Biochemistry Hemoglobinopathies Study Notes

Biochemistry Study Notes - Hemoglobinopathies

• Hemoglobinopathies are diseases related to hemoglobin.
• Globin genes produce globin protein first, followed by the heme group.
• Hemoglobin has two gene families: alpha and beta.
• The alpha gene family is located on chromosome 16 and has 2 genes for alpha-globin chains.
• Other chains remain throughout life.
• Each of these genes has 2 alleles (4 loci in total) for synthesizing hemoglobin.
• The beta gene family is located on chromosome 11 and has a single gene for the beta-globin chain.
• Chromosome 11 also contains 2 gamma and 1 delta gene.
• Hemoglobinopathies are serious, inherited diseases - common worldwide.
• About 5% of the global population are carriers, causing substantial morbidity.
• Approximately 300,000 babies are born each year with hereditary disorders.

Qualitative Hemoglobin Abnormalities

• Qualitative abnormalities affect the quality of the hemoglobin structure, leading to structural variants.
• Sickle cell hemoglobin (HbS): an amino acid substitution in the beta subunit (Glu to Val) causes hemoglobin aggregation at low oxygen tension (PaO2 < 40 mmHg)
• This aggregation causes red blood cell deformation, increased resistance to squeezing in capillaries, and blockage.
• This leads to hypoxia, potential organ damage (e.g., kidneys, heart, lungs), and a shorter lifespan (<20 days) for sickled red blood cells compared to normal cells (120 days).

Quantitative Hemoglobin Abnormalities: Thalassemias

• Thalassemias are caused by reduced production of alpha or beta globin proteins.
• Alpha-thalassemia involves underproduction of alpha globin chains, affecting HbA, HbF, and HbA2.
• Different levels of gene deletions vary the severity from asymptomatic trait to hydrops fetalis which is fatal.
• Beta-thalassemia involves underproduction of beta globin chains.

Hemoglobin C (HbC)

• A substitution in beta subunit (Glu to Lys) causes less soluble hemoglobin which crystallizes more easily than normal hemoglobin.
• HbC is less severe than HbS, but still results in a minor hemolytic disorder.
• HbSC disease arises when individuals have both beta-C and beta-S mutations.

Methemoglobinemia (HbM)

• Methemoglobin occurs when iron in heme group is oxidized to Fe3+.
• This reduced the ability of hemoglobin to bind to oxygen.
• It can result from certain drugs like nitrates and can lead to blue baby syndrome.

Hereditary Persistence of Fetal Hemoglobin (HPFH)

• Individuals with HPFH retain fetal hemoglobin (HbF) into adulthood; this is a benign variant.

Electrophoresis

• A technique to identify different types of hemoglobin (normal, HbS, HbC) based on charge differences.
• Different hemoglobin types migrate differently within the electrophoresis gel and can be identified by comparing their relative positions.