Pelizaeus-Merzbacher disease (PMD) (MIM 312080), together with the allelic disorder spastic paraplegia type 2 (SPG2) (MIM 312920), which also maps to Xq22, are leukodystrophies of widely varying severity. PMD is characterized chiefly by impaired motor development that presents within the first year and progresses throughout life: nystagmus, ataxia, spasticity, and mental retardation are usually encountered. SPG2 patients display spasticity of the lower limbs. In patients with the complicated form of SPG2, cerebellar ataxia, sensory loss, nystagmus, and optic atrophy may also be present.
A loss of myelin is evident by MRI or histopathology in both PMD and SPG2, and a loss of oligodendrocytes is obvious in the severe connatal form of PMD. Abnormal central nervous system conduction velocities, as analyzed by evoked potentials, reflect the myelin defect.
Mutations in the X-linked PLP gene (GenBank M27110), which encodes the major central nervous system myelin protein (PLP) and its alternatively spliced isoform an isoform of proteolipid protein with a MW of 20 kDa (DM20), are responsible for the pathogenesis of PMD and SPG2. Females are affected only infrequently in PMD, but in the relatively mild SPG2 the PLP mutation can act semidominantly.
PLP is a gene subject to dosage control, as overexpression of PLP is the most common type of mutation in PMD. Transgenic mice carrying multiple copies of PLP mimic the phenotype of PLP duplications found in the classical form of PMD.
At a cellular level, the extent of pathophysiology in PMD/SPG2 can be correlated with the type of mutation in the PLP gene. In the most severe mutations (the connatal form of PMD), nascent PLP and DM20 accumulate in the rough endoplasmic reticulum of oligodendrocytes and trigger apoptosis. Less severe mutations spare DM20, which can traffic to the sites of myelin assembly and participate in myelin sheath formation. Abnormal PLP and DM20 proteins generate phenotypes that span the PMD/SPG2 spectrum, while either too much or too little of these lipoproteins leads to intermediate phenotypes, such as the classical form of PMD or the complicated form of SPG2.