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Vanderbilt University Medical Center
Jeffrey Neul, MD, PhD: consultant/advisor/speaker: Alycone, GW Pharmaceuticals, Neurogene, Ovid, Roche, Taysha Gene Therapy.
Rett syndrome (RTT) is a neurodevelopmental disorder that has a characteristic pattern in which children—typically girls—have a normal birth and apparently normal development during the first six months of life followed by developmental delay, but at approximately 18-30 months of age, they have a regression in which they lose their ability to speak and their acquired hand skills. They also develop repetitive hand movements and difficulty walking or the inability to walk. Following this regression, they have a stabilization of skills but generally do not make meaningful gains in the skills lost. People with RTT subsequently develop numerous other clinical problems—such as seizures, growth failure, constipation, scoliosis, and other movement abnormalities. In their mid-teens to young adulthood, they might undergo late motor regression, where they become more stiff and rigid, develop parkinsonian features, and may even completely lose the ability to walk.
There is no evidence that the loss or death of neurons leads to the problems seen in RTT; thus, it is classified as a neurodevelopmental—not neurodegenerative—disorder.
In 1999, the genetic cause of most cases of RTT was discovered: mutations in a gene called methyl-CpG-binding protein 2 (MECP2), which is an X-linked transcriptional regulator that interacts with DNA and recruits other complexes that alter chromatin, changing transcriptional expression throughout the body. Most cases of RTT that have been discovered have a de novo mutation in MECP2, meaning it is a new mutation that is not found in the DNA of the mother or father. The expression and effects of MECP2 exist throughout the body, but they are at the highest levels in the brain—especially in the neurons.
RTT may be called “classic” or “atypical.” Classic RTT is defined as having these cardinal features with disease pattern or regression, with a loss of hand skills, loss of language, trouble walking, and repetitive hand movements; 95% to 97% of those with classic RTT will have mutations in MECP2. In atypical RTT, patients do not meet all of the criteria and cardinal features; only approximately 50% to 75% of people with atypical RTT have a mutation in MECP2. Thus, a person can clinically have RTT without a mutation in MECP2.
However, there are also people who have mutations in MECP2 but do not have RTT. They may be asymptomatic or affected with other developmental disabilities but do not display the regression and loss of skills or other characteristic features of RTT. This is important to understand: A person can have RTT without a MECP2 mutation, and having a MECP2 mutation does not mean that you have or will have RTT.
With our current understanding of RTT, we know that hundreds of individual mutations have been associated with the condition. Eight common recurrent point mutations account for 65% of the disease burden. In other words, 65% of people who have typical or classic RTT have a mutation in 1 of these 8 in mutation spots.
We can use that information to do a genotype–phenotype comparison between these common mutations and other common mutation groups, such as very large deletions that remove the entire gene. Then we can make a correlation between some mutations and mutation groups and the level of disease severity. (Severity is being defined by the amount of retained functional skills that a person has, how much retained speech or hand skills or walking ability they have, and other features such as seizures or breathing problems.)
Mutations that truncate the protein early are associated, on a group level, with more severe conditions (eg, arginine 168X [R168X] which truncates the protein at position 168), whereas later-truncating mutations or other missense mutations are associated with less severe conditions (eg, a missense mutation such as arginine 133 cysteine [R133C]). However, this really only holds true on the group level. This means that when we look at large groups of people we can say that collectively those with R168X have more severe phenotype as an overall group compared with the group with R133C. But when we look at individuals, the results vary: We can find individuals who have an R168X who are less severe than most of the people with R133C, and vice versa.
Genetic but Not Hereditary
Most often, it is thought that the RTT mutation is a spontaneous event that occurs just once during spermatogenesis. Thus, although it is a genetic disorder, it often is not seen in a family hereditary cluster.
However, there are rare familial cases in which multiple children may be affected. In fact, these rare familial cases are actually what enabled researchers to identify the genetics associated with RTT. In familial cases, often the mother is an asymptomatic carrier.
Rarely, multiple children in a family are affected by an identical mutation but neither the mother nor the father has a mutation detected in their DNA. In this case, it is thought that there may be a germline mosaic mutation—where a germline mutation may be affecting some, but not all, of the eggs in a person’s ovaries. Thus, they might have no mutation detected upon genetic testing but go on to have multiple children with RTT. Again, these are very rare cases. The majority of the time, we see RTT develop from de novo mutations that result in only a single affected person in a family.
A common misconception is that RTT occurs only in females. This is not true. Males can have RTT and have been noted to have a mutation in MECP2. There is not really any evidence that the MECP2 mutation is embryonically lethal in males. This presence of affected boys with MECP2 mutations was recognized in the aforementioned rare familial cases because it was identified that brothers of girls with RTT also could be very severely affected from birth—they have what we call a congenital or neonatal encephalopathy.
These boys were noticed to have problems right from birth, and they really had very limited development of skills. Their disease course began earlier than girls, and they started having severe problems very early, meaning they might need maximal medical support such as tracheostomies or ventilators, and often they would die in the first few years of life.
As we have developed a greater understanding of RTT, we now know that not all boys who have MECP2 mutations experience this severe disease course. In fact, there are boys who might have a somatic mosaic mutation in MECP2—this is a mutation that would have occurred after the egg and the sperm fused, while embryogenesis was occurring. Some of the cells in the boy’s body have the mutation, and some do not. In this case, they usually meet the clinical criteria for RTT and present exactly as a girl with classic/typical RTT would.
Similarly, there are boys who have Klinefelter’s syndrome, a genetic condition in which a person has 2 X chromosomes and 1 Y chromosome. So, they are phenotypically male but with 2 X chromosomes. An XXY male with MECP2 mutation on one, but not both, of their X chromosomes often presents as a girl with classic/typical RTT would. Again, although they are phenotypically male, they do have all of the criteria of RTT, and we would diagnose them as such.
In addition, we have had an increasing understanding of phenotypic presentation in boys with MECP2 mutation, which was much broader than we thought before, meaning that not all boys with MECP2 mutation have severe congenital encephalopathy or even classic RTT. Some boys have mutations in MECP2 and symptoms that are not the same as those seen in classic RTT. You can find such people in families that have an X-linked intellectual disability pattern: For example, the mother may have a mild intellectual or learning disability, and then she has male children who are more moderately intellectually disabled and have psychiatric issues and movement disorders.
The takeaway here is that genotype–phenotype relationships are not very good on the individual level when evaluating RTT. We cannot make a prognosis of severity based on mutation in an individual.
Numerous other factors or genetic modifiers likely influence individual clinical severity variation, some of which could be genetic variation and other gene interactions. These might not necessarily cause disease, but they may influence—either positively or negatively—the overall function of the pathway that is being disrupted by loss of MECP2.
Learning more about the genetic associations of RTT could be very helpful in understanding the overall disease process better and in providing new ideas for treatment approaches. However, until we have a better understanding of the genotype–phenotype relationship of RTT on an individual level, RTT remains a diagnosis based on clinical symptoms.
The current understanding of the genetics associated with RTT development is vast but still growing. Future research may focus on following those who are initially asymptomatic but with MECP2 mutations to see if RTT develops over the course of their lifetime. We also are likely to see some gene-targeting therapies emerge as we gain a more solid understanding of the genotype–phenotype relationship. Do you see people with RTT in clinical practice? Does information on the underlying genetics influence your comprehension of the disease? Let us know in the comments.
To learn more about RTT presentation and treatment options, be sure to tune in to the podcast series titled, “Rett Syndrome: Today and Tomorrow.”