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To characterize growth and anthropometric measurements in females with Rett syndrome and compare these measurements with functional outcomes.We obtained longitudinal growth and anthropometric measurements from 1154 females with classic and atypical Rett syndrome seen between 2006 and 2019 in the US Natural History Study. We calculated the Clinical Severity Score, Motor Behavior Assessment score, and arm and leg muscle areas and recorded the functional assessments of arm and hand use and ambulation. We compared growth and anthropometric variables from females with Rett syndrome in regard to normative data. We analyzed Clinical Severity Score, Motor Behavior Assessment, and anthropometric measurements in regard to functional assessments.Growth and anthropometric measurements were significantly lower in females with classic and severe atypical Rett syndrome compared with those classified as mild atypical Rett syndrome and deviated from normative patterns among all 3 groups. Suprailiac skinfold measurements correlated with body mass index measurements in each group. Lower leg muscle area measurements were significantly greater among females in all 3 Rett syndrome groups who ambulated independently compared with those who did not. In females with classic Rett syndrome, arm, thigh, and lower leg muscle area measurements increased significantly over time and were significantly greater among those who had purposeful arm and hand use and independent ambulation compared with those who did not.The pattern of growth and anthropometric measures in females with Rett syndrome differs from normative data and demonstrates clear differences between classic and mild or severe atypical Rett syndrome. Anthropometric measures correspond with functional outcomes and could provide markers supporting efficacy outcomes in clinical trials.

OBJECTIVE: We reviewed medical records and conducted a nationwide survey to characterize the clinical features and determine the prevalence of biliary tract disease in girls and women with Rett syndrome (RTT). METHODS: Sixty-two individuals with RTT and biliary tract disease were identified from the membership of Rett Syndrome Organization (RS.O) and patient files of the principal investigator. Medical records of 46 individuals were reviewed for presenting features, diagnostic tests, and treatment outcomes of biliary tract disease. We designed a questionnaire that probed the frequency of risk factors and treatment outcomes of biliary tract disease in RTT. The questionnaire was completed by 271 parents whose daughters met the clinical criteria for RTT and/or had MECP2 mutations and participated in the Natural History of Rett Syndrome Study. RESULTS: Presenting symptoms identified by record review included abdominal pain (94%), irritability (88%), weight loss (64%), and vomiting (52%). Biliary dyskinesia, cholecystitis, and cholelithiasis, were identified in 90%, 77%, and 70%, respectively, by cholescintigraphy, surgical pathology, and abdominal ultrasound. The prevalence of biliary tract disease was 4.4% (n=12) in the RTT cohort. Risk factors included older age (p

Background Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT. Methods Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019. Results Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002). Conclusion Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care. Trial registration NCT00299312 and NCT02738281

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 Rett syndrome, CDKL5-deficiency disorder, FOXG1 disorder, and MECP2 duplication disorder are developmental encephalopathies with shared and distinct features. Although they are historically linked, no direct comparison has been performed. The first head-to-head comparison of clinical features in these conditions is presented. Methods Comprehensive clinical information was collected from 793 individuals enrolled in the Rett and Rett-Related Disorders Natural History Study. Clinical features including clinical severity, regression, and seizures were cross-sectionally compared between diagnoses to test the hypothesis that these are 4 distinct disorders. Results Distinct patterns of clinical severity, seizure onset age, and regression were present. Individuals with CDKL5-deficency disorder were the most severely affected and had the youngest age at seizure onset (2 months), whereas children with MECP2 duplication syndrome had the oldest median age at seizure onset (64 months) and lowest severity scores. Rett syndrome and FOGX1 were intermediate in both features. Smaller head circumference correlates with increased severity in all disorders and earlier age at seizure onset in MECP2 duplication syndrome. Developmental regression occurred in all Rett syndrome participants (median = 18 months) but only 23 to 34% of the other disorders. Seizure incidence prior to the baseline visit was highest for CDKL5 deficiency disorder (96.2%) and lowest for Rett syndrome (47.5%). Other clinical features including seizure types and frequency differed among groups. Interpretation Although these developmental encephalopathies share many clinical features, clear differences in severity, regression, and seizures warrant considering them as unique disorders. These results will aid in the development of disease-specific severity scales, precise therapeutics, and future clinical trials. ANN NEUROL 2020;88:396-406.

