Thalassemia: Origin, Types, and Distribution

Overview of Thalassemias

• Thalassemias are inherited genetic conditions affecting hemoglobin synthesis
• Characterized by reduced or absent globin chain production
• One of the most prevalent single-gene disorders globally

Geographic Distribution of Thalassemias

• Commonly found in the Mediterranean, Middle East, India, and Southeast Asia
• Sporadic cases occur across most populations

Alpha (α)-Thalassemias

• Concentrated in populations from the China subcontinent, Malaysia, Indochina, and Africa.

Beta (β)-Thalassemias

• Concentrated among Mediterranean and African populations
• There are smaller but significant concentrations in the Middle East, India, Pakistan, and China

Origin and Malaria Influence

• Distribution correlates with malaria endemicity
• Heterozygous carriers have a selective advantage in malaria-prone areas, first noted in 1949 by Haldane
• Thalassaemia heterozygotes show decreased invasion, survival, and growth of Plasmodium falciparum
• Parasite multiplication decreases due to the parasite's reduced ability to obtain sufficient nutrients from digesting hemoglobin in thalassaemic red cells

Classification

• Classification is determined by the particular globin chain affected
• Knowledge of normal hemoglobin production during development is essential

Composition of Normal Hemoglobin

• From 0-8 weeks: Hb Gower I (ζ2 ε2), Hb Portland (ζ2 γ2), Hb Gower II (α2 ε2)
• Fetal life (8 weeks-birth): Hb F (α2γ2), Hb A (α2β2)
• Adult life (after birth): Hb A (α2β2, 97%), Hb A2 (α2δ2, 2.5%), Hb F (α2γ2, 0.5%)

Types of Thalassemias

• Alpha (α)-thalassaemias
• Beta (β)-thalassaemias
• Delta-beta (δβ)-thalassaemias
• Gamma (γ)-thalassaemias
• Delta (6) -thalassaemias
• Epsilon-gamma-delta-beta (εγδβ)-thalassaemias
• Hereditary Persistence of Foetal Haemoglobin (HPFH)
• Alpha and beta thalassemias are the most common

Thalassaemia Syndromes

• Thalassaemia populations often exhibit structural haemoglobin variants which can yield a clinical spectrum of syndromes
• Examples are Hb E-β-thalassaemia and Hb C-β-thalassaemia
• HbE, like HbS, results from a point mutation in the β-globin chain
• Glutamic acid is replaced by lysine at position 26
• Common in Southeast Asian, Northeast Indian, Sri Lankan, and Bangladeshi populations
• HbC features a point mutation in the β-globin chain where glutamic acid at position 121 is replaced by lysine

Inheritance and Severity

• Thalassaemic syndromes are inherited with one gene for a haemoglobin variant from one parent, plus a thalassaemic gene from the other
• Syndromes are typically severe without a universal cure
• Gene editing is a potential treatment

Pathogenesis

• Genes for α-like globin chains are on the short arm of chromosome 16
• Genes for β-like globin chains are on the short arm of chromosome 11
• Chromosome 16 has two α globin genes, while chromosome 11 has one β globin gene

Alpha-Thalassaemia Genetics

• Most cases arise from gene deletions
• Non-deletion types result from the loss or change of bases, e.g., Hb Constant Spring due to a single base mutation

Alpha-Thalassemia Haplotypes

• αα/ αα: Normal haplotype
• • α/ α α or αα/ -α: Silent carrier
• • α/- α or --/ α α or αα/ --
• --/- α
• --/--
• α+ thalassaemias: 2 and 3
• α0 thalassaemias: 5 and 6

Clinical Alpha-Thalassemia Syndromes

• • α/ α α or αα/ -α: Silent carrier
• • α/- α or --/ α α or αα/--: α-thalassaemia trait
• --/- α: Hb H disease
• --/--: Hydrops Foetalis

