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Rett Syndrome (rett + syndrome)
Selected AbstractsNeuropathology of Rett syndromeDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2002Dawna Duncan Armstrong Abstract Rett Syndrome is unlike any other pediatric neurologic disease, and its clinical-pathologic correlation can not be defined with standard histology techniques. Based on hypotheses suggested by careful clinical observations, the nervous system of the Rett child has been explored utilizing morphometry, golgi preparations, computerized tomography, magnetic resonance imaging, chemistry, immunocytochemistry, autoradiography, and molecular biologic techniques. From these many perspectives we conclude that Rett syndrome is not a typical degenerative disorder, storage disorder, nor the result of gross malformation, infectious or neoplastic processes. There remain regions of the brain that have not been studied in detail but the available data suggest that the neuropathology of Rett syndrome can be summarized as follows: the Rett brain is small for the age and the height of the patient; it does not become progressively smaller over three to four decades; it has small dendritic trees in pyramidal neurons of layers III and V in selected lobes (frontal, motor, and temporal); it has small neurons with an increased neuronal packing density; it has an immature expression of microtubular protein-2 and cyclooxygenase; it exhibits a changing pattern of neurotransmitter receptors with an apparent reduction in many neurotransmitters, possibly contributing to some symptomatology. A mutation in Mecp2 causes this unique disorder of brain development. Neuronal mosaicism for normal and mutated Mecp2 produces a consistent phenotype in the classic female patient and a small brain with some preserved islands of function, but with an inability to support hand use and speech. This paper summarizes our current observations about neuropathology of Rett syndrome. MRDD Research Reviews 2002;8:72,76. © 2002 Wiley-Liss, Inc. [source] Rett Syndrome and long-term disorder profileJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 10 2008E. Smeets Since the identification of mutations in MECP2 in females with clinical Rett syndrome, numerous efforts have been made to understand phenotype-genotype relationships. Most of these studies were conducted by examining the type and localization of these mutations in the gene in relation to clinical severity. It seemed unsatisfactory, in view of the age range and variable severity, to look only at the type and localization of the mutation in MECP2 in trying to establish a phenotype/genotype relationship. Describing each RTT individual after a long term follow up and grouping females with the same disorder history and same MECP2 mutation is therefore appropriate. Complete clinical and molecular data were obtained on 103 females. The guidelines for reporting manifestations common in Rett syndrome were used in the evaluation of clinical severity. The individuals were grouped according to similar disorder profiles on long-term follow up. In a cohort of 103 females clinically diagnosed with Rett syndrome, 91 had a detectable MECP2 mutation. 60% still sit and walk. Hand use is preserved or reduced in 44%. Speech has been lost in the majority (87%). Epilepsy was problematic in about 30%. Scoliosis, severe kyphosis or a combination of both was present in 27%, needing surgery in 13%. Description of the profile of the disorder and long-term clinical history facilitated the grouping of females with the same MECP2 mutation and a similar history. This approach will contribute more to the understanding of the ongoing pathology in Rett syndrome relative to the specific character of the involved MECP2 mutation. Some examples of these disorder profiles will be discussed. [source] Autonomic dysregulation in young girls with Rett Syndrome during nighttime in-home recordings,PEDIATRIC PULMONOLOGY, Issue 11 2008Debra E. Weese-Mayer MD Abstract This study was designed to specifically characterize the autonomic phenotype of cardiorespiratory dysregulation during the nighttime in young girls with MECP2 mutation-confirmed Rett Syndrome (RS), studied in their home environment. Computerized breath-to-breath and beat-to-beat characterization of at-home continuously recorded respiratory inductance plethysmography of chest/abdomen and ECG (VivoMetrics, Inc.) was obtained during overnight recordings in 47 girls with MECP2 mutation-confirmed RS and 47 age-, gender-, and ethnicity-matched screened controls (ages 2,7 years). We determined that although the breathing and heart rate appear more regular during the night compared to the day, young girls with RS demonstrate apparent nocturnal irregularities. Comparing daytime versus nighttime, breathing was more irregular, with an increased breathing frequency (and irregularity), mean amplitude of respiratory inductance plethysmography sum (AMP)/TI, and heart rate and decreased AMP in girls with RS. Comparing girls with RS versus controls during nighttime recording, breathing was more irregular, with an increased breathing frequency (and irregularity), mean AMP/TI, and heart rate. An increased uncoupling between measures of breathing and heart rate control indicates malregulation in the autonomic nervous system, and is apparent during the day as well as the night. This uncoupling may represent a mechanism that renders the girls with RS more vulnerable to sudden death. Pediatr Pulmonol. 