Alpha thalassemia

Deletions of the HBA1 and/or HBA2 genes are the most common cause of alpha thalassemia. Less commonly, variants (also known as mutations) in or near these genes cause the condition. The signs and symptoms of alpha thalassemia tend to be more severe when the disease results from variants in the alpha-globin genes than when it is caused by deletions of these genes.

People have two copies of the HBA1 gene and two copies of the HBA2 gene in each cell. Each copy is called an allele. For each gene, one allele is inherited from a person's father, and the other is inherited from a person's mother. As a result, there are four alleles that produce alpha-globin. The different types of alpha thalassemia result from the loss or alteration of some or all of these alleles.

Deletions and variants affecting one or more alleles reduce the amount of alpha-globin cells produce. Variants tend to reduce alpha-globin more than deletions.

Hb Bart syndrome, the most severe form of alpha thalassemia, results from the loss or alteration of all four alpha-globin alleles. This condition is characterized by a buildup of excess fluid in the body before birth (hydrops fetalis), a shortage of red blood cells (anemia), and an enlarged liver and spleen (hepatosplenomegaly). 

HbH disease, which is milder, is usually caused by loss of three of the four alpha-globin alleles. Because genetic variants affecting HBA1 or HBA2 can be more severe than deletions, variants in two of the four alpha-globin alleles can result in HbH disease. HbH disease is characterized by mild to moderate anemia, hepatosplenomegaly, and yellowing of the eyes and skin (jaundice). 

In Hb Bart syndrome and HbH disease, a shortage of alpha-globin hinders the production of normal hemoglobin. Instead, cells produce abnormal forms of hemoglobin called hemoglobin Bart (Hb Bart) or hemoglobin H (HbH). These abnormal hemoglobin molecules cannot effectively carry oxygen to the body's tissues. The substitution of Hb Bart or HbH for normal hemoglobin causes anemia and the other serious health problems associated with alpha thalassemia.

Two additional forms of alpha thalassemia are related to a reduced amount of alpha-globin. Because cells still produce some normal hemoglobin, these forms tend to cause few or no health problems. A loss of two of the four alpha-globin alleles results in alpha thalassemia trait. People with alpha thalassemia trait may have unusually small, pale red blood cells and mild anemia. A loss of one alpha-globin allele is found in alpha thalassemia silent carriers. These individuals typically have no thalassemia-related signs or symptoms.

Variants in one or two alpha-globin alleles cause a range of conditions, from alpha thalassemia silent carrier to HbH disease, depending on the alleles involved.

Other disorders

A condition called alpha-thalassemia-intellectual disability syndrome, chromosome 16-related (ATR-16) results from a large deletion of genetic material from the short (p) arm of chromosome 16. The signs and symptoms of this condition result from the loss of many genes, including HBA1 and HBA2.

A deletion of the HBA1 and HBA2 genes leads to alpha thalassemia trait in most people with ATR-16. The loss of other genes causes additional features of the disorder, including intellectual disability, severely delayed language skills, an unusually small head size (microcephaly), and distinctive facial features. Affected males may also have undescended testes (cryptorchidism) and the urethra opening on the underside of the penis (hypospadias).

The signs and symptoms of ATR-16 vary depending on the size of the deletion. A particularly large deletion may include the PKD1 gene, which is responsible for polycystic kidney disease. A loss of this gene leads to the growth of multiple cysts in the kidneys. If the deletion also includes the TSC2 gene, an affected individual will develop tuberous sclerosis complex. This condition is characterized by the growth of noncancerous tumors in many parts of the body.