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PubMed1977

[Osmotic resistance of erythrocytes as a screening method in detecting heterozygotes in beta-thalassemia].

Osmotic fragility of red blood cells in three different buffered solutions, i.e. 0,32%, 0,36% saline and 0,40% Tyrode solution was studied as a screening test for the detection of beta-thalassemia trait. 90 genetically designated beta-thalassemia heterozygotes were studied for the screening tests. In addition 514 school children and 161 patients suffering from anemia of different etiology were also examined for the osmotic fragility screening. The results of the studies indicated that the one tube method screening test with 0.36% buffered saline solution was the appropriate solution in screening for beta-thalassemia trait since the solution was able to detect 99 to 100% of the carriers. However, about 15% of normal individuals were also found to give a false positive for the 0.36% saline screening test. It is recommended that 0.36% buffered saline solution be used as a first screening test for the detection of beta-thalassemia trait since it is simple, rapid, cheap and applicable. Those who are positive with this test are required to be completely studied in hematology for the final diagnosis of either beta-thalassemia trait or other hematologic disorders.

Adolescent↗

PubMed1982

Developmental changes in hemoglobin F levels during the first two years of life in normal and heterozygous beta-thalassemia infants.

To study the developmental pattern of hemoglobin F (HbF) during the first two years of life, levels of HbF were estimated in two groups of infants: 117 normal infants and 98 heterozygotes for beta-thalassemia, all aged between 1 and 24 months. The results may be summarized as follows: (1) Levels of HbF in beta-thalassemia heterozygotes were significantly higher than those of normal infants of the same age (P less than .01). (2) A reference curve for the decline of HbF in infants with beta-thalassemia trait was established to facilitate the diagnosis of heterozygotes during this period of life. (3) Hemoglobin A2 (HbA2) was also higher in beta-thalassemia heterozygotes than in normal infants of the same age. HbA2 increases with increasing age, reaching normal adult values at age 5 to 6 months. It is postulated that the higher level of HbF in heterozygous infants during the first two years of life is associated with the presence of the beta-thalassemia gene, which influences the increased synthesis of HbF in red cell.

Aging↗

PubMedDate not supplied

Prenatal diagnosis of thalassemias and hemoglobinopathies.

Thalassemia syndromes and hemoglobinopathies are of clinical genetic significance because of the severity of the sequelae associated with particular genetic constitutions in these conditions, their occurrence at high frequencies in certain populations of Mediterranean, African, and Asian origin, and the high frequency of recurrence in pregnancies of at risk families. Application of recently developed techniques of molecular genetics to the antenatal diagnosis of the most deleterious of these conditions (homozygous beta-thalassemia [Cooley's anemia], homozygous alpha-thalassemia [Barts hydrops fetalis], sickle cell anemia, and related severe homoglobinopathies) now affords parents the option to interrupt a pregnancy in which the fetus has the genetic constitution causing one of these abnormalities. The two different analytical strategies utilize fetal cells obtained by aminocentesis. In one, fetal blood is obtained either by sonographically guided placental aspiration or by aspiration from a placental vein directed by fetoscopy. Globin chain synthesis is monitored by the incorporation of radiolabelled amino acids in the isolated erythrocytes and the determination of the ratio of radioactive label incorporated into the various globin chains separated by column chromatography or electrophoresis. This technique is applicable to the antenatal diagnosis of alpha-and beta-thalassemia and to selected hemoglobinopathies. However, in the most experienced centers, fetal blood sampling is associated with a greatly increased risk of fetal loss. The other analytical approach utilizes desoxyribonucleic acid (DNA) isolated from fibroblasts to evaluate the presence of quantitatively and/or qualitatively normal DNA sequences, which constitute the structural gene(s) encoding specific globin polypeptide chains. This approach is most generally applicable to the detection of structural gene deletions as in a alpha-thalassemia; maternal and fetal risk is the same as that for conventional amniocentesis.

Amniotic Fluid↗

PubMed1983

Alpha-thalassemia is related to prolonged survival in sickle cell anemia.

