Haemoglobin-H disease due to a unique haemoglobin variant with an elongated O-chain

The clinical and genetic properties of an unusual O-chain variant of human haemoglobin are described. It constitutes less than 1 percent of the total haemoglobin in heterozygotes and, when inherited together with an O-thalassaemia gene, produces the clinical picture of haemoglobin-H disease. Preliminary structural studies indicatge that, in addition to the 141 aminoacid residues which constitute the normal O-chain, this variant has about 31 extra residues attached to the C-terminal end.(SUMMARY)

Haemoglobin H disease caused by alpha-thalassaemia and a new abnormal haemoglobin with an elongated alpha-chain (Hb constant spring) - abstract

Of the 120 or so variants of human haemoglobin polypeptide chains so far described, nearly all are the result of the substitution of a single amino acid residue for another, or a deletion of one or more residues in the chain, caused by a point mutation in the codens of the chromosomal DNA. Hb H disease is also a genetically determined haemolytic anaemia, common in Orientals, but is caused by a reduced rate of synthesis of the O-chain of normal haemoglobin, resulting in an excess of á-chains (Hb H). A study of a Chinese family in Jamaica has revealed a slow moving haemoglobin in three children who have clinical haemoglobin H disease and in their fathers and siblings who have no haematological abnormality. The mothers have classical O-thalassaemia trait, as do some of the other siblings. Detailed biochemical analysis of this variant has shown that the O-chain is abnormal and is elongated by the addition of 31 residues to the 141 of the normal OA-chain. The extra residues are continuous with the normal C-terminal (O-141 Arg.) Biosynthetic studies, incorporating H(to 3rd power) leucine have indicated a low rate of synthesis for this abnormal chain. Interest lies in the nature of the genetic defect which could produce this abnormalty. While considering several hypotheses, the authors favour the theory that the genetic codon for 'end of chain' is the site of a mutation. This hypothesis is strengthened by finding Glutamine to be the next residue after the C-terminal Arginine. This extra piece of chain bears no resemblance to any known human globin chain sequence, so that it is unlikely that it has resulted from an unequal crossing over in a similar way to the Lepore haemoglobins. It may be that the messenge RNA for the normal OA-chain is longer than is required to direct synthesis of the chain. Further studies are in progress to try and define the nature of this genetic defect (AU)

Emergence of Western diseases in the tropical world: the experience with chronic cardiovascular diseases

Our knowledge of the disease burden components of tropical populations is fragmentary. Historically, the infectious diseases have been emphasized but, as some populations have undergone socio-economic changes, vital statistics have described a change in the pattern of disease. The picture is of a decline in infectious and a rise in chronic non-communicable disease. We focus here on the emergence of chronic cardiovascular diseases, and use hypertension as the paradigmic example. Early blood pressure surveys showed a virtual absence of hypertension among rural Africans and moderate prevalences in the Caribbean. Prevalence was highest among US and UK blacks. In a recent comparative study of blood pressure and its determinants in Nigeria, Jamaica and the US there was a steep gradient in prevalence from 15 percent through 26 percent to 33 percent. Body mass index and salt intake were the major determinants, accounting for 70 percent of the variance in hypertension prevalence. Additional information on mechanism comes from the exploration of the renin-angiotensin system across these populations. Angiotensinogen levels rise steadily from Africa to the US and are modestly associated with body mass index (BMI), and even more modestly with polymorphisms of the angiotensinogen gene. 30 percent of the variation in angiotensin-converting enzyme levels is attributable to the insertion/deletion polymorphism, and angiotensin-converting enzyme levels are modestly related to BMI and blood pressure. Thus, the steep gradient in prevalence is not attributable to the genetics as manifested in the renin-angiotensin system. The usefulness of these and other data on cardiovascular diseases include planning for primordial prevention in Africa and amelioration of existing epidemics in the Caribbean, the US and the UK. Additional long term surveillance data to define the burden and distribution of causes are necessary in Africa. Lastly, education and advocacy to transfer the information to policy makers and planners is required.(Au)

Fetal hemoglobin levels and beta s globin haplotypes in an Indian population with sickle cell disease

To further explore the cause for variation in hemoglobin F (HbF) levels in sickle cell disease, the á globin restriction-fragment length polymorphism haplotypes were determined in a total of 303 (126SS, 141AS, 17Sá§, 7Aá§, and 12AA) Indians from the state of Orissa. The ás globin gene was found to be linked almost exclusively to a ás haplotype (+++-++-), which is also common in Saudi Arabian patients from the Eastern province (referred to as the Asian ás haplotype). By contrast, the majority of áA and ᧠thalassemia globin genes are linked to hoplotypes common in all European and Asian populations (+-----[+/-];--++-++). Family studies showed that there is a genetic factor elevating HbF levels dominantly in homozygotes (SS). This factor appears to be related to the Asian ás globin haplotype, and a mechanism for its action is discussed. There is also a high prevalence of an independent Swiss type hereditary presistance of fetal hemoglobin (HPFH) determinant active in both the sickle cell trait and in sickle cell disease.(AU)

