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Sample records for rett syndrome brain

  1. Immature pattern of brain activity in Rett syndrome

    DEFF Research Database (Denmark)

    Nielsen, J B; Friberg, L; Lou, H;

    1990-01-01

    69 mL/100 g per minute), and the flows in prefrontal and temporoparietal association regions of the telencephalon were markedly reduced, whereas the primary sensorimotor regions were relatively spared. The flow distribution in Rett syndrome is very similar to the distribution of brain metabolic...... activity in infants of a few months of age. The abnormal regional cerebral blood flow distribution most likely reflects the widespread functional disturbances in the brain of patients with Rett syndrome, whereas computed tomographic and neuropathologic examination only reveal slight changes when compared...

  2. Rett Syndrome.

    Science.gov (United States)

    Culbert, Linda A.

    This pamphlet reviews the historical process involved in initially recognizing Rett Syndrome as a specific disorder in girls. Its etiology is unknown, but studies have considered factors as hyperammonemia, a two-step mutation, a fragile X chromosome, metabolic disorder, environmental causation, dopamine deficiency, and an inactive X chromosome.…

  3. Brain perfusion SPECT and EEG findings in Rett syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Lappalainen, R. [Children`s Castle Hospital, Dept. of Child Neurology, Helsinki (Finland); Liewendahl, K.; Nikkinen, P. [Univ. Central Hospital, Division of Nuclear Medicine, Laboratory Dept., Helsinki (Finland); Sainio, K.; Riikonen, R.S. [Univ. Central Hospital, Child Neurology, Helsinki (Finland)

    1997-01-01

    Thirteen patients (mean age 8.4 + 5.3 years) with Rett syndrome (RS) were studied with EEG and {sup 99m}Tc-HMPAO SPECT. Eleven patients had background abnormalities and 10 patients paroxysmal activity in EEG. Hypoperfusion of varying severity was detected in 11 patients, 7 patients having multiple lesions. Bifrontal hypoperfusion, observed in 6 patients, was the most distinctive finding. Hypoperfusion was observed also in other cortical regions, except for the occipital lobes. There was no correlation between severity of the background abnormality or presence of paroxysmal activity in EEG and grade of hypoperfusion. There was, however, an association between the severity of hypoperfusion and early manifestation of symptoms in patients with RS. Whether this early-onset group of patients represents a different disease entity or only reflects disease variability the basic pathology being the same, is a possibility that deserves further clarification. (au) 37 refs.

  4. Neuropathology of Rett syndrome.

    Science.gov (United States)

    Jellinger, K; Armstrong, D; Zoghbi, H Y; Percy, A K

    1988-01-01

    Rett syndrome is an increasingly recognized progressive disorder in females, commencing in infancy and characterized by autistic behavior, gait ataxia, stereotyped movements, seizures and generalized growth and mental retardation, possibly associated with disorders of central biogenic amine synthesis. The gene locus and pathogenesis of Rett syndrome are unknown. Autopsy studies in nine girls dying between 4 and 17 years, and sural nerve and muscle biopsies from two girls aged 3 and 17 years showed: (1) diffuse cortical atrophy/micrencephaly, with a decrease in brain weight by 12% to 34% of age-matched controls, apparently related to the duration of the disorder; (2) mild diffuse cortical atrophy with increased amounts of neuronal lipofuscin and occasional mild gliosis, but without signs of a storage disorder; (3) underpigmentation of the zona compacta nigrae, which showed fewer well-pigmented neurons for age and fewer melanin granules per neuron, while total numbers of nigral neurons and the substructure of neuromelanin were normal for age. No pathological changes were seen in other transmitter-specific brain stem nuclei; (4) immunoreactivity for tyrosine hydroxylase was slightly reduced in nigral and hypothalamic neurons, and the pituitary gland showed decreased immunoreaction for prolactin and growth hormone; (5) ultrastructurally, in frontal cortex and caudate nucleus, isolated abnormal neurites and reactive or degenerative axonal swellings were seen; the latter are possibly related to the nigral changes, suggesting some dysfunction of the dopaminergic nigrostriatal system, which is supported by neurochemical data; (6) preliminary biochemical studies revealed increased beta-endorphines in thalamus and cerebellum; (7) peripheral nerves demonstrated increase in small fibers without demyelination and increased numbers of neurofilaments in axons, suggesting distal axonopathy, while skeletal muscle showed alterations in the sarcoplasmic reticulum with circular

  5. Developmental Dynamics of Rett Syndrome.

    Science.gov (United States)

    Feldman, Danielle; Banerjee, Abhishek; Sur, Mriganka

    2016-01-01

    Rett Syndrome was long considered to be simply a disorder of postnatal development, with phenotypes that manifest only late in development and into adulthood. A variety of recent evidence demonstrates that the phenotypes of Rett Syndrome are present at the earliest stages of brain development, including developmental stages that define neurogenesis, migration, and patterning in addition to stages of synaptic and circuit development and plasticity. These phenotypes arise from the pleotropic effects of MeCP2, which is expressed very early in neuronal progenitors and continues to be expressed into adulthood. The effects of MeCP2 are mediated by diverse signaling, transcriptional, and epigenetic mechanisms. Attempts to reverse the effects of Rett Syndrome need to take into account the developmental dynamics and temporal impact of MeCP2 loss.

  6. International Rett Syndrome Foundation

    Science.gov (United States)

    ... Research awards Our research will help millions A cure for Rett will yield major advances toward treatments for millions of people around the world with Autism, Parkinson's, Alzheimers, Schizophrenia and Traumatic Brain Injuries. Make ...

  7. Urinary Peptides in Rett Syndrome.

    Science.gov (United States)

    Solaas, K. M.; Skjeldal, O.; Gardner, M. L. G.; Kase, B. F.; Reichelt, K. L.

    2002-01-01

    A study found a significantly higher level of peptides in the urine of 53 girls with Rett syndrome compared with controls. The elevation was similar to that in 35 girls with infantile autism. Levels of peptides were lower in girls with classic Rett syndrome than those with congenital Rett syndrome. (Contains references.) (Author/CR)

  8. Rett Syndrome -- an update.

    Science.gov (United States)

    Jellinger, K A

    2003-06-01

    Rett syndrome is a progressive, usually sporadic and rarely familial, disabling neurodevelopmental disorder with onset in early childhood presenting clinically with mental retardation, behavioral changes, late movement disturbances, loss of speech and hand skills, ataxia, apraxia, irregular breathing with hyperventilation while awake, and frequent seizures. It occurs almost exclusively in females with an estimated prevalence of 1 in 10-22000 births and is considered a manifestation of defective brain maturation caused by dominant mutation of the MeCP2 gene encoding the transcriptional repressor methyl-CpG-binding protein 2 related to the Xq28 locus. Although many different mutations of this protein are being studied in humans and in mice, the molecular pathogenesis of this disorder remains unclear. Electroencephalography is abnormal in the final stages of the syndrome. Neuroimaging showing brain atrophy may be required for differential diagnosis that includes neurodegenerative and metabolic disorders. Neuropathology shows decreased brain growth and reduced size of individual neurons, with thinned dendrites in some cortical layers and abnormalities in substantia nigra (decreased neuromelanin content), suggestive of deficient synaptogenic development, probably starting before birth. Neurometabolic changes include reduced levels of dopamine, serotonin, noradrenalin, choline acetyltransferase (ChAT), nerve growth factors, endorphines, glutamate, and other amino acids and their receptor levels in brain. Current treatment includes symptomatic, anticonvulsive and physiotherapy.

  9. Rett Syndrome Fact Sheet

    Science.gov (United States)

    ... gradually, mental and physical symptoms appear. As the syndrome progresses, the child loses purposeful use of her hands and the ... the difficulties with symptoms, many individuals with Rett syndrome continue to live well into middle age and beyond. Because the disorder is rare, ...

  10. The role of microglia in brain maintenance: implications for Rett syndrome.

    Science.gov (United States)

    Derecki, Noël C; Cronk, James C; Kipnis, Jonathan

    2013-03-01

    The role of microglia in central nervous system (CNS) pathology has been studied extensively, and more recently, examination of microglia in the healthy brain has yielded important insights into their many functions. It was long assumed that microglia were essentially quiescent cells, unless provoked into activation, which was considered a hallmark of disease. More recently, however, it has become increasingly clear that they are extraordinarily dynamic cells, constantly sampling their environment and adjusting to exquisitely delicate stimuli. Along these lines, our laboratory has identified a new and unexpected role for microglial phagocytosis - or lack thereof - in the pathophysiology of Rett syndrome, a neurodevelopmental disease caused by mutation of the gene encoding methyl-CpG binding protein (MECP)2. We have shown that specific expression of wild type Mecp2 in myeloid cells of Mecp2-null mice is sufficient to arrest major symptoms associated with this devastating disease. This beneficial effect, however, is abolished if phagocytic activity of microglia is inhibited. Here, we discuss microglial origins, the role of microglia in brain development and maintenance, and the phenomenon of microglial augmentation by myeloid progenitor cells in the adult brain. Finally, we address in some detail the beneficial roles of microglia as clinical targets in Rett syndrome and other neurological disorders.

  11. Metabolic fingerprints of altered brain growth, osmoregulation and neurotransmission in a Rett syndrome model.

    Directory of Open Access Journals (Sweden)

    Angèle Viola

    Full Text Available BACKGROUND: Rett syndrome (RS is the leading cause of profound mental retardation of genetic origin in girls. Since RS is mostly caused by mutations in the MECP2 gene, transgenic animal models such as the Mecp2-deleted ("Mecp2-null" mouse have been employed to study neurological symptoms and brain function. However, an interdisciplinary approach drawing from chemistry, biology and neuroscience is needed to elucidate the mechanistic links between the genotype and phenotype of this genetic disorder. METHODOLOGY/PRINCIPAL FINDINGS: We performed, for the first time, a metabolomic study of brain extracts from Mecp2-null mice by using high-resolution magnetic resonance spectroscopy. A large number of individual water-soluble metabolites and phospholipids were quantified without prior selection for specific metabolic pathways. Results were interpreted in terms of Mecp2 gene deletion, brain cell function and brain morphology. This approach provided a "metabolic window" to brain characteristics in Mecp2-null mice (n = 4, revealing (i the first metabolic evidence of astrocyte involvement in RS (decreased levels of the astrocyte marker, myo-inositol, vs. wild-type mice; p = 0.034; (ii reduced choline phospholipid turnover in Mecp2-null vs. wild-type mice, implying a diminished potential of cells to grow, paralleled by globally reduced brain size and perturbed osmoregulation; (iii alterations of the platelet activating factor (PAF cycle in Mecp2-null mouse brains, where PAF is a bioactive lipid acting on neuronal growth, glutamate exocytosis and other processes; and (iv changes in glutamine/glutamate ratios (p = 0.034 in Mecp2-null mouse brains potentially indicating altered neurotransmitter recycling. CONCLUSIONS/SIGNIFICANCE: This study establishes, for the first time, detailed metabolic fingerprints of perturbed brain growth, osmoregulation and neurotransmission in a mouse model of Rett syndrome. Combined with morphological and neurological findings

  12. Genetics Home Reference: Rett syndrome

    Science.gov (United States)

    ... Disorders ClinicalTrials.gov (1 link) ClinicalTrials.gov Scientific Articles on PubMed (1 link) PubMed OMIM (1 link) RETT SYNDROME Sources for This Page Chahrour M, Zoghbi HY. The story of Rett syndrome: from clinic to neurobiology. Neuron. 2007 Nov 8;56(3):422-37. ...

  13. The Invisible Enemy: Fighting Rett Syndrome.

    Science.gov (United States)

    Weisz, Chaudia Minden

    1986-01-01

    The mother of a child with Rett Syndrome, a degenerative brain disease, describes difficulties in obtaining a diagnosis and the relief she and her family felt once the diagnosis was made. She emphasizes the need for parents to offer each other support. (CL)

  14. Prolonged QT interval in Rett syndrome

    OpenAIRE

    1999-01-01

    Rett syndrome is a severe neurodevelopmental disorder of unknown aetiology. A prolonged QT interval has been described previously in patients with Rett syndrome. To investigate QT prolongation and the presence of cardiac tachyarrhythmias in Rett syndrome electrocardiography and 24 hour Holter monitoring were performed prospectively in a cohort of 34 girls with Rett syndrome. The corrected QT value was prolonged in nine patients. Compared with a group of healthy controls of a...

  15. Síndrome de Rett Rett syndrome

    Directory of Open Access Journals (Sweden)

    José Salomão Schwartzman

    2003-06-01

    Full Text Available A partir do que já se conhece sobre a síndrome de Rett, este artigo focaliza as informações mais recentes da literatura internacional sobre os aspectos genéticos e etiológicos desta condição, bem como sobre a sua identificação clínica e laboratorial, neuropatologia, eletrofisiologia, e evolução clínica (epilepsia, distúrbios respiratórios, distúrbios autonômicos e aspectos nutricionais, enfatizando, ainda, que, embora até recentemente tida como condição que afetava apenas o sexo feminino, também pode estar presente no sexo masculino, ainda que com fenótipo diverso.This article is focus on the currently knowledge about Rett syndrome, based on the more recent information in the international literature on genetic and epidemiological aspects of this condition, as well as on its clinical and laboratory diagnosis, neuropathology, electrophysiology. and clinical outcome (epilepsy, respiratory disorders, autonomic disturbances and nutritional aspects. Although it has been known as a female condition, nowadays it is described the possibility of affected males with a different phenotype.

  16. Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice.

    Science.gov (United States)

    Hao, Shuang; Tang, Bin; Wu, Zhenyu; Ure, Kerstin; Sun, Yaling; Tao, Huifang; Gao, Yan; Patel, Akash J; Curry, Daniel J; Samaco, Rodney C; Zoghbi, Huda Y; Tang, Jianrong

    2015-10-15

    Deep brain stimulation (DBS) has improved the prospects for many individuals with diseases affecting motor control, and recently it has shown promise for improving cognitive function as well. Several studies in individuals with Alzheimer disease and in amnesic rats have demonstrated that DBS targeted to the fimbria-fornix, the region that appears to regulate hippocampal activity, can mitigate defects in hippocampus-dependent memory. Despite these promising results, DBS has not been tested for its ability to improve cognition in any childhood intellectual disability disorder. Such disorders are a pressing concern: they affect as much as 3% of the population and involve hundreds of different genes. We proposed that stimulating the neural circuits that underlie learning and memory might provide a more promising route to treating these otherwise intractable disorders than seeking to adjust levels of one molecule at a time. We therefore studied the effects of forniceal DBS in a well-characterized mouse model of Rett syndrome (RTT), which is a leading cause of intellectual disability in females. Caused by mutations that impair the function of MeCP2 (ref. 6), RTT appears by the second year of life in humans, causing profound impairment in cognitive, motor and social skills, along with an array of neurological features. RTT mice, which reproduce the broad phenotype of this disorder, also show clear deficits in hippocampus-dependent learning and memory and hippocampal synaptic plasticity. Here we show that forniceal DBS in RTT mice rescues contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restores in vivo hippocampal long-term potentiation and hippocampal neurogenesis. These results indicate that forniceal DBS might mitigate cognitive dysfunction in RTT.

  17. Synaptic determinants of Rett syndrome

    Directory of Open Access Journals (Sweden)

    Elena M B Boggio

    2010-08-01

    Full Text Available There is mounting evidence showing that the structural and molecular organization of synaptic connections are affected both in human patients and in animal models of neurological and psychiatric diseases. As a consequence of these experimental observations, it has been introduced the concept of synapsopathies, a notion describing brain disorders of synaptic function and plasticity. A close correlation between neurological diseases and synaptic abnormalities is especially relevant for those syndromes including also mental retardation in their symptomatology, such as Rett Syndrome (RS. RS (MIM312750 is an X-linked dominant neurological disorder that is caused, in the majority of cases by mutations in methyl-CpG-binding protein 2 (MeCP2. This review will focus on the current knowledge of the synaptic alterations produced by mutations of the gene MeCP2 in mouse models of RS and will highlight prospects experimental therapies currently in use. Different experimental approaches have revealed that RS could be the consequence of an impairment in the homeostasis of synaptic transmission in specific brain regions. Indeed, several forms of experience-induced neuronal plasticity are impaired in the absence of MeCP2. Based on the results presented in this review, it is reasonable to propose that understanding how the brain is affected by diseases such as RS is at reach. This effort will bring us closer to identify the neurobiological bases of human cognition.

  18. Rett syndrome and gastric perforation.

    Science.gov (United States)

    Shah, Malay B; Bittner, James G; Edwards, Michael A

    2008-04-01

    Rett Syndrome is associated with decreased peristaltic esophageal waves and gastric dysmotility, resulting in swallowing difficulties and gastric dilation. Rarely, gastric necrosis and perforation occur. Our case represents the third reported case of gastric necrosis and perforation associated with Rett Syndrome. A 31-year-old female after 11 hours of intermittent emesis and constant, sharp abdominal pain presented with evidence of multiorgan system failure including hypovolemic shock, metabolic acidosis, coagulopathy, and hepatorenal failure. A chest radiograph revealed intra-abdominal free air necessitating emergent laparotomy. During exploration, a severely dilated, thin-walled stomach with an area of necrosis and gross perforation was noted. Wedge resection of the necrotic tissue and primary closure were performed. Despite aggressive perioperative resuscitation and ventilation support, the patient died 3 hours postoperatively secondary to refractory shock and hypoxemia. Severe gastric dilation can occur with Rett Syndrome and may cause gastric necrosis and perforation. Prolonged elevated gastric pressures can decrease perfusion and may contribute to perforation. Timely decompression via percutaneous endoscopic or surgical gastrostomy could decrease the risk of perforation particularly when significant gastric distention is present. Consideration of gastric necrosis and perforation in patients with Rett Syndrome may lead to earlier intervention and decreased mortality.

  19. Communication Abilities and Rett Syndrome.

    Science.gov (United States)

    Woodyatt, Gail; Ozanne, Anne

    1992-01-01

    The communicative behaviors of 6 girls with Rett syndrome (ages 2-13) were evaluated. Findings indicated that all subjects were at a preintentional level of communication, which was consistent with their profound intellectual disability and their lack of demonstration of "means-end" behavior beyond Piagetian Sensorimotor Stage III. (Author/DB)

  20. Communication Abilities and Rett Syndrome.

    Science.gov (United States)

    Woodyatt, Gail; Ozanne, Anne

    1992-01-01

    The communicative behaviors of 6 girls with Rett syndrome (ages 2-13) were evaluated. Findings indicated that all subjects were at a preintentional level of communication, which was consistent with their profound intellectual disability and their lack of demonstration of "means-end" behavior beyond Piagetian Sensorimotor Stage III.…

  1. Cerebral blood flow and oxygen metabolism in the Rett syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Yoshikawa, Hideto; Fueki, Noboru; Suzuki, Hisaharu; Sakuragawa, Norio; Iio, Masaaki (National Central Hospital for Mental, Nervous and Muscular Disorders, Tokyo (Japan))

    1992-05-01

    Positron emission tomography (PET) was performed on six patients with the Rett syndrome and the results were compared with the concurrent clinical status of the patients. The cerebral metabolic rate of oxygen (CMRO{sub 2}) was low in five patients, and oxygen extraction fraction (OEF) was low in four patients; both had a tendency to decline with advancing age. Although the cause is unknown, it is suggested that impaired oxidative metabolism exists in the Rett syndrome. An analysis of the distribution among brain regions showed that the ratios of values for the frontal cortex to those for the temporal cortex for both the cerebral blood flow (CBF) and CMRO{sub 2} were lower than those for the controls, which may indicate the loss of of hyperfrontality in the Rett syndrome. Distribution of brain metabolism may be immature in the Rett syndrome. (author).

  2. Validating the Rett Syndrome Gross Motor Scale

    DEFF Research Database (Denmark)

    Downs, Jenny; Stahlhut, Michelle; Wong, Kingsley;

    2016-01-01

    Rett syndrome is a pervasive neurodevelopmental disorder associated with a pathogenic mutation on the MECP2 gene. Impaired movement is a fundamental component and the Rett Syndrome Gross Motor Scale was developed to measure gross motor abilities in this population. The current study investigated...... the validity and reliability of the Rett Syndrome Gross Motor Scale. Video data showing gross motor abilities supplemented with parent report data was collected for 255 girls and women registered with the Australian Rett Syndrome Database, and the factor structure and relationships between motor scores, age...... and genotype were investigated. Clinical assessment scores for 38 girls and women with Rett syndrome who attended the Danish Center for Rett Syndrome were used to assess consistency of measurement. Principal components analysis enabled the calculation of three factor scores: Sitting, Standing and Walking...

  3. Alterations in the cholinergic system of brain stem neurons in a mouse model of Rett syndrome.

    Science.gov (United States)

    Oginsky, Max F; Cui, Ningren; Zhong, Weiwei; Johnson, Christopher M; Jiang, Chun

    2014-09-15

    Rett syndrome is an autism-spectrum disorder resulting from mutations to the X-linked gene, methyl-CpG binding protein 2 (MeCP2), which causes abnormalities in many systems. It is possible that the body may develop certain compensatory mechanisms to alleviate the abnormalities. The norepinephrine system originating mainly in the locus coeruleus (LC) is defective in Rett syndrome and Mecp2-null mice. LC neurons are subject to modulation by GABA, glutamate, and acetylcholine (ACh), providing an ideal system to test the compensatory hypothesis. Here we show evidence for potential compensatory modulation of LC neurons by post- and presynaptic ACh inputs. We found that the postsynaptic currents of nicotinic ACh receptors (nAChR) were smaller in amplitude and longer in decay time in the Mecp2-null mice than in the wild type. Single-cell PCR analysis showed a decrease in the expression of α3-, α4-, α7-, and β3-subunits and an increase in the α5- and α6-subunits in the mutant mice. The α5-subunit was present in many of the LC neurons with slow-decay nAChR currents. The nicotinic modulation of spontaneous GABAA-ergic inhibitory postsynaptic currents in LC neurons was enhanced in Mecp2-null mice. In contrast, the nAChR manipulation of glutamatergic input to LC neurons was unaffected in both groups of mice. Our current-clamp studies showed that the modulation of LC neurons by ACh input was reduced moderately in Mecp2-null mice, despite the major decrease in nAChR currents, suggesting possible compensatory processes may take place, thus reducing the defects to a lesser extent in LC neurons.

  4. Rett syndrome: A rare case

    Directory of Open Access Journals (Sweden)

    Deepika Verma

    2016-01-01

    Full Text Available Rett syndrome (RTT is rare, affects predominantly female children. It presents as a pervasive developmental disorder with a remarkable behavioral phenotype. The discovery that mutation in methyl-C-phosphate-G-binding protein 2 causes RTT has focused attention to the importance of epigenetic modifications in neuronal function. We report a case of RTT in a 7-year-old female child and use of behavioral techniques and social skill training to control the behavioral symptoms.

  5. Rett syndrome: a study of the face

    NARCIS (Netherlands)

    J.E. Allanson; R.C.M. Hennekam; U. Moog; E.E. Smeets

    2011-01-01

    Rett syndrome is a unique disorder of neurodevelopment that is characterized by an evolving behavioral and developmental phenotype, which emerges after an apparently normal early infantile period. It almost exclusively affects females. The face of Rett syndrome is said to resemble that of Angelman s

  6. Towards a Behavioral Phenotype for Rett Syndrome.

    Science.gov (United States)

    Mount, Rebecca H.; Hastings, Richard P.; Reilly, Sheena; Cass, Hilary; Charman, Tony

    2003-01-01

    A study compared 143 girls (ages 6-14) with Rett syndrome with 85 girls with severe mental retardation on the Developmental Behavior Checklist. Girls with Rett syndrome presented more "autistic relating" and fewer antisocial behaviors. When compared to children with autism, they did not present with classic autistic behavioral features. (Contains…

  7. Autistic Disorder Symptoms in Rett Syndrome

    Science.gov (United States)

    Wulffaert, Josette; Van Berckelaer-Onnes, Ina A.; Scholte, Evert M.

    2009-01-01

    According to the major classification systems it is not possible to diagnose a comorbid autistic disorder in persons with Rett syndrome. However, this is a controversial issue, and given the level of functioning of persons with Rett syndrome, the autistic disorder is expected to be present in a comparable proportion as in people with the same…

  8. Rett syndrome: An autoimmune disease?

    Science.gov (United States)

    De Felice, Claudio; Leoncini, Silvia; Signorini, Cinzia; Cortelazzo, Alessio; Rovero, Paolo; Durand, Thierry; Ciccoli, Lucia; Papini, Anna Maria; Hayek, Joussef

    2016-04-01

    Rett syndrome (RTT) is a devastating neurodevelopmental disease, previously included into the autistic spectrum disorders, affecting almost exclusively females (frequency 1:10,000). RTT leads to intellective deficit, purposeful hands use loss and late major motor impairment besides featuring breathing disorders, epilepsy and increased risk of sudden death. The condition is caused in up to 95% of the cases by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Our group has shown a number of previously unrecognized features, such as systemic redox imbalance, chronic inflammatory status, respiratory bronchiolitis-associated interstitial lung disease-like lung disease, and erythrocyte morphology changes. While evidence on an intimate involvement of MeCP2 in the immune response is cumulating, we have recently shown a cytokine dysregulation in RTT. Increasing evidence on the relationship between MeCP2 and an immune dysfunction is reported, with, apparently, a link between MECP2 gene polymorphisms and autoimmune diseases, including primary Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis. Antineuronal (i.e., brain proteins) antibodies have been shown in RTT. Recently, high levels of anti-N-glucosylation (N-Glc) IgM serum autoantibodies [i.e., anti-CSF114(N-Glc) IgMs] have been detected by our group in a statistically significant number of RTT patients. In the current review, the Authors explore the current evidence, either in favor or against, the presence of an autoimmune component in RTT.

  9. IgA Antibodies in Rett Syndrome

    Science.gov (United States)

    Reichelt, K. L.; Skjeldal, O.

    2006-01-01

    The level of IgA antibodies to gluten and gliadin proteins found in grains and to casein found in milk, as well as the level of IgG to gluten and gliadin, have been examined in 23 girls with Rett syndrome and 53 controls. Highly statistically significant increases were found for the Rett population compared to the controls. The reason for this…

  10. Rett syndrome: Neurologic and metabolic aspects

    NARCIS (Netherlands)

    Hagebeuk, E.E.O.

    2013-01-01

    Rett syndrome (RTT) is a neurodevelopmental disorder that occurs almost exclusively in females. It was described in 1954 by Andreas Rett, an Australian neuropediatrician. After a period of apparently normal development, affected patients experience loss of speech and purposeful handuse, stereotypic

  11. Rett syndrome: Neurologic and metabolic aspects

    NARCIS (Netherlands)

    Hagebeuk, E.E.O.

    2013-01-01

    Rett syndrome (RTT) is a neurodevelopmental disorder that occurs almost exclusively in females. It was described in 1954 by Andreas Rett, an Australian neuropediatrician. After a period of apparently normal development, affected patients experience loss of speech and purposeful handuse, stereotypic

  12. IgA Antibodies in Rett Syndrome

    Science.gov (United States)

    Reichelt, K. L.; Skjeldal, O.

    2006-01-01

    The level of IgA antibodies to gluten and gliadin proteins found in grains and to casein found in milk, as well as the level of IgG to gluten and gliadin, have been examined in 23 girls with Rett syndrome and 53 controls. Highly statistically significant increases were found for the Rett population compared to the controls. The reason for this…

  13. Validating the Rett Syndrome Gross Motor Scale.

    Science.gov (United States)

    Downs, Jenny; Stahlhut, Michelle; Wong, Kingsley; Syhler, Birgit; Bisgaard, Anne-Marie; Jacoby, Peter; Leonard, Helen

    2016-01-01

    Rett syndrome is a pervasive neurodevelopmental disorder associated with a pathogenic mutation on the MECP2 gene. Impaired movement is a fundamental component and the Rett Syndrome Gross Motor Scale was developed to measure gross motor abilities in this population. The current study investigated the validity and reliability of the Rett Syndrome Gross Motor Scale. Video data showing gross motor abilities supplemented with parent report data was collected for 255 girls and women registered with the Australian Rett Syndrome Database, and the factor structure and relationships between motor scores, age and genotype were investigated. Clinical assessment scores for 38 girls and women with Rett syndrome who attended the Danish Center for Rett Syndrome were used to assess consistency of measurement. Principal components analysis enabled the calculation of three factor scores: Sitting, Standing and Walking, and Challenge. Motor scores were poorer with increasing age and those with the p.Arg133Cys, p.Arg294* or p.Arg306Cys mutation achieved higher scores than those with a large deletion. The repeatability of clinical assessment was excellent (intraclass correlation coefficient for total score 0.99, 95% CI 0.93-0.98). The standard error of measurement for the total score was 2 points and we would be 95% confident that a change 4 points in the 45-point scale would be greater than within-subject measurement error. The Rett Syndrome Gross Motor Scale could be an appropriate measure of gross motor skills in clinical practice and clinical trials.

  14. The protocadherins, PCDHB1 and PCDH7, are regulated by MeCP2 in neuronal cells and brain tissues: implication for pathogenesis of Rett syndrome

    Directory of Open Access Journals (Sweden)

    Nakagawa Takayuki

    2011-08-01

    Full Text Available Abstract Background Rett syndrome is a neurodevelopmental and autistic disease caused by mutations of Methyl-CpG-binding protein 2 (MECP2 gene. MeCP2 protein is mainly expressed in neurons and binds to methylated gene promoters to suppress their expression, indicating that Rett syndrome is caused by the deregulation of target genes in neurons. However, it is likely that there are more unidentified neuronal MeCP2-targets associated with the neurological features of RTT. Results Using a genome-microarray approach, we found 22 genomic regions that contain sites potentially regulated by MeCP2 based on the features of MeCP2 binding, DNA methylation, and repressive histone modification in human cell lines. Within these regions, Chromatin immunoprecipitation (ChIP analysis revealed that MeCP2 binds to the upstream regions of the protocadherin genes PCDHB1 and PCDH7 in human neuroblastoma SH-SY5Y cells. PCDHB1 and PCDH7 promoter activities were down-regulated by MeCP2, but not by MBD-deleted MeCP2. These gene expression were up-regulated following MeCP2 reduction with siRNA in SH-SY5Y cells and in the brains of Mecp2-null mice. Furthermore, PCDHB1 was up-regulated in postmortem brains from Rett syndrome patients. Conclusions We identified MeCP2 target genes that encode neuronal adhesion molecules using ChIP-on-BAC array approach. Since these protocadherin genes are generally essential for brain development, aberrant regulation of these molecules may contribute to the pathogenesis of the neurological features observed in Rett syndrome.

  15. Modulation of Rho GTPases rescues brain mitochondrial dysfunction, cognitive deficits and aberrant synaptic plasticity in female mice modeling Rett syndrome.

    Science.gov (United States)

    De Filippis, Bianca; Valenti, Daniela; Chiodi, Valentina; Ferrante, Antonella; de Bari, Lidia; Fiorentini, Carla; Domenici, Maria Rosaria; Ricceri, Laura; Vacca, Rosa Anna; Fabbri, Alessia; Laviola, Giovanni

    2015-06-01

    Rho GTPases are molecules critically involved in neuronal plasticity and cognition. We have previously reported that modulation of brain Rho GTPases by the bacterial toxin CNF1 rescues the neurobehavioral phenotype in MeCP2-308 male mice, a model of Rett syndrome (RTT). RTT is a rare X-linked neurodevelopmental disorder and a genetic cause of intellectual disability, for which no effective therapy is available. Mitochondrial dysfunction has been proposed to be involved in the mechanism of the disease pathogenesis. Here we demonstrate that modulation of Rho GTPases by CNF1 rescues the reduced mitochondrial ATP production via oxidative phosphorylation in the brain of MeCP2-308 heterozygous female mice, the condition which more closely recapitulates that of RTT patients. In RTT mouse brain, CNF1 also restores the alterations in the activity of the mitochondrial respiratory chain (MRC) complexes and of ATP synthase, the molecular machinery responsible for the majority of cell energy production. Such effects were achieved through the upregulation of the protein content of those MRC complexes subunits, which were defective in RTT mouse brain. Restored mitochondrial functionality was accompanied by the rescue of deficits in cognitive function (spatial reference memory in the Barnes maze), synaptic plasticity (long-term potentiation) and Tyr1472 phosphorylation of GluN2B, which was abnormally enhanced in the hippocampus of RTT mice. Present findings bring into light previously unknown functional mitochondrial alterations in the brain of female mice modeling RTT and provide the first evidence that RTT brain mitochondrial dysfunction can be rescued by modulation of Rho GTPases.

  16. Mutation screening in Rett syndrome patients

    National Research Council Canada - National Science Library

    Xiang, F; Buervenich, S; Nicolao, P; Bailey, M E; Zhang, Z; Anvret, M

    2000-01-01

    Rett syndrome (RTT) was first described in 1966. Its biological and genetic foundations were not clear until recently when Amir et al reported that mutations in the MECP2 gene were detected in around 50% of RTT patients...

  17. Visual Evoked Potentials in Rett Syndrome

    Directory of Open Access Journals (Sweden)

    J. Gordon Millichap

    2015-11-01

    Full Text Available Investigators from the Boston Children's Hospital recorded pattern-reversal visual evoked potentials (VEPs in Mecp2 heterozygous female mice and in 34 girls with Rett syndrome (RTT.

  18. Patterns of Regression in Rett Syndrome

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2002-10-01

    Full Text Available Patterns and features of regression in a case series of 53 girls and women with Rett syndrome were studied at the Institute of Child Health and Great Ormond Street Children’s Hospital, London, UK.

  19. Early development and regression in Rett syndrome.

    Science.gov (United States)

    Lee, J Y L; Leonard, H; Piek, J P; Downs, J

    2013-12-01

    This study utilized developmental profiling to examine symptoms in 14 girls with genetically confirmed Rett syndrome and whose families were participating in the Australian Rett syndrome or InterRett database. Regression was mostly characterized by loss of hand and/or communication skills (13/14) except one girl demonstrated slowing of skill development. Social withdrawal and inconsolable crying often developed simultaneously (9/14), with social withdrawal for shorter duration than inconsolable crying. Previously acquired gross motor skills declined in just over half of the sample (8/14), mostly observed as a loss of balance. Early abnormalities such as vomiting and strabismus were also seen. Our findings provide additional insight into the early clinical profile of Rett syndrome.

  20. Is Rett Syndrome a Subtype of Pervasive Developmental Disorders?

    Science.gov (United States)

    Tsai, Luke Y.

    1992-01-01

    This paper reviews whether Rett syndrome is a subtype of pervasive developmental disorders (PDD). The paper analyzes internal and external diagnostic validity and discusses whether Rett syndrome is a neurological disorder or a mental disorder. The paper concludes that data support the idea of classifying Rett syndrome as a subtype of PDD.…

  1. Unexpected cellular players in Rett syndrome pathology.

    Science.gov (United States)

    Cronk, James C; Derecki, Noel C; Litvak, Vladimir; Kipnis, Jonathan

    2016-08-01

    Rett syndrome is a devastating neurodevelopmental disorder, primarily caused by mutations of methyl CpG-binding protein 2 (MeCP2). Although the genetic cause of disease was identified over a decade ago, a significant gap still remains in both our clinical and scientific understanding of its pathogenesis. Neurons are known to be primary players in pathology, with their dysfunction being the key in Rett syndrome. While studies in mice have demonstrated a clear causative - and potential therapeutic - role for neurons in Rett syndrome, recent work has suggested that other tissues also contribute significantly to progression of the disease. Indeed, Rett syndrome is known to present with several common peripheral pathologies, such as osteopenia, scoliosis, gastrointestinal problems including nutritional defects, and general growth deficit. Mouse models assessing the potential role of non-neuronal cell types have confirmed both roles in disease and potential therapeutic targets. A new picture is emerging in which neurons both initiate and drive pathology, while dysfunction of other cell types and peripheral tissues exacerbate disease, possibly amplifying further neurologic problems, and ultimately result in a positive feedback loop of progressively worsening symptoms. Here, we review what is known about neuronal and non-neuronal cell types, and discuss how this new, integrative understanding of the disease may allow for additional clinical and scientific pathways for treating and understanding Rett syndrome.

  2. Rett syndrome: genes, synapses, circuits and therapeutics

    Directory of Open Access Journals (Sweden)

    Abhishek eBanerjee

    2012-05-01

    Full Text Available Development of the nervous system proceeds through a set of complex checkpoints which arise from a combination of sequential gene expression and early neural activity sculpted by the environment. Genetic and environmental insults lead to neurodevelopmental disorders which encompass a large group of diseases that result from anatomical and physiological abnormalities during maturation and development of brain circuits. Rett syndrome (RTT is a postnatal neurological disorder of genetic origin, caused by mutations in the X-linked gene MECP2. It features neuropsychiatric abnormalities like motor dysfunctions and mild to severe cognitive impairment. This review discusses several key questions and attempts to evaluate recently developed animal models, cell-type specific function of MeCP2, defects in neural circuit plasticity and possible therapeutic strategies. Finally, we also discuss how genes, proteins and overlapping signaling pathways affect the molecular etiology of apparently unrelated neuropsychiatric disorders, an understanding of which can offer novel therapeutic strategies.

  3. Rett Syndrome: A Review of Current Knowledge.

    Science.gov (United States)

    Van Acker, Rick

    1991-01-01

    This review describes Rett syndrome as a disorder afflicting females and characterized by a progressive loss of cognitive and motor skills and development of stereotypic hand movements. The paper discusses its clinical manifestations, etiology, diagnostic criteria and differential diagnosis, prevalence, pathogenesis, treatment, and educational…

  4. Modeling Rett Syndrome with Stem Cells

    OpenAIRE

    Walsh, Ryan M.; Hochedlinger, Konrad

    2010-01-01

    The discovery that somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) raised the exciting possibility of modeling diseases with patient-specific cells. Marchetto et al. (2010) now use iPSC technology to generate, characterize, and treat an in vitro model for the autism spectrum disorder, Rett syndrome.

  5. Rett Syndrome: A Longitudinal Developmental Case Report.

    Science.gov (United States)

    Garber, Norman; Veydt, Nicole

    1990-01-01

    The clinical course of development of a 14-year-old girl with Rett Syndrome is outlined. Results indicated a general stagnation in gross and fine motor skills, self-help skills, communication, and cognition, beginning at approximately 15 months. No skills progressed beyond the 2-year level despite several years of intensive intervention.…

  6. Rett syndrome - Stimulation of endogenous biogenic amines

    Science.gov (United States)

    Pelligra, R.; Norton, R. D.; Wilkinson, R.; Leon, H. A.; Matson, W. R.

    1992-01-01

    Transient hypercapnic hyperoxemia was induced in two Rett syndrome children by the administration of a gaseous mixture of 80 percent O2 and 20 percent CO2. Time course studies of neurotransmitters and their metabolites showed an immediate and marked increase in central biogenic amine turnover following inhalation of the gas mixture. The increased turnover of biogenic amines was associated with improved clinical changes. This suggests a coupled relationship and provides further support for an etiological role of neurotransmitter dysfunction in Rett syndrome. In a complementary study, elevation of pulmonary CO2 by application of a simple rebreathing device resulted in improvement of abnormal blood gases and elimination of the Cheyne-Stokes-like respiratory pattern of the Rett syndrome. Near normalization of the EEG occurred when a normal respiratory pattern was imposed by means of a respirator. Taken together, these results lead to the preliminary conclusion that cerebral hypoxemia secondary to abnormal respiratory function may contribute to diminished production of biogenic amines in Rett syndrome.

  7. Communication Skills in Girls with Rett Syndrome

    Science.gov (United States)

    Bartolotta, Theresa E.; Zipp, Genevieve P.; Simpkins, Susan D.; Glazewski, Barbara

    2011-01-01

    Rett Syndrome (RS) is an X-linked, neurodevelopmental disorder that occurs primarily in females and causes significant impairment in cognition, motor control, and communication. Teachers and speech-language pathologists (SLPs) encounter girls with RS with increasing frequency as awareness of the disorder increases, yet the literature on clinical…

  8. Attention and Communication in Rett Syndrome

    Science.gov (United States)

    Fabio, Rosa Angela; Antonietti, Alessandro; Castelli, Ilaria; Marchetti, Antonella

    2009-01-01

    The study of selective attention and its influence on communication in patients with Rett Syndrome (RS), in which communication abilities are impaired is particularly relevant. The aim of this study was to analyse attention and communication abilities in RS. A sample of 20 children (10 girls with RS and 10 control girls, matched on mental age)…

  9. Nosology and Diagnosis of Rett Syndrome

    Science.gov (United States)

    Matson, Johnny L.; Fodstad, Jill C.; Boisjoli, Jessica A.

    2008-01-01

    Rett Syndrome is one of the least commonly occurring autism spectrum disorders (ASD), but certainly one of the most devastating. A genetic profile has been identified, but checklists still have an important role for prescreening, especially before expensive genetic testing, and to provide precise strengths and weaknesses with respect to the core…

  10. Rett's Syndrome in an Australian Child.

    Science.gov (United States)

    Rossiter, E. J. R.; Callaghan, C.

    1987-01-01

    Following a literature review on Rett's Syndrome, a case study is presented of a 15-year-old girl with normal development during the first months of life followed by manifestation of behavior abnormalities and deterioration of intellectual level. The child's medical history and the mother's description of the girl's development are included.…

  11. Recognizing and Treating Rett Syndrome in Schools

    Science.gov (United States)

    Wanzek, Megan; Jenson, William R.; Houlihan, Daniel

    2012-01-01

    A review of the literature on Rett syndrome (RS) for school-based professionals is presented from a behavioral perspective. A description of RS is provided, including distinctive physical, behavioral, and emotional features, diagnostic criteria for classic and "formes frustes" forms of RS, and stages of the disorder. The similarities and…

  12. Aging in Persons with Rett Syndrome: An Updated Review

    Directory of Open Access Journals (Sweden)

    Meir Lotan

    2010-01-01

    Full Text Available Rett syndrome (RS is a neurological disease affecting mainly females, characterized by an arrest of brain development caused by an X-linked mutation. Rett syndrome is the first human disease found to be caused by defects in a protein involved in regulating gene expression through its interaction with methylated DNA. The disease has been traced to a defective gene called MECP2. The case stories presented here and recent findings show that females with RS are able to live into old age. Due to the observed longevity of individuals with RS, and the fact that individuals with RS present the therapist/physician with specific clinical challenges, it is suggested that proper, long-term, and individually tailored, intensive care should be provided at all ages in the hope to prevent or at least reduce the age-related deterioration that is typical of this population.

  13. KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome.

    Science.gov (United States)

    Tang, Xin; Kim, Julie; Zhou, Li; Wengert, Eric; Zhang, Lei; Wu, Zheng; Carromeu, Cassiano; Muotri, Alysson R; Marchetto, Maria C N; Gage, Fred H; Chen, Gong

    2016-01-19

    Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K(+)-Cl(-) cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition. Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome. We further identified that RE1-silencing transcriptional factor, REST, a neuronal gene repressor, mediates the MeCP2 regulation of KCC2. Because KCC2 is a slow onset molecule with expression level reaching maximum later in development, the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. Our studies suggest that restoring KCC2 function in Rett neurons may lead to a potential treatment for Rett syndrome.

  14. Dysregulation of the long non-coding RNA transcriptome in a Rett syndrome mouse model.

    Science.gov (United States)

    Petazzi, Paolo; Sandoval, Juan; Szczesna, Karolina; Jorge, Olga C; Roa, Laura; Sayols, Sergi; Gomez, Antonio; Huertas, Dori; Esteller, Manel

    2013-07-01

    Mecp2 is a transcriptional repressor protein that is mutated in Rett syndrome, a neurodevelopmental disorder that is the second most common cause of mental retardation in women. It has been shown that the loss of the Mecp2 protein in Rett syndrome cells alters the transcriptional silencing of coding genes and microRNAs. Herein, we have studied the impact of Mecp2 impairment in a Rett syndrome mouse model on the global transcriptional patterns of long non-coding RNAs (lncRNAs). Using a microarray platform that assesses 41,232 unique lncRNA transcripts, we have identified the aberrant lncRNA transcriptome that is present in the brain of Rett syndrome mice. The study of the most relevant lncRNAs altered in the assay highlighted the upregulation of the AK081227 and AK087060 transcripts in Mecp2-null mice brains. Chromatin immunoprecipitation demonstrated the Mecp2 occupancy in the 5'-end genomic loci of the described lncRNAs and its absence in Rett syndrome mice. Most importantly, we were able to show that the overexpression of AK081227 mediated by the Mecp2 loss was associated with the downregulation of its host coding protein gene, the gamma-aminobutyric acid receptor subunit Rho 2 (Gabrr2). Overall, our findings indicate that the transcriptional dysregulation of lncRNAs upon Mecp2 loss contributes to the neurological phenotype of Rett syndrome and highlights the complex interaction between ncRNAs and coding-RNAs.

  15. Rett Syndrome: From Bed to Bench

    Directory of Open Access Journals (Sweden)

    Shih-Ming Weng

    2011-12-01

    Full Text Available Rett syndrome (RTT, a neurodevelopmental condition characterized by delayed-onset loss of spoken language and the development of distinctive hand stereotypies, affects approximately 1 in 10,000 live female births. Clinical diagnosis has been based on symptoms such as loss of acquired purposeful hand skills, autistic behaviors, motor dysfunctions, seizure disorders, and gait abnormalities. RTT is a genetic disease and is caused almost exclusively by mutations in the X-linked gene, MECP2, to produce a phenotype that is thought to be primarily of neurological origin. Clinical reports show RTT patients to have a smaller brain volume, especially in the cerebral hemispheres, and alterations in various neurotransmitter systems, including acetylcholine, dopamine, serotonin, glutamate, substance P, and various trophic factors. Because of its monogenetic characteristic, disruption of Mecp2 is readily recapitulated in mice to produce a prominent RTT-like phenotype and provide an excellent platform for understanding the pathogenesis of RTT. As shown in human studies, Mecp2 mutants also display subtle alterations in neuronal morphology, including smaller cortical neurons with a higher-packing density and reduced dendritic complexity. Neurophysiological studies in Mecp2-mutant mice consistently report alterations in synaptic function, notably, defects in synaptic plasticity. These data suggest that RTT might be regarded as a synaptopathy (disease of the synapse and thus potentially amenable to rational therapeutic intervention.

  16. Gait initiation in children with Rett syndrome.

    Directory of Open Access Journals (Sweden)

    Ioannis Ugo Isaias

    Full Text Available Rett syndrome is an X-linked neurodevelopmental condition mainly characterized by loss of spoken language and a regression of purposeful hand use, with the development of distinctive hand stereotypies, and gait abnormalities. Gait initiation is the transition from quiet stance to steady-state condition of walking. The associated motor program seems to be centrally mediated and includes preparatory adjustments prior to any apparent voluntary movement of the lower limbs. Anticipatory postural adjustments contribute to postural stability and to create the propulsive forces necessary to reach steady-state gait at a predefined velocity and may be indicative of the effectiveness of the feedforward control of gait. In this study, we examined anticipatory postural adjustments associated with gait initiation in eleven girls with Rett syndrome and ten healthy subjects. Muscle activity (tibialis anterior and soleus muscles, ground reaction forces and body kinematic were recorded. Children with Rett syndrome showed a distinctive impairment in temporal organization of all phases of the anticipatory postural adjustments. The lack of appropriate temporal scaling resulted in a diminished impulse to move forward, documented by an impairment in several parameters describing the efficiency of gait start: length and velocity of the first step, magnitude and orientation of centre of pressure-centre of mass vector at the instant of (swing-toe off. These findings were related to an abnormal muscular activation pattern mainly characterized by a disruption of the synergistic activity of antagonistic pairs of postural muscles. This study showed that girls with Rett syndrome lack accurate tuning of feedforward control of gait.

  17. Gait initiation in children with Rett syndrome.

    Science.gov (United States)

    Isaias, Ioannis Ugo; Dipaola, Mariangela; Michi, Marlies; Marzegan, Alberto; Volkmann, Jens; Rodocanachi Roidi, Marina L; Frigo, Carlo Albino; Cavallari, Paolo

    2014-01-01

    Rett syndrome is an X-linked neurodevelopmental condition mainly characterized by loss of spoken language and a regression of purposeful hand use, with the development of distinctive hand stereotypies, and gait abnormalities. Gait initiation is the transition from quiet stance to steady-state condition of walking. The associated motor program seems to be centrally mediated and includes preparatory adjustments prior to any apparent voluntary movement of the lower limbs. Anticipatory postural adjustments contribute to postural stability and to create the propulsive forces necessary to reach steady-state gait at a predefined velocity and may be indicative of the effectiveness of the feedforward control of gait. In this study, we examined anticipatory postural adjustments associated with gait initiation in eleven girls with Rett syndrome and ten healthy subjects. Muscle activity (tibialis anterior and soleus muscles), ground reaction forces and body kinematic were recorded. Children with Rett syndrome showed a distinctive impairment in temporal organization of all phases of the anticipatory postural adjustments. The lack of appropriate temporal scaling resulted in a diminished impulse to move forward, documented by an impairment in several parameters describing the efficiency of gait start: length and velocity of the first step, magnitude and orientation of centre of pressure-centre of mass vector at the instant of (swing-)toe off. These findings were related to an abnormal muscular activation pattern mainly characterized by a disruption of the synergistic activity of antagonistic pairs of postural muscles. This study showed that girls with Rett syndrome lack accurate tuning of feedforward control of gait.

  18. Addressing the Needs of Students with Rett Syndrome.

    Science.gov (United States)

    Katsiyannis, Antonis; Ellenburg, Jennifer S.; Acton, Olivia M.; Torrey, Gregory

    2001-01-01

    This article discusses symptoms of students with Rett Syndrome, a disability in females characterized by the development of multiple specific deficits following a period of normal functioning after birth. Specific interventions for students with Rett syndrome are provided and address communication, stereotypic movements, self-injurious behaviors,…

  19. Music Therapy: A Therapeutic Intervention for Girls with Rett Syndrome.

    Science.gov (United States)

    Coleman, Kathleen A.

    The paper reviews music therapy, the educational background of music therapists, music therapy's various settings, and its use as an intervention with girls with Rett Syndrome. Sample music therapy programs for three girls (aged 5, 14, and 20 years) with Rett Syndrome are presented. The sample programs provide: student descriptions; the girls'…

  20. Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1.

    Science.gov (United States)

    De Filippis, Bianca; Valenti, Daniela; de Bari, Lidia; De Rasmo, Domenico; Musto, Mattia; Fabbri, Alessia; Ricceri, Laura; Fiorentini, Carla; Laviola, Giovanni; Vacca, Rosa Anna

    2015-06-01

    Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene associated with severe intellectual disability, movement disorders, and autistic-like behaviors. Its pathogenesis remains mostly not understood and no effective therapy is available. High circulating levels of oxidative stress markers in patients and the occurrence of oxidative brain damage in MeCP2-deficient mouse models suggest the involvement of oxidative stress in RTT pathogenesis. However, the molecular mechanism and the origin of the oxidative stress have not been elucidated. Here we demonstrate that a redox imbalance arises from aberrant mitochondrial functionality in the brain of MeCP2-308 heterozygous female mice, a condition that more closely recapitulates that of RTT patients. The marked increase in the rate of hydrogen peroxide generation in the brain of RTT mice seems mainly produced by the dysfunctional complex II of the mitochondrial respiratory chain. In addition, both membrane potential generation and mitochondrial ATP synthesis are decreased in RTT mouse brains when succinate, the complex II respiratory substrate, is used as an energy source. Respiratory chain impairment is brain area specific, owing to a decrease in either cAMP-dependent phosphorylation or protein levels of specific complex subunits. Further, we investigated whether the treatment of RTT mice with the bacterial protein CNF1, previously reported to ameliorate the neurobehavioral phenotype and brain bioenergetic markers in an RTT mouse model, exerts specific effects on brain mitochondrial function and consequently on hydrogen peroxide production. In RTT brains treated with CNF1, we observed the reactivation of respiratory chain complexes, the rescue of mitochondrial functionality, and the prevention of brain hydrogen peroxide overproduction. These results provide definitive evidence of mitochondrial reactive oxygen species overproduction in RTT mouse brain and

  1. Building the repertoire of measures of walking in Rett syndrome

    DEFF Research Database (Denmark)

    Stahlhut, Michelle; Downs, Jenny; Leonard, Helen;

    2017-01-01

    BACKGROUND: The repertoire of measures of walking in Rett syndrome is limited. This study aimed to determine measurement properties of a modified two-minute walk test (2MWT) and a modified Rett syndrome-specific functional mobility scale (FMS-RS) in Rett syndrome. METHODS: Forty-two girls and women...... with Rett syndrome (median 18.4 years, range 2.4-60.9 years) were assessed for clinical severity, gross motor skills, and mobility. To measure walking capacity, 27 of this group completed a 2MWT twice on two different assessment days. To assess walking performance, the FMS-RS was administered to the total......) and the Rett syndrome-specific functional mobility scale (FMS-RS). The 2MWT and FMS-RS offer detailed information of the capacity and performance of walking, respectively, in girls and women with RTT....

  2. Rett Syndrome: A Comprehensive Review of the Literature.

    Science.gov (United States)

    Perry, Adrienne

    1991-01-01

    This nontechnical review of the literature on Rett Syndrome, a developmental disability found only in females, examines the syndrome's history, diagnostic criteria, clinical stages, incidence, differential diagnosis, etiology, genetics, treatment approaches, and prognosis. (Author/DB)

  3. Downstream targets of methyl CpG binding protein 2 and their abnormal expression in the frontal cortex of the human Rett syndrome brain

    Directory of Open Access Journals (Sweden)

    Minchenko Dimitri

    2010-04-01

    Full Text Available Abstract Background The Rett Syndrome (RTT brain displays regional histopathology and volumetric reduction, with frontal cortex showing such abnormalities, whereas the occipital cortex is relatively less affected. Results Using microarrays and quantitative PCR, the mRNA expression profiles of these two neuroanatomical regions were compared in postmortem brain tissue from RTT patients and normal controls. A subset of genes was differentially expressed in the frontal cortex of RTT brains, some of which are known to be associated with neurological disorders (clusterin and cytochrome c oxidase subunit 1 or are involved in synaptic vesicle cycling (dynamin 1. RNAi-mediated knockdown of MeCP2 in vitro, followed by further expression analysis demonstrated that the same direction of abnormal expression was recapitulated with MeCP2 knockdown, which for cytochrome c oxidase subunit 1 was associated with a functional respiratory chain defect. Chromatin immunoprecipitation (ChIP analysis showed that MeCP2 associated with the promoter regions of some of these genes suggesting that loss of MeCP2 function may be responsible for their overexpression. Conclusions This study has shed more light on the subset of aberrantly expressed genes that result from MECP2 mutations. The mitochondrion has long been implicated in the pathogenesis of RTT, however it has not been at the forefront of RTT research interest since the discovery of MECP2 mutations. The functional consequence of the underexpression of cytochrome c oxidase subunit 1 indicates that this is an area that should be revisited.

  4. Low bone turnover phenotype in Rett syndrome

    DEFF Research Database (Denmark)

    Roende, Gitte; Petersen, Janne; Ravn, Kirstine;

    2014-01-01

    Background:Patients with Rett syndrome (RTT) are at risk of having low bone mass and low-energy fractures.Methods:We characterised bone metabolism by both bone formation and resorption markers in blood in a RTT population of 61 girls and women and 122 well-matched healthy controls. Levels of N...... of the lumbar spine (vBMADspine) and femoral neck (vBMADneck). We examined biochemical bone marker levels overall, and stratified to persons younger than age 25 years or equal to or older than age 25 years.Results:The RTT patients had reduced levels of all biochemical bone markers (p...

  5. Positron emission tomography in the Rett syndrome; Clinical, biochemical and pathologicl correlates

    Energy Technology Data Exchange (ETDEWEB)

    Naidu, S. (Kennedy Institute, Baltimore, MD (United States)); Wong, D.F.; Kitt, C.; Wenk, G.; Moser, H.W.

    1992-05-01

    A consistent constellation of clinical signs and symptoms define the Rett syndrome, the most prominent of which are disorders of movement and tone. Preliminary pathologic and neurochemical data indicate predominant involvement of the nigrostriatal dopaminergic pathways and the cholinergic system of the basal forebrain region. The age of onset differentiates the Rett syndrome from Alzheimer and Parkinson disease with similar lesions. PET scanning makes it possible to relate the chemistry of the brain to function by measuring the number and affinity of neuroreceptors, metabolism in specific brain regions, and provide important determinants of the underlying mechanisms in disease states. (author).

  6. Abnormal expression of cerebrospinal fluid cation chloride cotransporters in patients with Rett syndrome.

    Directory of Open Access Journals (Sweden)

    Sofia Temudo Duarte

    Full Text Available OBJECTIVE: Rett Syndrome is a progressive neurodevelopmental disorder caused mainly by mutations in the gene encoding methyl-CpG-binding protein 2. The relevance of MeCP2 for GABAergic function was previously documented in animal models. In these models, animals show deficits in brain-derived neurotrophic factor, which is thought to contribute to the pathogenesis of this disease. Neuronal Cation Chloride Cotransporters (CCCs play a key role in GABAergic neuronal maturation, and brain-derived neurotrophic factor is implicated in the regulation of CCCs expression during development. Our aim was to analyse the expression of two relevant CCCs, NKCC1 and KCC2, in the cerebrospinal fluid of Rett syndrome patients and compare it with a normal control group. METHODS: The presence of bumetanide sensitive NKCC1 and KCC2 was analysed in cerebrospinal fluid samples from a control pediatric population (1 day to 14 years of life and from Rett syndrome patients (2 to 19 years of life, by immunoblot analysis. RESULTS: Both proteins were detected in the cerebrospinal fluid and their levels are higher in the early postnatal period. However, Rett syndrome patients showed significantly reduced levels of KCC2 and KCC2/NKCC1 ratio when compared to the control group. CONCLUSIONS: Reduced KCC2/NKCC1 ratio in the cerebrospinal fluid of Rett Syndrome patients suggests a disturbed process of GABAergic neuronal maturation and open up a new therapeutic perspective.

  7. Therapeutic Potential of Transcranial Focused Ultrasound for Rett Syndrome

    Science.gov (United States)

    Tsai, Shih-Jen

    2016-01-01

    Rett syndrome (RTT) is a severe neurodevelopmental disorder occurring almost exclusively in females and is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) in the majority of cases. MeCP2 is essential for the normal function of nerve cells, including neuronal development, maturation, and synaptic activity. RTT is characterized by normal early development followed by autistic-like features, slowed brain and head growth, gait abnormalities, seizures, breathing irregularities, and cognitive disabilities. Medical management in RTT remains supportive and symptomatic. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of RTT. Recent studies have shown a phenotypic reversal by increasing BDNF expression in a RTT mouse model. Thus, manipulation of BDNF expression/signaling in the brain could be therapeutic for this disease. Transcranial focused ultrasound for (tFUS) can noninvasively focally modulate human cortical function, stimulate neurogenesis, and increase BDNF in animal studies. Consequently, tFUS may be of therapeutic potential for Rett syndrome. Further evaluation of the therapeutic effects of tFUS in Mecp2 deficient animal models is needed before clinical trials can begin. PMID:27786169

  8. Mutations in JMJD1C are involved in Rett syndrome and intellectual disability.

    Science.gov (United States)

    Sáez, Mauricio A; Fernández-Rodríguez, Juana; Moutinho, Catia; Sanchez-Mut, Jose V; Gomez, Antonio; Vidal, Enrique; Petazzi, Paolo; Szczesna, Karolina; Lopez-Serra, Paula; Lucariello, Mario; Lorden, Patricia; Delgado-Morales, Raul; de la Caridad, Olga J; Huertas, Dori; Gelpí, Josep L; Orozco, Modesto; López-Doriga, Adriana; Milà, Montserrat; Perez-Jurado, Luís A; Pineda, Mercedes; Armstrong, Judith; Lázaro, Conxi; Esteller, Manel

    2016-04-01

    Autism spectrum disorders are associated with defects in social response and communication that often occur in the context of intellectual disability. Rett syndrome is one example in which epilepsy, motor impairment, and motor disturbance may co-occur. Mutations in histone demethylases are known to occur in several of these syndromes. Herein, we aimed to identify whether mutations in the candidate histone demethylase JMJD1C (jumonji domain containing 1C) are implicated in these disorders. We performed the mutational and functional analysis of JMJD1C in 215 cases of autism spectrum disorders, intellectual disability, and Rett syndrome without a known genetic defect. We found seven JMJD1C variants that were not present in any control sample (~ 6,000) and caused an amino acid change involving a different functional group. From these, two de novo JMJD1C germline mutations were identified in a case of Rett syndrome and in a patient with intellectual disability. The functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. We confirmed that JMJD1C protein is widely expressed in brain regions and that its depletion compromises dendritic activity. Our findings indicate that mutations in JMJD1C contribute to the development of Rett syndrome and intellectual disability.Genet Med 18 1, 378-385.

  9. Rett Syndrome. Guidelines for Individual Intervention

    Directory of Open Access Journals (Sweden)

    Meir Lotan

    2006-01-01

    Full Text Available Rett syndrome (RS is a neurological disorder affecting mainly females. RS is considered the second most frequent cause for severe and complex neurological dysfunction in females after Down syndrome. Patients with RS are characterized by an array of neurological and orthopedic difficulties that mandate an intensive therapeutic intervention program for the duration of the individual's life. Many aspects of the client’s well-being and functional status depend on the therapeutic intervention she receives and on her compliance to it. This article will briefly review common intervention approaches for individuals with RS and their present day's application. Due to the notion that individual intervention is the foundation on which progress and development of the functional gains rests, the present article will place basic guidelines for individual intervention with clients with RS. The article is mainly based on the clinical experience of the author and others working with individuals with RS.

  10. The association between behavior and genotype in Rett syndrome using the Australian Rett Syndrome Database.

    Science.gov (United States)

    Robertson, Laila; Hall, Sonĵa E; Jacoby, Peter; Ellaway, Carolyn; de Klerk, Nick; Leonard, Helen

    2006-03-05

    This study compared the behavior profile of cases in the Australian Rett Syndrome Database (ARSD) with those in a British study using the Rett Syndrome Behavior Questionnaire (RSBQ) and then examined behavioral patterns as measured by the RSBQ by genetic status. There were 145 Australian cases meeting the criteria for the first arm of the study and 135 for the second arm. Comparison of the scores obtained from the British and Australian cohorts indicated that the RSBQ was a satisfactory measure for describing behaviors in Rett Syndrome (RS). Overall, there were some differences among the behavior patterns of cases with the well-known common mutations. Fear/anxiety was more commonly reported in those with R133C and R306C. Those with the R294X mutation were more likely to have mood difficulties and body rocking but less likely to have hand behaviors and to display repetitive face movements. In contrast, hand behaviors were more commonly reported in those with R270X or R255X. We found the RSBQ is an appropriate instrument for measuring behavior in girls with RS. Some behaviors differ according to genetic mutation but there is both inter and intra mutation variation in behavior and there is a need for larger studies involving international collaboration to improve statistical power. (c) 2006 Wiley-Liss, Inc.

  11. The association between behaviour and genotype in Rett Syndrome using the Australian Rett Syndrome Database

    Science.gov (United States)

    Robertson, Laila; Hall, Sonĵa E; Jacoby, Peter; Ellaway, Carolyn; de Klerk, Nick; Leonard, Helen

    2008-01-01

    This study compared the behaviour profile of cases in the Australian Rett Syndrome Database (ARSD) with those in a British study using the Rett Syndrome Behaviour Questionnaire (RSBQ) then examined behavioural patterns as measured by the RSBQ by genetic status. There were 145 Australian cases meeting the criteria for the first arm of the study and 135 for the second arm. Comparison of the scores obtained from the British and Australian cohorts indicated that the RSBQ was a satisfactory measure for describing behaviours in Rett syndrome (RS). Overall, there were some differences amongst the behaviour patterns of cases with the well-known common mutations. Fear/anxiety was more commonly reported in those with R133C and R306C. Those with the R294X mutation were more likely to have mood difficulties and body rocking but less likely to have hand behaviours and to display repetitive face movements. In contrast, hand behaviours were more commonly reported in those with R270X or R255X. We found the RSBQ is an appropriate instrument for measuring behaviour in girls with RS. Some behaviours differ according to genetic mutation but there is both inter and intra mutation variation in behaviour and there is a need for larger studies involving international collaboration to improve statistical power. PMID:16389588

  12. Recent advances in understanding synaptic abnormalities in Rett syndrome [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Michael Johnston

    2015-12-01

    Full Text Available Rett syndrome is an extremely disabling X-linked nervous system disorder that mainly affects girls in early childhood and causes autism-like behavior, severe intellectual disability, seizures, sleep disturbances, autonomic instability, and other disorders due to mutations in the MeCP2 (methyl CpG-binding protein 2 transcription factor. The disorder targets synapses and synaptic plasticity and has been shown to disrupt the balance between glutamate excitatory synapses and GABAergic inhibitory synapses. In fact, it can be argued that Rett syndrome is primarily a disorder of synaptic plasticity and that agents that can correct this imbalance may have beneficial effects on brain development. This review briefly summarizes the link between disrupted synaptic plasticity mechanisms and Rett syndrome and early clinical trials that aim to target these abnormalities to improve the outcome for these severely disabled children.

  13. International Conference on Rett Syndrome (4th, Vienna, Austria, October 2-5, 1986). Synopsis.

    Science.gov (United States)

    Percy, Alan

    Presentations from speakers at a conference on Rett Syndrome are summarized. The presentations focused on Rett Syndrome's genetic basis and identification as a clinical syndrome, involving, among other things, mental subnormality, epilepsy, infantile spasms, hand stereotypes, and poor hand use. Also discussed were: Rett Syndrome's predictive…

  14. Rett syndrome: disruption of epigenetic control of postnatal neurological functions.

    Science.gov (United States)

    Pohodich, Amy E; Zoghbi, Huda Y

    2015-10-15

    Loss-of-function mutations in the X-linked gene Methyl-CpG-binding protein 2 (MECP2) cause a devastating pediatric neurological disorder called Rett syndrome. In males, these mutations typically result in severe neonatal encephalopathy and early lethality. On the other hand, owing to expression of the normal allele in ∼50% of cells, females do not suffer encephalopathy but instead develop Rett syndrome. Typically females with Rett syndrome exhibit a delayed onset of neurologic dysfunction that manifests around the child's first birthday and progresses over the next few years. Features of this disorder include loss of acquired language and motor skills, intellectual impairment and hand stereotypies. The developmental regression observed in patients with Rett syndrome arises from altered neuronal function and is not the result of neurodegeneration. Maintenance of an appropriate level of MeCP2 appears integral to the function of healthy neurons as patients with increased levels of MeCP2, owing to duplication of the Xq28 region encompassing the MECP2 locus, also present with intellectual disability and progressive neurologic symptoms. Despite major efforts over the past two decades to elucidate the molecular functions of MeCP2, the mechanisms underlying the delayed appearance of symptoms remain unclear. In this review, we will highlight recent findings that have expanded our knowledge of MeCP2's functions, and we will discuss how epigenetic regulation, chromatin organization and circuit dynamics may contribute to the postnatal onset of Rett syndrome.

  15. Rett Syndrome Turns 50: Themes From a Chronicle: Medical Perspectives and the Human Face of Rett Syndrome.

    Science.gov (United States)

    Ronen, Gabriel M; Rosenbaum, Peter L

    2016-08-01

    Fifty years ago Andreas Rett first described in great detail what came to be known as "Rett syndrome." Understanding girls and women with this syndrome and their families helped in many ways to revolutionize modern neurodevelopmental medicine. For some people the identification of the genetic underpinning of the syndrome and the ongoing biological research into this condition represented the peak of the scientific accomplishments in Rett syndrome. For others, it was developments in clinical research methodologies that were especially important. Above all, the patient- and family-oriented empathetic and collaborative approach to care by professionals collaborating with families has led to immense achievements, both scientific and humanistic. The aim of this narrative was to describe the medical and personal life story of a young woman with Rett syndrome and to offer a history that highlights developments in the unraveling of this condition from its initial recognition to our current understanding. We believe that much can be learned from the humanistic style of care provision combined with the best possible level of assisted autonomy and life enjoyment of the young woman with Rett syndrome. In addition, the approach to collaborative research by dedicated and often charitable leaders in the field can teach us many important lessons about the ethics of clinical and health services research. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. IGF1 as a Potential Treatment for Rett Syndrome: Safety Assessment in Six Rett Patients

    Directory of Open Access Journals (Sweden)

    Giorgio Pini

    2012-01-01

    Full Text Available Rett syndrome (RTT is a devastating neurodevelopmental disorder that affects one in ten thousand girls and has no cure. The majority of RTT patients display mutations in the gene that codes for the methyl-CpG-binding protein 2 (MeCP2. Clinical observations and neurobiological analysis of mouse models suggest that defects in the expression of MeCP2 protein compromise the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function, such as insulin-like growth factor 1 (IGF1, are good candidates for ameliorating the symptoms of RTT. IGF1 and its active peptide, (1–3 IGF1, cross the blood brain barrier, and (1–3 IGF1 ameliorates the symptoms of RTT in a mouse model of the disease; therefore they are ideal treatments for neurodevelopmental disorders, including RTT. We performed a pilot study to establish whether there are major risks associated with IGF1 administration in RTT patients. Six young girls with classic RTT received IGF1 subcutaneous injections twice a day for six months, and they were regularly monitored by their primary care physicians and by the unit for RTT in Versilia Hospital (Italy. This study shows that there are no risks associated with IGF1 administration.

