Pelizaeus-Merzbacher disease (PMD)
Incidence
PMD is an X-linked leukodystrophy. It is best to restrict the term Pelizaeus-Merzbacher disease to patients with X-linked inheritance of the classic or connatal form of the disease.
Clinical Characteristics
Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy characterized by nystagmus, ataxia, choreoathetosis, spasticity, and mental deterioration. Typically, PMD has an onset in early childhood but earlier onset in the first 3 months of life is noted in the more severe connatal form. Typically, Pelizaeus-Merzbacher has an onset in infancy or early childhood. The classic clinical features in affected males include eye rolling; nystagmus, which can be vertical, horizontal, or rotary; intermittent nodding; side-to-side tremor of the head; and poor head control. The infants are usually floppy early on and have significant psychomotor delay; speech typically does not develop, and patients are unable to walk. Choreoathetosis is a common clinical finding and, like the head tremor, it disappears during sleep. As the child matures, nystagmus disappears and cerebellar ataxia, spastic quadriparesis, and bowel and bladder dysfunction become apparent. The disease often progresses to cause death in late adolescence or young adulthood, although there are patients who survived until the sixth decade.
Precipitants
None
Provocation Tests
none
Diagnostic Procedures
Diagnosis: The diagnosis of Pelizaeus-Merzbacher disease is usually made on the basis of histopathological findings in the brain. The first report on the neuropathological findings was by Merzbacher in 1910, who found diffuse symmetrical white-matter atrophy that originated at the ventricular surface and spread peripherally. The myelin sheaths were severely affected with little islands of sparing, and the cerebellum and brain stem were found to be reduced in size. Additional neuropathological studies confirmed the earlier findings reported by Merzbacher. Typically, the brain was shrunken, particularly in the cerebellum and brain stem, and the white matter was atrophic and sclerotic. Lack of oligodendrocytes was apparent, and astrocytes were normal to increased, suggestive of gliosis. Discontinuous parts of preserved myelin islets were detected in the demyelinated areas; these were frequently found perivascularly as zones of preserved myelin along stretches of blood vessels, hence giving rise to the characteristic "tigroid" appearance. The Kleberg Cytogenetics Laboratory at Baylor offers a fluorescence in situ hybridization (FISH)-based assay for identifying the duplication of the proteolipid protein (PLP) gene associated with Pelizaeus-Merzbacher disease (PMD). FISH is the application of fluorescently labeled DNA molecules to metaphase chromosomes and interphase nuclei for the detection of chromosome abnormalities and alterations. It is a rapid, reliable and direct approach for identifying patients with microdeletions or microduplications. In most cases, (60-70%) PMD is caused by a duplication of the proteolipid protein (PLP) gene, located on Xq22. Many of the remaining cases (~30%) have point mutations or other mutations in the PLP gene, not detected by FISH.
Demyelination of the gray matter was also noted, indicating involvement of the myelinated fibers in that area. The neuropathological findings in the connatal form are similar to those in the typical cases except that demyelination is more extensive, involving all parts of the brain so that not a single myelinated fiber can be found. The myelin is replaced by fibrillary gliosis, the number of oligodendrocytes is reduced, and the number of reactive astrocytes is increased. For families for whom molecular data are not available, the diagnosis can be made based on clinical findings, pattern of inheritance, neuroimaging, and histopathological studies when available.