Partial PLP1 deletion causing X-linked dominant spastic paraplegia type 2.

Background: Proteolipid protein 1 gene (PLP1) mutations result in a continuum of neurological findings characterized by X-linked hypomyelinating leukodystrophies of the central nervous system, from mild spastic paraplegia type 2 to severe Pelizaeus-Merzbacher disease.

Patients: We report spastic paraplegia type 2 in three individuals in one family. A 29-year-old man developed progressive spastic quadriplegia from early childhood with dysarthria, ataxia, dysphagia, and intellectual delay, but he displayed no nystagmus. His mother developed adult-onset mild spastic diplegia with dementia developing in later life, whereas his sister exhibited spastic diplegia from childhood, complicated by motor developmental delay and dysphagia. All three individuals had initially mild but progressive neurological phenotypes, no nystagmus, normal brainstem auditory-evoked potentials, and demyelinating peripheral neuropathy, but with varying clinical severity.

Results: A 33-kb deletion encompassing exon 2 to 7 of PLP1 was identified in all three patients. Cloning of the junction fragment of the genomic recombination revealed a short palindromic sequence at the distal breakpoint, potentially facilitating a double-strand deoxyribonucleic acid break, followed by nonhomologous end joining. X-inactivation study and sequencing of the undeleted PLP1 alleles failed to explain the differences in severity between the two female patients.

Conclusions: PLP1 partial deletion is a rare cause of spastic paraplegia type 2 and exhibits X-linked dominant inheritance with variable expressivity.