Rarely inherited in the general population, Ataxia-Telangiectasia (AT) is a disorder that impacts the neurological system, the immune system, and other organs and tissues. Features that define it include these signs:
- Lack of coordination (Progressive Ataxia) brought on by a cerebellar abnormality that worsens over time (the part of the brain involved in coordinating the movement of muscles)
- Impairment of eye movement control is known as oculomotor apraxia (difficulty moving the eyes from side to side)
- Choreoathetosis (abnormal movements such as involuntary jerky movements of the arms, legs, and face along with slow, twisting movements of the hands, feet, and other body parts)
- Dilated blood vessels (Telangiectasias) on the skin and the whites of the eyes
- Illness due to a weakened immune system
- Sensitivity to ionizing radiation
- An increased risk of developing blood cancers like leukemia and lymphoma and other types of cancers
AT affects one in 40,000 to 100,000 U.S. births, and it does not discriminate based on race or gender. Affected individuals inherit two defective copies of the ATM gene. The term "carrier" describes people who have inherited a non-working gene but have two functional copies.
Individuals who carry a single copy of an ATM gene mutation do not develop AT or exhibit its clinical characteristics; however, they may be at higher risk of developing coronary artery disease. The risk of breast cancer in female carriers is always high.
Even though a defective gene can be passed down from generation to generation, an individual cannot inherit AT unless they have a non-functional copy of the ATM gene from both parents who are carriers of the disorder.
Causes
Alterations (mutations) in certain parts of an individual's genetic code generate AT. The vast amounts of genetic information in our DNA are divided into smaller segments called genes. Genes give the blueprints for how our cells should carry out their different roles in the body.
Alterations in the ATM gene on chromosome 11 at locus q22.3 lead to the development of AT. The protein encoded by the ATM gene is called “serine/threonine kinase,” which has multiple purposes.
- It inhibits cell proliferation and induces cell death, making it a potent tumor suppressor.
- When ionizing radiation causes DNA damage, it communicates with other proteins.
- The ATM enzyme acts as a coordinator for DNA repair by stimulating other proteins required for the repair process.
It is believed that the ATM enzyme helps prevent some forms of cancer, including leukemia and lymphoma, by combining several mechanisms.
All the cells of a person with AT carry a mutation in both copies of the ATM gene. The cells of an individual with AT carrying two mutated copies of the ATM gene will produce either insufficient quantities of ATM protein or a protein with impaired function.
Because the defective ATM proteins cannot effectively repair damaged DNA, cells become hypersensitive to radiation and accumulate mutations in other genes. Leukemia and lymphoma are more likely to develop in people with AT when this occurs. Cerebellar cells, in particular, may be particularly vulnerable to an untimely death when ATM genes are disrupted. The neurological signs of AT may develop because of this.
How Does a Person Inherit Ataxia-telangiectasia?
A person is considered to have an "autosomal recessive disorder" if they have two dysfunctional copies of a gene that ultimately leads to the development of the disease. An autosomal recessive condition such as AT is one such example. Since AT is autosomal recessive, each parent has two copies of the ATM gene—one that is healthy and one that has been mutated, causing the disease. For a child to have AT, a mutation in the ATM gene must have been passed down from both parents.
Each offspring of parents with the ATM mutation will have the following characteristics:
- About one-quarter, or one-in-four, people have AT (i.e., that child would need to inherit a mutation from each parent)
- If you are a woman, you have a 50% chance of being an asymptomatic carrier and so are at higher risk of developing breast cancer (i.e., this child would inherit one altered gene copy and one standard copy)
- There's a one-quarter chance that you won't be affected (i.e., this child would inherit two standard gene copies).
Diagnosis
Clinical Findings
The presence of specific clinical symptoms is crucial for making a diagnosis of AT.
Between the ages of 1 and 4, children with AT may exhibit symptoms including:
- Slurred speech and other symptoms of progressive cerebellar dysfunction
- Impairment of eye movement control is known as oculomotor apraxia (difficulty moving the eyes from side to side)
- Gait Ataxia (unstable walk)
- Truncal Ataxia (inability to maintain normal posture)
- A small cerebellum (often observed on magnetic resonance imaging [MRI] examination but may not be as obvious in very young children)
Over time, kids with this condition generally struggle to walk, lose balance and coordination, exhibit involuntary jerking motions (chorea), have muscle twitches (myoclonus), and experience disruptions in nerve function (neuropathy). When people have trouble moving around, they often need to rely on others for help when they are teenagers.
Clinical Features
Additional features that signify AT include:
- White-eyed telangiectases and other cutaneous telangiectases (usually present by 6 years of age)
- Immunologic defects (present in 60-80 percent of individuals with AT)
- Persistent Illnesses
- Sensitivity to ionizing radiation
- Age-related hair graying and thinning
- Difficulties with hormone regulation (such as type II diabetes, short stature, and delayed puberty)
- Exposure to radiation increases the risk of developing leukemia, lymphoma, and maybe other cancers.
Variability in the severity of AT's physical features has been linked to whether or not the ATM protein is completely absent. B-cell lymphoma is more common in patients with no ATM protein activity, and infections are more common in those with lower immunoglobulin levels. However, in the later stages of the disease, there is minimal variation in the clinical findings of AT from family to family.
People with AT often have average intelligence, but their slow potion and verbal responses are problematic. Mild intellectual disability or learning difficulties can occasionally be present. Despite the decrease in life expectancy, most individuals still make it to at least 25, and some even make it into their 40s and 50s.