Chapter 37 - Pelizaeus-Merzbacher Disease

Abstract

This chapter outlines the historical perspective of Pelizaeus-Merzbacher disease (PMD). Zeman and coworkers suggested that the defect in PMD resided in the proteolipid protein (PLP), commonly known as lipophilin or Folch-Lees protein, the major protein component of myelin. This chapter also discusses the genetics of PMD/SPG2. PLP is one of nature's most hydrophobic proteins. The extra hydrophobic character of this integral membrane is because of an unusual degree of fatty acid acylation. The exceptional nature of PLP as a protein is echoed in the gene, which is extremely well conserved. PLP gene structure is preserved among tetrapods and readily discernible in the primordial gene of the lipophilin family present in invertebrates. Mammals share a nearly identical coding capacity for PLP. Moreover, no amino acid polymorphisms have been detected in the thousands of coding regions sequenced in the human PLP gene. PLP is encoded by a single gene that is composed of seven exons located on the X chromosome. Furthermore, this chapter illustrates how mutations result in overexpression, or loss-of-function or gain-of-function of PLP. Molecular pathogenesis of PMD has also been described.