The Natural History Study (NHS) was a ground-breaking observational study that tracked the natural course of Rett syndrome from 2006-2021. This data is helping improve clinical trial design, uncover new insights into Rett syndrome, and raise the clinical standards of care.
Comparing the experiences of other patients can be a valuable tool in managing expectations and discussing care with providers and caregivers.
The leader, visionary and driver of this 15-year effort: Principal Investigator: Alan K Percy, MD University of Alabama at Birmingham
Here are a few select symptoms observed in Natural History Study:
See frequency in a day, by age and/or genetic variation, of common disordered breathing issues while awake such as hyperventilation, breath-holding or expelling air.
See frequency of preserved speech and non-verbal communicative intent by age and/or genetic variation.
See degree of modified textures, prolonged mealtimes or use of gastrostomy feeding by age and/or genetic variation.
See frequency of reaching for objects, degree of purposeful hand use, and percent-of-time in a day of hand stereotypies while awake by age and/or genetic variant.
See degree of skill including sitting, standing and walking at time of assessment by age and/or genetic variant.
See degree of sustained eye contact, social interest, screaming or crying, aggression, overactivity or underactivity by age and/or genetic variant.
See degree of spinal curvature over time by age and/or genetic variant.
See reported seizure frequency, with or without medication, at time of assessment by age and/or genetic variant.
See degree of dystonia, hypertonia/rigidity, or muscle reflexes at time of assessment by age and/or genetic variant.
Choose a variant, symptom, and age to view data comparing the experiences of over 1,000 Rett Syndrome Patients.
Choose a variant, symptom, and age to view data comparing the experiences of over 1,000 Rett Syndrome Patients.
This visualization tool offers a limited view into a subset of the NHS data collected around a sampling of common Rett syndrome symptoms. As such, it is for demonstration purposes of the much larger, more extensive, and powerful NHS data set. Outputs should serve a general purpose to guide care conversations or research inquiries, not as a predictor of phenotype for any one individual, or as a definitive portrait of all Rett syndrome symptoms.
Please refer to the Rett Syndrome Primary Care Guidelines and additional Resources for a more extensive symptom review.
Awake disordered breathing (hyperventilating, breath-holding, color change), and air swallowing is a common feature in Rett syndrome that can be exacerbated by feelings of anxiety. Breathing abnormalities can affect Quality of Life, disrupting attention, communication, feeding and more. While disordered breathing typically normalizes in sleep, nighttime apneas are not uncommon. A comprehensive sleep study or related referral (ENT or pulmonary) may be needed.
Speech is almost universally affected after the regression period in Rett syndrome. Receptive language is known to be much higher than expressive language. Alternative and augmentative communication assessments are needed. While this can be done by some speech therapists, a specific referral may be needed. Since eye gaze is typically the most effective form of communication, special eye gaze devices or partner-assisted scanning tools can give patients a voice. These referrals should be first made as early as possible to coincide with typical language development. It is also never too late to refer an older patient for assessment. Since eye gaze is the main way of communicating, assessment by a practitioner familiar with special needs patients is needed. Practitioner familiar with cortical visual impairment and ocular apraxia may also prove beneficial.
Seek an appropriate therapist or GI consult to assess, especially if there is concern for aspiration (coughing, choking, gagging with feeding or aspiration or unexplained pneumonia). In some cases, thickeners for liquids may be helpful to prevent aspiration and need for a gastrostomy tube. Prolonged feeding times can affect quality of life for patient and family; this may be an indication that a gastrostomy tube is needed.
Seek an appropriate therapist or GI consult to assess, especially if there is concern for aspiration (coughing, choking, gagging with feeding or aspiration or unexplained pneumonia). In some cases, thickeners for liquids may be helpful to prevent aspiration and need for a gastrostomy tube. Prolonged feeding times can affect quality of life for patient and family; this may be an indication that a gastrostomy tube is needed.
Gross motor skills such as sitting, standing, walking assisted and unassisted can change over time. Developmental regression typically stops between 2-3 years. Skills can be maintained and possibly regained. Therapies to consider in addition to Physical Therapy include hippotherapy (horse) and swim/pool therapy. Intensive therapy can be successful to regain skill loss after a prolonged illness or surgery. Refer for Durable Medical Equipment (DME) to assist with activities of daily living and to support therapy goals.
