Alpha-thalassemia X-linked mental retardation syndrome

Definition

Alpha-thalassemia X-linked mental retardation syndrome is a rare, inherited condition characterized by severe mental retardation, characteristic facial features, and mild anemia. Due to the inheritance pattern of this disorder, only males are affected.

Description

Alpha-thalassemia X-linked mental retardation syndrome is also known as ATRX syndrome, X-linked mental retardation hypotonic facies syndrome, and alpha thalassemia/mental retardation, X-linked. This condition is characterized by mental retardation, severe developmental delay, unique craniofacial features, skeletal abnormalities, hypotonia, and genital abnormalities. These patients often have a form of anemia, called alpha thalassemia , which results from a defect in the production of hemoglobin. The syndrome has been recognized fairly recently and, thus, information about it is still evolving.

Genetic profile

Alpha-thalassemia X-linked mental retardation syndrome is caused by mutations in the ATRX gene that is located on the X chromosome . Males only have one X chromosome, which they always inherit from their mother. Thus, males who inherit a mutation in the ATRX gene are affected with the disorder. Females who inherit a mutation in the ATRX gene are carriers of the disorder—this is because they have a second X chromosome with a functional copy of the ATRX gene. This functional copy compensates for the mutated copy. Carrier females rarely show clinical signs of the disorder. Due to the X-linked recessive inheritance pattern, only males can be affected with this condition.

If a male is affected with alpha-thalassemia X-linked mental retardation syndrome, it is impossible for him to reproduce due to the associated genital abnormalities. However, there are implications for other family members. For example, his mother may be a carrier of an ATRX mutation. If this is the case, each subsequent male child will have a 50% to inherit the abnormal ATRX gene. Since there is a 50% chance that a child will be male, this means that any given pregnancy from a carrier mother has a 25% (50% × 50%) chance to be affected with alpha-thalassemia X-linked mental retardation syndrome. It is important to remember that an ATRX mutation may also have implications for the affected individual's maternal aunts and their offspring.

However, it is also possible that the ATRX mutation is a new (de novo) mutation in the affected individual, meaning that his mother would not be a carrier. It is unknown how often a de novo mutation occurs in ATRX. The possibility of a de novo mutation is much less likely if there are two or more affected brothers in the family. If there are no other affected individuals in the family and if the mother's X-inactivation studies are normal, the mother is very unlikely to be a carrier. Thus, it is likely a de novo mutation in the affected male and the recurrence risk to siblings is very small.

Another possibility is germline mosaicism. In this case, the ATRX mutation may be present only in the egg cells of the mother. Thus, her blood cells would be normal and, therefore, X-inactivation studies and molecular genetic tests would be normal as well. However, the ATRX mutations present in her egg cells would leave a significant recurrence risk for future pregnancies.

Demographics

The prevalence of alpha-thalassemia X-linked mental retardation syndrome is not currently known. Between 150 and 200 affected patients are known worldwide. There are no reports of the condition being more common in specific ethnic groups or geographical regions.

Signs and symptoms

There are distinctive features that accompany alpha-thalassemia X-linked mental retardation syndrome. The most noticeable clinical sign is the severe developmental delay and mental retardation that is almost always present. From very early in life, affected individuals will be delayed in meeting developmental milestones. Some will fail to walk independently and many will not learn to speak coherently. Poor muscle tone (hypotonia), which is also very common in this condition, plays a role in the developmental delay. More recently, there have been reports of affected individuals with less severe developmental delay and mental retardation, however, it is unclear as to why this is.

There are unique craniofacial features associated with alpha-thalassemia X-linked mental retardation syndrome. Affected individuals often have a small head (microcephaly), widely spaced eyes (telecanthus), flat mid-facial area (mid-face hypoplasia), small and low-set ears, small triangular nose, tented upper lip, and full, everted lower lip with a protruding tongue. About twothirds of affected individuals have short stature. In some patients, growth retardation is present throughout life and, in other cases, it manifests around puberty. Other minor skeletal abnormalities have been observed as well, such as joint contractures, abnormalities of the fingers and toes, foot deformations, and scoliosis . Additionally, genitalia of affected individuals are often abnormal and underdeveloped. These abnormalities may be minor, such as undescended testes, or major, such as ambiguous genitalia that appears female in nature. In many cases, patients do not progress through puberty as expected, probably due to inadequate amounts of the male hormone testosterone.

In addition, patients with alpha-thalassemia X-linked mental retardation syndrome can have abnormal gut function and resulting problems with digestion. Feeding problems are fairly common as well, such as swallowing difficulties, regurgitation of food, and/or vomiting. Constipation becomes an issue in some patients. These difficulties often resolve with age. Seizures occur in approximately one-third of cases. Cleft palate, deafness, cardiac defects, and renal/urinary abnormalities are less common, but have been reported.

