Grażyna Truszkowska

Background/Objectives: PRKAG2 syndrome (PS) is a rare genocopy of hypertrophic cardiomyopathy (HCM). Our goal was to expand knowledge about PS by analyzing patient clinical, imaging, and follow-up data. Methods: The study included carriers of likely pathogenic or pathogenic PRKAG2 variants identified in the years 2011–2022. Cardiac involvement was assessed by electrocardiography, echocardiography, cardiac magnetic resonance imaging, and endomyocardial biopsy (EMB). We recorded concomitant diseases and cardiac events, including the implantation of electronic cardiac devices, arrhythmia, heart failure (HF), and death. Results: Seven patients from four families (median age 43 years) with PRKAG2 variants: Phe293Leu, Val336Leu, Arg302Gln, and His530Arg were included. At the first evaluation, 3 carriers were in New York Heart Association (NYHA) functional class II–III, while the remaining were in NYHA class I. Left ventricular hypertrophy (LVH) was present in 5 patients; 2 had ventricular pre-excitation, one was in atrial flutter and pacemaker-dependent; 2 had bradycardia. Two female carriers had concomitant chronic renal disease. In the EMB of one of the patients, staining for glycogen deposits was positive. Furthermore, we provide a link between the Val336Leu PRKAG2 variant and autophagy identified on EMB. After a median follow-up of 13.1 years, 6 carriers had LVH, 3 required admission for HF, and 1 had sustained ventricular tachycardia with subsequent cardioverter defibrillator implantation, and despite this, died suddenly; there were two de novo pacemaker implantations due to symptomatic bradycardia. Conclusions: PR is a distinctive disorder with an early onset of arrhythmic events, often leading to HF.

Background: LMNA-related dilated cardiomyopathy (LMNA-DCM) caused by mutations in the lamin A/C gene (LMNA) is one of the most common forms of hereditary DCM. Due to the high risk of mutation transmission to offspring and the high incidence of ventricular arrhythmia and sudden death even before the onset of heart failure symptoms, it is very important to identify LMNA-mutation carriers. However, many relatives of LMNA-DCM patients do not report to specialized centers for clinical or genetic screening. Therefore, an easily available tool to identify at-risk subjects is needed. Methods: We compared two cohorts of young, asymptomatic relatives of DCM patients who reported for screening: 29 LMNA mutation carriers and 43 individuals from the control group. Receiver operating characteristic (ROC) curves for potential indicators of mutation carriership status were analyzed. Results: PR interval, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity cardiac troponin T (hscTnT) serum levels were higher in the LMNA mutation carrier cohort. Neither group differed significantly with regard to creatinine concentration or left ventricular ejection fraction. The best mutation carriership discriminator was hscTnT level with an optimal cut-off value at 5.5 ng/L, for which sensitivity and specificity were 86% and 93%, respectively. The median hscTnT level was 11.0 ng/L in LMNA mutation carriers vs. p < 0.001. Conclusions: Wherever access to genetic testing is limited, LMNA mutation carriership status can be assessed reliably using the hscTnT assay. Among young symptomless relatives of LMNA-DCM patients, a hscTnT level >5.5 ng/L strongly suggests mutation carriers.

Familial thoracic aortic aneurysms and dissections may occur as an isolated hereditary trait or as part of connective tissue disorders with Mendelian inheritance, but severe cardiovascular disease in pediatric patients is extremely rare. There is growing knowledge on pathogenic variants causing the disease; however, much of the phenotypic variability and gene–gene interactions remain to be discovered. We present a case report of a 5.5-year-old girl with an aortic aneurysm and concomitant polycystic kidney disease. Whole exome sequencing was performed, followed by family screening by amplicon deep sequencing and diagnostic imaging studies. In the proband, two pathogenic variants were identified: p.Tyr257Ter in the LOX gene inherited from her mother, and p.Thr2977Ile in the PKD1 gene inherited from her father. All adult carriers of either of these variants showed symptoms of aortic disease. We conclude that the coexistence of two independent genetic variants in the proband may be the reason for an early onset of disease.

