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  1. Rett Syndrome

    MedlinePlus

    Rett syndrome is a rare genetic disease that causes developmental and nervous system problems, mostly in girls. It's related to autism spectrum disorder. Babies with Rett syndrome seem to grow and develop normally at first. ...

  2. Rett syndrome: clinical review and genetic update

    PubMed Central

    Weaving, L; Ellaway, C; Gecz, J; Christodoulou, J

    2005-01-01

    Rett syndrome (RS) is a severe neurodevelopmental disorder that contributes significantly to severe intellectual disability in females worldwide. It is caused by mutations in MECP2 in the majority of cases, but a proportion of atypical cases may result from mutations in CDKL5, particularly the early onset seizure variant. The relationship between MECP2 and CDKL5, and whether they cause RS through the same or different mechanisms is unknown, but is worthy of investigation. Mutations in MECP2 appear to give a growth disadvantage to both neuronal and lymphoblast cells, often resulting in skewing of X inactivation that may contribute to the large degree of phenotypic variation. MeCP2 was originally thought to be a global transcriptional repressor, but recent evidence suggests that it may have a role in regulating neuronal activity dependent expression of specific genes such as Hairy2a in Xenopus and Bdnf in mouse and rat. PMID:15635068

  3. Rett Syndrome

    PubMed Central

    Smeets, E.E.J.; Pelc, K.; Dan, B.

    2012-01-01

    Rett syndrome is one of the most common causes of complex disability in girls. It is characterized by early neurological regression that severely affects motor, cognitive and communication skills, by autonomic dysfunction and often a seizure disorder. It is a monogenic X-linked dominant neurodevelopmental disorder related to mutation in MECP2, which encodes the methyl-CpG-binding protein MeCP2. There are several mouse models either based on conditional knocking out of the Mecp2 gene or on a truncating mutation. We discuss the clinical aspects with special emphasis on the behavioral phenotype and we review current perspectives in clinical management alongside with perspectives in altering gene expression. PMID:22670134

  4. Rett Syndrome

    MedlinePlus

    ... binding protein 2 (MeCP2), which is needed for brain development and acts as one of the many biochemical ... the following criteria do not have Rett syndrome: brain injury secondary to ... abnormal psychomotor development in the first 6 months of life. Is ...

  5. Rett Syndrome.

    ERIC Educational Resources Information Center

    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.…

  6. The clinical recognition and differential diagnosis of Rett syndrome.

    PubMed

    Trevathan, E; Naidu, S

    1988-01-01

    Rett syndrome (RS) is characterized by progressive loss of intellectual functioning and fine and gross motor skills as well as development of stereotypic hand movement abnormalities, occurring after 6 to 18 months of normal development. Rett syndrome has been previously reported only in girls, but the possibility of the syndrome existing in male children cannot be currently excluded. Although the syndrome is thought to be relatively common, it was only described in the English literature 5 years ago. There is currently no marker for the syndrome; diagnosis is based on clinical criteria. The newly developed diagnostic criteria for RS are reviewed, with special attention given to the historical aspects of the diagnosis in the prenatal, perinatal, neonatal, and early childhood periods. Rett syndrome is characterized by a predictable, orderly progression of signs and symptoms. Four stages of RS have been described; each stage has special characteristics and offers different diagnostic challenges for the neurologist. Infantile autism is the most common incorrect diagnosis made for children with RS. The simultaneous regression of both motor and language skills, as well as the stereotypic hand movements, hyperventilation, bruxism, and seizures in early childhood are all typical in RS and help distinguish RS from infantile autism.

  7. Improving Treatment Trial Outcomes for Rett Syndrome: the development of Rett-specific anchors for the Clinical Global Impression Scale

    PubMed Central

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

    2015-01-01

    Rett syndrome is a genetically based neurodevelopmental disorder. While the clinical consequences of Rett syndrome are profound and life-long, 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 to 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. PMID:25895911

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

    PubMed

    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.

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

    PubMed

    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. PMID:27491553

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

    PubMed

    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.

  11. Rett networked database: an integrated clinical and genetic network of Rett syndrome databases.

    PubMed

    Grillo, Elisa; Villard, Laurent; Clarke, Angus; Ben Zeev, Bruria; Pineda, Mercedes; Bahi-Buisson, Nadia; Hryniewiecka-Jaworska, Anna; Bienvenu, Thierry; Armstrong, Judith; Roche-Martinez, Ana; Mari, Francesca; Veneselli, Edvige; Russo, Silvia; Vignoli, Aglaia; Pini, Giorgio; Djuric, Milena; Bisgaard, Anne-Marie; Mejaški Bošnjak, Vlatka; Polgár, Noémi; Cogliati, Francesca; Ravn, Kirstine; Pintaudi, Maria; Melegh, Béla; Craiu, Dana; Djukic, Aleksandra; Renieri, Alessandra

    2012-07-01

    Rett syndrome (RTT) is a neurodevelopmental disorder with one principal phenotype and several distinct, atypical variants (Zappella, early seizure onset and congenital variants). Mutations in MECP2 are found in most cases of classic RTT but at least two additional genes, CDKL5 and FOXG1, can 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 can expand indefinitely. Data are entered by a clinician in each center who supervises accuracy. This network was constructed to make available pooled international data for the study of RTT natural history and genotype-phenotype correlation and to indicate the proportion of patients with specific clinical features and mutations. We expect that the network will serve for the recruitment of patients into clinical trials and for developing quality measures to drive up standards of medical management. PMID:22415763

  12. Rett Syndrome: Crossing the Threshold to Clinical Translation

    PubMed Central

    Katz, David M.; Bird, Adrian; Coenraads, Monica; Gray, Steven J.; Menon, Debashish U.; Philpot, Benjamin D.; Tarquinio, Daniel C.

    2016-01-01

    Lying at the intersection between neurobiology and epigenetics, Rett syndrome (RTT) has garnered intense interest in recent years, not only from a broad range of academic scientists, but also from the pharmaceutical and biotechnology industries. In addition to the critical need for treatments for this devastating disorder, optimism for developing RTT treatments derives from a unique convergence of factors, including a known monogenic cause, reversibility of symptoms in preclinical models, a strong clinical research infrastructure highlighted by an NIH-funded natural history study and well-established clinics with significant patient populations. Here, we review recent advances in understanding the biology of RTT, particularly promising preclinical findings, lessons from past clinical trials, and critical elements of trial design for rare disorders. PMID:26830113

  13. Rett Syndrome: Crossing the Threshold to Clinical Translation.

    PubMed

    Katz, David M; Bird, Adrian; Coenraads, Monica; Gray, Steven J; Menon, Debashish U; Philpot, Benjamin D; Tarquinio, Daniel C

    2016-02-01

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

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

    PubMed

    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.

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

    PubMed

    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. PMID:27243819

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

    PubMed

    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.

  17. International Rett Syndrome Foundation

    MedlinePlus

    ... toward treatments for millions of people around the world with Autism, Parkinson's, Alzheimers, Schizophrenia and Traumatic Brain ... your state! State Resources Rettsyndrome.org is the world's leading Rett syndrome research funding organization We have ...

  18. Urinary Peptides in Rett Syndrome.

    ERIC Educational Resources Information Center

    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)

  19. How Do Health Care Providers Diagnose Rett Syndrome?

    MedlinePlus

    ... Information Clinical Trials Resources and Publications How do health care providers diagnose Rett syndrome? Skip sharing on social ... Rett syndrome may not always be present, so health care providers also need to evaluate the child's symptoms ...

  20. Two Sisters with Rett Syndrome. Brief Report.

    ERIC Educational Resources Information Center

    Haenggeli, Charles A.; And Others

    1990-01-01

    Clinical histories and physical findings are presented for 2 sisters with Rett syndrome. The older sister, age 25, was typically affected, whereas the younger sister, 22 years old, was affected with a seizure disorder showing an unusually early onset. The paper discusses hypotheses in genetic causation of Rett syndrome. (JDD)

  1. Validating the Rett Syndrome Gross Motor Scale.

    PubMed

    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.

  2. What Are the Symptoms of Rett Syndrome?

    MedlinePlus

    ... Lack of age-related decrease in sleep duration. Brain Development , Dec;23(Suppl 1). [top] Nomura, Y. (2005). ... behavior characteristics and sleep disturbance in Rett syndrome. Brain and Development , Nov;27(Suppl 1). [top] Rare Diseases Clinical ...

  3. Unexpected cellular players in Rett syndrome pathology.

    PubMed

    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.

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

    PubMed Central

    Jefferson, Amanda; Leonard, Helen; Siafarikas, Aris; Woodhead, Helen; Fyfe, Sue; Ward, Leanne M.; Munns, Craig; Motil, Kathleen; Tarquinio, Daniel; Shapiro, Jay R.; Brismar, Torkel; Ben-Zeev, Bruria; Bisgaard, Anne-Marie; Coppola, Giangennaro; Ellaway, Carolyn; Freilinger, Michael; Geerts, Suzanne; Humphreys, Peter; Jones, Mary; Lane, Jane; Larsson, Gunilla; Lotan, Meir; Percy, Alan; Pineda, Mercedes; Skinner, Steven; Syhler, Birgit; Thompson, Sue; Weiss, Batia; Witt Engerström, Ingegerd; Downs, Jenny

    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 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. Results 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. Conclusion 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. PMID:26849438

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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)

  8. Rett Syndrome: A Review of Current Knowledge.

    ERIC Educational Resources Information Center

    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…

  9. Rett Syndrome: A Longitudinal Developmental Case Report.

    ERIC Educational Resources Information Center

    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.…

  10. Developmental Dynamics of Rett Syndrome

    PubMed Central

    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. PMID:26942018

  11. Social preferences in Rett syndrome.

    PubMed

    Djukic, Aleksandra; McDermott, Maria Valicenti

    2012-04-01

    Children with Rett syndrome manifest profound impairments in their ability to speak and use their hands, and exhibit a very limited repertoire of abilities to express themselves, to be neuropsychologically tested, and consequently to be understood. This study examined nonverbal cognitive abilities and visual preferences by analyzing the pattern of visual fixation in 49 girls with Rett syndrome, compared with a group of typical control subjects. The girls with Rett syndrome demonstrated a tendency toward socially weighted stimuli/social preferences. They looked at people, and into people's eyes. Eye tracking represents a feasible method to assess cognition, and provide insights into the burden of isolation of these children and the mismatch between their social preferences and incompetence, caused by movement disorder and apraxia. PMID:22490770

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

    PubMed

    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. PMID:25820775

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

    PubMed

    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.

  14. Rett syndrome - Stimulation of endogenous biogenic amines

    NASA Technical Reports Server (NTRS)

    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.

  15. Communication Abilities and Rett Syndrome.

    ERIC Educational Resources Information Center

    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)

  16. Epidemiology of Rett syndrome: a population-based registry.

    PubMed

    Kozinetz, C A; Skender, M L; MacNaughton, N; Almes, M J; Schultz, R J; Percy, A K; Glaze, D G

    1993-02-01

    The Texas Rett Syndrome Registry maintains the largest population-based registry of cases and potential cases of Rett syndrome in the world. The most precise estimate of the prevalence of Rett syndrome of 1 per 22800 (0.44/10000) females aged 2 through 18 years of age was generated from this Registry. In addition, the first prevalence figures for black and Hispanic female cases were estimated. Registry cases are actively ascertained from multiple sources. Registry staff identify presumptive cases from review of information provided to the Registry by the parent or guardian. Preliminary diagnostic evaluation includes standardized review of medical records and videotape of key behaviors. Diagnosis is confirmed at clinical evaluation. The active surveillance system is monitored with the two-source capture-recapture methodology and case ascertainment is projected. The 1990 prevalence estimate of Rett syndrome indicates that the syndrome occurs less frequently than previously estimated. Until a biologic marker for Rett syndrome is identified or a standard definition for an incident case of Rett syndrome is designated, the prevalence of Rett syndrome will remain a major investigative issue of its epidemiology, and the Registry will be an important, systematic mean to gather case material for clinical and laboratory studies providing the foundation for the development of preventive interventions.

  17. Autistic Disorder Symptoms in Rett Syndrome

    ERIC Educational Resources Information Center

    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…

  18. Towards a Behavioral Phenotype for Rett Syndrome.

    ERIC Educational Resources Information Center

    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…

  19. A role for metabolism in Rett syndrome pathogenesis: New clinical findings and potential treatment targets.

    PubMed

    Justice, Monica J; Buchovecky, Christie M; Kyle, Stephanie M; Djukic, Aleksandra

    2013-01-01

    Rett syndrome (RTT), an X-linked neurological disorder caused by mutations in MECP2, may have a metabolic component. We reported a genetic suppressor screen in a Mecp2-null mouse model to identify pathways for therapeutic improvement of RTT symptoms. Of note, one suppressor mutation implied that cholesterol homeostasis was perturbed in Mecp2 null mice; indeed, cholesterol synthesis was elevated in the brain and body system. Remarkably, the genetic effect of downregulating the cholesterol pathway could be mimicked chemically by statin drugs, improving motor symptoms, and increasing longevity in the mouse. Our work linked cholesterol metabolism to RTT pathology for the first time. Both neurological and systemic effects of perturbed cholesterol homeostasis overlap with many RTT symptoms. Here we show in patients that peripheral cholesterol, triglycerides, and/or LDLs may be elevated early in RTT disease onset, providing a biomarker for patients that could be aided by therapeutic interventions that modulate lipid metabolism. PMID:25003017

  20. IgA Antibodies in Rett Syndrome

    ERIC Educational Resources Information Center

    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…

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

    PubMed

    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.

  2. Rett Syndrome: Revised Diagnostic Criteria and Nomenclature

    PubMed Central

    Neul, Jeffrey L.; Kaufmann, Walter E.; Glaze, Daniel G.; Christodoulou, John; Clarke, Angus J.; Bahi-Buisson, Nadia; Leonard, Helen; Bailey, Mark E. S.; Schanen, N. Carolyn; Zappella, Michele; Renieri, Alessandra; Huppke, Peter; Percy, Alan K.

    2010-01-01

    Objective Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Despite distinct clinical features, the accumulation of clinical and molecular information in recent years has generated considerable confusion regarding the diagnosis of RTT. The purpose of this work was revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials. Method RettSearch members, representing the majority of the international clinical RTT specialists, participated in an iterative process to come to a consensus on a revised and simplified clinical diagnostic criteria for RTT. Results The clinical criteria required for the diagnosis of classic and atypical RTT were clarified and simplified. Guidelines for the diagnosis and molecular evaluation of specific variant forms of RTT were developed. Interpretation These revised criteria provide clarity regarding the key features required for the diagnosis of RTT and reinforce the concept that RTT is a clinical diagnosis based on distinct clinical criteria, independent of molecular findings. We recommend that these criteria and guidelines be utilized in any proposed clinical research. PMID:21154482

  3. Self-Injurious Behavior in Rett Syndrome: Interactions between Features of Rett Syndrome and Operant Conditioning.

    ERIC Educational Resources Information Center

    Oliver, Chris; And Others

    1993-01-01

    In this case study, interactions were examined between features of Rett syndrome and operant conditioning as determinants of self-injurious behavior (SIB). Analysis suggested different functions for two forms of SIB: automatic reinforcement by sensory stimulation and escape from social interactions. Features of Rett syndrome tended to maximize the…

  4. Autism and Rett Syndrome: Behavioural Investigations and Differential Diagnosis.

    ERIC Educational Resources Information Center

    Olsson, Bo; Rett, Andreas

    1987-01-01

    Differential diagnosis of Rett syndrome and infantile autism among 63 female patients (22 months to 15 years) was investigated. Conclusions concerned: characteristics of some Rett subjects but no autistic subjects, characteristics of all Rett subjects but not all autistic subjects, and characteristics of most Rett subjects and some autistic…

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

    ERIC Educational Resources Information Center

    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.…

  6. Learning ability in children with Rett syndrome.

    PubMed

    Elefant, Cochavit; Wigram, Tony

    2005-11-01

    The purpose of this article is to present results of a research study examining learning ability in individuals with Rett syndrome. The material for this article was drawn from a more extensive doctoral study, designed to investigate intentional communication in this population, through the use of songs in music therapy. Rett syndrome is a neurological disorder resulting from an X-linked mutation, affecting mainly females, and found across racial and ethnic groups worldwide. One of the main areas affecting functioning in individuals with Rett syndrome is a severe impairment of receptive and expressive communication. This creates difficulties when attempting to reveal their potential learning abilities. This population has been observed as very responsive to music hence music therapy intervention has been advocated in promoting and motivating them to communicate and to learn. Seven girls with Rett syndrome, between ages 4 and 10 participated in the study. A single subject, multiple probe design was applied during 30-min trials, three times per week and lasted 8 months. During the trials the participants were asked to choose from a selection of 18 familiar and unfamiliar songs, while their ability to learn was observed and measured. Findings revealed that all seven girls demonstrated an ability to learn and to sustain learning over time. This intervention demonstrated that individuals with Rett syndrome could be promoted and motivated to communicate and learn when therapeutically employed by a trained music therapists.

  7. BDNF deregulation in Rett syndrome

    PubMed Central

    Li, Wei; Pozzo-Miller, Lucas

    2013-01-01

    BDNF is the best-characterized neurotrophin in terms of its gene structure and modulation, secretion processing, and signaling cascades following its release. In addition to diverse features at the genetic and molecular levels, the abundant expression in several regions of the central nervous system has implicated BDNF as a potent modulator in many aspects of neuronal development, as well as synaptic transmission and plasticity. Impairments in any of these critical functions likely contribute to a wide array of neurodevelopmental, neurodegenerative, and neuropsychiatric diseases. In this review, we focus on a prevalent neurodevelopmental disorder, Rett syndrome (RTT), which afflicts 1:15,000 women world-wide. We describe the consequences of loss-of-function mutations in the gene encoding the transcription factor methyl-CpG binding protein 2 (MeCP2) in RTT, and then elaborate on the current understanding of how MeCP2 controls BDNF expression. Finally, we discuss the literature regarding alterations in BDNF levels in RTT individuals and MeCP2-based mouse models, as well as recent progress in searching for rational therapeutic interventions. PMID:23597512

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

    PubMed

    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.

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

    ERIC Educational Resources Information Center

    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…

  10. Rett syndrome: An autoimmune disease?

    PubMed

    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. PMID:26807990

  11. A case of the Rett syndrome.

    PubMed

    Brunel, R; Gilly, R

    1985-01-01

    This is a case report of the Rett syndrome in a girl with normal general and psychomotor development during the first 12 mos. Afterwards developmental stagnation and retrogression appeared which led within one yr to dementia, autism, loss of purposeful hand use, truncal ataxia and apraxia of gait. Characteristic stereotypic movements of the hands occurred, and, furthermore, rhythmic truncal balancing and episodic hyperpnea. At 2 yrs, neurological examination showed slight hypertonia and hyperreflexia of the legs without extensor plantar signs, there was relative microcephaly, and visceral examination was normal. The diagnosis was made on the basis of clinical signs: all laboratory investigations were negative except EEG which showed unspecific modifications. We didn't find hyperammonemia. No progression of the symptoms appeared in the 15 mos following the diagnosis. PMID:4061764

  12. Rett's syndrome in the west of Scotland.

    PubMed Central

    Kerr, A M; Stephenson, J B

    1985-01-01

    Nineteen girls with characteristic features of Rett's syndrome, including normal initial development, regression at about 12 months of age, repetitive hand movements, and severe mental handicap were studied. This represents an estimated incidence of one in 30 000 live births (one in 15 000 girls) in the west of Scotland. Although the children were often initially considered to be autistic, they did not conform to this diagnosis as they made good personal contact within the limits of their mental development. The developmental regression was sometimes falsely attributed to vaccination. Each child showed striking involuntary movements and abnormality of tone, varying from hypotonia, which was found only in the youngest, to rigidity, which was common in older girls; this permitted classification into three clinical subtypes. The abnormalities were highly suggestive of an extrapyramidal disorder, and this has implications for further research and possible treatment. Images FIG 3 PMID:2412628

  13. Nosology and Diagnosis of Rett Syndrome

    ERIC Educational Resources Information Center

    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…

  14. The Invisible Enemy: Fighting Rett Syndrome.

    ERIC Educational Resources Information Center

    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)

  15. Attention and Communication in Rett Syndrome

    ERIC Educational Resources Information Center

    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)…

  16. Recognizing and Treating Rett Syndrome in Schools

    ERIC Educational Resources Information Center

    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…

  17. Communication Skills in Girls with Rett Syndrome

    ERIC Educational Resources Information Center

    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…

  18. Rett's Syndrome in an Australian Child.

    ERIC Educational Resources Information Center

    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.…

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

    PubMed

    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.

  20. Autistic disorder symptoms in Rett syndrome.

    PubMed

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

    2009-11-01

    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 level of functioning. To investigate, parents of 52 females with classical and atypical Rett syndrome (2.4-49.3 years) completed the Developmental Behavior Checklist (DBC), the Diagnostic Interview for Social and Communication Disorders (DISCO) and the Dutch Vineland Screener 0-6 (VS 0-6). All participants had a severe to profound intellectual disability (ID) according to the VS 0-6. Behavior indicated an autistic disorder in 42 (DBC) to 58 percent (DISCO) of the Rett cases. Autistic behavior had decreased in 19 percent such that they no longer met the criteria for autistic disorder. Some participants were suspected of having a comorbid autistic disorder, though not more often than can be expected at their level of functioning. Clinicians should be aware of the possibility of a comorbid autistic disorder as much as they should be in other people with this level of functioning.

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

    PubMed Central

    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

  2. Gait initiation in children with Rett syndrome.

    PubMed

    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.

  3. Perioperative management of a patient with Rett syndrome

    PubMed Central

    Kako, Hiromi; Martin, David P; Cartabuke, Richard; Beebe, Allan; Klamar, Jan; Tobias, Joseph D

    2013-01-01

    Rett syndrome is a neurodevelopmental disorder that results from mutations in the genes encoding methyl-cytosine-guanosine binding protein 2 located on the X chromosome. Clinical features of central nervous system involvement include regression of developmental milestones in the late infant and early toddler stages, mental retardation, seizures and other electroencephalographic abnormalities. Given the invariable association of this degenerative disorder with orthopedic deformities including scoliosis, patients with Rett syndrome may present for anesthetic care during various surgical procedures. The complexity of the end-organ involvement, specifically the progressive nature of respiratory and cardiac involvement, makes the anesthetic care of such patients challenging. Specific perioperative concerns include potential difficulties with airway management, an underlying seizure disorder, an increased sensitivity to anesthetic agents, prolonged QT syndrome, and diabetes mellitus. We present an 11-year-old girl with Rett syndrome who required anesthetic care for posterior spinal fusion. Previous reports of anesthetic care for these patients are reviewed, the end-organ involvement discussed, and options for anesthetic care presented. PMID:23724160

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

    ERIC Educational Resources Information Center

    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'…

  5. Addressing the Needs of Students with Rett Syndrome.

    ERIC Educational Resources Information Center

    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,…

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

    PubMed Central

    Wang, Hansen; Pati, Sandipan; Pozzo-Miller, Lucas; Doering, Laurie C.

    2015-01-01

    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. PMID:25767435

  7. Rett syndrome and MeCP2.

    PubMed

    Liyanage, Vichithra R B; Rastegar, Mojgan

    2014-06-01

    Rett syndrome (RTT) is a severe and progressive neurological disorder, which mainly affects young females. Mutations of the methyl-CpG binding protein 2 (MECP2) gene are the most prevalent cause of classical RTT cases. MECP2 mutations or altered expression are also associated with a spectrum of neurodevelopmental disorders such as autism spectrum disorders with recent links to fetal alcohol spectrum disorders. Collectively, MeCP2 relation to these neurodevelopmental disorders highlights the importance of understanding the molecular mechanisms by which MeCP2 impacts brain development, mental conditions, and compromised brain function. Since MECP2 mutations were discovered to be the primary cause of RTT, a significant progress has been made in the MeCP2 research, with respect to the expression, function and regulation of MeCP2 in the brain and its contribution in RTT pathogenesis. To date, there have been intensive efforts in designing effective therapeutic strategies for RTT benefiting from mouse models and cells collected from RTT patients. Despite significant progress in MeCP2 research over the last few decades, there is still a knowledge gap between the in vitro and in vivo research findings and translating these findings into effective therapeutic interventions in human RTT patients. In this review, we will provide a synopsis of Rett syndrome as a severe neurological disorder and will discuss the role of MeCP2 in RTT pathophysiology.

  8. A contribution regarding the Rett syndrome.

    PubMed

    Külz, J; Pohl, H; Schober, S

    1985-01-01

    Andreas Rett described a "cerebral atrophic syndrome accompanying hyperammonemia" for the first time in 1966, and by 1983 over 80 such cases had been identified and described not only in Austria but also in other countries. If the information at our disposal is correct, we have reported on what we believe is the first case of a patient with a definite Rett syndrome in the German Democratic Republic. We are, regrettably, still unable to contribute decisively to the clarification of the etiology and pathogenesis of the disease, but will, through further publications and papers at pediatric and child-neuropsychiatric meetings, continue to spread the knowledge of the symptomatology. It is remarkable that in the present case neither computer tomography nor electroencephalography showed definite abnormalities despite much effort. Definite proof of cerebral atrophy cannot, therefore, yet be furnished. But we still have no doubt that our diagnosis is correct. We intend, within the framework of a joint study being conducted by the University Pediatric Hospital Rostock and the Ludwig Boltzmann Institute, Vienna, as part of the scientific and technical cooperation between the Republic of Austria and the German Democratic Republic, to investigate further the epidemiology and etiology of this disease in cooperation with our Departments of Metabolic Disturbances and Genetics.

  9. Dendritic spine dysgenesis in Rett syndrome

    PubMed Central

    Xu, Xin; Miller, Eric C.; Pozzo-Miller, Lucas

    2014-01-01

    Spines are small cytoplasmic extensions of dendrites that form the postsynaptic compartment of the majority of excitatory synapses in the mammalian brain. Alterations in the numerical density, size, and shape of dendritic spines have been correlated with neuronal dysfunction in several neurological and neurodevelopmental disorders associated with intellectual disability, including Rett syndrome (RTT). RTT is a progressive neurodevelopmental disorder associated with intellectual disability that is caused by loss of function mutations in the transcriptional regulator methyl CpG-binding protein 2 (MECP2). Here, we review the evidence demonstrating that principal neurons in RTT individuals and Mecp2-based experimental models exhibit alterations in the number and morphology of dendritic spines. We also discuss the exciting possibility that signaling pathways downstream of brain-derived neurotrophic factor (BDNF), which is transcriptionally regulated by MeCP2, offer promising therapeutic options for modulating dendritic spine development and plasticity in RTT and other MECP2-associated neurodevelopmental disorders. PMID:25309341

  10. Brief report: MECP2 mutations in people without Rett syndrome.

    PubMed

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

    2014-03-01

    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 features of RTT. In this report we present four people with neurodevelopmental abnormalities and clear RTT-disease causing MECP2 mutation but lacking the characteristic clinical features of RTT. One patient's symptoms suggest an extension of the known spectrum of MECP2 associated phenotypes to include global developmental delay with obsessive compulsive disorder and attention deficit hyperactivity disorder. These results reemphasize that RTT should remain a clinical diagnosis, based on the recent consensus criteria.

  11. MECP2 Mutations in People without Rett Syndrome

    PubMed Central

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

    2013-01-01

    Mutations in Methyl-CpG-Binding protein 2 (MECP2) are commonly associated with and 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 features of RTT. In this report we present four people with neurodevelopmental abnormalities and clear RTT-disease causing MECP2 mutation but lacking the characteristic clinical features of RTT. One patient's symptoms suggest an extension of the known spectrum of MECP2 associated phenotypes to include Global Developmental Delay (GDD) with Obsessive Compulsive Disorder (OCD) and Attention Deficit Hyperactivity Disorder (ADHD). These results furthermore reemphasize that RTT should remain a clinical diagnosis, based on the recent refurbished consensus criteria. PMID:23921973

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

    PubMed

    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.

  13. Trends in the diagnosis of Rett syndrome in Australia

    PubMed Central

    Fehr, Stephanie; Bebbington, Ami; Nassar, Natasha; Downs, Jenny; Ronen, Gabriel M; de Klerk, Nicholas; Leonard, Helen

    2011-01-01

    Modifications to diagnostic criteria and introduction of genetic testing have likely affected the pattern and timing of Rett syndrome diagnosis. The trends in incidence and prevalence of Rett syndrome in Australia were examined; the cumulative risk of a female being diagnosed determined; and the impact of changes to diagnostic criteria and availability of genetic testing on these frequencies investigated. The population-based Australian Rett Syndrome Database was used to identify a total of 349 verified Rett syndrome females born 1976-2006 and diagnosed 1982-2008. The proportion of female cases born and diagnosed per year and the cumulative risk of a diagnosis were determined. The median age of Rett syndrome diagnosis decreased from 4.5 years if diagnosed before 2000 to 3.5 years if diagnosed after 1999. The cumulative risk of diagnosis had almost doubled by 32 y of age [1/8,905 or 11.23 per 100,000 person-years (95% CI, 10.03–12.45)] in comparison with 5 y of age [1/15,361 or 6.51 per 100,000 person-years (95% CI, 5.65–7.39)]. Earlier age of diagnosis may result in families experiencing less stress and emotional strain compared to those with delayed diagnosis. PMID:21587099

  14. [Rett syndrome: the state of research, and future perspectives].

    PubMed

    Matsuishi, Toyojiro

    2013-11-01

    Rett syndrome (RTT) is a neurodevelopmental disorder characterized by normal early psychomotor development followed by the loss of psychomotor and acquired purposeful hand skills and the onset of stereotyped movement of the hands and gait disturbance. The causative gene was discovered, and the disease was found to be caused by a mutation of methyl-CpG-binding protein 2. However, in many ways this clinically peculiar condition remains a mystery. I review the current status of clinical and basic research on RTT including data on the neurophysiology of the disease, neurotransmitter involvement, neuroimaging and neuropathology findings, molecular biology, animal models, regenerative medicine including ES cells and iPS cells, and other interventions and therapeutic trials.

  15. Normal Reactions to Orthostatic Stress in Rett Syndrome

    ERIC Educational Resources Information Center

    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…

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

    PubMed

    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.

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

    PubMed

    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. PMID:26017939

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

    ERIC Educational Resources Information Center

    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…

  19. Communication Intervention in Rett Syndrome: A Systematic Review

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

  3. Changing the Perspective on Early Development of Rett Syndrome

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

  5. Preliminary Assessment of Choice Making among Children with Rett Syndrome.

    ERIC Educational Resources Information Center

    Sigafoos, Jeff; And Others

    1995-01-01

    Choice making was studied among 7 students (ages 7-17) with Rett syndrome. Half the opportunities to choose food, beverage, and leisure items elapsed without a choice being made. Results suggest that the relationship between selecting and accepting items vary as a function of task configuration, and lack of choice may not necessarily indicate lack…

  6. Features of Autism in Rett Syndrome and Severe Mental Retardation.

    ERIC Educational Resources Information Center

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

    2003-01-01

    The Autism Behavior Checklist measured autistic symptoms in 15 girls (ages 11-16) with Rett Syndrome (RS) and 14 with severe mental retardation. Girls with RS scored higher on the Sensory and Relating subscales. There were no differences on the Body and Object Use, Language, and Social and Self-Help subscales. (Contains references.) (Author/CR)

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

    ERIC Educational Resources Information Center

    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…

  8. InterRett, a Model for International Data Collection in a Rare Genetic Disorder

    ERIC Educational Resources Information Center

    Louise, Sandra; Fyfe, Sue; Bebbington, Ami; Bahi-Buisson, Nadia; Anderson, Alison; Pineda, Merce; Percy, Alan; Zeev, Bruria Ben; Wu, Xi Ru; Bao, Xinhua; MacLeod, Patrick; Armstrong, Judith; Leonard, Helen

    2009-01-01

    Rett syndrome (RTT) is a rare genetic disorder within the autistic spectrum. This study compared socio-demographic, clinical and genetic characteristics of the international database, InterRett, and the population-based Australian Rett syndrome database (ARSD). It also explored the strengths and limitations of InterRett in comparison with other…

  9. How to prevent small stature in Rett syndrome-associated collapsing spine syndrome.

    PubMed

    Thorey, Fritz; Jäger, Marcus; Seller, Konrad; Wild, Alexander; Adam, Rüdiger A; Krauspe, Rüdiger

    2007-04-01

    Severe scoliosis in Rett syndrome is an important orthopedic, neurologic, and pediatric problem. The curve in Rett syndrome is of a neurologic type, has its highest incidence during early childhood, and shows rapid progression. In this study, the authors report the results of a 4-year follow-up of a 10-year-old Rett syndrome female patient with early onset and severe rapid progressive thoracolumbar scoliosis. The first signs of spinal deformity were documented at age 3 years. During adolescence, the patient developed a 115-degree thoracolumbal scoliosis with reduced respiratory volume due to a collapsing spine syndrome. To stop this life-threatening progression of the curve, the patient was treated by a 2-stage surgical procedure. The combination of an anterior release, halo traction, and posterior instrumented fusion from Th3 to L5 using a computer-assisted technique was performed. An excellent reduction of the deformity was achieved (postoperative 24-degree Cobb angle). After 4 years, the authors found a radiologically solid spinal fusion and no progression of the deformity. Operative treatment regimes and etiology of severe spinal deformities in Rett syndrome were discussed. The high perioperative risks in Rett syndrome patients who underwent spinal surgery may be reduced by an early cooperation between orthopedic and pediatric specialists. When considering recent data from literature, it can be concluded that an early correction of spine deformities in Rett syndrome patients may prevent a life-threatening collapsing spine syndrome.

  10. De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient.

    PubMed

    Hara, Munetsugu; Ohba, Chihiro; Yamashita, Yushiro; Saitsu, Hirotomo; Matsumoto, Naomichi; Matsuishi, Toyojiro

    2015-07-01

    Rett syndrome (RTT) is a neurodevelopmental disorder predominantly affecting females. Females with the MECP2 mutations exhibit a broad spectrum of clinical manifestations ranging from classical Rett syndrome to asymptomatic carriers. Mutations of genes encoding cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are also found in early onset RTT variants. Here, we present the first report of a female patient with RTT-like phenotype caused by SHANK3 (SH3 and multiple ankylin repeat domain 3) mutation, indicating that the clinical spectrum of SHANK3 mutations may extend to RTT-like phenotype in addition to (severe) developmental delay, absence of expressive speech, autistic behaviors and intellectual disability.

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

    PubMed

    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.

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

    PubMed

    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.

  13. Training communication abilities in Rett Syndrome through reading and writing

    PubMed Central

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

    2013-01-01

    The goal of this clinical case study is to investigate the possibility of training communication abilities in people with Rett Syndrome (RS). Usually, girls with RS never exceed the sensorimotor stage of development, but the inter-individual variability typical of RS may lead us to doubt the irrevocability of that developmental limit, especially for those girls who are engaged in cognitive rehabilitation. The case study reported here concerns a 21-year-old girl with RS who was engaged in cognitive rehabilitation training based upon the principles of Feuerstein's modificability and mediated learning theory. The training aimed to teach her basic concepts and enhance reading-writing abilities. Statistical analyses showed that the girl reached adequate reading-writing abilities, proving the validity of the cognitive intervention which allowed her to communicate by composing words with her forefinger on an alphabetic table. Although these results need to be cautiously considered as they derive from a single case study, they have implications for future cognitive rehabilitation for deeply impaired clinical conditions as in the case of RS. PMID:24367345

  14. Seizures and pain uncertainty associated with parenting stress and Rett syndrome.

    PubMed

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

    2014-04-01

    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 1 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, residential status) were significantly related to parenting stress. Factors related to chronic health concerns (seizures, ambiguous pain presentation) may be important when considering family stress issues in relation to general outcomes for girls with Rett syndrome and related developmental disorders.

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

    ERIC Educational Resources Information Center

    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)

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

    ERIC Educational Resources Information Center

    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…

  17. The trajectories of sleep disturbances in Rett syndrome.

    PubMed

    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.

  18. Brief report: systematic review of Rett syndrome in males.

    PubMed

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

    2015-10-01

    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 gene were present in 56 % of cases, and 68 % of cases reported other genetic abnormalities. This is the first review of published reports of RTT in male patients.

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

    PubMed Central

    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

    2016-01-01

    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. PMID:26733678

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

    PubMed

    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. PMID:26733678

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

    PubMed

    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.

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

    PubMed

    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. PMID:26686505

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

    PubMed

    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.

  4. Dysregulated brain immunity and neurotrophin signaling in Rett syndrome and autism spectrum disorders.

    PubMed

    Theoharides, Theoharis C; Athanassiou, Marianna; Panagiotidou, Smaro; Doyle, Robert

    2015-02-15

    Rett syndrome is a neurodevelopmental disorder, which occurs in about 1:15,000 females and presents with neurologic and communication defects. It is transmitted as an X-linked dominant linked to mutations of the methyl-CpG-binding protein (MeCP2), a gene transcription suppressor, but its definitive pathogenesis is unknown thus hindering development of effective treatments. Almost half of children with Rett syndrome also have behavioral symptoms consistent with those of autism spectrum disorders (ASDs). PubMed was searched (2005-2014) using the terms: allergy, atopy, brain, brain-derived neurotrophic factor (BDNF), corticotropin-releasing hormone (CRH), cytokines, gene mutations, inflammation, mast cells (MCs), microglia, mitochondria, neurotensin (NT), neurotrophins, seizures, stress, and treatment. There are a number of intriguing differences and similarities between Rett syndrome and ASDs. Rett syndrome occurs in females, while ASDs more often in males, and the former has neurologic disabilities unlike ASDs. There is evidence of dysregulated immune system early in life in both conditions. Lack of microglial phagocytosis and decreased levels of BDNF appear to distinguish Rett syndrome from ASDs, in which there is instead microglia activation and/or proliferation and possibly defective BDNF signaling. Moreover, brain mast cell (MC) activation and focal inflammation may be more prominent in ASDs than Rett syndrome. The flavonoid luteolin blocks microglia and MC activation, provides BDNF-like activity, reverses Rett phenotype in mouse models, and has a significant benefit in children with ASDs. Appropriate formulations of luteolin or other natural molecules may be useful in the treatment of Rett syndrome.