2008; 43:1045,1060. © 2008 Wiley-Liss, Inc. [source] Neuropathology of Rett syndromeDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2002Dawna Duncan Armstrong Abstract Rett Syndrome is unlike any other pediatric neurologic disease, and its clinical-pathologic correlation can not be defined with standard histology techniques. Based on hypotheses suggested by careful clinical observations, the nervous system of the Rett child has been explored utilizing morphometry, golgi preparations, computerized tomography, magnetic resonance imaging, chemistry, immunocytochemistry, autoradiography, and molecular biologic techniques. From these many perspectives we conclude that Rett syndrome is not a typical degenerative disorder, storage disorder, nor the result of gross malformation, infectious or neoplastic processes. There remain regions of the brain that have not been studied in detail but the available data suggest that the neuropathology of Rett syndrome can be summarized as follows: the Rett brain is small for the age and the height of the patient; it does not become progressively smaller over three to four decades; it has small dendritic trees in pyramidal neurons of layers III and V in selected lobes (frontal, motor, and temporal); it has small neurons with an increased neuronal packing density; it has an immature expression of microtubular protein-2 and cyclooxygenase; it exhibits a changing pattern of neurotransmitter receptors with an apparent reduction in many neurotransmitters, possibly contributing to some symptomatology. A mutation in Mecp2 causes this unique disorder of brain development. Neuronal mosaicism for normal and mutated Mecp2 produces a consistent phenotype in the classic female patient and a small brain with some preserved islands of function, but with an inability to support hand use and speech. This paper summarizes our current observations about neuropathology of Rett syndrome. MRDD Research Reviews 2002;8:72,76. © 2002 Wiley-Liss, Inc. [source] Genetic basis of rett syndromeDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2002Ignatia B. Van den Veyver Abstract The origin of Rett syndrome has long been debated, but several observations have suggested an X-linked dominant inheritance pattern. We and others have pursued an exclusion-mapping strategy using DNA from a small number of familial Rett syndrome cases. This work resulted in the narrowing of the region likely to harbor the mutated gene to Xq27.3-Xqter. After systematic exclusion of several candidate genes, we discovered mutations in MECP2, the gene that encodes the transcriptional repressor, methyl-CpG-binding protein 2. Since then, nonsense, missense, or frameshift mutations have been found in at least 80% of girls affected with classic Rett syndrome. Sixty-four percent of mutations are recurrent C > T transitions at eight CpG dinucleotides mutation hotspots, while the C-terminal region of the gene is prone to recurrent multinucleotide deletions (11%). Most mutations are predicted to result in total or partial loss of function of MeCP2. There is no clear correlation between the type and position of the mutation and the phenotypic features of classic and variant Rett syndrome patients, and XCI appears to be a major determinant of phenotypic severity. Further research focuses on the pathogenic consequences of these mutations along the hypothesis of loss of transcriptional repression of a small number of genes that are essential for neuronal function in the maturing brain. MRDD Research Reviews 2002;8:82,86. © 2002 Wiley-Liss, Inc. [source] Survival with Rett syndrome: comparing Rett's original sample with data from the Australian Rett Syndrome DatabaseDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 10 2010MICHAEL FREILINGER Aim, Rett syndrome is a severe neurodevelopmental disorder that typically affects females. Little is known about the natural history and survival time of these females. Method, We compared the survival of all Austrian female participants from Rett's historical cohort (1966) with that of affected females registered in the Australian Rett Syndrome Database. The analysis included both Kaplan,Meier analysis and a log-rank test for equality of survivor functions. Results, Of females in the original Austrian group, three are still alive. The median age at death was 13 years 4.8 months. The probability of survival up to the age of 25 years was 21%, compared with 71% in the Australian cohort (p<0.001). We found no practical or statistically significant differences in survival between the various birth year groups within the Australian cohort. Interpretation, Our data indicate that survival of females with Rett syndrome has improved since the late 1960s but that there has been shown no change in survival over the last 30 years, possibly because the follow-up time has been too short. [source] Level of purposeful hand function as a marker of clinical severity in Rett syndromeDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 9 2010JENNY DOWNS Aim, We investigated relationships between hand function and genotype and aspects of phenotype in Rett syndrome. Method, Video assessment in naturalistic settings was supplemented by parent-reported data in a cross-sectional study of 144 females with a mean age of 14 years 10 months (SD 7y 10mo; range 2y,31y 10mo), 110 of whom had a mutation of the methyl CpG binding protein 2 (MECP2) gene. Ordinal logistic regression was used to assess relationships between hand function and MECP2 mutation, age, a modified Kerr score, Functional Independence Measure for Children (WeeFIM), ambulation level, and frequency of hand stereotypies. Results, Approximately two-thirds of participants demonstrated purposeful hand function, ranging from simple grasping skills to picking up and manipulating small objects. In participants with a confirmed MECP2 mutation, those with the p.R168X mutation had the