UC Irvine

Juvenile PLA2G6-Associated Neurodegeneration (PLAN), an ultra-rare disorder characterized by variable features, is often discussed alongside its well-characterized counterpart, infantile PLAN. Despite detailed accounts of single cases of juvenile PLAN (n=1) and recent small cohorts (n=3 or 4), a comprehensive summary of its natural history remains elusive, presenting challenges in diagnosis. This study, utilizing data from Oregon Health & Science University, involves a semiannual questionnaire with 16 participants attending visits, ranging from one to 11. The questionnaire covered milestones, encompassing the regression of early developmental milestones (e.g., sitting, walking, etc.) and the progression of other disease-related milestones (e.g., feeding tube, seizures, etc.). The primary objective was to provide a quantitative review of the presence or absence of features relative to their age at onset, providing a detailed description of juvenile PLAN and its progression. The primary findings, represented by medians, were that individuals experienced frequent falls around 7.2 years, swallowing difficulties at 11.4 years, and abnormal autonomic function at 12.7 years. A cluster of gross motor skill loss spanned from 12.7 to 16.9 years, with wheelchair use beginning at 12.8 years. Fine motor skill loss appeared between 15.1 to 16.7 years, while seizures typically manifested at 15.6 years. Gastrostomy/feeding tube intervention was introduced at 15.9 years, and notably, none of the participants required a tracheostomy. During follow-up study visits, participants were questioned about regression relative to their skillset six months earlier. An analysis over five-year intervals showed a rising trend in regression reporting: 13% between ages 5.0 and 9.9 years, 44% between ages 10.0 and 14.9 years, and a substantial 95% between ages 15.0 and 19.9 years. Participants provided detailed descriptions of their regression symptoms extending beyond the initial questionnaire, encompassing changes in behavior, cognition, and dystonia, among other aspects. A retrospective analysis of medical records for a subset of participants (n=8) encompassed these features and more. This analysis improves the understanding of juvenile PLAN, thereby shortening the diagnostic odyssey, providing timely family support, informing best practices in PLAN, and laying the groundwork for future clinical trials to assess the statistical significance of interventions, such as gene therapy or devices.