The genetics and molecular basis of alpha thalassaemia in association with Hb S in Jamaican Negroes

We have studied seven Jamaican Negro families in whom the genes for O thalassaemia and the sickle cell mutation (ás) were independently segretated. Using a combination of techniques we identified two O thalassaemia phenotypes which resemble the reserve (O thalassaemia 1) and mild (O thalassaemia 2) determinants previously described in Orientals. This study has enabled us to clearly correlate the phenotype of O thalassaemia with the genotype in this population. Furthermore, since in each family O thalassaemia was present in association with the gene for the sickle cell mutation we have determined the proportion of Hb S in the peripheral blood of individuals with the OO/OO, -O/-O genotype who are also heterozygous for the ás mutation. Genetic analysis in these families shows that in each case subjects with the O thalassaemia 1 phenotype are homozygous for the O thalassaemia 2 defect (-O/-O). We have found no instances of the genotype --/OO in this population which may explain the rarity of the severe O thalassaemia 2 homozygotes from this population shows that the (-O/) haplotype results from a deletion of one of the linked pair of O globin and that this had probably arisen by an unequal crossover between non-homologous O genes (AU)

Benign sickle-cell an‘mia

Clinical, h‘matological, genetic, chemical, and oxygen-affinity studies have been carried out on a group of 18 Shiite Saudi Arabians with sickle-cell an‘mia. Apart from occasional attacks of mild musculo-skeletal pain they are well and have few of the complications which are usual in the sickling disorders. The unusually mild course of the illness is attributable, at least in part, to a genetically determined ability to produce large amounts of fetal h‘moglobin (Summary)

Interaction of the OOO globin gene haplotype and sickle haemoglobin

We have studied the interaction of the OOO/OO gene arrangements with various á globin genotypes (AA, AS, AC, SS and SC). Whereas this interaction has no detectable clinical or haematological effects in subjects with AA, SS or SC genotypes it is associated with a significantly increased level of Hb S or Hb C in heterozygotes for these variants. These findings indicate that the additional O globin gene in the OOO gene arrangement is functional (Summary)

Hb F synthesis in sickle cell anaemia: a comparison of Saudi Arab cases with those of African origin

Fetal haemoglobin (Hb F) synthesis has been studied in 22 cases of sickle cell anaemia (SS) from Saudi Arabia and compared with an equal number of cases of African origin. Among the Saudi Arabs y chain synthesis ranged from 4.0 percent to 19.9 percent of the total non-x chain synthesis (mean 8.1 percent) while the corresponding range for the Negro cases was <0.3 percent to 4.6 percent (mean 1.7 percent). In both groups the peripheral blood HB F level was on average 3-4 times higher than the proportion synthesized, indicating that the selective survival of Hb F containing cells (F cells) was an important factor in determining the final Hb F levels. Among the Saudi Arab cases there was a significant negative correlation between the degree of F cell enrichment and either the Hb F level or the percentage y chain synthesis. No such correlation was observed among the Negro cases. A high proportion of the cases in both groups were carriers of x thalassaemia in addition to SS, but no effect of x talassaemia on Hb F production was observed (AU)

A genetic marker for elevated levels of haemoglobin F in homozygous sickle cell disease

Ten patients with sickle cell (SS) disease from a Jamaican family were found to have unusually high levels of haemoglobin F for this population. Each of them has inherited one sickle cell gene on a chromosome characterized by an arrangement of restriction fragment length polymorphisms (haplotype) which is very rare in the Jamaican population. Genetic analysis of the family suggests that there is a determinant linked to the á-globin gene cluster, charaterized by this haplotype, which is responsible for increased haemoglobin F production in response to anaemia. Interestingly this particular haplotype appears to be common in patients with SS disease in eastern Saudi Arabia in whom a high level of haemoglobin F is the rule rather than the exception. Hence it is possible that this haplotype (++-++) acts as a genetic marker for elevated levels of haemoglobin F in sickle cell disease (AU)

Effect of alpha thalassaemia on the rheology of homozygous sickle cell disease

A study of rheological determinants (plasma viscosity, whole-blood viscosity, and erythrocyte deformability) was made in 24 matched pairs of patients with homozygous sickle cell disease, with and without homozygous x-thalassaemia. Patients with coexisting x-thalassaemia showed a significant increase in erythrocyte deformability measured as filtration of washed erythrocytes through 5 um diameter pores and also as viscosity of whole blood at high shear rate (230s-1) and standard haematocrit (0.45). This rheological advantage may explain the beneficial effect of x-thalassaemia 2 on haematological parameters and clinical events in homozygous sickle cell disease (AU)

Detection of alpha thalassaemia in Negro infants

A prospective study of 2191 Negro infants in Jamaica showed that approximately 7 percent of them had detectable levels of Hb Bart's (Y4) in the neonatal period. The red cell indices, globin chain biosynthesis and restriction endonuclease mapping of DNA from these infants were used to determine the significance of Hb Bart's at birth. The results indicate that the genotypes OO/OO, - O/OO and - O/-O are associated with 0 percent, 0.1-2 percent, and greater than 2 percent Hb Bart's respectively. Although trace amounts of Hb Bart's may be associated with the genotype - O/OO this is not always the case and therefore haemoglobin analysis in the neonatal period cannot be used to diagnose this genotype with any certainty (AU)

