Hemoglobinopathies Flashcards
Delta thalassemia
Clinically silent, but affects the level of HbA2 (decreased in Hets, absent in Homs)
As a result, diagnosis of coexisting thalassemias and hemoglobinopathies can become difficult
Hemoglobin E
Caused by β26 (Glu→Lys) mutation, which ultimately leads to poor splice efficiency of the mRNA and results in functional downregulation of gene product.
Hereditary Persistence of Fetal Hemoglobin
Group of disorders as described. Often on the DDx against the δβ and γδβ thalassemias since all have a relative increase in HbF.
What types of mutations tend to produce a β+ or β++ thalassemia?
Mutations in the 5′ promoter region (TATA box, proximal CACCC, distal CACCC box) tend to produce a 70-80% reduction in β chain production, producing a very mild/β++ phenotype.
Mutations in the 3’ tail affecting polyadenylation tend to produce similarly mild/β+ phenotypes.
Dominantly inherited beta thalassemias
Very rare, but several have been described
Often this is due to frameshift mutations that occur without an early stop after the frameshift transition point, resulting in a long strand of nonsensical protein translation. These nonsense strands tend to aggregate and contribute to red cell overload, resulting in worsening of ineffetive hematopoiesis.
HbE/β thalassemia
Most common severe form of thalassemia in Southeast Asia and parts of the Indian subcontinent
The clinical and hematological changes of HbE/β thalassemia are variable, ranging from severe anemia and transfusion dependency to thalassemia intermedia. There is nearly always anemia (hemoglobin values range from 4–9 g/dl) and splenomegaly
It can be difficult to differentiate homozygous HbE (HbE/E) from HbE/β° thalassemia on Hb electrophoresis alone since only HbE and F are observed in both cases. Genetic studies would be definitive since both parents would be HbE carriers in HbE/E, but HbE trait in one parent and β thalassemia trait in the other, in HbE/β thalassemia
HbC/β thalassemia
HbC/β thalassemia is largely asymptomatic and characterized by a mild hemolytic anemia and splenomegaly
The diagnosis is confirmed by demonstrating HbC trait in one parent and β thalassemia in the other.
δβ-, γδβ-thalassemias and HPFH syndromes
Characterized by a reduced or absent synthesis of β- and δ-globin chains and a variable compensatory increase in γ chain production
Heterozygotes for δβ thalassemia have a red cell picture similar to β thalassemia, with hypochromic microcytic red cells, but normal levels of HbA2 (<3.0%).
HPFH heterozygotes have essentially normal red cell indices, normal levels of HbA2 and higher levels of HbF (15–30%).
