Rett- Research:

Do you know what hope is? 
It's reaching past today
It's dreaming of tomorrow  
It's trying a new way
It's pushing past impossible
It's pounding on the door
It's questioning the Answer 
It's always seeking more.

Do you know what hope is?
It's rumors of a breakthrough
 It's whispers of a cure
A rollercoaster ride
Of remedies unsure

Do you know what hope is?
 It's candy for the soul
It's perfume for the spirit

To share it makes you whole

The discovery of the
 responsible gene of
 Rett-Syndrome allows research
 projects which can contribute
 to a better understanding of
 the disease and possible therapies.

At the moment a concrete german research project cannot be realized, due to the lack of financial resources.
This project could offer an approach of a therapy-possibility.
 Of course it is a research project with many 
question mark  which must be worked out.
Without the right financial resources, this will be impossible.

 And in course of the application of these resources 
at European level, vluable time is lost.
Please support this project with a donation.
It can be a contribution to a better live of a lot of these girls. 

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What does this discovery mean?

What makes this discovery so important?

What made the discovery so difficult?

How are genetics involved in Rett-Syndrome
Can males have Rett-Syndrome? 

What goes wrong in Rett- Syndrome?


What does this discovery mean?
A biological marker that may give a molecular diagnosis!
Note: Mutations in MeCP2 will not be equivalent to a diagnosis 
of Rett syndrome alone; RETT is clinically defined, 
while MeCP2 mutations are found in individuals who do not 
meet the clinical criteria for RS; they can be either more mildly 
or more severely affected (i.e. without a period of normal early development. )
A prenatal test to detect RS in families with an affected daughter 
(though the risk is less than 1%).
A test for sisters of girls with RS to determine if they are 
asymptomatic carriers.
A basis for developing strategies to prevent the 
disabling effects of Rett syndrome.


What makes the discovery so important?

Rett syndrome is the first human disease found to be caused 
by defects in a protein involved in regulation of gene 
expression through its interaction with methylated DNA. 

This discovery has revealed a new class of genetic 
disease that might extend far beyond RS and apply to other 
neurodevelopmental disorders, but much more research 
must be done before such a connection can be established.


What made the discovery so difficult?

The 23 human chromosome pairs carry some 
100,000 genes. 

Finding one specific gene on a chromosome - or worse, 
the defect lurking in one of its billions of nucleic acids 
- without some sort of clue to its location would be like looking 
for the proverbial needle in a haystack. 

But what if one took a magnet to that haystack? 
One might attract old nails, screws, and other metal scraps, 
but would eventually be able to pull out that needle. 

"Linkages" or genetic "markers" are segments of DNA 
that are inherited with the defective gene from 
one generation to the next. 

If traits caused by different genes are inherited together 
in numerous family members, then the genes are likely to be 
fairly close to each other on the chromosome. 
Using special enzymes that cut DNA at known spots 
along its length, geneticists can subdivide the material, 
always searching for a smaller piece that still 
contains the defective gene. 

Rett syndrome does not yield easily to this approach, 
because 99.5% of cases are sporadic, 
occurring only once in a family. 

It is much easier to map the location of a defective gene 
if one can compare DNA from many affected and normal 
members of one family, since these family members will have 
many DNA sequences in common, 
and thus provide genetic markers. 

In the rare families in which more than one child 
is affected by Rett syndrome, RS might occur in sisters, 
half-sisters, identical twins or other relatives.  
It almost always occurs in both identical twins and in only 
one of a set of fraternal twins.   

It has been shown to pass from RS mother to RS daughter. 
These very few families with more than one affected girl 
enabled researchers to eventually solve the puzzle.


How are genetics involved in 
Can males have Rett-Syndrome?

Each of us has 46 chromosomes in a set of 23 pairs 
in every cell of our bodies except eggs and sperm. 
These chromosomes are different sizes and 
shapes and contain thousands of genes that act as a 
"blueprint" for how each of us develops. 

Two determine our sex: the X and Y chromosomes. 
Females get one X chromosome from each parent (XX); 
males receive an X chromosome from their mothers 
and a Y chromosome from their fathers (XY).

Since females have two copies of the X chromosome 
and need only one working copy for its genetic information, 
they "turn off" the extra X in a process called " X inactivation". 

Normal females turn off one X chromosome in each of their 
cells (usually about half the cells turn off the mother's X, 
and half the father's X) in a random pattern that leaves 
them with one functional X in most cells. 
Because males lack a back-up copy of the X chromosome 
that could compensate for a defective one, mutations 
on the X chromosome are often devastating in boys. 

The first hypothesis to help narrow the search was 
based on the fact that RS is seen only in girls. 
This made it likely that RTT is caused by an X-linked 
dominant mutation that would be lethal in males. 
Exclusion mapping studies in the laboratories of Dr. Eric Hoffman 
and Dr. Sakkubai Naidu narrowed the probable location 
on the X chromosome to a region known as Xq28

The International Rett Syndrome Association (IRSA) 
collects information on family cases of RS for their kindred 
database, which is shared with researchers throughout the world. 
A few families with more than one girl affected by Rett 
helped researchers narrow the candidate region 
from several thousand to several hundred genes. 
The Zoghbi and Francke groups had analyzed about two 
dozen over a period of several years before locating the 
culprit, a gene called MeCP2. 

In the case of the RTT gene, MeCP2 the mutation affects 
brain development in such important ways that boys die either 
before or shortly after birth and never have the chance 
to develop actual Rett syndrome. 
We know that the severity of the syndrome in girls is a 
function of the percentage of cells with a normal copy 
of MeCP2 that are left to function after random X inactivation. 

If X inactivation happens to turn off the X chromosome 
carrying the mutated gene in a large proportion of cells,
 the symptoms will be mild. If, instead, a larger percentage 
of cells has the healthy X chromosome turned off, the 
onset could be earlier and the symptoms more severe. 
For example an affected girl might lack a period of 
normal infantile development.


What goes wrong in Rett-Syndrom? 


What goes wrong in Rett Syndrome?
During development, a multitude of genes are "expressed"
(translated into proteins) in different tissues of the
body at different times and at different levels.

For example, a hypothetical gene that "comes on"
in brain tissue at, say, day 11 in development may be
drastically reduced in its expression level a week later
when its primary job is done.

The RTT gene, MeCP2, encodes a protein (MeCP2)
involved in one of the many biochemical switches
needed to control the complex expression patterns
of other genes by telling them when to turn off.
This "housekeeping" protein is critical for brain development
and essential for life itself.

Scientists believe that lack of a properly functioning
MeCP2 protein could allow other genes to come on
or stay on at inappropriate stages in development,
disturbing the precisely regulated pattern of development.

If they can find out exactly how this protein works
in a normal brain, and how mutations affect
brain development, scientists may be able to devise
therapies that interrupt the cascade of deleterious
effects on development.