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PubMed2005

[Quantitative analysis of human globin gene expression in beta-thalassemia using real-time RT-PCR].

Whole blood samples were collected from 100 normal healthy adults, from umbilical cord of 33 newborn infants, 111 individuals with beta-thalassemia minor (beta(T)/beta(A),alphaalpha/alphaalpha) and 39 with beta-thalassemia major (beta(T)/beta(T),alphaalpha/alphaalpha). Prior to quantitative analysis of globin gene expression, DNA was extracted from all blood samples and used for beta-thalassemia genotype analysis. Different types of beta globin gene mutations were analyzed using reverse dot blotting (RDB) method. Total RNA were extracted and subjected to real-time RT-PCR for quantitative measurement of alpha, beta and gamma globin mRNA using three sets of primers and fluorescent-labeled probes, designed according to the sequences of alpha, beta and gamma human globin gene. Real-time RT-PCR was performed in ABI 7700 system. Following the real-time RT-PCR, the mean values of alpha, beta and gamma globin mRNA were calculated and the ratios of alpha/beta, alpha/(beta + gamma ) and gamma /(beta + gamma ) were determined to characterize the relative expression levels of different globin genes among normal adult, infant, beta-thalassemia minor and beta-thalassemia major patients. The resultant data were analyzed using SPSS 10.0 software to determine statistical significance of human globin gene expression among normal controls and beta-thalassemia patients. Due to vast variations of the mean globin gene mRNA levels among different groups, log conversion of alpha/beta + 1, alpha/(beta + gamma ) + 1 and gamma /(beta + gamma ) +1 was used for statistical analyses and intergroup comparison. The alpha/beta globin gene mRNA ratios were determined to be 4.62+/-1.20, 7.81+/-2.89, 13.51+/-5.12, and 188.24+/-374.04 for normal healthy adult (beta(A)/beta(A),alphaalpha/alphaalpha), infant (beta(A)/beta(A),alphaalpha/alphaalpha), beta- thalassemia minor (beta(T)/beta(A),alphaalpha/alphaalpha) and beta-thalassemia major(beta(T)/beta(T),alphaalpha/alphaalpha) respectively. The alpha/(beta+ gamma ) ratios were 4.43+/-1.17, 0.56+/-0.49, 9.62+/-4.37, and 2.14+/-1.58 for normal healthy adult (beta(A)/beta(A),alphaalpha/alphaalpha), infant (beta(A)/beta(A),alphaalpha/alphaalpha), beta- thalassemia minor (beta(T)/beta(A),alphaalpha/alphaalpha) and beta- thalassemia major(beta(T)/beta(T),alphaalpha/alphaalpha) respectively. The gamma /(beta+ gamma ) ratios were 0.04+/-0.03, 0.92+/-0.06, 0.28+/-0.18, and 0.95+/-0.04 for normal healthy adult (beta(A)/beta(A),alphaalpha/alphaalpha), infant (beta(A)/beta(A),alphaalpha/alphaalpha), beta- thalassemia minor (beta(T)/beta(A),alphaalpha/alphaalpha) and beta- thalassemia major (beta(T)/beta(T),alphaalpha/alphaalpha) respectively. Following statistical analyses, the alpha/beta and alpha/(beta+ gamma ) globin gene mRNA ratios were significantly different among four different groups (normal adult, normal infant, beta- thalassemia minor and beta- thalassemia major). The gamma /(beta + gamma ) globin gene mRNA ratio was significantly different among all groups except for between infant and beta- thalassemia major patients. Human beta globin gene mRNA levels decrease progressively and dramatically from normal adults to beta-thalassemia patients with beta-thalassemia major having the lowest levels. On the other hand, the gamma globin gene mRNA levels increase progressively from normal adult to beta-thalassemia patients with beta-thalassemia major having the highest levels. Infants have relatively lower levels of beta but higher levels of gamma globin gene mRNA as compared to those in normal adults. Thus, the relative expression levels of alpha, beta or gamma globin genes varied but inter-related among different ages of normal individuals and different beta-thalassemia genotypes.

Adult↗
PubMed2001

The thalassemia syndromes: molecular characterization in the Spanish population.

