Alpha hemoglobinophaties in Rosario, Argentina (original) (raw)
Related papers
European Journal of Haematology, 2010
Nowadays, haemoglobinopathies are the most common recessive traits in rapidly evolving multiethnic societies, and a correct diagnosis of these diseases are a matter of concern in many countries organising prevention either at the preconception level, in early pregnancy or after neonatal screening (1). Many problems are associated with the different interventions, and the recognition of the carriers at the laboratory level is one of them. Analysis based on haemoglobin (Hb) separation methods is reliable for the recognition of the common traits and diseases associated with Hbs S [b6(A3)Glu fi Val], C [b6(A3)Glu fi Lys], E [b26(B8)Glu fi Lys], D Punjab [b121(GH4) GlufiGln] and high Hb A 2 b-thalassaemia (b-thal). However, although the degree of sensitivity and specificity is high, provisional results have to be confirmed at the molecular level, especially in case of risk assessment or treatment. Moreover, carriers of these traits are usually not, or just slightly, anaemic, and this will prevent these carriers from being selected for laboratory analysis in the preconception phase, unless the local general practitioner also considers ethnic origin as an indication for carrier analysis (1). Because in most European countries the main reason for referral to the local laboratories is microcytic hypochromic anaemia not responding to iron therapy, the laboratories will usually identify carriers of high Hb A 2 b-thal and suspect a-thal carriers, but carriers of one of the common abnormal Hbs mentioned earlier will be referred for analysis only when associated with some anaemia which is mostly because of a coexisting a-thal.
Frequency and spectrum of hemoglobinopathy mutations in a Uruguayan pediatric population
Genetics and Molecular Biology, 2013
Hemoglobinopathies are the most common recessive diseases worldwide but their prevalence in Uruguay has not been investigated. In this study, 397 unrelated outpatient children from the Pereira Rosell Hospital Center (CHPR), as well as 31 selected patients with microcytic anemia and 28 b-thalassemia carriers were analyzed for hemoglobinopathies by using biochemical and molecular biology methods. Parametric and non-parametric methods were used to compare the hematological indices between groups of genotypes. Of the 397 patients in the first group, approximately 1% (0.76% HbS and 0.25% b-thalassemia) had a mutation in the HBB gene and 3.3% had a-thalassemia. These mutations had a heterogeneous distribution that varied according to individual ancestry. HbS was found exclusively in individuals with declared African ancestry and had a carrier frequency of 2.2%. The frequency of a-thalassemia carriers in outpatients of European and African ancestry was 1.2% and 6.5%, respectively. In contrast, the frequency of a-thalassemia carriers in patients with microcytic anemia was 25.8%, significantly higher (p < 0.01) than that observed in the sample as a whole and in Afro-descendants and Euro-descendants. Significant differences were observed in the hematological parameters between individuals with thalassemia genotypes and those with a normal genotype. These results indicate that hemoglobinopathies are a relevant health problem in Uruguay.
A complex haemoglobinopathy diagnosis in a family with both βo- and αo/+-thalassaemia homozygosity
European Journal of Human Genetics, 1999
The occurrence of point mutation α-thalassaemia and of complex combinations of haemoglobin defects is underestimated. Haemoglobinopathies, the most frequent monogenic recessive autosomal disorder in man, occur predominantly in Mediterranean, African and Asiatic populations. However, countries of immigration with a low incidence in the indigenous population, are now confronted with a highly heterogeneous array of imported defects. Furthermore, the occurrence of severe phenotypes is bound to increase in the near future because of the endogamous growth of the ethnical minorities and the lack of prevention. We describe an Afghan family in which both partners of a consanguineous relationship are carriers of a-as well as an α-thalassaemia determinant. The combination of