PO83
From EMF Suspicion to LAMP2 Pathogenicity: Genetic Testing Clarifying a Non-Ischaemic DCM Presentation

Danon disease (lysosome-associated membrane protein-2 [LAMP2]–related cardiomyopathy) is an X-linked lysosomal disorder that often presents within the cardiomyopathy spectrum and can progress rapidly to heart failure. Expression is sex-dependent: hemizygous males typically present earlier with hypertrophic cardiomyopathy that may evolve quickly, while heterozygous females present later with more variable phenotypes (hypertrophic, dilated, or mixed) and fewer extracardiac clues. Sex-dependent variability and imaging overlap with other cardiomyopathies make the initial diagnosis—based on clinical, imagiological, and epidemiological features—challenging.

We report a young woman from São Tomé e Príncipe with low-output decompensated heart failure, severe biventricular dysfunction, and a large left-ventricular (LV) apical thrombus. Echocardiography and local epidemiology initially suggested endomyocardial fibrosis (EMF) as a potential diagnosis, whereas cardiac magnetic resonance (CMR) showed a non-ischaemic dilated cardiomyopathy (DCM) pattern with diffuse fibrosis. Given high thromboembolic risk and persistent low output, she underwent urgent heart transplantation. Genotyping drawn during admission later identified a pathogenic LAMP2 splice-site variant, confirming Danon disease and enabling targeted family screening and long-term multidisciplinary care.

Clinical Case

A previously healthy young woman from São Tomé e Príncipe presented with weeks of escalating dyspnoea, orthopnoea, peripheral oedema, and low-output symptoms. On admission she had acute decompensated heart failure (HF) in a low-output state, requiring transient inotropic support with decongestive therapy.

Electrocardiogram (ECG) telemetry captured sinus tachycardia with frequent ventricular/supraventricular ectopy and non-sustained ventricular tachycardia (VT). Diuretic intensification and inotropes (dobutamine, up-titrated to about 5 µg/kg/min) were used as a bridge strategy, with a planned 6-hour levosimendan cycle. Blood pressure remained low-normal, oxygen saturation 96–98% on room air, and a negative fluid balance was achieved.

Testing reflected decompensated heart failure, with markedly elevated N-terminal pro–B-type natriuretic peptide (NT-proBNP) (peaking 18,918 pg/mL), low-output/congestive indices (mixed venous oxygen saturation [SvO₂] 28%, lactate 2.6 mmol/L), and a congestive/cyto-cholestatic pattern on the liver panel, without evidence of infection or acute coronary syndrome (apyrexia, no leukocytosis, negative microbiology/serologies, only mild C-reactive protein (CRP) rise; imaging supportive of a non-ischaemic aetiology).

Initial transthoracic echocardiography (TTE) showed a dilated LV with global systolic dysfunction (biplane left-ventricular ejection fraction [LVEF] ∼31%), conspicuous apical trabeculation and a suspicious apical mass; right-sided involvement and elevated filling pressures were present. Because of increased endocardial echogenicity/apical appearance, EMF was considered on echocardiographic grounds, a possibility reinforced by the patient’s origin in a region where EMF is relatively more prevalent.

Right-heart catheterization showed right atrial (RA) pressure 12 mmHg, pulmonary artery (PA) pressure 48/29 mmHg (mean 38), pulmonary capillary wedge pressure (PCWP) 29 mmHg, cardiac index (CI) 1.9 L/min/m², pulmonary artery pulsatility index (PAPI) 1.6, consistent with congestion and low output. Coronary angiogram was normal.

Cardiac magnetic resonance (CMR) was performed, showing:

Dilated (LV indexed end-diastolic volume [EDVi] 153 mL/m²) and hypertrophied (septal thickness 14 mm) left ventricle with severely compromised systolic function (LVEF 19%), with diffuse hypokinesis.

Overall, CMR favoured non-ischaemic DCM and stated the pattern was not typical of classic EMF, recommending genotyping.

Guideline-directed therapy was initiated cautiously given hypotensive profile with low-dose angiotensin-converting enzyme (ACE) inhibitor (captopril 6.25 mg every 8 hours (q8h)) and spironolactone 12.5 mg. Beta-blocker was deferred due to low output, loop diuretics were intensified, therapeutic enoxaparin was used for the LV thrombus, and ferric carboxymaltose was administered for iron repletion.

Anticoagulation for the LV thrombus was temporarily withheld for dental extraction, and an acute ischaemic stroke ensued. Endovascular thrombectomy achieved reperfusion (TICI 2a) with near-complete recovery of neurological deficits, after which full-dose anticoagulation was promptly and permanently reinstated.