  17. IGF1 as a Potential Treatment for Rett Syndrome: Safety Assessment in Six Rett Patients.

    Science.gov (United States)

    Pini, Giorgio; Scusa, Maria Flora; Congiu, Laura; Benincasa, Alberto; Morescalchi, Paolina; Bottiglioni, Ilaria; Di Marco, Pietro; Borelli, Paolo; Bonuccelli, Ubaldo; Della-Chiesa, Andrea; Prina-Mello, Adriele; Tropea, Daniela

    2012-01-01

    Rett syndrome (RTT) is a devastating neurodevelopmental disorder that affects one in ten thousand girls and has no cure. The majority of RTT patients display mutations in the gene that codes for the methyl-CpG-binding protein 2 (MeCP2). Clinical observations and neurobiological analysis of mouse models suggest that defects in the expression of MeCP2 protein compromise the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function, such as insulin-like growth factor 1 (IGF1), are good candidates for ameliorating the symptoms of RTT. IGF1 and its active peptide, (1-3) IGF1, cross the blood brain barrier, and (1-3) IGF1 ameliorates the symptoms of RTT in a mouse model of the disease; therefore they are ideal treatments for neurodevelopmental disorders, including RTT. We performed a pilot study to establish whether there are major risks associated with IGF1 administration in RTT patients. Six young girls with classic RTT received IGF1 subcutaneous injections twice a day for six months, and they were regularly monitored by their primary care physicians and by the unit for RTT in Versilia Hospital (Italy). This study shows that there are no risks associated with IGF1 administration.

  18. Normal Reactions to Orthostatic Stress in Rett Syndrome

    Science.gov (United States)

    Larsson, Gunilla; Julu, Peter O. O.; Engerstrom, Ingegerd Witt; Sandlund, Marlene; Lindstrom, Britta

    2013-01-01

    The aim of this study was to investigate orthostatic reactions in females with Rett syndrome (RTT), and also whether the severity of the syndrome had an impact on autonomic reactions. Based on signs of impaired function of the central autonomic system found in RTT, it could be suspected that orthostatic reactions were affected. The orthostatic…

  19. Divorce in families of children with Down Syndrome or Rett Syndrome.

    Science.gov (United States)

    Lederman, Vivian Renne Gerber; Alves, Bianca dos Santos; Negrão, Juliana; Maria, Juliana Negrão; Schwartzman, José Salomão; D'Antino, Maria Eloisa Famá; Brunoni, Decio

    2015-05-01

    This study evaluates the impact in the stability and management of the marriage of parents of a child with Down or Rett Syndrome. Morbidity of the syndromes and the marital status of the couples before and after the birth of the affected children were considered variables. The divorce rate in families with Down syndrome was 10%, similar to the Brazilian rate population. In Rett Syndrome, the divorce rate was significantly higher, 23.5%. The higher morbidity of Rett Syndrome, and the moment of diagnosis could be relevant factors for the increased divorce rate related to this syndrome.

  20. Divorce in families of children with Down Syndrome or Rett Syndrome

    Directory of Open Access Journals (Sweden)

    Vivian Renne Gerber Lederman

    2015-05-01

    Full Text Available This study evaluates the impact in the stability and management of the marriage of parents of a child with Down or Rett Syndrome. Morbidity of the syndromes and the marital status of the couples before and after the birth of the affected children were considered variables. The divorce rate in families with Down syndrome was 10%, similar to the Brazilian rate population. In Rett Syndrome, the divorce rate was significantly higher, 23.5%. The higher morbidity of Rett Syndrome, and the moment of diagnosis could be relevant factors for the increased divorce rate related to this syndrome.

  1. Rett Syndrome: A Focus on Gut Microbiota

    Science.gov (United States)

    Borghi, Elisa; Borgo, Francesca; Severgnini, Marco; Savini, Miriam Nella; Casiraghi, Maria Cristina; Vignoli, Aglaia

    2017-01-01

    Rett syndrome (RTT) is an X-linked neurodevelopmental disorder affecting 1 in 10,000 live female births. Changes in microbiota composition, as observed in other neurological disorders such as autism spectrum disorders, may account for several symptoms typically associated with RTT. We studied the relationship between disease phenotypes and microbiome by analyzing diet, gut microbiota, and short-chain fatty acid (SCFA) production. We enrolled eight RTT patients and 10 age- and sex-matched healthy women, all without dietary restrictions. The microbiota was characterized by 16S rRNA gene sequencing, and SCFAs concentration was determined by gas chromatographic analysis. The RTT microbiota showed a lower α diversity, an enrichment in Bacteroidaceae, Clostridium spp., and Sutterella spp., and a slight depletion in Ruminococcaceae. Fecal SCFA concentrations were similar, but RTT samples showed slightly higher concentrations of butyrate and propionate, and significant higher levels in branched-chain fatty acids. Daily caloric intake was similar in the two groups, but macronutrient analysis showed a higher protein content in RTT diets. Microbial function prediction suggested in RTT subjects an increased number of microbial genes encoding for propionate and butyrate, and amino acid metabolism. A full understanding of these critical features could offer new, specific strategies for managing RTT-associated symptoms, such as dietary intervention or pre/probiotic supplementation. PMID:28178201

  2. Subclinical Inflammatory Status in Rett Syndrome

    Science.gov (United States)

    Cortelazzo, Alessio; De Felice, Claudio; Guerranti, Roberto; Landi, Claudia; Valacchi, Giuseppe; Ciccoli, Lucia; Hayek, Joussef

    2014-01-01

    Inflammation has been advocated as a possible common central mechanism for developmental cognitive impairment. Rett syndrome (RTT) is a devastating neurodevelopmental disorder, mainly caused by de novo loss-of-function mutations in the gene encoding MeCP2. Here, we investigated plasma acute phase response (APR) in stage II (i.e., “pseudo-autistic”) RTT patients by routine haematology/clinical chemistry and proteomic 2-DE/MALDI-TOF analyses as a function of four major MECP2 gene mutation types (R306C, T158M, R168X, and large deletions). Elevated erythrocyte sedimentation rate values (median 33.0 mm/h versus 8.0 mm/h, P < 0.0001) were detectable in RTT, whereas C-reactive protein levels were unchanged (P = 0.63). The 2-DE analysis identified significant changes for a total of 17 proteins, the majority of which were categorized as APR proteins, either positive (n = 6 spots) or negative (n = 9 spots), and to a lesser extent as proteins involved in the immune system (n = 2 spots), with some proteins having overlapping functions on metabolism (n = 7 spots). The number of protein changes was proportional to the severity of the mutation. Our findings reveal for the first time the presence of a subclinical chronic inflammatory status related to the “pseudo-autistic” phase of RTT, which is related to the severity carried by the MECP2 gene mutation. PMID:24511209

  3. Subclinical Inflammatory Status in Rett Syndrome

    Directory of Open Access Journals (Sweden)

    Alessio Cortelazzo

    2014-01-01

    Full Text Available Inflammation has been advocated as a possible common central mechanism for developmental cognitive impairment. Rett syndrome (RTT is a devastating neurodevelopmental disorder, mainly caused by de novo loss-of-function mutations in the gene encoding MeCP2. Here, we investigated plasma acute phase response (APR in stage II (i.e., “pseudo-autistic” RTT patients by routine haematology/clinical chemistry and proteomic 2-DE/MALDI-TOF analyses as a function of four major MECP2 gene mutation types (R306C, T158M, R168X, and large deletions. Elevated erythrocyte sedimentation rate values (median 33.0 mm/h versus 8.0 mm/h, P<0.0001 were detectable in RTT, whereas C-reactive protein levels were unchanged (P=0.63. The 2-DE analysis identified significant changes for a total of 17 proteins, the majority of which were categorized as APR proteins, either positive (n=6 spots or negative (n=9 spots, and to a lesser extent as proteins involved in the immune system (n=2 spots, with some proteins having overlapping functions on metabolism (n=7 spots. The number of protein changes was proportional to the severity of the mutation. Our findings reveal for the first time the presence of a subclinical chronic inflammatory status related to the “pseudo-autistic” phase of RTT, which is related to the severity carried by the MECP2 gene mutation.

  4. OxInflammation in Rett syndrome.

    Science.gov (United States)

    Pecorelli, Alessandra; Cervellati, Carlo; Hayek, Joussef; Valacchi, Giuseppe

    2016-12-01

    Rett syndrome (RTT) is an orphan progressive neurodevelopmental disease affecting almost exclusively females (frequency 1:10,000). RTT clinical expression is typically characterized by loss of purposeful hand movements, severe mental retardation and motor impairment, breathing disorders, ataxia and increased risk of sudden death. Although the main genetic cause, i.e. mutation in the methyl-CpG binding protein 2 gene (MECP2), has been already identified, the molecular and pathogenic mechanisms by which MECP2 deficiency drives pathology in RTT remains not fully understood. A wealth of evidence from our and other laboratories suggests a potential causal relationship between MECP2 dysfunction and systemic redox imbalance, a condition that has been widely found in association with RTT. In turn, a "short-circuit" of redox pathways may contribute to the systemic immune dysfunction expressed as cytokines/chemokines dysregulation, a feature clearly emerged from two recent studies on RTT patients. In this light, the purpose of this review is to describe and to stimulate a new discussion on the idea that systemic subclinical inflammation and oxidative stress are crucial players of a detrimental vicious circle, driving the pathogenesis and clinical course of RTT.

  5. Rett Syndrome: A Focus on Gut Microbiota

    Directory of Open Access Journals (Sweden)

    Elisa Borghi

    2017-02-01

    Full Text Available Rett syndrome (RTT is an X-linked neurodevelopmental disorder affecting 1 in 10,000 live female births. Changes in microbiota composition, as observed in other neurological disorders such as autism spectrum disorders, may account for several symptoms typically associated with RTT. We studied the relationship between disease phenotypes and microbiome by analyzing diet, gut microbiota, and short-chain fatty acid (SCFA production. We enrolled eight RTT patients and 10 age- and sex-matched healthy women, all without dietary restrictions. The microbiota was characterized by 16S rRNA gene sequencing, and SCFAs concentration was determined by gas chromatographic analysis. The RTT microbiota showed a lower α diversity, an enrichment in Bacteroidaceae, Clostridium spp., and Sutterella spp., and a slight depletion in Ruminococcaceae. Fecal SCFA concentrations were similar, but RTT samples showed slightly higher concentrations of butyrate and propionate, and significant higher levels in branched-chain fatty acids. Daily caloric intake was similar in the two groups, but macronutrient analysis showed a higher protein content in RTT diets. Microbial function prediction suggested in RTT subjects an increased number of microbial genes encoding for propionate and butyrate, and amino acid metabolism. A full understanding of these critical features could offer new, specific strategies for managing RTT-associated symptoms, such as dietary intervention or pre/probiotic supplementation.

  6. Silent angels the genetic and clinical aspects of Rett syndrome

    Directory of Open Access Journals (Sweden)

    Dziwota Ewelina

    2016-12-01

    Full Text Available Rett syndrome is a neurodevelopmental genetic disorder and, because of some behavioral characteristics, individuals affected by the disease are known as silent angels. Girls with Rett syndrome perform stereotyped movements, they have learning difficulties, their reaction time is prolonged, and they seem alienated in the environment. These children require constant pediatric, neurological and orthopedic care. In the treatment of Rett syndrome physical therapy, music therapy, hydrotherapy, hippotherapy, behavioral methods, speech therapy and diet, are also used. In turn, psychological therapy of the syndrome is based on the sensory integration method, using two or more senses simultaneously. In 80% of cases, the syndrome is related to mutations of the MECP2 gene, located on chromosome X. The pathogenesis of Rett syndrome is caused by the occurrence of a non-functional MeCP2 protein, which is a transcription factor of many genes, i.e. Bdnf, mef2c, Sgk1, Uqcrc1. Abnormal expression of these genes reveals a characteristic disease phenotype. Clinical symptoms relate mainly to the nervous, respiratory, skeletal and gastrointestinal systems. Currently causal treatment is not possible. However, researchers are developing methods by which, perhaps in the near future, it will be possible to eliminate the mutations in the MECP2 gene, and this will give a chance to the patient for normal functioning.

  7. Epilepsy in Rett syndrome--lessons from the Rett networked database

    DEFF Research Database (Denmark)

    Nissenkorn, Andreea; Levy-Drummer, Rachel S; Bondi, Ori

    2015-01-01

    OBJECTIVE: Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene, and characterized by cognitive and communicative regression, loss of hand use, and midline hand stereotypies. Epilepsy is a core symptom, but literature is controversial regarding...... genotype-phenotype correlation. Analysis of data from a large cohort should overcome this shortcoming. METHODS: Data from the Rett Syndrome Networked Database on 1,248 female patients were included. Data on phenotypic and genotypic parameters, age of onset, severity of epilepsy, and type of seizures were...... collected. Statistical analysis was done using the IBM SPSS Version 21 software, logistic regression, and Kaplan-Meier survival curves. RESULTS: Epilepsy was present in 68.1% of the patients, with uncontrolled seizures in 32.6% of the patients with epilepsy. Mean age of onset of epilepsy was 4...

  8. Inflammatory Lung Disease in Rett Syndrome

    Directory of Open Access Journals (Sweden)

    Claudio De Felice

    2014-01-01

    Full Text Available Rett syndrome (RTT is a pervasive neurodevelopmental disorder mainly linked to mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2. Respiratory dysfunction, historically credited to brainstem immaturity, represents a major challenge in RTT. Our aim was to characterize the relationships between pulmonary gas exchange abnormality (GEA, upper airway obstruction, and redox status in patients with typical RTT (n = 228 and to examine lung histology in a Mecp2-null mouse model of the disease. GEA was detectable in ~80% (184/228 of patients versus ~18% of healthy controls, with “high” (39.8% and “low” (34.8% patterns dominating over “mixed” (19.6% and “simple mismatch” (5.9% types. Increased plasma levels of non-protein-bound iron (NPBI, F2-isoprostanes (F2-IsoPs, intraerythrocyte NPBI (IE-NPBI, and reduced and oxidized glutathione (i.e., GSH and GSSG were evidenced in RTT with consequently decreased GSH/GSSG ratios. Apnea frequency/severity was positively correlated with IE-NPBI, F2-IsoPs, and GSSG and negatively with GSH/GSSG ratio. A diffuse inflammatory infiltrate of the terminal bronchioles and alveoli was evidenced in half of the examined Mecp2-mutant mice, well fitting with the radiological findings previously observed in RTT patients. Our findings indicate that GEA is a key feature of RTT and that terminal bronchioles are a likely major target of the disease.

  9. Altered gut microbiota in Rett syndrome.

    Science.gov (United States)

    Strati, Francesco; Cavalieri, Duccio; Albanese, Davide; De Felice, Claudio; Donati, Claudio; Hayek, Joussef; Jousson, Olivier; Leoncini, Silvia; Pindo, Massimo; Renzi, Daniela; Rizzetto, Lisa; Stefanini, Irene; Calabrò, Antonio; De Filippo, Carlotta

    2016-07-30

    The human gut microbiota directly affects human health, and its alteration can lead to gastrointestinal abnormalities and inflammation. Rett syndrome (RTT), a progressive neurological disorder mainly caused by mutations in MeCP2 gene, is commonly associated with gastrointestinal dysfunctions and constipation, suggesting a link between RTT's gastrointestinal abnormalities and the gut microbiota. The aim of this study was to evaluate the bacterial and fungal gut microbiota in a cohort of RTT subjects integrating clinical, metabolomics and metagenomics data to understand if changes in the gut microbiota of RTT subjects could be associated with gastrointestinal abnormalities and inflammatory status. Our findings revealed the occurrence of an intestinal sub-inflammatory status in RTT subjects as measured by the elevated values of faecal calprotectin and erythrocyte sedimentation rate. We showed that, overall, RTT subjects harbour bacterial and fungal microbiota altered in terms of relative abundances from those of healthy controls, with a reduced microbial richness and dominated by microbial taxa belonging to Bifidobacterium, several Clostridia (among which Anaerostipes, Clostridium XIVa, Clostridium XIVb) as well as Erysipelotrichaceae, Actinomyces, Lactobacillus, Enterococcus, Eggerthella, Escherichia/Shigella and the fungal genus Candida. We further observed that alterations of the gut microbiota do not depend on the constipation status of RTT subjects and that this dysbiotic microbiota produced altered short chain fatty acids profiles. We demonstrated for the first time that RTT is associated with a dysbiosis of both the bacterial and fungal component of the gut microbiota, suggesting that impairments of MeCP2 functioning favour the establishment of a microbial community adapted to the costive gastrointestinal niche of RTT subjects. The altered production of short chain fatty acids associated with this microbiota might reinforce the constipation status of RTT

  10. Incontinence in Individuals with Rett Syndrome: A Comparative Study

    NARCIS (Netherlands)

    Giesbers, S.A.H.; Didden, H.C.M.; Radstaake, M.; Korzilius, H.P.L.M.; Gontard, A. von; Lang, R.; Smeets, E.E.J.; Curfs, L.M.G

    2012-01-01

    Frequency and type of incontinence and its association with other variables were assessed in females with Rett Syndrome (RS) (n = 63), using an adapted Dutch version of the ‘Parental Questionnaire: Enuresis/Urinary Incontinence’ (Beetz et al. 1994). Also, incontinence in RS was compared to a control

  11. Changing the Perspective on Early Development of Rett Syndrome

    Science.gov (United States)

    Marschik, Peter B.; Kaufmann, Walter E.; Sigafoos, Jeff; Wolin, Thomas; Zhang, Dajie; Bartl-Pokorny, Katrin D.; Pini, Giorgio; Zappella, Michele; Tager-Flusberg, Helen; Einspieler, Christa; Johnston, Michael V.

    2013-01-01

    We delineated the achievement of early speech-language milestones in 15 young children with Rett syndrome ("MECP2" positive) in the first two years of life using retrospective video analysis. By contrast to the commonly accepted concept that these children are normal in the pre-regression period, we found markedly atypical development of…

  12. Brief Report: Systematic Review of Rett Syndrome in Males

    Science.gov (United States)

    Reichow, Brian; George-Puskar, Annie; Lutz, Tara; Smith, Isaac C.; Volkmar, Fred R.

    2015-01-01

    Rett syndrome (RTT) is a neurogenetic disorder in which a period of typical development is followed by loss of previously acquired skills. Once thought to occur exclusively in females, increasing numbers of male cases of RTT have been reported. This systematic review included 36 articles describing 57 cases of RTT in males. Mutations of the MECP2…

  13. Communication Assessment for Individuals with Rett Syndrome: A Systematic Review

    Science.gov (United States)

    Sigafoos, Jeff; Kagohara, Debora; van der Meer, Larah; Green, Vanessa A.; O'Reilly, Mark F.; Lancioni, Giulio E.; Lang, Russell; Rispoli, Mandy; Zisimopoulos, Dimitrios

    2011-01-01

    We reviewed studies that aimed to determine whether behaviors, such as body movements, vocalizations, eye gaze, and facial expressions, served a communicative function for individuals with Rett syndrome. A systematic search identified eight studies, which were summarized in terms of (a) participants, (b) assessment targets, (c) assessment…

  14. Sensory-Motor Rehabilitation in Rett Syndrome: A Case Report

    Science.gov (United States)

    Pizzamiglio, Maria Rosa; Nasti, Marianna; Piccardi, Laura; Zotti, Antonella; Vitturini, Claudio; Spitoni, Grazia; Nanni, Maria Vittoria; Guariglia, Cecilia; Morelli, Daniela

    2008-01-01

    Rett syndrome (RS) is a severe neurodevelopmental disorder that mostly affects females. It is characterized by a regression of motor, cognitive, linguistic, and social abilities and by an inappropriate and stereotypical use of the hands. The purpose of the current study was to explore the possibility of rehabilitating purposeful use of the hands…

  15. Altered carbon dioxide metabolism and creatine abnormalities in rett syndrome

    NARCIS (Netherlands)

    Halbach, Nicky S J; Smeets, Eric E J; Bierau, Jörgen; Keularts, Irene M L W; Plasqui, Guy; Julu, Peter O O; Engerström, Ingegerd Witt; Bakker, Jaap A.; Curfs, Leopold M G

    2012-01-01

    Despite their good appetite, many females with Rett syndrome (RTT) meet the criteria for moderate to severe malnutrition. Although feeding difficulties may play a part in this, other constitutional factors such as altered metabolic processes are suspected. Irregular breathing is a common clinical fe

  16. Intentionality and Communication in Four Children with Rett Syndrome.

    Science.gov (United States)

    Woodyatt, Gail; Ozanne, Anne

    1994-01-01

    A multiple case study design was used to describe the cognitive and communicative behaviors of four girls with Rett syndrome (RS). Three subjects were at a preintentional level of communication. Communication levels for all subjects was consistent with cognitive status. Dyspraxia appeared to interfere with communicative attempts of the one subject…

  17. Parental experiences of scoliosis management in Rett syndrome.

    Science.gov (United States)

    Ager, Sarah; Downs, Jenny; Fyfe, Sue; Leonard, Helen

    2009-01-01

    Scoliosis is the most common orthopaedic complication of Rett syndrome. Parents of affected individuals are vital partners in the clinical management of scoliosis and this study explored parental experiences of various aspects of different management options. Publicly available Rettnet postings informed the development of an online questionnaire about scoliosis and its management in Rett syndrome. Parents of subjects who met the criteria for Rett syndrome participated in a survey using this questionnaire. One hundred and eighty families participated in this study with scoliosis having developed in 135 (75.4%) of subjects. Eighty-four (62.2% of subjects with scoliosis) had received specific treatment for scoliosis while 51 (37.8%) had not. Surgery was perceived as improving the scoliosis in the majority of subjects but had considerable emotional effects for families of subjects who were less severely affected (p = 0.055) or older (p = 0.063). Physiotherapy and bracing were perceived as not reducing the progression of the curve, but physiotherapy was frequently reported to be beneficial to the subject's quality of life and bracing was frequently associated with side effects such as decreased mobility and problems with pressure. Only half of respondents felt that information about scoliosis provided by clinicians was adequate. The perspectives of parents provided useful insights into the complexities of decision-making regarding scoliosis treatment in Rett syndrome. The provision of scoliosis information by clinicians should be more family-centred.

  18. The Role of Stereotypies in Overselectivity Process in Rett Syndrome

    Science.gov (United States)

    Fabio, Rosa Angela; Giannatiempo, Samantha; Antonietti, Alessandro; Budden, Sarojini

    2009-01-01

    Ten Rett syndrome (RS) girls and 10 control girls executed an attentional task in which a complex stimulus was shown followed by individual stimuli presented with distractors. Participants had to discriminate previously presented stimuli from distractors. RS girls carried out the task both in a condition with the containment of stereotypies and in…

  19. Rett syndrome diagnostic criteria: Lessons from the Natural History Study

    Science.gov (United States)

    Analysis of 819 participants enrolled in the Rett syndrome (RTT) Natural History Study, validates recently revised diagnostic criteria. Seven hundred sixty-five females fulfilled 2002 consensus criteria for classic (653/85.4%) or variant (112/14.6%) RTT. All participants classified as classic RTT fu...

  20. Functional Communication Training in Rett Syndrome: A Preliminary Study

    Science.gov (United States)

    Byiers, Breanne J.; Dimian, Adele; Symons, Frank J.

    2014-01-01

    Rett syndrome (RTT) is associated with a range of serious neurodevelopmental consequences including severe communicative impairments. Currently, no evidence-based communication interventions exist for the population (Sigafoos et al., 2009). The purpose of the current study was to examine the effectiveness of functional assessment (FA) and…

  1. Communication Intervention in Rett Syndrome: A Systematic Review

    Science.gov (United States)

    Sigafoos, Jeff; Green, Vanessa A.; Schlosser, Ralf; O'eilly, Mark F.; Lancioni, Giulio E.; Rispoli, Mandy; Lang, Russell

    2009-01-01

    We reviewed communication intervention studies involving people with Rett syndrome. Systematic searches of five electronic databases, selected journals, and reference lists identified nine studies meeting the inclusion criteria. These studies were evaluated in terms of: (a) participant characteristics, (b) target skills, (c) procedures, (d) main…

  2. Communication Assessment for Individuals with Rett Syndrome: A Systematic Review

    Science.gov (United States)

    Sigafoos, Jeff; Kagohara, Debora; van der Meer, Larah; Green, Vanessa A.; O'Reilly, Mark F.; Lancioni, Giulio E.; Lang, Russell; Rispoli, Mandy; Zisimopoulos, Dimitrios

    2011-01-01

    We reviewed studies that aimed to determine whether behaviors, such as body movements, vocalizations, eye gaze, and facial expressions, served a communicative function for individuals with Rett syndrome. A systematic search identified eight studies, which were summarized in terms of (a) participants, (b) assessment targets, (c) assessment…

  3. Variant of Rett syndrome and CDKL5 gene

    DEFF Research Database (Denmark)

    Pini, Giorgio; Bigoni, Stefania; Engerström, Ingegerd Witt;

    2012-01-01

    UNLABELLED: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have b...

  4. [Non-autistic pervasive developmental disorders: Rett syndrome, disintegrative disorder and pervasive developmental disorder not otherwise specified

    NARCIS (Netherlands)

    Mercadante, M.T.; Gaag, R.J. van der; Schwartzman, J.S.

    2006-01-01

    The category "Pervasive Developmental Disorders" includes autistic disorder, Asperger's syndrome, Rett's syndrome, childhood disintegrative disorder, and a residual category, named pervasive developmental disorder not otherwise specified. In this review, Rett's syndrome and childhood disintegrative

  5. A case of diabetes mellitus associated with Rett syndrome.

    Science.gov (United States)

    Akin, Leyla; Adal, Erdal; Akin, Mustafa Ali; Kurtoglu, Selim

    2012-01-01

    Rett syndrome (RS) is a neurodevelopmental disorder mainly affecting girls. It is characterized by a normal prenatal and perinatal period, apparently normal development for the first 6 months of life, and then a decelaration in head growth, loss of hand and communication skills, psychomotor retardation, as well as the development of sterotyped hand movement and truncal or gait apraxia. It has been shown to be related to mutations in the MECP2 gene located on Xq28. Diabetes mellitus (DM) type 1 may be associated with certain genetic disorders such as Down syndrome, Turner syndrome, and Klinefelter syndrome. In this work, we report the case of a 9-year-old girl with RS who developed DM at the age of 6. To our knowledge, our patient is the third case reported to date of DM associated with Rett syndrome.

  6. Improving Treatment Trial Outcomes for Rett Syndrome: The Development of Rett-specific Anchors for the Clinical Global Impression Scale.

    Science.gov (United States)

    Neul, Jeffrey L; Glaze, Daniel G; Percy, Alan K; Feyma, Tim; Beisang, Arthur; Dinh, Thuy; Suter, Bernhard; Anagnostou, Evdokia; Snape, Mike; Horrigan, Joseph; Jones, Nancy E

    2015-11-01

    Rett syndrome is a genetically based neurodevelopmental disorder. Although the clinical consequences of Rett syndrome are profound and lifelong, currently no approved drug treatments are available specifically targeted to Rett symptoms. High quality outcome measures, specific to the core symptoms of a disorder are a critical component of well-designed clinical trials for individuals with neurodevelopmental disorders. The Clinical Global Impression Scale is a measure of global clinical change with strong face validity that has been widely used as an outcome measure in clinical trials of central nervous system disorders. Despite its favorable assay sensitivity in clinical trials, as a global measure, the Clinical Global Impression Scale is not specific to the signs and symptoms of the disorder under study. Development of key anchors for the scale, specific to the disorder being assessed, holds promise for enhancing the validity and reliability of the measure for disorders such as Rett syndrome.

  7. SATB2-associated syndrome presenting with Rett-like phenotypes.

    Science.gov (United States)

    Lee, J S; Yoo, Y; Lim, B C; Kim, K J; Choi, M; Chae, J-H

    2016-06-01

    The SATB2-associated syndrome (SAS) was proposed recently, after the SATB2 gene was initially discovered to be associated with isolated cleft palate. This syndrome is characterized by intellectual disability with delayed speech development, facial dysmorphism, cleft or high-arched palate, and dentition problems. Here, we describe two novel SATB2 sequence variants in two unrelated patients presenting with Rett-like phenotypes. We performed trio-based whole-exome sequencing in a 17-month-old girl presenting with severe retardation and Rett-like phenotypes, which revealed a de novo missense variant in SATB2 (p.Glu396Gln). Moreover, targeted sequencing of the SATB2 gene was performed in a 2-year-old girl with severe psychomotor retardation, facial hypotonia, and cleft palate who also exhibited some features of Rett syndrome. A nonsense variant in SATB2 was identified in this patient (p.Arg459*). This study expanded the clinical and genetic spectrum of SAS. SATB2 variants should be considered in cases with psychomotor retardation alone or in any cases with Rett-like phenotypes, regardless of the typical features of SAS such as cleft palate.

  8. Rett syndrome molecular diagnosis and implications in genetic counseling

    Directory of Open Access Journals (Sweden)

    Noruzinia M

    2007-01-01

    Full Text Available Rett syndrome is a rare genetic X-linked dominant disorder. This syndrome is the most frequent cause of mental retardation in girls. In the classical form of the disease, the presenting signs and the course of development are characteristic. However clinical diagnosis can be very difficult when the expression is not in the classical form. Mutations in MeCP2 are responsible for 80% of cases. When MeCP2 mutation is found in an index case, genetic counseling is similar to that in other X-linked dominant genetic diseases. However, mutations in this gene can cause a spectrum of atypical forms. On the other hand, other genetic conditions like translocations, sex chromosome numerical anomalies, and mutations in other genes can complicate genetic counseling in this syndrome. We present the first case of molecular diagnosis of Rett syndrome in Iran and discuss the recent developments in its genetic counseling.

  9. Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome.

    Science.gov (United States)

    Olson, Heather E; Tambunan, Dimira; LaCoursiere, Christopher; Goldenberg, Marti; Pinsky, Rebecca; Martin, Emilie; Ho, Eugenia; Khwaja, Omar; Kaufmann, Walter E; Poduri, Annapurna

    2015-09-01

    Rett syndrome and neurodevelopmental disorders with features overlapping this syndrome frequently remain unexplained in patients without clinically identified MECP2 mutations. We recruited a cohort of 11 patients with features of Rett syndrome and negative initial clinical testing for mutations in MECP2. We analyzed their phenotypes to determine whether patients met formal criteria for Rett syndrome, reviewed repeat clinical genetic testing, and performed exome sequencing of the probands. Using 2010 diagnostic criteria, three patients had classical Rett syndrome, including two for whom repeat MECP2 gene testing had identified mutations. In a patient with neonatal onset epilepsy with atypical Rett syndrome, we identified a frameshift deletion in STXBP1. Among seven patients with features of Rett syndrome not fulfilling formal diagnostic criteria, four had suspected pathogenic mutations, one each in MECP2, FOXG1, SCN8A, and IQSEC2. MECP2 mutations are highly correlated with classical Rett syndrome. Genes associated with atypical Rett syndrome, epilepsy, or intellectual disability should be considered in patients with features overlapping with Rett syndrome and negative MECP2 testing. While most of the identified mutations were apparently de novo, the SCN8A variant was inherited from an unaffected parent mosaic for the mutation, which is important to note for counseling regarding recurrence risks.

  10. Adult Phenotypes in Angelman- and Rett-Like Syndromes

    Science.gov (United States)

    Willemsen, M.H.; Rensen, J.H.M.; van Schrojenstein-Lantman de Valk, H.M.J.; Hamel, B.C.J.; Kleefstra, T.

    2012-01-01

    Background Angelman- and Rett-like syndromes share a range of clinical characteristics, including intellectual disability (ID) with or without regression, epilepsy, infantile encephalopathy, postnatal microcephaly, features of autism spectrum disorder, and variable other neurological symptoms. The phenotypic spectrum generally has been well studied in children; however, evolution of the phenotypic spectrum into adulthood has been documented less extensively. To obtain more insight into natural course and prognosis of these syndromes with respect to developmental, medical, and socio-behavioral outcomes, we studied the phenotypes of 9 adult patients who were recently diagnosed with 6 different Angelman- and Rett-like syndromes. Methods All these patients were ascertained during an ongoing cohort study involving a systematic clinical genetic diagnostic evaluation of over 250, mainly adult patients with ID of unknown etiology. Results We describe the evolution of the phenotype in adults with EHMT1, TCF4, MECP2, CDKL5, and SCN1A mutations and 22qter deletions and also provide an overview of previously published adult cases with similar diagnoses. Conclusion These data are highly valuable in adequate management and follow-up of patients with Angelman- and Rett-like syndromes and accurate counseling of their family members. Furthermore, they will contribute to recognition of these syndromes in previously undiagnosed adult patients. PMID:22670143

  11. Progression of CT scan findings in Rett syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Suzuki, Hisaharu; Hirayama, Yoshito; Sakuragawa, Norio; Arima, Masataka (National Center of Neurology and Psychiatry, Kodaira, Tokyo (Japan))

    1989-07-01

    Progression of the lesions revealed by CT scan was observed in five girls with Rett syndrome. The most distinct and common finding was progressive dilatation of Sylvian fissures, frontal extracerebral space, interhemispheric fissure, and sulci mainly in frontal lobe. It may indicate progressive lesion in the frontal and the temporal lobes. In addition, dilatation of the anterior horns of the lateral ventricles and the third ventricle was noted in some cases. Brainstem and cerebellum were small at any age with some morphological development as the patients became elder. Neither malformations nor abnormalities in density were found in any case. It is concluded that the main lesion of Rett syndrome on CT scan is progressive and localized in the frontal and the temporal lobes. (author).

  12. Correlation between clinical features and MECP2 gene mutations in patients with Rett syndrome

    Directory of Open Access Journals (Sweden)

    Hisham Megahed

    2015-03-01

    Conclusions: Mutation screening for MECP2 is a fast and reliable method to diagnose patients clinically suspected to suffer from Rett syndrome or female patients with atypical Rett syndrome features, mental retardation, developmental delay and other neurological abnormalities who do not fit any specific diagnosis. Also, patients with MECP2 mutation presented with a more severe phenotype.

  13. Rett Syndrome Symptomatology of Institutionalized Adults with Mental Retardation: Comparison of Males and Females.

    Science.gov (United States)

    Burd, Larry; And Others

    1991-01-01

    The study of 297 institutionalized adults with mental retardation found no symptom of Rett syndrome occurred more frequently in males than in females and no single cluster of symptoms appeared to differentiate males from females. Only females were found to meet the necessary criteria for diagnosis of Rett syndrome. (Author/DB)

  14. Reduction of Stereotypical Hand Movements in Girls with Rett Syndrome: Two Case Studies.

    Science.gov (United States)

    Lotan, Meir; Roth, Dana

    This study explains the characteristics and treatment of individuals with Rett Syndrome and presents two case studies that investigated the use of interventions in reducing stereotypical hand movements (SHM). The case studies involve two girls (ages 5 and 7) with Rett Syndrome who were enrolled in a special education school. Information was…

  15. Contributing to the Early Detection of Rett Syndrome: The Potential Role of Auditory Gestalt Perception

    Science.gov (United States)

    Marschik, Peter B.; Einspieler, Christa; Sigafoos, Jeff

    2012-01-01

    To assess whether there are qualitatively deviant characteristics in the early vocalizations of children with Rett syndrome, we had 400 native Austrian-German speakers listen to audio recordings of vocalizations from typically developing girls and girls with Rett syndrome. The audio recordings were rated as (a) inconspicuous, (b) conspicuous or…

  16. Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related encephalopathies.

    Science.gov (United States)

    Guerrini, Renzo; Parrini, Elena

    2012-12-01

    Rett syndrome is an X-linked neurodevelopmental disorder that manifests in early childhood with developmental stagnation, and loss of spoken language and hand use, with the development of distinctive hand stereotypies, severe cognitive impairment, and autistic features. About 60% of patients have epilepsy. Seizure onset before the age of 3 years is unlikely, and onset after age 20 is rare. Diagnosis of Rett syndrome is based on key clinical elements that identify "typical" Rett syndrome but also "variant" or "atypical" forms. Diagnostic criteria have been modified only slightly over time, even after discovering that MECP2 gene alterations are present in >90% of patients with typical Rett syndrome but only in 50-70% of atypical cases. Over the last several years, intragenic or genomic alterations of the CDKL5 and FOXG1 genes have been associated with severe cognitive impairment, early onset epilepsy and, often, dyskinetic movement disorders, which have variably been defined as Rett variants. It is now clearly emerging that epilepsy has distinctive characteristics in typical Rett syndrome and in the different syndromes caused by CDKL5 and FOXG1 gene alterations. The progressive parting of CDKL5- and FOXG1-gene-related encephalopathies from the core Rett syndrome is reflected by the effort to produce clearer diagnostic criteria for typical and atypical Rett syndrome. Efforts to characterize the molecular pathology underlying these developmental encephalopathies are pointing to abnormalities of telencephalic development, neuronal morphogenesis, maturation and maintenance, and dendritic arborization.

  17. [Mutational analysis of the MECP2 gene by direct sequencing in Hungarian patients with Rett syndrome

    NARCIS (Netherlands)

    Karteszi, J.; Hollody, K.; Bene, J.; Morava, E.; Hadzsiev, K.; Czako, M.; Melegh, B.; Kosztolanyi, G.Y.

    2004-01-01

    INTRODUCTION: Rett syndrome is an X-linked neurodevelopmental disorder characterized by loss of acquired skills and stereotypical hand movements. Mutations in the gene encoding methyl-CpG-binding protein 2 have been identified as cause of Rett syndrome in 1999. AIM: The authors initialized mutation

  18. Music and Vibroacoustic Stimulation in People with Rett Syndrome

    DEFF Research Database (Denmark)

    Bergström-Isacsson, Märith

    2011-01-01

    Background: Rett syndrome (RTT) is a neurodevelopmental disorder which affects basic body functions including the central control of the autonomic nervous system in the brainstem. Music is used by parents and carers in different situations, e.g. to calm down, to activate, to motivate...... and in communication. The aim of the study was to examine what effect musical stimuli had on the control functions of the autonomic nervous system, and on cortical emotional reactions, in participants with RTT. Methods: The study included 35 participants with RTT who were referred to the Swedish Rett Center...... for routine brainstem assessment during the period 2006-2007, and 11 children with a normal development. A repeated measures design was used, and physiological data were collected from a neurophysiological brainstem assessment. To identify facial expressions elicited by possible pathological brainstem...

  19. Contributing to the early detection of Rett syndrome: the potential role of auditory Gestalt perception.

    Science.gov (United States)

    Marschik, Peter B; Einspieler, Christa; Sigafoos, Jeff

    2012-01-01

    To assess whether there are qualitatively deviant characteristics in the early vocalizations of children with Rett syndrome, we had 400 native Austrian-German speakers listen to audio recordings of vocalizations from typically developing girls and girls with Rett syndrome. The audio recordings were rated as (a) inconspicuous, (b) conspicuous or (c) not able to decide between (a) and (b). The results showed that participants were accurate in differentiating the vocalizations of typically developing children compared to children with Rett syndrome. However, the accuracy for rating verbal behaviors was dependent on the type of vocalization with greater accuracy for canonical babbling compared to cooing vocalizations. The results suggest a potential role for the use of rating child vocalizations for early detection of Rett syndrome. This is important because clinical criteria related to speech and language development remain important for early identification of Rett syndrome.

  20. Progress in Rett Syndrome: from discovery to clinical trials.

    Science.gov (United States)

    Percy, Alan K

    2016-09-01

    Fifty years ago, Andreas Rett described a disorder in 22 females featuring prominent regression of fine motor and communication skills, cognitive impairment, stereotypic movements, periodic breathing, and gait abnormalities. This disorder became known as Rett syndrome (RTT) following the report of Hagberg et al. in 1983. Although RTT was scarcely recognized at that time in the United States, here the efforts of Rett and Hagberg led to rapid progress in recognition and diagnosis, a clearer understanding of its clinical and pathological underpinnings, and, ultimately, identification of mutations in the methyl-CpG-binding protein 2 (MECP2) gene as the primary cause of this unique and challenging neurodevelopmental disorder. Thereafter, a natural history study and critical translational research in animal models paved the way for potential disease-modifying agents to be assessed in human clinical trials. To be successful, the energies of the international community at all levels, including researchers in clinical and basic science, funding agencies, pharmaceutical companies, patient advocates, and, above all, parents and their children are essential. Otherwise, hopes for effective treatment, if not, a cure, will remain unfulfilled.

  1. The trajectories of sleep disturbances in Rett syndrome.

    Science.gov (United States)

    Wong, Kingsley; Leonard, Helen; Jacoby, Peter; Ellaway, Carolyn; Downs, Jenny

    2015-04-01

    Rett syndrome is a rare neurodevelopmental disorder usually affecting females, and is associated with a mutation in the MECP2 gene. Sleep problems occur commonly and we investigated the trajectories and influences of age, mutation and treatments. Data were collected at six time points over 12 years from 320 families registered with the Australian Rett Syndrome Database. Regression analysis was used to investigate relationships between sleep disturbances, age, mutation type and use of treatment, and latent class growth analysis was performed to identify sleep problem phenotypes and model the effect of mutation type. The age range of subjects was 2.0-35.8 years. The study showed that sleep problems occurred in more than 80% of individuals and the prevalence decreased with age. Night laughing and night screaming occurred in 77 and 49%, respectively, when younger. Those with a large deletion had a higher prevalence of night laughing, which often occurred frequently. Treatment was associated with a 1.7% reduction in risk of further sleep problems. High and low baseline prevalence groups were identified. Approximately three-quarters of girls and women with sleep disturbances were in the high baseline group and problems persisted into adulthood. Conversely, 57% with night laughing and 42% with night screaming in the high baseline group exhibited mild improvement over time. Mutation type was not found to be a significant predictor of group membership. In conclusion, the evolution of sleep problems differed between subgroups of girls and women with Rett syndrome, in part explained by age and genotype. Treatment was not associated with improvement in sleep problems.

  2. Klinisk og molekylærgenetisk diagnostik af Retts syndrom i Danmark

    DEFF Research Database (Denmark)

    Schönewolf-Greulich, Bitten; Brøndum-Nielsen, Karen; Bisgaard, Anne-Marie

    2015-01-01

    The neurodevelopmental disorder Rett syndrome was first described in 1966 by Andreas Rett, who described girls with loss of speech and hand use displaying characteristic hand stereotypies. Since then, the disease has been linked to mutations in the gene MECP2. However, the basis of the diagnosis...

  3. Genotype and early development in Rett syndrome: the value of international data.

    Science.gov (United States)

    Leonard, Helen; Moore, Hannah; Carey, Mary; Fyfe, Susan; Hall, Sonj; Robertson, Laila; Wu, Xi Ru; Bao, Xinhua; Pan, Hong; Christodoulou, John; Williamson, Sarah; Klerk, Nick de

    2005-11-01

    Rett syndrome is a neurodevelopmental disorder mostly affecting females and caused by mutations in the MECP2 gene. Originally the syndrome was characterised as having a normal prenatal and perinatal period with later regression. Previous work has speculated that the girl with Rett syndrome may not be normal at birth. to examine whether early development between birth and ten months varies by genotype in Rett syndrome. cases were sourced from two databases, the Australian Rett Syndrome Database (est. 1993) and the newly formed InterRett - IRSA Rett Phenotype Database. Data available on 320 cases included information provided by parents on perinatal problems, early developmental behaviour and mobility. Problem scores, mobility scores and a total composite score for each mutation were generated and compared. overall, 58% of respondents noted unusual behaviour during the first six months and 70.6% from the period between 6 and 10 months of life. Statistically significant differences were detected between some of the common mutations. Infants with R294X (P=0.05) and R133C (P=0.03) were less likely than those with R255X to have problems in the perinatal period. The most severe profile overall for early development was associated with mutations R255X and R270X. This is the largest study to date examining the effects of individual mutations in Rett syndrome. With the ongoing case ascertainment and expansion of InterRett, sample size will increase rapidly and provide improved statistical power for future analyses. Results from this study will contribute to understanding the mechanism of early development in Rett syndrome and determining if and at which time(s) early intervention might be feasible.

  4. CT scan findings of patients with Rett syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Suzuki, Hisaharu; Takanashi, Aiko; Hirayama, Yoshito; Sakuragawa, Norio; Arima, Masataka; Tateno, Akihiko; Koide, Hiroyoshi.

    1989-05-01

    CT findings and clinical features were analyzed in 16 female patients with Rett syndrome, whose ages were between 4 and 20. Fifteen patients had microcrania. Twelve patients were able to stand and run; however, the remaining 4 patients had the only ability to sit. CT revealed an atrophy of the ponse and various degrees of dilatation in the Silvian fissure, frontal sulcus, and space between the cranium and the frontal polar lobe. An atrophy in the frontal lobe, cerebral cortex surrounding the Silvian fissure, and white matter directly below the cortex seemed to have an important role in the occurrence of this syndrome. There was, however, no definitive correlation between the degree of atrophy and both the patient's age and motor function. Serial CT scannings with clinical process are required. (Namekawa, K).

  5. Engaging and interacting through improvised music making with girls and wormen with Rett Syndrome

    DEFF Research Database (Denmark)

    Wigram, Anthony Lewis

    2003-01-01

    Music is a communicative medium that is effective in arousing and sustaining attention and communicative engagement with girsl and women with Rett Syndrome. Timing, expectation, anticipation and musical structure combine to stimuloate turn-taking, intentional communication and pleasure reactions...

  6. Klinisk og molekylærgenetisk diagnostik af Retts syndrom i Danmark

    DEFF Research Database (Denmark)

    Schönewolf-Greulich, Bitten; Dunø, Morten; Ravn, Kirstine;

    2015-01-01

    The neurodevelopmental disorder Rett syndrome was first described in 1966 by Andreas Rett, who described girls with loss of speech and hand use displaying characteristic hand stereotypies. Since then, the disease has been linked to mutations in the gene MECP2. However, the basis of the diagnosis...... is still clinical as defined by the latest clinical criteria as proposed by Neul and colleagues in 2010. This article presents a short clinical and molecular overview of the latest in Rett syndrome with emphasis on the Danish patients, headlines for making the diagnosis, differential diagnoses...

  7. Alternative Therapeutic Intervention for Individuals with Rett Syndrome

    Directory of Open Access Journals (Sweden)

    Meir Lotan

    2007-01-01

    Full Text Available The individual with Rett syndrome (RS displays an array of challenging difficulties in all areas of daily living. Since there is no cure for the disorder at this moment, parents of the individual with Rett search for different interventional modalities that will improve the condition and quality of life for their child. During the last few years, many individuals with RS have experienced different kinds of interventions. This paper presents these methods with relevant case stories for others to share the possibilities. This paper reviews the following interventions: animal-assisted therapy, such as dolphin therapy and dog-assisted therapy; auditory integration training; hyperbaric chamber; manual therapy, such as acupuncture/acupressure, aromatherapy, craniosacral therapy, Mayo facial release, Treager massage, chiropractor, and Reiki; mental modification techniques, such as Lovas and cognitive rehabilitation; motoric interventions, such as advanced biomechanical rehabilitation, patterning/Doman-DeLacato approach, and yoga. The present paper is not a recommendation for any of the above-mentioned techniques, but merely a review of different interventions available for the inquisitive parent of the individual with RS.

  8. Alternative therapeutic intervention for individuals with Rett syndrome.

    Science.gov (United States)

    Lotan, Meir

    2007-05-29

    The individual with Rett syndrome (RS) displays an array of challenging difficulties in all areas of daily living. Since there is no cure for the disorder at this moment, parents of the individual with Rett search for different interventional modalities that will improve the condition and quality of life for their child. During the last few years, many individuals with RS have experienced different kinds of interventions. This paper presents these methods with relevant case stories for others to share the possibilities. This paper reviews the following interventions: animal-assisted therapy, such as dolphin therapy and dog-assisted therapy; auditory integration training; hyperbaric chamber; manual therapy, such as acupuncture/acupressure, aromatherapy, craniosacral therapy, Mayo facial release, Treager massage, chiropractor, and Reiki; mental modification techniques, such as Lovas and cognitive rehabilitation; motoric interventions, such as advanced biomechanical rehabilitation, patterning/Doman-DeLacato approach, and yoga. The present paper is not a recommendation for any of the above-mentioned techniques, but merely a review of different interventions available for the inquisitive parent of the individual with RS.

  9. 14q12 Microdeletion syndrome and congenital variant of Rett syndrome.

    NARCIS (Netherlands)

    Mencarelli, M.A.; Kleefstra, T.; Katzaki, E.; Papa, F.T.; Cohen, M.; Pfundt, R.P.; Ariani, F.; Meloni, I.; Mari, F.; Renieri, A.

    2009-01-01

    Only two patients with 14q12 deletion have been reported to date. Here, we describe an additional patient with a similar deletion in order to improve the clinical delineation of this new microdeletion syndrome. The emerging phenotype is characterized by a Rett-like clinical course with an almost nor

  10. Conceptualizing a quality of life framework for girls with Rett syndrome using qualitative methods.

    Science.gov (United States)

    Epstein, Amy; Leonard, Helen; Davis, Elise; Williams, Katrina; Reddihough, Dinah; Murphy, Nada; Whitehouse, Andrew; Downs, Jenny

    2016-03-01

    Rett syndrome is a neurodevelopmental disorder mainly affecting females and associated with a mutation on the MECP2 gene. There has been no systematic evaluation of the domains of quality of life (QOL) in Rett syndrome. The aims of this study were to explore QOL in school-aged children with Rett syndrome and compare domains with those identified in other available QOL scales. The sample comprised 21 families registered with the Australian Rett Syndrome Database whose daughter with Rett syndrome was aged 6-18 years. Semi-structured telephone interviews were conducted with each parent caregiver (19 mothers, 2 fathers) to investigate aspects of their daughter's life that were satisfying or challenging to her. Qualitative thematic analysis using a grounded theory framework was conducted, and emerging domains compared with those in two generic and three disability parent-report child QOL measures. Ten domains were identified: physical health, body pain, and discomfort, behavioral and emotional well-being, communication skills, movement and mobility, social connectedness, variety of activities, provision of targeted services, stability of daily routines, and the natural environment. The two latter domains were newly identified and each domain contained elements not represented in the comparison measures. Our data articulated important aspects of life beyond the genetic diagnosis. Existing QOL scales for children in the general population or with other disabilities did not capture the QOL of children with Rett syndrome. Our findings support the construction of a new parent-report measure to enable measurement of QOL in this group.

  11. Patients with rett syndrome sustain low-energy fractures

    DEFF Research Database (Denmark)

    Roende, Gitte; Ravn, Kirstine; Fuglsang, Kathrine

    2011-01-01

    We present the first case-control study addressing both fracture occurrence and fracture mechanisms in Rett syndrome (RTT). Two previous studies have shown increased fracture risk in RTT. This was also our hypothesis regarding the Danish RTT population. Therefore, we investigated risk factors...... and x-ray evaluations. National register search on fracture diagnoses was done to obtain complete fracture histories. Our results showed that patients with RTT sustained significantly more low-energy fractures from early age compared with controls, even though overall fracture occurrence apparently...... was not increased. Low-energy fractures were significantly associated with less mobility and lack of ambulation. Associations with MECP2 mutations or epilepsy were not demonstrated, contrary to previous findings. Blood biochemistry indicated a possible need for D vitamin supplementation in RTT. Our study casts...

  12. Measuring Use and Cost of Health Sector and Related Care in a Population of Girls and Young Women with Rett Syndrome

    Science.gov (United States)

    Hendrie, Delia; Bebbington, Ami; Bower, Carol; Leonard, Helen

    2011-01-01

    This study measured use and cost of health sector and related services in Rett syndrome and effects of socio-demographic, clinical severity and genetic factors on costs. The study population consisted of individuals with Rett syndrome registered with the Australian Rett Syndrome Database in 2004. Descriptive analysis was used to examine patterns…

  13. Measuring Use and Cost of Health Sector and Related Care in a Population of Girls and Young Women with Rett Syndrome

    Science.gov (United States)

    Hendrie, Delia; Bebbington, Ami; Bower, Carol; Leonard, Helen

    2011-01-01

    This study measured use and cost of health sector and related services in Rett syndrome and effects of socio-demographic, clinical severity and genetic factors on costs. The study population consisted of individuals with Rett syndrome registered with the Australian Rett Syndrome Database in 2004. Descriptive analysis was used to examine patterns…

  14. 14q12 Microdeletion syndrome and congenital variant of Rett syndrome.

    Science.gov (United States)

    Mencarelli, Maria Antonietta; Kleefstra, Tjitske; Katzaki, Eleni; Papa, Filomena Tiziana; Cohen, Monika; Pfundt, Rolph; Ariani, Francesca; Meloni, Ilaria; Mari, Francesca; Renieri, Alessandra

    2009-01-01

    Only two patients with 14q12 deletion have been reported to date. Here, we describe an additional patient with a similar deletion in order to improve the clinical delineation of this new microdeletion syndrome. The emerging phenotype is characterized by a Rett-like clinical course with an almost normal development during the first months of life followed by a period of regression. A peculiar facial phenotype is also present and it is characterized by mild dysmorphisms such as downslanting palpebral fissures, bilateral epicanthic folds, depressed nasal bridge, bulbous nasal tip, tented upper lip, everted lower lip and large ears. The relationship between this microdeletion syndrome and the congenital variant of Rett syndrome due to point mutations in one of the genes included in the deleted region, FOXG1, is discussed.

  15. Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes

    Directory of Open Access Journals (Sweden)

    Hansen eWang

    2015-02-01

    Full Text Available Autism spectrum disorders (ASDs are genetically and clinically heterogeneous and lack effective medications to treat their core symptoms. Studies of syndromic ASDs caused by single gene mutations have provided insights into the pathophysiology of autism. Fragile X and Rett syndromes belong to the syndromic ASDs in which preclinical studies have identified rational targets for drug therapies focused on correcting underlying neural dysfunction. These preclinical discoveries are increasingly translating into exciting human clinical trials. Since there are significant molecular and neurobiological overlaps among ASDs, targeted treatments developed for fragile X and Rett syndromes may be helpful for autism of different etiologies. Here, we review the targeted pharmacological treatment of fragile X and Rett syndromes and discuss related issues in both preclinical studies and clinical trials of potential therapies for the diseases.

  16. Spinal Fusion for Scoliosis in Rett Syndrome With an Emphasis on Respiratory Failure and Opioid Usage.

    Science.gov (United States)

    Rumbak, Dania M; Mowrey, Wenzhu; W Schwartz, Skai; Sarwahi, Vishal; Djukic, Aleksandra; Killinger, James S; Katyal, Chhavi

    2016-02-01

    Our objective was to characterize our experience with 8 patients with Rett syndrome undergoing scoliosis surgery in regard to rates of respiratory failure and rates of ventilator-acquired pneumonia in comparison to patients with neurologic scoliosis and adolescent idiopathic scoliosis. This study was a retrospective chart review of patients undergoing scoliosis surgery at a tertiary children's hospital. Patients were divided into 3 groups: (1) adolescent idiopathic scoliosis, (2) neurologic scoliosis, and (3) Rett syndrome. There were 133 patients with adolescent idiopathic scoliosis, 48 patients with neurologic scoliosis, and 8 patients with Rett syndrome. We found that patients with Rett syndrome undergoing scoliosis surgery have higher rates of respiratory failure and longer ventilation times in the postoperative period when compared with both adolescent idiopathic scoliosis and neurologic scoliosis patients. There is insufficient evidence to suggest a difference in the incidence of ventilator-acquired pneumonia between the Rett syndrome and the neurologic scoliosis group. We believe our findings are the first in the literature to show a statistically significant difference between these 3 groups in regard to incidence of respiratory failure.

  17. How can clinical ethics guide the management of comorbidities in the child with Rett syndrome?

    Science.gov (United States)

    Downs, Jenny; Forbes, David; Johnson, Michael; Leonard, Helen

    2016-01-01

    Rett syndrome is a rare disorder caused by a mutation in the MECP2 gene. Those affected generally have severe functional impairments and medical comorbidities such as scoliosis and poor growth are common. There is a paucity of information on the natural history of many rare disorders and an even greater deficit of evidence to guide best practice. The population-based and longitudinal Australian Rett Syndrome Database established in 1993 has supported investigations of the natural history of Rett syndrome and effectiveness of treatments. This paper reviews the disorder Rett syndrome and evidence for the management of scoliosis and poor growth within a clinical ethics framework. Compared to conservative management, we have shown that spinal fusion is associated with reduced mortality and better respiratory health. We have also shown that gastrostomy insertion is associated with subsequent weight gain. Family counselling for both procedures necessarily must include family perspectives and careful clinical attention to family needs and wishes. Vignettes describing family decision-making and experiences are presented to illustrate the principals of beneficence and autonomy in determining the best interests of the child and family. A blend of evidence-based practice with a strong clinical ethics framework has capacity to build existing strengths in families and reduce the negative impacts of disability, and in so doing, optimize the health and wellbeing of those with Rett syndrome. PMID:27243819

  18. How can clinical ethics guide the management of comorbidities in the child with Rett syndrome?

    Science.gov (United States)

    Downs, Jenny; Forbes, David; Johnson, Michael; Leonard, Helen

    2016-08-01

    Rett syndrome is a rare disorder caused by a mutation in the MECP2 gene. Those affected generally have severe functional impairments, and medical comorbidities such as scoliosis and poor growth are common. There is a paucity of information on the natural history of many rare disorders and an even greater deficit of evidence to guide best practice. The population-based and longitudinal Australian Rett Syndrome Database established in 1993 has supported investigations of the natural history of Rett syndrome and effectiveness of treatments. This paper reviews the disorder Rett syndrome and evidence for the management of scoliosis and poor growth within a clinical ethics framework. Compared with conservative management, we have shown that spinal fusion is associated with reduced mortality and better respiratory health. We have also shown that gastrostomy insertion is associated with subsequent weight gain. Family counselling for both procedures necessarily must include family perspectives and careful clinical attention to their needs and wishes. Vignettes describing family decision-making and experiences are presented to illustrate the principals of beneficence and autonomy in determining the best interests of the child and family. A blend of evidence-based practice with a strong clinical ethics framework has capacity to build existing strengths in families and reduce the negative impacts of disability and in so doing, optimise the health and wellbeing of those with Rett syndrome.

  19. Quantitative and qualitative insights into the experiences of children with Rett syndrome and their families.

    Science.gov (United States)

    Downs, Jenny; Leonard, Helen

    2016-09-01

    Rett syndrome is a rare neurodevelopmental disorder caused by a mutation in the MECP2 gene. It is associated with severe functional impairments and medical comorbidities such as scoliosis and poor growth. The population-based and longitudinal Australian Rett Syndrome Database was established in 1993 and has supported investigations of the natural history of Rett syndrome and effectiveness of treatments, as well as a suite of qualitative studies to identify deeper meanings. This paper describes the early presentation of Rett syndrome, including regression and challenges for families seeking a diagnosis. We discuss the importance of implementing strategies to enhance daily communication and movement, describe difficulties interpreting the presence of pain and discomfort, and argue for a stronger evidence base in relation to management. Finally, we outline a framework for understanding quality of life in Rett syndrome and suggest areas of life to which we can direct efforts in order to improve quality of life. Each of these descriptions is illustrated with vignettes of child and family experiences. Clinicians and researchers must continue to build this framework of knowledge and understanding with efforts committed to providing more effective treatments and supporting the best quality of life for those affected.

  20. 4-hydroxynonenal protein adducts: Key mediator in Rett syndrome oxinflammation.

    Science.gov (United States)

    Valacchi, Giuseppe; Pecorelli, Alessandra; Cervellati, Carlo; Hayek, Joussef

    2017-01-05

    In the last 15 years a strong correlation between oxidative stress (OxS) and Rett syndrome (RTT), a rare neurodevelopmental disorder known to be caused in 95% of the cases, by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, has been well documented. Here, we revised, summarized and discussed the current knowledge on the role of lipid peroxidation byproducts, with special emphasis on 4-hydroxynonenal (4HNE), in RTT pathophysiology. The posttranslational modifications of proteins via 4HNE, known as 4HNE protein adducts (4NHE-PAs), causing detrimental effects on protein functions, appear to contribute to the clinical severity of the syndrome, since their levels increase significantly during the subsequent 4 clinical stages, reaching the maximum degree at stage 4, represented by a late motor deterioration. In addition, 4HNE-PA are only partially removed due to the compromised functionality of the proteasome activity, contributing therefore to the cellular damage in RTT. All this will lead to a characteristic subclinical inflammation, defined "OxInflammation", derived by a positive feedback loop between OxS byproducts and inflammatory mediators that in a long run further aggravates the clinical features of RTT patients. Therefore, in a pathology completely orphan of any therapy, aiming 4HNE as a therapeutic target could represent a coadjuvant treatment with some beneficial impact in these patients.‬‬‬.

  1. VPA alleviates neurological deficits and restores gene expression in a mouse model of Rett syndrome.

    Directory of Open Access Journals (Sweden)

    Weixiang Guo

    Full Text Available Rett syndrome (RTT is a devastating neurodevelopmental disorder that occurs once in every 10,000-15,000 live female births. Despite intensive research, no effective cure is yet available. Valproic acid (VPA has been used widely to treat mood disorder, epilepsy, and a growing number of other disorders. In limited clinical studies, VPA has also been used to control seizure in RTT patients with promising albeit somewhat unclear efficacy. In this study we tested the effect of VPA on the neurological symptoms of RTT and discovered that short-term VPA treatment during the symptomatic period could reduce neurological symptoms in RTT mice. We found that VPA restores the expression of a subset of genes in RTT mouse brains, and these genes clustered in neurological disease and developmental disorder networks. Our data suggest that VPA could be used as a drug to alleviate RTT symptoms.

  2. The diagnostic value of the EEG in Angelman and Rett syndrome at a young age

    NARCIS (Netherlands)

    Laan, LAEM; Brouwer, OF; Begeer, CH; Zwinderman, AH; van Dijk, JG

    1998-01-01

    We determined the diagnostic value of the EEG in young children with Angelman syndrome (AS) and Rett syndrome (RS). EEGs, recorded before 5 years of age, of 10 patients with AS, 10 with RS and 10 with mental retardation of other origin were studied blindly by two examiners for the presence of the fo

  3. Managing Scoliosis in a Young Child with Rett Syndrome: A Case Study

    Directory of Open Access Journals (Sweden)

    Meir Lotan

    2005-01-01

    Full Text Available Rett syndrome is a genetic disorder primarily affecting females. One of its most disabling features is the severe and rapid progression of scoliosis. So far, only surgical intervention has succeeded in reversing the development of scoliosis in Rett syndrome.The present study describes a new management approach implemented with a girl with Rett syndrome. The core of the management regime was intensive: asymmetrical activation of trunk muscles through equilibrium reactions. The X-rays accompanying the article (evaluated by four experienced orthopedic surgeons blinded to the intervention process suggested that the intervention was successful in reversing the progress of the scoliosis for the above-mentioned child. Discontinuation of treatment led to severe and rapid deterioration of the spinal curve.Due to the fact that this was a case study, generalization is limited, but we suggest further investigation and studies with this method.

  4. MECP2 deletions and genotype-phenotype correlation in Rett syndrome.

    Science.gov (United States)

    Scala, Elisa; Longo, Ilaria; Ottimo, Federica; Speciale, Caterina; Sampieri, Katia; Katzaki, Eleni; Artuso, Rosangela; Mencarelli, Maria Antonietta; D'Ambrogio, Tatiana; Vonella, Giuseppina; Zappella, Michele; Hayek, Giuseppe; Battaglia, Agatino; Mari, Francesca; Renieri, Alessandra; Ariani, Francesca

    2007-12-01

    Rett syndrome is a neurodevelopmental disorder that represents one of the most common genetic causes of mental retardation in girls. MECP2 point mutations in exons 2-4 account for about 80% of classic Rett cases and for a lower percentage of variant patients. We investigated the genetic cause in 77 mutation-negative Rett patients (33 classic, 31 variant, and 13 Rett-like cases) by searching missed MECP2 defects. DHPLC analysis of exon 1 and MLPA analysis allowed us to identify the defect in 17 Rett patients: one exon 1 point mutation (c.47_57del) in a classic case and 16 MECP2 large deletions (15/33 classic and 1/31 variant cases). One identical intragenic MECP2 deletion, probably due to gonadal mosaicism, was found in two sisters with discordant phenotype: one classic and one "highly functioning" preserved speech variant. This result indicates that other epigenetic or genetic factors, beside MECP2, may contribute to phenotype modulation. Three out of 16 MECP2 deletions extend to the adjacent centromeric IRAK1 gene. A putative involvement of the hemizygosity of this gene in the ossification process is discussed. Finally, results reported here clearly indicate that MECP2 large deletions are a common cause of classic Rett, and MLPA analysis is mandatory in MECP2-negative patients, especially in those more severely affected (P = 0.044). (c) 2007 Wiley-Liss, Inc.

  5. Breathing abnormalities in a female mouse model of Rett syndrome.

    Science.gov (United States)

    Johnson, Christopher M; Cui, Ningren; Zhong, Weiwei; Oginsky, Max F; Jiang, Chun

    2015-09-01

    Rett syndrome (RTT) is a female neurodevelopmental disease with breathing abnormalities. To understand whether breathing defects occur in the early lives of a group of female Mecp2(+/-) mice, a mouse model of RTT, and what percentage of mice shows RTT-like breathing abnormality, breathing activity was measured by plethysmography in conscious mice. Breathing frequency variation and central apnea in a group of Mecp2(+/-) females displayed a distribution pattern similar to Mecp2(-/Y) males, while the rest resembled the wild-type mice. Similar results were obtained using the k-mean clustering statistics analysis. With two independent methods, about 20% of female Mecp2(+/-) mice showed RTT-like breathing abnormalities that began as early as 3 weeks of age in the Mecp2(+/-) mice, and were suppressed with 3% CO2. The finding that only a small proportion of Mecp2(+/-) mice develops RTT-like breathing abnormalities suggests incomplete allele inactivation in the RTT-model Mecp2(+/-) mice.

  6. Assistive Technology and Supplementary Treatment for Individuals with Rett Syndrome

    Directory of Open Access Journals (Sweden)

    Meir Lotan

    2007-01-01

    Full Text Available Rett syndrome (RS is a neurological disorder, affecting mainly females, caused by MECP2 mutations usually resulting in severe physical disability. Due to the physical challenges faced by the individual with RS and her family, her rehabilitation program should support her throughout different daily activities, contexts, and surroundings. Rehabilitation interventions to reverse physical impairments include exercise of various types and different physical modalities. Nevertheless, in the vast majority of cases, hands-on therapeutic intervention opportunities are available for the client through a minute part of her waking hours. Hence, a supplementary system is required in order to engulf the child with a comprehensive network of support. Supplementary intervention can support physical impairment by introducing adaptive techniques, environmental modifications, and assistive technologies. The therapy program of an individual with RS should include the use of assistive technology when such devices improve the user's performance. The term “supplementary management” relates to the fact that this intervention may be performed by nonprofessionals with the supervision of a qualified therapist. Such an intervention can further support the therapeutic goals of the child, at a time when direct intervention is not supplied. The present article will review the available literature on the topic of assistive technology, incorporating the clinical knowledge of the author in the field of RS.

  7. A role for glia in the progression of Rett's syndrome.

    Science.gov (United States)

    Lioy, Daniel T; Garg, Saurabh K; Monaghan, Caitlin E; Raber, Jacob; Foust, Kevin D; Kaspar, Brian K; Hirrlinger, Petra G; Kirchhoff, Frank; Bissonnette, John M; Ballas, Nurit; Mandel, Gail

    2011-06-29

    Rett's syndrome (RTT) is an X-chromosome-linked autism spectrum disorder caused by loss of function of the transcription factor methyl-CpG-binding protein 2 (MeCP2). Although MeCP2 is expressed in most tissues, loss of MeCP2 expression results primarily in neurological symptoms. Earlier studies suggested the idea that RTT is due exclusively to loss of MeCP2 function in neurons. Although defective neurons clearly underlie the aberrant behaviours, we and others showed recently that the loss of MECP2 from glia negatively influences neurons in a non-cell-autonomous fashion. Here we show that in globally MeCP2-deficient mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern, and greatly prolonged lifespan compared to globally null mice. Furthermore, restoration of MeCP2 in the mutant astrocytes exerted a non-cell-autonomous positive effect on mutant neurons in vivo, restoring normal dendritic morphology and increasing levels of the excitatory glutamate transporter VGLUT1. Our study shows that glia, like neurons, are integral components of the neuropathology of RTT, and supports the targeting of glia as a strategy for improving the associated symptoms.

  8. CAGE-defined promoter regions of the genes implicated in Rett Syndrome

    DEFF Research Database (Denmark)

    Vitezic, Morana; Bertin, Nicolas; Andersson, Robin;

    2014-01-01

    BACKGROUND: Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other...... for each gene and the common transcription factors likely to regulate the three genes. Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum CONCLUSIONS: Our analyses provide a comprehensive picture of the regulatory regions of the three genes involved in Rett...... Syndrome....