We have determined the frequency of deletional alpha-thalassemia in black populations in the USA and Africa that harbor sickle cell anemia. In normals, the frequency of the chromosome bearing a deletion of one of the two normal alpha gene loci, designated (-alpha), ranged from 0.12 to 0.16, and in sickle trait subjects, the frequency ranged from 0.18 to 0.20. By contrast, in sickle cell anemia subjects, the frequency was significantly greater and ranged from 0.22 to 0.33. Analysis demonstrated that the greater frequency in the last group was primarily a result of an increased number of subjects with alpha-thalassemia trait (also called homozygous alpha-thalassemia-2). In addition, the frequency of the (-alpha) chromosome was found to increase progressively with age, supporting the hypothesis that alpha-thalassemia is favorable to the survival of subjects with sickle cell anemia. Thus, individuals who inherit alpha-thalassemia and sickle cell anemia may represent a subgroup of patients with a longer life expectancy.

Africa, Western↗

PubMed1984

Gene analysis in delta beta and delta (0) thalassemia.

Restriction mapping of the globin genes from a homozygous delta beta thalassemia patient from Israel indicates that at least a 10-kilobase deletion is present extending 3' from within the large intervening sequence (IVS 2) of the delta globin gene and including the entire beta globin gene. Unique bands are seen when cellular DNA from this patient is digested with a variety of restriction endonucleases and hybridized with a probe specific for the delta IVS 2. Extensive analysis of the Israeli delta beta thalassemia DNA as well as material from an Italian delta beta thalassemia homozygote with enzymes which cleave more frequently in delta IVS 2 has localized the 5' end of the deletion to a 107-base pair region within delta IVS 2. This region contains a unique repetitive sequence (TG)4 which has been reported to be a specific recognition signal for recombination and may be involved in the formation of these mutant genes. Two homozygous delta(0) thalassemia DNA samples from Japan were also analyzed for gene rearrangements or other changes by restriction enzyme mapping. No changes from normal were seen using 14 different enzymes indicating the absence of large deletions in the region around the delta globin gene. More specifically, both the 5' and 3' splice junctions of the IVS 2 appear to be normal from hybridization of restriction fragments generated by HphI and AluI, respectively, with a delta IVS 2 specific probe. We have also shown that point mutations which could lead to termination codons are not present at codons 35, 37, 43, 61, and 121, since restriction enzymes which recognize these sites produce normal patterns. The delta(0) thalassemia phenotype in these two subjects is most likely due to a point mutation either at one of the other 24 potential termination codons not accessible to restriction analysis or to other single nucleotide changes which could either decrease delta globin gene transcription or lead to abnormal processing or transport of delta globin mRNA.

Base Sequence↗

PubMed1983

Thalassemia among Chinese-Bostonians. Usefulness of the hemoglobin H preparation.

Microcytosis was noted in 14.7% of the complete blood cell count reports of Chinese subjects in a Boston Chinatown health center. One hundred forty-nine of these subjects' conditions were further evaluated by hemoglobin electrophoresis, Hb H inclusion bodies preparation, Hb A2 quantitation, and ferritin assay. Ninety-one cases of alpha-thalassemia-1 trait and 49 cases of beta-thalassemia trait were diagnosed. In this study population, the prevalence of thalassemia trait and of iron deficiency resulting in microcytosis was 13.8% and 3.4%, respectively. The Hb H preparation was found to be clinically useful and reliable for detecting alpha-thalassemia-1 trait in Chinese carriers, after the exclusion of iron deficiency and beta-thalassemia by routine studies.

Adolescent↗

PubMed1981

Beta-thalassemia and sickle cell disease in culture of early erythroid precursors: hemoglobin synthesis and ultrastructural study.

Hemoglobin synthesis was studied in culture of early erythroid precursors (BFU-E) from the blood of nine patients exhibiting sickle cell anemia and of 14 with various types of beta-thalassemia. The results concerning gamma gene expression and plating efficiency in heterozygotes for sickle cell anemia were similar to those of normal adults (gamma/alpha = 0.05; 65 BFU-E colonies/10(6) plated cells) while, in contrast, homozygotes for sickle cell disease exhibited average values higher than the controls (gamma/alpha = 0.18; 80 BFU-E colonies/10(6) plated cells). However, the results were very heterogeneous from one subject to another. In heterozygotes for beta-thalassemia, gamma gene expression and plating efficiency were both slightly higher than those for normal individuals (gamma/alpha = 0.095; 129 BFU-E colonies/10(6) plated cells). In patients homozygous for beta-thalassemia, a marked increase in plating efficiency and gamma-chain synthesis was constantly observed (gamma/alpha = 0.41; 221 BFU-E colonies/10(6) plated cells). The high proportion of gamma chain synthesis was not related to a positive selection of F cells, since the gamma/alpha ratio remained constant during the in vitro erythroid maturation. Furthermore, a major increase in free alpha chain proteolysis can be ruled out, since the beta/alpha ratio was of the same order of magnitude in culture and in freshly drawn cells. Thus, the increased Hb F synthesis in vitro was the consequence of a true stimulation of gamma gene expression, which permitted partial correction of the globin chain imbalance. Ultrastructural studies in two homozygotes for beta-thalassemia showed a marked decrease in the abnormalities of the erythroblasts derived from erythroid precursors in vitro in comparison to those from fresh bone marrow samples. In particular, Heinz bodies were much less numerous and a high frequency of mature erythroblasts and reticulocytes was observed in culture. These results support the view that, in sickle cell anemia and beta-thalassemia, a high potential for gamma gene expression exists and can be expressed in culture.

