HFE and non-HFE hemochromatosis

Hereditary hemochromatosis (HH) is a disorder of iron metabolism in which enhanced absorption of dietary iron causes increased iron accumulation in the liver, heart, and pancreas. Most individuals with HH are homozygous for a point mutation in the HFE gene, leading to a C282Y substitution in the HFE protein. The function of HFE protein is unknown, but the available evidence suggests that it acts in association with beta2-microglobulin and transferrin receptor 1 to regulate iron uptake from plasma transferrin by the duodenum, the proposed mechanism by which body iron levels are sensed. The identification of HFE has established the foundation for a better understanding of the molecular and cellular biology of iron homeostasis and its altered regulation in HH. Additionally, the ability to accurately diagnose iron overload disorders has been strengthened, family screening has been improved, and evaluation of patients with other forms of liver disease complicated by moderate-to-severe iron overload is now possible. However, the role of HFE testing in generalized population screening for HH is still controversial. Recently, other forms of HH have been described that are not related to HFE but are due to mutations in genes coding iron transport proteins.     

Function of reticuloendothelial system in splenectomised thalassemics

Summary The activity of reticuloendothelial system (RES) was estimated in 19 patients with -thalassemia major, 20±4 years old, who had undergone successful splenectomy 6±5 years previously. The kinetics of ¹²⁵I denatured human serum albumin in low and large doses was applied for this purpose and the parameters derived (effective RES blood flow-ERBF- and maximum phagocytic capacity-PC_max) were compared to those of nonsplenectomised thalassemics, detected in previous works, as well as to those of 13 healthy controls. In splenectomised thalassemics both parameters of RES activity were found significantly lower than those of nonsplenectomised patients (p<0.001). Compared to those of healthy controls, PC_max of splenectomised thalassemics was found not to be significantly different, while ERBF was significantly lower (p<0.001). No correlation was noted between the above parameters of RES function and the age of the patients, the age at which splenectomy was performed, the time lapsed since the operation, the amount of blood transfused to the patients after splenectomy or their serum ferritin levels. A pilot study performed in 6 out of the 19 splenectomised patients did not reveal any effect of blood transfusion on RES function parameters, by contrast to observations in nonsplenectomised thalassemics. The results of this study suggest that in splenectomised thalassemics the remaining RES reacts to the continuing hemolytic stimulus in a manner different than that of splenic RES of nonsplenectomised patients and account for, at least in part, the predisposition of the former group to infections.     

Study of platelet activation,hypercoagulable state,and the association with pulmonary hypertension in children with β-thalassemia

Background

The increased survival rate of thalassemic patients has led to unmasking of management related complications which were infrequently encountered.

孕早期经腹行绒毛活组织检查在地中海贫血基因产前诊断中的应用价值

目的探讨孕早期经腹行绒毛活组织检查(TA2CVS)用于地中海贫血基因产前诊断的应用价值。方法对35例夫妇双方均为地中海贫血基因携带者的高风险孕妇在孕11¹3+6周时进行B超引导下经腹抽取绒毛,并对其胎儿进行绒毛地中海贫血基因检测。结果 35例孕妇经腹抽取绒毛均一次成功,21例α-地中海贫血高风险胎儿中检出Hb Bart′s纯合子4例,左缺失型H病2例,右缺失型H病1例。14例β-地中海贫血的高风险胎儿检出2例IVS-nt 654/CD4113+6周时进行B超引导下经腹抽取绒毛,并对其胎儿进行绒毛地中海贫血基因检测。结果 35例孕妇经腹抽取绒毛均一次成功,21例α-地中海贫血高风险胎儿中检出Hb Bart′s纯合子4例,左缺失型H病2例,右缺失型H病1例。14例β-地中海贫血的高风险胎儿检出2例IVS-nt 654/CD41⁴2双重杂合子,1例β4142双重杂合子,1例β41⁴2纯合子,1例IVS-nt 654纯合子。结论孕早期B超引导下经腹行绒毛活检能对地中海贫血产前基因作出安全、早期、快速、准确的诊断,从而预防重症患儿的出生,达到优生目的。     

Preimplantation genetic diagnosis,an alternative to conventional prenatal diagnosis of the hemoglobinopathies

Prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) both represent highly important reproductive choices for couples with a high risk of transmitting a severe disease, such as a severe hemoglobinopathy. Conventional PND for hemoglobinopathies based on molecular analysis of trophoblast or amniocyte DNA has been applied for around 30 years, but the major disadvantages with this approach include ‘invasive’ fetal sampling, and the potential involvement of pregnancy termination when affected. In comparison, the major advantage of PGD over conventional PND is that it supports the initiation of unaffected pregnancies, avoiding the need to terminate affected pregnancies. However, it is a multistep technically demanding procedure requiring the close collaboration of experts from several fields. PGD is also limited by the need to involve assisted reproduction, even in couples without fertility problems. Furthermore, even for fertile couples, pregnancy rates rarely surpass 30–35%. Both PND and PGD have advantages and drawbacks. Before embarking on either procedure, couples should be carefully counseled by experts so that they can select the option most appropriate for them. Finally, whatever their choice, it is paramount that both prenatal and PGD be applied with the highest standards of clinical, laboratory, and ethical practice.     