Given persistent severe biventricular dysfunction and diffuse fibrosis with persistent low-output despite medical optimisation, the patient was listed and proceeded to urgent orthotopic heart transplantation. The multidisciplinary team proceeded with heart transplantation 33 days after admission, which was uneventful; sinus rhythm returned intra-operatively, the postoperative course under standard immunosuppression was uncomplicated, and the patient was discharged 20 days after heart transplant.

After discharge, the patient remained asymptomatic, with no signs of heart failure and with preserved graft function and no signs of rejection.

Results from genotyping performed while hospitalised later confirmed a pathogenic LAMP2 variant consistent with Danon disease (heterozygous LAMP2 splice-site variant [NM_002294.3:c.1093+1G>A]). The patient and her family were referred for genetic counselling and cascade testing, and she was referred for contraception counselling and for neuromuscular and ophthalmological screening as part of comprehensive Danon disease care.

Cardiomyopathies, including dilated phenotypes, often share clinical and imagiological features, creating substantial diagnostic overlap. In this case, initial TTE showed a dilated LV with global systolic dysfunction, increased endocardial echogenicity, conspicuous apical trabeculation, and a large apical mass consistent with thrombus; coupled with the patient’s epidemiological context, these findings brought EMF into the early differential. However, CMR demonstrated diffuse, heterogeneous fibrosis (extensive LGE with markedly elevated native T1) and biventricular involvement without the classic apical subendocardial pattern of EMF, supporting a broader non-ischaemic DCM footprint and prompting genotyping.

A key layer in this diagnostic puzzle is the sex-specific expression of LAMP2 pathogenic variants. In males, Danon cardiomyopathy typically manifests in the second decade with hypertrophy, rapid progression, frequent pre-excitation, and extracardiac clues (skeletal myopathy, elevated creatine kinase/transaminases, cognitive/ophthalmic findings). In contrast, heterozygous females often present later, with wider phenotypic variability driven in part by X-inactivation: some show hypertrophy, many present with dilated or mixed remodelling, and extracardiac features may be absent or subtle. Consequently, women can be under-recognized or misclassified within idiopathic or post-myocarditic DCM, particularly when the imaging signal is dominated by diffuse fibrosis rather than striking hypertrophy. Our patient exemplifies this: rapidly progressive biventricular failure, extensive LGE with high native T1, and a large LV thrombus fit a non-ischaemic DCM pattern that overlapped with EMF in her epidemiologic context, yet ultimately reflected Danon disease.

These sex-dependent trajectories influence management thresholds. While less frequent than in males, Danon cardiomyopathy in females can still progress rapidly with early heart failure, arrhythmias, and thromboembolism; neurohormonal therapy remains foundational but may not halt lysosome-driven remodelling. Extensive fibrosis and biventricular involvement on CMR should therefore lower the threshold for early referral for advanced therapies, including transplantation, irrespective of sex. The course here was further shaped by thromboembolic risk: a large LV thrombus in advanced cardiomyopathy demands meticulous periprocedural anticoagulation planning, as even brief interruptions can precipitate embolism, arguing for close multidisciplinary coordination and rapid access to reperfusion strategies when indicated.

Critically, this is where genetic testing adds decisive value. In women presenting with non-specific DCM or mixed phenotypes, early genotyping for LAMP2 and other cardiomyopathy genes can resolve ambiguity when imaging overlaps with endemic diseases, recalibrate risk (arrhythmic, thromboembolic, and heart-failure trajectories), inform timing for advanced therapies, and trigger cascade family screening with tailored surveillance, including for apparently healthy female relatives who may manifest later or variably. Beyond the individual, a molecular diagnosis directs targeted family evaluation and counselling, prompts surveillance for extracardiac manifestations (skeletal muscle, liver enzymes, ophthalmic review), and can open eligibility for emerging gene-targeted or pathway-directed therapies. In sum, integrating genotyping with imaging moves care from a broad DCM phenotype to a precise diagnosis, with concrete consequences for risk stratification, treatment timing, and cascade screening, particularly in women whose Danon phenotype is less “classic” at presentation.

A young woman from São Tomé e Príncipe presented with low-output decompensated HF, severe biventricular dysfunction, and a large LV thrombus. While TTE and epidemiology prompted consideration of EMF, CMR favoured non-ischaemic DCM; given refractory haemodynamics and high thromboembolic risk, she underwent urgent transplantation. Genotyping obtained during admission returned after surgery and confirmed Danon disease, refining prognosis and prompting cascade family screening. In advanced cardiomyopathy with overlapping phenotypes, integrating early genotyping with imaging can secure aetiology and inform long-term management with tangible clinical impact.