Alex E. Felice

Hb evans or α262(e11)val→metβ2; an unstable hemoglobin causing a mild hemolytic anemia

Structural analysis o f the α chain of the hemoglobin from a Caucasian female with a mild hemolytic anemia showed the presence of a variant with a Val→Met substitution at position α62. The valine at this position forms one o f the contacts with heme and its replacement by methionine will likely decrease heme binding and cause adistortion of the heme crevice and a decreased stability of the abnormal protein. Dot-blot analysis of amplified DNA with 32P-labeled synthetic oligonucleotide probes confirmed the suspected G→A mutation in the first position of codon 62, and also located the mutation in the α2-globin gene. The mutation was found in the proposita and one of her daughters but was most probably absent in her parents.

δβ-Thalassemia in a Mexican Family: Clinical Differences Among Homozygotes

Three delta beta-thalassemia homozygotes were found in a Mexican family. Both parents and two sibling had heterozygous delta beta-thalassemia with about 10% Hb F, mild microcytosis and mild hypochromia, while three siblings were normal. Hb F, which was the only Hb component in the homozygotes, had equal quantities of Ggamma and Agamma chains as in BgammaAgamma-delta beta-thalassemia. The homozygotes had comparable erythrocytic indices which were about the same as those of the heterozygotes. However, two were clinically and hematologically healthy but the third had a severe chronic hemolytic anemia and a more severe in vitro chain synthesis imbalance than her homozygous sisters. Comparison of these cases with other GgammaAgamma-delta beta-thalassemia homozygotes and with GgammaAgamma-HPFH homozygotes indicates the possibility that the proliferation of F-cell precursors may be defective in delta beta-thalassemia.

Alternate Organization of α G-Philadelphia Globin Genes Among U.S. Black and Italian Caucasian Heterozygotes

Seven Hb G-Philadelphia (Hb G) heterozygotes from three Caucasian families from Northern Italy and Sardegna were found to have proportions of Hb G averaging 23%. This value is considerably lower than the 34% or 48% found in Blacks from the Southeastern U.S.A. in whom the alpha G gene is in linkage with alpha-thalassemia-2, i.e. the alpha o alpha G/alpha alpha or alpha o alpha G/alpha o alpha genotypes. Gene mapping identified tandem organization of the alpha G gene in cis with a normal alpha A gene, i.e. the alpha alpha G/alpha alpha genotype, among the Hb G heterozygotes from Italy. The data on the Italian heterozygotes are similar to those obtained by Bruzdzinski et al (14) on a Black family. These results indicate alternate organization of the alpha G genes probably across racial or ethnic boundaries. Comparison of the mean cellular globin amount of alpha G/alpha G gene/cell among Hb G heterozygotes with 4, 3, 2 or 1 alpha globin genes (i.e. alpha A + alpha G) revealed considerable reactivation of individual alpha genes in conditions of mild to severe alpha globin deficiencies.

?-Thalassemia and the production of different ? chain variants in heterozygotes

The production of five α chain variants (Hb G-Georgia, Hb St. Lukes, Hb Lloyd, Hb Montgomery, and Hb G-Philadelphia) in heterozygotes was evaluated through hematological observations, hemoglobin quantification, and biosynthetic studies. All heterozygotes for Hb St. Lukes and Hb Lloyd and most heterozygotes with Hb G-Georgia and Hb Montgomery had normal hematology and average σα/β values of about 1.1. They were assigned a normal genotype (ααG/αα), although the proportions of Hb St. Lukes and Hb G-Georgia were low (10 to 13%) and those of Hb Lloyd and Hb Montgomery twice as high (20%). Data from short-term incubations confirmed this genotype for some of these heterozygotes. Isolated Hb St. Lukes and Hb G-Georgia gave low αG/β values (0.2 and 0.3) indicating that these Hb variants were defective at the level of Hb assembly. Isolated Hb Montgomery and Hb G-Philadelphia, however, gave higher αG/β values of 0.6 and 0.8, respectively. A second type of variability existed among Hb G-Georgia (20 vs. 13%), Hb Montgomery (28 vs. 20%), and Hb G-Philadelphia (47 vs. 34%) heterozygotes, in whom the levels of Hb G differed. The occurrence of higher levels of these three α chain heterozygosities was associated with hematological or biosynthetic evidence of a mild or moderate α chain deficiency due to an α-thalassemia-2 heterozygosity (ααG/α0α or α0αG/αα) or a homozygosity (α0αG/α0α), respectively.