  9. Determinants of sleep disturbances in Rett syndrome: Novel findings in relation to genotype.

    Science.gov (United States)

    Boban, Sharolin; Wong, Kingsley; Epstein, Amy; Anderson, Barbara; Murphy, Nada; Downs, Jenny; Leonard, Helen

    2016-09-01

    Rett syndrome is a rare but severe neurological disorder associated with a mutation in the methyl CpG binding protein 2 (MECP2) gene. Sleep problems and epilepsy are two of many comorbidities associated with this disorder. This study investigated the prevalence and determinants of sleep problems in Rett syndrome using an international sample. Families with a child with a confirmed Rett syndrome diagnosis and a MECP2 mutation registered in the International Rett Syndrome Phenotype Database (InterRett) were invited to participate. Questionnaires were returned by 364/461 (78.9%) either in web-based or paper format. Families completed the Sleep Disturbance Scale for Children and provided information on the presence, nature, and frequency of their child's sleep problems. Multivariate multinomial regression was used to investigate the relationships between selected sleep problems, age group, and genotype and linear regression for the relationships between sleep disturbance scales and a range of covariates. Night waking was the most prevalent sleep problem affecting over 80% with nearly half (48.3%) currently waking often at night. Initiating and maintaining sleep was most disturbed for younger children and those with a p.Arg294* mutation. Severe seizure activity was associated with poor sleep after adjusting for age group, mutation type, and mobility. We were surprised to find associations between the p.Arg294* mutation and some sleep disturbances given that other aspects of its phenotype are milder. These findings highlight the complexities of aberrant MECP2 function in Rett syndrome and explain some of the variation in manifestation of sleep disturbances. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  10. MeCP2 in the regulation of neural activity: Rett syndrome pathophysiological perspectives

    Directory of Open Access Journals (Sweden)

    Cuddapah VA

    2015-10-01

    Full Text Available Vishnu Anand Cuddapah,1,* Sinifunanya Elvee Nwaobi,1,* Alan K Percy,2 Michelle Lynne Olsen1 1Department of Cell, Developmental, and Integrative Biology, 2Civitan International Research Center, University of Alabama at Birmingham, Birmingham, AL, USA *These authors contributed equally to this workAbstract: Rett syndrome (RTT, an X-linked neurodevelopment disorder, occurs in approximately one out of 10,000 females. Individuals afflicted by RTT display a constellation of signs and symptoms, affecting nearly every organ system. Most striking are the neurological manifestations, including regression of language and motor skills, increased seizure activity, autonomic dysfunction, and aberrant regulation of breathing patterns. The majority of girls with RTT have mutations in the gene encoding for methyl-CpG binding protein 2 (MeCP2. Since the discovery of this genetic cause of RTT in 1999, there has been an accelerated pace of research seeking to understand the role of MeCP2 in the brain in the hope of developing a disease-modifying therapy for RTT. In this study, we review the clinical features of RTT and then explore the latest mechanistic studies in order to explain how a mutation in MeCP2 leads to these unique features. We cover in detail studies examining the role of MeCP2 in neuronal physiology, as well as recent evidence that implicates a key role for glia in the pathogenesis of RTT. In the past 20 years, these basic and clinical studies have yielded an extraordinary understanding of RTT; as such, we end this narrative review considering the translation of these studies into clinical trials for the treatment of RTT.Keywords: MeCP2, epigenetic regulation, Rett syndrome, neurons, glia, astrocyte, oligodendrocyte, microglia

  11. Neurophysiology versus clinical genetics in Rett syndrome: A multicenter study.

    Science.gov (United States)

    Halbach, Nicky; Smeets, Eric E; Julu, Peter; Witt-Engerström, Ingegerd; Pini, Giorgio; Bigoni, Stefania; Hansen, Stig; Apartopoulos, Flora; Delamont, Robert; van Roozendaal, Kees; Scusa, Maria F; Borelli, Paolo; Candel, Math; Curfs, Leopold

    2016-09-01

    Many studies have attempted to establish the genotype-phenotype correlation in Rett syndrome (RTT). Cardiorespiratory measurements provide robust objective data, to correlate with each of the different clinical phenotypes. It has important implications for the management and treatment of this syndrome. The aim of this study was to correlate the genotype with the quantitative cardiorespiratory data obtained by neurophysiological measurement combined with a clinical severity score. This international multicenter study was conducted in four European countries from 1999 to 2012. The study cohort consisted of a group of 132 well-defined RTT females aged between 2 and 43 years with extended clinical, molecular, and neurophysiological assessments. Diagnosis of RTT was based on the consensus criteria for RTT and molecular confirmation. Genotype-phenotype analyses of clinical features and cardiorespiratory data were performed after grouping mutations by the same type and localization or having the same putative biological effect on the MeCP2 protein, and subsequently on eight single recurrent mutations. A less severe phenotype was seen in females with CTS, p.R133C, and p.R294X mutations. Autonomic disturbances were present in all females, and not restricted to nor influenced by one specific group or any single recurrent mutation. The objective information from non-invasive neurophysiological evaluation of the disturbed central autonomic control is of great importance in helping to organize the lifelong care for females with RTT. Further research is needed to provide insights into the pathogenesis of autonomic dysfunction, and to develop evidence-based management in RTT. © 2016 Wiley Periodicals, Inc.

  12. Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome.

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    Kunio Miyake

    Full Text Available Monozygotic (identical twins have been widely used in genetic studies to determine the relative contributions of heredity and the environment in human diseases. Discordance in disease manifestation between affected monozygotic twins has been attributed to either environmental factors or different patterns of X chromosome inactivation (XCI. However, recent studies have identified genetic and epigenetic differences between monozygotic twins, thereby challenging the accepted experimental model for distinguishing the effects of nature and nurture. Here, we report the genomic and epigenomic sequences in skin fibroblasts of a discordant monozygotic twin pair with Rett syndrome, an X-linked neurodevelopmental disorder characterized by autistic features, epileptic seizures, gait ataxia and stereotypical hand movements. The twins shared the same de novo mutation in exon 4 of the MECP2 gene (G269AfsX288, which was paternal in origin and occurred during spermatogenesis. The XCI patterns in the twins did not differ in lymphocytes, skin fibroblasts, and hair cells (which originate from ectoderm as does neuronal tissue. No reproducible differences were detected between the twins in single nucleotide polymorphisms (SNPs, insertion-deletion polymorphisms (indels, or copy number variations. Differences in DNA methylation between the twins were detected in fibroblasts in the upstream regions of genes involved in brain function and skeletal tissues such as Mohawk Homeobox (MKX, Brain-type Creatine Kinase (CKB, and FYN Tyrosine Kinase Protooncogene (FYN. The level of methylation in these upstream regions was inversely correlated with the level of gene expression. Thus, differences in DNA methylation patterns likely underlie the discordance in Rett phenotypes between the twins.

  13. Revealing the complexity of a monogenic disease: rett syndrome exome sequencing.

    Directory of Open Access Journals (Sweden)

    Elisa Grillo

    Full Text Available Rett syndrome (OMIM#312750 is a monogenic disorder that may manifest as a large variety of phenotypes ranging from very severe to mild disease. Since there is a weak correlation between the mutation type in the Xq28 disease-gene MECP2/X-inactivation status and phenotypic variability, we used this disease as a model to unveil the complex nature of a monogenic disorder. Whole exome sequencing was used to analyze the functional portion of the genome of two pairs of sisters with Rett syndrome. Although each pair of sisters had the same MECP2 (OMIM*300005 mutation and balanced X-inactivation, one individual from each pair could not speak or walk, and had a profound intellectual deficit (classical Rett syndrome, while the other individual could speak and walk, and had a moderate intellectual disability (Zappella variant. In addition to the MECP2 mutation, each patient has a group of variants predicted to impair protein function. The classical Rett girls, but not their milder affected sisters, have an enrichment of variants in genes related to oxidative stress, muscle impairment and intellectual disability and/or autism. On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype. We demonstrate that genome analysis has the potential to identify genetic modifiers of Rett syndrome, providing insight into disease pathophysiology. Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches. Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

  14. Revealing the complexity of a monogenic disease: rett syndrome exome sequencing.

    Science.gov (United States)

    Grillo, Elisa; Lo Rizzo, Caterina; Bianciardi, Laura; Bizzarri, Veronica; Baldassarri, Margherita; Spiga, Ottavia; Furini, Simone; De Felice, Claudio; Signorini, Cinzia; Leoncini, Silvia; Pecorelli, Alessandra; Ciccoli, Lucia; Mencarelli, Maria Antonietta; Hayek, Joussef; Meloni, Ilaria; Ariani, Francesca; Mari, Francesca; Renieri, Alessandra

    2013-01-01

    Rett syndrome (OMIM#312750) is a monogenic disorder that may manifest as a large variety of phenotypes ranging from very severe to mild disease. Since there is a weak correlation between the mutation type in the Xq28 disease-gene MECP2/X-inactivation status and phenotypic variability, we used this disease as a model to unveil the complex nature of a monogenic disorder. Whole exome sequencing was used to analyze the functional portion of the genome of two pairs of sisters with Rett syndrome. Although each pair of sisters had the same MECP2 (OMIM*300005) mutation and balanced X-inactivation, one individual from each pair could not speak or walk, and had a profound intellectual deficit (classical Rett syndrome), while the other individual could speak and walk, and had a moderate intellectual disability (Zappella variant). In addition to the MECP2 mutation, each patient has a group of variants predicted to impair protein function. The classical Rett girls, but not their milder affected sisters, have an enrichment of variants in genes related to oxidative stress, muscle impairment and intellectual disability and/or autism. On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype. We demonstrate that genome analysis has the potential to identify genetic modifiers of Rett syndrome, providing insight into disease pathophysiology. Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches. Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

  15. 14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype.

    Science.gov (United States)

    Ellaway, Carolyn J; Ho, Gladys; Bettella, Elisa; Knapman, Alisa; Collins, Felicity; Hackett, Anna; McKenzie, Fiona; Darmanian, Artur; Peters, Gregory B; Fagan, Kerry; Christodoulou, John

    2013-05-01

    Rett syndrome is a clinically defined neurodevelopmental disorder almost exclusively affecting females. Usually sporadic, Rett syndrome is caused by mutations in the X-linked MECP2 gene in ∼90-95% of classic cases and 40-60% of individuals with atypical Rett syndrome. Mutations in the CDKL5 gene have been associated with the early-onset seizure variant of Rett syndrome and mutations in FOXG1 have been associated with the congenital Rett syndrome variant. We report the clinical features and array CGH findings of three atypical Rett syndrome patients who had severe intellectual impairment, early-onset developmental delay, postnatal microcephaly and hypotonia. In addition, the females had a seizure disorder, agenesis of the corpus callosum and subtle dysmorphism. All three were found to have an interstitial deletion of 14q12. The deleted region in common included the PRKD1 gene but not the FOXG1 gene. Gene expression analysis suggested a decrease in FOXG1 levels in two of the patients. Screening of 32 atypical Rett syndrome patients did not identify any pathogenic mutations in the PRKD1 gene, although a previously reported frameshift mutation affecting FOXG1 (c.256dupC, p.Gln86ProfsX35) was identified in a patient with the congenital Rett syndrome variant. There is phenotypic overlap between congenital Rett syndrome variants with FOXG1 mutations and the clinical presentation of our three patients with this 14q12 microdeletion, not encompassing the FOXG1 gene. We propose that the primary defect in these patients is misregulation of the FOXG1 gene rather than a primary abnormality of PRKD1.

  16. The Israeli Rett Syndrome Center. Evaluation and Transdisciplinary Play-Based Assessment

    Directory of Open Access Journals (Sweden)

    Meir Lotan

    2006-01-01

    Full Text Available Rett syndrome (RS is a neuro-developmental syndrome of genetic origin, which mainly affects women. Individuals diagnosed with RS exhibit a variety of functional difficulties, which impair their quality of life. The variety of impairments and the differences between each child makes it necessary to administer skilled treatment, individually tailored to each client. Since the foundation of proper treatment is based on a structured, well administered, insightful assessment, the individual with RS with her complex array of difficulties should benefit from such a procedure. This notion has led to the establishment of the Israel Rett Syndrome Center. The center includes a medical branch located at the Safra Shildren's Medical Center at Tel Hashomer and an education/rehabilitation team, who performs assessments in special education facilities and residential settings throughout Israel. The assessment team works by means of arena assessment according to the concept of play-based assessment. This article presents the working model used by the education/rehabilitation team at the Israeli Rett Syndrome Center. The principles and working characteristics of the Israel Rett Syndrome Center team are suggested here as a potential model for establishing additional teams, presenting similar evaluation services for other individuals with RS as well as for analogous populations.

  17. CAGE-defined promoter regions of the genes implicated in Rett Syndrome

    DEFF Research Database (Denmark)

    Vitezic, Morana; Bertin, Nicolas; Andersson, Robin;

    2014-01-01

    BACKGROUND: Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other...

  18. DXA measurements in rett syndrome reveal small bones with low bone mass

    DEFF Research Database (Denmark)

    Roende, Gitte; Ravn, Kirstine; Fuglsang, Kathrine

    2011-01-01

    Low bone mass is reported in growth-retarded patients harboring mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene causing Rett syndrome (RTT). We present the first study addressing both bone mineral density (BMD) and bone size in RTT. Our object was to determine whether patients...

  19. Development of a Video-Based Evaluation Tool in Rett Syndrome

    Science.gov (United States)

    Fyfe, S.; Downs, J.; McIlroy, O.; Burford, B.; Lister, J.; Reilly, S.; Laurvick, C. L.; Philippe, C.; Msall, M.; Kaufmann, W. E.; Ellaway, C.; Leonard, H.

    2007-01-01

    This paper describes the development of a video-based evaluation tool for use in Rett syndrome (RTT). Components include a parent-report checklist, and video filming and coding protocols that contain items on eating, drinking, communication, hand function and movements, personal care and mobility. Ninety-seven of the 169 families who initially…

  20. Clinical and electroencephalographic effects of folinic acid treatment in Rett syndrome patients

    NARCIS (Netherlands)

    E.E.O. Hagebeuk; J.H.T.M. Koelman; M. Duran; N.G. Abeling; A. Vyth; B.T. Poll-The

    2011-01-01

    Rett syndrome is characterized by the development of stereotypic hand movements and seizures, which are often difficult to treat. Previous studies have shown conflicting results during add-on folinic acid. Here, the authors reevaluate the response to folinic acid in terms of epilepsy control and ele

  1. Physical and Mental Health of Mothers Caring for a Child with Rett Syndrome

    Science.gov (United States)

    Laurvick, Crystal L.; Msall, Michael E.; Silburn, Sven; Bower, Carol; de Klerk, Nicholas; Leonard, Helen

    2007-01-01

    Objectives: Our goal was to investigate the physical and mental health of mothers who care for a child with Rett syndrome. Methods: We assessed maternal physical and mental health by using the SF-12 version 1 physical component summary and mental component summary scores as the outcome measures of interest. Mothers (n = 135) of children with Rett…

  2. The Rett Syndrome Complex: Communicative Functions in Relation to Developmental Level and Autistic Features.

    Science.gov (United States)

    Sandberg, Annika Dahlgren; Ehlers, Stephan; Hagberg, Bengt; Gillberg, Christopher

    2000-01-01

    Communicative functions, overall developmental level, and autistic features were studied in eight females (ages 11-36) with Rett Syndrome. Low levels of communicative abilities and overall functioning were demonstrated, and joint attention behaviors and expression of communicative intent were rare. Six subjects, however, showed clear examples of…

  3. Communication in Individuals with Rett Syndrome: an Assessment of Forms and Functions

    NARCIS (Netherlands)

    Didden, H.C.M.; Korzilius, H.P.L.M.; Smeets, E.E.J.; Green, V.A.; Lang, R.; Lancioni, G.E.; Curfs, L.M.G

    2010-01-01

    In the present study we assessed the forms and functions of prelinguistic communicative behaviors for 120 children and adults with Rett syndrome using the Inventory of Potential Communicative Acts (IPCA) (Sigafoos et al. Communication Disorders Quarterly 21:77-86, 2000a). Informants completed the

  4. Klinisk og molekylærgenetisk diagnostik af Retts syndrom i Danmark

    DEFF Research Database (Denmark)

    Schönewolf-Greulich, Bitten; Brøndum-Nielsen, Karen; Bisgaard, Anne-Marie;

    2015-01-01

    is still clinical as defined by the latest clinical criteria as proposed by Neul and colleagues in 2010. This article presents a short clinical and molecular overview of the latest in Rett syndrome with emphasis on the Danish patients, headlines for making the diagnosis, differential diagnoses...

  5. Progressive Encephalopathy in Boys with Symptoms of Rett Syndrome and MECP2 Mutations

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-08-01

    Full Text Available Four young boys with neonatal onset of encephalopathy, a progressive course, and MECP2 mutations are reported from the University of Alabama, Birmingham, AL Symptoms suggestive of Rett syndrome included failure to thrive, respiratory insufficiency, microcephaly, hypotonia, movement disorder, with myoclonic, dyskinetic, and choreiform patterns, and repetitive face scratching or nose rubbing stereotypies.

  6. Degraded neural and behavioral processing of speech sounds in a rat model of Rett syndrome.

    Science.gov (United States)

    Engineer, Crystal T; Rahebi, Kimiya C; Borland, Michael S; Buell, Elizabeth P; Centanni, Tracy M; Fink, Melyssa K; Im, Kwok W; Wilson, Linda G; Kilgard, Michael P

    2015-11-01

    Individuals with Rett syndrome have greatly impaired speech and language abilities. Auditory brainstem responses to sounds are normal, but cortical responses are highly abnormal. In this study, we used the novel rat Mecp2 knockout model of Rett syndrome to document the neural and behavioral processing of speech sounds. We hypothesized that both speech discrimination ability and the neural response to speech sounds would be impaired in Mecp2 rats. We expected that extensive speech training would improve speech discrimination ability and the cortical response to speech sounds. Our results reveal that speech responses across all four auditory cortex fields of Mecp2 rats were hyperexcitable, responded slower, and were less able to follow rapidly presented sounds. While Mecp2 rats could accurately perform consonant and vowel discrimination tasks in quiet, they were significantly impaired at speech sound discrimination in background noise. Extensive speech training improved discrimination ability. Training shifted cortical responses in both Mecp2 and control rats to favor the onset of speech sounds. While training increased the response to low frequency sounds in control rats, the opposite occurred in Mecp2 rats. Although neural coding and plasticity are abnormal in the rat model of Rett syndrome, extensive therapy appears to be effective. These findings may help to explain some aspects of communication deficits in Rett syndrome and suggest that extensive rehabilitation therapy might prove beneficial.

  7. Use of Equipment and Respite Services and Caregiver Health among Australian Families Living with Rett Syndrome

    Science.gov (United States)

    Urbanowicz, Anna; Downs, Jenny; Bebbington, Ami; Jacoby, Peter; Girdler, Sonya; Leonard, Helen

    2011-01-01

    This study assessed factors that could influence equipment and respite services use among Australian families caring for a girl/woman with Rett syndrome and examined relationships between use of these resources and the health of female caregivers. Data was sourced from questionnaires completed by families (n=170) contributing to the Australian…

  8. Coaching Communication Partners: A Preliminary Investigation of Communication Intervention during Mealtime in Rett Syndrome

    Science.gov (United States)

    Bartolotta, Theresa E.; Remshifski, Patricia A.

    2013-01-01

    Rett syndrome (RTT) occurs primarily in females and is characterized by deficits in cognition, communication, hand use and ambulation. This quasi-experimental study explored the use of a coaching program to increase communicative interactions between girls with RTT and their communication partners. Communication coaching strategies were provided…

  9. Expression profiling of clonal lymphocyte cell cultures from Rett syndrome patients

    Science.gov (United States)

    More than 85% of Rett syndrome (RTT) patients have heterozygous mutations in the X-linked MECP2 gene which encodes methyl-CpG-binding protein 2, a transcriptional repressor that binds methylated CpG sites. Because MECP2 is subject to X chromosome inactivation (XCI), girls with RTT express either the...

  10. Rett Syndrome: Of Girls and Mice--Lessons for Regression in Autism

    Science.gov (United States)

    Glaze, Daniel G.

    2004-01-01

    Rett syndrome (RTT) is a neurodevelopmental disorder occurring almost exclusively in females. Regression is a defining feature of RTT. During the regression stage, RTT girls display many autistic features, such as loss of communication and social skills, poor eye contact, and lack of interest, and initially may be given the diagnosis of autism.…

  11. Suggestions for Educational and Therapeutic Interventions with the Rett Syndrome Child.

    Science.gov (United States)

    International Rett Syndrome Association, Inc., Fort Washington, MD.

    This paper comprises a compilation of nine case studies of girls (aged 4-16 years) with Rett Syndrome. The educational settings involved are various and include private day school, public elementary school in both integrated and special needs classrooms, and a county-operated preschool program for handicapped children. Each case study outlines the…

  12. Social Impairments in Rett Syndrome: Characteristics and Relationship with Clinical Severity

    Science.gov (United States)

    Kaufmann, W. E.; Tierney, E.; Rohde, C. A.; Suarez-Pedraza, M. C.; Clarke, M. A.; Salorio, C. F.; Bibat, G.; Bukelis, I.; Naram, D.; Lanham, D. C.; Naidu, S.

    2012-01-01

    Background: While behavioural abnormalities are fundamental features of Rett syndrome (RTT), few studies have examined the RTT behavioural phenotype. Most of these reports have focused on autistic features, linked to the early regressive phase of the disorder, and few studies have applied standardised behavioural measures. We used a battery of…

  13. Brief Report:MECP2 Mutations in People without Rett Syndrome

    Science.gov (United States)

    Suter, Bernhard; Treadwell-Deering, Diane; Zoghbi, Huda Y.; Glaze, Daniel G.; Neul, Jeffrey L.

    2014-01-01

    Mutations in "Methyl-CpG-Binding protein 2" ("MECP2") are commonly associated with the neurodevelopmental disorder Rett syndrome (RTT). However, some people with RTT do not have mutations in "MECP2," and interestingly there have been people identified with "MECP2" mutations that do not have the clinical…

  14. Gastrostomy placement improves height and weight gain in girls with Rett syndrome

    Science.gov (United States)

    Growth failure and undernutrition complicate the clinical course of girls with Rett syndrome (RTT). These abnormalities are, in part, the consequence of oral motor dysfunction and inadequate dietary intake. We hypothesized that gastrostomy placement for nutritional therapy reverses the decline in he...

  15. Gastrostomy placement favorably alters the natural history of growth failure and undernutrition in Rett syndrome

    Science.gov (United States)

    Growth failure and undernutrition complicate the clinical course of girls with Rett syndrome (RTT). These abnormalities are, in part, the consequence of oral motor dysfunction and inadequate dietary intake. Our objective was to determine if gastrostomy placement for nutritional therapy alters the na...

  16. Peculiarities in the Gestural Repertoire: An Early Marker for Rett Syndrome?

    Science.gov (United States)

    Marschik, Peter B.; Sigafoos, Jeff; Kaufmann, Walter E.; Wolin, Thomas; Talisa, Victor B.; Bartl-Pokorny, Katrin D.; Budimirovic, Dejan B.; Vollmann, Ralf; Einspieler, Christa

    2012-01-01

    We studied the gestures used by children with classic Rett syndrome (RTT) to provide evidence as to how this essential aspect of communicative functions develops. Seven participants with RTT were longitudinally observed between 9 and 18 months of life. The gestures used by these participants were transcribed and coded from a retrospective analysis…

  17. Vitamin D deficiency is prevalent in girls and women with rett syndrome

    Science.gov (United States)

    The aim of the study was to determine the prevalence of vitamin D deficiency and identify the relation between 25-hydroxyvitamin D (25-(OH)D) levels and the consumption of dietary sources of vitamin D or exposure to anticonvulsants in girls and women with Rett syndrome (RTT). Retrospective review of...

  18. Aspects of speech-language abilities are influenced by MECP2 mutation type in girls with Rett syndrome.

    Science.gov (United States)

    Urbanowicz, Anna; Downs, Jenny; Girdler, Sonya; Ciccone, Natalie; Leonard, Helen

    2015-02-01

    This study investigates relationships between methyl-CpG-binding protein 2 gene (MECP2) mutation type and speech-language abilities in girls with Rett syndrome. Cross-sectional data on 766 girls, aged 15 years and under, with genetically confirmed Rett syndrome was obtained from the Australian Rett Syndrome Database (ARSD) (n = 244) and the International Rett Syndrome Phenotype Database (InterRett) (n = 522). Relationships between MECP2 mutation type and age of regression in speech-language abilities, and the level of speech-language abilities before and after this regression were investigated. The females had a median age of 4.95 years in the ARSD and 5.25 years in InterRett. The majority (89%, 685/766) acquired speech-language abilities in the form of babble or words at some point in time. Of those who acquired babble or words, 85% (581/685) experienced a regression in these abilities. Those with a p.Arg133Cys mutation were the most likely to use one or more words, prior to (RRR = 3.45; 95% CI 1.15-10.41) and after (RRR = 5.99; 95% CI 2.00-17.92), speech-language regression. Girls with Rett syndrome vary in their use of speech and language, and in their experience of speech-language regression and these variations are partly explained by genotype. © 2014 Wiley Periodicals, Inc.

  19. Disruption of DNA methylation-dependent long gene repression in Rett syndrome

    Science.gov (United States)

    Gabel, Harrison W.; Kinde, Benyam Z.; Stroud, Hume; Gilbert, Caitlin S.; Harmin, David A.; Kastan, Nathaniel R.; Hemberg, Martin; Ebert, Daniel H.; Greenberg, Michael E.

    2015-01-01

    Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism1. MECP2 encodes a methyl-DNA-binding protein2 that has been proposed to function as a transcriptional repressor, but despite numerous studies examining neuronal gene expression in Mecp2 mutants, no clear model has emerged for how MeCP2 regulates transcription3–9. Here we identify a genome-wide length-dependent increase in gene expression in MeCP2 mutant mouse models and human RTT brains. We present evidence that MeCP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MeCP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, we find that long genes as a population are enriched for neuronal functions and selectively expressed in the brain. These findings suggest that mutations in MeCP2 may cause neurological dysfunction by specifically disrupting long gene expression in the brain. PMID:25762136

  20. Deficient Purposeful Use of Forepaws in Female Mice Modelling Rett Syndrome

    Directory of Open Access Journals (Sweden)

    Bianca De Filippis

    2015-01-01

    Full Text Available Rett syndrome (RTT is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2 cause more than 95% of classic cases. Motor abnormalities represent a significant part of the spectrum of RTT symptoms. In the present study we investigated motor coordination and fine motor skill domains in MeCP2-308 female mice, a validated RTT model. This was complemented by the in vivo magnetic resonance spectroscopy (MRS analysis of metabolic profile in behaviourally relevant brain areas. MeCP2-308 heterozygous female mice (Het, 10-12 months of age were impaired in tasks validated for the assessment of purposeful and coordinated forepaw use (Morag test and Capellini handling task. A fine-grain analysis of spontaneous behaviour in the home-cage also revealed an abnormal handling pattern when interacting with the nesting material, reduced motivation to explore the environment, and increased time devoted to feeding in Het mice. The brain MRS evaluation highlighted decreased levels of bioenergetic metabolites in the striatal area in Het mice compared to controls. Present results confirm behavioural and brain alterations previously reported in MeCP2-308 males and identify novel endpoints on which the efficacy of innovative therapeutic strategies for RTT may be tested.

  1. WDR45 mutations in Rett (-like) syndrome and developmental delay: Case report and an appraisal of the literature.

    Science.gov (United States)

    Hoffjan, Sabine; Ibisler, Aysegül; Tschentscher, Anne; Dekomien, Gabriele; Bidinost, Carla; Rosa, Alberto L

    2016-02-01

    Mutations in the WDR45 gene have been identified as causative for the only X-linked type of neurodegeneration with brain iron accumulation (NBIA), clinically characterized by global developmental delay in childhood, followed by a secondary neurological decline with parkinsonism and/or dementia in adolescence or early adulthood. Recent reports suggest that WDR45 mutations are associated with a broader phenotypic spectrum. We identified a novel splice site mutation (c.440-2 A > G) in a 5-year-old Argentinian patient with Rett-like syndrome, exhibiting developmental delay, microcephaly, seizures and stereotypic hand movements, and discuss this finding, together with a review of the literature. Additional patients with a clinical diagnosis of Rett (-like) syndrome were also found to carry WDR45 mutations before (or without) clinical decline or signs of iron accumulation by magnetic resonance imaging (MRI). This information indicates that WDR45 mutations should be added to the growing list of genetic alterations linked to Rett-like syndrome. Further, clinical symptoms associated with WDR45 mutations ranged from early-onset epileptic encephalopathy in a male patient with a deletion of WDR45 to only mild cognitive delay in a female patient, suggesting that analysis of this gene should be considered more often in patients with developmental delay, regardless of severity. The increasing use of next generation sequencing technologies as well as longitudinal follow-up of patients with an early diagnosis will help to gain additional insight into the phenotypic spectrum associated with WDR45 mutations.

  2. Activities that girls and women with Rett syndrome liked or did not like to do.

    Science.gov (United States)

    Sernheim, Åsa-Sara; Hemmingsson, Helena; Witt Engerström, Ingegerd; Liedberg, Gunilla

    2016-11-06

    Activities occur in all people's lives. This study investigated over a period of time, 15 years, what activities were enjoyed or not enjoyed and what activities parents and staff liked to do with girls/women with Rett syndrome. A descriptive study was conducted using secondary data from three earlier questionnaires at the Swedish National Rett Center. The first questionnaire provided data on 123 girls/women with Rett syndrome, the second on 52 and the third questionnaire, on 39. Informants were parents and/or staff, in total 365. Open-ended questions were analysed using a content analysis approach. Three categories appeared: Being in motion, receiving impressions and having contact. Bathing/swimming, listening to music and being outdoors/walking were the most enjoyed activities over the years. Of the few activities that were reported as being unenjoyable, most were daily care activities. The activities that the parents/staff enjoyed doing with the girls/women were similar to those the girls/women themselves liked to do. A preliminary overview for both liked and disliked activities of girls/women with Rett syndrome was presented. This knowledge could facilitate the choice and use of activities.

  3. Rett Syndrome. A Case Presentation Síndrome de Rett. Presentación de un caso

    Directory of Open Access Journals (Sweden)

    Julio Padrón González

    2012-02-01

    Full Text Available

    Rett syndrome is a neurological disorder of genetic basis. It affects almost exclusively girls and women being the estimated incidence of this disease in the general population of one case per 10,000 women. In its classical type it is of one in every 15. 000 births. Its diagnosis is descriptive, based on a set of signs and symptoms, but not etiologic. Treatment is symptomatic and supportive. Rett syndrome is frequently misdiagnosed as autism or cerebral palsy. It should be suspected in female patients, diagnosed with child cerebral palsy or idiomatic mental retardation, supported by internationally established criteria. The case of an 11 years old girl visited at her home and attended by doctors of the Barrio Adentro mission in the Bolivarian Republic of Venezuela is presented. The patient was normal until about two years old when she began presenting impairment of psychomotor skills, social and behavioral disorders with infantile autism traits, seizures and considerable mental retardation.

    El síndrome de Rett es un trastorno neurológico de base genética. Afecta casi exclusivamente a niñas y mujeres; la incidencia estimada en la población general es de un caso por cada 10.000 mujeres, en su tipo clásico, es de 1 por cada 15. 000 nacimientos. Su diagnóstico es descriptivo, basado en un conjunto de signos y síntomas, pero no es etiológico; el tratamiento es sintomático y de apoyo. La enfermedad, frecuentemente, suele estar mal diagnosticada como autismo o parálisis cerebral. Debe sospecharse en pacientes del sexo femenino, con diagnóstico de parálisis cerebral infantil o retardo mental idiomático, apoyado en criterios establecidos internacionalmente. Se presenta el caso de una niña de 11 años de edad, visitada en el hogar por médicos de la Misión Barrio Adentro en la República Bolivariana de Venezuela, la cual fue normal hasta aproximadamente los 2 años, cuando comenzó con deterioro en sus destrezas psicomotoras

  4. Retracing Atypical Development: A Preserved Speech Variant of Rett Syndrome

    Science.gov (United States)

    Marschik, Peter B.; Einspieler, Christa; Oberle, Andreas; Laccone, Franco; Prechtl, Heinz F. R.

    2009-01-01

    The subject of the present study is the development of a girl with the preserved speech variant of Rett disorder. Our data are based on detailed retrospective and prospective video analyses. Despite achieving developmental milestones, movement quality was already abnormal during the girl's first half year of life. In addition, early hand…

  5. S-adenosylmethionine and S-adenosylhomocysteine in plasma and cerebrospinal fluid in Rett syndrome and the effect of folinic acid supplementation.

    Science.gov (United States)

    Hagebeuk, Eveline E O; Duran, Marinus; Abeling, Nico G G M; Vyth, Arno; Poll-The, Bwee Tien

    2013-11-01

    Rett syndrome is a neurodevelopmental disorder characterized by cognitive and locomotor regression and stereotypic hand movements. The disorder is caused by mutations in the X chromosomal MECP2 a gene encoding methyl CpG-binding protein. It has been associated with disturbances of cerebral folate homeostasis, as well as with speculations on a compromised DNA-methylation. Folinic acid is the stable form of folate. Its derived intermediate 5-MTHF supports the conversion of homocysteine to methionine, the precursor of S-adenosylmethionine (SAM). This in turn donates its methyl group to various acceptors, including DNA, thereby being converted to S-adenosylhomocysteine (SAH). The SAM/SAH ratio reflects the methylation potential. The goal of our study was to influence DNA methylation processes and ameliorate the clinical symptoms in Rett syndrome. Therefore we examined the hypothesis that folinic acid supplementation, besides increasing cerebrospinal fluid (CSF) 5-MTHF (p = 0.003), influences SAM and SAH and their ratio. In our randomized, double-blind crossover study on folinic acid supplementation, ten female Rett patients received both folinic acid and placebo for 1 year each. It was shown that both SAM and SAH levels in the CSF remained unchanged following folinic acid administration (p = 0.202 and p = 0.097, respectively) in spite of a rise of plasma SAM and SAH (p = 0.007; p = 0.009). There was no significant change in the SAM/SAH ratio either in plasma or CSF. The apparent inability of Rett patients to upregulate SAM and SAH levels in the CSF may contribute to the biochemical anomalies of the Rett syndrome. Our studies warrant further attempts to promote DNA methylation in the true region of interest, i.e. the brain.

  6. PTP1B inhibition suggests a therapeutic strategy for Rett syndrome.

    Science.gov (United States)

    Krishnan, Navasona; Krishnan, Keerthi; Connors, Christopher R; Choy, Meng S; Page, Rebecca; Peti, Wolfgang; Van Aelst, Linda; Shea, Stephen D; Tonks, Nicholas K

    2015-08-01

    The X-linked neurological disorder Rett syndrome (RTT) presents with autistic features and is caused primarily by mutations in a transcriptional regulator, methyl CpG-binding protein 2 (MECP2). Current treatment options for RTT are limited to alleviating some neurological symptoms; hence, more effective therapeutic strategies are needed. We identified the protein tyrosine phosphatase PTP1B as a therapeutic candidate for treatment of RTT. We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models. Pharmacological inhibition of PTP1B ameliorated the effects of MECP2 disruption in mouse models of RTT, including improved survival in young male (Mecp2-/y) mice and improved behavior in female heterozygous (Mecp2-/+) mice. We demonstrated that PTP1B was a negative regulator of tyrosine phosphorylation of the tyrosine kinase TRKB, the receptor for brain-derived neurotrophic factor (BDNF). Therefore, the elevated PTP1B that accompanies disruption of MECP2 function in RTT represents a barrier to BDNF signaling. Inhibition of PTP1B led to increased tyrosine phosphorylation of TRKB in the brain, which would augment BDNF signaling. This study presents PTP1B as a mechanism-based therapeutic target for RTT, validating a unique strategy for treating the disease by modifying signal transduction pathways with small-molecule drugs.

  7. Reflections on the Constraints and Opportunities in Therapy in Rett Syndrome

    Directory of Open Access Journals (Sweden)

    Alison M. Kerr

    2006-01-01

    Full Text Available More than 20 years of clinical and research experience with affected people in the British Isles has provided insight into particular challenges for therapists, educators, or parents wishing to facilitate learning and to support the development of skills in people with Rett syndrome. This paper considers the challenges in two groups: those due to constraints imposed by the disabilities associated with the disorder and those stemming from the opportunities, often masked by the disorder, allowing the development of skills that depend on less-affected areas of the brain. Because the disorder interferes with the synaptic links between neurones, the functions of the brain that are most dependent on complex neural networks are the most profoundly affected. These functions include speech, memory, learning, generation of ideas, and the planning of fine movements, especially those of the hands. In contrast, spontaneous emotional and hormonal responses appear relatively intact. Whereas failure to appreciate the physical limitations of the disease leads to frustration for therapist and client alike, a clear understanding of the better-preserved areas of competence offers avenues for real progress in learning, the building of satisfying relationships, and achievement of a quality of life.

  8. Reflections on the constraints and opportunities in therapy in Rett syndrome.

    Science.gov (United States)

    Kerr, Alison M

    2006-08-25

    More than 20 years of clinical and research experience with affected people in the British Isles has provided insight into particular challenges for therapists, educators, or parents wishing to facilitate learning and to support the development of skills in people with Rett syndrome. This paper considers the challenges in two groups: those due to constraints imposed by the disabilities associated with the disorder and those stemming from the opportunities, often masked by the disorder, allowing the development of skills that depend on less-affected areas of the brain. Because the disorder interferes with the synaptic links between neurones, the functions of the brain that are most dependent on complex neural networks are the most profoundly affected. These functions include speech, memory, learning, generation of ideas, and the planning of fine movements, especially those of the hands. In contrast, spontaneous emotional and hormonal responses appear relatively intact. Whereas failure to appreciate the physical limitations of the disease leads to frustration for therapist and client alike, a clear understanding of the better-preserved areas of competence offers avenues for real progress in learning, the building of satisfying relationships, and achievement of a quality of life.

  9. Cognitive training modifies frequency EEG bands and neuropsychological measures in Rett syndrome.

    Science.gov (United States)

    Fabio, Rosa Angela; Billeci, Lucia; Crifaci, Giulia; Troise, Emilia; Tortorella, Gaetano; Pioggia, Giovanni

    2016-01-01

    Rett syndrome (RS) is a childhood neurodevelopmental disorder characterized by a primary disturbance in neuronal development. Neurological abnormalities in RS are reflected in several behavioral and cognitive impairments such as stereotypies, loss of speech and hand skills, gait apraxia, irregular breathing with hyperventilation while awake, and frequent seizures. Cognitive training can enhance both neuropsychological and neurophysiological parameters. The aim of this study was to investigate whether behaviors and brain activity were modified by training in RS. The modifications were assessed in two phases: (a) after a short-term training (STT) session, i.e., after 30 min of training and (b) after long-term training (LTT), i.e., after 5 days of training. Thirty-four girls with RS were divided into two groups: a training group (21 girls) who underwent the LTT and a control group (13 girls) that did not undergo LTT. The gaze and quantitative EEG (QEEG) data were recorded during the administration of the tasks. A gold-standard eye-tracker and a wearable EEG equipment were used. Results suggest that the participants in the STT task showed a habituation effect, decreased beta activity and increased right asymmetry. The participants in the LTT task looked faster and longer at the target, and show increased beta activity and decreased theta activity, while a leftward asymmetry was re-established. The overall result of this study indicates a positive effect of long-term cognitive training on brain and behavioral parameters in subject with RS.

  10. Barriers to diagnosis of a rare neurological disorder in China--lived experiences of Rett syndrome families.

    Science.gov (United States)

    Lim, Faye; Downs, Jenny; Li, Jianghong; Bao, Xin-Hua; Leonard, Helen

    2012-01-01

    Rett syndrome is a rare neurological disorder affecting girls and usually caused by a mutation on the MECP2 gene. It is estimated that approximately 1,000 girls are born every year in China with Rett syndrome but far fewer have received a diagnosis. Fourteen of 74 Chinese families known to the International Rett Syndrome Phenotype Database participated in this qualitative study. Telephone interviews were conducted in Mandarin to explore pathways to a diagnosis of Rett syndrome in China and associated barriers. Families consulted multiple clinical centers and eventually received a diagnosis at a centrally located hospital. Over the course of this pathway, families encountered lack of knowledge and diagnostic expertise for Rett syndrome at local levels and a heavily over-burdened hospital system. There was a paucity of information available to guide management of this rare disorder after the diagnosis had been received. Our study suggests that the frustrations experienced by families could in part be addressed by the provision of information, education, and training related to Rett syndrome for clinicians, additional resources to allow clinicians to request genetic testing for confirmation of the clinical diagnosis and for information and support services for families.

  11. Characterization of seizure-like events recorded in vivo in a mouse model of Rett syndrome.

    Science.gov (United States)

    Colic, Sinisa; Wither, Robert G; Zhang, Liang; Eubanks, James H; Bardakjian, Berj L

    2013-10-01

    Rett syndrome is a neurodevelopmental disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2). Spontaneous recurrent discharge episodes are displayed in Rett-related seizures as in other types of epilepsies. The aim of this paper is to investigate the seizure-like event (SLE) and inter-SLE states in a female MeCP2-deficient mouse model of Rett syndrome and compare them to those found in other spontaneous recurrent epilepsy models. The study was performed on a small population of female MeCP2-deficient mice using telemetric local field potential (LFP) recordings over a 24 h period. Durations of SLEs and inter-SLEs were extracted using a rule-based automated SLE detection system for both daytime and nighttime, as well as high and low power levels of the delta frequency range (0.5-4 Hz) of the recorded LFPs. The results suggest SLE occurrences are not influenced by circadian rhythms, but had a significantly greater association with delta power. Investigating inter-SLE and SLE states by fitting duration histograms to the gamma distribution showed that SLE initiation and termination were associated with random and deterministic mechanisms, respectively. These findings when compared to reported studies on epilepsy suggest that Rett-related seizures share many similarities with absence epilepsy.

  12. Repeated Insulin-like Growth Factor 1 (IGF1 treatment in a patient with Rett Syndrome: a single case study

    Directory of Open Access Journals (Sweden)

    Giorgio ePini

    2014-06-01

    Full Text Available Rett syndrome (RTT is a devastating neurodevelopmental disorder that has no cure. Patients show regression of acquired skills, motor and speech impairment, cardio-respiratory distress, microcephaly and stereotyped hand movements. The majority of RTT patients display mutations in the gene that codes for the Methyl-CpG binding protein 2 (MeCP2, which is involved in the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function are good candidates for ameliorating the symptoms of RTT. In particular, Insulin-like growth Factor 1 (IGF1 and its active peptide (1-3IGF1 cross the Blood Brain Barrier, and therefore are ideal treatments for RTT Indeed, both (1-3IGF1 and IGF1 treatment significantly ameliorates RTT symptoms in a mouse model of the disease In a previous study we established that IGF1 is safe and well tolerated on Rett patients. In this open label clinical case study, we assess the safety and tolerability of IGF1 administration in two cycles of the treatment. Before and after each cycle we monitored the clinical and blood parameters, autonomic function and social and cognitive abilities, and we found that IGF1 was well tolerated each time and did not induce any side effect, nor it interfered with the other treatments that the patient was undergoing. We noticed a moderate improvement in the cognitive, social and autonomic abilities of the patient after each cycle but the benefits were not retained between the two cycles, consistent with the preclinical observation that treatments for RTT should be administered through life. We find that repeated IGF1 treatment is safe and well tolerated in Rett patients but observed effects are not retained between cycles. These results have applications to other pathologies considering that IGF1 has been shown to be effective in other disorders of the autism spectrum.

  13. Repeated insulin-like growth factor 1 treatment in a patient with rett syndrome: a single case study.

    Science.gov (United States)

    Pini, Giorgio; Scusa, M Flora; Benincasa, Alberto; Bottiglioni, Ilaria; Congiu, Laura; Vadhatpour, Cyrus; Romanelli, Anna Maria; Gemo, Ilaria; Puccetti, Chetti; McNamara, Rachel; O'Leary, Seán; Corvin, Aiden; Gill, Michael; Tropea, Daniela

    2014-01-01

    Rett syndrome (RTT) is a devastating neurodevelopmental disorder that has no cure. Patients show regression of acquired skills, motor, and speech impairment, cardio-respiratory distress, microcephaly, and stereotyped hand movements. The majority of RTT patients display mutations in the gene that codes for the Methyl-CpG binding protein 2 (MeCP2), which is involved in the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function are good candidates for ameliorating the symptoms of RTT. In particular, insulin-like growth factor 1 (IGF1) and its active peptide (1-3) IGF1 cross the Blood Brain Barrier, and therefore are ideal treatments for RTT Indeed, both (1-3) IGF1 and IGF1 treatment significantly ameliorates RTT symptoms in a mouse model of the disease In a previous study, we established that IGF1 is safe and well tolerated on Rett patients. In this open label clinical case study, we assess the safety and tolerability of IGF1 administration in two cycles of the treatment. Before and after each cycle, we monitored the clinical and blood parameters, autonomic function, and social and cognitive abilities, and we found that IGF1 was well tolerated each time and did not induce any side effect, nor it interfered with the other treatments that the patient was undergoing. We noticed a moderate improvement in the cognitive, social, and autonomic abilities of the patient after each cycle but the benefits were not retained between the two cycles, consistent with the pre-clinical observation that treatments for RTT should be administered through life. We find that repeated IGF1 treatment is safe and well tolerated in Rett patients but observed effects are not retained between cycles. These results have applications to other pathologies considering that IGF1 has been shown to be effective in other disorders of the autism spectrum.

  14. Reduced seizure threshold and altered network oscillatory properties in a mouse model of Rett syndrome.

    Science.gov (United States)

    McLeod, F; Ganley, R; Williams, L; Selfridge, J; Bird, A; Cobb, S R

    2013-02-12

    Rett syndrome (RTT) is a disorder with a pronounced neurological phenotype and is caused mainly by mutations in the X-linked gene MECP2. A common feature of RTT is an abnormal electroencephalography and a propensity for seizures. In the current study we aimed to assess brain network excitability and seizure propensity in a mouse model of RTT. Mice in which Mecp2 expression was silenced (Mecp2(stop/y)) showed a higher seizure score (mean=6 ± 0.8 compared to 4±0.2 in wild-type [WT]) and more rapid seizure onset (median onset=10 min in Mecp2(stop/y) and 32 min in WT) when challenged with the convulsant drug kainic acid (25mg/kg). Hippocampal slices from Mecp2(stop/y) brain displayed no spontaneous field potential activities under control conditions but showed higher power gamma frequency field potential oscillations compared to WT in response to kainic acid (400 nM) in vitro. Brain slices challenged with the GABA(A)-receptor antagonist bicuculline (0.1-10 μM) and the potassium channel blocker 4-aminopyridine (1-50 μM) also revealed differences between genotypes with hippocampal circuits from Mecp2(stop/y) mouse slices showing enhanced epileptiform burst duration and frequency. In contrast to these network level findings, single cell analysis of pyramidal cells by whole-cell patch clamp recording revealed no detectable differences in synaptic or biophysical properties between methyl-CpG-binding protein 2 (MeCP2)-containing and MeCP2-deficient neurons. These data support the proposal that loss of MeCP2 alters network level excitability in the brain to promote epileptogenesis. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype.

    Science.gov (United States)

    Romaniello, Romina; Saettini, Francesco; Panzeri, Elena; Arrigoni, Filippo; Bassi, Maria T; Borgatti, Renato

    2015-03-25

    This study reports on a 9-year-old girl who developed West syndrome and showed clinical features fulfilling the main revised diagnostic criteria for typical Rett syndrome (hand washing, severe cognitive impairment with absence of language, ataxic gait, progressive scoliosis and autistic features). Mutation analyses for methyl-CpG-binding protein 2 (MECP2), cyclin-dependent kinase-like 5 (CDKL5/STK9), ARX and Forkhead box G1 (FOXG1) genes were carried out, with negative results. A known de-novo c.1217G>A missense mutation in exon 14 leading to the substitution of a conserved residue, p.R406H in domain3b of the syntaxin-binding protein 1 (STXBP1) gene, was detected. The STXBP1 gene encodes the syntaxin-binding protein 1, a neuron-specific protein involved in synaptic vesicle release at both glutaminergic and GABAergic synapses. This function is also affected by MECP2 gene mutations, which are known to lead to a decrease in glutamate and GABA receptors' density. It is possible to speculate that the impairment in synaptic plasticity represents the pathogenic link between MECP2 and STXBP1 gene mutations. On reviewing the clinical features of the reported patients with the same mutation in the STXBP1 gene, it has been observed that poor eye contact, tremour, dyskinesia, head/hand stereotypies and both cognitive and motor progressive deterioration are common symptoms, although never considered as indicative of a Rett syndrome phenotype. In conclusion, the case described here suggests a relationship between the Rett syndrome and the STXBP1 gene not described so far, making the search for STXBP1 gene mutations advisable in patients with Rett syndrome and early onset of epilepsy.

  16. Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome.

    Directory of Open Access Journals (Sweden)

    Ronghui Li

    2016-06-01

    Full Text Available Mutations in the human MECP2 gene cause Rett syndrome (RTT, a severe neurodevelopmental disorder that predominantly affects girls. Despite decades of work, the molecular function of MeCP2 is not fully understood. Here we report a systematic identification of MeCP2-interacting proteins in the mouse brain. In addition to transcription regulators, we found that MeCP2 physically interacts with several modulators of RNA splicing, including LEDGF and DHX9. These interactions are disrupted by RTT causing mutations, suggesting that they may play a role in RTT pathogenesis. Consistent with the idea, deep RNA sequencing revealed misregulation of hundreds of splicing events in the cortex of Mecp2 knockout mice. To reveal the functional consequence of altered RNA splicing due to the loss of MeCP2, we focused on the regulation of the splicing of the flip/flop exon of Gria2 and other AMPAR genes. We found a significant splicing shift in the flip/flop exon toward the flop inclusion, leading to a faster decay in the AMPAR gated current and altered synaptic transmission. In summary, our study identified direct physical interaction between MeCP2 and splicing factors, a novel MeCP2 target gene, and established functional connection between a specific RNA splicing change and synaptic phenotypes in RTT mice. These results not only help our understanding of the molecular function of MeCP2, but also reveal potential drug targets for future therapies.

  17. Investigation of modifier genes within copy number variations in Rett syndrome.

    Science.gov (United States)

    Artuso, Rosangela; Papa, Filomena T; Grillo, Elisa; Mucciolo, Mafalda; Yasui, Dag H; Dunaway, Keith W; Disciglio, Vittoria; Mencarelli, Maria A; Pollazzon, Marzia; Zappella, Michele; Hayek, Giuseppe; Mari, Francesca; Renieri, Alessandra; Lasalle, Janine M; Ariani, Francesca

    2011-07-01

    MECP2 mutations are responsible for two different phenotypes in females, classical Rett syndrome and the milder Zappella variant (Z-RTT). We investigated whether copy number variants (CNVs) may modulate the phenotype by comparison of array-CGH data from two discordant pairs of sisters and four additional discordant pairs of unrelated girls matched by mutation type. We also searched for potential MeCP2 targets within CNVs by chromatin immunopreceipitation microarray (ChIP-chip) analysis. We did not identify one major common gene/region, suggesting that modifiers may be complex and variable between cases. However, we detected CNVs correlating with disease severity that contain candidate modifiers. CROCC (1p36.13) is a potential MeCP2 target, in which a duplication in a Z-RTT and a deletion in a classic patient were observed. CROCC encodes a structural component of ciliary motility that is required for correct brain development. CFHR1 and CFHR3, on 1q31.3, may be involved in the regulation of complement during synapse elimination, and were found to be deleted in a Z-RTT but duplicated in two classic patients. The duplication of 10q11.22, present in two Z-RTT patients, includes GPRIN2, a regulator of neurite outgrowth and PPYR1, involved in energy homeostasis. Functional analyses are necessary to confirm candidates and to define targets for future therapies.

  18. Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization.

    Science.gov (United States)

    Ciccoli, Lucia; De Felice, Claudio; Leoncini, Silvia; Signorini, Cinzia; Cortelazzo, Alessio; Zollo, Gloria; Pecorelli, Alessandra; Rossi, Marcello; Hayek, Joussef

    2015-11-01

    In this review, we summarize the current evidence on the erythrocyte as a previously unrecognized target cell in Rett syndrome, a rare (1:10 000 females) and devastating neurodevelopmental disorder caused by loss-of-function mutations in a single gene (i.e. MeCP2, CDKL5, or rarely FOXG1). In particular, we focus on morphological changes, membrane oxidative damage, altered membrane fatty acid profile, and aberrant skeletal organization in erythrocytes from patients with typical Rett syndrome and MeCP2 gene mutations. The beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) are also summarized for this condition to be considered as a 'model' condition for autism spectrum disorders.

  19. Seizures and Pain Uncertainty Associated with Parenting Stress and Rett Syndrome

    OpenAIRE

    Byiers, Breanne J.; Tervo, Raymond C.; Feyma, Timothy J.; Symons, Frank J

    2013-01-01

    Data were collected parenting stress, adaptive behavior, pain, and health issues from the caregivers of 35 girls and women with Rett syndrome (mean age = 20.3). A majority (60%) of parents reported stress in the clinical range on at least one subscale of the Parenting Stress Index – Short Form. Seizures and uncertainty about their daughter’s gastrointestinal pain experience were significantly associated with higher levels of parenting stress. No other child factors (adaptive behavior, age, re...

  20. Reflections on the Constraints and Opportunities in Therapy in Rett Syndrome

    OpenAIRE

    Alison M. Kerr

    2006-01-01

    More than 20 years of clinical and research experience with affected people in the British Isles has provided insight into particular challenges for therapists, educators, or parents wishing to facilitate learning and to support the development of skills in people with Rett syndrome. This paper considers the challenges in two groups: those due to constraints imposed by the disabilities associated with the disorder and those stemming from the opportunities, often masked by the disorder, allowi...

  1. Rett syndrome: basic features of visual processing-a pilot study of eye-tracking.

    Science.gov (United States)

    Djukic, Aleksandra; Valicenti McDermott, Maria; Mavrommatis, Kathleen; Martins, Cristina L

    2012-07-01

    Consistently observed "strong eye gaze" has not been validated as a means of communication in girls with Rett syndrome, ubiquitously affected by apraxia, unable to reply either verbally or manually to questions during formal psychologic assessment. We examined nonverbal cognitive abilities and basic features of visual processing (visual discrimination attention/memory) by analyzing patterns of visual fixation in 44 girls with Rett syndrome, compared with typical control subjects. To determine features of visual fixation patterns, multiple pictures (with the location of the salient and presence/absence of novel stimuli as variables) were presented on the screen of a TS120 eye-tracker. Of the 44, 35 (80%) calibrated and exhibited meaningful patterns of visual fixation. They looked longer at salient stimuli (cartoon, 2.8 ± 2 seconds S.D., vs shape, 0.9 ± 1.2 seconds S.D.; P = 0.02), regardless of their position on the screen. They recognized novel stimuli, decreasing the fixation time on the central image when another image appeared on the periphery of the slide (2.7 ± 1 seconds S.D. vs 1.8 ± 1 seconds S.D., P = 0.002). Eye-tracking provides a feasible method for cognitive assessment and new insights into the "hidden" abilities of individuals with Rett syndrome.

  2. Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: an overview of Down syndrome, autism, Fragile X and Rett syndrome.

    Science.gov (United States)

    Valenti, Daniela; de Bari, Lidia; De Filippis, Bianca; Henrion-Caude, Alexandra; Vacca, Rosa Anna

    2014-10-01

    Clinical manifestations typical of mitochondrial diseases are often present in various genetic syndromes associated with intellectual disability, a condition leading to deficit in cognitive functions and adaptive behaviors. Until now, the causative mechanism leading to intellectual disability is unknown and the progression of the condition is poorly understood. We first report latest advances on genetic and environmental regulation of mitochondrial function and its role in brain development. Starting from the structure, function and regulation of the oxidative phosphorylation apparatus, we review how mitochondrial biogenesis and dynamics play a central role in neurogenesis and neuroplasticity. We then discuss how dysfunctional mitochondria and alterations in reactive oxygen species homeostasis are potentially involved in the pathogenesis of various neurodevelopmental syndromes with a special focus on Down, Rett, Fragile X syndromes and autism spectrum disorders. Finally, we review and suggest novel therapeutic approaches aimed at improving intellectual disability by activating mitochondrial function and reducing oxidative stress to amiliorate the quality of life in the subjects affected.

  3. The Relationship between "MECP2" Mutation Type and Health Status and Service Use Trajectories over Time in a Rett Syndrome Population

    Science.gov (United States)

    Young, Deidra; Bebbington, Ami; de Klerk, Nick; Bower, Carol; Nagarajan, Lakshmi; Leonard, Helen

    2011-01-01

    This study aimed to investigate the trajectories over time of health status and health service use in Rett syndrome by mutation type. Data were obtained from questionnaires administered over 6 years to 256 participants from the Australian Rett Syndrome Database. Health status (episodes of illness and medication load) and health service use…

  4. Abnormalities of cell packing density and dendritic complexity in the MeCP2 A140V mouse model of Rett syndrome/X-linked mental retardation

    Directory of Open Access Journals (Sweden)

    Blue Mary

    2010-02-01

    Full Text Available Abstract Background Rett syndrome (RTT, a common cause of mental retardation in girls, is associated with mutations in the MECP2 gene. Most human cases of MECP2 mutation in girls result in classical or variant forms of RTT. When these same mutations occur in males, they often present as severe neonatal encephalopathy. However, some MECP2 mutations can also lead to diseases characterized as mental retardation syndromes, particularly in boys. One of these mutations, A140V, is a common, recurring missense mutation accounting for about 0.6% of all MeCP2 mutations and ranking 21st by frequency. It has been described in familial X-linked mental retardation (XLMR, PPM- X syndrome (Parkinsonism, Pyramidal signs, Macroorchidism, X-linked mental retardation and in other neuropsychiatric syndromes. Interestingly, this mutation has been reported to preserve the methyl-CpG binding function of the MeCP2 protein while compromising its ability to bind to the mental retardation associated protein ATRX. Results We report the construction and initial characterization of a mouse model expressing the A140V MeCP2 mutation. These initial descriptive studies in male hemizygous mice have revealed brain abnormalities seen in both RTT and mental retardation. The abnormalities found include increases in cell packing density in the brain and a significant reduction in the complexity of neuronal dendritic branching. In contrast to some MeCP2 mutation mouse models, the A140V mouse has an apparently normal lifespan and normal weight gain patterns with no obvious seizures, tremors, breathing difficulties or kyphosis. Conclusion We have identified various neurological abnormalities in this mouse model of Rett syndrome/X-linked mental retardation which may help to elucidate the manner in which MECP2 mutations cause neuronal changes resulting in mental retardation without the confounding effects of seizures, chronic hypoventilation, or other Rett syndrome associated symptoms.

  5. Homozygous c.1160C>T (P38L) in the MECP2 gene in a female Rett syndrome patient.

    Science.gov (United States)

    Bhanushali, Aparna A; Mandsaurwala, A; Das, Bibhu R

    2016-03-01

    Rett syndrome is a severe X-linked dominant neurodevelopmental disorder. Mutations in the MECP2 gene on chromosome Xq28 have been shown to be the cause of Rett syndrome. Sequencing of the MECP2 gene in a patient with clinical suspicion of Rett syndrome revealed c.1160C>T (P387L) in exon 4 of the MECP2 gene homozygously. Females with Rett syndrome are usually heterozygous for a mutation in MECP2. Uniparental disomy as a probable cause for the homozygous presence of this mutation was ruled out by quantitative fluorescence-polymerase chain reaction. Moreover to our knowledge this mutation has only been reported in males with X-linked mental retardation (MRX). We hypothesize that the presence of this mutation c.1160C>T (P387L) in the homozygous form is responsible for the Rett syndrome-like phenotype seen in this patient. This novel report reveals for the first time the homozygous presence of a mutation which has hitherto only been reported in males with MRX.

  6. Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes.

    Science.gov (United States)

    Ito-Ishida, Aya; Ure, Kerstin; Chen, Hongmei; Swann, John W; Zoghbi, Huda Y

    2015-11-18

    Inhibitory neurons are critical for proper brain function, and their dysfunction is implicated in several disorders, including autism, schizophrenia, and Rett syndrome. These neurons are heterogeneous, and it is unclear which subtypes contribute to specific neurological phenotypes. We deleted Mecp2, the mouse homolog of the gene that causes Rett syndrome, from the two most populous subtypes, parvalbumin-positive (PV+) and somatostatin-positive (SOM+) neurons. Loss of MeCP2 partially impairs the affected neuron, allowing us to assess the function of each subtype without profound disruption of neuronal circuitry. We found that mice lacking MeCP2 in either PV+ or SOM+ neurons have distinct, non-overlapping neurological features: mice lacking MeCP2 in PV+ neurons developed motor, sensory, memory, and social deficits, whereas those lacking MeCP2 in SOM+ neurons exhibited seizures and stereotypies. Our findings indicate that PV+ and SOM+ neurons contribute complementary aspects of the Rett phenotype and may have modular roles in regulating specific behaviors.

  7. Rett syndrome induced pluripotent stem cell-derived neurons reveal novel neurophysiological alterations.

    Science.gov (United States)

    Farra, N; Zhang, W-B; Pasceri, P; Eubanks, J H; Salter, M W; Ellis, J

    2012-12-01

    Rett syndrome (RTT) is a neurodevelopmental autism spectrum disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Here, we describe the first characterization and neuronal differentiation of induced pluripotent stem (iPS) cells derived from Mecp2-deficient mice. Fully reprogrammed wild-type (WT) and heterozygous female iPS cells express endogenous pluripotency markers, reactivate the X-chromosome and differentiate into the three germ layers. We directed iPS cells to produce glutamatergic neurons, which generated action potentials and formed functional excitatory synapses. iPS cell-derived neurons from heterozygous Mecp2(308) mice showed defects in the generation of evoked action potentials and glutamatergic synaptic transmission, as previously reported in brain slices. Further, we examined electrophysiology features not yet studied with the RTT iPS cell system and discovered that MeCP2-deficient neurons fired fewer action potentials, and displayed decreased action potential amplitude, diminished peak inward currents and higher input resistance relative to WT iPS-derived neurons. Deficiencies in action potential firing and inward currents suggest that disturbed Na(+) channel function may contribute to the dysfunctional RTT neuronal network. These phenotypes were additionally confirmed in neurons derived from independent WT and hemizygous mutant iPS cell lines, indicating that these reproducible deficits are attributable to MeCP2 deficiency. Taken together, these results demonstrate that neuronally differentiated MeCP2-deficient iPS cells recapitulate deficits observed previously in primary neurons, and these identified phenotypes further illustrate the requirement of MeCP2 in neuronal development and/or in the maintenance of normal function. By validating the use of iPS cells to delineate mechanisms underlying RTT pathogenesis, we identify deficiencies that can be targeted for in vitro translational screens.

  8. An optogenetic mouse model of rett syndrome targeting on catecholaminergic neurons.

    Science.gov (United States)

    Zhang, Shuang; Johnson, Christopher M; Cui, Ningren; Xing, Hao; Zhong, Weiwei; Wu, Yang; Jiang, Chun

    2016-10-01

    Rett syndrome (RTT) is a neurodevelopmental disorder affecting multiple functions, including the norepinephrine (NE) system. In the CNS, NE is produced mostly by neurons in the locus coeruleus (LC), where defects in intrinsic neuronal properties, NE biosynthetic enzymes, neuronal CO2 sensitivity, and synaptic currents have been reported in mouse models of RTT. LC neurons in methyl-CpG-binding protein 2 gene (Mecp2) null mice show a high rate of spontaneous firing, although whether such hyperexcitability might increase or decrease the NE release from synapses is unknown. To activate the NEergic axonal terminals selectively, we generated an optogenetic mouse model of RTT in which NEergic neuronal excitability can be manipulated with light. Using commercially available mouse breeders, we produced a new strain of double-transgenic mice with Mecp2 knockout and channelrhodopsin (ChR) knockin in catecholaminergic neurons. Several RTT-like phenotypes were found in the tyrosine hydroxylase (TH)-ChR-Mecp2(-/Y) mice, including hypoactivity, low body weight, hindlimb clasping, and breathing disorders. In brain slices, optostimulation produced depolarization and an increase in the firing rate of LC neurons from TH-ChR control mice. In TH-ChR control mice, optostimulation of presynaptic NEergic neurons augmented the firing rate of hypoglossal neurons (HNs), which was blocked by the α-adrenoceptor antagonist phentolamine. Such optostimulation of NEergic terminals had almost no effect on HNs from two or three TH-ChR-Mecp2(-/Y) mice, indicating that excessive excitation of presynaptic neurons does not benefit NEergic modulation in mice with Mecp2 disruption. These results also demonstrate the feasibility of generating double-transgenic mice for studies of RTT with commercially available mice, which are inexpensive, labor/time efficient, and promising for cell-specific stimulation. © 2016 Wiley Periodicals, Inc.

  9. Hyperexcitability of Mesencephalic Trigeminal Neurons and Reorganization of Ion Channel Expression in a Rett Syndrome Model.

    Science.gov (United States)

    Oginsky, Max F; Cui, Ningren; Zhong, Weiwei; Johnson, Christopher M; Jiang, Chun

    2017-05-01

    People with Rett syndrome (RTT) have defects in motor function also seen in Mecp2-null mice. Motor function depends on not only central motor commands but also sensory feedback that is vulnerable to changes in excitability of propriosensory neurons. Here we report evidence for hyperexcitability of mesencephalic trigeminal (Me5) neurons in Mecp2-null mice and a novel cellular mechanism for lowering its impact. In in vitro brain slices, the Me5 neurons in both Mecp2(-/Y) male and symptomatic Mecp2(+/-) female mice were overly excitable showing increased firing activity in comparison to their wild-type (WT) male and asymptomatic counterparts. In Mecp2(-/Y) males, Me5 neurons showed a reduced firing threshold. Consistently, the steady-state activation of voltage-gated Na(+) currents (INa ) displayed a hyperpolarizing shift in the Mecp2-null neurons with no change in the INa density. This seems to be due to NaV1.1, SCN1B and SCN4B overexpression and NaV1.2 and SCN3B under-expression. In contrast to the hyperexcitability, the sag potential and postinhibitory rebound (PIR) were reduced in Mecp2-null mice. In voltage-clamp, the IH density was deficient by ∼33%, and the steady-state half-activation had a depolarizing shift of ∼10 mV in the Mecp2-null mice. Quantitative PCR analysis indicated that HCN2 was decreased, HCN1 was upregulated with no change in HCN4 in Mecp2(-/Y) mice compared to WT. Lastly, blocking IH reduced the firing rate much more in WT than in Mecp2-null neurons. These data suggest that the Mecp2 defect causes an increase in Me5 neuronal excitability likely attributable to alterations in INa , meanwhile IH is reduced likely altering neuronal excitability as well. J. Cell. Physiol. 232: 1151-1164, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  10. Exploring the possible link between MeCP2 and oxidative stress in Rett syndrome.

    Science.gov (United States)

    Filosa, Stefania; Pecorelli, Alessandra; D'Esposito, Maurizio; Valacchi, Giuseppe; Hajek, Joussef

    2015-11-01

    Rett syndrome (RTT, MIM 312750) is a rare and orphan progressive neurodevelopmental disorder affecting girls almost exclusively, with a frequency of 1/15,000 live births of girls. The disease is characterized by a period of 6 to 18 months of apparently normal neurodevelopment, followed by early neurological regression, with a progressive loss of acquired cognitive, social, and motor skills. RTT is known to be caused in 95% of the cases by sporadic de novo loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene encoding methyl-CpG binding protein 2 (MeCP2), a nuclear protein able to regulate gene expression. Despite almost two decades of research into the functions and role of MeCP2, little is known about the mechanisms leading from MECP2 mutation to the disease. Oxidative stress (OS) is involved in the pathogenic mechanisms of several neurodevelopmental and neurodegenerative disorders, although in many cases it is not clear whether OS is a cause or a consequence of the pathology. Fairly recently, the presence of a systemic OS has been demonstrated in RTT patients with a strong correlation with the patients' clinical status. The link between MECP2 mutation and the redox imbalance found in RTT is not clear. Animal studies have suggested a possible direct correlation between Mecp2 mutation and increased OS levels. In addition, the restoration of Mecp2 function in astrocytes significantly improves the developmental outcome of Mecp2-null mice and reexpression of Mecp2 gene in the brain of null mice restored oxidative damage, suggesting that Mecp2 loss of function can be involved in oxidative brain damage. Starting from the evidence that oxidative damage in the brain of Mecp2-null mice precedes the onset of symptoms, we evaluated whether, based on the current literature, the dysfunctions described in RTT could be a consequence or, in contrast, could be caused by OS. We also analyzed whether therapies that at least partially treated some RTT

  11. Genetic syndromes in the family : child characteristics and parenting stress in Angelman, CHARGE, Cornelia de Lange, Prader-Willi, and Rett syndrome

    NARCIS (Netherlands)

    Wulffaert, Josette

    2010-01-01

    Aim of the dissertation: To expand the knowledge on the behavioural phenotypes, level of parenting stress and the relationship between child characteristics and parenting stress in five genetic syndromes. The included syndromes are Angelman, CHARGE, Cornelia de Lange, Prader-Willi, and Rett syndrome

  12. Genetic syndromes in the family : child characteristics and parenting stress in Angelman, CHARGE, Cornelia de Lange, Prader-Willi, and Rett syndrome

    NARCIS (Netherlands)

    Wulffaert, Josette

    2010-01-01

    Aim of the dissertation: To expand the knowledge on the behavioural phenotypes, level of parenting stress and the relationship between child characteristics and parenting stress in five genetic syndromes. The included syndromes are Angelman, CHARGE, Cornelia de Lange, Prader-Willi, and Rett syndrome

  13. Osteoporosis in Rett syndrome: a case study presenting a novel management intervention for severe osteoporosis.

    Science.gov (United States)

    Lotan, M; Reves-Siesel, R; Eliav-Shalev, R S; Merrick, J

    2013-12-01

    The present article describes a successful novel therapeutic intervention with Aredia with one child with Rett syndrome, after suffering from six pathological fractures within less than 3 years due to severe osteoporosis. Since the initiation of the treatment (3 years ago), the child has not suffered any fractures. Patients with chronic diseases and those with disabilities or on anticonvulsant medications are at risk for low bone density and possibly for the resultant pathologic fractures that define osteoporosis in children. Individuals with Rett syndrome (RS) have been shown to have low bone mineral density (or osteopenia) at a young age. If osteoporosis occurs in a girl with RS, it can inflict pain and seriously impair the child's mobility and quality of life. The present article describes a case study of a child with RS (showing an average of 1.75 fractures annually for the 4 years preceding the treatment) before and after a treatment with Aredia. Patient received 30 mg/day for 3 days on a once every 3-month cycle. There was a 45 % improvement in bone mass density (BMD) values from pre-post-intervention. The child had no fractures in the 3 years posttreatment. This finding is significant (p osteoporosis (Z-score of -3.8) at pre-intervention and are elevated to osteopenia levels (Z-score of -1.3) at post-intervention measurements. All measurements suggest that the treatment successfully reversed the osteoporotic process and prevented further fractures. This change caused great relief to the child and her family and an improvement in their quality of life. The findings support the ability (in one case) to reverse the progression of osteoporosis in individuals with Rett syndrome showing severe osteoporosis with multiple fractures.

