The Genetics Of Blood Disorders: Hereditary Hemoglobinopathies

Objective: To summarize recently published data on the pathophysiology, diagnosis and treatment of sickle cell diseases and β-Thalassemias, the most relevant hereditary hemoglobinopathies in the global population. Sources: Searches were run on the MEDLINE and SCIELO databases, limited to the period from 2003 to May 2008, using the terms hereditary hemoglobinopathies, sickle cell diseases and β-thalassemia. Two books and two chapters were also included. Summary of the findings: More than 2,000 articles were identified; those providing the most important information and broadest views were selected. Conclusions: Morbidity and mortality rates from sickle cell diseases and β-thalassemia are still very high and represent an important challenge. Increased understanding of pathophysiological aspects has lead to significant improvements in treatment and prevention of these diseases. 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Molecular identification of Sicilian (deltaß)º-thalassemia associated with ß-thalassemia and hemoglobin S in Brazil

We describe the clinical and molecular characteristics of two unrelated Brazilian families with an association of the Sicilian form of (deltaß)º-thalassemia with hemoglobin S and ß-thalassemia. Direct sequencing of the ß-globin gene showed only the hemoglobin S mutation in patient 1 and the ß-thalassemia IVS1-110 in patient 2. The other allele was deleted in both patients and PCR of DNA samples of the breakpoint region of both patients showed a band of approximately 1,150 bp, expected to be observed in the DNA of carriers of Sicilian (deltaß)º-thalassemia. The nucleotide sequence of this fragment confirmed the Sicilian deletion. There are few reports concerning the Hb S/(deltaß)º-thalassemia association and patient 2 is the first reported case of Sicilian type of (deltaß)º-thalassemia in association with ß-thalassemia documented at the molecular level.87387

High Prevalence Of α-thalassemia Among Individuals With Microcytosis And Hypochromia Without Anemia

In order to determine the contribution of α-thalassemia to microcytosis and hypochromia, 339 adult outpatients seen at Unicamp University Hospital (with the exception of the Clinical Hematology outpatient clinics), who showed normal hemoglobin (Hb) levels and reduced mean corpuscular volume and mean corpuscular hemoglobin, were analyzed. Ninety-eight were Blacks (28.9%) and 241 were Caucasians (71.1%). In all cases, Hb A2 and F levels were either normal or low. The most common deletional and nondeletional forms of α-thalassemia [-α3.7, -α4.2, -MED, -(α)20.5, αHphIα, αNcolα, ααNcoI and αTSAUDI] were investigated by PCR and restriction enzyme analyses. A total of 169 individuals (49.9%) presented α-thalassemia: 145 (42.8%) were heterozygous for the -α3.7 deletion (-α3.7/αα) and 18 (5.3%) homozygous (-α3.7/-α3.7), 5 (1.5%) were heterozygous for the nondeletional form αHPhlα/αα, and 1 (0.3%) was a -MED carrier (-MED/αα). Among the Blacks, 56 (57.1%) showed the -α3.7/ αα genotype, whereas 12 (12.2%) were -α3.7/-α3.7 and I (1.0%) was an αHPhlα carrier; among the Caucasians, 89 (36.9%) were -α3.7/αα, 6 (2.5%) had the -α3.7/-α3.7 genotype, 4 (1.7%) presented the nondeletional form (αHPhlα/αα), and 1 (0.4%) was a -MED carrier. These results demonstrate that α-thalassemia, mainly through the -α3.7 deletion, is an important cause of microcytosis and hypochromia in individuals without anemia. These data are of clinical relevance since these hematological alterations are often interpreted as indicators of iron deficiency.346759762Weatherall, D.J., Clegg, J.G., (1981) The Thalassaemia Syndromes. 3rd Edn., , Blackwell Scientific Publications, OxfordBunn, H.F., Forget, B.G., (1986) Hemoglobin: Molecular, Genetics and Clinical Aspects, , W.B. Saunders, PhiladelphiaHiggs, D.R., Vickers, M.A., Wilkie, A.O.M., Pretorius, I.M., Jarman, A.P., Weatherall, D.J., A review of the molecular genetics of the human α-globin gene cluster (1989) Blood, 73, pp. 1081-1104Kazazian H., Jr., The thalassemia syndromes: Molecular basis and prenatal diagnosis in 1990 (1990) Seminars in Hematology, 27, pp. 209-228Harteveld, K.L., Losekoot, M., Ajgam, H., Van Der Wielen, M., Giordano, P.C., Bernini, L.F., α-Thalassaemia in the Netherlands: A heterogeneous spectrum of both deletions and point mutations (1997) Human Genetics, 100, pp. 465-471Higgs, D.R., α-Thalassaemia (1993) Baillieres Clinical Haematology, 6, pp. 117-150Kattamis, A.C., Camaschella, C., Sivera, P., Surrey, S., Fortina, P., Human α-thalassemia syndromes: Detection of molecular defects (1996) American Journal of Hematology, 53, pp. 81-91Bianco, I., Cappabianca, M.P., Foglietta, E., Lerone, M., Deidda, G., Morlupi, L., Grisanti, P., Graziani, B., Silent thalassemias: Genotypes and phenotypes (1997) Haematologica, 82, pp. 269-280Galanello, R., Sollaino, C., Paglietti, E., Barella, S., Perra, C., Doneddu, I., Pirroni, M.G., Cao, A., α-Thalassemia carrier identification by DNA analysis in the screening for thalassemia (1998) American Journal of Hematology, 59, pp. 273-278Sonati, M.F., Costa, F.F., Hemoglobin Bart's in a Brazilian black population (1990) Brazilian Journal of Medical and Biological Research, 23, pp. 395-396Sonati, M.F., Farah, S.B., Ramalho, A.S., Costa, F.F., High prevalence of α-thalassemia in a Black population of Brazil (1991) Hemoglobin, 15, pp. 309-311Zago, M.A., Costa, F.F., Bottura, C., Hemoglobin H disease in three Brazilian families (1984) Revista Brasileira de Genética, 7, pp. 137-147Wenning, M.R.S.C., Kimura, E.M., Costa, F.F., Saad, S.T.O., Gervásio, S.A., De Jorge, S.B., Borges, E., Sonati, M.F., α-Globin genes: Thalassemic and structural alterations in a Brazilian population (2000) Brazilian Journal of Medical and Biological Research, 33, pp. 1041-1045Dodé, C., Krishnamoorthy, R., Lamb, J., Rochette, J., Rapid analysis of -α3.7 thalassaemia and αααanti 3.7 triplication by enzymatic amplification analysis (1993) British Journal of Haematology, 82, pp. 105-111Bowden, D.K., Vickers, M.A., Higgs, D.R., A PCR-based strategy to detect the common severe determinants of a thalassaemia (1992) British Journal of Haematology, 81, pp. 104-108Oron-Karni, V., Filon, D., Oppenheim, A., Rund, D., Rapid detection of the common Mediterranean α-globin deletions/rearrangements using PCR (1998) American Journal of Hematology, 58, pp. 306-310Hall, G.W., Thein, S.L., Newland, C.A., Chisholm, J.T.S., Kanavakis, E., Kattamis, C., Higgs, D.R., A base substitution (T→C) in codon 29 of the α2-globin gene causes α thalassemia (1993) British Journal of Haematology, 85, pp. 546-552Pearson, H.A., Ehrenkranz, R.A., Rinder, H.M., Hemosiderosis in a normal child secondary to oral iron medication (2000) Pediatrics, 105, pp. 429-43