Rett syndrome (RTT) requires total caregiver attention and leads to potential difficulties throughout life. The Caregiver Burden Inventory, designed for Alzheimer disease, was modified to a RTT Caregiver Inventory Assessment (RTT CIA). Reliability and face, construct, and concurrent validity were assessed in caregivers of individuals with RTT. Chi-square or Fisher’s exact test for categorical variables and t-tests or Wilcoxon two-sample tests for continuous variables were utilized. Survey completed by 198 caregivers; 70 caregivers completed follow-up assessment. Exploratory factor analysis revealed good agreement for Physical Burden, Emotional Burden, and Social Burden. Internal reliability was high (Cronbach’s alpha: 0.898). RTT CIA represents a reliable and valid measure, providing a needed metric of caregiver burden in this disorder.

PurposeRett syndrome (RTT) is a neurodevelopmental disorder caused primarily by de novo mutations in MECP2 and sometimes in CDKL5 and FOXG1. However, some RTT patients lack mutations in these genes.MethodsTwenty-two RTT patients without apparent MECP2, CDKL5, and FOXG1 mutations were subjected to both whole-exome sequencing and single-nucleotide polymorphism array-based copy-number variant (CNV) analyses.ResultsThree patients had MECP2 mutations initially missed by clinical testing. Of the remaining 19, 17 (89.5%) had 29 other likely pathogenic intragenic mutations and/or CNVs (10 patients had 2 or more). Interestingly, 13 patients had mutations in a gene/region previously reported in other neurodevelopmental disorders (NDDs), thereby providing a potential diagnostic yield of 68.4%. These mutations were significantly enriched in chromatin regulators (corrected P = 0.0068) and moderately enriched in postsynaptic cell membrane molecules (corrected P = 0.076), implicating glutamate receptor signaling.ConclusionThe genetic etiology of RTT without MECP2, CDKL5, and FOXG1 mutations is heterogeneous, overlaps with other NDDs, and complicated by a high mutation burden. Dysregulation of chromatin structure and abnormal excitatory synaptic signaling may form two common pathological bases of RTT.Genet Med 19 1, 13-19.

Background Scoliosis is prominent in Rett syndrome (RTT). Following the prior report from the US Natural History Study, the onset and progression of severe scoliosis (≥40° Cobb angle) and surgery were examined regarding functional capabilities and specific genotypes, addressing the hypothesis that abnormal muscle tone, poor oral feeding, puberty, and delays or absence of sitting balance and ambulation may be responsible for greater risk in RTT. Methods The multicenter RTT Natural History Study gathered longitudinal data for classic RTT, including mutation type, scoliosis, muscle tone, sitting, ambulation, hand function, and feeding. Cox regression models were used to examine the association between scoliosis and functional characteristics. All analyses utilized SAS 9.4; two-sided P values of Results A total of 913 females with classic RTT were included. Scoliosis frequency and severity increased with age. Severe scoliosis was found in 251 participants (27%), 113 of whom developed severe scoliosis during the follow-up assessments; 168 (18%) had surgical correction. Severe MECP2 mutations (R106W, R168X, R255X, R270X, and large deletions) showed a higher proportion of scoliosis. Individuals developing severe scoliosis or requiring surgery were less likely to sit, ambulate, or use their hands and were more likely to have begun puberty. Significant differences were absent for epilepsy rates, sleep problems, or constipation. Discussion Scoliosis requires vigilance regarding the risk factors noted, particularly specific mutations and the role of puberty and motor abilities. Bracing is recommended for moderate curves and surgery for severe curves in accordance with published guidelines for scoliosis management.

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.

