To get started you can go to Go to interrett.org.au

Take the Quick Link to Join InterRett

and fill in the blanks and submit.

If your child has MECP2 Duplication, be sure to click on “Yes, has duplication” Once you submit this, you will receive consent forms and complete information.

For reservations:
www.houstonplaza.hilton.com Phone: 713-313-467 : Group Name:   MECP2 Duplication Syndrome Meeting; Group Code:    MDS
Please contact Pam Albert for more detailed hotel information at :  mecp2dup@live.com
Contracted rate: $109/night per 2 room suite. Price listed above does not include 17% taxes.

MeCP2 is another substance that appears to play an important role in epigenetics. Research on MECP2 is important not only for a better understanding of Rett syndrome and MECP2 duplication syndrome, it is also important for a better understanding of normal physiological function. This is important, because Rett and MECP2 duplication syndromes are relative rare conditions, that might have difficulty attracting much research interest or much research funding. The fact that MECP2 research has the potential to move our basic understanding of epigenetic and might have a role in treating a much larger group of conditions, plays an important role in attracting research interest and research dollars.

Now, a new study published in Cell, a scientific journal focusing on molecular biology, appears to tie together research on 5hmC and MeCP2. There is a good summary of this research by Kelly Rae Chi on the Rett Syndrome Research Trust website. While the long-term influence of this study is hard to predict at this time, it has the potential to attract more research interest into the MECP2 gene and to be a step toward a better understanding of Rett syndrome and MECP2 duplication syndrome and might even be a first step toward identifying possible treatments.

There is also a great 8 minute audio clip of an interview with the researcher in fairly plain and understandable English.

To listen go to http://www.cell.com/

Go down the page to the section on “MeCP2 and 5hmC: A Cell-Type-Specific Epigenetic Code” and the play the “Paper Clip” audio

This research may help understand how MECP2 can up-regulate some functions and down-regulate others, by binding to both 5mC and 5hmC, if binding to one causes up-regulation and to the other causes down-regulation.

First, in May 2011, when families  got together in Houston for the first MECP2 Duplication Syndrome Family Conference, some of the researchers were surprised at the number of affected individuals who had experienced bone fractures.

Second, osteoporosis and problems with fractures have been identified as a problem among children and adults with Rett syndrome. While it doesn’t automatically follow that a characteristic of Rett syndrome is automatically a characteristic of people with MECP2 duplication syndrome, experience tells us that there is a strong similarity between the characteristics of each of these syndromes.

Third, although they are not consistent, there have been many reports in the literature of somewhat unusually shaped hands, feet, or skulls among children with MECP2 duplication syndrome. These could related to issues in bone formation.

Finally, an article in Human Medical Genetics in 2010, Brazilian researchers reported problems in the formation of bones in MECP2 Duplication mice.

Taking all of these things together, it is probably reasonable to conclude that it is likely that individual with MECP2 Duplication Syndrome have problems with developing or maintaining bones, although more conclusive research may be needed to reach a firmer conclusion.

If, in fact, children and adults with MECP2 Duplication Syndrome do have problems with bone density and bone fragility, we might ask: “is this a direct effect of MECP2 Duplication and overexpression of MECP2 or whether it is secondary to some other factor or multiple other factors?”

There may be a number of contributing factors that contribute to the problem. For example, many individuals with MECP2 Duplication Syndrome take medications that are known to interfere bone density. Exercise and muscle tone also contribute to bone strength. Low muscle tone and lack of activity may reduce bone strength. Some children with MECP2 Duplication Syndrome may also have poor dietary intake of calcium and vitamin D, and some may have limited exposure to sunlight reducing Vitamin D production in the body.

Nevertheless, it is unlikely that all the bone density and fracture problems in children and adults with MECP2 Duplication Syndrome are due to these other issues.

The previously mentioned article on pre-and postnatal development in mice with MECP2 duplications reported serious issues with bones that began before birth. These malformations of bony structures could not have resulted from diet, and did not seem to be secondary effects from neurological or muscle effects of MECP2 duplication. The authors felt that they were most likely the effects of MECP2 overactivity in osteoblasts, the cells that build bones. According to Alvarez-Saavedra and colleagues (2010):

We found that TM20dTg mice displayed diminished ossification resulting in severe kyphosis, a distorted sternum, spina bifida and a deformation in the base of the skull. These data suggest that the dysmorphic features seen in MeCP2 duplication and triplication patients might be the result of improper ossification due to MeCP2 dysfunction in skeletal tissues.

