Design and Validation of a Pelizaeus Merzbacher Disease (PMD) Severity Scale

Abstract: Pelizaeus Merzbacher Disease (PMD) is a rare X-linked hypomyelinating leukodystrophy caused by pathogenic variants in PLP, which encodes proteolipid protein 1 (PLP1) and the estimated prevalence is 1.9 per 100,000 male births in the United States. PMD affected individuals are currently anecdotally and empirically classified as severe (typically conatal in onset), classic or

mild but understanding surrounding early determination of disease subtype remains a critical gap and cannot be predicted from genotype. An existing PMD validated Functional Disability Rating Scale enables stratification of PMD by severity, but due to its age dependence and significant floor effect, it is insufficient to discriminate severity in the context of clinical trials. As therapies

emerge for PMD, there is an urgent need for tools to discriminate disease severity in PMD early in the disease course, which is often the optimum window for clinical trial enrollment. To address this urgent need for a clinically informed tool, our team has established a natural history study to collect data such as age at onset of disease and key medical events. We propose to use this

deep existing natural history data in the context of a rigorous tool-development approach. The CHOP Leukodystrophy Center of Excellence (CHOP LCE) is uniquely suited to addressing this gap in clinical readiness for PMD. As the data integration core for the Rare Disease Clinical Research Network (RDCRN) funded Global Leukodystrophy Initiative Clinical Trials Network

(GLIA-CTN), the CHOP LCE has collected data on over 60 individuals affected by PMD across the severity spectrum and curated for phenotypic and genotypic characteristics. Our team will be able to leverage this data to support the development of an empirically developed PMD severity scale with face and construct validity (Aim 1). We will then validate this scale prospectively in a

cohort of 30 PMD affected individuals defining its feasibility, reliability and criterion validity, and determine context of use for future clinical trials (Aim 2). This approach will yield a validated Clinician Reported Outcome (ClinRO) in the form of a PMD clinical severity marker, which can be used in the context of imminent clinical trials as a tool for cohort stratification and monitoring of

longitudinal changes in disease severity.