Hemoglobinopathies Overview

Study Notes

Hemoglobinopathies are inherited disorders caused by structural abnormalities or imbalances in hemoglobin production
Hemoglobin is the protein responsible for oxygen transport in red blood cells
They can range from mild anemia to severe, life-threatening complications
Hemoglobinopathy includes all genetic hemoglobin disorders
Divided into two main groups: reduced rate of hemoglobin synthesis and structural hemoglobin variants

Reduced rate of hemoglobin synthesis includes Alpha-thalassemia and Beta-thalassemia
Structural hemoglobin variants include Sickle Cell Disease (HbS), Hemoglobin (HbC), (HbE), (HbD)

Normal adult blood contains Hemoglobin A (HbA), Hemoglobin A2 (HbA2), and Hemoglobin F (HbF)
HbA is the major component (α2β2)
HbA2 is a minor component (α2δ2)
HbF is fetal hemoglobin (α2γ2) and less than 1%

Globin genes have three exons (coding regions) and two introns (non-coding regions)
RNA transcripts include both, but introns are removed during splicing
mRNA is stabilized by polyadenylation at the 3' end
Mutations can cause thalassemia in the coding, splicing, or regulatory regions
Promoters (5') control transcription initiation
Enhancers (5' or 3') regulate tissue-specific and developmental expression
Locus Control Region (LCR) enables transcription by opening chromatin

Synthesis of an abnormal haemoglobin includes Sickle cell disease, Hb C, D & E
Reduced rate of synthesis of normal a- or β-globin chains leads to Alpha- and Beta-Thalassemias

Thalassemia is a heterogeneous group of genetic disorders caused by reduced synthesis of a or β globin chains
β-thalassemia is more common in the Mediterranean region, while α-thalassemia is prevalent in the Far East
Types include Major, Intermedia, and Minor

Caused by a-globin gene deletions or less frequently mutations
Inherited in an autosomal recessive pattern
Severity depends on how many a-globin gene copies are affected
Forms include Silent Carrier, a-Thalassemia Trait (Minor), Hb H Disease, Hydrops Fetalis (Hb Barts)
Non-deletional forms are caused by mutations affecting the termination of translation
Rare forms associated with mental retardation involve ATR-16 Gene Mutations and ATR-X Gene Mutations

Majority of genetic lesions are point mutations, rather than gene deletions
Inherited in an autosomal recessive pattern
Types include Major, Intermedia, and Minor
Mutations are in the HBB gene, leading to absent or reduced β-globin production
Common mutations include nonsense and frameshift mutations, and splice site mutations

Severe form characterized by transfusion-dependent anemia
Genetic Basis: Homozygous or Compound Heterozygous mutations in the β-globin gene (HBB).
Mutations lead to absent (β⁰) or reduced (β⁺) β-globin production

Moderate anemia, typically non-transfusion-dependent
Genetic Basis: Heterozygous or Compound Heterozygous mutations (cis or trans) in HBB gene

Carrier state with typically mild anemia or asymptomatic presentation
Heterozygous mutation in one HBB gene allele
Mutation types include β⁺ mutation (reduced β-globin production) and β⁰ mutation (no β-globin production)

Inherited disorder caused by substitution of valine for glutamic acid at position 6 in the β-globin chain
Autosomal recessive inheritance pattern
Mutation results in the formation of hemoglobin S (HbS)

Homozygous Sickle Cell Anemia (Hb SS) is the most common and severe form
Sickle Cell Disease with Hb C (Hb SC) is a double heterozygote condition
Sickle Cell Disease with β-Thalassemia (Hb S/β-thal) is a double heterozygote condition

Involves carrier screening of parents, fetal DNA testing, PCR techniques, gene sequencing, and risk assessment
Allows early medical management and preparation