Pelizaeus-Merzbacher disease and the allelic disorder spastic paraplegia 2 (SPG2) are hereditary leukodystrophies caused by mutations of the proteolipid protein 1 (PLP1) gene. The clinical syndromes range from the severe connatal Pelizaeus-Merzbacher disease syndrome, characterized by congenital hypotonia, nystagmus, and stridor, to an uncomplicated spastic paraparesis syndrome. Mutations of the PLP1 gene on the X chromosome include deletion, duplication, triplication, and quadruplication of the entire gene, as well as intragenic mutations and complex rearrangements of the gene and neighboring loci. The nature of the mutation plays an important role in determining the cellular effects on oligodendrocytes, disease severity, and pattern of inheritance. In this article, the author describes the clinical features and complex molecular genetics of Pelizaeus-Merzbacher disease and spastic paraplegia 2.
Historical note and terminology
Pelizaeus-Merzbacher disease has historically been subdivided into clinical variants based on the age of onset and severity of clinical signs. "Classical" Pelizaeus-Merzbacher disease is the most common presentation and is that described by Pelizaeus (62) and Merzbacher (50). The "connatal" form of Pelizaeus-Merzbacher disease was described later and denotes clinically evident onset within the first few weeks of life and a more severe syndrome (68). Seitelberger described a “transitional” form of Pelizaeus-Merzbacher disease that was intermediate in clinical severity between connatal and classical disease (69). In 1964, Zeman and colleagues pointed out that Pelizaeus-Merzbacher disease is a dysmyelinating, rather than a demyelinating, entity and stressed the importance of clinical observation and the familial nature of the disorder rather than strict pathological criteria to define the condition (94). They also hypothesized that the defect in Pelizaeus-Merzbacher disease affected a myelin proteolipid. Saugier-Veber and colleagues discovered that some families with X-linked spastic paraparesis have PLP1 mutations (66). It must be noted that these syndromes overlap.
Notes on nomenclature. Gene names are italicized, whereas the protein names or abbreviations are not. The PLP1 gene was previously called the PLP gene but was renamed after discovery of a similar gene that was named PLP2. The protein is still abbreviated PLP, however. Historically, the numbering of PLP1 amino acids began with the glycine because the initiation methionine is post-translationally excised. The numbering of nucleotides has followed this convention in the past but should now conform to more accepted conventions, with numbering starting at the initiation codon and initiation methionine, as specified by the Human Genome Variation Society.