Titin truncating variants (TTNtv) are known as the leading cause of inherited dilated cardiomyopathy (DCM). Nevertheless, it is unclear whether circulating cardiac biomarkers are helpful in detection and risk assessment. We sought to assess 1) early indicators of cardiotitinopathy including the serum biomarkers high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in clinically stable patients, and 2) predictors of outcome among TTNtv carriers. Our single-center cohort consisted of 108 TTNtv carriers (including 70 DCM patients) from 43 families. Clinical, laboratory and follow-up data were analyzed. The earliest abnormality was left ventricular dysfunction, present in 8, 26 and 47% of patients in the second, third and fourth decade of life, respectively. It was followed by symptoms of heart failure, linked to NT-proBNP elevation and severe left ventricular systolic dysfunction, and later by arrhythmias. Hs-cTnT serum levels were increased in the late stage of the disease only. During the median follow-up of 5.2 years, both malignant ventricular arrhythmia (MVA) and end-stage heart failure (esHF) occurred in 12% of TTNtv carriers. In multivariable analysis, NT-proBNP level ≥650 pg/mL was the best predictor of both composite endpoints (MVA and esHF) and of MVA alone. In conclusion, echocardiographic abnormalities are the first detectable anomalies in the course of cardiotitinopathies. The assessment of circulating cardiac biomarkers is not useful in the detection of the disease onset but may be helpful in risk assessment.

We report on a 36-year-old man with cerebellar-extrapyramidal syndrome and severe heart failure because of dilated cardiomyopathy of unknown origin. Dysarthria and cardiac arrhythmia began at early childhood (4 years of age). Brain MRI (28 years of age) demonstrated severe cerebellar atrophy. At the age 32, he presented with dysarthria, ataxia, dystonia, and tremor of the right hand, bilateral slowed neural conduction in the visual pathways, and decreased mental acuity. At the age of 33 years, the patient underwent cardiac transplantation because of severe dilated cardiomyopathy. In the TPP1 gene, biallelic variants were identified: previously reported p.(Leu13Pro) and novel p.(Tyr508Cys) variant. Additionally, hemizygous novel missense variant in the ABCD1 gene was inherited from the mother p.(Arg17His). Normal very-long-chain fatty acids (VLCFA) levels both in patient and his mother excluded ABCD1 mutation as the pathogenic one. Tripeptidyl peptidase 1 (TPP1) activity was reduced (8,8 U/mg protein/h; reference range: 47.4 ± 10.7). In light microscopy the biopsy specimens obtained from explanted heart showed severe myocyte hypertrophy with perinuclear vacuolization with inclusions. Electron microscopy revealed absence of lipofuscin accumulation, no ultrastructural curvilinear profiles, fingerprint bodies, or granular osmiophilic deposits (GRODs) in lysosomes. As described here, the patient presents clinical symptoms observed in benign forms of ceroid lipofuscinosis type 2 (CLN2) and simultaneously some features of autosomal recessive spinocerebellar ataxia type 7 (SCAR7), which is also caused by mutations in the TPP1 gene.

Background: The most common cause of Unexplained Sudden Cardiac Arrest (USCA) are hereditary primary arrhythmic syndromes and subclinical forms of cardiomyopathies. Both of them may be difficult to diagnose. Objective: The aim of this study was to re-examine the role of genetic testing in patients after USCA during follow-up. Methods: In the years 2014–2017 we studied 44 unrelated patients (pts) (23 men (53%), mean age 36 years) after USCA. All pts underwent cardiac evaluation including ECG, Holter, echo, coronary angiography, stress exercise test and, if necessary cardiac MRI and provocative drug testing. Standard diagnostic criteria were used according to currently available ESC guidelines. We performed next generation sequencing with panel covered coding regions of >4800 genes (26pts), 194 genes (5pts) and whole exome sequencing >2ehab724.3204 genes (5pts). Variants of frequency no greater than 0,001 in existing variants' databases and classified as damaging by at least 3 of applied software algorithms were assessed for pathogenicity according to ACMG standards. The enrolled patients were followed up. During the follow up, the classification of rare variants according to ACMG standards was repeated. Results: Based on applicable standards and the clinical data collected, clinical diagnosis was made in 17 (39%) probands (Long QT Syndrome 21%, Brugada Syndrome 7%, Short QT Syndrome 7%, Early Repolarization Syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia 2%, both). Genetic tests were performed in 36 pts. We identified 27 rare variants in 22 pts, in genes associated with inherited arrhythmia or cardiomyopathies, of these 23 rare variants were identified in years 2014–2017. The first classification was in 2017, then only 2 variants (in FLNC) were considered pathogenic and the remaining 21 were classified as Variants of Unknown Significance (VUS). During the years 2019–2021, 23 earlier identified rare variants were reclassified according to The American College of Medical Genetics and Genomics (ACMG) standards, of these 5 VUS became pathogenic/likely pathogenic variants. In addition, we performed genetic tests in next 5 pts – we identified 4 rare variants – 3 pathogenic and 1 VUS. Detection of certain hereditary background of SCA increased from 6,5% in years 2014–2017, to 25% in years 2019–2021. The median follow-up period was 2366 days (interquartile range 1785–2903 days). 17/44 (39%) pts had adequate discharge of ICD. Two pts were observed with reduction of left ventricular contractility and the development of the initial stages of dilated cardiomyopathy. Conclusion: This study shows clinical utility of extensive clinical assessment and follow-up of patient after USCA. Routine genetic testing by next generation sequencing in the patients can help in diagnosis and re-evaluation of rare variants should be made during the follow-up. Funding Acknowledgement: Type of funding sources: Public Institution(s). Main funding source(s): grant of National Institute of Cardiology, Warsaw, Poland

