Clinical severity and quality of life in children and adolescents with Rett syndrome.

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.

Epilepsy and the natural history of Rett syndrome.

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.

Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome.

OBJECTIVE: To determine if a relationship exists between the clinical features of Rett syndrome, an X-linked dominant neurodevelopmental disorder, and specific mutations in MECP2. METHOD: 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. RESULTS: Participants with the R133C mutation are less severely affected than those with R168X or large DNA deletions (p < 0.05). Likewise, individuals with the R168X mutation are more severely affected than those with R294X and late carboxy-terminal truncating mutations (p < 0.05). Clinical differences are notable in ambulation, hand use, and language (p < 0.004), 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 (p < 0.001). The R306C mutation, previously found to confer milder features, adversely affects only one clinical feature, language (p < 0.05). CONCLUSIONS: 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.

Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype-phenotype correlations.

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder characterised by severe mental retardation, dysmorphic features, ataxia, seizures, and typical behavioural characteristics, including a happy sociable disposition. AS is caused by maternal deficiency of UBE3A (E6 associated protein ubiquitin protein ligase 3A gene), located in an imprinted region on chromosome 15q11-q13. Although there are four different molecular types of AS, deletions of the 15q11-q13 region account for approximately 70% of the AS patients. These deletions are usually detected by fluorescence in situ hybridisation studies. The deletions can also be subclassified based on their size into class I and class II, with the former being larger and encompassing the latter. METHODS: We studied 22 patients with AS due to microdeletions using a microarray based comparative genomic hybridisation (array CGH) assay to define the deletions and analysed their phenotypic severity, especially expression of the autism phenotype, in order to establish clinical correlations. RESULTS: Overall, children with larger, class I deletions were significantly more likely to meet criteria for autism, had lower cognitive scores, and lower expressive language scores compared with children with smaller, class II deletions. Children with class I deletions also required more medications to control their seizures than did those in the class II group. CONCLUSIONS: There are four known genes (NIPA1, NIPA2, CYFIP1, & GCP5) that are affected by class I but not class II deletions, thus raising the possibility of a role for these genes in autism as well as the development of expressive language skills.

Substance P immunoreactivity in Rett syndrome.

Severe autonomic dysfunction occurs in Rett syndrome (RS). Substance P, a tachykinin peptide that localizes to several brain regions, including the autonomic nervous system, is reduced in the cerebrospinal fluid of patients with RS. The anatomic localization and intensity of substance P immunoreactivity and glial fibrillary acidic protein-positive astrocytes in the brains of 14 patients with RS were compared with those in the brains of 10 age-matched normal patients. Substance P immunoreactivity expression was significantly decreased in RS tissue compared with control tissue in the following regions: dorsal horns, intermediolateral column of the spinal cord, spinal trigeminal tract, solitary tract and nucleus, parvocellular and pontine reticular nuclei, and locus ceruleus. A less significant decrease of substance P immunoreactivity occurred in the substantia nigra, central gray of the midbrain, frontal cortex, caudate, putamen, globus pallidus, and thalamus. Antiglial fibrillary acidic protein-positive astrocytes were increased in the areas in which substance P immunoreactivity was decreased and in other brain regions. Because many of the brain regions with the greatest decrease in substance P immunoreactivity are involved in the control of the autonomic nervous system, especially the solitary tracts and reticular formation, reduced substance P may contribute to the autonomic dysfunction in RS.

Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes.

We screened 71 sporadic and 7 familial Rett syndrome (RTT) patients for MECP2 mutations by direct sequencing and determined the pattern of X chromosome inactivation (XCI) in 39 RTT patients. We identified 23 different disease-causing MECP2 mutations in 54 of 71 (76%) sporadic patients and in 2 of 7 (29%) familial cases. We compared electrophysiological findings, cerebrospinal fluid neurochemistry, and 13 clinical characteristics between patients carrying missense mutations and those carrying truncating mutations. Thirty-one of 34 patients (91%) with classic RTT had random XCI. Nonrandom XCI was associated with milder phenotypes, including a mitigated classic RTT caused by a rare early truncating mutation. Patients with truncating mutations have a higher incidence of awake respiratory dysfunction and lower levels of cerebrospinal fluid homovanillic acid. Scoliosis is more common in patients with missense mutations. These data indicate that different MECP2 mutations have similar phenotypic consequences, and random XCI plays an important role in producing the full phenotypic spectrum of classic RTT. The association of early truncating mutations with nonrandom XCI, along with the fact that chimeric mice lacking methyl-CpG-binding protein 2 (MeCP2) function die during embryogenesis, supports the notion that RTT is caused by partial loss of MeCP2 function.

Oropharyngeal dysfunction and gastroesophageal dysmotility are present in girls and women with Rett syndrome.

