Rett syndrome
Rett syndrome is a rare developmental nervous system disorder that predominantly affects females, occurring in approximately 1 in every 10,000 to 23,000 female births. Characterized by a period of normal development followed by a regression in skills, the syndrome is typically marked by a loss of purposeful hand movements, speech, and social engagement, with symptoms often worsening between six months and four years of age. Individuals with Rett syndrome experience severe disabilities and generally require lifelong care, although many live into adulthood.
The condition is caused by mutations in the MECP2 gene located on the X chromosome, with most cases arising sporadically rather than through inheritance. Rett syndrome can be classified into classic and atypical forms, with the latter associated with mutations in the CDKL5 gene. Diagnosis often involves genetic testing and evaluating developmental milestones, and treatment focuses on symptom management through medications, therapy, and supportive care. While there is currently no cure for Rett syndrome, ongoing research aims to explore potential therapies that could mitigate its effects.
Rett syndrome
ALSO KNOWN AS: Rett’s disorder
DEFINITION Rett syndrome is a developmental nervous system disorder. It primarily affects girls. It is uncommon, but not rare. It occurs in 1 out of every 10,000-23,000 female births. Boys with the gene defect that causes this disorder are usually stillborn or die shortly after birth.
Rett syndrome can be classified into classic and atypical, depending on the symptoms. Many people with Rett syndrome live into adulthood. Most have severe disabilities. While many cannot talk or walk, they usually have a full range of feelings and often communicate through their eyes. People with Rett syndrome usually need daily care throughout their lives.
Risk Factors
There are no known risk factors for Rett syndrome, except being female. The mutation that causes the syndrome appears to be sporadic.
Etiology and Genetics
Classic Rett syndrome is caused by mutations in the MECP2 gene, which is located on the long arm of the X chromosome at position Xq28. The protein encoded by this gene is called the methyl CpG binding protein 2 (MeCP2), and it is normally present at high levels in mature nerve cells. While its exact molecular function remains unclear, it appears to be important for forming the proper synapses, or connections, between adjacent nerve cells so that essential chemical communication between cells can occur. MeCP2 also has a regulatory function, since it has been shown under some conditions to repress several other genes, thus preventing the accumulation of additional proteins when they are not necessary. It is not understood, however, how mutations that result in a missing or defective MeCP2 protein lead to the developmental problems and clinical symptoms of Rett syndrome.
An atypical form of Rett syndrome called the early-onset seizure variant is associated with mutations in another gene on the X chromosome called CDKL5 (at position Xp22). This gene specifies the enzyme known as cyclin-dependent kinase-like 5. Like MeCP2, it is essential for normal brain development and appears to be involved in the regulation of gene activity of other genes in nerve cells.
The pattern of inheritance for mutations in both of these genes is the same: They are inherited in an X-linked dominant fashion. A single copy of the defective gene is sufficient to cause the severe disease symptoms noted in girls with Rett syndrome. One normal copy of the gene is required in order to have sufficient brain function to be consistent with life. That is why Rett syndrome is found only in girls, since an affected boy would not have a second X chromosome that carried the normal allele. There are only scattered reports in the literature of affected females bearing children and passing the defective gene on to daughters in the next generation. As a consequence, more than 99 percent of Rett syndrome cases are sporadic, in that they result from new mutations in females with no previous family history of the disorder.
Symptoms
A girl with Rett syndrome will start developing normally. She will smile, move, and pick items up with her fingers. However, by eighteen months of age the developmental process seems to stop or reverse itself. The age of onset and the severity of symptoms can vary. There are four stages.
Stage I, the early-onset stage, occurs in children between the ages of six to eighteen months and lasts for months. Symptoms may include less eye contact with parents, less interest in toys and play, hand-wringing, slow head growth, and being a calm and quiet baby.
Stage II, the rapid destructive stage, occurs in children between the ages of one to four years old and lasts for weeks to months. Symptoms may include a small head; mental retardation; a loss of muscle tone; the inability to purposely use hands; the loss of (previous) ability to talk; repeatedly moving hands to mouth; and other hand movements, such as clapping, tapping, or random touching. Hand movements stop during sleep. Additional symptoms may include holding breath, gaps in breathing, or taking rapid breaths; irregular breathing stops during sleep. Teeth grinding, laughing or screaming spells, decreased social interactions, irritability, trouble sleeping, tremors, cold feet, and trouble crawling or walking may also be symptoms.
Stage III, the plateau stage, occurs in children who are in their preschool through school years and lasts for years. Symptoms may include difficulty controlling movement, seizures, and less irritability and crying. Communication may improve.
Stage IV, the late motor deterioration stage, occurs when stage III ceases, which can be anywhere from age five to twenty-five, and its duration lasts up to decades. Symptoms may include a decreased ability to walk, muscle weakness or wasting, stiffness of muscles, spastic movements, and scoliosis (curvature of the spine). Breathing trouble and seizures often decrease with age. Puberty usually begins at the expected age.