Anemia, Sickle Cell↗

PubMed1978

Serum ferritin in beta-thalassemia trait.

The diagnostic value of serum ferritin measurements in discriminating iron-deficiency anemia from thalassemia trait has been studied. In contrast to serum iron, percent transferrin saturation and total iron-binding capacity, where a high degree of overlap existed between the two groups, a clear-cut difference in serum ferritin levels was found between iron deficiency and thalassemia trait. The best separation of iron deficiency, thalassemia and normal controls was given by the combination of mean corpuscular volume and serum ferritin. Although definitive diagnosis of beta-thalassemia trait requires the demonstration of abnormal Hb A2 levels or beta-chain synthesis, serum ferritin is a useful screening test for the initial diagnosis of thalassemia trait. Because of the very small amounts of serum required for the measurement of ferritin, it is particularly suitable for surveying populations with a high prevalence of hypochromic-microcytic anemias.

Anemia, Hypochromic↗

PubMed1994

Interaction of rare illegitimate recombination event and a poly A addition site mutation resulting in a severe form of alpha thalassemia.

The clinical diversity of thalassemia depends on interaction of diverse genetic defects. We have characterized a severe form of alpha thalassemia caused by coinheritance of a rare alpha-globin gene deletion and a nondeletional defect in a southern Italian family. The proband, a 7-year-old girl, exhibited an abnormal hemoglobin electrophoresis pattern with hemoglobin H and hemoglobin Barts, indicating inheritance of H and hemoglobin Barts, indicating inheritance of a severe form of alpha thalassemia. Southern blot analysis of DNA showed normal as well as aberrant alpha-globin gene fragments indicating heterozygosity for a deletional form of alpha thalassemia in the proband and her mother. The coinheritance of a nondeletional form of alpha thalassemia (alpha alpha T) was suspected because of the severity of the proband's phenotype and the presence of normal alpha-globin gene fragments in the father. Selective polymerase chain reaction of the paternal alpha 1- and alpha 2-globin genes in the proband followed by DNA sequence analysis showed an AATAAA to AATGAA mutation in the polyadenylation signal sequence of the alpha 2-globin gene. Genomic DNA mapping and sequence analysis of a unique polymerase chain reaction product generated across the deletion breakpoint of the maternal allele showed a 5,201-bp deletion extending from 870 nucleotides 5' of the alpha 2-globin gene to nucleotide +519 in the alpha 1-globin gene. This deletion is similar to that previously suggested by blotting studies in a Greek family (Pressley et al, Nucleic Acids Res 8:4889, 1980) and removes the entire alpha 2-globin gene and a portion of the 5' end of the alpha 1-globin gene. Sequence characterization of the resultant aberrant truncated alpha 1-globin gene from the proband showed a 27 nucleotide duplication corresponding to the 3' end of the alpha-globin gene IVS-2 region separated by the insertion of a tetranucleotide (GGTT), suggesting that this deletion is caused by an illegitimate recombination event.

Base Sequence↗

PubMed1994

Bone marrow transplantation for thalassemia. The USA experience.