  5. The Preserved Speech Variant: A Subgroup of the Rett Complex: A Clinical Report of 30 Cases.

    ERIC Educational Resources Information Center

    Zappella, Michele; Gillberg, Christopher; Ehlers, Stephan

    1998-01-01

    Thirty females (ages 5-28) with autism also had many features of classic Rett syndrome (RS). The course of the disorder was more benign that in classic RS. A category of "Rett Complex" is proposed in which individuals have classic RS, but have a preserved speech variant. (Author/CR)

  6. Reversibility of functional deficits in experimental models of Rett syndrome.

    PubMed

    Cobb, Stuart; Guy, Jacky; Bird, Adrian

    2010-04-01

    Mutations in the X-linked MECP2 gene are the primary cause of the severe autism spectrum disorder RTT (Rett syndrome). Deletion of Mecp2 in mice recapitulates many of the overt neurological features seen in humans, and the delayed onset of symptoms is accompanied by deficits in neuronal morphology and synaptic physiology. Recent evidence suggests that reactivation of endogenous Mecp2 in young and adult mice can reverse aspects of RTT-like pathology. In the current perspective, we discuss these findings as well as other genetic, pharmacological and environmental interventions that attempt phenotypic rescue in RTT. We believe these studies provide valuable insights into the tractability of RTT and related conditions and are useful pointers for the development of future therapeutic strategies.

  7. A role for metabolism in Rett syndrome pathogenesis

    PubMed Central

    Justice, Monica J; Buchovecky, Christie M; Kyle, Stephanie M; Djukic, Aleksandra

    2013-01-01

    Rett syndrome (RTT), an X-linked neurological disorder caused by mutations in MECP2, may have a metabolic component. We reported a genetic suppressor screen in a Mecp2-null mouse model to identify pathways for therapeutic improvement of RTT symptoms. Of note, one suppressor mutation implied that cholesterol homeostasis was perturbed in Mecp2 null mice; indeed, cholesterol synthesis was elevated in the brain and body system. Remarkably, the genetic effect of downregulating the cholesterol pathway could be mimicked chemically by statin drugs, improving motor symptoms, and increasing longevity in the mouse. Our work linked cholesterol metabolism to RTT pathology for the first time. Both neurological and systemic effects of perturbed cholesterol homeostasis overlap with many RTT symptoms. Here we show in patients that peripheral cholesterol, triglycerides, and/or LDLs may be elevated early in RTT disease onset, providing a biomarker for patients that could be aided by therapeutic interventions that modulate lipid metabolism. PMID:25003017

  8. Functional communication training in rett syndrome: a preliminary study.

    PubMed

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

    2014-07-01

    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 functional communication training (FCT) methods for teaching 3 individuals (ages 15-47 years) with classic RTT novel communicative behaviors. Using single-case experimental designs, functional reinforcers were identified (FA) and each participant quickly learned to activate a voice-output switch to obtain a reinforcer (FCT). These results suggest that individuals with classic RTT can learn novel communicative responses, which has important implications for future intervention research.

  9. Neurophysiological responses to music and vibroacoustic stimuli in Rett syndrome.

    PubMed

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

    2014-06-01

    People with Rett syndrome (RTT) have severe communicative difficulties. They have as well an immature brainstem that implies dysfunction of the autonomic nervous system. Music plays an important role in their life, is often used as a motivating tool in a variety of situations and activities, and caregivers are often clear about people with RTTs favourites. The aim of this study was to investigate physiological and emotional responses related to six different musical stimuli in people with RTT. The study included 29 participants with RTT who were referred to the Swedish Rett Center for medical brainstem assessment during the period 2006-2007. 11 children with a typical developmental pattern were used as comparison. A repeated measures design was used, and physiological data were collected from a neurophysiological brainstem assessment. The continuous dependent variables measured were Cardiac Vagal Tone (CVT), Cardiac Sensitivity to Baroreflex (CSB), Mean Arterial Blood Pressure (MAP) and the Coefficient of Variation of Mean Arterial Blood Pressure (MAP-CV). These parameters were used to categorise brainstem responses as parasympathetic (calming) response, sympathetic (activating) response, arousal (alerting) response and unclear response. The results showed that all participants responded to the musical stimuli, but not always in the expected way. It was noticeable that both people with and without RTT responded with an arousal to all musical stimuli to begin with. Even though the initial expressions sometimes changed after some time due to poor control functions of their brainstem, the present results are consistent with the possibility that the RTT participants' normal responses to music are intact. These findings may explain why music is so important for individuals with RTT throughout life.

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

    PubMed Central

    Gharesouran, Jalal; Khalili, Azizeh Farshbaf; Azari, Noushin Sorkhkoh; Vahedi, Leila

    2015-01-01

    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. PMID:25737965

  11. Spectrum and distribution of MECP2 mutations in 64 Italian Rett syndrome girls: tentative genotype/phenotype correlation.

    PubMed

    Giunti, L; Pelagatti, S; Lazzerini, V; Guarducci, S; Lapi, E; Coviello, S; Cecconi, A; Ombroni, L; Andreucci, E; Sani, I; Brusaferri, A; Lasagni, A; Ricotti, G; Giometto, B; Nicolao, P; Gasparini, P; Granatiero, M; Uzielli, M L

    2001-12-01

    We report a direct DNA sequencing analysis of the MECP2 gene undertaken on a further 64 Italian patients with Rett syndrome by using a LICOR 4200 Automated Sequencer. All of the girls entering the study had a consistent clinical diagnosis for this disorder. All coding regions and the flanking intronic splice site sequences were amplified as three non-overlapping fragments by using both forward and reverse primers. The results were then compared to the MECP2 reference sequences published in GenBank. Mutations of the MECP2 gene were identified in 64 of 75 (85.33%) unrelated sporadic Rett syndrome girls. Genotype/phenotype correlation studies, in particular in groups of patients with the same mutation, did not offer definitive and interesting data. PMID:11738883

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

    PubMed

    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.

  13. Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X‐chromosome inactivation

    PubMed Central

    Archer, Hayley; Evans, Julie; Leonard, Helen; Colvin, Lyn; Ravine, David; Christodoulou, John; Williamson, Sarah; Charman, Tony; Bailey, Mark E S; Sampson, Julian; de Klerk, Nicholas; Clarke, Angus

    2007-01-01

    Introduction Rett syndrome (RTT) is an X‐linked dominant neurodevelopmental disorder that is usually associated with mutations in the MECP2 gene. The most common mutations in the gene are p.R168X and p.T158M. The influence of X‐chromosome inactivation (XCI) on clinical severity in patients with RTT with these mutations was investigated, taking into account the extent and direction of skewing. Methods Female patients and their parents were recruited from the UK and Australia. Clinical severity was measured by the Pineda Severity and Kerr profile scores. The degree of XCI and its direction relative to the X chromosome parent of origin were measured in DNA prepared from peripheral blood leucocytes, and allele‐specific polymerase chain reaction was used to determine the parental origin of mutation. Combining these, the percentage of cells expected to express the mutant allele was calculated. Results Linear regression analysis was undertaken for fully informative cases with p.R168X (n = 23) and p.T158M (n = 20) mutations. A statistically significant increase in clinical severity with increase in the proportion of active mutated allele was shown for both the p.R168X and p.T158M mutations. Conclusions XCI may vary in neurological and haematological tissues. However, these data are the first to show a relationship between the degree and direction of XCI in leucocytes and clinical severity in RTT, although the clinical utility of this in giving a prognosis for individual patients is unclear. PMID:16905679

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

    PubMed

    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. PMID:25991642

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

    PubMed

    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. PMID:27491552

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

    PubMed

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

    PubMed

    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.

  18. Investigation of Rett syndrome using pluripotent stem cells.

    PubMed

    Dajani, Rana; Koo, Sung-Eun; Sullivan, Gareth J; Park, In-Hyun

    2013-11-01

    Rett syndrome (RTT) is one of most prevalent female neurodevelopmental disorders. De novo mutations in X-linked MECP2 are mostly responsible for RTT. Since the identification of MeCP2 as the underlying cause of RTT, murine models have contributed to understanding the pathophysiology of RTT and function of MeCP2. Reprogramming is a procedure to produce induced pluripotent stem cells (iPSCs) by overexpression of four transcription factors. iPSCs obtain similar features as embryonic stem cells and are capable of self-renewing and differentiating into cells of all three layers. iPSCs have been utilized in modeling human diseases in vitro. Neurons differentiated from RTT-iPSCs showed the recapitulation of RTT phenotypes. Despite the early success, genetic and epigenetic instability upon reprogramming and ensuing maintenance of iPSCs raise concerns in using RTT-iPSCs as an accurate in vitro model. Here, we update the current iPSC-based RTT modeling, and its concerns and challenges. PMID:23744605

  19. The Quality of Life in Girls with Rett Syndrome.

    PubMed

    Parisi, Lucia; Di Filippo, Teresa; Roccella, Michele

    2016-05-18

    Nowadays, quality of life is receiving an increasing attention in all scientific areas. Rett syndrome (RTT) is a rare neurological development, affecting mainly females. The congenital disease affects the central nervous system, and is one of the most common causes of severe intellectual disability. The aim of our study is to evaluate the effect of RTT on the quality of life of people who are affected. Both parents of 18 subjects, all female, diagnosed with RTT, took part in the research. Quality of life was assessed using the Italian version of the Impact of Childhood Illness Scale. This scale consists of 30 questions that investigate the effect of illness on children, parents and families. For each question, the parent was asked to rate two variables: frequency and importance. Another questionnaire was administered to obtain medical history, diagnostic and therapeutic data of the persons with RTT. Our data show that RTT has a considerable impact on both the child's development and the entire family. Parents' answers demonstrated that their child's illness had consequences for the child and how the family coped with it. For this reason, attention should be directed at psychological and social aspects, as well as attitudes, manners, reactions and effects such disturbances can have on the entire family. PMID:27403274

  20. Behavioural biomarkers of typical Rett syndrome: moving towards early identification.

    PubMed

    Einspieler, Christa; Freilinger, Michael; Marschik, Peter B

    2016-09-01

    The dynamic course of Rett syndrome (RTT) is still said to begin with a period of apparently normal development although there is mounting evidence that individuals with RTT show behavioural peculiarities and abnormalities during their infancy. Their spontaneous general movements are abnormal from birth onwards. Normal cooing vocalisation and canonical babbling (if at all required) are interspersed with abnormalities such as proto-vowel and proto-consonant alternations produced on ingressive airstream, breathy voice characteristics, and pressed or high-pitched vocalisations. The gestural repertoire is limited. Certain developmental motor and speech-language milestones are not at all acquired or show a significant delay. Besides abnormal blinking, repetitive and/or long lasting tongue protrusion, and bizarre smiling, there are already the first body and/or hand stereotypies during the first year of life. We are currently on a promising way to define a specific set of behavioural biomarkers pinpointing RTT. PMID:27514944

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

    PubMed

    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.

  2. The Quality of Life in Girls with Rett Syndrome

    PubMed Central

    Parisi, Lucia; Di Filippo, Teresa; Roccella, Michele

    2016-01-01

    Nowadays, quality of life is receiving an increasing attention in all scientific areas. Rett syndrome (RTT) is a rare neurological development, affecting mainly females. The congenital disease affects the central nervous system, and is one of the most common causes of severe intellectual disability. The aim of our study is to evaluate the effect of RTT on the quality of life of people who are affected. Both parents of 18 subjects, all female, diagnosed with RTT, took part in the research. Quality of life was assessed using the Italian version of the Impact of Childhood Illness Scale. This scale consists of 30 questions that investigate the effect of illness on children, parents and families. For each question, the parent was asked to rate two variables: frequency and importance. Another questionnaire was administered to obtain medical history, diagnostic and therapeutic data of the persons with RTT. Our data show that RTT has a considerable impact on both the child’s development and the entire family. Parents’ answers demonstrated that their child’s illness had consequences for the child and how the family coped with it. For this reason, attention should be directed at psychological and social aspects, as well as attitudes, manners, reactions and effects such disturbances can have on the entire family. PMID:27403274

  3. Pathogenesis of Lethal Cardiac Arrhythmias in Mecp2 Mutant Mice: Implication for Therapy in Rett Syndrome

    PubMed Central

    McCauley, Mark D.; Wang, Tiannan; Mike, Elise; Herrera, Jose; Beavers, David L.; Huang, Teng-Wei; Ward, Christopher S.; Skinner, Steven; Percy, Alan K.; Glaze, Daniel G.; Wehrens, Xander H. T.; Neul, Jeffrey L.

    2013-01-01

    Rett Syndrome is a neurodevelopmental disorder typically caused by mutations in Methyl-CpG-Binding Protein 2 (MECP2) in which 26% of deaths are sudden and of unknown cause. To explore the hypothesis that these deaths may be due to cardiac dysfunction, we characterized the electrocardiograms (ECGs) in 379 people with Rett syndrome and found that 18.5% show prolongation of the corrected QT interval (QTc), indicating a repolarization abnormality that can predispose to the development of an unstable fatal cardiac rhythm. Male mice lacking MeCP2 function, Mecp2Null/Y, also have prolonged QTc and show increased susceptibility to induced ventricular tachycardia. Female heterozygous null mice, Mecp2Null/+, show an age-dependent prolongation of QTc associated with ventricular tachycardia and cardiac-related death. Genetic deletion of MeCP2 function in only the nervous system was sufficient to cause long QTc and ventricular tachycardia, implicating neuronally-mediated changes to cardiac electrical conduction as a potential cause of ventricular tachycardia in Rett syndrome. The standard therapy for prolonged QTc in Rett syndrome, β-adrenergic receptor blockers, did not prevent ventricular tachycardia in Mecp2Null/Y mice. To determine whether an alternative therapy would be more appropriate, we characterized cardiomyocytes from Mecp2Null/Y mice and found increased persistent sodium current, which was normalized when cells were treated with the sodium channel-blocking anti-seizure drug phenytoin. Treatment with phenytoin reduced both QTc and sustained ventricular tachycardia in Mecp2Null/Y mice. These results demonstrate that cardiac abnormalities in Rett syndrome are secondary to abnormal nervous system control, which leads to increased persistent sodium current. Our findings suggest that treatment in people with Rett syndrome would be more effective if it targeted the increased persistent sodium current in order to prevent lethal cardiac arrhythmias. PMID:22174313

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

    PubMed

    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).

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

    PubMed

    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.

  6. Breathing challenges in Rett Syndrome: Lessons learned from humans and animal models✩,✩✩

    PubMed Central

    Ramirez, Jan-Marino; Ward, Christopher Scott; Neul, Jeffrey Lorenz

    2013-01-01

    Breathing disturbances are a major challenge in Rett Syndrome (RTT). These disturbances are more pronounced during wakefulness; but irregular breathing occurs also during sleep. During the day patients can exhibit alternating bouts of hypoventilation and irregular hyperventilation. But there is significant individual variability in severity, onset, duration and type of breathing disturbances. Research in mouse models of RTT suggests that different areas in the ventrolateral medulla and pons give rise to different aspects of this breathing disorder. Pre-clinical experiments in mouse models that target different neuromodulatory and neurotransmitter receptors and MeCP2 function within glia cells can partly reverse breathing abnormalities. The success in animal models raises optimism that one day it will be possible to control or potentially cure the devastating symptoms also in human patients with RTT. PMID:23816600

  7. Technological aids to support choice strategies by three girls with Rett syndrome.

    PubMed

    Stasolla, Fabrizio; Perilli, Viviana; Di Leone, Antonia; Damiani, Rita; Albano, Vincenza; Stella, Anna; Damato, Concetta

    2015-01-01

    This study was aimed at extending the use of assistive technology (i.e., photocells, interface and personal computer) to support choice strategies by three girls with Rett syndrome and severe to profound developmental disabilities. A second purpose of the study was to reduce stereotypic behaviors exhibited by the participants involved (i.e., body rocking, hand washing and hand mouthing). Finally, a third goal of the study was to monitor the effects of such program on the participants' indices of happiness. The study was carried out according to a multiple probe design across responses for each participant. Results showed that the three girls increased the adaptive responses and decreased the stereotyped behaviors during intervention phases compared to baseline. Moreover, during intervention phases, the indices of happiness augmented for each girl as well. Clinical, psychological and rehabilitative implications of the findings are discussed.

  8. Italian Rett database and biobank.

    PubMed

    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.

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

    PubMed Central

    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. PMID:26930212

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

    PubMed

    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.

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

    PubMed

    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.

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

    ERIC Educational Resources Information Center

    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…

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

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

    ERIC Educational Resources Information Center

    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.…

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

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

    ERIC Educational Resources Information Center

    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…

  17. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.

    PubMed

    Chao, Hsiao-Tuan; Chen, Hongmei; Samaco, Rodney C; Xue, Mingshan; Chahrour, Maria; Yoo, Jong; Neul, Jeffrey L; Gong, Shiaoching; Lu, Hui-Chen; Heintz, Nathaniel; Ekker, Marc; Rubenstein, John L R; Noebels, Jeffrey L; Rosenmund, Christian; Zoghbi, Huda Y

    2010-11-11

    Mutations in the X-linked MECP2 gene, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2), cause Rett syndrome and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia and encephalopathy with early lethality. Rett syndrome is characterized by apparently normal early development followed by regression, motor abnormalities, seizures and features of autism, especially stereotyped behaviours. The mechanisms mediating these features are poorly understood. Here we show that mice lacking Mecp2 from GABA (γ-aminobutyric acid)-releasing neurons recapitulate numerous Rett syndrome and autistic features, including repetitive behaviours. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of Rett syndrome. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase 1 (Gad1) and glutamic acid decarboxylase 2 (Gad2) levels, and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes. PMID:21068835

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

    ERIC Educational Resources Information Center

    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…

  19. An Analogue Assessment of Repetitive Hand Behaviours in Girls and Young Women with Rett Syndrome

    ERIC Educational Resources Information Center

    Wales, L.; Charman, T.; Mount, R. H.

    2004-01-01

    Rett syndrome is a neuro-developmental disorder that almost exclusively affects females. In addition to neuro-developmental regression and loss of hand skills, apraxia, deceleration of head growth, and increasing spasticity and scoliosis, a number of behavioural features are also seen, including stereotypic hand movements, hyperventilation and…

  20. Cognitive Performance in Rett Syndrome Girls: A Pilot Study Using Eyetracking Technology

    ERIC Educational Resources Information Center

    Baptista, P. M.; Mercadante, M. T.; Macedo, E. C.; Schwartzman, J. S.

    2006-01-01

    Background: Rett syndrome (RS) is a pervasive developmental disorder with cognitive and neuromotor impairments (including loss of handiness and loss of communicative skills). Objective: To verify whether girls with RS use their gaze intentionally, by observing their performance in three cognitive tasks: (1) verbal instruction condition (look at…

  1. Modifying Adult Interactional Style as Positive Behavioural Intervention for a Child with Rett Syndrome.

    ERIC Educational Resources Information Center

    Evans, Ian M.; Meyer, Luanna H.

    1999-01-01

    A naturalistic behavioral assessment and intervention program over a 3-year period for a New Zealand girl (age 5) with Rett syndrome is described. The most significant reduction in hand mannerisms and other excess behaviors was related to positive social interactions and play that allowed for communication at the affective level. (Author/CR)

  2. Fostering Environmental Control in a Young Child with Rett Syndrome: A Case Study.

    ERIC Educational Resources Information Center

    Sullivan, Margaret Wolan; And Others

    1995-01-01

    The performance of a 3-year-old with Rett Syndrome in a Contingency Intervention Program using head and hand switches and adapted toys was assessed over 18 months. Learning contingent control of the stimuli positively motivated the child, promoted attention to toys and objects, and generalized to the classroom. (SW)

  3. Fostering Environmental Control in a Young Child with Rett Syndrome: A Case Study.

    ERIC Educational Resources Information Center

    Sullivan, Margaret Wolan; And Others

    The progress of a 4-year-old child with Rett Syndrome (a developmental disability resulting in severe mental and physical deficits in female children) in learning simple environmental control over an 18-month-period is described. A systematic program providing for contingency control of toys and music via switches was provided in the child's…

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

  6. Sleep Disturbance in Children with Rett Syndrome: A Qualitative Investigation of the Parental Experience

    ERIC Educational Resources Information Center

    McDougall, Allyson; Kerr, Alison M.; Espie, Colin A.

    2005-01-01

    Background: Sleep problems in children with intellectual disability can be precipitated and maintained by intrinsic and external factors. The present study comprised a qualitative investigation of the experiences of parents of children with Rett syndrome, a neurodevelopmental disorder where sleep disturbance is common. Method: Audio-taped…

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

    ERIC Educational Resources Information Center

    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…

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

    PubMed

    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.

  9. An Effective Computer-Based Requesting System for Persons with Rett Syndrome.

    ERIC Educational Resources Information Center

    Van Acker, Richard; Grant, Sharon H.

    1995-01-01

    This study explored the use of a computer-based requesting system, employing animated graphics and touch-sensitive screen input, with three girls with Rett syndrome (characterized by severe motor disorder, impaired cognitive function, and language disorder). All three girls displayed increased item requesting when provided computer-based…

  10. Supporting Communication of Girls with Rett Syndrome and Their Mothers in Storybook Reading.

    ERIC Educational Resources Information Center

    Koppenhaver, David A.; Erickson, Karen A.; Skotko, Brian G.

    2001-01-01

    In this study, mother-child storybook reading was explored as a context within which to support early symbolic communication of four girls (ages 3-7) with Rett syndrome. Access to communication symbols, assistive technologies, and parent training consistently enhanced children's frequency of labeling/commenting and appropriate symbolic…

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

  13. Parent Reading Behaviors and Communication Outcomes in Girls with Rett Syndrome

    ERIC Educational Resources Information Center

    Skotko, Brian G.; Koppenhaver, Dave A.; Erickson, Karen A.

    2004-01-01

    We describe evidence and intervention strategies for parents, educators, and researchers who seek to enhance communication and literacy in children with Rett syndrome (RS). Four girls with RS and their mothers videotaped their storybook interactions at home for 4 months. Parent-child storybook interactions were coded for child behaviors (e.g., use…

  14. Stress and Family Functioning in Parents of Girls with Rett Syndrome.

    ERIC Educational Resources Information Center

    Perry, Adrienne; And Others

    1992-01-01

    This survey of parents of 29 girls with Rett syndrome found that subjects reported more stress, lower marital satisfaction, and certain adaptations in family functioning compared to norms. However, most parents scored in the normal range. Scores were not related to socioeconomic status or characteristics of the affected child. (DB)

  15. Cognitive and Adaptive Functioning in 28 Girls with Rett Syndrome. Brief Report.

    ERIC Educational Resources Information Center

    Perry, Adrienne; And Others

    1991-01-01

    This study of 28 girls (ages 2-19) with Rett Syndrome found profound handicaps in the intellectual and adaptive areas, according to standardized tests. Subjects seemed capable of learning some self-help skills at a basic level. The Cattell Mental Age was significantly negatively correlated with chronological age. (JDD)

  16. The Borderland of Autism and Rett Syndrome: Five Case Histories to Highlight Diagnostic Difficulties.

    ERIC Educational Resources Information Center

    Gillberg, Christopher

    1989-01-01

    Case studies of 4 females and 1 male, aged 6-25, with pervasive developmental disorders are described. All met standard diagnostic criteria for autism and showed many Rett syndrome symptoms. It is concluded that there is considerable overlap between the 2 disorders and that symptomatic similarities might mirror common pathopsychological…

  17. The Use of Assistive Technology for Symbol Identification by Children with Rett Syndrome.

    ERIC Educational Resources Information Center

    Hetzroni, Orit; Rubin, Corinne; Konkol, Orna

    2002-01-01

    A study investigated whether the use of assistive technology would assist in the ability to identify symbols by three girls (ages 8-10) with Rett syndrome. Individualized multimedia programs resulted in a steady learning curve across symbol sets and a partial retention of knowledge throughout maintenance probes. (Contains references.) (CR)

  18. Improving Functional Skills and Physical Fitness in Children with Rett Syndrome

    ERIC Educational Resources Information Center

    Lotan, M.; Isakov, E.; Merrick, J.

    2004-01-01

    To investigate the feasibility of a physical exercise programme with treadmill for persons with Rett syndrome (RS) in order to promote fitness and health. A daily training programme on a treadmill was designed for four females with RS over a period of 2 months with tests performed in three intervals, at time 1, 2 and 3, 2 months apart with…

  19. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.

    PubMed

    Chao, Hsiao-Tuan; Chen, Hongmei; Samaco, Rodney C; Xue, Mingshan; Chahrour, Maria; Yoo, Jong; Neul, Jeffrey L; Gong, Shiaoching; Lu, Hui-Chen; Heintz, Nathaniel; Ekker, Marc; Rubenstein, John L R; Noebels, Jeffrey L; Rosenmund, Christian; Zoghbi, Huda Y

    2010-11-11

    Mutations in the X-linked MECP2 gene, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2), cause Rett syndrome and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia and encephalopathy with early lethality. Rett syndrome is characterized by apparently normal early development followed by regression, motor abnormalities, seizures and features of autism, especially stereotyped behaviours. The mechanisms mediating these features are poorly understood. Here we show that mice lacking Mecp2 from GABA (γ-aminobutyric acid)-releasing neurons recapitulate numerous Rett syndrome and autistic features, including repetitive behaviours. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of Rett syndrome. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase 1 (Gad1) and glutamic acid decarboxylase 2 (Gad2) levels, and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.

  20. Report of the first case of precocious puberty in Rett syndrome.

    PubMed

    Baş, Veysel Nijat; Çetinkaya, Semra; Ağladıoğlu, Sebahat Yılmaz; Aksoy, Ayşe; Gülpınar, Başak; Aycan, Zehra

    2013-01-01

    Rett syndrome is an X-linked dominant disorder frequently caused by the mutations in the methyl-CpG-binding protein 2 gene (MECP2). Its prevalence in the population is 1/15,000-20,000. Patients with Rett syndrome present apparently normal psychomotor developments during the first 6-18 months of life. Subsequently, they show a short period of developmental stagnation followed by a rapid regression in language and motor development. Precocious puberty is characterized by premature breast and pubic hair development, and advanced bone age development at 8 years of age. We present a case of Rett syndrome and precocious puberty in a 6-year-old girl. At the age of 6, the first signs of precocious puberty appeared (Tanner stage 3). Laboratory measurements were detected as follows: luteinizing hormone (LH), 0.2 mIU/mL; follicle-stimulating hormone (FSH), 1.1 mIU/mL; estradiol, 36 pg/mL; bone age, 9 years. The response to luteinizing hormone releasing hormone (gonadotropin-releasing hormone stimulation test) was characteristic for true precocious puberty (LH, 32 mIU/mL; FSH, 26 mIU/mL). This is the first reported case of precocious puberty related to Rett syndrome.

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

    PubMed Central

    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

    2016-01-01

    Purpose: 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. Genet Med 18 1, 378–385. Methods: 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. Genet Med 18 1, 378–385. Results: 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. Genet Med 18 1, 378–385. Conclusions: Our findings indicate that mutations in JMJD1C contribute to the development of Rett syndrome and intellectual disability. Genet Med 18 1, 378–385. PMID:26181491

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

    PubMed

    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.

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

    ERIC Educational Resources Information Center

    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…

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

    PubMed

    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.

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

    SciTech Connect

    Camus, P.; Abbadi, N.; Gilgenkrantz, S.

    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.

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

    PubMed

    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.

  7. Brief Report: Autistic Behaviors among Children with Fragile X or Rett Syndrome: Implications for the Classification of Pervasive Developmental Disorder.

    ERIC Educational Resources Information Center

    Mazzocco, Michele M. M.; Pulsifer, Margaret; Fiumara, Agata; Cocuzza, M.; Nigro, F.; Incorpora, G.; Barone, R.

    1998-01-01

    A study of 14 males with fragile X syndrome, 12 females with Rett Syndrome, and 25 individuals with other developmental disorders found that among those with fragile X syndrome, none of the 11 who did not have a diagnosis of autism met the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for pervasive developmental disorder.…

  8. Repeated Insulin-Like Growth Factor 1 Treatment in a Patient with Rett Syndrome: A Single Case Study

    PubMed Central

    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. PMID:24918098

  9. Mutational analysis of methyl-CpG binding protein 2 (MECP2) gene in Indian cases of Rett syndrome.

    PubMed

    Das, Dhanjit Kumar; Udani, Vrajesh; Sanghavi, Daksha; Adhia, Rashmi; Maitra, Anurupa

    2013-03-01

    Rett syndrome (RTT) is an X-linked postnatal neurological disorder, primarily affecting females and characterized by regression, epilepsy, stereotypical hand movements, and motor abnormalities. Its prevalence is about 1 in 10,000 female births. RTT is caused by mutations within methyl CpG-binding protein 2 (MECP2) gene. Over 200 individual nucleotide changes in the gene, which cause pathogenic mutations, have been reported; however, eight most commonly occurring missense and nonsense mutations account for almost 70% of all mutations. RTT cases have also been reported from India. The phenotype (classical and atypical inclusive) has many differentials. However, a genetically based confirmed diagnosis would help in management and counseling. In this pilot study we have analyzed MECP2 mutations in ten Indian sporadic patients diagnosed clinically as having RTT. Two mutations and one novel variant in MECP2 have been detected. Missense mutations p.R133C and c.806delG have been detected. The missence mutation p.R133C was the part of eight hotspots reported in Rett patients. This patient met all the essential criteria except delayed onset of regression. The other c.806delG mutation positive patient also fulfilled all the obligatory criteria of classical RTT. Another clinically atypical Rett patient showed a novel mutation p.C339S in MECP2 gene. The preliminary result necessitates a large-scale study of RTT patients to determine more precisely the influence of MECP2 mutations in Indian patients and their correlation with clinical phenotypes.

  10. A RETT SYNDROME CASE WITH NOVEL NON-IDENTICAL MUTATION IN MECP2 GENE.

    PubMed

    Güngör, O; Kirik, S; Cevizli, D; Karaokur, F; Ozer, L; Uysal, S; Dilber, C

    2015-01-01

    The Rett syndrome (RTT; OMIM #312750) is a rare genetic disease observed predominantly among girls that affects neurological development. The incidence of this disorder is approximately 1 in 10,000 female births. Diagnosis of the RTT is based on specific clinical criteria and the identification of a mutation in the methyl-CpG-binding protein (MECP), which mainly occurs on exons 3 and 4 of the gene. Mutations in the X-linked methyl-CpG binding protein 2 gene (MECP2) are observed in nearly 95% of RTT cases. RTT is associated with considerable genotypic and phenotypic heterogeneity. Recently, it has been observed that mutations in the genes Netrin G1 and cyclin-dependent kinase like 5 (CDKL5) also lead to clinical pictures resembling RTT. In this case report, we describe a 4-years-old female patient who met all the relevant criteria for the diagnosis of RTT. Sequence analyses performed on the patient identified a de novo, heterozygous c.489G>A mutation at exon 4 of the MECP2 gene.

  11. Evoking communication in Rett syndrome: comparisons with conversations and games in mother-infant interaction.

    PubMed

    Burford, B; Trevarthen, C

    1997-01-01

    Girls with Rett syndrome retain a responsiveness with care-givers that corresponds in many respects with the preverbal communication observed with normal infants. This has characteristic rhythmic patterns and phrases, mutual imitation, reciprocal emotional phases and rudimentary oral, vocal and gestural expressions. After individuals with Rett syndrome have passed the critical stage in dissolution of their attention, co-ordination and voluntary control, they retain positive orientation to human faces and eyes with smiling. Video analyses show that they can engage with rhythms and phrases of conversation, sometimes showing a sense of humour and sensitivity to playful teasing. They respond to repeated patterns of expression in rhythmic/prosodic play and to certain forms in music. It is suggested that sensitive and appropriately attuned support for the rudimentary motives for human contact that survive in Rett syndrome can help stabilisation of self-regulatory states, alleviate panic and confusion and facilitate learning. The effects of the disorder may be a consequence of a genetic fault in the elaboration of an Intrinsic Motive Formation in the reticular core of the embryo brain, leading to dysregulation of differentiation in higher cognitive systems and learning, but leaving partially intact motive principles for human intersubjective response.

  12. Evoking communication in Rett syndrome: comparisons with conversations and games in mother-infant interaction.

    PubMed

    Burford, B; Trevarthen, C

    1997-01-01

    Girls with Rett syndrome retain a responsiveness with care-givers that corresponds in many respects with the preverbal communication observed with normal infants. This has characteristic rhythmic patterns and phrases, mutual imitation, reciprocal emotional phases and rudimentary oral, vocal and gestural expressions. After individuals with Rett syndrome have passed the critical stage in dissolution of their attention, co-ordination and voluntary control, they retain positive orientation to human faces and eyes with smiling. Video analyses show that they can engage with rhythms and phrases of conversation, sometimes showing a sense of humour and sensitivity to playful teasing. They respond to repeated patterns of expression in rhythmic/prosodic play and to certain forms in music. It is suggested that sensitive and appropriately attuned support for the rudimentary motives for human contact that survive in Rett syndrome can help stabilisation of self-regulatory states, alleviate panic and confusion and facilitate learning. The effects of the disorder may be a consequence of a genetic fault in the elaboration of an Intrinsic Motive Formation in the reticular core of the embryo brain, leading to dysregulation of differentiation in higher cognitive systems and learning, but leaving partially intact motive principles for human intersubjective response. PMID:9452916

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

    PubMed

    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. PMID:22704012

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

    PubMed

    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.

  15. Neurotrophic effects of Cerebrolysin in the Mecp2308/Y transgenic model of Rett Syndrome

    PubMed Central

    Doppler, Edith; Rockenstein, Edward; Ubhi, Kiren; Inglis, Chandra; Mante, Michael; Adame, Anthony; Crews, Leslie; Hitzl, Monika; Moessler, Herbert; Masliah, Eliezer

    2009-01-01

    Rett syndrome is a childhood neurodevelopmental disorder caused by mutations in the gene encoding for methyl CpG binding protein (MeCP2). Neuropathological studies in patients with Rett syndrome and in MeCP2 mutant models have shown reduced dendritic arborization and abnormal neuronal packing. We have previously shown that Cerebrolysin (CBL), a neurotrophic peptide mixture, ameliorates the synaptic and dendritic pathology in models of aging and neurodegeneration. This study aimed to determine whether CBL was capable of reducing behavioral and neuronal alterations in Mecp2308/Y mutant mice. Two sets of experiments were performed, the first with 4 month old male Mecp2308/Y mutant mice treated with CBL or vehicle for 3 months (Group A) and the second with 1 month old mice treated for 6 months (Group B). Behavioral analysis showed improved motor performance with CBL in Group A and a trend toward improvement in Group B. Consistent with behavioral findings, neuropathological analysis of the basal ganglia showed amelioration of dendritic simplification in CBL-treated Mecp2308/Y mutant mice. CBL treatment also ameliorated dendritic pathology and neuronal loss in the hippocampus and neocortex in Mecp2308/Y mutant mice. In conclusion, this study demonstrates that CBL promotes recovery of dendritic and neuronal damage and behavioral improvements in young adult Mecp2308/Y mutant mice and suggests that CBL may have neurotrophic effects in this model. These findings support the possibility that CBL may have beneficial effects in the management of Rett syndrome. PMID:18600331

  16. [Epigenome: what we learned from Rett syndrome, a neurological disease caused by mutation of a methyl-CpG binding protein].

    PubMed

    Kubota, Takeo

    2013-01-01

    Epigenome is defined as DNA and histone modification-dependent gene regulation system. Abnormalities in this system are known to cause various neuro-developmental diseases. We recently reported that neurological symptoms of Rett syndrome, which is an autistic disorder caused by mutations in methyl-CpG binding protein 2 (MeCP2), was associated with failure of epigenomic gene regulation in neuronal cells, and that clinical differences in the identical twins with Rett syndrome in the differences in DNA methylation in neuronal genes, but not caused by DNA sequence differences. Since central nervus system requires precise gene regulation, neurological diseases including Alzheimer and Parkinson diseases may be caused by acquired DNA modification (epigenomic) changes that results in aberrant gene regulation as well as DNA sequence changes congenitally occurred (mutation). PMID:24291980

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

    ERIC Educational Resources Information Center

    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…

  18. Vascular Dysfunction in a Mouse Model of Rett Syndrome and Effects of Curcumin Treatment

    PubMed Central

    Panighini, Anna; Duranti, Emiliano; Santini, Ferruccio; Maffei, Margherita; Pizzorusso, Tommaso; Funel, Niccola; Taddei, Stefano; Bernardini, Nunzia; Ippolito, Chiara; Virdis, Agostino; Costa, Mario

    2013-01-01

    Mutations in the coding sequence of the X-linked gene MeCP2 (Methyl CpG–binding protein) are present in around 80% of patients with Rett Syndrome, a common cause of intellectual disability in female and to date without any effective pharmacological treatment. A relevant, and so far unexplored feature of RTT patients, is a marked reduction in peripheral circulation. To investigate the relationship between loss of MeCP2 and this clinical aspect, we used the MeCP2 null mouse model B6.129SF1-MeCP2tm1Jae for functional and pharmacological studies. Functional experiments were performed on isolated resistance mesenteric vessels, mounted on a pressurized myograph. Vessels from female MeCP2+/− mice show a reduced endothelium-dependent relaxation, due to a reduced Nitric Oxide (NO) availability secondary to an increased Reactive Oxygen Species (ROS) generation. Such functional aspects are associated with an intravascular increase in superoxide anion production, and a decreased vascular eNOS expression. These alterations are reversed by curcumin administration (5% (w/w) dietary curcumin for 21 days), which restores endothelial NO availability, decreases intravascular ROS production and normalizes vascular eNOS gene expression. In conclusion our findings highlight alterations in the vascular/endothelial system in the absence of a correct function of MeCP2, and uncover related cellular/molecular mechanisms that are rescued by an anti-oxidant treatment. PMID:23705018

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

    PubMed

    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. PMID:27517371

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

    PubMed

    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.

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

    PubMed

    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.

  2. F2-dihomo-isoprostanes as potential early biomarkers of lipid oxidative damage in Rett syndrome

    PubMed Central

    De Felice, Claudio; Signorini, Cinzia; Durand, Thierry; Oger, Camille; Guy, Alexandre; Bultel-Poncé, Valérie; Galano, Jean-Marie; Ciccoli, Lucia; Leoncini, Silvia; D'Esposito, Maurizio; Filosa, Stefania; Pecorelli, Alessandra; Valacchi, Giuseppe; Hayek, Joussef

    2011-01-01

    Oxidative damage has been reported in Rett syndrome (RTT), a pervasive developmental disorder caused in up to 95% of cases by mutations in the X-linked methyl-CpG binding protein 2 gene. Herein, we have synthesized F2-dihomo-isoprostanes (F2-dihomo-IsoPs), peroxidation products from adrenic acid (22:4 n-6), a known component of myelin, and tested the potential value of F2-dihomo-IsoPs as a novel disease marker and its relationship with clinical presentation and disease progression. F2-dihomo-IsoPs were determined by gas chromatography/negative-ion chemical ionization tandem mass spectrometry. Newly synthesized F2-dihomo-IsoP isomers [ent-7(RS)-F2t-dihomo-IsoP and 17-F2t-dihomo-IsoP] were used as reference standards. The measured ions were the product ions at m/z 327 derived from the [M–181]− precursor ions (m/z 597) produced from both the derivatized ent-7(RS)-F2t-dihomo-IsoP and 17-F2t-dihomo-IsoP. Average plasma F2-dihomo-IsoP levels in RTT were about one order of magnitude higher than those in healthy controls, being higher in typical RTT as compared with RTT variants, with a remarkable increase of about two orders of magnitude in patients at the earliest stage of the disease followed by a steady decrease during the natural clinical progression. hese data indicate for the first time that quantification of F2-dihomo-IsoPs in plasma represents an early marker of the disease and may provide a better understanding of the pathogenic mechanisms behind the neurological regression in patients with RTT PMID:21917727

  3. Scavenger receptor B1 post-translational modifications in Rett syndrome.

    PubMed

    Sticozzi, Claudia; Belmonte, Giuseppe; Pecorelli, Alessandra; Cervellati, Franco; Leoncini, Silvia; Signorini, Cinzia; Ciccoli, Lucia; De Felice, Claudio; Hayek, Joussef; Valacchi, Giuseppe

    2013-07-11

    The modulation of the HDL receptor scavenger receptor B1 (SRB1) was evaluated in skin fibroblasts isolated from patients with Rett syndrome (RTT), a genetic form of infantile autism. Patients showed an altered plasma lipid profile, while their skin fibroblasts showed a dramatic reduction in SRB1 (immunogold, Western blot and immunohistochemistry). The decreased SRB1 levels were demonstrated to be the consequence of its binding with 4-hydroxy-2-nonenal (4HNE), a product of lipid peroxidation, and its increased ubiquitination. Our findings show for the first time a loss of SRB1 in RTT cells and its relationship with a chronic oxidative stress status.

