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Learn about hemoglobinopathy, a group of rare inherited disorders involving abnormal structure of the hemoglobin molecule such as sickle cell anemia and thalassemia.
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Some disorders result when a mutation causes the product of a single gene to be altered or missing. These disorders are called Single Gene Disorder .
Form the view of pathogenesis, single gene disorders are divided into 2 groups: 1. molecular disease 2. inborn errors of metabolism
1. molecular disease Toward the end of World War II, Vannevar Bush, the head of the U.S. Office of Scientific Research and Development, contacted Pauling. Bush was seeking to restructure the way in which scientific research was conducted and funded in the United States.
Pauling was the only non-physician on Bush's medical research committee--a nod to his growing reputation outside of mainstream chemistry.
From his previous work with blood, he knew that red blood cells were little more than bags filled with hemoglobin, the molecule that carried oxygen from the lungs to the body.
If the sickled cells had changed shape, perhaps it was because the hemoglobin had been altered in some way, making it clump and stick to one another, as antigens stick to antibodies. Pauling had already shown that hemoglobin changed shape slightly when it was oxygenated.
In the fall of 1946, Pauling presented his ideas as a research problem to Harvey Itano, a young physician who was then working on a Ph.D. in his laboratory. Itano,worked for a year trying to see if sickle-cell hemoglobin was shaped differently from normal hemoglobin.
In 1949, using an exquisitely sensitive new technique called electrophoresis that separated molecules by their electric charge, they found their answer: sickle-cell hemoglobin carried more positive electric charges on its surface.
This was an astounding discovery. A slight change in the electrical charge of a single type of molecule in the body could spell the difference between life and death. This discovery--to which Pauling attached the memorable title "molecular disease"--received widespread attention.
Itano and Singer's subsequent work demonstrated a pattern of inheritance for the disease, firmly wedding molecular medicine to genetics.
Linus Carl Pauling, the only person to win two unshared Nobel Prizes, revolutionized the study of chemistry, helped found the field of molecular biology, and made important advances in medical research.
Linus Pauling, celebrating with Ava Helen, after receiving the Nobel Prize in Chemistry in 1954 "for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances."
1.1. Hemoglobinopathy Hemoglobinopathy is a group of rare, inherited disorders involving abnormal structure of the hemoglobin molecule. These disorders include hemoglobin C disease , hemoglobin S-C disease, sickle cell anemia, and various types of thalassemia.
1.1.1 hemoglobin and its genes Adult hemoglobin is a [a(2):b(2)] tetrameric hemeprotein found in erythrocytes where it is responsible for binding oxygen in the lung and transporting the bound oxygen throughout the body where it is used in aerobic metabolic pathways.
Heme Biosynthesis. The process begins in the mitochondrion with the condensation of succinyl-CoA and glycine to form 5-aminolevulinic acid. A series of steps in the cytoplasm produce coproporphrynogen III, which re-enters the mitochondrion. The final enzymatic steps produce heme.
1.1.2 sickle cell anemia, HbS，AR Sickle cell anemia is a blood disorder that affects hemoglobin, a protein found in red blood cells that helps carry oxygen throughout the body.
Sickle cell anemia occurs when an abnormal form of hemoglobin (HbS) is produced. HbS molecules tend to clump together, making red blood cells sticky, stiff, and more fragile, and causing them to form into a curved, sickle shape.
The mutation causing sickle cell anemia is a single nucleotide substitution (A to T) in the codon for amino acid 6. The change is converts a glutamic acid codon (GAG) to a valine codon (GTG). The form of hemoglobin is persons with sickle cell anemia is referred to as HbS.
1.1.3 α-thalassemia α-Thalassemia is the most common inherited disorder of hemoglobin (Hb) synthesis in the world, with gene frequencies varying between 1% and 98% throughout the tropics and subtropics.
α-thalassemia can occur in all ethnic groups but is more common in those of South East Asian descent. The American College of Obstetricians and Gynecologists recommends hemoglobinopathy screening for those of African, SE Asian and Mediterranean descent.
Alpha thalassemia develops because one or more of the four alpha globin genes fail to produce alpha globin protein. The defect in alpha thalassemia almost always involves the loss of one or more of the alpha globin genes from chromosome #16 .
The inheritance of alpha thalassemia is complex because each parent potentially passes two of their four alpha globin genes to the offspring. One aspect of the inheritance that simplifies predictions is that alpha genes are on the the same chromsosome and are inherited as pairs.
The key issue is whether two alpha genes on the same chromosome are deleted.
If so, the offspring has the chance of having a very severe alpha thalassemia condition in which two alpha globin genes are missing on one chromosome #16, and one is missing on the other chromsome #16 . In that instance, only the person has only one functional alpha globin gene. The result is a severe, transfusion-dependent anemia called Hemoglobin H Disease.
If all four alpha globin genes are missing, the condition is incompatible life. Most fetuses die in utero with this condition (hydrops fetalis). Alpha thalassemia in which two genes are missing on the same chromosome occurs commonly in people of Asian ancestry.
People of Asian ancestry often have two alpha globin genes deleted on the same chromosome #16. The parents each have the mild thalassemia that results with two functioning alpha globin genes. The offspring that inherits the double deletion from one parent and the single from the other will have Hemoglobin H disease (Scenario 1). The offspring who inherits no alpha genes from the parents dies in utero (Scenario 2; hydrops fetalis).
People of African ancestry usually have only one alpha globin gene deleted per chromosome. The parents each have the mild thalassemia that results with two functioning alpha globin genes. The offspring can, at most, inherit the relatively mild condition of the parents.
Polymerase chain reaction followed by agarose gel electrophoresis is used to characterize 6 of the most frequently observed determinants of α-thalassemia.
Hemoglobin Bart's hydrops fetalis syndrome 4 deletions;the pathological changes in this disorder are the result of intrauterine hypoxia: cardiac failure and edema, there is also heptosplenomegaly. Babies die either in utero or soon after birth. There is a high frequency of maternal complications including hypertension and antepartum hemorrhage which must be avoided.
Hemoglobin H disease 3 deletions ; presence of anemia and splenomegaly as well as reduction of the mean cell hemoglobin and mean cell volume. Nevertheless, depending to the molecular pathology, this clinical picture is extremely variable.
a-Thalassemia trait 2 deletions in cis or trans ; absence of clinical symptoms, but a very mild anemia, reduction of the mean cell hemoglobin and mean cell volume without iron deficiency characterises the disorder.