poorest hand function on multivariate analysis with C-terminal deletion as the baseline (odds ratio [OR] 0.19; 95% confidence interval [CI] 0.04,0.95), whereas those with the p.R133C or p.R294X mutation had better hand function. Participants aged 19 years or older had lower hand function than those aged less than 8 years (OR 0.36; 95% CI 0.14,0.92). Factors that were associated with better hand function were lower Kerr scores for a 1-point increase in score (OR 0.77; 95% CI 0.69,0.86), higher WeeFIM scores for a 1-point increase in score (OR 1.08; 95% CI 1.04,1.12), and greater ambulation than those completely dependent on carers for mobility (OR 22.64; 95% CI 7.02,73.08). The results for participants with a confirmed pathogenic mutation were similar to results obtained when participants without a mutation were also included. Interpretation, Our novel assessment of hand function in Rett syndrome correlated well with known profiles of common MECP2 mutations and overall clinical severity. This promising assessment could measure clinical responses to therapy. [source] Vagus nerve stimulation for treatment of epilepsy in Rett syndromeDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 8 2006Angus A Wilfong MD, Assistant Professor This case series presents the outcomes of seven females with Rett syndrome and medically refractory epilepsy who were treated with adjunctive vagus nerve stimulation (VNS) therapy for a minimum of 12 months. Patients ranged in age from 1 to 14 years (median age 9y) at the time of implantation, had experienced seizures for a median period of approximately 6 years, and had failed at least two trials of antiepileptic drugs before receiving VNS. The median number of seizures per month was 150 (range 12,3600). At 12 months, six females had ,50% reduction in seizure frequency. VNS was safe and well tolerated, with no surgical complications and no patients requiring explantation of the device. Quality of life outcomes of note among these patients included reports at 12 months of increased alertness among all seven patients. No change in mood or communication abilities was noted. [source] Findings from a multidisciplinary clinical case series of females with Rett syndromeDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 5 2003Hilary Cass BSc FRCPCH Systematic data from a multidisciplinary clinical assessment of a large series of females with Rett syndrome (RS; n=87) is presented. Participants' ages ranged from 2 years 1 month to 44 years 10 months. Areas assessed included oromotor skills, feeding problems, growth, breathing abnormalities, mobility, postural abnormalities and joint deformities, epilepsy, hand use and stereotypies, self-care, and cognitive and communication skills. Many previously reported trends in the presentation of RS over time were confirmed, notably the increasingly poor growth and near pervasiveness of fixed joint deformities and scoliosis in adulthood. In contrast, there was a slight trend towards improved autonomic function in adulthood, whereas feeding difficulties increased into middle childhood and then reached a plateau. Improvements in mobility into adolescence were followed by a decline in those skills in adulthood. Levels of dependency were high, confirming findings from previous studies. Despite the presence of repetitive hand movements, a range of hand-use skills was seen in individuals of all ages. Cognitive and communication skills were limited, but there was little evidence of deterioration of these abilities with age. These findings confirm that RS is not a degenerative condition and indicate that intervention and support to maintain and increase motor skills, daily living skills, and cognitive and communicative functioning are appropriate targets for individuals with RS. [source] Epigenetic dysregulation in cognitive disordersEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2009Johannes Gräff Abstract Epigenetic mechanisms are not only essential for biological functions requiring stable molecular changes such as the establishment of cell identity and tissue formation, they also constitute dynamic intracellular processes for translating environmental stimuli into modifications in gene expression. Over the past decade it has become increasingly clear that both aspects of epigenetic mechanisms play a pivotal role in complex brain functions. Evidence from patients with neurodegenerative and neurodevelopmental disorders such as Alzheimer's disease and Rett syndrome indicated that epigenetic mechanisms and chromatin remodeling need to be tightly controlled for proper cognitive functions, and their dysregulation can have devastating consequences. However, because they are dynamic, epigenetic mechanisms are also potentially reversible and may provide powerful means for pharmacological intervention. This review outlines major cognitive disorders known to be associated with epigenetic dysregulation, and discusses the potential of ,epigenetic medicine' as a promising cure. [source] Mutations and polymorphisms in the human methyl CpG-binding protein MECP2,,HUMAN MUTATION, Issue 2 2003Gabriel Miltenberger-Miltenyi Abstract Rett syndrome (RTT or RS) is a neurodevelopmental disorder and one of the most frequent genetic diseases in girls. Mutations of the MECP2 gene have been found in a variety of different RTT phenotypes. The MECP2 gene (Xq28) has been described in 1992. Up to now, 218 different mutations have been reported in a total group, of more than 2,100 patients. Mutations in the MECP2 gene are responsible for up to 75% of the classical RTT cases. The mutations, are distributed along the whole gene and are comprised of all types of mutations. Several polymorphisms