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Background: The ability to identify infants with sickle cell anemia who are likely to have severe complications later in life would permit accurate prognostication and tailoring of therapy to match disease-related risks and facilitate planning of clinical trials. We attempted to define the features of such babies by following the clinical course of 392 children with sickle cell disease from infancy to about the age of 10 years., Methods: We analyzed the records of 392 infants who received the diagnosis of homozygous sickle cell anemia or sickle cell-Beta(0)-thalassemia before the age of six months and for whom comprehensive clinical and laboratory data were recorded prospectively; data were available for a mean (+/-SD) of 10.0+/-4.8 years. Results obtained before the age of two years were evaluated to determine whether they predicted the outcome later in life., Results: Of the 392 infants in the cohort, 70 (18 percent) subsequently had an adverse outcome, defined as death (18 patients [26 percent]), stroke (25 [36 percent]) frequent pain (17 [24 percent]), or recurrent acute chest syndrome (10 [14 percent]). Using multivariate analysis, we found three statistically significant predictors of an adverse outcome: an episode of dactylitis before the age of one year (relative risk of an adverse outcome, 2.55; 95 percent confidence interval, 1.39 to 4.67), a hemoglobin level of less than 7 g per deciliter (relative risk, 2.47; 95 percent confidence interval, 1.14 to 5.33), and leukocytosis in the absence of infection (relative risk, 1.80; 95 percent confidence interval, 1.05 to 3.09)., Conclusions: Three easily identifiable manifestations of sickle cell disease that may appear in the first two years of life (dactylitis, severe anemia, and leukocytosis) can help to predict the possibility of severe sickle cell disease later in life.

The changes in bone mineral density (BMD) measured by single photon absorptiometry (SPA) using two observations conducted over a period of 2 years were examined in 54 thalassemic subjects [30 F(A) and 24 M(B)] with a chronological age ranging from 2.6 to 22.6 years and in 27 sex- and age-matched controls (C). Each category (A, B and C) was divided into three groups according to pubertal signs: pre-pubertal subjects (A1, B1 and C1); peri-pubertal subjects (A2, B2 and C2) and pubertal subjects from the first observation (A3, B3 and C3). Furthermore, each group of patients was divided into sub-groups on the basis of haematological phenotypes, those with a more severe form were called beta0/beta0 while those with other forms were called "others". The most significant findings were the following: the presence of a more severe reduction of the bone mineral density in patients with the beta0/beta0 phenotype than in patients with the "others" phenotype; patients with hypogonadism corresponded to the beta0/beta0 phenotype, while those with spontaneous puberty corresponded to the "others" phenotype. In conclusion, since puberty and the degree of bone mineral density are related to the haematological phenotype, puberty (spontaneous or induced) positively influences the bone mineral density only at the start of puberty, while subsequently, the degree of osteoporosis is the expression of widespread and chronic systemic damage due to the haematological phenotype.

We have determined the relative quantities of gamma- and beta-mRNAs and the alpha/beta-mRNA ratios in 37 patients with beta-thalassemia major with specific genotypes, namely 8 with a homozygosity for codon (CD) 39 (C-->T), 7 with a homozygosity for IVS-I-110 (G-->A), 5 with a homozygosity for IVS-I-6 (T-->C), for 15 patients with compound heterozygosities for 2 of these 3 mutations, and for 2 patients with the IVS-I-110 (G-->A)/-87 (C-->G) mutations. None had an alpha-thalassemia. Twelve patients had thalassemia intermedia and the remainder, transfusion-dependent severe conditions. Differences in phenotype were observed for compound heterozygotes involving the IVS-I-6 (T-->C) mutation in combination with either the IVS-I-110 (G-->A) or the CD 39 (C-->T) mutations: patients with thalassemia intermedia had a lower alpha/beta-mRNA ratio, about half of that of the patients with severe beta-thalassemia major. This might suggest a higher beta-mRNA synthesis in some patients than in others with the same genotype; mutations in promoter, enhancer, and/or locus control region sequences may be responsible for these differences. In vitro chain synthesis data were too incomplete to be helpful in this study. The RT-PCR procedure allowed the separation of abnormal (extended) mRNA from normal beta-RNA in subjects carrying the IVS-I-110 (G-->T) mutation. The relative quantities of this beta Th-mRNA (% of beta A + beta Th) were determined by scanning of the appropriate autoradiograms; they averaged 25% for homozygotes and about 4% for heterozygotes, indicating a considerable instability of the message.

The author summarizes the Hb A2 levels in over 600 beta-thalassemia heterozygotes with 32 different base changes or frameshifts and in 22 heterozygotes for 1 of 5 large deletions. Three major groups are recognized: persons with beta zero-thalassemia or beta (+)-thalassemia (severe) have Hb A2 levels between 4.5 and 5.5%, those with mild beta (+)-thalassemia alleles have levels between 3.6 and 4.2%, with still lower values for those with silent mutations. High values were observed in subjects with the 2 mild beta + alleles with mutations in the beta-globin gene promoter (-88, C-->T and -29, A-->G); unusually high Hb A2 values were also present in several -88 and -29 homozygotes. Data for several members of 8 families in which the -88 (C-->T) or the -29 (A-->G) mutation, or the -1,393-bp deletion, is present in cis or in trans to a delta-globin gene mutation support earlier observations that an increase in delta-chain synthesis occurs in cis to either one of these 3 alleles. A review of these data confirms the suggestion that the increase in Hb A2 levels results from at least two mechanisms: in a posttranslational system, the formation of alpha delta-dimers is promoted when excess alpha-chains are available, while certain promoter mutations increase the transcription of the delta-globin gene in cis because of a change in the binding of transcription factors.

