RESUMEN

The thalassemia issue is a growing worldwide health concern that anticipates the number of patients suffering from the disease will soon increase significantly. Patients with ß-thalassemia intermedia (ß-TI) manifest mild to intermediate levels of anemia, which is a reason for it to be clinically located between thalassemia minor and ß-thalassemia major (ß-TM). Notably, the determination of the actual rate of ß-TI is more complicated than ß-TM. The leading cause of this illness could be partial repression of ß-globin protein production; accordingly, the rate of ß-globin gene repression is different in patients, and the gene repression intensity creates a different clinical status. This review article provides an overview of functional mechanisms, advantages, and disadvantages of the classic to latest new treatments for this group of patients, depending on the disease severity divided into the typical management strategies for patients with ß-TI such as fetal hemoglobin (Hb) induction, splenectomy, bone marrow transplantation (BMT), transfusion therapy, and herbal and chemical iron chelators. Recently, novel erythropoiesis-stimulating agents have been added. Novel strategies are subclassified into molecular and cellular interventions. Genome editing is one of the efficient molecular therapies for improving hemoglobinopathies, especially ß-TI. It encompasses high-fidelity DNA repair (HDR), base and prime editing, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 procedure, nuclease-free strategies, and epigenetic modulation. In cellular interventions, we mentioned the approach pattern to improve erythropoiesis impairments in translational models and patients with ß-TI that involve activin II receptor traps, Janus-associated kinase 2 (JAK2) inhibitors, and iron metabolism regulation.

Asunto(s)

Talasemia , Talasemia beta , Humanos , Talasemia/genética , Talasemia/terapia , Talasemia/complicaciones , Talasemia beta/genética , Talasemia beta/terapia , Talasemia beta/complicaciones , Hierro/metabolismo , Quelantes del Hierro/uso terapéutico , Globinas beta/genética

RESUMEN

Homozygous or compound heterozygous mutations of the ß-globin gene lead to ß-thalassemia (ß-thal) major (ß-TM) or ß-thal intermedia (ß-TI), whereas heterozygotes usually show microcytosis with negligible or no hemolysis. Certain missense mutations in exon 3, however, produce unstable globins causing a dominant ß-thal phenotype or hemolytic anemia in heterozygotes. Here we report a mutation in exon 3 of the ß-globin gene, which results in an unstable globin (Hb Dieppe) [ß127(H5)Gln→Arg; HBB: c.383A>G] with a dominant ß-thal phenotype in two generations of a Chinese family. Physicians should be alerted to this mechanism of ß-thal considering its relative rarity.

Asunto(s)

Talasemia beta , Exones , Humanos , Mutación , Fenotipo , Globinas beta/genética , Talasemia beta/diagnóstico , Talasemia beta/genética

RESUMEN

We present case histories of three patients who had ß-thalassemia (ß-thal) trait with 'unusual severity' managed as ß-thal intermedia (ß-TI) where the basis of disease severity could not be explained with routine hematological and genetic investigations. The clinical diagnosis of 'thalassemia intermedia' was justifiable as they had a ß-thal mutation and disease severity that did not fit in with either ß-thal trait or with ß-thal major (ß-TM). As mutations of α, ß, and γ genes could not explain the unusual severity of the disease, further analysis with next-generation sequencing (NGS) for red cell diseases was carried out, which led to the diagnosis of coexisting membranopathies. This case series highlights the inherent difficulty in the diagnosis of ß-TI with certainty in some patients where the genetic basis is not clear-cut.

Asunto(s)

Talasemia alfa , Talasemia beta , Eritrocitos , Genotipo , Humanos , Mutación , Talasemia alfa/genética , Talasemia beta/diagnóstico , Talasemia beta/genética

RESUMEN

The -92 (C>T) (HBB: c.-142C>T) is a silent ß-thalassemia (ß-thal) mutation previously described in combination with several ß0 mutations and expressed as ß-thal intermedia (ß-TI). Heterozygous individuals are known to be completely asymptomatic showing borderline hemoglobin (Hb), mean corpuscular volume (MCV) and Hb A2 levels. Here, we report the first incidence of -92 in Eastern Europe and in Azerbaijan, and the first case in combination with codons 36/37 (-T) (HBB: c.112delT) mutation.

