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Ataxia-telangiectasia
This progressive neurological condition leads to problems with coordination, speech, and immune function, making individuals more susceptible to infections and certain cancers. It typically manifests in early childhood.
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Overview
Ataxia-telangiectasia (A-T) is a rare genetic disorder that impacts multiple body systems, most notably the nervous system and the immune system. It typically begins to show symptoms in early childhood, often before the age of five [PMID:33671077]. Individuals with A-T experience progressive neurological difficulties, meaning their symptoms tend to worsen over time. Beyond neurological issues, A-T can also lead to a weakened immune system, increasing susceptibility to infections, and a higher risk of developing certain types of cancer.
The condition is present from birth, though its effects become apparent as children develop. A-T is considered a complex disorder due to its wide-ranging impact on the body, affecting motor skills, speech, and the body's ability to fight off disease. Support and management for individuals with A-T focus on addressing these diverse challenges to improve quality of life.
Symptoms & clinical features
The symptoms of Ataxia-telangiectasia generally become noticeable in early childhood. One of the earliest and most prominent signs is ataxia, which refers to problems with coordination and balance. Children may experience unsteadiness when walking, difficulty with fine motor skills like writing, and a tendency to stumble or fall [PMID:20301402]. This unsteadiness often progresses, eventually requiring mobility aids.
Speech difficulties, known as dysarthria, are also common, making communication challenging. Eye movement abnormalities, such as oculomotor apraxia (difficulty moving the eyes quickly from one point to another), can also be present. Beyond these neurological symptoms, individuals with A-T often have a weakened immune system, leading to frequent and severe infections, particularly of the respiratory tract. Another characteristic feature that develops over time are telangiectasias - small, dilated blood vessels that appear on the skin and eyes, typically becoming noticeable by around 3 to 6 years of age [PMID:33671077].
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Affected organs
Ataxia-telangiectasia affects several key body systems. The central nervous system, particularly the cerebellum (which controls coordination and balance), is significantly impacted, leading to the characteristic neurological symptoms like ataxia and dysarthria. The immune system is also severely affected; a compromised immune response makes individuals more vulnerable to recurrent infections, especially affecting the lungs.
Other organs and systems can also be involved. The endocrine system may be affected, potentially leading to conditions such as diabetes. The skin and eyes often show telangiectasias, which are visible signs of blood vessel abnormalities. The increased risk of cancer, particularly leukaemia and lymphoma, indicates a broader impact on cellular processes throughout the body.
Risks & severity
Ataxia-telangiectasia is a progressive condition, meaning its symptoms typically worsen over time. The severity can vary between individuals, but generally, neurological decline continues, leading to increasing reliance on mobility aids, often including wheelchairs by adolescence [PMID:20301402]. Life expectancy is reduced, with complications from chronic lung disease and cancer being major concerns. The exact prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births.
Individuals with A-T have a significantly increased lifetime risk of developing certain cancers, particularly lymphomas and leukaemias, as well as an increased risk of solid tumours. The weakened immune system makes them prone to chronic respiratory infections, which can lead to permanent lung damage. Regular monitoring and proactive management are crucial to address these potential complications.
Genetic causes
Ataxia-telangiectasia is caused by pathogenic variants in the ATM gene. The ATM gene provides instructions for making a protein that plays a critical role in cellular function. This protein, called ATM (Ataxia-Telangiectasia Mutated), is essential for sensing and responding to DNA damage within cells, particularly double-strand breaks [PMID:33671077].
When DNA is damaged, the ATM protein helps to initiate a repair process, ensuring the cell's genetic material remains stable. If the damage is too severe to repair, ATM can trigger programmed cell death, preventing the reproduction of damaged cells. Pathogenic variants in the ATM gene impair the protein's ability to perform these vital functions. This disruption in DNA repair mechanisms leads to genomic instability, which is thought to underlie many of the symptoms observed in A-T, including neurological degeneration, immune deficiency, and an increased susceptibility to cancer.
- ATM ATM serine/threonine kinaseThe ATM gene provides instructions for a protein vital for DNA repair and cell cycle regulation, impacting genomic stability, immune function, and neurological development.
Inheritance pattern
Ataxia-telangiectasia is inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of the ATM gene - one from each parent - to develop the condition. If a person inherits only one altered copy of the gene, they are considered a 'carrier' and typically do not show symptoms of A-T [PMID:20301402].
When both parents are carriers of a pathogenic ATM variant, there is a 25% chance with each pregnancy that their child will inherit two altered copies and develop A-T. There is a 50% chance the child will be a carrier like their parents, and a 25% chance the child will inherit two normal copies of the gene. Genetic counselling is available for families to understand these inheritance risks and discuss family planning options.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
A diagnosis of Ataxia-telangiectasia is often suspected based on the characteristic clinical features, such as progressive ataxia, speech difficulties, recurrent infections, and telangiectasias [PMID:33671077]. Confirmation of the diagnosis relies on genetic testing to identify pathogenic variants in the ATM gene. The NHS Genomic Medicine Service provides comprehensive genetic testing, and samples are typically sent to specialist laboratories.
