Ataxia-telangiectasia is a rare inherited condition that slowly takes away a person’s ability to coordinate their movements while also weakening their immune system and increasing their risk of cancer. The condition affects children from their earliest years, causing them to wobble when they walk and gradually lose control over their body’s movements. Small clusters of blood vessels appear in their eyes, giving them a distinctive look that helps doctors recognize the disease.
Epidemiology
Ataxia-telangiectasia is an extremely rare condition that affects people all around the world. Studies estimate that approximately 1 in every 40,000 to 100,000 people worldwide are born with this condition[1][3]. The disease does not favor one gender over another, and it affects males and females equally[7]. Similarly, the condition appears across all races and ethnic backgrounds without preference.
Although the disease itself is rare, carrying a single copy of the mutated gene is more common than many people realize. Approximately 1 percent of people in the United States carry one altered copy of the ATM gene, which is the gene responsible for this condition[1][3]. In some studies, the carrier rate has been estimated as high as 2.8 percent in the United States[13]. These carriers do not develop the full disease because they have one normal copy of the gene that compensates for the altered one. However, if two carriers have children together, their child has a one-in-four chance of inheriting two altered copies and developing ataxia-telangiectasia.
Causes
Ataxia-telangiectasia is caused by mutations in a specific gene called the ATM gene, which stands for ataxia-telangiectasia mutated gene[3]. This gene is located on chromosome 11, specifically at position 11q22-23[4][5]. The ATM gene provides instructions for making a protein that plays a crucial role in maintaining the health of cells throughout the body.
The ATM protein acts like a supervisor that helps control how cells divide and repair damage to their DNA. DNA is the instruction manual inside every cell that tells the body how to form and function properly. When DNA strands break or become damaged, the ATM protein recognizes this problem and activates enzymes that fix the broken strands[3]. This repair process is essential for keeping cells stable and preventing them from dying or becoming cancerous.
When the ATM gene is mutated, it either produces a protein that doesn’t work properly or fails to produce the protein at all[4]. Without functional ATM protein, cells cannot effectively repair DNA damage. This leads to cells becoming unstable and eventually dying. The cerebellum, which is the part of the brain responsible for coordinating movements and maintaining balance, is particularly vulnerable to the loss of ATM protein[3]. As cells in the cerebellum die, the person gradually loses the ability to control their movements smoothly.
Ataxia-telangiectasia is inherited in an autosomal recessive pattern[3][7]. This means a child must inherit two copies of the mutated ATM gene, one from each parent, to develop the condition. Parents who each carry one mutated copy typically do not show any symptoms of the disease themselves, but they can pass the mutation to their children. When both parents are carriers, each of their children has a 25 percent chance of inheriting both mutated genes and developing ataxia-telangiectasia.
Risk Factors
The primary risk factor for developing ataxia-telangiectasia is genetic inheritance. A child is at risk if both parents carry a mutated copy of the ATM gene. There are no known environmental factors, lifestyle choices, or behaviors that increase or decrease the risk of developing this condition, since it is entirely determined by genetics.
For parents who know they are carriers of the ATM gene mutation, or who already have a child with ataxia-telangiectasia, genetic counseling and testing can help them understand the risks for future pregnancies[4]. Testing can be performed before a baby is born to determine if they have inherited two copies of the mutated gene. Some families may choose to pursue preimplantation genetic testing or testing during early pregnancy to make informed decisions about their reproductive options.
While carriers of a single ATM gene mutation do not develop ataxia-telangiectasia, research suggests they may face other health risks. Female carriers, in particular, appear to have a higher risk of developing breast cancer[3][4]. The degree of cancer risk associated with carrying an ATM mutation depends on the type of mutation involved, with some types conferring higher risks than others. Carriers may also have an increased risk of developing coronary artery disease and other cancers[7].