Over-activity, underactivity, fatigue, irritability, unexplained laughing spells, inattention, anxiety, depression or withdrawal may be observed and should be assessed. Auditory processing is delayed and may be misinterpreted as disinterest; allow for this delay when assessing non-verbal language by allowing additional time for responses to questions or commands. Behavioral inconsistency is typical and may be affected by physical factors such as sleep or environment. Assess for intolerance of excessive stimuli (i.e. bright lights, loud noises). Rule out underlying issues that may be affecting mood such as poor dietary intake, reflux, stomach bloating, constipation, ill-fitting equipment or braces, poor positioning, dental/vision/hearing, bone fractures, gallstones, UTI or kidney stones, assess home, school, program or placement for life changing events, an enriched stimulating environment, possible abuse or neglect.
Increased risk of neuromuscular scoliosis after age 6; risk typically abates after puberty. This can progress rapidly if present, necessitating re-observation every 6 months if present. Consider Orthopedic referral when present. Correction may be indicated when greater than 40 degrees. Kyphosis is more common in ambulatory individuals.
Refer to Neurology for seizures and spells suspicious for seizures. Neurology follow-up every 6 months if treated with an anticonvulsant. It is difficult to differentiate between a non-epileptic Rett Spell and a seizure (both may be present). Patients can have multiple types of seizures. Seizure logs by the family are needed with careful description of events that includes frequency and duration. Videos of events are helpful to the neurologist. The neurologist may order a video EEG to accurately characterize whether a type of event is a seizure or not. An overnight EEG may be necessary to capture sleep; an EEG is incomplete if sleep is not captured.
Ataxic gait and an impaired spatial awareness (proprioception) are common. Initially, most patients have low tone that progresses over years to high tone and dystonia. Neurologist or Rehabilitation specialist may prescribe botox or other medications to reduce tone to maintain function and prevent contractures.
Thank you to the many families who made this important research possible.
When we realized that the study was informing research into treatments/drugs to help alleviate symptoms, we were all in. Our diagnosis came in 2009. Trials then were very few and far between. Since the study, many trials are happening!
We decided to participate in the study because we were so new to Rett Syndrome and were eager for information. The opportunity to be a part of this information gathering while also learning about it was a double benefit.
Knowledge of natural history is essential for developing more efficient clinical trial designs. It also could help reduce the length and cost of drug development and, possibly, contribute toward greater predictability of clinical development programs.
We appreciated meeting with people that understood our daughter and the challenges we face. We found a family. What an unexpected benefit from this research study!
We’re here to keep you informed and empowered to get your child the best possible care and support. Explore our resources or check out what’s happening in research, and how you can get involved.
Download the Primary Care Guidelines to help facilitate discussions with your pediatrician or primary care physician.
We have articles, webinars, and educational information to learn more about symptoms, treatments, research, and care for Rett Syndrome.
Participate in our upcoming observational research project to contribute important knowledge to advance treatments and care.
Our Rett syndrome clinical database is the most comprehensive in the world. It contains:
Contact us to see how this database can boost your treatment development efforts. If you are interested in using the Natural History Study data set for scientific research, contact us to get started https://www.rettsyndrome.org/contact/
The purpose of this study is to advance understanding of the natural history of Rett syndrome (RTT), MECP2-duplication disorder (MECP2 Dup), CDKL5, FOXG1, and individuals with MECP2 mutations who do not have RTT including the range of clinical involvement and to correlate genotype-phenotype over a broad spectrum of phenotypes.
While much has been learned about RTT, improvements are required in understanding the role of factors such as X chromosome inactivation, genetic background, and others including the environment, on the great variability observed even between individuals with the same MECP2 mutation. These data will be essential to the development and conduct of clinical trials that are anticipated from ongoing studies in animal models for RTT. This study will not include clinical trials, but should set the stage for such trials and other translational research projects (e.g., development of biomarkers).
A comprehensive clinical research program will be performed including clinical, neurophysiologic, and molecular and biochemical markers across these different, but related disorders. This protocol will address the natural history components only and will serve as the basis for other study protocols including the neurophysiologic and biomarker studies. Thereby, these studies will represent a continuing pathway to focus and inform not only the ongoing but also the emerging clinical trials.