广西梧州籍汉族α-地中海贫血患者HLA-A、B等位基因多态性及单倍型分析

目的分析广西梧州籍汉族α-地中海贫血患者人类白细胞抗原（HLA）-A、B在高分辨基因分型水平上的等位基因多态性和单倍型的分布特征。方法采用聚合酶链反应-直接测序分型法（PCR-SBT）,对广西梧州籍汉族117例α-地中海贫血患者的HLA-A、B位点进行高分辨基因分型,用直接计数法计算等位基因频率,应用Arlequin V3.5软件,以最大似然法分析单倍型频率。结果在117例α-地中海贫血患者中共检出高分辨HLA-A等位基因17个,HLA-B等位基因33个。A位点等位基因频率最高的是A＊11：01（27.35%）,B位点等位基因频率最高的是B＊40：01（15.38%）和B＊46：01（14.96%）。频率最高的HLA-A-B单倍型有A＊33：03-B＊58：01（11.49%）、A＊02：07-B＊46：01（8.33%）、A＊11：01-B＊40：01（6.34%）。连锁不平衡最显著的单倍型是A＊33：03-B＊58：01、A＊02：07-B＊46：01、A＊74：02-B＊51：01、A＊02：03-B＊38：02、A＊11：02-B＊27：04。结论广西梧州籍汉族α-地中海贫血患者HLA-A、B等位基因具有较高的多态性,其双座位单倍型具有地区性遗传特征。     

HB Kaohsiung or New York: A T→A Substitution at Codon 113 of the β-Globin Chain Creates an Alu i Cutting Site

Epidemiological studies and experimental data suggest iron involvement in atherosclerosis. The relation between iron and atherosclerosis is complex and remains contradictory. In thalassemia patients, non transferrin bound iron (NTBI) and free hemoglobin (Hb) are present in plasma and may accelerate atherogenesis, but its progression may be inhibited by iron chelators.

The mechanism whereby iron may stimulate atherogenesis has been intensively investigated. Non transferrin bound iron and sera from subjects with hemochromatosis induced endothelial activation with expression of vascular adhesion molecules and endothelial inflammatory chemokines. Such events could be inhibited by iron chelators and oxygen radical scavengers with intracellular activity. Iron chelators may be effective in preventing vascular damage in patients with high concentrations of NTBI as found in thalassemia.     

Hb Paksé [(α2) CODON 142 (TA A→TA T OR Term→Tyr)] IN THAI PATIENTS WITH EABart's DISEASE AND Hb H DISEASE

Hb Paksé is caused by an α2-globin gene termination codon mutation, TA A→TA T or Term→Tyr, initially described in a Laotian family. We now report for the first time that the same mutation has been found in 14 Thai patients, seven with EABart's disease, four with Hb H disease, and three with α-thalassemia trait who were initially diagnosed as having Hb Constant Spring (Hb CS; α2-globin gene termination codon mutation T AA→C AA or Term→Gln). Co-inheritance of this mutation with α-thalassemia-1 (SEA type) leads to Hb H disease (hereafter designated as Hb H-Paksé disease) and to a complex thalassemia syndrome, namely EABart's-Paksé disease. Hematological data of these patients were compared with those of classical Hb H-CS and the EABart's patients. To facilitate epidemiological and diagnostic screening of Hb Paksé, a simple assay procedure based on allele specific polymerase chain reaction (PCR) amplifications was developed and validated. Using this allele specific PCR as a screening method, five additional individuals with Hb Paksé were found among 71 Thai subjects previously thought to have Hb CS.     

Hb G-CHINESE: A G → C SUBSTITUTION AT CODON 30 OF THE α2-GLOBIN GENE CREATES A PstI CUTTING SITE

We used magnetic resonance imaging (MRI) to compare the effect of iron chelation on liver, spleen and bone marrow. We examined 21 β-thalassemic patients undergoing deferoxamine (DFO) (9/21) or combined therapy [DFO and deferiprone (L1), 12/21] with two abdominal MRI studies using T1-w/Pd-w/T2*-wGRE and T1-wTSE sequences. Changes in serum ferritin (DF%), and liver, spleen and marrow to paraspinous muscles signal intensity ratios (SI) in T1-wTSE sequence were calculated as D%=[(2^ndvalue-1^st value)/1^st value] ×100%. Negative DF% and positive D(SI)% indicated reduction of iron. Although 17/21 (80.9%) patients demonstrated reduction in ferritin, only 8/21 (38%), 7/21 (33.3%) and 7/21 (33.3%) patients had decreased liver, spleen and marrow iron. Patients undergoing combined therapy showed significantly greater reduction (Student's t-test, p < 0.05) or less increase (t-test, p <0.05) in iron stores. Combined therapy is more effective than DFO for removing and preventing liver, spleen and bone marrow iron accumulation in β-thalassemic patients. Magnetic resonance imaging is valuable for organ-specific monitoring of chelation therapy.