and benign genetic variants have also been described. Apart from spared reported familial cases, almost all cases are sporadic. RTT syndrome has been considered to be a lethal trait in males. Studying the parental origin of the mutations, however, we and others have found a very high prevalence of de novo mutations on the paternal chromosome. In this work we summarize the mutational reports published until now. One of our aims was to check the mutations' descriptions for consistency and particularly to rename them according to the recommended mutation nomenclature. The increasing number of investigations on the functions of the MeCP2 can help to gain more information about the neuropathogenetic mechanisms causing RTT. Hum Mutat 22:107,115, 2003. © 2003 Wiley-Liss, Inc. [source] Five novel frameshift mutations in exon 3 and 4 of the MECP2 gene identified in Rett patients: Consequences for the molecular diagnosis strategyHUMAN MUTATION, Issue 3 2001Thierry Bienvenu Abstract Rett syndrome (RTT) is a severe progressive neurological disorder that affects almost exclusively females. The gene responsible for this disorder, MECP2, was recently identified by candidate gene strategy. Mutations were detected in 70-85% of RTT cases. We report here five novel frameshift mutations (named 345delC, 895del202, 989ins18del8, 996insAG and 1124del53) in exon 3 and 4 of the MECP2 gene. To avoid the missing of few small deletions in RTT patients using classical mutation screening approaches, we suggest that screening of the mutations in the MECP2 gene in RTT girls should include at least a large PCR to amplify exon 4 entirely. Hum Mutat 18:251,252, 2001. © 2001 Wiley-Liss, Inc. [source] Imbalanced genomic imprinting in brain development: an evolutionary basis for the aetiology of autismJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 4 2006C. BADCOCK Abstract We describe a new hypothesis for the development of autism, that it is driven by imbalances in brain development involving enhanced effects of paternally expressed imprinted genes, deficits of effects from maternally expressed genes, or both. This hypothesis is supported by: (1) the strong genomic-imprinting component to the genetic and developmental mechanisms of autism, Angelman syndrome, Rett syndrome and Turner syndrome; (2) the core behavioural features of autism, such as self-focused behaviour, altered social interactions and language, and enhanced spatial and mechanistic cognition and abilities, and (3) the degree to which relevant brain functions and structures are altered in autism and related disorders. The imprinted brain theory of autism has important implications for understanding the genetic, epigenetic, neurological and cognitive bases of autism, as ultimately due to imbalances in the outcomes of intragenomic conflict between effects of maternally vs. paternally expressed genes. [source] Rett Syndrome and long-term disorder profileJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 10 2008E. Smeets Since the identification of mutations in MECP2 in females with clinical Rett syndrome, numerous efforts have been made to understand phenotype-genotype relationships. Most of these studies were conducted by examining the type and localization of these mutations in the gene in relation to clinical severity. It seemed unsatisfactory, in view of the age range and variable severity, to look only at the type and localization of the mutation in MECP2 in trying to establish a phenotype/genotype relationship. Describing each RTT individual after a long term follow up and grouping females with the same disorder history and same MECP2 mutation is therefore appropriate. Complete clinical and molecular data were obtained on 103 females. The guidelines for reporting manifestations common in Rett syndrome were used in the evaluation of clinical severity. The individuals were grouped according to similar disorder profiles on long-term follow up. In a cohort of 103 females clinically diagnosed with Rett syndrome, 91 had a detectable MECP2 mutation. 60% still sit and walk. Hand use is preserved or reduced in 44%. Speech has been lost in the majority (87%). Epilepsy was problematic in about 30%. Scoliosis, severe kyphosis or a combination of both was present in 27%, needing surgery in 13%. Description of the profile of the disorder and long-term clinical history facilitated the grouping of females with the same MECP2 mutation and a similar history. This approach will contribute more to the understanding of the ongoing pathology in Rett syndrome relative to the specific character of the involved MECP2 mutation. Some examples of these disorder profiles will be discussed. [source] Review article: Breaking new ground with Rett syndromeJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 8 2003A. M. Kerr First page of article [source] Motion analysis of stereotyped hand movements in Rett syndromeJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 2 2003M. Wright Abstract Background Rett syndrome is a genetic developmental disorder, and stereotyped hand movements are a striking feature of this condition. The aim of the present study was to subject these movements to objective analysis and compare the results in one girl at different ages. Method The hand movements of a 10-year-old girl with Rett syndrome were subjected to accurate, three-dimensional (3D) computerized motion analysis and compared to two-dimensional (2D) video analysis of the same girl at 3 years of age. Results Three-dimensional computerized analysis revealed regular patterns with strong coupling between the hands. Frequency analysis showed a dominant frequency at 1.2 Hz, with a higher component at 2.4 Hz that may relate to