PO59 Severe hypertrophic cardiomyopathy in a patient with MYH7 and MYBPC3 variants of unknown significance and pathogenic GAA-mutation treated with myosin inhibitor

Background Pompe disease (PD) is a rare autosomal recessive disorder with a steady accumulation of glycogen substrate. Cardiac involvement and progress are incompletely understood in adults. Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease. Genetics could impact differently on disease severity. Recently, myosin inhibitors did not improve symptoms in a large HCM cohort. Purpose We present the complex case of a young patient with a symptomatic massive left ventricular hypertrophy, genetic diagnosis of PD and muscular bridge. Methods Data include routine clinical examinations performed at a European university hospital. Results Genetic findings included two variants of unknown significance (VUS) including a MYH7 mutation [NM_000257.4.:c.2828T>C p.(Leu943Pro), PM2, PP3, pathogenicity 33%] and a MYBPC3-mutation [NM_000256.3:c.2441_2443del p.(lys814del), PS4, PM2, pathogenicity 50%], as well as a pathogenic GAA-mutation (NM_000152.5:c.-32-13T>G IVS1-13T>G, PM3, PP4, PS3). Clinical onset of the disease was syncope under exertion at the age of 19 years, resulting in ICD implantation. Two years later, ventricular fibrillation occurred under exertion and the patient was presented with intermittent angina pectoris and NYHA class III at our cardiology department. Treatment included metoprolol and dapagliflozin. Echocardiography revealed massive hypertrophy (interventricular septum diameter 37mm) without obstruction at rest or during Valsalva. Cardiac index was 2,7l/min/m2. ECG showed variable PR intervals (110-140ms), positive Sokolow index ST elevations in V1-V3. Alpha-glucosidase activity was mild to moderately abnormal. Cardiac biopsy revealed typical HCM without signs of glycogen storage disorder. Coronary CT scan revealed a long muscular bridge of the medial LAD. Here, invasive measurement showed an iFR of 0.80. Pulmonary function showed a mild restrictive pattern, also potentially explained by stature. Neurologic assessment showed no clinical signs of PD and normal findings in neurophysiology and myosonography. There was a positive family history for HCM (father) and consanguinity. Probatory mavacamten treatment (5mg OD) resulted in a rapid and stable improvement of dyspnoea (NYHA II) at 6 months. Troponin mildly increased on follow-ups. Creatine kinase values remained normal. Rhythm disorders were potentially multifactorial and did not reoccur under amiodarone. Heart transplantation was currently declined by the patient. Conclusion The combination of two sarcomere mutations of unknown significance resulted in severe HCM. Biopsy excluded relevant cardiac involvement in PD. Further interdisciplinary assessment is ongoing to assess the indication for the start of enzyme replacement therapy. An interaction of subclinical late-onset PD with HCM is unclear. There could be a different treatment response regarding myosin inhibitors in specific subgroups of patients, depending on severity and genotype of HCM.