Symptoms
The symptoms of ataxia-telangiectasia typically begin to appear in early childhood, usually before the age of five, and they progressively worsen over time[2][3]. Parents often first notice problems when their toddler begins to walk. Instead of walking steadily, the child may sway, stagger, or wobble. They might appear unsteady when sitting without support or when standing still, such as when brushing their teeth at the sink[20].
The hallmark symptom that gives the condition its name is ataxia, which means difficulty coordinating movements. Children with ataxia-telangiectasia have trouble controlling their body movements smoothly. They may have difficulty walking, problems with balance, and trouble coordinating their hands[1][3]. As they grow older, they develop involuntary jerking movements called chorea, muscle twitches known as myoclonus, and disturbances in nerve function called neuropathy[1][3].
Speech becomes slurred and difficult to understand. Most children with ataxia-telangiectasia never develop completely normal speech because they have problems with articulation and tend to place emphasis on the wrong syllables or parts of words[1]. As the condition progresses, swallowing becomes difficult and dangerous, increasing the risk of food or liquid going into the lungs.
Another distinctive feature is trouble moving the eyes properly. Many children develop oculomotor apraxia, which means they cannot move their eyes smoothly from side to side to look at different objects[1][2]. Instead of just moving their eyes, they have to turn their entire head to look at something new. Some children also have jerky, involuntary eye movements called nystagmus.
The second part of the condition’s name comes from telangiectasias, which are small clusters of dilated blood vessels that create a zig-zag or spider-like pattern. These typically appear between ages 4 and 8, showing up on the white parts of the eyes and making them look bloodshot, as well as on sun-exposed areas of skin such as the cheeks and ears[1][4].
The immune system is significantly affected in people with ataxia-telangiectasia. The condition weakens both the humoral immune system (which produces antibodies) and the cellular immune system (which uses T cells to fight infections)[8][20]. This leads to frequent infections, particularly of the ears, sinuses, and lungs. Chronic lung infections and respiratory problems are common, and many people develop bronchitis and pneumonia repeatedly[1][2].
Growth and development are often affected. Children with ataxia-telangiectasia may experience poor growth, delayed puberty, and reproductive dysfunction[1][4]. Some develop type 2 diabetes, and premature graying of the hair is common[2]. People with this condition also feel tired more easily than others.
One of the most concerning aspects of ataxia-telangiectasia is the dramatically increased risk of cancer. Approximately one-third of people with this condition develop cancer, most commonly leukemia or lymphoma[4][13]. Younger children tend to develop acute lymphocytic leukemia, while older patients may develop other types of cancers including stomach, breast, ovarian, liver, and uterine cancers[13].
Another notable symptom is elevated levels of alpha-fetoprotein (AFP) in the blood. This protein is normally elevated in pregnant women, but about 95 percent of people with ataxia-telangiectasia have AFP levels above 10 nanograms per milliliter[3][4]. The reason for this elevation and what effects it might have are not well understood.
People with ataxia-telangiectasia are also extremely sensitive to ionizing radiation, such as X-rays and gamma rays[2][3]. This means that standard doses of radiation therapy or certain chemotherapy drugs can cause severe, sometimes fatal reactions. This sensitivity makes treating cancer in these individuals particularly challenging.
Prevention
Because ataxia-telangiectasia is a genetic condition determined at conception, there are no lifestyle changes, vaccinations, supplements, or other preventive measures that can stop someone who has inherited two mutated ATM genes from developing the disease. However, families who know they carry the ATM gene mutation do have options for preventing the condition in future children.
Genetic counseling is strongly recommended for couples who are carriers of an ATM gene mutation or who already have a child with ataxia-telangiectasia[4]. A genetic counselor can help families understand the 25 percent risk of having another affected child and discuss available reproductive options. Testing can identify whether a fetus has inherited two copies of the mutated gene, allowing families to make informed decisions about the pregnancy.
Preimplantation genetic testing is available for families using in vitro fertilization. This technique allows embryos to be tested for the ATM mutations before being implanted, ensuring that only embryos without two mutated copies are selected[4]. This approach can allow carrier parents to have children who will not be affected by ataxia-telangiectasia.