the activity of basic rhythm generators. The same coupling characteristics were extracted from standard, 2D video recordings made at the same time as the 3D capture. Conclusion An informal video of the same girl taken when she was 3 years of age was analysed in the same way as the 2D video and showed the same characteristics, indicating the possible future use of automated video analysis for early screening and intervention evaluation. [source] Aminoglycoside-mediated partial suppression of MECP2 nonsense mutations responsible for Rett syndrome in vitroJOURNAL OF NEUROSCIENCE RESEARCH, Issue 11 2010Andreea C. Popescu Abstract Rett syndrome is a pediatric neurological condition that affects primarily girls. Approximately 30% of Rett syndrome cases arise from point mutations that introduce a premature stop codon into the MECP2 gene. Several studies have now shown that certain aminoglycosides can facilitate read-through of some types of nonsense mutations in a context-dependent manner and allow the generation of a full-length protein. It remains mostly unclear whether different nonsense mutations of MECP2 will be responsive to aminoglycoside treatment. In this study, we tested whether the common premature terminating mutations of MECP2 seen in Rett syndrome cases can be partially suppressed by aminoglycoside administration. Our results show that aminoglycosides allow different mutant forms of MECP2 to be overcome in transiently transfected HEK293 cells, but with differing levels of efficiency. In addition, we also show that aminoglycosides increased the prevalence of full-length MeCP2 protein in a dose-dependent manner in a lymphocyte cell line derived from a Rett syndrome girl with the R255X mutation. This study helps to establish the "proof of principle" that some nonsense mutations causing Rett syndrome can be at least partially suppressed by drug treatment. © 2010 Wiley-Liss, Inc. [source] Trisomy 21 and Rett syndrome: A double burdenJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 7 2004H Leonard Abstract: Rett syndrome is a severe neurodevelopmental disorder generally affecting girls. Affected individuals are apparently normal at birth but later pass through a period of regression with loss of hand and communication skills and the development of hand stereotypies and dyspraxia. Mutations in the methyl-CpG binding protein 2 (MECP2) gene, have now been found to cause Rett syndrome in up to 80% of classical cases. We report a girl with Down syndrome, one of three children with birth defects in a family of five. From the age of 18 months she developed symptomatology considered by her primary physician to be very characteristic of Rett syndrome. However, this remained a clinical diagnosis till the age of 12 years. Laboratory confirmation of the dual diagnosis, which includes a R168X mutation in the MECP2 gene in addition to trisomy 21, has now been possible. The presence of one neurological or developmental disorder does not necessarily preclude a diagnosis of Rett syndrome. [source] Family data in Rett syndrome: Association with other genetic disordersJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 4 2000H Leonard Background: Rett syndrome is a neurological disorder, almost exclusively affecting girls. Methodology: Between 1993 and 1995 pedigree data were obtained from families of girls registered with the Australian Rett syndrome database. Results: Although 21 individual disorders were reported to be present in family members of affected girls, there was no apparent clustering of the same disorder in different families. However it was certain that a geneticist had been involved in only 10.9% of cases. Conclusions: Mutations in the MECP2 gene have now been reported in a proportion of sporadic cases. Thus, it will be important to examine this phenotype,genotype correlation in the Australian cohort. Where a mutation is found, prenatal diagnosis in a subsequent pregnancy will be a possibility. Using the Australian population database and in conjunction with the clinical genetic services in each state it is planned to contact families with an affected girl to offer testing and counselling. [source] Abnormal movements in Rett syndrome are present before the regression period: A case studyMOVEMENT DISORDERS, Issue 15 2007Teresa Temudo MD Abstract The suspicion of a diagnosis of Rett syndrome (RTT) is based on clinical criteria that are often not present in the first two stages of the disease, as many of its symptoms will appear at a later age. This sometimes postpones the genetic diagnosis and an early clinical intervention. We present the case of 19-months-old girl who came to the consultation because of an arrest of psychomotor development noticed 5 months earlier without change in sleep pattern, behavior, or social communication. In the observation of 1 hour videotape, she presented subtle stereotypic movements of the face and hands as well as repetitive dystonic posturing of her limbs. A genetic test confirmed the diagnosis of RTT, showing a truncating mutation in the MECP2 gene (R270X). This case confirms that stereotypic movement anomalies, albeit infrequent and subtle, are already present before the regression stage and while maintaining prehension and that, in addition, repetitive dystonic postures may occur. Recognition of these early movement disorders will improve clinicians' ability to perform an earlier diagnosis of RTT. © 2007 Movement Disorder Society [source] Etiologic yield of autistic spectrum disorders: A prospective studyAMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2006Agatino Battaglia Abstract Studies addressing etiologic yield in childhood developmental disabilities have mainly looked