Ataxia-Telangiectasia (A-T) is a rare, complex genetic disorder that affects multiple body systems. It progressively impacts coordination and immunity. A-T weakens the immune system, making individuals more susceptible to infections, and it impairs areas of the brain, particularly the cerebellum, leading to difficulties with movement and coordination.
Genetic Basis
Ataxia-Telangiectasia is caused by mutations in the ATM gene, which stands for Ataxia-Telangiectasia Mutated gene. This gene is located on chromosome 11 at position 11q22.3. The ATM gene provides instructions for making a protein that plays a significant role in DNA repair and cell cycle control. The ATM protein helps cells recognize and repair damaged or broken DNA strands, maintaining the stability of the cell’s genetic information.
A-T is inherited in an autosomal recessive pattern, meaning an individual must inherit two mutated copies of the ATM gene, one from each parent, to develop the condition. Parents who carry one mutated copy and one normal copy of the ATM gene are asymptomatic carriers; approximately 1% of the U.S. population carries one altered copy. If both parents are carriers, there is a 25% chance with each pregnancy that their child will inherit two mutated copies and develop A-T, and a 50% chance the child will be a carrier.
Recognizing the Manifestations
Neurological symptoms of A-T emerge in early childhood, often by age five. The primary neurological manifestation is ataxia, a lack of muscle coordination that leads to difficulties with balance and movement, resulting in an unsteady or wobbly gait. As the disease progresses, individuals may experience involuntary jerking movements (chorea) and muscle twitches (myoclonus). Speech difficulties, known as dysarthria, and problems with eye movements, specifically oculomotor apraxia, are also common.
Individuals with A-T develop immune system deficiencies, increasing their susceptibility to recurrent infections, particularly those affecting the lungs and sinuses. These immune problems can involve both B cells and T cells, impacting the body’s ability to fight off pathogens. Another feature of the condition is the appearance of telangiectasias, small, dilated blood vessels that resemble spider veins. These are most commonly observed in the corners of the eyes and on sun-exposed skin, such as the ears and cheeks, and become noticeable after the onset of walking difficulties, by six years of age.
The impaired DNA repair mechanism in individuals with A-T also leads to an increased risk of certain cancers. The lifetime risk of developing cancer for individuals with A-T is approximately 40%. The most common types of cancer are leukemias (blood cell cancers) and lymphomas (immune cell cancers), particularly in individuals under 20 years of age. As individuals with A-T age, there is also a risk for solid organ cancers, including breast, ovarian, thyroid, and stomach cancers.
Path to Diagnosis and Care
Diagnosis of Ataxia-Telangiectasia often begins with the observation of clinical symptoms in early childhood. The presence of progressive ataxia, along with telangiectasias, provides strong indicators for the condition, though telangiectasias may not appear until after five years of age. Confirmation of an A-T diagnosis relies on genetic testing to identify mutations in both copies of the ATM gene. This testing can determine if the ATM protein is absent or deficient in function.
Other diagnostic tests can help identify A-T. Elevated serum levels of alpha-fetoprotein (AFP) are a common finding, with over 95% of individuals with A-T having high levels. Immune function tests can reveal deficiencies in immunoglobulin levels, such as low IgA, present in about 70% of patients. Chromosome analysis may also show increased chromosomal breakage.
Current management for A-T is largely symptomatic and supportive, addressing the various manifestations of the disease. A multidisciplinary team approach is employed, involving specialists such as neurologists to manage movement difficulties, immunologists to address immune system deficiencies, and physical and speech therapists to improve mobility and communication. Supportive care includes managing infections, which may involve prophylactic antibiotics or immune globulin replacement therapy. Physical therapy aims to maintain mobility, while regular monitoring for cancer development is part of comprehensive care.
Outlook and Ongoing Progress
Ataxia-Telangiectasia is a progressive disease, meaning its symptoms worsen over time. This progression impacts the life expectancy of affected individuals, though there is variability among patients. While there is currently no cure for A-T, research efforts are underway to better understand the disease and develop effective treatments.
Promising areas of research include gene therapy, which aims to correct the underlying genetic defect by introducing functional copies of the ATM gene into cells, and drug development, which is exploring compounds that target DNA repair pathways or improve cellular responses to DNA damage. For instance, studies have investigated compounds like nicotinamide riboside, which showed some improvement in ataxia scores and immunoglobulin levels in small trials, and dexamethasone, which has demonstrated improvements in ataxia in clinical trials. Efforts are also focused on improving symptomatic treatments and supportive care, such as therapies for neurological symptoms and interventions for respiratory issues. Ongoing research and increasing understanding of A-T offer hope for individuals and families affected by this complex condition.