Shubhayan Sanatani

Rationale: The relationship between age of symptom-onset and disease course is currently unknown in pediatric Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) patients. We aim to compare clinical characteristics and screen for genetic modifiers based on age at symptom-onset in pediatric CPVT patients diagnosed 19 years of age. Methods: A retrospective, multicenter, international cohort of pediatric CPVT patients was categorized as early-onset (EOP; symptom-onset 10 years) or adolescent-onset (AOP; symptom-onset 10-18 years inclusive). Demographics, clinical tests, therapy, genetics and outcomes were compared among groups. A next-generation sequencing approach of 71 genes were used to screen for potential genetic modifiers among early and adolescent-onset CPVT trios. Results: We included 58 EOP and 76 AOP in our clinical characterization. Median age at symptom-onset was 6 (IQR: 4-8) years for EOP and 13 (IQR: 11-15) years for AOP. Implantable cardioverter-defibrillator (ICD) use for primary prevention was higher in EOP (n=10/23, 44%) versus AOP (n=3/26, 12%) (p=0.02). De novo variants were more frequent in EOP (n=24/35, 69%) than AOP (n=12/40, 30%) in 75 trios (p=0.001). Proband status was an independent predictor of early-onset disease (p=0.01, OR=16.56, 95% CI=1.91-143.80). Over a median follow-up of 6 (IQR: 3-10) and 7 (IQR: 3-19.75) years after symptom-onset, 24 (41%) EOP and 21 (28%) AOP experienced cardiac events (p=0.037), respectively, including 4 sudden cardiac deaths in EOP versus none in AOP. Proband status was an independent predictor of time to first cardiac event (p=0.007, HR=4.59, 95% CI=1.53-13.80). In a group of 11 trios, there was no difference in the total number of variants and deleterious variants between EOP and AOP (p=0.99). ANK2 was the only gene in which all variants categorized to one group (EOP) and all variants were rare (p.Val1486Leu, p.Glu1449Gly and p.Thr3062del).Conclusion: Proband status rather than age at symptom-onset is a predictor of early-onset disease and an earlier-onset of cardiac events after diagnosis. Genetic factors may contribute to risk in early-onset CPVT. ANK2 showed high susceptibility as a modifier gene for early-onset CPVT, however, further research in a larger cohort is needed to verify this finding.

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Rationale: Clinical digital messaging (CDM) (text messaging) improves communication and engagement between adolescent patients and their health care providers (HCP). Dysautonomia of Adolescence (DAOA) is a condition which results in transient dysfunction of the autonomic nervous system (ANS). Many adolescents who are affected withdraw from school, sport, recreational activities; experience social isolation; and have significant mental health challenges. Quality of life (QoL) is severely affected, symptoms are difficult to predict and control. Ongoing support by HCP is needed to support management of symptoms. We sought to implement CDM to support DAOA patients and evaluate patient engagement, satisfaction, QoL and symptom burden.Methods: A single-centre, 12-month intervention study was performed. CDM was supported by WelTel Inc. Participants received an automated weekly check-in text message asking “How are you?”. Responses were triaged by HCP. QoL and symptom data were collected at three 6-month intervals: T0 baseline, T1 CDM enrollment and T2 post-CDM intervention. Non-parametric Friedman tests were used to determine differences over time. Participant engagement with the CDM platform was assessed through response rate and number of care conversations (>2 text messages between participant and HCP). Participant satisfaction was assessed using surveys administered at T1 and T2. Frequency counts (%) were performed for categorical variables and a univariate analysis performed on continuous variables. Tests were two-sided and a p0.05 was considered statistically significant. Results: There was an 80% recruitment rate. Twenty-six participants completed the study. Median (IQR) age of participants was 16.8 (15.7-17.4). Duration of CDM intervention was 33 weeks (26.8-37.3). A total of 896 automated weekly check-in messages were sent, resulting in 206 care conversations. Ninety-five percent of participants found CDM useful. There was no change in total QoL, number of frequent or occasional symptoms (p=0.260, 0.260 and 0.790, respectively). Conclusion: Twenty-three percent of all messages received from DAOA patients required care conversations. Participants were receptive to and satisfied with the CDM platform. Total QoL and symptom burden remained unchanged over the study period. CDM facilitated ongoing management of care in participants. Use of CDM technology may teach adolescents to advocate for themselves and become active participants in their own healthcare.

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