at individuals with developmental delay/mental retardation. The few studies addressing the question of etiologic yield in patients with pervasive developmental disorders (PDDs) had a major drawback, in that the enrolled subjects were diagnosed as having the autistic spectrum disorders based only on history and clinical examination, and/or on unspecified instruments. In addition, only some of these patients underwent a complete laboratory evaluation. To investigate the etiologic yield of PDDs, we undertook a large prospective study on subjects selected according to very strict criteria and diagnosed as having PDD based on the present "gold standard" (ADI-R and ADOS-G), and a clinical diagnosis made by a child psychiatrist. Eighty-five (85) patients with PDD and their first degree relatives participated in this study. These patients were selected from a sample of 236 subjects who had received a clinical diagnosis of PDD at the Stella Maris Institute between March 2002 and 2005. Selection criteria for entering the study were: (1) a diagnosis of PDD (with exclusion of the Rett syndrome) confirmed after the administration of the ADI-R (autism diagnostic interview-revised) and the ADOS-G (autism diagnostic observation schedule-generic). In addition, a clinical diagnosis was made by the child psychiatrist, on the basis of presence or absence of DSM-IV symptoms of autism; (2) chronological age between 4 and 18 years; (3) IQ>30; (4) availability of both biologic parents. Patients, 65/85 (76.5%), had autism, 18/85 (21.2%) had PDD-NOS, and the remaining 2/85 (2.3%) had Asperger syndrome. Ages varied between 4 years 2 months and 12 years 5 months (mean 7.6 years), and there was a marked male preponderance (68/85). All subjects underwent various laboratory studies and neuroimaging. With respect to possible etiologic determination, a detailed history and physical examination in this group of patients with PDD was informative in 10.5% (9/85). HRB karyotype was diagnostic in one, and molecular fragile X studies in one child. Brain MRI was informative in two children (2.3%) with relative macrocrania but no neurological features; and EEG was helpful in one child, identifying a Landau,Kleffner disorder. Audiometry and brainstem auditory evoked potentials (BAEPs) showed a bilateral sensorineural loss in another child. Metabolic evaluation gave normal results in all subjects. The results suggest an evaluation paradigm with reference to etiologic determination for individuals with PDDs that does not presently justify metabolic or neuroimaging on a screening basis. Recurrence risk, treatment implications, and significant and long-lasting emotional relief for the parents suggest that serious consideration be given to clinical genetic examination, genetic testing, EEG study (during wakefulness and sleep), and audiometry, despite a relatively low yield. © 2006 Wiley-Liss, Inc. [source] The Rett Syndrome Behaviour Questionnaire (RSBQ): refining the behavioural phenotype of Rett syndromeTHE JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES, Issue 8 2002Rebecca H. Mount Background: Although physical features, including loss of hand skills, deceleration of head growth, spasticity and scoliosis, are cardinal features of Rett syndrome (RS), a number of behavioural features are also associated with the disorder, including hand stereotypies, hyperventilation and breath holding. No study has tested the specificity of these behavioural features to individuals with RS, compared to individuals with severe to profound mental retardation (SMR). Method: A novel checklist of characteristic RS behavioural and emotional features, the Rett Syndrome Behaviour Questionnaire (RSBQ), was developed to test the type and specificity of behavioural features of RS against those found in girls with SMR. Results: After controlling for the effects of RS-related physical disabilities, the RSBQ discriminated between the groups. Some aspects of the behaviours found to be specific to RS are included in the necessary or supportive RS diagnostic criteria, notably hand behaviours and breathing problems. Additional behavioural features were also more frequently reported in the RS than the SMR group, including mood fluctuations and signs of fear/anxiety, inconsolable crying and screaming at night, and repetitive mouth and tongue movements and grimacing. Conclusions: Full validation of the scale requires confirmation of its discriminatory power and reliability with independent samples of individuals with RS and SMR. Further delineation of the specific profile of behaviours seen in RS may help in identification of the function of the MECP2 gene and in improved differential diagnosis and management of individuals with RS. [source] Annotation: Rett syndrome: recent progress and implications for research and clinical practiceTHE JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES, Issue 3 2002Alison Kerr Background: Rett syndrome was first described 40 years ago as a profoundly disabling condition in girls. Method: Over the last 20 years' national surveys, neuropathological and neurophysiological research have steadily improved understanding of its character and natural history. Results: In the last two years identification of the causative mutations in the gene methyl CpG binding protein 2 (Xq28) has led to a sudden expansion in knowledge about the underlying developmental disorder, with important implications for clinical practice and new opportunities to develop more effective intervention. Conclusions: It is now clear that the disorder occurs in males and females and that there is a wide range in severity. [source] Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndromeTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 