A new deletion of the beta-globin gene cluster was characterized in a Turkish family. A 6-year-old male and his father were heterozygotes for this deletion. They presented with mild hypochromic microcytic anemia associated with elevated Hb F (15%) and normal Hb A2 levels (2.0%). This newly described Turkish type (delta beta)(0) thalassemia has a deletion of about 30 kb. The 5' breakpoint of this deletion starts approximately 1.5 kb downstream of an enhancer-like sequence of the A gamma-globin gene. The 3' endpoint is located in the L1 repeat sequence (Kpnl site) 3' to the beta-globin gene. The new deletion (Turkish type 3) is quite similar to that of the Indian (delta beta)(0)-thalassemia deletion in size and 5' breakpoint. However, the 3' endpoint in this new deletion is 2.5 kb shorter than the Indian type.

Early trials of allogeneic bone marrow transplantation (BMT) for homozygous beta-thalassemia and the analyses of results of transplantation in patients less than 16 years old have allowed us to identify three classes of risk based on the following criteria: (a) hepatomegaly, (b) presence of liver fibrosis at histological examination, and (c) quality of chelation treatment given before transplant. Patients with none of these adverse criteria were assigned to Class 1; patients with either one or two adverse criteria comprised Class 2; and patients for whom all three criteria were adverse constituted Class 3. Most patients older than 16 years have disease characteristics that place them in Class 3, with very few falling into Class 2. All patients with a histocompatibility leukocyte antigen (HLA)-identical donor are actually assigned to one of two conditioning regimens on the basis of the class they belong to at the time of BMT and independently of age. For Class 1, Class 2, and Class 3 patients, the probabilities of survival and event-free survival are 95 and 90%, 86 and 82%, and 87 and 63%, respectively. For those patients older than 16 years at the time of transplant, the probabilities of survival and of event-free survival are 78 and 74%, respectively. Allogeneic BMT is currently the only rational therapeutic modality for the eradication of beta-thalassemia.

Haemoglobinopathies are now common in Australia following the migration of people from areas of high prevalence. This article gives practical advice on the management of patients incidentally found to be heterozygotes for the more common forms and also outlines complications of major haemoglobinopathies that are seen in family practice.

The thalassemias are extremely heterogeneous in terms of their clinical severity, and their underlying pathophysiology relates directly to the extent of accumulation of excess unmatched globin chains: alpha in beta thalassemia and beta in the alpha thalassemias. However, the accumulation of each separate globin chain affects red cell membrane material properties and the state of red cell hydration very differently. These observations presumably account for the varying extent of ineffective erythropoiesis and peripheral blood hemolysis in the major variants of thalassemia. The thalassemias are a worldwide group of inherited disorders of globin-chain synthesis that developed in multiple geographic regions, probably because they provided partial protection against malaria. In normal assembly of adult hemoglobin (HbA-alpha 2 beta 2), alpha and beta globin are synthesized by genes on different chromosomes, whereas heme is synthesized primarily on mitochondria. The synthesis of these chains is very tightly coordinated so that the ratio of alpha globin to beta globin (beta in this case including the beta-like globins delta and gamma) is normally 1 +/- 0.05. Furthermore, specific erythroid proteases are designed to attack and destroy excess alpha or beta globin chains, demonstrating the deleterious impact of the accumulation of excess unmatched globin chains. In beta thalassemia, production of beta globin decreases and excess alpha globin accumulates. In alpha thalassemia, on the other hand, this process occurs in reverse. Perhaps in these disorders more than any others, molecular biologists have documented the deletional and transcriptional events leading to diminished synthesis of specific classes of globin chains.(ABSTRACT TRUNCATED AT 250 WORDS)

During recents the number of immigrants to Norway from Africa and South East Asia has risen considerably. These persons come from countries with a high prevalence of haemoglobinopathies. Most of the immigrants with haemoglobinopathies are silent carriers, but some have a serious disease or have offspring with serious disease. This situation calls for increasing awareness and knowledge of haemoglobinopathies, especially the thalassemias and sickle cell trait. Genetic counselling is particularly important, since the majority of these immigrants marry within small ethnic groups. This paper gives a survey of the most frequent haemoglobinopathies likely to be encountered in Norway.

We describe a direct method for detection of the Spanish and Sicilian (delta beta)zero-thalassemias. This method is based on the use of the deletion-junction sequences to design specific PCR primers. It permits a rapid screening of heterozygotes in populations at risk and provides a useful tool for early prenatal diagnosis of these forms of thalassemia.