  4. Cellular Origins of Auditory Event-Related Potential Deficits in Rett Syndrome

    PubMed Central

    Goffin, Darren; Brodkin, Edward S.; Blendy, Julie A.; Siegel, Steve J.; Zhou, Zhaolan

    2014-01-01

    Dysfunction in sensory information processing is a hallmark of many neurological disorders including autism spectrum disorders (ASDs), schizophrenia and Rett syndrome (RTT)1. Using mouse models of RTT, a monogenic disorder caused by mutations in MECP22, we demonstrate that the large scale loss of MeCP2 from forebrain GABAergic interneurons leads to deficits in auditory event-related potentials (ERPs) and seizure manifestation; but the restoration of MeCP2 in specific classes of interneurons ameliorates these deficits. PMID:24777420

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

    PubMed Central

    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

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

    PubMed Central

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

    2015-01-01

    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 Mecp2stop/y male mice in which Mecp2 is silenced in all cells and female Mecp2stop/+ 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. PMID:25445449

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

    PubMed

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

    PubMed

    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.

  9. MECP2 mutations in Czech patients with Rett syndrome and Rett-like phenotypes: novel mutations, genotype-phenotype correlations and validation of high-resolution melting analysis for mutation scanning.

    PubMed

    Zahorakova, Daniela; Lelkova, Petra; Gregor, Vladimir; Magner, Martin; Zeman, Jiri; Martasek, Pavel

    2016-07-01

    Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by developmental regression with loss of motor, communication and social skills, onset of stereotypic hand movements and often seizures. RTT is primarily caused by de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). We established a high-resolution melting (HRM) technique for mutation scanning of the MECP2 gene and performed analyses in Czech patients with RTT, autism spectrum conditions and intellectual disability with Rett-like features. In the cases with confirmed MECP2 mutations, we determined X-chromosome inactivation (XCI), examined the relationships between genotype and clinical severity and evaluated the modifying influence of XCI. Our results demonstrate that HRM analysis is a reliable method for the detection of point mutations, small deletions and duplications in the MECP2 gene. We identified 29 pathogenic mutations in 75 girls, including four novel mutations: c.155_1189del1035;909_932inv;insC, c.573delC, c.857_858dupAA and c.1163_1200del38. Skewed XCI (ratio >75%) was found in 19.3% of the girls, but no gross divergence in clinical severity was observed. Our findings confirm a high mutation frequency in classic RTT (92%) and a correlation between the MECP2 mutation type and clinical severity. We also demonstrate limitations of XCI in explaining all of the phenotypic differences in RTT.

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

    ERIC Educational Resources Information Center

    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.…

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

  14. A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome.

    PubMed

    Buchovecky, Christie M; Turley, Stephen D; Brown, Hannah M; Kyle, Stephanie M; McDonald, Jeffrey G; Liu, Benny; Pieper, Andrew A; Huang, Wenhui; Katz, David M; Russell, David W; Shendure, Jay; Justice, Monica J

    2013-09-01

    Mutations in MECP2, encoding methyl CpG-binding protein 2, cause Rett syndrome, the most severe autism spectrum disorder. Re-expressing Mecp2 in symptomatic Mecp2-null mice markedly improves function and longevity, providing hope that therapeutic intervention is possible in humans. To identify pathways in disease pathology for therapeutic intervention, we carried out a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis suppressor screen in Mecp2-null mice and isolated five suppressors that ameliorate the symptoms of Mecp2 loss. We show that a stop codon mutation in Sqle, encoding squalene epoxidase, a rate-limiting enzyme in cholesterol biosynthesis, underlies suppression in one line. Subsequently, we also show that lipid metabolism is perturbed in the brains and livers of Mecp2-null male mice. Consistently, statin drugs improve systemic perturbations of lipid metabolism, alleviate motor symptoms and confer increased longevity in Mecp2 mutant mice. Our genetic screen therefore points to cholesterol homeostasis as a potential target for the treatment of patients with Rett syndrome.

  15. Bone microarchitecture in Rett syndrome and treatment with teriparatide: a case report.

    PubMed

    Zanchetta, M B; Scioscia, M F; Zanchetta, J R

    2016-09-01

    We present the case of a 28-year-old female Rett syndrome patient with low bone mass and a recent fracture who was successfully treated with teriparatide. Bone mineral density and microarchitecture substantially improved after treatment. Rett syndrome (RTT), an X-linked progressive neuro-developmental disorder caused by mutations in the methyl-CpG-binding 2 (MECP2) gene, has been consistently associated with low bone mass. Consequently, patients with RTT are at increased risk of skeletal fractures. Teriparatide is a bone-forming agent for the treatment of osteoporosis that has demonstrated its effectiveness in increasing bone strength and reducing the risk of fractures in postmenopausal women, but, recently, its positive action has also been reported in premenopausal women. We present the case of a 28-year-old female RTT patient with low bone mass and a recent fracture who was successfully treated with teriparatide. Both bone mass measured by DXA and microarchitecture assessed by high resolution peripheral computed tomography (HR pQCT) were substantially improved after treatment.

  16. Odd MECP2-mutated Rett variant-long-term follow-up profile to age 25.

    PubMed

    Hagberg, Bengt; Erlandsson, Anna; Kyllerman, Mårten; Larsson, Gunillla

    2003-01-01

    A 25-year-old MECP2-mutated female with odd developmental and dyspraxic/ataxic features, followed up through two decades, is reported. She does not fit either the classical Rett syndrome or the criteria required for any Rett variant phenotypes so far described. Nevertheless, she belongs clinically to the latter group. This case deserves attention in order, among other things, to provide important clues to better understand the puzzling battery of neuroimpairments and behavioural abnormalities met in classical Rett phenotypes and Rett variants defined thus far. PMID:14623222

  17. Rett Syndrome Mutant Neural Cells Lacks MeCP2 Immunoreactive Bands

    PubMed Central

    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. Rett Syndrome Mutant Neural Cells Lacks MeCP2 Immunoreactive Bands.

    PubMed

    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

  19. Longitudinal bone mineral content and density in Rett syndrome and their contributing factors.

    PubMed

    Jefferson, Amanda; Fyfe, Sue; Downs, Jenny; Woodhead, Helen; Jacoby, Peter; Leonard, Helen

    2015-05-01

    Bone mass and density are low in females with Rett syndrome. This study used Dual energy x-ray absorptiometry to measure annual changes in z-scores for areal bone mineral density (aBMD) and bone mineral content (BMC) in the lumbar spine and total body in an Australian Rett syndrome cohort at baseline and then after three to four years. Bone mineral apparent density (BMAD) was calculated in the lumbar spine. Annual changes in lean tissue mass (LTM) and bone area (BA) were also assessed. The effects of age, genotype, mobility, menstrual status and epilepsy diagnosis on these parameters were also investigated. The baseline sample included 97 individuals who were representative of the total live Australian Rett syndrome population under 30years in 2005 (n=274). Of these 74 had a follow-up scan. Less than a quarter of females were able to walk on their own at follow-up. Bone area and LTM z-scores declined over the time between the baseline and follow-up scans. Mean height-standardised z-scores for the bone outcomes were obtained from multiple regression models. The lumbar spine showed a positive mean annual BMAD z-score change (0.08) and a marginal decrease in aBMD (-0.04). The mean z-score change per annum for those 'who could walk unaided' was more positive for LS BMAD (p=0.040). Total body BMD mean annual z-score change from baseline to follow-up was negative (-0.03). However this change was positive in those who had achieved menses prior to the study (0.03, p=0,040). Total body BMC showed the most negative change (-0.60), representing a decrease in bone mineral content over time. This normalised to a z-score change of 0.21 once adjusted for the reduced lean tissue mass mean z-score change (-0.21) and bone area mean z-score change (-0.14). Overall, the bone mineral content, bone mineral density, bone area and lean tissue mass z-scores for all outcome measures declined, with the TB BMC showing significant decreases. Weight, height and muscle mass appear to have

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

    PubMed

    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

  1. The pathophysiology of the Rett syndrome from the standpoint of polysomnography.

    PubMed

    Segawa, M; Nomura, Y

    1990-01-01

    Twelve polysomnographies were performed on eight cases of the Rett syndrome and the results were compared between cases under and over 5 years of age. There observed an increase in the ratio of stage REM (sREM) against slow wave sleep (SWS) with age. The ratio of the number of mentalis twitch movement (ment TM) during sREM against the number of rapid eye movements (REMs) (reflecting dopaminergic activities) was below normal in the younger cases but increased markedly. The ratio of ment TM in the period of REMs burst against the total ment TM during sREM (reflecting the noradrenergic hypofunction) was high in the younger group, while it decreased later. The nocturnal variation became inapparent with age in % SWS and the phasic components of sREM, while that of % sREM exaggerated at later ages. The early hypofunctions of the noradrenergic and dopaminergic neurons later modified by the serotonergic dysfunction and dopaminergic postsynaptic supersensitivity are suggested.

  2. Development of a video-based evaluation tool in Rett syndrome.

    PubMed

    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

    2007-10-01

    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 agreed to participate returned a videotape within 8 months of the first request. Subjects whose videos were returned had a similar age profile to those who did not provide a video but were more likely to have classical than atypical RTT. Evidence of the content and social validity and inter-rater reliability on 11 videos is provided. Video may provide detailed, objective assessment of function and behaviour in RTT.

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

    PubMed

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

    PubMed

    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.

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

    PubMed Central

    Ellison, K A; Fill, C P; Terwilliger, J; DeGennaro, L J; Martin-Gallardo, A; Anvret, M; Percy, A K; Ott, J; Zoghbi, H

    1992-01-01

    Rett syndrome is a neurologic disorder characterized by early normal development followed by regression, acquired deceleration of head growth, autism, ataxia, and stereotypic 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. Maternal and paternal X chromosomes from the affected sisters were separated in somatic cell hybrids and were examined for concordance/discordance of maternal alleles at the tested loci. Thirty-six markers were informative in at least one of the two families, and 25 markers were informative in both families. Twenty loci were excluded as candidates for the Rett syndrome gene, on the basis of discordance for maternal alleles in the half-sisters. 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 -2, we 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. This in turn will result in a defined region of the X chromosome that should be searched for candidate sequences for the Rett syndrome gene in both familial and sporadic cases. Images Figure 2 PMID:1734712

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

    PubMed

    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.

  7. Detection of rarely identified multiple mutations in MECP2 gene do not contribute to enhanced severity in Rett syndrome.

    PubMed

    Chapleau, Christopher A; Lane, Jane; Kirwin, Susan M; Schanen, Carolyn; Vinette, Kathy M B; Stubbolo, Danielle; MacLeod, Patrick; Glaze, Daniel G; Motil, Kathleen J; Neul, Jeffrey L; Skinner, Steven A; Kaufmann, Walter E; Percy, Alan K

    2013-07-01

    The objective of our study was to characterize the influence of multiple mutations in the MECP2 gene in a cohort of individuals with Rett syndrome. Further analysis demonstrated that nearly all resulted from de novo in cis mutations, where the disease severity was indistinguishable from single mutations. Our methods involved enrolling participants in the RTT Natural History Study (NHS). After providing informed consent through their parents or principal caretakers, additional molecular assessments were performed in the participants and their parents to assess the presence and location of more than one mutation in each. Clinical severity was assessed at each visit in those participants in the NHS. Non-contiguous MECP2 gene variations were detected in 12 participants and contiguous mutations involving a deletion and insertion in three participants. Thirteen of 15 participants had mutations that were in cis; four (of 13) had three MECP2 mutations; two (of 15) had mutations that were both in cis and in trans (i.e., on different alleles). Clinical severity did not appear different from NHS participants with a single similar mutation. Mutations in cis were identified in most participants; two individuals had mutations both in cis and in trans. The presence of multiple mutations was not associated with greater severity. Nevertheless, multiple mutations will require greater thought in the future, if genetic assignment to drug treatment protocols is considered.

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

    PubMed

    Miyake, Kunio; Yang, Chunshu; Minakuchi, Yohei; Ohori, Kenta; Soutome, Masaki; Hirasawa, Takae; Kazuki, Yasuhiro; Adachi, Noboru; Suzuki, Seiko; Itoh, Masayuki; Goto, Yu-Ichi; Andoh, Tomoko; Kurosawa, Hiroshi; Oshimura, Mitsuo; Sasaki, Masayuki; Toyoda, Atsushi; Kubota, Takeo

    2013-01-01

    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. PMID:23805272

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

    PubMed

    Leoncini, Silvia; De Felice, Claudio; Signorini, Cinzia; Zollo, Gloria; Cortelazzo, Alessio; Durand, Thierry; Galano, Jean-Marie; Guerranti, Roberto; Rossi, Marcello; Ciccoli, Lucia; Hayek, Joussef

    2015-01-01

    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.

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

    PubMed Central

    Leoncini, Silvia; De Felice, Claudio; Signorini, Cinzia; Zollo, Gloria; Cortelazzo, Alessio; Durand, Thierry; Galano, Jean-Marie; Guerranti, Roberto; Rossi, Marcello; Ciccoli, Lucia; Hayek, Joussef

    2015-01-01

    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. PMID:26236424

  11. Rett Syndrome

    MedlinePlus

    ... may be used to control seizures. Occupational therapy, physiotherapy, and hydrotherapy may prolong mobility. Some children may require special equipment and aids such as braces to arrest scoliosis, splints to modify hand movements, and nutritional programs ...

  12. Rett syndrome

    MedlinePlus

    ... the first sign Intellectual disabilities and learning difficulties Scoliosis Shaky, unsteady, stiff gait or toe walking Seizures ... help prevent hand problems Weight bearing exercises with scoliosis Supplemental feedings can help with slowed growth. A ...

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

    PubMed

    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. PMID:26936630

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

    PubMed

    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.

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

    PubMed Central

    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

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

    PubMed

    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.

  17. Rett syndrome and the urge of novel approaches to study MeCP2 functions and mechanisms of action.

    PubMed

    Bedogni, Francesco; Rossi, Riccardo L; Galli, Francesco; Cobolli Gigli, Clementina; Gandaglia, Anna; Kilstrup-Nielsen, Charlotte; Landsberger, Nicoletta

    2014-10-01

    Rett syndrome (RTT) is a devastating genetic disorder that worldwide represents the most common genetic cause of severe intellectual disability in females. Most cases are caused by mutations in the X-linked MECP2 gene. Several recent studies have demonstrated that RTT mimicking animal models do not develop an irreversible condition and phenotypic rescue is possible. However, no cure for RTT has been identified so far, and patients are only given symptomatic and supportive treatments. The development of clinical applications imposes a more comprehensive knowledge of MeCP2 functional role(s) and their relevance for RTT pathobiology. Herein, we thoroughly survey the knowledge about MeCP2 structure and functions, highlighting the necessity of identifying more functional domains and the value of molecular genetics. Given that, in our opinion, RTT ultimately is generated by perturbations in gene transcription and so far no genes/pathways have been consistently linked to a dysfunctional MeCP2, we have used higher-level bioinformatic analyses to identify commonly deregulated mechanisms in MeCP2-defective samples. In this review we present our results and discuss the possible value of the utilized approach.

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

    PubMed

    Kucukkal, Tugba G; Alexov, Emil

    2015-01-01

    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.

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

    PubMed

    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.

  20. Does microglial dysfunction play a role in autism and Rett syndrome?

    PubMed Central

    MAEZAWA, IZUMI; CALAFIORE, MARCO; WULFF, HEIKE; JIN, LEE-WAY

    2016-01-01

    Autism spectrum disorders (ASDs) including classic autism is a group of complex developmental disabilities with core deficits of impaired social interactions, communication difficulties and repetitive behaviors. Although the neurobiology of ASDs has attracted much attention in the last two decades, the role of microglia has been ignored. Existing data are focused on their recognized role in neuroinflammation, which only covers a small part of the pathological repertoire of microglia. This review highlights recent findings on the broader roles of microglia, including their active surveillance of brain microenvironments and regulation of synaptic connectivity, maturation of brain circuitry and neurogenesis. Emerging evidence suggests that microglia respond to pre- and postnatal environmental stimuli through epigenetic interface to change gene expression, thus acting as effectors of experience-dependent synaptic plasticity. Impairments of these microglial functions could substantially contribute to several major etiological factors of autism, such as environmental toxins and cortical underconnectivity. Our recent study on Rett syndrome, a syndromic autistic disorder, provides an example that intrinsic microglial dysfunction due to genetic and epigenetic aberrations could detrimentally affect the developmental trajectory without evoking neuroinflammation. We propose that ASDs provide excellent opportunities to study the influence of microglia on neurodevelopment, and this knowledge could lead to novel therapies. PMID:22717189

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

    PubMed

    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.

  2. Rett syndrome: a preliminary analysis of stereotypy, stress, and negative affect.

    PubMed

    Quest, Kelsey M; Byiers, Breanne J; Payen, Ameante; Symons, Frank J

    2014-05-01

    Rett syndrome (RTT) is a neurodevelopmental disorder primarily affecting females. It is characterized by apparently normative development of motor and communicative abilities followed by deterioration in these domains. Stereotypic hand movements are one of the core diagnostic criteria for RTT. There is some anecdotal but limited scientific evidence that changes in hand stereotypy may be a sign of increased anxiety or arousal (i.e., a 'stress response') in RTT. Understanding stress responsivity is difficult in RTT because almost all individuals are nonverbal or otherwise severely communicatively impaired. This study used direct behavioral observation to quantify and compare the frequency of hand stereotypy and signs of negative affect during presumed periods of high and low stress associated with functional analysis conditions (negative reinforcement ['escape'] and control ['free play'], respectively) for 5 females with RTT (mean age=17.8; range 4-47). Negative affect was more likely to occur during negative reinforcement ('stress') conditions for each participant whereas hand stereotypies did not differ across conditions for any of the participants. Although preliminary, the results suggest that hand stereotypy may not be a valid behavioral 'stress-response' indicator in females with RTT. Alternatively, the approach we used may have been limited and not sufficient to evoke a stress response. Either way, more work with direct relevance to improving our understanding of hand stereotypy and anxiety in RTT in relation to social context appears warranted.

  3. Global transcriptional and translational repression in human embryonic stem cells-derived Rett Syndrome neurons

    PubMed Central

    Li, Yun; Wang, Haoyi; Muffat, Julien; Cheng, Albert W.; Orlando, David A.; Lovén, Jakob; Kwok, Show-ming; Feldman, Danielle A.; Bateup, Helen S.; Gao, Qing; Hockemeyer, Dirk; Mitalipova, Maisam; Lewis, Caroline A.; Vander Heiden, Matthew G.; Sur, Mriganka; Young, Richard A.; Jaenisch, Rudolf

    2014-01-01

    Summary Rett Syndrome (RTT) is caused by mutations of MECP2, a methyl CpG binding protein thought to act as a global transcriptional repressor. Here we show, using an isogenic human embryonic stem cell model of RTT, that MECP2 mutant neurons display key molecular and cellular features of this disorder. Unbiased global gene expression analyses demonstrate that MECP2 functions as global gene activator in neurons but not in neural precursors. Decreased transcription in neurons was coupled with a significant reduction in nascent protein synthesis and lack of MECP2 was manifested as a severe defect in the activity of the AKT/mTOR pathway. Lack of MECP2 also leads to impaired mitochondrial function in mutant neurons. Activation of AKT/mTOR signaling by exogenous growth factors or by depleting PTEN boosted protein synthesis and ameliorated disease phenotypes in mutant neurons. Our findings indicate a vital function for MECP2 in maintaining active gene transcription in human neuronal cells. PMID:24094325

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

    PubMed

    Li, Ronghui; Dong, Qiping; Yuan, Xinni; Zeng, Xin; Gao, Yu; Chiao, Cassandra; Li, Hongda; Zhao, Xinyu; Keles, Sunduz; Wang, Zefeng; Chang, Qiang

    2016-06-01

    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. PMID:27352031

  5. PTP1B inhibition suggests a therapeutic strategy for Rett syndrome

    PubMed Central

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

    2015-01-01

    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. PMID:26214522

  6. GABAergic dysfunction mediates autism-like stereotypies and Rett syndrome phenotypes

    PubMed Central

    Chao, Hsiao-Tuan; Chen, Hongmei; Samaco, Rodney C.; Xue, Mingshan; Chahrour, Maria; Yoo, Jong; Neul, Jeffrey L.; Gong, Shiaoching; Lu, Hui-Chen; Heintz, Nathaniel; Ekker, Marc; Rubenstein, John L.R.; Noebels, Jeffrey L.; Rosenmund, Christian; Zoghbi, Huda Y.

    2010-01-01

    Summary Mutations in the X-linked MECP2, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT) and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia, and encephalopathy with early lethality. RTT is characterized by apparently normal early development followed by regression, motor abnormalities, seizures, and features of autism, especially stereotyped behaviors. The mechanisms mediating these striking features are poorly understood. Here we show that mice lacking Mecp2 from γ-amino-butyric-acid-(GABA)-ergic neurons recapitulate numerous RTT and autistic features, including repetitive behaviors. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of RTT. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size consistent with presynaptic reduction in glutamic acid decarboxylase-1 and -2 levels and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal GABAergic neuronal function and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes. PMID:21068835

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

    PubMed

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

    2015-06-01

    Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism. MECP2 encodes a methyl-DNA-binding protein that has been proposed to function as a transcriptional repressor, but despite numerous mouse studies examining neuronal gene expression in Mecp2 mutants, no clear model has emerged for how MeCP2 protein regulates transcription. 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.

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

    PubMed

    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.

  9. Quantification of functional abilities in Rett syndrome: a comparison between stages III and IV

    PubMed Central

    Monteiro, Carlos BM; Savelsbergh, Geert JP; Smorenburg, Ana RP; Graciani, Zodja; Torriani-Pasin, Camila; de Abreu, Luiz Carlos; Valenti, Vitor E; Kok, Fernando

    2014-01-01

    We aimed to evaluate the functional abilities of persons with Rett syndrome (RTT) in stages III and IV. The group consisted of 60 females who had been diagnosed with RTT: 38 in stage III, mean age (years) of 9.14, with a standard deviation of 5.84 (minimum 2.2/maximum 26.4); and 22 in stage IV, mean age of 12.45, with a standard deviation of 6.17 (minimum 5.3/maximum 26.9). The evaluation was made using the Pediatric Evaluation of Disability Inventory, which has 197 items in the areas of self-care, mobility, and social function. The results showed that in the area of self-care, stage III and stage IV RTT persons had a level of 24.12 and 18.36 (P=0.002), respectively. In the area of mobility, stage III had 37.22 and stage IV had 14.64 (P<0.001), while in the area of social function, stage III had 17.72 and stage IV had 12.14 (P=0.016). In conclusion, although persons with stage III RTT have better functional abilities when compared with stage IV, the areas of mobility, self-care, and social function are quite affected, which shows a great functional dependency and need for help in basic activities of daily life. PMID:25061307

  10. Altered cholinergic function in the basal forebrain of girls with Rett syndrome.

    PubMed

    Wenk, G L; Hauss-Wegrzyniak, B

    1999-06-01

    Rett syndrome (RS) is a neurodevelopmental disorder that is predominant in females and is associated with cortical atrophy, stereotyped hand movements and severe mental deficiency. Previous studies have demonstrated a significant decline in number of choline acetyltransferase (ChAT)-containing neurons throughout the forebrain of RS girls. The loss of these ChAT-positive cells may be caused by a lack of nerve growth factor (NGF). In the current study, cortical levels of NGF were normal in RS girls as compared to age-and sex-matched controls. The number of neurons within the basal forebrain that express the 75 kDa (p75) low-affinity receptor for NGF was unchanged. In contrast, the number of ChAT-positive neurons was significantly decreased. The results suggest that normal amounts of NGF are available for binding to the p75 receptor and for retrograde transport to forebrain cholinergic cells, however, these neurons do not respond by producing the ChAT protein that is necessary for the production of the neurotransmitter acetylcholine.

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

    PubMed

    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. PMID:23891731

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

    PubMed

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

    2015-06-01

    Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism. MECP2 encodes a methyl-DNA-binding protein that has been proposed to function as a transcriptional repressor, but despite numerous mouse studies examining neuronal gene expression in Mecp2 mutants, no clear model has emerged for how MeCP2 protein regulates transcription. 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

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

    PubMed

    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. PMID:26859707

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

    PubMed

    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.

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

    PubMed Central

    Li, Ronghui; Dong, Qiping; Yuan, Xinni; Zeng, Xin; Gao, Yu; Li, Hongda; Keles, Sunduz; Wang, Zefeng; Chang, Qiang

    2016-01-01

    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. PMID:27352031

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

    PubMed Central

    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

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

  20. Case report: Retracing atypical development: a preserved speech variant of Rett syndrome.

    PubMed

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

    2009-06-01

    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 stereotypies, idiosyncratic vocalizations, asymmetric eye opening, and abnormal facial expressions are early signs proving that this variant of the Rett complex, too, manifests itself within the first months of life.

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

    SciTech Connect

    Ellison, K.A.; Fill, C.P. ); Terwililger, J.; Percy, A.K.; Zobhbi, H. ); DeGennaro, L.J.; Ott, J. ); Anvret, M.; Martin-Gallardo, A. )

    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.

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

    PubMed Central

    Tarquinio, Daniel C.; Hou, Wei; Neul, Jeffrey L.; Lane, Jane B.; Barnes, Katherine V.; O’Leary, Heather M.; Bruck, Natalie M.; Kaufmann, Walter E.; Motil, Kathleen J.; Glaze, Daniel G.; Skinner, Steven A.; Annese, Fran; Baggett, Lauren; Barrish, Judy O.; Geerts, Suzanne P.; Percy, Alan K.

    2015-01-01

    Purpose Diagnosis of Rett syndrome (RTT) is often delayed. We sought to determine type of physician who typically makes the diagnosis of RTT and to identify risk factors for delayed diagnosis. Methods One-thousand eighty-five participants from the multicenter longitudinal RTT natural history study with classic and atypical RTT were recruited from 2006 to 2014. Age of diagnosis, diagnostician, diagnostic criteria, clinical and developmental data were collected. Results Among 919 classic and 166 atypical RTT participants, median diagnosis age was 2.7 years (interquartile range 2.0–4.1) in classic and 3.8 years (interquartile range 2.3–6.9) in atypical RTT. Pediatricians made the diagnosis of classic RTT rarely (5.2%); however, proportion diagnosed by pediatricians increased since 2006. Since the first diagnostic criteria, the age of diagnosis decreased among subspecialists but not pediatricians. Odds of a pediatrician making the diagnosis of classic RTT were higher if a child stopped responding to parental interaction, and lower if they possessed gastro-esophageal reflux, specific stereotypies, lost babbling or the ability to follow commands. Delayed acquisition of basic gross motor skills or finger feeding were associated with younger diagnosis; delayed acquisition of higher level fine motor skills, later onset of supportive features, and normal head circumference were associated with late diagnosis. 33% with microcephaly before 2.5 years were diagnosed after the median age of 2.7 years. Conclusions Age of RTT diagnosis has improved among subspecialists, and pediatricians have made the diagnosis of classic RTT more frequently since 2006. Strategies for educating diagnosticians should incorporate specific risk factors for delayed diagnosis. PMID:25801175

  3. Heightened Delta Power during Slow-Wave-Sleep in Patients with Rett Syndrome Associated with Poor Sleep Efficiency

    PubMed Central

    Ammanuel, Simon; Chan, Wesley C.; Adler, Daniel A.; Lakshamanan, Balaji M.; Gupta, Siddharth S.; Ewen, Joshua B.; Johnston, Michael V.; Marcus, Carole L.; Naidu, Sakkubai; Kadam, Shilpa D.

    2015-01-01

    Sleep problems are commonly reported in Rett syndrome (RTT); however the electroencephalographic (EEG) biomarkers underlying sleep dysfunction are poorly understood. The aim of this study was to analyze the temporal evolution of quantitative EEG (qEEG) biomarkers in overnight EEGs recorded from girls (2–9 yrs. old) diagnosed with RTT using a non-traditional automated protocol. In this study, EEG spectral analysis identified high delta power cycles representing slow wave sleep (SWS) in 8–9h overnight sleep EEGs from the frontal, central and occipital leads (AP axis), comparing age-matched girls with and without RTT. Automated algorithms quantitated the area under the curve (AUC) within identified SWS cycles for each spectral frequency wave form. Both age-matched RTT and control EEGs showed similar increasing trends for recorded delta wave power in the EEG leads along the antero-posterior (AP). RTT EEGs had significantly fewer numbers of SWS sleep cycles; therefore, the overall time spent in SWS was also significantly lower in RTT. In contrast, the AUC for delta power within each SWS cycle was significantly heightened in RTT and remained heightened over consecutive cycles unlike control EEGs that showed an overnight decrement of delta power in consecutive cycles. Gamma wave power associated with these SWS cycles was similar to controls. However, the negative correlation of gamma power with age (r = -.59; p<0.01) detected in controls (2–5 yrs. vs. 6–9 yrs.) was lost in RTT. Poor % SWS (i.e., time spent in SWS overnight) in RTT was also driven by the younger age-group. Incidence of seizures in RTT was associated with significantly lower number of SWS cycles. Therefore, qEEG biomarkers of SWS in RTT evolved temporally and correlated significantly with clinical severity. PMID:26444000

  4. Heightened Delta Power during Slow-Wave-Sleep in Patients with Rett Syndrome Associated with Poor Sleep Efficiency.

    PubMed

    Ammanuel, Simon; Chan, Wesley C; Adler, Daniel A; Lakshamanan, Balaji M; Gupta, Siddharth S; Ewen, Joshua B; Johnston, Michael V; Marcus, Carole L; Naidu, Sakkubai; Kadam, Shilpa D

    2015-01-01

    Sleep problems are commonly reported in Rett syndrome (RTT); however the electroencephalographic (EEG) biomarkers underlying sleep dysfunction are poorly understood. The aim of this study was to analyze the temporal evolution of quantitative EEG (qEEG) biomarkers in overnight EEGs recorded from girls (2-9 yrs. old) diagnosed with RTT using a non-traditional automated protocol. In this study, EEG spectral analysis identified high delta power cycles representing slow wave sleep (SWS) in 8-9h overnight sleep EEGs from the frontal, central and occipital leads (AP axis), comparing age-matched girls with and without RTT. Automated algorithms quantitated the area under the curve (AUC) within identified SWS cycles for each spectral frequency wave form. Both age-matched RTT and control EEGs showed similar increasing trends for recorded delta wave power in the EEG leads along the antero-posterior (AP). RTT EEGs had significantly fewer numbers of SWS sleep cycles; therefore, the overall time spent in SWS was also significantly lower in RTT. In contrast, the AUC for delta power within each SWS cycle was significantly heightened in RTT and remained heightened over consecutive cycles unlike control EEGs that showed an overnight decrement of delta power in consecutive cycles. Gamma wave power associated with these SWS cycles was similar to controls. However, the negative correlation of gamma power with age (r = -.59; p<0.01) detected in controls (2-5 yrs. vs. 6-9 yrs.) was lost in RTT. Poor % SWS (i.e., time spent in SWS overnight) in RTT was also driven by the younger age-group. Incidence of seizures in RTT was associated with significantly lower number of SWS cycles. Therefore, qEEG biomarkers of SWS in RTT evolved temporally and correlated significantly with clinical severity.

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

    PubMed

    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.

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

    PubMed

    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. PMID:27317352

  7. Impact of Rett Syndrome Mutations on MeCP2 MBD Stability.

    PubMed

    Kucukkal, Tugba G; Yang, Ye; Uvarov, Olga; Cao, Weiguo; Alexov, Emil

    2015-10-20

    Rett syndrome causing missense mutations in the methyl-CpG-binding domain (MBD) of methyl CpG-binding protein 2 (MeCP2) were investigated both in silico and in vitro to reveal their effect on protein stability. It is demonstrated that the vast majority of frequently occurring mutations in the human population indeed alter the MBD folding free energy by a fraction of a kcal/mol up to more than 1 kcal/mol. While the absolute magnitude of the change of the free energy is small, the effect on the MBD functionality may be substantial since the folding free energy of MBD is about 2 kcal/mol only. Thus, it is emphasized that the effect of mutations on protein integrity should be evaluated with respect to the wild-type folding free energy but not with the absolute value of the folding free energy change. Furthermore, it was observed that the magnitude of the effect is correlated neither with the burial of the mutation sites nor with the basic amino acid physicochemical property change. Mutations that strongly perturb the immediate structural features were found to have little effect on folding free energy, while very conservative mutations resulted in large changes of the MBD stability. This observation was attributed to the protein's ability to structurally relax and reorganize to reduce the effect of mutation. Comparison between in silico and in vitro results indicated that some Web servers perform relatively well, while the free energy perturbation approach frequently overpredicts the magnitude of the free energy change especially when a charged amino acid is involved.

  8. Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome.

    PubMed

    De Felice, Claudio; Della Ragione, Floriana; Signorini, Cinzia; Leoncini, Silvia; Pecorelli, Alessandra; Ciccoli, Lucia; Scalabrì, Francesco; Marracino, Federico; Madonna, Michele; Belmonte, Giuseppe; Ricceri, Laura; De Filippis, Bianca; Laviola, Giovanni; Valacchi, Giuseppe; Durand, Thierry; Galano, Jean-Marie; Oger, Camille; Guy, Alexandre; Bultel-Poncé, Valérie; Guy, Jacky; Filosa, Stefania; Hayek, Joussef; D'Esposito, Maurizio

    2014-08-01

    Rett syndrome (RTT) is a rare neurodevelopmental disorder affecting almost exclusively females, caused in the overwhelming majority of the cases by loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). High circulating levels of oxidative stress (OS) markers in patients suggest the involvement of OS in the RTT pathogenesis. To investigate the occurrence of oxidative brain damage in Mecp2 mutant mouse models, several OS markers were evaluated in whole brains of Mecp2-null (pre-symptomatic, symptomatic, and rescued) and Mecp2-308 mutated (pre-symptomatic and symptomatic) mice, and compared to those of wild type littermates. Selected OS markers included non-protein-bound iron, isoprostanes (F2-isoprostanes, F4-neuroprostanes, F2-dihomo-isoprostanes) and 4-hydroxy-2-nonenal protein adducts. Our findings indicate that oxidative brain damage 1) occurs in both Mecp2-null (both -/y and stop/y) and Mecp2-308 (both 308/y males and 308/+ females) mouse models of RTT; 2) precedes the onset of symptoms in both Mecp2-null and Mecp2-308 models; and 3) is rescued by Mecp2 brain specific gene reactivation. Our data provide direct evidence of the link between Mecp2 deficiency, oxidative stress and RTT pathology, as demonstrated by the rescue of the brain oxidative homeostasis following brain-specifically Mecp2-reactivated mice. The present study indicates that oxidative brain damage is a previously unrecognized hallmark feature of murine RTT, and suggests that Mecp2 is involved in the protection of the brain from oxidative stress.

  9. X-Chromosome Inactivation in Rett Syndrome Human Induced Pluripotent Stem Cells

    PubMed Central

    Cheung, Aaron Y. L.; Horvath, Lindsay M.; Carrel, Laura; Ellis, James

    2012-01-01

    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 (WT) 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 WT or mutant MECP2 allele to be isolated from the same patient. Post-XCI RTT-hiPSCs-derived neurons retain this allele-specific expression pattern of WT 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 WT 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. PMID:22470355

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

    PubMed Central

    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

    2016-01-01

    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 amnestic rats have demonstrated that DBS targeted to the fimbria-fornix1-3, the region that appears to regulate hippocampal activity, can mitigate defects in hippocampus-dependent memory3-5. Despite these promising results, DBS has not been tested for its ability to improve cognition in any childhood intellectual disability disorder (IDD). IDDs are a pressing concern: they affect as much as 3% of the population and involve hundreds of different genes. We hypothesized 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 MeCP26, RTT appears by the second year of life, causing profound impairment in cognitive, motor, and social skills along with an array of neurological features7; RTT mice, which reproduce the broad phenotype of this disorder, also show clear deficits in hippocampus-dependent learning and memory and hippocampal synaptic plasticity8-11. Here we show that forniceal DBS in RTT mice rescued contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restored in vivo hippocampal long-term potentiation (LTP) and hippocampal neurogenesis. These results indicate that forniceal DBS might mitigate cognitive dysfunction in RTT. PMID:26469053

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

    PubMed

    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.

  12. Pharmacological Stimulation of the Brain Serotonin Receptor 7 as a Novel Therapeutic Approach for Rett Syndrome

    PubMed Central

    De Filippis, Bianca; Nativio, Paola; Fabbri, Alessia; Ricceri, Laura; Adriani, Walter; Lacivita, Enza; Leopoldo, Marcello; Passarelli, Francesca; Fuso, Andrea; Laviola, Giovanni

    2014-01-01

    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 >95% of classic cases, and currently there is no cure for this devastating disorder. The serotonin receptor 7 (5-HT7R) is linked to neuro-physiological regulation of circadian rhythm, mood, cognition, and synaptic plasticity. We presently report that 5-HT7R density is consistently reduced in cortical and hippocampal brain areas of symptomatic MeCP2–308 male mice, a RTT model. Systemic repeated treatment with LP-211 (0.25 mg/kg once/day for 7 days), a brain-penetrant selective 5-HT7R agonist, was able to rescue RTT-related defective performance: anxiety-related profiles in a Light/Dark test, motor abilities in a Dowel test, the exploratory behavior in the Marble Burying test, as well as memory in the Novelty Preference task. In the brain of RTT mice, LP-211 also reversed the abnormal activation of PAK and cofilin (key regulators of actin cytoskeleton dynamics) and of the ribosomal protein (rp) S6, whose reduced activation in MECP2 mutant neurons by mTOR is responsible for the altered protein translational control. Present findings indicate that pharmacological targeting of 5-HT7R improves specific behavioral and molecular manifestations of RTT, thus representing a first step toward the validation of an innovative systemic treatment. Beyond RTT, the latter might be extended to other disorders associated with intellectual disability. PMID:24809912

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

    PubMed

    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.

