Ans. a. Point mutation (Ref: Ghai 7/e p310-312; Harper's 27/e p368-371; Robbins 9/e p635-638, 8/e p646)An afroamerican kid of 6 years of age presented with abdominal pain, chronic hemolysis and abnormal RBC shape on peripheral smear. This patient is suffering from sickle cell anemia. Most likely disorder responsible for this condition point mutation. (AIIMS November 2013 repeat)'Sickle cell anemia is an autosomal recessive disease that results from the substitution of valine from glutamic acid at position 6 of the beta-globin gene (Point mutation). - Ghai 7/e p310Point mutations within coding sequences:A point mutation may alter the code in a triplet of bases and lead to the replacement of one amino acid by another in the gene product.An excellent example of this type is the sickle mutation affecting the B-globin chain of hemoglobinQ. Here the nucleotide triplet CTC (or GAG in mRNA), which encodes glutamic acid, is changed to CAC (or GUG in mRNA), which encodes valine. This single amino acid substitution alters the physicochemical properties of hemoglobin, giving rise to sickle cell anemia.Sickle Cell DiseaseSickle cell disease is a common hereditary hemoglobinopathy that occurs primarily in individuals of African descend.Caused by a point mutation in the sixth codon of B-globin that leads to the replacement of a glutamate residue with a valine residueQ.In certain populations in Africa the prevalence of heterozygosity is as high as 30%. This high frequency probably stems from protection afforded by HbS against falciparum malariaQ.Pathogenesis:HbS molecules undergo polymerization when deoxygenated.Initially the red cell cytosol converts from a freely flowing liquid to a viscous gel as HbS aggregates form.With continued deoxygenation aggregated HbS molecules assemble into long needle-like fibers within red cells, producing a distorted sickle or holly-leaf shapeQ.Presence of HbS underlies the major pathologic manifestationsChronic hemolysisQMicrovascular occlusionsQTissue damageQMorphology:Peripheral blood demonstrates variable numbers of irreversibly sickled cells, retieulocytosis, and target cells, Howell-Jolly bodiesQ (small nuclear remnants).The bone marrow is hyperplastic as a result of a compensatory erythroid hyperplasiaQ.Expansion of the marrow leads to bone resorption and secondary new bone formation, resulting in prominent cheekbones and changes in the skull that resemble a crew-cut in x-raysQ.Increased breakdown of hemoglobin can cause pigment gallstones and hyperbilirubinemiaQ.Splenic infarction, fibrosis, and progressive shrinkage (autosplenectomy)Q