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.