Ataxia Telangiectasia: Symptoms, Types, Causes and Treatment

Ataxia Telangiectasia (A-T) is a rare, multisystem genetic disorder that disrupts the nervous and immune systems, leading to a complex array of symptoms and medical challenges. Its combination of progressive neurological decline, immune deficiency, and unique physical signs presents significant hurdles for affected individuals and their families. In this article, we explore the major features of A-T, how it is classified, what causes it, and the current approaches to its management.

Symptoms of Ataxia Telangiectasia

Ataxia Telangiectasia is notable for its wide array of symptoms affecting movement, immunity, and other body systems. The first signs often appear in early childhood, but symptoms tend to progress and diversify with age. Recognizing these early and later features is crucial for accurate diagnosis and timely intervention.

Symptom	Description	Onset/Age	Sources
Ataxia	Loss of coordination, unsteady gait	Early childhood	2 3 4 5
Telangiectasia	Enlarged blood vessels in eyes/skin	Later childhood	1 2 3 4
Oculomotor apraxia	Difficulty moving eyes side-to-side	Early childhood	2 3 4 5
Immune deficiency	Recurrent infections, especially lungs	Early childhood	1 2 3 4 13
Dysarthria	Slurred speech	Early childhood	2 4 5
Chorea/dystonia	Involuntary movements, tremor	Childhood/teens	2 5 4
Peripheral neuropathy	Nerve dysfunction (weakness, numbness)	Variable	2 4 5
Growth retardation	Poor growth, thinness	Childhood	1 2 4
Cancer risk	Lymphoid malignancies	Childhood/adult	3 7 13
Radiation sensitivity	Increased sensitivity to X-rays	Always present	2 3 7 13

Table 1: Key Symptoms of Ataxia Telangiectasia

Neurological Manifestations

The hallmark and often earliest symptom of A-T is progressive cerebellar ataxia—difficulty with movement coordination that typically begins when a child starts to walk. Over time, this may expand to affect both upper and lower limbs, leading to slurred speech (dysarthria), impaired hand coordination, and an unsteady gait. By adolescence, most affected individuals require a wheelchair for mobility 2 3 4 5.

Oculomotor apraxia—a difficulty moving the eyes quickly from one object to another—is another prominent feature, often accompanied by an impassive facial expression and slowed or awkward eye movements 2 4 5. Additional movement disorders such as chorea (involuntary jerking), dystonia (abnormal muscle tone), myoclonus (muscle twitching), tremor, and, less commonly, parkinsonism may develop during the disease course 2 4 5.

Telangiectasia and Other Physical Signs

Characteristic clusters of dilated blood vessels known as telangiectasia typically appear later in childhood, most noticeably on the bulbar conjunctiva of the eyes and sometimes on the face and skin 1 2 3 4. These red "spider veins" are a diagnostic hallmark.

Growth retardation is common, leading to excessive thinness and shorter stature. Despite these physical challenges, intelligence is often initially normal, though performance on tasks requiring visual-motor coordination may decline as ataxia progresses 1 2 4.

Immune Deficiency and Infections

A-T is also marked by immunodeficiency, leading to recurrent respiratory infections, especially of the sinopulmonary tract. These infections can become severe, with complications such as bronchiectasis. Laboratory findings often include deficiencies in immunoglobulins (especially IgA) and lymphopenia (low lymphocyte counts) 1 2 3 13.

Additional Features

• Cancer Susceptibility: Individuals with A-T have a markedly increased risk of developing lymphoid malignancies, particularly leukemia and lymphoma 3 7 13.
• Radiation Sensitivity: Cells from A-T patients are abnormally sensitive to ionizing radiation, which is a key laboratory clue for diagnosis 2 3 7 13.

Types of Ataxia Telangiectasia

Although Ataxia Telangiectasia is traditionally described as a single disorder, research has revealed important variations in its presentation and progression. Recognizing these types is essential for prognosis, genetic counseling, and management.

Type/Variant	Key Features	ATM Protein Activity	Sources
Classic A-T	Early, severe ataxia; full symptom spectrum	Absent/very low	7 8 13
Variant A-T	Milder, later onset; less severe neurodegeneration	Reduced (not absent)	5 7 8
Nijmegen Breakage Syndrome (NBS)	Overlaps with A-T in radiosensitivity, immune defects; lacks ataxia/telangiectasia	Different gene (NBS1)	3 6
A-T Fresno	Features of both A-T and NBS; ATM mutations	Partial function	3

Table 2: Types and Variants of Ataxia Telangiectasia

Classic Ataxia Telangiectasia

Classic A-T is the most common and severe form, presenting in early childhood with rapid neurological decline, early wheelchair dependence, pronounced telangiectasia, and severe immune deficiency. These cases are typically due to mutations that completely eliminate ATM protein function 7 13.

Variant Ataxia Telangiectasia

Variants of A-T are increasingly recognized. These forms typically have later onset, slower progression, and milder neurological symptoms. Some patients may present with predominant movement disorders other than ataxia, and immune or cancer risks may be less severe. These milder phenotypes are generally associated with mutations that permit some residual ATM kinase activity 5 7 8.

Overlapping Syndromes

Nijmegen Breakage Syndrome (NBS): Sometimes grouped as an A-T variant, NBS shares features such as cancer risk, chromosomal instability, and immune defects but typically lacks the ataxia and telangiectasia seen in A-T. NBS is caused by mutations in the NBS1 gene, not ATM 3 6.

A-T Fresno: This rare phenotype combines features of both A-T and NBS and is associated with specific ATM mutations 3.

