Rett Syndrome: The Epidemiology, Clinical Features, and Management

A previously healthy 24-month-old girl presents for her 2-year well child check. Her mom comments that she previously had been able to say multiple words and was even starting to put 2 words together, saying, "Where Mama" and "What this," but now she is no longer talking. Her mom also notes that she has started to wring her hands. Lastly, her mom feels like her gait has changed, and she seems more unstable when she previously could walk well. On examination, her weight has decelerated slightly, and her head circumference has dropped from the 50th percentile to the 15th percentile, but she has maintained normal height velocity. She is sitting happily in her mom's lap but is babbling with no words and is making multiple unusual hand movements. Her head, eyes, ears, nose, and throat; cardiac; pulmonary; abdominal; and musculoskeletal examination are normal. Developmentally, she is unable to point to any body parts or say any words, her pen grip is very poor, and she is unable to draw any vertical or horizontal lines.Rett syndrome is a neurodevelopmental disorder initially described by Dr Andreas Rett in 1966. It is an X-linked disorder found primarily in females, and the diagnosis is typically made from 6 to 30 months of age. It affects 1 in 10 000 female children under the age of 12 years old. The 4 hallmark characteristics of classic Rett syndrome include (1) the progressive loss of fine motor skills, (2) the development of stereotypic hand movements, (3) gait abnormalities, and (4) the loss of speech and language skills after seemingly normal development. All patients with Rett syndrome have intellectual disability and often autistic-like social skills. Microcephaly often develops over time. Additionally, there are several supporting features, including seizures, bruxism, scoliosis, difficulty feeding that often requires a gastrostomy tube placement, height deceleration after previously normal growth velocity, inappropriate emotional liability, abnormal responses to pain, sleep abnormalities, impaired mobility, prolonged QTC interval on electrocardiogram, and breathing disturbances—specifically hyperventilation and/or breath holding. A diagnosis of atypical Rett syndrome can be given with a period of developmental regression, 2 out of 4 hallmark criteria, and at least 5 of the supporting features. Patients with brain injury, neurometabolic disease, or neurological infection are excluded from the diagnosis. If a patient meets criteria for atypical Rett syndrome, genetic testing should be done to confirm the diagnosis. Of note, there are a few variants of Rett syndrome that are congenital and are associated with seizures and developmental delays very early in life.Infancy is initially marked by a period of developmental regression and loss of skills followed by a preschool- and school-age phase of stability in symptoms. In later life, these patients demonstrate a worsening of motor skills and significant autonomic dysfunction, which lasts until death. Sudden cardiac death, respiratory failure, or uncontrolled seizures can be seen in the last stages of life and are commonly the cause of death in this patient population. The lifespan varies, but some patients with Rett syndrome live until 70 years of age. Sudden cardiac death is the cause of death in approximately 25% of patients.Research resulted in the discovery in 1999 that the genetic cause of Rett syndrome is a de novo mutation of the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). This gene is heavily involved in both the repression and activation of methylated DNA throughout the body. MeCP2 is found in all tissues but primarily acts in the development of neurons both activating and inhibiting epigenetic changes. MeCP2 is extremely important in the maturation of nerve cells, which likely explains the primarily neurologic signs and symptoms seen in Rett syndrome. Levels of this gene increase progressively throughout the postnatal period, likely contributing to the delayed onset of symptoms of Rett syndrome. Through mouse models, it has become clear that appropriate levels of MeCP2 in various stages of life are critical for the correct development of neuronal circuitry and maturation. Over 800 different mutations have been identified in patients with Rett syndrome. Because of the innumerable functions and variable expression of the MeCP2 gene as well as random X chromosome inactivation leading to mosaicism, it is challenging to accurately define the downstream effects of each mutation.The diagnosis of Rett syndrome is based on the clinical phenotype (hallmark concepts mentioned above) followed by confirmation by genetic testing for MeCP2 mutations. Approximately 95% of patients with classic Rett syndrome and 75% of those with atypical Rett syndrome have an MeCP2 mutation. Next-generation sequencing, a tool that sequences millions of fragments of DNA to determine the order of nucleotides in certain regions of DNA or whole genomes, has allowed for patients to receive a more rapid genetic diagnosis, which aids genetic counseling, prognosis, and treatment planning. In areas where a center of excellence is available, primary care providers can refer and collaborate with that