What are the newer therapies for Ataxia Telangiectasia (AT)?

From the Guidelines

Newer therapies for Ataxia Telangiectasia (A-T) prioritize a multidisciplinary approach to manage symptoms, prevent infections, and improve quality of life, as there is currently no cure for this rare genetic disorder. The management of A-T involves a comprehensive approach, including routine immunological investigations, immunizations, and prophylactic antibiotic treatment to prevent respiratory infections 1.

Immunodeficiency Management

• Regular immunoglobulin replacement therapy (IVIG 400-600 mg/kg every 3-4 weeks or SCIG 100-200 mg/kg weekly) is essential to prevent recurrent infections, as patients with A-T are prone to immune dysfunction leading to recurrent upper and lower respiratory infections 1.
• Prophylactic antibiotic treatment is considered when the burden of respiratory infections is high, if there is associated specific polysaccharide antibody deficiency, and when there is established bronchiectasis 1.

Respiratory Management

• Respiratory muscle strength training (RMST) may be an effective adjunct therapy to improve ventilatory pattern, lung volume, respiratory muscle strength, and quality of life in patients with A-T 1.
• Airway clearance physiotherapy, such as chest physiotherapy, flutter valve therapy, and cough assist devices, may mobilize mucus in the lower airways and prevent atelectasis, especially in patients with advanced neurological decline 1.
• Inhalation therapy, including nebulised hypertonic saline, rhDNase, or inhaled mannitol, may offer some benefit in mobilizing mucus, although the evidence base is limited 1.

Multidisciplinary Care

• Comprehensive multidisciplinary care, including regular surveillance microbiology on respiratory samples, early aggressive treatment of infections, and proactive monitoring and treatment of various aspects of lung disease, is crucial to manage the complex and diverse manifestations of A-T 1.
• A multidisciplinary team, including experts in respiratory medicine, immunology, neurology, and physiotherapy, should work together to provide personalized care and address the unique needs of each patient with A-T.

From the Research

Newer Therapies in Ataxia Telangiectasia

• Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitivity 2.
• The treatment of A-T is currently symptomatic and supportive, with no treatments known to slow or stop the neurodegeneration 2.
• However, other manifestations of A-T, such as immunodeficiency, pulmonary disease, failure to thrive, and diabetes, can be treated effectively 2.
• Multidisciplinary management of A-T is recommended, including follow-up and treatment of neurologic, immunologic, pulmonologic, oncologic, endocrinologic, and nutritional aspects 3.
• Current clinical trials represent progress and hope towards disease-modifying therapies for A-T 4.

Epidemiology and Pathogenesis

• A-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene, which encodes a protein involved in cellular signaling pathways in response to DNA double-strand breaks, oxidative stress, and other genotoxic stress 2.
• The severity of symptoms in A-T patients depends on the severity of mutations, and the presence of various clinical and immunologic manifestations indicates that the identification of the role of defective ATM in phenotype can be helpful in better management and treatment 5.

Clinical Phenotype and Diagnosis

• Classic A-T is characterized by progressive ataxia, oculocutaneous telangiectasias, and sinopulmonary disease, and is usually associated with absence of ATM protein 4.
• Other laboratory features associated with A-T include elevated serum levels of alpha-fetoprotein (AFP) and increased chromosomal breakage with in vitro exposure to ionizing radiation 4.
• Diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of pathological mutations in the ATM gene 2.

Management and Prognosis

• A-T is currently managed with supportive care and symptomatic treatment, and premature death is often due to malignancies or chronic respiratory insufficiency 4.
• Early identification of swallowing alterations and rehabilitation could decrease the risk of aspiration pneumonia, and future studies are necessary to investigate the deterioration process of swallowing in A-T and the influence of rehabilitation in maintaining functional health 6.