Alpha-thalassemia/mental retardation syndrome, x-linked

Changes, or mutations, in the ATRX gene cause alpha-thalassemia X-linked intellectual disability syndrome. Genes are instructions for the production of proteins. Proteins do the "work" of making our bodies develop properly. When there is a change in a gene, its protein product may not work properly. The protein coded for by the ATRX gene, called ATRX protein, appears to work as a regulator of other genes in the cell. When there is a mutation in the ATRX gene, it is as if there is a spelling error in the gene’s instructions for creating the ATRX protein, which results in an abnormal protein product. The abnormal ATRX protein then incorrectly regulates genes important in development of the brain, nervous system, face, genitalia, other body parts, resulting in abnormal development of these features in people with ATRX syndrome. The abnormal ATRX protein also causes decreased activity of the genes that produce hemoglobin, resulting in anemia (deficiency of red blood cells), in people with ATRX syndrome.

If an individual has been diagnosed with alpha-thalassemia X-linked intellectual disability syndrome by genetic testing (confirmed to have a change or mutation in the ATRX gene), other relatives can be tested. The relatives who would benefit most from testing are other males with symptoms of the condition who are related through females to the person with the ATRX gene mutation, and females who are at risk to be carriers.

Prenatal diagnosis for pregnancies at increased risk is possible if the mutation in the ATRX gene in the family is known. This can be done during the pregnancy by testing of fetal cells obtained through CVS (chorionic villus sampling), performed between 10 to 13 weeks of pregnancy, or amniocentesis, performed between 15 to 20 weeks of pregnancy.

A medical geneticist and/or a genetic counselor is the best person to help identify appropriate individuals for testing as well as the most appropriate way to test those family members. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

If you are looking to speak with other families who have a loved one with alpha-thalassemia X-linked intellectual disability syndrome, consider asking your geneticist or genetic counselor if they are familiar with any local families who might be willing to do so. There is an online support group called X-Linked Alpha Thalassemia M/R Syndrome Support Group that you may also contact.

All individuals with alpha-thalassemia X-linked intellectual disability syndrome should be seen by a medical geneticist and a genetic counselor. These specialists can make sure that the person is being screened appropriately for possible medical and developmental issues. They can also make sure that up-to-date information on genetic testing is provided, as well as support resources and reproductive counseling.

The other specialists that an individual with alpha-thalassemia X-linked intellectual disability syndrome sees depend on the specific medical problems that person has. Because of the high incidence of developmental issues, speech, occupational and physical therapists are almost always involved in the care of affected individuals. Other specialists such as neurology, cardiology, hematology, orthopedics, surgery, and nutrition depend on the specific medical issues present in a given affected individual.

Alpha-thalassemia X-linked intellectual disability syndrome is a genetic condition that affects different parts of the body. Nearly all individuals with this condition are male. Males with this condition have distinctive facial features, abnormal genitalia, low muscle tone, global developmental delay, and mild-to-moderate anemia due to a problem with hemoglobin (known as alpha-thalassemia).

Because alpha-thalassemia X-linked intellectual disability syndrome is a rare condition, there is not a lot of information about how long affected individuals live. Many affected males have been known to live well into adulthood, but there are also reports of some passing away as young boys, often under the age of 5. The most frequent reason for early death is pneumonia. These types of respiratory infections are likely connected to the frequent feeding/swallowing problems seen in these individuals, leading to food going into the lungs.

Most individuals with alpha-thalassemia X-linked intellectual disability syndrome have good general physical health. Nonetheless, there are some medical problems more common in people with this disorder for which they should be watched. Infants with this disorder often have low muscle tone which can contribute to feeding issues, leading to poor nutrition. Therefore, the growth of these infants should be monitored closely, at least throughout childhood. Because digestive problems are also common in affected individuals, doctors should monitor for signs of swallowing problems, reflux, and/or recurrent vomiting. These problems can also affect nutrition and growth. Major anatomic structural problems are not typically associated with alpha-thalassemia X-linked intellectual disability syndrome; however, there have been rare reports of affected individuals having cleft palates, heart defects, and/or absent spleens ("asplenia"). Therefore, careful physical examination for signs of these problems is warranted. Eye problems have also been reported as a feature associated with this disorder, so doctors should routinely check affected individuals for structural eye defects and vision problems. Although a mild form of anemia known as hemoglobin H disease is seen in many individuals with this syndrome, it is typically not clinically significant.