PURPOSE: We have reviewed the results of bone marrow transplantation in 30 patients with thalassemia major who were treated in the United States. PATIENTS AND METHODS: Ten patients who underwent transplantation in Seattle and 20 patients from five other U.S. centers were identified through a survey of the International Bone Marrow Transplant Registry. These transplants were performed between November 1981 and April 1992 in patients with diverse ethnic backgrounds and ranged in age from 6 months to 14 years (median 4.0 years). Twenty-seven of the 30 patients received marrow from a human leukocyte antigen (HLA)-identical sibling or other family member, one patient received HLA-matched marrow from an unrelated donor, and two patients were given haploidentical but HLA-mismatched marrow from a related donor. Cytoreductive (preparative) therapy varied among institutions and pretransplant risk categories. In general, patients were given busulfan (12-24 mg/kg) or dimethylmyleran (5 mg/kg) in combination with cyclophosphamide (120-240 mg/kg). A subset of patients were given total body irradiation (TBI) at a dose of 720 cGy followed by cyclophosphamide (120 mg/kg). RESULTS: Sixteen of 27 patients (59%) who received marrow from an HLA-identical family member are event-free survivors, with a duration of follow-up ranging from 2 months to > 10 years after transplantation. Six of these 27 patients (22%) had recurrence of thalassemia and five (19%) died. The estimated actuarial rate of thalassemia recurrence was 24% and the rate of event-free survival was 57%. Only one of the three patients who received marrow from HLA-nonidentical or unrelated donors survives event-free. Liver biopsies were not routinely performed before transplant. Thus, classification of patients into Lucarelli risk groups was not possible. A modified risk classification was devised by using liver size and iron status assessed by the regularity of chelation and the serum ferritin level. With use of this classification, there was no significant difference in event-free survival between transplant risk groups. CONCLUSIONS: The findings observed in this small series of patients confirms that thalassemia can be cured with bone marrow transplantation. Although most patients are event-free survivors, a significant number experienced recurrence of their disease. A cooperative multicenter trial of U.S. transplant centers may be necessary to evaluate the use of marrow transplantation for thalassemia and to determine optimal treatment.

Adolescent↗

PubMed1977

Frequencies of thalassemia in American blacks.

The frequency of thalassemia was determined in a group of 541 healthy adult black males. Individuals with decreased mean corpuscular hemoglobin (MCH) values were evaluated further with hemoglobin analysis, iron studies, and globin chain synthesis. Of the males screened, 13.4% had MCH levels below 27.0 pg, while 1.4% had heterozygous beta thalassemia, 2.3% had iron deficiency, and 5.7% had globin synthesis findings compatible with the diagnosis of alpha thalassemia trait (alpha thalassemia-1). This study suggests that thalassemia is one of the most frequent hematologically depictable abnormalities in American blacks.

Adolescent↗

PubMed1995

The clinical severity of beta-thalassemia mutations in West Malaysia.

Beta-thalassemia in West Malaysia is caused by 14 molecular defects with differing clinical severity. In Chinese patients from West Malaysia, the main beta-thalassemia mutations seen were (a) a 4 base pair-TCTT deletion in codon 41-42 [frameshift mutation (FSC 41-42)]; (b) a C to T substitution at the second intervening sequence (IVS2-654); (c) an A to G substitution in the TATA box [-28 (A to G)], and (d) an A to T substitution in codon 17[17 A to T]. In the Malays, the main mutations seen were (a) a G to C in nucleotide 5 at the intervening sequence I [IVS1-5 (G to C)]; (b) G to T substitution in nucleotide I at the intervening sequence I [IVS1-1 (G to T)]; (c) a A to T substitution in codon 17 (17 A to T); (d) removal of C from codon 35 [codon 35 (-C)], and (e) a 4 base pairs-TCTT deletion in codon 41-42 [frameshift mutation (FSC 41-42)]. A scoring system (Tha1 CS) has been formulated to predict clinical severity. It is the type of beta-thalassemia mutation present that decides on the clinical phenotype. The most severe beta-thalassemia mutation is assigned a score of 4. A score of 8 indicates severe thalassemia.

China↗

PubMed1996

Malnutrition and growth abnormalities in children with beta thalassemia major.

