Neuropathology and genetics of Pelizaeus-Merzbacher disease

Abstract

The recent history of Pelizaeus-Merzbacher Disease (PMD) demonstrates paradigmatically the impact of basic biological research on clinical neurology and brain pathology: this rare and peculiar hereditary disease has become one of the best known disorders of its kind, through a cooperative research effort in neuropathology, human genetics, neurochemistry and molecular biology. PMD, a genetic dysmyelination restricted to the CNS, has been identified as a disease that involves the X chromosome-linked gene for myelin proteolipid protein (PLP), a major structural myelin component. Today more than 30 different mutations in this gene have been defined and associated with PMD or the clinically distinct form X-linked spastic paraplegia type-2 (SPG-2). Improved scanning techniques, specifically the non-invasive magnetic resonance imaging (MRI), allow its early diagnosis in the heterogeneous group of CNS myelin deficiencies. These remarkable achievements have, at the same time, caused a problem for disease classification. Myelin disorders have been grouped in the past on the basis of clinical and neuropathological criteria, creating a system that has now to be reconciled with molecular-genetic data.