Heterozygous β-thalassemia with thalassemia intermedia phenotype

In this study we investigated the molecular bases of the β-thalassemia intermedia phenotype in six patients belonging to two unrelated families of Sardinian descent. Sequence analysis of the β globin gene from these patients detected, as the sole abnormality, the heterozygosity for the codon 39 nonsense mutation. The Aγ and Gγ promoters as well as the HS2 and HS3 core sequences of the β globin LCR from these patients, did not show any non-polymorphic nucleotide variation from the consensus sequence. One of the parents was heterozygous for codon 39 nonsense mutation but showed the β-thalassemia carrier phenotype; the other was hematologically normal and had an entirely normal β globin gene sequence. In both families, other members showed the typical hematological phenotype, clinically silent, of heterozygous β thalassemia. To explain the thalassemia intermedia phenotype, we postulated the presence of an unknown molecular defect interacting with the β globin gene mutation. Haplotype analysis excluded that this postulated defect lies in the β globin gene cluster. Am. J. Hematol. 57:43–47, 1998. © 1998 Wiley-Liss, Inc.     

Peripheral T cell receptors αβ and γδ in patients with Hodgkin's lymphoma

Antigen recognition by T cells is determined by an antigen specific T cell receptor (TCR). Two heterodimeric TCR structures associated with CD3 have been defined: TCR αβ and TCR γδ. TCR αβ and its function are well described but the role of TCR γδ in normal and lymphoproliferative disorders is not well established. In newly diagnosed or relapsed/refractory Hodgkin's disease (HD), a disease associated with defective T cell functions and increased sIL-2R, We determined levels of seven TCR αβ variable regions [βV5(a), βV5(b), βV6(a), βV12(a), αβV(a), αV2(a)] and TCR γδ by using monoclonal antibodies (MCA). TCR γδ levels did not show any difference, but several variable regions of the TCR αβ differed when groups are compared with each other and the control group.     

Sickle cell disorder, β-globin gene cluster haplotypes and α-thalassemia in neonates and adults from Guadeloupe

We have studied haplotype of β^s chromosome and α-globin gene status in 534 patients (255 adults and 279 children of whom 159 neonates) from Guadeloupe with various sickle cell-related conditions, namely SS (n = 298), SC (n = 170), S-β -thal (n = 56), and other rare forms (n = 10). Haplotype data on β^s chromosomes confirm our previous observation that Benin type is the most prevalent (75%) β^s chromosome in Guadeloupe, in disagreement with the historical records. Comparison of the frequency of distribution of various β^s haplotypes between neonates and adults on the one hand and between SS and SC cases on the other shows that the current β^s haplotype distribution in this island is not distorted by haplotype-related differential survival. We also show that the frequency of α-thalassemia (-3.7 kb) in Guadeloupe is one of the highest recorded in this region involved in Atlantic slave trade and also failed to reveal any age-dependent increase in frequency. We conclude that the African component of Guadeloupe is distinct from that of Brazil and Cuba but is close to that of Jamaica. Am. J. Hematol. 55:24-27, 1997. © 1997 Wiley-Liss, Inc.     

β‐cell mass in people with type 2 diabetes

The early occurrence of β‐cell dysfunction has been broadly recognized as a critical determinant of the development and progression of type 2 diabetes. β‐cell dysfunction might be induced by insufficient β‐cell mass, by a dysfunction of the β‐cells, or both. Whether or not β‐cell dysfunction constitutes a cause of reduced β‐cells or vice‐versa currently remains unclear. The results of some studies have measured the loss of β‐cells in type 2 diabetic patients at between 22 and 63% by planimetric measurements. Because β‐cell hypertrophy has been noted in type 2 diabetic patients, the loss of β‐cell number should prove more profound than what has thus far been reported. Furthermore, β‐cell volumes are reduced even in patients with impaired fasting glucose. Such defects in β‐cell mass are associated with increased apoptosis rather than insufficient replication or neogenesis of β‐cells. With these results, although they still require clarification, the peak β‐cell mass might be determined at quite an early stage of life, and then might decline progressively over time as the result of exposure to harmful environmental influences over one’s lifetime. In this review, we have summarized the relevant studies regarding β‐cell mass in patients with type 2 diabetes, and then presented a review of the various causes of β‐cell loss in adults. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00072.x, 2010)     

α‐thalassaemia masked by β gene defects and a new polyadenylation site mutation on the α2‐globin gene

We report three examples of chronic anaemia involving complex combinations of α‐ and β‐globin gene defects. The first case had a potential Hb H disease caused by the classic SEA/RW deletions masked by Hb E [β26(B8)Glu→Lys] in the homozygous state. The second had an unusual Hb H disease caused by compound heterozygosity for two different α2 polyadenylation site mutations masked by a β‐thalassaemia heterozygosity. The third had an intermediate α‐thalassaemia with considerable anaemia caused by an as yet unknown polyadenylation site (AATAAA>AATAAC) mutation in combination with a common RW deletion masked by a common Hb C [β6(A3)Glu→Lys] heterozygosity. Diagnostic methods, genotype/phenotype correlations and the chance of overlooking these combinations during risk assessment in a multiethnic society are discussed.     

