Novel exon 3B proteolipid protein gene mutation causing late-onset spasticparaplegia type 2 with variable penetrance in female family members

Spastic paraplegia type 2 (SPG2) is allelic to Pelizaeus-Merzbacher disease (PMD), with both conditions resulting from mutations in the proteolipid pr otein gene (PLP). We report an SPG2 family in which 3 male members and a he terozygous female member were affected with spastic paraplegia characterize d by relatively late onset and mild clinical manifestations. A unique H147Y mutation in exon 3B of the PLP altering the proteolipid protein (PLP) but not the alternatively spliced DM20 isoform was identified as the cause of t his distinct disease phenotype. Cellular pathology studies of SPG2 mutation s offer an explanation for the paradoxical finding that mutations associate d with the mildest phenotype in male family members also affect female carr iers.