  14. Characterization of the MeCP2R168X knockin mouse model for Rett syndrome.

    Directory of Open Access Journals (Sweden)

    Eike Wegener

    Full Text Available Rett syndrome, one of the most common causes of mental retardation in females, is caused by mutations in the X chromosomal gene MECP2. Mice deficient for MeCP2 recapitulate some of the symptoms seen in patients with Rett syndrome. It has been shown that reactivation of silent MECP2 alleles can reverse some of the symptoms in these mice. We have generated a knockin mouse model for translational research that carries the most common nonsense mutation in Rett syndrome, R168X. In this article we describe the phenotype of this mouse model. In male MeCP2(R168X mice life span was reduced to 12-14 weeks and bodyweight was significantly lower than in wild type littermates. First symptoms including tremor, hind limb clasping and inactivity occurred at age 27 days. At age 6 weeks nest building, rotarod, open-field and elevated plus maze experiments showed impaired motor performance, reduced activity and decreased anxiety-like behavior. Plethysmography at the same time showed apneas and irregular breathing with reduced frequency. Female MeCP2R168X mice showed no significant abnormalities except decreased performance on the rotarod at age 9 months. In conclusion we show that the male MeCP2(R168X mice have a phenotype similar to that seen in MECP2 knockout mouse models and are therefore well suited for translational research. The female mice, however, have a much milder and less constant phenotype making such research with this mouse model more challenging.

  15. Characterization of the MeCP2R168X knockin mouse model for Rett syndrome.

    Science.gov (United States)

    Wegener, Eike; Brendel, Cornelia; Fischer, Andre; Hülsmann, Swen; Gärtner, Jutta; Huppke, Peter

    2014-01-01

    Rett syndrome, one of the most common causes of mental retardation in females, is caused by mutations in the X chromosomal gene MECP2. Mice deficient for MeCP2 recapitulate some of the symptoms seen in patients with Rett syndrome. It has been shown that reactivation of silent MECP2 alleles can reverse some of the symptoms in these mice. We have generated a knockin mouse model for translational research that carries the most common nonsense mutation in Rett syndrome, R168X. In this article we describe the phenotype of this mouse model. In male MeCP2(R168X) mice life span was reduced to 12-14 weeks and bodyweight was significantly lower than in wild type littermates. First symptoms including tremor, hind limb clasping and inactivity occurred at age 27 days. At age 6 weeks nest building, rotarod, open-field and elevated plus maze experiments showed impaired motor performance, reduced activity and decreased anxiety-like behavior. Plethysmography at the same time showed apneas and irregular breathing with reduced frequency. Female MeCP2R168X mice showed no significant abnormalities except decreased performance on the rotarod at age 9 months. In conclusion we show that the male MeCP2(R168X) mice have a phenotype similar to that seen in MECP2 knockout mouse models and are therefore well suited for translational research. The female mice, however, have a much milder and less constant phenotype making such research with this mouse model more challenging.

  16. Functional abilities in aging women with Rett syndrome - the Danish cohort

    DEFF Research Database (Denmark)

    Schönewolf-Greulich, Bitten; Stahlhut, Michelle; Larsen, Jane Lunding

    2017-01-01

    Rett syndrome (RTT) is a neurodevelopmental disorder, which mainly affects females and results in multiple disabilities. Many clinical descriptions of the symptoms and functional abilities have been made medically, though mainly in children with RTT. Previous reports have established that even...... of aging women with RTT can grab on to things - persons with hand function should be motivated to use this ability in the context of eating Communication is a difficult task especially for the aging RTT women - Communicative signs, their meaning and how to react to them should be written down for every...

  17. EEA1 restores homeostatic synaptic plasticity in hippocampal neurons from Rett syndrome mice.

    Science.gov (United States)

    Xu, Xin; Pozzo-Miller, Lucas

    2017-08-15

    Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Mecp2 deletion in mice results in an imbalance of excitation and inhibition in hippocampal neurons, which affects 'Hebbian' synaptic plasticity. We show that Mecp2-deficient neurons also lack homeostatic synaptic plasticity, likely due to reduced levels of EEA1, a protein involved in AMPA receptor endocytosis. Expression of EEA1 restored homeostatic synaptic plasticity in Mecp2-deficient neurons, providing novel targets of intervention in Rett syndrome. Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Deletion of Mecp2 in mice results in an imbalance of synaptic excitation and inhibition in hippocampal pyramidal neurons, which affects 'Hebbian' long-term synaptic plasticity. Since the excitatory-inhibitory balance is maintained by homeostatic mechanisms, we examined the role of MeCP2 in homeostatic synaptic plasticity (HSP) at excitatory synapses. Negative feedback HSP, also known as synaptic scaling, maintains the global synaptic strength of individual neurons in response to sustained alterations in neuronal activity. Hippocampal neurons from Mecp2 knockout (KO) mice do not show the characteristic homeostatic scaling up of the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and of synaptic levels of the GluA1 subunit of AMPA-type glutamate receptors after 48 h silencing with the Na(+) channel blocker tetrodotoxin. This deficit in HSP is bidirectional because Mecp2 KO neurons also failed to scale down mEPSC amplitudes and GluA1 synaptic levels after 48 h blockade of type A GABA receptor (GABAA R)-mediated inhibition with bicuculline. Consistent with the role of synaptic trafficking of AMPA-type of glutamate receptors in HSP, Mecp2 KO neurons

  18. Management of epilepsy in patients with Rett syndrome: perspectives and considerations

    Directory of Open Access Journals (Sweden)

    Krajnc N

    2015-06-01

    Full Text Available Natalija Krajnc Department of Child, Adolescent and Developmental Neurology, University Children’s Hospital, Ljubljana, Slovenia Abstract: Rett syndrome (RTT is a common neurodevelopmental disorder that appears in infancy with regression of acquired motor skills, loss of purposeful activity, hand stereotypies, loss of acquired spoken language, and seizures. Epilepsy affects the majority of patients in a specific clinical stage of the disease and is drug resistant in approximately one-third of cases. The association of epilepsy and even drug-resistant epilepsy has been reported in certain genotypes of the methyl-CpG-binding protein 2 mutation, which is present in a majority of patients with classical RTT. The evolution of electroencephalographic abnormalities accompanying the clinical development of the syndrome is well described, but much less is known about the seizure semiology and the effectiveness of specific antiepileptic drugs. The aim of this review is to present the clinical and electrophysiological aspects of epilepsy in RTT and the current treatment approach. Keywords: Rett syndrome, epilepsy, treatment

  19. Computer navigation-assisted spinal fusion with segmental pedicle screw instrumentation for scoliosis with rett syndrome:a case report

    Directory of Open Access Journals (Sweden)

    Nishida,Keiichiro

    2009-12-01

    Full Text Available Scoliosis is a common clinical manifestation of Rett syndrome, a neurodevelopmental disorder that almost exclusively affects females. The spinal curve in patients with Rett syndrome is typically a long C curve of a neuromuscular type. As the onset of the scoliosis is very early and shows rapid progression, early surgical intervention has been recommended to prevent a life-threatening collapsing spine syndrome. However, there are high perioperative risks in Rett syndrome patients who undergo spinal surgery, such as neurological compromise and respiratory dysfunction due to rigid spinal curve. We herein report the surgical result of treating severe rapid progressive thoracic scoliosis in a 16-year-old girl with Rett syndrome. Posterior segmental pedicle screw fixation was performed from T1 to L3 using a computer-assisted technique. Post-operative radiography demonstrated a good correction of the curve in both the sagittal and coronal alignment. There were no postoperative complications such as neurological compromise. The patient had maintained satisfactory spinal balance as of the 3-year follow-up examination.

  20. Astrocyte Transcriptome from the Mecp2(308)-Truncated Mouse Model of Rett Syndrome.

    Science.gov (United States)

    Delépine, Chloé; Nectoux, Juliette; Letourneur, Franck; Baud, Véronique; Chelly, Jamel; Billuart, Pierre; Bienvenu, Thierry

    2015-12-01

    Mutations in the gene encoding the transcriptional modulator methyl-CpG binding protein 2 (MeCP2) are responsible for the neurodevelopmental disorder Rett syndrome which is one of the most frequent sources of intellectual disability in women. Recent studies showed that loss of Mecp2 in astrocytes contributes to Rett-like symptoms and restoration of Mecp2 can rescue some of these defects. The goal of this work is to compare gene expression profiles of wild-type and mutant astrocytes from Mecp2(308/y) mice (B6.129S-MeCP2/J) by using Affymetrix mouse 2.0 microarrays. Results were confirmed by quantitative real-time RT-PCR and by Western blot analysis. Gene set enrichment analysis utilizing Ingenuity Pathways was employed to identify pathways disrupted by Mecp2 deficiency. A total of 2152 genes were statistically differentially expressed between wild-type and mutated samples, including 1784 coding transcripts. However, only 257 showed fold changes >1.2. We confirmed our data by replicative studies in independent primary cultures of cortical astrocytes from Mecp2-deficient mice. Interestingly, two genes known to encode secreted proteins, chromogranin B and lipocalin-2, showed significant dysregulation. These proteins secreted from Mecp2-deficient glia may exert negative non-cell autonomous effects on neuronal properties, including dendritic morphology. Moreover, transcriptional profiling revealed altered Nr2f2 expression which may explain down- and upregulation of several target genes in astrocytes such as Ccl2, Lcn2 and Chgb. Unraveling Nr2f2 involvement in Mecp2-deficient astrocytes could pave the way for a better understanding of Rett syndrome pathophysiology and offers new therapeutic perspectives.

  1. How Facial Expressions in a Rett Syndrome Population Are Recognised and Interpreted by Those around Them as Conveying Emotions

    Science.gov (United States)

    Bergstrom-Isacsson, Marith; Lagerkvist, Bengt; Holck, Ulla; Gold, Christian

    2013-01-01

    Rett syndrome (RTT) is a neurodevelopmental disorder, including autonomic nervous system dysfunctions and severe communication impairment with an extremely limited ability to use verbal language. These individuals are therefore dependent on the capacity of caregivers to observe and interpret communicative signals, including emotional expressions.…

  2. Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence

    DEFF Research Database (Denmark)

    Jefferson, Amanda; Leonard, Helen; Siafarikas, Aris

    2016-01-01

    OBJECTIVES: We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. METHODS: An initial guidelines draft was created which included statements based upon literature review and 11 open-ended que...

  3. Osteopenia is present at an early age and worsens across the life span in girls and women with Rett syndrome

    Science.gov (United States)

    Girls and women with Rett syndrome (RTT) are at increased risk for osteopenia and skeletal fractures. Our objective was to characterize the natural history of bone mineralization in RTT girls and women across their life span and to identify genetic, nutritional, physical, hormonal, or inflammatory ...

  4. Profiling Early Socio-Communicative Development in Five Young Girls with the Preserved Speech Variant of Rett Syndrome

    Science.gov (United States)

    Marschik, Peter B.; Kaufmann, Walter E.; Einspieler, Christa; Bartl-Pokorny, Katrin D.; Wolin, Thomas; Pini, Giorgio; Budimirovic, Dejan B.; Zappella, Michele; Sigafoos, Jeff

    2012-01-01

    Rett syndrome (RTT) is a developmental disorder characterized by regression of purposeful hand skills and spoken language, although some affected children retain some ability to speech. We assessed the communicative abilities of five young girls, who were later diagnosed with the preserved speech variant of RTT, during the pre-regression period…

  5. Bone mineral content and bone mineral density are lower in older than in younger females with Rett syndrome

    Science.gov (United States)

    Although bone mineral deficits have been identified in Rett syndrome (RTT), the prevalence of low bone mineral density (BMD) and its association with skeletal fractures and scoliosis has not been characterized fully in girls and women with RTT. Accordingly, we measured total body bone mineral conten...

  6. Psychological Well-Being of Mothers and Siblings in Families of Girls and Women with Rett Syndrome

    Science.gov (United States)

    Cianfaglione, Rina; Hastings, Richard P.; Felce, David; Clarke, Angus; Kerr, Michael P.

    2015-01-01

    Few published studies have reported on the psychological well-being of family members of individuals with Rett syndrome (RTT). Eighty-seven mothers of girls and women with RTT completed a questionnaire survey about their daughters' behavioral phenotype, current health, and behavior problems, and their own and a sibling's well-being. Mothers…

  7. A review of Rett syndrome (RTT) with induced pluripotent stem cells

    Science.gov (United States)

    Dhivya, Venkatesan; Gomathi, Mohan; Mohanadevi, Subramaniam; Venkatesh, Balasubramanian; Geetha, Bharathi

    2016-01-01

    Human induced pluripotent stem cells (hiPSCs) are pluripotent stem cells generated from somatic cells by the introduction of a combination of pluripotency-associated genes such as OCT4, SOX2, along with either KLF4 and c-MYC or NANOG and LIN28 via retroviral or lentiviral vectors. Most importantly, hiPSCs are similar to human embryonic stem cells (hESCs) functionally as they are pluripotent and can potentially differentiate into any desired cell type when provided with the appropriate cues, but do not have the ethical issues surrounding hESCs. For these reasons, hiPSCs have huge potential in translational medicine such as disease modeling, drug screening, and cellular therapy. Indeed, patient-specific hiPSCs have been generated for a multitude of diseases, including many with a neurological basis, in which disease phenotypes have been recapitulated in vitro and proof-of-principle drug screening has been performed. As the techniques for generating hiPSCs are refined and these cells become a more widely used tool for understanding brain development, the insights they produce must be understood in the context of the greater complexity of the human genome and the human brain. Disease models using iPS from Rett syndrome (RTT) patient’s fibroblasts have opened up a new avenue of drug discovery for therapeutic treatment of RTT. The analysis of X chromosome inactivation (XCI) upon differentiation of RTT-hiPSCs into neurons will be critical to conclusively demonstrate the isolation of pre-XCI RTT-hiPSCs in comparison to post-XCI RTT-hiPSCs. The current review projects on iPSC studies in RTT as well as XCI in hiPSC were it suggests for screening new potential therapeutic targets for RTT in future for the benefit of RTT patients. In conclusion, patient-specific drug screening might be feasible and would be particularly helpful in disorders where patients frequently have to try multiple drugs before finding a regimen that works. PMID:27777941

  8. MECP2 Duplication Syndrome: Evidence of Enhanced Oxidative Stress. A Comparison with Rett Syndrome.

    Science.gov (United States)

    Signorini, Cinzia; De Felice, Claudio; Leoncini, Silvia; Møller, Rikke S; Zollo, Gloria; Buoni, Sabrina; Cortelazzo, Alessio; Guerranti, Roberto; Durand, Thierry; Ciccoli, Lucia; D'Esposito, Maurizio; Ravn, Kirstine; Hayek, Joussef

    2016-01-01

    Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) are neurodevelopmental disorders caused by alterations in the methyl-CpG binding protein 2 (MECP2) gene expression. A relationship between MECP2 loss-of-function mutations and oxidative stress has been previously documented in RTT patients and murine models. To date, no data on oxidative stress have been reported for the MECP2 gain-of-function mutations in patients with MDS. In the present work, the pro-oxidant status and oxidative fatty acid damage in MDS was investigated (subjects n = 6) and compared to RTT (subjects n = 24) and healthy condition (subjects n = 12). Patients with MECP2 gain-of-function mutations showed increased oxidative stress marker levels (plasma non-protein bound iron, intraerythrocyte non-protein bound iron, F2-isoprostanes, and F4-neuroprostanes), as compared to healthy controls (P ≤ 0.05). Such increases were similar to those observed in RTT patients except for higher plasma F2-isoprostanes levels (P < 0.0196). Moreover, plasma levels of F2-isoprostanes were significantly correlated (P = 0.0098) with the size of the amplified region. The present work shows unique data in patients affected by MDS. For the first time MECP2 gain-of-function mutations are indicated to be linked to an oxidative damage and related clinical symptoms overlapping with those of MECP2 loss-of-function mutations. A finely tuned balance of MECP2 expression appears to be critical to oxidative stress homeostasis, thus shedding light on the relevance of the redox balance in the central nervous system integrity.

  9. MECP2 Duplication Syndrome: Evidence of Enhanced Oxidative Stress. A Comparison with Rett Syndrome.

    Directory of Open Access Journals (Sweden)

    Cinzia Signorini

    Full Text Available Rett syndrome (RTT and MECP2 duplication syndrome (MDS are neurodevelopmental disorders caused by alterations in the methyl-CpG binding protein 2 (MECP2 gene expression. A relationship between MECP2 loss-of-function mutations and oxidative stress has been previously documented in RTT patients and murine models. To date, no data on oxidative stress have been reported for the MECP2 gain-of-function mutations in patients with MDS. In the present work, the pro-oxidant status and oxidative fatty acid damage in MDS was investigated (subjects n = 6 and compared to RTT (subjects n = 24 and healthy condition (subjects n = 12. Patients with MECP2 gain-of-function mutations showed increased oxidative stress marker levels (plasma non-protein bound iron, intraerythrocyte non-protein bound iron, F2-isoprostanes, and F4-neuroprostanes, as compared to healthy controls (P ≤ 0.05. Such increases were similar to those observed in RTT patients except for higher plasma F2-isoprostanes levels (P < 0.0196. Moreover, plasma levels of F2-isoprostanes were significantly correlated (P = 0.0098 with the size of the amplified region. The present work shows unique data in patients affected by MDS. For the first time MECP2 gain-of-function mutations are indicated to be linked to an oxidative damage and related clinical symptoms overlapping with those of MECP2 loss-of-function mutations. A finely tuned balance of MECP2 expression appears to be critical to oxidative stress homeostasis, thus shedding light on the relevance of the redox balance in the central nervous system integrity.

  10. Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence.

    Directory of Open Access Journals (Sweden)

    Amanda Jefferson

    Full Text Available We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians.An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions.Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended.A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.

  11. Genetic syndromes in the family : child characteristics and parenting stress in Angelman, CHARGE, Cornelia de Lange, Prader-Willi, and Rett syndrome

    NARCIS (Netherlands)

    Wulffaert, Josette

    2010-01-01

    Aim of the dissertation: To expand the knowledge on the behavioural phenotypes, level of parenting stress and the relationship between child characteristics and parenting stress in five genetic syndromes. The included syndromes are Angelman, CHARGE, Cornelia de Lange, Prader-Willi, and Rett

  12. The Digestive System and Nutritional Considerations for Individuals with Rett Syndrome

    Directory of Open Access Journals (Sweden)

    Meir Lotan

    2006-01-01

    Full Text Available Rett syndrome (RS is a neurodevelopmental syndrome of genetic origin that mainly affects females. Individuals diagnosed with RS exhibit a variety of functional difficulties that impair their quality of life. One of the affected systems is the digestive system, where 74% of persons with RS have abnormal functioning. The affected digestive system causes this population to present an array of problems, such as gastroesophageal reflux (GER, constipation, and malnutrition, leading to failure to thrive (FTT, which resolves in reduced functional ability. Due to the severe effects of the dysfunctional digestive system of individuals with RS, this article will describe the problems common to this population, as well as propose some clinical suggestions for intervention. .

  13. Management of epilepsy in patients with Rett syndrome: perspectives and considerations

    Science.gov (United States)

    Krajnc, Natalija

    2015-01-01

    Rett syndrome (RTT) is a common neurodevelopmental disorder that appears in infancy with regression of acquired motor skills, loss of purposeful activity, hand stereotypies, loss of acquired spoken language, and seizures. Epilepsy affects the majority of patients in a specific clinical stage of the disease and is drug resistant in approximately one-third of cases. The association of epilepsy and even drug-resistant epilepsy has been reported in certain genotypes of the methyl-CpG-binding protein 2 mutation, which is present in a majority of patients with classical RTT. The evolution of electroencephalographic abnormalities accompanying the clinical development of the syndrome is well described, but much less is known about the seizure semiology and the effectiveness of specific antiepileptic drugs. The aim of this review is to present the clinical and electrophysiological aspects of epilepsy in RTT and the current treatment approach. PMID:26089674

  14. Infrared Thermal Analysis and Individual Differences in Skin Temperature Asymmetry in Rett Syndrome.

    Science.gov (United States)

    Symons, Frank J; Byiers, Breanne; Hoch, John; Dimian, Adele; Barney, Chantel; Feyma, Timothy; Beisang, Arthur

    2015-08-01

    We evaluated the feasibility of using a portable infrared thermal camera to quantify the degree of thermal dysregulation (cold hands/feet) and test for naturally occurring within-patient skin temperature asymmetry in Rett syndrome. Infrared thermal images were acquired passively from 15 patients (mean age = 13.7 years, range 4-47) with clinical diagnoses of Rett. Images were acquired using a FLIR T400 infrared thermal camera (still images recorded at 5 Hz, resolution of 320 × 240 pixels, thermal sensitivity = 0.05 °C; capture session lasted approximately 3 minutes). The infrared thermal camera was orthogonal to the body part (hands, feet) and positioned approximately 1 meter from the skin's surface. There were large intraindividual left/right differences in temperature. Seven (47%) and eight (53%) patients had statistically significant (P thermal asymmetry may reflect prolonged activity of the sympathetic nervous system and individual differences in sympathetic regulation. As clinical trials emerge and endpoints are considered, portable infrared thermal camera may provide one noninvasive means of evaluating changes in sympathetic regulation. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Rett Syndrome Mutant Neural Cells Lacks MeCP2 Immunoreactive Bands.

    Directory of Open Access Journals (Sweden)

    Carlos Bueno

    Full Text Available Dysfunctions of MeCP2 protein lead to various neurological disorders such as Rett syndrome and Autism. The exact functions of MeCP2 protein is still far from clear. At a molecular level, there exist contradictory data. MeCP2 protein is considered a single immunoreactive band around 75 kDa by western-blot analysis but several reports have revealed the existence of multiple MeCP2 immunoreactive bands above and below the level where MeCP2 is expected. MeCP2 immunoreactive bands have been interpreted in different ways. Some researchers suggest that multiple MeCP2 immunoreactive bands are unidentified proteins that cross-react with the MeCP2 antibody or degradation product of MeCP2, while others suggest that MeCP2 post-transcriptional processing generates multiple molecular forms linked to cell signaling, but so far they have not been properly analyzed in relation to Rett syndrome experimental models. The purpose of this study is to advance understanding of multiple MeCP2 immunoreactive bands in control neural cells and p.T158M MeCP2e1 mutant cells. We have generated stable wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Application of N- and C- terminal MeCP2 antibodies, and also, RFP antibody minimized concerns about nonspecific cross-reactivity, since they react with the same antigen at different epitopes. We report the existence of multiple MeCP2 immunoreactive bands in control cells, stable wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Also, MeCP2 immunoreactive bands differences were found between wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Slower migration phosphorylated band around 70kDa disappeared in p.T158M MeCP2e1-RFP mutant expressing cells. These data suggest that threonine 158 could represent an important phosphorylation site potentially involved in protein function. Our results clearly indicate that MeCP2 antibodies have no cross-reactivity with similar epitopes on others proteins, supporting the

  16. Rett Syndrome Mutant Neural Cells Lacks MeCP2 Immunoreactive Bands

    Science.gov (United States)

    Bueno, Carlos; Tabares-Seisdedos, Rafael; Moraleda, Jose M.; Martinez, Salvador

    2016-01-01

    Dysfunctions of MeCP2 protein lead to various neurological disorders such as Rett syndrome and Autism. The exact functions of MeCP2 protein is still far from clear. At a molecular level, there exist contradictory data. MeCP2 protein is considered a single immunoreactive band around 75 kDa by western-blot analysis but several reports have revealed the existence of multiple MeCP2 immunoreactive bands above and below the level where MeCP2 is expected. MeCP2 immunoreactive bands have been interpreted in different ways. Some researchers suggest that multiple MeCP2 immunoreactive bands are unidentified proteins that cross-react with the MeCP2 antibody or degradation product of MeCP2, while others suggest that MeCP2 post-transcriptional processing generates multiple molecular forms linked to cell signaling, but so far they have not been properly analyzed in relation to Rett syndrome experimental models. The purpose of this study is to advance understanding of multiple MeCP2 immunoreactive bands in control neural cells and p.T158M MeCP2e1 mutant cells. We have generated stable wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Application of N- and C- terminal MeCP2 antibodies, and also, RFP antibody minimized concerns about nonspecific cross-reactivity, since they react with the same antigen at different epitopes. We report the existence of multiple MeCP2 immunoreactive bands in control cells, stable wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Also, MeCP2 immunoreactive bands differences were found between wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Slower migration phosphorylated band around 70kDa disappeared in p.T158M MeCP2e1-RFP mutant expressing cells. These data suggest that threonine 158 could represent an important phosphorylation site potentially involved in protein function. Our results clearly indicate that MeCP2 antibodies have no cross-reactivity with similar epitopes on others proteins, supporting the idea that MeCP2 may

  17. Rett Syndrome Mutant Neural Cells Lacks MeCP2 Immunoreactive Bands.

    Science.gov (United States)

    Bueno, Carlos; Tabares-Seisdedos, Rafael; Moraleda, Jose M; Martinez, Salvador

    2016-01-01

    Dysfunctions of MeCP2 protein lead to various neurological disorders such as Rett syndrome and Autism. The exact functions of MeCP2 protein is still far from clear. At a molecular level, there exist contradictory data. MeCP2 protein is considered a single immunoreactive band around 75 kDa by western-blot analysis but several reports have revealed the existence of multiple MeCP2 immunoreactive bands above and below the level where MeCP2 is expected. MeCP2 immunoreactive bands have been interpreted in different ways. Some researchers suggest that multiple MeCP2 immunoreactive bands are unidentified proteins that cross-react with the MeCP2 antibody or degradation product of MeCP2, while others suggest that MeCP2 post-transcriptional processing generates multiple molecular forms linked to cell signaling, but so far they have not been properly analyzed in relation to Rett syndrome experimental models. The purpose of this study is to advance understanding of multiple MeCP2 immunoreactive bands in control neural cells and p.T158M MeCP2e1 mutant cells. We have generated stable wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Application of N- and C- terminal MeCP2 antibodies, and also, RFP antibody minimized concerns about nonspecific cross-reactivity, since they react with the same antigen at different epitopes. We report the existence of multiple MeCP2 immunoreactive bands in control cells, stable wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Also, MeCP2 immunoreactive bands differences were found between wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Slower migration phosphorylated band around 70kDa disappeared in p.T158M MeCP2e1-RFP mutant expressing cells. These data suggest that threonine 158 could represent an important phosphorylation site potentially involved in protein function. Our results clearly indicate that MeCP2 antibodies have no cross-reactivity with similar epitopes on others proteins, supporting the idea that MeCP2 may

  18. Long-lasting beneficial effects of central serotonin receptor 7 stimulation in female mice modeling Rett syndrome.

    Science.gov (United States)

    De Filippis, Bianca; Chiodi, Valentina; Adriani, Walter; Lacivita, Enza; Mallozzi, Cinzia; Leopoldo, Marcello; Domenici, Maria Rosaria; Fuso, Andrea; Laviola, Giovanni

    2015-01-01

    Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that specific behavioral and brain molecular alterations can be rescued in MeCP2-308 male mice, a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family-crucially involved in the regulation of brain structural plasticity and cognitive processes-can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective 5-HT7R agonist. The present study extends previous findings by demonstrating that the LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues RTT-related phenotypic alterations, motor coordination (Dowel test), spatial reference memory (Barnes maze test) and synaptic plasticity (hippocampal long-term-potentiation) in MeCP2-308 heterozygous female mice, the genetic and hormonal milieu that resembles that of RTT patients. LP-211 also restores the activation of the ribosomal protein (rp) S6, the downstream target of mTOR and S6 kinase, in the hippocampus of RTT female mice. Notably, the beneficial effects on neurobehavioral and molecular parameters of a seven-day long treatment with LP-211 were evident up to 2 months after the last injection, thus suggesting long-lasting effects on RTT-related impairments. Taken together with our previous study, these results provide compelling preclinical evidence of the potential therapeutic value for RTT of a pharmacological approach targeting the brain 5-HT7R.

  19. Long-lasting beneficial effects of central serotonin receptor 7 stimulation in female mice modeling Rett syndrome

    Directory of Open Access Journals (Sweden)

    Bianca eDe Filippis

    2015-04-01

    Full Text Available Rett syndrome (RTT is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2 cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that specific behavioral and brain molecular alterations can be rescued in MeCP2-308 male mice, a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R. This member of the serotonin receptor family – crucially involved in the regulation of brain structural plasticity and cognitive processes – can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective 5-HT7R agonist. The present study extends previous findings by demonstrating that the LP-211 treatment (0.25 mg/kg, once per day for 7 days rescues RTT-related phenotypic alterations, motor coordination (Dowel test, spatial reference memory (Barnes maze test and synaptic plasticity (hippocampal long-term-potentiation in MeCP2-308 heterozygous female mice, the genetic and hormonal milieu that resembles that of RTT patients. LP-211 also restores the activation of the ribosomal protein S6, the downstream target of mTOR and S6 kinase, in the hippocampus of RTT female mice. Notably, the beneficial effects on neurobehavioral and molecular parameters of a seven-day long treatment with LP-211 were evident up to two months after the last injection, thus suggesting long-lasting effects on RTT-related impairments. Taken together with our previous study, these results provide compelling preclinical evidence of the potential therapeutic value for RTT of a pharmacological approach targeting the brain 5-HT7R.

  20. Novel mutations in cyclin-dependent kinase-like 5 (CDKL5) gene in Indian cases of Rett syndrome.

    Science.gov (United States)

    Das, Dhanjit Kumar; Mehta, Bhakti; Menon, Shyla R; Raha, Sarbani; Udani, Vrajesh

    2013-03-01

    Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Both the classic and atypical forms of Rett syndrome are primarily due to mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with atypical Rett syndrome, X-linked infantile spasms sharing common features of generally early-onset seizures and mental retardation. CDKL5 is known as serine/threonine protein kinase 9 (STK9) and is mapped to the Xp22 region. It has a conserved serine/threonine kinase domain within its amino terminus and a large C-terminal region. Disease-causing mutations are distributed in both the amino terminal domain and in the large C-terminal domain. We have screened the CDKL5 gene in 44 patients with atypical Rett syndrome who had tested negative for MECP2 gene mutations and have identified 6 sequence variants, out of which three were novel and three known mutations. Two of these novel mutations p.V966I and p.A1011V were missense and p.H589H a silent mutation. Other known mutations identified were p.V999M, p.Q791P and p.T734A. Sequence homology for all the mutations revealed that the two mutations (p.Q791P and p.T734A) were conserved across species. This indicated the importance of these residues in structure and function of the protein. The damaging effects of these mutations were analysed in silico using PolyPhen-2 online software. The PolyPhen-2 scores of p.Q791P and p.T734A were 0.998 and 0.48, revealing that these mutations could be deleterious and might have potential functional effect. All other mutations had a low score suggesting that they might not alter the activity of CDKL5. We have also analysed the position of the mutations in the CDKL5 protein and found that all the mutations were present in the C-terminal domain of the protein. The C-terminal domain is required for

  1. MECP2 gene mutation analysis in Chinese patients with Rett syndrome

    Institute of Scientific and Technical Information of China (English)

    PanH; WangYP; BaoXH; MengHD; ZhangY; WuXR; ShenY

    2005-01-01

    Rett syndrome (RTT) is a progressive neurodevelopmental disorder that affects almost exclusively girls. Mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2) have been found to be a cause. In order to study the spectrum of MECP2 mutations in Chinese patients, we employed PCR and sequencing of the coding region of MECP2 gene in 31 Chinese cases of classical sporadic RTT. Mutations in MECP2 were found in about 55%. Twelve different mutations in exon 3 were identified in 17 of these 31 patients; two of these are novel. A novel missense variant was detected in the C-terminal region in a patient and her father who was normal. In addition, there was a single nucleotide variant in the 3'UTR.

  2. The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome.

    Science.gov (United States)

    Brown, Kyla; Selfridge, Jim; Lagger, Sabine; Connelly, John; De Sousa, Dina; Kerr, Alastair; Webb, Shaun; Guy, Jacky; Merusi, Cara; Koerner, Martha V; Bird, Adrian

    2016-02-01

    Rett syndrome is caused by mutations in the X-linked MECP2 gene, which encodes a chromosomal protein that binds to methylated DNA. Mouse models mirror the human disorder and therefore allow investigation of phenotypes at a molecular level. We describe an Mecp2 allelic series representing the three most common missense Rett syndrome (RTT) mutations, including first reports of Mecp2[R133C] and Mecp2[T158M] knock-in mice, in addition to Mecp2[R306C] mutant mice. Together these three alleles comprise ∼25% of all RTT mutations in humans, but they vary significantly in average severity. This spectrum is mimicked in the mouse models; R133C being least severe, T158M most severe and R306C of intermediate severity. Both R133C and T158M mutations cause compound phenotypes at the molecular level, combining compromised DNA binding with reduced stability, the destabilizing effect of T158M being more severe. Our findings contradict the hypothesis that the R133C mutation exclusively abolishes binding to hydroxymethylated DNA, as interactions with DNA containing methyl-CG, methyl-CA and hydroxymethyl-CA are all reduced in vivo. We find that MeCP2[T158M] is significantly less stable than MeCP2[R133C], which may account for the divergent clinical impact of the mutations. Overall, this allelic series recapitulates human RTT severity, reveals compound molecular aetiologies and provides a valuable resource in the search for personalized therapeutic interventions.

  3. Spectrum of MECP2 gene mutations in a cohort of Indian patients with Rett syndrome: report of two novel mutations.

    Science.gov (United States)

    Das, Dhanjit Kumar; Raha, Sarbani; Sanghavi, Daksha; Maitra, Anurupa; Udani, Vrajesh

    2013-02-15

    Rett syndrome (RTT) is an X-linked neurodevelopmental disorder, primarily affecting females and characterized by developmental regression, epilepsy, stereotypical hand movements, and motor abnormalities. Its prevalence is about 1 in 10,000 female births. Rett syndrome is caused by mutations within methyl CpG-binding protein 2 (MECP2) gene. Over 270 individual nucleotide changes which cause pathogenic mutations have been reported. However, eight most commonly occurring missense and nonsense mutations account for almost 70% of all patients. We screened 90 individuals with Rett syndrome phenotype. A total of 19 different MECP2 mutations and polymorphisms were identified in 27 patients. Of the 19 mutations, we identified 7 (37%) frameshift, 6 (31%) nonsense, 14 (74%) missense mutations and one duplication (5%). The most frequent pathogenic changes were: missense p.T158M (11%), p.R133C (7.4%), and p.R306C (7.4%) and nonsense p.R168X (11%), p.R255X (7.4%) mutations. We have identified two novel mutations namely p.385-388delPLPP present in atypical patients and p.Glu290AlafsX38 present in a classical patient of Rett syndrome. Sequence homology for p.385-388delPLPP mutation revealed that these 4 amino acids were conserved across mammalian species. This indicated the importance of these 4 amino acids in structure and function of the protein. A novel variant p.T479T has also been identified in a patient with atypical Rett syndrome. A total of 62 (69%) patients remained without molecular genetics diagnosis that necessitates further search for mutations in other genes like CDKL5 and FOXG1 that are known to cause Rett phenotype. The majority of mutations are detected in exon 4 and only one mutation was present in exon 3. Therefore, our study suggests the need for screening exon 4 of MECP2 as first line of diagnosis in these patients.

  4. Cholesterol Metabolism Is Altered in Rett Syndrome: A Study on Plasma and Primary Cultured Fibroblasts Derived from Patients

    Science.gov (United States)

    Segatto, Marco; Trapani, Laura; Di Tunno, Ilenia; Sticozzi, Claudia; Valacchi, Giuseppe; Hayek, Joussef; Pallottini, Valentina

    2014-01-01

    Rett (RTT) syndrome is a severe neurological disorder that affects almost exclusively females. Several detectable mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2) are responsible for the onset of the disease. MeCP2 is a key transcription regulator involved in gene silencing via methylation-dependent remodeling of chromatin. Recent data highlight that lipid metabolism is perturbed in brains and livers of MECP2-null male mice. In addition, altered plasma lipid profile in RTT patients has been observed. Thus, the aim of the work is to investigate the protein network involved in cholesterol homeostasis maintenance on freshly isolated fibroblasts and plasma from both RTT and healthy donors. To this end, protein expression of 3-hydroxy-3methyl glutaryl Coenzyme A reductase (HMGR), sterol regulatory element binding proteins (SREBPs), low density lipoprotein receptor (LDLr) and scavenger receptor B-1 (SRB-1) was assessed in cultured skin fibroblasts from unaffected individuals and RTT patients. In addition, lipid profile and the abundance of proprotein convertase subtilisin/kexin type 9 (PCSK9) were analyzed on plasma samples. The obtained results demonstrate that the main proteins belonging to cholesterol regulatory network are altered in RTT female patients, providing the proof of principle that cholesterol metabolism may be taken into account as a new target for the treatment of specific features of RTT pathology. PMID:25118178

  5. MeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome.

    Science.gov (United States)

    Tai, Derek J C; Liu, Yen C; Hsu, Wei L; Ma, Yun L; Cheng, Sin J; Liu, Shau Y; Lee, Eminy H Y

    2016-02-04

    The methyl-CpG-binding protein 2 (MeCP2) gene, MECP2, is an X-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT). However, the molecular mechanism of MECP2-mutation-caused RTT is less known. Here we find that MeCP2 could be SUMO-modified by the E3 ligase PIAS1 at Lys-412. MeCP2 phosphorylation (at Ser-421 and Thr-308) facilitates MeCP2 SUMOylation, and MeCP2 SUMOylation is induced by NMDA, IGF-1 and CRF in the rat brain. MeCP2 SUMOylation releases CREB from the repressor complex and enhances Bdnf mRNA expression. Several MECP2 mutations identified in RTT patients show decreased MeCP2 SUMOylation. Re-expression of wild-type MeCP2 or SUMO-modified MeCP2 in Mecp2-null neurons rescues the deficits of social interaction, fear memory and LTP observed in Mecp2 conditional knockout (cKO) mice. These results together reveal an important role of MeCP2 SUMOylation in social interaction, memory and synaptic plasticity, and that abnormal MeCP2 SUMOylation is implicated in RTT.

  6. Affective dysfunction in a mouse model of Rett syndrome: Therapeutic effects of environmental stimulation and physical activity.

    Science.gov (United States)

    Kondo, Mari A; Gray, Laura J; Pelka, Gregory J; Leang, Sook-Kwan; Christodoulou, John; Tam, Patrick P L; Hannan, Anthony J

    2016-02-01

    Rett syndrome (RTT) is a neurodevelopmental disorder associated with mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) and consequent dysregulation of brain maturation. Patients suffer from a range of debilitating physical symptoms, however, behavioral and emotional symptoms also severely affect their quality of life. Here, we present previously unreported and clinically relevant affective dysfunction in the female heterozygous Mecp2(tm1Tam) mouse model of RTT (129sv and C57BL6 mixed background). The affective dysfunction and aberrant anxiety-related behavior of the Mecp2(+/-) mice were found to be reversible with environmental enrichment (EE) from 4 weeks of age. The effect of exercise alone (via wheel running) was also explored, providing the first evidence that increased voluntary physical activity in an animal model of RTT is beneficial for some phenotypes. Mecp2(+/-) mutants displayed elevated corticosterone despite decreased Crh expression, demonstrating hypothalamic-pituitary-adrenal axis dysregulation. EE of Mecp2(+/-) mice normalized basal serum corticosterone and hippocampal BDNF protein levels. The enrichment-induced rescue appears independent of the transcriptional regulation of the MeCP2 targets Bdnf exon 4 and Crh. These findings provide new insight into the neurodevelopmental role of MeCP2 and pathogenesis of RTT, in particular the affective dysfunction. The positive outcomes of environmental stimulation and physical exercise have implications for the development of therapies targeting the affective symptoms, as well as behavioral and cognitive dimensions, of this devastating neurodevelopmental disorder.

  7. Cholesterol metabolism is altered in Rett syndrome: a study on plasma and primary cultured fibroblasts derived from patients.

    Directory of Open Access Journals (Sweden)

    Marco Segatto

    Full Text Available Rett (RTT syndrome is a severe neurological disorder that affects almost exclusively females. Several detectable mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2 are responsible for the onset of the disease. MeCP2 is a key transcription regulator involved in gene silencing via methylation-dependent remodeling of chromatin. Recent data highlight that lipid metabolism is perturbed in brains and livers of MECP2-null male mice. In addition, altered plasma lipid profile in RTT patients has been observed. Thus, the aim of the work is to investigate the protein network involved in cholesterol homeostasis maintenance on freshly isolated fibroblasts and plasma from both RTT and healthy donors. To this end, protein expression of 3-hydroxy-3methyl glutaryl Coenzyme A reductase (HMGR, sterol regulatory element binding proteins (SREBPs, low density lipoprotein receptor (LDLr and scavenger receptor B-1 (SRB-1 was assessed in cultured skin fibroblasts from unaffected individuals and RTT patients. In addition, lipid profile and the abundance of proprotein convertase subtilisin/kexin type 9 (PCSK9 were analyzed on plasma samples. The obtained results demonstrate that the main proteins belonging to cholesterol regulatory network are altered in RTT female patients, providing the proof of principle that cholesterol metabolism may be taken into account as a new target for the treatment of specific features of RTT pathology.

  8. First case report of Rett syndrome in the Azeri Turkish population and brief review of the literature

    Directory of Open Access Journals (Sweden)

    Jalal Gharesouran

    2015-01-01

    Full Text Available Rett syndrome is a dominant X-linked male-lethal disorder largely caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2. Clinical manifestations include neurodevelopmental disorder characterized by early-onset intractable seizures, severe developmental delay, intellectual disability, and abnormal electroencephalograms. Afflicted females show normal development until the age of 6 to 18 months, followed by gradual loss of speech abilities, microcephaly, social impairment, ataxia, and stereotypic hand movements. We report a 7-year-old girl who was born of a nonconsanguineous marriage presenting with mental retardation and delayed development. Physical examination revealed loss of speech, repetitive hand-wringing movement, short stature (120 cm, strabismus, microcephaly, and autistic behavior. The diagnosis was confirmed by sequencing MECP2 gene with heterozygous mutation C385A in exon 2. The current study aimed to report the first case of Rett syndrome in the Azeri Turkish population.

  9. Brain Fag Syndrome

    African Journals Online (AJOL)

    syndrome. BFS is a tetrad of somatic complaints; cognitive impairments; sleep related complaints; and other somatic impairments. ..... BFS is a history told over time and through space. Divisions ..... Social origins of the brain fag syndrome.

  10. 从Rett综合征看儿童神经发育性疾病的研究进展%Advances of research on childhood brain development diseases--from what we know about Rett syndrome

    Institute of Scientific and Technical Information of China (English)

    吴希如; 钟南; 姜玉武

    2005-01-01

    自1999年发现甲基CpG结合蛋白2(MeCP2)是Rett综合征(Rett yndrome,RTT)的致病基因以来,近来不仅在MeCP2基因本身,其与RTT发病机制关系的研究都有显著进展。与此同时,与RTT相关的神经发育性疾病,诸如孤独症、智力低下等的研究也有较大进展。值得关注的是,随着人们的不断探索,这一组难治疾病在发病机制中的许多共同点也逐步显露出来,为更深入研究这类疾病提供了重要基础。

  11. Age of diagnosis in Rett syndrome: patterns of recognition among diagnosticians and risk factors for late diagnosis

    OpenAIRE

    Tarquinio, DC; W Hou; Neul, JL; Lane, JB; Barnes, KV; O'Leary, HM; Bruck, NM; Kaufmann, WE; Motil, KJ; Glaze, DG; Skinner, SA; Annese, F.; Baggett, L; Barrish, JO; Geerts, SP

    2015-01-01

    © 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 Amo...

  12. Linking Epigenetics to Human Disease and Rett Syndrome: The Emerging Novel and Challenging Concepts in MeCP2 Research

    OpenAIRE

    Robby Mathew Zachariah; Mojgan Rastegar

    2012-01-01

    Epigenetics refer to inheritable changes beyond DNA sequence that control cell identity and morphology. Epigenetics play key roles in development and cell fate commitments and highly impact the etiology of many human diseases. A well-known link between epigenetics and human disease is the X-linked MECP2 gene, mutations in which lead to the neurological disorder, Rett Syndrome. Despite the fact that MeCP2 was discovered about 20 years ago, our current knowledge about its molecular function is ...

  13. Novel mutation in forkhead box G1 (FOXG1) gene in an Indian patient with Rett syndrome.

    Science.gov (United States)

    Das, Dhanjit Kumar; Jadhav, Vaishali; Ghattargi, Vikas C; Udani, Vrajesh

    2014-03-15

    Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by the progressive loss of intellectual functioning, fine and gross motor skills and communicative abilities, deceleration of head growth, and the development of stereotypic hand movements, occurring after a period of normal development. The classic form of RTT involves mutation in MECP2 while the involvement of CDKL5 and FOXG1 genes has been identified in atypical RTT phenotype. FOXG1 gene encodes for a fork-head box protein G1, a transcription factor acting primarily as transcriptional repressor through DNA binding in the embryonic telencephalon as well as a number of other neurodevelopmental processes. In this report we have described the molecular analysis of FOXG1 gene in Indian patients with Rett syndrome. FOXG1 gene mutation analysis was done in a cohort of 34 MECP2/CDKL5 mutation negative RTT patients. We have identified a novel mutation (p. D263VfsX190) in FOXG1 gene in a patient with congenital variant of Rett syndrome. This mutation resulted into a frameshift, thereby causing an alteration in the reading frames of the entire coding sequence downstream of the mutation. The start position of the frameshift (Asp263) and amino acid towards the carboxyl terminal end of the protein was found to be well conserved across species using multiple sequence alignment. Since the mutation is located at forkhead binding domain, the resultant mutation disrupts the secondary structure of the protein making it non-functional. This is the first report from India showing mutation in FOXG1 gene in Rett syndrome.

  14. Rett Syndrome

    Science.gov (United States)

    ... Some of these conditions include: Other genetic disorders Autism Cerebral palsy Hearing or vision problems Metabolic disorders, ... and helping with social interaction. Nutritional support. Proper nutrition is extremely important for normal growth and for ...

  15. Illness Severity, Social and Cognitive Ability, and EEG Analysis of Ten Patients with Rett Syndrome Treated with Mecasermin (Recombinant Human IGF-1

    Directory of Open Access Journals (Sweden)

    Giorgio Pini

    2016-01-01

    Full Text Available Rett Syndrome (RTT is a severe neurodevelopmental disorder characterized by an apparently normal development followed by an arrest and subsequent regression of cognitive and psychomotor abilities. At present, RTT has no definitive cure and the treatment of RTT represents a largely unmet clinical need. Following partial elucidation of the underlying neurobiology of RTT, a new treatment has been proposed, Mecasermin (recombinant human Insulin-Like Growth Factor 1, which, in addition to impressive evidence from preclinical murine models of RTT, has demonstrated safety in human studies of patients with RTT. The present clinical study examines the disease severity as assessed by clinicians (International Scoring System: ISS, social and cognitive ability assessed by two blinded, independent observers (RSS: Rett Severity Score, and changes in brain activity (EEG parameters of ten patients with classic RTT and ten untreated patients matched for age and clinical severity. Significant improvement in both the ISS (p=0.0106 and RSS (p=0.0274 was found in patients treated with IGF1 in comparison to untreated patients. Analysis of the novel RSS also suggests that patients treated with IGF1 have a greater endurance to social and cognitive testing. The present clinical study adds significant preliminary evidence for the use of IGF-1 in the treatment of RTT and other disorders of the autism spectrum.

  16. Illness Severity, Social and Cognitive Ability, and EEG Analysis of Ten Patients with Rett Syndrome Treated with Mecasermin (Recombinant Human IGF-1).

    Science.gov (United States)

    Pini, Giorgio; Congiu, Laura; Benincasa, Alberto; DiMarco, Pietro; Bigoni, Stefania; Dyer, Adam H; Mortimer, Niall; Della-Chiesa, Andrea; O'Leary, Sean; McNamara, Rachel; Mitchell, Kevin J; Gill, Michael; Tropea, Daniela

    2016-01-01

    Rett Syndrome (RTT) is a severe neurodevelopmental disorder characterized by an apparently normal development followed by an arrest and subsequent regression of cognitive and psychomotor abilities. At present, RTT has no definitive cure and the treatment of RTT represents a largely unmet clinical need. Following partial elucidation of the underlying neurobiology of RTT, a new treatment has been proposed, Mecasermin (recombinant human Insulin-Like Growth Factor 1), which, in addition to impressive evidence from preclinical murine models of RTT, has demonstrated safety in human studies of patients with RTT. The present clinical study examines the disease severity as assessed by clinicians (International Scoring System: ISS), social and cognitive ability assessed by two blinded, independent observers (RSS: Rett Severity Score), and changes in brain activity (EEG) parameters of ten patients with classic RTT and ten untreated patients matched for age and clinical severity. Significant improvement in both the ISS (p = 0.0106) and RSS (p = 0.0274) was found in patients treated with IGF1 in comparison to untreated patients. Analysis of the novel RSS also suggests that patients treated with IGF1 have a greater endurance to social and cognitive testing. The present clinical study adds significant preliminary evidence for the use of IGF-1 in the treatment of RTT and other disorders of the autism spectrum.

  17. Correlation of the Vesicular Acetylcholine Transporter Densities in the Striata to the Clinical Abilities of Women with Rett Syndrome (RTT)

    Science.gov (United States)

    BRAŠIĆ, JAMES ROBERT; BIBAT, GENILA; KUMAR, ANIL; ZHOU, YUN; HILTON, JOHN; YABLONSKI, MARYBETH E.; DOGAN, AHMET SEMIH; GUEVARA, MARIA RITA; STEPHANE, MASSOUD; JOHNSTON, MICHAEL; WONG, DEAN FOSTER; NAIDU, SAKKUBAI

    2012-01-01

    Rett syndrome (RTT) is a neurodevelopmental disability characterized by mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2) located at the Xq28 region. The severity is modified in part by X chromosomal inactivation resulting in wide clinical variability. We hypothesized that the ability to perform the activities of daily living (ADL) is correlated with the density of vesicular acetylcholine transporters in the striata of women with RTT. The density of the vesicular acetylcholine transporters in the living human brain can be estimated by single-photon emission-computed tomography (SPECT) after the administration of (−)-5-[123I]iodobenzovesamicol ([123I]IBVM). Twenty-four (24) hours following the intravenous injection of approximately 333 MBq (9 mCi) [123I]IBVM, four women with RTT and nine healthy adult volunteer control participants underwent SPECT brain scans for sixty (60) minutes. The Vesicular Acetylcholine Transporter Binding Site Index (VATBSI) (Kuhl et al., 1994), a measurement of the density of vesicular acetylcholine transporters, was estimated in the striatum and the reference structure, the cerebellum. The women with RTT were assessed for certain activities of daily living (ADL). Although striatal VATSBI was not significantly lower in RTT (5.2 ± 0.9) than in healthy adults (5.7 ± 1.6), RTT striatal VATSBI and ADL scores were linearly associated (ADL = 0.89*VATSBI + 4.5; R2=0.93; p<0.01), suggesting a correlation between the ability to perform ADL and the density of vesicular acetylcholine transporters in the striata of women with RTT. [123I]IBVM is a promising tool to characterize the pathophysiological mechanisms of RTT and other neurodevelopmental disabilities. PMID:22223404

  18. Evaluation of Rett Syndrome Symptom Improvement by Metabolic Modulators in Mecp2-Mutant Mice.

    Science.gov (United States)

    Buchovecky, Christie M; Hill, Misty G; Borkey, Jennifer M; Kyle, Stephanie M; Justice, Monica J

    2013-12-19

    Mouse models recapitulate many symptoms of Rett Syndrome, an X-linked disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2). The study of Mecp2-null male mice has provided insight into pathogenesis of the disorder-most recently, dysregulation of cholesterol and lipid metabolism. Perisymptomatic treatment with statin drugs successfully mitigates the effects of this metabolic syndrome, increases longevity, and improves motor function. Described here is a metabolic drug screening protocol and timeline for symptom evaluation in Mecp2-mutant mice. Specifically, mice are treated twice weekly with a compound of interest alongside subjective health assessments, bi-weekly body composition measurements, and blood chemistries. Throughout treatment, behavioral phenotyping tests are carried out at specific time points. This protocol is highly adaptable to other neurological diseases; however, the time for completion depends on the specific mutant model under study. The protocol highlights the use of techniques described in several different Current Protocols in Mouse Biology articles to carry out testing in a preclinical model. Curr. Protoc. Mouse Biol. 3:187-204 © 2013 by John Wiley & Sons, Inc.

  19. Having friends and Rett syndrome: how social relationships create meaningful contexts for limited skills.

    Science.gov (United States)

    Evans, I M; Meyer, L H

    The experiences of a teenage girl with Rett syndrome who was being educated in an inclusive middle school are described to provide a better understanding of how social relationships create meaningful contexts for individuals with limited skills. The case example is used to illustrate the principle that contexts (including expectancies, acceptance, philosophical principles) can be designed to support meaningful social relationships, despite social and intellectual disabilities. Naturalistic observations of social interactions over a two year period are reported to illustrate the possible types of social relationship between this young person and her adolescent friends and peers. While someone with this syndrome might be judged objectively to have minimal social skills, an accepting social environment willing to read minimal communicative cues provided the context for many typical social interactions. Since contexts require subjective judgement. the post-modern concept that disability represents a social construction can be viewed as a metaphor compatible with the reality that careful planning and structuring of the environment is in some instances the most appropriate intervention focus rather than the person with a disability. The sorts of positive friendship experiences described in this paper did not occur spontaneously, or by chance alone, nor were they the result of social skills instruction. Instead, they were associated with observable social behaviour by caregivers and peers who were extending their own repertoires to accommodate someone objectively determined to have a severe disability.

  20. Anxiety-like behavior in Rett syndrome: characteristics and assessment by anxiety scales.

    Science.gov (United States)

    Barnes, Katherine V; Coughlin, Francesca R; O'Leary, Heather M; Bruck, Natalie; Bazin, Grace A; Beinecke, Emily B; Walco, Alexandra C; Cantwell, Nicole G; Kaufmann, Walter E

    2015-01-01

    Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by regression of language and motor skills, cognitive impairment, and frequent seizures. Although the diagnostic criteria focus on communication, motor impairments, and hand stereotypies, behavioral abnormalities are a prevalent and disabling component of the RTT phenotype. Among these problematic behaviors, anxiety is a prominent symptom. While the introduction of the Rett Syndrome Behavioral Questionnaire (RSBQ) represented a major advancement in the field, no systematic characterization of anxious behavior using the RSBQ or other standardized measures has been reported. This study examined the profiles of anxious behavior in a sample of 74 girls with RTT, with a focus on identifying the instrument with the best psychometric properties in this population. The parent-rated RSBQ, Anxiety, Depression, and Mood Scale (ADAMS), and Aberrant Behavior Checklist-Community (ABC-C), two instruments previously employed in children with neurodevelopmental disorders, were analyzed in terms of score profiles, relationship with age and clinical severity, reliability, concurrent validity, and functional implications. The latter were determined by regression analyses with the Vineland Adaptive Behavior Scales-Second Edition (Vineland-II) and the Child Health Questionnaire (CHQ), a quality of life measure validated in RTT. We found that scores on anxiety subscales were intermediate in range with respect to other behavioral constructs measured by the RSBQ, ADAMS, and ABC-C. Age did not affect scores, and severity of general anxiety was inversely correlated with clinical severity. We demonstrated that the internal consistency of the anxiety-related subscales were among the highest. Test-retest and intra-rater reliability was superior for the ADAMS subscales. Convergent and discriminant validity were measured by inter-scale correlations, which showed the best profile for the social anxiety subscales. Of these

  1. Alterations in the carnitine cycle in a mouse model of Rett syndrome

    Science.gov (United States)

    Mucerino, Sabrina; Di Salle, Anna; Alessio, Nicola; Margarucci, Sabrina; Nicolai, Raffaella; Melone, Mariarosa A. B.; Galderisi, Umberto; Peluso, Gianfranco

    2017-01-01

    Rett syndrome (RTT) is a neurodevelopmental disease that leads to intellectual deficit, motor disability, epilepsy and increased risk of sudden death. Although in up to 95% of cases this disease is caused by de novo loss-of-function mutations in the X-linked methyl-CpG binding protein 2 gene, it is a multisystem disease associated also with mitochondrial metabolic imbalance. In addition, the presence of long QT intervals (LQT) on the patients’ electrocardiograms has been associated with the development of ventricular tachyarrhythmias and sudden death. In the attempt to shed light on the mechanism underlying heart failure in RTT, we investigated the contribution of the carnitine cycle to the onset of mitochondrial dysfunction in the cardiac tissues of two subgroups of RTT mice, namely Mecp2+/− NQTc and Mecp2+/− LQTc mice, that have a normal and an LQT interval, respectively. We found that carnitine palmitoyltransferase 1 A/B and carnitine acylcarnitine translocase were significantly upregulated at mRNA and protein level in the heart of Mecp2+/− mice. Moreover, the carnitine system was imbalanced in Mecp2+/− LQTc mice due to decreased carnitine acylcarnitine transferase expression. By causing accumulation of intramitochondrial acylcarnitines, this imbalance exacerbated incomplete fatty acid oxidation, which, in turn, could contribute to mitochondrial overload and sudden death. PMID:28150739

  2. DXA measurements in Rett syndrome reveal small bones with low bone mass.

    Science.gov (United States)

    Roende, Gitte; Ravn, Kirstine; Fuglsang, Kathrine; Andersen, Henrik; Nielsen, Jytte Bieber; Brøndum-Nielsen, Karen; Jensen, Jens-Erik Beck

    2011-09-01

    Low bone mass is reported in growth-retarded patients harboring mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene causing Rett syndrome (RTT). We present the first study addressing both bone mineral density (BMD) and bone size in RTT. Our object was to determine whether patients with RTT do have low BMD when correcting for smaller bones by examination with dual-energy X-ray absorptiometry (DXA). We compared areal BMD (aBMD(spine) and aBMD(total hip) ) and volumetric bone mineral apparent density (vBMAD(spine) and vBMAD(neck) ) in 61 patients and 122 matched healthy controls. Further, spine and hip aBMD and vBMAD of patients were associated with clinical risk factors of low BMD, low-energy fractures, MECP2 mutation groups, and X chromosome inactivation (XCI). Patients with RTT had reduced bone size on the order of 10% and showed lower values of spine and hip aBMD and vBMAD (p bone mass and small bones are evident in RTT, indicating an apparent low-bone-formation phenotype.

  3. Choline Ameliorates Disease Phenotypes in Human iPSC Models of Rett Syndrome.

    Science.gov (United States)

    Chin, Eunice W M; Marcy, Guillaume; Yoon, Su-In; Ma, Dongliang; Rosales, Francisco J; Augustine, George J; Goh, Eyleen L K

    2016-09-01

    Rett syndrome (RTT) is a postnatal neurodevelopmental disorder that primarily affects girls. Mutations in the methyl-CpG-binding protein 2 (MECP2) gene account for approximately 95 % of all RTT cases. To model RTT in vitro, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of two RTT patients with different mutations (MECP2 (R306C) and MECP2 (1155Δ32)) in their MECP2 gene. We found that these iPSCs were capable of differentiating into functional neurons. Compared to control neurons, the RTT iPSC-derived cells had reduced soma size and a decreased amount of synaptic input, evident both as fewer Synapsin 1-positive puncta and a lower frequency of spontaneous excitatory postsynaptic currents. Supplementation of the culture media with choline rescued all of these defects. Choline supplementation may act through changes in the expression of choline acetyltransferase, an important enzyme in cholinergic signaling, and also through alterations in the lipid metabolite profiles of the RTT neurons. Our study elucidates the possible mechanistic pathways for the effect of choline on human RTT cell models, thereby illustrating the potential for using choline as a nutraceutical to treat RTT.

  4. New insights in Rett syndrome using pathway analysis for transcriptomics data.

    Science.gov (United States)

    Ehrhart, Friederike; Coort, Susan L M; Cirillo, Elisa; Smeets, Eric; Evelo, Chris T; Curfs, Leopold

    2016-09-01

    The analysis of transcriptomics data is able to give an overview of cellular processes, but requires sophisticated bioinformatics tools and methods to identify the changes. Pathway analysis software, like PathVisio, captures the information about biological pathways from databases and brings this together with the experimental data to enable visualization and understanding of the underlying processes. Rett syndrome is a rare disease, but still one of the most abundant causes of intellectual disability in females. Cause of this neurological disorder is mutation of one single gene, the methyl-CpG-binding protein 2 (MECP2) gene. This gene is responsible for many steps in neuronal development and function. Although the genetic mutation and the clinical phenotype are well described, the molecular pathways linking them are not yet fully elucidated. In this study we demonstrate a workflow for the analysis of transcriptomics data to identify biological pathways and processes which are changed in a Mecp2 (-/y) mouse model.

  5. Stereotypical hand movements in 144 subjects with Rett syndrome from the population-based Australian database.

    Science.gov (United States)

    Carter, Philippa; Downs, Jenny; Bebbington, Ami; Williams, Simon; Jacoby, Peter; Kaufmann, Walter E; Leonard, Helen

    2010-02-15

    Stereotypic hand movements are a feature of Rett Syndrome but few studies have observed their nature systematically. Video data in familiar settings were obtained on subjects (n = 144) identified from an Australian population-based database. Hand stereotypies were demonstrated by most subjects (94.4%), 15 categories were observed and midline wringing was seen in approximately 60% of subjects. There was a median of two stereotypies per subject but this number decreased with age. Clapping and mouthing of hands were more prevalent in girls younger than 8 years and wringing was more prevalent in women 19 years or older. Clapping was commoner in those with p.R306C and early truncating mutations, and much rarer in those with p.R106W, p.R270X, p.R168X, and p.R255X. Stereotypies tended to be less frequent in those with more severe mutations. Otherwise, there were no clear relationships between our categories of stereotypies and mutation. Approximately a quarter each had predominantly right and left handed stereotypies and for the remaining half, no clear laterality was seen. Results were similar for all cases and when restricted to those with a pathogenic mutation. Hand stereotypies changed with increasing age but limited relationships with MECP2 mutations were identified.

  6. Early socio-communicative forms and functions in typical Rett syndrome.

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    Bartl-Pokorny, Katrin D; Marschik, Peter B; Sigafoos, Jeff; Tager-Flusberg, Helen; Kaufmann, Walter E; Grossmann, Tobias; Einspieler, Christa

    2013-10-01

    Rett syndrome (RTT) is a severe neurological disorder characterized by a developmental regression in motor and speech-language domains. There is, however, limited research on socio-communicative development of affected children before the onset of regression. We analyzed audio-video recordings made by parents of six 9- to 12-month old girls later diagnosed with typical RTT, applying the Inventory of Potential Communicative Acts (IPCA) to identify early communicative forms and functions. Each girl used at least one communicative form (e.g., body movement, eye gaze, or vocalizations) to gain attention and answer, but none were observed to make choices or request information. Varying numbers of children were observed to perform other communicative functions according to the IPCA including social convention, rejecting or requesting an object. Non-verbal forms (e.g., reaching, moving closer, eye contact, smiling) were more common than non-linguistic verbal forms (e.g., unspecified vocalizations, pleasure vocalizations, crying). (Pre-)linguistic verbal forms (e.g., canonical or variegated babbling, proto-words) were not used for communicative purposes. These data suggest that atypical developmental patterns in the socio-communicative domain are evident prior to regression in young individuals later diagnosed with RTT.

  7. Management of Rett Syndrome in the Controlled Multisensory (Snoezelen Environment. A Review with Three Case Stories

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    Meir Lotan

    2006-01-01

    Full Text Available Rett syndrome (RS is a neurological disorder resulting from an X-linked dominant mutation. It is characterized by a variety of physical and perceptual disabilities, resulting in a need for continuous intervention programs to be administered on a regular basis throughout life. Many of these individuals with RS show fear of movement and, therefore, find it hard to accept external facilitation (so common in physical therapy intervention. In a search for novel intervention techniques that might improve their ability to cope with difficulties in daily situations, while also reducing their difficulty in handling motion inflicted by an external physical facilitator, we examined the use of the Snoezelen room. The Snoezelen, also known as the controlled multisensory environment, can provide a soothing atmosphere that appeals to the individual with RS, while at the same time it can improve physical, sensorial, and functional abilities. This article suggests various intervention goals that are appropriate for individuals with RS at different stages of the disorder. Since the management of young children with RS in the multisensory environment has been discussed at length in the past, this article will mainly describe intervention with adults with RS, focusing on three case stories. The present article reviews the available scientific materials on the topic of Snoezelen, incorporating clinical knowledge in the field of RS and suggesting this approach as an appropriate intervention method for this population.

  8. Communication in Individuals with Rett Syndrome: an Assessment of Forms and Functions.

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    Didden, Robert; Korzilius, Hubert; Smeets, Eric; Green, Vanessa A; Lang, Russell; Lancioni, Giulio E; Curfs, Leopold M

    2010-04-01

    In the present study we assessed the forms and functions of prelinguistic communicative behaviors for 120 children and adults with Rett syndrome using the Inventory of Potential Communicative Acts (IPCA) (Sigafoos et al. Communication Disorders Quarterly 21:77-86, 2000a). Informants completed the IPCA and the results were analysed to provide a systematic inventory and objective description of the communicative forms and functions present in each individual's repertoire. Results show that respondents reported a wide variety of communicative forms and functions. By far most girls used prelinguistic communicative behaviors of which eye contact/gazing was the most common form. The most often endorsed communicative functions were social convention, commenting, answering, requesting and choice-making. Problematic topographies (e.g., self-injury, screaming, non-compliance) were being used for communicative purposes in 10 to 41% of the sample. Exploratory analyses revealed that several communicative forms and functions were related to living environment, presence/absence of epilepsy, and age. That is, higher percentages of girls who showed some forms/functions were found in those who lived at home, who had no epilepsy and who were relatively young.

  9. Effects of ω-3 Polyunsaturated Fatty Acids on Plasma Proteome in Rett Syndrome

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    Claudio De Felice

    2013-01-01

    Full Text Available The mechanism of action of omega-3 polyunsaturated fatty acids (ω-3 PUFAs is only partially known. Prior reports suggest a partial rescue of clinical symptoms and oxidative stress (OS alterations following ω-3 PUFAs supplementation in patients with Rett syndrome (RTT, a devastating neurodevelopmental disorder with transient autistic features, affecting almost exclusively females and mainly caused by sporadic mutations in the gene encoding the methyl CpG binding protein 2 (MeCP2 protein. Here, we tested the hypothesis that ω-3 PUFAs may modify the plasma proteome profile in typical RTT patients with MECP2 mutations and classic phenotype. A total of 24 RTT girls at different clinical stages were supplemented with ω-3 PUFAs as fish oil for 12 months and compared to matched healthy controls. The expression of 16 proteins, mainly related to acute phase response (APR, was changed at the baseline in the untreated patients. Following ω-3 PUFAs supplementation, the detected APR was partially rescued, with the expression of 10 out of 16 (62% proteins being normalized. ω-3 PUFAs have a major impact on the modulation of the APR in RTT, thus providing new insights into the role of inflammation in autistic disorders and paving the way for novel therapeutic strategies.