Adult and Fetal Hemoglobin Production in Erythroid Colonies from Subjects with β-Thalassemia or with Hereditary Persistence of Fetal Hemoglobin (HPFH)

The synthesis of alpha and non-alpha chains (beta, delta, G gamma, and A gamma) was studied in cultures of peripheral blood mononuclear cells from eleven beta-thalassemia heterozygotes, two HPFH heterozygotes, and one HPFH homozygote. The synthesis of Hb F in the thalassemia colonies (average value: 12.6%) was comparable to that in normal adult colonies (average value: 12.6%) was comparable to that in normal adult colonies (average value: 12.2%). The percent G gamma chain in the Hb F varied greatly but a relationship between the G gamma chain percentage in the Hb F from colonies and that from peripheral blood was established. The relative synthesis of Hb A2 in colonies of beta-thalassemia heterozygotes (average value: 5.8%) was 1.6 times as much as that in colonies of normal adults (average value: 3.6%). Hb A2 and Hb A were absent in the colonies of the HPFH homozygote. The alpha/non-alpha (i.e., beta, gamma, and delta) ratio of the hemoglobins in the cultured cells of the beta-thalassemia heterozygotes and the alpha/beta and alpha/beta ratios of isolated Hb A and Hb A2 were about one (range 0.74 to 1.38). The alpha/gamma ratio of the Hb F synthesized in BFUe-derived colonies of the HPFH homozygote, however, was 1.5. These results suggest a deficiency in the in vitro culture system resulting in decreased levels of alpha-mRNA or in a partial inhibition of initiation of protein synthesis which is known to reduce the synthesis of alpha chains more than that of the beta chains.

Hb Nottingham (α;2β;2 (FG5) 98 VAL→GLY) in a Caucasian Male: Clinical and Biosynthetic Studies

A second instance of the unstable mutant Hb Nottingham (α;2β;2 (FG5) 98 Val→Gly) is reported in a 7-year-old boy. Because of splenomegaly, cholelithiasis, and frequent episodes of abdominal pain, he underwent a splenectomy and cholecystectomy at age 6. The surgery resulted in both an amelioration of his RBC destruction and an acceleration of his rate of growth.Biosynthetic studies were carried out using reticulocytes obtained from his peripheral blood. These analyses disclosed an exceedingly high specific activity ratio for Hb N/Hb A. In addition as the incubation proceeded, more radioactivity accumulated in the α; chain fraction than in the β; chains (β;A+β;N). This observation is presumed secondary to degradation of the unstable β;N chains.

Clinical and Hematological Evaluation of two δ0 δ0 - Thalassemia Homozygotes

Two homozygous δ0 β0-thalassemia patients, one with the GγAγ type and the other with the Gγ type, and their heterozygous parents are described. Red cell indices among the heterozygotes with the GγAγ type of δ0β0-thalassemia were markedly different from those in heterozygotes with the Gγ type. However, the imbalance in in vitro hemoglobin synthesis was quite similar in the two heterozygous conditions. The same was observed for the homozygous patients; the in vitro chain synthesis was severely imbalanced as seen in β-thalassemia major. The clinical and some of the hematological findings were milder in the Gγ-δ0 β0-thalassemia homozygote than in the GγAγ - δ0 β0-thalassemia homozygote. The death of a sibling of the Gγ - δ0 β0-thalassemia homozygote with a diagnosis of thalassemia major suggests that both types of δ0 β0 -thalassemia could follow a severe clinical and hematological course. The discovery of the Gγ type of δ0 β0-thalassemia in a Turkish child shows that two types of δ0 β0 - thalassemia can be fo...