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Pelizaeus-Merzbacher Disease (PMD) can be caused by duplication, mutation, or deletion of the proteolipid protein gene 1 (PLP1). Duplications have been detected in approximately 50% of cases and mutations have been detected in approximately 25%. Several cases of complete deletion of the PLP1 gene have been reported. Pelizaeus-Merzbacher-like disease (PMLD) is clinically indistinguishable from PMD. It is caused by mutations in the connexin 46.6 (GJA12) gene. The incidence of PMLD is not yet known. For the remainder of patients, a "molecular" diagnosis has not been determined. Some of these patients may have a mutation in a region of the PLP1 gene or the connexin 46.6 gene that has not been tested, while others may have a mutation in another gene. A condition that is closely related to PMD, X-linked spastic paraplegia (SPG2), can also be caused by mutations in PLP1.  Click here for up-to-date information about PLP1-related diseases.

Detection of duplications

There are two basic methods for detecting duplications. One is a quantitative "PCR" approach. PCR stands for polymerase chain reaction, and it is a way to amplify a region of a gene. We can tell how many copies of PLP1 a boy has by amplifying a region of the PLP1 gene along with a region of a gene that is not duplicated. A boy with duplication of PLP1 (two copies of the gene) has double the ratio of that in a normal boy. The other method is called FISH, which stands for fluorescent in situ hybridization. In this method, we use a "probe" that will stick to the PLP1 gene and not to any of the other genes. Using a microscope, we can see where the probe is stuck inside the nucleus of a cell because the probe is fluorescent. In boys with a duplication of PLP1 we see two fluorescent spots in each cell where the probe has stuck, while in normal boys we see only one spot.

Detection of mutations

To understand detection of mutations, you need to have a basic understanding of what a gene is. Each gene contains the genetic code that tells cells how to make a specific protein. The genetic code is made up of a string of bases that are represented by the letters A, C, G and T. This string of bases represents a small region of the PLP1 gene: TAGGACATCCCGACAAG. A mutation is a mistake that gets made when the string or sequence gets copied as cells divide. A base can get changed to a different base in the sequence (TAGGACATCCCGACAAT). One or more bases can get added to the sequence (TACCGGACATCCCGACAAG). One or more bases can get deleted from the sequence (TAGG^^^^^CCGACAAG). If this happens, the instructions for making the PLP1 protein or the GJA12 protein are wrong and PMD, SPG2, or PMLD can result. To detect mutations, we use a method called "sequence analysis," that allows us to detect the sequence of bases of the PLP1 gene.

ORDERING TESTS FROM CLINICAL TESTING LABS

CLINICAL TESTING for Pelizaeus-Merzbacher Disease is done as part of a medical diagnostic evaluation, just the way, for example, that blood sugar or cholesterol testing is routinely done. These labs comply with the Clinical Laboratory Improvement Act (CLIA) and must meet federal quality standards. These labs charge a fee for testing and results are provided in writing. It is important to understand that the methods used in clinical testing can vary from lab to lab - and only the most important part of the PLP1 gene (the part that codes for the protein, or the "exon") is examined. Prenatal testing may be offered by the lab.  Labs that offer testing for PMD are listed on the Genetests website, and are required to update their information every year.  

Please click here to get contact information on labs that perform testing for PMD.

Please click here to get contact information on labs that perform testing for PMLD.

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