team if a patient seems to meet criteria for Rett syndrome. However, if no center of excellence is available, genetic testing should be ordered to expedite diagnosis while developing the team of providers necessary to provide the appropriate treatment.Despite awareness of the disease and genetic causes, most treatments are limited to supportive care and the off-label use of medications to palliate symptoms. There remains no cure; however, because of improved access to genetic testing and evolving treatment options, most children with Rett syndrome live into adulthood, and 60% live into middle age. Treatment is best done at a center that specializes in Rett syndrome in a multidisciplinary context involving geneticists, dentists, genetic counselors, dieticians, speech therapists, occupational therapists, physical therapists, and music therapy. There are, as of this publication, approximately 21 Rett syndrome Centers of Excellence across the United States. Primary care providers can access rettsyndrome.org for an up-to-date listing of specialty clinics nearby.Treatments are primarily aimed at 3 categories: (1) neurotransmitter pathways, (2) growth factor signaling, and (3) metabolic signaling. Currently, there is only 1 US Food and Drug Administration–approved medication for Rett syndrome: trofinetide. This medication, approved in 2023, is an analogue of a portion of insulin-like growth factor 1, and studies have shown that patients may demonstrate improvement in neurobehavioral symptoms. Although it is currently the only medication approved by the US Food and Drug Administration, there are several other treatments being studied or undergoing randomized controlled trials.Medications used for other neurological diseases have shown promise in relieving certain symptoms in Rett syndrome. For instance, ketamine, which acts on the N-methyl-D-aspartate receptor, has been used to reduce the hand-wringing movements as well as respiratory aberrancies. Multiple studies have evaluated brain-derived neurotrophic factor (BDNF) as a potential target, as its levels are highly affected by MeCP2 regulation. In rodent models, normal levels of BDNF significantly reduced the symptoms seen in Rett syndrome. Additionally, the muscarinic, glutamate, and GABA signaling pathways are affected in Rett syndrome, causing significant abnormalities in the excitatory and inhibitory pathways, making medications that affect these pathways potential options for treatment. Lamotrigine and topiramate have been shown to be effective both for seizures as well as some motor symptoms. Epidiolex or cannabidiol is also being studied in patients with Rett syndrome given its success in refractory epilepsies at modifying the excitatory/inhibitory pathways of the brain. Unfortunately, responses to medications have generally been variable, with limited ability to quantitatively measure success. As such, there is a now movement toward gene replacement therapy.Rett syndrome is a disease with a wide phenotype and genotype, optimally treated with early diagnosis, genetic testing, and aggressive treatment aimed at ameliorating symptoms and maintaining function. This is best done at a multidisciplinary clinic specializing in the treatment of patients with Rett syndrome. Through continued research involving both animal models and clinical studies, there is still much work to be done for a potential cure in the future.Comments: This In Brief assists all of us who are general pediatricians in the recognition and care of patients diagnosed with Rett syndrome. As more life-altering diseases are discovered, it emphasizes the important role that primary care pediatricians have in assisting families in understanding the lifelong ramifications of chronic pediatric illnesses, to either refer them to a center of excellence if geographically feasible (rettsyndrome.org) and collaborate with that team or assemble the multiple consultants needed to provide optimal care and assist in transitions of care to adult internists during this lifelong journey. In order to make a timely diagnosis, it is imperative that pediatricians conduct longitudinal assessments of motor and language development and identify when abnormalities may exist. The article by Cosemtimo et al ("Rett Syndrome Before Regression," listed in suggested readings) reviews retrospective studies that suggest up to 50% of children who eventually meet the diagnostic criteria of Rett syndrome may have demonstrated some mild abnormalities earlier than previously described in their young lives: empty gaze with deep sleep, infant with deep sleep who is required to be awakened to be fed, and lower responsiveness. Although there is still no medical cure, future research may lead to this; at present, early diagnosis may enhance the eventual outcomes for patients. Families may also benefit from support groups to talk with others who have traveled the same medical journeys. Through a Google search, I identified several support groups for patients and families that include the International Rett Syndrome Foundation and Rett Syndrome Research Trust, which provide some inspiring stories of children and families living their best lives with a family member with Rett syndrome.Janet Serwint, MDAssociate Editor, In Brief