Video2_Case report: Aborted sudden cardiac death as a first presentation of severe mitral annulus disjunction—a case series and review of the literature.mp4

Mitral annulus disjunction (MAD) is defined as a systolic displacement between the ventricular myocardium and the posterior mitral annulus supporting the posterior mitral leaflet. This structural abnormality is associated with the loss of mechanical annular function manifested as an abnormal systolic excursion of the leaflet hinge point into the left atrium but with maintained electrical function, separating the left atrium and ventricle electrophysiologically. The mitro-aortic fibrous continuity limits MAD anteriorly, between the aortic cusps and the anterior leaflet of the mitral valve. Consequently, MAD has been observed only at the insertion of the posterior leaflet. It can extend preferentially at the central posterior scallop. The first diagnostic modality aiding the diagnosis is transthoracic echocardiography (TTE), although in some cases adjunctive cardiac imaging modality might be suggested. MAD carries a strong association with malignant ventricular arrhythmogenesis and a profound predisposition for sudden cardiac death (SCD). In this context, a thorough investigation of this morphological and functional abnormality is vital in estimating the risk assessment and stratification for optimal management and elimination of the risk of the patient for SCD. Based on the current scientific data and literature, we will discuss the diagnosis, clinical implications, risk stratification, and therapeutic management of MAD.</p

Video1_Case report: Aborted sudden cardiac death as a first presentation of severe mitral annulus disjunction—a case series and review of the literature.mp4

Mitral annulus disjunction (MAD) is defined as a systolic displacement between the ventricular myocardium and the posterior mitral annulus supporting the posterior mitral leaflet. This structural abnormality is associated with the loss of mechanical annular function manifested as an abnormal systolic excursion of the leaflet hinge point into the left atrium but with maintained electrical function, separating the left atrium and ventricle electrophysiologically. The mitro-aortic fibrous continuity limits MAD anteriorly, between the aortic cusps and the anterior leaflet of the mitral valve. Consequently, MAD has been observed only at the insertion of the posterior leaflet. It can extend preferentially at the central posterior scallop. The first diagnostic modality aiding the diagnosis is transthoracic echocardiography (TTE), although in some cases adjunctive cardiac imaging modality might be suggested. MAD carries a strong association with malignant ventricular arrhythmogenesis and a profound predisposition for sudden cardiac death (SCD). In this context, a thorough investigation of this morphological and functional abnormality is vital in estimating the risk assessment and stratification for optimal management and elimination of the risk of the patient for SCD. Based on the current scientific data and literature, we will discuss the diagnosis, clinical implications, risk stratification, and therapeutic management of MAD.</p

Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece

Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked COL4A5 (NM_000495.5) gene or recessive variants in the COL4A3/COL4A4 (NM_000091.4/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1/50,000, a recent publication reported a predicted rate of pathogenic COL4A5 variants of 1/2320. We herewith present 98 patients (40 M/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the COL4A5 gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the COL4A5-p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M/4 F) reached kidney failure and 11 (10 M/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis