Key result
Pre-excitation or short PR in LVH flags metabolic phenocopies rather than sarcomeric HCM.
Why the study?
LVH accompanied by a short PR interval or ventricular pre-excitation requires distinguishing conventional sarcomeric HCM from genetic and metabolic phenocopies such as PRKAG2 cardiomyopathy, Danon disease, and selected Fabry and Pompe diseases.
Distinguishing the exact electrophysiologic mechanism and underlying molecular etiology in patients with left ventricular hypertrophy and pre-excitation directly alters arrhythmia management, family screening, disease-specific therapy, and heart transplant planning.
Answers are grounded in this paper and cite their sources.
May prompt targeted genetic evaluation in LVH with pre-excitation; leaves open prospective validation before routine adoption.
Left ventricular hypertrophy (LVH) accompanied by a short PR interval or ventricular pre-excitation should prompt consideration of diagnoses beyond conventional sarcomeric hypertrophic cardiomyopathy (HCM).This critical review examines the clinical, electrophysiologic, imaging, biochemical, genetic, and mechanistic features that distinguish sarcomeric HCM from PRKAG2 cardiomyopathy, Danon disease, and selected Fabry and Pompe disease phenocopies.Particular emphasis is placed on defining the electrical phenotype because a short PR interval, a true atrioventricular accessory pathway, and a fasciculoventricular pathway are not interchangeable findings.PRKAG2 cardiomyopathy combines autosomal dominant cardiac glycogenosis with variable hypertrophy, preexcitation, atrial arrhythmias, and progressive conduction disease; emerging preclinical data also suggest early glycogen-independent AMPKγ2-myosin and calcium-handling abnormalities.Danon disease, caused by LAMP2 deficiency, is an aggressive X-linked cardioskeletal disorder in which fasciculoventricular and true atrioventricular accessory pathways may coexist, and phase 1 AAV9-LAMP2B gene-replacement data have now been reported.Cardiovascular magnetic resonance can refine the differential, including histologically validated low native T1 as a marker of myocardial glycosphingolipid accumulation in Fabry disease.A practical diagnostic strategy integrates the ECG mechanism, pedigree, extracardiac phenotype, echocardiography, cardiovascular magnetic resonance, disease-directed biochemical testing, genetic confirmation, and electrophysiology when pathway mechanism or risk remains uncertain.Correct molecular diagnosis directly changes surveillance, family screening, treatment, and advanced heart-failure planning.
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Aphivantrakul et al. (2026) conducted a review in Left ventricular hypertrophy with ventricular pre-excitation or short PR interval (Sarcomeric HCM vs. PRKAG2 cardiomyopathy, Danon disease, Fabry disease, and Pompe disease). Integrated diagnostic evaluation (ECG mechanism, pedigree, extracardiac phenotype, imaging, biochemical, genetic, and electrophysiologic testing) vs. Conventional sarcomeric hypertrophic cardiomyopathy evaluation was evaluated. Ventricular pre-excitation or a short PR interval in patients with left ventricular hypertrophy serves as a key diagnostic clue to distinguish PRKAG2, Danon, Fabry, and Pompe disease from sarcomeric HCM.
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