Pelizaeus-Merzbacher Disease In Female Carriers

Pelizaeus-Merzbacher disease (PMD) in female carriers is the presentation of PMD (see this term) in some women carrying mutations in the PLP1 gene (Xq22).

Epidemiology

Prevalence is unknown.

Clinical description

Heterozygous females are not usually affected in families with the more severe PMD forms, including classical, transitional and connatal forms (see these terms), but are more likely to develop symptoms, possibly during adulthood, in families with more mildly affected males, such as in the null syndrome and SPG2 kindreds (see these terms). In some of the families with more severe male phenotypes, heterozygous females may manifest transient neurologic signs similar to those of boys with PMD, but from which they recover as they reach late childhood or adolescence.

Etiology

PMD is due to mutations or dosage alterations of the PLP1 gene (on Xq22) that cause hypomyelination of the central nervous system. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20). PMD is inherited as an X-linked disorder, usually with only males being affected. With the severe forms of the disease, oligodendrocytes undergo apoptosis. In heterozygous females, the degenerating oligodendrocytes are replaced by oligodendrocytes that have inactivated the mutated PLP1 allele. Therefore, unless there is severely unfavourably skewed X-inactivation, such females will be unaffected, and the disorder will have an X-linked recessive inheritance pattern. In contrast, in families where the PLP1 mutation causes little or no oligodendrocyte apoptosis, such as in the null syndrome, the defective oligodendrocytes survive in heterozygous females, who are more likely to have neurologic signs, typically later in adult life. In such cases, the disorder can be argued to have an X-linked dominant transmission pattern with variable penetrance.