PMD and other hypomyelinating leukodystrophies

Pelizaeus-Merzbacher disease (PMD), so named after the two German doctors who first described the disease, is a rare condition caused by mutations in the gene responsible for making the protein proteolipid 1 (PLP1, formerly called PLP), the main myelin protein in the central nervous system.

Genetics of PMD

Two main aspects of the disease are important in understanding the disease. The first is the genetics of PMD and the second is related to the effect of PLP1 mutations on the nervous system.

Genetic diseases such as PMD occur when there is a change or mutation in the basic material of the body. This basic material, called genes, codes for the proteins that make up much of the body and control how it works. Most genes come in pairs. One pair’s gene comes from the mother and the other from the father. Among the tens of thousands of pairs of genes, a pair can sometimes be modified or mutated. The mutation can be inherited from the parents or can arise spontaneously. Sometimes a mutated gene may not be a problem. Other times, the mutated gene will cause a genetic disease like PMD. Genes are carried by chromosomes. The chromosome can be thought of as a library and the gene as a book in the library. DNA (deoxyribonucleic acid) bases are the chemicals that make up genes and are like the letters in a book. Genetic information is stored and passed on from generation to generation in the form of DNA sequences. There are 46 chromosomes in humans. Chromosomes come in 23 pairs, the first 22 pairs are the same in males and females. The last pair represents the sex chromosomes: women have two X chromosomes while men have one X chromosome and one Y chromosome.


Because the PMD gene is located on the X chromosome, the disease typically affects only boys or men in a family. This is referred to as X-linked transmission. Remember that women have two X chromosomes while men have one X chromosome and one Y chromosome. If a gene on the X chromosome does not work properly, men will be affected more often than women since women probably have one normal copy of the gene on the other X chromosome which usually compensates for the defective X chromosome. Women carrying the PMD gene are therefore not typically affected since the PLP1 gene on the other X chromosome is normal.

Men with PMD usually cannot have children, which is why the disease is usually passed on from women who are said to be carriers of the PMD mutation. Women carrying the PMD gene have a 1 in 2 chance of passing it on to their sons and daughters. This chance is the same for each pregnancy. What happens in one pregnancy has no influence on the next pregnancy. Sons inheriting the gene will be affected while daughters will be carriers. If a girl does not inherit the PMD gene, she will not pass PMD to her children. Women who are carriers rarely develop neurological problems. In women whose male relatives have relatively mild symptoms of the disease, there is a risk.

The other important aspect of PMD is understanding how different mutations disrupt cell function. The main types of mutations are:

1) PLP1 duplications

2) pPoint transfers

3) Null mutations.