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

    PubMed

    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.

  15. Pharmacological stimulation of the brain serotonin receptor 7 as a novel therapeutic approach for Rett syndrome.

    PubMed

    De Filippis, Bianca; Nativio, Paola; Fabbri, Alessia; Ricceri, Laura; Adriani, Walter; Lacivita, Enza; Leopoldo, Marcello; Passarelli, Francesca; Fuso, Andrea; Laviola, Giovanni

    2014-10-01

    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 >95% of classic cases, and currently there is no cure for this devastating disorder. The serotonin receptor 7 (5-HT7R) is linked to neuro-physiological regulation of circadian rhythm, mood, cognition, and synaptic plasticity. We presently report that 5-HT7R density is consistently reduced in cortical and hippocampal brain areas of symptomatic MeCP2-308 male mice, a RTT model. Systemic repeated treatment with LP-211 (0.25 mg/kg once/day for 7 days), a brain-penetrant selective 5-HT7R agonist, was able to rescue RTT-related defective performance: anxiety-related profiles in a Light/Dark test, motor abilities in a Dowel test, the exploratory behavior in the Marble Burying test, as well as memory in the Novelty Preference task. In the brain of RTT mice, LP-211 also reversed the abnormal activation of PAK and cofilin (key regulators of actin cytoskeleton dynamics) and of the ribosomal protein (rp) S6, whose reduced activation in MECP2 mutant neurons by mTOR is responsible for the altered protein translational control. Present findings indicate that pharmacological targeting of 5-HT7R improves specific behavioral and molecular manifestations of RTT, thus representing a first step toward the validation of an innovative systemic treatment. Beyond RTT, the latter might be extended to other disorders associated with intellectual disability. PMID:24809912

  16. 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

    ERIC Educational Resources Information Center

    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…

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

    PubMed

    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.

  18. A qualitative motion analysis study of voluntary hand movement induced by music in patients with Rett syndrome

    PubMed Central

    Go, Tohshin; Mitani, Asako

    2009-01-01

    Patients with Rett syndrome are known to respond well to music irrespective of their physical and verbal disabilities. Therefore, the relationship between auditory rhythm and their behavior was investigated employing a two-dimensional motion analysis system. Ten female patients aged from three to 17 years were included. When music with a simple regular rhythm started, body rocking appeared automatically in a back and forth direction in all four patients who showed the same rocking motion as their stereotyped movement. Through this body rocking, voluntary movement of the hand increased gradually, and finally became sufficient to beat a tambourine. However, the induction of body rocking by music was not observed in the other six patients who did not show stereotyped body rocking in a back and forth direction. When the music stopped suddenly, voluntary movement of the hand disappeared. When the music changed from a simple regular rhythm to a continuous tone without an auditory rhythm, the periodic movement of both the hand and body prolonged. Auditory rhythm shows a close relationship with body movement and facilitates synchronized body movement. This mechanism was demonstrated to be preserved in some patients with Rett syndrome, and stimulation with music could be utilized for their rehabilitation. PMID:19851517

  19. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells.

    PubMed

    Marchetto, Maria C N; Carromeu, Cassiano; Acab, Allan; Yu, Diana; Yeo, Gene W; Mu, Yangling; Chen, Gong; Gage, Fred H; Muotri, Alysson R

    2010-11-12

    Autism spectrum disorders (ASD) are complex neurodevelopmental diseases in which different combinations of genetic mutations may contribute to the phenotype. Using Rett syndrome (RTT) as an ASD genetic model, we developed a culture system using induced pluripotent stem cells (iPSCs) from RTT patients' fibroblasts. RTT patients' iPSCs are able to undergo X-inactivation and generate functional neurons. Neurons derived from RTT-iPSCs had fewer synapses, reduced spine density, smaller soma size, altered calcium signaling and electrophysiological defects when compared to controls. Our data uncovered early alterations in developing human RTT neurons. Finally, we used RTT neurons to test the effects of drugs in rescuing synaptic defects. Our data provide evidence of an unexplored developmental window, before disease onset, in RTT syndrome where potential therapies could be successfully employed. Our model recapitulates early stages of a human neurodevelopmental disease and represents a promising cellular tool for drug screening, diagnosis and personalized treatment. PMID:21074045

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

    PubMed Central

    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

  1. Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor.

    PubMed

    Lyst, Matthew J; Ekiert, Robert; Ebert, Daniel H; Merusi, Cara; Nowak, Jakub; Selfridge, Jim; Guy, Jacky; Kastan, Nathaniel R; Robinson, Nathaniel D; de Lima Alves, Flavia; Rappsilber, Juri; Greenberg, Michael E; Bird, Adrian

    2013-07-01

    Rett syndrome (RTT) is a severe neurological disorder that is caused by mutations in the MECP2 gene. Many missense mutations causing RTT are clustered in the DNA-binding domain of MeCP2, suggesting that association with chromatin is critical for its function. We identified a second mutational cluster in a previously uncharacterized region of MeCP2. We found that RTT mutations in this region abolished the interaction between MeCP2 and the NCoR/SMRT co-repressor complexes. Mice bearing a common missense RTT mutation in this domain exhibited severe RTT-like phenotypes. Our data are compatible with the hypothesis that brain dysfunction in RTT is caused by a loss of the MeCP2 'bridge' between the NCoR/SMRT co-repressors and chromatin.

  2. Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice.

    PubMed

    Kishi, Noriyuki; MacDonald, Jessica L; Ye, Julia; Molyneaux, Bradley J; Azim, Eiman; Macklis, Jeffrey D

    2016-01-29

    Mutations in the transcriptional regulator Mecp2 cause the severe X-linked neurodevelopmental disorder Rett syndrome (RTT). In this study, we investigate genes that function downstream of MeCP2 in cerebral cortex circuitry, and identify upregulation of Irak1, a central component of the NF-κB pathway. We show that overexpression of Irak1 mimics the reduced dendritic complexity of Mecp2-null cortical callosal projection neurons (CPN), and that NF-κB signalling is upregulated in the cortex with Mecp2 loss-of-function. Strikingly, we find that genetically reducing NF-κB signalling in Mecp2-null mice not only ameliorates CPN dendritic complexity but also substantially extends their normally shortened lifespan, indicating broader roles for NF-κB signalling in RTT pathogenesis. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-κB pathway modulation.

  3. Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice

    PubMed Central

    Kishi, Noriyuki; MacDonald, Jessica L.; Ye, Julia; Molyneaux, Bradley J.; Azim, Eiman; Macklis, Jeffrey D.

    2016-01-01

    Mutations in the transcriptional regulator Mecp2 cause the severe X-linked neurodevelopmental disorder Rett syndrome (RTT). In this study, we investigate genes that function downstream of MeCP2 in cerebral cortex circuitry, and identify upregulation of Irak1, a central component of the NF-κB pathway. We show that overexpression of Irak1 mimics the reduced dendritic complexity of Mecp2-null cortical callosal projection neurons (CPN), and that NF-κB signalling is upregulated in the cortex with Mecp2 loss-of-function. Strikingly, we find that genetically reducing NF-κB signalling in Mecp2-null mice not only ameliorates CPN dendritic complexity but also substantially extends their normally shortened lifespan, indicating broader roles for NF-κB signalling in RTT pathogenesis. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-κB pathway modulation. PMID:26821816

  4. Comparing social reciprocity in preserved speech variant and typical Rett syndrome during the early years of life.

    PubMed

    Townend, Gillian S; Bartl-Pokorny, Katrin D; Sigafoos, Jeff; Curfs, Leopold M G; Bölte, Sven; Poustka, Luise; Einspieler, Christa; Marschik, Peter B

    2015-01-01

    This study compared early markers of social reciprocity in children with typical Rett syndrome (RTT) and in those with the preserved speech variant (PSV) of RTT. Retrospective video analysis of 10 toddlers with typical RTT and five with PSV investigated participants' orientation to their name being called between the ages of 5 and 24 months, prior to their diagnosis. From analysis of the recordings two distinct profiles were apparent. Although response rate was higher in girls with typical RTT than PSV at 5 to 8 months this noticeably reversed from 9 to 12 months onwards. By two years of age there was a markedly higher rate and range of responses from girls with PSV. This study contributes to the delineation of different profiles for the variants of RTT.

  5. A Novel Mutation p.A59P in N-Terminal Domain of Methyl-CpG-Binding Protein 2 Confers Phenotypic Variability in 3 Cases of Tunisian Rett Patients: Clinical Evaluations and In Silico Investigations.

    PubMed

    Kharrat, Marwa; Hsairi, Ines; Fendri-Kriaa, Nourhene; Kenoun, Houda; Othmen, Houda Ben; Ben Mahmoud, Afif; Ghorbel, Rania; Abid, Imen; Triki, Chahnez; Fakhfakh, Faiza

    2015-11-01

    Rett syndrome is a monogenic X-linked dominant neurodevelopmental disorder related to mutation in MECP2, which encodes the methyl-CpG-binding protein MeCP2. The aim of this study was to search for mutations of MECP2 gene in Tunisian Rett patients and to evaluate the impact of the found variants on structural and functional features of MeCP2. The result of mutation analysis revealed that 3 Rett patients shared the same novel heterozygous point mutation c.175G>C (p.A59P). The p.A59P mutation was located in a conserved amino acid in the N-terminal segment of MeCP2. This novel mutation confers a phenotypic variability with different clinical severity scores (3, 8, and 9) and predicted by Sift and PolyPhen to be damaging. Modeling results showed that p.A59P adds 2 hydrogen bonds and changes the structural conformation of MeCP2 with a significant root mean square deviation value (9.66 Å), suggesting that this mutation could probably affect the conformation, function and stability of MeCP2.

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

    PubMed

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

    2016-01-01

    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. PMID:27328321

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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. PMID:26590342

  10. Reduced neuronal size and mTOR pathway activity in the Mecp2 A140V Rett syndrome mouse model

    PubMed Central

    Rangasamy, Sampathkumar; Olfers, Shannon; Gerald, Brittany; Hilbert, Alex; Svejda, Sean; Narayanan, Vinodh

    2016-01-01

    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 ( Mecp2 A140V/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”). PMID:27781091

  11. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases.

    PubMed

    Hagberg, B; Aicardi, J; Dias, K; Ramos, O

    1983-10-01

    Thirty-five patients, exclusively girls, from three countries had a uniform and striking progressive encephalopathy. After normal general and psychomotor development up to the age of 7 to 18 months, developmental stagnation occurred, followed by rapid deterioration of higher brain functions. Within one-and-a-half years this deterioration led to severe dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and acquired microcephaly. The destructive stage was followed by apparent stability lasting through decades. Additional insidious neurological abnormalities supervened, mainly spastic parapareses, vasomotor disturbances of the lower limbs, and epilepsy. Prior extensive laboratory investigations have not revealed the cause. The condition is similar to a virtually overlooked syndrome described by Rett in the German literature. The exclusive involvement of females, correlated with findings in family data analyses, suggests a dominant mutation on one X chromosome that results in affected girls and nonviable male hemizygous conceptuses. PMID:6638958

  12. Alagille syndrome: clinical perspectives.

    PubMed

    Saleh, Maha; Kamath, Binita M; Chitayat, David

    2016-01-01

    Alagille syndrome is an autosomal dominant, complex multisystem disorder characterized by the presence of three out of five major clinical criteria: cholestasis with bile duct paucity on liver biopsy, congenital cardiac defects (with particular involvement of the pulmonary arteries), posterior embryotoxon in the eye, characteristic facial features, and butterfly vertebrae. Renal and vascular abnormalities can also occur. Inter- and intrafamilial variabilities in the clinical manifestations are common. We reviewed the clinical features and management as well as the molecular basis of Alagille syndrome. PMID:27418850

  13. Alagille syndrome: clinical perspectives

    PubMed Central

    Saleh, Maha; Kamath, Binita M; Chitayat, David

    2016-01-01

    Alagille syndrome is an autosomal dominant, complex multisystem disorder characterized by the presence of three out of five major clinical criteria: cholestasis with bile duct paucity on liver biopsy, congenital cardiac defects (with particular involvement of the pulmonary arteries), posterior embryotoxon in the eye, characteristic facial features, and butterfly vertebrae. Renal and vascular abnormalities can also occur. Inter- and intrafamilial variabilities in the clinical manifestations are common. We reviewed the clinical features and management as well as the molecular basis of Alagille syndrome. PMID:27418850

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

    PubMed

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

    2013-02-01

    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 to investigate if the Facial Action Coding System (FACS) could be used to identify facial expressions, and differentiate between those that expressed emotions and those that were elicited by abnormal brainstem activation in RTT. The sample comprised 29 participants with RTT and 11 children with a normal 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 brainstem activation. This knowledge may be a great help to an uninitiated observer, who otherwise might incorrectly interpret the latter as an expression of emotion. PMID:23220055

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

    PubMed

    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.

  16. MeCP2-mediated alterations of striatal features accompany psychomotor deficits in a mouse model of Rett syndrome.

    PubMed

    Kao, Fang-Chi; Su, San-Hua; Carlson, Gregory C; Liao, Wenlin

    2015-01-01

    Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Affected individuals develop motor deficits including stereotypic hand movements, impaired motor learning and difficulties with movement. To understand the neural mechanisms of motor deficits in RTT, we characterized the molecular and cellular phenotypes in the striatum, the major input nucleus of the basal ganglia that controls psychomotor function, in mice carrying a null allele of Mecp2. These mice showed significant hypoactivity associated with impaired motor coordination and motor skill learning. We found that dopamine content was significantly reduced in the striatum of Mecp2 null mice. Reduced dopamine was accompanied by down-regulation of tyrosine hydroxylase and up-regulation of dopamine D2 receptors, particularly in the rostral striatum. We also observed that loss of MeCP2 induced compartment-specific alterations in the striatum, including reduced expression of μ-opioid receptors in the striosomes and increased number of calbindin-positive neurons in the striatal matrix. The total number of parvalbumin-positive interneurons and their dendritic arborization were also significantly increased in the striatum of Mecp2 null mice. Together, our findings support that MeCP2 regulates a unique set of genes critical for modulating motor output of the striatum, and that aberrant structure and function of the striatum due to MeCP2 deficiency may underlie the motor deficits in RTT.

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

    PubMed

    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. Bone Mineral Content and Bone Mineral Density Are Lower in Older than in Younger Females with Rett Syndrome

    PubMed Central

    Motil, Kathleen J.; Ellis, Kenneth J.; Barrish, Judy O.; Caeg, Erwin; Glaze, Daniel G.

    2008-01-01

    Although bone mineral deficits have been identified in Rett syndrome (RTT), the prevalence of low bone mineral density 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 content (BMC) and bone mineral density (BMD) using dual energy x-ray absorptiometry in a cross-sectional group of 50 females, ages 2-38 y, with RTT. Methyl-CpG-binding 2 (MECP2) mutations, skeletal fractures, and scoliosis were documented. The prevalence of BMC and BMD z-scores <-2 SD was 59% and 45%, respectively. Although absolute BMC and BMD increased significantly with increasing age, BMC and BMD z-scores were significantly lower in older than in younger females. The prevalence of fractures and scoliosis was 28% and 64%, respectively. Low BMD z-scores were positively associated with fractures and scoliosis. Deficits in BMD were identified across a broad range of MECP2 mutations. This study identified associations among low bone mineral density, fractures, and scoliosis, and underscored the need for better understanding of the molecular mechanisms of MECP2 in the regulation of bone mineral metabolism. PMID:18535484

  19. Profiling early socio-communicative development in five young girls with the preserved speech variant of Rett syndrome.

    PubMed

    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 (aged 12-24 months). Videotapes, obtained by parents during routine family situations and celebrations, were analyzed to identify communicative forms and functions used by these toddlers. Non-verbal communicative forms dominated over verbal-communicative forms for six of the eight identified communication functions. Although the girls used various non-verbal forms to make requests, for example, none of the individuals were observed to make choices or request information. Early peculiarities in the speech-language domain during the first year of life became more prominent and evident during the second year of life as general differences between typical development and atypical development become more obvious in RTT. These findings highlight the importance of assessing socio-communicative forms and functions at early age in children with RTT. The results suggest that speech-language functions did not appear to play a major role in the children's communicative attempts. We conclude that, even among children with the preserved speech variant, socio-communicative deficits are present before regression and persist after this period.

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

    PubMed

    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.

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

    PubMed Central

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

    2016-01-01

    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. PMID:26842955

  2. Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome.

    PubMed

    Plummer, J T; Evgrafov, O V; Bergman, M Y; Friez, M; Haiman, C A; Levitt, P; Aldinger, K A

    2013-10-22

    Single nucleotide variants (SNV) in the gene encoding the MET receptor tyrosine kinase have been associated with an increased risk for autism spectrum disorders (ASD). The MET promoter SNV rs1858830 C 'low activity' allele is enriched in ASD, associated with reduced protein expression, and impacts functional and structural circuit connectivity in humans. To gain insight into the transcriptional regulation of MET on ASD-risk etiology, we examined an interaction between the methyl CpG-binding protein 2 (MeCP2) and the MET 5' promoter region. Mutations in MeCP2 cause Rett syndrome (RTT), a predominantly female neurodevelopmental disorder sharing some ASD clinical symptoms. MeCP2 binds to a region of the MET promoter containing the ASD-risk SNV, and displays rs1858830 genotype-specific binding in human neural progenitor cells derived from the olfactory neuroepithelium. MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2. In the postmortem temporal cortex, a region normally enriched in MET, gene expression is reduced dramatically in females with RTT, although not due to enrichment of the rs1858830 C 'low activity' allele. We newly identified a sex-based reduction in MET expression, with male ASD cases, but not female ASD cases compared with sex-matched controls. The experimental data reveal a prominent allele-specific regulation of MET transcription by MeCP2. The mechanisms underlying the pronounced reduction of MET in ASD and RTT temporal cortex are distinct and likely related to factors unique to each disorder, including a noted sex bias.

  3. Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model.

    PubMed

    Ananiev, Gene; Williams, Emily Cunningham; Li, Hongda; Chang, Qiang

    2011-01-01

    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. PMID:21966470

  4. Antibody recognition in multiple sclerosis and Rett syndrome using a collection of linear and cyclic N-glucosylated antigenic probes.

    PubMed

    Real Fernández, Feliciana; Di Pisa, Margherita; Rossi, Giada; Auberger, Nicolas; Lequin, Olivier; Larregola, Maud; Benchohra, Amina; Mansuy, Christelle; Chassaing, Gerard; Lolli, Francesco; Hayek, Joussef; Lavielle, Solange; Rovero, Paolo; Mallet, Jean-Maurice; Papini, Anna Maria

    2015-09-01

    Antibody detection in autoimmune disorders, such as multiple sclerosis (MS) and Rett syndrome (RTT) can be achieved more efficiently using synthetic peptides. The previously developed synthetic antigenic probe CSF114(Glc), a type I' β-turn N-glucosylated peptide structure, is able to recognize antibodies in MS and RTT patients' sera as a sign of immune system derangement. We report herein the design, synthesis, conformational analysis, and immunological evaluation of a collection of glycopeptide analogs of CSF114(Glc) to characterize the specific role of secondary structures in MS and RTT antibody recognition. Therefore, we synthesized a series of linear and cyclic short glucosylated sequences, mimicking different β-turn conformations, which were evaluated in inhibition enzyme-linked immunosorbent assays (ELISA). Calculated IC50 ranking analysis allowed the selection of the candidate octapeptide containing two (S)-2-amino-4-pentynoic acid (L-Pra) residues Ac-Pra-RRN(Glc)GHT-Pra-NH2 , with an IC50 in the nanomolar range. This peptide was adequately modified for solid-phase ELISA (SP-ELISA) and surface plasmon resonance (SPR) experiments. Pra-RRN(Glc)GHT-Pra-NH2 peptide was modified with an alkyl chain linked to the N-terminus, favoring immobilization on solid phase in SP-ELISA and differentiating IgG antibody recognition between patients and healthy blood donors with a high specificity. However, this peptide displayed a loss in IgM specificity and sensitivity. Moreover, an analog was obtained after modification of the octapeptide candidate Ac-Pra-RRN(Glc)GHT-Pra-NH2 to favor immobilization on SPR sensor chips. SPR technology allowed us to determine its affinity (KD  = 16.4 nM), 2.3 times lower than the affinity of the original glucopeptide CSF114(Glc) (KD  = 7.1 nM). PMID:25973844

  5. Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene.

    PubMed

    Pitcher, Meagan R; Herrera, José A; Buffington, Shelly A; Kochukov, Mikhail Y; Merritt, Jonathan K; Fisher, Amanda R; Schanen, N Carolyn; Costa-Mattioli, Mauro; Neul, Jeffrey L

    2015-05-01

    Rett syndrome (RTT) is a severe neurodevelopmental disorder that is usually caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). Four of the eight common disease causing mutations in MECP2 are nonsense mutations and are responsible for over 35% of all cases of RTT. A strategy to overcome disease-causing nonsense mutations is treatment with nonsense mutation suppressing drugs that allow expression of full-length proteins from mutated genes with premature in-frame stop codons. To determine if this strategy is useful in RTT, we characterized a new mouse model containing a knock-in nonsense mutation (p.R255X) in the Mecp2 locus (Mecp2(R255X)). To determine whether the truncated gene product acts as a dominant negative allele and if RTT-like phenotypes could be rescued by expression of wild-type protein, we genetically introduced an extra copy of MECP2 via an MECP2 transgene. The addition of MECP2 transgene to Mecp2(R255X) mice abolished the phenotypic abnormalities and resulted in near complete rescue. Expression of MECP2 transgene Mecp2(R255X) allele also rescued mTORC1 signaling abnormalities discovered in mice with loss of function and overexpression of Mecp2. Finally, we treated Mecp2(R255X) embryonic fibroblasts with the nonsense mutation suppressing drug gentamicin and we were able to induce expression of full-length MeCP2 from the mutant p.R255X allele. These data provide proof of concept that the p.R255X mutation of MECP2 is amenable to the nonsense suppression therapeutic strategy and provide guidelines for the extent of rescue that can be expected by re-expressing MeCP2 protein.

  6. Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome.

    PubMed

    Yasui, Dag H; Gonzales, Michael L; Aflatooni, Justin O; Crary, Florence K; Hu, Daniel J; Gavino, Bryant J; Golub, Mari S; Vincent, John B; Carolyn Schanen, N; Olson, Carl O; Rastegar, Mojgan; Lasalle, Janine M

    2014-05-01

    Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT OMIM 312750). Alternative inclusion of MECP2/Mecp2 exon 1 with exons 3 and 4 encodes MeCP2-e1 or MeCP2-e2 protein isoforms with unique amino termini. While most MECP2 mutations are located in exons 3 and 4 thus affecting both isoforms, MECP2 exon 1 mutations but not exon 2 mutations have been identified in RTT patients, suggesting that MeCP2-e1 deficiency is sufficient to cause RTT. As expected, genetic deletion of Mecp2 exons 3 and/or 4 recapitulates RTT-like neurologic defects in mice. However, Mecp2 exon 2 knockout mice have normal neurologic function. Here, a naturally occurring MECP2 exon 1 mutation is recapitulated in a mouse model by genetic engineering. A point mutation in the translational start codon of Mecp2 exon 1, transmitted through the germline, ablates MeCP2-e1 translation while preserving MeCP2-e2 production in mouse brain. The resulting MeCP2-e1 deficient mice developed forelimb stereotypy, hindlimb clasping, excessive grooming and hypo-activity prior to death between 7 and 31 weeks. MeCP2-e1 deficient mice also exhibited abnormal anxiety, sociability and ambulation. Despite MeCP2-e1 and MeCP2-e2 sharing, 96% amino acid identity, differences were identified. A fraction of phosphorylated MeCP2-e1 differed from the bulk of MeCP2 in subnuclear localization and co-factor interaction. Furthermore, MeCP2-e1 exhibited enhanced stability compared with MeCP2-e2 in neurons. Therefore, MeCP2-e1 deficient mice implicate MeCP2-e1 as the sole contributor to RTT with non-redundant functions.

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

    PubMed

    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.

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

    PubMed

    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.

  9. Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene

    PubMed Central

    Pitcher, Meagan R.; Herrera, José A.; Buffington, Shelly A.; Kochukov, Mikhail Y.; Merritt, Jonathan K.; Fisher, Amanda R.; Schanen, N. Carolyn; Costa-Mattioli, Mauro; Neul, Jeffrey L.

    2015-01-01

    Rett syndrome (RTT) is a severe neurodevelopmental disorder that is usually caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). Four of the eight common disease causing mutations in MECP2 are nonsense mutations and are responsible for over 35% of all cases of RTT. A strategy to overcome disease-causing nonsense mutations is treatment with nonsense mutation suppressing drugs that allow expression of full-length proteins from mutated genes with premature in-frame stop codons. To determine if this strategy is useful in RTT, we characterized a new mouse model containing a knock-in nonsense mutation (p.R255X) in the Mecp2 locus (Mecp2R255X). To determine whether the truncated gene product acts as a dominant negative allele and if RTT-like phenotypes could be rescued by expression of wild-type protein, we genetically introduced an extra copy of MECP2 via an MECP2 transgene. The addition of MECP2 transgene to Mecp2R255X mice abolished the phenotypic abnormalities and resulted in near complete rescue. Expression of MECP2 transgene Mecp2R255X allele also rescued mTORC1 signaling abnormalities discovered in mice with loss of function and overexpression of Mecp2. Finally, we treated Mecp2R255X embryonic fibroblasts with the nonsense mutation suppressing drug gentamicin and we were able to induce expression of full-length MeCP2 from the mutant p.R255X allele. These data provide proof of concept that the p.R255X mutation of MECP2 is amenable to the nonsense suppression therapeutic strategy and provide guidelines for the extent of rescue that can be expected by re-expressing MeCP2 protein. PMID:25634563

  10. A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map.

    PubMed Central

    Schanen, N C; Dahle, E J; Capozzoli, F; Holm, V A; Zoghbi, H Y; Francke, U

    1997-01-01

    Although familial recurrences of Rett syndrome (RTT) comprise only approximately 1% of the reported cases, it is these cases that hold the key for the understanding of the genetic basis of the disorder. Families in which RTT occurs in mother and daughter, aunt and niece, and half sisters are consistent with dominant inheritance and variable expressivity of the phenotype. Recurrence of RTT in sisters is likely due to germ-line mosaicism in one of the parents, rather than to recessive inheritance. The exclusive occurrence of classic RTT in females led to the hypothesis that it is X-linked and may be lethal in males. In an X-linked dominant disorder, unaffected obligate-carrier females would be expected to show nonrandom or skewed inactivation of the X chromosome bearing the mutant allele. We investigated the X chromosome inactivation (XCI) patterns in the female members of a newly identified family with recurrence of RTT in a maternal aunt and a niece. Skewing of XCI is present in the obligate carrier in this family, supporting the hypothesis that RTT is an X-linked disorder. However, evaluation of the XCI pattern in the mother of affected half sisters shows random XCI, suggesting germ-line mosaicism as the cause of repeated transmission in this family. To determine which regions of the X chromosome were inherited concordantly/discordantly by the probands, we genotyped the individuals in the aunt-niece family and two previously reported pairs of half sisters. These combined exclusion-mapping data allow us to exclude the RTT locus from the interval between DXS1053 in Xp22.2 and DXS1222 in Xq22.3. This represents an extension of the previous exclusion map. Images Figure 1 Figure 2 PMID:9326329

  11. Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation

    PubMed Central

    Cheung, Aaron Y.L.; Horvath, Lindsay M.; Grafodatskaya, Daria; Pasceri, Peter; Weksberg, Rosanna; Hotta, Akitsu; Carrel, Laura; Ellis, James

    2011-01-01

    Rett syndrome (RTT) is a neurodevelopmental autism spectrum disorder that affects girls due primarily to mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). The majority of RTT patients carry missense and nonsense mutations leading to a hypomorphic MECP2, while null mutations leading to the complete absence of a functional protein are rare. MECP2 is an X-linked gene subject to random X-chromosome inactivation resulting in mosaic expression of mutant MECP2. The lack of human brain tissue motivates the need for alternative human cellular models to study RTT. Here we report the characterization of a MECP2 mutation in a classic female RTT patient involving rearrangements that remove exons 3 and 4 creating a functionally null mutation. To generate human neuron models of RTT, we isolated human induced pluripotent stem (hiPS) cells from RTT patient fibroblasts. RTT-hiPS cells retained the MECP2 mutation, are pluripotent and fully reprogrammed, and retained an inactive X-chromosome in a nonrandom pattern. Taking advantage of the latter characteristic, we obtained a pair of isogenic wild-type and mutant MECP2 expressing RTT-hiPS cell lines that retained this MECP2 expression pattern upon differentiation into neurons. Phenotypic analysis of mutant RTT-hiPS cell-derived neurons demonstrated a reduction in soma size compared with the isogenic control RTT-hiPS cell-derived neurons from the same RTT patient. Analysis of isogenic control and mutant hiPS cell-derived neurons represents a promising source for understanding the pathogenesis of RTT and the role of MECP2 in human neurons. PMID:21372149

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

    PubMed Central

    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. PMID:25926782

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

    PubMed Central

    Li, Wei; Xu, Xin

    2016-01-01

    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. PMID:26929363

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

    PubMed Central

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

    2016-01-01

    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. DOI: http://dx.doi.org/10.7554/eLife.14198.001 PMID:27328321

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

    PubMed

    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.

  16. Immune dysfunction in Rett syndrome patients revealed by high levels of serum anti-N(Glc) IgM antibody fraction.

    PubMed

    Papini, Anna Maria; Nuti, Francesca; Real-Fernandez, Feliciana; Rossi, Giada; Tiberi, Caterina; Sabatino, Giuseppina; Pandey, Shashank; Leoncini, Silvia; Signorini, Cinzia; Pecorelli, Alessandra; Guerranti, Roberto; Lavielle, Solange; Ciccoli, Lucia; Rovero, Paolo; De Felice, Claudio; Hayek, Joussef

    2014-01-01

    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. PMID:25389532

  17. Immune Dysfunction in Rett Syndrome Patients Revealed by High Levels of Serum Anti-N(Glc) IgM Antibody Fraction

    PubMed Central

    Papini, Anna Maria; Real-Fernandez, Feliciana; Rossi, Giada; Tiberi, Caterina; Sabatino, Giuseppina; Pandey, Shashank; Lavielle, Solange; Ciccoli, Lucia; Hayek, Joussef

    2014-01-01

    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. PMID:25389532

  18. Abnormal N-glycosylation pattern for brain nucleotide pyrophosphatase-5 (NPP-5) in Mecp2-mutant murine models of Rett syndrome.

    PubMed

    Cortelazzo, Alessio; De Felice, Claudio; Guerranti, Roberto; Signorini, Cinzia; Leoncini, Silvia; Pecorelli, Alessandra; Scalabrì, Francesco; Madonna, Michele; Filosa, Stefania; Della Giovampaola, Cinzia; Capone, Antonietta; Durand, Thierry; Mirasole, Cristiana; Zolla, Lello; Valacchi, Giuseppe; Ciccoli, Lucia; Guy, Jacky; D'Esposito, Maurizio; Hayek, Joussef

    2016-04-01

    Neurological disorders can be associated with protein glycosylation abnormalities. Rett syndrome is a devastating genetic brain disorder, mainly caused by de novo loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. Although its pathogenesis appears to be closely associated with a redox imbalance, no information on glycosylation is available. Glycoprotein detection strategies (i.e., lectin-blotting) were applied to identify target glycosylation changes in the whole brain of Mecp2 mutant murine models of the disease. Remarkable glycosylation pattern changes for a peculiar 50kDa protein, i.e., the N-linked brain nucleotide pyrophosphatase-5 were evidenced, with decreased N-glycosylation in the presymptomatic and symptomatic mutant mice. Glycosylation changes were rescued by selected brain Mecp2 reactivation. Our findings indicate that there is a causal link between the amount of Mecp2 and the N-glycosylation of NPP-5.

  19. Oral health in a group of patients with Rett syndrome in the regions of Valencia and Murcia (Spain): A case-control study

    PubMed Central

    Fuertes-González, María C.

    2014-01-01

    Objectives: Rett syndrome (RS) is a rare disease with oral manifestations that have not been described in detail or in a standardized manner in the literature. The present study describes the oral health of the population with RS in two Spanish regions, following the protocol of the World Health Organization for conducting common oral health surveys. Study Design: A prospective, observational case-control study was carried out, involving a group of patients with RS (n1=41) and a mean age of 13.37±3.19 years, and an age- and gender-matched control group without RS (n0=82). The data referred to oral health and habits were recorded by means of a questionnaire and oral examination was used to document caries indicators (prevalence of caries, df(t), df(s), DMF(T), DMF(S) and indices referred to dental loss, morbidity, restoration), the Community Periodontal Index (CPI), and the most characteristic oral manifestations. Results: The most frequent oral habit in the patients with RS was diurnal bruxism, followed by stereotyped tongue movements and oral breathing. The caries scores were lower in the RS population than in the control group, but patients with RS showed greater periodontal alterations and a greater prevalence of drooling, dental wear, high-arched palate and anterior open bite. Conclusions: The population with RS exhibits characteristic and early oral habits and alterations, and periodontal problems that are more notorious than caries disease, so that our efforts should focus on the diagnosis and early correction of the parafunctional habits, promoting restorative treatment, and providing instructions on correct oral hygiene. Key words:Rett syndrome, oral habits, bruxism, caries. PMID:25350594

  20. 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.

    PubMed

    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

  1. 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.

    PubMed

    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

  2. Currarino syndrome: Rare clinical variants

    PubMed Central

    Kumar, Bindey; Sinha, Amit Kumar; Kumar, Prem; Kumar, Anil

    2016-01-01

    Currarino syndrome (CS) is a rare clinical condition. The classical presentation includes a triad of sacral anomaly, anorectal malformations, and presacral mass. This syndrome belongs to the group of persistent neuroenteric malformations. This article presents two cases of Currarino syndrome, where there was rare clinical variants such as rectal atresia in the first case and rectal stenosis in the second case. The clinical presentations were very deceptive as the first case presented as high anorectal malformation and the second case was simulating Hirschprung's disease.

  3. Currarino syndrome: Rare clinical variants

    PubMed Central

    Kumar, Bindey; Sinha, Amit Kumar; Kumar, Prem; Kumar, Anil

    2016-01-01

    Currarino syndrome (CS) is a rare clinical condition. The classical presentation includes a triad of sacral anomaly, anorectal malformations, and presacral mass. This syndrome belongs to the group of persistent neuroenteric malformations. This article presents two cases of Currarino syndrome, where there was rare clinical variants such as rectal atresia in the first case and rectal stenosis in the second case. The clinical presentations were very deceptive as the first case presented as high anorectal malformation and the second case was simulating Hirschprung's disease. PMID:27695213

  4. Clinical characteristics of CHARGE syndrome.

    PubMed

    Ahn, B S; Oh, S Y

    1998-12-01

    CHARGE syndrome, first described by Pagon, was named for its six major clinical features. They are: coloboma of the eye, heart defects, atresia of the choanae, retarded growth and development including CNS anomalies, genital hypoplasia and/or urinary tract anomalies, and ear anomalies and/or hearing loss. We experienced three cases of CHARGE syndrome who displayed ocular coloboma, heart defects, retarded growth and development, and external ear anomalies, and we also review the previously reported literature concerning CHARGE syndrome. PMID:10188375

  5. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice.

    PubMed

    Heckman, Laura Dean; Chahrour, Maria H; Zoghbi, Huda Y

    2014-06-26

    Loss of function of the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2) causes the progressive neurological disorder Rett syndrome (RTT). Conversely, duplication or triplication of Xq28 causes an equally wide-ranging progressive neurological disorder, MECP2 duplication syndrome, whose features overlap somewhat with RTT. To understand which MeCP2 functions cause toxicity in the duplication syndrome, we generated mouse models expressing endogenous Mecp2 along with a RTT-causing mutation in either the methyl-CpG binding domain (MBD) or the transcriptional repression domain (TRD). We determined that both the MBD and TRD must function for doubling MeCP2 to be toxic. Mutating the MBD reproduces the null phenotype and expressing the TRD mutant produces milder RTT phenotypes, yet both mutations are harmless when expressed with endogenous Mecp2. Surprisingly, mutating the TRD is more detrimental than deleting the entire C-terminus, indicating a dominant-negative effect on MeCP2 function, likely due to the disruption of a basic cluster.

  6. What Causes Rett Syndrome?

    MedlinePlus

    ... is caused by mutations in X-linked MECP2 . Nature Genetics , Oct;23(2), 185–188. [top] Schollen, ... 1581. Retrieved June 23, 2012, from http://www.nature.com/ejhg/journal/v17/n12/full/ejhg200995a.html [ ...

  7. Improvement of the Rett Syndrome Phenotype in a Mecp2 Mouse Model Upon Treatment with Levodopa and a Dopa-Decarboxylase Inhibitor

    PubMed Central

    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

    2014-01-01

    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. PMID:24917201

  8. Sotos Syndrome. Clinical Exchange.

    ERIC Educational Resources Information Center

    Shuey, Elaine M.; Jamison, Kristen

    1996-01-01

    Sotos syndrome is characterized by high birth length, rapid bone growth, distinctive facial features, and possible verbal and motor delays. It is more common in males than females. Developmental deficits, specific learning problems, and speech/language delays may also occur. (DB)

  9. [Clinical guideline 'Turner syndrome'].

    PubMed

    van den Akker, Erica L T; van Alfen, A A E M Janiëlle; Sas, Theo C J; Kerstens, Michiel N; Cools, Martine; Lambalk, Cornelis B

    2014-01-01

    Turner syndrome occurs in women who are missing one X chromosome. The most obvious symptoms are small stature and ovarian failure. Turner patients have an increased risk of a large number of disorders, and should therefore have lifelong medical supervision. Recent insights into patient management have been incorporated into the guidelines. Patients are increasingly involved in their own treatment. In patients with 45,X karyotype, Y-chromosomal material is actively sought in a larger number of cells and/or other tissues, using FISH. Pubertal induction therapy, if required, is initiated at an appropriate age. Egg donation or vitrification are new therapeutic options for fertility treatment. Monitoring for cardiac and vascular disease using cardiac ultrasound and MRI is performed more often, partly in connection with the risk of aortal dissection. The coordination of care of patients with Turner syndrome is concentrated in specialized centres in the Netherlands and Belgium.

