In the year 1960 in Vienna, Austria, a little 100-bed clinic founded by pediatric specialist and physician Dr. Andreas Rett struggled to keep its doors open ever since its establishment a few years earlier. Its adversary was simply prejudice, but despite the disapproval of his peers, Dr. Rett accepted into his small practice all the children in Vienna with intellectual disabilities. He was the only one in the city who did, and families from all over the city came to him to have their children treated by a medical professional.
Two such families sat in his waiting room one day, two mothers with their small daughters. Dr. Rett observed both girls in the waiting room, sitting on their mothers’ laps and wringing their hands. Upon separate examination of both girls, he discovered they had similar stories.
Both girls had begun their lives developing typically, only to regress rapidly as toddlers, losing control of their hands until the characteristic hand-wringing Rett had observed became a constant compulsion. After becoming aware of these two girls, Rett observed the same progression of symptoms in four additional female patients in his practice. Convinced he had discovered a new syndrome, Rett took meticulous notes, made films documenting the girls’ symptoms, and published his findings in several under-read medical journals.
Universally ignored by his contemporaries, little did he know that another researcher would later note the characteristics of that same syndrome. Although Swedish doctor Bengt Hagberg was aware of Rett’s earlier findings, he discounted them as being part of the same syndrome due to some statistical anomalies, which were later explained as being due to faulty lab equipment.
When Hagberg presented his findings at a medical conference in Toronto comparing them to the earlier findings, Rett jumped out of his seat in the audience and enthusiastically made his presence known. Interrupting his own presentation, Hagberg retreated with Rett to discuss their findings together in private.
Later, Hagberg continued his presentation and published his findings with the knowledge that what he had discovered was the very syndrome Rett had already observed for two decades. And with that knowledge in mind, Hagberg christened the disorder “Rett syndrome.” It was Hagberg’s report which led to the international recognition of Rett syndrome as a legitimate disorder in its own right.
Two years after the death of Andreas Rett, a team of scientists discovered the specific genetic mutation that most often causes the syndrome bearing his name. Rett syndrome, also called cerebroatrophic hyperammonemia, is only one of many genetic disorders caused by mutations on the MECP2 gene. Science continues to provide insights into this condition.
So What Is It?
Rett syndrome is a neurodevelopmental genetic disorder which affects girls almost exclusively. It is found in all racial and ethnic groups around the globe, and it is estimated that 1 in every 10,000 to 15,000 girls born will be affected by this condition.
The syndrome is most strongly associated with typical development early in life, followed by developmental regression (loss of skills and functions previously acquired), which is often sudden and swift. In addition, a decreased rate of head growth called microcephaly typically accompanies Rett syndrome, although this sign is usually not marked enough to be observed until later in an affected individual’s development.
The condition is characterized by loss of control in motor functions and muscles, especially in the hands and eyes, though sometimes later encompassing more global involvement. A social component is frequently present as well, resulting in difficulties with communication and symptoms that look very similar to some of those found in Autism Spectrum Disorder.
The extent to which Rett syndrome affects each individual varies greatly, as the severity of the syndrome is dependent upon multiple genetic factors. However, professionals describe four distinct stages of Rett syndrome, each with its own unique timeline and presentation of symptoms.
These stages vary as greatly in each individual as the syndrome itself, but the four stages are usually apparent in any person affected by the classic variant of Rett syndrome. Some atypical variants of Rett syndrome exist, the differences of which can generally be attributed to the specific genetic mutation causing the disorder.
What Causes It?
As with most genetic disorders, the specific cause of Rett syndrome is difficult to blame on just one mutation, or even one gene. The biggest offenders in this case are 8 specific, common, spontaneous mutations of the MECP2 gene, but over 200 mutations on this gene have been discovered in connection to Rett syndrome.
MECP2 stands for methyl CpG binding protein 2, a gene that contains within its code instructions for the synthesis of the protein for which it is named: methyl cytosine binding protein. This protein is thought to be needed for brain development.
The MECP2 gene not only holds the assembly manual for its specific protein, but also acts as one of many biochemical switches – genes that issue orders to other genes about how much to produce, when to produce, and when to stop producing altogether. This means that any active mutation within the code of a biochemical switch like MECP2 will have effects far beyond its own specific genetic function, and thus is the case with Rett syndrome.
But MECP2 cannot be held solely responsible. Other genes such as CDKL5 and FOXG1 have been identified in association with atypical cases of Rett syndrome, and it is assumed that more culpable genes will be pinpointed as research continues and genetic technology and mapping advances.
However, even though Rett syndrome is genetic, in more than 99% of cases it is not inherited. Much like Cornelia de Lange syndrome, Rett syndrome is most often caused by de novo mutations in the genes. This means that the mutations causing the disorder develop spontaneously in an individual.
There can be asymptomatic female carriers of MECP2 mutations (women in whom a mutation is present, but who show no symptoms or only mild symptoms). These women have a slightly higher chance of being found in a family where Rett syndrome is present. When a mother is a known carrier of a MECP2 mutation, there is a 50% chance she will pass it on to the next generation.
Males can be affected by a mosaic variant of Rett syndrome in some extremely rare cases. However, in the majority of boys with MECP2 mutations, the effects of these mutations do not present in the classic form of Rett syndrome. Most often, MECP2 mutations in boys are much more severe and life-threatening than in girls.
