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Yes, there are cases of girls who have a duplication of Xq28 that includes MECP2 that is translocated to an autosome (non-sex chromosome; remember, MECP2 is normally located on the X chromosome). When the duplication is present on an autosome, it is not subject to X chromosome inactivation and will result in the same syndrome that is typically observed in boys.

There are many reports in the literature suggesting that females who carry MECP2 duplications on the X chromosome are “normal” or “asymptomatic,” but no objective study had been performed to formally test this notion.

We thought it would be naïve to assume that carrier females are completely unaffected. It took some time to learn, for example, that female carriers of the X-linked Duchenne or Becker muscular dystrophy are at risk for dilated cardiomyopathy. But because of this knowledge, clinicians are able to screen for signs of heart failure and provide appropriate counseling and treatment to this group of women.

So we examined the female carriers of MECP2 duplications more closely. Among the eight women available for the study, we noted a significant tendency to autoimmune and endocrine disorders. We also found that their intelligence can range from normal to superior, but they also show some tendency to depression, anxiety, compulsions that predated the birth of a child with the duplication. Psychological testing (the Broad Autism Phenotype Questionnaire) revealed signs of rigid personality and difficulty with the social use of language, along with a tendency to have higher scores in nonverbal as opposed to verbal reasoning.

Whether these traits are due to their carrier status is uncertain: first, the traits are all present in the “normal” population, and second, the women expressed normal levels of MeCP2 mRNA and showed 100% skewed X inactivation, meaning that the chromosome containing the duplication is not expressed. Nevertheless, among women who seek therapy for such traits, it is important to consider the possibility of MeCP2 duplication syndrome and to make an accurate diagnosis because of the risk of having boys with the duplication syndrome. Based on our current knowledge, clinicians should definitely consider this syndrome when evaluating a woman who provides a family history of X-linked mental retardation and/or early male deaths due to pneumonia, GI problems, or unexplained causes.

 


The 1st MECP2 Duplication Syndrome International Family Conference took place from May 25-May 27, 2011 in Houston, Texas.

The second conference took place March28-March 30th, 2013 in Houston TX.


We are conducting studies to establish whether symptoms are reversible in the duplication mouse model.

The problem with trying to treat a neurodevelopmental disease in humans, however, is that we can never give back to a child or adult the years of social and developmental milestones that he or she missed. Nevertheless, we may one day be able to intervene so that individuals can make better intellectual progress, develop better motor and language skills, have fewer effects from epileptic seizures, and/or suffer fewer infections.

It is important to realize that it is impossible to predict which line of research will produce results that lead to viable treatments. Speaking even more broadly, the vast majority of Nobel laureates in the sciences and members of the National Academy of Sciences play musical instruments or pursue a visual art at a high level of skill. Who are we to say that the creativity and craft they developed in the arts did not spur their scientific creativity?  We can never know where the next great idea might come from, or when a new approach might yield a viable treatment.


We know that too much or too little MeCP2 protein is bad for the brain. Because of the brain’s sensitivity to the right level of MeCP2, therapies that directly target the MeCP2 protein run the risk of overshooting or undershooting the mark. Furthermore, any drug that will be useful needs to be able to penetrate the blood-brain barrier. It is likely that randomized clinical trials that target some symptoms or aspects of the disorder will be available in the near future, but specific therapies that circumvent the action of the MeCP2 protein in the brain are likely still many years away. The fact that the neurological symptoms in a mouse model lacking MeCP2 were at least partially reversed when MECP2 expression was restored provides hope for viable treatment options.


We know from human studies that duplication of the MECP2 and IRAK1 genes as well as part of an adjacent group of genes encoding proteins important for color vision (the smallest region of overlap among affected patients) is sufficient to cause the core neurological and immunological aspects of the syndrome. Duplication of other genes in this region of the X chromosome such as the FLNA gene may cause other, more variable aspects of the syndrome.