BACKGROUND: Feeding impairment frequently complicates the course of children with neurologic disorders and places them at risk for malnutrition and growth failure. Although feeding abnormalities have been reported in female patients with Rett syndrome, the mechanisms that account for these findings have not been elucidated fully. This study was designed to characterize the clinical features of oropharyngeal and gastroesophageal dysfunction and their impact on the dietary intake and nutritional status of female subjects with Rett syndrome. METHODS: The clinical features of oropharyngeal and gastroesophageal dysfunction in 13 female patients with Rett syndrome, (age range, 3.7 to 25.7 years) were characterized by an oral feeding assessment, swallowing function study, and upper gastrointestinal series. Growth, nutritional status, and body composition were determined by stadiometry and anthropometry. Dietary intakes were determined from 3-day food records. RESULTS: Oropharyngeal dysfunction and gastroesophageal dysmotility were present in 100% and 69%, respectively, of the study patients with Rett syndrome. The scope and severity of these abnormalities were apparent only by videofluoroscopy. Abnormalities of oropharyngeal function included poor tongue mobility, reduced oropharyngeal clearance, and laryngeal penetration of liquids and solid food during swallowing. Esophageal dysmotility included absent primary or secondary waves, delayed emptying, atony, the presence of tertiary waves, spasm, and gastroesophageal reflux. Gastric dysmotility included diminished peristalsis or atony. Lower dietary energy intakes were associated with persistence of residue in the valleculae and pyriform sinuses and less body fat. CONCLUSION: The prevalence of oropharyngeal dysfunction and gastroesophageal dysmotility warrants early diagnostic evaluation and intervention strategies to improve the nutritional status of girls and women with RS.

Organ growth in Rett syndrome: a postmortem examination analysis.

Rett syndrome is a disorder of unknown etiology in females that manifests as severe mental and motor retardation during the first years of life. A postnatal pattern of altered growth is its earliest clinical expression. Head growth decelerates during the first year of age and is followed by a decline in somatic (height/weight) growth. The decreased occipitofrontal circumference (OFC) is reflected in decreased brain size, and measurements of the dendrites of cortical neurons suggest that a developmental and growth arrest have occurred. To further document growth in Rett syndrome, measurements of organ weights, as recorded in 39 postmortem examination studies were compared with normal organ weights for females of comparable age and height. These organ weights suggest that the pattern of growth failure in Rett syndrome, as compared with other forms of mental handicap, such as Down syndrome and Turner's syndrome, may be unique. In Rett syndrome the rate of brain growth, as derived from OFC, decelerates after birth. The increment in normal brain weight after 4 years of age, the age of the first postmortem examinations, is not observed in the Rett brain. The heart, kidneys, liver, and spleen grow at the normally defined rate until 8-12 years of age, when their growth rate decelerates, but their growth continues achieving organ weights that are appropriate for the height of the female. Adrenal weights are normal. These observations suggest that despite a generalized decreased growth in Rett syndrome the brain may be preferentially affected in this syndrome.

Rett syndrome: characterization of seizures versus non-seizures.

Epileptic seizures are reported to occur frequently in Rett syndrome (RS). We evaluated the hypothesis that many events classified as seizures in RS represent other paroxysmal, non-epileptic events; thus, the overall incidence of seizures in RS is overestimated. We conducted video/polygraphic/EEG monitoring sessions (8-120 h duration) in 82 RS females (ages 2-30 years). Fifty-five patients (67%) had a history of seizures and 43 (52%) were receiving anticonvulsants. All had abnormal EEGs. These abnormalities included epileptiform findings, the frequency of which ranged from 60% of patients in clinical stage IV to 97% of patients in clinical stage III. During monitoring, electrographic seizures were recorded in only 13 patients (16%) and included both partial and generalized events. Clinical events correlating with EEG seizure discharges were identified by parents during only 5 of these recordings. The parents of 23 (42%) of the 55 patients with a history of seizures identified events during monitoring that they felt were representative of the child's typical 'seizures', but which were not associated with EEG seizure discharges. These 'non-seizure' events included episodes of motor activity, such as twitching, jerking, head turning, falling forward, and trembling, as well as episodes of staring, laughing, pupil dilatation, breath holding and hyperventilation. These studies confirm that the occurrence of epileptic seizures is overestimated in RS, and further suggest that actual seizures may be under-recognized. Video/EEG monitoring can provide definitive information regarding the need for anticonvulsant therapy in RS.

Increased energy expenditure associated with repetitive involuntary movement does not contribute to growth failure in girls with Rett syndrome.

