Sickle cell anemia is due to a defect in the HBB gene.

The HBB gene, located on the short arm of chromosome 11, codes for the formation of the globin-β gene product of 146 amino acids. A single base mutation in the coding region at amino acid position 6 in the protein results in the conversion of a GAG codon to GTG, leading to the nonconservative substitution of a hydrophobic valine residue for a hydrophilic glutamate in the protein, which is now called HbS. This conversion brings about the profound structural changes in the deoxygenated HbS described below. Because sickle cell anemia is an autosomal recessive disease, an individual must carry 2 copies of the HbS variant to develop the symptoms of the disease. Individuals with 1 variant (HbS) and 1 normal (HbA) allele are carriers and are generally free of symptoms. If one parent has sickle cell trait (HbAS) and the other parent is homozygous for HbA, then no offspring will have sickle cell disease, but some may be carriers (HbAS) and some homozygous for hemoglobin A (HbAA). By contrast, if both parents have sickle trait, there is a 1 out of 4 chance that the child will be homozygous for HbA (HbAA), a 2 out of 4 chance that the offspring will be heterozygous (HbAS) and carry sickle cell trait, and a 1 out of 4 chance that the offspring will have sickle cell disease (HbSS), as illustrated.

 

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Genetics of the sickle cell disease when both parents are heterozygous for HbS (sickle cell trait).

The intrinsic oxygen-binding properties of HbA and HbS are the same; however, the solubility of deoxy HbS is reduced because exposure of Val-6 at the surface of the β-chain leads to a hydrophobic interaction with hydrophobic residues on another β-chain. Because hemoglobin is present at very high concentrations in the red blood cell, deoxy HbS will polymerize and precipitate inside the cell. The precipitate takes the form of elongated fibers because of the association of complementary hydrophobic surfaces on the β- and α-chains of deoxy HbS. At oxygen saturations found in arterial blood, the oxy HbS predominates and HbS does not precipitate because Val-6 of the β-chain is not exposed to the surface.

The tendency for deoxy HbS to precipitate is why clinical manifestations of sickle cell anemia are brought on by exertion and why treatment includes oxygen administration. The stiff fibrous precipitate causes the red blood cell to deform into the characteristic sickle shape and makes the normally malleable cell susceptible to hemolysis.

Although sickle cell disease may be the most widely known condition resulting from a variant in the HBB gene, other conditions are also recognized. Hemoglobin C is produced when the glutamate at position 6 is changed to a lysine residue. Hemoglobin SC disease occurs when an individual has 1 HbS and 1 HbC allele, resulting in symptoms similar to sickle cell anemia, and the severity of the condition may range from mild to equivalent to sickle cell disease. However, 2 hemoglobin C alleles have a milder resultant disease that causes anemia (hemoglobin C disease). Hemoglobin E results when amino acid position 26 of the β-globin gene is changed from glutamic acid to lysine. When an individual carries both HbS and HbE, symptoms may be as severe as in sickle cell disease. Hemoglobin S and hemoglobin C variants are more common in West African lineages, while hemoglobin E variants are more common in those with Southeast Asian lineages.

 


  • Sickle cell anemia results from the nonconservative substitution of valine for glutamate at the sixth residue of the β chain of hemoglobin.

  • Precipitation of HbS is more likely to occur from exertion and deoxygenation. Therefore, treatment consists of oxygen and hydration.

  • The stiff fibrous precipitate of HbS causes the red blood cell to deform into the characteristic sickle shape and makes the normally malleable cell susceptible to hemolysis.

 

 

 

 

 

 

 
  • Precipitation of HbS is more likely to occur from exertion and deoxygenation. Therefore, treatment consists of oxygen and hydration.

  • The stiff fibrous precipitate of HbS causes the red blood cell to deform into the characteristic sickle shape and makes the normally malleable cell susceptible to hemolysis.

FIGURE 1–1.

 

 

 

 

Content 3

Content 13

A 15-year-old African-American girl presents to the emergency department with complaints of bilateral thigh and hip pain. The pain has been present for 1 day and is steadily increasing in severity. Acetaminophen and ibuprofen have not relieved her symptoms. She denies any recent trauma or excessive exercise. She does report feeling fatigued and has been having burning with urination along with urinating frequently. She reports having similar pain episodes in the past, sometimes requiring hospitalization. On examination, she is afebrile (without fever) and in no acute distress. No one in her family has similar episodes. Her conjunctiva and mucosal membranes are slightly pale in coloration. She has nonspecific bilateral anterior thigh pain with no abnormalities appreciated. The remainder of her examination is normal. Her white blood cell count is elevated at 17,000/mm3, and her hemoglobin level is decreased at 7.1 g/dL. Urinalysis demonstrated an abnormal number of numerous bacteria.

Questions

What is the most likely diagnosis?

Answer

 

What is the molecular genetics behind this disorder?

What is the pathophysiologic mechanism of her symptoms?

Summary: A 15-year-old African-American girl with recurrent bilateral thigh and hip pain, anemia, and symptoms and laboratory evidence of a urinary tract infection.

  • Most likely diagnosis: 

  • Biochemical mechanism of disease: Single amino acid substitution on hemoglobin β chain, inherited in an autosomal recessive fashion (1 in 12 African Americans in United States are carriers of the trait).

  • Pathophysiologic mechanism of symptoms: The sickled red blood cells cause infarction of the bone, lung, kidney, and other tissue from vasoocclusion.

Clinical Correlation

This 15-year-old girl's description of her pain is typical of a sickle cell pain crisis. Many times, infection is a trigger, most commonly pneumonia or urinary tract infection. This case is consistent with urinary tract infection, indicated by her symptoms of urinary frequency and burning with urination (dysuria). Her white blood cell count is elevated in response to the infection. The low hemoglobin level is consistent with sickle cell anemia. Because she is homozygous (both genes coding for sickle hemoglobin), both her parents have sickle cell trait (heterozygous) and, thus, do not have symptoms. The diagnosis can be established with hemoglobin electrophoresis. Treatment includes searching for an underlying cause of crisis (infection, hypoxia, fever, excessive exercise, and extreme changes in temperature), administration of oxygen, intravenous fluids for hydration, pain management, and consideration of blood transfusion.

 

A 25-year-old African-American man with sickle cell anemia, who has been hospitalized several times for painful sickle cell crises, has successfully been free of these crises since he has been on hydroxyurea therapy. Treatment with hydroxyurea results in which of the following?

The correct answer is B.

B By inhibiting the enzyme ribonucleotide reductase, hydroxyurea has been shown to increase the levels of fetal hemoglobin (HbF, α2γ2) by mechanisms not fully understood. The increase in HbF concentrations has the effect of decreasing HbS levels in the red blood cell. The increased concentration of HbF disrupts the polymerization of HbS and decreases the incidence of sickle cell crises. Hydroxyurea does not affect the oxygen affinity or cooperativity of oxygen binding of HbS, nor does it react with HbS to cause a post-translational modification or affect 2,3-BPG binding.

 


 

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