Polymorphism of soluble glutamic-pyruvic transaminase: a new genetic marker in man.

Soluble glutamic-pyruvic transaminase (GPT) has three common phenotypes, each representing the homozygous and heterozygous expression of two alleles, Gpt(1) and Gpt(2) at an autosomal locus. The frequencies of these alleles vary considerably from one population to another.

6-phosphogluconate dehydrogenase: hemizygous manifestation in a patient with leukemia.

In a study of 41 patients with chronic myelocytic leukemia, two were found to have the 6-phosphogluconate dehydrogenase heterozygous phenotype A-B, and two had the phenotype characteristic of Pd(B) homozygosity. Since one of the two with Pd(B) homozygosity was the mother of two children with the A phenotype, it was presumed that she carried a Pd(A) gene not expressed in her blood cells. his was confirmed by electrophoretic analysis of her fibroblasts, which had the A-B phenotypic pattern. Gene deletion is considered to be the most likely explanation.

Detection of the carrier state in combined immunodeficiency disease associated with adenosine deaminase deficiency.

A large pedigree containing a child with severe combined immunodeficiency disease (CID) associated with adenosine deaminase (ADA) deficiency was investigated to ascertain if heterozygotes could be detected by measuring red cell ADA activity. 9 of 17 individuals in three generations who were at risk for being heterozygous had decreased red cell ADA activity. This genetic information establishes one form of CID as an autosomal recessive disorder. The identified heterozygote population had a mean ADA value of 19.2 U/g hemoglobin (0.95 confidence interval; 14.0 to 24.4 U/g hemoglobin), which was approximately one-half the mean, 36.1 U/g hemoglobin, of a randomly selected control population (0.95 confidence interval; 22.5-58.1 U/g hemoglobin). Statistical comparisons of the heterozygotes to the normal population indicates that within a high-risk family heterozygotes may be identified with 90% confidence.

Adenosine deaminase deficiency: disappearance of adenine deoxynucleotides from a patient's erythrocytes after successful marrow transplantation.

Accumulation of adenine deoxynucleotides (dATP and dADP) in the erythrocytes of a patient with adenosine deaminase (ADA) deficiency was confirmed. The patient, now 18 mo old, was treated with a bone marrow transplantation from his HLA identical sister at 7 mo of age. Before and after the transplant, his erythrocyte and lymphocyte ADA activities, as well as his erythrocyte nucleotide profiles, were measured. 10 wk after the marrow transplant, no ADA activity could be detected in his erythrocytes, whereas there was a mixture of donor and patient lymphocytes as measured by ADA assays and karyotyping. At the same time, both dATP and dADP had disappeared from his erythrocytes, which were entirely of patient origin. These findings indicate that partial engraftment of donor lymphocytes into an ADA-deficient patient is capable of "correcting" alterations of deoxynucleotide concentrations in the patient's ADA-deficient erythrocytes.

Purine nucleoside phosphorylase deficiency. Evidence for molecular heterogeneity in two families with enzyme-deficient members.

Purine-nucleoside phosphorylase (NP) deficiency is associated with severely defective thymus-derived (T)-cell and normally functioning bone marrow-derived (B)-cell immunity. In this study, two unrelated families with a total of three NP deficient members were investigated. High pressure liquid chromatography of the plasma of the three patients showed inosine levels greater than 66 muM. This nucleoside was absent from the plasma of their parents and control samples.NP was purified from normal human erythrocytes by affinity chromatography and an antiserum prepared in rabbits was used to study the NP variants in the two families. In family M the patient had no detectable erythrocyte NP activity and no detectable immunological-reacting material (irm) to the NP antibody. The parents, who are second cousins, had less than one-half of normal enzyme activity and approximately 14% irm attributable to a variant protein. Their electrophoretic patterns revealed a series of isozymes with slower than normal migration. In family B the patients had 0.5% residual enzyme activity and about one-half normal irm. Their electrophoretic pattern showed faintly staining bands which migrated faster than normal NP. The mother of the patients had one-half normal enzyme activity, 11% irm attributable to her variant protein, and a normal electrophoretic pattern. The father had less than one-half normal enzyme activity, equal amounts of normal and variant irm, and an electrophoretic pattern that showed increased activity of the more rapidly migrating isozyme bands.The combined use of immunological and electrophoretic techniques has shown the presence of three separate mutations; one in family M and two in family B associated with severely defective T-cell function.

Autologous marrow recovery and sensitization to non-HLA antigens after HLA-identical marrow transplantation for aplastic anemia.

One hundred seventy-five patients with severe aplastic anemia were treated by high-dose cyclophosphamide and HLA-A, -B, and -D-identical sibling marrow transplants. Thirty-eight patients rejected their grafts. Four of the 38 showed autologous marrow recovery as determined by blood genetic markers. The remarkable feature of one case following autologous marrow recovery was the presence of unidirectional proliferative and cytotoxic responses of circulating host lymphocytes to marrow donor lymphocytes in mixed lymphocyte culture and cell-mediated lympholysis. Presumably these responses were the result of in vivo sensitization to those non-HLA antigens for which donor and recipient differed.

Recovery from aplastic anemia following attempted marrow transplantation.