We conducted a nationwide survey to determine the prevalence of common gastrointestinal and nutritional disorders in Rett syndrome (RTT) based on parental reporting and related the occurrence of these problems to age and methyl-CpG-binding protein 2 (MECP2) gene status.We designed a questionnaire that probed symptoms, diagnoses, diagnostic tests, and treatment interventions related to gastrointestinal and nutritional problems in RTT. The International Rett Syndrome Foundation distributed the questionnaire to 1666 family-based members and forwarded their responses for our review. We interrogated the Rare Disease Clinical Research Network database to supplement findings related to medications used to treat gastrointestinal problems in RTT.Parents of 983 female patients with RTT (59%) responded and identified symptoms and diagnoses associated with gastrointestinal dysmotility (92%), chewing and swallowing difficulties (81%), weight deficits or excess (47%), growth deficits (45%), low bone mineral content or fractures (37%), and biliary tract disorders (3%). Height-for-age, weight-for-age, and body mass index z scores decreased significantly with age; height- and weight-, but not body mass index-for-age z scores were significantly lower in female subjects with MECP2 mutations than in those without. Vomiting, nighttime awakening, gastroesophageal reflux, chewing difficulty, and choking with feeding were significantly less likely to occur with increasing age. Short stature, low bone mineral content, fractures, and gastrostomy placement were significantly more likely to occur with increasing age. Chewing difficulty, choking with feeding, and nighttime awakening were significantly less likely to occur, whereas short stature was significantly more likely to occur, in female subjects with MECP2 mutations than in those without. Diagnostic evaluations and therapeutic interventions were used less frequently than the occurrence of symptoms or diagnoses in the RTT cohort.Gastrointestinal and nutritional problems perceived by parents are prevalent throughout life in girls and women with RTT and may pose a substantial medical burden for their caregivers. Physician awareness of these features of RTT may improve the health and quality of life of individuals affected with this disorder.

Objective: The clinical features and genetics of Rett syndrome (RTT) have been well studied, but examination of quality of life (QOL) is limited. This study describes the impact of clinical severity on QOL among female children and adolescents with classic RTT. Methods: Cross-sectional and longitudinal analyses were conducted on data collected from an NIH-sponsored RTT natural history study. More than 200 participants from 5 to 18 years of age with classic RTT finished their 2-year follow-up at the time of analysis. Regression models after adjustment for their MECP2 mutation type and age at enrollment were used to examine the association between clinical status and QOL. Results: Severe clinical impairment was highly associated with poor physical QOL, but worse motor function and earlier age at onset of RTT stereotypies were associated with better psychosocial QOL; conversely, better motor function was associated with poorer psychosocial QOL. Conclusions: Standard psychosocial QOL assessment for children and adolescents with RTT differs significantly with regard to their motor function severity. As clinical trials in RTT emerge, the Child Health Questionnaire 50 may represent one of the important outcome measures. Neurology ® 2011;77:1812–1818

To understand scoliosis, related co-morbidities, and phenotype-genotype correlations in individuals with Rett syndrome (RTT), the Rare Disease Clinical Research Network database for RTT was probed. Clinical evaluations included a detailed history and physical examination, comprehensive anthropometric measurements, and two quantitative measures of clinical status, Clinical Severity Scale (CSS) and Motor-Behavioral Analysis (MBA). All data were exported to the Data Technology Coordinating Center (DTCC) at the University of South Florida. Scoliosis assessment was based on direct examination and curvature measurements by radiography (Cobb angle). Statistical analyses included univariate and multiple logistic regression models, adjusting for age at enrollment or mutation type. Scoliosis data were available from 554 classic RTT participants, mean age = 10 years (0–57 yr). Scoliosis was noted in 292 (53%); mean age = 15 yr with scoliosis and 6 yr without. Using multiple regression analysis, MBA severity score, later acquisition, loss, or absent walking, and constipation were associated with scoliosis. Two common methyl-CpG-binding protein 2 (MECP2) mutations, R294X and R306C, had reduced risk for scoliosis. These findings corroborated previous reports on scoliosis and extended understanding of co-morbidities, clinical severity, and relative risk reduction for specific mutations. Clinical trial design should account for scoliosis and related factors judiciously.

Objective: Subtle signs and symptoms of Huntington disease (HD) are often present before impairments reach a point where the neurologic disease is manifest and a diagnosis must be considered. The objective is to examine the prognostic significance of these early clinical signs and symptoms regarding time until unequivocal clinical HD diagnosis. Methods: We analyzed longitudinal data from 218 at-risk but healthy participants in the Huntington Study Group database who had either normal motor examination results or minimal soft motor signs at first observation. This group was followed periodically in HD clinics for up to 4.5 years. We used survival analysis to examine predictors of time until HD diagnosis. Results: Diagnostic prediction was significantly improved using specific, nonredundant items from the Unified Huntington9s Disease Rating Scale. When a movement disorder specialist initially had a global impression of “soft signs” present, cumulative relative risk of diagnosis was 4.68 times greater at 1.5 years of follow-up and 3.58 at 3 years. A neuropsychological test pattern with psychomotor speed 1 SD worse than a semantic knowledge measure increased cumulative risk by 1.99 times at 1.5 years and 1.81 at 3 years. Finally, reports of various subjective HD symptoms increased 3-year relative risk by 2.6 to 3.4. Conclusions: Findings demonstrate that neuropsychological performance and both the clinician rating and the patient subjective perception of motor difficulties contribute nonredundantly to a prediction of Huntington disease diagnosis. These findings may have implications for prognostic assessment of persons at risk and eventually assist with early interventions.

