Misdiagnosis of 99mTc-PYP-positive Danon disease as ATTR-CA: a case report and molecular imaging pitfalls

Transthyretin amyloid cardiomyopathy (ATTR-CA) results from extracellular misfolded transthyretin deposition. Technetium-99 m pyrophosphate (99mTc-PYP) scintigraphy serves as the noninvasive diagnostic gold standard when Perugini grade 2-3 myocardial uptake accompanies characteristic infiltrative features and exclusion of light-chain amyloidosis (specificity ≈ 100%). Danon disease, an X-linked disorder caused by lysosome-associated membrane protein-2 gene mutations, manifests as vacuolar cardiomyopathy due to glycogen accumulation, mimicking ATTR-CA clinically but lacking amyloid fibrils.

A 26-year-old male presented with exertional chest discomfort following his brother's sudden death. Laboratory studies revealed elevated creatine kinase (259 U/L) with normal serum free light chains. Electrocardiography showed Wolff-Parkinson-White syndrome. Echocardiography demonstrated concentric left ventricular hypertrophy (maximal wall thickness 13 mm), reduced global longitudinal strain (-15.1%) with apical sparing, and patchy hyperechogenicity. Cardiac MRI confirmed diffuse hypertrophy, mid-wall late gadolinium enhancement, elevated native T1 (1700 ms), and extracellular volume (52%). 99mTc-PYP scintigraphy revealed Perugini grade 3 uptake, initially suggesting ATTR-CA. Endomyocardial biopsy, however, identified glycogen-filled cytoplasmic vacuoles and Congo red negativity, confirming Danon disease.

This case exposes a critical diagnostic pitfall: intense 99mTc-PYP uptake (Perugini grade 3) may occur in non-amyloid conditions like Danon disease, likely due to myocardial microcalcification, challenging scintigraphy's specificity for ATTR-CA. Key discriminators include younger age, Wolff-Parkinson-White syndrome, marked creatine kinase elevation, and neurocognitive impairment in Danon disease versus elderly male predominance, low-voltage QRS complexes, and refractory heart failure in ATTR-CA. Pathological confirmation remains essential for young patients with "ATTR-like" scintigraphy, particularly when atypical features (e.g., skeletal muscle involvement or preexcitation syndromes) are present. Comprehensive integration of demographic, electrocardiographic, biomarker, and imaging data is imperative to prevent misdiagnosis and ensure appropriate management.