Introduction
In 1885 Friedrich Pelizaeus, a German physician, first identified a genetic disorder in five boys in a single family with nystagmus, spasticity of the limbs, and developmental delay.1Twenty-five years later in 1910, Ludwig Merzbacher independently reexamined this family and described further the neuropathology of 14 affected individuals and found that all affected members shared a common ancestor.2 Together, Pelizaeus and Merzbacher identified this rare X-linked inherited white matter disorder.
Pelizaeus-Merzbacher disease (PMD) is today recognized as part of a group of disorders caused by mutations in the PLP1 gene. The gene encodes both PLP, a major component of central nervous system myelin, and an alternatively spliced isoform, DM20, which is a minor component of both central and peripheral nervous system myelin.3Duplications of the PLP1 gene cause the majority (50-75%) ofPMD . Point mutations in the coding or splice site regions are found in most of the remaining patients, although a very small portion is caused by deletions of the PLP1 gene. 4,5The disorder is thus genetically heterogeneous.
Individuals with PLP1 -related disorders are not only genetically heterogenesou, but also clinically heterogeneous. They can, however, can be loosely grouped into three main clinical phenotypes : 1) classic PMD, characterized by nystagmus, hypotonia, and delay in motor development with onset in the first year of life 6,7 2) connatal PMD characterized by severe hypotonia and stridor with onset at birth, and death within the first ten years of life.6,8, and 3) SPG2, characterized by a slowly progressive X-linked spastic paraparesis3,6,8 Classic PMD is usually caused by a duplication of the PLP1 gene within its locus on the X-chromosome. The mechanism(s) causing disease are not clear, but may be associated with alterations in oligodendrocyte energy metabolism. Conatatal PMD is often caused by point mutations within the PLP1 gene producing misfolding of PLP1, ER retention and activation of the unfolded protein response (UPR). SPG2 is caused by PLP1 mutations that allow the protein to traverse the ER and become inserted in myelin. Other intermediate phenothpes depend on the specifics of the nature and location of the PLP1 mutation.
In order to facilitate future treatment interventions and to understand the natural history of PMD, in this work we have evaluated the clinical presentation and progression of a group of patients with PLP1 duplications. This was done both retrospectively, through chart review, and prospectively, by collecting clinical data. Taken together, these results will be useful for future treatment strategies, developing biomarkers, and timing of treatment interventions in this disease.