Characterization of alpha thalassemic genotypes by multiplex ligation-dependent probe amplification in the Brazilian population

Alpha-thalassemia is the most common inherited disorder of hemoglobin synthesis. Genomic deletions involving the alpha-globin gene cluster on chromosome 16p13.3 are the most frequent molecular causes of the disease. Although common deletions can be detected by a single multiplex gap-PCR, the rare and novel deletions depend on more laborious techniques for their identification. The multiplex ligation-dependent probe amplification (MLPA) technique has recently been used for this purpose and was successfully used in the present study to detect the molecular alterations responsible for the alpha-thalassemic phenotypes in 8 unrelated individuals (3 males and 5 females; age, 4 months to 30 years) in whom the molecular basis of the disease could not be determined by conventional methods. A total of 44 probe pairs were used for MLPA, covering approximately 800 kb from the telomere to the MSLN gene in the 16p13.3 region. Eight deletions were detected. Four of these varied in size from 240 to 720 kb and affected a large region including the entire alpha-globin gene cluster and its upstream regulatory element (alpha-MRE), while the other four varied in size from 0.4 to 100 kb and were limited to a region containing this element. This study is the first in Brazil to use the MLPA method to determine the molecular basis of alpha-thalassemia. The variety of rearrangements identified highlights the need to investigate all cases presenting microcytosis and hypochromia, but without iron deficiency or elevated hemoglobin A2 levels and suggests that these rearrangements may be more frequent in our population than previously estimated.162

α-chain Hemoglobin Variants With Electrophoretic Mobility Similar To That Of Hemoglobin S In Newborn Screening Programs