Point Mutations in Beta-Thalassaemia

• Beta-thalassaemia is primarily caused by point mutations, numbering over 40, rather than gene deletions
• β/ β: Normal
• β+/ β or β/ β+: Silent carrier
• β0/ β or β/β0: β-thalassaemia trait
• β+/ β + or β+/ β 0: β-thalassaemia intermedia
• β0/ β0 : β-thalassaemia major

Beta-Thalassaemia Genetics and Haplotypes

• Clinical syndromes cannot be explained by gene number alone in cells with two β-globin chain coding genes
• β+ denotes reduced production; β0 denotes total absence
• β+/ β : Silent carrier (Heterozygote)
• β0/ β: β-thal trait (Heterozygote)
• β+/ β+: Beta-thal intermedia (Homozygote)
• β0/ β0: Beta-thal major (Homozygote)

Severity and Compatibility with Life

• Severe forms of α-thalassaemias are not compatible with life due to the absence of other α-like globin chains
• β-thalassaemia production can switch to γ-globin production if β-genes are mutated
• Severe α-thalassaemias are rare in adulthood
• Severe β-thalassaemia forms are typically seen in adulthood

Pathophysiology: Ratio of Globin Chains

• A normal alpha to beta globin chain ratio should be 1:1
• 1 mol α + 1 mol β → 1 mol αβ
• 1½ mol α + 1 mol β → ½mol αβ + ½ mol β precipitate
• ¾ mol α + 1 mol β → ¾mol αβ+ ¼ mol β precipitate

Pathophysiology: Globin Chain Imbalance

• Deficiency in one chain leads to reduced haemoglobin
• Excess globin chains precipitate producing α, γ, and β haemichromes
• Haemichromes act as inclusion bodies in RBCs and their precursors

Pathophysiology: Haemoglobin Production and Erythropoiesis

• Haemoglobin precursors are preformed, switching off once adequate amounts are formed
• Red cell precursors with inclusion bodies are destroyed in the bone marrow, causing ineffective erythropoiesis
• Some of these cells escape into circulation as mature red cells, which are then destroyed in the RES, causing extravascular haemolysis
• The degree of destruction depends on haemichrome quantity and the degree of α or β globin chain deficiency

Pathophysiology: Production of Red Cells

• Reduced haemoglobin causes excessive division of red cell precursors
• Results in severely microcytic and hypochromic red cells

Clinical Syndromes of α-Thalassemias

• Deficiency or absence of α-globin chain, β haemichromes precipitate in red cells and precursors

Silent Carrier

• Patients usually haematologically normal
• May show mild microcytic hypochromic anaemia

Alpha-Thalassemia Trait

• Mild anaemia with microcytosis and hypochromia

Hb-H Disease

• Commonly found in S/E Asia and the Middle East
• Clinical features range from moderate to severe anaemia (7-10g/dl), splenomegaly, and sometimes hepatomegaly
• Normal physical development in nearly all patients
• Peripheral blood film findings
• Hypochromia
• Microcytosis
• Poikilocytosis
• Polychromasia
• Target cells
• Rare forms of the disease associated with severe mental retardation

Hydrops Foetalis

• Also called Haemoglobin-Barts syndrome
• Frequent in S/E Asia and the Mediterranean
• Complete absence of α globin; γ globin forms γ4 (Hb Barts)
• Incompatible with life beyond the fetal stage
• Affected babies are either stillborn (28-40 weeks gestation) or survive only a few hours if born alive
• Babies are severely anaemic (Hb 5-8g/dl) and oedematous

Beta-Thalassemia Major

• Homozygous β-thalassaemia
• Severe reduction or absence of β-chain production; excess α-chain precipitates as α-haemichrome
• Extensive intramedullary and extravascular destruction of red cell precursors and red cells
• Occurs in one in four offspring when both parents carry the β-thal trait
• Anaemia becomes apparent at 3-6 months of life with the switch from γ- to β-chain production

