Hemoglobinopathies and Sickle Cell Disease

Hemoglobinopathies

• Inherited disorders causing structurally abnormal globin chains

• Qualitative defects due to amino acid substitutions

• Changes in red blood cell (RBC) deformability and electrophoretic mobility can occur

• Homozygous condition (both globin chains affected) is more serious than heterozygous (only one globin chain affected)

• Target cells are associated with hemoglobinopathies

• Diagnosis confirmed via hemoglobin electrophoresis, isoelectric focusing, or DNA analysis

• Hgb S formation (most common amino acid substitution) is the most common cause

• Hgb C (second) and Hgb E (third) are also common

Sickle Cell Disease (Hgb SS)

• Valine replaces glutamic acid at position 6 on both beta chains

• Results in decreased hemoglobin solubility and function

• Defect inherited from both parents

• Primarily present in sub-Saharan Africa (64.4%)

• Other regions include Arab-India (22.7%), The Americas (7.4%), Eurasia (5.4%), and Southeast Asian (0.1%)

• Approximately 230,000 babies are born with sickle cell disease in sub-Saharan Africa each year

• Production of Hgb A is absent with ~80% Hgb S and 20% Hgb F compensation

• Hgb insolubility results in crystallization within erythrocytes, creating characteristic sickled shapes

Sickle Cell Trait (Hgb AS)

• Valine replaces glutamic acid at position 6 on one beta chain
• Inherited from one parent
• Produces approximately 60% Hgb A and 40% Hgb S
• Common hemoglobinopathy in the USA

Hemoglobin C Disease (Hgb CC)

• Lysine replaces glutamic acid at position 6 on both beta chains

• Inherited from both parents

• Found in African Americans (2-3%) and West Africans (17-28%)

• Approximately 90% Hgb C, 2% Hgb A2 and 7% Hgb F

• Mild anemia is possible

Hemoglobin C-Harlem (Hgb C-George town)

• Double substitution on beta chain (Valine for glutamic acid at position 6 and aspartic acid for asparagine at position 73)

• Heterozygous forms are asymptomatic

• Compound heterozygosity (HbS and HbC-Harlem) is similar to Hgb SS disease

Hemoglobin SC Disease

• Abnormal sickle gene from one parent and abnormal C gene from the other parent

• Glutamic acid replaced by valine in one beta chain, and by lysine in the other

• Common in West African, Mediterranean and Middle Eastern populations

• Approximately 50% Hgb S and 50% Hgb C are produced

Hemoglobin E (HbEE)

• Lysine replaces glutamic acid at position 26 on the beta chain

• Common in Southeast Asian, African, and African-American populations

• Homozygous form results in mild anemia with microcytes and target cells

• Heterozygous forms are usually asymptomatic

Hemoglobin D

• Glycine replaces glutamic acid at position 121 on the beta chain
• Found predominantly in Middle Eastern and Indian populations
• Most variants are named for the region of discovery.
• Homozygous and heterozygous forms are usually asymptomatic

Hemoglobin G

• Lysine replaces asparagine at position 68 in alpha chain
• Common variant in African-Americans

Hemoglobin M

• Point mutations in alpha or beta globin genes result in methemoglobin production

Hemoglobin-Arab

• Lysine replaces glutamic acid at position 121
• In Kenya, Israel, Egypt, and Bulgaria; it represents a prevalence of 0.4% in African-Americans
• No clinical symptoms; only mild splenomegaly in homozygotes

Thalassemias

• Group of inherited disorders characterized by a decreased rate of synthesis of normal globin chains.
• Grouped by affected globin chains:
  • Alpha Thalassemias
  • Beta Thalassemias
• Varying severity in affected population, ranging from asymptomatic conditions to severe transfusion-dependent disease.