Asunto(s)

Talasemia beta , Codón , Genotipo , Humanos , Mutación , Globinas beta/genética , Talasemia beta/diagnóstico , Talasemia beta/epidemiología , Talasemia beta/genética

RESUMEN

ß-Thalassemia intermedia (ß-TI) is a clinical condition characterized by moderate, non transfusional anemia and hepatosplenomegaly. The main objective of this study was to determine the molecular basis of the clinical phenotype of ß-TI in Iran. To elucidate the mild phenotype of many patients with ß-TI, we screened for three prevalent ß-globin gene mutations [IVS-II-1 (G>A) HBB: c.315+1G>A, IVS-I-110 (G>A) HBB: c.93-21G>A and IVS-I-5 (G>C) [HBB: c.92+5G>C], deletions on the α-globin genes, XmnI polymorphisms and restriction fragment length polymorphism (RFLP) haplotypes on the ß-globin gene cluster in 50 ß-TI patients. Fifty-eight percent of the patients (29 cases) were associated with the mentioned mutations. We showed that the HBB: c.315+1G>A mutation is linked to haplotype [+ - + +] (57.69%). This haplotype is in linkage disequilibrium with the XmnI polymorphism (NG_000007.3: g.42677C>T) and has been associated with increased expression of Hb F in ß-TI patients. The XmnI polymorphism is defined in association with this prevalent mutation. Two patients had a single α-globin gene deletion [-α3.7 (rightward) deletion]. The main genetic factor in mild phenotype ß-TI patients is the linkage of an XmnI polymorphism (NG_000007.3: g.42677C>T) with the HBB: c.315+1G>A (80.76%), which is associated with increased production of Hb F and coinheritance of haplotype [+ - + +] with ß-TI, especially with the homozygous HBB: c.315+1G>A mutation. Molecular basis of ß-TI could be explained by the involvement of different factors that tend to develop the disease phenotype.

Asunto(s)

Anemia Hipocrómica/genética , Hemoglobina Fetal/genética , Hemoglobinas Anormales/genética , Mutación , Globinas alfa/genética , Globinas beta/genética , Talasemia beta/genética , Adulto , Anemia Hipocrómica/diagnóstico , Anemia Hipocrómica/patología , Femenino , Expresión Génica , Haplotipos , Hepatomegalia/diagnóstico , Hepatomegalia/genética , Hepatomegalia/patología , Humanos , Irán , Desequilibrio de Ligamiento , Masculino , Fenotipo , Polimorfismo de Longitud del Fragmento de Restricción , Análisis de Secuencia de ADN , Esplenomegalia/diagnóstico , Esplenomegalia/genética , Esplenomegalia/patología , Globinas alfa/deficiencia , Globinas beta/deficiencia , Talasemia beta/diagnóstico , Talasemia beta/patología

RESUMEN

We report a de novo heterozygous variant of the ß-globin chain that showing a mild ß-thalassemia intermedia (ß-TI) phenotype. He presented with mild anemia, splenomegaly, reticulocytosis, and poikilocytosis and tear drop cells on the blood smear; Immune mediated hemolysis, red cell membrane and enzyme defects, were excluded; hemoglobin (Hb) electrophoresis showed an elevation of Hb F. Molecular analysis of the ß-globin gene showed a heterozygous variation in exon 3 (HBB: c.379delG, p.Val127Cysfs*32) in the absence of an α-globin gene mutation or mutations that modulate Hb F expression.