defects was revealed by the in vitro measurement of the /α biosynthetic ratio and was characterised at the DNA level. The molecular defects involved are the Cd5(-CT), a Mediterranean o-thalassaemia mutation, and the α o/ + 2-thalassaemia AATA(-AA) polyadenylation defect. The α-thalassemia defect is a rare RNA-processing mutant described only twice before in heterozygous form in Asian-Indian patients. The mutation suppresses the expression of a α 2 gene and reduces the expression of the less efficient, 3' located α 1 gene as well, inducing a near α o-thalassaemia phenotype. This defect is now described for the first time in the homozygous condition in one of the children who, in addition to being homozygous for the α-thalassaemia point mutation, is also a carrier of the o-thalassaemia defect. A previously described homozygous case of the α o/ +-thalassaemia condition, caused by a similar polyadenylation defect, was characterised by a severe HbH disease. However, the patient described here present at 7 years of age with severe caries, like his-thalassaemia homozygous brother but without hepatosplenomegaly, haemolysis or severe anaemia. The haematological analysis revealed 9.5 g/dl Hb; 5.4 ؋ 10 12 /I RBC; 0.33 I/I PCV; 61 fl MCV; 17.6 pg MCH and 6.2% of HbA 2. The biosynthetic ratio :α was 1.6 and no HbH fraction was detectable either on electrophoresis or as inclusion bodies. The
Molecular and hematological profiles of hemoglobin EE disease with different forms of α-thalassemia
Annals of Hematology, 2006
We describe hematologic and DNA characterization of hemoglobin (Hb) E homozygote with various forms of α-thalassemia in Thai individuals. Altogether, 131 unrelated adult subjects with Hb EE at routine Hb analysis were studied. Forty-two cases were found to carry α-thalassemia with ten different genotypes. These included 21 cases with α +-thalassemia heterozygote (-α 3.7 /αα), one case with α +-thalassemia heterozygote (-α 4.2 /αα), six cases with Hb Constant Spring heterozygote (α CS α/αα), four cases with homozygous α +thalassemia (-α 3.7 /-α 3.7), one case with homozygous α +-thalassemia (-α 4.2 /-α 4.2), two cases with compound α +-thalassemia/Hb Constant Spring (-α 3.7 /α CS α), one case with compound α +-thalassemia/Hb Paksé (-α 3.7 /α PS α), four cases with α 0-thalassemia heterozygote (-SEA /αα), and, unexpectedly, two cases with compound α 0-thalassemia/α +-thalassemia [(-SEA /-α 3.7) and (-SEA /-α 4.2)]. The hematological expression of these Hb E homozygotes with various forms of αthalassemia was presented comparatively with those of the 89 cases of pure Hb E homozygotes. Overlapping levels of Hb E, Hb F, and other hematological parameters were observed which did not predict clinical severity, indicating a need for α-globin gene analysis for accurate diagnosis and improved genetic counseling.
b-Thalassemia (b-thal) is a hemolytic anemia that is caused by point mutations in most cases. The Brazilian population is highly heterogeneous and knowledge of the mutations that make up the genotypic profile of individuals can contribute information about the formation of the population and clinical condition of patients. In this study, we evaluated the mutations present in homozygous b-thal patients from Rio de Janeiro, Brazil. We analyzed 24 samples of peripheral blood of patients with homozygous b-thal. To identify the mutations, we carried out allele-specific-polymerase chain reaction (AS-PCR) and DNA sequencing. We found 11 different mutations on the b-globin gene. Among the most frequent mutations observed were HBB: c.92 þ 6T>C, followed by HBB: c.93-21G>A, HBB: c.118C>T and HBB: c.92 þ 1G>A. We also identified the rare mutation HBB: c.75T>A that was reported in an individual carrying Hb S (HBB: c.20A>T)/b-thal (HBB: c.75T>A) but not in Brazilian thalassemic patients, thus, this is the first report of this mutation in Brazilian b-thal patients. For its multiethnic character, Brazil has different mutations that cause b-thal and that are distributed with different frequencies according to the regions of the country. Our findings contribute to the description of the mutational profile of Brazilian thalassemic patients, showing wide heterogeneity and genetic variability.
