Alpha thalassemia X-linked intellectual disability syndrome

Description

Alpha thalassemia X-linked intellectual disability syndrome is an inherited disorder that affects intellectual functioning, red blood cells, and other body systems. This condition occurs almost exclusively in males.

Individuals with alpha thalassemia X-linked intellectual disability syndrome have intellectual disabilities and certain aspects of their development may be delayed. These can include speech and language development, and some affected individuals never speak or sign more than a few words. Most affected children have weak muscle tone (hypotonia), which contributes to the characteristic facial features and delays the development of motor skills such as sitting and walking. Some people with this disorder are never able to walk independently. Individuals with this condition have seizures, although this is less common.

About 75 percent of individuals with alpha thalassemia X-linked intellectual disability syndrome 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. Without sufficient hemoglobin, not enough oxygen can reach the body's tissues. In rare cases, affected individuals also have a shortage of red blood cells (anemia).

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 face may appear flatter or the nose can become shorter.

Additional features of alpha thalassemia X-linked intellectual disability syndrome can include an unusually small head size (microcephaly) and short stature. Some people with this condition have skeletal abnormalities that affect the spine, hands, or feet. 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 may be on the underside of the penis (hypospadias). In some cases, the external genitalia do not look clearly male or female.

Frequency

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 in the scientific literature. Because the signs and symptoms of alpha thalassemia X-linked intellectual disability syndrome overlap with those of many other conditions, it can be challenging to diagnose.

Causes

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the ATRX gene cause alpha thalassemia X-linked intellectual disability syndrome. The ATRX gene provides instructions for making a protein that plays an essential role in normal development. The ATRX protein has many functions, such as helping to repair DNA damage and regulating the activity (expression) of other genes. Two of the genes that the ATRX protein helps regulate are HBA1 and HBA2, which are necessary for normal hemoglobin production.

Pathogenic variants in the ATRX gene lead to changes in the ATRX protein, which likely impair its ability to regulate gene expression. Reduced activity of the HBA1 and HBA2 genes causes alpha thalassemia. The lack of functioning ATRX proteins likely affects the expression of other genes as well, leading to the intellectual disabilities, distinctive facial features, and the other signs and symptoms of alpha thalassemia X-linked intellectual disability syndrome.

Inheritance

This condition is inherited in an X-linked pattern. A condition is considered X-linked if the altered gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), a pathogenic variant in the only copy of the gene in each cell is sufficient to cause the condition.  A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. It is estimated that 80 to 90 percent of males with alpha thalassemia X-linked intellectual disability syndrome inherit the ATRX gene variant from their mother. The remaining cases of this condition result from new (de novo) variants in the gene that occur during the formation of reproductive cells (eggs) in an affected individual's mother or in early embryonic development.

In females (who have two copies of the X chromosome), a pathogenic variant in one copy of the ATRX gene typically does not cause the health problems that are associated with alpha thalassemia X-linked intellectual disability syndrome. In rare cases, these females may have intellectual disabilities and other signs and symptoms.

Other Names for This Condition

• Alpha thalassemia/intellectual disability syndrome X-linked
• Alpha-thalassemia/impaired intellectual development syndrome
• ATR-X syndrome
• ATRX syndrome
• XLMR-hypotonic face syndrome

Where this page came from

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