Rett syndrome

Definitions & Key takeaways

Rett syndrome, originally termed cerebroatrophic hyperammonemia, is a rare genetic neurological disorder of the gray matter of the brain that almost exclusively affects females, though it has also been found in male patients. It is caused by a mutation of the MECP2 gene and is inherited in an X-linked dominant pattern.

The symptoms of Rett syndrome typically appear between 6 and 18 months of age and include slowed growth, loss of language and social skills, and the development of repetitive hand movements. Other symptoms can include seizures, scoliosis, and breathing abnormalities.

The diagnosis of Rett syndrome is based on a genetic test looking for the MECP2 mutation, and the treatment focuses on managing symptoms with selective serotonin reuptake inhibitors (SSRIs) to help manage behavioral issues. Additionally, a multidisciplinary team that includes occupational, speech, and physical therapists can help optimize a child's life.

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Rett syndrome is a rare neurological disorder that mostly in young girls and causes severe impairments in their ability to talk, walk, eat, and even breathe.
A classic feature is that children often make repetitive hand movements - like flapping their hands or clasping their hands together tightly.
The disease was named after Dr. Andreas Rett, a pediatrician who discovered the syndrome in the 1960s.
To begin, the brain is composed of billions of interconnected neurons, each of which is made of up dendrites, that receive signals from other neurons, the soma, or cell body, which has all of the neuron’s main organelles, and the axon which sends signals to other neurons.
In Rett syndrome there’s an X-linked dominant mutation of the Methyl-CpG-binding protein 2 gene, or MECP2 gene, which codes for MeCP2 protein.
The mutation in the MECP2 gene usually occurs sporadically, meaning that it’s usually not inherited from a parent. It’s thought that the MeCP2 protein helps to silence or turn off other genes.
Males have only one X chromosome, so if there’s a mutation in the MECP2 gene, then they cannot make functional MeCP2 protein, and that might be why males with the mutation typically die in utero or shortly after birth.
Very rarely a male with Klinefelter syndrome, where there’s an XXY set of chromosomes, might develop Rett syndrome. Females have 2 X chromosomes, however, so one mutated MECP2 gene can be compensated for by a normal MeCP2 gene on the other X chromosome.
The genes that are regulated by MeCP2 proteins are particularly important for brain development, specifically to help establish neuronal connections.
So in young girls, when they’re first born, the low levels of MeCP2 proteins are sufficient for normal brain development.
But as the brain grows more complex, the level of MeCP2 becomes insufficient and the brain fails to develop normally. In addition to neurologic effects, Rett syndrome is also associated with prolonged QT syndrome, which is when it takes longer than usual for the heart to repolarize.
Rett syndrome can be thought of in four main stages. The first stage is the early onset stage and occurs between ages 6 to 18 months.
Before 6 months of age, children with Rett syndrome develop normally, but starting around the 6 months, children start to lose interest in play and no longer maintain eye contact.
The second stage is the rapid deterioration stage and occurs between ages 1 to 4 years. In this stage there is a dramatic regressions in speech and motor skills.
For example, a child who could initially speak a few words may no longer be able to speak and a child who used to grasp things with their hands may no longer be able to do that.
During this stage, children often demonstrate classic repetitive hand movements like flapping their hands or clasping their hands together tightly.
There may also be changes in the way they breathe like hyperventilating or breath-holding. Also during this stage, children can have acquired microcephaly which is when there’s a rapid deceleration of head growth.
The third stage is called the plateau stage and occurs between 2 to 10 years old. During this stage, some things improve - children are less irritable, have an improved attention span, have better communication skills, and make more eye contact.
But other things worsen - some children have seizures, and can develop apraxia which is an inability to perform purposeful movements.
That’s why the third stage is sometimes called the “pseudo stationary” stage. Finally, there’s the fourth stage which is called the late motor deterioration stage and starts when a child is around 10 years old and lasts for a person's lifespan.
Usually, there’s progressive muscle weakness, rigidity, and spasticity, and the spine begins to develop scoliosis - a sideways curvature of the spine.
Usually, a person’s remains cognitively stable in this stage. The diagnosis of Rett syndrome is based on a genetic test looking for the MEPC2 mutation.
There’s no cure for Rett syndrome, but some medications like Selective Serotonin Reuptake Inhibitors or SSRIs can help manage behavioral issues.
Typically, a multidisciplinary team that includes occupational, speech, and physical therapists help optimize a child’s life.
All right, as a quick recap...Rett syndrome is a neurodevelopmental condition caused by an X-linked dominant mutation of the MEPC2 gene and occurs mainly in girls.
The classic pattern is that there’s normal development in the first 6 months of life, followed by the early onset stage and the the rapid deterioration stage where developmental milestones are lost, and then a plateau stage which is a period of improvements and setbacks, and finally the late motor deterioration stage where there’s muscular deterioration and bony changes.