Version May 2024
INTRODUCTION — Rett syndrome (RTT) is a neurodevelopmental disorder that occurs almost exclusively in females. After a brief period of initially normal development, affected patients experience loss of speech and purposeful hand use, stereotypic hand movements, and gait abnormalities. Additional manifestations include deceleration of head growth, seizures, autistic features, and breathing abnormalities. RTT is not a degenerative disorder. Rather, it is a progressive disorder with multisystem symptom evolution over the lifespan [1].
This topic will review the treatment and prognosis of RTT. Other aspects of RTT are reviewed separately. (See "Rett syndrome: Genetics, clinical features, and diagnosis".)
COUNSELING AND SUPPORT — RTT is a chronic and devastating neurodevelopmental disorder that has a tremendous impact on affected individuals, families, and caregivers. The first important step in management is confirming the diagnosis of RTT (see "Rett syndrome: Genetics, clinical features, and diagnosis", section on 'Diagnosis'). This is often a relief to families and caregivers who have searched for an explanation for the child's problems. It may also be the beginning of the grief process for the loss of a normal child. At the time of diagnosis, anticipatory guidance should be provided regarding the spectrum of clinical problems. All parents should be taught cardiopulmonary resuscitation.
●Education and healthcare – Support of a comprehensive educational program for RTT individuals may require completing forms, informing teachers and therapists about RTT, and promoting a communication program rather than speech therapy alone [2]. Since expected survival in RTT is beyond the fifth decade (see 'Prognosis' below), issues pertaining to adulthood and adult health care should be discussed with the family and guardians, including identification of appropriate health care providers for children and adults with RTT, guardianship, and long-term financial planning.
●Caregiver burden – Individuals with RTT are totally dependent for all activities of living throughout their life. In our experience, most individuals with RTT live at home even as adults. Clinicians have long recognized the life-long burden of RTT on families and caregivers, but there are few systematic studies investigating caregiver burden. Careful monitoring of the ability of older parents to care for their adult daughters with RTT is important to parental health, and supports the care of those older individuals with RTT. One study found that caregiver burden increased as caregiver health declined [3]. There was a stronger association between the caregiver burden and parental health than with demands related to the individual with RTT. Another report found that mothers of individuals with RTT had lower physical and mental health scores compared with standard average scores [4]. These studies highlight the importance of assessing the physical and mental well-being of RTT caregivers. Encouraging parents to take "time off" and utilize respite care are important to their mental and physical health.
●Resources and advocacy – Resources and information about advocacy, ongoing research, and care of individuals affected by RTT are available from national and local organizations, including:
•International Rett Syndrome Foundation
DISEASE-MODIFYING THERAPY
Trofinetide — Trofinetide was approved in the United States by the FDA in March 2023 for the treatment of RTT in adults and children two years of age and older [5]. It is the first disease-modifying treatment available for RTT. FDA approval was primarily based on results from the LAVENDER trial, discussed below.
Given the short duration of the LAVENDER study, the modest effect sizes demonstrated, and the high rate of adverse effects (mainly diarrhea), we advise that treatment decisions regarding trofinetide should be individualized and guided by shared decision-making involving the treating clinician, family, and caregivers. This process involves discussions of the benefits and risks of therapy, and accounts for patient values and preferences.
Trofinetide is a synthetic analog of glycine-proline-glutamate (GPE), the N-terminal tripeptide of the insulin-like growth factor 1 (IGF-1). Its mechanism of action is not completely understood, but purported actions include anti-inflammatory, anti-oxidant, and trophic effects that stabilize dendritic morphology, synaptic protein synthesis, and neuronal signaling [6,7].
●Efficacy – The 12-week LAVENDER trial randomly assigned 187 females (5 to 20 years of age) with typical RTT to trofinetide (dosed based on patient weight) or matching placebo in a 1:1 ratio [8,9]. The trial used the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impressions-Improvement (CGI-I) to assess outcomes. The RSBQ is a 45-item rating scale rated by caregivers that measures RTT symptoms and signs, including breathing, hand movements or stereotypies, repetitive behaviors, night-time behaviors, vocalizations, facial expressions, eye gaze, and mood; lower scores indicate less severe RTT. The CGI-I is a 7-point scale ranging from 1 (very much improved) to 7 (very much worse) rated by clinicians; lower scores indicate improvement.
