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Last Updated: 11/20/2017

Article of Interest - Rett Syndrome

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Bridges4Kids LogoRosetta Stone Explains Rett Syndrome

Rosetta Stone of Neurologic Diseases; article from the International Rett Syndrome Association (IRSA) website located at:; also see the Rett Syndrome Research Foundation
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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 neurological conditions.

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 21st Century.

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 Syndrome.

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 to boyhood.

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 sexual organs.)

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 MECP2.

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

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) anomalies.

In patients with ICF, DNA methylation is greatly reduced and the chromatin is not as compact as it is in people without this mutation.

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 mechanism.

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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