1 2008Nadia P. Belichenko Abstract Rett syndrome (RTT) is caused by mutations in the X-linked gene MECP2. While patients with RTT show widespread changes in brain function, relatively few studies document changes in brain structure and none examine in detail whether mutations causing more severe clinical phenotypes are linked to more marked changes in brain structure. To study the influence of MeCP2-deficiency on the morphology of brain areas and axonal bundles, we carried out an extensive morphometric study of two Mecp2-mutant mouse models (Mecp2B and Mecp2J) of RTT. Compared to wildtype littermates, striking changes included reduced brain weight (,13% and ,9%) and the volumes of cortex (,11% and ,7%), hippocampus (both by ,8%), and cerebellum (,12% and 8%) in both mutant mice. At 3 weeks of age, most (24 of 47) morphological parameters were significantly altered in Mecp2B mice; fewer (18) were abnormal in Mecp2J mice. In Mecp2B mice, significantly lower values for cortical area were distributed along the rostrocaudal axis, and there was a reduced length of the olfactory bulb (,10%) and periaqueductal gray matter (,16%). In Mecp2J mice, while there was significant reduction in rostrocaudal length of cortex, this parameter was also abnormal in hippocampus (,10%), periaqueductal gray matter (,13%), fimbria (,18%), and anterior commissure (,10%). Our findings define patterns of Mecp2 mutation-induced changes in brain structure that are widespread and show that while some changes are present in both mutants, others are not. These observations provide the underpinning for studies to further define microarchitectural and physiological consequences of MECP2 deficiency. J. Comp. Neurol. 508:184,195, 2008. © 2008 Wiley-Liss, Inc. [source] Brain metabolism in rett syndrome: Age, clinical, and genotype correlations,ANNALS OF NEUROLOGY, Issue 1 2009Alena Horská PhD Objective Brain metabolism, as studied by magnetic resonance spectroscopy (MRS), has been previously shown to be abnormal in Rett syndrome (RTT). This study reports the relation of MRS findings to age, disease severity, and genotype. Methods Forty RTT girls (1,14 years old) and 12 age-matched control subjects were examined. Single-voxel proton MRS of left frontal white matter was performed. Results NAA/Cr ratios decreased and myoinositol/Cr ratios increased with age in RTT patients (both p < 0.03), whereas these ratios were stable in control. The mean glutamate and glutamine/Cr ratio was 36% greater in RTT patients than in control (p = 0.043). The mean NAA/Cr ratio was 12.6% lower in RTT patients with seizures compared with those without seizures (p = 0.017). NAA/Cr ratios decreased with increasing clinical severity score (p = 0.031). Compared with patients with T158X, R255X, and R294X mutations, and C-terminal deletions, patients with the R168X mutation tended to have the greatest severity score (0.01 , p , 0.11) and the lowest NAA/Cr ratio (0.029 , p < 0.14). Interpretation Decreasing NAA/Cr and increasing myoinositol/Cr with age are suggestive of progressive axonal damage and astrocytosis in RTT, respectively, whereas increased glutamate and glutamine/Cr ratio may be secondary to increasing glutamate/glutamine cycling at the synaptic level. The relations between NAA/Cr, presence or absence of seizures, and disease severity suggest that MRS provides a noninvasive measure of cerebral involvement in RTT. Ann Neurol 2009;65:90,97 [source] Association by guilt: identification of DLX5 as a target for MeCP2 provides a molecular link between genomic imprinting and Rett syndromeBIOESSAYS, Issue 7 2005Sharmila Bapat Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder affecting almost exclusively girls. Although mutations in methyl-CpG-binding protein (MeCP2) are known to be associated with RTT, gene expression patterns are not significantly altered in MeCP2-deficient cells. A recent study1 identified MeCP2-mediated histone modification and formation of a higher-order chromatin loop structure specifically associated with silent chromatin at the Dlx5,Dlx6 locus in normal cells, and its absence thereof in RTT patients. This altered expression of Dlx5 through loss of silent chromatin loop formation provides a molecular mechanism underlying RTT and proposes a novel role for MeCP2 in chromatin organization and imprinting. © 2005 Wiley Periodicals, Inc. BioEssays 27:676,680, 2005. © 2005 Wiley Periodicals, Inc. [source] Genomic imprinting in the development and evolution of psychotic spectrum conditionsBIOLOGICAL REVIEWS, Issue 4 2008Bernard Crespi Abstract I review and evaluate genetic and genomic evidence salient to the hypothesis that the development and evolution of psychotic spectrum conditions have been mediated in part by alterations of imprinted genes expressed in the brain. Evidence from the genetics and genomics of schizophrenia, bipolar disorder, major depression, Prader-Willi syndrome, Klinefelter syndrome, and other neurogenetic conditions support the hypothesis that the etiologies of psychotic spectrum conditions commonly involve genetic and epigenetic imbalances in the effects of imprinted genes, with a bias towards increased relative effects from imprinted genes with maternal expression or other genes favouring maternal interests. By contrast, autistic spectrum conditions, including Kanner autism, Asperger syndrome, Rett syndrome, Turner syndrome, Angelman syndrome, and Beckwith-Wiedemann syndrome, commonly engender increased relative effects from paternally expressed imprinted genes, or reduced effects from genes favouring maternal interests. Imprinted-gene effects on the etiologies of autistic and psychotic