At 12 weeks, there was greater improvement from baseline on the RSBQ for patients assigned to trofinetide compared with placebo (least-squares [LS] mean change from baseline, -4.9 versus -1.7, LS mean treatment difference -3.2, 95% CI -5.7 to -0.6) and the CGI-I (mean score 3.5 versus 3.8, LS mean treatment difference 0.3, 95% CI -0.5 to -0.1) [8]; the number of patients considered to have clinically significant improvement (as represented by a CGI-I score of 2 or 1) was greater in the trofinetide group (13 percent, versus 4.7 percent in the placebo group) [10]. However, the available data provide no information regarding which specific symptoms were considered meaningfully improved.
Trofinetide led to improvements in two preceding short-term trials, one in adults with RTT and one in a population with more pediatric patients [6,11]. Whether trofinetide results in clinically meaningful long-term benefit for a majority of individuals affected by RTT remains to be established.
●Adverse effects – In clinical trials, most patients (85 percent) treated with trofinetide developed diarrhea, which was generally mild or moderate in severity, leading to treatment discontinuation in 18 percent of patients [8,12]. Vomiting was seen in approximately 30 percent. Weight loss greater than 7 percent from baseline affected 12 percent of patients.
Patients should be advised to stop laxatives prior to treatment. Diarrhea may be manageable in some patients with dose adjustments antidiarrheal treatment and increased oral fluids as needed; patients should be monitored for hydration status [8].
There are no human data on risks of trofinetide with use during pregnancy or lactation. Animal data suggest no adverse developmental effects with trofinetide administration [8].
●Dosing and administration – Trofinetide is formulated as an oral solution (200 mg/mL) and is dosed according to patient weight [8]:
•9 kg to <12 kg: 5000 mg twice daily (25 mL twice daily)
•12 kg to <20 kg: 6000 mg twice daily (30 mL twice daily)
•20 kg to <35 kg; 8000 mg twice daily (40 mL twice daily)
•35 kg to <50 kg: 10,000 mg twice daily (50 mL twice daily)
•50 kg or more: 12,000 mg twice daily (60 mL twice daily)
Trofinetide can be given orally, by gastrostomy tube, or by gastrojejunal tube if administered through the G-port. There are no contraindications.
Investigational therapies — Studies in Mecp2-mutant mice suggest potential therapeutic targets [13-15]. Potentially promising approaches include:
●Glatiramer acetate – An open-label trial of 10 females with RTT, age ≥10 years found that treatment with glatiramer acetate was associated with improved gait velocity [16]. Glatiramer is a mixture of four amino acid polymers that has been approved for treatment of multiple sclerosis. The finding of improved gait in RTT requires confirmation in larger, more rigorous trials.
●Gene therapy – In theory, inserting a working "normal" copy of the MECP2 gene into the MeCP2-deficient cells could lead to significant improvements in RTT signs and symptoms. Genetic therapies to boost MeCP2 protein levels are being explored but have significant hurdles to overcome [17-20].
MANAGEMENT — Apart from trofinetide, no specific therapy is available for RTT. Management consists of treating the associated conditions. A multidisciplinary approach is optimal. Aggressively addressing current health problems and multisystem screening for evolving health problems is important to improve the wellbeing and quality of life of patients with RTT and their families and caregivers [1]. Nutritional, gastrointestinal, and motor problems are nearly universal among patients with RTT. These individuals also can be affected by seizures and nonepileptic behaviors, which should be identified to optimize therapy. Addressing psychosocial function, including that of the family and caregivers, and educational support are also essential. (See 'Counseling and support' above.)
Nutrition — Somatic growth should be closely monitored with attention to weight, height, and body mass index [1,21]. Nutritional screening is recommended every six months, with particular attention to energy, protein, fluids, sodium, potassium, calcium and vitamin D intake [1].
A high calorie, well-balanced diet should be provided with vitamins and minerals at the recommended dietary allowance. Energy intake should be increased with high-calorie supplements, either orally or by gastrostomy feeding, if needed to maintain adequate growth. Oromotor function should be assessed by videofluoroscopy in children who have choking, decreased control of secretions, frequent upper or lower respiratory infections, or weight loss. An individualized treatment plan should be developed including appropriate food and beverage consistencies, positioning, and the use of selected feeding utensils.
Nutritional support improves growth in RTT, confirming the importance of dietary energy intake. In a cohort of 92 females with RTT, gastrostomy placement for nutritional supplementation was associated with statistically significant increases in Z score slopes for height, weight, and body mass index [22].
Gastrointestinal dysfunction — Patients with a history of eating difficulty, eructation, emesis, or irritability should be evaluated for possible gastroesophageal reflux disease, delayed gastric emptying, or biliary tract disease [1]. The Gastrointestinal Health Questionnaire is a validated tool that can be used to assess gastrointestinal health, mood and behaviors, and parent and caregiver concerns in these individuals [23]. (See "Clinical manifestations and diagnosis of gastroesophageal reflux disease in children and adolescents" and "Management of gastroesophageal reflux disease in children and adolescents".)
