PRKAG2 mutations presenting in infancy
Rachel D Torok1, Stephanie L Austin2, Chanika Phornphutkul3
1Divisions of Pediatric Cardiology, Duke University Medical Center, Durham, NC, USA.
Insights
Mutations in PRKAG2, a gene regulating cardiac metabolism, can mimic Pompe disease in infants. Early diagnosis requires confirmatory genetic testing due to variable presentations.
Area of Science:
- Genetics
- Cardiology
- Metabolic Disorders
Background:
- PRKAG2 gene encodes the AMP-activated protein kinase (AMPK) gamma-2 subunit, crucial for cardiac metabolism.
- Mutations in PRKAG2 are linked to a cardiac syndrome (ventricular hypertrophy, pre-excitation, conduction disease), typically diagnosed in adolescence/adulthood.
- Infantile presentation of PRKAG2-related cardiac syndrome is underrecognized and challenging to diagnose.
Observation:
- Three infant cases initially suspected of having Pompe disease were ultimately diagnosed with PRKAG2 mutations.
- A novel PRKAG2 missense mutation was identified in one patient.
- PRKAG2 mutations can present symptomatically in infancy, mimicking other genetic metabolic disorders.
Findings:
- Confirms that PRKAG2 mutations can manifest in infancy with symptoms overlapping those of Pompe disease.
- Identifies a novel disease-causing mutation in the PRKAG2 gene.
- Demonstrates the diagnostic challenge in differentiating PRKAG2 cardiac syndrome from Pompe disease in infants.
Implications:
- Highlights the critical need for genetic testing for PRKAG2 mutations in infants presenting with cardiac symptoms suggestive of Pompe disease.
- Suggests that earlier diagnosis of PRKAG2-related cardiac syndrome is possible with increased clinical awareness.
- Emphasizes the importance of comprehensive genetic evaluation to avoid misdiagnosis and ensure appropriate management of infantile cardiac conditions.
Abstract:
PRKAG2 encodes the γ2 subunit of AMP-activated protein kinase (AMPK), which is an important regulator of cardiac metabolism. Mutations in PRKAG2 cause a cardiac syndrome comprising ventricular hypertrophy, pre-excitation, and progressive conduction-system disease, which is typically not diagnosed until adolescence or young adulthood. However, significant variability exists in the presentation and outcomes of patients with PRKAG2 mutations, with presentation in infancy being underrecognized. The diagnosis of PRKAG2 can be challenging in infants, and we describe our experience with three patients who were initially suspected to have Pompe disease yet ultimately diagnosed with mutations in PRKAG2. A disease-causing PRKAG2 mutation was identified in each case, with a novel missense mutation described in one patient. We highlight the potential for patients with PRKAG2 mutations to mimic Pompe disease in infancy and the need for confirmatory testing when diagnosing Pompe disease.
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