Alpha thalassemia X-linked intellectual disability syndrome is an inherited disorder that affects many parts of the body. This condition occurs almost exclusively in males.

Males with alpha thalassemia X-linked intellectual disability syndrome have intellectual disability and delayed development. Their speech is significantly delayed, and most never speak or sign more than a few words. Most affected children have weak muscle tone (hypotonia), which delays motor skills such as sitting, standing, and walking. Some people with this disorder are never able to walk independently.

Almost everyone with alpha thalassemia X-linked intellectual disability syndrome has distinctive facial features, including widely spaced eyes, a small nose with upturned nostrils, and low-set ears. The upper lip is shaped like an upside-down "V," and the lower lip tends to be prominent. These facial characteristics are most apparent in early childhood. Over time, the facial features become coarser, including a flatter face with a shortened nose.

Most affected individuals have mild signs of a blood disorder called alpha thalassemia. This disorder reduces the production of hemoglobin, which is the protein in red blood cells that carries oxygen to cells throughout the body. A reduction in the amount of hemoglobin prevents enough oxygen from reaching the body's tissues. Rarely, affected individuals also have a shortage of red blood cells (anemia), which can cause pale skin, weakness, and fatigue.

Additional features of alpha thalassemia X-linked intellectual disability syndrome include an unusually small head size (microcephaly), short stature, and skeletal abnormalities. Many affected individuals have problems with the digestive system, such as a backflow of stomach acids into the esophagus (gastroesophageal reflux) and chronic constipation. Genital abnormalities are also common; affected males may have undescended testes and the opening of the urethra on the underside of the penis (hypospadias). In more severe cases, the external genitalia do not look clearly male or female.

Alpha thalassemia X-linked intellectual disability syndrome results from mutations in the ATRX gene. This gene provides instructions for making a protein that plays an essential role in normal development. Although the exact function of the ATRX protein is unknown, studies suggest that it helps regulate the activity (expression) of other genes. Among these genes are HBA1 and HBA2, which are necessary for normal hemoglobin production.

Mutations in the ATRX gene change the structure of the ATRX protein, which likely prevents it from effectively regulating gene expression. Reduced activity of the HBA1 and HBA2 genes causes alpha thalassemia. Abnormal expression of other genes, which have not been identified, probably causes developmental delay, distinctive facial features, and the other signs and symptoms of alpha thalassemia X-linked intellectual disability syndrome.

Normal Function

The ATRX gene provides instructions for making a protein that plays an essential role in normal development. Although the specific function of the ATRX protein is unknown, studies suggest that it helps regulate the activity (expression) of other genes through a process known as chromatin remodeling. Chromatin is the complex of DNA and protein that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. Chromatin remodeling is one way gene expression is regulated during development. When DNA is tightly packed, gene expression is lower than when DNA is loosely packed.

The ATRX protein appears to regulate the expression of two genes, HBA1 and HBA2, that are necessary for the production of hemoglobin. Hemoglobin is the protein in red blood cells that carries oxygen to cells throughout the body. Other genes regulated by the ATRX protein have not been identified.

Health Conditions Related to Genetic Changes

Alpha thalassemia X-linked intellectual disability syndrome

More than 125 mutations in the ATRX gene have been identified in people with alpha thalassemia X-linked intellectual disability syndrome. The most common mutations change single protein building blocks (amino acids) in the ATRX protein. Other mutations insert or delete genetic material in the ATRX gene or alter how the gene's instructions are used to make the protein.

Mutations may destabilize the ATRX protein or affect its interactions with other proteins. These changes prevent the ATRX protein from effectively regulating gene expression. Reduced activity of the HBA1 and HBA2 genes causes a blood disorder called alpha thalassemia. Abnormal expression of additional genes likely causes developmental delay, distinctive facial features, and the other signs and symptoms of alpha thalassemia X-linked intellectual disability syndrome.

Other disorders

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are not inherited, are called somatic mutations. Somatic mutations of the ATRX gene have been found in some people with blood and bone marrow disorders. In particular, researchers have found somatic ATRX gene mutations in some cases of myelodysplastic syndrome (MDS), which is a bone marrow disorder that usually occurs in older males.

Somatic ATRX gene mutations do not cause MDS; instead, they occur as the condition progresses. Like inherited mutations in the ATRX gene, somatic mutations reduce the activity of the HBA1 and HBA2 genes and cause alpha thalassemia. When alpha thalassemia occurs in people with MDS, the combination of disorders is often referred to as alpha thalassemia myelodysplastic syndrome (ATMDS).

Other Names for This Gene

• alpha thalassemia/mental retardation syndrome X-linked
• alpha thalassemia/mental retardation syndrome X-linked (RAD54 homolog, S. cerevisiae)
• ATR2
• ATRX_HUMAN
• DNA dependent ATPase and helicase
• helicase 2, X-linked
• MGC2094
• MRXHF1
• RAD54
• RAD54L
• SFM1
• SHS
• transcriptional regulator ATRX
• X-linked nuclear protein
• XH2
• XNP
• Zinc finger helicase
• ZNF-HX

Genomic Location

Alpha-thalassemia x-linked intellectual disability (ATRX) syndrome is caused by a mutation in the ATRX gene and is inherited in an x-linked way. The chance that a relative may have ATRX syndrome depends on whether the mutation in the first affected family member was inherited from his mother or happened by chance (a de novo mutation). If the mutation happened by chance, there is very little risk that other relatives could be affected by this condition. If the mutation was inherited from his mother, each of his mother's sisters has a 50% of being a carrier of ATRX syndrome. If a woman is a carrier of an ATRX mutation, she has a 25% chance of having a son with the mutation who is affected with ATRX syndrome; a 25% chance of having a son who does not have the mutation and does not have ATRX syndrome; a 25% chance of having a daughter with the mutation who is a carrier of ATRX syndrome; and a 25% chance of having a daughter who does not have the mutation and is not a carrier.

The type of treatment a person receives depends on how severe the thalassemia is. The more severe the thalassemia, the less hemoglobin the body has, and the more severe the anemia may be.

One way to treat anemia is to provide the body with more red blood cells to carry oxygen. This can be done through a blood transfusion, a safe, common procedure in which you receive blood through a small plastic tube inserted into one of your blood vessels. Some people with thalassemia – usually with thalassemia major – need regular blood transfusions because their body makes such low amounts of hemoglobin. People with thalassemia intermedia (not as severe as major, but not as mild as trait) may need blood transfusions sometimes, such as when they have an infection or an illness. People with thalassemia minor or trait usually do not need blood transfusions because they either do not have anemia or have only a mild anemia.

Many times people with thalassemia are prescribed a supplemental B vitamin, known as folic acid, to help treat anemia. Folic acid can help red blood cells develop. Treatment with folic acid is usually done in addition to other therapies.

Alpha thalassemia X-linked intellectual disability syndrome appears to be a rare condition, although its exact prevalence is unknown. More than 200 affected individuals have been reported.