This work compiles the results of our research on alpha- and beta-thalassemias, and includes a literature review of the molecular genetics of alpha- and beta-thalassemias in Spain. We studied 1,564 subjects with thalassemia (294 with beta-thalassemia and 1,264 with alpha-thalassemia) by molecular biology techniques. In relation to beta-thalassemia, a total of 15 different mutations were characterized in a study of 308 chromosomes belonging to 294 unrelated subjects. Eleven were homozygotes (22 alleles), three compound heterozygotes (6 alleles), and the remaining 280 were heterozygotes (280 alleles). A total of 86.6% of the alleles identified can be grouped into five different mutations [IVS-I-1 (G-->A), IVS-I-6 (T-->C), IVS-I-110 (G-->A), codon 39 (C-->T), codons 8/9 (+G)]. In 14 subjects (4.5%), all heterozygotes, it was not possible to identify the alteration responsible for the beta-thalassemia. For alpha-thalassemia, 911 subjects showed heterozygous alpha(+)-thalassemia (872 with -3.7 kb; 14 with -4.2 kb; two with the deletion of 3.5 kb of DNA, and 23 with nondeletional alpha-thalassemia). Two hundred and thirty-three subjects had homozygous alpha(+)-thalassemia (223 for -alpha(-3.7)/-alpha(-3.7)); one for -alpha(-4.2)/-alpha(-4.2); six for -alpha(-3.7)/-alpha(-4.2); one for -alpha(-3.5)/-alpha(-3.7); one for alphaalpha(Nco)/alphaalpha(Nco); one for alpha(HPh)/alpha(Hph)). One hundred patients presented with heterozygous alpha(0)-thalassemia (18 of whom were progenitors of patients with Hb H disease). The alpha(0) determinant was found in 20 patients with Hb H disease associated with -alpha(-3.7). From the DNA analysis were identified the - -(MED), - -(SEA), - -(SPAN) deletions and the - -(MA) mutations; in three cases, a break that affects the distal portion of the short arm of chromosome 16; one of these was associated with the ATR-16 (alpha-thal with mental retardation) syndrome. Triplication of the alpha genes (alphaalphaalpha(-3.7)/alphaalpha) was found in 25 subjects, 16 of whom were associated with a heterozygous beta-thalassemia. Only one patient was homozygous for the triplication of alpha genes (alphaalphaalpha(-3.7)/alphaalphaalpha(-3.7)) that was associated with a heterozygous beta-thalassemia. In the Mediterranean region preventive programs for thalassemia, based on the detection of heterozygote carriers and genetic advice, are not sufficient to reduce the incidence of newborns with major thalassemia. Prenatal diagnosis of thalassemias has given a new dimension to the prevention of these, but in order to implement this, a knowledge of the mutations and the incidence of these, is essential. This study, therefore, aims to give a general picture of the molecular genetics of thalassemia and its geographical distribution in our area.

Alleles↗
PubMed2004

Thalassemia.

New developments in the epidemiology, treatment and prognosis of thalassemia have dramatically altered the approach to the care of affected patients, and these developments are likely to have an even greater impact in the next few years. Demographic changes have required an awareness and understanding of the unique features of thalassemia disorders that were previously uncommon in North America but are now seen more frequently in children and recognized more consistently in adults. New methods for measuring tissue iron accumulation and new drugs to remove excessive iron are advancing two of the most challenging areas in the management of thalassemia as well as other transfusion-dependent disorders. Improved survival of patients with thalassemia has given new importance to adult complications such as endocrinopathies and hepatitis that have a major impact on the quality of life. This chapter describes how these changes are redefining the clinical management of thalassemia. In Section I, Dr. Renzo Galanello describes recent advances in iron chelation therapy. Several new chelators are either licensed in some countries, are in clinical trials or are in the late stages of preclinical development. Some of these iron chelators, such as deferiprone (DFP) and ICL670, are orally active. Others, such as hydroxybenzyl-ethylenediamine-diacetic acid (HBED) and starch deferoxamine, require parenteral administration but may be effective with less frequent administration than is currently required for deferoxamine. Chelation therapy employing two chelators offers the possibility of more effective removal of iron without compromising safety or compliance. Other strategies for chelation therapy may take advantage of the ability of particular chelators to remove iron from specific target organs such as the heart and the liver. In Section II, Dr. Dudley Pennell addresses cardiac iron overload, the most frequent cause of death from chronic transfusion therapy. The cardiac complications related to excessive iron may result from long-term iron deposition in vulnerable areas or may be due to the more immediate effects of nontransferrin-bound iron. Cardiac disease is reversible in some patients with intensive iron chelation therapy, but identification of cardiac problems prior to the onset of serious arrhythmias or congestive heart failure has proven difficult. New methods using magnetic resonance imaging (MRI) have recently been developed to assess cardiac iron loading, and studies suggest a clinically useful relationship between the results using these techniques and critical measures of cardiac function. Measurements such as T2* may help guide chelation therapy in individual patients and may also enhance the assessment of new chelators in clinical trials. The use of MRI-based technology also holds promise for wider application of non-invasive assessment of cardiac iron in the management of patients with thalassemia. In Section III, Dr. Melody Cunningham describes some of the important complications of thalassemia that are emerging as patients survive into adulthood. Hepatitis C infection is present in the majority of patients older than 25 years. However, antiviral therapy in patients with thalassemia has been held back by the absence of large clinical trials and concern about ribavirin-induced hemolysis. More aggressive approaches to the treatment of hepatitis C may be particularly valuable because of the additive risks for cirrhosis and hepatocellular carcinoma that are posed by infection and iron overload. Thrombosis is recognized with increasing frequency as a significant complication of thalassemia major and thalassemia intermedia, and pulmonary hypertension is now the focus of intense study. Risk factors for thrombosis such as splenectomy are being identified and new approaches to anticoagulation are being initiated. Pregnancies in women with thalassemia are increasingly common with and without hormonal therapy, and require a better understanding of the risks of iron overload and cardiac disease in the mother and exposure of the fetus to iron chelators. In Section IV, Dr. Elliott Vichinsky describes the dramatic changes in the epidemiology of thalassemia in North America. Hemoglobin E-beta thalassemia is seen with increasing frequency and poses a particular challenge because of the wide variability in clinical severity. Some affected patients may require little or no intervention, while others need chronic transfusion therapy and may be appropriate candidates for hematopoietic stem cell transplantation. Enhancers of fetal hemoglobin production may have a unique role in Hb E-beta thalassemia since a modest increase in hemoglobin level may confer substantial clinical benefits. Alpha thalassemia is also being recognized with increasing frequency in North America, and newborn screening for Hemoglobin Barts in some states is leading to early detection of Hb H disease and Hb H Constant Spring. New data clarify the importance of distinguishing these two disorders because of the increased severity associated with Hb H Constant Spring. The use of intrauterine transfusions to sustain the viability of fetuses with homozygous alpha thalassemia has created a new population of patients with severe thalassemia and has raised new and complex issues in genetic counseling for parents with alpha thalassemia trait.