OBJECTIVE: To determine whether increased total daily energy expenditure (TDEE) associated with repetitive, involuntary movements contributes to growth failure in girls with Rett syndrome (RS). STUDY DESIGN: Fourteen girls with RS and 11 healthy girls were studied for 10 days to obtain measurements of height, weight, body circumference, and skin-fold thickness with stadiometric and anthropometric methods; whole-body potassium by potassium 40 counting; 72-hour dietary energy intakes by test weighing; 24-hour activity patterns using observational methods; and TDEE using the doubly-labeled water technique. RESULTS: TDEE, when adjusted for differences in lean body mass, did not differ significantly between girls with RS and healthy girls. Although girls with RS spent more waking hours in physical activity than their healthy counterparts (85%+/-10% vs. 73%+/-11% awake time per day, p < 0.05), their repetitive movements were not sufficiently intense to increase TDEE. However, girls with RS had significantly less lean body mass, but not body fat, which contributed to their lower absolute TDEE in comparison with that of healthy girls (845+/-251 vs. 1453+/-534 kcal/day, p < 0.01). Dietary energy intake, when adjusted for differences in body weight, was not significantly different in girls with RS compared with healthy girls. CONCLUSIONS: Increased TDEE as a result of repetitive, involuntary movements does not explain the alterations in growth and body composition of girls with RS.

Population-based registries using multidisciplinary reporters: a method for the study of pediatric neurologic disorders.

Few registries are available for evaluating population differences for rare, newly, or ill-defined pediatric neurologic disorders. The purpose of this article is to present standard methodologies for establishing a population-based registry and evaluating the completeness of a registry's case ascertainment. The Texas Rett Syndrome Registry (TRSR) is used as a model. The combination of health care and education resources has identified approx. 89-100% of the Rett syndrome cases in Texas. Cases reported by non-physician sources, although older on average (10.7 vs 7.7 years of age), did not differ by other demographic characteristics from those reported by physicians. Non-physician health and education professionals participated with the TRSR at a significantly higher rate than physicians, 89 and 37% (p < 0.05), respectively. Capture-recapture techniques, both two-sample and log-linear modeling, were used to quantitatively evaluate case ascertainment. Standardized national and international population-based registries could be the basis of an initiative to identify the etiology and perhaps preventive measures for pediatric neurologic disorders.

Alpha rhythm slowing during initiation of carbamazepine therapy: implications for future cognitive performance.

A prospective study comparing the immediate changes in occipital electroencephalographic (EEG) frequency following institution of carbamazepine therapy to long-term alterations of neuropsychological performance is reported. The patient group consisted of 16 previously untreated children in the 5-14-year age range who had recent onset partial seizures and were managed for at least 1 year with carbamazepine monotherapy. EEG changes following initiation of carbamazepine therapy, as compared to baseline, were determined by a computer-based quantitative method. Neuropsychological factors were assessed at baseline and after 1 year of therapy. While the alpha frequency decreased following institution of carbamazepine in most subjects, a greater decline (typically > 0.5 Hz) was observed in the subset who subsequently demonstrated decreased neuropsychological performance at 1 year. The major effects could be attributed to the Arithmetic and Picture Completion subtests of the Wechsler Intelligence Scale for Children-Revised (WISC-R). The findings suggest that quantitative EEG analysis may be useful for identifying individuals at increased risk for developing anticonvulsant-related long-term cognitive changes.

Electrocardiographic findings in Rett syndrome: an explanation for sudden death?

Girls with Rett syndrome had significantly longer corrected QT intervals (p < 0.001) and more T-wave abnormalities (p < 0.001) than were found in age-matched healthy girls. With advancing stages of the syndrome, the proportion of corrected QT interval prolongations and T-wave changes increased. The findings suggest a possible cardiac basis for sudden, unexpected death in Rett syndrome.

Coupling of focal electrical seizure discharges with infantile spasms: incidence during long-term monitoring in newly diagnosed patients.

To investigate the coupling of focal electrical seizure discharges (FS) and infantile spasms, we analyzed the video/polygraphic monitoring studies performed on 96 consecutive patients newly diagnosed with infantile spasms and hypsarrhythmic EEGs. A FS was considered to be coupled with infantile spasms if it occurred during a cluster of spasms (a series of individual spasms separated by < 1 min) or within 10 s of spasm onset or cessation. Ten patients demonstrated FS. In five patients (5% of the entire population) an apparent coupling of some FS with infantile spasms was observed during the baseline monitoring study. However, in three patients (only 3% of the entire population) was the observed coupling of FS and infantile spasms significant (p < 0.05). These results indicate that coupling of FS and infantile spasms occurs rarely, and that, in some instances, apparent couplings of FS and infantile spasms are best explained by chance coincidence. These findings do not support the hypothesis that the generation of infantile spasms at a subcortical level is dependent on a focal cortical discharge.

Altered energy balance may account for growth failure in Rett syndrome.