  10. Studies of X inactivation and isodisomy in twins provide further evidence that the X chromosomes is not involved in Rett syndrome

    SciTech Connect

    Migeon, B.R.; Dunn, M.A.; Schmeckpeper, B.J.; Naidu, S.; Thomas, G. |

    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. miR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes.

    PubMed

    Tsujimura, Keita; Irie, Koichiro; Nakashima, Hideyuki; Egashira, Yoshihiro; Fukao, Yoichiro; Fujiwara, Masayuki; Itoh, Masayuki; Uesaka, Masahiro; Imamura, Takuya; Nakahata, Yasukazu; Yamashita, Yui; Abe, Takaya; Takamori, Shigeo; Nakashima, Kinichi

    2015-09-22

    Rett syndrome (RTT) is a neurodevelopmental disorder caused by MECP2 mutations. Although emerging evidence suggests that MeCP2 deficiency is associated with dysregulation of mechanistic target of rapamycin (mTOR), which functions as a hub for various signaling pathways, the mechanism underlying this association and the molecular pathophysiology of RTT remain elusive. We show here that MeCP2 promotes the posttranscriptional processing of particular microRNAs (miRNAs) as a component of the microprocessor Drosha complex. Among the MeCP2-regulated miRNAs, we found that miR-199a positively controls mTOR signaling by targeting inhibitors for mTOR signaling. miR-199a and its targets have opposite effects on mTOR activity, ameliorating and inducing RTT neuronal phenotypes, respectively. Furthermore, genetic deletion of miR-199a-2 led to a reduction of mTOR activity in the brain and recapitulated numerous RTT phenotypes in mice. Together, these findings establish miR-199a as a critical downstream target of MeCP2 in RTT pathogenesis by linking MeCP2 with mTOR signaling.

  12. Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X.

    PubMed

    Bissonnette, J M; Schaevitz, L R; Knopp, S J; Zhou, Z

    2014-05-16

    Respiratory disturbances are a primary phenotype of the neurological disorder, Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Mouse models generated with null mutations in Mecp2 mimic respiratory abnormalities in RTT girls. Large deletions, however, are seen in only ∼10% of affected human individuals. Here we characterized respiration in heterozygous females from two mouse models that genetically mimic common RTT point mutations, a missense mutation T158A (Mecp2(T158A/)(+)) or a nonsense mutation R168X (Mecp2(R168X/+)). MeCP2 T158A shows decreased binding to methylated DNA, while MeCP2 R168X retains the capacity to bind methylated DNA but lacks the ability to recruit complexes required for transcriptional repression. We found that both Mecp2(T158A/+) and Mecp2(R168X/+) heterozygotes display augmented hypoxic ventilatory responses and depressed hypercapnic responses, compared to wild-type controls. Interestingly, the incidence of apnea was much greater in Mecp2(R168X/+) heterozygotes, 189 per hour, than Mecp2(T158A/+) heterozygotes, 41 per hour. These results demonstrate that different RTT mutations lead to distinct respiratory phenotypes, suggesting that characterization of the respiratory phenotype may reveal functional differences between MeCP2 mutations and provide insights into the pathophysiology of RTT.

  13. Loss and Gain of MeCP2 Cause Similar Hippocampal Circuit Dysfunction that Is Rescued by Deep Brain Stimulation in a Rett Syndrome Mouse Model.

    PubMed

    Lu, Hui; Ash, Ryan T; He, Lingjie; Kee, Sara E; Wang, Wei; Yu, Dinghui; Hao, Shuang; Meng, Xiangling; Ure, Kerstin; Ito-Ishida, Aya; Tang, Bin; Sun, Yaling; Ji, Daoyun; Tang, Jianrong; Arenkiel, Benjamin R; Smirnakis, Stelios M; Zoghbi, Huda Y

    2016-08-17

    Loss- and gain-of-function mutations in methyl-CpG-binding protein 2 (MECP2) underlie two distinct neurological syndromes with strikingly similar features, but the synaptic and circuit-level changes mediating these shared features are undefined. Here we report three novel signs of neural circuit dysfunction in three mouse models of MECP2 disorders (constitutive Mecp2 null, mosaic Mecp2(+/-), and MECP2 duplication): abnormally elevated synchrony in the firing activity of hippocampal CA1 pyramidal neurons, an impaired homeostatic response to perturbations of excitatory-inhibitory balance, and decreased excitatory synaptic response in inhibitory neurons. Conditional mutagenesis studies revealed that MeCP2 dysfunction in excitatory neurons mediated elevated synchrony at baseline, while MeCP2 dysfunction in inhibitory neurons increased susceptibility to hypersynchronization in response to perturbations. Chronic forniceal deep brain stimulation (DBS), recently shown to rescue hippocampus-dependent learning and memory in Mecp2(+/-) (Rett) mice, also rescued all three features of hippocampal circuit dysfunction in these mice. PMID:27499081

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

    PubMed Central

    2010-01-01

    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. PMID:20420693

  15. Deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in twins with a Rett syndrome-like phenotype.

    PubMed

    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.

  16. MECP2e1 isoform mutation affects the form and function of neurons derived from Rett syndrome patient iPS cells.

    PubMed

    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.

  17. Synaptic circuit abnormalities of motor-frontal layer 2/3 pyramidal neurons in a mutant mouse model of Rett syndrome

    PubMed Central

    Wood, Lydia; Shepherd, Gordon M. G.

    2010-01-01

    Motor and cognitive functions are severely impaired in Rett syndrome (RTT). Here, we examined local synaptic circuits of layer 2/3 (L2/3) pyramidal neurons in motor-frontal cortex of male hemizygous MeCP2-null mice at 3–4 weeks of age. We mapped local excitatory input to L2/3 neurons using glutamate uncaging and laser scanning photostimulation, and compared synaptic input maps recorded from MeCP2-null and wild type (WT) mice. Local excitatory input was significantly reduced in the mutants. The strongest phenotype was observed for lateral (horizontal, intralaminar) inputs, that is, L2/3→2/3 inputs, which showed a large reduction in MeCP2−/y animals. Neither the amount of local inhibitory input to these L2/3 pyramidal neurons nor their intrinsic electrophysiological properties differed by genotype. Our findings provide further evidence that excitatory networks are selectively reduced in RTT. We discuss our findings in the context of recently published parallel studies using selective MeCP2 knockdown in individual L2/3 neurons. PMID:20138994

  18. Deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in twins with a Rett syndrome-like phenotype

    PubMed Central

    Williamson, Sarah L; Ellaway, Carolyn J; Peters, Greg B; Pelka, Gregory J; Tam, Patrick PL; Christodoulou, John

    2015-01-01

    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. PMID:25424712

  19. Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

    PubMed Central

    2012-01-01

    This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies. PMID:22958744

  20. Abnormal general movements in girls with Rett disorder: the first four months of life.

    PubMed

    Einspieler, Christa; Kerr, Alison M; Prechtl, Heinz F R

    2005-11-01

    An apparently normal early development was one of the initial criteria for classical Rett syndrome. However, several investigators considered Rett syndrome to be a developmental disorder manifesting very soon after birth. Videos of 14 infants with Rett disorder were carefully assessed for their spontaneous movements, in particular general movements (GMs), during the first 4 months of life. A detailed analysis clearly demonstrated that none of the infants had normal GMs. However, a specific abnormal GM pattern could not be detected for Rett disorder. The abnormal GMs described here, and their individual developmental trajectories are different from the abnormal GMs described in infants with acquired brain lesion. Our study is the first to apply specific standardised measures of early spontaneous movements to infants with Rett syndrome, proving conclusively that the disorder is manifest within the first weeks of life.

  1. People with "MECP2" Mutation-Positive Rett Disorder Who Converse

    ERIC Educational Resources Information Center

    Kerr, A. M.; Archer, H. L.; Evans, J. C.; Prescott, R. J.; Gibbon, F.

    2006-01-01

    Background: People with useful speech after regression constitute a distinct group of those with mutation-positive Rett disorder, 6% (20/331) reported among mutation-positive people in the British Survey. We aimed to determine the physical, mental and genetic characteristics of this group and to gain insight into their experience of Rett syndrome.…

  2. Clinical biomarkers in metabolic syndrome.

    PubMed

    Barazzoni, Rocco; Silva, Veronica; Singer, Pierre

    2014-04-01

    A biomarker can be defined as a measurable variable that may be used as an indicator of a given biological state or condition. Biomarkers have been used in health and disease for diagnostic purposes, as tools to assess effectiveness of nutritional or drug intervention, or as risk markers to predict the development of certain diseases. In nutrition studies, selecting appropriate biomarkers is important to assess compliance, or incidence of a particular dietary component in the biochemistry of the organism, and in the diagnosis and prognosis of nutrition-related diseases. Metabolic syndrome is a cluster of cardiovascular risk factors that occur simultaneously in the same individual, and it is associated with systemic alterations that may involve several organs and tissues. Given its close association with obesity and the increasing prevalence of obesity worldwide, identifying obese individuals at risk for metabolic syndrome is a major clinical priority. Biomarkers for metabolic syndrome are therefore potential important tools to maximize the effectiveness of treatment in subjects who would likely benefit the most. Choice of biomarkers may be challenging due to the complexity of the syndrome, and this article will mainly focus on nutrition biomarkers related to the diagnosis and prognosis of the metabolic syndrome.

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

    PubMed Central

    Janc, Oliwia A.; Müller, Michael

    2014-01-01

    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 (methyl-CpG-binding protein 2)-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 synaptic short-term plasticity, and fully restored synaptic long-term potentiation (LTP). 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 the hypoxia tolerance. Therefore, radical scavengers are promising compounds for the treatment of neuronal dysfunction in RS and deserve further detailed evaluation. PMID:24605086

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

    PubMed

    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.

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

    PubMed

    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

  6. 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

    PubMed Central

    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.

  7. 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

    PubMed Central

    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

  8. 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.

    PubMed

    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 (Mecp2 (stop/y)). Unrestrained whole-body-plethysmography at postnatal day P60 revealed a low respiratory rate and prolonged respiratory pauses in Mecp2 (stop/y) mice. In contrast, GlyT2-Cre positive Mecp2 (stop/y) mice (Cre(+) ; Mecp2 (stop/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

  9. The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype

    PubMed Central

    van Bon, Bregje WM; Koolen, David A; Brueton, Louise; McMullan, Dominic; Lichtenbelt, Klaske D; Adès, Lesley C; Peters, Gregory; Gibson, Kate; Novara, Francesca; Pramparo, Tiziano; Bernardina, Bernardo Dalla; Zoccante, Leonardo; Balottin, Umberto; Piazza, Fausta; Pecile, Vanna; Gasparini, Paolo; Guerci, Veronica; Kets, Marleen; Pfundt, Rolph; de Brouwer, Arjan P; Veltman, Joris A; de Leeuw, Nicole; Wilson, Meredith; Antony, Jayne; Reitano, Santina; Luciano, Daniela; Fichera, Marco; Romano, Corrado; Brunner, Han G; Zuffardi, Orsetta; de Vries, Bert BA

    2010-01-01

    Six submicroscopic deletions comprising chromosome band 2q23.1 in patients with severe mental retardation (MR), short stature, microcephaly and epilepsy have been reported, suggesting that haploinsufficiency of one or more genes in the 2q23.1 region might be responsible for the common phenotypic features in these patients. In this study, we report the molecular and clinical characterisation of nine new 2q23.1 deletion patients and a clinical update on two previously reported patients. All patients were mentally retarded with pronounced speech delay and additional abnormalities including short stature, seizures, microcephaly and coarse facies. The majority of cases presented with stereotypic repetitive behaviour, a disturbed sleep pattern and a broad-based gait. These features led to the initial clinical impression of Angelman, Rett or Smith–Magenis syndromes in several patients. The overlapping 2q23.1 deletion region in all 15 patients comprises only one gene, namely, MBD5. Interestingly, MBD5 is a member of the methyl CpG-binding domain protein family, which also comprises MECP2, mutated in Rett's syndrome. Another gene in the 2q23.1 region, EPC2, was deleted in 12 patients who had a broader phenotype than those with a deletion of MBD5 only. EPC2 is a member of the polycomb protein family, involved in heterochromatin formation and might be involved in causing MR. Patients with a 2q23.1 microdeletion present with a variable phenotype and the diagnosis should be considered in mentally retarded children with coarse facies, seizures, disturbed sleeping patterns and additional specific behavioural problems. PMID:19809484

  10. The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype.

    PubMed

    van Bon, Bregje W M; Koolen, David A; Brueton, Louise; McMullan, Dominic; Lichtenbelt, Klaske D; Adès, Lesley C; Peters, Gregory; Gibson, Kate; Moloney, Susan; Novara, Francesca; Pramparo, Tiziano; Dalla Bernardina, Bernardo; Zoccante, Leonardo; Balottin, Umberto; Piazza, Fausta; Pecile, Vanna; Gasparini, Paolo; Guerci, Veronica; Kets, Marleen; Pfundt, Rolph; de Brouwer, Arjan P; Veltman, Joris A; de Leeuw, Nicole; Wilson, Meredith; Antony, Jayne; Reitano, Santina; Luciano, Daniela; Fichera, Marco; Romano, Corrado; Brunner, Han G; Zuffardi, Orsetta; de Vries, Bert B A

    2010-02-01

    Six submicroscopic deletions comprising chromosome band 2q23.1 in patients with severe mental retardation (MR), short stature, microcephaly and epilepsy have been reported, suggesting that haploinsufficiency of one or more genes in the 2q23.1 region might be responsible for the common phenotypic features in these patients. In this study, we report the molecular and clinical characterisation of nine new 2q23.1 deletion patients and a clinical update on two previously reported patients. All patients were mentally retarded with pronounced speech delay and additional abnormalities including short stature, seizures, microcephaly and coarse facies. The majority of cases presented with stereotypic repetitive behaviour, a disturbed sleep pattern and a broad-based gait. These features led to the initial clinical impression of Angelman, Rett or Smith-Magenis syndromes in several patients. The overlapping 2q23.1 deletion region in all 15 patients comprises only one gene, namely, MBD5. Interestingly, MBD5 is a member of the methyl CpG-binding domain protein family, which also comprises MECP2, mutated in Rett's syndrome. Another gene in the 2q23.1 region, EPC2, was deleted in 12 patients who had a broader phenotype than those with a deletion of MBD5 only. EPC2 is a member of the polycomb protein family, involved in heterochromatin formation and might be involved in causing MR. Patients with a 2q23.1 microdeletion present with a variable phenotype and the diagnosis should be considered in mentally retarded children with coarse facies, seizures, disturbed sleeping patterns and additional specific behavioural problems.

  11. [Clinical aspects of Marfan syndrome].

    PubMed

    Belsing, Tina Zimmermann; Lund, Allan Meldgaard; Søndergaard, Lars; Friis-Hansen, Lennart; Abildstrøm, Steen Zabell

    2011-01-31

    Marfan syndrome (MFS) and MFS-related diseases are inherited connective tissue disorders involving several organ systems. The diagnosis of MFS is difficult as the many symptoms overlap with those of other systemic connective tissue diseases. The phenotype is progressive. Effective surgical therapy and standardized follow-up programs have led to an improved lifespan for the affected individuals. Selective angiotensin II, type 1 (AT1) blockers may improve several manifestations of MFS, but the outcome of clinical trials is presently unknown. This review describes the importance of a coordinated strategy for diagnosis, treatment and follow-up. PMID:21276396

  12. Clinical pharmacology of old age syndromes

    PubMed Central

    Broadhurst, C; Wilson, K C M; Kinirons, M T; Wagg, A; Dhesi, J K

    2003-01-01

    Several syndromes occur in old age. They are often associated with increased mortality and in all there is a paucity of basic and clinical research. The recent developments in the clinical pharmacology of three common syndromes of old age (delirium, urinary incontinence, and falls) are discussed along with directions for future research. PMID:12919174

  13. Update on clinically isolated syndrome.

    PubMed

    Thouvenot, Éric

    2015-04-01

    Optic neuritis, myelitis and brainstem syndrome accompanied by a symptomatic MRI T2 or FLAIR hyperintensity and T1 hypointensity are highly suggestive of multiple sclerosis (MS) in young adults. They are called "clinically isolated syndrome" (CIS) and correspond to the typical first multiple sclerosis (MS) episode, especially when associated with other asymptomatic demyelinating lesions, without clinical, radiological and immunological sign of differential diagnosis. After a CIS, the delay of apparition of a relapse, which corresponds to the conversion to clinically definite MS (CDMS), varies from several months to more than 10 years (10-15% of cases, generally called benign RRMS). This delay is generally associated with the number and location of demyelinating lesions of the brain and spinal cord and the results of CSF analysis. Several studies comparing different MRI criteria for dissemination in space and dissemination in time of demyelinating lesions, two hallmarks of MS, provided enough substantial data to update diagnostic criteria for MS after a CIS. In the last revision of the McDonald's criteria in 2010, diagnostic criteria were simplified and now the diagnosis can be made by a single initial scan that proves the presence of active asymptomatic lesions (with gadolinium enhancement) and of unenhanced lesions. However, time to conversion remains highly unpredictable for a given patient and CIS can remain isolated, especially for idiopathic unilateral optic neuritis or myelitis. Univariate analyses of clinical, radiological, biological or electrophysiological characteristics of CIS patients in small series identified numerous risk factors of rapid conversion to MS. However, large series of CIS patients analyzing several characteristics of CIS patients and the influence of disease modifying therapies brought important information about the risk of CDMS or RRMS over up to 20 years of follow-up. They confirmed the importance of the initial MRI pattern of

  14. Asperger syndrome, violent thoughts and clinically isolated syndrome.

    PubMed

    Vanderbruggen, N; Van Geit, N; Bissay, V; Zeeuws, D; Santermans, L; Baeken, C

    2010-12-01

    A young man, 23 years old, with a clinically isolated syndrome (CIS), presented violent thoughts during a neurological consultation. He was diagnosed with Asperger Syndrome based on a psychiatric and (neuro)psychological examination. Possible risk factors for acting-out and the implications for treatment, if CIS would evolve to MS, are discussed based on a review of the literature.

  15. Refeeding syndrome: a clinical review.

    PubMed

    Ormerod, Clare; Farrer, Kirstine; Harper, Lindsay; Lal, Simon

    2010-12-01

    Refeeding syndrome can result in a wide variety of complications and may be life threatening. Although well described in hospital practice, refeeding syndrome is often under-recognized and inadequately treated.

  16. Teriparatide in the treatment of recurrent fractures in a Rett patient

    PubMed Central

    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

  17. Serotonin syndrome versus neuroleptic malignant syndrome: a challenging clinical quandary.

    PubMed

    Dosi, Rupal; Ambaliya, Annirudh; Joshi, Harshal; Patell, Rushad

    2014-06-23

    Serotonin syndrome and neuroleptic malignant syndrome are two drug toxidromes that have often overlapping and confusing clinical pictures. We report a case of a young man who presented with alteration of mental status, autonomic instability and neuromuscular hyperexcitability following ingestion of multiple psychiatric and antiepileptic medications. The patient satisfied criteria for serotonin syndrome and neuroleptic malignant syndrome, and based on the characteristic clinical features, laboratory findings and clinical course it was concluded that the patient had both toxidromes. The patient was managed with cyproheptadine and supportive measures, and recovered over the course of 3 weeks. A brief review of literature highlighting the diagnostic clues as well as the importance of recognising and distinguishing the often missed and confounding diagnoses follows.

  18. Serotonin syndrome versus neuroleptic malignant syndrome: a challenging clinical quandary

    PubMed Central

    Dosi, Rupal; Ambaliya, Annirudh; Joshi, Harshal; Patell, Rushad

    2014-01-01

    Serotonin syndrome and neuroleptic malignant syndrome are two drug toxidromes that have often overlapping and confusing clinical pictures. We report a case of a young man who presented with alteration of mental status, autonomic instability and neuromuscular hyperexcitability following ingestion of multiple psychiatric and antiepileptic medications. The patient satisfied criteria for serotonin syndrome and neuroleptic malignant syndrome, and based on the characteristic clinical features, laboratory findings and clinical course it was concluded that the patient had both toxidromes. The patient was managed with cyproheptadine and supportive measures, and recovered over the course of 3 weeks. A brief review of literature highlighting the diagnostic clues as well as the importance of recognising and distinguishing the often missed and confounding diagnoses follows. PMID:24957740

  19. [Clinical heterogeneity of the autistic syndrome: a study of 60 families].

    PubMed

    Moreno, H; Borjas, L; Arrieta, A; Sáez, L; Prassad, A; Estévez, J; Bonilla, E

    1992-01-01

    Sixty families ascertained through a single proband, has helped to better define infantile autism as a heterogeneous group of disorders. Forty four patients showed a characteristic facio- auricular dysplasia. Twenty four of these, showed increased pyruvate and lactate and laboratory findings of metabolic acidosis i.e., anion gap above 18 mEq/L or serum bicarbonate below 21 mEq/L but only nine of these probands demonstrated reduction of plasma bicarbonate below 18 mEq/lt. Plasma amino acids in 17 probands and matched controls showed increased taurine with the rest of amino acids significantly (p less than 0.05) below the control level. Glutamate and aspartate were also significantly elevated (p less than 0.05; Student t-test). Segregation analysis in thirty four of these families which linked through at least one ancestral family name, suggested autosomal recessive inheritance (p = 0.20). Three out of eight probands who received megadoses of pyridoxine (Vitamin B6), subjectively gained in language abilities, affectivity and response to behavior modification therapy. Five autistic patients proved to have clinically defined syndromes: two with the Martin-Bell syndrome, and three girls affected respectively with the Rett syndrome, phenylketonuria and dicarboxylic aciduria. PMID:1391074

  20. A Clinical Perspective of the Takotsubo Syndrome.

    PubMed

    Sharkey, Scott W

    2016-10-01

    This article provides a contemporary review of the clinical features of the takotsubo syndrome. The author discusses hallmark elements that distinguish this novel acute cardiac condition from the more common acute coronary syndrome. This review includes relevant clinical detail surrounding findings on ECG, biochemical testing, and cardiac imaging and a discussion of complications, including acute decompensated heart failure, arrhythmias, ventricular thrombi, and left ventricular outflow obstruction. The review concludes with discussion of proper treatment, long-term survival, and recurrence. PMID:27638021

  1. Genetics Home Reference: Rett syndrome

    MedlinePlus

    ... involved in maintaining connections ( synapses ) between nerve cells (neurons). It may also be necessary for the normal ... which appears to disrupt the normal function of neurons and other cells in the brain. Specifically, studies ...

  2. Clinical Features of Turner Syndrome

    MedlinePlus

    ... growth is attenuated in utero, and statural growth lags during childhood and adolescence, resulting in adult heights ... easily treated with thyroid hormone supplements. Cognitive Function/Educational Issues In general, individuals with Turner syndrome have ...

  3. Key Clinical Features to Identify Girls with "CDKL5" Mutations

    ERIC Educational Resources Information Center

    Bahi-Buisson, Nadia; Nectoux, Juliette; Rosas-Vargas, Haydee; Milh, Mathieu; Boddaert, Nathalie; Girard, Benoit; Cances, Claude; Ville, Dorothee; Afenjar, Alexandra; Rio, Marlene; Heron, Delphine; Morel, Marie Ange N'Guyen; Arzimanoglou, Alexis; Philippe, Christophe; Jonveaux, Philippe; Chelly, Jamel; Bienvenu, Thierry

    2008-01-01

    Mutations in the human X-linked cyclin-dependent kinase-like 5 ("CDKL5") gene have been shown to cause infantile spasms as well as Rett syndrome (RTT)-like phenotype. To date, less than 25 different mutations have been reported. So far, there are still little data on the key clinical diagnosis criteria and on the natural history of…

  4. Molecular and Clinical Aspects of Angelman Syndrome

    PubMed Central

    Dagli, A.; Buiting, K.; Williams, C.A.

    2012-01-01

    The Angelman syndrome is caused by disruption of the UBE3A gene and is clinically delineated by the combination of severe mental disability, seizures, absent speech, hypermotoric and ataxic movements, and certain remarkable behaviors. Those with the syndrome have a predisposition toward apparent happiness and paroxysms of laughter, and this finding helps distinguish Angelman syndrome from other conditions involving severe developmental handicap. Accurate diagnosis rests on a combination of clinical criteria and molecular and/or cytogenetic testing. Analysis of parent-specific DNA methylation imprints in the critical 15q11.2–q13 genomic region identifies 75–80% of all individuals with the syndrome, including those with cytogenetic deletions, imprinting center defects and paternal uniparental disomy. In the remaining group, UBE3A sequence analysis identifies an additional percentage of patients, but 5–10% will remain who appear to have the major clinical phenotypic features but do not have any identifiable genetic abnormalities. Genetic counseling for recurrence risk is complicated because multiple genetic mechanisms can disrupt the UBE3A gene, and there is also a unique inheritance pattern associated with UBE3A imprinting. Angelman syndrome is a prototypical developmental syndrome due to its remarkable behavioral phenotype and because UBE3A is so crucial to normal synaptic function and neural plasticity. PMID:22670133

  5. Reye's syndrome: a clinical review.

    PubMed Central

    Crocker, J F; Bagnell, P C

    1981-01-01

    Reye's syndrome is a virus-associated biphasic disease that causes acute encephalopathy in infants and children. Epidemiologic and experimental data support the hypothesis that it is a multifactorial disease of modern civilization. Just as young patients seem to be recovering uneventfully from the first phase of the illness, usually a nonspecific viral-like illness such as a respiratory tract infection or gastroenteritis, the second phase, encephalopathy, starts unexpectedly, with vomiting and sensorial changes. Identifying the syndrome early ;in the second phase and referring the child to a specialized centre with the experience, staff and facilities to manage this phase has improved the numbers and neurologic condition of survivors, though the overall mortality is still about 20%. Therapy is primarily directed at facilitating adequate cerebral perfusion pressure. PMID:6783291

  6. Racism as a clinical syndrome.

    PubMed

    Dobbins, J E; Skillings, J H

    2000-01-01

    This paper examines the clinical effects of racism on its targets and, in particular, on its agents, the individuals who, wittingly or not, partake of the culture of racial privilege. It proposes a paradigm shift in regard to the clinical study of racism, and presents a structural model of racism, analogous to addiction as a disease, which holds that racism has an etiology and a clinical taxonomy that lends itself to differential diagnosis and treatment of those who manifest symptoms.

  7. Clinical and molecular findings in IPEX syndrome

    PubMed Central

    Myers, A K; Perroni, L; Costigan, C; Reardon, W

    2006-01-01

    IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X linked syndrome) is a rare disorder which usually results in death in early infancy or childhood. Clinical awareness remains the cornerstone of diagnosis, and provided that the diagnosis is entertained, mutation analysis for FOXP3 gene mutations can be confirmatory. Two new patients in whom IPEX was diagnosed retrospectively are reported. PMID:16371377

  8. RIN2 syndrome: Expanding the clinical phenotype.

    PubMed

    Rosato, Simonetta; Syx, Delfien; Ivanovski, Ivan; Pollazzon, Marzia; Santodirocco, Daniela; De Marco, Loredana; Beltrami, Marina; Callewaert, Bert; Garavelli, Livia; Malfait, Fransiska

    2016-09-01

    Biallelic defects in the RIN2 gene, encoding the Ras and Rab interactor 2 protein, are associated with a rare autosomal recessive connective tissue disorder, with only nine patients from four independent families reported to date. The condition was initially termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis), based on the clinical features of the first identified family; however, with the expansion of the clinical phenotype in additional families, it was subsequently coined RIN2 syndrome. Hallmark features of this condition include dysmorphic facial features with striking, progressive facial coarsening, sparse hair, normal to enlarged occipitofrontal circumference, soft redundant and/or hyperextensible skin, and scoliosis. Patients with RIN2 syndrome present phenotypic overlap with other conditions, including EDS (especially the dermatosparaxis and kyphoscoliosis subtypes). Here, we describe a 10th patient, the first patient of Caucasian origin and the oldest reported patient so far, who harbors the previously identified homozygous RIN2 mutation c.1878dupC (p. (Ile627Hisfs*7)). Besides the hallmark features, this patient also presents problems not previously associated with RIN2 syndrome, including cervical vertebral fusion, mild hearing loss, and colonic fibrosis. We provide an overview of the clinical findings in all reported patients with RIN2 mutations and summarize some of the possible pathogenic mechanisms that may underlie this condition. © 2016 Wiley Periodicals, Inc. PMID:27277385

  9. Kallmann's syndrome: clues to clinical diagnosis.

    PubMed

    John, H; Schmid, C

    2000-04-01

    Hypogonadotropic patients may visit pediatricians, general practitioners, endocrinologists or urologists, presenting with microphallus, cryptochidism or pubertas tarda and delayed bone maturation. Congenital hypogonadotropic hypogonadism is characterized, apart from small testes, by the constellation of low serum levels of testosterone, LH and FSH. Kallman's syndrome is characterized by congenital hypogonadotropic hypogonadism with midline defects such as anosmia (a deficiency of the sense of smell). The first case report dates back to 1856, and genetic defects causing the syndrome have been recently described. The diagnosis can be clinically suspected and is established by confirming hormonal studies. PMID:11052640

  10. Noonan syndrome and clinically related disorders

    PubMed Central

    Tartaglia, Marco; Gelb, Bruce D.; Zenker, Martin

    2010-01-01

    Noonan syndrome is a relatively common, clinically variable developmental disorder. Cardinal features include postnatally reduced growth, distinctive facial dysmorphism, congenital heart defects and hypertrophic cardiomyopathy, variable cognitive deficit and skeletal, ectodermal and hematologic anomalies. Noonan syndrome is transmitted as an autosomal dominant trait, and is genetically heterogeneous. So far, heterozygous mutations in nine genes (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 and CBL) have been documented to underlie this disorder or clinically related phenotypes. Based on these recent discoveries, the diagnosis can now be confirmed molecularly in approximately 75% of affected individuals. Affected genes encode for proteins participating in the RAS-mitogen-activated protein kinases (MAPK) signal transduction pathway, which is implicated in several developmental processes controlling morphology determination, organogenesis, synaptic plasticity and growth. Here, we provide an overview of clinical aspects of this disorder and closely related conditions, the molecular mechanisms underlying pathogenesis, and major genotype-phenotype correlations. PMID:21396583

  11. Drug Hypersensitivity: Pharmacogenetics and Clinical Syndromes

    PubMed Central

    Phillips, Elizabeth J.; Chung, Wen-Hung; Mockenhaupt, Maja; Roujeau, Jean-Claude; Mallal, Simon A.

    2011-01-01

    Severe cutaneous adverse reactions (SCARs) include syndromes such as drug reaction, eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS) and Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN). An important advance has been the discovery of associations between HLA alleles and many of these syndromes including abacavir hypersensitivity reaction, allopurinol DRESS/DIHS and SJS/TEN and SJS/TEN associated with aromatic amine anticonvulsants. These HLA associations have created the promise for prevention through screening and have additionally shed further light on the immunopathogenesis of SCARs. The roll-out of HLA-B*5701 into routine clinical practice as a genetic screening test to prevent abacavir hypersensitivity provides a translational roadmap for other drugs. Numerous hurdles exist in the widespread translation of several other drugs such as carbamazepine where the positive predictive value of HLA-B*1502 is low and the negative predictive value of HLA-B*1502 for SJS/TEN may not be 100% in all ethnic groups. International collaborative consortia have been formed with the goal of developing phenotype standardization and undertaking HLA and genome-wide analyses in diverse populations with these syndromes. PMID:21354501

  12. Primary Sjogren syndrome: clinical and immunopathologic features.

    PubMed

    Fox, R I; Howell, F V; Bone, R C; Michelson, P

    1984-11-01

    Primary Sjogren syndrome is an autoimmune condition in which dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) result from lymphocytic infiltration of lacrimal and salivary glands. Clinical and laboratory features of 60 primary Sjogren syndrome patients seen at our clinic during the past three years are presented. These patients illustrate the wide spectrum of extraglandular features that may occur as a result of lymphoid infiltration of lung, kidney, skin, stomach, liver, and muscle. They further emphasize the difficulty in classifying a patient as primary or secondary Sjogren syndrome (ie, sicca symptoms associated with systemic lupus erythematosus, rheumatoid arthritis, or scleroderma), particularly early in the disease course. As an initial step in understanding the pathogenesis, the lymphocytes that infiltrate the salivary glands and lymph nodes were characterized by using monoclonal antibodies that recognize distinct lymphocyte subsets and by using in vitro functional assays. These studies have demonstrated that affected tissues have infiltrates of T cells with helper/inducer activity and with a high frequency of "activation antigens." The immunohistologic techniques are useful in differentiating "benign" and "pseudolymphoma" lesions (both due predominantly to T cells) from non-Hodgkin lymphoma (usually due to B-cell infiltrates). Although there is no "cure" for primary Sjogren syndrome patient's symptoms may be significantly improved by measures aimed at prevention of ocular and dental complications and by the recognition of extraglandular features that may be amenable to specific treatment.

  13. MECP2 disorders: from the clinic to mice and back

    PubMed Central

    Lombardi, Laura Marie; Baker, Steven Andrew; Zoghbi, Huda Yahya

    2015-01-01

    Two severe, progressive neurological disorders characterized by intellectual disability, autism, and developmental regression, Rett syndrome and MECP2 duplication syndrome, result from loss and gain of function, respectively, of the same critical gene, methyl-CpG–binding protein 2 (MECP2). Neurons acutely require the appropriate dose of MECP2 to function properly but do not die in its absence or overexpression. Instead, neuronal dysfunction can be reversed in a Rett syndrome mouse model if MeCP2 function is restored. Thus, MECP2 disorders provide a unique window into the delicate balance of neuronal health, the power of mouse models, and the importance of chromatin regulation in mature neurons. In this Review, we will discuss the clinical profiles of MECP2 disorders, the knowledge acquired from mouse models of the syndromes, and how that knowledge is informing current and future clinical studies. PMID:26237041

  14. A case of Lennox-Gastaut syndrome in a patient with FOXG1-related disorder.

    PubMed

    Terrone, Gaetano; Bienvenu, Thierry; Germanaud, David; Barthez-Carpentier, Marie-Anne; Diebold, Bertrand; Delanoe, Catherine; Passemard, Sandrine; Auvin, Stéphane

    2014-11-01

    Lennox-Gastaut syndrome (LGS) is a drug-resistant epileptic encephalopathy of childhood with a heterogeneous etiology. Recently, genome-wide association studies have led to the identification of new de novo mutations associated with this epileptic syndrome. Herein, we report an 8-year-old child with intellectual disability, severe postnatal microcephaly, Rett-like features, and LGS, carrying a de novo missense mutation in the forkhead box G1 (FOXG1) gene. This gene is responsible for FOXG1 syndrome, characterized by severe postnatal microcephaly, moderate postnatal growth deficiency, mental retardation with poor social interaction, stereotyped behavior and dyskinesias, absent language, sleep disorders, and epilepsy. Nonspecific epilepsy syndromes have been associated with this genetic disorder. Thus, we hypothesize that FOXG1 might be a new candidate gene in the etiology of LGS and suggest screening for this gene in cases of LGS with concomitant microcephaly and clinical features overlapping with Rett syndrome.

  15. Clinical spectrum of Treacher Collins syndrome.

    PubMed

    Mehrotra, Divya; Hasan, Mahdi; Pandey, Rahul; Kumar, Sumit

    2011-01-01

    Treacher Collins syndrome (TCS) is the most common of the human mandibulofacial dysostosis disorders. It is an autosomal-dominant disorder of the craniofacial development occurring between the fifth and the eighth weeks of embryonic development with an incidence of 1/50,000 live births, range between 1-40,000 and 1-70,000. We present here the various clinical, radiographical and other diagnostic findings of the TCS to correlate the clinical assessment with the diagnostic imaging and review the various investigations and management options being carried out to improve their facial deformity.

  16. [Clinical and echocardiographic characteristics of scimitar syndrome].

    PubMed

    Espinola-Zavaleta, Nilda; Játiva-Chávez, Silvio; Muñoz-Castellanos, Luis; Zamora-González, Carlos

    2006-03-01

    Seven patients with scimitar syndrome underwent retrospective clinical and echocardiographic examination. The findings were: respiratory infection with dyspnea on moderate exercise in 90%, scimitar sign in four (57%), dextrocardia in five (71%), and interatrial septal defect in five (71%), one of whom had patent ductus arteriosus. Overall, two patients had patent ductus arteriosus: one also had aortic coarctation and the other, a bicuspid aortic valve. Dilation of the right cavities was found in five (71%) and blunt edge in five (71%). In two patients, anomalous drainage was into the right atrium; in another two, into the inferior vena cava; and in three, towards the junction of the right atrium and the inferior vena cava. In three patients, drainage was obstructed. Six patients with cardiac abnormalities proceeded to surgery. Scimitar syndrome is a rare entity. In the large majority of patients (86%), diagnosis and follow-up can be performed echocardiographically.

