Stone Explains Rett Syndrome
of Neurologic Diseases; article from the International Rett
Syndrome Association (IRSA) website
For more articles like this
Rett Syndrome (RS), a neurological orphan disease of children
that was long relegated to obscure articles and the fervent
concern of parents, might soon be adopted into a family of
higher-profile neurologic disorders.
This change from medical oddity to the focus of avid researchers
reflects the exciting discovery of genetic similarities between
RS and disorders as disparate as autism and Alzheimer disease.
And if this early promise holds true, RS will no longer be a
medical trivia question. Rather, it could become a medical
Rosetta Stone for translating a tangle of genetic and
biochemical evidence into a real understanding of some terrible
That ancient slab of writing, found in the Nile delta area in
1799, was inscribed in multiple languages--Egyptian
hieroglyphics, a simpler form of Egyptian writing, and Greek.
By comparing how the same messages were written in these
different languages, a French scholar was able to decode the
language of hieroglyphics by 1822. This monumental breakthrough
in understanding an important age in ancient history occurred
because the Rosetta stone shed light on the similarities between
known and unknown languages. Likewise, medical scholars are now
decoding the mysteries of certain brain disorders by comparing
them to RS.
RS seems to be a classic example of a "chromatin disease," a
general term for a specific mutation that cripples the ability
of cells to control the activity of a variety of genes.
Chromatin is the "storage" form of DNA inside the nucleus of a
cell. This highly condensed form of DNA lets the enormous
lengths of chromosomes remain tightly packed; but it permits
specific genes to be accessed and activated when the cell needs
them to perform their assigned tasks.
In chromatin, the long chains of DNA making up the chromosomes
are wrapped around proteins called histones. This reduces the
space the DNA takes up, while leaving genes available for duty
in the cell. This is like a twenty-foot length of thread being
wrapped around a spool, greatly reducing the space it takes up,
even while leaving it available to make or repair clothes. (In
the case of histones, however, the continuous length of DNA is
wrapped around a series of histone proteins rather than around
just one; this keeps DNA from being bunched up on a single
"spool" and allows access to many genes at once.)
Chromatin diseases are attracting increased attention because of
their direct link to a variety of disorders, ranging from mental
illness to cancer. And RS stands at the center of the growing
excitement over chromatin diseases. As investigators peel away
the layers of molecular mysteries around RS, they are uncovering
evidence that may help them treat other neurologic diseases.
Indeed, investigators are now hot on the trail of a cure for the
blood cancer promyelocytic leukemia, based on their
understanding of chromatin diseases.
The Long and Winding Road of RS
Clearly, RS has come a long way from the day Dr. Andreas Rett
first became aware that he had some very special patients.
In 1954, Dr. Rett, a Viennese physician, first noticed this
syndrome in two girls as they sat in his waiting room with their
mothers. He observed these children making the same repetitive
hand-washing motions. Curious, he compared their clinical and
developmental histories and discovered they were very similar.
Dr. Rett checked with his nurse and learned that he had six
other girls with similar behavior in his practice. Surely, he
thought, all these girls must have the same disorder. Not
content with studying his own patients, Dr. Rett made a film of
these girls and traveled throughout Europe seeking other
children with these symptoms.
Meanwhile, in 1960, young female patients in Sweden with quite
similar symptoms caught the eye of their own physician, Dr.
Bengt Hagberg. Dr. Hagberg collected the records of these girls
and put them aside, intending to return to them when he had more
time to study this curious phenomenon.
Then, in 1966, Dr. Rett published his findings in several German
medical journals, which, however well-known in that part of the
world, were hardly mainstream reading for much of the rest of
the worldís medical community. Even after Dr. Rett published a
description of the disease in English in 1977, RS remained in
the backwaters of medical concern: The pre-Internet world lacked
the electronic information highways taken for granted in the
But in 1983 an article on RS appeared in the mainstream,
English-language journal, Annals of Neurology. Written by none
other than Dr. Hagberg and his colleagues, the report finally
raised the profile of RS and put it on the radar screen of many
more investigators. This article was a breakthrough in
communicating details of the disease to a wide audience, and the
authors honored its pioneering researcher by naming it Rett
As investigators continued to chip away at the shell of mystery
surrounding RS, increased research funding ensured that the work
would continue. A team of scientists from Baylor University
(Houston, TX) and Stanford University (Palo Alto, CA), toiled in
the labs and clinics trying to pinpoint the cause of RS.
