Pelizaeus Merzbacher disease (PMD) is a rare X linked dysmyelinating disorde r resulting from mutation of the proteolipid protein gene (PLP1). Clinical featu res of PMD include progressive psychomotor developmental delay, nystagmus, spast ic quadriplegia, dystonia, and cerebellar ataxia. PMD is clinically classified i nto three subtypes according to the severity of the disease: connatal, transitio nal, and classic forms. Patients with PMD have been identified with duplication, point mutations, and deletion of PLP1. In addition, spastic paraplegia 2 (SPG2) is allelic to PMD and typically caused by missense mutations in the second extr acellular domain of PLP1 or in the PLP1 specific region that is spliced out dur ing formation of the DM20 isoform. The authors describe a Korean boy diagnosed w ith SPG2 caused by a mutation that results in a Pro215Leu substitution in the se cond extracellular domain. Analysis of phenotypes resulting from mutations affec ting PLP1 has been valuable in identifying functional domains of this still inco mpletely understood major myelin protein. Null mutations and mutations affecting the PLP1 specific domain cause peripheral neuropathy. The PLP1 specific domai n also is important in the long term maintenance of axonal integrity. This pati ents phenotype was relatively mild, in contrast with other mutations at positi on 215 of PLP1 that cause severe PMD. One of these severe mutations is also a mi ssense mutation substituting an aliphatic residue, alanine, for proline. The dis tinct severity difference between the Pro215Leu and Pro215Ala substitutions sugg ests that this region of the protein is very sensitive to subtle structural chan ges and likely plays a critical role in PLP1 function.
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