We do not yet know the cause of the vulnerability to infection in these children.  It could be partly mechanical (for example, the boys’ hypotonia combined with tendency to drool may mean they frequently aspirate saliva into their lungs); it could be that there is a subtle endocrine component (hypothyroidism, which is prevalent among carrier females, increases susceptibility to respiratory infections). The only approach we can currently recommend in boys with MECP2 duplication syndrome is to recognize the onset of illness promptly and provide early antibiotic treatment with a change to pathogen-specific treatment as soon as possible. In other words, it is very important to try to determine and to treat the cause of the infection as early as possible.

We recommend that all children with the syndrome have an evaluation with a pediatric immunologist. If infection history and risk factors documented via laboratory testing suggest that a child is at great risk, then the immunologist may recommend sub-cutaneous immunoglobulin therapy, preventive antibiotic treatment (though this carries its own risks of disrupting the microflora in the gut), and/or to limit exposure to the public. We hope that with further studies, we will have a better answer to this question.


Duplication means that the region of the chromosome containing the MeCP2 gene was inadvertently duplicated (or sometimes triplicated) during a faulty recombination event when the earliest cells were dividing.  Mouse studies also showed that doubling MeCP2 levels produces all the problems observed in human patients, indicating that the main cause of the syndrome is the duplication of MeCP2 and not just other genes that might be included in the same genomic region.


There are several different methods that can be used to test for increased copy number of the MECP2 gene. These methods include high resolution chromosome microarray analysis, chromosome microarray SNP analysis, FISH analysis, quantitative PCR analysis, Southern blot analysis, or MLPA analysis. Depending on the clinical situation and your medical insurance, your physician will decide which of the tests is the appropriate test to order.

It is best that the initial screening test(s) be performed in consultation with a geneticist or pediatric neurologist. Depending on the age of the child and his/her clinical signs and symptoms, there may be additional metabolic or genetic tests that should be performed. Typically the diagnostic lab will double-check a positive result by confirming the genomic alteration with a second testing method. If your doctor would like more information about the syndrome or what testing is available, then please refer him or her to the NIH Gene Tests web-site using the following links:

The link to the page that discusses the MECP2 duplication syndrome
(written by Dr. Van Esch)

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mecp2-dup#mecp2-dup.Molecular_Genetics

The link to the page that shows options for specific genetic testing
(This page does not include information about microarray-based testing. Insurance companies typically contract with a specific lab to provide this service.)

http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/297387?db=genetests

The link to the general Gene Tests search page is:

http://www.ncbi.nlm.nih.gov/sites/GeneTests/review?db=GeneTests

 


Most cases (95%) of Rett syndrome are caused by mutations in the MECP2 gene that cause the MeCP2 protein to not be able to perform all its functions (or any of them). In other words, Rett is caused by too little MeCP2, while duplication syndrome is caused by too much.

Girls with Rett syndrome have a period of apparently normal development until around age 6-18 months when they lose acquired language skills, social interaction skills, and motor skills. They develop characteristic hand stereotypies such as hand-flapping or hand-wringing, anxiety, microcephaly, epileptic seizures, and impaired motor and autonomic control.

There are rare boys who have Rett syndrome (for example, if they also have Klinefelter syndrome and so have an extra X chromosome that happens to carry a mutant MECP2). In this regard, MECP2 duplication syndrome is the opposite of Rett syndrome, as it primarily affects boys, but rare girls are affected.

Boys with MECP2 duplication syndrome do not have normal development as their motor skills are typically delayed from birth (e.g., low tone and difficulty feeding). Similar to Rett syndrome, however, boys affected with MECP2 duplication syndrome can still undergo regression, and they show intellectual disability, motor deficits, and autistic features including poor to absent expressive language, stereotyped and repetitive behaviors (often including midline hand stereotypies), and significant deficits in reciprocal social behavior. Many boys also develop epilepsy, severe gastroesophageal reflux, constipation, and autonomic symptoms similar to girls with Rett syndrome.

The recurrent infections and problems that occur in other organ systems in many boys with MECP2 duplication syndrome are not typically seen in Rett, perhaps because girls with Rett have 50% of their cells with a healthy dose of MECP2. These problems may also be due to other genes in the duplication region such as FLNA.


