Pathophysiology of Compound Heterozygotes Involving Hemoglobinopathies and Thalassemias

Tim R Randolph

doi:10.29074/ascls.21.4.240

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Tim R Randolph, PhD MT(ASCP) CLS(NCA)⇑
1. is associate professor, Department of Clinical Laboratory Science, Doisy College of Health Sciences, Saint Louis University, St. Louis MO

Address for Correspondence: Tim R Randolph MS MT(ASCP) CLS(NCA), associate professor, Department of Clinical Laboratory Science, Doisy College of Health Sciences, Saint Louis University Allied Health Professions Building, 3437 Caroline Street, St. Louis MO 63104-1111. (314) 977-8688. randoltr{at}slu.edu.

Compare and contrast hemoglobinopathies and thalassemias.
Describe the most common type of mutation found in the majority of hemoglobinopathies and α-thalassemias.
List the five categories of mutations common in β-thalassemia.
Discuss why compound heterozygotes involving HbS and either a β-chain hemoglobinopathy or β⁺-thalassemia are less severe than sickle cell disease but more severe than sickle cell trait.
Discuss why an α-thalassemia mutation occurring in a HbSS patient lessens the severity of the existing sickle cell disease.
List two compound heterozygotes that mimic other hemoglobinopathy and/or thalassemia conditions.

Extract

Hemoglobinopathies and thalassemias are both hematologic diseases involving mutations in the genes that control the synthesis of globin chains that compose hemoglobin. Some hematologists use the term hemoglobinopathy to describe any hemoglobin disorder to include the hemoglobin variants (e.g., sickle cell) and thalassemia. Other hematologists use the term hemoglobinopathy to describe only the qualitative hemoglobin variants and the term thalassemia to describe disorders producing a quantitative reduction in hemoglobin synthesis. The latter approach will be used in this review.

GENETIC MUTATIONS Single nucleotide substitutions (point mutations) are the most common types of lesions occurring in the hemoglobinopathies. To date over 900 distinct mutations have been identified that are known to cause a hemoglobinopathy.¹ In most cases the nucleotide alteration found in the hemoglobinopathies is a simple substitution causing the nucleotide sequence to remain “in frame” resulting in a single amino acid substitution that will not change the overall size of the globin protein product. Thus the defect in the globin molecule is ordinarily an amino acid substitution that changes the amino acid sequence affecting protein structure and function rather than quantity. Typical alterations in hemoglobin function include changes in oxygen binding affinity, molecular solubility, and the manner in which the individual hemoglobin molecules interact within the red blood cell (RBC). See Table 1.

In contrast, the types of mutations encountered in the thalassemias are broad and diverse and ultimately affect the quantity of protein manufactured inside the developing RBC. Although over 300 different mutations have been identified as the cause…

ABBREVIATIONS: Ala = alanine; Arg = arginine; Asn = asparagine; DNA = deoxyribonucleic acid; Gln = glutamine; Glu = glutamic acid (glutamate); Gly = glycine; Hb = hemoglobin; HPLC = high performance liquid chromatography; IVSII-745 = intervening sequence at codon 745; Leu = leucine; Lys = lysine; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; RBC = red blood cell; Term = termination codon; Thr = threonine; Val = valine.

Compare and contrast hemoglobinopathies and thalassemias.
Describe the most common type of mutation found in the majority of hemoglobinopathies and α-thalassemias.
List the five categories of mutations common in β-thalassemia.
Discuss why compound heterozygotes involving HbS and either a β-chain hemoglobinopathy or β⁺-thalassemia are less severe than sickle cell disease but more severe than sickle cell trait.
Discuss why an α-thalassemia mutation occurring in a HbSS patient lessens the severity of the existing sickle cell disease.
List two compound heterozygotes that mimic other hemoglobinopathy and/or thalassemia conditions.