This is because the syndrome is X-linked, meaning the genes that cause it are found on the X-chromosome. Females possess two X-chromosomes, but only one of those X-chromosomes is active in any given cell. Therefore in a female, a mutation will only be expressed in those cells in which the active X-chromosome is the one with the mutated gene(s).
Males, however, possess an X- and a Y-chromosome. Without an additional unaffected X-chromosome to sometimes assert dominance in a cell, an X-chromosome with mutated genes will be active in every cell of a male’s body. This causes much more severe symptoms throughout a boy’s body, and often results in early death.
Signs & Symptoms
In Classic Rett syndrome, there are four stages that typify the progression of symptoms in an affected individual. The first of these is called the early onset stage, beginning sometime between a child’s 6th and 18th month of life. The signs of this stage are subtle and somewhat vague, and are often completely overlooked, or mistaken for another syndrome such as Autism Spectrum Disorder.
Stage I includes symptoms such as less eye contact, a reduced interest in toys and play, small delays in gross motor skills like sitting or crawling, and general irritability or restlessness beyond average levels. Sometimes early signs of subtle or infrequent hand-wringing will be present, and a very slight decrease in head growth may also be observed by the especially fastidious researcher.
Stage II generally begins between ages 1 and 4. It is known as the rapid destruction stage, though symptoms may be rapid or gradual, and can last anywhere from a few short weeks to several months depending on the individual.
In this second stage, people affected by Rett syndrome begin to lose their purposeful hand movements and any spoken language they may have previously acquired. They begin displaying the stereotypical hand movements associated with Rett syndrome, including wringing, washing, clapping, squeezing, tapping, and repeatedly bring the hands to the mouth. These hand motions are constant during a child’s waking hours, but discontinue entirely when the child is sleeping.
It is also during the second stage that some symptoms like those of autism may begin to appear. A child affected by Rett syndrome may also develop an unsteady or irregular gait during this stage. Microcephaly can become more pronounced during Stage II, as can difficulty with motor functions in general.
A decline in intellectual function may become evident during this stage, alongside emotional instability that can include inconsolable crying or screaming in some individuals. Depending on the severity, some individuals with Rett syndrome may also experience seizures, teeth-grinding, tremors, and apraxia (a disconnect between intentional neural signals and motor function).
Many people with Rett syndrome also begin to have breathing difficulties during the rapid destruction stage, including everything from breath-holding and apnea (spontaneous cessation of breathing), to aerophagia (swallowing air), hyperventilating and hypo-ventilating, and sudden expulsion of air and saliva. These irregular breathing patterns tend to worsen with stress, but disappear when a child with Rett syndrome is sleeping.
In the third stage, known as the plateau or pseudo-stationary stage, the symptoms of affected children begin to even out, usually somewhere between two and ten years of age. Any apraxia, motor difficulties, seizures, teeth-grinding, and/or breathing irregularities that appeared in Stage II will remain, but they will generally not worsen or deteriorate any further.
Meanwhile, Stage III can bring some improvement to other functions, such as behavior and irritability, resulting in an increased alertness and attention span, and allowing for the possible development of communication skills that may have been lost or previously unattainable. This stage can last for most of an affected individual’s life.
Stage IV, if reached, brings late motor deterioration. It can last for years or decades, and is characterized by reduced mobility, muscle weakness sometimes accompanied by rigidity or spasticity, and some bone issues such as scoliosis (curvature of the spine) and osteopenia (fragility and weakness in the bones). Depending on the severity, joint contractures and abnormal posturing may begin during this stage.
The plateau generally continues during Stage IV for cognition, communication, and hand skills. Seizures may be less frequent during late motor deterioration. Sometimes, improvement is even possible for hand movements and eye gaze during this final stage.
Scientists are investigating the possibility of a link between Rett syndrome and the development of an irregular heartbeat, which if uncorrelated accounts for a statistically unlikely number of sudden deaths in individuals with Rett syndrome.
Some other symptoms that may accompany Rett syndrome in its classic progression include difficulties chewing and swallowing, digestion issues, increased risk of gallbladder complications, and unusual eye movements such as frequent blinking or winking, intermittent crossed eyes, and staring. Some parents believe that there may be fairly consistent pain associated with their child’s Rett syndrome.
What Does Success Look Like?
Though Rett syndrome’s severity varies greatly, many people affected by the syndrome achieve a certain degree of independence in daily function, and can reach relatively high levels of communication through the use of Alternative and Augmentative Communication methods. Many people with Rett syndrome are emotionally engaged, active members of their communities.
Meanwhile, early intervention and comprehensive symptom- and support-based treatment typically lead to a life expectancy well into adulthood. That life expectancy is only expected to increase as advances in treatments and technology continue.
There is no cure for Rett syndrome. Yet.
Research is being conducted throughout the world in hopes of better understanding this syndrome’s causes and effects, in hopes that we might one day find a way to reverse its symptoms. Until that day, researchers and medical professionals will continue to make efforts to improve the lives of the people affected by this syndrome.
Here at High Hopes, we hope to contribute to a global community that, as they experience the challenges Rett syndrome might cause, fully supports and encourages affected individuals and their families.