Asunto(s)

Mutación , Globinas beta/genética , Talasemia beta/genética , Niño , Hemoglobina Fetal/análisis , Hemoglobinas Anormales/genética , Heterocigoto , Humanos , Masculino , Fenotipo , Turquía

RESUMEN

Thalassemia is a hereditary disease with an autosomal recessive inheritance pattern resulting in reduced production of globin chains. Mutations in modifier genes can cause or affect thalassemia. Krüppel-like factor 1 (KLF1) is a modifier gene that was investigated in this study. Thirty-five Iranian ß-thalassemia (ß-thal) minor patients with hematological symptoms including Hb A2 3.0%, mean corpuscular volume (MCV) <75.0 fL, mean corpuscular hemoglobin (Hb) (MCH) <25.0 pg, and two ß-thal intermedia (ß-TI) patients in 50 subjects who carried no mutations on the HBB and HBA2 or HBA1 genes were investigated for all exons of the KLF1 gene by polymerase chain reaction (PCR) and sequencing methods. Of the 35 patients with a ß-thal minor phenotype, one patient was heterozygous for the c.544T>C mutation in exon 2 of KLF1 and HBB: c.380T>G variant, Hb Dhonburi [also known as Hb Neapolis or codon 126 (T>G)]. The c.340T>C mutation was also found in exon 2 of the KLF1 gene with an allele frequency of 16.6% in the studied ß-thal carriers. The two ß-TI patients were homozygous for a new mutation c.942delA in exon 3 of KLF1. Mutations in modifier genes can cause or affect thalassemia. Therefore, exact investigation of globin genes and modifiers such as KLF1 is necessary in areas where globin gene disorders are most prevalent to understand the reason of clinical and hematological symptoms of thalassemia and facilitate newborn screening or prenatal diagnosis (PND) programs.

Asunto(s)

Factores de Transcripción de Tipo Kruppel/genética , Mutación , Talasemia beta/diagnóstico , Talasemia beta/genética , Adulto , Alelos , Biomarcadores , Análisis Mutacional de ADN , Índices de Eritrocitos , Exones , Femenino , Genotipo , Humanos , Irán , Masculino , Linaje , Globinas beta/genética , Talasemia beta/sangre

RESUMEN

The rare point mutation Cap +1570 (T>C) (HBB: c*96T>C) has been reported in families of Czech, Greek, Turkish and Italian origin. The mutation contributes to a reduction of the ß-globin chain synthesis, and in heterozygous carriers, it causes a silent phenotype, while in compound heterozygosity with severe ß-thalassemia (ß-thal) mutations, it leads to a non transfusion dependent ß-thal intermedia (ß-TI) state. We report a case of compound heterozygosity for codon 39 (C>T) (HBB: c.118C>T) and Cap +1570, in addition to the presence of αααanti-3.7/αα.

Asunto(s)

Heterocigoto , Mutación , Globinas beta/genética , Talasemia beta/genética , Frecuencia de los Genes , Grecia , Humanos , Mutación Silenciosa , Globinas alfa/genética

RESUMEN

Globin switching is a significant factor on blood hemoglobin (Hb) level but its molecular mechanisms have not yet been identified, however, several quantitative trait loci (QTL) and polymorphisms involved regions on chromosomes 2p, 6q, 8q and X account for variation in the γ-globin expression level. We studied the effect of interaction between a region on intron six of the TOX gene, chromosome 8q (chr8q) and XmnI locus on the γ-globin promoter, chr11p on γ-globin expression in 150 ß-thalassemia intermedia (ß-TI) patients, evaluated by statistical interaction analysis. Our results showed a significant interaction between one QTL on intron six of the TOX gene (rs9693712) and XmnI locus that effect γ-globin expression. Interchromosomal interaction mediates through transcriptional machanisms to preserve true genome architectural features, chromosomes localization and DNA bending. This interaction can be a part of the unknown molecular mechanism of globin switching and regulation of gene expression.

