Combined analysis of DNA polymorphisms in the human β-globin gene cluster and in cloned β-genes has revealed the association of specific β-thalassaemia mutations and β-gene polymorphisms with particular flanking polymorphisms. A systematic study of cloned genes identified several new mutations, one of which possibly affects transcription. The strategy used may be applicable to other diseases of single-copy genes.

Linkage of β-thalassaemia mutations and β-globin gene polymorphisms with DNA polymorphisms in human β-globin gene cluster

Background To determine whether deferoxamine prevents the complications of transfusional iron overload in thalassemia major, we evaluated 59 patients (30 were female and 29 male; age range, 7 to 31 years) periodically for 4 to 10 years or until death. Methods At each follow-up visit, we performed a detailed clinical and laboratory evaluation and measured hepatic iron stores with a noninvasive magnetic device. Results The body iron burden as assessed by magnetic measurement of hepatic iron stores was closely correlated (R = 0.89, P<0.001) with the ratio of cumulative transfusional iron load to cumulative deferoxamine use (expressed in millimoles of iron per kilogram of body weight, in relation to grams of deferoxamine per kilogram, transformed into the natural logarithm). Each increase of one unit in the natural logarithm of the ratio (transfusional iron load to deferoxamine use) was associated with an increased risk of impaired glucose tolerance (relative risk, 19.3; 95 percent confidence interval, 4.8 to...

https://www.nejm.org/doi/pdf/10.1056/NEJM199409013310902

Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major.

We report the development of a rapid nonradioactive technique for the genetic prediction of human disease and its diagnostic application to hemophilia A. This method is based on enzymatic amplification of short segments of human genes associated with inherited disorders. A novel feature of the procedure is the use of a heat-stable DNA polymerase, which allows the repeated rounds of DNA synthesis to proceed at 63 degrees C. The high sequence specificity of the amplification reaction at this elevated temperature permits restriction-site polymorphisms, contained in the amplified samples, to be analyzed by visual inspection of their digestion products on polyacrylamide gels. By means of this method, we have performed carrier detection and prenatal diagnosis of hemophilia in two families with use of the factor VIII intragenic polymorphisms identified by the restriction enzymes BclI and XbaI. Predictions can be made directly from chorionic villi, without previous DNA extraction, and fetal sex can be determined by amplification of sequences specific for the Y chromosome. Specific amplification of genomic sequences with heat-stable DNA polymerase is applicable to the diagnosis of a wide variety of inherited disorders. These include diseases diagnosed by restriction-site variation, such as Duchenne's muscular dystrophy and sickle cell anemia, those due to a collection of known mutations, such as beta-thalassemia, and those due to gene deletion, such as alpha-thalassemia.

An improved method for prenatal diagnosis of genetic diseases by analysis of amplified DNA sequences. Application to hemophilia A.

The remarkable phenotypic diversity of the beta-thalassaemias reflects the heterogeneity of mutations at the beta-globin locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors. It is likely that phenotype-genotype relationships will be equally complex in the case of many monogenic diseases. These findings highlight the problems that might be encountered in defining the relationship between the genome and the environment in multifactorial disorders, in which the degree of heritability might be relatively low and several environmental agents are involved. They also emphasize the value of an understanding of phenotype-genotype relationships in designing approaches to gene therapy.

Phenotype—genotype relationships in monogenic disease: lessons from the thalassaemias

Survival and causes of death in thalassaemia major.

Will reading habit influence your life? Many say yes. Reading the clinical approach to thalassaemia is a good habit; you can develop this habit to be such interesting way. Yeah, reading habit will not only make you have any favourite activity. It will be one of guidance of your life. When reading has become a habit, you will not make it as disturbing activities or as boring activity. You can gain many benefits and importances of reading.

The Clinical Approach to Thalassaemia

Direct gene analysis of chorionic villi: A possible technique for first-trimester antenatal diagnosis of haemoglobinopathies.

We have identified 14 Asian patients with homozygous beta zero thalassaemia who had a mild clinical disorder related to an augmented production of haemoglobin F. None of their parents had an elevated level of Hb F. Restriction fragment length polymorphism analysis of the beta-globin cluster of these patients and a control group of Asian thalassaemia major patients showed that 6/14 of the thalassaemia intermedia patients were homozygous for a particular 5' beta-globin haplotype (-+-++), in contrast to 1/42 of the thalassaemia major patients. Furthermore, the -+-++ beta haplotype is also associated with amelioration of disease severity in beta thalassaemia in an Italian population. This beta haplotype is linked to a DNA sequence variation 5' (at position -158) to the G gamma globin gene which can be detected by the presence (+) of an Xmn I restriction enzyme site. The possible role of the Xmn I-gamma polymorphism in relation to this variant HPFH is discussed. We conclude that much of the observed clinical variability of beta thalassaemia can now be explained by the inheritance of beta thalassaemia chromosomes with different propensities for fetal haemoglobin production.

Association of thalassaemia intermedia with a beta-globin gene haplotype

Polymorphisms of DNA restriction sites within the human fetal globin genes have been used to identify chromosomes that carry beta-thalassaemia genes in individuals heterozygous for this disease. This has allowed an antenatal diagnosis for beta-thalassaemia to be carried out by observation of the pattern of the inherited polymorphism of a linked DNA sequence not involved in the genetic pathogenesis of the disease. In the populations we have investigated there is no constant pattern of polymorphism that segregates with the beta-thalassaemia gene. The use of linked polymorphisms should, therefore, be applicable to antenatal diagnosis both of beta-thalassaemia and of any other single-gene defect for which there is a DNA probe specific for a sequence linked to the affected locus.

Model for antenatal diagnosis of β -thalassaemia and other monogenic disorders by molecular analysis of linked DNA polymorphisms

In one southern Italian and one Pakistani patient with homozygous beta0 thalassaemia in which no detectable beta-globin synthesis occurs and no beta-globin messenger RNA is found, the gene for beta globin has been shown to be present using complementary DNA. This demonstrates that for these patients the imbalance in chain synthesis is not attributable to a gene deletion.

B. Modell

Papers

The Clinical Approach to Thalassaemia

Direct gene analysis of chorionic villi: A possible technique for first-trimester antenatal diagnosis of haemoglobinopathies.

Association of thalassaemia intermedia with a beta-globin gene haplotype

Model for antenatal diagnosis of β -thalassaemia and other monogenic disorders by molecular analysis of linked DNA polymorphisms

Presence of gene for beta globin in homozygous beta0 thalassaemia.