Causes of Ataxia Telangiectasia

Understanding the causes of A-T requires a look at genetics, cellular biology, and the critical role of the ATM protein in DNA repair and cellular health. The underlying defect is both simple—mutations in a single gene—and complex, given how broadly it affects human physiology.

Cause	Mechanism/Effect	Inheritance	Sources
ATM gene mutation	Defective DNA damage response, cell cycle control	Autosomal recessive	10 11 12 13
Chromosomal instability	Increased DNA breaks, genetic errors	Secondary to ATM defect	10 11 12 13
Oxidative stress	Increased tissue damage, especially brain	Secondary to ATM loss	9 16 14

Table 3: Causes and Mechanisms of Ataxia Telangiectasia

Genetics and Inheritance

A-T is caused by mutations in the ATM (Ataxia Telangiectasia Mutated) gene on chromosome 11q23. The disorder follows an autosomal recessive inheritance pattern, meaning both copies of the gene must be mutated for the disease to manifest. Carriers (with one mutated copy) are typically asymptomatic but may have a slightly increased cancer risk 10 12 13.

Role of the ATM Protein

The ATM protein is a master regulator of the cellular response to DNA double-strand breaks, oxidative stress, and other genotoxic stresses. It coordinates cell cycle checkpoints, activates DNA repair machinery, and helps maintain genome stability. Without functional ATM, cells are unable to halt the cell cycle in response to DNA damage, leading to genetic instability, increased apoptosis (cell death), and impaired immune system development 10 11 12 13.

Cellular and Molecular Effects

• Chromosomal Instability: A-T cells show frequent chromosomal breaks and translocations, particularly involving chromosomes 7 and 14, contributing to cancer risk 10 11.
• Radiation Sensitivity: A-T cells are extremely sensitive to ionizing radiation due to defective DNA repair and checkpoint control 2 3 7 13.
• Oxidative Damage: Loss of ATM increases oxidative stress in tissues, especially in the cerebellum, leading to neurodegeneration 9 16 14.
• Chronic Inflammation & Senescence: Recent research highlights abnormal activation of inflammatory pathways (e.g., cGAS-STING) and premature cellular aging as contributors to disease progression 17.

Treatment of Ataxia Telangiectasia

Despite advances in understanding, there is currently no cure for A-T. Treatment is supportive and multidisciplinary, focusing on managing symptoms, preventing complications, and improving quality of life.

Treatment	Purpose/Target	Effectiveness	Sources
Supportive care	Symptom management (physio, speech, nutrition)	Improves function	8 13 15 16
Immunoglobulin therapy	Prevent infections	Reduces infection risk	8 16
Antibiotics	Treat/prophylax infections	Essential for acute management	1 8
Cancer surveillance	Early detection/treatment	Reduces mortality	8 16
Antioxidants	Reduce oxidative stress	Experimental benefit	9 16 14
NAD+ supplementation	Improve mitochondrial/DNA repair	Promising in models	14
cGAS-STING inhibitors	Reduce neuroinflammation	Experimental	17

Table 4: Current and Emerging Treatments for Ataxia Telangiectasia

Symptomatic and Supportive Management

A-T requires coordinated care from neurologists, immunologists, pulmonologists, and rehabilitation specialists 8 13. Supportive strategies include:

• Physical Therapy: Maintains mobility and helps manage ataxia and movement disorders.
• Speech Therapy: Assists with dysarthria and swallowing difficulties.
• Nutritional Support: Addresses feeding problems and maintains growth.
• Respiratory Care: Regular monitoring to prevent and treat lung complications.

Immunodeficiency Management

Immunoglobulin replacement therapy is often used to reduce the frequency and severity of infections. Prompt antibiotic treatment is essential for managing acute infections 1 8 16.

Cancer Risk and Surveillance

Given the elevated cancer risk, especially for lymphoid malignancies, regular screening and prompt oncological intervention are vital. However, traditional cancer treatments (like radiotherapy) must be used with caution due to the extreme radiosensitivity of A-T patients 7 8 16.

Experimental and Emerging Therapies

• Antioxidants: Since oxidative stress contributes to neurodegeneration, antioxidants are being explored as a potential therapy, although clinical data are limited 9 16.
• NAD+ Replenishment: Animal studies suggest that boosting NAD+ levels can improve mitochondrial function, DNA repair, and delay neurodegeneration, offering a promising avenue for therapy 14.
• cGAS-STING Pathway Inhibitors: Targeting neuroinflammatory pathways may reduce premature senescence and neurodegeneration in the brain, as shown in experimental models 17.

Genetic Counseling and Future Prospects

Genetic counseling is crucial for affected families, both for reproductive planning and for understanding the risks to other family members 13. Research into gene therapy, stem cell transplantation, and targeted molecular therapies continues, but these approaches are not yet available for routine clinical use.

Conclusion

Ataxia Telangiectasia is a complex, multisystem disorder that presents unique clinical challenges and opportunities for research. Here are the main points covered:

• Symptoms: Early-onset neurodegeneration, movement disorders, immune deficiency, characteristic telangiectasia, and increased cancer risk define the clinical picture 1 2 3 4 5 13.
• Types: Classic and variant forms exist, with differing severity and progression. Overlapping syndromes like NBS share some features but have distinct causes 3 5 6 7 8.
• Causes: Mutations in the ATM gene disrupt DNA damage response, leading to genome instability, oxidative stress, and defective immunity 10 11 12 13.
• Treatment: No cure exists, but multidisciplinary supportive care, infection prevention, cancer surveillance, and emerging therapies offer hope for improved outcomes 8 9 14 16 17.

Ongoing research into the molecular underpinnings of A-T is paving the way for future breakthroughs that may one day offer more effective, disease-modifying therapies for those affected by this rare and challenging disorder.