Asunto(s)

Regulación de la Expresión Génica , Sitios de Carácter Cuantitativo , Talasemia beta/genética , gamma-Globinas/metabolismo , Cromosomas Humanos Par 8/metabolismo , ADN/ultraestructura , Proteínas del Grupo de Alta Movilidad/genética , Proteínas del Grupo de Alta Movilidad/metabolismo , Humanos , Intrones , Regiones Promotoras Genéticas , gamma-Globinas/genética

RESUMEN

We report a clinical update of the hemoglobin (Hb) variant [ß27(B9)Ala→Gly; HBB: c.83C>G], named Hb Siirt, that was previously described as a silent variant in a 23-year-old Kurdish female. The patient was also a carrier of the codon 5 (-CT) (HBB: c.17_18delCT) frameshift mutation and of the ααα anti 3.7 triplication. Her initial moderate ß-thalassemia intermedia (ß-TI) phenotype worsened with time, causing the patient to become a transfusion-dependent subject at the age of ∼40 years. Subsequent molecular characterization of both parents revealed that the Hb Siirt variant was inherited by the mother, while the other two globin alterations (HBB: c.17_18delCT and αααanti 3.7 triplication) were genetically transmitted by the father. The latter remained a carrier of a mild ß-TI phenotype throughout his life, at least until the age of 65 years. We hypothesize that the worsened clinical conditions in the daughter were due to the additional, maternally inherited Hb Siirt variant. However, protein 3D conformational analysis did not seem to reveal substantial overall structural changes. Among the other three described variants [Hb Volga (HBB: c.83C>A), Hb Knossos (HBB: c.82 G>T), Hb Grange-Blanche (HBB: c.83C>T] that are due to nucleotide substitutions at codon 27 of the ß-globin gene; only Hb Knossos causes a ß+-thalassemia (ß+-thal) phenotype.

Asunto(s)

Alelos , Sustitución de Aminoácidos , Codón , Hemoglobinas Anormales/genética , Globinas beta/genética , Índices de Eritrocitos , Femenino , Estudios de Asociación Genética , Genotipo , Hemo/química , Hemo/metabolismo , Hemoglobinas Anormales/química , Hemoglobinas Anormales/metabolismo , Heterocigoto , Humanos , Modelos Moleculares , Conformación Molecular , Oxígeno/metabolismo , Fenotipo , Unión Proteica , Adulto Joven , Globinas alfa/genética , Globinas beta/química , Globinas beta/metabolismo , Talasemia beta/sangre , Talasemia beta/diagnóstico , Talasemia beta/genética

RESUMEN

Recognition of risk factors of morbidities in patients with ß-thalassemia intermedia (ß-TI) is an important issue that must be evaluated. Non transfusion-dependent thalassemia patients referred to the outpatient clinic of Shiraz University of Medical Science, Shiraz, South Iran were enrolled in this study between 2013 and 2014. Two peripheral blood smears were prepared for evaluating developmental stage of normoblasts. One hundred and thirty-one patients with ages ranging from 3 to 42 years (mean: 23.35 ± 7.9) were selected. Sixty-seven patients had at least one morbidity (51.1%). Osteoporosis and gallstones were the most common morbidities (33.6 and 24.4%, respectively). In the univariate model, hemoglobin (Hb), ferritin, Hb F, developmental stage of normoblasts and hydroxyurea (HU) therapy did not differ between patients with and without morbidity (p > 0.05) but mean age of patients and mean number of normoblasts were higher in patients with morbidity (p = 0.026 and p = 0.012, respectively). In the regression model, sex and splenectomy status were different between patients with and without morbidity. It seems that females and splenectomy are risk factors for morbidity in non transfusion-dependent thalassemia patients. [Sex: odds ratio (OR) = 2.21, 95% confidence interval (95% CI): 1.04-4.72, p = 0.39. Splenectomy: OR = 3.10, 95% CI: 1.12-8.59, p = 0.029.] This study shows that Hb F level and developmental stage of normoblasts does not effect the incidence of morbidities in non transfusion-dependent thalassemia patients but sex and splenectomy were effective factors in development of morbidities. Thus, splenectomy should be avoided as much as possible in patients with non transfusion-dependent thalassemia.

