Limited treatment options make diagnosis of AT more devastating for families to hear

Dr. Jeff Hersh

A friend and colleague told me about an amazing event, the Illumination Biopharma Leadership Ball, which will be held on Saturday, May 11, at the Museum of Fine Arts in Boston. The event benefits families and patients with the genetic disease ataxia-telangiectasia (AT).

"Ataxia" refers to poor muscle control, causing clumsy or compromised walking/muscle movements. And "telangiectasia" means bulging/dilatation of capillaries — thin-walled blood vessels that bring oxygen and nutrients to the body’s cells.

AT is a rare disease, affecting 1 in 40,000 live births. The genetic defect is in a gene on chromosome 11 (we normally have 23 pairs of chromosomes, so 46 in total) that codes for the ATM protein serine/threonine kinase. AT is inherited in an autosomal recessive manner, so to manifest the condition you must inherit an abnormal gene for the ATM protein from each parent; those with only one abnormal gene are "carriers" and would have a 50% chance of passing the abnormal gene to their child, but would not manifest the condition.

Dr. Jeff Hersh
Dr. Jeff Hersh

Sometimes, when cells multiply rapidly (for example, blood cells in our bone marrow), they're hit by ionizing radiation. In other cases, where the DNA strands — the part of our cells that carry our genetic code — are broken, an error in the DNA of the cell occurs. The ATM protein works with other proteins to repair these errors to fix the "broken" DNA code of cells, suppress tumor/cancer cells, ensure the integrity of the immune system, prevent compromise of cells in the neurological system, etc. One normally functioning ATM protein coded from the gene on either chromosome 11 (remember we have pairs of chromosomes) allows for the DNA repair process to work adequately; that is why a patient with AT needs to receive mutated copies of the gene from both parents.

Unrepaired cells most commonly affect the nervous system (including the cerebellum, which is the part of the brain responsible for coordinating muscle movement); the eyes; the immune system (which combats infections and other conditions); and some of our rapidly multiplying blood cells.

Symptoms and complications of AT begin in childhood, so it's young children and their families who are devastated by this relentless disease. They can include:

  • Compromised coordination/movements of certain muscle groups, for example causing unstable/compromised walking, abnormal posture (due to difficulty maintaining the trunk of the body in a normal position), tremor, jerky/twitchy movements, other symptoms.

  • Disruption in cerebellar function, causing slurred speech and/or other symptoms, possibly including cognitive issues in patients who survive to early adulthood.

  • Predisposition to certain infections due to immune system compromise (possibly leading to pneumonia, urine infection, other infections).

  • Certain endocrine conditions such as diabetes, growth compromise, others.

  • Predisposition to certain cancers. For example, leukemia or lymphoma develop in as many as 40% of AT patients. There is also an increased risk for other cancers, including ovarian, breast, thyroid, stomach, salivary gland and others.

  • Skin issues, ranging from discoloration of some skin areas (e.g. café au lait spots, vitiligo) to increased risk of melanoma to other conditions.

AT may be suspected based on the presence of its symptoms and/or a physical exam, including a thorough neurological exam and evaluation for abnormal blood vessels. A family history of AT increases the suspicion. However, not all patients have these, and so the diagnosis of AT is often missed or delayed. Therefore, a high degree of suspicion needs to be maintained in order to make the diagnosis as early as possible.

So while there are certain specialized blood tests that can be done to evaluate suspected AT cases, such as measurements of certain protein levels in the blood (alpha-fetoprotein, ATM protein, immunoglobulin M, others) and/or chromosome testing, the diagnosis needs to be confirmed by specific genetic testing.

AT patients need to be monitored for the possible development of one or more of the conditions/complications noted above. They need to be given supportive care, as well as specific care as needed for any complication that develops. Specialized devices to evaluate early changes in motor function have been developed to monitor patients more closely.

The limitation of treatment options today leads to a concerning prognosis, and is devastating to hear for parents/families. Most AT patients are unable to walk by age 10 to 15, and most die by their teenage years to early adulthood (from infections, cancer or other causes).

Although there is no specific treatment for these patients, advances in gene and cell therapy to address the lack of a correctly functioning ATM protein are promising. This research is what is being supported by the AT Children’s Project, which was started by two parents of AT kids, and works tirelessly to make this hope a reality. Please visit https://atcp.org to learn more and to see how you can help.

Jeff Hersh, Ph.D., M.D., can be reached at DrHersh@juno.com.

This article originally appeared on MetroWest Daily News: Ataxia-telangiectasia is genetic disease with poor muscle control

Advertisement