Hemoglobinopathy is a group of blood disorders passed down through families (inherited) in which there is abnormal production or structure of the hemoglobin molecule. Common hemoglobinopathies include sickle-cell disease. It is estimated that 7% of worlds population (420 million) are carriers, with 60% of total and 70% pathological being in Africa. Hemoglobinopathies are most common in ethnic populations from Africa, the Mediterranean basin and Southeast Asia.

Most significant hemoglobinopathies cause mild to acute anemia, in rare cases hemolytic anemia. In sickle cell disease the red blood cells tend to assume a different shape under anaerobic conditions, leading to organ damage and circulatory problems, while in thalassemia there is ineffective production of red blood cells.

• Hb S
• Hb C
• Hb E
• Hb D-Punjab
• Hb O- Arab
• Hb G- Philadelphia
• Hb Harsharon
• Hb Korle- Bu
• Hb Lepore
• Hb M

• Hb S
  
  The first Hb variant described by scientists was named sickle cell Hb (HbS). The prevalence of this variant is highest in West and Central Africa, Northeast Saudi Arabia and Kuwait, and East Central India. In heterozygous individuals, HbS provides some protection against the malaria parasite Plasmodium falciparum. But homozygous individuals have shortened life expectancies resulting from the complications of sickle cell disease, with studies reporting an average life expectancy of 42 and 48 years for males and females, respectively.
  
  Today, sickle cell disease is recognized as a severe chronic condition. The substitution of valine in position 6 on the β-globin chain causes a decrease in the solubility of deoxyhemoglobin. This altered Hb molecule forms rigid S polymers that produce the classic sickle-shaped red blood cells for which the disease is named.
  
  People with sickle cell conditions make a different form of hemoglobin A called hemoglobin S (S stands for sickle). Red blood cells containing mostly hemoglobin S do not live as long as normal red blood cells (normally about 16 days). They also become stiff, distorted in shape and have difficulty passing through small blood vessels. When sickle-shaped cells block small blood vessels, blood supply becomes less to that particular organ. Tissue that does not receive a normal blood flow eventually becomes damaged. This is what causes the complications of sickle cell disease
  
  There are several types of sickle cell disease. The most common are: Sickle Cell Anemia (SS), Sickle-Hemoglobin C Disease (SC). Sickle Beta-Plus Thalassemia and Sickle Beta-Zero Thalassemia.
  
  Sickle Cell trait (AS) is an inherited condition in which both hemoglobin A and S are produced in the red blood cells, always more A than S. Sickle cell trait is not a type of sickle cell disease. People with sickle cell trait are generally healthy but can be carriers.
  
  Sickle cells are destroyed rapidly in the body causing anemia, jaundice and the formation of gallstones. Acute chest syndrome, pain in arms, legs, chest and abdomen, stroke and damage to most organs are also common.
  
• Hb C


Hb C originated in West Africa and occurs in about 3% of African Americans. Individuals with one copy of HbC may show mild microcytosis, with occasional target cells seen on the peripheral smear and 35 to 40% HbC. However, there are no other hematologic abnormalities.

Hemoglobin C (Hb C) is an abnormal hemoglobin with substitution of a lysine residue for a glutamic acid residue at the 6th position of the β-globin chain.

This mutated form reduces the normal plasticity of host erythrocytes causing a hemoglobinopathy. In those who are heterozygous for the mutation, about 28–44% of total hemoglobin (Hb) is HbC, and no anemia develops

Hb C can also be inherited along with other β-chain variants such as HbS. HbSC disease is a sickling disorder, with a milder presentation than sickle cell disease. While the exact mechanism of this sickling is unclear, these patients have mild to moderate anemia, with less frequent and less disabling vaso-occlusive crisis. Hb analysis of these individuals shows 50% HbS, with slightly less HbC.

In homozygotes, nearly all Hb is in the HbC form, resulting in mild hemolytic anemia. Some cases may not be diagnosed until adulthood. Mild hemolytic anemia may result, accompanied by a mild-to-moderate reduction in the red blood cell lifespan. Persons with hemoglobin C disease have sporadic episodes of musculoskeletal (joint) pain. Continued hemolysis may produce pigmented gallstones, an unusual type of gallstone composed of the dark-colored contents of red blood cells. The cause of pigmented gallstones is uncertain.