Asunto(s)

Eritroblastos/patología , Hemoglobina Fetal/análisis , Talasemia/epidemiología , Adolescente , Adulto , Niño , Preescolar , Recuento de Eritrocitos , Femenino , Cálculos Biliares , Humanos , Irán , Masculino , Morbilidad , Osteoporosis , Factores de Riesgo , Factores Sexuales , Esplenectomía

RESUMEN

Inheritance of mild mutations within the ß-globin gene and coinheritance of α-thalassemia (α-thal) are known as two important genetic modifiers in ß-thalassemia (ß-thal) intermedia (ß-TI). We aimed to evaluate the spectrum of ß- and α-thal mutations in ß-TI patients in Southeast Iran. Common ß- and α-globin gene mutations were detected by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and multiplex gap-PCR, respectively. There were 26 male (57.8%) and 19 female (42.2%) patients. HBB: c.92 + 5T > C [IVS-I-5 (G > C)] and HBB: c.-138C + 1G > A [IVS-II-I (G > A)] represented the prevalent alleles with respective frequencies of 60.0 and 10.0%. Other ß-globin mutations included HBB: c.-138C > T [-88 (C > T)], HBB: c.27_28insG [frameshift codons (FSC) 8/9 (+G)], HBB: c.46delT [codon 15 (-T)], HBB: c.93-22_95del (IVS-I, 25 del), and the 619 bp deletion (NG_000007.3: g.71609_72227del619). The predominant genotypic combinations were ß(0)/ß(0) (68.9%), ß(0)/ß(+ )(8.9%) and ß(+)/ß(+ )(2.2%). Coinheritance of α-thal was observed in 33.0% of the patients, with the -α(3.7) (rightward) (NG_000006.1: g.34164_37967del3804) as the most common deletion (86.0%). One patient was diagnosed with the -α(4.2) (leftward) (AF221717) and one with the - -(MED) (g.24664_41064del16401) deletions, while no patients carried the -(α)(20.5) (g.15164_37864del22701), α(-5 nt) (HBA2: c.95 + 2_95_6delTGAGG) or codon 19 (-G) (HBA2: c.56delG) mutations. The alleviating molecular mechanism was not explainable by ß(+ )or concurrent α-thal in more than half of our ß-TI patients. This encourages conducting more studies to identify other contributing factors, especially Hb F-inducing genetic modifiers.

Asunto(s)

Frecuencia de los Genes , Mutación , Talasemia beta/genética , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Irán/epidemiología , Masculino , Epidemiología Molecular , Reacción en Cadena de la Polimerasa , Globinas alfa/genética , Talasemia alfa/genética , Globinas beta/genética , Talasemia beta/epidemiología

RESUMEN

Increased Hb F levels can ameliorate the symptoms of ß-thalassemia (ß-thal). Due to the genetic heterogenicity of ß-thal, the relationship between genetic variants in modifier genes and Hb F level has been studied in different populations. The Chinese Zhuang has the second largest population in China and has 6.78% prevalence of ß-thal. However, the effects of these single nucleotide polymorphism (SNP) variants on the Hb F levels of ß-thal intermedia (ß-TI) patients in this population have not been reported. To explore the association between modifier loci (ß-globin gene cluster, HBS1L-MYB intergenic region and BCL11A) and Hb F levels in Chinese Zhuang ß-TI patients, 96 unrelated ß-TI patients (50 males and 46 females) with different Hb F levels were recruited and genotyped by mass spectrometry. A total of 13 SNPs were confirmed to be in a significant relationship with Hb F levels in this population. Of these, high-risk genotypes of six Hb F-associated SNPs, rs9376090, rs7776054, rs9399137, rs9389268, rs9402685 in the HBS1L-MYB intergenic region and rs189984760 in the BCL11A locus, showed association with high Hb F levels, especially for SNPs in linkage disequilibrium. One novel Hb F-associated SNP, rs189984760, was identified in our study. Our findings will be of valuable reference for correlation between modifier genes and Hb F in Chinese Zhuang populations and may lead to better understand the modifying mechanisms for ß-thal.

