Introduction

• Definition: Ataxia Telangiectasia (AT) is a rare neurocutaneous disorder caused by biallelic pathogenic variants in the ATM gene.
• Core Manifestations:
  • Cerebellar ataxia in early toddler years.
  • Oculocutaneous telangiectasias in school-aged children.
• Multisystemic Disorder:
  • Neurologic, immunologic, oncologic, respiratory, and endocrinologic involvement.
• Incidence: Ranges from 1:40,000 to 1:300,000 live births.
• Median Survival: ~25 years.

II. ATM Gene and Its Function

• ATM Gene: Encodes serine/threonine kinase involved in:
  1. DNA Repair (double-strand breaks).
  2. Telomere Maintenance.
  3. Cell-cycle Control.
  4. Redox Homeostasis.
  5. Mitophagy/Pexophagy.
  6. Apoptosis.
  7. Chromatin Remodeling.

DNA Damage and ATM Activation

• ATM facilitates DNA repair and induces apoptosis when repair fails.
• Genome Instability: Causes cellular senescence and premature aging.
• Telomere Shortening: Accelerates aging and neurodegeneration.

III. Neurologic Pathology and Manifestations

1. Cerebellar Degeneration:

   • Starts at 6–18 months; ataxia prominent in toddler years.
   • Symptoms:
     • Truncal/gait ataxia, scanning speech, dysphagia.
   • Wheelchair dependence by ~10 years.

2. Movement Disorders:

   • Chorea, dystonia, tremors, and myoclonus.

3. Cognitive Impact:

   • Subtle deficits in:
     • Visuospatial processing, executive function, and working memory.

4. Ocular Findings:

   • Oculomotor apraxia.
   • Nystagmus and strabismus.

5. Neuropathology:

   • Loss of Purkinje and granule cells.
   • Imaging: Cerebellar atrophy (vermis and hemispheres).
   • Intracerebral telangiectasias may appear.

6. Peripheral Neuropathy:

   • Sensorimotor polyneuropathy detectable early but often subclinical.

IV. Non-Neurologic Manifestations

1. Telangiectasias:

   • Seen on the sclera and sun-exposed skin by ~6 years.

2. Dermatologic Findings:

   • Café-au-lait macules, hypopigmented macules, nevi, papulosquamous rash.

3. Immunodeficiency:

   • B-/T-cell lymphopenia and hypogammaglobulinemia → recurrent respiratory infections.

4. Respiratory Complications:

   • Bronchiectasis, aspiration pneumonia, fibrosis.

5. Oncologic Risk:

   • Hematologic cancers: T-ALL, T-PLL in childhood.
   • Solid tumors (breast, liver) in adults.

6. Endocrine and Gastrointestinal:

   • Poor growth, gonadal failure, liver steatosis, diabetes.

V. Diagnosis and Clinical Mimickers

1. Diagnostic Tests:

   • Serum Alpha Fetoprotein (AFP): Elevated in AT.
   • Genetic Testing: Confirms biallelic ATM mutations.

2. Comparison with Mimicking Conditions:

   • AT shares features with other ataxia and DNA repair disorders. The following table summarizes the comparison:

Key Notes:

• AT and RIDDLE syndrome both present with high AFP levels.
• ATLD1 and ATLD2 are radiosensitive but lack immunodeficiency.
• AOA1/2 present with neuropathy but do not feature telangiectasias or malignancy.

VI. Treatment and Research

1. Symptomatic Management:

   • Movement Disorders: Baclofen, botulinum toxin, valbenazine.
   • Ocular: Prism glasses, clonazepam, propranolol.
   • Multidisciplinary therapy: PT/OT, speech therapy.

2. Research Therapies:

   • Acetyl-DL-Leucine (ADLL): Improves nystagmus and ataxia.
   • Nicotinamide Riboside (NAD+): Reduces oxidative stress and improves DNA repair.
   • Erythrocyte-Encapsulated Dexamethasone: Provides temporary improvement without steroid side effects.
   • Triheptanoin: Corrects mitochondrial dysfunction.

VII. Prognosis and Future Directions

• Median Survival: ~25 years.
• Primary Causes of Death:
  • Respiratory failure.
  • Hematologic malignancies.
• Future Directions:
  • Biomarker discovery.
  • Clinical guidelines for screening.
  • Gene therapy trials, including micro-ATM constructs.

VIII. References

Collyer J, Rajan DS (2024) Ataxia telangiectasia. Semin Pediatr Neurol 52 ():101169. DOI: 10.1016/j.spen.2024.101169 PMID: 39622612.