How is ataxia-telangiectasia, associated with MRE11, managed?

Management of Ataxia-Telangiectasia Associated with MRE11

Ataxia-telangiectasia-like disorder (ATLD) caused by MRE11 mutations requires aggressive multidisciplinary respiratory management as the primary mortality-reducing intervention, since respiratory disease is the leading cause of premature death in these patients. 1

Critical Clarification: MRE11 vs ATM

MRE11 mutations cause ataxia-telangiectasia-like disorder (ATLD), not classic ataxia-telangiectasia (A-T). 2, 3 While ATLD shares the progressive cerebellar ataxia and oculomotor apraxia with classic A-T, key differences exist:

• ATLD patients typically lack telangiectasias, elevated alpha-fetoprotein, and have absent or minimal immunodeficiency 3
• Cancer risk appears lower in ATLD compared to classic A-T 3
• The neurological phenotype is similar but may progress differently 2, 4

Despite these differences, the European Respiratory Society guidelines for A-T management provide the best available framework for ATLD respiratory care, as both conditions share similar respiratory complications from progressive neurodegeneration. 1

Multidisciplinary Care Structure

Refer immediately to a specialized multidisciplinary clinic with expertise in rare neurodegenerative disorders. 1 These clinics exist across Europe (UK, Netherlands, Norway, France, Germany), Israel, Baltimore, and Brisbane. 1

The multidisciplinary team must include: 1

• Respiratory physicians (leading cause of death is respiratory disease)
• Immunologists
• Neurologists
• Nutritionists
• Physical therapists
• Genetic counselors

Respiratory Management (Primary Mortality Reduction Strategy)

Baseline Assessment and Monitoring

Perform baseline spirometry in all patients capable of completing the test, with reassessment at minimum twice yearly. 1 This detects subtle progression even without clinical symptoms and allows proactive intervention.

Measure peak cough flow rate alongside forced vital capacity at each visit - these are mainstays of clinical assessment. 1

Implement overnight polysomnography in adolescents, particularly those with: 1

• Clinical suspicion of sleep-related breathing abnormalities
• Rapid or progressive lung function decline
• Developing scoliosis

Airway Clearance

Prescribe regular airway clearance techniques as standard care, intensifying during any respiratory symptoms. 1

Add nebulized hypertonic saline or inhaled mannitol as adjuncts to airway clearance in appropriate patients. 1 These enhance mucociliary clearance in this population with inefficient cough mechanisms.

Infection Management

Since ATLD patients may have less severe immunodeficiency than classic A-T, tailor the following based on individual immunological assessment: 3

Perform comprehensive immunological workup including: 1

• Total immunoglobulin levels and subclasses
• Specific IgG antibodies to tetanus, Haemophilus influenzae B, and pneumococcal serotypes
• Immunophenotyping of peripheral blood

Administer all available immunizations against respiratory pathogens (pneumococcal conjugate followed by polysaccharide vaccine, annual inactivated influenza vaccine), as vaccine-preventable illnesses carry potentially fatal risks. 1

Define recurrent respiratory tract infections as >3 per winter season requiring antibiotics or severe/atypical response to single infection. 1 When this threshold is met, institute early aggressive antibiotic treatment with concurrent airway clearance.

Consider prophylactic antibiotics when: 1

• Respiratory infection burden is high
• Specific polysaccharide antibody deficiency is present
• Bronchiectasis is established
• Clinical judgment by caretakers, patient, and physician supports this approach

Initiate immunoglobulin replacement therapy when: 1

• Hypogammaglobulinemia and/or specific antibody deficiency exists with recurrent respiratory infections or established bronchiectasis
• Vaccinations and prophylactic antibiotics fail to improve symptoms regardless of immunological abnormality severity

Obtain regular surveillance microbiology on respiratory samples and treat aggressively based on results. 1

Progressive Diffuse Lung Disease

When progressive diffuse lung disease responds poorly to aggressive antibiotics, physiotherapy, and immunoglobulin replacement, and aspiration does not appear contributory, investigate non-infectious causes including interstitial lung disease and pulmonary fibrosis. 1 Consider corticosteroids in this scenario. 5

Nutritional Management

Perform annual assessment of nutritional adequacy and swallowing safety. 5 Malnutrition is a significant comorbidity affecting outcomes. 1

Provide supplemental calories orally or enterally for worsening nutritional status. 5

Consider early gastrostomy placement when: 5

• Swallowing is unsafe
• Nutrition is inadequate despite oral supplementation
• Feeding disrupts daily activities

Neurological and Orthopedic Support

Implement early and continued physiotherapy to mitigate contractures and scoliosis. 5 This is preventive rather than curative.

Consider spinal stabilization surgery for progressive scoliosis based on regular surveillance. 5 Note that chest wall bracing may temporarily help but can negatively impact vital capacity. 5

Perioperative Management

When surgery is required (bronchoscopy, gastrostomy, scoliosis correction): 1

Perform disease-specific perioperative optimization of pulmonary function. 1, 5

Anticipate increased aspiration risk and potential need for post-operative ventilatory support. 1, 5

Monitor perioperative glucose closely - patients may have impaired insulin secretion, insulin resistance, or glucose intolerance. 1, 5

Avoid succinylcholine - it may cause hyperkalemia in patients with significant neuropathy and muscle weakness. 1, 5

Radiosensitivity Considerations

Exercise caution with radiological investigations due to increased radiosensitivity. 1 While classic A-T patients have marked radiosensitivity, MRE11's role in DNA double-strand break repair suggests ATLD patients may share this vulnerability. 3, 4

Prefer MRI over CT when feasible - MRI with diffusion-weighted imaging can detect lung alterations comparably to CT without radiation exposure. 1

Common Pitfalls

• Underestimating respiratory decline - lung function deteriorates even without obvious symptoms, making twice-yearly monitoring essential 1
• Delaying gastrostomy - waiting too long increases surgical risk as respiratory function declines 5
• Assuming normal immunodeficiency protocols apply - ATLD immunological patterns differ from classic A-T and require individualized assessment 3
• Missing sleep-disordered breathing - this accelerates respiratory decline and requires polysomnography for detection 1