Abstract 2439: Clinical Profile and Risk of Sudden Death in Children with Timothy Syndrome
Timothy Syndrome (TS) is the most malignant form of Long QT Syndrome (LQTS): patients (pts) have the LQTS cardiac phenotype and multisystem disorders such as neuropsychiatric manifestations, syndactyly, immune system dysfunction, hypoglicemia and cardiac malformations. TS is caused by a single mutation (G406R) in the CACNA1C gene encoding the cardiac voltage-gated calcium channel (Cav1.2). We report here clinical data on the largest series of TS patients (22 patients from 24 families) derived from our TS Registry. Data were available since birth and the mean age at last contact was 6 + 6 years. Genetic diagnosis was available in 16/24 pts while for 8 pts DNA could not be obtained. The ECG showed a mean QTc of 600 msec (range 510 –700 msec); 13 patients had a QTc > 600 msec; functional 2:1 AV block was present in 18 pts and macroscopic T wave alternans in 7 pts. Sustained ventricular tachyarrhythmias occurred in 19/24 (79%) pts. Congenital heart disease was diagnosed in 55%. Hand/feet syndactyly was present in all patients, facial dysmorphisms in 91%, sepsis occurred in 50% (9/18) and neuropsychiatric disorders in 83%. Response to antiarrhythmic therapy is reported in the table⇓. In 3 families multiple children were affected despite parents did not carry the G406R CACNA1C mutation in genomic DNA: in 2 cases the mutation was identified in DNA extracted from tissues (somatic mutation), in the third case prenatal diagnosis identified the mutation in the fetus.
Timothy syndrome is a rare, highly malignant disease that mandates an aggressive management
SCD occurs at very young age despite betablockers even when combined with PM and/or LSGx
death occurs not only for cardiac arrhythmias but also for extracardiac conditions that should therefore be carefully monitored
transmission through somatic mutations warrants careful genetic counseling for TS families.