ObjectiveRett syndrome is a severe neurodevelopmental disorder affecting approximately one in 10,000 female births. The clinical features of Rett syndrome are known to impact both patients' and caretakers' quality of life in Rett syndrome. We hypothesized that more severe clinical features would negatively impact caretaker physical quality of life but would positively impact caretaker mental quality of life.MethodsParticipants were individuals enrolled in the Rett Natural History Study with a diagnosis of classic Rett syndrome. Demographic data, clinical disease features, caretaker quality of life, and measures of family function were assessed during clinic visits. The Optum SF-36v2 Health Survey was used to assess caretaker physical and mental quality of life (higher scores indicate better quality of life). Descriptive, univariate, and multivariate analyses were used to characterize relationships between child and caretaker characteristics and caretaker quality of life.ResultsCaretaker physical component scores (PCS) were higher than mental component scores (MCS): 52.8 (9.7) vs 44.5 (12.1). No differences were demonstrated between the baseline and 5-year follow-up. In univariate analyses, disease severity was associated with poorer PCS (P=0.006) and improved MCS (P=0.003). Feeding problems were associated with poorer PCS (P=0.007) and poorer MCS (P=0.018). In multivariate analyses, limitations in caretaker personal time and home conflict adversely affected PCS. Feeding problems adversely impacted MCS.ConclusionsCaretaker quality of life in Rett syndrome is similar to that for caretakers in other chronic diseases. Disease characteristics significantly impact quality of life, and feeding difficulties may represent an important clinical target for improving both child and caretaker quality of life. The stability of quality-of-life scores between baseline and five years adds important value.

Rett syndrome is a neurodevelopmental disorder that primarily affects girls, most of whom have mutations in the transcription regulatory gene MECP2. However, mutations in MECP2 also have been identified in normal carrier female individuals, female individuals with mild learning disabilities and features of Angelman syndrome, and male individuals with Klinefelter syndrome or Rett syndrome—like features, fatal neonatal encephalopathy, and familial X-linked mental retardation with or without motor abnormalities. Therefore, molecular testing should be considered for a wide spectrum of individuals. As such, Rett syndrome remains a clinical diagnosis. In this article, we also discuss three recent developments: (1) the recognition of significant gallbladder dysfunction, especially in those 20 years of age or younger; (2) a clinical trial of folate and betaine, which produced no objective improvement but did yield a subjective increase in attention and interaction; and (3) measurement of cerebrospinal fluid folate levels in a large cohort, which yielded normal values, indicating no need for supplementation. ( J Child Neurol 2005;20:718—721).

© 2015 Elsevier Inc. Purpose Diagnosis of Rett syndrome (RTT) is often delayed. We sought to determine the type of physician who typically makes the RTT diagnosis and to identify risk factors for delayed diagnosis. Methods A total of 1085 participants from the multicenter longitudinal RTT natural history study with classic and atypical RTT were recruited between 2006 and 2014. Age of diagnosis, diagnostician, diagnostic criteria, and clinical and developmental data were collected. Results Among 919 classic and 166 atypical RTT participants, the median diagnosis age was 2.7 years (interquartile range 2.0-4.1) in classic and 3.8 years (interquartile range 2.3-6.9) in atypical RTT. Pediatricians made the diagnosis of classic RTT rarely (5.2%); however, the proportion diagnosed by pediatricians has increased since 2006. Since the first diagnostic criteria, the age of diagnosis decreased among subspecialists but not pediatricians. Odds of a pediatrician making the diagnosis of classic RTT were higher if a child stopped responding to parental interaction, and lower if they possessed gastroesophageal reflux, specific stereotypies, lost babbling, or the ability to follow commands. Delayed acquisition of basic gross motor skills or finger feeding was associated with younger diagnosis; delayed acquisition of higher level fine motor skills, later onset of supportive features, and normal head circumference were associated with late diagnosis. Thirty-three percent with microcephaly before 2.5 years were diagnosed after the median age of 2.7 years. Conclusions Age of RTT diagnosis has improved among subspecialists, and pediatricians have made the diagnosis of classic RTT more frequently since 2006. Strategies for educating diagnosticians should incorporate specific risk factors for delayed diagnosis.