About 85% of the time, blood tests in affected individuals show a mild form of anemia, also known as alpha thalassemia. This results from a defect in the production of an important component of hemoglobin. However, this mild anemia does not appear to have any adverse consequences in patients with the disorder.

Diagnosis

Alpha-thalassemia X-linked mental retardation syndrome can be suspected clinically in an individual who has mental retardation, hypotonia, characteristic physical features (i.e., craniofacial, skeletal, genital), and a family history consistent with X-linked recessive inheritance. Usually, the most obvious signs of the disorder are developmental delay and severely impaired cognitive function.

The most ideal way to diagnose this condition is to identify a gene mutation in the affected individual via molecular genetic testing of the ATRX gene. Then, the mother can be tested for this mutation to determine her carrier status. This type of analysis will detect mutations in approximately 90% of individuals with alpha-thalassemia X-linked mental retardation syndrome. This testing is done by gene sequence analysis either of the entire ATRX gene or of a portion of the gene that is known to contain 40–50% of ATRX mutations.

If molecular genetic testing is not available or is uninformative in a family, linkage analysis may be helpful. In this genetic test, DNA markers that are located very close to the ATRX gene are used to track the damaged copy through a family. This technique is most effective in large families with multiple affected males.

In some cases, blood abnormalities can be detected by various laboratory tests. For example, molecules called hemoglobin H (HbH) inclusions may be seen in the red blood cells of affected individuals. This is a feature of the alpha thalassemia that is associated with this condition. HbH inclusions are less helpful in identifying female carriers and are only seen in approximately 25% of women who carry an ATRX mutation. Additionally, microcytic, hypochromic anemia can be detected by a blood test and may be a sign of alpha thalassemia and, therefore, alpha-thalassemia X-linked mental retardation syndrome. However, the absence of either of these blood abnormalities does not rule out this condition—many affected individuals will not demonstrate these abnormalities.

Another option for detecting female carriers of the ATRX gene is X-chromosome inactivation studies. In a typical female, each cell has two X chromosomes (X1 and X2) and one of them will be inactivated. This inactivation is a random process meaning that, if one were to look at a significant number of cells, X1 would be inactivated in approximately the same number of cells as X2. This process is skewed in females who are carriers of the ATRX gene mutation because the X chromosome that carries the ATRX mutation will be preferentially inactivated. A laboratory test can detect this skewed X inactivation. However, this characteristic is not always present in carriers of ATRX mutations and, also, can be present for other reasons. Thus, it is not diagnostic and must be interpreted in the context of the clinical findings and family history. X-chromosome inactivation studies can be especially useful if molecular testing is not available or is uninformative in a family.

Prenatal testing is available for pregnancies that are at risk for alpha-thalassemia X-linked mental retardation syndrome. For pregnancies in which the mother is a definite carrier of the ATRX mutation, fetal sex is determined via cells obtained from amniocentesis or chorionic villus sampling (CVS). If the fetus is male, DNA from the fetal cells can be analyzed for the ATRX mutation that has been found in the family. For pregnancies in which the mother has tested negative for the ATRX mutation but has previously birthed an affected child, prenatal diagnosis should still be offered to all male fetuses. This is due to the possibility of germline mosaicism.

Treatment and management

Very few of the abnormalities that result from alpha-thalassemia X-linked mental retardation syndrome are life-threatening. Thus, treatment and management are often unnecessary. However, some interventions can be helpful depending on the clinical signs and symptoms that are present. For example, feeding problems can be managed with tube feeding in the early months and, in rare cases, with a permanent feeding tube passed through the abdominal wall into the stomach (feeding gastrostomy). An operation known as fundoplication may be necessary to correct problems with regurgitation. Additionally, other surgeries may be required for certain clinical manifestations, such as cleft palate, cardiac defects, and abnormal genitalia. Again, the anemia that often accompanies this condition is mild and does not require any treatment.

Prognosis

Alpha-thalassemia X-linked mental retardation syndrome was discovered and characterized fairly recently. Thus, detailed information about prognosis has not been collected. There are reports of adults surviving into their 30s. However, some children will die at an early age. One of the main causes of early death in this condition is pneumonia, which can result from food entering the lungs due to vomiting and regurgitation problems.

Resources

PERIODICALS

Gibbons, R. J., and D. R. Higgs. "Molecular-clinical Spectrum of the ATR-X Syndrome." American Journal of Medical Genetics 97 (2000): 204–212.

WEB SITES

"ATRX Syndrome." The Gibbons Laboratory. (April 3, 2005.) <http://www.imm.ox.ac.uk/mhu/Home_Pages/Gibbons/index.html>.

Stevenson, Roger E. "Alpha-thalassemia X-linked mental retardation syndrome." Gene Reviews. (April 3, 2005.) http://www.genetests.org/servlet/access?db=geneclinics&site=gt&id=8888891&key=FnPPkPSrKElS&gry=&fcn=y&fw=CjU5&filename=/profiles/xlmr/index.html.

Mary E. Freivogel, MS, CGC