  10. Redox Imbalance and Morphological Changes in Skin Fibroblasts in Typical Rett Syndrome

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    Amabile, Sonia; Belmonte, Giuseppe; Valacchi, Giuseppe; Galano, Jean-Marie; Ciccoli, Lucia; Renieri, Alessandra; Hayek, Joussef

    2014-01-01

    Evidence of oxidative stress has been reported in the blood of patients with Rett syndrome (RTT), a neurodevelopmental disorder mainly caused by mutations in the gene encoding the Methyl-CpG-binding protein 2. Little is known regarding the redox status in RTT cellular systems and its relationship with the morphological phenotype. In RTT patients (n = 16) we investigated four different oxidative stress markers, F2-Isoprostanes (F2-IsoPs), F4-Neuroprostanes (F4-NeuroPs), nonprotein bound iron (NPBI), and (4-HNE PAs), and glutathione in one of the most accessible cells, that is, skin fibroblasts, and searched for possible changes in cellular/intracellular structure and qualitative modifications of synthesized collagen. Significantly increased F4-NeuroPs (12-folds), F2-IsoPs (7.5-folds) NPBI (2.3-folds), 4-HNE PAs (1.48-folds), and GSSG (1.44-folds) were detected, with significantly decreased GSH (−43.6%) and GSH/GSSG ratio (−3.05 folds). A marked dilation of the rough endoplasmic reticulum cisternae, associated with several cytoplasmic multilamellar bodies, was detectable in RTT fibroblasts. Colocalization of collagen I and collagen III, as well as the percentage of type I collagen as derived by semiquantitative immunofluorescence staining analyses, appears to be significantly reduced in RTT cells. Our findings indicate the presence of a redox imbalance and previously unrecognized morphological skin fibroblast abnormalities in RTT patients. PMID:24987493

  11. Redox Imbalance and Morphological Changes in Skin Fibroblasts in Typical Rett Syndrome

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    Cinzia Signorini

    2014-01-01

    Full Text Available Evidence of oxidative stress has been reported in the blood of patients with Rett syndrome (RTT, a neurodevelopmental disorder mainly caused by mutations in the gene encoding the Methyl-CpG-binding protein 2. Little is known regarding the redox status in RTT cellular systems and its relationship with the morphological phenotype. In RTT patients (n = 16 we investigated four different oxidative stress markers, F2-Isoprostanes (F2-IsoPs, F4-Neuroprostanes (F4-NeuroPs, nonprotein bound iron (NPBI, and (4-HNE PAs, and glutathione in one of the most accessible cells, that is, skin fibroblasts, and searched for possible changes in cellular/intracellular structure and qualitative modifications of synthesized collagen. Significantly increased F4-NeuroPs (12-folds, F2-IsoPs (7.5-folds NPBI (2.3-folds, 4-HNE PAs (1.48-folds, and GSSG (1.44-folds were detected, with significantly decreased GSH (−43.6% and GSH/GSSG ratio (−3.05 folds. A marked dilation of the rough endoplasmic reticulum cisternae, associated with several cytoplasmic multilamellar bodies, was detectable in RTT fibroblasts. Colocalization of collagen I and collagen III, as well as the percentage of type I collagen as derived by semiquantitative immunofluorescence staining analyses, appears to be significantly reduced in RTT cells. Our findings indicate the presence of a redox imbalance and previously unrecognized morphological skin fibroblast abnormalities in RTT patients.

  12. A Plasma Proteomic Approach in Rett Syndrome: Classical versus Preserved Speech Variant

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    Alessio Cortelazzo

    2013-01-01

    Full Text Available Rett syndrome (RTT is a progressive neurodevelopmental disorder mainly caused by mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2. Although over 200 mutations types have been identified so far, nine of which the most frequent ones. A wide phenotypical heterogeneity is a well-known feature of the disease, with different clinical presentations, including the classical form and the preserved speech variant (PSV. Aim of the study was to unveil possible relationships between plasma proteome and phenotypic expression in two cases of familial RTT represented by two pairs of sisters, harbor the same MECP2 gene mutation while being dramatically discrepant in phenotype, that is, classical RTT versus PSV. Plasma proteome was analysed by 2-DE/MALDI-TOF MS. A significant overexpression of six proteins in the classical sisters was detected as compared to the PSV siblings. A total of five out of six (i.e., 83.3% of the overexpressed proteins were well-known acute phase response (APR proteins, including alpha-1-microglobulin, haptoglobin, fibrinogen beta chain, alpha-1-antitrypsin, and complement C3. Therefore, the examined RTT siblings pairs proved to be an important benchmark model to test the molecular basis of phenotypical expression variability and to identify potential therapeutic targets of the disease.

  13. Developmental abnormalities of cortical interneurons precede symptoms onset in a mouse model of Rett syndrome.

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    Tomassy, Giulio Srubek; Morello, Noemi; Calcagno, Eleonora; Giustetto, Maurizio

    2014-10-01

    Rett syndrome (RTT, MIM312750), a neurodevelopmental disorder predominantly occurring in females, is caused in the majority of cases by sporadic mutations in the gene encoding the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). In mice, impaired MeCP2 function results in severe motor, cognitive, and emotional defects. The lack of Mecp2 in γ-aminobutyric acid-(GABA) releasing forebrain interneurons (INs) recapitulate many RTT features, however, the role of this gene in the development of the cortical inhibitory system is still unknown. Here, we found that MeCP2 expression varies among the three major classes of cortical INs and its nuclear localization differs between neuronal types. The density of calretinin(+) and parvalbumin(+) INs increases in Mecp2 knockout mice (Mecp2(-/y) ) already at early post-natal developmental stages. In contrast, the density of somatostatin(+) INs is not affected. We also found that the development of multipolar-calretinin(+) INs is selectively affected by the absence of Mecp2. Additionally, we show that in Mecp2 heterozygous female mice, a model closely mimicking human RTT condition, IN abnormalities are similar to those observed in Mecp2(-/y) mice. Together, our study indicates that loss of function of Mecp2 strongly interferes with the correct establishment of the neocortical inhibitory system producing effects that are specific to different IN subtypes.

  14. A national survey of Rett syndrome: age, clinical characteristics, current abilities, and health.

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    Cianfaglione, Rina; Clarke, Angus; Kerr, Mike; Hastings, Richard P; Oliver, Chris; Felce, David

    2015-07-01

    As part of a wider study to investigate the behavioral phenotype of a national sample of girls and women with Rett syndrome (RTT) in comparison to a well-chosen contrast group and its relationship to parental well-being, the development, clinical severity, current abilities and health of 91 participants were analyzed in relation to diagnostic, clinical and genetic mutation categories. Early truncating mutations or large deletions were associated with greater severity. Early regression was also associated with greater severity. All three were associated with lower current abilities. Epilepsy and weight, gastrointestinal and bowel problems were common co-morbidities. Participants with classic RTT had greater health problems than those with atypical RTT. A substantial minority of respondents reported fairly frequent signs of possible pain experienced by their relative with RTT. Overall, the study provides new data on the current abilities and general health of people with RTT and adds to the evidence that the severity of the condition and variation of subsequent disability, albeit generally within the profound range, may be related to gene mutation. The presence of certain co-morbidities represents a substantial ongoing need for better health. The experience of pain requires further investigation.

  15. Unconventional transcriptional response to environmental enrichment in a mouse model of Rett syndrome.

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    Bredford Kerr

    Full Text Available BACKGROUND: Rett syndrome (RTT is an X-linked postnatal neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2 and one of the leading causes of mental retardation in females. RTT is characterized by psychomotor retardation, purposeless hand movements, autistic-like behavior and abnormal gait. We studied the effects of environmental enrichment (EE on the phenotypic manifestations of a RTT mouse model that lacks MeCP2 (Mecp2(-/y. PRINCIPAL FINDINGS: We found that EE delayed and attenuated some neurological alterations presented by Mecp2(-/y mice and prevented the development of motor discoordination and anxiety-related abnormalities. To define the molecular correlate of this beneficial effect of EE, we analyzed the expression of several synaptic marker genes whose expression is increased by EE in several mouse models. CONCLUSIONS/SIGNIFICANCE: We found that EE induced downregulation of several synaptic markers, suggesting that the partial prevention of RTT-associated phenotypes is achieved through a non-conventional transcriptional program.

  16. Family functioning mediates adaptation in caregivers of individuals with Rett syndrome.

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    Lamb, Amanda E; Biesecker, Barbara B; Umstead, Kendall L; Muratori, Michelle; Biesecker, Leslie G; Erby, Lori H

    2016-11-01

    The objective of this study was to investigate factors related to family functioning and adaptation in caregivers of individuals with Rett syndrome (RS). A cross-sectional quantitative survey explored the relationships between demographics, parental self-efficacy, coping methods, family functioning and adaptation. A forward-backward, step-wise model selection procedure was used to evaluate variables associated with both family functioning and adaptation. Analyses also explored family functioning as a mediator of the relationship between other variables and adaptation. Bivariate analyses (N=400) revealed that greater parental self-efficacy, a greater proportion of problem-focused coping, and a lesser proportion of emotion-focused coping were associated with more effective family functioning. In addition, these key variables were significantly associated with greater adaptation, as was family functioning, while controlling for confounders. Finally, regression analyses suggest family functioning as a mediator of the relationships between three variables (parental self-efficacy, problem-focused coping, and emotion-focused coping) with adaptation. This study demonstrates the potentially predictive roles of expectations and coping methods and the mediator role of family functioning in adaptation among caregivers of individuals with RS, a chronic developmental disorder. A potential target for intervention is strengthening of caregiver competence in the parenting role to enhance caregiver adaptation. Published by Elsevier Ireland Ltd.

  17. Reduced synaptic activity in neuronal networks derived from embryonic stem cells of murine Rett syndrome model.

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    Barth, Lydia; Sütterlin, Rosmarie; Nenniger, Markus; Vogt, Kaspar E

    2014-01-01

    Neurodevelopmental diseases such as the Rett syndrome (RTT) have received renewed attention, since the mechanisms involved may underlie a broad range of neuropsychiatric disorders such as schizophrenia and autism. In vertebrates early stages in the functional development of neurons and neuronal networks are difficult to study. Embryonic stem cell-derived neurons provide an easily accessible tool to investigate neuronal differentiation and early network formation. We used in vitro cultures of neurons derived from murine embryonic stem cells missing the methyl-CpG-binding protein 2 (MECP2) gene (MeCP2-/y) and from wild type cells of the corresponding background. Cultures were assessed using whole-cell patch-clamp electrophysiology and immunofluorescence. We studied the functional maturation of developing neurons and the activity of the synaptic connections they formed. Neurons exhibited minor differences in the developmental patterns for their intrinsic parameters, such as resting membrane potential and excitability; with the MeCP2-/y cells showing a slightly accelerated development, with shorter action potential half-widths at early stages. There was no difference in the early phase of synapse development, but as the cultures matured, significant deficits became apparent, particularly for inhibitory synaptic activity. MeCP2-/y embryonic stem cell-derived neuronal cultures show clear developmental deficits that match phenotypes observed in slice preparations and thus provide a compelling tool to further investigate the mechanisms behind RTT pathophysiology.

  18. Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome.

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    Veeraragavan, Surabi; Wan, Ying-Wooi; Connolly, Daniel R; Hamilton, Shannon M; Ward, Christopher S; Soriano, Sirena; Pitcher, Meagan R; McGraw, Christopher M; Huang, Sharon G; Green, Jennie R; Yuva, Lisa A; Liang, Agnes J; Neul, Jeffrey L; Yasui, Dag H; LaSalle, Janine M; Liu, Zhandong; Paylor, Richard; Samaco, Rodney C

    2016-08-01

    Mouse models of the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) have advanced our understanding of Rett syndrome (RTT). RTT is a 'prototypical' neurodevelopmental disorder with many clinical features overlapping with other intellectual and developmental disabilities (IDD). Therapeutic interventions for RTT may therefore have broader applications. However, the reliance on the laboratory mouse to identify viable therapies for the human condition may present challenges in translating findings from the bench to the clinic. In addition, the need to identify outcome measures in well-chosen animal models is critical for preclinical trials. Here, we report that a novel Mecp2 rat model displays high face validity for modelling psychomotor regression of a learned skill, a deficit that has not been shown in Mecp2 mice. Juvenile play, a behavioural feature that is uniquely present in rats and not mice, is also impaired in female Mecp2 rats. Finally, we demonstrate that evaluating the molecular consequences of the loss of MeCP2 in both mouse and rat may result in higher predictive validity with respect to transcriptional changes in the human RTT brain. These data underscore the similarities and differences caused by the loss of MeCP2 among divergent rodent species which may have important implications for the treatment of individuals with disease-causing MECP2 mutations. Taken together, these findings demonstrate that the Mecp2 rat model is a complementary tool with unique features for the study of RTT and highlight the potential benefit of cross-species analyses in identifying potential disease-relevant preclinical outcome measures. © The Author 2016. Published by Oxford University Press.

  19. Caracterização das habilidades funcionais na síndrome de Rett Characterization of functional abilities in Rett syndrome

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    Carlos Bandeira de Mello Monteiro

    2009-12-01

    Full Text Available O objetivo deste estudo foi identificar as áreas de maior comprometimento nas habilidades funcionais na síndrome de Rett (SR. Foram avaliadas 64 pacientes que preenchiam os critérios para a forma clássica da doença, com idade entre 2 e 26 anos. Foi aplicado o Inventário de avaliação pediátrica de incapacidade (PEDI que contém 197 itens nas áreas de autocuidado, mobilidade e função social. Dentre as 73 atividades da área de autocuidado, 52 (71,2% não foram realizadas por qualquer paciente; na mobilidade, dentre as 59 atividades propostas, 8 (13,5%; e na área de função social, dentre as 65 atividades, 50 (76,9% não foram realizadas por paciente alguma. O desempenho médio ajustado em escala de 0 a 100 para a área de autocuidado foi de 8,9/100, variando de 0 a 19; na área de mobilidade, foi de 30,2/100, variando de 1 a 44; e na de função social, 5,2/100, com variação de 0 a 14. Foi possível verificar fortes correlações entre a área de autocuidado e as de mobilidade e função social; no entanto, entre as áreas de mobilidade e função social não foi detectada correlação significativa. Infelizmente, devido à gravidade da síndrome, o menor comprometimento da mobilidade, comparado ao das áreas de autocuidado e função social, não traz vantagens adaptativas ou maior independência às pacientes com SR.The purpose of this study was to determine the areas of greater impairment in functional abilities of patients with Rett syndrome. Sixty-four patients aged 2 to 26 years old, who filled out criteria for the classic form of the disease, were assessed by the Pediatric Evaluation of Disability Inventory (PEDI of which 197 items are grouped in the areas of self-care, mobility, and social function. From the 73 activities in self-care area, 52 (71.2% were not accomplished by any patient; in mobility area, among the 59 proposed activities, 8 (13.5%; and in social function area, from 65 activities, 50 (76.9% could not be

  20. Medical care of adolescents and women with Rett syndrome: an Italian study.

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    Vignoli, Aglaia; La Briola, Francesca; Peron, Angela; Turner, Katherine; Savini, Miriam; Cogliati, Francesca; Russo, Silvia; Canevini, Maria Paola

    2012-01-01

    Rett syndrome (RTT) is a rare neurodevelopmental disorder, linked to MECP2 gene mutations in the majority of cases, which results in severe disability and is associated with several comorbidities. The clinical condition of RTT patients tends to stabilize over time, and prolonged survival has recently been demonstrated. However, limited information is available on the long-term course of older patients with RTT, especially among those in Southern Europe. The aim of our study is to evaluate the main clinical features and state of health of adult Italian patients with RTT and to present their evolution over time, identifying major clinical issues present at different ages. A total of 130 families of patients with RTT aged ≥14 years were asked to complete a questionnaire, 84 of which were returned (65%). Among the clinical characteristics of RTT, stereotypies and poor hand function and feeding ability remained stable over time, while nonverbal communication tended to improve. With regard to the main pathologies, sleep, behavioral, and autonomic disorders persisted into adulthood, while epilepsy improved and musculoskeletal problems worsened. In our sample, older patients with R294X and R133C mutations and with C-terminal deletions showed lower levels of clinical severity. The development of guidelines for the clinical management of patients with RTT will assist health care providers in dealing with the complex RTT phenotype. More extensive data about the long-term course of the condition could help in the design of programs for secondary prevention of disabilities for younger females affected by the syndrome.

  1. Recent insights into genotype-phenotype relationships in patients with Rett syndrome using a fine grain scale.

    Science.gov (United States)

    Fabio, Rosa Angela; Colombo, Barbara; Russo, Silvia; Cogliati, Francesca; Masciadri, Maura; Foglia, Silvia; Antonietti, Alessandro; Tavian, Daniela

    2014-11-01

    Mutations in MECP2 gene cause Rett syndrome (RTT), a neurodevelopmental disorder affecting around 1 in 10,000 female births. The clinical picture of RTT appears quite heterogeneous for each single feature. Mutations in MECP2 gene have been associated with the onset of RTT. The most known gene function consists of transcriptional repression of specific target genes, mainly by the binding of its methyl binding domain (MBD) to methylated CpG nucleotides and recruiting co-repressors and histone deacetylase binding to DNA by its transcription repressor domain (TRD). This study aimed at evaluating a cohort of 114 Rett syndrome (RTT) patients with a detailed scale measuring the different kinds of impairments produced by the syndrome. The sample included relatively large subsets of the most frequent mutations, so that genotype-phenotype correlations could be tested. Results revealed that frequent missense mutations showed a specific profile in different areas of impairment. The R306C mutation, considered as producing mild impairment, was associated to a moderate phenotype in which behavioural characteristics were mainly affected. A notable difference emerged by comparing mutations truncating the protein before and after the nuclear localization signal; such a difference concerned prevalently the motor-functional and autonomy skills of the patients, affecting the management of everyday activities.

  2. Examination of X chromosome markers in Rett syndrome: Exclusion mapping with a novel variation on multilocus linkage analysis

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    Ellison, K.A.; Fill, C.P. (Baylor College of Medicine, Houston, TX (United States)); Terwililger, J.; Percy, A.K.; Zobhbi, H. (Columbia University, NY (United States)); DeGennaro, L.J.; Ott, J. (University of Massachusetts Medical School, Worcester (United States)); Anvret, M.; Martin-Gallardo, A. (National Institutes of Health, Bethesda, MD (United States))

    1992-02-01

    Rett syndrome is a neurologic disorder characterized by early normal development followed by regression, acquired deceleration of head growth, autism, ataxia, and sterotypic hand movements. The exclusive occurrence of the syndrome in females and the occurrence of a few familial cases with inheritance through maternal lines suggest that this disorder is most likely secondary to a mutation on the X chromosome. To address this hypothesis and to identify candidate regions for the Rett syndrome gene locus, genotypic analysis was performed in two families with maternally related affected half-sisters by using 63 DNA markers from the X chromosome. Nineteen of the loci studied were chosen for multipoint linkage analysis because they have been previously genetically mapped using a large number of meioses from reference families. Using the exclusion criterion of a lod score less than [minus]2, the authors were able to exclude the region between the Duchenne muscular dystrophy locus and the DXS456 locus. This region extends from Xp21.2 to Xq21-q23. The use of the multipoint linkage analysis approach outlined in this study should allow the exclusion of additional regions of the X chromosome as new markers are analyzed.

  3. Pain experience and expression in Rett syndrome: Subjective and objective measurement approaches

    Science.gov (United States)

    Barney, Chantel C.; Feyma, Timothy; Beisang, Arthur; Symons, Frank J.

    2015-01-01

    Rett syndrome (RTT) is associated with myriad debilitating health issues and significant motor and communicative impairments. Because of the former there is concern about the possibility of recurrent and chronic pain but because of the latter it remains difficult to determine what pain ‘looks like’ in RTT. This study investigated pain experience and expression using multiple complementary subjective and objective approaches among a clinical RTT sample. Following informed consent, 18 participants (all female) with RTT (mean age= 12.8 years, SD= 6.32) were characterized in terms of pain experience and interference, typical pain expression, and elicited pain behavior during a passive range of motion-like examination procedure. Parents completed the Dalhousie Pain Interview (DPI; pain type, frequency, duration, intensity), the Brief Pain Inventory (BPI; pain interference), and the Non-Communicating Children’s Pain Checklist – Revised (NCCPC-R; typical pain expression). A Pain Examination Procedure (PEP) was conducted and scored using the Pain and Discomfort Scale (PADS). The majority of the sample (89%) were reported to experience pain in the previous week which presented as gastrointestinal (n=8), musculoskeletal (n=5), and seizure related pain (n=5) that was intense (scored 0–10; M= 5.67, SD= 3.09) and long in duration (M= 25.22 hours, SD= 53.52). Numerous pain-expressive behaviors were inventoried (e.g., vocal, facial, mood/interaction changes) when parents reported their child’s typical pain behaviors and based on independent direct observation during a reliably coded pain exam. This study provides subjective and objective evidence that individuals with RTT experience recurring and chronic pain for which pain expression appears intact. PMID:26425056

  4. Osteoblast function and bone histomorphometry in a murine model of Rett syndrome.

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    Blue, Mary E; Boskey, Adele L; Doty, Stephen B; Fedarko, Neal S; Hossain, Mir Ahamed; Shapiro, Jay R

    2015-07-01

    Rett syndrome (RTT) is an X-linked neurodevelopmental disorder due to mutations affecting the neural transcription factor MeCP2. Approximately 50% of affected females have decreased bone mass. We studied osteoblast function using a murine model of RTT. Female heterozygote (HET) and male Mecp2-null mice were compared to wild type (WT) mice. Micro-CT of tibia from 5 week-old Mecp2-null mice showed significant alterations in trabecular bone including reductions in bone volume fraction (-29%), number (-19%), thickness (-9%) and connectivity density (-32%), and increases in trabecular separation (+28%) compared to WT. We also found significant reductions in cortical bone thickness (-18%) and in polar moment of inertia (-45%). In contrast, cortical and trabecular bone from 8 week-old WT and HET female mice were not significantly different. However, mineral apposition rate, mineralizing surface and bone formation rate/bone surface were each decreased in HET and Mecp2-null mice compared to WT mice. Histomorphometric analysis of femurs showed decreased numbers of osteoblasts but similar numbers of osteoclasts compared to WT, altered osteoblast morphology and decreased tissue synthesis of alkaline phosphatase in Mecp2-null and HET mice. Osteoblasts cultured from Mecp2-null mice, which unlike WT osteoblasts did not express MeCP2, had increased growth rates, but reductions in mRNA expression of type I collagen, Runx2 and Osterix compared to WT osteoblasts. These results indicate that MeCP2 deficiency leads to altered bone growth. Osteoblast dysfunction was more marked in Mecp2-null male than in HET female mice, suggesting that expression of MeCP2 plays a critical role in bone development.

  5. [Anesthetic management of a patient with Rett syndrome associated with trismus and apnea attacks].

    Science.gov (United States)

    Kawasaki, Eri; Mishima, Yasunori; Ito, Takahiko; Ito, Asuka; Takaseya, Hikari; Kameyama, Naomitsu; Fukugasako, Hisato; Ushijima, Kazuo

    2012-01-01

    Rett syndrome (RTT) is a congenital neurological disorder associated with mutations in the gene encoding MECP2 on the X chromosome. An 18-year-old woman (150 cm in height and 29 kg in weight) had been diagnosed with RTT and showed myotonic trismus, frequent attacks of apnea, mental retardation, spastic paraplegia, scoliosis, and microcephalus with micrognathia. She was scheduled to undergo laparoscopic fundoplication and gastrostomy under general anesthesia. Nasal bronchofiberscopic intubation (BFI) was planned because difficult airway due to trismus and micrognathia was expected. Referring to the bispectral index (BIS), anesthesia was induced with intermittent intravenous thiopental (total 125 mg), resulting in successful opening of the mouth by 1.5 of a finger width and establishment of manual ventilation. Following intravenous administration of rocuronium (20 mg), oral BFI was easily accomplished despite Cormack grade III. Anesthesia was satisfactorily maintained with inhalation of sevoflurane (1.0-1.5%) and continuous infusion of remifentanil (0.1-0.2 microg x kg(-1) x min(-1)) with the BIS value ranging from 30 to 50. She recovered smoothly from anesthesia using sugammadex (50 mg). However, she immediately demonstrated trismus and an attack of apnea with shivering, which were successfully resolved by warming the body and intravenous fentanyl (50 microg bolus and subsequent infusion at a rate of 10 microg x hr(-1)). The postoperative course was uneventful. Characteristically, RTT shows an extremely wide range of neurological symptoms. Therefore, it is of great importance to respond to each of those symptoms during the perioperative management of patients with RTT.

  6. X-chromosome inactivation in Rett Syndrome human induced pluripotent stem cells

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    Aaron YL Cheung

    2012-03-01

    Full Text Available Rett Syndrome (RTT is a neurodevelopmental disorder that affects girls due primarily to heterozygous mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MECP2. Random X-chromosome inactivation (XCI results in cellular mosaicism in which some cells express wild-type MECP2 while other cells express mutant MECP2. The generation of patient-specific human induced Pluripotent Stem cells (hiPSCs facilitates the production of RTT-hiPSC-derived neurons in vitro to investigate disease mechanisms and identify novel drug treatments. The generation of RTT-hiPSCs has been reported by many laboratories, however, the XCI status of RTT-hiPSCs has been inconsistent. Some report RTT-hiPSCs retain the inactive X-chromosome (post-XCI of the founder somatic cell allowing isogenic RTT-hiPSCs that express only the wild-type or mutant MECP2 allele to be isolated from the same patient. Post-XCI RTT-hiPSCs-derived neurons retain this allele-specific expression pattern of wild-type or mutant MECP2. Conversely, others report RTT-hiPSCs in which the inactive X-chromosome of the founder somatic cell reactivates (pre-XCI upon reprogramming into RTT-hiPSCs. Pre-XCI RTT-hiPSC-derived neurons exhibit random XCI resulting in cellular mosaicism with respect to wild-type and mutant MECP2 expression. Here we review and attempt to interpret the inconsistencies in XCI status of RTT-hiPSCs generated to date by comparison to other pluripotent systems in vitro and in vivo and the methods used to analyze XCI. Finally, we discuss the relative strengths and weaknesses of post- and pre-XCI hiPSCs in the context of RTT, and other X-linked and autosomal disorders for translational medicine.

  7. Biomechanical properties of bone in a mouse model of Rett syndrome.

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    Kamal, Bushra; Russell, David; Payne, Anthony; Constante, Diogo; Tanner, K Elizabeth; Isaksson, Hanna; Mathavan, Neashan; Cobb, Stuart R

    2015-02-01

    Rett syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (MECP2) gene are the primary cause of the disorder. Despite the dominant neurological phenotypes, MECP2 is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as scoliosis, reduced bone mineral density and skeletal fractures are also common and important clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any defects, we have conducted a series of histological, imaging and biomechanical tests of bone in a functional knockout mouse model of RTT. Both hemizygous Mecp2(stop/y) male mice in which Mecp2 is silenced in all cells and female Mecp2(stop/+) mice in which Mecp2 is silenced in ~50% of cells as a consequence of random X-chromosome inactivation, revealed significant reductions in cortical bone stiffness, microhardness and tensile modulus. Microstructural analysis also revealed alterations in both cortical and cancellous femoral bone between wild-type and MeCP2-deficient mice. Furthermore, unsilencing of Mecp2 in adult mice cre-mediated stop cassette deletion resulted in a restoration of biomechanical properties (stiffness, microhardness) towards wild-type levels. These results show that MeCP2-deficiency results in overt, but potentially reversible, alterations in the biomechanical integrity of bone and highlights the importance of targeting skeletal phenotypes in considering the development of pharmacological and gene-based therapies.

  8. Synaptic maturation at cortical projections to the lateral amygdala in a mouse model of Rett syndrome.

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    Frédéric Gambino

    Full Text Available Rett syndrome (RTT is a neuro-developmental disorder caused by loss of function of Mecp2--methyl-CpG-binding protein 2--an epigenetic factor controlling DNA transcription. In mice, removal of Mecp2 in the forebrain recapitulates most of behavioral deficits found in global Mecp2 deficient mice, including amygdala-related hyper-anxiety and lack of social interaction, pointing a role of Mecp2 in emotional learning. Yet very little is known about the establishment and maintenance of synaptic function in the adult amygdala and the role of Mecp2 in these processes. Here, we performed a longitudinal examination of synaptic properties at excitatory projections to principal cells of the lateral nucleus of the amygdala (LA in Mecp2 mutant mice and their wild-type littermates. We first show that during animal life, Cortico-LA projections switch from a tonic to a phasic mode, whereas Thalamo-LA synapses are phasic at all ages. In parallel, we observed a specific elimination of Cortico-LA synapses and a decrease in their ability of generating presynaptic long term potentiation. In absence of Mecp2, both synaptic maturation and synaptic elimination were exaggerated albeit still specific to cortical projections. Surprisingly, associative LTP was unaffected at Mecp2 deficient synapses suggesting that synaptic maintenance rather than activity-dependent synaptic learning may be causal in RTT physiopathology. Finally, because the timing of synaptic evolution was preserved, we propose that some of the developmental effects of Mecp2 may be exerted within an endogenous program and restricted to synapses which maturate during animal life.

  9. Acetyl-L-carnitine improves behavior and dendritic morphology in a mouse model of Rett syndrome.

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    Laura R Schaevitz

    Full Text Available Rett syndrome (RTT is a devastating neurodevelopmental disorder affecting 1 in 10,000 girls. Approximately 90% of cases are caused by spontaneous mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2. Girls with RTT suffer from severe motor, respiratory, cognitive and social abnormalities attributed to early deficits in synaptic connectivity which manifest in the adult as a myriad of physiological and anatomical abnormalities including, but not limited to, dimished dendritic complexity. Supplementation with acetyl-L-carnitine (ALC, an acetyl group donor, ameliorates motor and cognitive deficits in other disease models through a variety of mechanisms including altering patterns of histone acetylation resulting in changes in gene expression, and stimulating biosynthetic pathways such as acetylcholine. We hypothesized ALC treatment during critical periods in cortical development would promote normal synaptic maturation, and continuing treatment would improve behavioral deficits in the Mecp2(1lox mouse model of RTT. In this study, wildtype and Mecp2(1lox mutant mice received daily injections of ALC from birth until death (postnatal day 47. General health, motor, respiratory, and cognitive functions were assessed at several time points during symptom progression. ALC improved weight gain, grip strength, activity levels, prevented metabolic abnormalities and modestly improved cognitive function in Mecp2 null mice early in the course of treatment, but did not significantly improve motor or cognitive functions assessed later in life. ALC treatment from birth was associated with an almost complete rescue of hippocampal dendritic morphology abnormalities with no discernable side effects in the mutant mice. Therefore, ALC appears to be a promising therapeutic approach to treating early RTT symptoms and may be useful in combination with other therapies.

  10. Molecular Screening of "MECP2" Gene in a Cohort of Lebanese Patients Suspected with Rett Syndrome: Report on a Mild Case with a Novel Indel Mutation

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    Corbani, S.; Chouery, E.; Fayyad, J.; Fawaz, A.; El Tourjuman, O.; Badens, C.; Lacoste, C.; Delague, V.; Megarbane, A.

    2012-01-01

    Background: Rett syndrome (RTT), an X-linked, dominant, neurodevelopment disorder represents 10% of female subjects with profound intellectual disability. Mutations in the "MECP2" gene are responsible for up to 95% of the classical RTT cases, and nearly 500 different mutations distributed throughout the gene have been reported. Methods: We report…

  11. The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome

    DEFF Research Database (Denmark)

    Schönewolf-Greulich, B; Tejada, M-I; Stephens, K;

    2016-01-01

    Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pai...

  12. Molecular Screening of "MECP2" Gene in a Cohort of Lebanese Patients Suspected with Rett Syndrome: Report on a Mild Case with a Novel Indel Mutation

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    Corbani, S.; Chouery, E.; Fayyad, J.; Fawaz, A.; El Tourjuman, O.; Badens, C.; Lacoste, C.; Delague, V.; Megarbane, A.

    2012-01-01

    Background: Rett syndrome (RTT), an X-linked, dominant, neurodevelopment disorder represents 10% of female subjects with profound intellectual disability. Mutations in the "MECP2" gene are responsible for up to 95% of the classical RTT cases, and nearly 500 different mutations distributed throughout the gene have been reported. Methods:…

  13. A comparative study of dual-X-ray absorptiometry and quantitative ultrasonography for the evaluating bone status in subjects with Rett syndrome.

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    Caffarelli, C; Hayek, J; Tomai Pitinca, M D; Nuti, R; Gonnelli, S

    2014-09-01

    Rett syndrome, an X-linked neurodevelopmental disorder primarily affecting girls, is frequently characterized by a reduced bone mineral density (BMD) with an increased risk of fragility fractures. The aim of the study was to assess bone status by DXA technique and by quantitative ultrasound (QUS) in subjects with Rett syndrome and to evaluate which DXA or QUS parameters better correlate with clinical features. In 156 Rett subjects (mean age 13.6 ± 8.2 years) and in 62 controls, we measured BMD at femoral neck (BMD-FN) and at total femur (BMD-TF). Apparent volumetric bone mineral density (vBMAD) was also calculated. In all subjects, QUS parameters at phalanges by Bone Profiler-IGEA (amplitude-dependent speed of sound: AD-SoS and bone transmission time: BTT) were evaluated. We found that both DXA parameters and QUS parameters were significantly lower in Rett subjects than in controls. All clinical characteristics were positively correlated to BMD-FN, BMD-TF, AD-SoS, and BTT (p Rett subjects BMD-FN was predicted primarily by weight and movement capacity, whereas vBMAD-FN was predicted by weight, height, and calcium intake. Moreover, AD-SoS was predicted by weight, height, and age, while BTT was predicted only by height. In conclusion, in our study the performance of QUS at phalanges was similar to those of BMD at femur, therefore, both areal BMD at femur and QUS at phalanges (AD-SoS and BTT) may be equally useful in the evaluation of skeletal status in Rett patients.

  14. [Subchromosomal microdeletion identified by molecular karyotyping using DNA microarrays (array CGH) in Rett syndrome girls negative for MECP2 gene mutations].

    Science.gov (United States)

    Vorsanova, S G; Iurov, I Iu; Voinova, V Iu; Kurinnaia, O S; Zelenova, M A; Demidova, I A; Ulas, E V; Iurov, Iu B

    2013-01-01

    Molecular karyotyping using DNA microarrays (array CGH) was applied for identification of subchromosomal microdeletions in a cohort of 12 girls with clinical features of RETT syndrome, but negative for MECP2 gene mutations. Recurrent microdeletions of MECP2 gene in chromosome X (locus Xq28) were identified in 5 girls of 12 studied. Probably RTT girls with subchromosomic microdeletions in Xq28 could represent a special subtype of the disease, which appears as clinically milder than the classic form of disease. In one case, an atypical form of RTT was associated with genomic abnormalities affecting CDKL5 gene and region critical for microdeletion Prader-Willi and Angelman syndromes (15q11.2). In addition, data are presented for the first time that genetic variation in regions 3p13, 3q27.1, and 1q21.1-1q21.2 could associate with RTT-like clinical manifestations. Without application of molecular karyotyping technology and bioinformatic method of assessing the pathogenic significance of genomic rearrangements these RTT-like girls negative for MECP2 gene mutations were considered as cases of idiopathic mental retardation associated with autism. It should be noted that absence of intragenic mutations in MECP2 gene is not sufficient criteria to reject the clinical diagnosis of RTT. To avoid errors in the genetic diagnosis of this genetically heterogeneous brain disease molecular cytogenetic studies using high resolution oligonucleotide array CGH (molecular karyotyping) are needed.

  15. Italian Rett database and biobank.

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    Sampieri, Katia; Meloni, Ilaria; Scala, Elisa; Ariani, Francesca; Caselli, Rossella; Pescucci, Chiara; Longo, Ilaria; Artuso, Rosangela; Bruttini, Mirella; Mencarelli, Maria Antonietta; Speciale, Caterina; Causarano, Vincenza; Hayek, Giuseppe; Zappella, Michele; Renieri, Alessandra; Mari, Francesca

    2007-04-01

    Rett syndrome is the second most common cause of severe mental retardation in females, with an incidence of approximately 1 out of 10,000 live female births. In addition to the classic form, a number of Rett variants have been described. MECP2 gene mutations are responsible for about 90% of classic cases and for a lower percentage of variant cases. Recently, CDKL5 mutations have been identified in the early onset seizures variant and other atypical Rett patients. While the high percentage of MECP2 mutations in classic patients supports the hypothesis of a single disease gene, the low frequency of mutated variant cases suggests genetic heterogeneity. Since 1998, we have performed clinical evaluation and molecular analysis of a large number of Italian Rett patients. The Italian Rett Syndrome (RTT) database has been developed to share data and samples of our RTT collection with the scientific community (http://www.biobank.unisi.it). This is the first RTT database that has been connected with a biobank. It allows the user to immediately visualize the list of available RTT samples and, using the "Search by" tool, to rapidly select those with specific clinical and molecular features. By contacting bank curators, users can request the samples of interest for their studies. This database encourages collaboration projects with clinicians and researchers from around the world and provides important resources that will help to better define the pathogenic mechanisms underlying Rett syndrome. Copyright 2006 Wiley-Liss, Inc.

  16. X inactivation in Rett syndrome: A preliminary study showing partial preferential inactivation of paternal X with the M27{beta} probe

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    Camus, P.; Abbadi, N.; Gilgenkrantz, S. [Laboratoire de Genetique, Vandoeuvre les Nancy (France)

    1994-04-15

    Rett syndrome (RS) is a severe progressive neurological disorder occurring exclusively in females. Most cases are sporadic. The few familial cases (less than 1%) cannot be explained by a simple mode of inheritance. Several hypotheses have been proposed: X-linked male lethal mutation, maternal uniparental disomy, fresh mutation on the X chromosome, involvement of mitochondrial DNA and differential inactivation with metabolic interference of X-borne alleles. The authors have examined the pattern of X inactivation in 10 affected girls who were selected according to the clinical criteria previously described and accepted by the French Rett Scientific Committee. The X inactivation pattern was studied by analysis of methylation at the hypervariable locus DXS255 with the M27{beta} probe. The results show a more-or-less skewed inactivation of paternal X in 8 Rett females, and 2 cases of symmetrical inactivation. In control girls, inactivation was symmetrical cases and the maternal X has been preferentially inactivated in the other 2 cases. In no case was a total skewed inactivation observed. Though there was clear evidence for a preferential paternal X inactivation that was statistically significant further studies are necessary to establish a relationship between X inactivation pattern and Rett syndrome.

  17. Three different profiles: early socio-communicative capacities in typical Rett syndrome, the preserved speech variant and normal development.

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    Marschik, Peter B; Bartl-Pokorny, Katrin D; Tager-Flusberg, Helen; Kaufmann, Walter E; Pokorny, Florian; Grossmann, Tobias; Windpassinger, Christian; Petek, Erwin; Einspieler, Christa

    2014-02-01

    This is the first study aiming to compare pre-diagnostic socio-communicative development of a female with typical Rett syndrome (RTT), a female with the preserved speech variant of RTT (PSV) and a control toddler. We analysed 1275 min of family videos at the participants' age between 9 and 24 months and used the Inventory of Potential Communicative Acts (IPCA) to delineate their repertoires of communicative forms and functions. The results revealed different profiles for the three different conditions. The repertoire of communicative gestures and (pre)linguistic vocalizations was most comprehensive in the control toddler, followed by the female with PSV and the female with RTT. These findings contribute to the growing knowledge about early developmental abnormalities in RTT. In order to define distinctive profiles for typical and atypical RTT and evaluate their specificity, a larger body of evidence is needed.

  18. The eye-tracking of social stimuli in patients with Rett syndrome and autism spectrum disorders: a pilot study

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    José Salomão Schwartzman

    2015-05-01

    Full Text Available Objective To compare visual fixation at social stimuli in Rett syndrome (RT and autism spectrum disorders (ASD patients. Method Visual fixation at social stimuli was analyzed in 14 RS female patients (age range 4-30 years, 11 ASD male patients (age range 4-20 years, and 17 children with typical development (TD. Patients were exposed to three different pictures (two of human faces and one with social and non-social stimuli presented for 8 seconds each on the screen of a computer attached to an eye-tracker equipment. Results Percentage of visual fixation at social stimuli was significantly higher in the RS group compared to ASD and even to TD groups. Conclusion Visual fixation at social stimuli seems to be one more endophenotype making RS to be very different from ASD.

  19. Developmental profile of speech-language and communicative functions in an individual with the preserved speech variant of Rett syndrome.

    Science.gov (United States)

    Marschik, Peter B; Vollmann, Ralf; Bartl-Pokorny, Katrin D; Green, Vanessa A; van der Meer, Larah; Wolin, Thomas; Einspieler, Christa

    2014-08-01

    We assessed various aspects of speech-language and communicative functions of an individual with the preserved speech variant of Rett syndrome (RTT) to describe her developmental profile over a period of 11 years. For this study, we incorporated the following data resources and methods to assess speech-language and communicative functions during pre-, peri- and post-regressional development: retrospective video analyses, medical history data, parental checklists and diaries, standardized tests on vocabulary and grammar, spontaneous speech samples and picture stories to elicit narrative competences. Despite achieving speech-language milestones, atypical behaviours were present at all times. We observed a unique developmental speech-language trajectory (including the RTT typical regression) affecting all linguistic and socio-communicative sub-domains in the receptive as well as the expressive modality. Future research should take into consideration a potentially considerable discordance between formal and functional language use by interpreting communicative acts on a more cautionary note.

  20. How facial expressions in a Rett syndrome population are recognised and interpreted by those around them as conveying emotions

    DEFF Research Database (Denmark)

    Bergström-Isacsson, Märith; Lagerkvist, Bengt; Holck, Ulla

    2013-01-01

    Rett syndrome (RTT) is a neurodevelopmental disorder, including autonomic nervous system dysfunctions and severe communication impairment with an extremely limited ability to use verbal language. These individuals are therefore dependent on the capacity of caregivers to observe and interpret...... communicative signals, including emotional expressions. People in general, including therapists tend to focus on changes in facial expressions to interpret a person's emotional state or choices, but with this population it is difficult to know if the interpretations are correct. The aims of this study were...... developmental pattern, exposed to six different musical stimuli during non-invasive registration of autonomic brainstem functions. The results indicate that FACS makes it possible both to identify facial expressions and to differentiate between those that stem from emotions and those caused by abnormal...

  1. The eye-tracking of social stimuli in patients with Rett syndrome and autism spectrum disorders: a pilot study.

    Science.gov (United States)

    Schwartzman, José Salomão; Velloso, Renata de Lima; D'Antino, Maria Eloísa Famá; Santos, Silvana

    2015-05-01

    To compare visual fixation at social stimuli in Rett syndrome (RT) and autism spectrum disorders (ASD) patients. Visual fixation at social stimuli was analyzed in 14 RS female patients (age range 4-30 years), 11 ASD male patients (age range 4-20 years), and 17 children with typical development (TD). Patients were exposed to three different pictures (two of human faces and one with social and non-social stimuli) presented for 8 seconds each on the screen of a computer attached to an eye-tracker equipment. Percentage of visual fixation at social stimuli was significantly higher in the RS group compared to ASD and even to TD groups. Visual fixation at social stimuli seems to be one more endophenotype making RS to be very different from ASD.

  2. A selective histone deacetylase-6 inhibitor improves BDNF trafficking in hippocampal neurons from Mecp2 knockout mice: implications for Rett syndrome

    Science.gov (United States)

    Xu, Xin; Kozikowski, Alan P.; Pozzo-Miller, Lucas

    2014-01-01

    Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). One of the most prominent gene targets of MeCP2 is brain-derived neurotrophic factor (Bdnf), a potent modulator of activity-dependent synaptic development, function and plasticity. Dysfunctional BDNF signaling has been demonstrated in several pathophysiological mechanisms of RTT disease progression. To evaluate whether the dynamics of BDNF trafficking is affected by Mecp2 deletion, we analyzed movements of BDNF tagged with yellow fluorescent protein (YFP) in cultured hippocampal neurons by time-lapse fluorescence imaging. We found that both anterograde and retrograde vesicular trafficking of BDNF-YFP are significantly impaired in Mecp2 knockout hippocampal neurons. Selective inhibitors of histone deacetylase 6 (HDAC6) show neuroprotective effects in neurodegenerative diseases and stimulate microtubule-dependent vesicular trafficking of BDNF-containing dense core vesicles. Here, we show that the selective HDAC6 inhibitor Tubastatin-A increased the velocity of BDNF-YFP vesicles in Mecp2 knockout neurons in both directions by increasing α–tubulin acetylation. Tubastatin-A also restored activity-dependent BDNF release from Mecp2 knockout neurons to levels comparable to those shown by wildtype neurons. These findings demonstrate that a selective HDAC6 inhibitor is a potential pharmacological strategy to reverse cellular and synaptic impairments in RTT resulting from impaired BDNF signaling. PMID:24639629

  3. A selective histone deacetylase-6 inhibitor improves BDNF trafficking in hippocampal neurons from Mecp2 knockout mice:implications for Rett syndrome

    Directory of Open Access Journals (Sweden)

    Xin eXu

    2014-03-01

    Full Text Available Rett syndrome (RTT is a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2. One of the most prominent gene targets of MeCP2 is brain-derived neurotrophic factor (Bdnf, a potent modulator of activity-dependent synaptic development, function and plasticity. Dysfunctional BDNF signaling has been demonstrated in several pathophysiological mechanisms of RTT disease progression. To evaluate whether the dynamics of BDNF trafficking is affected by Mecp2 deletion, we analyzed movements of BDNF tagged with yellow fluorescent protein (YFP in cultured hippocampal neurons by time-lapse fluorescence imaging. We found that both anterograde and retrograde vesicular trafficking of BDNF-YFP are significantly impaired in Mecp2 knockout hippocampal neurons. Selective inhibitors of histone deacetylase 6 (HDAC6 show neuroprotective effects in neurodegenerative diseases and stimulate microtubule-dependent vesicular trafficking of BDNF-containing dense core vesicles. Here, we show that the selective HDAC6 inhibitor Tubastatin-A increased the velocity of BDNF-YFP vesicles in Mecp2 knockout neurons in both directions by increasing αtubulin acetylation. Tubastatin-A also restored activity-dependent BDNF release from Mecp2 knockout neurons to levels comparable to those shown by wildtype neurons. These findings demonstrate that a selective HDAC6 inhibitor is a potential pharmacological strategy to reverse cellular and synaptic impairments in RTT resulting from impaired BDNF signaling.

  4. Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome.

    Science.gov (United States)

    Ure, Kerstin; Lu, Hui; Wang, Wei; Ito-Ishida, Aya; Wu, Zhenyu; He, Ling-Jie; Sztainberg, Yehezkel; Chen, Wu; Tang, Jianrong; Zoghbi, Huda Y

    2016-06-21

    The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2(+/-) mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome.

  5. Isoprostanes and 4-Hydroxy-2-nonenal: Markers or Mediators of Disease? Focus on Rett Syndrome as a Model of Autism Spectrum Disorder

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    Cinzia Signorini

    2013-01-01

    Full Text Available Lipid peroxidation, a process known to induce oxidative damage to key cellular components, has been implicated in several diseases. Following three decades of explorations mainly on in vitro models reproducible in the laboratories, lipid peroxidation has become increasingly relevant for the interpretation of a wide range of pathophysiological mechanisms in the clinical setting. This cumulative effort has led to the identification of several lipid peroxidation end-products meeting the needs of the in vivo evaluation. Among these different molecules, isoprostanes and 4-hydroxy-2-nonenal protein adducts appear to be particularly interesting. This review shows how specific oxidation products, deriving from polyunsaturated fatty acids precursors, are strictly related to the clinical manifestations and the natural history of Rett syndrome, a genetically determined neurodevelopmental pathology, currently classified among the autism spectrum disorders. In our experience, Rett syndrome offers a unique setting for physicians, biologists, and chemists to explore the borders of the lipid mediators concept.

  6. Eating practices, nutritional status and constipation in patients with Rett syndrome Práticas alimentares, estado nutricional e constipação intestinal na síndrome de Rett

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    Flavia Schwartzman

    2008-12-01

    Full Text Available BACKGROUND: Disturbance in chewing, swallowing and digestive motility may predispose to feeding and nutritional abnormalities in patients with Rett syndrome. OBJECTIVE: To evaluate the dietary habits, nutritional status and the prevalence of constipation in patients with classical Rett syndrome. METHODS: Twenty seven female patients between the ages of 2.6 and 21.8 years were studied. The following parameters were evaluated: food register, weight, height and intestinal movement characteristics. Weight and height were compared with the National Center for Health Statistics standards. RESULTS: The inability to ingest solid foods was observed in 80.8% of the patients. A height-to-age deficit was observed in 13 (48.1% of the girls, being more intense in patients at stage IV. Weight-for-height deficit was found in 10 (37.0% patients, 15 (55.6% showed normal weight and 2 (7.4% were overweight for their height. The median ingestion of energy, according to weight-for-height, was equal to 106.6%. Insufficient iron ingestion was observed in 63.0% and insufficient calcium in 55.6% of the patients. Constipation was verified in 74.1% of the patients and did not show a relationship with the quantity of fiber in the diet. CONCLUSION: Various nutritional problems, as well as, intestinal constipation were observed in these patients with Rett syndrome, and they must be considered in the multidisciplinary therapeutic planning of these individuals.RACIONAL: Distúrbios na mastigação, deglutição e motilidade digestiva podem predispor pacientes com síndrome de Rett à ocorrência de anormalidades nutricionais. OBJETIVOS: Avaliar as práticas alimentares, o estado nutricional e a prevalência de constipação na síndrome de Rett clássica. MÉTODOS: Estudaram-se 27 pacientes do sexo feminino, com idade entre 2,6 e 21,8 anos. Avaliaram-se os seguintes parâmetros: registros alimentares, peso, estatura, características do hábito intestinal. Peso e estatura foram

  7. Retention of Mitochondria in Mature Human Red Blood Cells as the Result of Autophagy Impairment in Rett Syndrome.

    Science.gov (United States)

    Sbardella, Diego; Tundo, Grazia Raffaella; Campagnolo, Luisa; Valacchi, Giuseppe; Orlandi, Augusto; Curatolo, Paolo; Borsellino, Giovanna; D'Esposito, Maurizio; Ciaccio, Chiara; Cesare, Silvia Di; Pierro, Donato Di; Galasso, Cinzia; Santarone, Marta Elena; Hayek, Joussef; Coletta, Massimiliano; Marini, Stefano

    2017-09-26

    Rett Syndrome (RTT), which affects approximately 1:10.000 live births, is a X-linked pervasive neuro-developmental disorder which is caused, in the vast majority of cases, by a sporadic mutation in the Methyl-CpG-binding protein-2 (MeCP2) gene. This is a transcriptional activator/repressor with presumed pleiotropic activities. The broad tissue expression of MeCP2 suggests that it may be involved in several metabolic pathways, but the molecular mechanisms which provoke the onset and progression of the syndrome are largely unknown. In this paper, we report that primary fibroblasts that have been isolated from RTT patients display a defective formation of autophagosomes under conditions of nutrient starvation and that the mature Red Blood Cells of some RTT patients retain mitochondria. Moreover, we provide evidence regarding the accumulation of the p62/SQSTM1 protein and ubiquitin-aggregated structures in the cerebellum of Mecp2 knockout mouse model (Mecp2 (-/y) ) during transition from the non-symptomatic to the symptomatic stage of the disease. Hence, we propose that a defective autophagy could be involved in the RTT clinical phenotype, which introduces new molecular perspectives in the pathogenesis of the syndrome.

  8. Disruption of MeCP2 attenuates circadian rhythm in CRISPR/Cas9-based Rett syndrome model mouse.

    Science.gov (United States)

    Tsuchiya, Yoshiki; Minami, Yoichi; Umemura, Yasuhiro; Watanabe, Hitomi; Ono, Daisuke; Nakamura, Wataru; Takahashi, Tomoyuki; Honma, Sato; Kondoh, Gen; Matsuishi, Toyojiro; Yagita, Kazuhiro

    2015-12-01

    Methyl-CpG-binding protein 2 (Mecp2) is an X-linked gene encoding a methylated DNA-binding nuclear protein which regulates transcriptional activity. The mutation of MECP2 in humans is associated with Rett syndrome (RTT), a neurodevelopmental disorder. Patients with RTT frequently show abnormal sleep patterns and sleep-associated problems, in addition to autistic symptoms, raising the possibility of circadian clock dysfunction in RTT. In this study, we investigated circadian clock function in Mecp2-deficient mice. We successfully generated both male and female Mecp2-deficient mice on the wild-type C57BL/6 background and PER2(Luciferase) (PER2(Luc)) knock-in background using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. Generated Mecp2-deficient mice recapitulated reduced activity in mouse models of RTT, and their activity rhythms were diminished in constant dark conditions. Furthermore, real-time bioluminescence imaging showed that the amplitude of PER2(Luc)-driven circadian oscillation was significantly attenuated in Mecp2-deficient SCN neurons. On the other hand, in vitro circadian rhythm development assay using Mecp2-deficient mouse embryonic stem cells (ESCs) did not show amplitude changes of PER2(Luc) bioluminescence rhythms. Together, these results show that Mecp2 deficiency abrogates the circadian pacemaking ability of the SCN, which may be a therapeutic target to treat the sleep problems of patients with RTT.

  9. Effects of ω-3 PUFAs Supplementation on Myocardial Function and Oxidative Stress Markers in Typical Rett Syndrome

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    Silvia Maffei

    2014-01-01

    Full Text Available Rett syndrome (RTT is a devastating neurodevelopmental disorder with a 300-fold increased risk rate for sudden cardiac death. A subclinical myocardial biventricular dysfunction has been recently reported in RTT by our group and found to be associated with an enhanced oxidative stress (OS status. Here, we tested the effects of the naturally occurring antioxidants ω-3 polyunsaturated fatty acids (ω-3 PUFAs on echocardiographic parameters and systemic OS markers in a population of RTT patients with the typical clinical form. A total of 66 RTT girls were evaluated, half of whom being treated for 12 months with a dietary supplementation of ω-3 PUFAs at high dosage (docosahexaenoic acid ~71.9 ± 13.9 mg/kg b.w./day plus eicosapentaenoic acid ~115.5 ± 22.4 mg/kg b.w./day versus the remaining half untreated population. Echocardiographic systolic longitudinal parameters of both ventricles, but not biventricular diastolic measures, improved following ω-3 PUFAs supplementation, with a parallel decrease in the OS markers levels. No significant changes in the examined echocardiographic parameters nor in the OS markers were detectable in the untreated RTT population. Our data indicate that ω-3 PUFAs are able to improve the biventricular myocardial systolic function in RTT and that this functional gain is partially mediated through a regulation of the redox balance.

  10. Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs.

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    Herrera, José A; Ward, Christopher S; Pitcher, Meagan R; Percy, Alan K; Skinner, Steven; Kaufmann, Walter E; Glaze, Daniel G; Wehrens, Xander H T; Neul, Jeffrey L

    2015-04-01

    One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with β-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a β-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na(+) channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na(+) channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na(+) channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na(+) channel blocker antiepileptic therapies. Thus, Na(+) channel blockers should be considered for the clinical management of LQT in individuals with RTT.

  11. Effects of ω-3 PUFAs Supplementation on Myocardial Function and Oxidative Stress Markers in Typical Rett Syndrome

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    De Felice, Claudio; Montomoli, Barbara; Lunghetti, Stefano; Ciccoli, Lucia; Favilli, Roberto; Hayek, Joussef

    2014-01-01

    Rett syndrome (RTT) is a devastating neurodevelopmental disorder with a 300-fold increased risk rate for sudden cardiac death. A subclinical myocardial biventricular dysfunction has been recently reported in RTT by our group and found to be associated with an enhanced oxidative stress (OS) status. Here, we tested the effects of the naturally occurring antioxidants ω-3 polyunsaturated fatty acids (ω-3 PUFAs) on echocardiographic parameters and systemic OS markers in a population of RTT patients with the typical clinical form. A total of 66 RTT girls were evaluated, half of whom being treated for 12 months with a dietary supplementation of ω-3 PUFAs at high dosage (docosahexaenoic acid ~71.9 ± 13.9 mg/kg b.w./day plus eicosapentaenoic acid ~115.5 ± 22.4 mg/kg b.w./day) versus the remaining half untreated population. Echocardiographic systolic longitudinal parameters of both ventricles, but not biventricular diastolic measures, improved following ω-3 PUFAs supplementation, with a parallel decrease in the OS markers levels. No significant changes in the examined echocardiographic parameters nor in the OS markers were detectable in the untreated RTT population. Our data indicate that ω-3 PUFAs are able to improve the biventricular myocardial systolic function in RTT and that this functional gain is partially mediated through a regulation of the redox balance. PMID:24526821

  12. Genes Related to Mitochondrial Functions, Protein Degradation, and Chromatin Folding Are Differentially Expressed in Lymphomonocytes of Rett Syndrome Patients

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    Leoni, Guido; Cervellati, Franco; Canali, Raffaella; Cortelazzo, Alessio; De Felice, Claudio; Ciccoli, Lucia; Hayek, Joussef

    2013-01-01

    Rett syndrome (RTT) is mainly caused by mutations in the X-linked methyl-CpG binding protein (MeCP2) gene. By binding to methylated promoters on CpG islands, MeCP2 protein is able to modulate several genes and important cellular pathways. Therefore, mutations in MeCP2 can seriously affect the cellular phenotype. Today, the pathways that MeCP2 mutations are able to affect in RTT are not clear yet. The aim of our study was to investigate the gene expression profiles in peripheral blood lymphomonocytes (PBMC) isolated from RTT patients to try to evidence new genes and new pathways that are involved in RTT pathophysiology. LIMMA (Linear Models for MicroArray) and SAM (Significance Analysis of Microarrays) analyses on microarray data from 12 RTT patients and 7 control subjects identified 482 genes modulated in RTT, of which 430 were upregulated and 52 were downregulated. Functional clustering of a total of 146 genes in RTT identified key biological pathways related to mitochondrial function and organization, cellular ubiquitination and proteosome degradation, RNA processing, and chromatin folding. Our microarray data reveal an overexpression of genes involved in ATP synthesis suggesting altered energy requirement that parallels with increased activities of protein degradation. In conclusion, these findings suggest that mitochondrial-ATP-proteasome functions are likely to be involved in RTT clinical features. PMID:24453408

  13. Genes Related to Mitochondrial Functions, Protein Degradation, and Chromatin Folding Are Differentially Expressed in Lymphomonocytes of Rett Syndrome Patients

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    Alessandra Pecorelli

    2013-01-01

    Full Text Available Rett syndrome (RTT is mainly caused by mutations in the X-linked methyl-CpG binding protein (MeCP2 gene. By binding to methylated promoters on CpG islands, MeCP2 protein is able to modulate several genes and important cellular pathways. Therefore, mutations in MeCP2 can seriously affect the cellular phenotype. Today, the pathways that MeCP2 mutations are able to affect in RTT are not clear yet. The aim of our study was to investigate the gene expression profiles in peripheral blood lymphomonocytes (PBMC isolated from RTT patients to try to evidence new genes and new pathways that are involved in RTT pathophysiology. LIMMA (Linear Models for MicroArray and SAM (Significance Analysis of Microarrays analyses on microarray data from 12 RTT patients and 7 control subjects identified 482 genes modulated in RTT, of which 430 were upregulated and 52 were downregulated. Functional clustering of a total of 146 genes in RTT identified key biological pathways related to mitochondrial function and organization, cellular ubiquitination and proteosome degradation, RNA processing, and chromatin folding. Our microarray data reveal an overexpression of genes involved in ATP synthesis suggesting altered energy requirement that parallels with increased activities of protein degradation. In conclusion, these findings suggest that mitochondrial-ATP-proteasome functions are likely to be involved in RTT clinical features.

  14. Beta-actin deficiency with oxidative posttranslational modifications in Rett syndrome erythrocytes: insights into an altered cytoskeletal organization.

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    Alessio Cortelazzo

    Full Text Available Beta-actin, a critical player in cellular functions ranging from cell motility and the maintenance of cell shape to transcription regulation, was evaluated in the erythrocyte membranes from patients with typical Rett syndrome (RTT and methyl CpG binding protein 2 (MECP2 gene mutations. RTT, affecting almost exclusively females with an average frequency of 1∶10,000 female live births, is considered the second commonest cause of severe cognitive impairment in the female gender. Evaluation of beta-actin was carried out in a comparative cohort study on red blood cells (RBCs, drawn from healthy control subjects and RTT patients using mass spectrometry-based quantitative analysis. We observed a decreased expression of the beta-actin isoforms (relative fold changes for spots 1, 2 and 3: -1.82±0.15, -2.15±0.06, and -2.59±0.48, respectively in pathological RBCs. The results were validated by western blotting and immunofluorescence microscopy. In addition, beta-actin from RTT patients also showed a dramatic increase in oxidative posttranslational modifications (PTMs as the result of its binding with the lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE. Our findings demonstrate, for the first time, a beta-actin down-regulation and oxidative PTMs for RBCs of RTT patients, thus indicating an altered cytoskeletal organization.

  15. Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome.

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    Garg, Saurabh K; Lioy, Daniel T; Cheval, Hélène; McGann, James C; Bissonnette, John M; Murtha, Matthew J; Foust, Kevin D; Kaspar, Brian K; Bird, Adrian; Mandel, Gail

    2013-08-21

    De novo mutations in the X-linked gene encoding the transcription factor methyl-CpG binding protein 2 (MECP2) are the most frequent cause of the neurological disorder Rett syndrome (RTT). Hemizygous males usually die of neonatal encephalopathy. Heterozygous females survive into adulthood but exhibit severe symptoms including microcephaly, loss of purposeful hand motions and speech, and motor abnormalities, which appear after a period of apparently normal development. Most studies have focused on male mouse models because of the shorter latency to and severity in symptoms, yet how well these mice mimic the disease in affected females is not clear. Very few therapeutic treatments have been proposed for females, the more gender-appropriate model. Here, we show that self-complementary AAV9, bearing MeCP2 cDNA under control of a fragment of its own promoter (scAAV9/MeCP2), is capable of significantly stabilizing or reversing symptoms when administered systemically into female RTT mice. To our knowledge, this is the first potential gene therapy for females afflicted with RTT.

  16. Structural, Dynamical, and Energetical Consequences of Rett Syndrome Mutation R133C in MeCP2

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    Tugba G. Kucukkal

    2015-01-01

    Full Text Available Rett Syndrome (RTT is a progressive neurodevelopmental disease affecting females. RTT is caused by mutations in the MECP2 gene and various amino acid substitutions have been identified clinically in different domains of the multifunctional MeCP2 protein encoded by this gene. The R133C variant in the methylated-CpG-binding domain (MBD of MeCP2 is the second most common disease-causing mutation in the MBD. Comparative molecular dynamics simulations of R133C mutant and wild-type MBD have been performed to understand the impact of the mutation on structure, dynamics, and interactions of the protein and subsequently understand the disease mechanism. Two salt bridges within the protein and two critical hydrogen bonds between the protein and DNA are lost upon the R133C mutation. The mutation was found to weaken the interaction with DNA and also cause loss of helicity within the 141-144 region. The structural, dynamical, and energetical consequences of R133C mutation were investigated in detail at the atomic resolution. Several important implications of this have been shown regarding protein stability and hydration dynamics as well as its interaction with DNA. The results are in agreement with previous experimental studies and further provide atomic level understanding of the molecular origin of RTT associated with R133C variant.

  17. Altered erythrocyte membrane fatty acid profile in typical Rett syndrome: effects of omega-3 polyunsaturated fatty acid supplementation.

    Science.gov (United States)

    Signorini, Cinzia; De Felice, Claudio; Leoncini, Silvia; Durand, Thierry; Galano, Jean-Marie; Cortelazzo, Alessio; Zollo, Gloria; Guerranti, Roberto; Gonnelli, Stefano; Caffarelli, Carla; Rossi, Marcello; Pecorelli, Alessandra; Valacchi, Giuseppe; Ciccoli, Lucia; Hayek, Joussef

    2014-11-01

    This study mainly aims at examining the erythrocyte membrane fatty acid (FAs) profile in Rett syndrome (RTT), a genetically determined neurodevelopmental disease. Early reports suggest a beneficial effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on disease severity in RTT. A total of 24 RTT patients were assigned to ω-3 PUFAs-containing fish oil for 12 months in a randomized controlled study (average DHA and EPA doses of 72.9, and 117.1mg/kgb.w./day, respectively). A distinctly altered FAs profile was detectable in RTT, with deficient ω-6 PUFAs, increased saturated FAs and reduced trans 20:4 FAs. FAs changes were found to be related to redox imbalance, subclinical inflammation, and decreased bone density. Supplementation with ω-3 PUFAs led to improved ω-6/ω-3 ratio and serum plasma lipid profile, decreased PUFAs peroxidation end-products, normalization of biochemical markers of inflammation, and reduction of bone hypodensity as compared to the untreated RTT group. Our data indicate that a significant FAs abnormality is detectable in the RTT erythrocyte membranes and is partially rescued by ω-3 PUFAs.

  18. Meisjes met een gestoorde ontwikkeling door het syndroom van Rett

    NARCIS (Netherlands)

    Pruissen, D M; Sinke, R J; Terhal, P A; Beemer, F A; Peters, A C

    2003-01-01

    Three girls with Rett syndrome are presented. Patients A and B had initially exhibited normal development, patient C showed severe developmental delay from birth on. In all three stereotypical hand movements arose which led to Rett syndrome being suspected. For patients A and B the clinical diagnosi

  19. Gene expression patterns vary in clonal cell cultures from Rett syndrome females with eight different MECP2 mutations

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    Lazzeroni Laura

    2002-11-01

    Full Text Available Abstract Background Females with the neurological disorder Rett syndrome are heterozygous for mutations in X-linked MECP2 that encodes methyl-CpG binding protein 2 (MeCP2 thought to act as a transcriptional repressor. To identify target genes for MeCP2 modulation, we studied global gene expression in single cell-derived wild-type and mutant MECP2 expressing fibroblast clones with four common mutations (R106W, R306C, 705delG, 1155del32 and in lymphoblastoid cell lines (LCLs that included four mutant MeCP2 (T158M, 803delG, R168X and 1159del28 expressing, and five (1159del28, R106W, R255X, 803delG, 803delG wild-type MeCP2 expressing lines. Methods Clonality and mutation status were verified by androgen receptor methylation assays for X-inactivation and by sequencing MECP2 transcripts. Expression studies were done with oligonucleotide microarrays (Affymetrix U95 and verified with real-time quantitative RT-PCR using Sybr Green. Results Expression of 49 transcripts was increased, and expression of 21 transcripts was decreased, in at least 3 of 4 mutant/wild-type fibroblast comparisons. Transcript levels of 11 genes, determined by quantitative RT-PCR, were highly correlated with the microarray data. Therefore, multiple additional clones from two Rett individuals were tested by RT-PCR only. Striking expression differences were found in both mutant and wildtype MeCP2 expressing clones. Comparing expression profiles of lymphoblastoid cell lines yielded 16 differentially expressed genes. Conclusions MeCP2 deficiency does not lead to global deregulation of gene expression. Either MeCP2's in vivo function does not involve widespread transcriptional repression, or its function is redundant in cell types that also express other methyl-CpG binding proteins. Our data suggest that clonal fibroblast strains may show substantial inter-strain variation, making them a difficult and unstable resource for genome-wide expression profiling studies.

  20. Habituation without NMDA receptor-dependent desensitization of Hering-Breuer apnea reflex in a Mecp2+/- mutant mouse model of Rett syndrome

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    Gang eSong

    2011-05-01

    Full Text Available Nonassociative learning is a basic neuroadaptive behavior exhibited in almost all animal species and sensory modalities but its functions and mechanisms in the mammalian brain are poorly understood. Previous studies have identified two distinct forms of nonassociative learning in the classic Hering-Breuer inflation reflex (HBIR induced apnea in rats: NMDA receptor (NMDAR-independent habituation in a primary vagal pathway and NMDAR-dependent desensitization in a secondary pontine pathway. Here, we show that abnormal nonassociative learning of the HBIR may underlie the endophenotypic tachypnea in an animal model of Rett syndrome (RTT, an autism-spectrum disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2. Mecp2+/- symptomatic mice on a mixed-strain background demonstrated significantly increased resting respiratory frequency with shortened expiration and normal inspiratory duration compared with asymptomatic mutants and wild-type controls, a phenotype that is characteristic of girls with RTT. Low-intensity electrical stimulation of the vagus nerve elicited fictive HBIR with time-dependent habituation in both Mecp2+/- and wild-type mice. However, time-dependent desensitization of the HBIR was evidenced only in wild-type controls and asymptomatic mutant mice but was absent or suppressed in Mecp2+/- symptomatic mice or in wild-type mice after blockade of NMDAR with dizocilpine. Remarkably, ~50% of the Mecp2+/- mice developed these X-linked phenotypes despite somatic mosaicism. Such RTT-like respiratory endophenotypes in mixed-strain Mecp2+/- mice differed from those previously reported in Mecp2-/y mice on pure C57BL/6J background. These findings provide the first evidence indicating that impaired NMDAR-dependent desensitization of the HBIR may contribute to the endophenotypic tachypnea in RTT.