Linkage relationships between beta- and delta-structural loci and African forms of beta thalassaemia

Five families are described in which there have been matings between individuals doubly heterozygous for beta thalassaemia and the delta-chain variant haemoglobin A2' to normal persons. In all there were 24 informative offspring. There were no crossovers between the beta-thalassaemia and delta-chain loci; in three of the families the genes were linked in cis and in two families the genes were found in trans.Together with previously reported families there have now been 58 opportunities for crossing over between the beta-thalassaemia and delta-chain loci and there have been two possible and one highly probable crossovers. Of the total of 9 families reported to date 4 have had the genes for beta thalassaemia and Hb A2' in cis and 5 in trans. These findings are contrasted with the findings in families where a beta-chain structural variant and Hb A2' have been observed together and these genes have always been found in trans and never in cis. The reasons for linkage disequilibrium of this type are discussed. It is concluded tentatively that the distance between the delta-structural and beta-thalassaemia loci is greater than that between the delta-structural and beta-structural loci. To date this conclusion can only be applied to the beta+ -thalassaemia and beta-thalassaemia genes as found in the African population, since this is the only population with a high incidence of delta-chain mutants which allow linkage analysis of this type to be carried out. (AU)

Alpha-Thalassemia changes erythrocyte heterogeniety in sickle cell disease

Homozygous alpha thalassemia has the beneficial effect in sickle cell anaemia of reducing the hemolytic severity while changing several other hematological parameters. We examined in detail some of these hematological alterations. We find that the broad distribution in erythrocyte density and the large proportion of dense cells associated with sickle cell anaemia are both reduced with co-existing alpha-thalassemia. Measurements of glycosylated hemoglobin levels as a function of cell density indicate that the accelerated increase in cell density, beyond normal cell ageing, in sickle cell anaemia is also reduced with alpha thalassemia. The patients with homozygous alpha-thalassemia and sickle cell disease have slightly lower levels of hemoglobin F than non-thalassemic patients. Examination of hemoglobin F production revealed that the proportion of hemoglobin F containing reticulocytes remained unchanged, as did the proportion of hemoglobin F in cells containing hemoglobin F (F cells). Preferential survival of F cells occurs in sickle cell anaemia, with or without alpha-thalassemia, and the slight difference in hemoglobin F levels appear to reflect differences in numbers of circulating F cells. Thus in sickle cell disease with co-existing alpha-thalassemia, the change in the erythrocyte density profile, possibly due to inhibition of polymerisation-related increases in cell density, explains the hematological improvement.(Summary)

Alpha thalassemia and the hematology of homozygous sickle cell disease in childhood

Alpha thalassemia modifies the gematolic expression of homozygous sickle cell (SS) disease, resulting in increased total hemoglobin and HbA2 and decreased HbF, mean cell volume, reticulocytes, irreversibly sickled cells, and biliru-bin levels. The age at which these changes develop in children with SS disease is unknown. Ascertainment of globin gene status in a large representative sample of study the gematologic indices in nine children homozygous for Alpha thalassemia 2 (two-gene group), 90 children heterozygous for Alpha thalassemia 2 (three-gene group), and 167 children with a normal Alpha globin gene complement (four-gene group). The two-gene group had significantly lower mean cell volumes from birth, higher red cell counts from one month, lower reticulocytes from three months, and higher HbA2 levels from one year, as compared with the four-gene group. Children with three genes had intermediate indices but resembled more closely the four-gene group. Differences in total hemoglobin or in fetal hemoglobin between the groups were not apparent by eight years of age. The most characteristic differences of the two-gene group were the raised proportional HbA2 level and low mean cell volume, the latter having some predictive value for Alpha thalassemia status at birth.(AU)

The interaction of alpha-thalassemia and homozygous sickle-cell disease

Patients with homozygous sickle-cell disease may be homozygous for alpha-thalassemia 2 (O-/O-), may be heterozygous for alpha-thalessemia 2 (O-/OO), or may have a normal alpha-globin-gene complement (OO/OO). We compared the clinical and hematologic features of 44 patients who had sickle-cell disease and homozygous alpha-thalassemia 2 with those of controls with the two hematologic conditions. The patients with homozygous alpha-thalassemia 2 had significantly higher red-cell counts and levels of hemoglobin and hemoglobin Aý, as well as significantly lower hemoglobin F, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, reticulocyte counts, irreversibly-sickled-cell counts, and serum total billirubin levels, than those with a normal alpha-globin-gene complement. Heterozygotes (O-/OO) had intermediate values. In the group with homozygous alpha-thalassemia 2, fewer patients had episodes of acute chest syndrome and chronic leg ulceration and more patients had splenomegaly, as compared with patients in the other two subgroups. These data confirmed previous suggestions that alpha-thalassemia inhibits in vivo sickling in homozygous sickle-cell disease and may be an important genetic determinant of its hematologic severity.