  17. Prader-Willi Syndrome: Clinical Aspects

    PubMed Central

    Elena, Grechi; Bruna, Cammarata; Benedetta, Mariani; Stefania, Di Candia; Giuseppe, Chiumello

    2012-01-01

    Prader-Willi Syndrome (PWS) is a complex multisystem genetic disorder that shows great variability, with changing clinical features during a patient's life. The syndrome is due to the loss of expression of several genes encoded on the proximal long arm of chromosome 15 (15q11.2–q13). The complex phenotype is most probably caused by a hypothalamic dysfunction that is responsible for hormonal dysfunctions and for absence of the sense of satiety. For this reason a Prader-Willi (PW) child develops hyperphagia during the initial stage of infancy that can lead to obesity and its complications. During infancy many PW child display a range of behavioural problems that become more noticeable in adolescence and adulthood and interfere mostly with quality of life. Early diagnosis of PWS is important for effective long-term management, and a precocious multidisciplinary approach is fundamental to improve quality of life, prevent complications, and prolong life expectancy. PMID:23133744

  18. The clinics of acute coronary syndrome

    PubMed Central

    Rastelli, Gianni

    2016-01-01

    Risk stratification and management of patients with chest pain continues to be challenging despite considerable efforts made in the last decades by many clinicians and researchers. The throutful evaluation necessitates that the physicians have a high index of suspicion for acute coronary syndrome (ACS) and always keep in mind the myriad of often subtle and atypical presentations of ischemic heart disease, especially in certain patient populations such as the elderly ones. In this article we aim to review and discuss the available evidence on the value of clinical presentation in patients with a suspected ACS, with special emphasis on history, characteristics of chest pain, associated symptoms, atypical presentations, precipitating and relieving factors, drugs, clinical rules and significance of clinical Gestalt. PMID:27294087

  19. Kabuki syndrome: clinical and molecular characteristics

    PubMed Central

    Cheon, Chong-Kun

    2015-01-01

    Kabuki syndrome (KS) is a rare syndrome characterized by multiple congenital anomalies and mental retardation. Other characteristics include a peculiar facial gestalt, short stature, skeletal and visceral abnormalities, cardiac anomalies, and immunological defects. Whole exome sequencing has uncovered the genetic basis of KS. Prior to 2013, there was no molecular genetic information about KS in Korean patients. More recently, direct Sanger sequencing and exome sequencing revealed KMT2D variants in 11 Korean patients and a KDM6A variant in one Korean patient. The high detection rate of KMT2D and KDM6A mutations (92.3%) is expected owing to the strict criteria used to establish a clinical diagnosis. Increased awareness and understanding of KS among clinicians is important for diagnosis and management of KS and for primary care of KS patients. Because mutation detection rates rely on the accuracy of the clinical diagnosis and the inclusion or exclusion of atypical cases, recognition of KS will facilitate the identification of novel mutations. A brief review of KS is provided, highlighting the clinical and genetic characteristics of patients with KS. PMID:26512256

  20. Pineal region tumors: Clinical symptoms and syndromes.

    PubMed

    Rousselle, C; des Portes, V; Berlier, P; Mottolese, C

    2015-01-01

    The present paper investigates the clinical picture and the different clinical signs that reveal pineal region tumors or appear during the course of the follow-up. Biological malignancy and tumor extension determine the semiology and its setting up mode. Typical endocrine signs, dominated by abnormal puberty development, are frequently a part of the clinical scene. Bifocal or ectopic localization in the hypothalamic-pituitary region is accompanied by other endocrine signs such as ante- or post-pituitary insufficiencies which occur several months or even years after the first neurological signs appear. Due to a mass syndrome and obstructive hydrocephalus, intracranial hypertension signs are frequent but unspecific. A careful ophthalmologic examination is essential to search upward gaze paralysis and other signs of the Parinaud's tetrad or pentad. Midbrain dysfunction, including extrinsic aqueduct stenosis, are also prevalent. Except for abnormal pubertal signs, hyper-melatoninemia (secretory tumors) or a-hypo-melatoninemia (tumors destructing pineal) generally remains dormant. Some patients present sleep problems such as narcolepsy or sleepiness during the daytime as well as behavioral problems. This suggests a hypothalamic extension rather than a true consequence of melatonin secretion anomalies. Similarly, some patients may present signs of a "pinealectomized" syndrome, including (cluster) headaches, tiredness, eventually responsive to melatonin. PMID:24439798

  1. [Asperger syndrome. Diagnosis criteria and clinical picture].

    PubMed

    Wahlberg, Ernesto

    2005-01-01

    Asperger syndrome (A.S) is not a very well-known disorder due to its recent incorporation to the international nosography of mental disorders during the early 90s. The intention of this article is to describe the clinical picture with its symptomatic diversity. It will show how the diagnostic criteria were developed since the presentation by Asperger in 1944, to the classification consensed nowadays. It also presents the situations in which this diagnosis is most frequent to facilitate its detection and to permit a more extensive assessment leading to a more accurate treatment. PMID:16077869

  2. Piriformis Syndrome in Fibromyalgia: Clinical Diagnosis and Successful Treatment

    PubMed Central

    Siddiq, Md Abu Bakar; Khasru, Moshiur Rahman; Rasker, Johannes J.

    2014-01-01

    Piriformis syndrome is an underdiagnosed extraspinal association of sciatica. Patients usually complain of deep seated gluteal pain. In severe cases the clinical features of piriformis syndrome are primarily due to spasm of the piriformis muscle and irritation of the underlying sciatic nerve but this mysterious clinical scenario is also described in lumbar spinal canal stenosis, leg length discrepancy, piriformis myofascial pain syndrome, following vaginal delivery, and anomalous piriformis muscle or sciatic nerve. In this paper, we describe piriformis and fibromyalgia syndrome in a 30-year-old young lady, an often missed diagnosis. We also focus on management of the piriformis syndrome. PMID:25328750

  3. Piriformis syndrome in fibromyalgia: clinical diagnosis and successful treatment.

    PubMed

    Siddiq, Md Abu Bakar; Khasru, Moshiur Rahman; Rasker, Johannes J

    2014-01-01

    Piriformis syndrome is an underdiagnosed extraspinal association of sciatica. Patients usually complain of deep seated gluteal pain. In severe cases the clinical features of piriformis syndrome are primarily due to spasm of the piriformis muscle and irritation of the underlying sciatic nerve but this mysterious clinical scenario is also described in lumbar spinal canal stenosis, leg length discrepancy, piriformis myofascial pain syndrome, following vaginal delivery, and anomalous piriformis muscle or sciatic nerve. In this paper, we describe piriformis and fibromyalgia syndrome in a 30-year-old young lady, an often missed diagnosis. We also focus on management of the piriformis syndrome.

  4. Good's Syndrome Accompanied by Agranulocytosis Following a Rapid Clinical Course.

    PubMed

    Okusu, Takahiro; Sato, Taiki; Ogata, Yoshitaka; Nagata, Shinpei; Kozumi, Kazuhiro; Kim, Sung-Ho; Yamamoto, Suguru; Yamayoshi, Shigeru

    2016-01-01

    Good's syndrome is an immunodeficiency disease involving thymoma accompanied by hypogammaglobulinemia. We encountered a case of Good's syndrome accompanied by agranulocytosis that followed a rapid clinical course. A 72-year-old man visited our hospital with a two-week history of a sore throat. Candida albicans was detected in the pharynx, and hypogammaglobulinemia was detected in addition to granulocytopenia. The patient subsequently developed septic shock and followed a rapid clinical course which ended in death. Good's syndrome with agranulocytosis was diagnosed at autopsy. Good's syndrome accompanied by agranulocytosis can follow a rapid clinical course and some cases remain asymptomatic until old age. Its prompt treatment is crucial. PMID:26935379

  5. [Psychomotor disadaptation syndrome: a poorly known clinical entity].

    PubMed

    Lepage, S; Gillain, S; Petermans, J

    2012-02-01

    Psychomotor disadaptation syndrome is a typical geriatric clinical syndrome. It includes postural disorders such as body retropulsion, specific gait disorders, with axial akinesia and hypertonia, and psychobehavioral disorders akin to those found in depression. The diagnosis is essentially based on clinical observation rather than on iconographic data. This syndrome causes falls which induce a fear of falling. The old patient has a tendency to put himself down, to withdraw from society and to lose autonomy. This article briefly describes the physiopathology of the syndrome, recalls the diagnostic tools, and makes some suggestions regarding the care of patients suffering from this clinical entity.

  6. Postural orthostatic tachycardia syndrome: a clinical review.

    PubMed

    Johnson, Jonathan N; Mack, Kenneth J; Kuntz, Nancy L; Brands, Chad K; Porter, Coburn J; Fischer, Philip R

    2010-02-01

    Postural orthostatic tachycardia syndrome was defined in adult patients as an increase >30 beats per minute in heart rate of a symptomatic patient when moving from supine to upright position. Clinical signs may include postural tachycardia, headache, abdominal discomfort, dizziness/presyncope, nausea, and fatigue. The most common adolescent presentation involves teenagers within 1-3 years of their growth spurt who, after a period of inactivity from illness or injury, cannot return to normal activity levels because of symptoms induced by upright posture. Postural orthostatic tachycardia syndrome is complex and likely has numerous, concurrent pathophysiologic etiologies, presenting along a wide spectrum of potential symptoms. Nonpharmacologic treatment includes (1) increasing aerobic exercise, (2) lower-extremity strengthening, (3) increasing fluid/salt intake, (4) psychophysiologic training for management of pain/anxiety, and (5) family education. Pharmacologic treatment is recommended on a case-by-case basis, and can include beta-blocking agents to blunt orthostatic increases in heart rate, alpha-adrenergic agents to increase peripheral vascular resistance, mineralocorticoid agents to increase blood volume, and serotonin reuptake inhibitors. An interdisciplinary research approach may determine mechanistic root causes of symptoms, and is investigating novel management plans for affected patients.

  7. [Clinical phenotypes and prognosis of antisynthetase syndrome].

    PubMed

    Hervier, B; Benveniste, O

    2014-07-01

    Antisynthetase syndrome (ASS) was first described in 1989 as an inflammatory myopathy associated with the presence of specific auto-antibodies, namely the anti-tRNA-synthetase antibodies (ASA). To date, the ASA family comprises eight different auto-antibodies, among which anti-hystidyl-tRNA-synthetase (anti-Jo1) is the most prevalent. In addition to myositis, a constellation of clinical features has also been described in ASS, including interstitial lung disease, Raynaud's phenomenon, polyarthritis, fever and mechanic's hands. Large variations in the distribution and the severity of each of these symptoms are reported from one patient to another, and also over the course of the disease. The heterogeneity of this autoimmune connective tissue disease has led to difficulties in the early identification of patients with a poor outcome (those who will require the most intensive treatments). Additionally, very few prospective trials have so far compared the efficacy of the different immunosuppressive drugs available, and evidence is lacking to help adapting therapeutic strategies to all of the different ASS clinical situations. We will review the different characteristics of ASS (namely biological, clinical, functional, and morphological ASS parameters) that have recently been shown to correlate with patients' outcome, our aim being to discuss the usefulness of patient stratification for elaborating targeted therapeutic trials for ASS in the future.

  8. 2008 Clinical approach to irritable bowel syndrome.

    PubMed

    Astegiano, M; Pellicano, R; Sguazzini, C; Berrutti, M; Simondi, D; Reggiani, S; Rizzetto, M

    2008-09-01

    Irritable bowel syndrome (IBS), as defined by Rome III diagnostic criteria, affects 10-20% of the general population, with women 20-40 years old accounting for the majority of patients. Although variable and intermittent, IBS symptoms may persist for many years. Repeated referrals for medical consultation and diagnostic studies generate huge healthcare costs. Since there is no evidence that IBS leads to more severe gastrointestinal disorders, in absence of alarm symptoms or signs, an invasive diagnostic algorithm is not indicated. Optimal treatment for IBS still needs to be defined. The clinical approach is based on treatment of the prevalent symptom. When pain predominates, antispasmodics are the first choice. In case of diarrhea, loperamide is useful for reducing bowel frequency. Soluble fiber represents the first option in subjects with IBS and constipation or mixed IBS. Dietary integrators composed of probiotics and serotonin precursors are a promising therapeutic option. PMID:18614974

  9. Prader-Willi Syndrome: Clinical and Genetic Findings

    PubMed Central

    Butler, Merlin G.; Thompson, Travis

    2016-01-01

    Since the initial medical description by Prader, Labhart and Willi in 1956 of individuals with overlapping features, the Prader-Willi syndrome has become recognized as a classical but sporadic genetic syndrome. Prader-Willi syndrome is the most common genetic cause of life-threatening obesity in humans. It is estimated that there are 350,000–400,000 people with this syndrome worldwide. Prader-Willi Syndrome Association USA knows of more than 3,400 persons with Prader-Willi syndrome in the USA out of an approximate 17,000–22,000. Prader-Willi syndrome with an incidence of 1 in 10,000 to 25,000 individuals and Angelman syndrome, an entirely different clinical condition, were the first examples in humans of genetic imprinting. Genetic imprinting or the differential expression of genetic information depending on the parent of origin plays a significant role in other conditions including malignancies. PMID:27570435

  10. Irritable bowel syndrome: A clinical review

    PubMed Central

    Soares, Rosa LS

    2014-01-01

    Irritable bowel syndrome (IBS) remains a clinical challenge in the 21st century. It’s the most commonly diagnosed gastrointestinal condition and also the most common reason for referral to gastroenterology clinics. Its can affect up to one in five people at some point in their lives, and has a significantly impact of life quality and health care utilization. The prevalence varies according to country and criteria used to define IBS. Various mechanisms and theories have been proposed about its etiology, but the biopsychosocial model is the most currently accepted for IBS. The complex of symptoms would be the result of the interaction between psychological, behavioral, psychosocial and environmental factors. The diagnosis of IBS is not confirmed by a specific test or structural abnormality. It is made using criteria based on clinical symptoms such as Rome criteria, unless the symptoms are thought to be atypical. Today the Rome Criteria III is the current gold-standard for the diagnoses of IBS. Secure positive evidence of IBS by means of specific disease marker is currently not possible and cannot be currently recommended for routine diagnosis. There is still no clinical evidence to recommend the use of biomarkers in blood to diagnose IBS. However, a number of different changes in IBS patients were demonstrated in recent years, some of which can be used in the future as a diagnostic support. IBS has no definitive treatment but could be controlled by non-pharmacologic management eliminating of some exacerbating factors such certain drugs, stressor conditions and changes in dietary habits.The traditional pharmacologic management of IBS has been symptom based and several drugs have been used. However, the cornerstone of its therapy is a solid patient physician relationship. This review will provide a summary of pathophysiology, diagnostic criteria and current and emerging therapies for IBS. PMID:25232249

  11. Clinical Characteristics of Fuchs’ Uveitis Syndrome

    PubMed Central

    Nalçacıoğlu, Pınar; Çakar Özdal, Pınar; Şimşek, Mert

    2016-01-01

    Objectives: To evaluate the clinical and demographic properties of Fuchs’ uveitis syndrome (FUS) in Turkish patients. Materials and Methods: The medical records of 161 patients with FUS followed in the Uveitis Division of Ulucanlar Eye Hospital between 1996 and 2014 were respectively reviewed. The mean age at diagnosis, sex, the number of affected eyes, follow-up period, clinical findings at presentation, complications during the follow-up period, medical and surgical treatments, and best corrected visual acuity at the initial and final visits were recorded. Results: The study included 171 eyes of 161 patients diagnosed with FUS. Of the patients, 94 (58.4%) were female and 67 (41.6%) were male. The mean age at presentation was 35.2±11.0 (11-65) years. The mean follow-up period was 23.5±32.8 (2-216) months. Ten (6.2%) patients had bilateral involvement. The most common symptoms at presentation were decreased visual acuity or blurred vision in 63 (39.1%) and floaters in 19 (11.8%) patients. Clinical findings at presentation included diffuse small, round, white keratic precipitates in 128 (74.8%) eyes, anterior chamber reaction in 82 (47.9%), vitreous cells in 122 (71.3%), heterochromia in 47 (27.4%) and iris nodules in 32 (18.7%) eyes. During the follow-up period, elevated intraocular pressure occured in 31 (18.1%) eyes and the most common complication was cataract development (89 eyes, 52.0%). Conclusion: Heterochromia was observed in 27.4% of patients in our study. However, the diffuse small, round keratic precipitates, low-grade anterior chamber reaction and varying degrees of vitreous reaction are more common clinical characteristics that are helpful in making the diagnosis. PMID:27800260

  12. Thromboembolic complications in the nephrotic syndrome: pathophysiology and clinical management.

    PubMed

    Singhal, Rajni; Brimble, K Scott

    2006-01-01

    Patients with the nephrotic syndrome are at increased risk of developing venous and arterial thromboembolism, the most common of which is renal vein thrombosis. There are several unanswered or controversial issues relating to the nephrotic syndrome and thromboembolism, which include the mechanism of thromboembolism, and optimal diagnostic and anticoagulant management strategies. This review will discuss several of these issues: the epidemiology and clinical spectrum of thromboembolic disease occurring in patients with the nephrotic syndrome; the pathophysiology of the hypercoagulable state associated with the nephrotic syndrome; the diagnosis of renal vein thrombosis in the nephrotic syndrome; and the evidence for prophylactic and therapeutic anticoagulation strategies in such patients.

  13. A 3 Mb deletion in 14q12 causes severe mental retardation, mild facial dysmorphisms and Rett-like features.

    PubMed

    Papa, Filomena Tiziana; Mencarelli, Maria Antonietta; Caselli, Rossella; Katzaki, Eleni; Sampieri, Katia; Meloni, Ilaria; Ariani, Francesca; Longo, Ilaria; Maggio, Angela; Balestri, Paolo; Grosso, Salvatore; Farnetani, Maria Angela; Berardi, Rosario; Mari, Francesca; Renieri, Alessandra

    2008-08-01

    The present report describes a 7-year-old girl with a de novo 3 Mb interstitial deletion of chromosome 14q12, identified by oligo array-CGH. The region is gene poor and contains only five genes two of them, FOXG1B and PRKD1 being deleted also in a previously reported case with a very similar phenotype. Both patients present prominent metopic suture, epicanthic folds, bulbous nasal tip, tented upper lip, everted lower lip and large ears and a clinical course like Rett syndrome, including normal perinatal period, postnatal microcephaly, seizures, and severe mental retardation. FOXG1B (forkhead box G1B) is a very intriguing candidate gene since it is known to promote neuronal progenitor proliferation and to suppress premature neurogenesis and its disruption is reported in a patient with postnatal microcephaly, corpus callosum agenesis, seizures, and severe mental retardation.

  14. Is the early development of girls with Rett disorder really normal?

    PubMed

    Einspieler, Christa; Kerr, Alison M; Prechtl, Heinz F R

    2005-05-01

    An apparently normal early development was one of the initial criteria for classical Rett syndrome. However, several investigators considered Rett syndrome to be a developmental disorder manifesting very soon after birth. Videos of 22 Rett cases were assessed carefully for movements, posture, and behavior during the first 6 mo of life. All signs that deviated from the normal standard were recorded meticulously. Special attention was paid to the face, the hands, and body movements. A detailed analysis clearly demonstrated an abnormal quality of general movements (100%), tongue protrusion (62%), postural stiffness (58%), asymmetric eye opening and closing (56%), abnormal finger movements (52%), hand stereotypies (42%), bursts of abnormal facial expressions (42%), bizarre smile (32%), tremor (28%), and stereotyped body movements (15%). Our study is the first to apply specific standardized measures of early spontaneous movements to Rett infants, proving conclusively that the disorder is manifested within the first months of life. Although not necessarily specific, the signs that we have observed will be of value in alerting clinicians to the possibility of the diagnosis at an early stage, when intervention is likely to be most effective.

  15. [Asperger syndrome: evolution of the concept and current clinical data].

    PubMed

    Aussilloux, C; Baghdadli, A

    2008-05-01

    Although Asperger syndrome is described by international classifications as a category of pervasive developmental disorder (PDD), its validity as a specific entity distinct from autistic disorders remains controversial. The syndrome, first described by Hans Asperger, could not be distinguished from high functioning autism (onset, symptoms, outcome...). However, international classifications propose a distinction between the two syndromes based on a delayed onset, the absence of speech delay, the presence of motor disorders and a better outcome in Asperger syndrome. This categorical differentiation is not confirmed by current studies and in the absence of biological markers, no clinical, neuropsychological or epidemiological criteria makes it possible to distinguish high functioning autism from Asperger syndrome. From a clinical perspective, it is nevertheless of interest to isolate Asperger syndrome from other autistic disorders to propose specific assessment and therapy.

  16. Olmsted syndrome: clinical, molecular and therapeutic aspects.

    PubMed

    Duchatelet, Sabine; Hovnanian, Alain

    2015-03-17

    Olmsted syndrome (OS) is a rare genodermatosis classically characterized by the combination of bilateral mutilating transgredient palmoplantar keratoderma (PPK) and periorificial keratotic plaques, but which shows considerable clinical heterogeneity. The disease starts usually at birth or in early childhood. About 73 cases have been reported worldwide. OS is observed in both sexes, although male cases are more frequent. The most suggestive symptoms associate PPK with pseudoainhum and periorificial keratotic plaques. Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections. Pain and itching are variable but can be severe. Most of reported OS cases are sporadic, although familial cases with different mode of inheritance were also described. Mutations in TRPV3 (Transient receptor potential vanilloid-3) gene have recently been identified as a cause of autosomal dominant (gain-of-function mutations) or recessive OS. Mutations in MBTPS2 (membrane-bound transcription factor protease, site 2) gene were identified in a recessive X-linked form. The diagnosis relies mainly on clinical features associating severe PPK and periorificial keratotic plaques, but can be challenging in patients with incomplete phenotype or atypical features. OS has to be differentiated from other severe forms of PPK including Vohwinkel, Clouston, Papillon-Lefèvre or Haim-Munk syndromes, Mal de Meleda, pachyonychia congenita, Tyrosinemia type II and acrodermatitis enteropathica. When differential diagnoses are difficult to exclude, genetic studies are essential to search for a TRPV3 or MBTPS2 mutation. However, additional genes remain to be identified. No specific and satisfactory therapy is currently available for OS. Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief. Specific management of pain and

  17. LEOPARD Syndrome: Clinical Features and Gene Mutations

    PubMed Central

    Martínez-Quintana, E.; Rodríguez-González, F.

    2012-01-01

    The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD (LS), neurofibromatosis type 1, Costello and cardio-facio-cutaneous syndromes. LEOPARD is an acronym, mnemonic for the major manifestations of this disorder, characterized by multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. Though it is not included in the acronym, hypertrophic cardiomyopathy is the most frequent cardiac anomaly observed, representing a potentially life-threatening problem in these patients. PTPN11, RAF1 and BRAF are the genes known to be associated with LS, identifying molecular genetic testing of the 3 gene mutations in about 95% of affected individuals. PTPN11 mutations are the most frequently found. Eleven different missense PTPN11 mutations (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Pro) have been reported so far in LS, 2 of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases. Here, we provide an overview of clinical aspects of this disorder, the molecular mechanisms underlying pathogenesis and major genotype-phenotype correlations. PMID:23239957

  18. [Alagille's syndrome. Clinical and histo-pathologic study].

    PubMed

    Moreno Giménez, J C; del Rio Mapelli, L; Camacho Martinez, F

    1984-01-01

    Alagille 's syndrome, described in 1970, associates a chronic intrahepatic cholestasis (hypoplasia of the interlobulary biliary ducts), vertebral and visceral malformations, retarded physical, mental and sexual development and neonatal jaundice. A series of cutaneous manifestations are reviewed in their clinical, histological and ultrastructural aspects. Its relation with the zinc deficiency syndrome is discussed. PMID:6732121

  19. Smith-Magenis Syndrome: Genetic Basis and Clinical Implications

    ERIC Educational Resources Information Center

    Finucane, Brenda; Haas-Givler, Barbara

    2009-01-01

    Smith-Magenis syndrome (SMS) is a neurobehavioral disorder associated with deletions and mutations of the "RAI1" gene on chromosome 17p11.2. Clinical features of the syndrome include intellectual disability, sleep disturbance, craniofacial differences, and a distinctive profile of stereotypic and self-injurious behaviors. Although the functional…

  20. Ellis-van Creveld syndrome: A rare clinical entity.

    PubMed

    Kamal, Reet; Dahiya, Parveen; Kaur, Simerpreet; Bhardwaj, Rohit; Chaudhary, Karun

    2013-01-01

    Ellis-van Creveld (EVC) syndrome is a genetic disorder with autosomal recessive transmission, which may clinically present as small stature, short limbs, fine sparse hair, hypoplastic fingernails, multiple musculofibrous frenula, conical teeth, hypoplasia of the enamel, hypodontia, and malocclusion. Heart defects, especially abnormalities of atrial septation, have been found in about 60% of cases. The mutation in EVC and EVC2 gene is responsible for this syndrome. The presence of multiple orodental findings makes this syndrome important for dentists. The aim of this article is to present a rare case of EVC syndrome in a 10-year-old girl along with the review of literature.

  1. Expanding the clinical picture of Simpson-Golabi-Behmel syndrome.

    PubMed

    Young, Esther L; Wishnow, Robin; Nigro, Michael A

    2006-02-01

    This report describes a 14-year-old male with Simpson-Golabi-Behmel overgrowth syndrome. He was born via cesarean section because of macrocephaly and subsequently exhibited significant developmental delay in motor, language, and cognitive skills with mental retardation and epilepsy. He manifests the characteristic dysmorphic ("bulldog") facial features of Simpson-Golabi-Behmel syndrome. His molecular genetic testing has substantiated the clinical diagnosis of Simpson-Golabi-Behmel syndrome; however, he is unique in that he has mental retardation, hydrocephalus, and epilepsy, which have not been previously documented in Simpson-Golabi-Behmel syndrome in the literature.

  2. Clinical features of the exploding head syndrome.

    PubMed Central

    Pearce, J M

    1989-01-01

    Fifty patients suffering from the "exploding head syndrome" are described. This hitherto unreported syndrome is characterised by a sense of an explosive noise in the head usually in the twilight stage of sleep. The associated symptoms are varied, but the benign nature of the condition is emphasised and neither extensive investigation nor treatment are indicated. PMID:2769286

  3. Tumor lysis syndrome: A clinical review.

    PubMed

    Mirrakhimov, Aibek E; Voore, Prakruthi; Khan, Maliha; Ali, Alaa M

    2015-05-01

    Tumor lysis syndrome is an oncometabolic emergency resulting from rapid cell death. Tumor lysis syndrome can occur as a consequence of tumor targeted therapy or spontaneously. Clinicians should stratify every hospitalized cancer patient and especially those receiving chemotherapy for the risk of tumor lysis syndrome. Several aspects of prevention include adequate hydration, use of uric acid lowering therapies, use of phosphate binders and minimization of potassium intake. Patients at high risk for the development of tumor lysis syndrome should be monitored in the intensive care unit. Established tumor lysis syndrome should be treated in the intensive care unit by aggressive hydration, possible use of loop diuretics, possible use of phosphate binders, use of uric acid lowering agents and dialysis in refractory cases. PMID:25938028

  4. An unusual presentation of Kabuki syndrome: clinical overlap with CHARGE syndrome.

    PubMed

    Verhagen, Judith M A; Oostdijk, Wilma; Terwisscha van Scheltinga, Cecilia E J; Schalij-Delfos, Nicoline E; van Bever, Yolande

    2014-09-01

    Kabuki syndrome is a rare genetic disorder characterized by intellectual disability and multiple congenital anomalies, including short stature, peculiar facial appearance, skeletal anomalies, a variety of visceral malformations and abnormal dermatoglyphic patterns. We describe a case of Kabuki syndrome presenting with atypical features, consisting of bilateral microphthalmia, coloboma, anal atresia and panhypopituitarism, showing considerable phenotypic overlap with CHARGE syndrome. This report demonstrates that clinical follow-up and molecular genetic testing can be useful for establishing the correct diagnosis. PMID:24862881

  5. Pitt-Hopkins Syndrome and Differential Diagnosis: A Molecular and Clinical Challenge.

    PubMed

    Marangi, Giuseppe; Zollino, Marcella

    2015-09-01

    Pitt-Hopkins syndrome is an emerging neurodevelopmental disorder caused by haploinsufficiency of the TCF4 gene on chromosome 18q21. It is characterized by severe intellectual disability, seizures, microcephaly, constipation and a distinctive facial gestalt. Although the overlapping phenotype of microcephaly, epilepsy, absent speech and constipation represents a challenge for the differential diagnosis with Angelman syndrome, Rett syndrome and Mowat-Wilson syndrome, distinctive of Pitt-Hopkins syndrome are breathing abnormalities, that can occur as either hyperventilation episodes or apnea crises, and a typical facial dysmorphism, including bitemporal narrowing, squared forehead, deep-set eyes, peculiar nose conformation, with broad nasal bridge, down-turned nasal tip and flaring nostrils, typical shape of the mouth, with a tented and M shaped upper lip, and widely spaced teeth. The occurrence of these signs in variable association of uncoordinated movements, microcephaly of postnatal onset, eye abnormalities, constipation, epilepsy and subtle brain abnormalities is highly predictive of a TCF4 mutation, making it possible to plan a genetic test of choice among severe encephalopathies. Angelman syndrome represents the nosological condition closest to Pitt-Hopkins syndrome. PMID:27617128

  6. Clinical Audit of Gastrointestinal Conditions Occurring among Adults with Down Syndrome Attending a Specialist Clinic

    ERIC Educational Resources Information Center

    Wallace, Robyn A.

    2007-01-01

    Background: Adults with Down syndrome (DS) are predisposed to syndromic and environmental gastrointestinal conditions. Method: In a hospital-based clinic for adults with DS, a chart audit was conducted to assess the range and frequency of gastrointestinal conditions. Results: From January 2003 to March 2005, 57 patients attended the clinic,…

  7. [Battered child syndrome: clinical and radiological aspects].

    PubMed

    Jlalia, Zied; Znaigui, Talel; Smida, Mahmoud

    2016-01-01

    Physical child abuse or battered child syndrome is responsible for over 75.000 deaths per year in France. This public health problem is under-diagnosed in Tunisia and in the world. The path toward the recognition of battered child syndrom was arduous even in some western societies. This study aims to highlight this problem to healthcare practitioners in order that accurate diagnosis and appropriate management may be provided. Physical child abuse has wrongly been referred to as Silverman syndrome that includes only skeletal lesions in children such as fractures. PMID:27642408

  8. Predictors of clinical pain intensity in patients with fibromyalgia syndrome.

    PubMed

    Staud, Roland

    2004-08-01

    Central changes in pain processing have been previously reported in patients with fibromyalgia syndrome. These changes include decreased thresholds to mechanical and thermal stimuli (allodynia) and central sensitization, both of which are fundamental to the generation of clinical pain. Therefore, psychophysical measures of central pain processing may be useful predictors of clinical pain intensity of fibromyalgia syndrome patients. Previous studies of fibromyalgia syndrome patients have shown statistically significant correlations of psychophysical test results with clinical pain intensity. The tests used to characterize this important relationship were dependent on spinal cord pain mechanisms and included temporal summation of pain or wind-up and wind-up after-sensations. Particularly, the magnitude of wind-up after-sensations appeared to be one of the best predictors for clinical pain intensity of fibromyalgia syndrome patients (27%). Furthermore, the combination of tender point count, negative affect, and wind-up after-sensations accounted for approximately 50% of the variance in clinical pain intensity of fibromyalgia syndrome patients. Therefore, wind-up after-sensations, tender point count, and negative affect not only seem to represent relevant pain mechanisms but also strongly emphasize their importance for fibromyalgia syndrome pain.

  9. Clinical Syndromes among the Learning Disabled.

    ERIC Educational Resources Information Center

    Lewandowski, Lawrence J.

    1985-01-01

    Four physiological conditions associated with later learning disabilities are noted: Turner Syndrome (a chromosomal abnormality), preterm children with intracranial hemorrhage, children with incompletely developed connecting fibers between the cerebral hemispheres, and children with acquired brain injury. (CL)

  10. Hantavirus pulmonary syndrome: a concise clinical review.

    PubMed

    Vinh, Donald C; Embil, John M

    2009-06-01

    In 1978, hantaviruses were first described as the etiological agent of hemorrhagic fever with renal syndrome (HFRS) in Korea. Since then, numerous related, enveloped, negative-stranded RNA viruses have been identified, forming the genus Hantavirus within the family Bunyaviridae. These pathogens are distributed worldwide and thus can be classified, on the basis of phylogenetic origins, into Old World viruses or New World viruses (ie North, Central, and South America). Similarly, these viruses cause two major types of syndromes, corresponding respectively to their phylogenies: the original HFRS or the more recently described hantavirus pulmonary syndrome (HPS). As the hantavirus pulmonary syndrome is the primary hantaviral disease in North America, it will thus be the focus of this review. PMID:19434035

  11. Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes.

    PubMed

    Cantó, Ester; Tintoré, Mar; Villar, Luisa M; Costa, Carme; Nurtdinov, Ramil; Álvarez-Cermeño, José C; Arrambide, Georgina; Reverter, Ferran; Deisenhammer, Florian; Hegen, Harald; Khademi, Mohsen; Olsson, Tomas; Tumani, Hayrettin; Rodríguez-Martín, Eulalia; Piehl, Fredrik; Bartos, Ales; Zimova, Denisa; Kotoucova, Jolana; Kuhle, Jens; Kappos, Ludwig; García-Merino, Juan Antonio; Sánchez, Antonio José; Saiz, Albert; Blanco, Yolanda; Hintzen, Rogier; Jafari, Naghmeh; Brassat, David; Lauda, Florian; Roesler, Romy; Rejdak, Konrad; Papuc, Ewa; de Andrés, Clara; Rauch, Stefan; Khalil, Michael; Enzinger, Christian; Galimberti, Daniela; Scarpini, Elio; Teunissen, Charlotte; Sánchez, Alex; Rovira, Alex; Montalban, Xavier; Comabella, Manuel

    2015-04-01

    Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10(-11)). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10(-5) using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10(-6) for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10(-8)). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10(-9) using Poser criteria; P = 5.6 × 10(-11) for McDonald criteria

  12. Munchausen Syndrome by Proxy: A Clinical Vignette

    PubMed Central

    Zylstra, Robert G.; Miller, Karl E.; Stephens, Walter E.

    2000-01-01

    Munchausen syndrome by proxy is the act of one person fabricating or inducing an illness in another to meet his or her own emotional needs through the treatment process. The diagnosis is poorly understood and controversial. We report here the case of a 6-year-old boy who presented with possible pneumonia, nausea, vomiting, and diarrhea and whose mother was suspected of Munchausen syndrome by proxy. PMID:15014581

  13. [Clinical studies of pediatric malabsorption syndromes].

    PubMed

    Hosoyamada, Takashi

    2006-11-01

    Multiple cases with various types of pediatric malabsorption syndromes were evaluated. The clinical manifestations, laboratory findings, pathophysiology, and histopathological descriptions of each patient were analyzed in an effort to clear the pathogenesis of the malabsorption syndromes and the treatments were undertaken. The cases studied, included one patient with cystic fibrosis, two with lactose intolerance with lactosuria (Durand type), one with primary intestinal lymphangiectasia, two with familial hypobetalipoproteinemia, one with Hartnup disease, one with congenital chroride diarrhea, one with acrodermatitis enteropathica, one with intestinal nodular lymphoid hyperplasia (NLH), five with intractable diarrhea of early infancy and four with glycogenosis type Ia. Each case description and outcome is described below: 1. A 15-year-old Japanese boy with cystic fibrosis presented with severe symptoms, including pancreatic insufficiency, bronchiectasis, pneumothorax and hemoptysis. His prognosis was poor. Analysis of the CFTR genes of this patient revealed a homozygous large deletion from intron 16 to 17b. 2. In the sibling case of Durand type lactose intolerance, the subjects'disaccaridase activity of the small bowel, including lactase, were within normal limits. The results of per oral and per intraduodenal lactose tolerance tests confirmed lactosuria in both. These observations suggested, not only an abnormal gastric condition, but also duodenal and intestinal mucosal abnormal permeability of lactose. 3. In the case of primary intestinal lymphangiectasia, the subject had a lymphedematous right arm and hand, a grossly coarsened mucosal pattern of the upper gastrointestinal tract (identified via radiologic examination) and the presence of lymphangiectasia (confirmed via duodenal mucosal biopsy). The major laboratory findings were hypoalbuminemia, decreased immunoglobulin levels and lymphopenia resulting from loss of lymph fluid and protein into the gastro

  14. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.

    PubMed

    Tatton-Brown, Katrina; Murray, Anne; Hanks, Sandra; Douglas, Jenny; Armstrong, Ruth; Banka, Siddharth; Bird, Lynne M; Clericuzio, Carol L; Cormier-Daire, Valerie; Cushing, Tom; Flinter, Frances; Jacquemont, Marie-Line; Joss, Shelagh; Kinning, Esther; Lynch, Sally Ann; Magee, Alex; McConnell, Vivienne; Medeira, Ana; Ozono, Keiichi; Patton, Michael; Rankin, Julia; Shears, Debbie; Simon, Marleen; Splitt, Miranda; Strenger, Volker; Stuurman, Kyra; Taylor, Clare; Titheradge, Hannah; Van Maldergem, Lionel; Temple, I Karen; Cole, Trevor; Seal, Sheila; Rahman, Nazneen

    2013-12-01

    Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.

  15. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.

    PubMed

    Tatton-Brown, Katrina; Murray, Anne; Hanks, Sandra; Douglas, Jenny; Armstrong, Ruth; Banka, Siddharth; Bird, Lynne M; Clericuzio, Carol L; Cormier-Daire, Valerie; Cushing, Tom; Flinter, Frances; Jacquemont, Marie-Line; Joss, Shelagh; Kinning, Esther; Lynch, Sally Ann; Magee, Alex; McConnell, Vivienne; Medeira, Ana; Ozono, Keiichi; Patton, Michael; Rankin, Julia; Shears, Debbie; Simon, Marleen; Splitt, Miranda; Strenger, Volker; Stuurman, Kyra; Taylor, Clare; Titheradge, Hannah; Van Maldergem, Lionel; Temple, I Karen; Cole, Trevor; Seal, Sheila; Rahman, Nazneen

    2013-12-01

    Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve. PMID:24214728

  16. Personality Disorders and Clinical Syndromes in ADHD Prisoners

    ERIC Educational Resources Information Center

    Gudjonsson, Gisli H.; Wells, June; Young, Susan

    2012-01-01

    Objective: The main objective of this article is to investigate the type of personality disorders and clinical syndromes (CSs) that were best related to ADHD symptoms among prisoners. Method: The authors screened for childhood and adult ADHD symptoms and administered the Millon Clinical Multiaxial Inventory-III (MCMI-III) to 196 serving prisoners.…

  17. Early onset marfan syndrome: Atypical clinical presentation of two cases

    PubMed Central

    Ozyurt, A; Baykan, A; Argun, M; Pamukcu, O; Halis, H; Korkut, S; Yuksel, Z; Gunes, T; Narin, N

    2015-01-01

    Early onset Marfan Syndrome (eoMFS) is a rare, severe form of Marfan Syndrome (MFS). The disease has a poor prognosis and most patients present with resistance to heart failure treatment during the newborn period. This report presents two cases of eoMFS with similar clinical features diagnosed in the newborn period and who died at an early age due to the complications related to the involvement of the cardiovascular system. PMID:26929908

  18. Clinical management of the uraemic syndrome in chronic kidney disease.

    PubMed

    Vanholder, Raymond; Fouque, Denis; Glorieux, Griet; Heine, Gunnar H; Kanbay, Mehmet; Mallamaci, Francesca; Massy, Ziad A; Ortiz, Alberto; Rossignol, Patrick; Wiecek, Andrzej; Zoccali, Carmine; London, Gérard Michel

    2016-04-01

    The clinical picture of the uraemic syndrome is a complex amalgam of accelerated ageing and organ dysfunction, which progress in parallel to chronic kidney disease. The uraemic syndrome is associated with cardiovascular disease, metabolic bone disease, inflammation, protein energy wasting, intestinal dysbiosis, anaemia, and neurological and endocrine dysfunction. In this Review, we summarise specific, modern management options for the uraemic syndrome in chronic kidney disease. Although large randomised controlled trials are scarce, based on data from randomised controlled trials and observational studies, as well as pathophysiological reasoning, a therapeutic algorithm can be developed for this complex and multifactorial condition, with interventions targeting several modifiable factors simultaneously. PMID:26948372

  19. Clinical management of the uraemic syndrome in chronic kidney disease.

    PubMed

    Vanholder, Raymond; Fouque, Denis; Glorieux, Griet; Heine, Gunnar H; Kanbay, Mehmet; Mallamaci, Francesca; Massy, Ziad A; Ortiz, Alberto; Rossignol, Patrick; Wiecek, Andrzej; Zoccali, Carmine; London, Gérard Michel

    2016-04-01

    The clinical picture of the uraemic syndrome is a complex amalgam of accelerated ageing and organ dysfunction, which progress in parallel to chronic kidney disease. The uraemic syndrome is associated with cardiovascular disease, metabolic bone disease, inflammation, protein energy wasting, intestinal dysbiosis, anaemia, and neurological and endocrine dysfunction. In this Review, we summarise specific, modern management options for the uraemic syndrome in chronic kidney disease. Although large randomised controlled trials are scarce, based on data from randomised controlled trials and observational studies, as well as pathophysiological reasoning, a therapeutic algorithm can be developed for this complex and multifactorial condition, with interventions targeting several modifiable factors simultaneously.