Asunto(s)

Proteínas Portadoras/genética , Hemoglobina Fetal/análisis , Proteínas de Unión al GTP/genética , Variación Genética , Proteínas HSP70 de Choque Térmico/genética , Proteínas Nucleares/genética , Factores de Elongación de Péptidos/genética , Proteínas Proto-Oncogénicas c-myb/genética , Talasemia beta/genética , Adolescente , Adulto , Pueblo Asiatico , Niño , Preescolar , ADN Intergénico , Femenino , Genes Modificadores , Humanos , Masculino , Proteínas Represoras , Adulto Joven

RESUMEN

Compound heterozygosity for one of the Hb Lepore mutations and ß-thalassemia (ß-thal) is a rare cause of non transfusion-dependent thalassemia. We report a 4-year-old boy who presented clinically as homozygous/compound heterozygous ß-thal intermedia (ß-TI), an impression that was corroborated by the initial hemoglobin (Hb) high performance liquid chromatography (HPLC). However, the correct diagnosis of a rare compound heterozygous Hb Lepore-Hollandia/ß-thal was revealed after parental studies and molecular analyses including ß-globin gene sequencing. Our patient highlights the importance of a logical stepwise multi modality approach and the vital importance of parental screening and molecular studies in accurate characterization of complex hemoglobinopathies. Correct diagnosis is especially crucial if pre natal detection is anticipated for future pregnancies. Molecular analyses alone may not compensate for the unavailability of parental testing. This is because the molecular results may be misinterpreted, especially if limited tests are conducted. The infrequent prior reports of this combination from distant parts of the Indian subcontinent suggests that the origin of Hb Lepore-Hollandia from sporadic mutations occurs in isolated families.

Asunto(s)

Hemoglobinas Anormales/genética , Heterocigoto , Mutación , Talasemia beta/diagnóstico , Talasemia beta/genética , Adulto , Preescolar , Codón , Índices de Eritrocitos , Femenino , Humanos , India , Intrones , Masculino

RESUMEN

A 4-year-old male child of Caucasian ethnicity was investigated for moderate hemolytic and non immune-mediated anemia. The presence of splenomegaly and the elevation of Hb A(2) and Hb F and the exclusion of a defect of protein of red blood cell (RBC) membranes defined a clinical picture of ß-thalassemia intermedia (ß-TI). The molecular analysis showed a heterozygous IVS-II-1 (HBB: c.315G > A) mutation on the ß-globin gene, in the absence of extra α-globin genes or unstable hemoglobin (Hb) chains.

Asunto(s)

Mutación , Globinas beta/genética , Talasemia beta/diagnóstico , Talasemia beta/genética , Preescolar , Índices de Eritrocitos , Humanos , Intrones , Masculino , Fenotipo

RESUMEN

Because of insufficient erythropoiesis, peripheral hemolysis and increased gastrointestinal iron absorption, iron overload is still a matter of debate in ß-thalassemia intermedia (ß-TI) patients, which can be overcome using iron chelators. However, data on use of iron chelators in ß-TI patients is highly restricted. The aim of this study was to evaluate the efficacy of oral administration of deferasirox (Exjade(®) or DFX) by assessment of serum ferritin levels in ß-TI patients. In this quasi-experimental study, 50 ß-TI patients with serum ferritin levels >1000 ng/mL were selected and received oral DFX for 12 consecutive months. Iron overload was measured by checking serum ferritin levels every 2 months and the results were compared with the baseline level. The mean serum ferritin was decreased during 1 year of chelation therapy without any toxic effect. Although the difference between baseline ferritin and ferritin levels at the end of second month was not remarkable (p = 0.88), a significant reduction in serum ferritin was observed after 4 (p = 0.01), 6 (p = 0.001), 8 (p < 0.001), 10 (p < 0.001) and 12 months (p < 0.001) of chelation therapy compared to its baseline levels. There was no correlation between baseline ferritin levels and age (p = 0.574). In addition, no statistically significant difference was observed about change in serum ferritin levels after 6 and also 12 months of therapy between patients who had undergone splenectomy and those who did not (p = 0.796 and 0.859, respectively). Iron chelation therapy with DFX is safe and effective in reducing serum ferritin levels in ß-TI patients who suffer from side effects of iron overload.

