Pelizaeus-Merzbacher disease (PMD, MIM 312080) is an X linked disorder characterised by dysmyelination of the central nervous system (CNS)^1,2 (see review by Koeppen and Robitaille³). Two main forms of the disease, a connatal and a classical type, are recognised. The connatal type has a severe course with feeding problems, progressive pyramidal and extrapyramidal symptoms, laryngeal stridor, microcephaly, very little development, and a natural disease duration of 5–7 years. The classical type evolves into spastic tetraparesis, ataxia, choreoathetoid movements of the limbs, and cognitive impairment. The disorder progresses at a variable rate and some children are able to sit with support or occasionally walk, before slow regression sets in. Seizures may occur in both types (table 1). PMD has been shown to be caused by mutations in the proteolipid protein (PLP1) gene, encoding the major myelin component in the CNS.^4,5PLP1 is also involved in the aetiology of X linked spastic paraplegia (SPG2), which manifests as progressive weakness and spasticity of the lower extremities with or without CNS involvement.^6,7 Mutations causing PMD can be divided into two main categories: duplications of PLP1, which account for the majority of cases (60–70%), and sequence variations within the gene (15–20%).⁸ The remaining 10–20% of patients have no detectable mutation within PLP1, suggesting that mutations in regulatory regions or other gene loci can also cause PMD. Disease severity ranges from severe connatal PMD to mild PMD/SPG2 with an intermediate classical form. Patients with PLP1 duplications have a predominantly milder classical phenotype, whereas patients with missense mutations show a much wider spectrum, ranging from more severely affected to SPG2.⁸ Duplication sizes vary significantly.^9,10 Absence of the PLP protein caused either by gene deletions or null mutations causes a specific mild form of PMD …