[No abstract available]3528586Sonati, M., Costa, F.F., The genetics of blood disorders: Hereditary hemoglobinopathies (2008) J Pediatr (Rio J), 84 (4 SUPPL.), pp. S40-S51Berry, P.A., Cross, T.J., Thein, S.L., Portmann, B.C., Wendon, J.A., Karani, J.B., Hepatic dysfunction in sickle cell disease: A new system of classification based on global assessment (2007) Clin Gastroenterol Hepatol, 5 (12), pp. 1469-1476Di Nuzzo, D.V., Fonseca, S.F., Sickle cell disease and infection (2004) J Pediatr, 80 (5), pp. 347-354. , http://www.jped.com.br/conteudo/04-80-05-347/ing.asp, Rio J, Internet, citado 2009 Dez 21, Comment in: J Pediatr (Rio J). 2005;81(1):88. Disponível emAdorno, E.V., Couto, F.D., Moura, N.J.P., Menezes, J.F., Rêgo, M., Reis, M.G., Hemoglobinopathies in newborns from Salvador, Bahia, Northeast Brazil (2005) Cad Saude Publica, 21 (1), pp. 292-298Dacie, J.V., Lewis, S.M., (2006) Hematologia Prática De Dacie E Lewis, , 9th ed. Porto Alegre: Artmed(2013) Nnsylvania: Laboratories of Computer Science & Engineering and Biochemistry & Molecular Biology, , http://globin.cse.psu.edu, Globin Gene Server [Internet], cited 2013 February 14, Available fromCalder, D., Etienne-Julan, M., Romana, M., Watkins, N., Knight-Madden, J.M., Sickle retinopathy in a person with hemoglobin s/New York disease (2012) Case Rep GenetWenning, M.R., Kimura, E.M., Costa, F.F., Saad, S.T., Gervásio, S., de Jorge, S.B., Alpha-globin genes: Thalassemic and structural alterations in a Brazilian population (2000) Braz J Med Biol Res, 33 (9), pp. 1041-1045Wenning, M.R., Kimura, E.M., Jorge, S.B., Costa, F.F., Sonati, M.F., Molecular characterization of hemoglobins Kurosaki [alpha7 Lys-->Glu], G-Pest [alpha74 Asp-->Asn], Stanleyville-II [alpha78 Asn-->Lys] and J-Rovigo [alpha53 Ala-->Asp] (1999) Acta Haematol, 102 (4), pp. 203-205Geva, A., Clark, J.J., Zhang, Y., Popowicz, A., Manning, J.M., Neufeld, E.J., Hemoglobin Jamaica plain--a sickling hemoglobin with reduced oxygen affinity (2004) N Engl J Med, 351 (15), pp. 1532-1538. , Comment in: N Engl J Med. 2004;35(15):1490-2Jorge, S.E., Petruk, A.A., Kimura, E.M., Oliveira, D.M., Caire, L., Suemasu, C.N., Hb S-São Paulo: A new sickling hemoglobin with stable polymers and decreased oxygen affinity (2012) Arch Biochem Biophys, 519 (1), pp. 23-31Costa, F.F., Zago, M.A., Sonati, M.F., Bottura, C., The association of Hb Stanleyville II with alpha thalassemia and Hb S (1987) Nouv Rev Fr Hematol, 29 (6), pp. 387-390de Oliveira, R.G., Zamaro, P.J., Bonini-Domingos, C.R., Comparing electrophoresis at alkaline pH and high performance liquid chromatography to diagnose Hb S-like hemoglobin (2012) Rev Bras Hematol Hemoter, 34 (2), pp. 170-171Kimura, E.M., Oliveira, D.M., Jorge, S.E., Abreu, C.F., Albuquerque, D.M., Costa, F.F., Identificação e caracterização de variantes novas e raras da hemoglobina humana (2008) Rev Bras Hematol Hemoter, 30 (4), pp. 316-319Silva, M.R., Sendin, S.M., Pimentel, F.S., Velloso-Rodrigues, C., Romanha, A.J., Viana, M.B., Hb Stanleyville-II [α78(EF7)Asn→Lys (α2)HbA2: C.237C>A]: Incidence of 1:11,500 in a newborn screening program in Brazil (2012) Hemoglobin, 36 (4), pp. 388-394Silva, M.R., Sendin, S.M., Araujo, I.C., Pimentel, F.S., Viana, M.B., (2012) Clinical and Molecular Characterization of Hemoglobin Maputo [beta 47 (CD6) Asp > Tyr HBB: C.142G > T] and G-Ferrara [beta 57 (E1) Asn > Lys HBB: C.174C > A] In a Newborn Screening In Brazil, , ForthcomingSilva, M.R., Sendin, S.M., Araujo, I.C., Pimentel, F.S., Viana, M.B., Alpha chain hemoglobins with electrophoretic mobility similar to that of hemoglobin S in a newborn screening program Rev Bras Hematol Hemoter, 35 (2), pp. 109-11

Hemoglobin Bart's In A Brazilian Black Population.

Hemoglobin Bart's was measured spectrophotometrically after electrophoresis on cellulose acetate strips in cord blood from 320 full-term randomly selected black newborns from the University Hospital of Campinas, State of São Paulo, in the southeast of Brazil. Hb Bart's was detected in 38 of the 320 newborns (11.9%), with the levels presenting the following bimodal distribution: 10.3% of the infants in the 1-3.5% range and 1.6% in the 5-10% range. The data suggest that the frequency of alpha-thalassemia gene in the Brazilian black population is 0.125 since individuals with Bart's Hb in the 5-10% range are usually alpha(+)-thalassemia homozygotes.23539539