Rett Syndrome (RTT), a neurodevelopmental disorder that primarily affects girls, is characterized by a period of apparently normal development until 6–18 months of age, when motor and communication abilities regress. More than 95% of people with RTT have mutations in Methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. Surprisingly, although the disorder is caused by mutations in a single gene, disease severity in affected individuals can be quite variable. To explore the source of this phenotypic variability, we propose that specific MECP2 mutations lead to different degrees of disease severity. Using a database of 1052 participants assessed over 4940 unique visits, the largest cohort of both typical and atypical RTT patients studied to date, we examined the relationship between MECP2 mutation status and measures of growth, motor coordination, communicative abilities, respiratory function, autonomic symptoms, scoliosis, and seizures over time. In general agreement with previous studies, we found that particular mutations, such as p.Arg133Cys, p.Arg294X, p.Arg306Cys, 3′ Truncations, and Other Point Mutations, were relatively less severe in both typical and atypical RTT. In contrast, p.Arg106Trp, p.Arg168X, p.Arg255X, p.Arg270X, Splice Sites, Large Deletions, Insertions, and Deletions were significantly more severe. We also demonstrated that, for most mutation types, clinical severity increases with age. Furthermore, of the clinical features of RTT, ambulation, hand use, and age at onset of stereotypies are strongly linked to overall disease severity. Thus, we have confirmed that MECP2 mutation type is a strong predictor of disease severity. However, clinical severity continues to become progressively worse with advancing age regardless of initial severity. These findings will allow clinicians and families to anticipate and prepare better for the needs of individuals with RTT.

Lying at the intersection between neurobiology and epigenetics, Rett syndrome (RTT) has garnered intense interest in recent years, not only from a broad range of academic scientists, but also from the pharmaceutical and biotechnology industries. In addition to the critical need for treatments for this devastating disorder, optimism for developing RTT treatments derives from a unique convergence of factors, including a known monogenic cause, reversibility of symptoms in preclinical models, a strong clinical research infrastructure highlighted by an NIH-funded natural history study and well-established clinics with significant patient populations. Here, we review recent advances in understanding the biology of RTT, particularly promising preclinical findings, lessons from past clinical trials, and critical elements of trial design for rare disorders.

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Considering both age-related and spontaneous fluctuation in seizure frequency and the unknown impact of many AEDs or KD on cognition, our data may help defining realistic treatment goals and avoiding overtreatment in patients with CDKL5 mutations. There is a strong need to develop new treatment strategies for patients with this rare mutation.

Objectives: Prominent growth failure typifies Rett syndrome (RTT). Our aims were to 1) develop RTT growth charts for clinical and research settings, 2) compare growth in children with RTT with that of unaffected children, and 3) compare growth patterns among RTT genotypes and phenotypes.Methods: A cohort of the RTT Rare Diseases Clinical Research Network observational study participants was recruited, and cross-sectional and longitudinal growth data and comprehensive clinical information were collected. A reliability study confirmed interobserver consistency. Reference curves for height, weight, head circumference, and body mass index (BMI), generated using a semiparametric model with goodness-of-fit tests, were compared with normative values using Student's t test adjusted for multiple comparisons. Genotype and phenotype subgroups were compared using analysis of variance and linear regression.Results: Growth charts for classic and atypical RTT were created from 9,749 observations of 816 female participants. Mean growth in classic RTT decreased below that for the normative population at 1 month for head circumference, 6 months for weight, and 17 months for length. Mean BMI was similar in those with RTT and the normative population. Pubertal increases in height and weight were absent in classic RTT. Classic RTT was associated with more growth failure than atypical RTT. In classic RTT, poor growth was associated with worse development, higher disease severity, and certain MECP2 mutations (pre-C-terminal truncation, large deletion, T158M, R168X, R255X, and R270X). Conclusions:RTT-specific growth references will allow effective screening for disease and treatment monitoring. Growth failure occurs less frequently in girls with RTT with better development, less morbidity typically associated with RTT, and late truncation mutations. Neurology ® 2012;79:1653-1661 GLOSSARY ANOVA ϭ analysis of variance; BMI ϭ body mass index; CSS ϭ Clinical Severity Score; EDF ϭ equivalent degrees of freedom; FDR ϭ false discovery rate; FOC ϭ fronto-occipital head circumference; MBA ϭ Motor Behavioral Assessment; non-RTT ϭ participants possessing MECP2 mutation but without Rett syndrome; RNHS ϭ Rett Natural History Study; RTT ϭ Rett syndrome.Growth failure is a prominent feature in Rett syndrome (RTT); however, no RTT-specific growth charts exist. Many comorbid disorders have an impact on growth in RTT, such as oropharyngeal and gastrointestinal dysfunction, scoliosis, seizures, and osteopenia. The pattern of growth in female patients with RTT trends well below the lowest centile on standard growth references, 1 which fail to differentiate a normal RTT growth pattern from one caused by malnutrition or illness.Disease-specific standards screen for disease [2][3][4][5][6][7][8][9][10][11][12][13] and measure the effect of therapeutic interventions designed to improve nutrition and neurologic function.14,15 With more than 200 mutation sites identified in the methyl-CpG-binding protein 2 gene (MECP2), the clinical severity in RTT var...