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.

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 Student9s 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.

Neurodevelopmental disorders are a large family of conditions of genetic or environmental origin that are characterized by deficiencies in cognitive and behavioral functions. The therapeutic management of individuals with these disorders is typically complex and is limited to the treatment of specific symptoms that characterize each disorder. The neurodevelopmental disorder Rett syndrome (RTT) is the leading cause of severe intellectual disability in females. Mutations in the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MECP2), located on the X chromosome, have been confirmed in more than 95% of individuals meeting diagnostic criteria for classical RTT. RTT is characterized by an uneventful early infancy followed by stagnation and regression of growth, motor, language, and social skills later in development. This review will discuss the genetics, pathology, and symptoms that distinguish RTT from other neurodevelopmental disorders associated with intellectual disability. Because great progress has been made in the basic and clinical science of RTT, the goal of this review is to provide a thorough assessment of current pharmacotherapeutic options to treat the symptoms associated with this disorder. Furthermore, we will highlight recent discoveries made with novel pharmacological interventions in experimental preclinical phases, and which have reversed pathological phenotypes in mouse and cell culture models of RTT and may result in clinical trials.

Analysis of 819 participants enrolled in the Rett syndrome (RTT) Natural History Study validates recently revised diagnostic criteria. 765 females fulfilled 2002 consensus criteria for classic (653/85.4%) or variant (112/14.6%) RTT. All participants classified as classic RTT fulfilled each revised main criterion; supportive criteria were not uniformly present. All variant RTT participants met at least 3 of 6 main criteria in the 2002, 2 of 4 main criteria in the current format, and 5 of 11 supportive criteria in both. This analysis underscores the critical role of main criteria for classic RTT; variant RTT requires both main and supportive criteria.

Background: Rett syndrome (RTT) is a neurodevelopmental disorder primarily seen in females, most with a mutation in MECP2. Epilepsy has been reported in 50%–80%. Previous reports were based on small sample sizes or parent-completed questionnaires, or failed to consider the impact of specific MECP2 mutations.Methods: The Rare Disease Consortium Research Network for RTT is an NIH-funded project to characterize the clinical spectrum and natural history of RTT in advance of clinical trials. Evaluations include clinical status (classic vs atypical RTT), MECP2 mutations, clinical severity, and presence, frequency, and treatment of seizures.Results: Enrollment as of June 2008 is 602; 528 (88%) meet clinical criteria for classic RTT. Of these, 493 (93%) have MECP2 mutations. Age range was 8 months to 64 years. A total of 360 (60%) were reported to have seizures, including 315 (60%) classic and 45 (61%) atypical RTT. Physician assessment of the 602 indicated that 48% had seizures. There was no significant difference in seizure occurrence by race/ethnicity. A significant age impact for seizures was seen and seizures were infrequent before age 2 years. MECP2 mutations most frequently associated with epilepsy were T158M (74%) and R106W (78%), and less frequently R255X and R306C (both 49%). Individuals with seizures had greater overall clinical severity, and greater impairment of ambulation, hand use, and communication.Discussion: Seizures are common in Rett syndrome, have an age-related onset and occurrence, vary by mutation, and are associated with greater clinical severity. This information represents a key consideration for designing clinical trials.