Alpha-thalassemia X-linked intellectual disability syndrome is caused by changes in the ATRX gene. This gene is thought to be important in regulating the way other genes function. Changes in ATRX are thought to cause problems with the functioning of genes essential to normal neurologic and anatomic development as well as genes that are essential for hemoglobin production. Problems with the functioning of these genes results in the physical and developmental symptoms seen in people with this condition.

One of the main features of alpha-thalassemia X-linked intellectual disability syndrome is that it almost exclusively affects males and has so far been described in only one female (as of March 2016). Females with a genetic mutation in ATRX typically do not show any signs of this disorder; however, all males with a genetic mutation in ATRX are expected to have some of the main symptoms, which include: intellectual disability, hypotonia (low muscle tone), specific facial features, abnormal genitalia, and alpha-thalassemia.

Getting a diagnosis of alpha-thalassemia X-linked intellectual disability syndrome can be overwhelming for a family. Because it is a relatively rare condition, most families have not heard of this condition prior to the diagnosis being made. The first step to take once the diagnosis is made is to have a visit with a genetics professional such as a medical geneticist and/or a genetic counselor to discuss what the condition is, what this means for your family, and how to manage the medical and developmental issues that may come from having this diagnosis. They can make sure that the appropriate management and treatment plan is in place. It is also essential to get information from trustworthy sources. Your genetic counselor can provide you with additional, specific written and online sources of information about alpha-thalassemia X-linked intellectual disability syndrome. Some general information about alpha-thalassemia X-linked intellectual disability syndrome is available through Genetics Home Reference: https://ghr.nlm.nih.gov/condition/alpha-thalassemia-x-linked-intellectual-disability-syndrome. General information about rare diseases and peer support can be found though the National Organization for Rare Disorders: http://rarediseases.org/.

Dr. Richard Gibbons and Dr. Doug Higgs are professors and researchers at the University of Oxford in Oxford, England. Both have spent over two decades studying alpha-thalassemia X-linked intellectual disability syndrome. Dr. Gibbons’ research group was responsible for identifying the ATRX gene and he and Dr. Higgs remain committed to understanding this condition better. Information about their work can be found at this website, with specific information about their research summarized here.

As of June 2019, we are not able to locate any other clinical research happening on alpha-thalassemia X-linked intellectual disability syndrome. However, for a listing of current clinical trials in the United States visit clinicaltrials.gov and search for the condition.

There is no cure for alpha-thalassemia X-linked intellectual disability syndrome. Nevertheless, there are many treatments that can help with the individual symptoms that an affected person may have. Because every person with this condition is different, the particular treatments one affected individual undergoes will likely be different from another affected individual. Treatments are also dependent on the age of the affected individual.

Some treatments for the most common symptoms of alpha-thalassemia X-linked intellectual disability syndrome may include:

To the best of our knowledge, all males with changes in the ATRX gene that cause abnormal ATRX protein function have alpha-thalassemia X-linked intellectual disability syndrome. There is a range of severity from mild to severe; therefore, some males with this disorder may have subtle enough symptoms that they have not yet been diagnosed. Females with causative changes in the ATRX gene almost never show signs of the disorder. In fact, there is only one reported case of a female with a change in this gene having enough signs of alpha-thalassemia X-linked intellectual disability syndrome to be diagnosed with this condition.

Alpha-thalassemia X-linked intellectual disability syndrome is inherited in an X-linked recessive manner. This means that the gene for the disorder, ATRX is located on the X chromosome, and mutations in this gene affect males and females differently. The X chromosome is one of the two chromosomes that determine whether you are male or female. Most females have two X chromosomes and most males have one X chromosome and one Y chromosome. The term recessive means that only one functioning, unchanged copy of the gene is needed for normal development. When a female has a change in the ATRX gene on one of her copies of the X chromosome, her unchanged copy of the gene on her other X chromosome will almost always compensate, leading to her being an unaffected carrier for the condition. Males, on the other hand, have only one X chromosome. If their copy of ATRX is changed, they do not have a backup copy to allow for normal gene function. Therefore, the symptoms of alpha-thalassemia X-linked intellectual disability syndrome are present in all males with ATRX gene changes.

Changes in the ATRX gene in males with alpha-thalassemia X-linked intellectual disability syndrome can be inherited or de novo. When the gene change is inherited, the abnormal ATRX gene is passed down from the patient’s mother, who has the gene change in half of the X chromosomes in every cell of her body and is called a "carrier" of the condition. A woman who is a carrier for this condition has a 50% risk with each pregnancy to pass the gene on to her offspring. If the offspring is male, he will be affected. If the offspring is female, she will almost certainly be an unaffected carrier. There has been one report of a female with one changed copy of ATRX having significant symptoms of alpha-thalassemia X-linked intellectual disability disorder; however, this is incredibly rare. When the gene change is de novo, this means that the single egg cell from the mother that was passed on to her son had a spontaneous change in the ATRX gene. In de novo cases, the mother would not be expected to have the abnormal gene in other cells of her body or in other egg cells and would not be expected to have additional affected children. Males with this disorder have not been known to reproduce.

A doctor may suspect alpha-thalassemia X-linked intellectual disability syndrome in a person (usually a male) who has specific physical and developmental symptoms, such as characteristic facial features, microcephaly (small head), anomalies of the genitalia, anomalies of the skeletal system (short stature, clubfoot, sunken chest, curved spine, abnormally developed fingers), severe to profound intellectual disability, and blood test results suggestive of alpha-thalassemia (specific type of anemia). The blood tests that are used to diagnose alpha-thalassemia include looking at the size of the person’s red blood cells and looking for the presence of HbH inclusions (an abnormal type of globin molecule found in people with alpha-thalassemia X-linked intellectual disability syndrome that causes problems with the transport oxygen and iron through the bloodstream).

Because many other genetic conditions have similar symptoms to alpha-thalassemia X-linked intellectual disability syndrome, the only way to know for sure if a person has this specific condition is through molecular genetic testing (looking at the person’s DNA for changes in the person’s ATRX gene). Depending on what symptoms are present in a person, testing may be done on just the ATRX gene, on a whole panel of genes that are responsible for many different conditions that are similar to alpha-thalassemia X-linked intellectual disability syndrome, or even on a person’s whole genome (complete set of DNA including all genes) to confirm the diagnosis. The best person to help figure out if a person has alpha-thalassemia X-linked intellectual disability syndrome is a medical geneticist (doctor) or genetic counselor who are specially trained to diagnose, treat, and support families who have, or are suspected to have, genetic conditions. To find a medical genetics professional in your area, you may wish to ask for a referral from your regular doctor or other doctors in the area. GA medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

Dr. Richard Gibbons, a professor and researcher at the University of Oxford in Oxford, England, is the foremost expert in regards to alpha-thalassemia X-linked intellectual disability syndrome. His contact information is located here.

You can also periodically check this website to see if any new studies are recruiting. Once you are at the website, just enter key words such as "X-linked" and "alpha-thalassemia" into the search box in the upper right to see if there are any available studies.

There are no centers of excellence that are specifically devoted to caring for individuals with or research on alpha-thalassemia X-linked intellectual disability syndrome. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website.

There are several organizations that focus on rare genetic diseases, including increasing awareness and funding research. A donation to these organizations will help individuals with alpha-thalassemia X-linked intellectual disability syndrome and other rare genetic diseases. Genetic Alliance is a non-profit health advocacy group that seeks to ensure access to quality genetic services for all individuals. The National Organization for Rare Disorders is another organization that seeks to increase awareness of rare diseases, provide support for families of individuals with rare diagnoses, and helps individuals access the healthcare they need when they have these rare diagnoses.

Alpha-thalassemia X-linked intellectual disability syndrome (ATRX) is very rare. There are only a few hundred ATRX families described in published literature. However, it is possible that some individuals with milder symptoms are not recognized as having the condition and therefore are not clinically diagnosed.

Typically the diagnosis of alpha-thalassemia X-linked intellectual disability syndrome is made after birth. However, if there is already a family history of this disorder, and especially if a woman is known to be a carrier of a causative change in the ATRX gene, prenatal diagnosis is possible. This can be done as early as 10 weeks gestation through a procedure known as chorionic villus sampling or around 15 weeks or later through a procedure known as amniocentesis. Before proceeding with such testing, it is recommended that any pregnant woman at risk for offspring with this disorder meet with a genetic counselor to discuss the benefits, risks and limitations of her testing options. Genetic counselors can be found on the National Society of Genetic Counselors website.