Heart↗
PubMed2005

[Diagnosis of thalassemia by using genechips].

OBJECTIVE: The new technology of genechip is exerting a significant impact on the identification of thalassemia, and allows to rapidly and efficiently detect a number of molecular disorders. The aim of the present study was to explore the application value of the diagnostic genechip in determining thalassemia. METHODS: The subjects group consisted of 62 children with alpha thalassemia and 93 children with beta thalassemia (60 with thalassemia trait, 33 with thalassemia major) from Guangdong province were tested from July 2002 to July 2003; 115 were males and 40 were females, the age ranged from 1 day to 11 years. These children had mild, moderate or severe anemia. Laboratory examinations showed microcytosis and hypochromocytosis. DNA was extracted from ACD coagulated blood with Invisorb DNA extraction kit. After preparation, the alpha and beta globin gene organization and structure of sample was analyzed by genechip technology. RESULTS: (1) Heterozygotes, homozygotes and compound heterozygotes of the three commonest deletional alpha thalassemia (--(SEA), -alpha(3.7), -alpha(4.2)) and two non-deletional alpha thalassemia (HbCS, HbQS) were successfully detected. (2) Eight different mutations were identified in 126 chromosomes among 60 cases with beta thalassemia traits and 33 cases with beta thalassemia major, namely CD41-42, IVS-II-654, TATAbox-28, CD17, CD71-72 (+A), betaE(26) CD27-28 (+C) and CD71-72 (+T), with the frequencies of 33.5%, 23.9%, 15.0%, 15.0%, 4.8%, 2.4%, 2.4% and 1.5% respectively. (3) Eight cases (13.3%) in 60 thalassemia traits, two cases (6%) 33 cases with thalassemia major were detected to be combined with alpha thalassemia mutation. CONCLUSION: (1) The usage of genechip in identifying thalassemia mutations has the advantages of simplicity, economy and shorter time. This technique does not use radioisotope and could also detect alpha and beta thalassemia mutations simultaneously. (2) The occurrence of alpha and beta thalassemia dual heterozygotes is frequent in Guangdong province and the genechip technology is important in genetic counseling and prenatal diagnosis of thalassemia in this area.

Child↗
PubMed2004

Prevalence of thalassemia in pregnant women at Maharaj Nakorn Chiang Mai Hospital.