spectrum conditions parallel the diametric effects of imprinted genes in placental and foetal development, in that psychotic spectrum conditions tend to be associated with undergrowth and relatively-slow brain development, whereas some autistic spectrum conditions involve brain and body overgrowth, especially in foetal development and early childhood. An important role for imprinted genes in the etiologies of psychotic and autistic spectrum conditions is consistent with neurodevelopmental models of these disorders, and with predictions from the conflict theory of genomic imprinting. [source] MECP2 mutations in Serbian Rett syndrome patientsACTA NEUROLOGICA SCANDINAVICA, Issue 6 2007A. Djarmati Background,,, Rett syndrome is a severe neurodevelopmental X-linked dominant disorder affecting 1/15,000 girls worldwide. Eight years ago, the MECP2 gene was associated with the devastating clinical features observed in Rett syndrome patients. Objectives,,, To investigate the spectrum and the frequency of MECP2 mutations in Serbian Rett syndrome patients. Patients and methods,,, We screened the MECP2 coding region by conventional mutational screening (single-strand conformation polymorphism/sequencing) in 24 patients of Serbian origin and in their 41 unaffected family members. In search for gene dosage alterations in seemingly mutation-negative girls, we developed a new, specific quantitative PCR method. Results,,, Nineteen patients (79%) carried MECP2 mutations, five of which were novel (one nonsense mutation, one duplication and three deletions). Fourteen previously described disease-causing sequence changes and one polymorphism were also detected. Detailed case reports are given for the carriers of the novel mutations. Large MECP2 rearrangements cause Rett syndrome in a significant number of girls without ,classic' mutations in this gene. Therefore, we developed a specific quantitative PCR method, covering MECP2 exons 3 and 4, which previously has not been used for screening. No dosage alterations of the two exons were found in the four tested mutation-negative girls. Conclusions,,, This is the first genetic study of Rett syndrome in Serbian patients describing the MECP2 mutational and phenotypic spectrum in this population. Detailed clinical descriptions of this ethnically homogeneous patient population add to our knowledge of genotype/phenotype correlations in this severe condition. [source] De novo duplication of MECP2 in a girl with mental retardation and no obvious dysmorphic featuresCLINICAL GENETICS, Issue 2 2010P Makrythanasis Makrythanasis P, Moix I, Gimelli S, Fluss J, Aliferis K, Antonarakis SE, Morris MA, Béna F, Bottani A. De novo duplication of MECP2 in a girl with mental retardation and no obvious dysmorphic features. Loss-of-function mutations of MECP2 are responsible for Rett syndrome (RTT), an X-linked neurodevelopmental disorder affecting mainly girls. The availability of MECP2 testing has led to the identification of such mutations in girls with atypical RTT features and the recognition of milder forms. Furthermore, duplication of the entire gene has recently been described in boys with mental retardation and recurrent infections. We describe a girl with a heterozygous de novo MECP2 duplication. The patient, at the age of 19, has mental retardation with no autistic features. She is friendly but gets frequently anxious. She has neither dysmorphic features nor malformations. Her motor development was delayed with walking at 20 months. Speech is fluid with good pronunciation but is simple and repetitive. Diagnosis was made after single-strand conformation analysis (SSCA) and multiplex ligation-dependent probe amplification (MLPA) analysis of MECP2. Array comparative genomic hybridization (aCGH) analysis showed a duplication of 29 kb including MECP2 and part of IRAK1. Fluorescent in situ hybridization (FISH) has revealed that the duplicated region is inserted near the telomere of the short arm of chromosome 10. X-chromosome inactivation in leukocyte DNA was not skewed. We conclude that it is likely that this MECP2 duplication is responsible for the mental retardation in this patient. This case broadens the phenotypic spectrum of MECP2 abnormalities with consequent implication in diagnosis and genetic counselling of girls with non-syndromic mental retardation. [source] Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literatureCLINICAL GENETICS, Issue 4 2009C Nemos The CDKL5 gene has been implicated in the molecular etiology of early-onset intractable seizures with infantile spasms (IS), severe hypotonia and atypical Rett syndrome (RTT) features. So far, 48 deleterious alleles have been reported in the literature. We screened the CDKL5 gene in a cohort of 177 patients with early-onset seizures, including 30 men and 10 girls with Aicardi syndrome. The screening was negative for all men as well as for women with Aicardi syndrome, excluding the CDKL5 gene as a candidate for this neurodevelopmental disorder. We report 11 additional de novo mutations in CDKL5 in female patients. For the first time, the MLPA approach allowed the identification of a partial deletion encompassing the promoter and the first two exons of CDKL5. The 10-point mutations consist of five missenses (with recurrent amino acid changes at p.Ala40 and p.Arg178), four splicing variants and a 1-base pair duplication. We present a review of all mutated alleles published in the literature. In our study, the overall frequency of mutations in CDKL5 in women with early-onset seizures is around 8.6%, a result comparable with previous reports. Noteworthy, the CDKL5 mutation rate is high (28%) in women with early-onset seizures and IS. [source] | |||||||||||||