To determine if a relationship exists between the clinical features of Rett syndrome, an X-linked dominant neurodevelopmental disorder, and specific mutations in MECP2.Cross-sectional study of 245 girls and women with typical Rett syndrome seen between 1990 and 2004 in tertiary academic outpatient specialty clinics and who had complete MECP2 mutation analysis. A structured clinical evaluation was completed for each participant. The results were grouped by MECP2 mutation and compared.Participants with the R133C mutation are less severely affected than those with R168X or large DNA deletions (p0.05). Likewise, individuals with the R168X mutation are more severely affected than those with R294X and late carboxy-terminal truncating mutations (p0.05). Clinical differences are notable in ambulation, hand use, and language (p0.004), three cardinal features of Rett syndrome. Individuals with R168X are less likely to walk (p = 0.008), retain hand use (p = 0.002), or use words (p = 0.001). In contrast, those with carboxy-terminal truncations are more likely to walk (p = 0.007) and use words (p0.001). The R306C mutation, previously found to confer milder features, adversely affects only one clinical feature, language (p0.05).Specific mutations in MECP2 confer different severity. These results allow the design of therapies targeted toward the amelioration of expected problems. Furthermore, the distinct effects of MECP2 mutations on clinical severity must be considered in clinical intervention trials.

The International Rett Syndrome Association (IRSA) North American database is the first comprehensive compilation of information in the United States and Canada on individuals with Rett syndrome or with another diagnosis in association with MECP2 mutations. The database contains specific information by diagnosis, mutation status, and mutation type and frequency on 1928 participants. Among the 1928 participants, 85.5% were typical, 13.4% were atypical, and 1.1% had MECP2 mutations but did not have Rett syndrome. MECP2 mutations were identified in 914 of 1059 participants (86%): 799 of 870 (92%) participants with typical Rett syndrome had an MECP2 mutation, 94 of 162 (58%) with atypical Rett syndrome had a mutation, and all 21 individuals diagnosed as Not Rett syndrome had a mutation. Missense-type mutations (39.0%) were slightly more common than nonsense type (35.1%). Individual mutation frequency for the 8 common mutations varied from 11.9% for T158M to 4.4% for R106W; large deletions accounted for 6.4% and C-terminal truncations occurred in 8.8%. The remaining mutations (14.3%) occurred singly or in small numbers. This database provides a unique resource for expanding our understanding of Rett syndrome, for comparison with other national databases, and for future study including organization of clinical trials based on the expected emergence of fundamental therapies.

Purpose of review New information on the clinical and molecular aspects of Rett syndrome has emerged at an accelerated pace since the identification of mutations in methyl-CpG-binding protein 2 gene (MECP2) was first reported in 1999. Recent reports not only present new insights into the clinical and molecular understanding of this unique disorder but also have important implications for the neurobiology beyond Rett syndrome. Recent findings This review covers recent advances in Rett syndrome from clinical management issues to laboratory-based genetic discoveries. Summary Clinical management issues include electrocardiographic findings, scoliosis, osteopenia, and motor control. Interesting phenotype-genotype correlations have resulted from the recognition of large-scale deletions in MECP2 as a cause of Rett syndrome, and the more recent identification of an alternate splicing isoform of the gene product. These are beginning to provide a more coherent picture of the spectrum of disease caused by mutations in MECP2. The neurobiologic role of the MECP2 gene in Rett syndrome and normal development has been greatly elucidated with the development of animal models of Rett syndrome and the study of MECP2 in humans and rodents.

Since the identification of mutations in MECP2 in girls and women with apparent Rett syndrome, numerous efforts have been made to develop phenotype-genotype correlations. These studies have produced conflicting results in part related to use of different clinical severity scales, different diagnostic criteria, and different stratification by age and mutation group as well as the possible effects of unbalanced X-chromosome inactivation. The present study applied a revised ordinal scoring system that allowed for correction for patient ages. We analyzed 85 patients with mutation in MECP2. Sixty-five (76%) had one of eight common mutations. Patients with missense mutations had lower total severity scores and better language performance than those with nonsense mutations. No difference was noted between severity scores for mutations in the methyl-binding domain (MBD) and the transcriptional repression domain (TRD). However, patients with missense mutations in TRD had the best overall scores and better preservation of head growth and language skills. Analysis of specific mutation groups demonstrated a striking difference for patients with the R306C mutation including better overall score, later regression, and better language with less motoric impairment. Indeed, these patients as a group accounted for the differences in overall scores between the missense and nonsense groups. Thus, the impact of specific mutations coupled with possible variation in X-chromosome inactivation must be considered carefully in the derivation of phenotype-genotype correlations. These results emphasize the limitations of such analyses in larger mutation groups, either by type or position.

