When to consider transfusion therapy for patients with non-transfusion-dependent thalassaemia.

Non-transfusion-dependent thalassaemia (NTDT) refers to all thalassaemia disease phenotypes that do not require regular blood transfusions for survival. Thalassaemia disorders were traditionally concentrated along the tropical belt stretching from sub-Saharan Africa through the Mediterranean region and the Middle East to South and South-East Asia, but global migration has led to increased incidence in North America and Northern Europe. Transfusionists may be familiar with ß-thalassaemia major because of the lifelong transfusions needed by these patients. Although patients with NTDT do not require regular transfusions for survival, they may require transfusions in some instances such as pregnancy, infection or growth failure. The complications associated with NTDT can be severe if not properly managed, and many are directly related to chronic anaemia. Awareness of NTDT is important, and this review will outline the factors that should be taken into consideration when deciding whether to initiate and properly plan for transfusion therapy in these patients in terms of transfusion interval and duration of treatment.

What is the evidence of a role for host genetics in susceptibility to influenza A/H5N1?

The apparent family clustering of avian influenza A/H5N1 has led several groups to postulate the existence of a host genetic influence on susceptibility to A/H5N1, yet the role of host factors on the risk of A/H5N1 disease has received remarkably little attention compared to the efforts focused on viral factors. We examined the epidemiological patterns of human A/H5N1 cases, their possible explanations, and the plausibility of a host genetic effect on susceptibility to A/H5N1 infection. The preponderance of familial clustering of cases and the relative lack of non-familial clusters, the occurrence of related cases separated by time and place, and the paucity of cases in some highly exposed groups such as poultry cullers, are consistent with a host genetic effect. Animal models support the biological plausibility of genetic susceptibility to A/H5N1. Although the evidence is circumstantial, host genetic factors are a parsimonious explanation for the unusual epidemiology of human A/H5N1 cases and warrant further investigation.

Common origin of a rare beta-globin initiation codon mutation (ATG-->AGG) in Asians.

In this report, we describe two Thai siblings presenting with mild hypochromic microcytic anaemia and splenomegaly since 2(1/2) years of age. However, both patients were otherwise well with normal weight and height development and did not require transfusion during the 6-year follow-up period. Haematological and haemoglobin analyses were consistent with the clinical diagnosis of Hb E/beta-thalassaemia disease. To provide proper genetic counselling for this family, a definitive diagnosis of beta-thalassaemia was achieved using molecular analysis. We identified a rare initiation codon mutation (ATG-->AGG) of the beta-globin gene in combination with the Hb E mutation (codon 26: GAG-->AAG). The initiation codon mutation has previously been reported in several East Asian populations but has never been found in Southeast Asia and in combination with Hb E before. The haplotype analysis revealed a common origin of this mutation in the Asian population (5': - + - + + - +: 3', type IV with framework 3 according to Orkin S, et al.). Although this rare mutation abolished the beta-globin expression and was considered as beta(0)-thalassaemia, the relatively mild phenotype in our patients may be attributed to a strong association between this mutation and the -158 (G)gamma (C-->T) polymorphism, an XmnI cleavage site (+), resulting in a high propensity of postnatal gamma-globin expression and ameliorating the clinical phenotypes.

Haemoglobin E beta thalassaemia in Sri Lanka.

Haemoglobin E beta thalassaemia is the commonest form of severe thalassaemia in many Asian countries, but little is known about its natural history, the reasons for clinical diversity, or its management. We studied 109 Sri Lankan patients with the disorder over 5 years. 25 patients were not receiving transfusion; transfusion was stopped with no deleterious effect in a further 37. We identified several genetic and environmental factors that might contribute to the phenotypic diversity of the disorder, including modifiers of haemoglobin F production, malaria, and age-related changes in adaptive function. Our findings suggest that haemoglobin E beta thalassaemia can be managed without transfusion in many patients, even with low haemoglobin levels. Age-related changes in the pattern of adaptation to anaemia suggest that different and more cost-effective approaches to management should be explored.

Recent advances in understanding haemochromatosis: a transition state.

Mutations in the hepcidin gene HAMP and the hemojuvelin gene HJV have recently been shown to result in juvenile haemochromatosis (JH). Hepcidin is an antimicrobial peptide that plays a key role in regulating intestinal iron absorption. Hepcidin levels are reduced in patients with haemochromatosis due to mutations in the HFE and HJV genes. Digenic inheritance of mutations in HFE and HAMP can result in either JH or hereditary haemochromatosis (HH) depending upon the severity of the mutation in HAMP. Here we review these findings and discuss how understanding the different types of haemochromatosis and our increasing knowledge of iron metabolism may help to elucidate the host's response to infection.

Mutations in the general transcription factor TFIIH result in beta-thalassaemia in individuals with trichothiodystrophy.

The transcription factor TFIIH is involved in both basal transcription and DNA repair. Mutations in the XPD helicase component of TFIIH can result in the diverse clinical features associated with xeroderma pigmentosum (XP) and trichothiodystrophy (TTD). It is generally believed that the multi-system abnormalities associated with TTD are the result of a subtle deficiency in basal transcription. However, to date, there has been no clear demonstration of a defect in expression of any specific gene in individuals with these syndromes. Here we show that the specific mutations in XPD that cause TTD result in reduced expression of the beta-globin genes in these individuals. Eleven TTD patients with characterized mutations in the XPD gene have the haematological features of beta-thalassaemia trait, and reduced levels of beta-globin synthesis and beta-globin mRNA. All these parameters were normal in three patients with XP. These findings provide the first evidence for reduced expression of a specific gene in TTD. They support the hypothesis that many of the clinical features of TTD result from inadequate expression of a diverse set of highly expressed genes.

Linear growth in homozygous beta-thalassemia and beta-thalassemia/hemoglobin E patients under different treatment regimens.

The effects on linear growth and development among thalassemic patients under different treatment regimens were compared. Twelve homozygous beta-thalassemia (homozygous beta-thal) and 36 beta-thalassemia/Hb E (beta-thal/Hb E) were studied longitudinally between 1977 and 1998. Eighteen cases (10 homozygous beta-thal and 8 beta-thal/Hb E) received hypertransfusion with iron chelation by desferrioxamine. Another 30 cases (2 homozygous beta-thal and 28 beta-thal/Hb E) were given a low transfusion (depending on their clinical requirement). Their heights were measured serially and are presented as a standard deviation score (SDS). There was no significant difference in initial basic hematological data and ferritin levels between either group. However, the hypertransfused group, seemed to be clinically more severely affected than the other group as evidenced by early age at initial transfusion, the early onset of anemia and diagnosis and also their large acquired iron load after a period of transfusion. The average height SDS of the hypertransfused patients was within the 50th percentile +/- 1 SD during the first decade of life in both sexes and both genotypes. Whereas, in patients who were transfused infrequently, the SDS was always below the -1 SD and decreased gradually. In severe beta-thal/Hb E cases, their growth SDS showed no difference from those with homozygous beta-thal. Normal linear growth in those with homozygous beta thal and severe beta-thal/Hb E was only seen in the group that underwent hypertransfusion and this regimen contributed to normal growth during the first ten years of life. However, adequate iron chelation and hormonal treatment in these patients were also required in order to achieve normal adult height.