Familial Pelizaeus-Merzbacher disease caused by a 320.6-kb Xq22.2 duplication and the pathological findings of a male fetus.

Background: Pelizaeus-Merzbacher disease (PMD) is a recessive, X-linked leukoencephalopathy attributed to impaired myelination during central nervous system development, caused by defects in the proteolipid protein 1 (PLP1) gene. PMD presents clinical variability, ranging from the severe connatal form to the classic form.

Cases: We report the clinical and molecular findings of two affected males, three carrier females, and an aborted male fetus with familial PMD. The two male probands presented with severe PMD phenotype and intellectual disability. High-resolution oligonucleotide-based array comparative genomic hybridization (aCGH) identified an Xq22.2 duplication of 320.6 kb (102641391-102961998, hg18), including the PLP1 gene and surrounding chromosomal region. Postmortem examination of the aborted fetus at 25 weeks' gestation showed focal subcortical white matter degeneration, focal gliosis, and cerebellar atrophy.

Conclusions: Genotype-phenotype correlation is provided. In the connatal form of PMD, leukodystrophy and cerebellar atrophy can occur antenatally and be established at 25 weeks' gestation. The observation of degenerative brain lesions occurring before the onset of subcortical myelination suggests that the PLP1 gene has a more complex role in human brain development, exceeding its structural function in myelin formation.