Previous research has found that Rett syndrome with MECP2 underactivity directly affects bone development.  While one might not expect underactivity and overactivity to have the same effects, this demonstrates that MECP2 plays some role, and many otehr symptoms of Rett syndrome are very similar to effects of MECP2 Duplication Syndrome.

Considering this evidence, it is a reasonable hypothesis that MECP2 Duplication directly results in problems in the development of bones and that this leads to a vulnerability to bone fractures among people with MECP2 Duplication Syndrome. More research is needed to take this theory beyond the tentative stage, but it appears to be a good working theory at this time.

Nevertheless, even if proven conclusively, a direct genetic effect does not mean that other factors (e.g., lack of normal activity level, side effects of medication, dietary limitations) should be ignored. In fact, attention to possible contributions to the problem from these other factors may be more important because of the genetic factors. In the next, entry on this topic, I will discuss some of these other factors in greater detail, and suggest possible approaches for minimizing risks for fractures.

[1] Alvarez-Saavedra, M., Carrasco, L., Sura-Trueba, S., Demarchi Aiello, V., Walz, K., Neto, J. X., et al. (2010) Elevated expression of MeCP2 in cardiac and skeletal tissues is detrimental for normal development. Human Molecular Genetics, 19(11), 2177-2190.

Distal Duplication Xq This is a broader category that includes MECP2 Duplication Syndrome and also some others caused by gene duplications that don’t include MECP2

dup MECP2 This is a short simple term for MECP2 Duplication Syndrome, but it may be ambiguous. Symptom free carriers DO have dup MECP2 but they do not have MECP2 Duplication Syndrome which refers to the constellation fo symptoms caused by the duplication.

Intellectual Disability X-linked Lubs Type Also note, older versions of these names use (Mental Retardation X-linked Lubs Type) which has been updated to Intellectual Disability with the modernization of terminology, so both versions are still in use.Before MECP2 Duplication Syndrome was clearly identified Lubs described a syndrome that was X-linked and included many of the features of MECP2 duplication syndrome. We didn’t have the precise genetic testing, so it is difficult to say whether it was precisely the same as MECP2 duplication syndrome, but it appears to have been pretty much the same thing. So this might be considered an older less precise name for the syndrome but it is still used in some cases.

Lubs-Arena Syndrome This is another leftover version of the Lubs terminology.

Lubs X-linked Intellectual Disability (Lubs XLID) This is another leftover version of the Lubs terminology. Also note, older versions of these names use Lubs X-linked Mental Retardation (Lubs XLMR), which has been updated to Intellectual Disability with the modernization of terminology, so both versions are still in use. For many of us Mental Retardation  is a stigmatized and stigmatizing word, but some people continue to use it, even if it is outdated. (They same people probably still call their cars horseless carriages.)

OMIM 300260 or OMIM #300260 OMIM stands for Online Mendelian Inheritance in Man. It catalogs genetic disorders and the number of each number far a disorder is unique even when there are multiple names used. The # sign is often used to indicate that it is caused by an extra copy of a gene.

Telomeric Duplication Xq There appear to be some other Xq duplications that do not include MECP2 duplication and produce different symptoms, so MECP2 Duplication appears to be part of this broader category.

Trisomy Xq28

XLID – Hypotonia – Recurrent Infections

Xq28 Duplication Like Telomeric Duplication Xq this refers to a duplication in this region and typically includes MECP2. The X refers to the X chromosome, the q refers to the long arm and the 28 refers to the region. Regions start at 1 where the long and short arms come together and 28 is at the tail end.

This was our experience when our son Dave was born 22 years ago. He arrived pretty much when expected. My wife identified her pregnancy early on, she saw her doctor and the pregnancy was confirmed. So based on when her pregnancy was confirmed, Dave could not have arrived more than 10 days early. The pediatrician who examined him, however, insisted that he had to be at least 6 weeks early based on a physical examination:

Here is what the Doctor found: (1)  low muscle tone, (2) the cartilage in his ears was not fully formed, (3) his breast tissue was not fully formed, (4) his gums were not fully formed and it looked like some teeth could be seen through his gums, (5) there were few creases on the soles of his feet. We were told his physical exam score indicated that he was about 33 or 34 weeks gestation, and that anything else was impossible.

