Discussion
This study aimed to characterize the clinical features, developmental milestones, and the natural history of Pelizaeus-Merzbacher disease in a cohort of subjects, ranging in age from 7 to 48, who had a documentedPLP1 gene duplication (PMD). We examined and analyzed the medical and developmental histories of subjects utilizing medical history questionnaires, medical record reviews, and a 31-point functional disability scale.9 Characterizing the natural history, to what extent the condition progresses over time, and the variability in both is important in providing genetic counseling and anticipatory guidance to parents and guardians of individuals with PMD. Understanding the natural history is also critical in the event that treatments to alter the disease course become available in the future.
The presenting symptoms, developmental milestones achieved, and progression of symptoms reported in our cohort were consistent with many previous studies of patients with PLP1 duplications. All our patients exhibited onset within the first year of life, with nystagmus predominating as the first symptom noticed, consistent with previous reports. 7,8, 10,11 In addition, most had nystagmus at some point in their lives and all had hypotonia, key characteristics of the classic PMD phenotype. Velasco Parra et al. (2018) reported on 7 Columbian patients with Pelizaeus Merzbacher disease ranging in age from 6-16 and with various PLP1 pathogenic variants. Unlike in our cohort. In their series, only 28.7% had early onset nystagmus and only 57% had hypotonia.12 However, in a recent cohort study of 111 Chinese individuals with PMD and various PLP1 pathogenic variants who were followed for a median of 53 months, 99.1% presented with nystagmus and 83.8% with hypotonia.13
In our cohort, all of our subjects exhibited delays in both motor and language development; however, many individuals were able to meet several developmental milestones. Similar to previous studies, a subset of the PMD patients in our study were able to obtain head control, the ability to sit, the ability to speak several words or sentences, and some were even able to walk with assistance. 7,8,11, 13 All individuals exhibited some degree of continued motor impairment with none of the participants having the ability to walk independently. We found that all individuals relied on the use of wheelchairs for most or all their ambulation. Like previous studies the patients in our cohort seemed to exhibit large phenotypic variability.11 This variability occurred not only within the cohort but between siblings.
In terms of cognitive achievement, previous studies have observed that individuals with PLP1 duplications often have some degree of intellectual disability, ranging from mild to severe.7,11 All individuals in our cohort were able to complete at least some of the cognition achievements such as knowing or responding to their name and following two-step commands. Although not all individuals were verbal, a number were able to use communication devices to complete these tasks. Additionally, many were able to read, although the reading levels were variable between individuals.
By utilizing the functional disability scale9, we were able to quantify the clinical course of PMD, and for several individuals, we were able to gather this information at more than one point in time. The clinical course of PMD has previously been described as slowly progressive; however, to date, this has not been adequately characterized. In a study by Regis, et al (2008)7, five patients were followed for a period ranging from five to twelve years. In this study, the clinical course remained stable for four patients, while one showed a mild worsening in the last year of follow-up. It is interesting to note that in our study population, there were individuals who scored both lower and higher on FDS2 versus FDS1 (as well as an individual with an FDS score that remained unchanged). Given the limited number of individuals in our study with more than one FDS score, a comparison between FDS1 and FDS2 scores was not significant; however, our study failed to depict a progressive clinical course. Given the limited number of follow-up years in our study, it remains possible that our population is consistent with previous studies suggesting a slowly progressive disorder. Further research using a larger study population and FDS scores at additional time points would be necessary to characterize the clinical course more fully. Additionally, a pattern may exist whereby individuals with PMD gain skills for a period before deteriorating, as has been previously suggested;8 however, our data set did not allow us to look for any such potential patterns.