2014
Background: β-thalassemias are prevalent heritable single gene disorders affecting the quantity of the hemoglobin molecule. Rarely, a co-inheritance of these impairments with α-thalassemia and/or a hemoglobinopathy occurs and makes an important double heterozygote or homozygous state. Thus finding these cases is essential for genetic counseling. The present study aimed to identify the prevalence of coexistent α-thalassemia mutations, hemoglobinopathies, and β-thalassemia determinants. Methods: This descriptive study was performed on 5760 patients. We used complete blood cell count, Hb electrophoresis, and HbA2 measurement for thalassemia carrier identification. Increased HbA 2 (≥ 3.5%) is the standard diagnostic marker for β-thalassemia, while normal HbA 2 with low MCH and MCV can indicate an α-thalassemia carrier or atypical β-thalassemia minor. Individuals with MCV ˂ 80 fL, MCH ˂ 27 pg, and hemoglobin ≤ 15.3 g/dL in men or ≤ 14 g/dL in women, were candidates for molecular thalassemia investigations. Patients with abnormal hemoglobin varieties in hemoglobin electrophoresis were referred to a genetics laboratory for hemoglobinopathy detection. Results: 141 subjects out of 5760 were affected by α and β-thalassemia or a β-hemoglobinopathy simultaneously, including: 13 (11.1%) fetuses, 55 (38.2%) male cases, and 73 (50.7%) females. Among these 141 α-thalassemia patients, 92 cases (65.24% ) were β-thalassemia carriers and 3 (2.12% ) were β-thalassemia major, 43(30.49%) had β-hemoglobinopathies, and 3 cases (2.12%) had co-inherited β-thalassemia and variant hemoglobins. 31 β-gene mutations were observed in this population, the most common being HbS Cd6 (A > T) ( 24%). These thalassemia determinants account for about 46% of all detected mutations. As for α-gene mutations, -3.7 detection was the most prevalent. Conclusions: The relatively high prevalence of co-inherited α-thalassemia and hemoglobinopathies among β-thalassemia carriers indicates the importance of molecular analysis to diagnose these double heterozygous or sole homozygous cases for prenatal diagnostic purposes and putting forth strategies to prevent more complicated and dangerous combinations. (Clin. Lab. 2014;60:941-949.
Laboratory Investigation of Hemoglobinopathies and Thalassemias: Review and Update
Clinical Chemistry, 2000
Structural hemoglobin (Hb) variants typically are based on a point mutation in a globin gene that produce a single amino acid substitution in a globin chain. Although most are of limited clinical significance, a few important subtypes have been identified with some frequency. Homozygous Hb C and Hb S (sickle cell disease) produce significant clinical manifestations, whereas Hb E and Hb D homozygotes may be mildly symptomatic. Although heterozygotes for these variants are typically asymptomatic, diagnosis may be important for genetic counseling. Thalassemia, in contrast, results from quantitative reductions in globin chain synthesis. Those with diminished -globin chains are termed -thalassemias, whereas those with decreased ␣-chain production are called ␣-thalassemias. Severity of clinical manifestations in these disorders relates to the amount of globin chain produced and the stability of residual chains present in excess. The thalassemia minor syndromes are characterized clinically by mild anemia with persistent microcytosis. Thalassemia intermedia (i.e., Hb H disease) is typified by a moderate, variably compensated hemolytic anemia that may present with clinical symptoms during a period of physiologic stress such as infection, pregnancy, or surgery. The thalassemia major syndromes produce severe, life-threatening anemia. ␣-Thalassemia major usually is incompatible with extrauterine life; -thalassemia major presents in infancy and requires life-long transfusion therapy and/or bone marrow transplantation for successful control of the disease. Double heterozygosity for certain structural variants and/or thalassemia syndromes may also lead to severe clinical disease. Several guidelines have been published that outline the required steps for hemoglobinopathy and thalassemia investigation. The availability of HPLC has streamlined many of these requirements, allowing an efficient stepwise diagnostic strategy for these complex disorders.
Indian Journal of Clinical Biochemistry, 2017
a-Thalassemia (a-thal) is considered as the most common inherited hemoglobin disorder worldwide. The present study describes the first observation of a combination of rare a-chain variants, and b-globin gene cluster deletion. A 21-year-old woman with thalassemia trait, marked microcytosis, mild anemia, and normal range of Hb F was referred to Amirkola genetic center in the North of Iran for routine molecular test of thalassemia in the context of carrier detection and prevention of thalassemia major birth. Nucleotide sequencing revealed a novel compound heterozygosity status for two non-deletional mutations on HBA2, Hb O Indonesia (a116(GH4)Glu ? Lys), and Hb Matsue-Oki (a75 (EF4) Asp ? Asn), together with heterozygosity for the sicilian (db) 0-thal mutation. This finding highlights the necessity of deep molecular investigation of thalassemia in regions where thalassemia is abundant, and present highly heterogeneous population.