Constipation can be a severe and chronic problem for many patients. One approach is a program of daily prophylaxis. Options include polyethylene glycol 3350 (17 g) dissolved in 8 oz of water, juice, or milk daily with titration up or down to tolerance, or magnesium hydroxide 0.5 to 1.0 mL/kg once a day with titration down to tolerance.
Bone quality and fractures — Low bone mineral density is common and may lead to fractures. Consensus guidelines from an expert group recommend the following [24]:
●A comprehensive assessment of bone health for patients with RTT that includes fracture history and assessment for risk factors such as more severe pathogenic variants in MECP2 (R168X, R255X, R270X, or T158M), antiepileptic medications, pubertal development, mobility level, dietary intake, and biochemical bone markers.
●Bone densitometry at baseline, with subsequent monitoring every one to two years according to the presence of risk factors.
●Lateral spine radiographs.
To improve bone health, the following measures are recommended [24]:
●Increased physical activity to increase muscle strength and bone density.
●Calcium supplementation when dietary intake is low.
●Vitamin D supplementation when levels are below normal.
●Bisphosphonate therapy for children and adolescents who meet criteria for osteoporosis from the International Society for Clinical Densitometry, which require both a clinically significant history of bone fractures and low bone mineral content or low bone mineral density [25,26]. (See "Overview of dual-energy x-ray absorptiometry", section on 'Children'.)
Scoliosis — Scoliosis should be identified as early as possible. However, the optimal treatment of scoliosis in RTT is uncertain, and high-quality evidence supporting management strategies is limited. Guidelines for the management of scoliosis in patients with RTT, published in 2009, are based largely upon consensus opinion [27]. The guidelines recommend a life-span approach that starts prior to the development of scoliosis and involves a comprehensive management team that includes medical, surgical, and physical therapy specialists. Physical assessment of the spine is recommended at least every six months. Referral to an orthopedic surgeon is advised if curvature exceeds 20° [1].
Although there is no evidence that physiotherapy can prevent progression of scoliosis, the guidelines recommend a therapy program that aims to prolong ambulation and maintain range of motion and proper seating [27]. Bracing to control progression of the scoliosis does not appear to be helpful [27-29], but it may be used for truncal stability [27].
Retrospective evidence suggests that surgical management can be beneficial for certain cases of scoliosis [30-32]; the guidelines recommend consideration of spinal fusion when the Cobb angle is 40 to 50 degrees [27]. (See "Adolescent idiopathic scoliosis: Clinical features, evaluation, and diagnosis", section on 'Cobb angle'.)
Seizures — Seizures may occur during sleep or may not be recognized by caregivers. Conversely, many behavioral events identified by parents as seizures are nonepileptic. Thus, video-electroencephalography (EEG) monitoring may be necessary to differentiate nonepileptic behavioral events from actual seizures and to identify unrecognized seizures.
Most seizures associated with RTT are easily controlled and respond to standard antiepileptic medications. Nevertheless, some patients with RTT have intractable seizures, and polytherapy with three or more anticonvulsant medications has been used in up to 19 percent of patients with RTT and seizures [33,34]. A ketogenic diet [35-37] or vagus nerve stimulator [38,39] may improve intractable seizures. (See "Ketogenic dietary therapies for the treatment of epilepsy" and "Vagus nerve stimulation therapy for the treatment of epilepsy".)
Hormonal therapy or treatment with vigabatrin may be helpful in patients with infantile spasms. (See "Infantile epileptic spasms syndrome: Management and prognosis".)
Breathing disturbances — There is no known treatment for the awake breathing disturbances with alternating hyperventilation and apneic episodes that is often associated with RTT. (See "Rett syndrome: Genetics, clinical features, and diagnosis", section on 'Disorders of respiratory control'.)
In our experience, treatment with supplemental oxygen or rebreathing of carbon dioxide has not resulted in improvement; rebreathing has occasionally worsened the apnea. Naltrexone and magnesium citrate have been reported to lessen the severity of disordered breathing. In our experience, these have been beneficial to a small number of females. Serotonin agonists such as buspirone have been suggested as potential treatments for the awake breathing abnormalities observed in RTT based upon studies in a mouse model of RTT [40-43]. However, a randomized controlled trial of a serotonin agonist (sarizotan) in patients with RTT who have respiratory abnormalities was discontinued due to lack of efficacy [44].
Apnea during sleep is not characteristic of RTT. It should be evaluated as in any patient with sleep apnea. (See "Evaluation of suspected obstructive sleep apnea in children".)