  1. Third harmonic generation imaging of intact human cerebral organoids to assess key components of early neurogenesis in Rett Syndrome (Conference Presentation)

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    Yildirim, Murat; Feldman, Danielle; Wang, Tianyu; Ouzounov, Dimitre G.; Chou, Stephanie; Swaney, Justin; Chung, Kwanghun; Xu, Chris; So, Peter T. C.; Sur, Mriganka

    2017-02-01

    Rett Syndrome (RTT) is a pervasive, X-linked neurodevelopmental disorder that predominantly affects girls. It is mostly caused by a sporadic mutation in the gene encoding methyl CpG-binding protein 2 (MeCP2).The clinical features of RTT are most commonly reported to emerge between the ages of 6-18 months and implicating RTT as a disorder of postnatal development. However, a variety of recent evidence from our lab and others demonstrates that RTT phenotypes are present at the earliest stages of brain development including neurogenesis, migration, and patterning in addition to stages of synaptic and circuit development and plasticity. We have used RTT patient-derived induced pluripotent stem cells to generate 3D human cerebral organoids that can serve as a model for human neurogenesis in vitro. We aim to expand on our existing findings in order to determine aberrancies at individual stages of neurogenesis by performing structural and immunocytochemical staining in isogenic control and MeCP2-deficient organoids. In addition, we aim to use Third Harmonic Generation (THG) microscopy as a label-free, nondestructive 3D tissue visualization method in order to gain a complete understanding of the structural complexity that underlies human neurogenesis. As a proof of concept, we have performed THG imaging in healthy intact human cerebral organoids cleared with SWITCH. We acquired an intrinsic THG signal with the following laser configurations: 400 kHz repetition rate, 65 fs pulse width laser at 1350 nm wavelength. In these THG images, nuclei are clearly delineated and cross sections demonstrate the depth penetration capacity (Imaging control and MeCP2-deficient human cerebral organoids in 2D sections reveals structural and protein expression-based alterations that we expect will be clearly elucidated via both THG and three-photon fluorescence microscopy.

  2. Ex vivo treatment with a novel synthetic aminoglycoside NB54 in primary fibroblasts from Rett syndrome patients suppresses MECP2 nonsense mutations.

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    Manuela Vecsler

    Full Text Available BACKGROUND: Nonsense mutations in the X-linked methyl CpG-binding protein 2 (MECP2 comprise a significant proportion of causative MECP2 mutations in Rett syndrome (RTT. Naturally occurring aminoglycosides, such as gentamicin, have been shown to enable partial suppression of nonsense mutations related to several human genetic disorders, however, their clinical applicability has been compromised by parallel findings of severe toxic effects. Recently developed synthetic NB aminoglycosides have demonstrated significantly improved effects compared to gentamicin evident in substantially higher suppression and reduced acute toxicity in vitro. RESULTS: We performed comparative study of suppression effects of the novel NB54 and gentamicin on three MECP2 nonsense mutations (R294X, R270X and R168X common in RTT, using ex vivo treatment of primary fibroblasts from RTT patients harboring these mutations and testing for the C-terminal containing full-length MeCP2. We observed that NB54 induces dose-dependent suppression of MECP2 nonsense mutations more efficiently than gentamicin, which was evident at concentrations as low as 50 µg/ml. NB54 read-through activity was mutation specific, with maximal full-length MeCP2 recovery in R168X (38%, R270X (27% and R294X (18%. In addition, the recovered MeCP2 was translocated to the cell nucleus and moreover led to parallel increase in one of the most important MeCP2 downstream effectors, the brain derived neurotrophic factor (BDNF. CONCLUSION: Our findings suggest that NB54 may induce restoration of the potentially functional MeCP2 in primary RTT fibroblasts and encourage further studies of NB54 and other rationally designed aminoglycoside derivatives as potential therapeutic agents for nonsense MECP2 mutations in RTT.

  3. MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome.

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    Chen, Lin; Chen, Kaifu; Lavery, Laura A; Baker, Steven Andrew; Shaw, Chad A; Li, Wei; Zoghbi, Huda Y

    2015-04-28

    Epigenetic mechanisms, such as DNA methylation, regulate transcriptional programs to afford the genome flexibility in responding to developmental and environmental cues in health and disease. A prime example involving epigenetic dysfunction is the postnatal neurodevelopmental disorder Rett syndrome (RTT), which is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2). Despite decades of research, it remains unclear how MeCP2 regulates transcription or why RTT features appear 6-18 months after birth. Here we report integrated analyses of genomic binding of MeCP2, gene-expression data, and patterns of DNA methylation. In addition to the expected high-affinity binding to methylated cytosine in the CG context (mCG), we find a distinct epigenetic pattern of substantial MeCP2 binding to methylated cytosine in the non-CG context (mCH, where H = A, C, or T) in the adult brain. Unexpectedly, we discovered that genes that acquire elevated mCH after birth become preferentially misregulated in mouse models of MeCP2 disorders, suggesting that MeCP2 binding at mCH loci is key for regulating neuronal gene expression in vivo. This pattern is unique to the maturing and adult nervous system, as it requires the increase in mCH after birth to guide differential MeCP2 binding among mCG, mCH, and nonmethylated DNA elements. Notably, MeCP2 binds mCH with higher affinity than nonmethylated identical DNA sequences to influence the level of Bdnf, a gene implicated in the pathophysiology of RTT. This study thus provides insight into the molecular mechanism governing MeCP2 targeting and sheds light on the delayed onset of RTT symptoms.

  4. The free radical scavenger Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance in a mouse model of Rett syndrome

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    Oliwia Alicja Janc

    2014-02-01

    Full Text Available Rett syndrome (RS causes severe cognitive impairment, loss of speech, epilepsy, and breathing disturbances with intermittent hypoxia. Also mitochondria are affected; a subunit of respiratory complex III is dysregulated, the inner mitochondrial membrane is leaking protons, and brain ATP levels seem reduced. Our recent assessment of mitochondrial function in MeCP2-deficient mouse (Mecp2-/y hippocampus, confirmed early metabolic alterations, an increased oxidative burden, and a more vulnerable cellular redox balance. As these changes may contribute to the manifestation of symptoms and disease progression, we now evaluated whether free radical scavengers are capable of improving neuronal and mitochondrial function in RS. Acute hippocampal slices of adult mice were incubated with the vitamin E derivative Trolox for 3-5 h. In Mecp2-/y slices this treatment dampened neuronal hyperexcitability, improved short-term plasticity, and fully restored synaptic long-term potentiation. Furthermore, Trolox specifically attenuated the increased hypoxia susceptibility of Mecp2-/y slices. Also, the anticonvulsive effects of Trolox were assessed, but the severity of 4-aminopyridine provoked seizure-like discharges was not significantly affected. Adverse side effects of Trolox on mitochondria can be excluded, but clear indications for an improvement of mitochondrial function were not found. Since several ion-channels and neurotransmitter receptors are redox modulated, the mitochondrial alterations and the associated oxidative burden may contribute to the neuronal dysfunction in RS. We confirmed in Mecp2-/y hippocampus that Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance. Therefore, radical scavengers are promising compounds for the treatment of neuronal dysfunction in RS and deserve further detailed evaluation.

  5. Genotype-specific effects of Mecp2 loss-of-function on morphology of Layer V pyramidal neurons in heterozygous female Rett Syndrome model mice

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    Leslie eRietveld

    2015-04-01

    Full Text Available Rett Syndrome (RTT is a progressive neurological disorder primarily caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2. The heterozygous female brain consists of mosaic of neurons containing both wildtype MeCP2 (MeCP2+ and mutant MeCP2 (MeCP2-. 3-dimensional morphological analysis was performed on individually genotyped layer V pyramidal neurons in the primary motor cortex of heterozygous (Mecp2+/- and wild-type (Mecp2+/+ female mice (>6 mo. from the Mecp2tm1.1Jae line. Comparing basal dendrite morphology, soma and nuclear size of MeCP2+ to MeCP2- neurons reveals a significant cell autonomous, genotype specific effect of Mecp2. MeCP2- neurons have 15% less total basal dendritic length, predominantly in the region 70-130 μm from the cell body and on average 3 fewer branch points, specifically loss in the 2nd and 3rd branch orders. Soma and nuclear areas of neurons of mice were analyzed across a range of ages (5-21 mo. and X-chromosome inactivation (XCI ratios (12-56%. On average, MeCP2- somata and nuclei were 15% and 13% smaller than MeCP2+ neurons respectively. In most respects branching morphology of neurons in wild-type brains (MeCP2 WT was not distinguishable from MeCP2+ but somata and nuclei of MeCP2 WT neurons were larger than those of MeCP2+ neurons. These data reveal cell autonomous effects of Mecp2 mutation on dendritic morphology, but also suggest non-cell autonomous effects with respect to cell size. MeCP2+ and MeCP2- neuron sizes were not correlated with age, but were correlated with XCI ratio. Unexpectedly the MeCP2- neurons were smallest in brains where the XCI ratio was highly skewed towards MeCP2+, i.e. wild-type. This raises the possibility of cell non-autonomous effects that act through mechanisms other than globally secreted factors; perhaps competition for synaptic connections influences cell size and morphology in the genotypically mosaic brain of RTT model mice.

  6. Genotype-specific effects of Mecp2 loss-of-function on morphology of Layer V pyramidal neurons in heterozygous female Rett syndrome model mice.

    Science.gov (United States)

    Rietveld, Leslie; Stuss, David P; McPhee, David; Delaney, Kerry R

    2015-01-01

    Rett syndrome (RTT) is a progressive neurological disorder primarily caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). The heterozygous female brain consists of mosaic of neurons containing both wild-type MeCP2 (MeCP2+) and mutant MeCP2 (MeCP2-). Three-dimensional morphological analysis was performed on individually genotyped layer V pyramidal neurons in the primary motor cortex of heterozygous (Mecp2(+/-) ) and wild-type (Mecp2(+/+) ) female mice ( > 6 mo.) from the Mecp2(tm1.1Jae) line. Comparing basal dendrite morphology, soma and nuclear size of MeCP2+ to MeCP2- neurons reveals a significant cell autonomous, genotype specific effect of Mecp2. MeCP2- neurons have 15% less total basal dendritic length, predominantly in the region 70-130 μm from the cell body and on average three fewer branch points, specifically loss in the second and third branch orders. Soma and nuclear areas of neurons of mice were analyzed across a range of ages (5-21 mo.) and X-chromosome inactivation (XCI) ratios (12-56%). On average, MeCP2- somata and nuclei were 15 and 13% smaller than MeCP2+ neurons respectively. In most respects branching morphology of neurons in wild-type brains (MeCP2 WT) was not distinguishable from MeCP2+ but somata and nuclei of MeCP2 WT neurons were larger than those of MeCP2+ neurons. These data reveal cell autonomous effects of Mecp2 mutation on dendritic morphology, but also suggest non-cell autonomous effects with respect to cell size. MeCP2+ and MeCP2- neuron sizes were not correlated with age, but were correlated with XCI ratio. Unexpectedly the MeCP2- neurons were smallest in brains where the XCI ratio was highly skewed toward MeCP2+, i.e., wild-type. This raises the possibility of cell non-autonomous effects that act through mechanisms other than globally secreted factors; perhaps competition for synaptic connections influences cell size and morphology in the genotypically mosaic brain of RTT model mice.

  7. Rett syndrome: clinical and molecular characterization of two Brazilian patients Síndrome de Rett: caracterização clínica e molecular de dois casos brasileiros

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    Andrea Stachon

    2007-03-01

    Full Text Available BACKGROUND: Rett syndrome (RS is recognized as a pan-ethnic condition. Since the identification of mutations in the MECP2 gene, more patients have been diagnosed, and a broad spectrum of phenotypes has been reported. There is a lack of phenotype-genotype studies. OBJECTIVE: To describe two cases of Brazilian patients with identified MECP2 mutations. METHOD: We present two female Brazilian patients with RS. RESULTS: Both patients presented with regression at 2-3 years of age, when stereotypic hand movements, social withdrawal and postnatal deceleration of head growth rate were observed. Both patients presented verbal communication impairment. Case 1 had loss of purposeful hand movements, and severe seizure episodes. Case 2 had milder impairment of purposeful hand movements, and no seizures. They had different mutations, D97Y and R294X, found in exons 3 and 4 of MECP2 gene, respectively. CONCLUSION: Testing for MECP2 mutations is important to confirm diagnosis and to establish genotype/phenotype correlations, and improve genetic counseling.CONTEXTO: Síndrome de Rett (RS é doença pan-étnica de fenótipo bastante variado desde que foram identificadas mutações no gene MECP2 e um número maior de pacientes tem sido diagnosticadas. Existe uma demanda por estudos que investiguem a relação genótipo-fenotipo. OBJETIVO: Descrever dois casos brasileiros de RS com mutações identificadas. MÉTODO: Duas pacientes brasileiras com diagnóstico clínico-molecular de RS foram descritas buscando-se correlacionar genótipo-fenótipo. RESULTADOS: Ambas pacientes apresentaram regressão aos 2-3 anos de idade, movimentos esteriotipados de mãos, retraimento social e desaceleração do crescimento encefálico. Ambas apresentaram déficit de comunicação verbal. Caso 1 também apresentou perda dos movimentos manuais intencionados e crises convulsivas graves. Caso 2 apresentou-se com comprometimento parcial dos movimentos manuais e sem história de crise

  8. Organic brain syndrome

    Science.gov (United States)

    ... state Intoxication from drug or alcohol use Wernicke-Korsakoff syndrome (a long-term effect of excessive alcohol consumption ... Substance use Transient ischemic attack Vascular dementia Wernicke-Korsakoff syndrome Review Date 2/27/2016 Updated by: Amit ...

  9. Binding of the Rett syndrome protein, MeCP2, to methylated and unmethylated DNA and chromatin.

    Science.gov (United States)

    Hansen, Jeffrey C; Ghosh, Rajarshi P; Woodcock, Christopher L

    2010-10-01

    Methylated CpG Binding Protein 2 (MeCP2) is a nuclear protein named for its ability to selectively recognize methylated DNA. Much attention has been focused on understanding MeCP2 structure and function in the context of its role in Rett syndrome, a severe neurodevelopmental disorder that afflicts one in 10,000-15,000 girls. Early studies suggested a connection between DNA methylation, MeCP2, and establishment of a repressive chromatin structure at specific gene promoters. However, it is now recognized that MeCP2 can both activate and repress specific genes depending on the context. Likewise, in the cell, MeCP2 is bound to unmethylated DNA and chromatin in addition to methylated DNA. Thus, to understand the molecular basis of MeCP2 functionality, it is necessary to unravel the complex interrelationships between MeCP2 binding to unmethylated and methylated regions of the genome. MeCP2 is unusual and interesting in that it is an intrinsically disordered protein, that is, much of its primary sequence fails to fold into secondary structure and yet is functional. The unique structure of MeCP2 is the subject of the first section of this article. We then discuss recent investigations of the in vitro binding of MeCP2 to unmethylated and methylated DNA, and the potential ramifications of this work for in vivo function. We close by focusing on mechanistic studies indicating that the binding of MeCP2 to chromatin results in compaction into local (secondary) and global (tertiary) higher order structures. MeCP2 also competes with histone H1 for nucleosomal binding sites. The recent finding that MeCP2 is found at near stoichiometric levels with nucleosomes in neuronal cells underscores the multiple modes of engagement of MeCP2 with the genome, which include the cooperative tracking of methylation density.

  10. Síndrome de Rett: 50 años de historia de un trastorno aun no bien conocido Rett syndrome: 50 years' history of a still not well known condition

    Directory of Open Access Journals (Sweden)

    Jaime Campos-Castello

    2007-01-01

    Full Text Available Desde que fue descrito por primera vez por Andreas Rett hace 50 años, el síndrome de Rett (SR ha sido objeto de muchas investigaciones, sin embargo continúa siendo un trastorno aún no bien conocido. Presentamos nuestra propia experiencia y una revisión de la literatura sobre el SR. Se trata de un trastorno del neurodesarrollo, dominante ligado a X, que afecta casi siempre a mujeres, la mayoría de los casos de forma esporádica. El diagnóstico de SR debe hacerse en base a la observación clínica. Las principales características son la aparición de un retraso mental, cambios conductuales, estereotipias, pérdida del lenguaje y, sobre todo, del uso propositivo de las manos, aparición de una apraxia de la marcha, presencia de alteraciones de la respiración y, frecuentemente, crisis epilépticas. Los criterios diagnósticos consensuados internacionalmente son aquí revisados. El SR se debe en la mayoría de casos a mutaciones del gen MECP2, si bien una proporción de casos atípicos puede estar causada por mutaciones de CDKL5, particularmente la variante con epilepsia precoz. Sin embargo, los mecanismos patogénicos moleculares no son bien conocidos, así como la relación entre las mutaciones de MECP2 y otros trastornos del desarrollo. Revisamos también los hallazgos de neuroimagen, neuropatológicos y neurobioquímicos descritos en el SR. Respecto al tratamiento, aparte del sintomático, no hay ninguno que se haya mostrado eficaz. Un trabajo reciente abre perspectivas terapéuticas futuras al haber demostrado mediante un modelo animal de ratón la reversión de los síntomas neurológicos mediante la activación de la expresión de MeCP2.Since it was first described by Andrea Rett 50 years ago, Rett syndrome (RS has been the subject of further investigations, nonetheless it continues to be a not well known condition. Our own experience and an updated literature review on RS is presented. RS is a severe dominant X chromosome

  11. Loss of MeCP2 Causes Urological Dysfunction and Contributes to Death by Kidney Failure in Mouse Models of Rett Syndrome.

    Science.gov (United States)

    Ward, Christopher S; Huang, Teng-Wei; Herrera, José A; Samaco, Rodney C; Pitcher, Meagan R; Herron, Alan; Skinner, Steven A; Kaufmann, Walter E; Glaze, Daniel G; Percy, Alan K; Neul, Jeffrey L

    2016-01-01

    Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills during development, autonomic dysfunction, and an increased risk for premature lethality. Clinical experience identified a subset of individuals with RTT that present with urological dysfunction including individuals with frequent urinary tract infections, kidney stones, and urine retention requiring frequent catheterization for bladder voiding. To determine if urologic dysfunction is a feature of RTT, we queried the Rett Syndrome Natural History Study, a repository of clinical data from over 1000 individuals with RTT and found multiple instances of urological dysfunction. We then evaluated urological function in a mouse model of RTT and found an abnormal pattern of micturition. Both male and female mice possessing Mecp2 mutations show a decrease in urine output per micturition event. Furthermore, we identified signs of kidney failure secondary to urethral obstruction. Although genetic strain background significantly affects both survival and penetrance of the urethral obstruction phenotype, survival and penetrance of urethral obstruction do not directly correlate. We have identified an additional phenotype caused by loss of MeCP2, urological dysfunction. Furthermore, we urge caution in the interpretation of survival data as an endpoint in preclinical studies, especially where causes of mortality are poorly characterized.

  12. Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and ω-3 PUFAs

    Directory of Open Access Journals (Sweden)

    Silvia Leoncini

    2015-01-01

    Full Text Available An involvement of the immune system has been suggested in Rett syndrome (RTT, a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2 or, more rarely, cyclin-dependent kinase-like 5 (CDKL5. To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg response, as well as chemokines, were investigated in MECP2- (MECP2-RTT (n=16 and CDKL5-Rett syndrome (CDKL5-RTT (n=8, before and after ω-3 polyunsaturated fatty acids (PUFAs supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. In MECP2-RTT, a Th2-shifted balance was evidenced, whereas in CDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4 were upregulated. In MECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced in CDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.

  13. Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors.

    Science.gov (United States)

    Li, Wei; Xu, Xin; Pozzo-Miller, Lucas

    2016-03-15

    Deficits in long-term potentiation (LTP) at central excitatory synapses are thought to contribute to cognitive impairments in neurodevelopmental disorders associated with intellectual disability and autism. Using the methyl-CpG-binding protein 2 (Mecp2) knockout (KO) mouse model of Rett syndrome, we show that naïve excitatory synapses onto hippocampal pyramidal neurons of symptomatic mice have all of the hallmarks of potentiated synapses. Stronger Mecp2 KO synapses failed to undergo LTP after either theta-burst afferent stimulation or pairing afferent stimulation with postsynaptic depolarization. On the other hand, basal synaptic strength and LTP were not affected in slices from younger presymptomatic Mecp2 KO mice. Furthermore, spine synapses in pyramidal neurons from symptomatic Mecp2 KO are larger and do not grow in size or incorporate GluA1 subunits after electrical or chemical LTP. Our data suggest that LTP is occluded in Mecp2 KO mice by already potentiated synapses. The higher surface levels of GluA1-containing receptors are consistent with altered expression levels of proteins involved in AMPA receptor trafficking, suggesting previously unidentified targets for therapeutic intervention for Rett syndrome and other MECP2-related disorders.

  14. Loss of MeCP2 Causes Urological Dysfunction and Contributes to Death by Kidney Failure in Mouse Models of Rett Syndrome

    Science.gov (United States)

    Ward, Christopher S.; Huang, Teng-Wei; Herrera, José A.; Samaco, Rodney C.; Pitcher, Meagan R.; Herron, Alan; Skinner, Steven A.; Kaufmann, Walter E.; Glaze, Daniel G.; Percy, Alan K.; Neul, Jeffrey L.

    2016-01-01

    Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills during development, autonomic dysfunction, and an increased risk for premature lethality. Clinical experience identified a subset of individuals with RTT that present with urological dysfunction including individuals with frequent urinary tract infections, kidney stones, and urine retention requiring frequent catheterization for bladder voiding. To determine if urologic dysfunction is a feature of RTT, we queried the Rett Syndrome Natural History Study, a repository of clinical data from over 1000 individuals with RTT and found multiple instances of urological dysfunction. We then evaluated urological function in a mouse model of RTT and found an abnormal pattern of micturition. Both male and female mice possessing Mecp2 mutations show a decrease in urine output per micturition event. Furthermore, we identified signs of kidney failure secondary to urethral obstruction. Although genetic strain background significantly affects both survival and penetrance of the urethral obstruction phenotype, survival and penetrance of urethral obstruction do not directly correlate. We have identified an additional phenotype caused by loss of MeCP2, urological dysfunction. Furthermore, we urge caution in the interpretation of survival data as an endpoint in preclinical studies, especially where causes of mortality are poorly characterized. PMID:27828991

  15. A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome

    Directory of Open Access Journals (Sweden)

    Miriam Kron

    2014-09-01

    Full Text Available Reduced levels of brain-derived neurotrophic factor (BDNF are thought to contribute to the pathophysiology of Rett syndrome (RTT, a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2. In Mecp2 mutant mice, BDNF deficits have been associated with breathing abnormalities, a core feature of RTT, as well as with synaptic hyperexcitability within the brainstem respiratory network. Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2-null mice, suggesting that therapies targeting BDNF or its receptor, TrkB, could be effective at acute reversal of respiratory abnormalities in RTT. Therefore, we examined the ability of LM22A-4, a small-molecule BDNF loop-domain mimetic and TrkB partial agonist, to modulate synaptic excitability within respiratory cell groups in the brainstem nucleus tractus solitarius (nTS and to acutely reverse abnormalities in breathing at rest and during behavioral arousal in Mecp2 mutants. Patch-clamp recordings in Mecp2-null brainstem slices demonstrated that LM22A-4 decreases excitability at primary afferent synapses in the nTS by reducing the amplitude of evoked excitatory postsynaptic currents and the frequency of spontaneous and miniature excitatory postsynaptic currents. In vivo, acute treatment of Mecp2-null and -heterozygous mutants with LM22A-4 completely eliminated spontaneous apneas in resting animals, without sedation. Moreover, we demonstrate that respiratory dysregulation during behavioral arousal, a feature of human RTT, is also reversed in Mecp2 mutants by acute treatment with LM22A-4. Together, these data support the hypothesis that reduced BDNF signaling and respiratory dysfunction in RTT are linked, and establish the proof-of-concept that treatment with a small-molecule structural mimetic of a BDNF loop domain and a TrkB partial agonist can acutely reverse abnormal breathing at rest and in response to

  16. Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome

    DEFF Research Database (Denmark)

    Borg, Isabella; Freude, Kristine; Kübart, Sabine;

    2005-01-01

    hybridisations, utilizing probes derived from breakpoint spanning BACs, detected several aberrant fragments specific for the patient. Sequence analysis of the cloned junction fragment indicated that on chromosome 1 the predominantly brain-expressed Netrin G1 (NTNG1) gene is disrupted, whereas on chromosome 7...

  17. Variant Rett syndrome in a girl with a pericentric X-chromosome inversion leading to epigenetic changes and overexpression of the MECP2 gene.

    Science.gov (United States)

    Vieira, José Pedro; Lopes, Fátima; Silva-Fernandes, Anabela; Sousa, Maria Vânia; Moura, Sofia; Sousa, Susana; Costa, Bruno M; Barbosa, Mafalda; Ylstra, Bauke; Temudo, Teresa; Lourenço, Teresa; Maciel, Patrícia

    2015-11-01

    Rett syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene. We investigated the genetic basis of disease in a female patient with a Rett-like clinical. Karyotype analysis revealed a pericentric inversion in the X chromosome -46,X,inv(X)(p22.1q28), with breakpoints in the cytobands where the MECP2 and CDKL5 genes are located. FISH analysis revealed that the MECP2 gene is not dislocated by the inversion. However, and in spite of a balanced pattern of X inactivation, this patient displayed hypomethylation and an overexpression of the MECP2 gene at the mRNA level in the lymphocytes (mean fold change: 2.55±0.38) in comparison to a group of control individuals; the expression of the CDKL5 gene was similar to that of controls (mean fold change: 0.98±0.10). No gains or losses were detected in the breakpoint regions encompassing known or suspected transcription regulatory elements. We propose that the de-regulation of MECP2 expression in this patient may be due to alterations in long-range genomic interactions caused by the inversion and hypothesize that this type of epigenetic de-regulation of the MECP2 may be present in other RTT-like patients.

  18. Immune Dysfunction in Rett Syndrome Patients Revealed by High Levels of Serum Anti-N(Glc IgM Antibody Fraction

    Directory of Open Access Journals (Sweden)

    Anna Maria Papini

    2014-01-01

    Full Text Available Rett syndrome (RTT, a neurodevelopmental disorder affecting exclusively (99% female infants, is associated with loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2 and, more rarely, cyclin-dependent kinase-like 5 (CDKL5 and forkhead box protein G1 (FOXG1. In this study, we aimed to evaluate the function of the immune system by measuring serum immunoglobulins (IgG and IgM in RTT patients (n=53 and, by comparison, in age-matched children affected by non-RTT pervasive developmental disorders (non-RTT PDD (n=82 and healthy age-matched controls (n=29. To determine immunoglobulins we used both a conventional agglutination assay and a novel ELISA based on antibody recognition by a surrogate antigen probe, CSF114(Glc, a synthetic N-glucosylated peptide. Both assays provided evidence for an increase in IgM titer, but not in IgG, in RTT patients relative to both healthy controls and non-RTT PDD patients. The significant difference in IgM titers between RTT patients and healthy subjects in the CSF114(Glc assay (P=0.001 suggests that this procedure specifically detects a fraction of IgM antibodies likely to be relevant for the RTT disease. These findings offer a new insight into the mechanism underlying the Rett disease as they unveil the possible involvement of the immune system in this pathology.

  19. Two new Rett syndrome families and review of the literature: expanding the knowledge of MECP2 frameshift mutations

    Directory of Open Access Journals (Sweden)

    Eiklid Kristin L

    2011-08-01

    Full Text Available Abstract Background Rett syndrome (RTT is an X-linked dominant neurodevelopmental disorder, which is usually caused by de novo mutations in the MECP2 gene. More than 70% of the disease causing MECP2 mutations are eight recurrent C to T transitions, which almost exclusively arise on the paternally derived X chromosome. About 10% of the RTT cases have a C-terminal frameshift deletion in MECP2. Only few RTT families with a segregating MECP2 mutation, which affects female carriers with a phenotype of mental retardation or RTT, have been reported in the literature. In this study we describe two new RTT families with three and four individuals, respectively, and review the literature comparing the type of mutations and phenotypes observed in RTT families with those observed in sporadic cases. Based on these observations we also investigated origin of mutation segregation to further improve genetic counselling. Methods MECP2 mutations were identified by direct sequencing. XCI studies were performed using the X-linked androgen receptor (AR locus. The parental origin of de novo MECP2 frameshift mutations was investigated using intronic SNPs. Results In both families a C-terminal frameshift mutation segregates. Clinical features of the mutation carriers vary from classical RTT to mild mental retardation. XCI profiles of the female carriers correlate to their respective geno-/phenotypes. The majority of the de novo frameshift mutations occur on the paternally derived X chromosome (7/9 cases, without a paternal age effect. Conclusions The present study suggests a correlation between the intrafamilial phenotypic differences observed in RTT families and their respective XCI pattern in blood, in contrast to sporadic RTT cases where a similar correlation has not been demonstrated. Furthermore, we found de novo MECP2 frameshift mutations frequently to be of paternal origin, although not with the same high paternal occurrence as in sporadic cases with C to T

  20. Concepts of color, shape, size and position in ten children with Rett syndrome Conceitos de cor, forma, tamanho e posição em dez crianças com síndrome de Rett

    Directory of Open Access Journals (Sweden)

    Renata de Lima Velloso

    2009-03-01

    Full Text Available Individuals with Rett syndrome (RS present severe motor, language and cognitive deficits, as well as spontaneous hand movement loss. On the other hand, there are strong evidence that these individuals use the eyes with intentional purpose. Ten girls aged 4y8m to 12y10m with RS were assessed with a computer system for visual tracking regarding their ability of indicating with eyes the recognition of concepts of color (red, yellow and blue, shape (circle, square and triangle, size (big and small and spatial position (over and under to which they were first exposed to. Results from comparing the time of eyes fixation on required and not required concepts did not differ significantly. Children did not show with eyes the recognition of the required concepts when assessed with eye tracking system.Pessoas com síndrome de Rett (SR apresentam severos prejuízos psicomotores, verbais, cognitivos e perda das habilidades manuais proposicionais que impedem o conhecimento de suas reais aquisições intelectuais. Entretanto, estudos relatam que essas pessoas utilizam o olhar com finalidade intencional. O objetivo deste estudo foi avaliar se crianças com SR, após terem sido expostas aos conceitos de cor (vermelho, amarelo e azul, forma (círculo, quadrado e triângulo, tamanho (grande e pequeno e posição espacial (em cima e em baixo, manifestam o reconhecimento desses conceitos com o olhar, avaliado com equipamento computadorizado de rastreamento ocular. Foram avaliadas dez crianças com diagnóstico de SR, com idades entre 4 anos e 8 meses e 12 anos e 10 meses. Os resultados não indicaram diferenças significativas no tempo de fixação do olhar das crianças quando comparados os conceitos solicitados e os não solicitados. Concluiu-se que, com o método utilizado, as crianças não reconheceram os conceitos avaliados.

  1. Normal histone modifications on the inactive X chromosome in ICF and Rett syndrome cells: implications for methyl-CpG binding proteins

    Directory of Open Access Journals (Sweden)

    Canfield Theresa K

    2004-09-01

    Full Text Available Abstract Background In mammals, there is evidence suggesting that methyl-CpG binding proteins may play a significant role in histone modification through their association with modification complexes that can deacetylate and/or methylate nucleosomes in the proximity of methylated DNA. We examined this idea for the X chromosome by studying histone modifications on the X chromosome in normal cells and in cells from patients with ICF syndrome (Immune deficiency, Centromeric region instability, and Facial anomalies syndrome. In normal cells the inactive X has characteristic silencing type histone modification patterns and the CpG islands of genes subject to X inactivation are hypermethylated. In ICF cells, however, genes subject to X inactivation are hypomethylated on the inactive X due to mutations in the DNA methyltransferase (DNMT3B genes. Therefore, if DNA methylation is upstream of histone modification, the histones on the inactive X in ICF cells should not be modified to a silent form. In addition, we determined whether a specific methyl-CpG binding protein, MeCP2, is necessary for the inactive X histone modification pattern by studying Rett syndrome cells which are deficient in MeCP2 function. Results We show here that the inactive X in ICF cells, which appears to be hypomethylated at all CpG islands, exhibits normal histone modification patterns. In addition, in Rett cells with no functional MeCP2 methyl-CpG binding protein, the inactive X also exhibits normal histone modification patterns. Conclusions These data suggest that DNA methylation and the associated methyl-DNA binding proteins may not play a critical role in determining histone modification patterns on the mammalian inactive X chromosome at the sites analyzed.

  2. Transtornos invasivos do desenvolvimento não-autísticos: síndrome de Rett, transtorno desintegrativo da infância e transtornos invasivos do desenvolvimento sem outra especificação Non-autistic pervasive developmental disorders: Rett syndrome, disintegrative disorder and pervasive developmental disorder not otherwise specified

    Directory of Open Access Journals (Sweden)

    Marcos T Mercadante

    2006-05-01

    Full Text Available A categoria "transtorno invasivos do desenvolvimento" inclui o autismo, a síndrome de Asperger, a síndrome de Rett, o transtorno desintegrativo da infância e uma categoria residual denominada transtornos invasivos do desenvolvimento sem outra especificação. Nesta revisão, a síndrome de Rett e o transtorno desintegrativo da infância, que são categorias bem definidas, serão discutidas, assim como as categorias não tão bem definidas que foram incluídas no grupo transtornos invasivos do desenvolvimento sem outra especificação. Diferentes propostas de categorização têm sido feitas, algumas baseadas em abordagem fenomenológica descritiva, outras baseadas em outras perspectivas teóricas, tais como a neuropsicologia. As propostas atuais são apresentadas e discutidas, seguidas por avaliações críticas sobre as vantagens e desvantagens desses conceitos.The category "Pervasive Developmental Disorders" includes autistic disorder, Asperger's syndrome, Rett's syndrome, childhood disintegrative disorder, and a residual category, named pervasive developmental disorder not otherwise specified. In this review, Rett's syndrome and childhood disintegrative disorder, which are well-defined categories, will be discussed, as well as the not well defined categories that have been included in the Pervasive Developmental Disorder Not Otherwise Specified group. Different proposals of categorization have been created, some of which based on descriptive phenomenological approach, and others based upon other theoretical perspectives, such as neuropsychology. Current proposals are presented and discussed, followed by critical appraisals on the clinical advantages and disadvantages of these concepts.

  3. The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome.

    Science.gov (United States)

    Schönewolf-Greulich, B; Tejada, M-I; Stephens, K; Hadzsiev, K; Gauthier, J; Brøndum-Nielsen, K; Pfundt, R; Ravn, K; Maortua, H; Gener, B; Martínez-Bouzas, C; Piton, A; Rouleau, G; Clayton-Smith, J; Kleefstra, T; Bisgaard, A-M; Tümer, Z

    2016-06-01

    Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues.

  4. Co-occurrence of Dystonic and Dyskinetic Tongue Movements with Oral Apraxia in Post-regression Dysphagia in Classical Rett Syndrome Years of Life 1 Through 5.

    Science.gov (United States)

    Abraham, Suzanne S; Taragin, Ben; Djukic, Alesandra

    2015-04-01

    We do not know the natural history of dysphagia in classical Rett syndrome (RTT) by stage or age. This study investigated swallowing physiology in 23 females ages 1:7 to 5:8 (years, months) with classical Rett syndrome to determine common and distinguishing features of dysphagia in post-regression early Pseudostationary Stage III. In-depth analysis of videofluoroscopic swallowing studies (VFSS) found dysmotility of oral stage events across subjects implicating oral apraxia. Impaired motility was further compromised by recurrent dystonic and dyskinetic movements that co-occurred with oral apraxia during oral ingestion in 78 % (n = 18) of the subjects with RTT. Of this group, 44 % displayed rocking and/or rolling lingual pattern, 56 % had recurrent oral tongue retroflexions, and/or elevated posturing of the tongue tip, and, 72 % displayed multi-wave oropharyngeal transfer pattern. The proportion of subjects whose swallowing motility was disrupted by aberrant involuntary tongue movements did not differ significantly between bolus types (liquid, puree, and solid) trialed. Liquid ingestion was significantly more efficient in subjects using bottles with nipples than their counterparts who used spouted or straw cups. Dystonic and dyskinetic tongue movements disrupted liquid ingestion in subjects using cups with spouts or straws significantly more than those using bottles. Analysis of food ingestion revealed that significantly more subjects were able to orally form, transport, and transfer a puree bolus into the pharynx than they were a solid bolus. A significantly larger number of subjects aspirated and penetrated liquid than they did puree or solid. No significant relationship was found between subjects with airway contamination and those with dystonic and dyskinetic tongue movements. Subjects' rocking and rolling lingual patterns were consistent with those evidenced in adults with Parkinson's disease. Subjects' tongue retroflexions were classified as provisionally

  5. What Causes Rett Syndrome?

    Science.gov (United States)

    ... hybridization: Case report and review of literature. European Journal of Human Genetics , 17, 1577–1581. Retrieved June 23, 2012, from http://www.nature.com/ejhg/journal/v17/n12/full/ejhg200995a.html [top] Percy, A. ...

  6. Artrodese de coluna: avaliação da satisfação dos cuidadores de pacientes com síndrome de Rett Artrodesis de la columna: evaluación de la satisfacción de los cuidadores de pacientes con síndrome de Rett Arthrodesis spine: satisfaction evaluation of the caregivers of patients with Rett syndrome

    Directory of Open Access Journals (Sweden)

    Cleverson Tadeu Sidoli

    2010-12-01

    cirugía sobre los cuidados personales, en la función y locomoción, y además, el tiempo de permanencia en la silla de ruedas aumentó. Para el 66,7%, de los cuidadores, la frecuencia de internamientos por problemas médicos y la frecuencia de neumonía disminuyeron con la cirugía. También hicieron una evaluación positiva sobre la estética de la deformidad de la columna. La gran mayoría de los cuidadores (el 85,7% sometería nuevamente sus hijos a la cirugía y recomendaría a otro niño con el mismo problema hacer este tipo de corrección. CONCLUSIÓN: hubo una reducción significativa en el promedio del ángulo de Cobb entre el pre y postoperatorio y una mejoría en todos los aspectos del paciente. Los cuidadores manifestaron que someterían sus hijos de nuevo al procedimiento quirúrgico.OBJECTIVE: to evaluate the satisfaction of the caregivers of Rett Syndrome (RS patients. METHODS: For this retrospective study, statistical data were presented by the medical records of 10 patients with RS, nine females and only one male. With the radiological data presented in the medical records, a questionnaire was prepared with 31 questions to be answered by family. RESULTS: the average reduction of the angle that occurred between the preoperative evaluation and the postoperative evaluation was of 72.4%. Postoperative complications occurred in only one case, and 87.5% of the caregivers said that there was significant improvement with respect to the effect of surgery on personal care, function, locomotion; the time in the wheelchair increased. To 66.7% of the caregivers, with the surgery, the frequency of medical admissions and the frequency of pneumonia decreased. They also made a positive evaluation about the aesthetic deformity of the spine. The vast majority of the caregivers (87.5% said that their children could undergo surgery again and they would recommend it to another child with the same problem. CONCLUSION: there was a significant reduction in the mean Cobb angle

  7. Improvement of the Rett syndrome phenotype in a MeCP2 mouse model upon treatment with levodopa and a dopa-decarboxylase inhibitor.

    Science.gov (United States)

    Szczesna, Karolina; de la Caridad, Olga; Petazzi, Paolo; Soler, Marta; Roa, Laura; Saez, Mauricio A; Fourcade, Stéphane; Pujol, Aurora; Artuch-Iriberri, Rafael; Molero-Luis, Marta; Vidal, August; Huertas, Dori; Esteller, Manel

    2014-11-01

    Rett Syndrome is a neurodevelopmental autism spectrum disorder caused by mutations in the gene coding for methyl CpG-binding protein (MeCP2). The disease is characterized by abnormal motor, respiratory, cognitive impairment, and autistic-like behaviors. No effective treatment of the disorder is available. Mecp2 knockout mice have a range of physiological and neurological abnormalities that resemble the human syndrome and can be used as a model to interrogate new therapies. Herein, we show that the combined administration of Levodopa and a Dopa-decarboxylase inhibitor in RTT mouse models is well tolerated, diminishes RTT-associated symptoms, and increases life span. The amelioration of RTT symptomatology is particularly significant in those features controlled by the dopaminergic pathway in the nigrostratium, such as mobility, tremor, and breathing. Most important, the improvement of the RTT phenotype upon use of the combined treatment is reflected at the cellular level by the development of neuronal dendritic growth. However, much work is required to extend the duration of the benefit of the described preclinical treatment.

  8. Rett's 综合征%Rett's syndrome

    Institute of Scientific and Technical Information of China (English)

    陈艳妮; 左雪梅

    2007-01-01

      患儿,女,5岁6个月,以"运动、语言能力进行性退步3年"就诊.患儿2岁6个月生长发育基本同正常同龄儿,2岁6个月后无明显原因手部"捏"、"撕"等精细动作逐渐消失,出现无目的的"扭手"、"搓手"表现,主动语言逐渐减少至消失,常有过度换气发作,面部常表露一种"社交性微笑",并凝视他人,行走时出现左右摇摆,步态僵硬,患病以来无抽搐.否认孕母期及分娩期异常,否认曾患脑部疾病.多家医院诊断为"孤独症".……

  9. Reduced neuronal size and mTOR pathway activity in the Mecp2 A140V Rett syndrome mouse model [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Sampathkumar Rangasamy

    2016-09-01

    Full Text Available Rett syndrome (RTT is a neurodevelopmental disorder caused by mutation in the X-linked MECP2 gene, encoding methyl-CpG-binding protein 2. We have created a mouse model (Mecp2 A140V “knock-in” mutant expressing the recurrent human MECP2 A140V mutation linked to an X-linked mental retardation/Rett syndrome phenotype. Morphological analyses focused on quantifying soma and nucleus size were performed on primary hippocampus and cerebellum granule neuron (CGN cultures from mutant (Mecp2A140V/y and wild type (Mecp2+/y male mice. Cultured hippocampus and cerebellar granule neurons from mutant animals were significantly smaller than neurons from wild type animals. We also examined soma size in hippocampus neurons from individual female transgenic mice that express both a mutant  (maternal allele and a wild type Mecp2 gene linked to an eGFP transgene (paternal allele. In cultures from such doubly heterozygous female mice, the size of neurons expressing the mutant (A140V allele also showed a significant reduction compared to neurons expressing wild type MeCP2, supporting a cell-autonomous role for MeCP2 in neuronal development. IGF-1 (insulin growth factor-1 treatment of neuronal cells from Mecp2 mutant mice rescued the soma size phenotype. We also found that Mecp2  mutation leads to down-regulation of the mTOR signaling pathway, known to be involved in neuronal size regulation. Our results suggest that i reduced neuronal size is an important in vitro cellular phenotype of Mecp2 mutation in mice, and ii MeCP2 might play a critical role in the maintenance of neuronal structure by modulation of the mTOR pathway. The definition of a quantifiable cellular phenotype supports using neuronal size as a biomarker in the development of a high-throughput, in vitro assay to screen for compounds that rescue small neuronal phenotype (“phenotypic assay”.

  10. Studies of X inactivation and isodisomy in twins provide further evidence that the X chromosomes is not involved in Rett syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Migeon, B.R.; Dunn, M.A.; Schmeckpeper, B.J.; Naidu, S. [Johns Hophins Univ., Baltimore, MD (United States); Thomas, G. [Johns Hopkins Univ., Baltimore, MD (United States)]|[Kennedy-Kreiger Institute, Baltimore, MD (United States)

    1995-03-01

    Rett syndrome (RS), a progressive encephalopathy with onset in infancy, has been attributed to an X-linked mutation, mainly on the basis of its occurrence almost exclusively in females and its concordance in female MZ twins. The underlying mechanisms proposed are an X-linked dominant mutation with male lethality, uniparental disomy of the X chromosome, and/or some disturbance in the process of X inactivation leading to unequal distribution of cells expressing maternal or paternal alleles (referred to as a {open_quotes}nonrandom{close_quotes} or {open_quotes}skewed {close_quotes} inactivation). To determine if the X chromosome is in fact involved in RS, we studied a group of affected females including three pairs of MZ twins, two concordant for RS and one uniquely discordant for RS. Analysis of X-inactivation patterns confirms the frequent nonrandom X inactivation previously observed in MZ twins but indicates that this is independent of RS. Analysis of 29 RS females reveals not one instance of uniparental X disomy, extending the observations previously reported. Therefore, our findings contribute no support for the hypothesis that RS is an X-linked disorder. Furthermore, the concordant phenotype in most MZ females twins with RS, which has not been observed in female twins with known X-linked mutations, argues against an X mutation. 41 refs., 2 figs.

  11. Deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in twins with a Rett syndrome-like phenotype.

    Science.gov (United States)

    Williamson, Sarah L; Ellaway, Carolyn J; Peters, Greg B; Pelka, Gregory J; Tam, Patrick P L; Christodoulou, John

    2015-09-01

    Rett syndrome (RTT), a neurodevelopmental disorder that predominantly affects females, is primarily caused by variants in MECP2. Variants in other genes such as CDKL5 and FOXG1 are usually associated with individuals who manifest distinct phenotypes that may overlap with RTT. Individuals with phenotypes suggestive of RTT are typically screened for variants in MECP2 and then subsequently the other genes dependent on the specific phenotype. Even with this screening strategy, there are individuals in whom no causative variant can be identified, suggesting that there are other novel genes that contribute to the RTT phenotype. Here we report a de novo deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in identical twins with a RTT-like phenotype. We also demonstrate the reduced expression of Ptpn4 in a Mecp2 null mouse model of RTT, as well as the activation of the PTPN4 promoter by MeCP2. Our findings suggest that PTPN4 should be considered for addition to the growing list of genes that warrant screening in individuals with a RTT-like phenotype.

  12. Regulation mechanism and research progress of MeCP2 in Rett syndrome%MeCP2在Rett综合征中的调控机制

    Institute of Scientific and Technical Information of China (English)

    杨文旭; 潘虹

    2014-01-01

    Rett综合征(Rett syndrome,RTT)是一种X连锁的神经发育障碍性遗传病,是导致女性严重智力障碍的主要原因之一.编码甲基化CpG结合蛋白2(Methyl-CpG-binding protein 2,MeCP2)基因突变是RTT主要的遗传病理学改变,MeCP2作为转录抑制因子调控基因表达.在RTT发病机制中,由于缺乏MeCP2与甲基化DNA的正确结合,阻碍了它对下游靶基因表达的正常调控,最终导致脑功能障碍.目前,对MeCP2在脑发育过程中的作用以及如何导致RTT的发生,其机制尚不清楚.文章从MECP2基因和MeCP2蛋白两个方面,对基因结构、蛋白质功能以及在分子水平上的调控机制进行了综述,以期为RTT的发病机制研究提供新思路.

  13. MECP2e1 isoform mutation affects the form and function of neurons derived from Rett syndrome patient iPS cells.

    Science.gov (United States)

    Djuric, Ugljesa; Cheung, Aaron Y L; Zhang, Wenbo; Mok, Rebecca S; Lai, Wesley; Piekna, Alina; Hendry, Jason A; Ross, P Joel; Pasceri, Peter; Kim, Dae-Sung; Salter, Michael W; Ellis, James

    2015-04-01

    MECP2 mutations cause the X-linked neurodevelopmental disorder Rett Syndrome (RTT) by consistently altering the protein encoded by the MECP2e1 alternative transcript. While mutations that simultaneously affect both MECP2e1 and MECP2e2 isoforms have been widely studied, the consequence of MECP2e1 deficiency on human neurons remains unknown. Here we report the first isoform-specific patient induced pluripotent stem cell (iPSC) model of RTT. RTTe1 patient iPS cell-derived neurons retain an inactive X-chromosome and express only the mutant allele. Single-cell mRNA analysis demonstrated they have a molecular signature of cortical neurons. Mutant neurons exhibited a decrease in soma size, reduced dendritic complexity and decreased cell capacitance, consistent with impaired neuronal maturation. The soma size phenotype was rescued cell-autonomously by MECP2e1 transduction in a level-dependent manner but not by MECP2e2 gene transfer. Importantly, MECP2e1 mutant neurons showed a dysfunction in action potential generation, voltage-gated Na(+) currents, and miniature excitatory synaptic current frequency and amplitude. We conclude that MECP2e1 mutation affects soma size, information encoding properties and synaptic connectivity in human neurons that are defective in RTT.

  14. [Soluble brain proteins in autosomal trisomy syndromes].

    Science.gov (United States)

    Mikhneva, L M; Baryshevskaia, V D

    1981-01-01

    The authors examined the soluble proteins of the brain frontal lobes in the newborn with trisomias of the 13th, 18th, and 21st chromosomes (Down's, Patau's, and Edwards' syndromes). The examinations were carried out on autopsy material (the post-mortem period not exceeding 24 hours) by the method of disc electrophoresis in polyacrylamide gel. The brain tissue was taken from 17 newborn infants with Down's syndrome; 9 infants with Patau's syndrome; and 7 infants with Edwards' syndrome. For the control the brain of 21 newborn infants without defects of the CNS development (the death cause being analogous) was taken. In all the syndromes studied diversely directed but relatively specific shifts were revealed on the proteinograms. It was the albumin section which appeared to be the most sensitive to the chromosomal pathology: in cases of Down's and Patau's syndromes the protein content in it was reduced, whereas in cases of Edwards' syndrome it was increased. In the latter syndrome the relative amount of neuronines S-5 and S-6, and in Patau's syndrome the amount of neuronine S-6 were lowered, this lowering being statistically significantly. In all the trisomias a tendency to a diminution of the zone of the acidic neurospecific cerebral proteins was noted. This is, possibly, due to the lower level of the CNS functional activity in chromosomal pathologies.

  15. Rett综合征相关基因MeCP2敲除大鼠模型的构建及分析%Generation and analysis of the Rett syndrome-associated MeCP2-null rat model

    Institute of Scientific and Technical Information of China (English)

    翟伟; 王晓英; 匡世焕; 胡克平; 胡宏秀; 乐亮; 庄峰峰; 王克柱; 赵英; 王凯; 刘新民; 孙迪安

    2016-01-01

    MeCP2 mutations are associated with the Rett syndrome (RTT). Currently, there is an urgent need for new animal models for RTT as the existing MeCP2 knockout mouse models fail to fully mimic the pathogenesis and symptoms of RTT patients. In order to investigate the role of MeCP2 in brain development and RTT pathogenesis, we aimed to set up the MeCP2-null rat model using the CRISPR/Cas9 technology. Firstly we constructed the MeCP2 targeting vector and then microinjected Cas9 mRNA and sgRNA mixtures into fertilized ova of SD rats. The sgRNA was designed to target the exon 2 of MeCP2. Next, knockout rats were confirmed using DNA sequencing and Western blotting. Lastly, phenotypes including growth and behaviors of MeCP2 knockout rats were analyzed. The results indicated that the MeCP2 knockout rats showed body weight loss, anxiety tendency and cognitive deficits. The MeCP2-null rat model established in this study recapitulates the major symptoms of RTT patients and provides an alternative tool for future studies of MeCP2 functions.%MeCP2(Methyl CpG binding protein 2)基因突变可导致Rett综合征(Rett syndrome, RTT)。目前已报道的MeCP2敲除小鼠表型与RTT病人症状存在显著差异。为探索MeCP2在脑发育中的作用及其导致RTT的机制,本研究利用CRISPR/Cas9技术构建了MeCP2基因敲除大鼠模型。通过构建靶向敲除MeCP2基因的载体,体外将Cas9 mRNA和sgRNA显微注射到SD大鼠受精卵中,在MeCP2基因exon2中造成移码突变,从而获得MeCP2基因敲除大鼠。利用测序和Western blotting方法鉴定MeCP2敲除大鼠,并对其表型和行为学特征进行分析,发现MeCP2敲除大鼠体重降低,存在焦虑倾向和认知缺陷。本研究成功构建了MeCP2基因敲除大鼠模型,其表型类似人类RTT患者的症状,为后续MeCP2功能研究提供了更好的动物模型。

  16. Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC lines from Rett syndrome patients as in vitro disease model.

    Directory of Open Access Journals (Sweden)

    Gene Ananiev

    Full Text Available Rett syndrome (RTT is an autism spectrum developmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MECP2 gene. Excellent RTT mouse models have been created to study the disease mechanisms, leading to many important findings with potential therapeutic implications. These include the identification of many MeCP2 target genes, better understanding of the neurobiological consequences of the loss- or mis-function of MeCP2, and drug testing in RTT mice and clinical trials in human RTT patients. However, because of potential differences in the underlying biology between humans and common research animals, there is a need to establish cell culture-based human models for studying disease mechanisms to validate and expand the knowledge acquired in animal models. Taking advantage of the nonrandom pattern of X chromosome inactivation in female induced pluripotent stem cells (iPSC, we have generated isogenic pairs of wild type and mutant iPSC lines from several female RTT patients with common and rare RTT mutations. R294X (arginine 294 to stop codon is a common mutation carried by 5-6% of RTT patients. iPSCs carrying the R294X mutation has not been studied. We differentiated three R294X iPSC lines and their isogenic wild type control iPSC into neurons with high efficiency and consistency, and observed characteristic RTT pathology in R294X neurons. These isogenic iPSC lines provide unique resources to the RTT research community for studying disease pathology, screening for novel drugs, and testing toxicology.

  17. Rett综合征的诊断和治疗研究进展%Progress of diagnosis and treatment of Rett syndrome

    Institute of Scientific and Technical Information of China (English)

    何雯洁; 代英; 钟敏

    2013-01-01

    Rett综合征(RTT)是一组以语言倒退、手部失用及刻板样动作,伴有严重精神运动发育迟滞及倒退的疾病,出生6~18个月起病,大多数累及女性.MECP2基因突变与RTT发病密切相关.2010年新的RTT诊断标准为全球范围内RTT的诊治及临床研究提供更新的统一基础.其临床治疗尚无重大突破,但部分极有价值的治疗基础研究正在进行中.现综述RTT的遗传学研究、临床诊断与治疗研究进展,促进大家对RTT新诊断标准及基础研究的认识.%Rett syndrome (RTT) is a disorder characterized by regression of spoken language and hand use,distinctive hand stereotypies,accompanying with severe psychomotor developmental retardation and retrogression.RTT becomes recognizable at 6-18 months and female are absolutely susceptive.MECP2 mutations are closely related to the development of RTT.Revised diagnostic criteria for RTT (2010) ensure a high degree of homogeneity in cases enrolled in treatment and clinical studies throughout the world.As for the treatment,no crucial advancement has been clinically applied recently,but some valuable basic research is in progress.This paper reviews the genetic research,clinical diagnosis and treatment of RTT,and promotes understanding of the new diagnostic criteria and basic research.

  18. Rett syndrome and dopaminergic system dysfunction%雷特综合征与多巴胺系统功能障碍

    Institute of Scientific and Technical Information of China (English)

    陆斌; 杨灿; 熊志奇

    2014-01-01

    雷特综合征(Rett syndrome)属于神经发育障碍类疾病,主要由×性染色体上mecp2基因突变所致,患者多数为女孩.临床症状于出生后6~18个月逐渐显现,主要表现为头部发育缓慢,已获得的语言及手部目的性运动技能消退,智力障碍,呼吸功能障碍及自闭倾向等.多巴胺系统的功能包括运动调节、奖赏学习、情感、内分泌调控以及药物成瘾等多个方面.由于多巴胺系统在运动和精神方面与雷特综合征部分临床症状存在表面相关性,早期有学者根据临床特征提出雷特综合征患者可能存在多巴胺系统功能障碍,但两者之间是否具有实质性的内在联系以及mecp2基因是否会通过影响多巴胺系统导致相关临床症状是目前雷特综合征研究的一个热点.本文将针对雷特综合征与多巴胺系统功能障碍的相关研究进展作一综述.

  19. GlyT2-Dependent Preservation of MECP2-Expression in Inhibitory Neurons Improves Early Respiratory Symptoms but Does Not Rescue Survival in a Mouse Model of Rett Syndrome

    Science.gov (United States)

    Hülsmann, Swen; Mesuret, Guillaume; Dannenberg, Julia; Arnoldt, Mauricio; Niebert, Marcus

    2016-01-01

    Mutations in methyl-CpG-binding protein 2 (MECP2) gene have been shown to manifest in a neurodevelopmental disorder that is called Rett syndrome. A typical problem that occurs during development is a disturbance of breathing. To address the role of inhibitory neurons, we generated a mouse line that restores MECP2 in inhibitory neurons in the brainstem by crossbreeding a mouse line that expresses the Cre-recombinase (Cre) in inhibitory neurons under the control of the glycine transporter 2 (GlyT2, slc6a5) promotor (GlyT2-Cre) with a mouse line that has a floxed-stop mutation of the Mecp2 gene (Mecp2stop/y). Unrestrained whole-body-plethysmography at postnatal day P60 revealed a low respiratory rate and prolonged respiratory pauses in Mecp2stop/y mice. In contrast, GlyT2-Cre positive Mecp2stop/y mice (Cre+; Mecp2stop/y) showed greatly improved respiration and were indistinguishable from wild type littermates. These data support the concept that alterations in inhibitory neurons are important for the development of the respiratory phenotype in Rett syndrome. PMID:27672368

  20. Teriparatide in the treatment of recurrent fractures in a Rett patient

    Science.gov (United States)

    Caffarelli, Carla; Hayek, Jussef; Nuti, Ranuccio; Gonnelli, Stefano

    2015-01-01

    Summary Rett syndrome is a common X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene. Patients with Rett syndrome have a low bone mineral density and increased risk of fracture. The present case report describes a successful novel therapeutic intervention with teriparatide with one patient with Rett syndrome, after suffering from recurrent low-trauma fractures at intervals of several years. Because of the severity of bone involvement, the decision was made to treat with teriparatide and subsequently with intravenous bisphosphonate. Since the initiation of the treatment, there was an evident improvement at densitometric and QUS parameters. Furthermore, until the present, no new fractures have appeared. This is the first report in which teriparatide was administered to a subjects with Rett syndrome. In conclusion, this report has shown the effectiveness of teriparatide in the management of osteoporotic fractures in one subjects with Rett syndrome. This report provides evidence that increased knowledge of bone pathology and fracture prevention in Rett subjects is important and should be addressed in future studies. PMID:26811706

  1. 中国人群Rett综合征的遗传特点与机制研究%Genetic features and mechanism of Rett syndrome in Chinese population

    Institute of Scientific and Technical Information of China (English)

    张晓英; 赵滢; 包新华; 张晶晶; 曹广娜; 吴希如

    2014-01-01

    Objective To analyze the genetic characteristics and molecular mechanism of Chinese patients with Rett syndrome (RTT) and assess the recurrent risk in order to provide genetic counseling for the family with RTT patient.Methods Methyl-CpG-binding protein 2 (MECP2) gene mutation analysis were performed on 405 Chinese RTT cases and 292 mothers of the patients with MECP2 mutations with polymerase chain reaction (PCR),direct sequencing and multiplex ligation-dependent probe amplification (MLPA).Then cyclin-dependent kinase-like 5 (CDKL5) and forkhead box protein G1 (FOXG1) genes mutation analysis were performed on the patients without MECP2 mutation.Parental origin of mutated MECP2 gene was detected with allele specific PCR analysis.Based on the difference methylation in CpG island of the first exon of human androgen-receptor gene on active and inactive X-chromosomes,methylation sensitive restriction endonuclease digestion was used to analyze the X-chromosome inactive (XCI) patterns.Results MECP2 gene mutation was found in 86.9% RTT cases.CDKL5 gene mutation was found in only 3 cases with early-onset seizures variant.No FOXG1 mutation was found.There were 94.4% MECP2 mutations of paternal origin,and point mutations were common.However,microdeletions were common in maternal origin mutation.MECP2 gene mutation was found in only 1 (0.34%,1/292) mother with normal phenotype and non-random XCI pattern.Her daughter was a RTT patient with preserved speech variant,and her XCI pattern was random.Conclusion MECP2 is the main pathogenic gene in RTT.CDKL5 gene should be screened in patients with early-onset seizures variant without MECP2 gene mutation.The majority of RTT patients had paternally derived de novo MECP2 gene mutation,which may explain the high female to male ratio in RTT.Only 0.34 % mothers carried the pathogenic mutation,indicating a lower recurrent risk for RTT families,The XCI may modulate the phenotype of RTT,so MECP2 gene mutation screening in the mothers

  2. Report on the Integrated Medicine in the Treatment of Rett Syndrome for One Case%中西医结合治疗Rett综合征1例报道

    Institute of Scientific and Technical Information of China (English)

    马帅统; 宋兆普; 吴丽; 郭素云

    2015-01-01

    Rett综合征(Rett syndrome,RTT)是一种严重影响儿童精神运动发育的非神经系统退化性疾病,主要累及女性.临床表现以孤独行为、手的失用及刻板动作为特征,伴有严重的精神运动发育迟滞及倒退.本病至今尚无有效的治疗方法,主要采取对症治疗.中医对此病症有独到的认识,采用中西医结合的方法治疗1例Rett综合征患者,取得了一定疗效.

  3. Profile of altered brain iron acquisition in restless legs syndrome

    Science.gov (United States)

    Ponnuru, Padmavathi; Wang, Xin-Sheng; Patton, Stephanie M.; Allen, Richard P.; Earley, Christopher J.

    2011-01-01

    Restless legs syndrome is a neurological disorder characterized by an urgency to move the legs during periods of rest. Data from a variety of sources provide a compelling argument that the amount of iron in the brain is lower in individuals with restless legs syndrome compared with neurologically normal individuals. Moreover, a significant percentage of patients with restless legs syndrome are responsive to intravenous iron therapy. The mechanism underlying the decreased iron concentrations in restless legs syndrome brains is unknown. We hypothesize that the source of the brain iron deficit is at the blood–brain interface. Thus we analysed the expression of iron management proteins in the epithelial cells of the choroid plexus and the brain microvasculature in post-mortem tissues. The choroid plexus, obtained at autopsy, from 18 neurologically normal controls and 14 individuals who had primary restless legs syndrome was subjected to histochemical staining for iron and immunostaining for iron management proteins. Iron and heavy chain ferritin staining was reduced in the epithelial cells of choroid plexus in restless legs syndrome. Divalent metal transporter, ferroportin, transferrin and its receptor were upregulated in the choroid plexus in restless legs syndrome. Microvessels were isolated from the motor cortex of 11 restless legs syndrome and 14 control brains obtained at autopsy and quantitative immunoblot analyses was performed. Expression of heavy chain ferritin, transferrin and its receptor in the microvessels from restless legs syndrome was significantly decreased compared with the controls but divalent metal protein 1, ferroportin, prohepcidin, mitochondrial ferritin and light-chain ferritin remained unchanged. The presence of an iron regulatory protein was demonstrated in the brain microvasculature and the activity of this protein is decreased in restless legs syndrome; a finding similar to our earlier report in neuromelanin cells from the substantia

  4. Profile of altered brain iron acquisition in restless legs syndrome.

    Science.gov (United States)

    Connor, James R; Ponnuru, Padmavathi; Wang, Xin-Sheng; Patton, Stephanie M; Allen, Richard P; Earley, Christopher J

    2011-04-01

    Restless legs syndrome is a neurological disorder characterized by an urgency to move the legs during periods of rest. Data from a variety of sources provide a compelling argument that the amount of iron in the brain is lower in individuals with restless legs syndrome compared with neurologically normal individuals. Moreover, a significant percentage of patients with restless legs syndrome are responsive to intravenous iron therapy. The mechanism underlying the decreased iron concentrations in restless legs syndrome brains is unknown. We hypothesize that the source of the brain iron deficit is at the blood-brain interface. Thus we analysed the expression of iron management proteins in the epithelial cells of the choroid plexus and the brain microvasculature in post-mortem tissues. The choroid plexus, obtained at autopsy, from 18 neurologically normal controls and 14 individuals who had primary restless legs syndrome was subjected to histochemical staining for iron and immunostaining for iron management proteins. Iron and heavy chain ferritin staining was reduced in the epithelial cells of choroid plexus in restless legs syndrome. Divalent metal transporter, ferroportin, transferrin and its receptor were upregulated in the choroid plexus in restless legs syndrome. Microvessels were isolated from the motor cortex of 11 restless legs syndrome and 14 control brains obtained at autopsy and quantitative immunoblot analyses was performed. Expression of heavy chain ferritin, transferrin and its receptor in the microvessels from restless legs syndrome was significantly decreased compared with the controls but divalent metal protein 1, ferroportin, prohepcidin, mitochondrial ferritin and light-chain ferritin remained unchanged. The presence of an iron regulatory protein was demonstrated in the brain microvasculature and the activity of this protein is decreased in restless legs syndrome; a finding similar to our earlier report in neuromelanin cells from the substantia nigra

  5. Rett networked database

    DEFF Research Database (Denmark)

    Grillo, Elisa; Villard, Laurent; Clarke, Angus

    2012-01-01

    underlie some (usually variant) cases. There is only limited correlation between genotype and phenotype. The Rett Networked Database (http://www.rettdatabasenetwork.org/) has been established to share clinical and genetic information. Through an "adaptor" process of data harmonization, a set of 293...... clinical items and 16 genetic items was generated; 62 clinical and 7 genetic items constitute the core dataset; 23 clinical items contain longitudinal information. The database contains information on 1838 patients from 11 countries (December 2011), with or without mutations in known genes. These numbers...

  6. Increased brain fatty acid uptake in metabolic syndrome

    DEFF Research Database (Denmark)

    Karmi, Anna; Iozzo, Patricia; Viljanen, Antti

    2010-01-01

    To test whether brain fatty acid uptake is enhanced in obese subjects with metabolic syndrome (MS) and whether weight reduction modifies it.......To test whether brain fatty acid uptake is enhanced in obese subjects with metabolic syndrome (MS) and whether weight reduction modifies it....

  7. Brain stem hypoplasia associated with Cri-du-Chat syndrome.

    Science.gov (United States)

    Hong, Jin Ho; Lee, Ha Young; Lim, Myung Kwan; Kim, Mi Young; Kang, Young Hye; Lee, Kyung Hee; Cho, Soon Gu

    2013-01-01

    Cri-du-Chat syndrome, also called the 5p-syndrome, is a rare genetic abnormality, and only few cases have been reported on its brain MRI findings. We describe the magnetic resonance imaging findings of a 1-year-old girl with Cri-du-Chat syndrome who showed brain stem hypoplasia, particularly in the pons, with normal cerebellum and diffuse hypoplasia of the cerebral hemispheres. We suggest that Cri-du-Chat syndrome chould be suspected in children with brain stem hypoplasia, particularly for those with high-pitched cries.

  8. Brain stem hypoplasia associated with Cri-du-Chat syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Jin Ho; Lee, Ha Young; Lim, Myung Kwan; Kim, Mi Young; Kang, Young Hye; Lee, Kyung Hee; Cho, Soon Gu [Dept. of Radiology, Inha University Hospital, Inha University School of Medicine, Incheon (Korea, Republic of)

    2013-12-15

    Cri-du-Chat syndrome, also called the 5p-syndrome, is a rare genetic abnormality, and only few cases have been reported on its brain MRI findings. We describe the magnetic resonance imaging findings of a 1-year-old girl with Cri-du-Chat syndrome who showed brain stem hypoplasia, particularly in the pons, with normal cerebellum and diffuse hypoplasia of the cerebral hemispheres. We suggest that Cri-du-Chat syndrome chould be suspected in children with brain stem hypoplasia, particularly for those with high-pitched cries.

  9. 中国Rett综合征患儿突变基因的亲源分析%Analysis of the parental origin of MECP2 mutations in patients with Rett syndrome

    Institute of Scientific and Technical Information of China (English)

    张晶晶; 包新华; 曹广娜; 姜胜玲; 朱兴旺; 卢红梅; 贾利芳; 潘虹; 吴希如

    2010-01-01

    目的 明确中国Rett综合征(Rett syndrome,RTT)患儿致病基因甲基化CpG结合蛋白2(methyl-CpG-binding protein 2,MECP2)的突变亲源.方法 对115例经基因突变分析证实存在MECP2突变的患儿进行第3内含子测序分析,寻找单核苷酸多态性(single nucleotide polymorphism,SNP)位点.对发现SNP患儿行等位基因特异性PCR扩增,通过比较患儿及其父亲SNP碱基序列,判定患儿突变基因所在染色体亲源.结果 115例患儿中76例存在至少一种SNP.在中国RTT患儿中发现3个热点SNP.76例患儿中73例突变位于父源X染色体,3例突变位于母源X染色体.结论 我国RTT患儿MECP2突变以父源突变为主.%Objective To identify the parental origin of methyl-CpG-binding protein 2 (MECP2)gene mutations in Chinese patients with Rett syndrome. Methods Single nucleotide polymorphisms (SNPs) in intron 3 of the MECP2 gene were analyzed by PCR and sequencing in 115 patients with Rett syndrome.Then sequencing of the SNP region was performed for the fathers of the patients who had at least one SNP,to determine which allele was from the father. Then allele-specific PCR was performed and the products were sequenced to see whether the allele from father or mother harbored the mutation. Results Seventy-six of the 115 patients had at least one SNP. Three hot SNPs were found in these patients. They were: IVS3+22C>G, IVS3+266C>T and IVS3+683C>T. Among the 76 cases, 73 had a paternal origin of MECP2 mutations, and the other 3 had a maternal origin. There were multiple types of MECP2 mutation of the paternal origin, including 4 frame shift, 2 deletion and 67 point (56 C>T, 6 C>G, 2 A>G, 2 G>T and 1 A>T) mutations. The mutation types of the 3 ptients with maternal origin included 2 frame shift and 1 point (C>T) mutation. Conclusion In Chinese RTT patients, the MECP2 mutations are mostly of paternal origin.

