Question 1: A 6-year-old Afroamerican boy presented with abdominal pain, chronic hemolysis, and abnormal RBC shape on peripheral smear. What is the most likely underlying molecular disorder responsible for this condition?
- A. Point mutation (Correct Answer)
- B. Trinucleotide repeat
- C. Antibody against RBC membrane
- D. Genomic imprinting
Explanation: ### Explanation
The clinical presentation of a young African American child with **chronic hemolysis**, **abdominal pain** (likely due to vaso-occlusive crises or splenic sequestration), and **abnormal RBC morphology** (sickle cells) is diagnostic of **Sickle Cell Anemia (SCA)** [1], [2].
**1. Why "Point Mutation" is Correct:**
Sickle Cell Anemia is caused by a specific **missense point mutation** in the $\beta$-globin gene located on chromosome 11. Specifically, there is a substitution of **Adenine by Thymine (GAG $\rightarrow$ GTG)**. This results in the replacement of the amino acid **Glutamic acid** (polar/hydrophilic) with **Valine** (non-polar/hydrophobic) at the **6th position** of the $\beta$-globin chain [1]. This single amino acid change causes Hemoglobin S (HbS) to polymerize under deoxygenated conditions, leading to the characteristic "sickling" of erythrocytes [2].
**2. Why Incorrect Options are Wrong:**
* **Trinucleotide repeat:** This is the mechanism for "Anticipation" seen in neurological disorders like Huntington’s disease or Fragile X syndrome, not hemoglobinopathies.
* **Antibody against RBC membrane:** This describes **Autoimmune Hemolytic Anemia (AIHA)** [2]. While it causes hemolysis, it is an acquired immune-mediated process, not a molecular genetic disorder, and typically presents with spherocytes.
* **Genomic imprinting:** This involves epigenetic silencing of genes (e.g., Prader-Willi or Angelman syndromes) and does not play a role in the inheritance of structural hemoglobin variants.
**High-Yield Clinical Pearls for NEET-PG:**
* **Inheritance:** Autosomal Recessive [2].
* **Protective Effect:** Heterozygotes (Sickle cell trait) are protected against *Plasmodium falciparum* malaria.
* **Diagnosis:** **Hb Electrophoresis** is the gold standard (HbS moves slower than HbA toward the anode).
* **Complications:** Autosplenectomy (by age 6-8), Howell-Jolly bodies on smear, and increased risk of *Salmonella* osteomyelitis [3].
**References:**
[1] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. Common Clinical Problems From Blood And Bone Marrow Disease, pp. 598-599.
[2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Red Blood Cell and Bleeding Disorders, pp. 652-654.
[3] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Red Blood Cell and Bleeding Disorders, pp. 645-646.