Asunto(s)

Benzoatos/uso terapéutico , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/etiología , Triazoles/uso terapéutico , Talasemia beta/complicaciones , Adolescente , Adulto , Niño , Deferasirox , Femenino , Ferritinas/sangre , Humanos , Sobrecarga de Hierro/diagnóstico , Sobrecarga de Hierro/metabolismo , Masculino , Resultado del Tratamiento , Adulto Joven

RESUMEN

Although not regularly transfused, patients with non-transfusion-dependent thalassemia (NTDT) are prone to iron overload and its complications. Their molecular, phenotypical and laboratory characteristics vary in different populations and there is a need to document local prevailing patterns. We have reviewed the records of our patients with NTDT in Kuwait and documented their clinical and molecular characteristics in addition to iron status [serum ferritin and liver magnetic resonance imaging (MRI) T2*], management and complications. There were 41 patients, made up of 20 with ß-thalassemia intermedia (ß-TI), 18 with Hb H (ß4) disease and three with Hb E (HBB: c.79G > A)-ß-thalassemia (Hb E-ß-thal); their ages ranged from 3 to 36 years (mean 12.5 ± 7.7). While 18 (43.9%) had been transfused at least once, only three (7.3%) had been transfused on multiple occasions. Three patients had serum ferritin >500 ng/mL; while four of 38 had mild or moderate liver iron overload. Seven (35.0%) of the ß-TI patients were managed with hydroxyurea (HU) with good response. Other complications included five patients with gallstones and one each of hypothyroidism and moyamoya. The most common mutations among the ß-TI patients were IVS-II-1 (G > A) and IVS-I-6 (T > C), while among the Hb H patients, the Saudi α2-globin gene polyadenylation (polyA) (AATAAA > AATAAG) mutation was responsible for all cases either as homozygotes (61.1%) or compound heterozygotes with the α-thal-2 (-α(3.7)) allele (33.3%). Although the pattern of NTDT in Kuwaiti patients is generally mild, there is a need to follow them to adulthood as the complications are cumulative and more prevalent in this group.

Asunto(s)

Talasemia/sangre , Talasemia/genética , Adolescente , Adulto , Niño , Preescolar , Índices de Eritrocitos , Femenino , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Hemoglobina E/genética , Hemoglobina E/metabolismo , Hemoglobina H/genética , Hemoglobina H/metabolismo , Humanos , Kuwait , Masculino , Mutación , Talasemia/diagnóstico , Adulto Joven , Globinas alfa/genética , Globinas alfa/metabolismo , Globinas beta/genética , Globinas beta/metabolismo

RESUMEN

The 3.7 kb triplicated α-globin gene (ααα(anti 3.7)) mutation has been found in most populations. It results from an unequal crossover between misaligned homologous segments in the α-globin gene cluster during meiosis. The pathophysiology and clinical severity of ß-thalassemia (ß-thal) are associated with the degree of α chain imbalance. The excess of α-globin chains plays an important role in the pathophysiology of ß-thal. When heterozygous/homozygous ß-thal coexists with an α gene numerical alteration, the clinical and hematological phenotype of thalassemia could change to mild anemia in case of an α deletion (-α/αα) or severe anemia in the case of an α triplication (αα/ααα). The coexistence of an ααα(anti 3.7) triplication is considered an important factor in the severity of ß-thal, exacerbating the phenotypic severity of ß-thal by causing more globin chain imbalance. This study shows that the ααα(anti 3.7) triplication is an important factor in the causation of ß-thal intermedia (ß-TI) in heterozygous ß-thal. This type of phenotype modification has rarely been observed and reported in the Iranian population. Here we report the coinheritance of a triplicated α-globin gene arrangement and heterozygous/homozygous ß-thal in 23 cases, presenting with a ß-TI or ß-thal major (ß-TM) phenotype. Some of these patients were considered to have a mild ß-TI phenotype as they needed no blood transfusions; some occasionally received blood transfusions in their lifetime (for example on delivery) but some are dependent on regular blood transfusions (every 20 to 40 days). Our study was focused on the importance of detecting the α-globin gene triplication in genotype/phenotype prediction in Iranian thalassemia patients.

