BETA THALASSEMIA DISCUSSION

Presenting the case of Patient M.W.I., a 17-year-old male hailing from Taguig. Currently in the twelfth grade, he presents with the
chief complaint of pallor.

CC: For Blood transfusion- Pallor

HPI
The patient is a documented case of Beta Thalassemia Intermedia, which was initially diagnosed in 2009. Prior to this, the patient’s
relative reported persistent pallor, easy fatigue and stunted growth between the ages of 1 to 3. The initial presentation was marked by
pallor, following a bout of pneumonia. A complete blood count (CBC) at the time revealed microcytic hypochromic anemia,
indicative of Beta Thalassemia Intermedia. The recommended course of treatment was monthly blood transfusions to maintain normal
hemoglobin (Hgb) levels. Subsequently, the patient has received intermittent blood transfusions, averaging around 2 per year. The
most recent transfusion took place in October 2022, consisting of one unit of packed red blood cells (pRBC), making it a total of
approximately 3 transfusions in the past year.

The patient's inconsistent blood transfusion schedule can be attributed to financial constraints. In terms of clinical presentation, the
patient has been experiencing pallor, icteric sclerae, intermittent low-grade fever undocumented, occasional abdominal pain, fatigue,
jaundice, and generalized weakness.

Approximately 2 months ago, in September, the patient observed an increase in jaundice, along with persistent pallor, fatigue, and
generalized weakness. However, the patient refrained from seeking medical consultation due to financial limitations.

With improved financial circumstances, the patient has now decided to pursue a follow-up for their blood transfusion and is seeking
medical consultation.

DISCUSSION:

Beta thalassemia arises from deletions in the beta-globin gene. In a normal human, there are two beta-globin genes. Deletions in these
genes lead to an unbalanced synthesis of alpha-globins and beta-globins. Consequently, surplus free alpha-globin chains accumulate
and precipitate in red cell precursors, hindering maturation and causing intramedullary destruction of erythroid precursors—an
occurrence referred to as ineffective erythropoiesis. Red blood cells entering circulation contain varying amounts of free alpha-globin,
the quantity increasing with the phenotypic severity of beta thalassemia. The alpha-globin and its breakdown products adversely affect
the red cell membrane, causing increased rigidity and shortened red cell survival.

Beta thalassemia trait manifests when one beta gene is non-functional or encodes a mutation leading to a reduced rate of beta-chain
synthesis. It is characterized by mild hypochromic, microcytic anemia, and patients are typically asymptomatic. The red blood cell
count is usually higher than expected for the degree of anemia due to ineffective erythropoiesis. Hemoglobin electrophoresis in
individuals with beta thalassemia trait reveals an increased Hb A2. However, caution is necessary when interpreting results in the
presence of concurrent iron deficiency, as iron deficiency lowers the Hb A2 fraction.

Distinguishing between beta thalassemia intermedia and major hinges on transfusion dependence. Patients with beta thalassemia
intermedia (non-transfusion-dependent thalassemia, NTDT) exhibit moderate anemia with hepatosplenomegaly, ongoing hemolysis,
and potential features of extra-medullary hematopoiesis. They may also experience iron overload. On the other hand, patients with
beta thalassemia major are transfusion-dependent due to severe or absent beta-chain production. They present with a characteristic
facial appearance resulting from bone marrow expansion in childhood, severe anemia, and face a risk of mortality in childhood
without initiation of a transfusion program. Additionally, they are susceptible to iron overload and its associated complications.

ß thalassaemia is inherited in an autosomal recessive fashion. Because there are a number of mutations in the ß globin gene that can
result in ß thalassaemia, the exact clinical phenotype depends on whether the ß globin gene is functional, and the severity of the
functional impairment. The example below shows a patient with ß thalassaemia intermedia from ß +/ß0 and her husband with ß
thalassaemia trait.
In this example, the mother has ß thalassaemia intermedia (ß+/ß0). Her partner has ß thalassaemia trait (ß/ß0). They have a 25% chance
of having a child with ß thalassaemia major, a 25% chance of having a child with ß thalassaemia intermedia, and a 50% chance of
having a child with ß thalassaemia trait.

Beta thalassemia is an autosomal recessive genetic disorder that affects the synthesis of hemoglobin, the protein responsible for
carrying oxygen in red blood cells. Here's an explanation of the autosomal recessive inheritance pattern of beta thalassemia:

1. **Autosomal Recessive Inheritance:**

 - "Autosomal" refers to the fact that the gene responsible for beta thalassemia is located on an autosome, which is a non-sex
chromosome (chromosomes 1 to 22 in humans).
- "Recessive" means that the disorder manifests only when an individual inherits two mutated copies of the gene, one from each
parent. Individuals carrying only one mutated copy (heterozygous carriers) are usually asymptomatic carriers of the trait.

2. **Gene Locus and Mutations:**

- The gene associated with beta thalassemia is located on chromosome 11. It is called the HBB gene, which provides instructions for
making beta-globin, a crucial component of hemoglobin.
- Individuals with beta thalassemia have mutations in both copies (alleles) of the HBB gene. There are various types of mutations
that can lead to beta thalassemia, resulting in reduced or absent synthesis of beta-globin chains.

3. **Homozygous Inheritance:**
- To develop beta thalassemia, an individual must inherit two mutated alleles, one from each parent. This is known as homozygous
inheritance.
- Individuals who inherit one normal allele and one mutated allele (heterozygous carriers) generally do not exhibit symptoms of the
disorder. However, they can pass the mutated allele to their offspring.