An association between Type 2 diabetes and α1‐antitrypsin deficiency

Aims α₁‐Antitrypsin (AAT) is a serine protease inhibitor which recently has been shown to prevent Type 1 diabetes development, to prolong islet allograft survival and to inhibit pancreatic B‐cell apoptosis in vivo. It has also been reported that Type 1 diabetic patients have significantly lower plasma concentrations of AAT, suggesting the potential role of AAT in the pathogenesis of Type 1 diabetes. We have investigated whether plasma AAT levels are altered in Type 2 diabetes. Methods The study included patients with Type 2 diabetes (n = 163) and non‐diabetic control subjects matched for age, sex and smoking habits (n = 158) derived from the population‐based Malmö Diet and Cancer study. Plasma samples were analysed for AAT concentration and phenotype and serum glucose, insulin, C‐reactive protein and lipid levels were measured. Glycated haemoglobin was also measured. Results In the diabetic group, the women had higher mean plasma AAT levels than men (P < 0.05). The mean plasma AAT levels did not differ between diabetic and control subjects. However, the number of individuals with low AAT levels (< 1.0 mg/ml) was 50% higher in the diabetic group (P < 0.05) and the frequency of AAT deficiency genotypes was 50% higher (NS) in diabetic compared with control subjects. In the group of diabetic patients with AAT < 1 mg/ml, AAT directly correlated with systolic blood pressure (P = 0.048) and inversely correlated with waist–hip ratio (P = 0.031). Conclusions Our results provide evidence that deficiency of AAT may be associated with an increased risk of developing Type 2 diabetes.     

SYTO9 and SYBR GREEN1 with a high‐resolution melting analysis for prenatal diagnosis of β0‐thalassemia/hemoglobin‐E

The β⁰‐thalassemia/Hb‐E causes a wide range of severe conditions. A high medical cost is incurred in severe cases. Thus, the prevention of new cases of β⁰‐thalassemia/Hb‐E is required. The aim of this study is to use the SYTO9 and SYBR GREEN1 high‐resolution melting (HRM) analysis for prenatal diagnosis of β⁰‐thalassemia/Hb‐E. DNA samples were extracted from amniotic fluid or cord blood of 11 pregnancies whose fetuses were at risk for β‐thalassemia/Hb‐E. PCR products from multiplex amplification refractory mutation system PCR for the detection of β⁰‐thalassemia mutations at codons 17(A>T), 41/42(?TCTT), and 71/72(+A) and from amplification refractory mutation system PCR for the detection of Hb‐E were characterized by SYTO9 HRM analysis. Moreover, β⁰‐thalassemia 3.5‐ kb deletion was detected using real‐time PCR with SYBR GREEN1 HRM analysis. Seven of 11 fetuses (64%) were diagnosed as β⁰‐thalassemia/Hb‐E (4 fetuses with mutation at codon 17, 2 with mutation at codon 41/42, and 1 with 3.5‐ kb deletion). Results from HRM analysis were completely consistent with those from fetal blood samplings analyzed at the time of delivery or pregnancy termination using HPLC. Therefore, the HRM analysis is easy to use. It is simple, flexible, non‐destructive and has superb sensitivity and specificity. This approach might facilitate the laboratory diagnosis and genetic counseling for regions with a high prevalence of β⁰‐thalassemia/Hb‐E.     

Effect of combination therapy of hydroxyurea with l‐carnitine and magnesium chloride on hematologic parameters and cardiac function of patients with β‐thalassemia intermedia

Background: l‐Carnitine and magnesium have antioxidant properties. They have the potential to stimulate production of fetal hemoglobin and stabilize the RBC membrane, respectively. Several studies have also shown the beneficial effects of hydroxyurea in thalassemic patients. We assessed the effect of combination therapy of hydroxyurea with l ‐carnitine and magnesium chloride on hematologic parameters and cardiac function of patients with β‐thalassemia intermedia. Methods: One‐hundred‐and‐twenty patients with thalassemia intermedia (range, 4–35 yr; mean, 19 ± 6.4 yr) who had no need for blood transfusion or requirement for blood transfusion with an interval of >6 months were randomly selected. All patients had been on hydroxyurea for >6 months. They were randomly divided into four groups: group A (hydroxyurea alone); group B (hydroxyurea and l ‐carnitine); group C (hydroxyurea and magnesium chloride); and group D (hydroxyurea, l ‐carnitine and magnesium chloride). Results: In groups B, C, and D, mean Hb and hematocrit increased during 6‐month treatment (P < 0.001). Echocardiographic studies revealed a significant decrease in left ventricular end‐diastolic diameter in group B (P = 0.032), increase in pulmonary acceleration time in group C (P = 0.012), and increase in left ventricular ejection fraction in groups C and D (P < 0.000 and 0.006, respectively). Conclusion: Combination of hydroxyurea with l ‐carnitine or magnesium could be more effective in improving hematologic parameters and cardiac status in patients with β‐thalassemia intermedia than hydroxyurea alone.     

α-Thalassemia and β-thalassemia in a turkish family

A Turkish family is described in which three children have a clinical picture similar to that of thalassemia major, with typical red cell morphology and indices, and with about 10% Hb Bart's but without measurable amounts of Hb H. Hematological evaluation of six members of this family that included in vitro hemoglobin synthesis suggests that β- (or δβ-) thalassemia, β-silent thalassemia, and mild and severe α-thalassemia genes are present in different combinations. The data indicate that β/α chain ratios in patients with more than one type of thalassemia should be evaluated in relationship to values obtained for several relatives even though some of the thalassemia determinants may be silent in the parents.