FCPS Paediatrics TOACS · ECG in Pompe Disease (GSD II)

✅ Candidate's answer:
• Characteristic ECG findings in Pompe disease (infantile-onset):
  1️⃣ Short PR interval – less than 0.08 seconds in infants (normal 0.08-0.12 sec). This is a hallmark finding.
  2️⃣ Giant QRS voltages – severe left ventricular hypertrophy (LVH) with tall R waves in V5-V6 (often >98th percentile).
  3️⃣ Deep narrow Q waves – in leads I, aVL, V5-V6 (pseudo-infarct pattern).
  4️⃣ ST segment depression and T-wave inversion in lateral leads (strain pattern).
  5️⃣ Left atrial enlargement – broad, notched P waves (P mitrale) in lead II.
  6️⃣ Left axis deviation – may be present.
• Why these changes occur:
  - Glycogen accumulation in the myocardium leads to massive ventricular hypertrophy with a characteristic "electric shock" appearance on ECG.
  - The short PR interval is due to accelerated AV conduction (often associated with glycogen storage diseases, especially Pompe).
  - The deep Q waves are due to septal hypertrophy (pseudo-infarct pattern).
• Differential diagnosis: Other causes of short PR + LVH: Fabry disease, Danon disease, PRKAG2 syndrome, severe anemia, and thyrotoxicosis.

✅ Candidate's answer:
• Clinical features of infantile-onset Pompe disease (GSD II):
  - Onset: Typically within the first 2-6 months of life.
  - Cardiac: Massive hypertrophic cardiomyopathy (cardiomegaly, heart failure).
  - Neuromuscular: Severe hypotonia (floppy infant), poor head control, weak cry, difficulty feeding.
  - Oropharyngeal: Macroglossia (enlarged tongue due to glycogen accumulation).
  - Respiratory: Respiratory insufficiency, recurrent infections, respiratory failure.
  - Musculoskeletal: Delayed motor milestones, progressive weakness.
  - Hepatomegaly: Mild to moderate (less prominent than in GSD I).
  - Dysphagia – due to muscle weakness and macroglossia.
• Why macroglossia and hypotonia?
  - Macroglossia: Glycogen accumulation in the tongue muscle leads to enlargement.
  - Hypotonia: Glycogen accumulation in skeletal muscle (especially type II fibers) causes muscle weakness and hypotonia.
  - Pathophysiology: Deficiency of acid α-glucosidase (GAA) → failure to degrade glycogen to glucose → glycogen accumulation in lysosomes → cellular dysfunction in cardiac, skeletal, and smooth muscle.

✅ Candidate's answer:
• Diagnostic approach for Pompe disease:
  1️⃣ GAA enzyme activity assay: The gold standard. Can be performed on:
    - Dried blood spot (DBS): First-line screening test.
    - Leukocytes, fibroblasts, or muscle biopsy.
  - Reduced GAA activity (<10% of normal) confirms the diagnosis of Pompe disease.
  2️⃣ Genetic testing: Sequencing of the GAA gene (chromosome 17q25) – identifies the causative mutations. This is important for confirming the diagnosis, genetic counseling, and prenatal diagnosis.
  3️⃣ Newborn screening: Dried blood spot GAA assay is increasingly used in newborn screening programs.
  4️⃣ Other tests:
    - Echocardiogram: Shows severe concentric LVH, with normal or hyperdynamic systolic function in early stages.
    - CK: May be elevated (due to muscle involvement).
    - ECG: Short PR interval, LVH, giant QRS voltages.
  - Muscle biopsy: Glycogen accumulation (PAS-positive vacuoles) in muscle tissue (less commonly used now).

✅ Candidate's answer:
• Treatment of Pompe disease:
  1️⃣ Enzyme replacement therapy (ERT):
    - Alglucosidase alfa (Myozyme): Recombinant human acid α-glucosidase.
    - Dose: 20 mg/kg IV every 2 weeks.
    - Infusion: Given via IV infusion over 2-4 hours. Life-long therapy.
    - Effectiveness: Improves cardiac function, reduces LVH, improves survival and motor outcomes, especially when started early (before 6 months of age).
  2️⃣ Supportive care:
    - Respiratory support: Non-invasive ventilation (BiPAP), mechanical ventilation if needed.
    - Nutritional support: High-calorie diet, feeding tube (G-tube) if dysphagia.
    - Physical therapy: To maintain muscle function.
  3️⃣ Clinical trials: Gene therapy is under investigation.
  4️⃣ Prognosis: Without treatment, infantile Pompe disease is fatal by 1 year (due to cardiorespiratory failure). With ERT, survival and quality of life are significantly improved, but patients may develop progressive muscle weakness (anti-GAA antibodies can reduce efficacy).