• Hb E


Hemoglobin E (HbE) is an abnormal hemoglobin with a single point mutation in the β chain. At position 26 there is a change from a glutamate to a lysine. People with the hemoglobin E trait have a mild hemolytic anemia and mild splenomegaly. Hemoglobin E trait is asymptomatic. In combination with certain thalassemia mutations, it provides an increased resistance to malaria (P. falciparum). Hemoglobin E is most prevalent in Southeast Asia (Thailand, Indonesia, Bangladesh, Vietnam) and North-East India, where in certain areas carrier rates reach 60% of the population. The mutation is estimated to have arisen within the last 5,000 years.

If one member of a couple has hemoglobin E trait, and the other has beta thalassemia trait, there is a 25% chance with each pregnancy that their child will co-inherit both traits. This leads to a disease called hemoglobin E/ beta thalassemia in that child.


• Hb G- Philadelphia
  

The most common α-chain variant seen in the U.S. is HbG-Philadelphia, with a 1 in 5,000 prevalence in African Americans. This variant has no hematologic or clinical effect. As an α-chain variant, it can be co-inherited with β-chain variants, such as HbC and HbS. Interpretation of laboratory findings for these individuals can be difficult, as the combination of Hbs results in multiple bands by electrophoretic analysis and multiple peaks on HPLC.


• α-Thalassemias


Thalassemias are caused either by mutations that reduce the rate of synthesis of a globin chain or by deletion of one or more of the globin genes. α-Thalassemias usually are caused by deletions of one or more of the four α-globin genes. These deletions decrease the synthesis of the protein, thereby creating an overabundance of γ-chains in a fetus or β-chains after HbF disappears. These γ- or β- chains can aggregate and form HbBart’s or HbH, respectively.

For patients whose Hb electrophoresis or HPLC analyses and iron studies are normal and the MCV is low, α-thalassemia trait should be considered. However, DNA studies are required for a definitive diagnosis.


• β-Thalassemias
  

At least 150 mutations are known to cause β-thalassemia. The condition occurs mainly in people from the Mediterranean region, the Middle East, India, and Southeast Asia. These mutations have been divided into two categories: β0-thalassemias, which involve complete absence of β-chain production; and β+-thalassemias, which result in reduced synthesis of the β-chain. The severity of the disorder varies widely depending on the amount of β-globin produced.

Laboratory findings for individuals with β-thalassemia trait include microcytosis, hypochromia, no or mild anemia, and normal or slightly increased RBCs. HbA2 levels are elevated in these individuals, and HbF may be normal or increased. Inheritance of two β-thalassemia genes causes more severe disease ranging from β-thalassemia intermedia to Cooley’s anemia or β-thalassemia major.


• δβ-Thalassemia


δβ-thalassemia is caused by large deletions of both the δ- and β-globin genes. These individuals have persistent increased levels of HbF, although the increased production of γ-chains is not enough to completely compensate for the decrease in β-chain production. This situation leads to imbalance of the two globin chains and the classic thalassemic RBC indices. In individuals with δβ-thalassemia trait, HbF levels are increased to 5 to 15%, and HbA2 is normal or decreased. There have been rare cases of homozygous δβ-thalassemia. These individuals have 100% HbF for their entire lives.


• Hereditary Persistence of HbF


Hereditary persistence of fetal Hb (HPFH) is a group of disorders in which HbF levels remain persistently elevated, ranging from 5 to 35% of the total Hb. Several different mutations can be found in different ethnic groups. Individuals with HPFH may have normal or slightly decreased MCV but no anemia. The condition can also be co-inherited with other β-chain variants, such as HbS. The high HbF levels in these individuals appears to moderate the severity of the sickling disorder.

Follow-up after the confirmatory test:

• Parents should understand the importance of twice-daily doses of prophylactic penicillin as an effective measure to reduce both morbidity and mortality from pneumococcal infections in infants with all forms of sickle cell diseases.
  
  
• Parents of infants with sickle cell disease should be instructed in all aspects of routine child care. They should be able to accurately check the infant’s temperature.
  
  
• They must be able to recognize early symptoms of complications, including the warning signs of inactivity, fever, pallor and respiratory distress
  
  
• Parents should be taught to palpate the infant’s spleen and to recognize splenic enlargement. Parents must understand the importance of prompt assessment of the infant by a pediatric hematologist when fever, pallor, unexplained irritability, diarrhea, vomiting or other signs of illness are present.
  
  
• Fever of 101° F or greater requires immediate medical evaluation.

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