OBJECTIVE: To determine the prevalence of thalassemia including alpha-thalassemia-1 trait (SEA type), beta-thalassemia trait, hemoglobin E (HbE) trait, homozygous HbE, the combination of alpha-thalassemia-1 (SEA type) and beta-thalassemia trait, alpha-thalassemia-1 (SEA type) and hemoglobin E trait, and beta-thalassemia hemoglobin E disease in pregnant women. METHOD: A cross-sectional descriptive study was conducted on pregnant women who attended the antenatal clinic at Maharaj Nakorn Chiang Mai Hospital, from 1 August to 31 October 2001. All subjects had blood taken for diagnosis of thalassemia trait or diseases, based on quantitative electrophoresis, and PCR (polymerase chain reaction) technique RESULTS: 516 pregnant women were recruited 81.0% resided in Chiang Mai province, and the remainder were in other northern provinces of Thailand. The mean (+/-SD) age was 27.7+/-6.3 years old. 5.6% of cases had anemia. Overall prevalence of thalassemia trait was 25.4% which were classified as follows: alpha-thalassemia-1 (SEA type) trait 6.6%, beta-thalassemia trait 3.7%, hemoglobin E trait 11.6%, homozygous hemoglobin E 0.8%, the combination of alpha-thalassemia-1 (SEA type) and beta-thalassemia trait 1.2% and the combination of alpha-thalassemia-1 (SEA type) and hemoglobin E trait 1.5%. Additionally, the authors also found beta-thalassemia hemoglobin/E disease 0.2%. CONCLUSION: The prevalence of thalassemia carriers among pregnant women at Maharaj Nakorn Chiang Mai hospital was high, indicating the necessity of a screening thalassemia program aimed at prevention and control of this disease.

Adolescent↗
PubMed2001

The studies of hemoglobinopathies and thalassemia in China--the experiences in Shanghai Institute of Medical Genetics.

BACKGROUND: In the past two decades, a large-scale survey of hemoglobinopathies and thalassemia was carried out in mainland China, involving nearly one million people in 28 provinces. The incidences of hemoglobin (Hb) variants, alpha-thalassemia and beta-thalassemia were 0.33%, 2.64% and 0.66%, respectively. The chemical structural analysis identified 67 Hb variants. Among them, 20 are new variants. The analysis of the alpha-globin gene organization in 111 HbH patients showed 76 cases (68.5%) were of the deletion type, 8 had Hb Constant Spring and the other cases were of non-deletion type. The results of the molecular characterization of more than 200 beta-thalassemia alleles showed that the most common types of beta-thalassemia mutations in China are CD 41/42 (-4 bp), IVS-II-nt.654 C-->T, CD 17 A-->T, CD 71/72 (+A) and -28 A-->G. METHODS: To explore the simple method for molecular diagnosis of beta-thalassemia, multiplex allele-specific amplification (MAS-PCR) was used that could simultaneously detect the above five common types of beta-thalassemia mutations. RESULTS: Based on the molecular analysis of beta-thalassemia intermedia, beta-thalassemia homozygotes or compound heterozygotes combined with alpha-thalassemia, as well as the conjunctive abnormalities of beta-thalassemia heterozygote with triplicated haplotype of alpha-globin genes, were the most common cause of thalassemia intermedia in China. We also used the RT-PCR quantitation method to show that the most common beta-thalassemia allele, IVS-II-nt.654 C-->T, still produced a small amount (about 15%) of normally spliced beta-globin mRNA, therefore, causing beta+-thalassemia. In clinical trials of hydroxyurea (HU) treatment for beta-thalassemia patients, we found that HU may enhance the expression of the beta-globin gene in some patients, leading to an alleviation of clinical symptoms. In the studies of the reversal of aberrant splicing of IVS-II-nt.654 C-->T allele by the antisense approach, we constructed a mammalian expression vector that can produce an antisense RNA targeting against the aberrant splice sites of IVS-II-nt.654 C-->T pre-mRNA. CONCLUSIONS: The results indicated that the antisense RNA produced from the vector could efficiently suppress the aberrant splicing pattern and restore the correct splicing pathway in vitro and in vivo, leading to the improvement of globin chain biosynthesis in thalassemia cells.

China↗
PubMed1994

The molecular basis of normal HbA2 (type 2) beta-thalassemia in Greece.

Heterozygotes for beta-thalassemia usually have raised levels of HbA2, but in Greece about 5% of beta-thalassemia carriers are observed to have normal or borderline levels. It is postulated that such cases have mild beta+ thalassemia mutations or coinheritance of delta-thalassemia. We selected 18 heterozygotes with the hematological phenotype of normal HbA2 (type 2) beta thalassemia who were negative for the delta beta Corfu mutation, and screened them for previously defined Mediterranean beta-thalassemia and delta-thalassemia mutations. The coinheritance of beta and delta-thalassemia was demonstrated in four cases with the following genotypes: in cis beta+ IVSII -n745/delta+ 27, beta 0NS39/delta 059(-A), beta+ IVSI-n110/delta 059(-A) and in trans beta+ IVSI-n6 and delta+ 27. A further nine heterozygotes had mild beta(+)-thalassemia mutations (eight with the beta+ IVSI-n6 mutation, one with the beta+ polyA (A-->G) mutation). In four heterozygotes with severe beta-thalassemia chromosomes (2 beta+ IVSI-n110, 1 beta 0 FSC-6, 1 beta 0 IVSI-n1) no known delta-thalassemia mutations were observed. One case had a delta beta deletion chromosome. These results indicate that the hematological phenotype of normal HbA2 (type 2) beta-thalassemia in Greece is genetically heterogeneous; it is mainly associated with the delta beta Corfu mutation or coinheritance of beta and delta thalassemia mutations or with very mild beta(+)-thalassemia mutations, mainly beta+ IVSI-n6. In the rare cases with severe beta-thalassemia mutations, the normal levels of HbA2 may be due to coinheritance of as yet undefined delta thalassemia mutations.