✅ Candidate's answer:
• Differential diagnosis of infantile hypotonia, macroglossia, and cardiomyopathy:
  1️⃣ Pompe disease (GSD II) – most classic association.
  2️⃣ Danon disease (LAMP2 deficiency) – X-linked, HCM + WPW + mental retardation + skeletal myopathy.
  3️⃣ PRKAG2 syndrome – HCM + WPW + conduction disease (glycogen storage).
  4️⃣ Fabry disease (X-linked) – HCM + angiokeratomas + renal failure + stroke.
  5️⃣ Mitochondrial disorders – can cause cardiomyopathy and hypotonia.
  6️⃣ Congenital hypothyroidism – macroglossia, hypotonia, but no cardiomyopathy.
  7️⃣ Beckwith-Wiedemann syndrome – macroglossia, visceromegaly, but no cardiomyopathy.
  8️⃣ Noonan syndrome – HCM, but no macroglossia typically.
  9️⃣ Congenital myopathies – hypotonia, but no cardiomyopathy.
• Key differentiating features: ECG (short PR + giant QRS = Pompe), associated WPW (Danon, PRKAG2), pattern of inheritance (X-linked for Danon/Fabry, AR for Pompe).

✅ Candidate's answer:
• Mechanism of short PR in Pompe: Glycogen accumulation in the myocardium and conduction system leads to accelerated atrioventricular (AV) conduction, resulting in a short PR interval. This is a characteristic ECG feature.
• Other causes of short PR interval (<0.08 sec in infants):
  1️⃣ Wolff-Parkinson-White (WPW) syndrome – short PR + delta wave + wide QRS.
  2️⃣ Lown-Ganong-Levine (LGL) syndrome – short PR without delta wave (James fibers).
  3️⃣ Glycogen storage diseases: Pompe (GSD II), Danon disease (LAMP2), PRKAG2 syndrome.
  4️⃣ Thyrotoxicosis – increases AV conduction.
  5️⃣ Hyperkalemia – can shorten PR (but usually with peaked T waves).
  6️⃣ Severe anemia – increased stroke volume → accelerated conduction.
  7️⃣ Digitalis toxicity.
• Differentiation: In Pompe, there is no delta wave, and the QRS is widened due to LVH (giant QRS voltages).

✅ Candidate's answer:
• Giant QRS voltages: Due to massive left ventricular hypertrophy from glycogen accumulation in the myocardium. The thickness of the ventricular wall increases the electrical forces, producing tall R waves in the left precordial leads (V5-V6) and deep S waves in V1-V2.
• Deep Q waves: Due to septal hypertrophy – the hypertrophied septum produces a pseudo-infarct pattern (deep narrow Q waves in lateral leads).
• Differential diagnosis of giant QRS voltages (LVH):
  1️⃣ Hypertrophic cardiomyopathy (HCM): Sarcomeric (MYH7, MYBPC3).
  2️⃣ Pompe disease (GSD II).
  3️⃣ Danon disease (LAMP2).
  4️⃣ PRKAG2 syndrome.
  5️⃣ Noonan syndrome (RASopathy).
  6️⃣ Friedreich ataxia.
  7️⃣ Aortic stenosis.
  8️⃣ Coarctation of aorta.
• Key to differentiation: In Pompe, the short PR + giant QRS + deep Q waves + infantile presentation (hypotonia, macroglossia) is highly characteristic.

✅ Candidate's answer:
• Untreated infantile Pompe disease:
  - Natural history: Rapidly progressive hypertrophic cardiomyopathy, severe hypotonia, macroglossia, and respiratory insufficiency.
  - Death: Usually by 1 year of age (median survival ~8-12 months) due to cardiorespiratory failure.
  - Progressive weakness: Leads to failure to thrive, feeding difficulties, and recurrent respiratory infections.
• With enzyme replacement therapy (ERT):
  - Cardiac outcomes: LVH reverses or stabilizes, heart failure improves.
  - Survival: Significant improvement – many patients survive into childhood and beyond.
  - Motor outcomes: Delayed but improved compared to untreated; patients may achieve sitting, standing, and walking (with variable degrees).
  - Challenges: Progressive muscle weakness may continue (especially if anti-GAA antibodies develop), requiring respiratory support and feeding tubes.
  - Optimal timing: Early initiation of ERT (before 6 months of age, ideally before symptoms) is associated with the best outcomes.

✅ Candidate's answer:
• Echocardiographic findings in Pompe disease:
  - Severe concentric left ventricular hypertrophy (LVH): LV wall thickness is markedly increased (z-score >5).
  - Normal or hyperdynamic LV systolic function in early stages (EF >60%).
  - Diastolic dysfunction – impaired relaxation (E/A reversal).
  - Left ventricular outflow tract (LVOT) obstruction: May be present (but less common than in sarcomeric HCM).
  - Biventricular hypertrophy: RV involvement is common.
  - Valvular abnormalities: Mitral valve thickening may occur (due to glycogen deposition).
  - Progression: LV function may deteriorate over time if untreated.
• Differences from sarcomeric HCM:
  - Pompe: More severe concentric hypertrophy, early onset (infancy), associated with hypotonia and macroglossia.
  - Sarcomeric HCM: Asymmetric septal hypertrophy, LVOT obstruction more common, typically later onset (childhood/adolescence).