Since then, we have heard very similar stories from some of the otehr families who have children with MECP2 Duplication. So, we are not the only ones who had this experience. But if this is true and it can be verified by research, DOES IT REALLY MATTER?

I  think it might for at least two reasons:

First, if confirmed this is very unusual.  IUGR, Intrauterine Growth Restriction (or Intra-Uterine Growth Retardation), is a well known phenomena. Babies who experience it are small for gestational age. They typically are below typically expected weight and length at full-time birth, but their features are fully developed. This makes it easy to tell the difference between an IUGR baby and a premature baby. That is why doctor simple would not consider that our son was full-term. So, if this is a fairly common finding among babies with MECP2 Duplication Syndrome and extremely rare among others, it could be a valuable sign to help recognize children with MECP2 Duplication Syndrome earlier in life.

Second, if confirmed it may provide some valuable clues into the mechanisms of MECP2 Duplication early in life. Interestingly, some researchers have already suggested that when typical IUGR occurs, it affects the regulation of MECP2, which in turn affects the development of the lungs. The apparent pseudo-prematurity being reported among infants with MECP2 Duplication Syndrome may help better understand the role of MECP2 in prenatal development.

This might be an area of study that could be moved forward quickly in MECP2 Duplication Mice. It would be great to see this on someone’s research agenda.

At this point there seems to be inadequate data to draw a conclusion. However, one research study crossed MECP2 Duplication Lab mice with other lab mice. Simple genetics would have predicted that 25% of offspring would have MECP2 Duplications, but researches found that only 11% of surviving offspring had the duplication (Alvarez-Saavedra et al., 2010). This strongly suggests that MECP2 duplication reduces the chances of fetal survival, but there might be some other explanation. In addition, even if true, the applications of these findings to humans is unclear.

So the question remains open at this time pending further research.

Alvarez-Saavedra, M., Carrasco, L., Sura-Trueba, S., Demarchi Aiello, V., Walz, K., Neto, J. X., et al. Elevated expression of MeCP2 in cardiac and skeletal tissues is detrimental for normal development. Human Molecular Genetics, 19(11), 2177-2190. [e-publication 2010/03/06].

Another study found that about 25% of all individuals are carriers for at least one genetic disorder and almost 6% were carriers of two or more. These percentages also are expected to increase as science progresses. Most of us, however, will not find out about these deleterious gene variations unless our children or grandchildren happen to be affected. So, while we tend to think about people being carriers or not, the real categories may be between who KNOW or don’t know if they are carriers.

Lazarin GA, Haque IS, Nazareth S, Iori K, Patterson AS, Jacobson JL, Marshall JR, Seltzer WK, Patrizio P, Evans EA, Srinivasan BS.  An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. Genet Med. 2012 Sep 13. doi: 10.1038/gim.2012.114.

Here are a few examples of recent news coverage on their activities.

Flemington tricky tray raises $11,190 for MECP2 Duplication Syndrome

Londonderry Township boy inspires ‘ultramarathon’ athlete, who raises money for van

Blake McMillan Trust receive £350 from youngsters

Families have already raised enough to fund one major research project and are making progress toward funding a second. Contributions can be made to the MECP2 Duplication Syndrome Fund at the Rett Syndrome Research Trust.

For those families who took part in the research study at the 2011 MECP2 Duplication Family Conference, your participation played an important role in this study. The MECP2 Duplication mice also play an important role because demonstrating this problem in these mice makes it clear that this is an effect of duplicated MECP2 genes and not other duplicated genes, which may or may not have some additional role.

These research results have the potential play an important part in progress toward preventing and treating infections in individuals with MECP2 Duplication Syndrome.

Tianshu Yang, Melissa B. Ramocki, Jeffrey L. Neul, Wen Lu, Luz Roberts, John Knight, Christopher S. Ward, Huda Y. Zoghbi, Farrah Kheradmand, David B. Corry. (2012, Dec 5). Overexpression of Methyl-CpG Binding Protein 2 Impairs TH1 Responses. Science Translational Medicine, 4 (163), DOI:10.1126/scitranslmed.3004430.