Thalasemia & SCA Flashcards
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Inherited diseases caused by reduced or abnormal synthesis of globin, a component of hemoglobin, affect about 7% of the global population. Understanding normal hemoglobin synthesis in the fetus and adult is crucial to grasping these disorders
What are the Types of Hemoglobin in Adults? & their percentage
Hb A (α2β2): The major component of adult hemoglobin.
Hb A2 (α2δ2): Minor component, 1.5–3.5% of total hemoglobin.
Hb F (α2γ2): Fetal hemoglobin, about 0.5% in adults.
What she the types of Embryonic and Fetal Hemoglobins:
Hb Gower 1: Primary embryonic hemoglobin.
Hb Gower 2 and Hb Portland: Minor early gestational hemoglobins.
These hemoglobins include ζ- and ε-globins instead of α- and β-globins.
Fetal
Alpha & gamma
There are ____ types of Globin Gene Clusters & their number of chromosome
:
β-Globin Cluster (chromosome 11): Contains ε, γ, δ, and β genes.
α-Globin Cluster (chromosome 16): Contains ζ and α genes
Gene Structure and Function:
Each globin gene has ____exons (coding regions) and ____ introns (non-coding regions).
RNA Splicing: Introns are removed from the initial RNA transcript to form mature mRNA.
Polyadenylation: Stabilizes mRNA by adding a poly-A tail at the 3′ end.
three exons
two introns
Regulation of Globin Synthesis:
Promoters: Found upstream (5′) of the gene, initiate transcription.
Enhancers: Can be upstream (5′) or downstream (3′), regulate tissue-specific expression and fetal vs. postnatal synthesis.
Locus Control Region (LCR): Controls the β-globin cluster by opening chromatin for transcription factors.
HS-40 Region: Regulates α-globin synthesis, sensitive to DNA cleavage.
Transcription Factors: Such as GATA1, influence gene expression and can cause syndromes if mutated.
What’s thalasemia
Thalassemia, a group of inherited hemoglobin disorders, arises from mutations or deletions in globin genes or their regulatory sequences, leading to imbalanced globin chain synthesis. This can result in reduced or abnormal hemoglobin production, causing varying degrees of anemia and related complications.
Globin Gene Expression
Chromosomes 11 and 16: The globin genes are arranged in the order of their expression during development.
Embryonic Hemoglobins: Expressed in yolk sac erythroblasts.
Beta-Globin Gene: Initially expressed at low levels in early fetal life; the switch to adult hemoglobin occurs ____ to ____months after birth when γ-globin synthesis is largely replaced by β-globin.
3-6 months
What’s the major transcriptional regulator of the switch from fetal to adult hemoglobin.
BCL11A
Regulatory Mechanisms
BCL11A: A major transcriptional regulator of the switch from fetal to adult hemoglobin.
Transcription Factors: Other nuclear factors also play a role.
Cytosine Methylation: Expressed genes have hypomethylated cytosine bases in the promoter regions, whereas non-expressed genes are hypermethylated.
Chromosome Packaging: Histone protein status and DNA enhancer sequences contribute to gene transcription regulation.
What are the general Causes of Hemoglobin Abnormalities
Causes of Hemoglobin Abnormalities
Synthesis of Abnormal Hemoglobin: Altered amino acid sequence.
Reduced Synthesis Rate of Normal Globin Chains: Leads to globin deficit and imbalance, as seen in α- and β-thalassemias.
Examples of Abnormal Hemoglobins
Sickle Cell Disease (Hb S): The most clinically important, results from homozygous Hb S.
Hb C, D, and E: Common variants resulting from amino acid changes in the β chain.
Hb C: Common in sub-Saharan Africans.
Hb D: Found in western China and South Asia.
Hb E: Predominant in Southeast Asia.
Geographic Distribution and Evolutionary Aspects
Prevalence: These genetic defects are the most common worldwide, primarily in tropical and subtropical regions.
Evolutionary Advantage: The carrier state of these abnormalities offers some protection against malaria, explaining their high prevalence in certain areas
What are the possible conditions that thalasemia/ abnormal hemoglobin can cause
Unstable Hemoglobins
Chronic Hemolytic Anemia
Cause: Unstable hemoglobins lead to this condition.
Mechanism: Hemoglobin becomes unstable and breaks down easily. This leads to the destruction of red blood cells (hemolysis) within the blood vessels (intravascular hemolysis).
Effect: The destruction of red blood cells faster than they can be produced causes anemia, a condition where there are not enough red blood cells to carry sufficient oxygen to the body’s tissues.
Heinz Bodies
Definition: Heinz bodies are clumps of denatured (damaged and non-functional) hemoglobin found inside red blood cells.
Detection: They can be seen using special stains in blood films (slides of blood examined under a microscope).
Significance: The presence of Heinz bodies is an indication of hemoglobin instability and ongoing hemolysis.
Polycythemia or Erythrocytosis
Definition: Both terms refer to an increased number of red blood cells in the bloodstream.