  10. Brain anatomy and sensorimotor gating in Asperger's syndrome.

    Science.gov (United States)

    McAlonan, Grainne M; Daly, Eileen; Kumari, Veena; Critchley, Hugo D; van Amelsvoort, Therese; Suckling, John; Simmons, Andrew; Sigmundsson, Thordur; Greenwood, Kathyrn; Russell, Ailsa; Schmitz, Nicole; Happe, Francesca; Howlin, Patricia; Murphy, Declan G M

    2002-07-01

    Asperger's syndrome (an autistic disorder) is characterized by stereotyped and obsessional behaviours, and pervasive abnormalities in socio-emotional and communicative behaviour. These symptoms lead to social exclusion and a significant healthcare burden; however, their neurobiological basis is poorly understood. There are few studies on brain anatomy of Asperger's syndrome, and no focal anatomical abnormality has been reliably reported from brain imaging studies of autism, although there is increasing evidence for differences in limbic circuits. These brain regions are important in sensorimotor gating, and impaired 'gating' may partly explain the failure of people with autistic disorders to inhibit repetitive thoughts and actions. Thus, we compared brain anatomy and sensorimotor gating in healthy people with Asperger's syndrome and controls. We included 21 adults with Asperger's syndrome and 24 controls. All had normal IQ and were aged 18-49 years. We studied brain anatomy using quantitative MRI, and sensorimotor gating using prepulse inhibition of startle in a subset of 12 individuals with Asperger's syndrome and 14 controls. We found significant age-related differences in volume of cerebral hemispheres and caudate nuclei (controls, but not people with Asperger's syndrome, had age-related reductions in volume). Also, people with Asperger's syndrome had significantly less grey matter in fronto-striatal and cerebellar regions than controls, and widespread differences in white matter. Moreover, sensorimotor gating was significantly impaired in Asperger's syndrome. People with Asperger's syndrome most likely have generalized alterations in brain development, but this is associated with significant differences from controls in the anatomy and function of specific brain regions implicated in behaviours characterizing the disorder. We hypothesize that Asperger's syndrome is associated with abnormalities in fronto-striatal pathways resulting in defective sensorimotor

  11. Intranasal Inhalations of Bioactive Factors Produced by M2 Macrophages in Patients With Organic Brain Syndrome

    Science.gov (United States)

    2016-11-04

    Organic Brain Syndrome, Nonpsychotic; Neurocognitive Disorders; Mental Disorder, Organic; Delirium, Dementia, Amnestic, Cognitive Disorders; Nonpsychotic Organic Brain Syndrome; Organic Mental Disorder; Encephalopathy, Post-Traumatic, Chronic; Encephalopathy, Ischemic; Brain Ischemia

  12. Transtornos invasivos do desenvolvimento não-autísticos: síndrome de Rett, transtorno desintegrativo da infância e transtornos invasivos do desenvolvimento sem outra especificação Non-autistic pervasive developmental disorders: Rett syndrome, disintegrative disorder and pervasive developmental disorder not otherwise specified

    OpenAIRE

    2006-01-01

    A categoria "transtorno invasivos do desenvolvimento" inclui o autismo, a síndrome de Asperger, a síndrome de Rett, o transtorno desintegrativo da infância e uma categoria residual denominada transtornos invasivos do desenvolvimento sem outra especificação. Nesta revisão, a síndrome de Rett e o transtorno desintegrativo da infância, que são categorias bem definidas, serão discutidas, assim como as categorias não tão bem definidas que foram incluídas no grupo transtornos invasivos do desenvolv...

  13. Metabolic Syndrome, Brain Magnetic Resonance Imaging, and Cognition

    OpenAIRE

    2010-01-01

    OBJECTIVE We explored cognitive impairment in metabolic syndrome in relation to brain magnetic resonance imaging (MRI) findings. RESEARCH DESIGN AND METHODS We studied 819 participants free of clinical stroke and dementia of the population-based Austrian Stroke Prevention Study who had undergone brain MRI, neuropsychological testing, and a risk factor assessment relevant to National Cholesterol Education Program Adult Treatment Panel III criteria–defined metabolic syndrome. High-sensitivity C...

  14. Brain FDG-PET Scan and Brain Perfusion SPECT in the Diagnosis of Neuroacanthocytosis Syndromes

    Directory of Open Access Journals (Sweden)

    Eylem Değirmenci

    2015-06-01

    Full Text Available Neuroacanthocytosis syndromes (NA include autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome consisting of a choreatic movement disorder, psychiatric manifestations and cognitive decline, and additional multi-system features including myopathy and axonal neuropathy. Fluor 18 -2-fluoro-2-deoxyglucose (18F-FDG-PET positron emission tomography (PET and technetium 99m -d, l-hexamethyl-propylene amine oxime (99mTc-HMPAO brain single photon emission computed tomography (SPECT have been increasingly used for the detection of neurologic disorders, such as dementia, epilepsy, and movement disorders. In this case report, we report two patients with neuroacanthocytosis syndromes with the imaging features of brain metabolism by PET and brain perfusion by SPECT. Brain PET and brain SPECT findings of patients with neuroacanthocytosis syndromes were also reviewed.

  15. Chediak-Higashi syndrome: brain MRI and MR spectroscopy manifestations

    Energy Technology Data Exchange (ETDEWEB)

    Lolli, Valentina; Soto Ares, Gustavo; Pruvo, Jean-Pierre [Roger Salengro Hospital, CHRU, Neuroradiology Department, Lille (France); Abou Chahla, Wadih [Jeanne de Flandre Hospital, Pediatric Hematology and Oncology Department, Lille (France); Jissendi-Tchofo, Patrice [University Hospital Saint-Pierre, Radiology Department - Pediatric Neuroradiology Section, Brussels (Belgium)

    2015-08-15

    Chediak-Higashi syndrome is a rare inherited metabolic disorder characterized by partial oculocutaneous albinism, immunodeficiency, and neurological dysfunction. We present the brain magnetic resonance imaging (MRI) and MR spectroscopy (MRS) findings obtained during the accelerated phase of the disorder in an 8-year-old. The brain MRI manifestations at recurrences 15 months and 24 months later are reported as well. (orig.)

  16. Brain Plasticity and Disease: A Matter of Inhibition

    Directory of Open Access Journals (Sweden)

    Laura Baroncelli

    2011-01-01

    Full Text Available One major goal in Neuroscience is the development of strategies promoting neural plasticity in the adult central nervous system, when functional recovery from brain disease and injury is limited. New evidence has underscored a pivotal role for cortical inhibitory circuitries in regulating plasticity both during development and in adulthood. This paper summarizes recent findings showing that the inhibition-excitation balance controls adult brain plasticity and is at the core of the pathogenesis of neurodevelopmental disorders like autism, Down syndrome, and Rett syndrome.

  17. Laterality of brain and ocular lesions in Aicardi Syndrome

    Science.gov (United States)

    Cabrera, Michelle T.; Winn, Bryan J.; Porco, Travis; Strominger, Zoe; Barkovich, A. James; Hoyt, Creig S.; Wakahiro, Mari; Sherr, Elliott H.

    2011-01-01

    This study reports a large case series of children with Aicardi syndrome. A new severity scoring system is established to assess sidedness of ocular and brain lesions. Thirty-five children were recruited from Aicardi syndrome family conferences. All children received dilated ophthalmologic exams, and brain MRI’s were reviewed. Ocular and brain MRI Aicardi lesion severity scores were devised. A linear mixed model was used to compare each side for the ocular and brain MRI severity scores of Aicardi associated disease. Twenty-six children met inclusion criteria for the study. All subjects were female, ages 3 months to 19 years. Rates per child of optic nerve coloboma, severe lacunae, and microphthalmos in one or both eyes (among those with complete fundus exams available) were 10/24 (42%), 8/22 (36%), and 7/26 (27%), respectively. Ocular and brain MRI asymmetry was found in 18% (4/22) and 58% (15/26) of subjects, respectively, with more right sided brain lesions than left (V=52, P=0.028). A significant correlation between sidedness of brain disease and microphthalmos was seen (T = 2.54, P = 0.02). This study substantiates the range and severity of Aicardi syndrome associated ophthalmologic and brain MRI lesions from prior smaller case series. PMID:21824560

  18. 一例典型的Rett综合征患儿MECP2基因分子遗传学研究%Molecular genetic study of MECP2 gene for a patient with typical Rett syndrome

    Institute of Scientific and Technical Information of China (English)

    朱海燕; 胡娅莉; 朱瑞芳; 杨滢; 朱湘玉; 王皖骏; 段红蕾

    2011-01-01

    Objective To provide genetic diagnosis and counseling for a 2-year-old girl with typical Rett syndrome through analyzing the methyl-CpG binding protein 2 (MECP2) gene. Methods Potential mutation of the MECP2 gene was screened by DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis of members of the family as well as normal controls.Lymphocyte culture for karyotype analysis was carried out for the patient to exclude chromosomal abnormalities.Results The karyotype of the girl was normal.No variation of the MECP2 gene was detected in the patient by direct sequencing.A heterozygosis variation,c.1072G>A in exon 4 of the MECP2 gene was detected in a normal female control,which was not found in other controls.The son and daughter of the female control were respectively heterozygous and homozygous carriers of the same mutation. By MLPA analysis, a heterozygosis deletion of exon 3 and part of exon 4 was detected in the patient,eDNA amplification and sequencing confirmed the presence of a 1176 bp deletion (c.27-1202de11176).The same deletion was not detected in the parents.Conclusion A large deletion in MECP2 gene was detected with MLPA in a patient featuring typical Rett syndrome. The same deletion was missed by sequencing analysis. With eDNA sequencing,the breakage point of the mutation can be mapped precisely mapped.%目的 通过对甲基化CpG结合蛋白2(methyl-CpG binding protein 2,MECP2)基因的分子遗传学分析,对1例典型的Rett综合征患儿进行基因诊断,为罹患家庭提供遗传咨询.方法 综合应用序列分析及多重连接依赖性探针扩增(muhiplex ligation-dependent probe amplification,MLPA)对MECP2基因进行突变分析,同时对患儿进行核型分析以排除染色体异常.结果 患儿核型正常.针对MECP2基因各外显子的序列分析未发现MECP2基因序列的变异,但在1名正常女性对照中检测到该基因第4外显子序列的杂合改变(c.1072G>A),随后对其子女进

  19. Clinical features, gene mutation and genetic counseling in Rett syndrome patients%儿童散发Rett综合征临床特征、基因突变与遗传咨询

    Institute of Scientific and Technical Information of China (English)

    白欣立; 王秀霞; 张会丰; 孙艳霞; 李震中

    2013-01-01

    目的 寻找散发典型Rett综合征患儿甲基化CpG结合蛋白2基因(MECP2基因)突变,探讨基因型和表型之间的关系,并为遗传咨询提供帮助.方法 提取患者及其父母静脉血白细胞基因组DNA,使用MECP2基因外显子特异引物进行PCR扩增和DNA测序检测.结果 2例患者MECP2基因外显子1、2、3未发现突变,外显子4分别存在一种杂合错义突变,核苷酸变化分别为c.C473T和c.C397T,导致相应的氨基酸变化p.T158M和p.R133C;其父母均无相应突变;c.C397T患者的临床表型较c.C473T轻.结论 典型Rett综合征患者多数存在MECP2基因突变,应行基因检测,阳性结果患者应检测其父母相应变化,为遗传咨询提供依据.%Objective To investigate the mutations in methyl-CpG-binding protein 2 gene (MECP2 gene) from typical sporadic Rett syndrome patients,explore the correlations between their genotype and phenotype,assist in genetic counseling.Methods Genomic DNA was extracted from peripheral blood leukocytes from 2 patients and their parents using standard protocols.Polymerase chain reaction and direct sequencing were performed using specific primers from 4 exons in MECP2 gene.Results No mutations were found in exon 1,2,3.Two different heterozygous missense mutations in exon 4 within MECP2 gene were identified from 2 patients.Their nuclear acid changes were:c.C473T and c.C397T,leading to amino acid change accordingly:p.T158M and p.R133C.There were no same mutations from their parents.Phenotype of patient with c.C397T was milder than patient with c.C473T.Conclusions Most of typical Rett syndrome patients had mutations in MECP2 gene.Gene test should be performed.Their biological parents should be detected accordingly if the patient had positive found to support genetic counseling.

  20. Nerve growth factor metabolic dysfunction in Down's syndrome brains.

    Science.gov (United States)

    Iulita, M Florencia; Do Carmo, Sonia; Ower, Alison K; Fortress, Ashley M; Flores Aguilar, Lisi; Hanna, Michael; Wisniewski, Thomas; Granholm, Ann-Charlotte; Buhusi, Mona; Busciglio, Jorge; Cuello, A Claudio

    2014-03-01

    Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer's disease and Down's syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer's disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF's extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down's syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down's syndrome and age-matched controls (age range 31-68 years). We further examined primary cultures of human foetal Down's syndrome cortex (17-21 gestational age weeks) and brains from Ts65Dn mice (12-22 months), a widely used animal model of Down's syndrome. We report a significant increase in proNGF levels in human and mouse Down's syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down's syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down's syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in pro

  1. Brain fag syndrome: a culture-bound syndrome that may be approaching extinction

    OpenAIRE

    Ayonrinde, Oyedeji A.; Obuaya, Chiedu; Adeyemi, Solomon Olusola

    2015-01-01

    Aims and method To explore the current salience of ‘brain fag’ as a nosological, diagnostic and clinical construct in modern West African psychiatry. A semi-structured questionnaire and vignette based on classical symptoms of brain fag syndrome were used to explore current knowledge, explanatory models and practice among Nigerian psychiatrists. Results Of 102 psychiatrists who responded, 98% recognised the term ‘brain fag syndrome’ and most recognised the scenario presented. However, only 22%...

  2. The metabolic syndrome: a brain disease?

    NARCIS (Netherlands)

    Buijs, R.M.; Kreier, F.

    2006-01-01

    The incidence of obesity with, as consequence, a rise in associated diseases such as diabetes, hypertension and dyslipidemia--the metabolic syndrome--is reaching epidemic proportions in industrialized countries. Here, we provide a hypothesis that the biological clock which normally prepares us each

  3. Rett syndrome in a child treated with adrenocorticotrophic hormone%促肾上腺皮质激素治疗Rett综合征1例及文献复习

    Institute of Scientific and Technical Information of China (English)

    陈蔚; 廖建湘; 陈黎

    2009-01-01

    Rett综合征(Rett syndrome)是一种与自闭症有相似之处的遗传性疾病,它与X染色体连锁的MeCP2基因突变有关,目前尚无有效治疗方法。Rett综合征多发生于女孩,发病率约为1/10 000,很少影响男童。我院收治1例Rett综合征患儿,女,3岁11个月,因手部刻板动作1年半,反复抽搐3个月入院。患儿生后1年未见异常,无喂养困难史,智力、发育、运动正常。3个月会抬头,6个月会坐,1岁3个月左右会走路、说简单的话。2岁左右患儿出现反应逐渐迟钝,行动不稳,易摔倒,2岁半左右手部出现刻板动作,表现为反复拍手、双手抓捏、揉搓,逐渐加重,手部功能逐渐废用,上肢不能主动拿物,不能拿碗、勺自己进食,甚至摔倒时没有保护性手部撑地动作;下肢运动功能受到影响,能走路,但协调性及平衡能力差,易摔跤。语言功能逐渐丧失,不能表达,对外界事物不感兴趣,不与人交流,甚至没有目光交流;情绪易怒,易出现凝视、傻笑、尖叫动作,经常有阵发性过度换气。3个月前患儿无明显诱因出现反复抽搐发作,表现为双眼凝视,口唇发绀,口吐泡沫,四肢僵硬抽动,每次持续约2~3 m in,可自行缓解,每天可发作1~2次。母孕期体健,足月顺产,出生时顺利,家族中...

  4. The metabolic syndrome: a brain disease?

    Science.gov (United States)

    Buijs, Ruud M; Kreier, Felix

    2006-09-01

    The incidence of obesity with, as consequence, a rise in associated diseases such as diabetes, hypertension and dyslipidemia--the metabolic syndrome--is reaching epidemic proportions in industrialized countries. Here, we provide a hypothesis that the biological clock which normally prepares us each morning for the coming activity period is altered due to a modern life style of low activity during the day and late-night food intake. Furthermore, we review the anatomical evidence supporting the proposal that an unbalanced autonomic nervous system output may lead to the simultaneous occurrence of diabetes type 2, dyslipidemia, hypertension and visceral obesity.

  5. Increased Brain Fatty Acid Uptake in Metabolic Syndrome

    Science.gov (United States)

    Karmi, Anna; Iozzo, Patricia; Viljanen, Antti; Hirvonen, Jussi; Fielding, Barbara A.; Virtanen, Kirsi; Oikonen, Vesa; Kemppainen, Jukka; Viljanen, Tapio; Guiducci, Letizia; Haaparanta-Solin, Merja; Någren, Kjell; Solin, Olof; Nuutila, Pirjo

    2010-01-01

    OBJECTIVE To test whether brain fatty acid uptake is enhanced in obese subjects with metabolic syndrome (MS) and whether weight reduction modifies it. RESEARCH DESIGN AND METHODS We measured brain fatty acid uptake in a group of 23 patients with MS and 7 age-matched healthy control subjects during fasting conditions using positron emission tomography (PET) with [11C]-palmitate and [18F]fluoro-6-thia-heptadecanoic acid ([18F]-FTHA). Sixteen MS subjects were restudied after 6 weeks of very low calorie diet intervention. RESULTS At baseline, brain global fatty acid uptake derived from [18F]-FTHA was 50% higher in patients with MS compared with control subjects. The mean percentage increment was 130% in the white matter, 47% in the gray matter, and uniform across brain regions. In the MS group, the nonoxidized fraction measured using [11C]-palmitate was 86% higher. Brain fatty acid uptake measured with [18F]-FTHA-PET was associated with age, fasting serum insulin, and homeostasis model assessment (HOMA) index. Both total and nonoxidized fractions of fatty acid uptake were associated with BMI. Rapid weight reduction decreased brain fatty acid uptake by 17%. CONCLUSIONS To our knowledge, this is the first study on humans to observe enhanced brain fatty acid uptake in patients with MS. Both fatty acid uptake and accumulation appear to be increased in MS patients and reversed by weight reduction. PMID:20566663

  6. Deep Brain Stimulation in Tourette’s Syndrome

    OpenAIRE

    Fraint, Avram; Pal, Gian

    2015-01-01

    Objective Tourette’s syndrome (TS) is defined by 1 year of persistent motor and vocal tics. Often, the tics are refractory to conventional pharmacologic and psychobehavioral interventions. In these patients, deep brain stimulation (DBS) may be an appropriate intervention. This paper reviews different DBS targets in TS, discusses existing evidence on the efficacy of DBS in TS, highlights adverse effects of the procedure, discusses indications and patient selection as well as future directio...

  7. Resperidone treatment of 25 patients with Tou-rette's syndrome%利培酮治疗抽动秽语综合征25例

    Institute of Scientific and Technical Information of China (English)

    谭庆荣; 李彦华; 吴保仁; 张光运; 崔弘

    2002-01-01

    目的了解利培酮治疗抽动秽语综合征(Tourette syndrome,TS)的临床疗效.方法对25例TS患者应用利培酮治疗,其中20例完成了该项试验,在治疗前及治疗4 wk后进行耶鲁综合抽动严重程度量表(YGTSS)评分,用减分率来评估治疗效果.结果治疗后YGTSS的总的运动抽动分数,总的发声抽动分数,全部损伤率及总的严重程度分数均小于治疗前,经检验有统计学意义,将资料进行相关回归分析发现减分率同总的运动抽动分数及总的严重程度分数的变化相关更大,标准回归系数分别为0.539,0.513 (P0.05).结论利培酮治疗TS症状明显改善,疗效肯定,副作用轻微.

  8. Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders

    Science.gov (United States)

    Many postnatal onset neurological disorders such as autism spectrum disorders (ASDs) and intellectual disability are thought to arise largely from disruption of excitatory/inhibitory homeostasis. Although mouse models of Rett syndrome (RTT), a postnatal neurological disorder caused by loss-of-functi...

  9. Acute respiratory distress syndrome assessment after traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Shahrooz Kazemi

    2016-01-01

    Full Text Available Background: Acute respiratory distress syndrome (ARDS is one of the most important complications associated with traumatic brain injury (TBI. ARDS is caused by inflammation of the lungs and hypoxic damage with lung physiology abnormalities associated with acute respiratory distress syndrome. Aim of this study is to determine the epidemiology of ARDS and the prevalence of risk factors. Methods: This prospective study performed on patients with acute traumatic head injury hospitalization in the intensive care unit of the Shohaday-e Haftom-e-Tir Hospital (September 2012 to September 2013 done. About 12 months, the data were evaluated. Information including age, sex, education, employment, drug and alcohol addiction, were collected and analyzed. The inclusion criteria were head traumatic patients and exclusion was the patients with chest trauma. Questionnaire was designed with doctors supervision of neurosurgery. Then the collected data were analysis. Results: In this study, the incidence of ARDS was 23.8% and prevalence of metabolic acidosis was 31.4%. Most injury with metabolic acidosis was Subarachnoid hemorrhage (SAH 48 (60% and Subdural hemorrhage (SDH was Next Level with 39 (48% Correlation between Glasgow Coma Scale (GCS and Respiratory Distress Syndrome (ARDS were significantly decreased (P< 0.0001. The level of consciousness in patients with skull fractures significantly lower than those without fractures (P= 0.009 [(2.3±4.6 vs (4.02±7.07]. Prevalence of metabolic acidosis during hospitalization was 80 patients (31.4%. Conclusion: Acute respiratory distress syndrome is a common complication of traumatic brain injury. Management and treatment is essential to reduce the mortality. In this study it was found the age of patients with ARDS was higher than patients without complications. ARDS risk factor for high blood pressure was higher in men. Most victims were pedestrians. The most common injury associated with ARDS was SDH. Our analysis

  10. Agitation, aggression, and disinhibition syndromes after traumatic brain injury.

    Science.gov (United States)

    Kim, Edward

    2002-01-01

    Traumatic brain injury (TBI) is frequently complicated by disinhibition and aggression. These often profound changes in personality, present obstacles to rehabilitative treatments and community reentry. Syndromal presentations may involve a loss of impulse control, spontaneous aggression, and dysphoric bipolar states. Common neuropathological findings of inferior frontal lobe dysfunction support both disinhibition and kindling models of TBI-induced aggression. Assessment of these highly disruptive symptoms requires detailed historical, clinical, and neuropsychological information to formulate appropriate strategies. Management of TBI-related aggression may involve pharmacological, environmental, and psychotherapeutic strategies that incorporate caregiver training and support.

  11. Hyponatremia in acute brain disease: the cerebral salt wasting syndrome.

    Science.gov (United States)

    Betjes, Michiel G.H.

    2002-02-01

    Hyponatremia in acute brain disease is a common occurrence, especially after an aneurysmal subarachnoid hemorrhage. Originally, excessive natriuresis, called cerebral salt wasting, and later the syndrome of inappropriate antidiuretic hormone secretion (SIADH), were considered to be the causes of hyponatremia. In recent years, it has become clear that most of these patients are volume-depleted and have a negative sodium balance, consistent with the original description of cerebral salt wasting. Elevated plasma concentrations of atrial or brain natriuretic peptide have been identified as the putative natriuretic factor. Hyponatremia and volume depletion may aggravate neurological symptoms, and timely treatment with adequate replacement of water and NaCl is essential. The use of fludrocortisone to increase sodium reabsorption by the renal tubules may be an alternative approach.

  12. Brain involvement in Alström syndrome

    Directory of Open Access Journals (Sweden)

    Citton Valentina

    2013-02-01

    Full Text Available Abstract Background Alström Syndrome (AS is a rare ciliopathy characterized by cone–rod retinal dystrophy, sensorineural hearing loss, obesity, type 2 diabetes mellitus and cardiomyopathy. Most patients do not present with neurological issues and demonstrate normal intelligence, although delayed psychomotor development and psychiatric disorders have been reported. To date, brain Magnetic Resonance Imaging (MRI abnormalities in AS have not been explored. Methods We investigated structural brain changes in 12 genetically proven AS patients (mean-age 22 years; range: 6–45, 6 females and 19 matched healthy and positive controls (mean-age 23 years; range: 6–43; 12 females using conventional MRI, Voxel-Based Morphometry (VBM and Diffusion Tensor Imaging (DTI. Results 6/12 AS patients presented with brain abnormalities such as ventricular enlargement (4/12, periventricular white matter abnormalities (3/12 and lacune-like lesions (1/12; all patients older than 30 years had vascular-like lesions. VBM detected grey and white matter volume reduction in AS patients, especially in the posterior regions. DTI revealed significant fractional anisotropy decrease and radial diffusivity increase in the supratentorial white matter, also diffusely involving those regions that appeared normal on conventional imaging. On the contrary, axial and mean diffusivity did not differ from controls except in the fornix. Conclusions Brain involvement in Alström syndrome is not uncommon. Early vascular-like lesions, gray and white matter atrophy, mostly involving the posterior regions, and diffuse supratentorial white matter derangement suggest a role of cilia in endothelial cell and oligodendrocyte function.

  13. Presumptive Ischemic Brain Infarction in a Dog with Evans’ Syndrome

    Directory of Open Access Journals (Sweden)

    Angelo Pasquale Giannuzzi

    2014-01-01

    Full Text Available A ten-year-old neutered female mixed breed dog was referred for pale mucous membrane and acute onset of right prosencephalic clinical signs. Brain magnetic resonance imaging was suggestive for right middle cerebral artery ischemic stroke. Based on cell blood count, serum biochemistry and serologic tests and flow cytometric detection of anti-platelets and anti-red blood cells antibodies, a diagnosis of immunomediated haemolytic anemia associated with thrombocytopenia of suspected immunomediated origin was done. Immunosuppresive therapy with prednisone was started and the dog clinically recovered. Two months later complete normalization of CBC and serum biochemistry was documented. The dog remained stable for 7 months without therapy; then she relapsed. CBC revealed mild regenerative anemia with spherocytosis and thrombocytopenia. A conclusive Evans’ syndrome diagnosis was done and prednisone and cyclosporine treatment led to normalization of physical and CBC parameters. The dog is still alive at the time the paper submitted. Possible thrombotic etiopathogenetic mechanisms are illustrated in the paper and the authors suggest introducing Evans’ syndrome in the differential diagnosis list for brain ischemic stroke in dogs.

  14. MeCP2 Rett mutations affect large scale chromatin organization

    DEFF Research Database (Denmark)

    Gupta, Noopur Agarwal; Becker, Annette; Jost, K Laurence

    2011-01-01

    Rett syndrome is a neurological, X chromosomal-linked disorder associated with mutations in the MECP2 gene. MeCP2 protein has been proposed to play a role in transcriptional regulation as well as in chromatin architecture. Since MeCP2 mutant cells exhibit surprisingly mild changes in gene...... expression, we have now explored the possibility that Rett mutations may affect the ability of MeCP2 to bind and organize chromatin. We found that all but one of the 21 missense MeCP2 mutants analyzed accumulated at heterochromatin and about half of them were significantly affected. Furthermore, two......-thirds of all mutants showed a significantly decreased ability to cluster heterochromatin. Three mutants containing different proline substitutions (P101H, P101R and P152R) were severely affected only in heterochromatin clustering and located far away from the DNA interface in the MeCP2 methyl-binding domain...

  15. Cerebral salt-wasting syndrome due to hemorrhagic brain infarction: a case report

    OpenAIRE

    Tanaka, Tomotaka; Uno, Hisakazu; Miyashita, Kotaro; Nagatsuka, Kazuyuki

    2014-01-01

    Introduction Cerebral salt-wasting syndrome is a condition featuring hyponatremia and dehydration caused by head injury, operation on the brain, subarachnoid hemorrhage, brain tumor and so on. However, there are a few reports of cerebral salt-wasting syndrome caused by cerebral infarction. We describe a patient with cerebral infarction who developed cerebral salt-wasting syndrome in the course of hemorrhagic transformation. Case presentation A 79-year-old Japanese woman with hypertension and ...

  16. Radionuclide brain imaging in acquired immunodeficiency syndrome (AIDS)

    Energy Technology Data Exchange (ETDEWEB)

    Costa, D.C.; Gacinovic, S.; Miller, R.F. [London University College Medical School, Middlesex Hospital, London (United Kingdom)

    1995-09-01

    Infection with the Human Immunodeficiency Virus type 1 (HIV-1) may produce a variety of central nervous system (CNS) symptoms and signs. CNS involvement in patients with the Acquired Immunodeficiency Syndrome (AIDS) includes AIDS dementia complex or HIV-1 associated cognitive/motor complex (widely known as HIV encephalopathy), progressive multifocal leucoencephalopathy (PML), opportunistic infections such as Toxoplasma gondii, TB, Cryptococcus and infiltration by non-Hodgkin`s B cell lymphoma. High resolution structural imaging investigations, either X-ray Computed Tomography (CT scan) or Magnetic Resonance Imaging (MRI) have contributed to the understanding and definition of cerebral damage caused by HIV encephalopathy. Atrophy and mainly high signal scattered white matter abnormalities are commonly seen with MRI. PML produces focal white matter high signal abnormalities due to multiple foci of demyelination. However, using structural imaging techniques there are no reliable parameters to distinguish focal lesions due to opportunistic infection (Toxoplasma gondii abscess) from neoplasm (lymphoma infiltration). It is studied the use of radionuclide brain imaging techniques in the investigation of HIV infected patients. Brain perfusion Single Photon Emission Tomography (SPET), neuroreceptor and Positron Emission Tomography (PET) studies are reviewed. Greater emphasis is put on the potential of some radiopharmaceuticals, considered to be brain tumour markers, to distinguish intracerebral lymphoma infiltration from Toxoplasma infection. SPET with {sup 201}Tl using quantification (tumour to non-tumour radioactivity ratios) appears a very promising technique to identify intracerebral lymphoma.

  17. Clinical analysis of Rett syndrome and a research of methylation CpG binding protein-2 gene%Rett综合征临床分析及甲基化CpG结合蛋白-2基因调查

    Institute of Scientific and Technical Information of China (English)

    程芹; 吕康模; 康涵; 邓佳; 刘平; 蒋利萍

    2015-01-01

    目的:探讨甲基化CpG结合蛋白2(MECP2)基因突变在4例疑似Rett综合征(RTT)患者中的致病作用及基因测序对协助诊断RTT的意义。方法选择2014年4~8月重庆医科大学附属成都市妇女儿童中心医院收治的4例疑似RTT患者,即病例1、2、3、4,病例1为家族先证者,病例2为病例1的母亲,病例3、4为散发患者,家系依次为A、B、C。对4例患者进行临床资料分析、家系调查、核型分析等,并对患者及其父母MECP2基因进行聚合酶链反应扩增测序。结果病例1、4通过2010年最新RTT的修订诊断标准及基因诊断确诊,病例2、3的临床诊断不成立但发现致病基因突变,病例1、2为国内首例母女同患RTT,其MECP2基因测序为同一个国内未报道的突变位点,病例3、4家系中发现已有文献报道的致病位点突变。结论 RTT临床诊断可能与基因诊断结果不一致,基因诊断对确诊RTT,尤其是临床症状不典型的病例具有重要价值;疑诊患者早期完成基因诊断可降低医疗成本、早期开始康复训练并辅助优生优育。%Objective To explore methylation CpG binding protein-2 gene mutation′s pathopoiesia effect on 4 suspected Rett syndrome (RTT) patients and gene sequencing′s significance in assist diagnosing RTT. Methods Selected 4 suspected RTT patients admitted in Chengdu Women′s&Children′s Central Hospital from April to August,2014,i.e. case 1,2,3,4. Case 1 was fam-ily propositus,case 2 was case 1′s mother,case 3 and 4 were sporadic patients,pedigree was successively A,B,C. Did clinical data analysis,pedigree investigation,karyotype analysis on 4 patients. Did polymerase chain reaction amplification sequencing on patients and their parents' MECP2 gene. Results Case 1 and 4 were confirmed by the latest 2010 Revised RTT diagnostic criteria and genet-ic diagnosis. Case 2 and 3′s clinical diagnosis was disconfirmed but virulence gene mutation

  18. Altered functional brain networks in Prader-Willi syndrome.

    Science.gov (United States)

    Zhang, Yi; Zhao, Heng; Qiu, Siyou; Tian, Jie; Wen, Xiaotong; Miller, Jennifer L; von Deneen, Karen M; Zhou, Zhenyu; Gold, Mark S; Liu, Yijun

    2013-06-01

    Prader-Willi syndrome (PWS) is a genetic imprinting disorder characterized mainly by hyperphagia and early childhood obesity. Previous functional neuroimaging studies used visual stimuli to examine abnormal activities in the eating-related neural circuitry of patients with PWS. It was found that patients with PWS exhibited both excessive hunger and hyperphagia consistently, even in situations without any food stimulation. In the present study, we employed resting-state functional MRI techniques to investigate abnormal brain networks related to eating disorders in children with PWS. First, we applied amplitude of low-frequency fluctuation analysis to define the regions of interest that showed significant alterations in resting-state brain activity levels in patients compared with their sibling control group. We then applied a functional connectivity (FC) analysis to these regions of interest in order to characterize interactions among the brain regions. Our results demonstrated that patients with PWS showed decreased FC strength in the medial prefrontal cortex (MPFC)/inferior parietal lobe (IPL), MPFC/precuneus, IPL/precuneus and IPL/hippocampus in the default mode network; decreased FC strength in the pre-/postcentral gyri and dorsolateral prefrontal cortex (DLPFC)/orbitofrontal cortex (OFC) in the motor sensory network and prefrontal cortex network, respectively; and increased FC strength in the anterior cingulate cortex/insula, ventrolateral prefrontal cortex (VLPFC)/OFC and DLPFC/VLPFC in the core network and prefrontal cortex network, respectively. These findings indicate that there are FC alterations among the brain regions implicated in eating as well as rewarding, even during the resting state, which may provide further evidence supporting the use of PWS as a model to study obesity and to provide information on potential neural targets for the medical treatment of overeating.

  19. Twiddler's syndrome in a patient with a deep brain stimulation device for generalized dystonia

    DEFF Research Database (Denmark)

    Astradsson, Arnar; Schweder, Patrick M; Joint, Carole

    2011-01-01

    Deep brain stimulation (DBS) is the technique of neurostimulation of deep brain structures for the treatment of conditions such as essential tremor, dystonia, Parkinson's disease and chronic pain syndromes. The procedure uses implanted deep brain stimulation electrodes connected to extension leads...

  20. Relationship between brain and cognitive processes in Down syndrome.

    Science.gov (United States)

    Menghini, Deny; Costanzo, Floriana; Vicari, Stefano

    2011-05-01

    We investigated regional grey matter (GM) density in adolescents with Down syndrome (DS) compared to age-matched controls and correlated MRI data with neuropsychological measures in the DS group. Inter-group comparisons documented several GM concentration abnormalities in the participants with DS compared to controls. In the adolescents with DS, intra-group results also showed associations between regional GM density and the neuropsychological measures considered. In particular, GM density of the cerebellum and middle and inferior temporal gyrus was associated with linguistic measures. Short-term memory performances were correlated with the inferior parietal lobule, insula, superior temporal gyrus, medial occipital lobe, and cerebellum. Long-term memory abilities were correlated with GM density in the orbitofrontal cortex, lateral and medial temporal lobe regions, and anterior cingulum and visuo-perceptual abilities with GM density the left middle frontal gyrus. Results of this preliminary study are consistent with a not always efficient brain organization in DS.

  1. Irritable bowel syndrome, the microbiota and the gut-brain axis

    DEFF Research Database (Denmark)

    Raskov, Hans; Burcharth, Jakob; Pommergaard, Hans-Christian

    2016-01-01

    Irritable bowel syndrome is a common functional gastrointestinal disorder and it is now evident that irritable bowel syndrome is a multi-factorial complex of changes in microbiota and immunology. The bidirectional neurohumoral integrated communication between the microbiota and the autonomous...... nervous system is called the gut-brain-axis, which integrates brain and GI functions, such as gut motility, appetite and weight. The gut-brain-axis has a central function in the perpetuation of irritable bowel syndrome and the microbiota plays a critical role. The purpose of this article is to review...... recent research concerning the epidemiology of irritable bowel syndrome, influence of microbiota, probiota, gut-brain-axis, and possible treatment modalities on irritable bowel syndrome....

  2. Hallermann–Streiff syndrome with severe bilateral enophthalmos and radiological evidence of silent brain syndrome: a new congenital silent brain syndrome?

    Directory of Open Access Journals (Sweden)

    Nucci P

    2011-07-01

    Full Text Available Paolo Nucci¹, Carlo de Conciliis², Matteo Sacchi¹, Massimiliano Serafino¹¹Eye Clinic, San Giuseppe Hospital, University of Milan, ²Eye Clinic, Istituto Auxologico Italiano, Milan, ItalyBackground: We present the first case of a congenital form of silent brain syndrome (SBS in a young patient affected by Hallermann–Streiff syndrome (HSS and the surgical management of the associated eyelid anomalies.Methods: HSS signs were evaluated according to the Francois criteria. Orbital computed tomography (CT and genetic analysis were performed. An upper eyelid retractor-free recession was performed. Follow-up visits were performed at day 1, weeks 1 and 3, and months 3, 6, 9 (for both eyes, and 12 (for left eye after surgery.Results: The patient exhibited six of the seven signs of HSS. Orbital CT showed bilateral enophthalmos and upward bowing of the orbital roof with air entrapment under the upper eyelid as previously described for SBS. Genetic analysis showed a 2q polymorphism. During follow-up, the cornea showed absence of epithelial damage and the upper eyelids were lowered symmetrically, with a regular contour.Conclusion: Our HSS patient shares features with SBS. We postulate that SBS could include more than one pattern, ie, an acquired form following ventriculoperitoneal shunting and this newly reported congenital form in our HSS patient in whom typical syndromic skull anomalies led to this condition. The surgical treatment has been effective in restoring an appropriate lid level, with good globe apposition and a good cosmetic result.Keywords: Hallermann–Streiff syndrome, silent brain syndrome, upper eyelid entropion

  3. Irritable bowel syndrome: Is it "irritable brain" or "irritable bowel"?

    Directory of Open Access Journals (Sweden)

    Susanta Kumar Padhy

    2015-01-01

    Full Text Available Irritable bowel syndrome (IBS has been recognized as one of the most common and best studied disorders among the group of functional gastrointestinal disorders. It is a functional bowel disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habit. In the Western world, IBS appears to affect up to 20% of the population at any given time but in Asian countries, the median value of IBS prevalence defined by various criteria ranges between 6.5% and 10.1%, and community prevalence of 4% is found in North India. Those attending gastroenterology clinics represent only the tip of the iceberg. The disorder substantially impairs the quality of life, and the overall health-care costs are high. IBS has therefore gained increased attention from clinicians, researchers, and pharmaceutical industries. It is often frustrating to both patients and physicians as the disease is usually chronic in nature and difficult to treat. However, the understanding of IBS has been changing from time to time and still most of its concepts are unknown. In this review we have discussed, debated, and synthesized the evidence base, focusing on underlying mechanisms in the brain and bowel. We conclude that it is both brain and bowel mechanisms that are responsible. The clinical implication of such mechanisms is discussed.

  4. Brain Perfusion in Corticobasal Syndrome with Progressive Aphasia

    Directory of Open Access Journals (Sweden)

    Yoshitake Abe

    2016-04-01

    Full Text Available Background: Brain perfusion may differ between patients with corticobasal syndrome (CBS with and without aphasia. Methods: Twenty-six (9 males and 17 females; mean age 76 ± 5.3 years patients with CBS were enrolled in the study. Brain MRI and single-photon emission computed tomography were performed in all subjects. Language was evaluated using the Standard Language Test of Aphasia. The patients were divided into two subgroups according to the presence or absence of progressive aphasia. Differences in the regional cerebral blood flow (rCBF between the two groups were detected based on voxel-by-voxel group analysis using Statistical Parametric Mapping 8. Results: All patients exhibited asymmetric motor symptoms and signs, including limb apraxia, bradykinesia, and akinetic rigidity. Of 26 patients, 9 had a clinically obvious language disturbance, characterized as nonfluent aphasia. Almost all CBS patients with aphasia exhibited cortical atrophy predominantly in the left frontal and temporal lobes with widening of the Sylvian fissure on MRI. The rCBF in the left middle frontal gyrus differed significantly between CBS patients with and without aphasia. Conclusion: CBS patients with aphasia exhibit motor symptoms predominantly on the right side and cortical atrophy mainly in the left perisylvian cortices. In particular, left frontal dysfunction might be related to nonfluent aphasia in CBS.

  5. Dural Reduction Surgery: A Treatment Option for Frontotemporal Brain Sagging Syndrome.

    Science.gov (United States)

    Mostofi, Emily; Schievink, Wouter I; Sim, Valerie L

    2016-07-01

    Frontotemporal brain sagging syndrome is a dementia associated with hypersomnolence, personality changes, and features of intracranial hypotension on magnetic resonance imaging. The literature is sparse with respect to treatment options; many patients simply worsen. We present a case in which this syndrome responded to lumbar dural reduction surgery. Postoperative magnetic resonance imaging indicated normalization of brain sagging and lumbar intrathecal pressure. Although no evidence of cerebrospinal leak was found, extremely thin dura was noted intraoperatively, suggesting that a thin and incompetent dura could result in this low-pressure syndrome. Clinicians who encounter this syndrome should consider dural reduction surgery as a treatment strategy.

  6. Central neurogenic diabetes insipidus, syndrome of inappropriate secretion of antidiuretic hormone, and cerebral salt-wasting syndrome in traumatic brain injury.

    Science.gov (United States)

    John, Cynthia A; Day, Michael W

    2012-04-01

    Central neurogenic diabetes insipidus, syndrome of inappropriate secretion of antidiuretic hormone, and cerebral salt-wasting syndrome are secondary events that affect patients with traumatic brain injury. All 3 syndromes affect both sodium and water balance; however, they have differences in pathophysiology, diagnosis, and treatment. Differentiating between hypernatremia (central neurogenic diabetes insipidus) and the 2 hyponatremia syndromes (syndrome of inappropriate secretion of antidiuretic hormone, and cerebral salt-wasting syndrome) is critical for preventing worsening neurological outcomes in patients with head injuries.

  7. Rett综合征的致病基因彻CECP2的研究进展——MECP2的基因结构、功能及调控基因%Research progress of Rett syndrome causing gene MECP2-The structure, function and modulation of MECP2

    Institute of Scientific and Technical Information of China (English)

    张晶晶; 包新华

    2009-01-01

    @@ Rett综合征(Rett syndrome,RTT)是一种神经系统发育异常性疾病,主要累及女孩,是导致女性智力低下的主要原因之一.女孩发病率大约为1:10 000~1:15 000.典型RTT的临床特征为:出生后6~18个月生长发育基本正常,随后出现神经发育停滞或倒退,丧失已获得的技能(如手的功能、语言等),头围增长缓慢,呼吸异常,出现手的刻板动作(如搓手、绞手、吃手等),伴有孤独症样行为,此外,惊厥发作也是常见症状之一,到疾病后期还可能出现骨骼改变、脊柱侧弯及强直等~([1-2]).

  8. Síndrome de Rett: un nuevo reto para los pediatras. Revisión bibliográfica

    Directory of Open Access Journals (Sweden)

    Carlos Coronel Carvajal

    2002-06-01

    Full Text Available Se ofrece una revisión actualizada sobre el síndrome de Rett, un trastorno neurodegenerativo con un cuadro clínico característico. Ocurre solo en niñas, la mayoría de los casos son esporádicos y es genéticamente determinado. Recientemente se ha hallado en pacientes estudiando la proteína MECP2, que codifica el gen en la banda 8 de la región 2 del brazo largo del cromosomo X (Xq 28, lo cual sugiere mutación de novo de carácter dominante ligada al cromosoma X. El diagnóstico del síndrome de Rett se lleva a cabo por la observación y la valoración clínica, pues no existen marcadores bioquímicos, ni genéticos que faciliten la determinación del síndrome, y su origen se desconoce; se utilizan los criterios establecidos internacionalmente que incluyen criterios necesarios, complementarios y componentes de exclusión. El síndrome de Rett debe sospecharse en pacientes del sexo femenino, con diagnóstico de parálisis cerebral infantil o retardo mental idiopático al apoyarse en criterios establecidos internacionalmente.An updated literature review on Rett syndrome is presented. This neurodegenerative disorder with a characteristic clinical picture only occurs in girls, most of the cases are sporadic and genetically determined. It has been recently found in patients after studying the MECP2 protein that codifies the gene in band 8 of region 2 in the long arm of X chromosome(Xq 28, which suggests a dominant X chromosome-linked dominant de novo mutation. The diagnosis of Rett syndrome is made based on observation and clinical assessment since there are no biochemical or genetic markers facilitating the determination of the syndrome and besides its origin is unknown. The internationally established criteria including necessary, complementary criteria and exclusion elements are used. Rett syndrome should be considered in female patients with infantile cerebral palsy or idiopathic mental retardation, with the support of internationally set

  9. A case of organic brain syndrome following head injury successfully treated with carbamazepine.

    Science.gov (United States)

    Bouvy, P F; van de Wetering, B J; Meerwaldt, J D; Bruijn, J B

    1988-03-01

    A case of organic brain syndrome occurring in relation to psychological stress 2 years after a severe head injury is described. Treatment with haloperidol resulted only in slight improvement. A dramatic improvement was achieved with carbamazepine.

  10. Brain serotonin concentration and crude synaptosomal uptake in mice with the Chediak-Higashi syndrome.

    Science.gov (United States)

    Meyers, K M; Chen, M

    1976-12-01

    The Chediak-Higashi syndrome is characterized by a serotonin platelet defect and neuronal dysfunction. Whole blood serotonin concentration, serotonin brain concentration, and synaptosomal uptake of serotonin were determined in mice with the syndrome. While brain serotonin uptake in the affected mice was not significantly different from that in nonaffected mice, whole blood serotonin concentration was markedly reduced. These data suggest that in human neuropathies with platelet serotonin defect, a parallel neuronal serotonin disorder may not be assumed.

  11. Violence: heightened brain attentional network response is selectively muted in Down syndrome.

    Science.gov (United States)

    Anderson, Jeffrey S; Treiman, Scott M; Ferguson, Michael A; Nielsen, Jared A; Edgin, Jamie O; Dai, Li; Gerig, Guido; Korenberg, Julie R

    2015-01-01

    The ability to recognize and respond appropriately to threat is critical to survival, and the neural substrates subserving attention to threat may be probed using depictions of media violence. Whether neural responses to potential threat differ in Down syndrome is not known. We performed functional MRI scans of 15 adolescent and adult Down syndrome and 14 typically developing individuals, group matched by age and gender, during 50 min of passive cartoon viewing. Brain activation to auditory and visual features, violence, and presence of the protagonist and antagonist were compared across cartoon segments. fMRI signal from the brain's dorsal attention network was compared to thematic and violent events within the cartoons between Down syndrome and control samples. We found that in typical development, the brain's dorsal attention network was most active during violent scenes in the cartoons and that this was significantly and specifically reduced in Down syndrome. When the antagonist was on screen, there was significantly less activation in the left medial temporal lobe of individuals with Down syndrome. As scenes represented greater relative threat, the disparity between attentional brain activation in Down syndrome and control individuals increased. There was a reduction in the temporal autocorrelation of the dorsal attention network, consistent with a shortened attention span in Down syndrome. Individuals with Down syndrome exhibited significantly reduced activation in primary sensory cortices, and such perceptual impairments may constrain their ability to respond to more complex social cues such as violence. These findings may indicate a relative deficit in emotive perception of violence in Down syndrome, possibly mediated by impaired sensory perception and hypoactivation of medial temporal structures in response to threats, with relative preservation of activity in pro-social brain regions. These findings indicate that specific genetic differences associated

  12. Anomalous brain functional connectivity contributing to poor adaptive behavior in Down syndrome.

    Science.gov (United States)

    Pujol, Jesus; del Hoyo, Laura; Blanco-Hinojo, Laura; de Sola, Susana; Macià, Dídac; Martínez-Vilavella, Gerard; Amor, Marta; Deus, Joan; Rodríguez, Joan; Farré, Magí; Dierssen, Mara; de la Torre, Rafael

    2015-03-01

    Research in Down syndrome has substantially progressed in the understanding of the effect of gene overexpression at the molecular level, but there is a paucity of information on the ultimate consequences on overall brain functional organization. We have assessed the brain functional status in Down syndrome using functional connectivity MRI. Resting-state whole-brain connectivity degree maps were generated in 20 Down syndrome individuals and 20 control subjects to identify sites showing anomalous synchrony with other areas. A subsequent region-of-interest mapping served to detail the anomalies and to assess their potential contribution to poor adaptive behavior. Down syndrome individuals showed higher regional connectivity in a ventral brain system involving the amygdala/anterior temporal region and the ventral aspect of both the anterior cingulate and frontal cortices. By contrast, lower functional connectivity was identified in dorsal executive networks involving dorsal prefrontal and anterior cingulate cortices and posterior insula. Both functional connectivity increases and decreases contributed to account for patient scoring on adaptive behavior related to communication skills. The data overall suggest a distinctive functional organization with system-specific anomalies associated with reduced adaptive efficiency. Opposite effects were identified on distinct frontal and anterior temporal structures and relative sparing of posterior brain areas, which is generally consistent with Down syndrome cognitive profile. Relevantly, measurable connectivity changes, as a marker of the brain functional anomaly, could have a role in the development of therapeutic strategies addressed to improve the quality of life in Down syndrome individuals.

  13. Genes, Brain Development and Psychiatric Phenotypes in Velo-Cardio-Facial Syndrome

    Science.gov (United States)

    Gothelf, Doron; Schaer, Marie; Eliez, Stephan

    2008-01-01

    Velo-cardio-facial syndrome (VCFS) has been in the focus of intensive research over the last 15 years. The syndrome represents a homogeneous model for studying the effect of a decreased dosage of genes on the development of brain structure and function and, consequently, on the emergence of schizophrenia-like psychotic disorder. In this review, we…

  14. Brain and ventricular volume in patients with syndromic and complex craniosynostosis

    NARCIS (Netherlands)

    T. de Jong (Tim); B.F.M. Rijken (Bianca); M. Leguin (Maarten); M.L.C. van Veelen; I.M.J. Mathijssen (Irene)

    2012-01-01

    textabstractPurpose: Brain abnormalities in patients with syndromic craniosynostosis can either be a direct result of the genetic defect or develop secondary to compression due to craniosynostosis, raised ICP or hydrocephalus. Today it is unknown whether children with syndromic craniosynostosis have

  15. Micronized progesterone as a neuroprotector in pregnant women with post-trauma brain syndrome

    OpenAIRE

    2014-01-01

    The present article is concerned with the study of glial fibrillary acidic protein (GFAP) level in the blood serum of pregnant women  with post–trauma brain injury syndrome (post-TBI syndrome) as the marker of  hematoencephalic barrier status and predictor of obstetric and perinatal complications development.

  16. Micronized progesterone as a neuroprotector in pregnant women with post-trauma brain syndrome

    Directory of Open Access Journals (Sweden)

    Irina Vasilivna Tsyganenko

    2014-05-01

    Full Text Available The present article is concerned with the study of glial fibrillary acidic protein (GFAP level in the blood serum of pregnant women  with post–trauma brain injury syndrome (post-TBI syndrome as the marker of  hematoencephalic barrier status and predictor of obstetric and perinatal complications development.

  17. MeCP2基因热点突变分析在Rett综合征诊断中的应用%MeCP2 gene mutational hotspots in diagnosis of Rett syndrome

    Institute of Scientific and Technical Information of China (English)

    孟洪弟; 潘虹; 包新华; 王艳萍; 沈岩; 吴希如

    2002-01-01

    目的探讨MeCP2基因常见突变是否对Rett综合征临床诊断有帮助.方法对23例Rett综合征患儿,部分患儿家长和4名正常女性分别提取外周血基因组DNA.采用PCR方法扩增MeCP2基因第3外显子 nt22643~nt23022片段,限制性内切酶HphⅠ和Nla Ⅲ酶切分析T158M和R168X突变,6%聚丙烯酰胺凝胶电泳及银染检验酶切结果,突变点经DNA直接测序证实.结果 23例Rett 综合征患儿中4例有T158M突变,21例患儿中2例有R168X突变.在患儿双亲及正常女性对照均未发现以上2种突变.结论 T158M和R168X 2个突变在Rett综合征均较多发.PCR产物的限制酶分析,方法简便、快捷,有助于Rett综合征的临床诊断.

  18. Globus Pallidus Interna Deep Brain Stimulation in a Patient with Medically Intractable Meige Syndrome

    Directory of Open Access Journals (Sweden)

    Dae-Woong Bae

    2014-10-01

    Full Text Available Medical therapies in patients with Meige syndrome, including botulinum toxin injection, have been limited because of incomplete response or adverse side effects. We evaluated a patient with Meige syndrome who was successfully treated with deep brain stimulation (DBS in the globus pallidus interna (GPi. This case report and other previous reports suggest that bilateral GPi DBS may be an effective treatment for medically refractory Meige syndrome, without significant adverse effects.

  19. Brain Size and Cerebral Glucose Metabolic Rate in Nonspecific Retardation and Down Syndrome.

    Science.gov (United States)

    Haier, Richard J.; And Others

    1995-01-01

    Brain size and cerebral glucose metabolic rate were determined for 10 individuals with mild mental retardation (MR), 7 individuals with Down syndrome (DS), and 10 matched controls. MR and DS groups both had brain volumes of about 80% compared to controls, with variance greatest within the MR group. (SLD)

  20. The Pathogenesis of Climacteric Syndrome and Principle of Acupuncture Treatment Based on TCM Theory about Brain

    Institute of Scientific and Technical Information of China (English)

    Shen Xiaoming; Du Yuanhao; Shi Xuemin

    2005-01-01

    The brain is the sea of marrow, stores the cerebral spirit and dominates all the life activities of the human body, which are the basic TCM knowledge about the brain. Based on this knowledge, the pathogenesis of climacteric syndrome is considered as consumption and deficiency of kidney-essence, and incoordination between the brain and kidney. The principle of acupuncture treatment should be soothing the mind and tonifying the kidney.

  1. Electrical storm in the brain and in the heart: epilepsy and Brugada syndrome.

    Science.gov (United States)

    Sandorfi, Gabor; Clemens, Bela; Csanadi, Zoltan

    2013-10-01

    We describe a patient with the coincidence of 2 ion channel disorders with autosomal dominant inheritance: Brugada syndrome, a potentially fatal cardiac condition, and cryptogenic focal epilepsy, likely due to a neurologic channelopathy. Although Brugada syndrome was discovered incidentally, most of the clinical features of epilepsy in this patient shared the risk factor characteristics of sudden unexplained death in epilepsy syndrome. This case provides additional information on the potential interaction between ion channel abnormalities in the heart and in the brain. Furthermore, it may suggest that patients with epilepsy at increased risk for sudden unexplained death in epilepsy syndrome should undergo a careful cardiac evaluation.

  2. Transcranial brain sonography in Parkinson's disease with restless legs syndrome.

    Science.gov (United States)

    Kwon, Do-Young; Seo, Woo-Keun; Yoon, Ho-Kyoung; Park, Moon-Ho; Koh, Seong-Beom; Park, Kun-Woo

    2010-07-30

    Substantia nigra (SN) hyperechogenicity assessed by transcranial brain sonography (TCS) is a characteristic finding in idiopathic Parkinson's disease (PD). In contrast, SN hypoechogenicity on TCS has been recently demonstrated in restless legs syndrome (RLS). RLS is one of the most common sleep problems in PD, but the pathophysiologic relationship between these two disorders has not been thoroughly elucidated. We compared the SN echogenicities of PD patients with and without RLS to investigate whether comorbid RLS in PD affects SN echogenicity and to explain the echogenic differences between idiopathic RLS (iRLS) and secondary PD-related RLS (pRLS). Sixty-three PD patients (median age 64.6 +/- 10.6 years), 40 iRLS patients (53.1 +/- 11.7 years), and 40 healthy controls (69.1 +/- 2.3 years) were enrolled in our study. All subjects answered a sleep questionnaire and underwent TCS. PD patients were subdivided into two groups, PD with RLS (PD+RLS, n = 26) and PD without RLS (PD-RLS, n = 37), and the sonographic findings of each group were compared. Although significant hyperechogenicity was detected in both the SN and SN/midbrain ratios in both PD subgroups compared with the controls and the iRLS group (P hypoechogenicity. In conclusion, comorbid RLS in PD did not have an impact on the sonographic SN findings. These results suggest that the pathogenesis of pRLS and iRLS involve different mechanisms. Further study will be required to clarify the association between RLS and PD.

  3. Failure of the Nemo trial: bumetanide is a promising agent to treat many brain disorders but not newborn seizures

    Directory of Open Access Journals (Sweden)

    Yehezkel eBen-Ari

    2016-04-01

    Full Text Available The diuretic bumetanide failed to treat acute seizures due to hypoxic ischemic encephalopathy (HIE in newborn babies and was associated with hearing loss (NEMO trial; 1. On the other hand, clinical and experimental observations suggest that the diuretic might provide novel therapy for many brain disorders including autistic spectrum disorder, schizophrenia, Rett syndrome and Parkinson disease. Here, we discuss the differences between the pathophysiology of severe recurrent seizures in the neonates and neurological and psychiatric disorders stressing the uniqueness of severe seizures in newborn in comparison to other disorders.

  4. Failure of the Nemo Trial: Bumetanide Is a Promising Agent to Treat Many Brain Disorders but Not Newborn Seizures.

    Science.gov (United States)

    Ben-Ari, Yehezkel; Damier, Philippe; Lemonnier, Eric

    2016-01-01

    The diuretic bumetanide failed to treat acute seizures due to hypoxic ischemic encephalopathy (HIE) in newborn babies and was associated with hearing loss (NEMO trial, Pressler et al., 2015). On the other hand, clinical and experimental observations suggest that the diuretic might provide novel therapy for many brain disorders including Autism Spectrum Disorders (ASD), schizophrenia, Rett syndrome, and Parkinson disease. Here, we discuss the differences between the pathophysiology of severe recurrent seizures in the neonates and neurological and psychiatric disorders stressing the uniqueness of severe seizures in newborn in comparison to other disorders.

  5. Aging and Intellectual Disability: Insights from Mouse Models of Down Syndrome

    Science.gov (United States)

    Ruparelia, Aarti; Pearn, Matthew L.; Mobley, William C.

    2013-01-01

    Down syndrome (DS) is one of many causes of intellectual disability (ID), others including but not limited to, fetal alcohol syndrome, Fragile X syndrome, Rett syndrome, Williams syndrome, hypoxia, and infection. Down syndrome is characterized by a number of neurobiological problems resulting in learning and memory deficits and early onset…

  6. Aging and Intellectual Disability: Insights from Mouse Models of Down Syndrome

    Science.gov (United States)

    Ruparelia, Aarti; Pearn, Matthew L.; Mobley, William C.

    2013-01-01

    Down syndrome (DS) is one of many causes of intellectual disability (ID), others including but not limited to, fetal alcohol syndrome, Fragile X syndrome, Rett syndrome, Williams syndrome, hypoxia, and infection. Down syndrome is characterized by a number of neurobiological problems resulting in learning and memory deficits and early onset…

  7. Prenatal pharmacotherapy rescues brain development in a Down's syndrome mouse model.

    Science.gov (United States)

    Guidi, Sandra; Stagni, Fiorenza; Bianchi, Patrizia; Ciani, Elisabetta; Giacomini, Andrea; De Franceschi, Marianna; Moldrich, Randal; Kurniawan, Nyoman; Mardon, Karine; Giuliani, Alessandro; Calzà, Laura; Bartesaghi, Renata

    2014-02-01

    Intellectual impairment is a strongly disabling feature of Down's syndrome, a genetic disorder of high prevalence (1 in 700-1000 live births) caused by trisomy of chromosome 21. Accumulating evidence shows that widespread neurogenesis impairment is a major determinant of abnormal brain development and, hence, of intellectual disability in Down's syndrome. This defect is worsened by dendritic hypotrophy and connectivity alterations. Most of the pharmacotherapies designed to improve cognitive performance in Down's syndrome have been attempted in Down's syndrome mouse models during adult life stages. Yet, as neurogenesis is mainly a prenatal event, treatments aimed at correcting neurogenesis failure in Down's syndrome should be administered during pregnancy. Correction of neurogenesis during the very first stages of brain formation may, in turn, rescue improper brain wiring. The aim of our study was to establish whether it is possible to rescue the neurodevelopmental alterations that characterize the trisomic brain with a prenatal pharmacotherapy with fluoxetine, a drug that is able to restore post-natal hippocampal neurogenesis in the Ts65Dn mouse model of Down's syndrome. Pregnant Ts65Dn females were treated with fluoxetine from embryonic Day 10 until delivery. On post-natal Day 2 the pups received an injection of 5-bromo-2-deoxyuridine and were sacrificed after either 2 h or after 43 days (at the age of 45 days). Untreated 2-day-old Ts65Dn mice exhibited a severe neurogenesis reduction and hypocellularity throughout the forebrain (subventricular zone, subgranular zone, neocortex, striatum, thalamus and hypothalamus), midbrain (mesencephalon) and hindbrain (cerebellum and pons). In embryonically treated 2-day-old Ts65Dn mice, precursor proliferation and cellularity were fully restored throughout all brain regions. The recovery of proliferation potency and cellularity was still present in treated Ts65Dn 45-day-old mice. Moreover, embryonic treatment restored

  8. Children experience cognitive decline despite reversal of brain atrophy one year after resolution of Cushing syndrome.

    Science.gov (United States)

    Merke, Deborah P; Giedd, Jay N; Keil, Margaret F; Mehlinger, Sarah L; Wiggs, E A; Holzer, Stuart; Rawson, Erin; Vaituzis, A Catherine; Stratakis, Constantine A; Chrousos, George P

    2005-05-01

    Adults with Cushing syndrome frequently develop brain atrophy, memory impairment, and depression, with partial to complete resolution after cure. The effect of excess glucocorticoid exposure on the brain of children has not been systematically studied. Eleven children (six girls, five boys; ages, 8-16 yr) with endogenous Cushing syndrome seen at the National Institutes of Health Clinical Center from 1999-2000 and 10 healthy age- and sex-matched control subjects were studied. Cognitive and psychological evaluations and magnetic resonance imaging of the brain were done before and 1 yr after cure for patients with Cushing syndrome and once for controls. The estimated duration of Cushing syndrome was 4.4 +/- 1.2 yr. When compared with control subjects, children with Cushing syndrome had significantly smaller cerebral volumes (P Cushing syndrome experienced a significant (P brain of children appears to be different from adults. Despite rapid reversibility of cerebral atrophy, children experience a significant decline in cognitive function 1 yr after correction of hypercortisolism.

  9. Abnormal brain magnetic resonance imaging in two patients with Smith-Magenis syndrome.

    Science.gov (United States)

    Maya, Idit; Vinkler, Chana; Konen, Osnat; Kornreich, Liora; Steinberg, Tamar; Yeshaya, Josepha; Latarowski, Victoria; Shohat, Mordechai; Lev, Dorit; Baris, Hagit N

    2014-08-01

    Smith-Magenis syndrome (SMS) is a clinically recognizable contiguous gene syndrome ascribed to an interstitial deletion in chromosome 17p11.2. Seventy percent of SMS patients have a common deletion interval spanning 3.5 megabases (Mb). Clinical features of SMS include characteristic mild dysmorphic features, ocular anomalies, short stature, brachydactyly, and hypotonia. SMS patients have a unique neurobehavioral phenotype that includes intellectual disability, self-injurious behavior and severe sleep disturbance. Little has been reported in the medical literature about anatomical brain anomalies in patients with SMS. Here we describe two patients with SMS caused by the common deletion in 17p11.2 diagnosed using chromosomal microarray (CMA). Both patients had a typical clinical presentation and abnormal brain magnetic resonance imaging (MRI) findings. One patient had subependymal periventricular gray matter heterotopia, and the second had a thin corpus callosum, a thin brain stem and hypoplasia of the cerebellar vermis. This report discusses the possible abnormal MRI images in SMS and reviews the literature on brain malformations in SMS. Finally, although structural brain malformations in SMS patients are not a common feature, we suggest baseline routine brain imaging in patients with SMS in particular, and in patients with chromosomal microdeletion/microduplication syndromes in general. Structural brain malformations in these patients may affect the decision-making process regarding their management.

  10. Increased levels of carbonic anhydrase II in the developing Down syndrome brain.

    Science.gov (United States)

    Palminiello, Sonia; Kida, Elizabeth; Kaur, Kulbir; Walus, Marius; Wisniewski, Krystyna E; Wierzba-Bobrowicz, Teresa; Rabe, Ausma; Albertini, Giorgio; Golabek, Adam A

    2008-01-23

    By using a proteomic approach, we found increased levels of carbonic anhydrase II (CA II) in the brain of Ts65Dn mice, a mouse model for Down syndrome (DS). Further immunoblot analyses showed that the levels of CA II are increased not only in the brain of adult Ts65Dn mice but also in the brain of infants and young children with DS. Cellular localization of the enzyme in human brain, predominantly in the oligodendroglia and primitive vessels in fetal brain and in the oligodendroglia and some GABAergic neurons postnatally, was similar in DS subjects and controls. Given the role of CA II in regulation of electrolyte and water balance and pH homeostasis, up-regulation of CA II may reflect a compensatory mechanism mobilized in response to structural/functional abnormalities in the developing DS brain. However, this up-regulation may also have an unfavorable effect by increasing susceptibility to seizures of children with DS.

  11. Diminished brain resilience syndrome: A modern day neurological pathology of increased susceptibility to mild brain trauma, concussion, and downstream neurodegeneration

    OpenAIRE

    Morley, Wendy A.; Stephanie Seneff

    2014-01-01

    The number of sports-related concussions has been steadily rising in recent years. Diminished brain resilience syndrome is a term coined by the lead author to describe a particular physiological state of nutrient functional deficiency and disrupted homeostatic mechanisms leading to increased susceptibility to previously considered innocuous concussion. We discuss how modern day environmental toxicant exposure, along with major changes in our food supply and lifestyle practices, profoundly red...

  12. Divergent structural brain abnormalities between different genetic subtypes of children with Prader–Willi syndrome

    OpenAIRE

    Lukoshe, Akvile; White, Tonya; Schmidt, Marcus N.; van der Lugt, Aad; Hokken-Koelega, Anita C.

    2013-01-01

    Background Prader–Willi syndrome (PWS) is a complex neurogenetic disorder with symptoms that indicate not only hypothalamic, but also a global, central nervous system (CNS) dysfunction. However, little is known about developmental differences in brain structure in children with PWS. Thus, our aim was to investigate global brain morphology in children with PWS, including the comparison between different genetic subtypes of PWS. In addition, we performed exploratory cortical and subcortical foc...

  13. Brain imaging in cerebellar ataxia associated with autoimmune polyglandular syndrome type 2.

    Science.gov (United States)

    Manto, Mario; Jissendi, P

    2012-07-01

    Autoimmune polyglandular syndrome (APS) type 2 (Schmidt syndrome) is a disorder characterized by a combination of autoimmune adrenal insufficiency, autoimmune thyroid disease, and type 1 autoimmune diabetes mellitus. We describe the first case of subacute cerebellar syndrome associated with APS type 2. Brain magnetic resonance imaging showed atrophy of the cerebellum and the vermis, as well as of the anterior pituitary gland. Magnetic resonance spectroscopy showed decreased N-acetylaspartate/creatine ratio in the cerebellum and in the pons. Our findings expand the spectrum of neurological deficits in APS type 2 and underlines that cerebellar pathways may be a main target of the disorder. © 2010 by the American Society of Neuroimaging.

  14. Epidermal Nevus Syndrome Associated with Brain Malformations and Medulloblastoma

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-01-01

    Full Text Available Researchers at Juntendo University and Tokyo Women’s Medical University, Japan; and University of California, San Francisco, Ca, report a male infant with epidermal nevus syndrome associated with brainstem and cerebellar malformations and neonatal medulloblastoma.

  15. Multispectral brain morphometry in Tourette syndrome persisting into adulthood.

    OpenAIRE

    Draganski, B.; Martino, D.; Cavanna, A. E.; Hutton, C.; Orth, M; Robertson, M M; Critchley, H. D.; Frackowiak, R S

    2010-01-01

    Tourette syndrome is a childhood-onset neuropsychiatric disorder with a high prevalence of attention deficit hyperactivity and obsessive-compulsive disorder co-morbidities. Structural changes have been found in frontal cortex and striatum in children and adolescents. A limited number of morphometric studies in Tourette syndrome persisting into adulthood suggest ongoing structural alterations affecting frontostriatal circuits. Using cortical thickness estimation and voxel-based analysis of T1-...

  16. Brain-derived neurotrophic factor and neuropsychiatric disorders.

    Science.gov (United States)

    Autry, Anita E; Monteggia, Lisa M

    2012-04-01

    Brain derived neurotrophic factor (BDNF) is the most prevalent growth factor in the central nervous system (CNS). It is essential for the development of the CNS and for neuronal plasticity. Because BDNF plays a crucial role in development and plasticity of the brain, it is widely implicated in psychiatric diseases. This review provides a summary of clinical and preclinical evidence for the involvement of this ubiquitous growth factor in major depressive disorder, schizophrenia, addiction, Rett syndrome, as well as other psychiatric and neurodevelopmental diseases. In addition, the review includes a discussion of the role of BDNF in the mechanism of action of pharmacological therapies currently used to treat these diseases, such antidepressants and antipsychotics. The review also covers a critique of experimental therapies such as BDNF mimetics and discusses the value of BDNF as a target for future drug development.