Base Sequence↗
PubMed1998

Molecular study and prenatal diagnosis of alpha- and beta-thalassemias in Chinese.

Thalassemia is one of the most common single gene diseases worldwide. Populations in southern China and Taiwan have high prevalence rates of alpha- and beta-thalassemias. This review summarizes the current status of molecular studies, carrier screening, and prenatal diagnosis of thalassemia in Chinese. There are three genotypes of alpha-thalassemia 1 and at least six of alpha-thalassemia 2 in Chinese. For alpha-thalassemia 1, the South-East Asian deletion is the most common, followed by the Thai then Philippino deletions. For alpha-thalassemia 2, the rightward deletion is the most common, followed by the leftward deletion, and the nondeletional defects Hb Constant Spring and Hb Quong Sze. Twenty-eight different beta-thalassemia mutations have been reported. Four mutations, IVS-II-654 (C-->T), codons 41/42 frameshift (-TCTT), and nonsense codons 17 (A-->T) and -28 (A-->G), account for more than 90% of mutant alleles. For detection of alpha-thalassemia, polymerase chain reaction-related techniques are mainly used. Southern blot hybridization is still useful, especially for prenatal diagnosis. For detection of beta-thalassemia mutations, analysis of amplification-created restriction sites and reverse dot blot hybridization have been extensively used. In Taiwan, a national screening program incorporating hematological and molecular biological methods for thalassemia detection in pregnant women has been in progress for 5 years. Prenatal diagnosis has been performed in more than 1,800 pregnancies, including 1,500 cases at risk for homozygous alpha-thalassemia 1 and 300 for beta-thalassemia major, resulting in early prenatal diagnosis and termination of pregnancies affected with homozygous alpha-thalassemia 1 and an approximately 70% decrease in the number of newborns affected with beta-thalassemia major. In mainland China, only one large-scale screening program is in place. Characterization of undefined alleles, a higher awareness of the disease among physicians and the general public, and improvement of the service network will be important for early prenatal diagnosis and prevention of the disease in the future.

China↗
PubMed1996

Molecular characterization of beta-thalassemia mutations in Guadeloupe.

In order to perform genetic counselling and prenatal diagnosis of Hb-S-beta-thalassemia disease and beta-thalassemia, we have delineated the spectrum of beta-thalassemia alleles in the Guadeloupean population. A sample of 63 unrelated families was analyzed including 70 beta-thalassemia carriers, 52 Hb-S-beta-thalassemia, and 8 patients with different beta-thalassemic hemoglobinopathies. Among the eleven mutations identified, four of them [-29 (A --> G), IVS-I-5 (G --> A), IVS-II-1 (G --> A), and IVS-I-5 (G --> C)] account for 77.6% of the beta-thalassemia chromosomes present in the studied families. The seven other variants, CD 24 (T --> A), IVS-I-2 (T --> C), Poly A (T --> C), -88 (C --> T), IVS- 11-849 (A --> G), Hb E, and Hb Lepore are less frequent. As a result, Hb S-beta+-thalassemia type 1 (low Hb A values: 5-15%) together with Hb S-beta(omicron)-thalassemia phenotypes are as frequent as Hb S-beta+-thalassemia type 2 (high Hb A values: 20-30%) in the Guadeloupean population. Patients with Hb S-beta+-thalassemia type 2 have milder hematological manifestations of the disease compared to patients with Hb S-beta(omicron)-thalassemia and Hb S-beta+-thalassemia type 1. This first report on the type and nature of beta-thalassemia mutations in Guadeloupe shows that prenatal diagnosis of Hb S-beta-thalassemia and beta-thalassemia should be feasible by direct detection of point mutation in most cases.

Africa, Western↗
PubMed2001

Combine-ARMS: a rapid and cost-effective protocol for molecular characterization of beta-thalassemia in Malaysia.

