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Q1: Definition and classification (2 min)
- Define thalassaemia. Inherited quantitative defect of globin chain synthesis causing microcytic hypochromic anaemia; autosomal recessive (Kattamis/Muncie).
- Classify alpha-thalassaemia by gene dose. GeneReviews: Hb Bart hydrops = deletion/inactivation of all four alpha alleles (--/--); HbH disease most often three alleles (--/-α). Muncie ladder: silent carrier / trait / HbH / Hb Bart hydrops.
- Classify beta-thalassaemia. Major (transfusion-dependent from infancy), intermedia (not regularly transfused from early childhood), minor/trait (raised HbA2, high RBC count).
- Which chromosomes? Muncie: alpha — two genes on each chromosome 16; beta — one gene on each chromosome 11. GeneReviews loci: HBA1/HBA2 16p13.3, HBB 11p15.4.
Q2: Clinical features and diagnosis (3 min)
- At what age does beta-thalassaemia major present, and why? GeneReviews six to 24 months; Muncie second six months of life, after the healthy-infant switch to mostly HbA by about six months.
- Describe the classical clinical features of thalassaemia major. Pallor, poor weight gain, stunted growth, jaundice, hepatosplenomegaly; craniofacial bone change from marrow expansion.
- How do you distinguish thalassaemia trait from iron deficiency? Trait: high/normal RBC count, normal ferritin/iron, HbA2 greater than 3.5% (GeneReviews). Mentzer index (MCV/RBC): <13 supports thalassaemia, >13 iron deficiency (Muncie; Yogalakshmi accuracy 82.61%). Do not give iron to trait.
- Why is Hb electrophoresis normal in alpha-thalassaemia trait? Muncie: electrophoresis is usually normal in adults with alpha-thal trait; diagnosis needs genetic testing.
Q3: Management and complications (3 min)
- Outline the management of thalassaemia major. Regular lifelong transfusion (Muncie Hb >9.5 g/dL; GeneReviews 9.5–10.5 g/dL) + mandatory iron chelation (DEEP-2: DFP 75–100 or DFX 20–40 mg/kg/day; EPIC DFX start 20 mg/kg/day on 2–4 units/month) + folate; splenectomy for hypersplenism (vaccinate; delay until ≥4 years — Muncie); curative HSCT or beti-cel.
- What is the leading cause of death and why? Iron-overload cardiomyopathy (Pennell); Muncie: often by age 30 if untreated. No physiological iron excretory route.
- How is iron overload monitored? Serum ferritin trends (EPIC 3-monthly titration) and cardiac MRI T2* — Pennell: T2* <10 ms is the most important HF predictor; ferritin/LIC are not cardiac surrogates.
- When is splenectomy indicated and what precautions are needed? Hypersplenism (Kumar; pre-op Hb 9 g/dL, platelets 50,000/µL). Brigden: education, immunoprophylaxis, chemoprophylaxis. Fever is an emergency.
Q4: Counselling and prognosis (2 min)
- A couple are both alpha-thalassaemia carriers from a South-East Asian background. What is the risk at each pregnancy? If both carry a cis two-gene deletion, a four-gene Hb Bart fetus is possible (Muncie: same vs different chromosomes alters outcome). Offer prenatal diagnosis (CVS/PCR — Muncie). Hb Bart is usually fatal hydrops.
- What is the role of gene therapy? Betibeglogene autotemcel (beti-cel) — autologous CD34+ cells transduced with a lentiviral βA-T87Q vector — produced transfusion independence in 20/22 (91%) evaluable non-β0/β0 patients (Locatelli 2022; TI = Hb ≥9 g/dL without transfusion ≥12 months; median follow-up 29.5 months). Do not confuse with exa-cel (CRISPR-Cas9 BCL11A editing).
- Overall prognosis? Kattamis: transfusion plus chelation prolongs life expectancy. GeneReviews: HSCT DFS greater than 90% in children without hepatomegaly/fibrosis/heavy iron. India: ISHBT notes millions of carriers and over 12,000 affected births annually (Dolai).