  17. Progressive brain atrophy in Schinzel-Giedion syndrome with a SETBP1 mutation.

    Science.gov (United States)

    Takeuchi, Akihito; Okamoto, Nobuhiko; Fujinaga, Shoko; Morita, Hirosuke; Shimizu, Junya; Akiyama, Tomoyuki; Ninomiya, Shinsuke; Takanashi, Jun-ichi; Kubo, Toshihide

    2015-08-01

    Schinzel-Giedion syndrome is a rare congenital malformation syndrome. Recently, SETBP1 was identified as the causative gene. Herein, we present a Japanese boy with Schinzel-Giedion syndrome resulting from a novel mutation in SETBP1 in order to establish the clinical features and serial MRI findings associated with the syndrome. On the third day of life, the boy was referred to our hospital because of facial abnormalities and feeding difficulty. Midfacial retraction, frontal bossing, deep groove under the eyes, upturned nose, low-set ears, bilateral cryptorchidism, and generalized hypertrichosis were identified on admission. At the age of 7 months, epileptic spasms in series occurred. Based on characteristic facial and skeletal abnormalities and severe developmental delay, we clinically diagnosed him with Schinzel-Giedion syndrome. Direct sequencing of the SETBP1 gene revealed a heterozygous mutation (p.Ile871Ser) in exon 4. Although neither cardiac defect nor choanal stenosis were present in our case, the phenotype of our case was nearly identical to those of previously reported cases confirmed by genetic analysis. Serial MRI from the age of 1 month-3 years revealed progressive brain atrophy, especially in the white matter and basal ganglia. However, myelination was age-appropriate and no obvious abnormal signals in the white matter were seen. Diffusion weighted imaging revealed no abnormal findings. Accumulation of MRI data including diffusion weighted imaging from Schinzel-Giedion syndrome cases is needed to understand the mechanism underlying progressive brain atrophy in this syndrome.

  18. A case of a Tunisian Rett patient with a novel double-mutation of the MECP2 gene

    Energy Technology Data Exchange (ETDEWEB)

    Fendri-Kriaa, Nourhene, E-mail: nourhene.fendri@gmail.com [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Hsairi, Ines [Service de Neurologie Infantile, C.H.U. Hedi Chaker de Sfax (Tunisia); Kifagi, Chamseddine [Laboratoire internationale associe LIA135, Centre de Biotechnologie de Sfax (Tunisia); Ellouze, Emna [Service de Neurologie Infantile, C.H.U. Hedi Chaker de Sfax (Tunisia); Mkaouar-Rebai, Emna [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Triki, Chahnez [Service de Neurologie Infantile, C.H.U. Hedi Chaker de Sfax (Tunisia); Fakhfakh, Faiza [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia)

    2011-06-03

    Highlights: {yields} Sequencing of the MECP2 gene, modeling and comparison of the two variants were performed in a Tunisian classical Rett patient. {yields} A double-mutation: a new and de novo mutation c.535C > T and the common one c.763C > T of the MECP2 gene was identified. {yields} The P179S transition may change local electrostatic properties which may affect the function and stability of the protein MeCP2. -- Abstract: Rett syndrome is an X-linked dominant disorder caused frequently by mutations in the methyl-CpG-binding protein 2 gene (MECP2). Rett patients present an apparently normal psychomotor development during the first 6-18 months of life. Thereafter, they show a short period of developmental stagnation followed by a rapid regression in language and motor development. The aim of this study was to perform a mutational analysis of the MECP2 gene in a classical Rett patient by sequencing the corresponding gene and modeling the found variants. The results showed the presence of a double-mutation: a new and de novo mutation c.535C > T (p.P179S) and the common c.763C > T (p.R255X) transition of the MECP2 gene. The p.P179S mutation was located in a conserved amino acid in CRIR domain (corepressor interacting region). Modeling results showed that the P179S transition could change local electrostatic properties by adding a negative charge due to serine hydroxyl group of this region of MeCP2 which may affect the function and stability of the protein. The p.R255X mutation is located in TRD-NLS domain (transcription repression domain-nuclear localization signal) of MeCP2 protein.

  19. Association of Symptoms Following Mild Traumatic Brain Injury With Posttraumatic Stress Disorder vs Postconcussion Syndrome

    DEFF Research Database (Denmark)

    Lagarde, E.; Salmi, L. R.; Holm, L. W.

    2014-01-01

    IMPORTANCE A proportion of patients experience long-lasting symptoms following mild traumatic brain injury (MTBI). The postconcussion syndrome (PCS), included in the DSM-IV, has been proposed to describe this condition. Because these symptoms are subjective and common to other conditions, there i...

  20. Reduced cell number in the neocortical part of the human fetal brain in Down syndrome

    DEFF Research Database (Denmark)

    Larsen, K.B.; Laursen, H.; Graem, N.

    2008-01-01

    Mental retardation is seen in all individuals with Down syndrome (DS) and different brain abnormalities are reported. The aim of this study was to investigate if mental retardation at least in part is a result of a lower cell number in the neocortical part of the human fetal forebrain. We therefore...

  1. Trajectories of Early Brain Volume Development in Fragile X Syndrome and Autism

    Science.gov (United States)

    Hazlett, Heather Cody; Poe, Michele D.; Lightbody, Amy A.; Styner, Martin; MacFall, James R.; Reiss, Allan L.; Piven, Joseph

    2012-01-01

    Objective: To examine patterns of early brain growth in young children with fragile X syndrome (FXS) compared with a comparison group (controls) and a group with idiopathic autism. Method: The study included 53 boys 18 to 42 months of age with FXS, 68 boys with idiopathic autism (autism spectrum disorder), and a comparison group of 50 typically…

  2. Brief Report: CANTAB Performance and Brain Structure in Pediatric Patients with Asperger Syndrome

    Science.gov (United States)

    Kaufmann, Liane; Zotter, Sibylle; Pixner, Silvia; Starke, Marc; Haberlandt, Edda; Steinmayr-Gensluckner, Maria; Egger, Karl; Schocke, Michael; Weiss, Elisabeth M.; Marksteiner, Josef

    2013-01-01

    By merging neuropsychological (CANTAB/Cambridge Neuropsychological Test Automated Battery) and structural brain imaging data (voxel-based-morphometry) the present study sought to identify the neurocognitive correlates of executive functions in individuals with Asperger syndrome (AS) compared to healthy controls. Results disclosed subtle group…

  3. Functional brain asymmetry, attentional modulation, and interhemispheric transfer in boys with Tourette syndrome

    DEFF Research Database (Denmark)

    Plessen, Kerstin J; Lundervold, Arvid; Grüner, Renate

    2007-01-01

    We tested the hypothesis that children with Tourette syndrome (TS) would exhibit aberrant brain lateralization compared to a healthy control (HC) group in an attention-modulation version of a verbal dichotic listening task using consonant-vowel syllables. The modulation of attention to focus...

  4. Gene, Brain, and Behavior Relationships in Fragile X Syndrome: Evidence from Neuroimaging Studies

    Science.gov (United States)

    Lightbody, Amy A.; Reiss, Allan L.

    2009-01-01

    Fragile X syndrome (FraX) remains the most common inherited cause of intellectual disability and provides a valuable model for studying gene-brain-behavior relationships. Over the past 15 years, structural and functional magnetic resonance imaging studies have emerged with the goal of better understanding the neural pathways contributing to the…

  5. European clinical guidelines for Tourette syndrome and other tic disorders. Part IV : deep brain stimulation

    NARCIS (Netherlands)

    Mueller-Vahl, Kirsten R.; Cath, Danielle C.; Cavanna, Andrea E.; Dehning, Sandra; Porta, Mauro; Robertson, Mary M.; Visser-Vandewalle, Veerle

    2011-01-01

    Ten years ago deep brain stimulation (DBS) has been introduced as an alternative and promising treatment option for patients suffering from severe Tourette syndrome (TS). It seemed timely to develop a European guideline on DBS by a working group of the European Society for the Study of Tourette Synd

  6. Gene, Brain, and Behavior Relationships in Fragile X Syndrome: Evidence from Neuroimaging Studies

    Science.gov (United States)

    Lightbody, Amy A.; Reiss, Allan L.

    2009-01-01

    Fragile X syndrome (FraX) remains the most common inherited cause of intellectual disability and provides a valuable model for studying gene-brain-behavior relationships. Over the past 15 years, structural and functional magnetic resonance imaging studies have emerged with the goal of better understanding the neural pathways contributing to the…

  7. Stimulant: A correlate of brain fag syndrome among undergraduate ...

    African Journals Online (AJOL)

    2014-07-29

    Jul 29, 2014 ... “brain fag” since this was a phrase used by the students to describe the .... year for students, hence the motivation to use psychoactive substances”. ... began lectures. Approval .... was less number of females attending school.

  8. Circadian cycle-dependent MeCP2 and brain chromatin changes.

    Science.gov (United States)

    Martínez de Paz, Alexia; Sanchez-Mut, Jose Vicente; Samitier-Martí, Mireia; Petazzi, Paolo; Sáez, Mauricio; Szczesna, Karolina; Huertas, Dori; Esteller, Manel; Ausió, Juan

    2015-01-01

    Methyl CpG binding protein 2 (MeCP2) is a chromosomal protein of the brain, very abundant especially in neurons, where it plays an important role in the regulation of gene expression. Hence it has the potential to be affected by the mammalian circadian cycle. We performed expression analyses of mice brain frontal cortices obtained at different time points and we found that the levels of MeCP2 are altered circadianly, affecting overall organization of brain chromatin and resulting in a circadian-dependent regulation of well-stablished MeCP2 target genes. Furthermore, this data suggests that alterations of MeCP2 can be responsible for the sleeping disorders arising from pathological stages, such as in autism and Rett syndrome.

  9. Malignant neuroleptic syndrome following deep brain stimulation surgery: a case report

    Directory of Open Access Journals (Sweden)

    Stavrinou Lampis C

    2011-06-01

    Full Text Available Abstract Background The neuroleptic malignant syndrome is an uncommon but dangerous complication characterized by hyperthermia, autonomic dysfunction, altered mental state, hemodynamic dysregulation, elevated serum creatine kinase, and rigor. It is most often caused by an adverse reaction to anti-psychotic drugs or abrupt discontinuation of neuroleptic or anti-parkinsonian agents. To the best of our knowledge, it has never been reported following the common practice of discontinuation of anti-parkinsonian drugs during the pre-operative preparation for deep brain stimulation surgery for Parkinson's disease. Case presentation We present the first case of neuroleptic malignant syndrome associated with discontinuation of anti-parkinsonian medication prior to deep brain stimulation surgery in a 54-year-old Caucasian man. Conclusion The characteristic neuroleptic malignant syndrome symptoms can be attributed to other, more common causes associated with deep brain stimulation treatment for Parkinson's disease, thus requiring a high index of clinical suspicion to timely establish the correct diagnosis. As more centers become eligible to perform deep brain stimulation, neurologists and neurosurgeons alike should be aware of this potentially fatal complication. Timely activation of the deep brain stimulation system may be important in accelerating the patient's recovery.

  10. Alzheimer-like neurotransmitter deficits in adult Down's syndrome brain tissue.

    Science.gov (United States)

    Godridge, H; Reynolds, G P; Czudek, C; Calcutt, N A; Benton, M

    1987-01-01

    Brain tissue taken at necropsy from five cases of Down's syndrome and six controls was analysed for changes in neurotransmitter markers. Concentrations of noradrenaline (NA), dopamine (DA) and its major metabolite homovanillic acid (HVA), 5-hydroxytryptamine (5HT) and its metabolite 5-hydroxyindoleacetic acid (5HIAA) were determined by means of HPLC, whilst choline acetyltransferase (ChAT) was measured by a radiochemical technique. Significant reductions in NA, 5HT and ChAT were found in most cortical and subcortical regions of the Down's syndrome tissue investigated. The neuropathological lesions were assessed using a fluorescent stain for neuritic plaques and neurofibrillary tangles. These were present to varying extents in every Down's syndrome case except the youngest but were not found in control tissue of comparable age. The results indicate profound transmitter deficits and neuropathological abnormalities in adult patients with Down's syndrome, which closely resemble those of Alzheimer's disease. PMID:2440994

  11. Marble brain syndrome: osteopetrosis, renal acidosis and calcification of the brain

    Energy Technology Data Exchange (ETDEWEB)

    Jacquemin, C.; Mullaney, P.; Svedberg, E. [King Khaled Eye Specialist Hospital, Riyadh (Saudi Arabia)

    1998-10-01

    Cerebral calcification in children is frequently associated with systemic metabolic disease. We present a case of ``marble brain syntrome``, which showed this abnormality. (orig.) (orig.) With 2 figs.

  12. Differential Diagnosis Tool for Parkinsonian Syndrome Using Multiple Structural Brain Measures

    Directory of Open Access Journals (Sweden)

    Miho Ota

    2013-01-01

    Full Text Available Clinical differentiation of parkinsonian syndromes such as the Parkinson variant of multiple system atrophy (MSA-P and cerebellar subtype (MSA-C from Parkinson's disease is difficult in the early stage of the disease. To identify the correlative pattern of brain changes for differentiating parkinsonian syndromes, we applied discriminant analysis techniques by magnetic resonance imaging (MRI. T1-weighted volume data and diffusion tensor images were obtained by MRI in eighteen patients with MSA-C, 12 patients with MSA-P, 21 patients with Parkinson’s disease, and 21 healthy controls. They were evaluated using voxel-based morphometry and tract-based spatial statistics, respectively. Discriminant functions derived by step wise methods resulted in correct classification rates of 0.89. When differentiating these diseases with the use of three independent variables together, the correct classification rate was the same as that obtained with step wise methods. These findings support the view that each parkinsonian syndrome has structural deviations in multiple brain areas and that a combination of structural brain measures can help to distinguish parkinsonian syndromes.

  13. Metabolic syndrome and the immunologic affair with the blood-brain barrier

    Directory of Open Access Journals (Sweden)

    Claudio eMauro

    2015-01-01

    Full Text Available Epidemiological studies reveal an increased incidence of obesity worldwide, which is associated with increased prevalence and severity of cognitive disorders. The blood brain barrier represents the interface between the peripheral circulation and the brain, and plays a fundamental role in the cross-talk between these two compartments. The homeostatic function of the blood-brain barrier is the protection of the brain from peripheral insult/inflammation. Alterations in the function of the blood-brain barrier lead to pathologies of the central nervous system. Recently, metabolic imbalance has been shown to be an important risk factor associated with the decline of blood-brain barrier integrity and function. This has direct etiological consequences to a variety of cerebrovascular and neurodegenerative pathologies with great impact to society. Priority areas for future preclinical research include strategies to improve clinicians’ ability to diagnose, prevent, and manage blood-brain barrier abnormalities. In sharp contrast with epidemiological studies and clinical needs, little is known about the mechanisms that link metabolic syndrome to blood-brain barrier functionality and cognitive disorders. Our view is that immune responses caused by metabolic stress might play a major role in this conundrum.

  14. Neuroinflammation in the Aging Down Syndrome Brain; Lessons from Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Donna M. Wilcock

    2012-01-01

    Full Text Available Down syndrome (DS is the most genetic cause of mental retardation and is caused by the triplication of chromosome 21. In addition to the disabilities caused early in life, DS is also noted as causing Alzheimer's-disease-like pathological changes in the brain, leading to 50–70% of DS patients showing dementia by 60–70 years of age. Inflammation is a complex process that has a key role to play in the pathogenesis of Alzheimer's disease. There is relatively little understood about inflammation in the DS brain and how the genetics of DS may alter this inflammatory response and change the course of disease in the DS brain. The goal of this review is to highlight our current understanding of inflammation in Alzheimer's disease and predict how inflammation may affect the pathology of the DS brain based on this information and the known genetic changes that occur due to triplication of chromosome 21.

  15. Neuroinflammation in the aging down syndrome brain; lessons from Alzheimer's disease.

    Science.gov (United States)

    Wilcock, Donna M

    2012-01-01

    Down syndrome (DS) is the most genetic cause of mental retardation and is caused by the triplication of chromosome 21. In addition to the disabilities caused early in life, DS is also noted as causing Alzheimer's-disease-like pathological changes in the brain, leading to 50-70% of DS patients showing dementia by 60-70 years of age. Inflammation is a complex process that has a key role to play in the pathogenesis of Alzheimer's disease. There is relatively little understood about inflammation in the DS brain and how the genetics of DS may alter this inflammatory response and change the course of disease in the DS brain. The goal of this review is to highlight our current understanding of inflammation in Alzheimer's disease and predict how inflammation may affect the pathology of the DS brain based on this information and the known genetic changes that occur due to triplication of chromosome 21.

  16. Diminished brain resilience syndrome: A modern day neurological pathology of increased susceptibility to mild brain trauma, concussion, and downstream neurodegeneration.

    Science.gov (United States)

    Morley, Wendy A; Seneff, Stephanie

    2014-01-01

    The number of sports-related concussions has been steadily rising in recent years. Diminished brain resilience syndrome is a term coined by the lead author to describe a particular physiological state of nutrient functional deficiency and disrupted homeostatic mechanisms leading to increased susceptibility to previously considered innocuous concussion. We discuss how modern day environmental toxicant exposure, along with major changes in our food supply and lifestyle practices, profoundly reduce the bioavailability of neuro-critical nutrients such that the normal processes of homeostatic balance and resilience are no longer functional. Their diminished capacity triggers physiological and biochemical 'work around' processes that result in undesirable downstream consequences. Exposure to certain environmental chemicals, particularly glyphosate, the active ingredient in the herbicide, Roundup(®), may disrupt the body's innate switching mechanism, which normally turns off the immune response to brain injury once danger has been removed. Deficiencies in serotonin, due to disruption of the shikimate pathway, may lead to impaired melatonin supply, which reduces the resiliency of the brain through reduced antioxidant capacity and alterations in the cerebrospinal fluid, reducing critical protective buffering mechanisms in impact trauma. Depletion of certain rare minerals, overuse of sunscreen and/or overprotection from sun exposure, as well as overindulgence in heavily processed, nutrient deficient foods, further compromise the brain's resilience. Modifications to lifestyle practices, if widely implemented, could significantly reduce this trend of neurological damage.

  17. Functional Brain Imaging in Cornelia de Lange Syndrome: Case Report and Literature review.

    Science.gov (United States)

    Silva-Hernández, Frieda; Rodríguez-Cuadrado, Gloria I; Martin-Ruaigip, Ralph J; Barreras-Ávila, Lourdes; González-Chevere, Brenda; Valentin-Rivera, Roberto; Labat-Alvarez, Eduardo

    2015-01-01

    Functional brain imaging with brain single photon emission computer tomography (Brain SPECT) has been used for many years in the evaluation of multiple neuro-degenerative and neuro-developmental disorders. Brain SPECT is a nuclear medicine tomographic study performed with a lipophilic radiopharmaceutical labeled with 99mTc-pertechnetate. It is a cerebral perfusion agent that depicts the global and regional perfusion patterns in the cortical gray matter and subcortical structures. Cornelia de Lange syndrome (CdLS) is a rare neuro-developmental and genetic condition, associated to several malformations. There are a limited number of cases reported in the medical literature and few of them report neuro-radiological and/or neuro-pathologic abnormalities. We report a case of a 15 year old patient, clinically diagnosed at birth with CdLS, who presents limited anatomical findings on Computed Tomography and Magnetic Resonance Imaging. To the best of our knowledge, this is the first report of the Brain SPECT findings in this syndrome.

  18. Brain and behavioral pathology in an animal model of Wernicke's encephalopathy and Wernicke-Korsakoff Syndrome.

    Science.gov (United States)

    Vetreno, Ryan P; Ramos, Raddy L; Anzalone, Steven; Savage, Lisa M

    2012-02-03

    Animal models provide the opportunity for in-depth and experimental investigation into the anatomical and physiological underpinnings of human neurological disorders. Rodent models of thiamine deficiency have yielded significant insight into the structural, neurochemical and cognitive deficits associated with thiamine deficiency as well as proven useful toward greater understanding of memory function in the intact brain. In this review, we discuss the anatomical, neurochemical and behavioral changes that occur during the acute and chronic phases of thiamine deficiency and describe how rodent models of Wernicke-Korsakoff Syndrome aid in developing a more detailed picture of brain structures involved in learning and memory.

  19. Altered brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease).

    Science.gov (United States)

    Earley, Christopher J; Connor, James; Garcia-Borreguero, Diego; Jenner, Peter; Winkelman, John; Zee, Phyllis C; Allen, Richard

    2014-11-01

    Restless legs syndrome (RLS), also known as Willis-Ekbom Disease (WED), is a sensorimotor disorder for which the exact pathophysiology remains unclear. Brain iron insufficiency and altered dopaminergic function appear to play important roles in the etiology of the disorder. This concept is based partly on extensive research studies using cerebrospinal fluid (CSF), autopsy material, and brain imaging indicating reduced regional brain iron and on the clinical efficacy of dopamine receptor agonists for alleviating RLS symptoms. Finding causal relations, linking low brain iron to altered dopaminergic function in RLS, has required however the use of animal models. These models have provided insights into how alterations in brain iron homeostasis and dopaminergic system may be involved in RLS. The results of animal models of RLS and biochemical, postmortem, and imaging studies in patients with the disease suggest that disruptions in brain iron trafficking lead to disturbances in striatal dopamine neurotransmission for at least some patients with RLS. This review examines the data supporting an iron deficiency-dopamine metabolic theory of RLS by relating the results from animal model investigations of the influence of brain iron deficiency on dopaminergic systems to data from clinical studies in patients with RLS. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Cognitive functioning in relation to brain amyloid-β in healthy adults with Down syndrome.

    Science.gov (United States)

    Hartley, Sigan L; Handen, Benjamin L; Devenny, Darlynne A; Hardison, Regina; Mihaila, Iulia; Price, Julie C; Cohen, Annie D; Klunk, William E; Mailick, Marsha R; Johnson, Sterling C; Christian, Bradley T

    2014-09-01

    Nearly all adults with Down syndrome show neuropathology of Alzheimer's disease, including amyloid-β deposition, by their fifth decade of life. In the current study, we examined the association between brain amyloid-β deposition, assessed via in vivo assessments of neocortical Pittsburgh compound B, and scores on an extensive neuropsychological battery of measures of cognitive functioning in 63 adults (31 male, 32 female) with Down syndrome aged 30-53 years who did not exhibit symptoms of dementia. Twenty-two of the adults with Down syndrome were identified as having elevated neocortical Pittsburgh compound B retention levels. There was a significant positive correlation (r = 0.62, P Down syndrome who had elevated neocortical Pittsburgh compound B retention levels and those who did not on any of the neuropsychological measures. Similarly, when examining Pittsburgh compound B as a continuous variable, after controlling for mental age and chronological age, only the Rivermead Picture Recognition score was significantly negatively associated with neocortical Pittsburgh compound B retention. Our findings indicate that many adults with Down syndrome can tolerate amyloid-β deposition without deleterious effects on cognitive functioning. However, we may have obscured true effects of amyloid-β deposition by controlling for chronological age in our analyses. Moreover, our sample included adults with Down syndrome who were most 'resistant' to the effects of amyloid-β deposition, as adults already exhibiting clinical symptoms of dementia symptoms were excluded from the study.

  1. Muscle-Eye-Brain Disease; a Rare Form of Syndromic Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Gosal Gurinder S

    2011-03-01

    Full Text Available Congenital muscular dystrophy (CMD is a heterogeneous group of disorders characterized by muscular hypotonia since birth and the histologic features of muscular dystrophy. Syndromic congenital muscular dystrophies are clinically similar autosomal recessive disorders characterized by congenital muscular dystrophy, lissencephaly, and eye anomalies. We present a case of a rare form of syndromic congenital muscular dystrophy in an eight year old girl, born of first- degree consanguinity. She had: global developmental delay; a seizure disorder; hypotonia; progressive muscle contractures including bilateral symmetrical flexion contractures of hips, knees, equinus contracture and thoracolumbar scoliosis; diminished deep tendon reflexes: bilateral premature cataract; pseudophakia; and nystagmus. The patient was also highly myopic. Based on clinical features, muscle biopsy and MRI of the brain, a diagnosis of muscle- eye- brain disease was made. Identification of these patients may help to prevent this crippling disorder in the future siblings of probands by utilizing genetic counselling and mutation analysis.

  2. Anesthetic management of deep brain stimulator implantation in Meige′s syndrome

    Directory of Open Access Journals (Sweden)

    Kalpesh V Bhoyar

    2012-01-01

    Full Text Available Meige′s syndrome is rare form of orofacial dystonia. There is unfortunately no cure, but occasionally patients may improve with time. We present the successful management of a palladial deep brain stimulator (DBS implantation for Meige′s syndrome. Dexmedetomidine infusion was used for sedation. The procedure lasted for around 12 h and the patient was comfortable, responsive, and cooperative over the extended period of time. The surgeons were comfortable with electrophysiologic brain mapping and clinical testing. DBS were implanted, through a burr hole, into the globus pallidus neurophysiological testing under guidance. The pulse generator battery was subcutaneously implanted into the chest wall under general anesthesia. The implanted pulse generator battery was started 2 days later and the patient showed dramatic improvement in his symptoms.

  3. Brain aging and metabolic syndrome: a study in Cenischia Valley (Piedmont).

    OpenAIRE

    Marianna Rinaldi; Giuseppe Graffi; Salvatore Gallone; Emma Rabino Massa

    2011-01-01

    The Metabolic Syndrome (MetS) is a set of conditions, each of which represents a risk factor for cardiovascular disease (central obesity, hyperglycemia, dyslipidemia and hypertension). Recent studies have identified an association between MetS and increased risk of dementia (Vascular Dementia and Late Onset Alzheimer's Disease ). The purpose of our research is the study of brain aging and cognitive decline in a sample of elderly people (n=200) belonging to a rural alpine community, in r...

  4. Multimodal imaging of mild traumatic brain injury and persistent postconcussion syndrome

    OpenAIRE

    Dean, PJA; Sato, JR; Vieira, G.; McNamara, A; Sterr, A

    2014-01-01

    Background: Persistent postconcussion syndrome (PCS) occurs in around 5– 10% of individuals after mild traumatic brain injury (mTBI), but research into the underlying biology of these ongoing symptoms is limited and inconsistent. One reason for this could be the heterogeneity inherent to mTBI, with individualized injury mechanisms and psychological factors. A multimodal imaging study may be able to characterize the injury better. Aim: To look at the relationship between functional (fMRI), str...

  5. Hind brain agenesis a rare imaging findings in cerebro cerebellar lissencephalic syndrome.

    Science.gov (United States)

    Mundaganur, Praveen M; Solwalkar, Pradeep; Nimbal, Vishal

    2014-01-01

    A case report of cerebro cerebellar lissencephaly shows complete agenesis of cerebellum and brainstem which is rare imaging finding of group lissencephaly (type I lissencephaly). Though agenesis of cerebellum and brainstem were included in literature, in most of the cases we saw a hypoplasia or atrophy of cerebellum in lissencephaly syndrome. The CT scan findings of this patient shows features of lissencephaly with complete agenesis of brain stem and cerebellum associated with multiple congenital abnormalities.

  6. [Lowe syndrome revealed by prenatal diagnosis of congenital cataract with brain abnormalities].

    Science.gov (United States)

    Zéphir, P; Decramer, S; Sartor, A; Vayssière, C

    2014-05-01

    Congenital cataract is a rare disease whose incidence is estimated to 0.5% of birth in France. A study of the literature shows that congenital cataract is idiopathic in 50% of cases, hereditary forms representing 25% of cases. Other causes of congenital cataract are represented by viral embryofoetopathies acquired during pregnancy, metabolic disorders and chromosomal aberrations within the scope of malformative syndromes. The authors report the case of a neonatal diagnosis of Lowe syndrome suspected by the discovery of bilateral cataract initially isolated. The morphological exploration was completed by secondary brain abnormalities (periventricular lesions). The etiological prenatal exploration was negative. Lowe syndrome is a rare cause of antenatal cataract, which so far only one case has been reported.

  7. Chronic pain and evoked responses in the brain: A magnetoencephalographic study in Complex Regional Pain Syndrome I and II

    NARCIS (Netherlands)

    Theuvenet, P.J.

    2012-01-01

    Complex Regional Pain Syndrome (CRPS) type I and II are chronic pain syndromes with comparable symptoms, only in CRPS II a peripheral nerve injury is present. No objective tests are currently available to differentiate the two types which hampers diagnosis and treatment. Non-invasive brain imaging t

  8. Brain MR Contribution to the Differential Diagnosis of Parkinsonian Syndromes: An Update

    Science.gov (United States)

    De Blasi, Roberto; Grasso, Daniela; Savica, Rodolfo

    2016-01-01

    Brain magnetic resonance (MR) represents a useful and feasible tool for the differential diagnosis of Parkinson's disease. Conventional MR may reveal secondary forms of parkinsonism and may show peculiar brain alterations of atypical parkinsonian syndromes. Furthermore, advanced MR techniques, such as morphometric-volumetric analyses, diffusion-weighted imaging, diffusion tensor imaging, tractography, proton MR spectroscopy, and iron-content sensitive imaging, have been used to obtain quantitative parameters useful to increase the diagnostic accuracy. Currently, many MR studies have provided both qualitative and quantitative findings, reflecting the underlying neuropathological pattern of the different degenerative parkinsonian syndromes. Although the variability in the methods and results across the studies limits the conclusion about which technique is the best, specific radiologic phenotypes may be identified. Qualitative/quantitative MR changes in the substantia nigra do not discriminate between different parkinsonisms. In the absence of extranigral abnormalities, the diagnosis of PD is more probable, whereas basal ganglia changes (mainly in the putamen) suggest the diagnosis of an atypical parkinsonian syndrome. In this context, changes in pons, middle cerebellar peduncles, and cerebellum suggest the diagnosis of MSA, in midbrain and superior cerebellar peduncles the diagnosis of PSP, and in whole cerebral hemispheres (mainly in frontoparietal cortex with asymmetric distribution) the diagnosis of Corticobasal Syndrome. PMID:27774334

  9. Brain MR Contribution to the Differential Diagnosis of Parkinsonian Syndromes: An Update

    Directory of Open Access Journals (Sweden)

    Giovanni Rizzo

    2016-01-01

    Full Text Available Brain magnetic resonance (MR represents a useful and feasible tool for the differential diagnosis of Parkinson’s disease. Conventional MR may reveal secondary forms of parkinsonism and may show peculiar brain alterations of atypical parkinsonian syndromes. Furthermore, advanced MR techniques, such as morphometric-volumetric analyses, diffusion-weighted imaging, diffusion tensor imaging, tractography, proton MR spectroscopy, and iron-content sensitive imaging, have been used to obtain quantitative parameters useful to increase the diagnostic accuracy. Currently, many MR studies have provided both qualitative and quantitative findings, reflecting the underlying neuropathological pattern of the different degenerative parkinsonian syndromes. Although the variability in the methods and results across the studies limits the conclusion about which technique is the best, specific radiologic phenotypes may be identified. Qualitative/quantitative MR changes in the substantia nigra do not discriminate between different parkinsonisms. In the absence of extranigral abnormalities, the diagnosis of PD is more probable, whereas basal ganglia changes (mainly in the putamen suggest the diagnosis of an atypical parkinsonian syndrome. In this context, changes in pons, middle cerebellar peduncles, and cerebellum suggest the diagnosis of MSA, in midbrain and superior cerebellar peduncles the diagnosis of PSP, and in whole cerebral hemispheres (mainly in frontoparietal cortex with asymmetric distribution the diagnosis of Corticobasal Syndrome.

  10. Vici Syndrome: A Rare Autosomal Recessive Syndrome with Brain Anomalies, Cardiomyopathy, and Severe Intellectual Disability

    Directory of Open Access Journals (Sweden)

    R. Curtis Rogers

    2011-01-01

    Full Text Available Purpose. The objective of this study was to present and describe two additional patients diagnosed with Vici syndrome. Methods. Clinical, laboratory, and imaging findings of the two siblings are discussed in detail. The two patients' descriptions are compared with the other eleven patients reported in the literature. We also presented detailed autopsy results on the male sibling, which demonstrated cytoplasmic vacuoles of the cardiomyocytes and confirmed the clinical findings. Results. The patients reported here include the 13th and 14th patients reported with Vici syndrome. The summary of findings present in these patients includes postnatal growth retardation, developmental delay, bilateral cataracts, agenesis of the corpus callosum, cerebellar anomalies, gyral abnormalities, seizures, hypotonia, and cardiomyopathy. Conclusion. Vici syndrome should be suspected in any child with agenesis of the corpus callosum and one of the following findings: cardiomyopathy, cataracts, immune deficiency, or cutaneous hypopigmentation.

  11. Apert and Crouzon syndromes-Cognitive development, brain abnormalities, and molecular aspects.

    Science.gov (United States)

    Fernandes, Marilyse B L; Maximino, Luciana P; Perosa, Gimol B; Abramides, Dagma V M; Passos-Bueno, Maria Rita; Yacubian-Fernandes, Adriano

    2016-06-01

    Apert and Crouzon are the most common craniosynostosis syndromes associated with mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. We conducted a study to examine the molecular biology, brain abnormalities, and cognitive development of individuals with these syndromes. A retrospective longitudinal review of 14 patients with Apert and Crouzon syndromes seen at the outpatient Craniofacial Surgery Hospital for Rehabilitation of Craniofacial Anomalies in Brazil from January 1999 through August 2010 was performed. Patients between 11 and 36 years of age (mean 18.29 ± 5.80), received cognitive evaluations, cerebral magnetic resonance imaging, and molecular DNA analyses. Eight patients with Apert syndrome (AS) had full scale intelligence quotients (FSIQs) that ranged from 47 to 108 (mean 76.9 ± 20.2), and structural brain abnormalities were identified in five of eight patients. Six patients presented with a gain-of-function mutation (p.Ser252Trp) in FGFR2 and FSIQs in those patients ranged from 47 to78 (mean 67.2 ± 10.7). One patient with a gain-of-function mutation (p.Pro253Arg) had a FSIQ of 108 and another patient with an atypical splice mutation (940-2A →G) had a FSIQ of 104. Six patients with Crouzon syndrome had with mutations in exons IIIa and IIIc of FGFR2 and their FSIQs ranged from 82 to 102 (mean 93.5 ± 6.7). These reveal that molecular aspects are another factor that can be considered in studies of global and cognitive development of patients with Apert and Crouzon syndrome (CS). © 2016 Wiley Periodicals, Inc.

  12. Quantitative magnetic resonance imaging and studies of degenerative diseases of the developing human brain

    Energy Technology Data Exchange (ETDEWEB)

    Caviness, V.S. Jr. (Massachusetts General Hospital, Boston, MA (United States)); Phil, D.; Filipek, P.A.; Kennedy, D.N.

    1992-05-01

    The Rett syndrome is a progressive disorder which is associated with regression of psychomotor development and precipitous deceleration of brain growth during the first year of life. General histopathological surveys in postmortem specimens have identified degeneration of subpopulations of neurons of the nigrostriatal system but no other evidence of degenerative process. Magnetic resonance imaging-based morphometry may usefully guide application of rigorous but demanding quantitative histologic search for evidence of neuronal degeneration. The volumes of the principal set of cortical and nuclear structures of principal interest in the disorder may be measured by currently avaiable MRI-based methods. Opimized levels of precision now allow detection of volumetric changes over time in the same brain of approximately 10% at the 95% confidence level. (author).

  13. Deep brain electrophysiological recordings provide clues to the pathophysiology of Tourette syndrome.

    Science.gov (United States)

    Priori, Alberto; Giannicola, Gaia; Rosa, Manuela; Marceglia, Sara; Servello, Domenico; Sassi, Marco; Porta, Mauro

    2013-07-01

    Although ample evidence suggests that high-frequency deep brain stimulation (DBS) is an effective therapy in patients with Tourette syndrome (TS), its pathophysiology and the neurophysiological mechanisms underlying these benefits remain unclear. The DBS targets mainly used to date in TS are located within the basal ganglia-thalamo-cortical circuit compromised in this syndrome: the medial and ventral thalamic nuclei, which are way stations within the circuit, the globus pallidus and the nucleus accumbens. Neuronal activity can be electrophysiologically recorded from deep brain structures during DBS surgery (intraoperative microrecordings) or within few days after DBS electrode implantation (local field potentials, LFPs). Recordings from the thalamus in patients with TS showed that the power in low-frequency oscillations (2-15 Hz) was higher than power in high frequency oscillations (Neurophysiological recordings from deep brain structures suggest that tics originate not from the cortex but from neuronal dysfunction in deep brain structures such as the thalamus and globus pallidus. In conclusion, DBS can induce its beneficial effects in TS by modulating specific neural rhythms in the cortico-basal ganglia thalamic network. DBS could reduce tics related increased low-frequency activity by shifting the basal ganglia-thalamic oscillation power to higher frequencies. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Posterior reversible encephalopathy syndrome (PRES, an acute neurological syndrome due to reversible multifactorial brain edema: a case report

    Directory of Open Access Journals (Sweden)

    Camilla Cicognani

    2013-04-01

    Full Text Available Background: The essential features of Posterior Reversible Encephalopathy Syndrome (PRES are headache, mental changes, seizures, visual symptoms and often arterial hypertension. Brain RMN typically shows cortico-sottocortical parieto-occipital edema, with a bilateral and symmetric distribution. PRES develops in clinical conditions as hypertensive encephalopathy, preeclampsia/ eclampsia, autoimmune diseases, after transplantation, infections and as an adverse effect of immunosuppressive drugs or chemotherapy. It usually completely reverses with treatment, although permanent sequelae are possible in case of delayed or missed diagnosis. Case report: We describe the case of a transsexual (M!F and tetraplegic patient, admitted for neck and low back pain. She suddenly developed headache, confusion, seizures and severe hypertension with normal blood tests. RMN showed multiple cortico-sottocortical areas of vasogenic and citotoxic edema in temporo-occipital, parietal, frontal, and cerebellar regions. Soon after the beginning of the antihypertensive therapy, clinical recovery was observed, as well as the disappearance of edema at RMN. Discussion and conclusions: Although PRES is usually associated with definite pathological conditions, it is not always the case, as was for the patient here described, who had no predisposing factors in her past clinical history, and presented hypertension only in the acute phase of the syndrome. Since, moreover, PRES usually presents with acute non specific features and it can be misdiagnosed with other serious diseases, the clinician will be helped by the knowledge of this syndrome to promptly start diagnostic workup and treatments, and avoid permanent neurological deficits.

  15. Integration of Brain and Skull in Prenatal Mouse Models of Apert and Crouzon Syndromes

    Directory of Open Access Journals (Sweden)

    Susan M. Motch Perrine

    2017-07-01

    Full Text Available The brain and skull represent a complex arrangement of integrated anatomical structures composed of various cell and tissue types that maintain structural and functional association throughout development. Morphological integration, a concept developed in vertebrate morphology and evolutionary biology, describes the coordinated variation of functionally and developmentally related traits of organisms. Syndromic craniosynostosis is characterized by distinctive changes in skull morphology and perceptible, though less well studied, changes in brain structure and morphology. Using mouse models for craniosynostosis conditions, our group has precisely defined how unique craniosynostosis causing mutations in fibroblast growth factor receptors affect brain and skull morphology and dysgenesis involving coordinated tissue-specific effects of these mutations. Here we examine integration of brain and skull in two mouse models for craniosynostosis: one carrying the FGFR2c C342Y mutation associated with Pfeiffer and Crouzon syndromes and a mouse model carrying the FGFR2 S252W mutation, one of two mutations responsible for two-thirds of Apert syndrome cases. Using linear distances estimated from three-dimensional coordinates of landmarks acquired from dual modality imaging of skull (high resolution micro-computed tomography and magnetic resonance microscopy of mice at embryonic day 17.5, we confirm variation in brain and skull morphology in Fgfr2cC342Y/+ mice, Fgfr2+/S252W mice, and their unaffected littermates. Mutation-specific variation in neural and cranial tissue notwithstanding, patterns of integration of brain and skull differed only subtly between mice carrying either the FGFR2c C342Y or the FGFR2 S252W mutation and their unaffected littermates. However, statistically significant and substantial differences in morphological integration of brain and skull were revealed between the two mutant mouse models, each maintained on a different strain. Relative

  16. Diminished brain resilience syndrome: A modern day neurological pathology of increased susceptibility to mild brain trauma, concussion, and downstream neurodegeneration

    Directory of Open Access Journals (Sweden)

    Wendy A Morley

    2014-01-01

    Full Text Available The number of sports-related concussions has been steadily rising in recent years. Diminished brain resilience syndrome is a term coined by the lead author to describe a particular physiological state of nutrient functional deficiency and disrupted homeostatic mechanisms leading to increased susceptibility to previously considered innocuous concussion. We discuss how modern day environmental toxicant exposure, along with major changes in our food supply and lifestyle practices, profoundly reduce the bioavailability of neuro-critical nutrients such that the normal processes of homeostatic balance and resilience are no longer functional. Their diminished capacity triggers physiological and biochemical ′work around′ processes that result in undesirable downstream consequences. Exposure to certain environmental chemicals, particularly glyphosate, the active ingredient in the herbicide, Roundup; , may disrupt the body′s innate switching mechanism, which normally turns off the immune response to brain injury once danger has been removed. Deficiencies in serotonin, due to disruption of the shikimate pathway, may lead to impaired melatonin supply, which reduces the resiliency of the brain through reduced antioxidant capacity and alterations in the cerebrospinal fluid, reducing critical protective buffering mechanisms in impact trauma. Depletion of certain rare minerals, overuse of sunscreen and/or overprotection from sun exposure, as well as overindulgence in heavily processed, nutrient deficient foods, further compromise the brain′s resilience. Modifications to lifestyle practices, if widely implemented, could significantly reduce this trend of neurological damage.

  17. Diffusion tensor imaging and magnetic resonance spectroscopy of the brain in a patient with Sturge-Weber syndrome

    NARCIS (Netherlands)

    Sijens, P. E.; Gieteling, E. W.; Meiners, L. C.; Sival, D. A.; Potze, J. H.; Irwan, R.; Oudkerk, M.

    2006-01-01

    Quantitative brain MR spectroscopy (MRS) and diffusion tensor imaging (DTI) were used to characterize one patient with Sturge-Weber syndrome. Choline increases and N-acetylaspartate decreases were observed in pathologic frontal gray matter tissue compared to contralateral unaffected brain tissue wit

  18. Classification of Parkinsonian Syndromes from FDG-PET Brain Data Using Decision Trees with SSM/PCA Features

    NARCIS (Netherlands)

    Mudali, D.; Teune, L. K.; Renken, R. J.; Leenders, K. L.; Roerdink, J. B. T. M.

    2015-01-01

    Medical imaging techniques like fluorodeoxyglucose positron emission tomography (FDG-PET) have been used to aid in the differential diagnosis of neurodegenerative brain diseases. In this study, the objective is to classify FDG-PET brain scans of subjects with Parkinsonian syndromes (Parkinson's dise

  19. Gene, environment, and brain-gut interactions in irritable bowel syndrome.

    Science.gov (United States)

    Fukudo, Shin; Kanazawa, Motoyori

    2011-04-01

    The genetic predisposition and influence of environment may underlie in the pathogenesis and/or pathophysiology of irritable bowel syndrome (IBS). This phenomenon, gene x environment interaction together with brain-gut interactions is emerging area to be clarified in IBS research. Earlier studies focused on candidate genes of neurotransmitters, cytokines, and growth factors. Among them, some studies but not all studies revealed association between phenotypes of IBS and 5-hydroxytryptamine (5-HT)-related genes, noradrenaline-related genes, and cytokine genes. Recent prospective cohort study showed that genes encoding immune and adhesion molecules were associated with post-infectious etiology of IBS. Psychosocial stressors and intraluminal factors especially microbiota are keys to develop IBS. IBS patients may have abnormal gut microbiota as well as increased organic acids. IBS is disorder that relates to brain-gut interactions, emotional dysregulation, and illness behaviors. Brain imaging with or without combination of visceral stimulation enables us to depict the detailed information of brain-gut interactions. In IBS patients, thalamus, insula, anterior cingulate cortex, amygdala, and brainstem were more activated in response to visceral stimulation than controls. Corticotropin-releasing hormone and 5-HT are the candidate substances which regulate exaggerated brain-gut response. In conclusion, gene x environment interaction together with brain-gut interactions may play crucial roles in IBS development. Further fundamental research on this issue is warranted.

  20. Metabolic syndrome--psycho neuropathogenesis and human brain evolution.

    Science.gov (United States)

    Perumal, Madhusoothanan Bhagavathi

    2011-01-01

    Metabolic syndrome (MS) is a major risk factor for coronary artery disease. Heightened hypothalamo-pituitary-adrenal axis activity is associated with pathogenesis of MS. Life style, food habits and physical activity also play critical role in the pathogenesis of MS. However, the precise neurophysiology behind chronic stress leading on to such effects is unknown. Review of recent animal and human studies have shown the subtle differences in morphological changes associated with chronic stress between medial prefrontal cortex and amygdaloid complex. The loss of dendritic spines in pyramidal neurons of medial prefrontal cortex, dendritic hypertrophy in basolateral amygdala and dendritic loss in central nucleus of amygdala causes increased basal output from amygdaloid complex to HPA axis and other targets whose networks are evolutionarily well conserved. The increased HPA axis activity, elevated blood pressure and appetite for high calorie diet leads to MS. The evolution of isocortex in primates and associated regression in size of limbic structures predisposed to increased synaptic noise in amygdaloid complex which in turn cause heighetened output from amygdala during chronic stress. Copyright © 2010 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  1. Wernicke-Korsakoff syndrome and the use of brain imaging.

    Science.gov (United States)

    Jauhar, P; Montaldi, D

    2000-01-01

    The proportion of patients with Korsakoff psychosis (KP) who have a history of Wernicke's encephalopathy is smaller in recent studies compared to previous studies. Neuropsychological tests, magnetic resonance imaging (MRI), and single photon emission computed tomography were conducted in eight patients with KP, only four of whom had had a documented Wernicke episode. All subjects showed amnesia without intellectual deterioration. MRI abnormalities were seen in each group to the same extent (atrophy of mammillary bodies, to a less extent thalamus and some generalized gyral atrophy). No MRI measure differentiated the groups. Cerebral blood flow showed reduction of flow to the anterior temporal regions bilaterally, extending to the parietal lobes, to the same degree in each group. Despite the small number of patients examined, the study supports the belief that patients with an insidious onset of KP have the same pathology as those with classical Wernicke-Korsakoff syndrome. This raises the question of whether episodes of alcohol withdrawal without adequate thiamine protection result in occasionally subclinical Wernicke's events, followed by a subsequently diagnosable KP.

  2. Brief report: CANTAB performance and brain structure in pediatric patients with Asperger syndrome.

    Science.gov (United States)

    Kaufmann, Liane; Zotter, Sibylle; Pixner, Silvia; Starke, Marc; Haberlandt, Edda; Steinmayr-Gensluckner, Maria; Egger, Karl; Schocke, Michael; Weiss, Elisabeth M; Marksteiner, Josef

    2013-06-01

    By merging neuropsychological (CANTAB/cambridge neuropsychological test automated battery) and structural brain imaging data (voxel-based-morphometry) the present study sought to identify the neurocognitive correlates of executive functions in individuals with Asperger syndrome (AS) compared to healthy controls. Results disclosed subtle group differences regarding response speed on only one CANTAB subtest that is thought to tap fronto-executive network functions (SWM/spatial working memory). Across all participants, SWM performance was significantly associated with two brain regions (precentral gyrus white matter, precuneus grey matter), thus suggesting a close link between fronto-executive functions (SWM) and circumscribed fronto-parietal brain structures. Finally, symptom severity (ADOS total score) was best predicted by response speed on a set-shifting task (IES) thought to tap fronto-striatal functions (corrected R2 56%).

  3. Familial Alzheimer's disease: genetic analysis related to disease heterogeneity, Down syndrome and human brain evolution.

    Science.gov (United States)

    Schapiro, M B; Rapoport, S I

    1989-01-01

    Etiologically heterogeneous subgroups of patients with Alzheimer's disease (AD) exist and need to be distinguished so as to better identify genetic causes of familial cases. Furthermore, the presence of AD neuropathology in Down syndrome (trisomy 21) subjects older than 35 years suggests that AD in some cases is caused by dysregulation of expression of genes on chromosome 21. Cerebral metabolic abnormalities in life, and the distribution of AD neuropathology in the post-mortem brain, indicate that AD involves the association neocortices and subcortical regions with which they evolved during evolution of the human brain. Accordingly, understanding the molecular basis of this evolution should elucidate the genetic basis of AD, whereas knowing the genetics of AD should be informative about the genomic changes which promoted brain evolution.

  4. Olfaction evaluation and correlation with brain atrophy in Bardet-Biedl syndrome.

    Science.gov (United States)

    Braun, J-J; Noblet, V; Durand, M; Scheidecker, S; Zinetti-Bertschy, A; Foucher, J; Marion, V; Muller, J; Riehm, S; Dollfus, H; Kremer, S

    2014-12-01

    Bardet-Biedl syndrome (BBS) is a well-recognized ciliopathy characterized by cardinal features namely: early onset retinitis pigmentosa, polydactyly, obesity, hypogonadism, renal and cognitive impairment. Recently, disorders of olfaction (anosmia, hyposmia) have been also described in BBS patients. Moreover, morphological brain anomalies have been reported and prompt for further investigations to determine whether they are primary or secondary to peripheral organ involvement (i.e. visual or olfactory neuronal tissue). The objective of this article is to evaluate olfactory disorders in BBS patients and to investigate putative correlation with morphological cerebral anomalies. To this end, 20 BBS patients were recruited and evaluated for olfaction using the University of Pennsylvania Smell Identification Test (UPSIT). All of them underwent a structural magnetic resonance imaging (MRI) scan. We first investigated brain morphological differences between BBS subjects and 14 healthy volunteers. Then, we showed objective olfaction disorders in BBS patients and highlight correlation between gray matter volume reduction and olfaction dysfunction in several brain areas.

  5. Caught in the thickness of brain fog: exploring the cognitive symptoms of Chronic Fatigue Syndrome

    Directory of Open Access Journals (Sweden)

    Anthony James Ocon

    2013-04-01

    Full Text Available Chronic Fatigue Syndrome (CFS is defined as greater than 6 months of persistent fatigue that is experienced physically and cognitively. The cognitive symptoms are generally thought to be a mild cognitive impairment, but individuals with CFS subjectively describe them as brain fog. The impairment is not fully understood and often is described as slow thinking, difficulty focusing, confusion, lack of concentration, forgetfulness, or a haziness in thought processes. Causes of brain fog and mild cognitive impairment have been investigated. Possible physiological correlates may be due to the effects of chronic orthostatic intolerance in the form of the Postural Tachycardia Syndrome and decreases in cerebral blood flow. In addition, fMRI studies suggest that individuals with CFS may require increased cortical and subcortical brain activation to complete difficult mental tasks. Furthermore, neurocognitive testing in CFS has demonstrated deficits in speed and efficiency of information processing, attention, concentration, and working memory. The cognitive impairments are then perceived as an exaggerated mental fatigue. As a whole, this is experienced by those with CFS as brain fog and may be viewed as the interaction of physiological, cognitive, and perceptual factors. Thus, the cognitive symptoms of CFS may be due to altered cerebral blood flow activation and regulation that are exacerbated by a stressor, such as orthostasis or a difficult mental task, resulting in the decreased ability to readily process information, which is then perceived as fatiguing and experienced as brain fog. Future research looks to further explore these interactions, how they produce cognitive impairments, and explain the perception of brain fog from a mechanistic standpoint.

  6. Higher frequency of brain abnormalities in neuromyelitis optica spectrum disorder patients without primary Sjögren’s syndrome

    Institute of Scientific and Technical Information of China (English)

    Li-na Gu; Min Zhang; Hui Zhu; Jing-yao Liu

    2016-01-01

    Neuromyelitis optica spectrum disorder otfen co-exists with primary Sjögren’s syndrome. We compared the clinical features of 16 neuro-myelitis optica spectrum disorder patients with (n = 6) or without primary Sjögren’s syndrome (n = 10). All patients underwent extensive clinical, laboratory, and MRI evaluations. hTere were no statistical differences in demographics or ifrst neurological involvement at onset between neuromyelitis optica spectrum disorder patients with and without primary Sjögren’s syndrome. The laboratory findings of cerebrospinal lfuid oligoclonal banding, serum C-reactive protein, antinuclear autoantibody, anti-Sjögren’s-syndrome-related antigen A an-tibodies, anti-Sjögren’s-syndrome-related antigen B antibodies, and anti-Sm antibodies were signiifcantly higher in patients with primary Sjö gren’s syndrome than those without. Anti-aquaporin 4 antibodies were detectable in 67% (4/6) of patients with primary Sjögren’s syndrome and in 60% (6/10) of patients without primary Sjögren’s syndrome. More brain abnormalities were observed in patients without primary Sjögren’s syndrome than in those with primary Sjögren’s syndrome. Segments lesions (> 3 centrum) were noted in 50% (5/10) of patients without primary Sjögren’s syndrome and in 67% (4/6) of patients with primary Sjögren’s syndrome. hTese ifndings indicate that the clinical characteristics of neuromyelitis optica spectrum disorder patients with and without primary Sjögren’s syndrome are similar. However, neu-romyelitis optica spectrum disorder patients without primary Sjögren’s syndrome have a high frequency of brain abnormalities.

  7. Higher frequency of brain abnormalities in neuromyelitis optica spectrum disorder patients without primary Sjögren's syndrome.

    Science.gov (United States)

    Gu, Li-Na; Zhang, Min; Zhu, Hui; Liu, Jing-Yao

    2016-10-01

    Neuromyelitis optica spectrum disorder often co-exists with primary Sjögren's syndrome. We compared the clinical features of 16 neuromyelitis optica spectrum disorder patients with (n = 6) or without primary Sjögren's syndrome (n = 10). All patients underwent extensive clinical, laboratory, and MRI evaluations. There were no statistical differences in demographics or first neurological involvement at onset between neuromyelitis optica spectrum disorder patients with and without primary Sjögren's syndrome. The laboratory findings of cerebrospinal fluid oligoclonal banding, serum C-reactive protein, antinuclear autoantibody, anti-Sjögren's-syndrome-related antigen A antibodies, anti-Sjögren's-syndrome-related antigen B antibodies, and anti-Sm antibodies were significantly higher in patients with primary Sjögren's syndrome than those without. Anti-aquaporin 4 antibodies were detectable in 67% (4/6) of patients with primary Sjögren's syndrome and in 60% (6/10) of patients without primary Sjögren's syndrome. More brain abnormalities were observed in patients without primary Sjögren's syndrome than in those with primary Sjögren's syndrome. Segments lesions (> 3 centrum) were noted in 50% (5/10) of patients without primary Sjögren's syndrome and in 67% (4/6) of patients with primary Sjögren's syndrome. These findings indicate that the clinical characteristics of neuromyelitis optica spectrum disorder patients with and without primary Sjögren's syndrome are similar. However, neuromyelitis optica spectrum disorder patients without primary Sjögren's syndrome have a high frequency of brain abnormalities.

  8. Effects of long-term treatment on brain volume in patients with obstructive sleep apnea syndrome.

    Science.gov (United States)

    Kim, Hosung; Joo, EunYeon; Suh, Sooyeon; Kim, Jae-Hun; Kim, Sung Tae; Hong, Seung Bong

    2016-01-01

    We assessed structural brain damage in obstructive sleep apnea syndrome (OSA) patients (21 males) and the effects of long-term continuous positive airway pressure (CPAP) treatment (18.2 ± 12.4 months; 8-44 months) on brain structures and investigated the relationship between severity of OSA and effects of treatment. Using deformation-based morphometry to measure local volume changes, we identified widespread neocortical and cerebellar atrophy in untreated patients compared to controls (59 males; Cohen's D = 0.6; FDR brain volume following treatment (FDR 64) presented with prefrontal atrophy and displayed an additional volume increase in this area following treatment. Higher impairment of working memory in patients prior to treatment correlated with prefrontal volume increase after treatment. The large overlap between the initial brain damage and the extent of recovery after treatment suggests partial recovery of nonpermanent structural damage. Volume increases in the dentate gyrus and the dentate nucleus possibly likely indicate compensatory neurogenesis in response to diminishing oxidative stress. Such changes in other brain structures may explain gliosis, dendritic volume increase, or inflammation. This study provides neuroimaging evidence that revealed the positive effects of long-term CPAP treatment in patients with OSA.

  9. Decreased serum levels of brain-derived neurotrophic factor in schizophrenic patients with deficit syndrome

    Directory of Open Access Journals (Sweden)

    Akyol ES

    2015-03-01

    Full Text Available Esra Soydas Akyol,1 Yakup Albayrak,2 Murat Beyazyüz,3 Nurkan Aksoy,4 Murat Kuloglu,5 Kenji Hashimoto6 1Deparment of Psychiatry, Yenimahalle Education and Research Hospital, Ankara, Turkey; 2Department of Psychiatry, Faculty of Medicine, Namik Kemal University, Tekirdag, Turkey; 3Department of Psychiatry, Biga State Hospital, Çanakkale, Turkey; 4Department of Biochemistry, Yenimahalle Education and Research Hospital, Ankara, Turkey; 5Department of Psychiatry, Faculty of Medicine, Akdeniz University, Antalya, Turkey; 6Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan Background: Brain-derived neurotrophic factor (BDNF is a well-established neurotrophin that plays a role in the pathophysiology of numerous psychiatric disorders. Many studies have investigated the serum BDNF levels in patients with schizophrenia. However, there are restricted data in the literature that compare the serum BDNF levels in patients with deficit and nondeficit syndromes. In this study, we aimed to compare the serum BDNF levels between schizophrenic patients with deficit or nondeficit syndrome and healthy controls.Methods: After fulfilling the inclusion and exclusion criteria, 58 patients with schizophrenia and 36 healthy controls were included in the study. The patients were grouped as deficit syndrome (N=23 and nondeficit syndrome (N=35 according to the Schedule for the Deficit Syndrome. Three groups were compared in terms of the sociodemographic and clinical variants and serum BDNF levels.Results: The groups were similar in terms of age, sex, body mass index, and smoking status. The serum BDNF levels in patients with deficit syndrome were significantly lower than those in healthy controls. In contrast, the serum BDNF levels in patients with nondeficit syndrome were similar to those in healthy controls.Conclusion: This study suggests that decreased BDNF levels may play a role in the pathophysio­logy of schizophrenic

  10. Brain-derived neurotrophic factor and exercise in fibromyalgia syndrome patients: a mini review.

    Science.gov (United States)

    Nugraha, Boya; Karst, Matthias; Engeli, Stefan; Gutenbrunner, Christoph

    2012-09-01

    Fibromyalgia syndrome (FMS) is a common chronic pain condition characterized by chronic widespread pain and decreased pain threshold, with hyperalgesia and allodynia. Associated signs include fatigue, morning stiffness, non-restorative sleep, mood disturbance, depression, irritable bowel syndrome, and headache. In addition to the administration of drugs, psychological therapies treatment of FMS mainly consists of physical therapies. Although the precise pathogenesis of FMS remains elucidated, modern understanding conceptualizes FMS as central sensitization as a consequence of altered endogenous pain- and stress-response system and continuous nociceptive input. Altered brain-derived neurotrophic factor (BDNF) levels in FMS suggest that BDNF--well known for its effects on neuronal plasticity--is involved in this sensitization process. Exercise leads to changes in serum BDNF levels, too. This association highlights the importance of exercise in FMS and other chronic pain conditions.

  11. [Cerebral salt wasting syndrome in a patient with posttraumatic brain injury].

    Science.gov (United States)

    Krysiak, Robert; Okopień, Bogusław

    2012-01-01

    In patients with central nervous system disease, life-threatening hyponatremia can result from either the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or cerebral salt wasting syndrome (CSWS). Both clinical entities share many similar laboratory and clinical findings, and are characterized by low serum osmolality, inappropriately high urine osmolality, and high urine sodium levels. Despite outward similarities, the pathophysiology and treatment of these two conditions are very different. The former is treated with fluid restriction because of the increased level of free water and its dilutional effect causing hyponatremia, whereas the latter is treated with fluid and sodium resuscitation because of the increased loss of high urinary sodium. We present a 24-year-old man who developed CSWS after traumatic brain injury, showing diagnostic and treatment strategies undertaken in this patient and their impact on the course of CSWS. This case report illustrates the need for clinical awareness of CSWS in patients after head trauma.

  12. Sturge-Weber Syndrome: Brain Magnetic Resonance Imaging and Neuropathology Findings.

    Science.gov (United States)

    Pinto, Anna L; Chen, Liam; Friedman, Rachel; Grant, Patricia E; Poduri, Annapurna; Takeoka, Masanori; Prabhu, Sanjay P; Sahin, Mustafa

    2016-05-01

    We describe the brain magnetic resonance imaging (MRI) abnormalities and neuropathologic findings of patients with Sturge-Weber syndrome and medically refractory epilepsy. We reviewed the clinical features, preoperative MRI studies, and pathologic findings of all patients with Sturge-Weber syndrome who underwent excisional surgery for intractable epilepsy at Boston Children's Hospital between 1993 and 2011. Eleven patients (male/female = 4/7) with Sturge-Weber syndrome were identified who underwent surgery for intractable epilepsy (mean age 13 ± 6.2 months), including hemispherectomy (n = 10) and focal cortical resection (n = 1). Mean age at seizure onset was 15 ± 11 weeks. Fifty-five percent (n = 6) of patients exhibited two different types of seizures, and 18% (n = 2) had three types of seizures. Focal clonic seizures were the most common type, occurring in nine patients; apnea was the second most common, occurring in four patients. Brain MRIs were reviewed in five patients. Histopathologic examination revealed varied degrees of cortical morphologic anomaly in seven of 11 patients. Overall, there were no abnormalities in the MRIs that corresponded directly with the pathologic findings except in one patient with polymicrogyria. In spite of pathologic findings of cortical anomalies in varied degrees, these findings could not be readily detected on brain MRIs. The failure to detect focal cortical dysplasia on MRIs may be attributable to the subtle microscopic nature of the abnormalities; in some of the older individuals, the imaging studies available for review were done during an advanced stage of the disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Beneficial effects of herbs, spices and medicinal plants on the metabolic syndrome, brain and cognitive function.

    Science.gov (United States)

    Panickar, Kiran S

    2013-03-01

    Herbs and spices have been used since ancient times to not only improve the flavor of edible food but also to prevent and treat chronic health maladies. While the scientific evidence for the use of such common herbs and medicinal plants then had been scarce or lacking, the beneficial effects observed from such use were generally encouraging. It is, therefore, not surprising that the tradition of using such herbs, perhaps even after the advent of modern medicine, has continued. More recently, due to an increased interest in understanding the nutritional effects of herbs/spices more comprehensively, several studies have examined the cellular and molecular modes of action of the active chemical components in herbs and their biological properties. Beneficial actions of herbs/spices include anti-inflammatory, antioxidant, anti-hypertensive, gluco-regulatory, and anti-thrombotic effects. One major component of herbs and spices is the polyphenols. Some of the aforementioned properties are attributed to the polyphenols and they are associated with attenuating the metabolic syndrome. Detrimental changes associated with the metabolic syndrome over time affect brain and cognitive function. Metabolic syndrome and type-2 diabetes are also risk factors for Alzheimer's disease and stroke. In addition, the neuroprotective effects of herbs and spices have been demonstrated and, whether directly or indirectly, such beneficial effects may also contribute to an improvement in cognitive function. This review evaluates the current evidence available for herbs/spices in potentially improving the metabolic syndrome, as well as their neuroprotective effects on the brain, and cognitive function in animal and human studies.

  14. Neuroinflammation in the Aging Down Syndrome Brain; Lessons from Alzheimer's Disease

    OpenAIRE

    Wilcock, Donna M.

    2012-01-01

    Down syndrome (DS) is the most genetic cause of mental retardation and is caused by the triplication of chromosome 21. In addition to the disabilities caused early in life, DS is also noted as causing Alzheimer's-disease-like pathological changes in the brain, leading to 50–70% of DS patients showing dementia by 60–70 years of age. Inflammation is a complex process that has a key role to play in the pathogenesis of Alzheimer's disease. There is relatively little understood about inflammation ...

  15. From psychosurgery to neuromodulation: deep brain stimulation for intractable Tourette syndrome.

    Science.gov (United States)

    Neuner, Irene; Podoll, Klaus; Janouschek, Hildegard; Michel, Tanja M; Sheldrick, Abigail J; Schneider, Frank

    2009-01-01

    Tourette syndrome is a neuropsychiatric disorder characterized by motor and vocal tics. It is often associated with depression, obsessive-compulsive symptoms, self-injurious behaviour and attention deficit-hyperactivity disorder (ADHD). In intractable patients, neuromodulation using deep brain stimulation (DBS) has widely replaced psychosurgery. Three different key structures are defined for DBS, the medial portion of the thalamus, the globus pallidus internus and the anterior limb of the internal capsule/nucleus accumbens. This is a comprehensive overview on the effect of DBS on motor and non-motor symptoms using different case series and two larger studies.

  16. Antiphospholipid syndrome leading to venous brain thrombosis in an elderly patient

    Directory of Open Access Journals (Sweden)

    Joseph Bruno Bidin Brooks, MD, MSc

    2014-09-01

    Full Text Available Antiphospholipid syndrome (APS is a systemic autoimmune condition characterized by hypercoagulability, venous and/or arterial thromboses, and miscarriages. APS can be diagnosed according to specific criteria and is usually observed in young adults. We report a case of an elderly woman with past history of thrombosis and miscarriages who developed severe brain parenchymal hemorrhage and extensive thrombosis of the superior sagittal sinus due to APS. This case emphasizes that, although rare, APS may be diagnosed in elderly individuals and require effective anticoagulation.

  17. Functional brain asymmetry, attentional modulation, and interhemispheric transfer in boys with Tourette syndrome

    DEFF Research Database (Denmark)

    Plessen, Kerstin J; Lundervold, Arvid; Grüner, Renate

    2007-01-01

    We tested the hypothesis that children with Tourette syndrome (TS) would exhibit aberrant brain lateralization compared to a healthy control (HC) group in an attention-modulation version of a verbal dichotic listening task using consonant-vowel syllables. The modulation of attention to focus...... by exploring the correlations between CC size and left ear score in the forced-left condition. Twenty boys with TS were compared with 20 age- and handedness-matched healthy boys. Results indicated similar performance in the TS and HC groups for lateralization of hemispheric function. TS subjects were also able...

  18. Clinical analysis of the syndrome of inappropriate antidiuretic hormone secretion after brain injury

    Institute of Scientific and Technical Information of China (English)

    蔡加宁; 王国良; 易俊

    2003-01-01

    Objective: To study the diagnosis and treatment of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) after brain injury. Methods: A retrospective analysis was conducted on 12 patients suffered from SIADH after brain injury. The clinical features of these patients were similar to those of common hyponatremia. Most of the hyponatremia were detected by routine examinations. Supplement of salt as the initial treatment was used in these patients. If natremia did not rise or descended 2-3 days after treatment, SIADH was considered or diagnosed. Treatment scheme should be adjusted to limit water and natrium instead of supplying salt. Frusemide and albumin were the first choice for dehydration therapy. Conclusions: Diagnosis of SIADH is difficult before treatment though effective treatment can be obtained if we adopt correct strategy. In these patients, the diagnosis of SIADH is confirmed in the course of treatment.

  19. Neuropsychiatric Outcome of an Adolescent Who Received Deep Brain Stimulation for Tourette's Syndrome

    Directory of Open Access Journals (Sweden)

    S. J. Pullen

    2011-01-01

    Full Text Available This case study followed one adolescent patient who underwent bilateral deep brain stimulation of the centromedian parafascicular complex (CM-Pf for debilitating, treatment refractory Tourette's syndrome for a period of 1.5 years. Neurocognitive testing showed no significant changes between baseline and follow-up assessments. Psychiatric assessment revealed positive outcomes in overall adaptive functioning and reduction in psychotropic medication load in this patient. Furthermore, despite significant baseline psychiatric comorbidity, this patient reported no suicidal ideation following electrode implantation. Deep brain stimulation is increasingly being used in children and adolescents. This case reports on the positive neurologic and neuropsychiatric outcome of an adolescent male with bilateral CM-Pf stimulation.

  20. Location of brain lesions predicts conversion of clinically isolated syndromes to multiple sclerosis

    DEFF Research Database (Denmark)

    Giorgio, Antonio; Battaglini, Marco; Rocca, Maria Assunta

    2013-01-01

    OBJECTIVES: To assess in a large population of patients with clinically isolated syndrome (CIS) the relevance of brain lesion location and frequency in predicting 1-year conversion to multiple sclerosis (MS). METHODS: In this multicenter, retrospective study, clinical and MRI data at onset...... and clinical follow-up at 1 year were collected for 1,165 patients with CIS. On T2-weighted MRI, we generated lesion probability maps of white matter (WM) lesion location and frequency. Voxelwise analyses were performed with a nonparametric permutation-based approach (p ... in 26% of patients. The converting group, despite a greater baseline lesion load compared with the nonconverting group (7 ± 8.1 cm(3) vs 4.6 ± 6.7 cm(3), p distribution (18% vs 25% of brain voxels occupied by lesions). High lesion frequency was found...