To determine whether motor, behavioral, or psychiatric symptoms in Huntington disease (HD) predict skilled nursing facility (SNF) placement.Subjects were participants in the Huntington Study Group's Unified Huntington Disease Rating Scale Database (Rochester, NY) between January 1994 and September 1999. Specific motor, psychiatric, and behavioral variables in subjects residing at home and in SNF were analyzed using chi2 and Student's t-tests. For a subset of subjects for whom longitudinal data existed, a Cox proportional hazards model controlling for age, sex, and disease duration was used.Among 4,809 subjects enrolled, 3,070 had clinically definite HD. Of these, 228 (7.4%) resided in SNF. The SNF residents' average age was 52 years, average disease duration was 8.6 years, and they were predominantly women (63%). The SNF residents had worse motor function (chorea, bradykinesia, gait abnormality, and imbalance, p0.0001); were more likely to have obsessions, compulsions, delusions, and auditory hallucinations; and had more aggressive, disruptive (p0.0001), and irritable behaviors (p = 0.0012). For 1,559 subjects, longitudinal data existed (average length of follow-up, 1.9 years), and 87 (5%) moved from home to SNF. In the Cox model, bradykinesia (HR 1.965, 95% CI 1.083 to 3.564), impaired gait (HR 3.004, 95% CI 1.353 to 6.668), and impaired tandem walking (HR 2.546, 95% CI 1.460 to 4.439) were predictive of SNF placement.Institutionalized patients with HD are more motorically, psychiatrically, and behaviorally impaired than their counterparts living at home. However, motor variables alone predicted institutionalization. Treatment strategies that delay the progression of motor dysfunction in HD may postpone the need for institutionalization.

Objective: To determine whether pergolide, a mixed D1/D2/D3 dopamine agonist, is efficacious and safe in the treatment of children with chronic tic disorders and Tourette syndrome.Background: Neuroleptics, which block dopamine transmission, are currently used to treat children with severe tics, but major side effects and limited efficacy reduce clinical utility. Prior open-label and crossover studies of pergolide suggest potential benefit.Methods: The authors enrolled 57 children and adolescents, ages 7 to 17 years, randomizing them in a 2:1 ratio to either pergolide (0.15 to 0.45 mg per day) or placebo. Tic symptoms had to be >30 on the Yale Global Tic Severity Scale (YGTSS). The primary outcome measure was change in tic severity assessed by YGTSS.Results: Compared to placebo treatment, pergolide treatment was associated with lower tic severity scores (treatment effect 8.8, pergolide vs placebo; 95% CI 0.1 to 17.6; p = 0.05) and attention-deficit hyperactivity disorder symptoms scores (treatment effect 3.8; 95% CI 0.7 to 6.8; p = 0.02). No patient had a serious adverse event and pergolide was well tolerated.Conclusions: In this randomized, placebo-controlled trial, pergolide appeared to be an efficacious and safe medication for tic reduction in children, and may also improve attention-deficit hyperactivity disorder symptoms.

Rett syndrome arises from a mutation on the X chromosome and occurs with prevalence in the general population in 1:10,000 women. Its major nutritional consequences require that health providers recognize early signs of eating difficulties and slowing of growth parameters. Retrospective record review of 44 girls, in two equal-sized groups matched by age, showed that the Rett syndrome group was significantly different, with lower body weights, more respiratory difficulties, more gastrointestinal symptoms interfering with eating, more swallowing problems, less self-feeding, and lower texture tolerance for chewy and crunchy foods compared with the developmental disability group. Microcephaly was noted for half of the Rett syndrome group compared with seven in the developmental disability group. Parents expressed concern about their child's difficulties in eating; eight of the Rett syndrome girls and 13 of the girls in the developmental disability group were reported to have a poor appetite. Distinctive features of Rett syndrome consistent with those in the literature were documented reasonably well in the nutrition assessment records. Detailed food intake information was analyzed for food texture characteristics to recognize early eating and texture tolerance problems. Recommendations were offered for conducting a thorough nutrition assessment of Rett syndrome patients, including analysis of the texture of consumed foods. Additional recommendations for improving nutrition services to those with Rett syndrome and other developmental disabilities include ruling out microcephaly, early identification of eating difficulties, with modifications in food texture as appropriate, and self-feeding goals. J Am Diet Assoc. 2003;103:224-230.