Cardiac abnormalities — An electrocardiogram (ECG) should be obtained when the diagnosis of RTT is made. If the QTc interval is >0.45, a cardiologist should be consulted. The ECG should be monitored annually.
Medications associated with prolongation of the QT interval (eg, tricyclic antidepressants, erythromycin) should be avoided. Beta blockers such as propranolol may be appropriate in some cases. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Drugs that prolong the QT interval'.)
Sleep disturbance — Evaluation of sleep disturbance should include characterization of night and daytime routines, time of occurrence and related factors, and impact on the family and caregivers. Specific disorders that disturb sleep should be considered, such as sleep apnea secondary to tonsillar and/or adenoidal hypertrophy, gastroesophageal reflux, and seizures.
Behavioral intervention should be attempted to treat dysfunctional sleep patterns. Good sleep hygiene should be encouraged [45,46]. Measures include maintaining regular day and night routines, allowing the child only to sleep in bed, establishing a bedtime conducive to rapid sleep onset, removing the child from the bed if she does not fall asleep within one hour, and avoiding daytime sleep except for scheduled naps [47]. Other measures that may be helpful are taking a warm bath one to two hours before sleep, avoiding caffeine, exercising no later than three to four hours before bedtime, and following a routine bedtime ritual. Bright light exposure in the early morning promotes early sleep time, while evening exposure promotes later sleep time and should be avoided [48].
Pharmacologic agents are not consistently successful at correcting sleep disorders. Many disrupt the normal sleep architecture and/or have persistent effects on the following day. Alternative therapies may include short-acting, non-benzodiazepine receptor agonists such as zaleplon or zolpidem. Other sleep-inducing agents such as trazodone and clonidine have also been utilized. Melatonin has improved sleep disturbances in some patients with RTT, but further studies are needed before it can be recommended [49-51].
Motor dysfunction — A program of physical, occupational, and communication therapy should be provided for patients with RTT. Physical therapy is thought to promote ambulation and balance, prevent or retard the development of contractures, and control deformities [52,53]. A 2020 systematic review and meta-analysis of 22 studies found some evidence that multimodal individualized physical therapy programs help preserve autonomy and quality of life [54]. Modalities included applied behavior analysis, conductive education, environmental enrichment, traditional physiotherapy with or without aids, hydrotherapy, treadmill, music therapy, computerized systems, and sensory-based treatment.
The goal of occupational therapy is to promote purposeful use of the hands. Hand stereotypies can often be diminished by providing elbow or hand restraints. It may only be necessary to restrain the non-dominant hand or elbow. In several small series, splinting to inhibit repetitive hand activity was associated with improvements such as increased socialization and interaction with the environment [55-58]. In our clinical experience, many therapists employ this technique with success. However, larger studies evaluating the effectiveness of hand splints are needed.
Communication therapy may enhance communication skills. Observation-based assessment approaches may be useful for communication intervention planning.
Other types of therapy may also be helpful, although few data are available to support their use. Music therapy may facilitate sustained focus, attention, and improve interaction [59-61]. Hydrotherapy may promote movement and balance. Horseback riding may promote balance and protective responses that help maintain mobility and avert falls.
Reproductive issues — Females with RTT go through puberty, menstruate, and may become pregnant. Issues and options concerning birth control and hygiene should be discussed with parents or guardians of patients with RTT.
PROGNOSIS — The natural history of typical RTT in childhood is well described (see "Rett syndrome: Genetics, clinical features, and diagnosis", section on 'Typical RTT'). After a period of initially normal development, affected children experience regression with partial or complete loss of speech and purposeful hand use, and onset of stereotypic hand movements, gait abnormalities, and other manifestations of RTT. Following the regression phase, there is a period of some recovery of nonverbal communication, with improved eye contact and nonverbal interactions with the environment. This is followed by a slow, insidious deterioration in gross motor function through adulthood [62,63].
The type of pathogenic variant in MECP2 appears to impact outcome in RTT, as reviewed separately (see "Rett syndrome: Genetics, clinical features, and diagnosis", section on 'Genotype-phenotype correlations'). The R133C, R294X, and C-terminal truncating mutations are associated with somewhat milder disease, while the R168X, R255X, R270X, and T158M mutations are associated with more severe disease.
Most patients with RTT survive well into adulthood [63-66]:
●In an analysis of the North American RTT database comprising patients with typical RTT (n = 1648) and atypical RTT (n = 259), the median survival of patients with typical RTT was approximately age 45 years [64]. Survival for individuals with atypical RTT was significantly longer than for those with typical RTT.