A major breakthrough occurred in 1999, when a research fellow at
Baylor named Ruthie Amir discovered MECP2, the gene that, when
mutated, causes RS. The discovery of the gene, located at the
Xq28 site on the X chromosome was a triumph for the Baylor team,
led by Huda Y. Zoghbi, MD, a professor in the departments of
pediatrics, neurology, neuroscience, and molecular human
genetics at the Howard Hughes Medical Institute. (Dr. Zoghbiís
multiple department affiliations reflect the need to bring to
bear the knowledge of a variety of specialties to solve the
mysteries of RS.)
This discovery of the gene also vindicated the investment in Dr.
Amir made by IRSA, which funded her position. Although the IRSA
grant was small by the standards of other funders, such the
National Institutes of Health and the Howard Hughes Medical
Institute, the fact that IRSA money supported the scientist most
directly involved in finding the gene (and who was the first
author on the published paper announcing the discovery),
demonstrated the extraordinary contributions such grass roots
organizations can make to the cause of medical science.
The discovery that MECP2 is on the X chromosome proved that RS
is an X-linked disease. And because only one of the two X
chromosomes need have the mutation in order for it to cause the
disease, this is a dominant disease as well. The fact that RS is
an X-linked dominant disease also helps explain why it is
usually found only in girls.
Normal males and females have 23 pairs of chromosomes. One
member of each pair comes from the mother; the other comes from
the father. Therefore, a baby might inherit a gene for blue eyes
from the mother and a gene for brown eyes from the father. Or
perhaps the child may inherit two genes for brown eyes.
The two chromosomes making up the so-called sex chromosomes are
also inherited from individual parents. These are the X and Y
chromosomes. Girls inherit two X chromosomes; boys get one X and
one Y chromosome.
The X chromosome is big and has plenty of genes; the Y
chromosome is short and stubby and carries the genes needed to
swing a developing fetus from the path to girlhood to the road
Both of the X chromosomes tend to be active. This could be
deadly to girls, since duplication of gene activity would almost
certainly disrupt the cellís ability to live a normal life. To
prevent this, each of the bodyís cells turns off one of the X
chromosomes. Which X chromosome gets inactivated in each cell is
usually a random process. According to the laws of probability,
the X chromosome with the MECP2 mutation will be turned on in
half of their cells. But enough X chromosomes with the mutation
will be activated to produce the symptoms of RS. (If, by some
chance, a large majority of cells express only the normal X
chromosome, the girl has only mild symptoms or none at all.)
Mutations in MECP2 are almost always sporadic, that is, they
occur spontaneously rather than through heredity. That means
that parents rarely pass on the disease to their children. Even
if a child does inherit the mutation, however, boys donít
usually get RS. Thatís because the father canít pass it on to
them. In order for the fetus to become a boy, the father must
pass on a Y chromosome, not an X chromosome. Since the MECP2
gene is located only on the X chromosome, the boy, by virtue of
being XY, avoids RS.
Another reason few boys are diagnosed with RS is that most
pediatricians would not have thought to check a baby boy with
respiratory problems and severe encephalopathy ( including
abnormally small brain size) for mutations in MECP2.
An exception to the XY rule of boys not getting RS occurs in
Klinefelter syndrome. In this disorder, boys are XXY; that is,
they have an extra X chromosome, if one of these X chromosomes
has the MECP2 mutation, RS can occur. (Among other symptoms,
boys with Klinefelter syndrome have disrupted development of
RS is classified as a developmental disease: it doesnít cause
the brain to degenerate. Rather, RS interferes with maturation
of specific areas of the brain.
The role of MECP2 is to silence certain genes. In RS, the MECP2
gene is unable to perform this task, leaving those genes to act
like overzealous electricians ignoring the wiring plans for a
new house. Instead of installing a network of carefully placed
wires and switches, these neuronal electricians create a
hodgepodge of wires that cause short-circuits and blown fuses.
The areas of the brain disrupted in RS are the frontal, motor,
and temporal cortex, brainstem, basal forebrain, basal ganglia,
which control many basic functions, such as movement. They are
also critical to the normal development of the cortex, or higher
brain center, in late infancy. RS, then, ravages centers that
control both motion and emotion.
In fact, RS is now known to be one of the leading causes of
mental retardation in females, occurring with a frequency of up
to 1 in 10,000 live female births.
Not surprisingly, investigators have recently learned that,
although active MECP2 occurs widely throughout the body, it is
especially abundant in the brain. Moreover, mouse studies
strongly suggest that the brain is the main site of action for
The disastrous neurodevelopmental mishaps in RS arise from the
disruption of the obscure and subtle mechanism by which the
normal MeCP2 protein works. This disruption is also a classic
example of a chromatin disease.
