor XIII Deficiency Associated with Klippel-Weber Disease, Platelet Dysfunction and Cryofibrinogenemia

A 23-year-old woman with factor XIII deficiency was presented. The patient had no consanguinity, but familial traits were present. A bleeding tendency and poor wound healing had been noted in the patient since birth. She had hemangiomas in the leg and vulva (Klippel-Weber disease). Hematologic studies revealed platelet dysfunction, cryofibrinogenemia and mild chronic disseminated intravascular coagulation with prolonged PT and PTT, hypofibrinogenemia, a high turnover rate of 125I-fibrinogen and mild elevation of fibrinogen-fibrin degradation products, beta-thromboglobulin and platelet factor 4. A decrease in clot retraction and a marked reduction in maximal amplitude of thrombelastogram were also found. The assay of the factor XIII level was 10% by the antiserum inhibition method, and the assay of subunits A and S were 16 and 29%, respectively, by the electroimmunoassay method. Transamidase activity of factor XIII was 26%. The level of factor XIII of her sister was low, similar to that of the patient. The concentration of cold-insoluble globulin in EDTA-plasma was 36.5 mg/dl.

Purification and Immuno- histochemical Localization of a 17-kD Porcine Renal Puromycin Aminonucleoside Binding Protein

We have purified a 17-kD puromycin aminonucleoside (PAN) binding protein from porcine kidney and identified it as the reported 17-kD protein kinase C inhibitor on the basis of its partial amino acid sequence. Of 54 determined amino acid sequences of the 17-kD porcine renal protein, 51 residues were identical to those of the 17-kD bovine brain protein kinase C inhibitor. However, our purified protein did not carry the inhibitory activity on protein kinase C. Immunohistochemical studies showed a unique intrarenal distribution of the 17-kD PAN-binding protein at the apical side of epithelial cells of Henles loops in the inner medulla and of distal convoluted tubules. Immunoblot analysis revealed that the 17-kD PAN-binding protein was extractable by an isotonic buffer without sodium deoxycholate extraction. These results suggest that this protein binds loosely to the apical membranes of epithelial cells of Henles loops and distal tubules and has specific functions related to tubular functions of these nephron segments at the apical side. Whether this protein is a real inhibitor of protein kinase C or not remains to be investigated.

Kappa Light Chain Nodular Glomerulosclerosis with Conspicuous Crescent Formation and Tubulointerstitial Injury

We describe a 39‐year‐old man who developed kappa light chain nodular glomerulosclerosis with superimposed conspicuous crescent formation and extensive tubulointerstitial injury. The clinical picture was characterized by nephrotic syndrome and rapidly progressive glomerulonephritis. Incessantly progressive loss of renal function culminated in irreversible renal failure 7 weeks after initial manifestation of renal insufficiency. The patient has since been maintained on thrice weekly hemodialysis with chemotherapy for five years. At the time of pathologic diagnosis by renal biopsy, there was no evidence of multiple myeloma, and no serum M‐component or Bence‐Jones proteinuria was detected. An initial bone marrow aspirate revealed the presence of 0.6% atypical lymphocytes as the sole abnormality, although these were later identified as atypical plasma cells. These cells had also infiltrated the renal interstitium. Crescentic kappa light chain nodular glomerulosclerosis lacking evidence of plasma cell dyscrasia should be included in the differential diagnosis of rapidly progressive glomerulonephritis.