A 23-year-old man with severe idiopathic aplastic anemia was prepared for marrow transplantation by the administration of cyclophosphamide (CY) 50 mg/kg on each of 4 days. He then received an intravenous infusion of 9.5 x 10(9) marrow cells from an HL-A matched and mixed leukocyte culture non-reactive sister. The graft was successfully established as shown by cytogenetic studies but was rejected after approximately 4 weeks. In preparation for a second transplant he was given procarbazine 12.5 mg/kg and goat antihuman thymocyte globulin (ATG) 7 mg/kg administered on alternate days for a total of 4 doses of each agent. At the end of this therapy his white blood cell count was noted to be going up and the second transplant was not carried out. Complete hematologic recovery of host type marrow ensued and persists now 20 months later. The various pathophysiologic mechanisms that may be involved are discussed.

Immunoglobulin production of donor origin after marrow transplantation for acute leukemia or aplastic anemia.

Four patients with acute leukemia and one with aplastic anemia were not transfused within 90 days before marrow transplantation from the HLA-identical sibling. When studied 4 to 12 1/2 months after transplantation their immunoglobulin allotypes were those of their donors.

The HLA system in the Korean population.

The frequencies of HLA-A, B, C, DR, and DQ antigens, HLA-D (HTC-defined) haplotypes, and the HLA-linked genetic markers glyoxalase I (GLO), factor B (Bf), C2 and C4 were studied in 162 healthy unrelated Koreans. Antigens A2, A24, A26, B44, B51, Bw62, B35, Cw1, Cw3, DR2, DR4, DRw6, DR7, and DRw8 were observed at frequencies of 15% or greater, and GLO-2, BfS, C4A*3, C2C, C4A*4, C4B*1, and C4B*2 were also frequently observed. The antigens A23, A25, B18, Bw42, Bw47, and B21 were not observed at all. HLA-DR4 was the most common class II antigen and was associated with a series of HLA-D-defined haplotypes including Dw4, Dw10, Dw13, and Dw15. The HLA-DRw6, DR2,Dw8, and DRw8 haplotypes were also found frequently. DR2 haplotypes were either Dw2 or Dw12, while all DRw8 haplotypes tested corresponded to the DB7 or Dw "8.3" specificity that has been described in other Oriental populations. Significant linkage disequilibrium was found between the alleles A2,Cw1; A30,B13; A30,Cw6; A30,DR7; Cw1,Bw22; Cw5,B12; Cw6,B13; Cw6,DR7; B7,DR1; B12,Dw6; B12,DR7; B12,Dw7; B13,DR7, B17,DR3; Bw22,C4B*6; DRw6,BfF; and C4A*4,C4B*2. A comparison of gene frequencies and commonly observed haplotypes between Koreans, Chinese, Japanese, and Caucasians showed that while Koreans share several characteristics in common with other Oriental populations, there are allelic frequencies and haplotypes in Koreans that are distinct.

Multiplicity of genetic polymorphisms of blood in the Schmiedeleut Hutterites.

Ninety-eight alleles in 38 polymorphisms of blood are identified in the Schmiedeleut Hutterites. The study was initiated because of the presence of Wda, an allele found almost exclusively in Hutterites. Eight of the other alleles also have an exceedingly low incidence in a random white population: r'' (.006), R2w (less than .001), LWb (less than .01), ESD*rare (less than .001), GPT*0 (.004), NP*4 (less than .001), GOT2*3 (.001), and C6*0 (.002). The occurrence of this many rare alleles in a population with an estimated maximum of 124 ancestral genomes was surprising but consistent with observations in other isolates. The degree of heterozygosity and large family size make the population ideal for genetic linkage studies.

Transfusions shortly before HLA-matched marrow transplantation for leukemia are associated with a decrease in chronic graft-versus-host disease.

The effect of random red cell transfusions given shortly before allogeneic bone marrow transplantation (BMT) was evaluated in 969 leukemic patients transplanted from an HLA-identical sibling donor. Patients were divided into two groups: 501 who received a transfusion shortly before BMT, and 468 who did not. Both groups had a similar incidence of acute graft-versus-host disease (GVHD), but the recently-transfused group had a significantly lower incidence of chronic GVHD (35.9% vs 48.9%). These differences remained significant in a multivariate analysis of time to chronic GVHD (p = 0.022), taking into account other differences between the two groups and known risk factors for chronic GVHD.

Hereditary retinoschisis linkage studies in a family and considerations in genetic counselling.

We report a family with X-linked juvenile retinoschisis. In addition to the three males with severe visual impairment, six other males in this family were found to have hitherto undiagnosed disease. The findings in these mildly affected males are described in detail. The wide range of clinical manifestations found among the affected relatives initially hampered recognition of the correct diagnosis. Once the correct diagnosis was made, proper genetic counselling could be given. The data are compatible with loose linkage between the loci for juvenile retinoschisis and the red cell antigen marker Xga.

Blood group alloantibodies: an assessment of some laboratory practices.

Over a 20-year period, the number of blood donors and transfusion recipients previously immunized by blood group antigens was determined in a large blood center. During that period, the proportion of patients found to have anti-D declined, while those with other antibodies in the Rh system, as well as in the Kell, Duffy, and Kidd systems, increased sharply. As expected, the rate of sensitization was much lower among blood donors than among recipients. In both groups, sensitized females greatly outnumbered sensitized males. Some of the findings summarized here raise questions about current practices in transfusion laboratories and emphasize the responsibilities of blood bank professionals to donors as well as to patients.