Chromatin diseases represent failures of the cell to control the
timing of activity of certain chromatin genes during growth and
development. Such control is a critical task: many genes that
are required for proper growth, development and function of the
body usually must be active only at certain times, often in a
particular sequence. (Imagine having your fingers develop before
your hands develop.)
Cells have a set of precise tools for activating and silencing
genes while they are in the tight chromatin configuration.
Various sorts of molecules land on DNA during the course of a
cellís day in order to activate or deactivate specific genes.
For example, some proteins attach to DNA in response to stimuli
from the surface of the cell (such as hormones); other proteins
are enzymes that transcribe (rewrite into another genetic
"language") the DNA into RNA, the de-coded form of the gene the
cell uses to make proteins. The process of making RNA from DNA
is called transcription.
Another way the cell controls gene transcription is called "gene
silencing." One way certain genes get silenced is by wearing a
molecular hat called a methyl group (CH3). This so-called
methylated DNA attracts a protein called methyl-CpG binding
protein. The process continues with the binding protein
attracting yet another molecule, for example, histone
deacetylase (HDAC). And it is HDAC that finally shuts off the
gene. This may seem like a lot of molecular work simply to shut
down a gene, but itís necessary. The cell must be very
deliberate in turning on and off genes; hair-trigger mechanisms
could raise havoc, especially in the developing child, whose
organ systems are slowly taking shape.
Methyl-CpG binding protein comes in three variations, one of
which is called MECP2. In other words, the gene that codes for
one of the crucial methyl-CpG binding proteins is the same gene
disabled in RS.
The RS gene mutation usually occurs in either one of two
sections of the MECP2 protein. A mutation in the methyl binding
domain (MBD) of the protein blocks MeCP2 from attaching to the
methlylated DNA. If the mutation lies in the transcriptional
repression domain (TRD), the protein will not be able to recruit
the other proteins that join MeCP2 in shutting down the gene.
Since the discovery in 1999 of the link between the MeCP2
mutation and RS, there have been reports of more mild forms of
X-linked mental retardation (XMR) in males caused by the same
mutation. Although the damage found in XMR is relatively small,
it is enough to impair brain function. This suggests that the
reach of MeCP2 mutation extends beyond RS.
Even more intriguing, the reach of chromatin diseases as a whole
extends beyond RS and XMR. The importance of DNA methlyation and
the disruption of the gene silencing mechanism based on
methylation causes a variety of diseases. For example, mutation
of the gene DNMT3B, responsible for keeping certain genes
methlylated, was initially observed in patients with ICF
syndrome. This rare autosomal (non-sex chromosome) disorder is
recessive. That is, the mutation must appear on both copies of
the gene pair inherited from parents in order to cause disease.
The disease itself is characterized by immunodeficiency (I),
unstable functioning of a part of chromosomes 1, 9, and 16
called the peri-centromeric (C) heterochromatin, and facial (F)
In patients with ICF, DNA methylation is greatly reduced and the
chromatin is not as compact as it is in people without this
More recent research showed that in patients lacking a properly
functioning DNMT3B gene, the mutation permitted over-activity of
the SYBL1 gene. It now appears that certain autosomal genes may
escape the normal restraints on their transcription (silencing)
in cells that lack a fully functioning DNMT3B protein.
The far reaching affects of the lack of chromatin gene silencing
may have broader implications than even these diseases suggest.
Disruption of neuron connections in various areas of the
developing brain can have any of a variety of devastating
effects. Autism, for example, may be caused by a loss of
chromatin gene silencing proteins. And the lines of evidence
stretch farther as investigators probe the possible neurologic
reverberations of chromatin diseases.
Finally, investigators continue to make significant progress
toward understanding RS and devising prevention strategies. For
example, researchers in Scotland, Boston, and Houston have
developed a male mouse model for RS. These mice, which have
either a defective or no MECP2 genes on the X chromosome,
develop symptoms within four weeks of life, have an advanced
form by week seven, and die by week ten. The female mouse model
develops and RS-like disease within 6 months of life, well into
adulthood for that animal.
The mouse model is proving to be a valuable tool for studying
how the disease develops and, potentially, how to cure it. There
are already clinical trials in progress using drugs to help
increase repression of transcription in order to prevent the
problems caused by runaway genes in brain neurons.
Success in these trials may bode well for other chromatin
diseases, as investigators apply their hard-won knowledge from
RS studies to these other disorders of the methylation silencing
Thus, the once obscure disease RS may be not only coming into
its own, but bringing other, more notorious brain diseases into
the bright spotlight of discovery, understanding, and, perhaps
one day, prevention.
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