What is PRKAG2 (Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 2) syndrome?

PRKAG2 Syndrome: A Distinct Metabolic Storage Disease

PRKAG2 syndrome is a rare metabolic storage disease characterized by left ventricular hypertrophy (LVH), ventricular pre-excitation (Wolff-Parkinson-White syndrome), and progressive conduction system disease that should be distinguished from true hypertrophic cardiomyopathy. 1

Clinical Features

PRKAG2 syndrome presents with several key clinical manifestations:

• Cardiac features:

  • Left ventricular hypertrophy resembling hypertrophic cardiomyopathy
  • Ventricular pre-excitation (Wolff-Parkinson-White syndrome)
  • Progressive conduction system disease and heart block
  • Atrial fibrillation (occurring in approximately 29% of patients) 2
  • Need for pacemaker implantation at a young age (median age 36-37 years) 3, 2

• Natural disease progression:

  • Early onset of symptoms, often in childhood or adolescence
  • Progressive conduction abnormalities requiring pacemaker implantation
  • Risk of sudden cardiac death or aborted cardiac arrest (8%) 2
  • Development of advanced heart failure (14%) 2
  • Potential need for heart transplantation (4%) 2

• Extracardiac manifestations (reported in some cases):

  • Neurocognitive disorders
  • Psychiatric disorders
  • Possible association with pregnancy complications 3

Pathophysiology

PRKAG2 syndrome is caused by missense mutations in the gene encoding the gamma-2-regulatory subunit of the AMP-activated protein kinase (PRKAG2), a regulator of cellular energy homeostasis. 1

Key pathophysiological features include:

• Glycogen accumulation in cardiac myocytes (distinguishing it from sarcomeric HCM)
• Absence of classical histopathology such as myocyte disarray
• Impaired myocyte glucose uptake and metabolism
• Disturbed cellular energy homeostasis 1

Diagnosis

The diagnosis of PRKAG2 syndrome should be considered in patients presenting with:

• LVH with concomitant ventricular pre-excitation
• Early-onset conduction system disease
• Family history of similar cardiac manifestations with autosomal dominant inheritance

Diagnostic workup should include:

1. Electrocardiography: May show ventricular pre-excitation (WPW pattern), conduction abnormalities, bundle branch blocks, or bradyarrhythmias 4

2. Echocardiography: Typically reveals LVH that may be symmetric in early stages and become asymmetric over time 4

3. Cardiac MRI: Can help distinguish from sarcomeric HCM by identifying specific patterns of hypertrophy

4. Genetic testing: Identification of mutations in the PRKAG2 gene confirms the diagnosis 5, 6

5. Endomyocardial biopsy: May show glycogen accumulation in cardiac myocytes (though rarely needed for diagnosis) 6

Clinical Course and Management

The clinical course of PRKAG2 syndrome is progressive, with several important considerations:

• Arrhythmia management:

  • Monitoring for and treatment of atrial fibrillation
  • Assessment for accessory pathway ablation in symptomatic WPW
  • Early consideration of pacemaker implantation for progressive conduction disease

• Heart failure management:

  • Regular assessment of cardiac function
  • Standard heart failure therapy for those who develop systolic dysfunction
  • Consideration of heart transplantation in advanced cases

• Risk stratification:

  • Regular assessment for sudden cardiac death risk
  • Family screening due to autosomal dominant inheritance pattern

Important Distinctions from Sarcomeric HCM

It is crucial to distinguish PRKAG2 syndrome from sarcomeric HCM because:

1. The underlying pathophysiology is different (glycogen storage vs. sarcomeric protein mutation)
2. The natural history and progression differ significantly
3. Management strategies, particularly regarding risk assessment, may vary
4. The presence of progressive conduction disease is more characteristic of PRKAG2 syndrome 1

Genetic Counseling

Given the autosomal dominant inheritance pattern with incomplete penetrance:

• First-degree relatives should be offered genetic testing
• Genetic counseling is essential for family planning
• Cascade screening should be considered for families with identified mutations 1, 5

Pitfalls and Caveats

1. Misdiagnosis as sarcomeric HCM is common due to phenotypic overlap, potentially leading to inappropriate management strategies

2. Variable expressivity within families means that some mutation carriers may have minimal or no symptoms while others have severe disease 5, 4

3. Progressive nature of conduction disease means that patients require lifelong monitoring even if initially asymptomatic

4. Early-onset symptoms in children and adolescents may be subtle and require high clinical suspicion

5. Extracardiac manifestations may be underrecognized and require multidisciplinary care in some cases 3