●Among 1189 participants in the Rett Syndrome Natural History study recruited from 2006 to 2015, survival into the fifth decade was typical; survival for classic and atypical RTT at age 45 years was >75 percent [65]. During the nine-year follow-up period, there were a total of 51 deaths affecting individuals ranging in age from approximately 4 to 67 years. Mortality affected 36 females (4 percent) with classic RTT and 5 females (6 percent) with atypical severe RTT. All females with atypical mild RTT remained alive during this period. Most deaths were caused by cardiopulmonary factors. Risk factors associated with mortality in classic RTT included inability to walk, low body weight, and frequent seizures. Specific MECP2 variants were not significantly associated with mortality. This report suggested that aggressive health management and therapeutic approaches could further improve the prognosis for patients with RTT.
●In another report of 396 females with RTT who were followed for up to 20 years, the likelihood of survival at age 25 years was approximately 72 percent, and at age 37 years was approximately 60 percent [66]. Information on the cause of death was available for 57 deceased females; the most common causes were respiratory illnesses (lower respiratory tract infection, aspiration, asphyxiation, and respiratory failure) in 82 percent, and seizure-related causes in 5 percent.
●There are only a limited number of studies of RTT in adulthood. In a combined cross-sectional cohort of 423 cases of females with RTT ≥18 years of age, the following outcomes were reported [66]:
•The median age of the cohort was 25 years (range 18 to 54 years)
•The proportion living in their parental home was 71 percent; the remainder were living in group homes or institutions
•The proportion who walked independently was 18 percent, while those who walked with assistance accounted for 43 percent
•Scoliosis affected 86 percent
•Constipation affected 83 percent
•Abnormal breathing patterns were reported for 66 percent
•Anticonvulsant medications were used by 64 percent
•Sleep disturbance affected 63 percent
•Low weight for age was present in 53 percent
•Gallbladder disorders affected 5 percent
●A Danish longitudinal study of 24 females with RTT with a mean age of 44 years who were followed for roughly a decade reported the following outcomes [63]:
•Eighty-eight percent lived at a residential facility
•One hundred percent had a decline in gross motor skills with age; however, 58 percent retained the ability to walk unassisted or with support
•Eighty-seven percent had scoliosis, and two underwent spinal fusion surgery to address complications arising from severe scoliosis
•Seventy-nine percent were diagnosed with epilepsy
•Thirty-eight percent received antidepressant or antipsychotic medications
•Feeding issues were prevalent, with 20.8 percent being fed by gastrostomy tube
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rett syndrome".)
SUMMARY AND RECOMMENDATIONS
●Psychosocial support – Rett syndrome (RTT) has a tremendous impact on affected individuals, families, and caregivers. Most individuals require intensive health care support and live at home throughout adulthood, leading to a life-long burden on families and caregivers. The well-being of RTT caregivers should be assessed, and they should be encouraged to take time off and use respite care as needed for their own mental and physical health. Resources and information are available from organization listed above. (See 'Counseling and support' above.)
●Disease-modifying therapy – Trofinetide is the first disease-modifying therapy for RTT. Given limitations of the evidence (modest benefit in short-term trials and absence of long-term data), treatment decisions regarding trofinetide should be individualized and guided by shared decision-making involving the treating clinician, family, and caregivers. Trofinetide is dosed according to patient weight, as described above. The most common adverse effect is diarrhea. (See 'Trofinetide' above.)
●Management – Symptomatic management of RTT consists of treating the associated conditions. A multidisciplinary approach is optimal. A program of physical, occupational, and communication therapy should be provided. Specific issues that commonly require attention include (see 'Management' above):
•Growth and nutrition (see 'Nutrition' above)
•Gastrointestinal (see 'Gastrointestinal dysfunction' above)
•Bone health (see 'Bone quality and fractures' above and 'Scoliosis' above)
•Epilepsy (see 'Seizures' above)
•Breathing dysfunction (see 'Breathing disturbances' above)
•Cardiac abnormalities (see 'Cardiac abnormalities' above)
•Sleep disturbance (see 'Sleep disturbance' above)
•Motor dysfunction (see 'Motor dysfunction' above)
●Natural history – The natural history of typical RTT is notable for a period of normal development for the first 6 to 18 months of life followed by a regression phase, with partial or complete loss of speech and purposeful hand use, and onset of stereotypic hand movements, gait abnormalities, and other manifestations. The regression phase is followed by a period of some recovery of nonverbal communication, but the long-term course is one of a slow deterioration in gross motor function. Respiratory illnesses and seizure-related conditions are the most common causes of death. However, most patients with RTT survive into adulthood. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel G Glaze, MD, who contributed to earlier versions of this topic review.
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