  20. Rieger syndrome: a clinical, molecular, and biochemical analysis.

    PubMed

    Amendt, B A; Semina, E V; Alward, W L

    2000-10-01

    Rieger syndrome (RIEG 1; MIM 180500) is an autosomal dominant disorder of morphogenesis. It is a phenotypically heterogeneous disorder characterized by malformations of the eyes, teeth, and umbilicus. RIEG belongs to the Axenfeld-Rieger group of anomalies, which includes Axenfeld anomaly and Rieger anomaly (or Rieger eye malformation), which display ocular features only. Recently, mutations in the homeodomain transcription factor, PITX2, have been shown to be associated with Rieger syndrome. This review discusses the clinical manifestations of Rieger syndrome and how they correlate with the current molecular and biochemical studies on this human disorder. PMID:11092457

  1. [Sneddon syndrome new clinical and immunological data].

    PubMed

    Kalashnikova, L A; Chapman, I; Nasonov, E L; Korchin, A; Aleksandrova, E N; Shavit, S; Reshetniak, T M; Kosheleva, N M

    1998-01-01

    In 27 of 47 patients with Sneddon's syndrome (33 females, 14 males age 40 years) enzyme immunoassay has detected IgG-antibodies to prothrombin (aPT)--one of cofactor proteins responsible for binding of antiphospholipid antibodies (aPL) to phospholipids. Other aPL were also found: antibodies to cardiolipin (aCL), lupus anticoagulant (LA) in 14 and 27 patients, respectively. 37 (79%) patients had at least one of the studied aPL suggesting that such patients belong to patients with primary antiphospholipid syndrome. A correlation exists between aPT and LA: LA is detectable in 67% of aPT-positive patients compared to 45% of aPT-negative patients (p < 0.05). This is in agreement with the fact that prothrombin is a cofactor for most aPL registered as LA. Comparison of two subgroups of aPL patients different by dominant antigenic specificity (18 patients with aPT but free of ACL and 6 patients with aCP but free of aPT) demonstrated that the latter developed disorders of cerebral circulation, head ache, dementia and renal syndrome less frequently. aPT in Sneddon's syndrome seems to be a marker of comparatively low risk of thrombosis and less severe course of the disease. PMID:9693498

  2. Phenotypic variability in gap junction syndromic skin disorders: experience from KID and Clouston syndromes' clinical diagnostics.

    PubMed

    Kutkowska-Kaźmierczak, Anna; Niepokój, Katarzyna; Wertheim-Tysarowska, Katarzyna; Giza, Aleksandra; Mordasewicz-Goliszewska, Maria; Bal, Jerzy; Obersztyn, Ewa

    2015-08-01

    Connexins belong to the family of gap junction proteins which enable direct cell-to-cell communication by forming channels in adjacent cells. Mutations in connexin genes cause a variety of human diseases and, in a few cases, result in skin disorders. There are significant differences in the clinical picture of two rare autosomal dominant syndromes: keratitis-ichthyosis-deafness (KID) syndrome and hidrotic ectodermal dysplasia (Clouston syndrome), which are caused by GJB2 and GJB6 mutations, respectively. This is despite the fact that, in both cases, malfunctioning of the same family proteins and some overlapping clinical features (nail dystrophy, hair loss, and palmoplantar keratoderma) is observed. KID syndrome is characterized by progressive vascularizing keratitis, ichthyosiform erythrokeratoderma, and neurosensory hearing loss, whereas Clouston syndrome is characterized by nail dystrophy, hypotrichosis, and palmoplantar keratoderma. The present paper presents a Polish patient with sporadic KID syndrome caused by the mutation of p.Asp50Asn in GJB2. The patient encountered difficulties in obtaining a correct diagnosis. The other case presented is that of a family with Clouston syndrome (caused by p.Gly11Arg mutation in GJB6), who are the first reported patients of Polish origin suffering from this disorder. Phenotype diversity among patients with the same genotypes reported to date is also summarized. The conclusion is that proper diagnosis of these syndromes is still challenging and should always be followed by molecular verification. PMID:25575739

  3. Clinical predictors of lacunar syndrome not due to lacunar infarction

    PubMed Central

    2010-01-01

    Background Lacunar syndrome not due to lacunar infarct is poorly characterised. This single centre, retrospective study was conducted to describe the clinical characteristics of patients with lacunar syndrome not due to lacunar infarct and to identify clinical predictors of this variant of lacunar stroke. Methods A total of 146 patients with lacunar syndrome not due to lacunar infarction were included in the "Sagrat Cor Hospital of Barcelona Stroke Registry" during a period of 19 years (1986-2004). Data from stroke patients are entered in the stroke registry following a standardized protocol with 161 items regarding demographics, risk factors, clinical features, laboratory and neuroimaging data, complications and outcome. The characteristics of these 146 patients with lacunar syndrome not due to lacunar infarct were compared with those of the 733 patients with lacunar infarction. Results Lacunar syndrome not due to lacunar infarct accounted for 16.6% (146/879) of all cases of lacunar stroke. Subtypes of lacunar syndromes included pure motor stroke in 63 patients, sensorimotor stroke in 51, pure sensory stroke in 14, atypical lacunar syndrome in 9, ataxic hemiparesis in 5 and dysarthria-clumsy hand in 4. Valvular heart disease, atrial fibrillation, sudden onset, limb weakness and sensory symptoms were significantly more frequent among patients with lacunar syndrome not due to lacunar infarct than in those with lacunar infarction, whereas diabetes was less frequent. In the multivariate analysis, atrial fibrillation (OR = 4.62), sensorimotor stroke (OR = 4.05), limb weakness (OR = 2.09), sudden onset (OR = 2.06) and age (OR = 0.96) were independent predictors of lacunar syndrome not due to lacunar infarct. Conclusions Although lacunar syndromes are highly suggestive of small deep cerebral infarctions, lacunar syndromes not due to lacunar infarcts are found in 16.6% of cases. The presence of sensorimotor stroke, limb weakness and sudden onset in a patient with atrial

  4. Epileptic syndromes: From clinic to genetic

    PubMed Central

    Tafakhori, Abbas; Aghamollaii, Vajiheh; Faghihi-Kashani, Sara; Sarraf, Payam; Habibi, Laleh

    2015-01-01

    Epilepsy is one of the most common neurological disorders. Studies have demonstrated that genetic factors have a strong role in etiology of epilepsy. Mutations in genes encoding ion channels, neurotransmitters and other proteins involved in the neuronal biology have been recognized in different types of this disease. Moreover, some chromosomal aberration including ring chromosomes will result in epilepsy. In this review, we intend to highlight the role of molecular genetic in etiology of epilepsy syndromes, inspect the most recent classification of International League against Epilepsy and discuss the role of genetic counseling and genetic testing in management of epilepsy syndromes. Furthermore, we emphasize on collaboration of neurologists and geneticists to improve diagnosis and management. PMID:25874049

  5. Schmahmann's syndrome - identification of the third cornerstone of clinical ataxiology.

    PubMed

    Manto, Mario; Mariën, Peter

    2015-01-01

    Schmahmann's syndrome represents a novel clinical condition consisting of a constellation of cognitive and affective deficits following cerebellar disease. The complex was first described in 1998 as cerebellar cognitive affective syndrome (CCAS) on the basis of a careful neurological examination, detailed bedside mental state tests, neuropsychological investigations and anatomical neuroimaging of a group of 20 patients with focal cerebellar disorders. The syndrome was characterized by four clusters of symptoms including: (a) impairment of executive functions such as planning, set-shifting, verbal fluency, abstract reasoning and working memory, (b) impaired visuo-spatial cognition, (c) personality changes with blunting of affect or abnormal behaviour, and (d) language deficits including agrammatism, wordfinding disturbances, disruption of language dynamics and dysprosodia. This complex of neurocognitive and behavioural-affective symptoms was ascribed to a functional disruption of the reciprocal pathways that connect the cerebellum with the limbic circuitry and the prefrontal, temporal and parietal association cortices. With the introduction of Schmahmann's syndrome, clinical ataxiology has found its third cornerstone, the two others being the cerebellar motor syndrome (CMS) mainly delineated by the pioneer French and English neurologists of the 19(th) and early 20(th) century, and the vestibulo-cerebellar syndrome (VCS) consisting of ocular instability, deficits of oculomotor movements and ocular misalignment. PMID:26331045

  6. Patellofemoral pain syndrome: validity of clinical and radiological features.

    PubMed

    Haim, Amir; Yaniv, Moshe; Dekel, Samuel; Amir, Hagay

    2006-10-01

    Data regarding validity of clinical and radiographic findings in diagnosing patellofemoral pain syndrome are inconclusive. We prospectively assessed how sensitive and specific key patellofemoral physical examination tests are, and evaluated the prevalence of physical examination and radiographic findings. Sixty-one infantry soldiers with patellofemoral pain syndrome and 25 control subjects were evaluated. The sensitivity of the patellar tilt, active instability, patella alta, and apprehension tests was low (less than 50%); specificity ranged between 72% and 100%. Although the prevalence of positive patellar tilt and active instability tests was significantly greater in subjects with patellofemoral pain syndrome, there were no significant differences between the groups in the results of the other two tests. Soldiers with patellofemoral pain syndrome presented with increased quadriceps angle, lateral and medial retinacular tenderness, patellofemoral crepitation, squinting patella, and reduced mobility of the patella. There were no differences between the groups in the prevalence of lower limb and foot posture alignment and knee effusion. Plain radiography showed increased patellar subluxation in soldiers with patellofemoral pain syndrome. Other radiographic measures (sulcus angle, Laurin angle, Merchant angle, and Insall-Salvati index) were similar in both groups. We provide evidence regarding the validity of clinical and radiographic features commonly used for diagnosing patellofemoral pain syndrome. Physical examinations were more useful than plain radiography. PMID:16788411

  7. Carpal tunnel syndrome - anatomical and clinical correlations.

    PubMed

    Iskra, Tomasz; Mizia, Ewa; Musial, Agata; Matuszyk, Aleksandra; Tomaszewski, Krzysztof A

    2013-01-01

    Carpal tunnel syndrome (CTS) is the most common and widely known of the entrapment neuropathies in which the body's peripheral nerves are compressed. Common symptoms of CTS involve the hand and result from compression of the median nerve within the carpal tunnel. In general, CTS develops when the tissues around the median nerve irritate or compress on the nerve along its course through the carpal tunnel, however often it is very difficult to determine cause of CTS. Proper treatment (conservative or surgical) usually can relieve the symptoms and restore normal use of the wrist and hand.

  8. Rapid clinical deterioration in an individual with Down syndrome.

    PubMed

    Jacobs, Julia; Schwartz, Alison; McDougle, Christopher J; Skotko, Brian G

    2016-07-01

    A small percentage of adolescents and young adults with Down syndrome experience a rapid and unexplained deterioration in cognitive, adaptive, and behavioral functioning. Currently, there is no standardized work-up available to evaluate these patients or treat them. Their decline typically involves intellectual deterioration, a loss of skills of daily living, and prominent behavioral changes. Certain cases follow significant life events such as completion of secondary school with friends who proceed on to college or employment beyond the individual with DS. Others develop this condition seemingly unprovoked. Increased attention in the medical community to clinical deterioration in adolescents and young adults with Down syndrome could provide a framework for improved diagnosis, evaluation, and treatment. This report presents a young adult male with Down syndrome who experienced severe and unexplained clinical deterioration, highlighting specific challenges in the systematic evaluation and treatment of these patients. © 2016 Wiley Periodicals, Inc.

  9. Clinical Presentations of Coenzyme Q10 Deficiency Syndrome

    PubMed Central

    Quinzii, Catarina M.; Emmanuele, Valentina; Hirano, Michio

    2014-01-01

    Coenzyme Q10 (CoQ10) deficiency is a clinically and genetically heterogeneous syndrome which has been associated with 5 major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) nephropathy, (4) cerebellar ataxia, and (5) isolated myopathy. Of these phenotypes, cerebellar ataxia and syndromic or isolated nephrotic syndrome are the most common. CoQ10 deficiency predominantly presents in childhood. To date, causative mutations have been identified in a small proportion of patients, making it difficult to identify a phenotype-genotype correlation. Identification of CoQ10 deficiency is important because the disease, in particular muscle symptoms and nephropathy, frequently responds to CoQ10 supplementation. PMID:25126046

  10. Hyperinsulinism Hyperammonemia Syndrome, a Rare Clinical Constellation.

    PubMed

    Hussain, Jonathan; Schlachterman, Alexander; Kamel, Amir; Gupte, Anand

    2016-01-01

    We present the unique case of adult hyperinsulinism hyperammonemia syndrome (HI/HA). This condition is rarely seen in children and even more infrequently in adults. A 27-year-old female with HI/HA, generalized tonic-clonic seizures, staring spells, and gastroesophageal reflux disease presented with diffuse abdominal pain, hypoglycemia, confusion, and sweating. She reported a history of significant nausea, vomiting, and diarrhea, which had been present intermittently over the past year. On examination, she was found to have a soft, nontender, and mildly distended abdomen without splenomegaly or masses. She had a normal blood pressure and was tachycardic (130 bpm). Her initial complete blood count and basic metabolic panel, excluding glucose, were within normal limits. She was found to have an elevated peripherally drawn venous ammonia (171 mmol/L) and near hypoglycemia (blood glucose 61 mg/dL), which were drawn given her history of HI/HA. She was continued on home carglumic acid and diazoxide, glucose was supplemented intravenously, and she was started on levetiracetam for seizure prophylaxis. An upper endoscopy (esophagogastroduodenoscopy [EGD]) was performed and was unremarkable, and biopsies taken were within normal limits. Following the EGD, she underwent a gastric emptying study that showed delayed emptying (216 minutes), consistent with a new diagnosis of gastroparesis, the likely etiology of her initial abdominal pain on presentation. This was subsequently treated with azithromycin oral solution. We present this case to raise awareness of this rarely encountered syndrome and to provide the basic principles of treatment. PMID:26962538

  11. Hyperinsulinism Hyperammonemia Syndrome, a Rare Clinical Constellation.

    PubMed

    Hussain, Jonathan; Schlachterman, Alexander; Kamel, Amir; Gupte, Anand

    2016-01-01

    We present the unique case of adult hyperinsulinism hyperammonemia syndrome (HI/HA). This condition is rarely seen in children and even more infrequently in adults. A 27-year-old female with HI/HA, generalized tonic-clonic seizures, staring spells, and gastroesophageal reflux disease presented with diffuse abdominal pain, hypoglycemia, confusion, and sweating. She reported a history of significant nausea, vomiting, and diarrhea, which had been present intermittently over the past year. On examination, she was found to have a soft, nontender, and mildly distended abdomen without splenomegaly or masses. She had a normal blood pressure and was tachycardic (130 bpm). Her initial complete blood count and basic metabolic panel, excluding glucose, were within normal limits. She was found to have an elevated peripherally drawn venous ammonia (171 mmol/L) and near hypoglycemia (blood glucose 61 mg/dL), which were drawn given her history of HI/HA. She was continued on home carglumic acid and diazoxide, glucose was supplemented intravenously, and she was started on levetiracetam for seizure prophylaxis. An upper endoscopy (esophagogastroduodenoscopy [EGD]) was performed and was unremarkable, and biopsies taken were within normal limits. Following the EGD, she underwent a gastric emptying study that showed delayed emptying (216 minutes), consistent with a new diagnosis of gastroparesis, the likely etiology of her initial abdominal pain on presentation. This was subsequently treated with azithromycin oral solution. We present this case to raise awareness of this rarely encountered syndrome and to provide the basic principles of treatment.

  12. Hyperinsulinism Hyperammonemia Syndrome, a Rare Clinical Constellation

    PubMed Central

    Hussain, Jonathan; Schlachterman, Alexander; Kamel, Amir; Gupte, Anand

    2016-01-01

    We present the unique case of adult hyperinsulinism hyperammonemia syndrome (HI/HA). This condition is rarely seen in children and even more infrequently in adults. A 27-year-old female with HI/HA, generalized tonic-clonic seizures, staring spells, and gastroesophageal reflux disease presented with diffuse abdominal pain, hypoglycemia, confusion, and sweating. She reported a history of significant nausea, vomiting, and diarrhea, which had been present intermittently over the past year. On examination, she was found to have a soft, nontender, and mildly distended abdomen without splenomegaly or masses. She had a normal blood pressure and was tachycardic (130 bpm). Her initial complete blood count and basic metabolic panel, excluding glucose, were within normal limits. She was found to have an elevated peripherally drawn venous ammonia (171 mmol/L) and near hypoglycemia (blood glucose 61 mg/dL), which were drawn given her history of HI/HA. She was continued on home carglumic acid and diazoxide, glucose was supplemented intravenously, and she was started on levetiracetam for seizure prophylaxis. An upper endoscopy (esophagogastroduodenoscopy [EGD]) was performed and was unremarkable, and biopsies taken were within normal limits. Following the EGD, she underwent a gastric emptying study that showed delayed emptying (216 minutes), consistent with a new diagnosis of gastroparesis, the likely etiology of her initial abdominal pain on presentation. This was subsequently treated with azithromycin oral solution. We present this case to raise awareness of this rarely encountered syndrome and to provide the basic principles of treatment. PMID:26962538

  13. Epilepsy in Down Syndrome: Clinical Aspects and Possible Mechanisms.

    ERIC Educational Resources Information Center

    Stafstrom, Carl E.

    1993-01-01

    This review examines clinical aspects of seizures among individuals with Down's syndrome and explores possible mechanisms by which the trisomy 21 brain may generate seizures. Evidence suggests an interplay between pathologically hyperexcitable membrane properties, altered neuronal structure, and abnormal inhibitory neurotransmission. (Author/JDD)

  14. Sjögren-Larsson syndrome in clinical practice.

    PubMed

    Fuijkschot, Joris; Theelen, Thomas; Seyger, Marieke M B; van der Graaf, Marinette; de Groot, Imelda J M; Wevers, Ron A; Wanders, Ronald J A; Waterham, Hans R; Willemsen, Michèl A A P

    2012-11-01

    This review article gives a state-of-the-art synopsis of current pathophysiological concepts in Sjögren-Larsson syndrome (SLS) mainly based upon original research data of the authors in one of the world's largest clinical SLS study cohorts. Clinical features are discussed in order of appearance, and diagnostic tests are set out to guide the clinician toward the diagnosis SLS. Furthermore, current and future treatment strategies are discussed to render a comprehensive review of the topic.

  15. Delineation of a clinical syndrome caused by mosaic trisomy 15

    SciTech Connect

    Buehler, E.M.; Bienz, G.; Straumann, E.; Bosceh, N.

    1996-03-15

    We report on a boy with mosaic trisomy 15. The clinical manifestations are compared with those of the few cases reported up to now. A clinical syndrome is delineated consisting of a characteristic shape of the nose and other minor craniofacial anomalies, as well as typical deformities of the hands and feet. Different degrees of mosaicism may explain the more or less severe manifestations in individual patients. 10 refs., 4 figs., 1 tab.

  16. Fat embolism syndrome: Case report of a clinical conundrum.

    PubMed

    Nandi, Roneeta; Venkategowda, Pradeep Marur; Mutkule, Dnyaneshwar; Rao, Surath Manimala

    2014-07-01

    Fat embolism syndrome is a rare clinical condition associated with trauma, particularly of long bones. FES after fracture of neck of femur or head of humerus is uncommon. We report a case of FES following fracture in neck of femur and head of humerus in a man with history of mitral valve replacement, on long-term oral anticoagulant therapy, with an alleged history of convulsions. Our dilemma in clinical diagnosis is discussed. PMID:25190956

  17. Genetics Home Reference: MECP2-related severe neonatal encephalopathy

    MedlinePlus

    ... onset encephalopathy with microcephaly Patient Support and Advocacy Resources (2 links) Rare Disease Clinical Research Network: Rett Syndrome, MECP2 Duplication and Rett-Related Disorders Natural History Study RettSyndrome.org GeneReviews (1 link) MECP2- ...

  18. LEOPARD syndrome: clinical dilemmas in differential diagnosis of RASopathies

    PubMed Central

    2014-01-01

    Background Diagnosis within RASopathies still represents a challenge. Nevertheless, many efforts have been made by clinicians to identify specific clinical features which might help in differentiating one disorder from another. Here, we describe a child initially diagnosed with Neurofibromatosis-Noonan syndrome. The follow-up of the proband, the clinical evaluation of his father together with a gene-by-gene testing approach led us to the proper diagnosis. Case presentation We report a 8-year-old male with multiple café-au-lait macules, several lentigines and dysmorphic features that suggest Noonan syndrome initially diagnosed with Neurofibromatosis-Noonan syndrome. However, after a few years of clinical and ophthalmological follow-up, the absence of typical features of Neurofibromatosis type 1 and the lack of NF1 mutation led us to reconsider the original diagnosis. A new examination of the patient and his similarly affected father, who was initially referred as healthy, led us to suspect LEOPARD syndrome, The diagnosis was then confirmed by the occurrence in both patients of a heterozygous mutation c.1403 C > T, p.(Thr468Met), of PTPN11. Subsequently, the proband was also found to have type-1 Arnold-Chiari malformation in association with syringomyelia. Conclusion Our experience suggests that differential clinical diagnosis among RASopathies remains ambiguous and raises doubts on the current diagnostic clinical criteria. In some cases, genetic tests represent the only conclusive proof for a correct diagnosis and, consequently, for establishing individual prognosis and providing adequate follow-up. Thus, molecular testing represents an essential tool in differential diagnosis of RASophaties. This view is further strengthened by the increasing accessibility of new sequencing techniques. Finally, to our knowledge, the described case represents the third report of the occurrence of Arnold Chiari malformation and the second description of syringomyelia with

  19. Comprehensive clinical management of polycystic ovary syndrome.

    PubMed

    Setji, T L; Brown, A J

    2007-06-01

    Polycystic ovary syndrome (PCOS) affects 6-7% of reproductive-aged women. Although the diagnostic criteria for PCOS have been debated, it is frequently characterized by hyperandrogenism (hirsutism, acne, male-pattern hair loss), oligo-anovulation, and polycystic ovaries on ultrasound. The reproductive and metabolic complications associated with the syndrome can be serious, so a comprehensive approach to the evaluation and treatment of affected women is important. Menstrual cycle control is necessary to prevent endometrial hyperplasia, and this can be accomplished with hormonal contraception, progesterone therapy, and weight loss (if overweight). In women desiring pregnancy, commonly used ovulation induction therapies include weight loss, clomiphene citrate, and/or metformin. Cosmetic issues such as hirsutism, acne and male-pattern hair loss can be challenging to cope with. Treatment options include estrogen-containing hormonal contraceptive agents, antiandrogens, and topical agents. More permanent hair reduction can be achieved with electrolysis and laser therapy. Evaluation of metabolic complications includes risk assessment for diabetes, dyslipidemia, hypertension, and nonalcoholic fatty liver disease. Women with PCOS should also be screened for sleep apnea, as this has been reported to occur more commonly in women with PCOS. Finally, mental health issues such as depression and eating disorders may be present. Many of the complications associated with PCOS can be managed with therapeutic lifestyle change, including a healthy diet, exercise, weight loss (if overweight), and psychological support. Pharmacological therapies are also available to effectively regulate menstrual cycles and manage cosmetic complications. This article will review the current diagnostic and therapeutic strategies in PCOS.

  20. Clinical study of 39 patients with atypical lacunar syndrome.

    PubMed

    Arboix, A; López-Grau, M; Casasnovas, C; García-Eroles, L; Massons, J; Balcells, M

    2006-03-01

    The aim of this study was to describe the clinical characteristics of atypical lacunar syndrome (ALS) based on data collected from a prospective acute stroke registry. In total, 2500 acute stroke patients were included in a hospital based prospective stroke registry over a 12 year period, of whom 39 were identified as having ALS and radiologically proven (by computed tomography or magnetic resonance imaging) lacunes. ALS accounted for 1.8% of all acute stroke patients, 2.1% of acute ischaemic stroke, and 6.8% of lacunar syndromes. ALS included dysarthria facial paresis (n = 12) or isolate dysarthria (n = 9), isolated hemiataxia (n = 4), pure motor hemiparesis with transient internuclear ophthalmoplegia (n = 4), pure motor hemiparesis with transient subcortical aphasia (n = 3), unilateral (n = 2) or bilateral (n = 3) paramedian thalamic infarct syndrome, and hemichorea hemiballismus (n = 2). Atypical lacunar syndromes were due to small vessel disease in 96% of patients. Atherothrombotic infarction occurred in one patient and cardioembolic infarct in another, both presenting pure dysarthria. Outcome was good (in hospital mortality 0%, symptom free at discharge 28.2%). After multivariate analysis, the variables of speech disturbances, nausea/vomiting, ischaemic heart disease, and sensory symptoms were found to be significantly associated with ALS. In conclusion, atypical lacunar syndrome is an infrequent stroke subtype (one of each 14 lacunar strokes). ALS occurred in 6.8% of lacunar strokes. Isolated dysarthria or dysarthria facial paresis were the most frequent presenting forms. The prognosis of this infrequent non-classic lacunar syndrome is good.

  1. Pathology and sensitivity of current clinical criteria in corticobasal syndrome.

    PubMed

    Ouchi, Haruka; Toyoshima, Yasuko; Tada, Mari; Oyake, Mutsuo; Aida, Izumi; Tomita, Itsuro; Satoh, Akira; Tsujihata, Mitsuhiro; Takahashi, Hitoshi; Nishizawa, Masatoyo; Shimohata, Takayoshi

    2014-02-01

    The aim of this study was to investigate corticobasal syndrome with respect to underlying pathologies, the ability of current clinical criteria to detect early stages of disease, and symptoms and signs predicting background pathologies. We retrospectively analyzed the clinicopathological findings from patients with corticobasal syndrome. We also analyzed whether those findings fulfilled the diagnostic criteria for corticobasal degeneration (CBD). Finally, we investigated characteristic clinical features that are specific to each background pathology. Of 10 consecutive autopsied patients who had corticobasal syndrome (mean age ± standard deviation, 67.9 ± 9.3 years; male:female ratio, 6:4), three had corticobasal degeneration pathology, three had progressive supranuclear palsy, three had Alzheimer's disease, and one had atypical four-repeat tauopathy. Nine patients fulfilled Mayo criteria, and all 10 patients fulfilled modified Cambridge criteria at the later stage, but only two patients fulfilled either clinical criteria within 2 years of disease onset. Five patients fulfilled the clinical criteria for possible CBD (p-CBD), and one patient fulfilled the clinical research criteria for probable sporadic CBD (cr-CBD) at the later stage. Only two patients fulfilled the criteria for either p-CBD or cr-CBD within 2 years of disease onset. Although we could not find any predictive characteristic clinical features that were specific to CBD pathology, only patients with progressive supranuclear palsy developed apraxia of eyelid opening and cerebellar ataxia. Myoclonus and memory impairment, especially if they appear at an early stage of the disease, may predict Alzheimer's disease pathology. Sensitivity of the available clinical criteria for corticobasal syndrome was poor within 2 years of disease onset.

  2. Spinal Cord Anatomy and Clinical Syndromes.

    PubMed

    Diaz, Eric; Morales, Humberto

    2016-10-01

    We review the anatomy of the spinal cord, providing correlation with key functional and clinically relevant neural pathways, as well as magnetic resonance imaging. Peripherally, the main descending (corticospinal tract) and ascending (gracilis or cuneatus fasciculi and spinothalamic tracts) pathways compose the white matter. Centrally, the gray matter can be divided into multiple laminae. Laminae 1-5 carry sensitive neuron information in the posterior horn, and lamina 9 carries most lower motor neuron information in the anterior horn. Damage to the unilateral corticospinal tract (upper motor neuron information) or gracillis-cuneatus fasciculi (touch and vibration) correlates with ipsilateral clinical findings, whereas damage to unilateral spinothalamic tract (pain-temperature) correlates with contralateral clinical findings. Damage to commissural fibers correlates with a suspended bilateral "girdle" sensory level. Autonomic dysfunction is expected when there is bilateral cord involvement. PMID:27616310

  3. Clinical manifestations and clinical syndromes of Filipino patients with systemic lupus erythematosus.

    PubMed

    Villamin, Charles A C; Navarra, Sandra V

    2008-01-01

    The aim of this study was to describe the presenting clinical manifestations and syndromes of Filipino patients on diagnosis of systemic lupus erythematosus (SLE). We performed a retrospective review of medical records of Filipino SLE patients included in the lupus database of the University of Santo Tomas (UST) in Manila, Philippines. All patients fulfilled the American College of Rheumatology criteria for SLE. The following data were recorded: (1) demographic profile, (2) clinical manifestations on SLE diagnosis, and (3) clinical syndromes prior to and during fulfillment of diagnostic criteria for SLE and disease interval from diagnosis of a clinical syndrome to SLE diagnosis. Clinical data of 1,070 patients entered into the UST lupus database as of October 2005 were analyzed. The average age at SLE diagnosis was 28.5 +/- 11.5 (range 5-71) years, with 1,025 female and 45 male subjects. The most common presenting manifestation was arthritis (68%), followed by malar rash (49%), renal involvement (47%), photosensitivity (33%), and oral ulcers (33%). The following clinical syndromes were recorded prior to or during SLE diagnosis: nephrotic syndrome (30%), undifferentiated connective tissue disease (UCTD) (22%), autoimmune hemolytic anemia (AIHA) (6%), and idiopathic thrombocytopenic purpura (ITP) (6%). Among these, AIHA preceded the diagnosis of SLE at the longest interval (20.3 +/- 30.6, range 1-194 months). In this large database of Filipino patients with SLE, the most common presenting manifestation was arthritis, with renal involvement occurring in almost 50%. Among the clinical syndromes, nephrotic syndrome was the most common, whereas AIHA recorded the longest interval preceding SLE diagnosis, at an average of 20.3 months. Our findings are similar to data from other countries and emphasize the broad range of manifestations of SLE. The findings also reinforce the need to establish and maintain SLE databases to enhance awareness, early diagnosis, and more

  4. Serrated polyposis syndrome: molecular, pathological and clinical aspects.

    PubMed

    Guarinos, Carla; Sánchez-Fortún, Cristina; Rodríguez-Soler, María; Alenda, Cristina; Payá, Artemio; Jover, Rodrigo

    2012-05-28

    Hyperplastic polyps have traditionally been considered not to have malignant potential. New pathological classification of serrated polyps and recent discoveries about the serrated pathway of carcinogenesis have revolutionized the concepts and revitalized the research in this area. Until recently, it has been thought that most colorectal cancers arise from conventional adenomas via the traditional tumor suppressor pathway initiated by a mutation of the APC gene, but it has been found that this pathway accounts for only approximately 70%-80% of colorectal cancer (CRC) cases. The majority of the remaining colorectal cancer cases follow an alternative pathway leading to CpG island methylator phenotype carcinoma with BRAF mutation and with or without microsatellite instability. The mechanism of carcinomas arising from this alternative pathway seems to begin with an activating mutation of the BRAF oncogene. Serrated polyposis syndrome is a relatively rare condition characterized by multiple and/or large serrated polyps of the colon. Clinical characteristics, etiology and relationship of serrated polyposis syndrome to CRC have not been clarified yet. Patients with this syndrome show a high risk of CRC and both sporadic and hereditary cases have been described. Clinical criteria have been used for diagnosis and frequent colonoscopy surveillance should be performed in order to prevent colorectal cancer. In this review, we try to gather new insights into the molecular pathogenesis of serrated polyps in order to understand their possible clinical implications and to make an approach to the management of this syndrome.

  5. Ocular lateropulsion in Wallenberg's syndrome: a prospective clinical study.

    PubMed

    Crevits, L; vander Eecken, H

    1982-03-01

    In order to evaluate the occurrence and clinical value of ocular lateropulsion in Wallenberg's syndrome, a prospective study was carried out. Lateropulsion of the horizontal and vertical refixation saccades was a rather regular finding, especially in complete Wallenberg's syndrome. Lateral ocular deviation after elimination of fixation was present in nearly all cases. The tonic lateral vector was always directed to the involved side. It is concluded that ocular lateropulsion is an easily elicited sign with a lateralizing value in lateral bulbar infarction. Further systematic search of ocular lateropulsion in other posterior fossa disorders is needed to determine its topographical significance.

  6. Early Repolarization Syndrome; Mechanistic Theories and Clinical Correlates

    PubMed Central

    Mercer, Ben N.; Begg, Gordon A.; Page, Stephen P.; Bennett, Christopher P.; Tayebjee, Muzahir H.; Mahida, Saagar

    2016-01-01

    The early repolarization (ER) pattern on the 12-lead electrocardiogram is characterized by J point elevation in the inferior and/or lateral leads. The ER pattern is associated with an increased risk of ventricular arrhythmias and sudden cardiac death (SCD). Based on studies in animal models and genetic studies, it has been proposed that J point elevation in ER is a manifestation of augmented dispersion of repolarization which creates a substrate for ventricular arrhythmia. A competing theory regarding early repolarization syndrome (ERS) proposes that the syndrome arises as a consequence of abnormal depolarization. In recent years, multiple clinical studies have described the characteristics of ER patients with VF in more detail. The majority of these studies have provided evidence to support basic science observations. However, not all clinical observations correlate with basic science findings. This review will provide an overview of basic science and genetic research in ER and correlate basic science evidence with the clinical phenotype. PMID:27445855

  7. [Hemolytic uremic syndrome. Clinical manifestations. Treatment].

    PubMed

    Exeni, Ramón A

    2006-01-01

    Clinical manifestation are described in children with epidemic HUS. The intestinal involvement in the prodromic period, is outlined and the most common disturbances such acute renal failure, thrombocytopenia, hemolytic anemia, leucocitosis hypertension, neurological, pancreatic and cardiac manifestations are described. We discuss the acid-base and electrolyte disturbances, metabolic acidosis, hyponatremia, hyperkalemia. The etiopathogenic treatment and the control of renal sequelae are also discussed.

  8. Autism--genetics, electrophysiology and clinical syndromes.

    PubMed

    Pop-Jordanova, Nada; Plasevska-Karanfilska, Dijana

    2014-01-01

    Autism is a severe and the most heritable developmental disorder, whose pathogenesis is still largely unknown. The rising incidence of autism in the last decade has increased the scientific interest and research. More than a thousand papers concerned with information about the etiology of this "static disorder of the immature brain" can be found on Pub Med. The aim of this paper is to give a review of published genetic chromosomal anomalies associated with autistic spectrum disorders, as well as to discuss common syndromes associated with autistic traits. In addition, some of our own findings in genetics, as well as in quantitative electroencephalography and neurofeedback training in autistic children, will be presented and discussed. Generally, the subsequent analyses indicate that the causes of autism include fewer common single-gene mutations and chromosomal abnormalities, as well as multiple interacting genes of weak effect. Genome-wide linkage analysis has identified several susceptibility loci and positional and functional candidate genes which appear to represent possible risks of the autistic spectrum. Electrophysiological findings showed high delta/theta activity in frontal-central regions, while in 25% high beta activity was detected as a result of anxiety. Neurofeedback is a promising therapy for symptom mitigation.

  9. Syndrome of endemic arsenism and fluorosis. A clinical study.

    PubMed

    Huang, Y Z; Qian, X C; Wang, G Q; Gu, Y L; Wang, S Z; Cheng, Z H; Xiao, B Y; Gang, J M; Wu, J Y; Kan, M Y

    1992-07-01

    Sixty-five patients in Xinjiang with syndrome of endemic arsenism and fluorosis (SEAF) were investigated clinically from March 1982 to August 1989. SEAF is a kind of chronic syndrome resulting from the combined, harmful effects of two trace elements, arsenic and fluorine. Peripheral neuritis and cardiovascular changes were observed in this syndrome more often than in simple arsenism or simple fluorosis. The excessive quantities of these two trace elements in blood might have a synergic, harmful effect on the nervous and circulatory systems. No definite conclusion could be reached with regard to the morbidity of skin and visceral tumors in this series. The incidence of associated skin cancer was found to be 7.7% and an associated Grade II squamous cell carcinoma of the esophagus was encountered in one patient.

  10. [Clinical findings, pathogenesis and treatment of Bartter's syndrome (author's transl)].

    PubMed

    Ploier, R; Tulzer, W

    1981-01-01

    In three children Bartter's syndrome was diagnosed on the basis of the typical laboratory findings and the characteristic histological changes of the kidney. Apart from the description of three cases especially the latest pathogenic findings are represented because of their important therapeutic consequences. In one of the patients the therapeutic effect of the prostaglandin synthetase inhibitor Indomethazin was statistically proved in a balance study performed under inpatient conditions and so it was indirectly proved that the prostaglandines play an essential role in the pathogenesis of Bartter's syndrome. The patients have now received Indomethazin for a period of 11 months up to two and a half years with the result of an impressive improvement of the clinical symptoms and an unequivocal increase of the serum potassium. The fact that despite of normal renin and aldosterone levels there was no complete normalization of the serum potassium level indicates that in addition of prostaglandines probably a superior mechanism plays a part in the origin Bartter's syndrome.

  11. Atypical clinical manifestations of multiple endocrine neoplasia type 1 syndrome.

    PubMed

    Krysiak, Robert; Kajdaniuk, Dariusz; Marek, Bogdan; Okopień, Bogusław

    2009-03-01

    Multiple endocrine neoplasia type 1 (MEN1) is a hereditary tumor syndrome characterized by a genetic predisposition to develop a variety of neuroendocrine tumors and hormone excess syndromes. The major components of MEN1 are hyperparathyroidism due to multiple parathyroid adenomas or hyperplasia, duodenopancreatic neuroendocrine tumors and pituitary adenomas, most often producing prolactin. Physicians' inadequate knowledge of this clinical entity and sometimes its atypical presentation result in a probable significant underdiagnosis of MEN1. This describes the case of a 65-year-old female in whom primary hyperparathyroidism, limited to only one parathyroid gland, was preceded by acromegaly that was diagnosed 23 years earlier. This case shows that MEN1 manifests itself even in older groups and hyperparathyroidism may not be the first symptom of this syndrome. Therefore, we believe that all subjects who, regardless of age, gender and initial manifestation present with whichever the major symptom should be followed up regularly for the early detection of MEN1. PMID:19514648

  12. Strawberries, blueberries, and cranberries in the metabolic syndrome: clinical perspectives.

    PubMed

    Basu, Arpita; Lyons, Timothy J

    2012-06-13

    Emerging science supports therapeutic roles of strawberries, blueberries, and cranberries in metabolic syndrome, a prediabetic state characterized by several cardiovascular risk factors. Interventional studies reported by our group and others have demonstrated the following effects: strawberries lowering total and LDL-cholesterol, but not triglycerides, and decreasing surrogate biomarkers of atherosclerosis (malondialdehyde and adhesion molecules); blueberries lowering systolic and diastolic blood pressure and lipid oxidation and improving insulin resistance; and low-calorie cranberry juice selectively decreasing biomarkers of lipid oxidation (oxidized LDL) and inflammation (adhesion molecules) in metabolic syndrome. Mechanistic studies further explain these observations as up-regulation of endothelial nitric oxide synthase activity, reduction in renal oxidative damage, and inhibition of the activity of carbohydrate digestive enzymes or angiotensin-converting enzyme by these berries. These findings need confirmation in future studies with a focus on the effects of strawberry, blueberry, or cranberry intervention in clinical biomarkers and molecular mechanisms underlying the metabolic syndrome.