Abnormal linear growth (stunting) is characteristic of children with beta thalassemia major and has been variably and inconsistently attributed to multiple different mechanisms. Despite the coexistence of beta thalassemia with deficits of several micronutrients, global undernutrition as a principle cause of growth abnormalities has not been adequately studied. We prospectively studied 115 nonsplenectomized children (6 months-6 years, 54 males, 61 girls) with beta thalassemia major who has not previously received chelation therapy. Most children had abnormal weight-for-age (WAZ) and height-for-age (HAZ) Z scores, however female children had lower WAZ (p < 0.0001) and HAZ (p < 0.02) compared to males. Mild to moderate degrees of acute wasting was also usual, and two males and one female had severe wasting. Severe weight deficits were more prevalent in the youngest (p < 0.01) and severe stunting in the older (p = 0.01) children. Nearly all children were < 50th percentile for both weight-for-age and height-for-age, and the majority were < 5th percentile. Of note, children were also disproportionately distributed below the 50th percentile for weight-for-height. Pre-transfusion hemoglobin was variably associated with anthropometric measurements. We conclude that not only is linear growth failure pervasive in our population with beta thalassemia major, but varying degrees of wasting are also typical. Further, weight deficits occur at an early age and appear to precede deficits in linear growth. Abnormal growth is not due to chelation therapy and is inconsistently associated with the degree of anemia. These patterns of growth abnormalities indicate general malnutrition as an important cause of growth failure in children with beta thalassemia.

Acute Disease↗

PubMed1997

Molecular diagnosis and carrier screening for beta thalassemia.

Thalassemias are common autosomal recessive disorders especially in populations of Mediterranean, Middle Eastern, and Far Eastern descent. Relatively high incidence is also observed in people of Asian Indian origin but the incidence is more limited in those of African descent. Beta Thalassemias are heterogeneous at the molecular level, with more than 150 different molecular defects identified to date. Despite this heterogeneity, each at-risk population has its own spectrum of common mutations, usually from 5 to 10, a finding that simplifies mutation analysis. Homozygosity for beta thalassemias usually results in transfusion-dependent thalassemia major and, rarely, in mild non-transfusion-dependent conditions. Molecular diagnosis may be used to define genotypes associated with mild forms. Advances in carrier diagnosis using hematologic analysis followed by mutation analysis have made possible the population screening of women at childbearing age and prenatal diagnosis. This approach in combination with nondirective genetic counseling has resulted in a consistent decline of the birth of affected homozygotes in several Mediterranean at-risk populations, as well as knowledge of the risks of being a carrier. Molecular diagnosis of homozygotes and identification of carriers of beta thalassemia may lead to improved clinical management of patients with the disorder and prevention of the birth of affected homozygotes.

DNA Mutational Analysis↗

PubMedDate not supplied

Feasibility of molecular diagnosis of alpha-thalassemia in the evaluation of microcytosis.

Microcytosis is a common hematological finding, usually related to iron deficiency or beta-thalassemia. When both of these conditions are excluded, alpha-thalassemia must be considered in the differential diagnosis. No simple biochemical test is able to diagnose the alpha-thalassemia trait. Using PCR amplification of the breakpoint in deletional forms, and amplification of the alpha 2 gene and restriction enzyme digestion in non-deletional forms, we identified the alpha-thalassemia carrier status in 42 out of 51 (82%) patients with microcytosis or slight microcytic anemia, unrelated to iron deficiency or beta-thalassemia. Our results underline the usefulness of molecular tests in clinical practice.

Anemia, Iron-Deficiency↗

PubMed1998

The effect of dietary magnesium supplementation on the cellular abnormalities of erythrocytes in patients with beta thalassemia intermedia.

BACKGROUND AND OBJECTIVE: Reduced serum or erythrocyte Mg have been reported in human beta thalassemia. These deficiencies may play a role in the cellular abnormalities characteristic of this disorder. We have therefore studied the effect of dietary Mg supplementation in patients with beta thalassemia intermedia in order to establish whether it improves the abnormalities of thalassemic erythrocytes. DESIGN AND METHODS: Plasma and erythrocyte Mg were determined in 11 patients with b thalassemia intermedia, not requiring chronic transfusion therapy, and in 17 normal controls. Inclusion criteria included normal renal and liver function and performance status of 70% or greater. Seven patients were enrolled for the Mg supplementation study, after the appropriate informed consent was obtained. They were given a starting dose of 0.6 mEq/kg/day of magnesium pidolate, divided into two oral daily doses, for four weeks. In a 70-kg subject, a daily Mg dose of 42 mEq corresponds to 504 mg of Mg, with the daily Mg intake of normal subjects being 418 +/- 120 mg for males and 343 +/- 94 mg for females. After 28 days of treatment, five of the patients continued the protocol with a daily dosage increased to 1.2 mEq magnesium pidolate/kg/day, divided into two oral administrations, for an additional four weeks. RESULTS: In patients with untransfused beta thalassemia intermedia we found reduced erythrocyte Mg (in mmol/kg Hb, 6.12 +/- 1.5, n = 11 vs. 8.69 +/- 0.89, n = 17, respectively, p < 0.0001) and normal serum Mg. In the seven patients given oral Mg supplements, at Mg dosages of 0.6 mEq/kg/day we observed significant increases in erythrocyte Mg, and significant improvement in some of the characteristic abnormalities of beta that erythrocytes (increased Na-K pump, KCl cotransport, cell dehydration, increased osmotic resistance). These changes were maintained in the 5 patients who were treated with 1.2 mEq of Mg/kg/day. Follow-up studies showed a return to baseline conditions. There were no signs of Mg toxicity, with the only side effect being diarrhea, which was generally mild, but led to discontinuation for one patient after the first four weeks. INTERPRETATION AND CONCLUSIONS: These data indicate that dietary Mg supplementation improves some of the characteristic cellular function abnormalities of b thalassemia intermedia. The possible therapeutic value of this strategy should be further tested in these patients.

