Genetic factors and risk of agranulocytosis from metamizol.

The role of genetic factors in the pathogenesis of agranulocytosis was investigated in agranulocytosis patients by phenotyping for N-acetyltransferase and glucose-6-phosphate polymorphism; by typing for gene products of the major histocompatability complex, ABO- and RH-blood groups, and haemoglobins; and by performing cytogenetic analysis of chromosome aberrations. Nine persons were identified as agranulocytosis cases in the period from 1982 to 1987 among the population of Sofia. They were contacted again 10 years after recovery from the disease. Five of them were associated with metamizol (dipyrone) use. The results obtained revealed significant differences between the agranulocytosis patients and the healthy population in the human lymphocyte antigen (HLA) allele frequencies, and in the degree and the frequency of chromosome aberrations. A higher frequency of the HLA24 antigen (relative risk 13.60, p = 0.05) and a lower frequency of the DQA1*0501 allele were evident for the ex-agranulocytosis patients as compared to the controls (11% versus 57% respectively, p = 0.05). In the patients exposed to metamizol, an A24-B7 haplotype was found with a frequency higher than that in the non-exposed patients and the reference group (p < 0.05). The HLA-DQwl antigen and metamizol-related agranulocytosis were evidently associated in all cases (5/5;100%) in contrast to the patients not exposed to metamizol and the controls. The HL-A2 antigen was absent in four of the five metamizol-associated agranulocytosis cases (20%), while in the control group it was present in 56%. The degree of structural rearrangements (0.62 +/- 0.2%) and the frequency of chromosome breakages (7.75 +/- 0.68%) in agranulocytosis patients were higher than those in the healthy population (0.3 +/- 0.12%, p < 0.05 and 1.42 +/- 0.27%, p < 0.01, respectively). The abnormalities affected predominantly chromosomes 1(1p13), 2(2p12) and 5(5p12). No differences were found between the agranulocytosis patients and the healthy population when considering the haemoglobin subtypes, ABO-and RH-blood groups, glucose-6-phosphate dehydrogenase activity and the rates of slow and rapid acetylators.

Detection of low level sex-chromosomal mosaicism.

In this report we present the cytogenetic findings of low frequency (X or Y)-mosaicism (1.0%-3.6%) in six patients aged between 28 and 36 years (average age 32.17) among sixteen individuals (analysis of 5402 mitoses) referred for genetic counseling after unsuccessful assisted reproductive treatment. For the detection of low level mosaicism, analysis of 500 metaphases is necessary to prove the presence of 1% abnormal clones, if the "background" level of the same aberraitons in controls is 0.1%. Low frequency mosaicism of sex chromosomes may be responsible for the unsuccessful results of in vitro fertilization and related techniques. The question may be raised whether diagnosis in subsequent pregnancies is indicated in these patients.

[Familial idiopathic congestive cardiomyopathy in 2 brothers with a similar course]. / Familna idiopatichna kongestivna kardiomiopatiia u dvama bratia sus skhodno protichane.

The course of idiopathic congestive cardiomyopathy in two full brothers is described. The diagnosis was made on the base of the existing cardiomegaly, gallop rhythm and congestive cardiac insufficiency, in the absence of any connection with some of the well known causes for hypertrophy and dilation of the heart. It was confirmed at necropsy in one of the brothers. A similarity was established in their case history, namely: considerable physical activity until the first signs of cardiac insufficiency, advancement of decompensation at the same age (20 years) with an already existing cardiomegaly, identical complaints--rhythm disturbances and pulmonary thromboembolism, similar electrocardiographic changes with formation of "pseudoinfarct" image, ventricular flutter--immediate cause for the death of one of the brothers, sudden death--for the other. The origination of the disease cannot be associated with the effect of exogenous morbid factors. There are no data on advancing of autoimmune process. With the genealogical study, covering four generations, the family was established to have a stillborn child, no other sick members of the family, no data about multiple deaths. The cytogenetic analysis showed no chromosomal aberrations. The possibility the disease to be transmitted via autosomal recessive mode or via autosomal-dominant gene with a low penetration is discussed.

Glucose-6-phosphate dehydrogenase deficiency and Rh factor.

The incidence of carriers of the Gd(-) gene and the Rh(+) and Rh(-) alleles was studied in 10 342 Bulgarian individuals living in 306 villages in 5 districts at different altitudes above the sea level. The results showed that the presence of the Gd(-) gene is considerably less frequent in Rh(-) than in Rh(+) individuals. In populations with a high frequency of G6PD deficiency the frequency of the Rh(-) allele is low.

[Clinicogenetic studies of a patient with the Corinth type of glucose-6-phosphate dehydrogenase deficiency]. / Kliniko-genetichni prouchvaniia pri bolen s gliukozo-6-fosfat dekhidrogenazen defitsit tip Korint.

A patient with repeated hemolytic episodes since early childhood of undistinguished etiology is described. The patient was three times admitted to hospital--infectious and internal diseases clinics on the occasion of the manifested hemolytic-icteric syndrome. The clinical, biochemical, genealogical and other investigations carried out, confirmed the presence of G-6-PD deficiency. That genetic effect was found in 6 of all 17 subjects, examined of the family. The patient had inherited the genetic defect from his mother. The studies in accordance with WHO programme, revealed that a G-6-PD, type Corinth variant, was concerned. The male-patient, presented by us is of particular interest in a clinical and differentiation diagnostic aspect.

Frequency of glucose-6-phosphate dehydrogenase deficiency in relation to altitude: a malaria hypothesis.

Genetic markers have recently been found to be much more polymorphic than expected. Such extensive human polymorphisms may be partly explained by a number of genetic and environmental factors, including infectious diseases. Malaria, which was very widespread in the past and still poses a problem in many countries today, is a good candidate for research. The association between malaria and glucose-6-phosphate dehydrogenase (G6PD) deficiency is well-known, but more should be done to determine the mechanisms responsible for this positive correlation and to confirm that malaria is a strong selective factor for many other genotypes also. The present paper refers to a WHO project on genetic markers and susceptibility to infectious diseases, which is concerned mainly with G6PD deficiency and the following genetic markers: haemoglobinopathies, including the beta-thalassaemia trait and ABO, Rh, MN, Duffy, secretory types (Ss), and human leukocyte antigens (HLA). Since malaria was eradicated in Bulgaria many years ago, human populations from this country, living at different altitudes above sea-level, were used as a model for analysis of the malaria hypothesis. The data for G6PD deficiency confirm that malaria was a selective factor in lowland areas where malaria infection was more frequent in the past. It is, moreover, apparent that in addition to malaria some other factors also play a selective role.

Variants of erythrocyte glucose-6-phosphate dehydrogenase (G6PD) in Bulgarian populations.

Ten variants of erythrocyte glucose-6-phosphate dehydrogenase were identified in 22 patients with G6PD deficiency from three districts of Bulgaria. Corinth-like and Fayoum-like variants were the most frequent; Mediterranean, Ohut II, Kilgore, Boston, Poznan, and Panay variants and two new variants, Petrich and Gotze Delchev, were each found in one or two carriers. No correlation was revealed between clinical and biochemical polymorphism.