Sickle Cell Anaemia — Clinical Significance

Pathophysiology: HbS polymerization under low $O_{2}$ → sickle-shaped RBCs → vaso-occlusion (blocked capillaries) + haemolysis (destruction of RBCs by spleen). Clinical crises: Painful vaso-occlusive crises (bone pain, chest syndrome), splenic sequestration, stroke, aplastic crisis. Population relevance: High frequency in sub-Saharan Africa, Mediterranean, Middle East, India — corresponds to malaria-endemic regions (heterozygous advantage). Treatment: Hydroxyurea (increases HbF production), blood transfusions, bone marrow transplant, gene therapy (experimental).

Thalassemia — Clinical Significance

Beta-thalassemia major: Severe anaemia requiring monthly blood transfusions from infancy; iron overload from transfusions → organ damage; managed with iron chelation therapy. Screening: Carrier couples $\frac{HbA}{HbThal}$ should be identified prenatally; prenatal diagnosis by amniocentesis or chorionic villus sampling (CVS).

PKU — Clinical Significance

Neonatal screening: Detected on day 2–5 of life by heel-prick blood spot test (Guthrie test). Early diagnosis is critical. Treatment: Low-phenylalanine diet (avoid high-protein foods, use special formula) started within days of birth → prevents intellectual disability completely. Monitoring: Blood phenylalanine levels monitored regularly; dietary restriction continued lifelong.

Haemophilia A — Clinical Significance

Presentation: Joint bleeds (haemarthroses), prolonged bleeding after minor injury, intracranial haemorrhage (severe cases). Treatment: Factor VIII concentrate infusions (prophylactic or on-demand); gene therapy trials ongoing. Historical context: "Royal disease" — traced through European royal families from Queen Victoria (carrier) to affected grandsons in Russian, Spanish, and German royal families.