Biological Transport, Active↗

PubMed1998

[Thalassemia intermedia caused by interaction of IVS-1 1(G--A) mutation in the beta-globin gene and heterozygotic triplication in the alpha-globin gene].

Thalassemia intermedia is a clinical entity characterized by moderate, non-transfusional anemia and hepatosplenomegaly. This phenotype can result from different genetic combinations and is sometimes present in patients with only one parent showing the thalasemia minor phenotype. We report here a family with seven members with the thalassemia beta trait, four of them with thalasemia minor and the other three with thalassemia intermedia. The genetic study of patients with thalassemia intermedia revealed the presence of the mutation IVS-1 1(G-->A) in the beta-globin gene and the heterozygous triplication of the alpha-globin gene, an uncommon association in Spain. The interaction of a mutation in the beta-globin gene with triplication of the alpha-globin gene should be considered in the diagnosis and genetic counselling in those patients with thalassemia intermedia and one normal parent.

Adolescent↗

PubMed1997

Screening for thalassemia: an economics viewpoint.

Thalassemia presents individual, social and economic burdens: a key question is whether medical and economic viewpoints converge or not. Using precise molecular probes, prenatal diagnosis of the various thalassemia genotypes is available in the case of parents who are known carriers, so identified because of a previous affected child or a positive family genetic history. However, the ideal option of prevention of the birth of a first affected child requires community screening. The only practical approach thereto is prenatal screening of women in early pregnancy at ante-natal clinics (ANC). The initial steps (OF, DCIP) are simple, cheap and easily coupled with standard prenatal procedures. In the second phase, spouse screening, compliance is suboptimal and involves non-routine opportunity costs. Subsequent steps (secondary screening of positive pairs, genotyping of positives, and fetal diagnosis [PND]) represent greater costs to provider and consumer, and, as they are relatively expensive, reduced compliance at each step if the major part of the economic burden (direct and indirect costs) is to be borne by the consumer. Thus, only a proportion of cases is likely to face the final decision to terminate pregnancy or not. Some broad estimates of costs of each phase (ANC-->PND) have been made for comparison with the estimated costs of case management of the several thalassemia disease classes for their projected lifetimes, while several more detailed studies are in progress to fine tune the real costs (direct and indirect) of diagnosis. In a purely economic sense the situation presents opportunity to consider trade-offs between PND and disease case management, in terms of benefit:cost ratio. Viewed from a health systems vantage point this ratio depends substantially on compliance, as the system must consider the cost of caring for all thalassemia cases, including those births which could have been avoided by optimal compliance. In ideal circumstances the rough estimates indicate a probable benefit:cost ratio > 1, supporting the notion of community-based screening. Such a result, however, compares procedures in a short, finite time frame (diagnosis) with a less predictable, longer life-time (case management), requiring bureaucratic flexibility (if the public provider is to pay) or family emotional/fiscal investment (if the consumer is to pay) or both (cost-sharing): either way there is an inescapable element of long term investment planning that requires squaring off of the emotional, social and fiscal ingredients in the equation. In this sense the thalassemia syndromes represent an example of decision-making pathways involved in assessing and handling chronic disease burdens at family, community and national levels: at the latter level regional incidence varies considerably, a geopolitical factor which may require differential demographic planning.

Cost-Benefit Analysis↗