Approximately 120 cases of boys with MECP2 duplication syndrome have been published, but the true number of males and females who have Xq28 duplications spanning MECP2 is much greater.


Yes, we are aware of a handful of cases of MECP2 triplication. These boys have the same problems as boys with MECP2 duplication but their problems are much more severe.


A De novo duplication means it is neither in the DNA of the mother nor the father.  It can only be established that the diagnosis of a MECP2 duplication (or any genetic defect) is de novo after the biological parents of the child with MECP2 duplication have been tested and the duplication is not found in their DNA.  Fathers typically are not carriers, because they would have MECP2 duplication syndrome themselves and would not be able to father children. If the mother is not a carrier then the recurrence risk is very low, close to that of the general population.  However, there is a very small chance that a mother or father can have a mosaic genetic change (i.e. mosaic duplication), whereby only a few cells in their body have the duplication. In that case, if those cells include some of the mother's eggs or some of the father's sperm, they could pass on the duplication to their children.  [A father with a mosaic change can only pass on the change to his daughters, who can be carriers. A mother with a mosaic change can pass It on to a son or a daughter]. Such a mosaic change is often not detectable in the parents' blood. The only sure way to exclude this latter possibility is by performing preimplantation or prenatal genetic testing in a future pregnancy.


A carrier female has two X chromosomes: one that is intact and one that has a  duplication spanning MECP2. The risk of passing the X chromosome with the duplication is 50% (1/2) for each pregnancy. This means that a carrier female has a 50% chance of having another boy with the duplication and hence he will have the syndrome, and a 50% of having  a girl with the duplication. Depending on patterns of X chromosome inactivation, the girl might develop symptoms of the syndrome or might be a carrier like the mother.

It is also important to consider that women who carry a MECP2 duplication may have inherited this themselves. If they have sisters, they may also be at risk of carrying the duplication and pass it on to their children.  It is recommended that women carrying the duplication have genetic counseling to find out if other family members may be at risk. The genetic counselor can provide information and help them make decisions on how to notify their family members of this potential risk.


If a boy has a duplication that he inherited from his mother, each of his sisters has  a 50% risk of being a carrier. If the daughters of carrier mothers are healthy, testing can be postponed until they are of childbearing age, or otherwise mature enough to make this decision and wish to know. If they have neurological symptoms, testing might help discern if the symptoms are due to the duplication. It is recommended that families speak with a genetic counselors before considering testing healthy daughters of mothers carrying a MECP2 duplication.


We do not yet know. In some neurodevelopmental disorders, seizures and regression go hand in hand, suggesting that there is something about the underlying disease mechanism that causes both to co-occur. Medications can cause regression, but in most cases, the regression improves when the medications are stopped. In most instances with MECP2 duplication syndrome and regression, I do not think that medications are the culprit. Not all individuals with this syndrome develop epilepsy and regression early in life, but all boys seem to lose motor skills as they age. We need detailed clinical studies to better understand the natural history of the disease over time.


It is a syndrome that is caused by an extra copy of some of the genetic material on the X chromosome that spans the MECP2 gene, which in turn causes problems with learning and memory, motor control of the body, seizures, and recurrent infections.

MECP2 Duplication Syndrome was not formally recognized until 2005.

 


The MECP2 gene provides instructions for making a protein (MeCP2) that is essential for normal brain function. This protein seems to be important for the function of almost all nerve cells and support cells in the brain and is present in high levels in mature nerve cells.

Studies suggest that the MeCP2 protein plays a role in forming connections (synapses) between nerve cells, where cell-to-cell communication occurs. This protein orchestrates how the DNA and some other specialized proteins interact when nerve cells are stimulated to insure that the cells are responsive and that they express the right amount of genes at the right time to do their functions.

 


The official name of this gene is “methyl CpG binding protein 2.”


The MECP2 gene is located on the long (q) arm of the X chromosome at position 28.


~Answers provided by Dr. Huda Zoghbi and Dr. Melissa Ramocki.~