Conclusion
This is one of only a small number of natural history studies examining the clinical course of a cohort of patients with PLP1 pathogenic variants and is unique in that it is limited to subjects withPLP1 gene duplications. This study demonstrated many commonalities with other studies that have characterized the features of PMD and other PLP1-related disorders but also some new insights into the natural history.
There are several limitations of the current study. First, the size of the cohort is small (n=16), with fewer individuals having completed a second or third FDS. This limitation is a reflection of the day-to-day demands that are required in providing time-intensive care for PMD patients. For this reason, many statistical analyses were not possible. Given the small sample size, it may be difficult to generalize or extrapolate a conclusion from this study to a larger population of PMD patients, particularly given the extensive variability observed within and between families. Future research utilizing a larger cohort will be necessary to further clarify the natural history and clinical course of PMD. This work certainly provides a good foundation that opens a new window into the natural history of patients with PLP1duplications.
A second limitation arises due to the potential for inconsistency between measurements, given that some FDS scores were completed via self-report, and others were completed based on in-person physical examinations. Additionally, questionnaires were filled out based on the self-report or report of a parent or guardian. An important strength is the ability to quantify and analyze the FDS through self-report.
A third limitation was the small number of time points available for several of the participants, which limited our ability to comment on whether PMD was progressive. In addition, there were differences in the number of years of follow-up between participants, and initial questionnaires and FDS scores were gathered at a wide range of ages.
Finally, there were several sibling pairs analyzed in the study. If the natural history and clinical course of PMD are assumed to vary less between members of the same family than it does between members of different families, the inclusion of multiple members of the same family in our study has the potential to bias our results.