Symptoms and Complications of Beta-Thalassaemia

• Marrow expansion due to severe anaemia
• Anaemia results from ineffective erythropoiesis via intramedullary destruction and extravascular haemolysis
• Presents as severe anaemia in the first or second year of life, requiring regular transfusions for survival

Clinical Presentation of Beta-Thalassemia Major if Neglected

• Protuberant abdomen
• Poor musculoskeletal development
• Spindly legs
• Thalassaemic facies (skull bossing)
• Hypertrophic maxilla
• Prominent malar eminences
• Common serious complications include infections, spontaneous fractures, hypersplenism, and leg ulcers

Infections Associated with Beta-Thalassemia Major

• Patients are prone to bacterial infections, especially with encapsulated organisms (Pneumococcal, Haemophilus, Meningococcal)
• Occurs after splenectomy without prophylactic penicillin or vaccination
• Osteoporosis may accompany endocrine deficiencies

Other Conditions of Beta-Thalassemia Major if Neglected

• Adolescent growth spurt failure
• Hepatic, endocrine and cardiac complications of iron overloading
  • Diabetes
  • Hypoparathyroidism
  • Adrenal insufficiency
  • Progressive liver failure
• Skin hyperpigmentation (slatey grey) due to excess melanin and haemosiderin from iron overload
• Delayed or absent secondary sexual development
• Short stature leads to psychological problems
• Progressive cardiac damage is the most common cause of death in the second or third decade
• Death occurs via protracted cardiac failure or acute arrhythmia, often precipitated by infection

Laboratory Diagnosis

• Blood Film: Severe hypochromic, microcytic anaemia with raised reticulocyte count, numerous target cells, and basophilic stippling
• Haemoglobin Electrophoresis: Total or partial absence of Hb A; primarily Hb F; Hb A2 % may be normal, low, or slightly raised
• DNA Analysis: Used to identify defects on each allele

Beta-Thalassemia Minor

• Heterozygous β-thalassaemia
• Most patients are asymptomatic with mild anaemia
• Red cell indices (MCV, MCH and MCHC) are close to the lower limits of normal
• Raised levels of Hb A2 (4-7%) and Hb F (1-3%) is a diagnostic feature

Treatment

• Supportive, comprised of
  • Regular blood transfusions to sustain life, keeping hemoglobin levels at 10-12g/dl started early in life
  • Complications of iron overload as well as transfusion of hepatitis and HIV are problematic concerns
  • Regular folic acid supplement (5mg daily)
• Splenectomy: Splenomegaly worsens anaemia and transfusion needs, this is generally done after age 6
• Iron Chelation Therapy: Blood unit contains 200-250mg of iron, thus overload is common after 50 units of transfusion
  • Typically, iron overload begins in the 2nd/3rd decade
  • Chelation via deferoxamine (subcutaneously), deferiprone, or deferasirox (oral chelators) is necessary due to iron related mortality risk
• Hormone Replacement Therapy
  • Used to treat sexual underdevelopment and delayed puberty
  • Synthetic growth hormone is used for short stature, diabetes mellitus, Vitamin D to manage osteoporosis, and testosterone for hypogonadism
• Immunization against hepatitis B
• Treat any Transfusion-transmitted viral infections, e.g hepatitis B and C, with a-interferon and ribavirin to improve living
• Bone marrow transplantation
• Gene therapy

Delta-Beta (δβ)-Thalassaemia

• Rare
• Failure of both δ and β chain production due to fusion of the δ and β genes
• Elevated Haemoglobin F in heterozygotes similar to thalassaemia minor
• Homozygous state features resemble thalassaemia intermedia

Hereditary Persistence of Foetal Haemoglobin (HPFH)

• Similar to δβ-thalassaemia with a reduction in both δ and β globin chain production
• Elevated Haemoglobin F
• Heterozygotes have normal red cell indices with up to 25% Hb F

Thalassemias are inherited genetic disorders affecting hemoglobin synthesis, with a high prevalence worldwide. Their distribution correlates with malaria endemicity. Heterozygous carriers have a selective advantage in malaria-prone areas.