Referral for genetic testing often comes from a paediatrician or a neurologist who suspects a genetic condition. In the UK, genetic testing for A-T falls under specific R-codes within the National Genomic Test Directory, allowing clinicians to request tests for patients who meet the clinical criteria. Genetic counsellors can also help guide families through the diagnostic process and explain the implications of the results.
Management & lifestyle
While there is currently no cure for Ataxia-telangiectasia, management focuses on alleviating symptoms, preventing complications, and improving quality of life. A multidisciplinary team of specialists, including neurologists, immunologists, respiratory specialists, and physiotherapists, typically provides care. Physiotherapy, occupational therapy, and speech therapy are often recommended to help manage neurological symptoms and maintain motor skills.
Individuals with A-T require close monitoring for immune system issues and regular screening for potential cancers. Immunoglobulin replacement therapy may be used to boost immune function and reduce the frequency of infections. Proactive management of respiratory infections is vital to prevent chronic lung disease. Lifestyle considerations often include avoiding excessive sun exposure due to increased radiation sensitivity, and discussions about nutrition to manage any potential endocrine issues.
UK care pathway
In the UK, individuals with suspected Ataxia-telangiectasia are generally referred to a clinical genetics service or specialist paediatric/neurology clinics. These services can coordinate the diagnostic pathway and offer genetic counselling. Genetic testing for A-T is available through the NHS Genomic Medicine Service, following established R-codes outlined in the National Genomic Test Directory. This ensures that eligible patients can access appropriate testing.
Following diagnosis, care is typically managed by a multidisciplinary team within the NHS, often centred at specialist hospitals. Genetic counsellors are an integral part of this pathway, providing information and support to families about the condition, inheritance patterns, and implications for other family members.
Frequently asked questions
What does 'autosomal recessive' inheritance mean for my family?
Autosomal recessive inheritance means that both parents must carry a change in the same gene for their child to have the condition. If you and your partner are both carriers, there is a 1 in 4 chance with each pregnancy that your child will inherit the condition. Carriers usually do not have symptoms themselves.
When do symptoms of Ataxia-telangiectasia usually appear?
Symptoms of Ataxia-telangiectasia typically begin in early childhood, often between the ages of one and five years. The first signs are usually problems with coordination and balance, such as unsteadiness when walking.
Is there a cure for Ataxia-telangiectasia?
Currently, there is no cure for Ataxia-telangiectasia. Management focuses on treating symptoms, preventing complications, and improving quality of life through therapies like physiotherapy and speech therapy, and managing immune system issues.
What are telangiectasias?
Telangiectasias are small, dilated blood vessels that can appear on the skin and in the eyes, particularly in individuals with Ataxia-telangiectasia. They are often described as 'spider veins' and usually become noticeable by around 3 to 6 years of age.
Why is there an increased risk of cancer in Ataxia-telangiectasia?
The increased cancer risk in Ataxia-telangiectasia is due to changes in the ATM gene, which plays a crucial role in repairing damaged DNA. When the ATM protein is not working correctly, cells are less able to fix DNA errors, leading to genomic instability and a higher chance of developing cancers like leukaemia and lymphoma.
References
- Collyer J, Rajan DS. Ataxia telangiectasia. Seminars in pediatric neurology. 2024. PMID: 39622612
- Podralska MJ, Stembalska A, Ślęzak R. Ten new ATM alterations in Polish patients with ataxia-telangiectasia. Molecular genetics & genomic medicine. 2014. PMID: 25614872
- Fiévet A, Bellanger D, Rieunier G. Functional classification of ATM variants in ataxia-telangiectasia patients. Human mutation. 2019. PMID: 31050087
- Crawford TO. Ataxia telangiectasia. Seminars in pediatric neurology. 1998. PMID: 9874856
- Fortuna J, Rodrigues AL, Pires P. Ataxia-telangiectasia syndrome. Pediatrics and neonatology. 2022. PMID: 35431147
- Subramanian GN, Yeo AJ, Gatei MH. Metabolic Stress and Mitochondrial Dysfunction in Ataxia-Telangiectasia. Antioxidants (Basel, Switzerland). 2022. PMID: 35453338
- Perlman SL, Boder Deceased E, Sedgewick RP. Ataxia-telangiectasia. Handbook of clinical neurology. 2012. PMID: 21827897
- Becker-Catania SG, Gatti RA. Ataxia-telangiectasia. Advances in experimental medicine and biology. 2001. PMID: 11774566