Beta-thalassemia major patients have chronic anemia and are dependent on blood transfusions to sustain life. Molecular characterization and prenatal diagnosis of beta3-thalassemia is essential in Malaysia because about 4.5% of the population are heterozygous carriers for beta-thalassemia. The high percentage of compound heterozygosity (47.62%) found in beta-thalassemia major patients in the Thalassaemia Registry, University of Malaya Medical Centre (UMMC), Malaysia, also supports a need for rapid, economical, and sensitive protocols for the detection of beta-thalassemia mutations. Molecular characterization of beta-thalassemia mutations in Malaysia is currently carried out using ARMS, which detects a single beta-thalassemia mutation per PCR reaction. We developed and evaluated Combine amplification refractory mutation system (C-ARMS) techniques for efficient molecular detection of two to three beta-thalassemia mutations in a single PCR reaction. Three C-ARMS protocols were evaluated and established for molecular characterization of common beta-thalassemia mutations in the Malay and Chinese ethnic groups in Malaysia. Two C-ARMS protocols (cd 41-42/IVSII #654 and -29/cd 71-72) detected the beta-thalassemia mutations in 74.98% of the Chinese patients studied. The CARMS for cd 41-42/IVSII #654 detected beta-thalassemia mutations in 72% of the Chinese families. C-ARMS for cd 41-42/IVSI #5/cd 17 allowed detection of beta-thalassemia mutations in 36.53% of beta-thalassemia in the Malay patients. C-ARMS for cd 41-42/IVSI #5/cd 17 detected beta-thalassemia in 45.54% of the Chinese patients. We conclude that C-ARMS with the ability to detect two to three mutations in a single reaction provides more rapid and cost-effective protocols for beta-thalassemia prenatal diagnosis and molecular analysis programs in Malaysia.

Asian People↗
PubMed1977

Genetic patterns in thalassemia intermedia (constitutional microcytic anemia). Familial, hematologic and biosynthetic studies.

Globin chain synthesis has been studied in 17 patients with thalassemia intermedia, and their relatives, also investigated by routine hematologic and hemoglobinic tests. The mean a/non a ratio was always around 2.20-2.30. In patients with severe thalassemia major, used as a control, the mean a/non a ratio was significantly higher, that is 3.11-3.07. Therefore, the hypothesis that the cause of the lesser severity of the thalassemia intermedia is a lesser imbalance of globin chain synthesis, is suggested. One or both the parents of patients with thalassemia intermedia have mild beta-thalassemia and normal alpha/beta ratio, whereas the parents of patients with severe thalassemia major show a marked beta-thalassemia and a mean alpha/beta ration of 1.76. These data suggest that genes for beta +-thalassemia are responsible for thalassemia intermedia, and genes for beta o-thalassemia are responsible for thalassemia major. In two patients with thalassemia intermedia, the association of an alpha-thalassemia gene with homozygous beta-thalassemia that it is well known to reduce the globin chain imbalance typical of the beta-thalassemia, has also been observed.

Adolescent↗
PubMed1991

Thalassemias in Sardinia: molecular pathology, phenotype-genotype correlation, and prevention.

This article reviews the molecular bases of alpha- and beta-thalassemias in Sardinia. In addition, it describes the characteristics and the effects of a genetic program designed to prevent homozygous beta-thalassemia. In the large majority of the cases (95.7%), beta-thalassemia is caused by the nonsense mutation at codon 39, followed by frameshifts at codon 6 (2.1%). Homozygous beta-thalassemia most commonly results in thalassemia major, but in a small proportion this genotype produces milder forms referred to as thalassemia intermedia. The reasons for the attenuated forms were determined only in a small proportion of the cases. The reduced clinical severity was due to either of two factors: (a) There could be the presence of cytosine-thymidine (C----T) substitution of position - 158 G gamma, which is able to increase the G gamma chain output (as in homozygotes for frameshift at codon 6 or compound heterozygote for frameshift at codon 6 and codon 39 nonsense mutation). (b) Reduced clinical severity could be the result of co-inheritance of alpha-thalassemia in the form of two alpha-globin gene deletions of functional loss of the alpha 2-globin gene (homozygote for codon 39 nonsense mutation). The most prominent clinical form of alpha-thalassemia is hemoglobin H disease, which may result from the compound heterozygous state for deletion alpha 0- and alpha(+)-thalassemia (in 83.1% of cases) or deletion and nondeletion alpha-thalassemia (in 16.9%). Deletion Hb disease shows a milder clinical picture as compared to the nondeletion form. The most common nondeletion alpha-thalassemia is the ATG----ACG substitution at the initiation codon of the alpha 2 gene. Double heterozygotes of alpha (-alpha/-alpha) and beta-thalassemia or delta- and beta-thalassemia are relatively common and may cause confusion in carrier identification. The preventive program aimed to control beta-thalassemia is based on voluntary carrier screening., counselling, and prenatal diagnosis. Prenatal diagnosis is carried out by dot blot analysis with allelic specific oligonucleotides on amplified trophoblast DNA. This procedure gave very reliable results; in fact, no misdiagnosis has occurred so far. The preventive program was highly effective, resulting in a decline of the incidence of thalassemia major from 1:250 to 1:1,000 live births.

Base Sequence↗
PubMed2006

[Relationship between the genotype and hematologic characteristics in the fetuses with thalassemia].

