The syndrome was first discovered in 2005.
The MECP2 Duplication Syndrome is usually caused by duplication of DNA on the Xq28 region of the chromosome. Most reported duplications are sub-microscopic (cannot be seen with a microscope by standard chromosome analysis) and span 0.3 to 4 megabases of DNA in size. Many cases of “functional disomy” of the Xq28 region (meaning an extra copy of the Xq28 region that occurs somewhere other than directly at Xq28) due to chromosome Xq-Yq translocation, chromosome Xq-Xp rearrangements, and chromosome X-autosomal chromosome translocations have also been reported. Many of these cases were reported before the name “MECP2 Duplication Syndrome” was assigned.
MECP2 Duplication Syndrome is most commonly inherited in an X-linked manner. Most affected males have inherited the MeCP2 duplication from a carrier mother, however, spontaneous (also known as de novo) duplications have been reported. If the mother has a MECP2 duplication, the chance of transmitting it in each pregnancy is 50%. In the case of de novo duplications, the possibility exists that the mother can have mosaicism and therefore only carry the duplicated X chromosome in her ova or egg cells (or only in some of these cells). Because ova or germ-line mosaicism cannot be ruled out in de novo cases, the risk to subsequent pregnancies in de novo cases is approximated to be about 5%. Because the duplication affects the X chromosome, MECP2duplication syndrome occurs in all males who have the duplication. In females who have symptoms, it is thought that the X chromosome with the duplicated allele is active in a number of cells (one copy of the X chromosome is turned off in every somatic cell in females, a normal process called X chromosome inactivation).
When MECP2 Duplication Syndrome results from a duplication that is present on the Y chromosome, or one of the autosomes (chromosomes 1-22), then it is important to assess if either parent is a carrier. To date, no cases of men transmitting the duplication have been reported. This is because, as far as we know, all boys/men who have the duplication have MECP2 Duplication Syndrome. Therefore, in the majority of boys who have the duplication syndrome due to the Xq28 duplication being present on the Y chromosome, the duplication event likely occurred spontaneously when the sperm developed in the father. Just like in females, however, men can have germ-line mosaicism, and so the risk to subsequent pregnancies in de novo cases is estimated to be 5%. If the Xq28 duplication is carried on one of the autosomes, then the duplication may be de novo, carried by the mother, or be a result of germ-line mosaicism.
The Xq28 region contains several genes, and one of these is MECP2(methyl-CpG binding protein 2). The beginning and end of the duplicated region (breakpoints) vary among different individuals, but the finding that MECP2 is the only duplicated gene in all patients with a significant role in the nervous system supports its important role in causing MECP2 Duplication Syndrome. Furthermore, genetically engineered mice that have twice the normal levels of MeCP2 protein develop the features of the duplication syndrome. These studies pinpoint increased levels of MeCP2 (rather than other proteins) as the culprit of this syndrome. This is why the syndrome is now called “MECP2Duplication Syndrome.”
It is important to note however, that some boys have larger duplications that include many other genes. The full extent of phenotypes due to duplication of other genes is not completely understood. We do know, however, that boys who also have duplication of the Filamin A (FLNA) gene are at risk for intestinal pseudo-obstruction and perhaps other phenotypes that have been associated with other types of mutations inFLNA. Therefore, it is helpful for all boys with MECP2 Duplication Syndrome to have a study to map the extent and gene content of their duplication. When detailed studies are performed, some boys are found to have triplication of Xq28 which appears to result in a syndrome that is more severe, especially when the MECP2 gene is included in the triplicated region. Finally, some cases of duplication of Xq28 actually have breakpoints (ends) that are located within the MECP2 gene. In these cases, it may be that disruption of one copy of the MECP2 gene, rather than duplication, causes the phenotype.
Characteristics of MECP2 duplication in affected boys:
*As a result of hypotonia, motor development including sitting, crawling, and walking is severely delayed or impaired
*Mental retardation (in 100%)
*Recurrent respiratory infections (in 75%)
*Epilepsy (in 50%)
*Constipation and/or reflux
*Limited or absent speech
*Progressive spasticity (usually noticed in the legs more than the arms)
*Stereotyped movements of hands
*Developmental regression occurs in some boys
Characteristics of FLNA duplication:
*Perhaps other problems