A 32-year-old woman presents with progressive neurological decline, ataxia, and oculomotor apraxia. Genetic testing reveals biallelic mutations in the ATM gene (Ataxia Telangiectasia Mutated). MRI brain shows cerebellar atrophy. She is counselled about increased cancer risk. What is the most appropriate immediate next step in management?

Explanation

## Clinical Context: Ataxia-Telangiectasia (AT) **Key Point:** AT is an autosomal recessive disorder caused by mutations in the ATM gene, which encodes a protein essential for DNA double-strand break (DSB) recognition and repair via the homologous recombination and non-homologous end joining (NHEJ) pathways. ## Pathophysiology of DNA Repair Defect The ATM protein is a serine/threonine kinase that: 1. Detects DNA double-strand breaks 2. Activates cell cycle checkpoints (G1/S and G2/M) 3. Triggers p53-mediated apoptosis of damaged cells 4. Initiates homologous recombination repair Without functional ATM: - DSBs accumulate in rapidly dividing cells (especially lymphocytes and cerebellar neurons) - Cell cycle checkpoints fail → genomic instability - Defective apoptosis → survival of cells with unrepaired DNA damage - **Result:** 40–100× increased lifetime cancer risk (lymphomas, leukaemias, solid tumours) ## Management Strategy **High-Yield:** The standard of care for AT patients is **surveillance, not prevention**. Prophylactic chemotherapy is neither indicated nor evidence-based; antioxidants lack proven benefit in AT. ### Appropriate Surveillance Protocol | Investigation | Frequency | Rationale | | --- | --- | --- | | Clinical examination | Every 3–6 months | Early detection of lymphadenopathy, hepatosplenomegaly | | Complete blood count | Every 6 months | Screen for haematologic malignancy | | Abdominal ultrasound | Annually | Detect lymphomas, hepatic involvement | | Chest X-ray | Annually | Lung cancer, mediastinal lymphoma | | Age-appropriate tumour markers (AFP, CEA) | As indicated | Baseline and periodic monitoring | | Genetic counselling | Once | Discuss inheritance, family screening | **Clinical Pearl:** Patients with AT should **avoid ionizing radiation** (including unnecessary CT scans) because their cells cannot repair radiation-induced DSBs, increasing secondary malignancy risk. ## Why Surveillance is the Next Step 1. **Establish baseline:** Document current health status and malignancy risk profile 2. **Early detection:** Most AT-associated cancers are treatable if caught early 3. **Individualize care:** Tailor frequency and modality based on age, family history, and prior malignancy 4. **Avoid harm:** Prophylactic chemotherapy causes secondary malignancies; unnecessary imaging increases radiation exposure **Mnemonic:** **ATMS** = ATM → Surveillance - **A**ccumulated DSBs - **T**umour risk increased - **M**onitoring essential - **S**urveillance (not prevention) is standard [cite:Robbins 10e Ch 7]