Epilepsy is common in Rett syndrome, an X-linked dominant disorder caused by mutations in the MECP2 gene, and in Rett-related disorders, such as MECP2 duplication. However, neither the longitudinal course of epilepsy nor the patterns of seizure onset and remission have been described in Rett syndrome and related conditions. The present study summarizes the findings of the Rett syndrome Natural History study. Participants with clinical Rett syndrome and those with MECP2 mutations without the clinical syndrome were recruited through the Rett Natural History study from 2006 to 2015. Clinical details were collected, and cumulative lifetime prevalence of epilepsy was determined using the Kaplan-Meier estimator. Risk factors for epilepsy were assessed using Cox proportional hazards models. Of 1205 participants enrolled in the study, 922 had classic Rett syndrome, and 778 of these were followed longitudinally for 3939 person-years. The diagnosis of atypical Rett syndrome with a severe clinical phenotype was associated with higher prevalence of epilepsy than those with classic Rett syndrome. While point prevalence of active seizures ranged from 30% to 44%, the estimated cumulative lifetime prevalence of epilepsy using Kaplan-Meier approached 90%. Specific MECP2 mutations were not significantly associated with either seizure prevalence or seizure severity. In contrast, many clinical features were associated with seizure prevalence; frequency of hospitalizations, inability to walk, bradykinesia, scoliosis, gastrostomy feeding, age of seizure onset, and late age of diagnosis were independently associated with higher odds of an individual having epilepsy. Aggressive behaviour was associated with lower odds. Three distinct patterns of seizure prevalence emerged in classic Rett syndrome, including those who did not have seizures throughout the study, those who had frequent relapse and remission, and those who had relentless seizures. Although 248 of those with classic Rett syndrome and a history of seizures were in terminal remission at last contact, only 74 (12% of those with a history of epilepsy) were seizure free and off anti-seizure medication. When studied longitudinally, point prevalence of active seizures is relatively low in Rett syndrome, although lifetime risk of epilepsy is higher than previously reported. While daily seizures are uncommon in Rett syndrome, prolonged remission is less common than in other causes of childhood onset epilepsy. Complete remission off anti-seizure medications is possible, but future efforts should be directed at determining what factors predict when withdrawal of medications in those who are seizure free is propitious.

Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, is associated with a peculiar breathing disturbance exclusively during wakefulness that is distressing, and can even prompt emergency resuscitation. Through the RTT Natural History Study, we characterized cross sectional and longitudinal characteristics of awake breathing abnormalities in RTT and identified associated clinical features. Participants were recruited from 2006 to 2015, and cumulative lifetime prevalence of breathing dysfunction was determined using the Kaplan-Meier estimator. Risk factors were assessed using logistic regression. Of 1205 participants, 1185 had sufficient data for analysis, including 922 females with classic RTT, 778 of whom were followed longitudinally for up to 9.0 years, for a total of 3944 person-years. Participants with classic or atypical severe RTT were more likely to have breathing dysfunction (nearly 100% over the lifespan) compared to those with atypical mild RTT (60-70%). Remission was common, lasting 1 year on average, with 15% ending the study in terminal remission. Factors associated with higher odds of severe breathing dysfunction included poor gross and fine motor function, frequency of stereotypical hand movements, seizure frequency, prolonged corrected QT interval on EKG, and two quality of life metrics: caregiver concern about physical health and contracting illness. Factors associated with lower prevalence of severe breathing dysfunction included higher body mass index and head circumference Z-scores, advanced age, and severe scoliosis or contractures. Awake breathing dysfunction is common in RTT, more so than seizures, and is associated with function, quality of life and risk for cardiac dysrhythmia.

Objective: To assess pharmacokinetics and safety of diazepam nasal spray (NRL-1; VALTOCO®) in pediatric and adult patients with epilepsy in seizure and nonseizure states. Methods: A single dose of diazepam nasal spray (5, 10, 15, or 20 mg based on weight) was administered during each of two conditions (ictal/peri-ictal and interictal condition) to patients 6-65 years old with partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness; a second dose was permitted if needed for persistent seizures. Dosing could be interictal or ictal/peri-ictal first, with a washout of ≥14 days. Blood samples for pharmacokinetic analysis were taken at prespecified time points. Treatment-emergent adverse events (TEAEs), sedation, nasal irritation, nasal mucosal pain, and olfactory changes were assessed. Results: Of 57 patients in the study (mean age = 28.1 years [range = 6-59], 54.4% female, 80.7% white), 49 were included in the primary pharmacokinetic analyses. Diazepam pharmacokinetic profiles were similar under both conditions, with approximately 2-hour median time to mean (SD) maximum plasma concentrations of 164 (88) and 189 (110) ng/mL for ictal/peri-ictal and interictal conditions, respectively; drug exposure during the first 6 hours postdosing was 532 (313) and 615 (368) h•ng/ mL, respectively. Seventeen patients (29.8%) reported TEAEs, of whom eight (14%)had treatment-related TEAEs, with those reported in ≥2 patients being dysgeusia (n = 3, 5.3%) and nasal discomfort (n = 2, 3.5%). One patient had serious TEAEs (recurrent seizures, metabolic encephalopathy), which were deemed unrelated to study treatment. No changes in respiratory rate were observed, nor were there clinically relevant changes in sedation, olfaction, nasal irritation, or acute nasal mucosal pain.