This entry starts a short series on bone density and risk of fractures in children and adults with MECP2 Duplication Syndrome. May be a good place to start is to say that bone density issues are not well recognized as a characteristic of MECP2 Duplication Syndrome. Nevertheless there are a number of reasons to suspect that bone density issues and fractures are special concerns for individuals with MECP2 Duplication Syndrome.
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.
 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.