ABSTRACT Objective This study aimed to provide a long-term follow-up of PRKAG2 syndrome and describe the new phenotypic aspects of the condition. PRKAG2 syndrome is a rare autosomal-dominant glycogen storage disease characterized by cardiac hypertrophy, ventricular pre-excitation, and conduction system disease. Fatal arrhythmias occur frequently. Methods A family cohort of 66 participants was recruited. Clinical and genetic analyses were performed. Results Median age of 36.97±17.28 years, with 69.9% being men. Nineteen subjects carried the deleterious variant p.K290I of the PRKAG2 gene. This group experienced many malignant events, including eight pacemaker implants, three sudden cardiac deaths, five aborted cardiac arrests, four strokes, four premature neonatal deaths, two spontaneous abortions, five forceps deliveries, and 12 cesarean procedures. Extracardiac involvement, such as in neurocognitive and psychiatric disorders, has been observed only in carriers of mutations. Palpitations, Syncope, atrial fibrillation, atrial flutter, sinus pauses, and bradycardia were strongly and significantly associated with major or severe adverse events (sudden cardiac death, aborted cardiac arrest, pacemaker use, stroke, and congestive heart failure). Early diagnosis and intervention through antiarrhythmic drugs, anticoagulation, pacemaker implantation, radiofrequency catheter ablation, and cesarean section surgery improved the symptoms and survival rates. Mutations carriers were advised to avoid pregnancy. Conclusion This study identified that the p.K291I_PRKAG2 mutation is associated with poor prognosis, highlighting the need for early intervention. Further research may uncover the potential connections between intellectual disability, miscarriage, and neonatal death in individuals with this syndrome. longterm long term followup follow up PRKAG condition autosomaldominant autosomal dominant hypertrophy preexcitation, preexcitation pre excitation, excitation pre-excitation frequently 6 recruited performed 36971728 36 97 17 28 36.97±17.2 years 699 69 9 69.9 men pK290I pKI p K290I K I gene implants deaths arrests strokes abortions deliveries 1 procedures involvement disorders mutations Palpitations Syncope fibrillation flutter pauses arrest use stroke failure. failure . failure) drugs anticoagulation implantation ablation rates pregnancy pK291IPRKAG2 pKIPRKAG K291I p.K291I_PRKAG prognosis disability miscarriage 3697172 3 2 36.97±17. 69. pK KI IPRKAG pK291IPRKAG 369717 36.97±17 36971 36.97±1 3697 36.97± 369 36.97 36.9 36.

Abstract Currently, there are a significant percentage of autopsies left without a conclusive diagnosis of death, especially when this lethal event occurs suddenly. Genetic analysis has been recently incorporated into the field of forensic medicine, especially in patients with sudden death and where no conclusive cause of death is identified after a complete medical- legal autopsy. Inherited arrhythmogenic diseases are the main cause of death in these cases. To date, more than 40 genes have been associated with arrhythmogenic disease, and causing sudden cardiac death has been described. The main arrhythmogenic diseases are Long QT Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia, Brugada Syndrome, and Short QT Syndrome. These post-mortem genetic studies, not only allow a diagnosis of the cause of death, but also allow a clinical translation in relatives, focusing on the early identification of individuals at risk of syncope, as well as adopting personalised therapeutic measures for the prevention of a lethal arrhythmic episode.

Resumen Actualmente hay un porcentaje importante de autopsias que quedan sin un diag nóstico concluyente del fallecimiento, especialmente cuando este evento letal se produce súbitamente. El análisis genético se ha ido incorporando recientemente al campo de la medicina forense, sobre todo en aquellos pacientes que han fallecido de forma repentina, y donde no se identifica causa concluyente del fallecimiento tras una autopsia médico-legal completa. En estos casos las enfermedades eléctricas primarias son las principales responsables del fallecimiento. Hasta la fecha se han descrito más de 40 genes asociados a afecciones arritmogénicas causantes de muerte súbita cardiaca. Las principales enfermedades arritmogénicas son el síndrome de QT largo y la taquicardia ventricular; estudios genéticos post-mortem no solo permiten llevar a cabo un diagnóstico de la causa del fallecimiento, sino que también permiten una traslación clínica hacia los familiares, focalizado en la identificación precoz de individuos en riesgo de síncope, así como adopción de medidas terapéuticas personalizadas para la prevención de un episodio arrítmico letal.