Spotlight on ATR-X syndrome for Rare Disease Day 2025

Image: Brothers Benjamin, seven, and Gabriel, three, both have ATR-X syndrome

By Rebekah Tillotson, Chancellor’s Fellow at the Institute of Genetics and Cancer

With Ben Harris and Jennifer Martinez-Harris, ATRX Research Alliance (a parent-led global group of families committed to accelerating research)

ATR-X (Alpha-thalassemia X-linked intellectual disability) syndrome is a rare genetic disorder that affects at least 200 families worldwide.

How was ATR-X syndrome discovered?

In 1981, a team of haematologists (led by David Weatherall and Doug Higgs) described a new syndrome in a group of male patients with intellectual disability and alpha thalassemia – a type of anaemia that results when the level of alpha-globin in the blood is too low. The team hypothesised that these patients carried a mutation in a gene that codes for a protein that controls the level of alpha-globin production; and that the causative gene was on the X chromosome (explaining why all the patients were male). In 1995, Richard Gibbons led the discovery of the gene mutated in ATR-X syndrome, which became known as the ATRX gene. Most patients with ATR-X syndrome have inherited the ATRX mutation from their mother, who is a carrier (protected from developing the condition by the unaffected copy of the ATRX gene on her second X chromosome). A small proportion of patients have new mutations.

We now know that ~25% of patients with ATR-X syndrome do not have alpha-thalassemia. Historically, this led to several alternative names for the condition (e.g. intellectual disability-hypotonic facies syndrome, X-linked), complicating diagnosis. I have used “ATR-X syndrome” because it is the most commonly used name, but would be supportive of the adoption of the more inclusive new gene-based name ‘ATRX-Related Syndrome’ (used by Simons Searchlight, an international research programme focused on rare genetic neurodevelopmental disorders that is funded by the Simons Initiative).

What are the clinical symptoms?

Intellectual disability due to a mutation in the ATRX gene is essential for a diagnosis of ATR-X syndrome. The degree of intellectual disability varies, even between patients with identical mutations, including between members of the same family. There are several other common features present in up to 80% of patients: alpha-thalassemia, a distinctive face shape, small head circumference, short stature, curvature of the spine, genital abnormalities, low muscle tone and seizures.

Ben Harris and Jennifer Martinez-Harris described their two sons who both have ATR-X syndrome:

Benjamin is the older sibling who is currently seven. He walked at three years old, and is still working on forming sounds to communicate, as well as learning sign language and potentially a communication device, but struggles with finger isolation. His brother, Gabriel, is three years old. Gabriel walked at 18 months, and is able to form basic syllables and has approximately nine words he can speak, and due to his ability to better isolate his fingers he also can point and has picked up some basic sign language. Their levels of hypotonia differ, Benjamin being moderate and Gabriel being less so. Gabriel can crawl and climb on playground equipment, while Benjamin needs additional assistance accessing and navigating his world.

To improve our understanding of the proportion of patients with these features and how the condition manifests over patients’ lives, Simons Searchlight, in conjunction with the ATRX Research Alliance, have recently set up a registry for patients. ATR-X syndrome is thought to be greatly underdiagnosed, and this registry will help improve diagnosis, leading to a more accurate estimate of the number of people affected.

What does the ATRX gene do?

Each of our genes is a recipe for a protein. Different cell types (e.g. neurons and muscle cells) need a different mixture of proteins. Some proteins control the level by which the other recipes are used to result in the correct mixture of proteins in each cell type. ATRX is one of these controller proteins, acting by altering how the DNA in our cells is packaged. Mutations in ATRX affect the level of hundreds of other genes – often including alpha-globin in developing red blood cells.

ATRX is best-known in the scientific community as a tumour suppressor, and it is frequently mutated in cancer – mostly childhood glioma. Developing cancer cells acquire mutations in several genes; and loss of ATRX protein allows cancer cells to lengthen the ends of their chromosomes (telomeres) to enable continued cell division. The link between ATRX and cancer can make families worry that their loved one with ATR-X syndrome is predisposed to cancer. However, individuals with ATR-X syndrome do not have an elevated risk of cancer. The only reports of cancer in patients with ATR-X syndrome are five cases of osteosarcoma. These numbers are too low to conclude that there is a causal link.

What support is there for patients?

When families reach the end of their diagnostic odyssey, what happens next? There are currently limited treatment options available to manage symptoms, including physiotherapy, speech-language therapy, help with feeding (e.g. feeding tube), and anti-epileptic drugs (AEDs) for seizures.

Families affected by rare disease can feel isolated and lost, and patient communities provide essential support. The ATRX Research Alliance (ARA) is a global family-led organisation, that uses private Facebook groups: a main one for all families and local ones for those located in some countries (including the UK). ARA is very dedicated to supporting their patient community. Patients with ATR-X syndrome are so loving and face their challenges with courage and bravery. The patients work extremely hard to reach every milestone, and they do so with a smile. Get to know some of the members of the community by clicking here.

ARA is focused on helping advance research into scientific knowledge and curative therapies associated with this syndrome. I am honoured to have recently joined their scientific advisory board to work with others in the field to pursue patient-informed research aimed at treating this disorder. ARA hosts community calls that give affected families a chance to ask members of the scientific advisory board questions to better understand the condition and recent progress in research. Please visit https://atrxresearch.org/ for more information.

Could ATR-X syndrome be curable in the future?

The ATRX research community is pursuing two types of treatment in parallel: repurposing existing drugs, and gene-based therapies. These studies use cell and mouse models where patient mutations have been introduced with CRISPR gene editing technology; as well as patient-derived cells. Simons Searchlight uses whole blood to generate induced pluripotent stem cells (iPSCs) for multiple genetic disorders including ATR-X syndrome. iPSCs can be converted into various cell types including neurons to test therapeutic strategies. Please email coordinator@simonssearchlight.org for information about donating blood.

Existing drugs could ameliorate symptoms of ATR-X syndrome, for example improving neurological function and communication. This would bring rapid and cheap symptomatic relief to patients, improving their quality of life. Using a mouse model of ATR-X syndrome, 5-aminolevulinic acid (5-ALA) was shown to reduce neurobehavioural defects. This drug is currently being tested in a small cohort of patients.

Gene-based therapies are seen as the ultimate cure for genetic disorders. The amazing progress in the Rett syndrome field provides hope that similar disorders, like ATR-X syndrome, can also be treated using these technologies. To learn more about the Rett syndrome story, I recommend this podcast interview with Monica Coenraads, founder and CEO of the Rett Syndrome Research Trust: https://open.spotify.com/episode/2lDcZCZMy2fomaq7iAQUG8.