For people already diagnosed with ataxia-telangiectasia, certain preventive measures can help reduce complications. Regular monitoring for infections and prompt treatment with antibiotics can prevent respiratory infections from becoming severe. Some doctors recommend regular injections of gamma-globulin, which provides antibodies to help fight infections[2][9]. Avoiding unnecessary exposure to X-rays and other sources of ionizing radiation is crucial because of the heightened sensitivity to radiation damage.
Cancer screening is an important preventive strategy for people with ataxia-telangiectasia because of their elevated cancer risk. Regular medical monitoring can help detect cancers early when they may be more treatable, although the sensitivity to radiation and certain chemotherapy drugs complicates treatment options[11].
Pathophysiology
The pathophysiology of ataxia-telangiectasia centers on the loss of function of the ATM protein and the widespread cellular consequences that follow. The ATM protein belongs to a family of proteins called phosphatidylinositol-3-kinase-related kinases, which play critical roles in controlling cell division, transporting proteins within cells, and responding to DNA damage[5].
When DNA strands break, which happens naturally during cell division and in response to various environmental stresses, the ATM protein acts as a first responder. It recognizes the broken DNA and activates a cascade of cellular responses. The protein phosphorylates (adds phosphate groups to) numerous other proteins that are involved in repairing DNA, stopping cell division until repairs are complete, or triggering cell death if the damage is too severe to fix[8].
In ataxia-telangiectasia, mutations in the ATM gene typically result in either no ATM protein being produced or a protein that cannot function properly. Most commonly, the mutations are protein truncating or loss-of-function variants that lead to complete absence of the ATM protein[4]. Without this protein, cells cannot properly detect and repair DNA damage, particularly double-strand DNA breaks, which are the most dangerous type of DNA damage.
The inability to repair DNA damage has several profound consequences. First, damaged DNA accumulates in cells, making them unstable. This instability leads to chromosomal instability and breakage, where chromosomes fragment or rearrange abnormally[8]. Eventually, cells with too much DNA damage die. This cell death is particularly devastating in the cerebellum, where neurons (brain cells) cannot be replaced once they are lost. The progressive death of cerebellar neurons causes the worsening ataxia that characterizes the disease.
It remains unclear why the cerebellum is so particularly vulnerable to the loss of ATM protein, especially since the protein is important for all cells in the body[3][13]. However, the cerebellum shows specific patterns of degeneration, particularly in areas called the frontal and posterior vermis and both hemispheres[4]. Brain imaging studies reveal cerebellar atrophy, meaning the cerebellum shrinks as neurons die.
The accumulation of DNA damage also explains the dramatically increased cancer risk. When cells cannot repair DNA damage or recognize when damage is too severe, they may continue dividing despite having mutations. These mutations can accumulate and eventually lead to uncontrolled cell growth, which is cancer[3]. The types of cancers most common in ataxia-telangiectasia—leukemia and lymphoma—involve blood and immune cells, which divide frequently and are therefore particularly susceptible to accumulated DNA damage.
The immune system problems in ataxia-telangiectasia result from several factors. The thymus, an organ crucial for the development of T cells (a type of white blood cell), often develops abnormally or fails to mature properly in people with this condition. B cells, which produce antibodies, also function poorly. Together, these defects create a combined immunodeficiency that makes people susceptible to repeated infections[20].
The delayed puberty and reproductive dysfunction seen in ataxia-telangiectasia result from what is called gonadal dysgenesis, meaning the reproductive organs do not develop normally[6]. The endocrine system, which produces hormones, is also affected, leading to growth problems and metabolic issues like diabetes.
The reason for the telangiectasias—the dilated blood vessels that give the condition part of its name—is not fully understood. These appear as cells in blood vessel walls accumulate damage and possibly as part of premature aging processes (progeric changes) that affect multiple body systems[6]. The elevated alpha-fetoprotein levels remain a mystery, with no clear explanation for why this protein increases or what role it might play in the disease process.