Rett syndrome, a neurodevelopmental disorder predominantly affecting girls, is characterized by regression of psychomotor development, communication dysfunction, and hand stereotypies. Brain morphologic studies demonstrate increased neuronal packing density and reduced dendritic arborizations, suggesting an arrest or interruption of normal maturation. Numerous neurotransmitter systems have been implicated. Among these, cerebrospinal fluid glutamate levels are elevated and glutamate receptors, particularly in putamen, are reduced. Therefore, 1H spectroscopy at 4.1 Tesla was used to evaluate glutamate, creatine, and N-acetylaspartate in six girls with Rett syndrome and four normal sibling controls. The ratio of creatine to N-acetylaspartate was significantly elevated in white matter, primarily reflecting reduced N-acetylaspartate levels, and normal in gray matter. The glutamate to N-acetylaspartate ratio was elevated in gray matter and normal in white matter. These findings are consistent with previous neuropathologic and neurochemical findings and indicate the feasibility of imaging these metabolites in vivo. (J Child Neurol 1999;14:524-528).

To examine the developmental profile of myelin basic protein-like material (MBPLM) in urine. If urinary MBPLM exhibits a developmental profile corresponding to that of forebrain myelination, certain inferences should follow deviations from normal. Thus, MBPLM might provide a marker for monitoring the neurodevelopmental status in infants at risk for adverse outcomes.MBPLM in different immunochemical forms is detectable in human CSF and urine, presumably a result of myelin basic protein (MBP) catabolism. Urinary MBPLM has been used successfully as a marker of disease status in adults with MS. Urinary MBPLM increases in MS patients changing from a relapsing-remitting to a progressive course, possibly reflecting attempted or failed remyelination. Scant information exists concerning the presence or specific levels of urinary MBPLM during infancy and childhood when myelination is most active.MBPLM was assayed in 402 urine specimens from 398 infants and children ranging in age from birth to 17 years according to previously described methods.MBPLM is detectable in urine from newborns, although at substantially lower levels than in adults (157.3 +/- 83.9 ng/mg creatinine). Whether expressed as nanograms per milliliter urine or nanograms per milligram creatinine, MBPLM levels are lower (p0.05) from birth through 12 months and greater (p0.05) between ages 2 to 8 years than in adults.Human urinary MBPLM exhibits a developmental profile that parallels the onset of normal myelination and exceeds normal adult values through early childhood. Thus, urinary MBPLM could serve as a useful marker of myelination in the developing child.

The treatment of children with attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS) has been problematic because methylphenidate (MPH)--the most commonly used drug to treat ADHD--has been reported to worsen tics and because clonidine (CLON)--the most commonly prescribed alternative--has unproven efficacy.The authors conducted a multicenter, randomized, double-blind clinical trial in which 136 children with ADHD and a chronic tic disorder were randomly administered CLON alone, MPH alone, combined CLON + MPH, or placebo (2 x 2 factorial design). Each subject participated for 16 weeks (weeks 1-4 CLON/placebo dose titration, weeks 5-8 added MPH/placebo dose titration, weeks 9-16 maintenance therapy).Thirty-seven children were administered MPH alone, 34 were administered CLON alone, 33 were administered CLON + MPH, and 32 were administered placebo. For our primary outcome measure of ADHD (Conners Abbreviated Symptom Questionnaire--Teacher), significant improvement occurred for subjects assigned to CLON (p0.002) and those assigned to MPH (p0.003). Compared with placebo, the greatest benefit occurred with combined CLON + MPH (p0.0001). CLON appeared to be most helpful for impulsivity and hyperactivity; MPH appeared to be most helpful for inattention. The proportion of individual subjects reporting a worsening of tics as an adverse effect was no higher in those treated with MPH (20%) than those being administered CLON alone (26%) or placebo (22%). Compared with placebo, measured tic severity lessened in all active treatment groups in the following order: CLON + MPH, CLON alone, MPH alone. Sedation was common with CLON treatment (28% reported moderate or severe sedation), but otherwise the drugs were tolerated well, including absence of any evident cardiac toxicity.Methylphenidate and clonidine (particularly in combination) are effective for ADHD in children with comorbid tics. Prior recommendations to avoid methylphenidate in these children because of concerns of worsening tics are unsupported by this trial.