OBJECTIVES: To investigate the relationship between the genotype and the hematologic characteristics in the fetuses with different types of thalassemia. METHODS: Fetal blood samples were taken by cordocentesis, and hemograms from 572 fetuses at the gestational age of 18 to 38 weeks were examined. According to the genotypes of thalassemia, there were 117 fetuses with heterozygous alpha-thalassemia-1, and 60 with homozygous alpha-thalassemia-1. Twenty had beta-thalassemia mild, and 9 had beta-thalassemia major, respectively. The hematological parameters in these groups were compared with reference group in which 366 cases were included. RESULTS: In alpha-thalassemia groups, hemoglobin (Hb), hematocrit (HCT), mean cell volume (MCV), mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC) significantly decreased (P < 0.001), but in heterozygous alpha-thalassemia-1, red blood cell (RBC) increased. In homozygous alpha-thalassemia-1, RBC decreased significantly (P < 0.001), but white blood cell and nucleated erythrocyte increased (P < 0.001). There were no significant differences between beta-thalassemia and reference group in most hematological parameters except for decrease of MCHC. CONCLUSIONS: In the fetal period, the hemogram of the fetuses with alpha-thalassemia changes significantly, while it does not change in beta-thalassemia. For the couple with heterozygous alpha-thalassemia, hemogram can provide some information for prenatal screening and diagnosis for those fetuses with alpha-thalassemia, especially for homozygous, but genotype detection is necessary for confirming the diagnosis.

Blood Cell Count↗
PubMedDate not supplied

Molecular characterization of homozygous (high HbA2) beta-thalassemia intermedia in Greece.

Homozygous beta-thalassemia is usually characterized by severe anemia requiring regular blood transfusion for survival. For homozygous patients with milder clinical manifestations and no dependence on transfusion therapy, the term thalassemia intermedia is usually applied. Genetic mechanisms that may ameliorate the clinical expression of homozygous beta-thalassemia include coinheritance of alpha-thalassemia, inheritance of mild beta-globin gene mutations, and increased gamma-globin chain production, which may partially compensate for the lack of beta-globin chain synthesis. To identify which of these factors may contribute to the modification of childhood homozygous, high-hemoglobin A2 (HbA2) beta-thalassemia in Greece, the interaction of alpha-thalassemia, types of beta-thalassemia mutations, and the presence of a polymorphic site 5' to the G gamma-globin gene, which has been described as associated with increased gamma-globin chain production in some cases, was assessed. The results were analyzed in light of similar studies in 150 randomly selected, homozygous, high-HbA2 beta-thalassemia patients with the aim of assessing whether thalassemia genotypes can provide information useful for prognosis and/or more appropriate management of homozygous beta-thalassemia patients. The results indicate that, in general, the major factor modifying the clinical expression of homozygous, high-HbA2 beta-thalassemia in Greece is the inheritance of mild beta-thalassemia mutations. Although there is not always a complete correlation of genotype with clinical phenotype, the inheritance of two mild beta-thalassemia alleles results in almost all cases (11 of 12 cases in this study) in thalassemia intermedia phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗
PubMed2001

Clinical phenotype of triplicated alpha-globin genes and heterozygosity for beta0-thalassemia in Chinese subjects.

The presence of extra copies of alpha-globin gene has been shown to worsen the degree of anemia in beta-thalassemia heterozygotes. We describe the clinical phenotype of eight Chinese subjects with heterozygosity for both triplicated alpha-globin gene and a beta0-thalassemia allele. They were identified through genotyping of beta-thalassemia intermedia and major patients, and through community-based thalassemia screening program in Hong Kong. Standard molecular techniques were used in the determination of genotype. All subjects in this series showed five copies of alpha-globin genes (alphaalphaalpha/alphaalpha) in association with a beta0-thalassemia allele. Although genotypically identical, six subjects showed a beta-thalassemia intermedia phenotype while two were clinically indistinguishable from beta-thalassemia minor, implying the presence of genetic modifying factors that remained undefined. Triplication of alpha-globin gene and heterozygosity for beta0-thalassemia accounted for 15% of beta-thalassemia intermedia patients at our locality and was associated with a mild clinical phenotype. This genotype was not found among beta-thalassemia major patients. They presented in adulthood and were usually not transfusion dependent. When compared with simple beta-thalassemia heterozygotes, they showed obvious red cell abnormalities (hypochromasia, anisopoikilocytosis, circulating normoblasts), lower hemoglobin (Hb) and higher HbF levels. The presence of triplicated alpha-globin genes should always be considered in apparent beta-thalassemia carriers who were more symptomatic than expected, so that unnecessary investigations for the cause of anemia could be avoided. Finally, triplication of alpha-globin genes should be looked for in families with children affected by beta-thalassemia intermedia in which only one parent showed a picture of beta-thalassemia on Hb analysis.