4. **Reduced or Absent Beta-Globin Synthesis:**

- The mutations in the HBB gene lead to reduced or absent synthesis of beta-globin chains. This imbalance in globin chain
production disrupts the normal structure and function of hemoglobin.
- Hemoglobin is composed of four globin chains—two alpha-globin and two beta-globin. In beta thalassemia, the inadequate
production of beta-globin disrupts the formation of functional hemoglobin molecules, resulting in anemia and other associated
symptoms.

5. **Clinical Manifestations:**
- Individuals with beta thalassemia major, who inherit mutated alleles from both parents, typically experience severe anemia and
require regular blood transfusions for survival.
- Beta thalassemia minor (heterozygous carriers) generally leads to mild or no symptoms, but carriers have a 25% chance of having
a child with beta thalassemia if both parents are carriers.

Understanding the autosomal recessive inheritance of beta thalassemia is crucial for genetic counseling, family planning, and early
intervention in affected individuals.

Epidemiological Trends:

Historically, β-thalassemia has exhibited a higher prevalence in specific global regions, notably the Mediterranean, Middle East, and
Southeast Asia. Nevertheless, the incidence of β-thalassemia is on the rise in other areas, such as Northern Europe and North America,
largely attributed to increased migration.

In the Philippines, hemoglobinopathy accounts for 27.8% of the most prevalent causes of anemia. The accurate prevalence is not
precisely known, but hemoglobin disorders affect 76.1 individuals per 100,000 in the population.

The pathogenesis of beta thalassemia is rooted in genetic mutations that affect the synthesis of hemoglobin, the vital protein
responsible for oxygen transport in red blood cells. Here's an overview of the pathogenesis:

1. **Genetic Basis:**
- Beta thalassemia is an autosomal recessive disorder caused by mutations in the HBB gene, located on chromosome 11. This gene
provides instructions for the synthesis of beta-globin chains, a crucial component of hemoglobin.
- Individuals with beta thalassemia inherit mutations in both copies (alleles) of the HBB gene, leading to a deficiency or absence of
functional beta-globin chains.

2. **Imbalanced Globin Chain Synthesis:**

- The mutations in the beta-globin gene disrupt the normal balance between alpha-globin and beta-globin chain synthesis. In beta
thalassemia, there is a reduced or absent synthesis of beta-globin chains.

3. **Accumulation of Free Alpha-Globin Chains:**

- With insufficient beta-globin chains, excess free alpha-globin chains accumulate within the red blood cell precursors in the bone
marrow.

4. **Ineffective Erythropoiesis:**
 - The surplus alpha-globin chains precipitate within the red cell precursors, interfering with their maturation and leading to
intramedullary destruction of erythroid precursors.
- This process is termed ineffective erythropoiesis, as it results in the production of immature and non-functional red blood cells.

5. **Clinical Consequences:**
- The immature and ineffective red blood cells that enter circulation contribute to anemia, one of the hallmark features of beta
thalassemia.
- Additionally, the accumulation of free alpha-globin chains can be deleterious to the red cell membrane, causing increased rigidity
and a shortened lifespan of the red blood cells.

6. **Clinical Spectrum:**
- The severity of beta thalassemia can vary, leading to different clinical manifestations.
- Beta thalassemia trait occurs when an individual inherits one mutated beta-globin gene and one normal gene. This condition
usually results in mild symptoms.
- Beta thalassemia major or intermedia occurs when an individual inherits two mutated beta-globin genes. This leads to more severe
symptoms, including transfusion dependence in beta thalassemia major.

Understanding the pathogenesis of beta thalassemia is crucial for diagnosis, management, and genetic counseling. It guides
interventions aimed at addressing the specific challenges associated with imbalanced globin chain synthesis and ineffective
erythropoiesis.

The pathogenesis of beta-thalassemia involves a disruption in the normal synthesis of hemoglobin, the oxygen-carrying protein in red
blood cells. Here's an overview of the pathophysiological mechanisms:

1. **Genetic Basis:**
- Beta-thalassemia is a hereditary disorder caused by mutations in the HBB gene, located on chromosome 11. This gene encodes the
beta-globin subunit of hemoglobin.
- Mutations can result in reduced or absent production of functional beta-globin chains.

2. **Imbalanced Globin Chain Synthesis:**

- Hemoglobin is a tetramer composed of two alpha-globin and two beta-globin chains. In beta-thalassemia, the reduced or absent
synthesis of beta-globin leads to an imbalance in globin chain production.
- Excess alpha-globin chains accumulate because there are fewer beta-globin chains available for pairing.

3. **Ineffective Erythropoiesis:**
- The imbalanced globin chain synthesis causes ineffective erythropoiesis, a process where the production of red blood cells is
inefficient and results in their premature destruction in the bone marrow.
- Accumulation of excess alpha-globin chains leads to the formation of insoluble aggregates, which precipitate in red cell precursors.
This interferes with normal maturation and contributes to the destruction of erythroid precursors.

4. **Anemia and Clinical Manifestations:**

- Ineffective erythropoiesis leads to a decreased number of mature red blood cells, resulting in anemia.
- Clinical manifestations of beta-thalassemia include fatigue, pallor, and other symptoms associated with anemia.

5. **Hemolysis and Rigid Red Blood Cells:**

- The breakdown of red blood cells (hemolysis) contributes to the release of heme and iron, which can lead to additional
complications such as iron overload.
- The presence of excess alpha-globin and its breakdown products can be deleterious to the red cell membrane, causing it to become
more rigid. This increased rigidity shortens the survival of red blood cells.

6. **Severity Spectrum:**
- Beta-thalassemia exists along a spectrum of severity, ranging from asymptomatic carriers (thalassemia trait) to severe forms
requiring regular blood transfusions (thalassemia major).

Understanding the pathogenesis of beta-thalassemia is crucial for developing targeted treatments and interventions to manage the
complications associated with this genetic disorder.