Mono-allelic dominant mutations in the desmoplakin gene (DSP) have been linked to known cardiac disorders, such as arrhythmogenic right ventricular cardiomyopathy and dilated cardiomyopathy. During the course of DSP cardiomyopathy, episodes of acute myocardial injury may occur. While their mechanisms remain unclear, myocarditis has been postulated as an underlying cause. We report on an adolescent girl with arrhythmogenic biventricular cardiomyopathy and three acute myocarditis-like episodes in whom we found a novel truncating DSP variant accompanied by a known low penetrance R490K variant in the NLRP3. Upon family screening, other carriers of the DSP variant have been identified in whom only mild cardiac abnormalities were found. We hypothesized that the uncommon course of cardiomyopathy in the proband as well as striking discrepancies in the phenotype observed in her family may be explained by the co-existence of her low penetrance genetic autoinflammatory predisposition.

Mutations in the lamin A/C gene are variably phenotypically expressed; however, it is unclear whether circulating cardiac biomarkers are helpful in the detection and risk assessment of cardiolaminopathies. We sought to assess (1) clinical characteristics including serum biomarkers: high sensitivity troponin T (hsTnT) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in clinically stable cardiolaminopathy patients, and (2) outcome among pathogenic/likely pathogenic lamin A/C gene (LMNA) mutation carriers. Our single-centre cohort included 53 patients from 21 families. Clinical, laboratory, follow-up data were analysed. Median follow-up was 1522 days. The earliest abnormality, emerging in the second and third decades of life, was elevated hsTnT (in 12% and in 27% of patients, respectively), followed by the presence of atrioventricular block, heart failure, and malignant ventricular arrhythmia (MVA). In patients with missense vs. other mutations, we found no difference in MVA occurrence and, surprisingly, worse transplant-free survival. Increased levels of both hsTnT and NT-proBNP were strongly associated with MVA occurrence (HR > 13, p ≤ 0.02 in both) in univariable analysis. In multivariable analysis, NT-proBNP level > 150 pg/mL was the only independent indicator of MVA. We conclude that assessment of circulating cardiac biomarkers may help in the detection and risk assessment of cardiolaminopathies.

The vast majority of cardiomyopathies have an autosomal dominant inheritance; hence, genetic testing is typically offered to patients with a positive family history. A de novo mutation is a new germline mutation not inherited from either parent. The purpose of our study was to search for de novo mutations in patients with cardiomyopathy and no evidence of the disease in the family. Using next-generation sequencing, we analyzed cardiomyopathy genes in 12 probands. In 8 (66.7%), we found de novo variants in known cardiomyopathy genes (TTN, DSP, SCN5A, TNNC1, TPM1, CRYAB, MYH7). In the remaining probands, the analysis was extended to whole exome sequencing in a trio (proband and parents). We found de novo variants in genes that, so far, were not associated with any disease (TRIB3, SLC2A6), a possible disease-causing biallelic genotype (APOBEC gene family), and a de novo mosaic variant without strong evidence of pathogenicity (UNC45A). The high prevalence of de novo mutations emphasizes that genetic screening is also indicated in cases of sporadic cardiomyopathy. Moreover, we have identified novel cardiomyopathy candidate genes that are likely to affect immunological function and/or reaction to stress that could be especially relevant in patients with disease onset associated with infection/infestation.

Mutations of the SCN5A gene are reported in 2-4% of patients with dilated cardiomyopathy (DCM). In such cases, DCM is associated with different rhythm disturbances such as the multifocal ectopic Purkinje-related premature contractions and atrial fibrillation. Arrhythmia often occurs at a young age and is the first symptom of heart disease. We present the case of 55-year old male with a 30-year history of heart failure (HF) in the course of familial DCM and complex ventricular tachyarrhythmias, which constituted 50-80% of the whole rhythm. The patient was qualified for heart transplantation because of the increasing symptoms of HF. We revealed the heterozygotic R222Q mutation in SCN5A by means of whole exome sequencing. After the quinidine treatment, a rapid and significant reduction of ventricular tachyarrhythmias and an improvement in the myocardial function were observed and this effect remained constant in the 2.5-year follow-up. This effect was observed even in the presence of concomitant coronary artery disease. Patients with familial DCM and Purkinje-related ventricular arrhythmias should be offered genetic screening. The quinidine treatment for the SCN5A R222Q mutation can be life saving for patients.