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The<jats:italic>PLP1<\/jats:italic>duplications are heterogeneous in size, unlike duplications causing many other genomic disorders, and arise by a distinct molecular mechanism. Other causes of PMD include<jats:italic>PLP1<\/jats:italic>deletions, triplications and point mutations. Mutations in the<jats:italic>PLP1<\/jats:italic>gene can also give rise to spastic paraplegia type 2 (SPG2), an allelic form of the disease. Thus, there is a spectrum of CNS disorder from mild SPG2 to severe connatal PMD.<jats:italic>PLP1<\/jats:italic>encodes a major protein in CNS myelin and is abundantly expressed in oligodendrocytes, the myelinating cells of the CNS. Significant advances in our understanding of PMD have been achieved by investigating mutant<jats:italic>PLP1<\/jats:italic>in PMD patients, animal models and in vitro studies. How the different<jats:italic>PLP1<\/jats:italic>mutations and dosage effects give rise to PMD is being revealed. Interestingly, the underlying causes of pathogenesis are distinct for each of the different genetic abnormalities. 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