Thalassemia and genetics

ALSO KNOWN AS: Mediterranean anemia; Cooley’s anemia; thalassemia major; thalassemia minor

DEFINITION Thalassemia is an inherited disorder. It leads to the decreased production and increased destruction of red blood cells. Hemoglobin in the red blood cells carry oxygen to all organs in the body. The loss of red blood cells results in low hemoglobin, which leads to anemia. The decreased oxygen will impair the ability to maintain normal functions.

Hemoglobin is made of two separate amino acid chains: alpha and beta. Thalassemias are categorized by the specific chain and number of genes affected. In alpha thalassemia, the alpha chain is affected. Silent carrier thalassemia affects one gene; thalassemia trait affects two genes; Hemoglobin H disease affects three genes; alpha hydrops fetalis, the most severe form, affects four genes and results in fetal or newborn death. In beta thalassemia, the beta chain is affected. Thalassemia minor involves one abnormal gene; thalassemia major (Cooley’s anemia) involves two abnormal genes.

Risk Factors

Risk factors that increase an individual’s chance of thalassemia include the geographic location of his or her ancestors. Individuals with ancestors from Southeast Asia, Malaysia, and southern China are at risk for alpha thalassemias; individuals of southeast Asian, Chinese, and Filipino ancestry are at risk for alpha hydrops fetalis; those with ancestors from Africa, areas surrounding the Mediterranean Sea, and Southeast Asia are at risk for beta thalassemias. A family history of the disorder is another risk factor.

Etiology and Genetics

Mutations in the HBB gene, located on the short arm of chromosome 11 at position 11p15.5, are the cause of beta thalassemia. This gene encodes the beta-globin polypeptide, which is one of the major components of hemoglobin. Some mutations completely inactivate the gene and stop the production of beta-globin (β0 thalassemia), while others result in only a decreased amount of beta-globin in red blood cells (β+ thalassemia). In either case, insufficient amounts of are formed, and anemia and other growth problems associated with beta thalassemia result. The inheritance pattern for this disease is usually autosomal recessive, meaning that both copies of the gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected.

The inheritance of alpha thalassemia is more complex, since two genes are involved. The HBA1 and HBA2 genes are virtually identical copies of each other, and they are found in adjacent positions on the short arm of chromosome 16 at position 16p13.3. Each encodes an alpha-globin polypeptide, one of the four subunits of a mature hemoglobin molecule. Alpha thalassemia results when one or more copies of these genes are deleted from the genome. Since each individual has two copies of each gene, there are four functional genes that encode alpha-globin in healthy individuals. Different degrees or severities of alpha thalassemia are recognized when one, two, three, or all four copies of the gene are missing. If both parents are missing at least one copy of either HBA1 or HBA2, their children could inherit anywhere from zero to four alpha-globin genes and present clinically with anywhere from the most severe form of alpha thalassemia to no thalassemia at all. The precise risk in each particular case depends entirely on the number and orientation of the missing genes in each parent.

Symptoms

Symptoms most often begin within three to six months of birth. Symptoms may include anemia, which may be mild, moderate, or severe; jaundice; an enlarged spleen; fatigue (tiredness); listlessness; and reduced appetite. Another symptom may be enlarged and fragile bones, including thickening and roughening of facial bones, bones that break easily, and teeth that do not line up properly. Growth problems, increased susceptibility to infection, and skin that is paler than usual may also be symptoms. Additional symptoms may be hormone problems, such as delayed or absent puberty, diabetes, and thyroid problems. Heart failure, shortness of breath, liver problems, and gallstones may be other symptoms.

Alpha thalassemia usually causes milder forms of the disease with varying degrees of anemia.

Beta thalassemia can be asymptomatic or be a mild form of disease. The mild form is known as thalassemia intermedia. This form rarely needs extensive medical care.

Beta thalassemia major (Cooley’s anemia) has symptoms within the first two years of a child’s life. Children are pale and listless. They often have poor appetites. They grow slowly and often develop jaundice (yellowing of skin). This disease requires regular blood transfusions and extensive medical care.

Without treatment, the spleen, liver, and heart soon become very enlarged. Bones become thin and brittle. Abnormal deposits of iron in body organs can lead to organ failure. This is called secondary hemochromatosis. It most often affects the heart, liver, and pancreas. Heart failure and infection are the leading causes of death among children with untreated thalassemia major.

Screening and Diagnosis

The doctor will ask about a patient’s symptoms and medical history. A physical exam will be done. Blood tests may include a complete blood count, which is a count of the different types of blood cells; a blood smear; hemoglobin electrophoresis; quantitative hemoglobin analysis; and iron levels.

Treatment and Therapy

Treatment may include blood transfusions. These are done to replace abnormal red blood cells with healthy new ones.

Iron chelation therapy is another form of treatment. Excess iron can accumulate in the body after repeated blood transfusions. Too much iron can damage the heart, liver, and other vital organs. A drug called deferoxamine (Desferal) can be given to bind to excess iron in the body. It is then carried out through the urine. This drug is given through the skin or by vein using a small infusion pump. There is a drug for the therapy called deferasirox (Exjade). It can be given as a drink or mixed with water or juice.

Splenectomy is a surgical procedure done to remove the spleen. It may help reduce the number of blood transfusions that are needed.

In a bone marrow transplant, healthy stem cells from a donor’s bone marrow are injected into a patient’s vein. The new cells travel through the bloodstream to the bone cavities; there they can produce new blood cells, including red blood cells. This is usually only done in severe cases. A compatible sibling donor is required.

Prevention and Outcomes

This disease is inherited. Blood tests and family genetic studies will show if an individual is a carrier. A genetic counselor can discuss the risks of passing on the disease. The counselor can also provide information on testing. In 2024, the FDA approved a CRISPR treatment for beta thalassemia.

Bibliography

Goodman, Brenda. "FDA Clears First CRISPR Treatment For a Second Disease, Beta Thalassemia." CNN, 16 Jan. 2024, www.cnn.com/2024/01/16/health/crispr-casgevy-beta-thalassemia/index.html. Accessed 5 Sept. 2024.

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Weatherall, D. J., and J. B. Clegg. The Thalassaemia Syndromes. 4th ed. Malden: Blackwell Science, 2001. Print.

Yaman, Ayhan, et al. "Common Complications in Beta-Thalassemia Patients." Intl. Journ. of Hematology & Oncology 23.3 (2013): 193–99. Print.