Alpha-thalassemia X-linked intellectual disability syndrome used to be called alpha-thalassemia/mental retardation syndrome, X-linked; however, the term "mental retardation" has fallen from favor in recent years and thus has been replaced with the term "intellectual disability". Similarly, X-linked mental retardation-hypotonic face syndrome is an outdated name for this disorder. This condition is also known as ATR-X syndrome or ATRX syndrome in reference to the gene which causes this disorder.

The ATRX gene, changes in which cause alpha-thalassemia X-linked intellectual disability syndrome, has also been associated with the following disorders: Carpenter-Waziri syndrome, Holmes-Gang syndrome, Chudley-Lowry syndrome, XLID-arch fingerprints-hypotonia disorder, XLID with spastic paraplegia, XLID with epilepsy, and nonsyndromic XLID. Because these syndromes are associated with intellectual disability, hypotonia, and other symptoms that can be seen in alpha-thalassemia X-linked intellectual disability syndrome and because they are caused by changes in the same gene, their names should no longer be used and instead they should be included within the spectrum of alpha-thalassemia X-linked intellectual disability syndrome.

Because of the rarity of alpha-thalassemia X-linked intellectual disability syndrome, there are no large networks or support groups specifically focused on this disorder. Nonetheless, there are a couple of dedicated contact groups worldwide which can be located here . Additionally, there is an online support group, X-Linked Alpha Thalassemia M/R Syndrome Support Group which has about 260 members as of June 2019. Membership requires approval by group administration.

There are other diseases that share similar symptoms with alpha-thalassemia X-linked intellectual disability syndrome. Coffin-Lowry syndrome is also inherited in an X-linked fashion and is associated with severe to profound intellectual disability in affected males. One difference in Coffin-Lowry syndrome is that females can be affected as well. Although there are typical facial features associated with Coffin-Lowry syndrome, they are different than those seen in alpha-thalassemia X-linked intellectual disability syndrome. Finally, individuals with Coffin-Lowry syndrome have distinctive looking hands and fingers.

Another disorder that shares features with alpha-thalassemia X-linked intellectual disability syndrome is MECP2 duplication syndrome. This disorder is X-linked as well, but again, can affect both females and males, with half of affected males dying by early adulthood. The facial features are more subtle in this condition than in alpha-thalassemia X-linked intellectual disability syndrome and small head size ("microcephaly") is not a common feature. Seizures are more common in this condition than in alpha-thalassemia X-linked intellectual disability syndrome.

Isolated Alpha-thalassemia, where anemia is seen without intellectual disability, is typically due to changes in the genes for alpha-hemoglobin. Isolated alpha-thalassemia is not an X-linked condition and affects males and females equally. It is inherited in an autosomal recessive manner and is more common in individuals of Southeast Asian, African, or Mediterranean descent. Alpha-thalassemia X-linked intellectual disability syndrome is pan-ethnic, meaning it is not more or less common in individuals of any particular ethnicity.

Another condition that is separate from ATRX syndrome but is also associated with alpha-thalassemia and intellectual disability is called alpha-thalassemia mental retardation chromosome 16 syndrome (ATR-16). ATR-16 happens when an individual is missing a large piece of chromosome 16 where the alpha-globin gene and other important genes for global development are located. Depending on the size of this missing piece of chromosome 16, or chromosome 16 deletion, the features of the condition will vary. Although individuals affected with ATR-16 share many similar features as those with ATRX syndrome, individuals with ATR-16 are more likely to have clubfoot, where the foot or feet are rotated in an abnormal position. Furthermore, ATR-16 affects both males and females equally, whereas ATRX affects males.

Juberg-Marsidi syndrome is a very rare disorder which, like alpha-thalassemia X-linked intellectual disability syndrome, is only seen in males and causes similar intellectual and developmental disabilities, low muscle tone, short stature and other features. Initially, Juberg-Marsidi syndrome was thought to be caused by changes in ATRX; however, a subsequent study has identified changes in a different gene that suggests it is a distinct disorder from alpha-thalassemia X-linked intellectual disability syndrome.

Smith-Fineman-Myers syndrome is a condition which may or may not be distinct from alpha-thalassemia X-linked intellectual disability syndrome. It is extremely rare and it is unclear whether it is caused by changes in ATRX or a different gene. The features are very similar to those with alpha-thalassemia X-linked intellectual disability syndrome. Further studies are needed to determine whether these are the same condition or distinct from one another.