Polycythemia: Generally refers to an increase in the total red blood cell mass.
Erythrocytosis: Specifically refers to an increase in the number of circulating red blood cells.
Cause: Some abnormal hemoglobins can stimulate the production of more red blood cells, leading to these conditions.
Effect: This can make the blood thicker and increase the risk of clotting problems.
Congenital Methemoglobinemia
Definition: A condition where an abnormal amount of methemoglobin (a form of hemoglobin that is unable to carry oxygen) is produced.
Cause: Certain hemoglobin abnormalities can cause methemoglobinemia.
Effect: This leads to reduced oxygen delivery to tissues, causing symptoms such as cyanosis (a bluish color of the skin and mucous membranes) and hypoxia (low levels of oxygen in the tissues
Benign Amino Acid Substitutions
Definition: Amino acid substitutions refer to changes in the sequence of amino acids in hemoglobin proteins.
Benign: Many of these changes do not affect the function of hemoglobin or cause any clinical problems.
Significance: Although some amino acid substitutions can lead to diseases like sickle cell disease or thalassemias, many do not have any significant effect on health.
The primary issue in thalassaemia is a reduced rate of synthesis of these globin chains, which leads to imbalances and various clinical symptoms.
What are the Geographic Prevalence: of thalasemia
β-Thalassaemia: More common in the Mediterranean region.
α-Thalassaemia: More common in South and Southeast Asia
What are the types of Thalassaemia
:
Thalassaemia Major (Transfusion-Dependent):
This is the most severe form, requiring regular blood transfusions to manage the severe anemia it causes.
Patients often present with significant symptoms early in life and require ongoing medical care to manage complications.
Thalassaemia Intermedia (Non-Transfusion-Dependent):
Characterized by a moderate degree of anemia.
Unlike thalassaemia major, patients with thalassaemia intermedia do not need regular blood transfusions but may require them occasionally, especially during periods of stress or illness.
This form results from a variety of genetic defects that are less severe than those causing thalassaemia major.
Thalassaemia Minor (Carrier State):
Typically, individuals with thalassaemia minor are carriers of the gene mutation but do not show significant symptoms.
Characterized by microcytosis (smaller than normal red blood cells) and usually mild or no anemia.
Individuals often lead normal lives without needing medical treatment.
Overview on alpha thalasemia?
What is it?
The N No. Of alpha chain
What determines the severity?
What Causes α-Thalassaemia? α-Thalassaemia syndromes are primarily caused by deletions (and less commonly, mutations) in the genes responsible for producing α-globin chains. Each person normally has four α-globin genes (two on each chromosome 16), and the clinical severity of α-thalassaemia depends on how many of these genes are missing or inactive.
What are the Clinical Severity Based on Gene Deletions:
Loss of All Four α-Globin Genes:
Condition: Complete suppression of α chain synthesis.
Outcome: This condition is incompatible with life because α chains are essential for both fetal and adult hemoglobin. The fetus cannot survive, leading to a condition called hydrops fetalis, resulting in death in utero.
Loss of Three α-Globin Genes:
Condition: Known as Hb H disease.
Symptoms: Causes moderately severe anemia, characterized by hemoglobin levels between 70–110 g/L. This type of anemia is microcytic (small red blood cells) and hypochromic (pale red blood cells). Patients often have splenomegaly (enlarged spleen).
Detection: Hemoglobin H (Hb H), which is a tetramer of β-globin chains (β4), can be detected in the red cells of these patients using electrophoresis or by examining reticulocyte preparations. In fetal and early infant life, before β-globin chains are produced in high levels, an alternative form called Hb Barts (γ4) can occur
Loss of One or Two Genes:
Symptoms: Usually not associated with anemia.
Blood Tests:
Mean Corpuscular Volume (MCV): Low (indicating smaller than normal red blood cells).
Mean Corpuscular Hemoglobin (MCH): Low (indicating less hemoglobin in each red blood cell).
Red Cell Count: Typically over 5.5 × 10¹²/L.
Diagnosis: Hemoglobin electrophoresis usually appears normal, so DNA analysis is necessary for a definitive diagnosis.
Non-Deletional Forms of α-Thalassaemia:
Cause: Point mutations that lead to dysfunctional genes or mutations affecting translation termination.
Examples:
Hb Constant Spring: A mutation that results in an elongated but unstable α-globin chain.
What are the Rare Forms Associated with Neurological Abnormalities:
ATR-16 Syndrome:
Cause: Small chromosomal deletions on chromosome 16, including the α-globin gene cluster.
Symptoms: Developmental neurological abnormalities along with α-thalassaemia.
ATRX Syndrome:
Cause: Mutation of the ATRX gene on the X chromosome, which controls the transcription of the globin and other genes.
Symptoms: Affects males and leads to both α-thalassaemia and developmental neurological issues.