✅ Candidate's answer:
• Newborn screening for Pompe disease: Many states/countries have implemented newborn screening for Pompe disease using dried blood spot (DBS) GAA enzyme assay.
• Why early detection is important:
  - Early initiation of ERT: Starting alglucosidase alfa before 6 months of age (ideally in the first few weeks of life) significantly improves outcomes.
  - Prevention of irreversible cardiomyopathy: ERT can reverse or halt the progression of LVH.
  - Improved motor outcomes: Early treatment leads to better motor milestones (sitting, walking).
  - Reduced mortality: Without newborn screening, many infants are diagnosed late (after symptoms develop), leading to poor outcomes.
  - Cost-effectiveness: Early detection reduces the need for intensive care and improves quality of life.

✅ Candidate's answer:
• Inheritance pattern: Autosomal recessive (parents are carriers, usually asymptomatic).
• Gene: GAA gene located on chromosome 17q25.
• Recurrence risk:
  - For each future pregnancy, there is a 25% chance of having an affected child (inheriting both mutant alleles).
  - 50% chance of the child being a carrier (heterozygote).
  - 25% chance of being unaffected (homozygous normal).
• Prenatal diagnosis: Available through chorionic villus sampling (CVS) or amniocentesis to test for GAA mutations or enzyme activity.
• Genetic counseling: Offer genetic testing to the parents (carrier testing) and to other family members. Prenatal diagnosis should be discussed. Preimplantation genetic diagnosis (PGD) is also an option.

✅ Candidate's answer:
• Complications of ERT (alglucosidase alfa):
  1️⃣ Infusion-related reactions: Fever, rash, urticaria, flushing, and anaphylaxis. Premedication with antihistamines and corticosteroids is often given.
  2️⃣ Anti-GAA antibody formation: Some patients develop antibodies that may reduce the efficacy of ERT. Immunomodulation (e.g., with rituximab, methotrexate) may be considered in some centers.
  3️⃣ Progressive muscle weakness: Despite ERT, some patients develop respiratory muscle weakness and require ventilatory support. Physical therapy and respiratory support are essential.
  4️⃣ Cardiac complications: While LVH improves, arrhythmias may persist.
  5️⃣ Hepatotoxicity: Liver enzymes should be monitored (rare).
• Management:
  - Premedication for infusions.
  - Monitor for antibodies and adjust therapy.
  - Multidisciplinary care (cardiologist, pulmonologist, neurologist, geneticist).

✅ Candidate's answer:
• Other GSDs with cardiomyopathy:
  1️⃣ Danon disease (LAMP2): X-linked, HCM + WPW + mental retardation + skeletal myopathy. ECG: short PR, delta wave (WPW), LVH.
  2️⃣ PRKAG2 syndrome: Autosomal dominant, HCM + WPW + conduction disease. ECG: short PR, delta wave, LVH, progressive AV block.
  3️⃣ GSD III (Cori/Forbes, debrancher deficiency): Can cause cardiomyopathy (hypertrophic or dilated) in addition to hepatomegaly and hypoglycemia.
  4️⃣ GSD IV (Andersen, branching enzyme deficiency): Liver cirrhosis, but cardiomyopathy can occur.
  5️⃣ Pompe (GSD II): Most severe cardiomyopathy in infancy, with characteristic ECG (short PR, giant QRS, no delta wave).
• Key differences:
  - Danon/PRKAG2: Associated with WPW (delta wave), mental retardation (Danon).
  - Pompe: No delta wave, infantile presentation with macroglossia and hypotonia.
  - GSD III: Hepatomegaly, hypoglycemia, muscle weakness, cardiomyopathy (later onset).

✅ Candidate's structured answer:
• “Your baby has a condition called Pompe disease – a rare genetic disorder where the body cannot break down a type of sugar (glycogen) in the muscle cells, including the heart muscle.”
• “This causes the heart to become very thick (hypertrophic cardiomyopathy) and the muscles to be weak (hypotonia). The ECG shows characteristic changes – a very short PR interval and giant QRS voltages – which are classic for this condition.”
• “The good news is that we have a very effective treatment called enzyme replacement therapy (ERT) – a medication given through an IV every 2 weeks. It replaces the missing enzyme and can significantly improve heart function, muscle strength, and survival.”
• “The earlier we start treatment, the better the outcomes. Your baby will need lifelong ERT, and we will also provide supportive care – respiratory support, nutrition, and physical therapy.”
• “We will monitor the heart with regular echocardiograms and ECGs. Most children with Pompe disease who are treated early can live into adulthood.”
• “This is an autosomal recessive condition, meaning both you and your partner are carriers. For future pregnancies, there is a 25% recurrence risk. We can discuss prenatal testing options.”
• “You are not alone – we have a team of specialists who will support you and your baby every step of the way.”