Screening and Diagnosis
The doctor will ask a parent about a child’s symptoms and medical history, do a physical and neurological exam, and exclude other disorders, such as autism. The doctor can also do genetic testing, which can often confirm the diagnosis. The MECP2 gene mutation is present in 95 percent of girls with Rett Syndrome and in 50 percent of those with the atypical form. However, not everyone with this mutation will have Rett syndrome. Some females may be normal or have only mild symptoms. However, these women can pass the gene to their daughters, and the daughters may then be more severely affected.
Some of the motor functions of Rett syndrome are similar to those of autism. Children with autism, who are more often boys, do not maintain person-to-person contact. Most girls with Rett syndrome, however, prefer human contact to focusing on inanimate objects. These differences may give the first clue in diagnosing Rett syndrome.
Aside from genetic testing, the diagnosis is confirmed by comparing the physical and developmental findings with those typically found in Rett syndrome. Tests may include a blood test to check for genetic mutation (MECP2 gene); an electroencephalogram (EEG), a test that records the electrical activity of the brain; and a video EEG, a test that combines EEG with a video to see if some of the child’s movements are caused by seizures.
Treatment and Therapy
There is no cure for Rett syndrome, although animal studies have suggested that the effects may be at least partially reversible using PTP1B inhibitors (PTP1B being an enzyme whose function is usually regulated by the MECP2 gene). The first human trials with DPM-1003, developed to target PTP1B inhibitors, were approved in 2024. Another potential gene therapy treatment called NGN-401 was granted regenerative medicine advanced therapy (RMAT) status in 2024 and given approval for clinical trials.
Patients with Rett syndrome condition need to be monitored for skeletal problems and heart problems. Treatment aims to control symptoms and includes medication, such as anticonvulsants to control seizure activity; stool softeners or laxatives, if the patient is constipated; drugs to help with breathing; and drugs to ease agitation. Scientists are investigating a group of medications called histone deacetylase inhibitors as a possible treatment for Rett syndrome.
Patients should eat small, frequent meals and take supplements, and may be tube fed if they are unable to consume enough food. Their diet should also include fluids and high-fiber foods to help control constipation.
Rehabilitation therapies may include occupational therapy to help patients learn to perform daily activities, such as dressing and eating; and physical therapy to help patients improve coordination and movement (can sometimes prolong the ability to walk). The use of braces and splints may be recommended. Speech therapy aides can help build communication skills, and social workers can help a family cope with caring for a child with Rett syndrome.
Parents can use various techniques to try to limit their children’s problem behaviors. They can keep a diary of their children’s behaviors and activities to help determine the cause of agitation. Other techniques that may help to prevent or control behavior problems include giving children warm baths and massages, playing soothing music, and creating a quiet environment.
Prevention and Outcomes
There is no way to prevent Rett syndrome. Individuals who have questions about the risk of Rett syndrome in their families can talk to a genetic counselor.
Further Reading
Bryson, Stephen. "FDA Gives NGN-401, Potential Rett Gene Therapy, RMAT Status." Rett Syndrome News, 14 Aug. 2024, rettsyndromenews.com/news/fda-gives-ngn-401-rett-gene-therapy-rmat-status/. Accessed 30 Aug. 2024.
"FDA Approves DepYmed's Phase 1 Trial for Rett Syndrome Drug DPM-1003." Synapse by PatSnap, 19 May 2024, synapse.patsnap.com/blog/fda-approves-depymeds-phase-1-trial-for-rett-syndrome-drug-dpm-1003. Accessed 30 Aug. 2024.
Kazantsev, A. G., and L. M. Thompson. “Therapeutic Application of Histone Deacetlyase Inhibitors for Central Nervous System Disorders.” Nature Reviews. Drug Discovery 7.10 (2008): 854-68. Print.
Kleigman, Robert M., et al., eds. Nelson Textbook of Pediatrics. 18th ed. Philadelphia: Saunders, 2007. Print.
"Rett Syndrome." Mayo Clinic. Mayo Foundation for Medical Education and Research, 17 Sept. 2015. Web. 1 Dec. 2015.
"Rett Syndrome Fact Sheet." National Institute of Neurological Disorders and Stroke. Natl. Inst. of Health, 27 July 2015. Web. 1 Dec. 2015.
Singer, H. S., and S. Naidu. “Rett Syndrome: 'We’ll Keep the Genes on for You.'” Neurology 56.5 (2001): 582-84. Print.
Tarr, Peter. "In Mice, an Experimental Drug Treatment for Rett Syndrome Suggests the Disorder Is Reversible." Cold Spring Harbor Laboratory. Cold Spring Harbor Laboratory, 27 July 2015. Web. 1 Dec. 2015.
Tasman, Allan, et al. Psychiatry. 3rd ed. Hoboken: Wiley, 2008. Print.