Asunto(s)

Epistasis Genética , Dosificación de Gen , Mutación , Globinas alfa/genética , Globinas beta/genética , Talasemia beta/genética , Adulto , Transfusión Sanguínea , Índices de Eritrocitos , Femenino , Genotipo , Humanos , Irán , Masculino , Persona de Mediana Edad , Fenotipo , Talasemia beta/diagnóstico , Talasemia beta/terapia

RESUMEN

ß-Thalassemia intermedia (ß-TI) is a clinical term describing a range of clinical phenotypes that are intermediate in severity between the carrier state and ß-thalassemia major (ß-TM). To characterize the molecular basis of ß-TI in Erbil Province, Northern Iraq, 83 unrelated patients were investigated. Detection of ß-globin gene mutations was carried out by reverse hybridization assay and direct gene sequencing. All patients were screened for the XmnI polymorphism by direct sequencing of HBG2 ((G)γ promoter gene). Detection of α-globin gene deletions and triplication was carried out using the reverse hybridization assay. Four main molecular patterns were identified in association with the ß-TI phenotype, namely: ß(+)/ß(+) (38.5%), ß(+)/ß(0) (21.6%), ß(0)/ß(0) (31.3%), and ß(0)/wild type (8.4%). IVS-I-6 (T > C) was the most frequently encountered mutation (55 alleles, 34.6%), followed by IVS-II-1 (G > A) and codon 8 (-AA); furthermore, we report for the first time from Iraq two ß(+) mutations, -87 (C > G) and 5' untranslated region (5'UTR) +22 (G > A). The XmnI polymorphism was detected in 47.0% of patients, mainly in association with the ß(0)/ß(0) genotype. The α-globin gene deletions were encountered in four cases, including one case with (- -(FIL)) double gene deletion, a report that is the first from our country. The α-globin gene triplication was detected in five of the seven heterozygous ß-thalassemia (ß-thal) patients. Similar to other Mediterranean countries, inheritance of mild ß-globin mutations was the main molecular pattern underlying ß-TI in our patients followed by the ameliorating effect of the XmnI polymorphism.

Asunto(s)

Etnicidad/genética , Mutación , Globinas beta/genética , Talasemia beta/epidemiología , Talasemia beta/genética , Adolescente , Adulto , Alelos , Niño , Preescolar , Codón , Índices de Eritrocitos , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Irak/epidemiología , Masculino , Persona de Mediana Edad , Fenotipo , Adulto Joven , Talasemia beta/diagnóstico

RESUMEN

In this short communication, we describe the clinical presentation of unusual hemoglobin (Hb), variants in three Sri Lankan cases under study for ß-thalassemia intermedia (ß-TI). We believe this is the first report on their occurrence in Sri Lanka as well as from the Indian subcontinent. During a molecular study performed on ß-TI patients, we identified three unusual Hb variants as Hb G-Szuhu (HBB: c.243C>G), Hb G-Coushatta (HBB: c.68A>C) and Hb Mizuho (HBB: c.206T>C) in three unrelated families. Hb G-Szuhu and Hb G-Coushatta were found in combination with the common ß-thalassemia (ß-thal) mutation, IVS-I-5 (G>C). Both probands had mild anemia with greatly reduced red cell indices and had non palpable livers and spleens, however, by ultrasound, both were observed to be enlarged. The final Hb variant, Hb Mizuho, was identified as a heterozygous mutation found in both proband and his mother. Both family members had severe anemia and were regularly transfused and had increased red cell parameters.

Asunto(s)

Hemoglobinas Anormales/genética , Talasemia beta/genética , Secuencia de Bases , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Sri Lanka/epidemiología , Adulto Joven , Talasemia beta/sangre , Talasemia beta/epidemiología