How does Acquired α-Thalassaemia occur in Myelodysplastic Syndromes
Acquired α-Thalassaemia in Myelodysplastic Syndromes Explained
Cause:
Acquired Mutation: This form of α-thalassaemia arises not from inherited genetic mutations, but from mutations acquired during a person’s lifetime. Specifically, it involves mutations in the ATRX gene. The ATRX gene is crucial for regulating the expression of the α-globin gene and other genes.
Symptoms:
Similarity to Other α-Thalassaemias: The symptoms of acquired α-thalassaemia due to ATRX mutations are similar to those seen in inherited forms of the condition. These symptoms may include:
Low hemoglobin levels
Microcytic (small) and hypochromic (pale) red blood cells
Mild to moderate anemia
Splenomegaly (enlarged spleen)
Context of Myelodysplastic Syndromes (MDS): The key difference is that these symptoms occur within the context of myelodysplastic syndromes. MDS are a group of disorders caused by poorly functioning bone marrow, leading to ineffective blood cell production. Patients with MDS might have additional symptoms and complications related to bone marrow dysfunction, such as:
Fatigue
Increased risk of infections
Easy bruising or bleeding due to low platelet counts
What is Myelodysplastic Syndrome (MDS)?
Bone Marrow Disorder: MDS is a condition where the bone marrow does not produce enough healthy blood cells. This can lead to various types of blood cell deficiencies:
Anemia: Due to insufficient red blood cells
Neutropenia: Due to a lack of white blood cells, increasing infection risk
Thrombocytopenia: Due to a shortage of platelets, leading to bleeding and bruising
Link to α-Thalassaemia:
Mutation in ATRX Gene: In the case of acquired α-thalassaemia in MDS, mutations in the ATRX gene disrupt normal α-globin production, mimicking the effects of inherited α-thalassaemia.
Resulting Symptoms: The disruption causes typical α-thalassaemia symptoms but within the broader clinical picture of MDS.
Summary:
Acquired α-thalassaemia in myelodysplastic syndromes occurs due to mutations in the ATRX gene acquired during life. It presents with symptoms similar to inherited α-thalassaemia (like anemia and small, pale red blood cells) but arises in the context of MDS, a bone marrow disorder characterized by ineffective blood cell production.
Inheritance: If both parents carry the β-thalassaemia trait, there is a 25% chance for each child to have β-thalassaemia major.
What are the Types of β Chains Synthesized:
β⁰: No β chains are produced.
β⁺: Only small amounts of β chains are produced.
What can you say about beta thalasemia?
It’s severity?
& how gama might might help
Pathophysiology:
Excess α Chains: In the absence or deficiency of β chains, unpaired α chains accumulate. These excess α chains precipitate in erythroblasts (immature red blood cells) and mature red cells, leading to:
Severe Ineffective Erythropoiesis: The process of producing new red blood cells is highly inefficient.
Chronic Haemolysis: Ongoing destruction of red blood cells.
Severity of Anaemia:
The severity of anaemia correlates with the amount of excess α chains. More α chains mean more severe anaemia.
γ Chains: The production of γ chains can mitigate the condition by binding with some of the excess α chains, reducing their harmful effects.
Genetic Diversity:
Genetic Mutations: Over 400 different genetic mutations can cause β-thalassaemia. Most of these mutations are point mutations rather than gene deletions.
Location of Mutations: These mutations can occur within the gene itself or in regulatory regions like promoters or enhancers.
Ethnic Specificity: Certain mutations are more common in specific ethnic groups, which can aid in antenatal (before birth) diagnosis by targeting these known mutations in fetal DNA.
What thalasemia Major?
Thalassaemia major is a severe inherited condition caused by mutations affecting β-globin synthesis
Thalassaemia major often results from inheriting two different mutations affecting β-globin synthesis. This means the person has two distinct defective genes, one from each parent.
What are the types of gene mutations in thalasemia?
Types of Genetic Mutations:
Gene Deletions: In some cases, there is a deletion of the β gene, δ and β genes, or even δ, β, and γ genes.
Lepore Syndrome: This occurs due to unequal crossing-over during chromosome replication, producing δβ fusion genes. It is named after the Italian-American family where it was first identified.
Point Mutations: Most common in β-thalassaemia, these mutations can occur within the gene itself or in regulatory regions affecting gene expression. They are also found in some cases of α-thalassaemia.
Compound Heterozygosity: Individuals with two different mutations (e.g., one deletion and one point mutation) can exhibit a spectrum of clinical severity, from thalassaemia major to intermedia.
Non-Deletional Mutations: In α-thalassaemia, non-deletional mutations such as point mutations can lead to dysfunctional α-globin chains, contributing to disease severity.
What are the types of gene Deletions that can happen?
Gene Deletions:
β-Thalassaemia Major: Complete deletion of the β-globin gene can result in no production of β-globin chains, leading to severe disease.
β-Thalassaemia Intermedia: Partial deletions or less severe deletions can cause a milder form of the disease.
α-Thalassaemia: Deletions of one or more of the four α-globin genes cause varying degrees of α-thalassaemia, ranging from mild (silent carriers) to severe (Hb H disease or hydrops fetalis)