To determine whether alterations in energy balance account for growth failure in Rett syndrome, we measured dietary energy intakes, fecal fat losses, activity patterns, and sleeping as well as quietly and actively awake metabolic rates in Rett syndrome girls and healthy controls. Dietary energy intakes and fecal fat losses did not differ between the groups. Metabolic rates while sleeping and quietly awake were 23% lower (P < .05) in Rett syndrome girls than in controls; metabolic rates while actively awake did not differ between the groups. However, because of the 2.4-fold greater time (P < .001) spent in involuntary motor movement, energy expenditure associated with activity was twofold greater (P < .05) in Rett syndrome girls than in controls. Although total daily energy expenditure of the two groups did not differ significantly, energy balance was less positive in the Rett syndrome girls than in the controls. This small difference in energy balance, if sustained over months to years, is sufficient to account for growth failure in Rett syndrome girls.

High-dose, long-duration versus low-dose, short-duration corticotropin therapy for infantile spasms.

Fifty patients in whom the diagnosis of infantile spasms had recently been made and who had hypsarrhythmic electroencephalographic findings were randomly assigned to receive either high- or low-dose therapy with corticotropin (adrenocorticotropic hormone; ACTH). Twenty-six patients receiving the high-dose therapy were treated as follows: 150 U/m2 per day for 3 weeks, 80 U/m2 per day for 2 weeks, 80 U/m2 every other day for 3 weeks, and 50 U/m2 per day every other day for 1 week, with the dosage then tapered to zero during a 3-week period. The 24 patients assigned to the low-dose therapy group received 20 to 30 U/day for 2 to 6 weeks; the dosage was then tapered to zero during a 1-week period. Population characteristics (cryptogenic vs symptomatic, treatment lag, and age at start of treatment) of the two groups were similar. Response, defined as cessation of spasms and disappearance of hypsarrhythmia, was determined objectively by serial prolonged video and polygraphic monitoring studies. Of the 26 patients treated with the high-dose therapy, 13 (50%) responded; of the 24 patients treated with the low-dose therapy, 14 (58%) responded (p value not significant). No significant difference in the relapse rate between the two groups was observed. The side effects seen in both treatment groups were similar, except that hypertension occurred more frequently in the high-dose group. These results indicate that there is no major difference in the effectiveness of these two regimens in the treatment of infantile spasms with respect to spasm cessation and improvement in the patients' electroencephalographic findings.

Rett syndrome: controlled study of an oral opiate antagonist, naltrexone.

HYPOTHESIS: The opiate antagonist, naltrexone, will be beneficial in Rett syndrome. SUBJECTS: Twenty-five individuals fulfilling the criteria for Rett syndrome. METHOD: Randomized, double-blind, placebo-controlled crossover trial with two treatment periods, 4 months each, and an intervening 1-month washout period. Clinical stage, motor and cognitive development, motor-behavioral analysis, neurophysiological parameters (computerized electroencephalographic analysis, breathing characteristics, quantification of stereotyped hand movements, and sleep characteristics), and cerebrospinal fluid beta-endorphin measurements were evaluated at baseline and at the end of each treatment period. RESULTS: Only data from the first period of this study were analyzed due to significant sequence effects in the crossover design. This analysis indicated positive effects on certain respiratory characteristics including decreased disorganized breathing during wakefulness. Four (40%) of the individuals receiving naltrexone progressed one or more clinical stages versus none of the individuals receiving placebo. The adjusted (for baseline value and Rett stage) end of treatment psychomotor test age (Bayley Scales) was significantly higher for the placebo group. There was no significant change for the other parameters. CONCLUSION: Naltrexone may modify some of the respiratory disturbance in Rett syndrome. Declines in motor function and more rapid progression of the disorder suggest a deleterious effect.

The pattern of growth failure in Rett syndrome.

OBJECTIVE: To define the growth pattern of girls with Rett syndrome with respect to height, weight, and fronto-occipital head circumference. DESIGN: Longitudinal with irregular intervals between measurements. SETTING: Rett Syndrome Program Project at Baylor College of Medicine, Houston, Tex. PARTICIPANTS: Ninety-six girls fulfilling criteria for Rett syndrome; comparison group with standard growth curves. SELECTION PROCEDURE: Consecutive entries into the Rett Syndrome Program Project. INTERVENTION: None. MEASUREMENTS/MAIN RESULTS: Height, weight, and fronto-occipital head circumference data were grouped into intervals. Group medians were then generated. Regression lines were fitted through the median points and plotted on standard growth charts. Deceleration of growth velocities began at age 3 months and persisted through age 18 years. CONCLUSIONS: Early deceleration of head growth, followed by deceleration of weight and height measurements, appears to be a growth pattern characteristic of Rett syndrome. This pattern of growth may provide the earliest clinical indicator for the diagnosis of Rett syndrome.