Adolescent↗
PubMed1994

Oxidative damage and erythrocyte membrane transport abnormalities in thalassemias.

Oxidative damage induced by free globin chains has been implicated in the pathogenesis of the membrane abnormalities observed in alpha and beta thalassemia. We have evaluated transport of Na+ and K+ in erythrocytes of patients with thalassemias as well as in two experimental models that use normal human red blood cells, one for alpha thalassemia (methylhydrazine treatment, alpha thalassemia like) and one for beta thalassemia (phenylhydrazine treatment, beta thalassemia like). With the exception of the Na-K pump, similar alterations in membrane transport were observed in thalassemia and thalassemia-like erythrocytes. These were: increased K-Cl cotransport, Na-Li countertransport and reduced Na-K-Cl cotransport. The Na-K pump was reduced in thalassemia-like cells, whereas it was increased in severe alpha thalassemia and in beta thalassemia cells. The increased K-Cl cotransport activity could be observed in light and dense fractions of beta-thalassemic cells. K-Cl cotransport in thalassemic and thalassemia-like erythrocytes was partially inhibited by [(dihydro-indenyl) oxy] alkanoic acid and completely abolished by dithiothreitol. Thus, oxidative damage represents an important factor in the increased activity of the K-Cl cotransport observed in thalassemias, and of the K+ loss observed in beta-thalassemia erythrocytes.

Chlorides↗
PubMed1997

Prenatal diagnosis of thalassemia in the Chinese.

There is a high prevalence of thalassemia in the Taiwan area. Prenatal diagnosis of severe forms of thalassemia is important for the prevention of this disease. We performed prenatal diagnosis in 167 cases, of which 59 cases were diagnosed by chorionic villi biopsy, 91 cases by amniotic fluid analysis, and 17 cases by cord blood analysis. Hb Bart's hydrops was detected by amplifying the break junction area of the alpha-thalassemia-1 Southeast Asia (SEA)-type gene, and beta-thalassemia major was detected by using naturally occurring restriction sites and the amplified created restriction sites (ACRS) method. Screening for hemoglobin (Hb) Bart's hydrops revealed 26 cases of Hb Bart's hydrops, 67 cases of alpha-thalassemia-1 (including 6 Hb Bart's hydrops falsely diagnosed as alpha-thalassemia-1 from chorionic villi samples), and 38 normal cases. Screening for beta-thalassemia major revealed 8 cases of beta-thalassemia major, 17 cases of beta-thalassemia minor, and 11 normal cases. In cases of alpha-thalassemia, maternal tissue contamination in the chorionic villi samples occurred in the diagnosis of the carrier state and further amniotic fluid analysis will be necessary. There were no any false-positive or false-negative results in beta-thalassemia major screening. We conclude that prenatal diagnosis is a reliable and accurate screening method for thalassemia and may be valuable in other areas of high prevalence for thalassemia in Southeast Asia and in Southern China.

Gene Frequency↗
PubMed2002

Thalassemia and abnormal hemoglobin.

Thalassemia and abnormal hemoglobins are common genetic disorders in Asia. Thalassemia is not only an important public health problem but also a socio-economic problem of many countries in the region. The approach to deal with the thalassemic problem is to prevent and control birth of new cases. This requires an accurate identification of the couple at high risk for thalassemia. However, the diagnosis of thalassemia carrier states need several tests which are not practical for screening the population at large. Recently we have used two simple laboratory tests to screen for potential thalassemia carriers and hemoglobin E individuals. There is also a new development in using the automatic HPLC to diagnose thalassemic diseases and the carriers. This system gives both qualitative and quantitative analysis of hemoglobin components in the same run with good precision and reproducibility. The system has been applied to study thalassemia and abnormal Hb in adult and cord blood. This system has enabled us to do both prenatal and postnatal diagnosis of thalassemia within the few minutes. However, none of these screening tests can accurately give specific diagnosis of the thalassemia genotype. Specific thalassemia mutation can be carried out by DNA analysis. Many DNA techniques have been used for point mutation detection and small deletion. For the last few years there is a development of DNA chip technology that has been applied for thalassemia mutation as well. Clinically, thalassemia is very heterogeneous in the manifestation. In spite of seemingly identical genotypes, severity of beta thalassemic patients can vary greatly. Heterogeneity in the clinical manifestation of beta thalassemic diseases may occur from the nature of beta globin gene mutation, alpha thalassemia gene interaction and difference in the amount of Hb F production which is partly associated with a specific beta globin haplotype. However, there is still some beta thalassemia cases that have a mild clinical symptom without those known genetic fators interaction suggesting that there are other additional factors responsible for the mildness of the disease.

Asia↗