  13. Phenotypic Delineation of Emanuel Syndrome (Supernumerary Derivative 22 syndrome): Clinical features of 63 individuals

    PubMed Central

    Carter, Melissa T; Pierre, Stephanie A St.; Zackai, Elaine H; Emanuel, Beverly S; Boycott, Kym M

    2009-01-01

    Emanuel syndrome is characterized by multiple congenital anomalies and developmental disability. It is caused by the presence of a supernumerary derivative chromosome that contains material from chromosomes 11 and 22. The origin of this imbalance is 3:1 malsegregation of a parental balanced translocation between chromosomes 11 and 22, which is the most common recurrent reciprocal translocation in humans. Little has been published on the clinical features of this syndrome since the 1980s and information on natural history is limited. We designed a questionnaire to collect information from families recruited through an international online support group, Chromosome 22 Central. Data gathered include information on congenital anomalies, medical and surgical history, developmental and behavioural issues, and current abilities. We received information on 63 individuals with Emanuel syndrome, ranging in age from newborn to adulthood. As previously recognized, congenital anomalies were common, the most frequent being ear pits (76%), micrognathia (60%), heart malformations (57%), and cleft palate (54%). Our data suggest that vision and hearing impairment, seizures, failure to thrive and recurrent infections, particularly otitis media, are common in this syndrome. Psychomotor development is uniformly delayed, however the majority of individuals (over 70%) eventually learn to walk with support. Language development and ability for self-care are also very impaired. This study provides new information on the clinical spectrum and natural history of Emanuel syndrome for families and physicians caring for these individuals. PMID:19606488

  14. Perceived vertical and lateropulsion: clinical syndromes, localization, and prognosis.

    PubMed

    Brandt, T; Dieterich, M

    2000-01-01

    We present a clinical classification of central vestibular syndromes according to the three major planes of action of the vestibulo-ocular reflex: yaw, roll, and pitch. The plane-specific syndromes are determined by ocular motor, postural, and perceptual signs. Yaw plane signs are horizontal nystagmus, past pointing, rotational and lateral body falls, deviation of perceived straight-ahead to the left or right. Roll plane signs are torsional nystagmus, skew deviation, ocular torsion, tilts of head, body, and perceived vertical in a clockwise or counterclockwise direction. Pitch plane signs are upbeat/downbeat nystagmus, forward/backward tilts and falls, deviations of the perceived horizon. The thus defined vestibular syndromes allow a precise topographic analysis of brainstem lesions according to their level and side. Special emphasis is placed on the vestibular roll plane syndromes of ocular tilt reaction, lateropulsion in Wallenberg's syndrome, thalamic and cortical astasia and their association with roll plane tilt of perceived vertical. Recovery is based on a functionally significant central compensation of a vestibular tone imbalance, the mechanism of which is largely unknown. Physical therapy may facilitate this central compensation, but this has not yet been proven in prospective studies.

  15. The clinical presentation of Ehlers-Danlos syndrome.

    PubMed

    Lawrence, Elizabeth J

    2005-12-01

    Ehlers-Danlos syndrome (EDS), a heterogeneous group of inheritable connective tissue disorders, is attributed to mutations in connective tissue genes. These mutations cause defects in collagen. Collagen, a connective tissue protein that acts like glue, gives strength to the body and provides support and elasticity for movement. Thus, the altered gene affects the mechanical properties of skin, joints, ligaments, and blood vessels. Ehlers-Danlos syndrome is transmitted through autosomal dominant, autosomal recessive, or x-linked patterns of inheritance. The life expectancy of an affected infant varies with the type of EDS. This article provides an overview of the 6 major classifications of EDS, their unique clinical presentations, a focused physical assessment guide, considerations for nursing care, and resources for parents. Ehlers-Danlos syndrome can be a potentially debilitating syndrome. It requires preventative and protective measures starting at birth to preserve joint function to improve infant outcomes. Caring for patients with EDS requires an understanding of the potential associated complications to help minimize the physical and emotional impact of the syndrome and improve the quality of life for affected individuals. PMID:16338669

  16. Clinical Characteristics of Childhood Guillain-Barré Syndrome

    PubMed Central

    Koul, Roshan; Al-Futaisi, Amna; Chacko, Alexander; Fazalullah, Mohammed; Nabhani, Susan Al; Al-Awaidy, Salah; Al-Busaidy, Suleiman; Al-Mahrooqi, Salim

    2008-01-01

    Objectives To find the incidence, clinical pattern and outcome of Guillain-Barre syndrome in the Sultanate of Oman in children less than 15 years of age. Methods All children under fifteen years with acute flaccid paralysis were admitted to identify the underlying cause. The diagnosis of Gullain Barre syndrome was made by clinical criteria, cerebrospinal fluid findings and nerve conduction studies. Intravenous immunoglobulins were given to all and two needed plasmapharesis. Results Sixty-one children were diagnosed as Guillan-Barré syndrome and constituted 20% of cases of acute flaccid paralysis. Males 39 (63.9%) outnumbered females (36.1%).The annual incidence below 15 years was 0.45/100,000. Cranial nerves were involved in 31 (50.8%) children. Albumino-cytological dissociation in cerebrospinal fluid was seen in 42/45(93.3%) cases. Acute relapse was seen in six (9.8%) cases. Eleven children (18.3%) needed ventilation. Complete recovery was seen in 45 to 310 days (mean 69.1 days). Three children (4.9%) were left with minimal residual deficit. There was no mortality. Conclusions Guillain Barre syndrome is a serious disease, although recovery is the rule in children. The disease is associated with very low mortality and long term morbidity. Immunoglobulins have reduced the duration of hospital stay and the total time needed for recovery. PMID:22359705

  17. Iliac vein compression syndrome: Clinical, imaging and pathologic findings

    PubMed Central

    Brinegar, Katelyn N; Sheth, Rahul A; Khademhosseini, Ali; Bautista, Jemianne; Oklu, Rahmi

    2015-01-01

    May-Thurner syndrome (MTS) is the pathologic compression of the left common iliac vein by the right common iliac artery, resulting in left lower extremity pain, swelling, and deep venous thrombosis. Though this syndrome was first described in 1851, there are currently no standardized criteria to establish the diagnosis of MTS. Since MTS is treated by a wide array of specialties, including interventional radiology, vascular surgery, cardiology, and vascular medicine, the need for an established diagnostic criterion is imperative in order to reduce misdiagnosis and inappropriate treatment. Although MTS has historically been diagnosed by the presence of pathologic features, the use of dynamic imaging techniques has led to a more radiologic based diagnosis. Thus, imaging plays an integral part in screening patients for MTS, and the utility of a wide array of imaging modalities has been evaluated. Here, we summarize the historical aspects of the clinical features of this syndrome. We then provide a comprehensive assessment of the literature on the efficacy of imaging tools available to diagnose MTS. Lastly, we provide clinical pearls and recommendations to aid physicians in diagnosing the syndrome through the use of provocative measures. PMID:26644823

  18. Expanding the mutation and clinical spectrum of Roberts syndrome.

    PubMed

    Afifi, Hanan H; Abdel-Salam, Ghada M H; Eid, Maha M; Tosson, Angie M S; Shousha, Wafaa Gh; Abdel Azeem, Amira A; Farag, Mona K; Mehrez, Mennat I; Gaber, Khaled R

    2016-07-01

    Roberts syndrome and SC phocomelia syndrome are rare autosomal recessive genetic disorders representing the extremes of the spectrum of severity of the same condition, caused by mutations in ESCO2 gene. We report three new patients with Roberts syndrome from three unrelated consanguineous Egyptian families. All patients presented with growth retardation, mesomelic shortening of the limbs more in the upper than in the lower limbs and microcephaly. Patients were subjected to clinical, cytogenetic and radiologic examinations. Cytogenetic analysis showed the characteristic premature separation of centromeres and puffing of heterochromatic regions. Further, sequencing of the ESCO2 gene identified a novel mutation c.244_245dupCT (p.T83Pfs*20) in one family besides two previously reported mutations c.760_761insA (p.T254Nfs*27) and c.764_765delTT (p.F255Cfs*25). All mutations were in homozygous state, in exon 3. The severity of the mesomelic shortening of the limbs and craniofacial anomalies showed variability among patients. Interestingly, patient 1 had abnormal skin hypopigmentation. Serial fetal ultrasound examinations and measurements of long bones diagnosed two affected fetuses in two of the studied families. A literature review and case comparison was performed. In conclusion, we report a novel ESCO2 mutation and expand the clinical spectrum of Roberts syndrome.

  19. Common recurrent microduplication syndromes: diagnosis and management in clinical practice.

    PubMed

    Berg, Jonathan S; Potocki, Lorraine; Bacino, Carlos A

    2010-05-01

    Details on the phenotypic consequences of genomic microdeletions and microduplications are rapidly emerging in the wake of increased utilization of high-resolution methods for the detection of genomic copy number variants (CNVs). Due to their recent discovery, the complete phenotypic characterization of these syndromes is still in progress. For practicing clinicians, this unprecedented molecular diagnostic capability has in many cases outpaced our ability to convey conclusive information regarding these conditions to patients and family members. In particular, genomic microduplication syndromes are frequently associated with variable phenotypes and incomplete penetrance, leading to difficulty in counseling regarding the potential future consequences of a given microduplication. In this review, we have attempted to provide an initial set of recommendations for the management of patients with recurrent microduplication syndromes. We summarize the clinical information for microduplications of 14 different genomic regions and provide a framework for clinical evaluation and anticipatory guidance in these conditions. It is our expectation that these preliminary guidelines will be revised further for each microduplication syndrome as more information becomes available.

  20. Chronic pelvic pain syndrome: a clinical enigma.

    PubMed

    Stein, Avi; May, Tal; Dekel, Yoram

    2014-07-01

    Chronic nonbacterial prostatitis is an ill-defined, painful clinical condition that is characterized by various nonspecific symptoms, some of which are related to urination or the male reproductive organs. Urologists diagnose this particular condition when the symptoms are not associated with urinary bacterial growth before and after transrectal prostate massage. In this review, we describe the recommended and optional tests that can be performed in these cases. There is significant overlap between chronic nonbacterial prostatitis and other unexplained pain conditions, raising the question as to whether the prostate is the culprit. The sources and mediators of pain and the psychological aspects of this complex condition are discussed. Treatments consist of traditional antibiotics and α-blockers. Because the pain relief is often temporary, patients seek other solutions. Various therapeutics have been introduced to satisfy the expectations of patients and physicians. We discuss other pain medications, as well as intraprostatic drug injections and shockwave therapy. Importantly, however, not all of these suggestions have been widely accepted by urologists or pain clinics.

  1. Clinical features of hepatopulmonary syndrome in cirrhotic patients

    PubMed Central

    Alizadeh, Amir Houshang Mohammad; Fatemi, Seyed Reza; Mirzaee, Vahid; Khoshbaten, Manoochehr; Talebipour, Bahman; Sharifian, Afsaneh; Khoram, Ziba; Haj-sheikh-oleslami, Farhad; Gholamreza-shirazi, Masoomeh; Zali, Mohammad Reza

    2006-01-01

    AIM: To evaluate the frequency, clinical and paraclinical features of hepatopulmonary syndrome (HPS) and to determine their predictive values in diagnosis of this syndrome in patients in Iran. METHODS: Fifty four cirrhotic patients underwent contrast enhanced echocardiography to detect intrapulmonary and intracardiac shunts by two cardiologists. Arterial blood oxygen, O2 gradient (A-a) and orthodoxy were measured by arterial blood gas (ABG) test. The patients positive for diagnostic criteria of HPS were defined as clinical HPS cases and those manifesting the intrapulmonary arterial dilation but no other criteria (arterial blood hypoxemia) were defined as lHPS cases. HPS frequency, sensitivity, positive and negative predictive values of clinical and paraclinical features were studied. RESULTS: Ten (18.5%) and seven (13%) cases had clinical and subclinical HPS, respectively. The most common etiology was hepatitis B. Dyspnea (100%) and cyanosis (90%) were the most prevalent clinical features. Dyspnea and clubbing were the most sensitive and specific clinical features respectively. No significant relationship was found between HPS and splenomegaly, ascites, edema, jaundice, oliguria, and collateral veins. HPS was more prevalent in hepatitis B. PaO2 < 70 and arterial-alveolar gradient had the highest sensitivity in HPS patients. Orthodoxy specificity was 100%. CONCLUSION: Clubbing with positive predictive value (PPV) of 75% and dyspnea with negative predictive value (NPV) of 75% are the best clinical factors in diagnosis of HPS syndrome. PaO2 < 70 and P (A-a) O2 > 30 and their sum, are the most valuable negative and positive predictive values in HPS patients. PMID:16610006

  2. Cockayne syndrome without typical clinical manifestations including neurologic abnormalities.

    PubMed

    Miyauchi-Hashimoto, H; Akaeda, T; Maihara, T; Ikenaga, M; Horio, T

    1998-10-01

    Although patients with mild symptoms of atypical Cockayne syndrome (CS) have been described, there has not been a report of a patient with CS whose only clinical manifestation was cutaneous photosensitivity. Cells from patients with CS show UV sensitivity, reduced recovery of RNA synthesis, but normal UV-induced unscheduled DNA synthesis. On the other hand, the patients with UV-sensitive syndrome have only cutaneous photosensitivity and skin freckles, whereas those cells respond to UV radiation in a similar fashion to the CS cells. We describe a patient with CS who showed only photosensitivity without typical clinical manifestations of CS, but his cells showed UV sensitivity, reduced recovery of RNA synthesis, and normal unscheduled DNA synthesis after UV radiation similar to CS cells. Furthermore, the patient was assigned to complementation group B of CS on the basis of the results of complementation analysis. The present report suggests that CS has a wider spectrum than that considered previously. PMID:9777763

  3. Aging and Intellectual Disability: Insights from Mouse Models of Down Syndrome

    ERIC Educational Resources Information Center

    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…

  4. Association of Parental Origin with Clinical Profile in Klinefelter Syndrome

    PubMed Central

    Rajangam, Sayayee; C, Lalitha

    2015-01-01

    Introduction: Several genomic imprinting mechanisms have been postulated to report the parent-of-origin in Klinefelter syndrome. It was stated in the literature, parental origin has an effect on behavioral phenotype of Klinefelter individuals, but the association of the same on clinical profile was less reported. The detailed clinical phenotype when studied with the known origin of extra X may possibly explain the imprinting effect that may be helpful to derive diagnostic criteria in the syndrome. In the present study, we investigated the parental-of-origin of extra X chromosome in Klinefelter syndrome probands with an aim to report the association between the phenotype with that of its karyotype and the parental origin of supernumerary X. Materials and Methods: Seventy two probands that were referred to division of Human Genetics, St.John’s Medical College, Bangalore with variable complaints and phenotypic features were diagnosed with informed consent as Klinefelter syndrome with a confirmed karyotype. The Karyotype was prepared by peripheral lymphocyte culture and GTG banding method. The parental origin was studied in 9 families of Klinefelter probands with standard protocol for GENE SCAN using X-chromosome specific Short Tandem Repeat markers. The outcome was analyzed to determine the parental origin by GENE MAPPER. Statistical analysis: Statistical analysis was conducted to ascertain the significance of parental origin of supernumerary X with the phenotypic profile with confirmed karyotype. Results: Seven of nine probands had 47, XXY karyotype and 2 were mosaic with 47,XXY/46,XY karyotype. Five probands had their supernumerary X from maternal side and four were paternally derived. Sixteen features as framed proforma were tabulated against the originated X in Klinefelter probands. 55.56% of Klinefelter stigmata were seen in prob and who had maternally derived X and the rest were with paternal X. Conclusion: The findings of the present study points on parent

  5. Thrombocytopenia-absent radius syndrome: a clinical genetic study

    PubMed Central

    Greenhalgh, K; Howell, R; Bottani, A; Ancliff, P; Brunner, H; Verschuuren-Bemel..., C; Vernon, E; Brown, K; Newbury-Ecob, R

    2002-01-01

    The thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation syndrome characterised by bilateral absence of the radii and a thrombocytopenia. The lower limbs, gastrointestinal, cardiovascular, and other systems may also be involved. Shaw and Oliver in 1959 were the first to describe this condition, but it was Hall et al in 1969 who reported the first major series of patients. Since then most reports have been based on single or small numbers of cases. We report the results of a clinical study looking at the phenotype of 34 patients with TAR syndrome. All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies. Congenital anomalies not previously described in association with TAR syndrome included facial capillary haemangiomata, intracranial vascular malformation, sensorineural hearing loss, and scoliosis. Karyotype analysis, chromosome breakage studies including premature centromeric separation and fluorescence in situ hybridisation studies looking for a deletion of chromosome 22q11 were undertaken. Two abnormal karyotypes were identified. PMID:12471199

  6. [Algodystrophic syndrome in hemiplegia. Clinical and therapeutic study].

    PubMed

    Perrigot, M; Bergego, C; Hocini, A; Pierrot-Deseilligny, E

    1982-01-01

    The work here exposed is divided in two studies: clinical and therapeutical. 1--Clinical. The occurrence of shoulder hand syndrome has been studied in 130 patients with hemiplegia. Although the preventive treatment was correct in all cases, 90 of them developed neurodystrophy. It is shown that the appearance and the intensity of this syndrome can be predicted with some certainly as soon as three weeks after the onset of hemiplegia, since there is a statistically significant correlation with the aetiology and the existence of some associated factors. 2--Therapeutical. The efficacy of eight treatments (calcitonin, blocking agents, intravenous clomipramine, blocking agents, periarterial injections of local anaesthetics, local or general corticotherapy, physiotherapy, kinesitherapy), randomly given to the patients, was compared (90 patients and 130 treatments). Local corticotherapy was the most efficient treatment. Physiotherapy was less efficient but always well tolerated. All the other treatments were much less active. Kinesitherapy was however always necessary to prevent joint ankylosis. No correlation was found between the intensity of the shoulder hand syndrome and the efficacy of treatments.

  7. [Cutaneous radiation syndrome: clinical features, diagnosis and therapy].

    PubMed

    Gottlöber, P; Krähn, G; Peter, R U

    2000-08-01

    Accidental exposure to ionizing radiation may occur during such catastrophic events as the Chernobyl accident in 1986 or over days to weeks as in Goiania in 1987 and in the military camp during the training of soldiers in Lilo/Georgia in 1997, as well as in medical institutions. The cutaneous symptoms after radiation exposure are based on a combination of inflammatory processes and alteration of cellular proliferation as a result of a specific pattern of transcriptionally activated proinflammatory cytokines and growth factors. They follow a time course consisting of prodromal erythema, latency period, acute stage, chronic stage and late stage. The entire complex is referred to as cutaneous radiation syndrome. The time course depends on several factors such as the radiation dose, radiation quality, individual radiation sensitivity, the extent of contamination and absorption and amount of skin exposed. For the diagnosis of the cutaneous radiation syndrome the following procedures are used: 7.5 MHz to 20 MHz-B-scan sonography, thermography, capillary microscopy, profilometry, nuclear magnetic resonance imaging, bone scintigraphy and histology. Based on the results of experimental and clinical research, today treatment may include topical or systemic corticosteroids, gamma-interferon, pentoxifylline, vitamin E and superoxide dismutase. The treatment depends on the stage of the cutaneous radiation syndrome. Due to the complexity of the clinical manifestations of radiation disease, most patients require interdisciplinary treatment in specialized centres. Dermatologists are essential partners in the life-long follow-up and therapy of such patients.

  8. [Clinical picture and pathogenesis of the Refsum syndrome].

    PubMed

    Shevchenko, A M

    1977-01-01

    The author reports of 2 cases (sisters of 13 and 15 years old) with the Refsum syndrome. The disease had its onset at the age of 12 and 5 years with a progressive development and remissions. The clinical picture was characterized by a recurrent syndrome of polyradiculoneurites with a slight protein cellular dissociation in the CSF, an expressed sensitive ataxia with elements of cerebellar disorders, a drop in the acuity of sight, audition, intellectual level and a deformation of the talipes of the Friedreich type. In a single examination of fatty acids in the blood serum by the method of gas chromotography there were no data pointing to the existence of 3, 7, 11, 15-tetra metylhexadecone acids. On the basis of an immunological study the author discusses the role of autoimmune reactions in the pathogenesis of the diseases. A differential diagnosis was conducted between acanthocytosis and porphyria with recommendations in regard to treatment.

  9. Severe acute respiratory syndrome (SARS): epidemiology and clinical features

    PubMed Central

    Hui, D; Chan, M; Wu, A; Ng, P

    2004-01-01

    Severe acute respiratory syndrome (SARS) is a newly emerged infectious disease with a significant morbidity and mortality. The major clinical features include persistent fever, chills/rigor, myalgia, malaise, dry cough, headache, and dyspnoea. Older subjects may present without the typical febrile response. Common laboratory features include lymphopenia, thrombocytopenia, raised alanine transaminases, lactate dehydrogenase, and creatine kinase. The constellation of compatible clinical and laboratory findings, together with certain characteristic radiological features and lack of clinical response to broad spectrum antibiotics, should arouse suspicion of SARS. Measurement of serum RNA by real time reverse transcriptase-polymerase chain reaction technique has a detection rate of 75%–80% in the first week of the illness. PMID:15254300

  10. Clinical Experience of the Klippel-Trenaunay Syndrome

    PubMed Central

    Sung, Hyung Min; Lee, Seok Jong; Lee, Jong Min; Huh, Seung; Lee, Jeong Woo; Choi, Kang Young; Yang, Jung Dug; Cho, Byung Chae

    2015-01-01

    Background The Klippel-Trenaunay syndrome (KTS) is characterized by three clinical features, namely cutaneous capillary malformations, venous malformations, and soft tissue and/or bony hypertrophy of the extremities. The varied manifestations are attributed to the unpredictable clinical nature and prognosis of the syndrome. To elucidate the clinical characteristics of this disease, we reviewed a relatively large number of KTS patients who presented to our vascular anomalies center. Methods We conducted a retrospective study with 19 patients who were diagnosed with KTS and treated in our vascular anomalies clinic between 2003 and 2014, and examined their demographic characteristics, their clinical features, and the treatments administered. Results The sex distribution was balanced, with 9 (47%) males and 10 (53%) females. The mean follow-up period was 4.1 years (range, 7 months-9 years). Most of the patients received conservative treatments such as medication or physiotherapy. Compression therapies such as wearing of elastic garments/bandages were also administered, and surgical interventions were considered only when the patients became excessively symptomatic. Other treatments included laser therapy and sclerotherapy, and all the treatments were adjusted according to each case, tailored to the conditions of the individual patients. Conclusions KTS is an extremely rare, multifactorial disorder that induces widely varied symptoms. Because of this unique feature, plastic surgeons, when not careful, tend to attach a one-sided importance to typical symptoms such as limb hypertrophy or capillary malformation and thus overlook other symptoms and clinical features. KTS can be suspected in all infants who show capillary malformations or limb hypertrophy and require a multi-disciplinary approach for comprehensive management. PMID:26430625

  11. Clinical Characteristics of Dysphagia in Children with Down Syndrome.

    PubMed

    Jackson, Arwen; Maybee, Jennifer; Moran, Maura K; Wolter-Warmerdam, Kristine; Hickey, Francis

    2016-10-01

    Aspiration is an often unrecognized comorbidity in children with Down syndrome with serious medical consequences. This retrospective chart review of swallow study reports characterizes oral and pharyngeal phase dysphagia and diet modifications on videofluoroscopic swallow studies (VFSS) in a large cohort of children with Down syndrome. A total of 158 pediatric patients (male = 95; female = 63; mean age 2.10 years, SD 3.17 years) received an initial VFSS at a pediatric teaching hospital as part of their medical care. A total of 56.3 % (n = 89) children had pharyngeal phase dysphagia with aspiration and deep laryngeal penetration occurring most frequently. Of the 61 patients who aspirated, 90.2 % (n = 55) did so silently with no cough or overt clinical symptoms. In 76.7 % of cases of pharyngeal phase dysphagia, a functional feeding plan, with use of thickened liquids or change in feeding system to control flow rate and/or bolus size, was able to be established, which allowed children to continue eating by mouth. Thickened liquids (76.7 %, n = 46) were the most effective adaptation, with change in feeding system alone effective in only 8.3 % (n = 5) cases. Oral phase dysphagia was reported in the majority of patients (63.8 %, n = 88/138); however, this was not predictive of pharyngeal phase dysphagia. Age, sex, and reason for referral, including prior clinical symptoms, did not have a statistically significant impact on the presence of dysphagia. This comprehensive review has application to clinical understanding and management of dysphagia in children with Down syndrome.

  12. Clinical Characteristics of Dysphagia in Children with Down Syndrome.

    PubMed

    Jackson, Arwen; Maybee, Jennifer; Moran, Maura K; Wolter-Warmerdam, Kristine; Hickey, Francis

    2016-10-01

    Aspiration is an often unrecognized comorbidity in children with Down syndrome with serious medical consequences. This retrospective chart review of swallow study reports characterizes oral and pharyngeal phase dysphagia and diet modifications on videofluoroscopic swallow studies (VFSS) in a large cohort of children with Down syndrome. A total of 158 pediatric patients (male = 95; female = 63; mean age 2.10 years, SD 3.17 years) received an initial VFSS at a pediatric teaching hospital as part of their medical care. A total of 56.3 % (n = 89) children had pharyngeal phase dysphagia with aspiration and deep laryngeal penetration occurring most frequently. Of the 61 patients who aspirated, 90.2 % (n = 55) did so silently with no cough or overt clinical symptoms. In 76.7 % of cases of pharyngeal phase dysphagia, a functional feeding plan, with use of thickened liquids or change in feeding system to control flow rate and/or bolus size, was able to be established, which allowed children to continue eating by mouth. Thickened liquids (76.7 %, n = 46) were the most effective adaptation, with change in feeding system alone effective in only 8.3 % (n = 5) cases. Oral phase dysphagia was reported in the majority of patients (63.8 %, n = 88/138); however, this was not predictive of pharyngeal phase dysphagia. Age, sex, and reason for referral, including prior clinical symptoms, did not have a statistically significant impact on the presence of dysphagia. This comprehensive review has application to clinical understanding and management of dysphagia in children with Down syndrome. PMID:27405422

  13. Thoracic outlet syndrome: a controversial clinical condition. Part 1: anatomy, and clinical examination/diagnosis

    PubMed Central

    Hooper, Troy L; Denton, Jeff; McGalliard, Michael K; Brismée, Jean-Michel; Sizer, Phillip S

    2010-01-01

    Thoracic outlet syndrome (TOS) is a frequently overlooked peripheral nerve compression or tension event that creates difficulties for the clinician regarding diagnosis and management. Investigators have categorized this condition as vascular versus neurogenic, where vascular TOS can be subcategorized as either arterial or venous and neurogenic TOS can subcategorized as either true or disputed. The thoracic outlet anatomical container presents with several key regional components, each capable of compromising the neurovascular structures coursing within. Bony and soft tissue abnormalities, along with mechanical dysfunctions, may contribute to neurovascular compromise. Diagnosing TOS can be challenging because the symptoms vary greatly amongst patients with the disorder, thus lending to other conditions including a double crush syndrome. A careful history and thorough clinical examination are the most important components in establishing the diagnosis of TOS. Specific clinical tests, whose accuracy has been documented, can be used to support a clinical diagnosis, especially when a cluster of positive tests are witnessed. PMID:21655389

  14. Diagnosis and Clinical Genetics of Cushing Syndrome in Pediatrics.

    PubMed

    Stratakis, Constantine A

    2016-06-01

    Endogenous Cushing syndrome (CS) in pediatrics is rare; it may be caused by tumors that produce corticotropin in the pituitary gland or elsewhere, tumors that produce corticotropin-releasing hormone anywhere, and adrenocortical masses that produce cortisol. Adrenocortical cancer is a rare cause of CS in children but should be excluded first. CS in children is often caused by germline or somatic mutations with implications for patient prognosis and for their families. CS should be recognized early in children; otherwise, it can lead to significant morbidity and mortality. Patients with suspected CS should be referred to specialized clinical centers for workup. PMID:27241967

  15. Clinical guides for atypical hemolytic uremic syndrome in Japan.

    PubMed

    Kato, Hideki; Nangaku, Masaomi; Hataya, Hiroshi; Sawai, Toshihiro; Ashida, Akira; Fujimaru, Rika; Hidaka, Yoshihiko; Kaname, Shinya; Maruyama, Shoichi; Yasuda, Takashi; Yoshida, Yoko; Ito, Shuichi; Hattori, Motoshi; Miyakawa, Yoshitaka; Fujimura, Yoshihiro; Okada, Hirokazu; Kagami, Shoji

    2016-07-01

    Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In 2013, we developed diagnostic criteria to enable early diagnosis and timely initiation of appropriate treatment for aHUS. Recent clinical and molecular findings have resulted in several proposed classifications and definitions of thrombotic microangiopathy and aHUS. Based on recent advances in this field and the emerging international consensus to exclude secondary TMAs from the definition of aHUS, we have redefined aHUS and proposed diagnostic algorithms, differential diagnosis, and therapeutic strategies for aHUS. PMID:27460397

  16. Clinical guides for atypical hemolytic uremic syndrome in Japan.

    PubMed

    Kato, Hideki; Nangaku, Masaomi; Hataya, Hiroshi; Sawai, Toshihiro; Ashida, Akira; Fujimaru, Rika; Hidaka, Yoshihiko; Kaname, Shinya; Maruyama, Shoichi; Yasuda, Takashi; Yoshida, Yoko; Ito, Shuichi; Hattori, Motoshi; Miyakawa, Yoshitaka; Fujimura, Yoshihiro; Okada, Hirokazu; Kagami, Shoji

    2016-08-01

    Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In 2013, we developed diagnostic criteria to enable early diagnosis and timely initiation of appropriate treatment for aHUS. Recent clinical and molecular findings have resulted in several proposed classifications and definitions of thrombotic microangiopathy and aHUS. Based on recent advances in this field and the emerging international consensus to exclude secondary TMAs from the definition of aHUS, we have redefined aHUS and proposed diagnostic algorithms, differential diagnosis, and therapeutic strategies for aHUS. PMID:27422619

  17. Cytokines profile and peripheral blood mononuclear cells morphology in Rett and autistic patients.

    PubMed

    Pecorelli, Alessandra; Cervellati, Franco; Belmonte, Giuseppe; Montagner, Giulia; Waldon, PhiAnh; Hayek, Joussef; Gambari, Roberto; Valacchi, Giuseppe

    2016-01-01

    A potential role for immune dysfunction in autism spectrum disorders (ASD) has been well established. However, immunological features of Rett syndrome (RTT), a genetic neurodevelopmental disorder closely related to autism, have not been well addressed yet. By using multiplex Luminex technology, a panel of 27 cytokines and chemokines was evaluated in serum from 10 RTT patients with confirmed diagnosis of MECP2 mutation (typical RTT), 12 children affected by classic autistic disorder and 8 control subjects. The cytokine/chemokine gene expression was assessed by real time PCR on mRNA of isolated peripheral blood mononuclear cells (PBMCs). Moreover, ultrastructural analysis of PBMCs was performed using transmission electron microscopy (TEM). Significantly higher serum levels of interleukin-8 (IL-8), IL-9, IL-13 were detected in RTT compared to control subjects, and IL-15 shows a trend toward the upregulation in RTT. In addition, IL-1β and VEGF were the only down-regulated cytokines in autistic patients with respect to RTT. No difference in cytokine/chemokine profile between autistic and control groups was detected. These data were also confirmed by ELISA real time PCR. At the ultrastructural level, the most severe morphological abnormalities were observed in mitochondria of both RTT and autistic PBMCs. In conclusion, our study shows a deregulated cytokine/chemokine profile together with morphologically altered immune cells in RTT. Such abnormalities were not quite as evident in autistic subjects. These findings indicate a possible role of immune dysfunction in RTT making the clinical features of this pathology related also to the immunology aspects, suggesting, therefore, novel possible therapeutic interventions for this disorder.

  18. Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline

    PubMed Central

    Nieman, Lynnette K.; Biller, Beverly M. K.; Findling, James W.; Murad, M. Hassan; Newell-Price, John; Savage, Martin O.; Tabarin, Antoine

    2015-01-01

    Objective: The objective is to formulate clinical practice guidelines for treating Cushing's syndrome. Participants: Participants include an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. The European Society for Endocrinology co-sponsored the guideline. Evidence: The Task Force used the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: The Task Force achieved consensus through one group meeting, several conference calls, and numerous e-mail communications. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Conclusions: Treatment of Cushing's syndrome is essential to reduce mortality and associated comorbidities. Effective treatment includes the normalization of cortisol levels or action. It also includes the normalization of comorbidities via directly treating the cause of Cushing's syndrome and by adjunctive treatments (eg, antihypertensives). Surgical resection of the causal lesion(s) is generally the first-line approach. The choice of second-line treatments, including medication, bilateral adrenalectomy, and radiation therapy (for corticotrope tumors), must be individualized to each patient. PMID:26222757

  19. Severe congenital thrombocytopaenia – first clinical manifestation of Noonan syndrome

    PubMed Central

    Nunes, Paula; Aguilar, Sara; Prado, Sara Noéme; Palaré, Maria João; Ferrão, Anabela; Morais, Anabela

    2012-01-01

    This report focuses on a male infant, the first born of non-consanguineous parents diagnosed with polyhydramnios at 26 weeks of gestation. The newborn was admitted during the neonatal period with bleeding diathesis associated with a low platelet count at birth (5×109/l).The authors registered a persistent low platelet count (9000–129 000/l) during the infants 1st year of life. Physical examination revealed a petechial rash, a dysmorphic face and bilateral cryptorchidism, in the absence of organomegaly. Additionally, cardiologic evaluation revealed an aortic valve dysplasia and an atrial septal defect, while bone marrow biopsy and aspiration were found normal. Throughout the investigation, the authors excluded congenital infection, alloimmune and familiar thrombocytopaenia, Fanconi anaemia and thrombocytopaenia absent radius syndrome. The cytogenetic analysis revealed a mutation in the PTPN11 gene associated with Noonan syndrome. Here the author highlights that severe neonatal thrombocytopaenia is a manifestation that should be considered in the diagnosis and clinical management of Noonan’s syndrome. PMID:22605701

  20. [Constitutional syndrome: clinical entity or a mixed bag].

    PubMed

    Suárez-Ortega, Saturnino; Puente-Fernández, Alicia; Santana-Baez, Sergio; Godoy-Díaz, Davinia; Serrano-Fuentes, Miriam; Sanz-Peláez, Oscar

    2013-01-01

    Fatigue, anorexia and involuntary weight loss have been included under the term constitutional syndrome. These manifestations accompany many diseases in which the diagnosis is made by specific symptoms and signs. However, these events are generally the main reason for consultation and the patient does not report other specific data. This forces us to rigorously investigate the possible causes of the disorder. Usually, three manifestations coexist: asthenia, anorexia and weight loss, but sometimes the patient has only one or two of them. The causes of constitutional symptoms are varied and can be divided into three groups: psychiatric diseases, neoplasms and non-neoplastic diseases. The etiological identification is usually done with a simple protocol, which rules out malignancy; the rest of the cases of uncertain etiology are subject to evolution. The constitutional syndrome correlates well with good prognosis or medical functional processes. Although no clinical guidelines have been developed, score scales may help for the etiological assessment. Given the myriad of different causes of the constitutional syndrome, the treatment of this illness depends primarily on the etiology.

  1. Clinical and genetic characteristics for the Urofacial Syndrome (UFS)

    PubMed Central

    Tu, Yaqin; Yang, Ping; Yang, Jia; Xu, Yuchen; Xiong, Fei; Yu, Qilin; Gu, Weikuan; Pond, Dinel; Mendelsohn, Nancy; Lachmeijer, Guus AMA; Zhang, Shu; Wang, Cong-Yi

    2014-01-01

    The Urofacial (Ochoa) Syndrome (UFS) is a rare autosomal recessive disorder and over 100 patients have been reported thus far. UFS is characterized by the abnormal facial expression and dysfunctional voiding. The patients show a peculiar distortion of the facial expression (grimacing as if in pain or sadness when they tried to smile or laugh) along with urinary tract infection, enuresis, vesicoureteral reflux and hydronephrosis without any underlying neurological lesion and previous urinary obstruction. Some patients are also noted with nocturnal lagophthalmos. Until 2010, HPSE2, the gene encodes Heparanse 2 on chromosome 10, was thought to be the only culprit gene for this syndrome. However, another criminal gene, LRIG2, which encodes leucine-rich repeats and immunoglobulin-like domains 2, was also come into the light in 2012. Studies for dissecting the biological functions of HPSE2 and LRIG2 in urinary abnormalities are ongoing. In this minireview, we will update the discovery of novel clinical manifestations relevant to this syndrome and discuss with focus for the impact of HPSE2 on voiding dysfunction. PMID:24966895

  2. Moyamoya disease and syndromes: from genetics to clinical management.

    PubMed

    Guey, Stéphanie; Tournier-Lasserve, Elisabeth; Hervé, Dominique; Kossorotoff, Manoelle

    2015-01-01

    Moyamoya angiopathy is characterized by a progressive stenosis of the terminal portion of the internal carotid arteries and the development of a network of abnormal collateral vessels. This chronic cerebral angiopathy is observed in children and adults. It mainly leads to brain ischemic events in children, and to ischemic and hemorrhagic events in adults. This is a rare condition, with a marked prevalence gradient between Asian countries and Western countries. Two main nosological entities are identified. On the one hand, moyamoya disease corresponds to isolated moyamoya angiopathy, defined as being "idiopathic" according to the Guidelines of the Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis. This entity is probably multifactorial and polygenic in most patients. On the other hand, moyamoya syndrome is a moyamoya angiopathy associated with an underlying condition and forms a very heterogeneous group with various clinical presentations, various modes of inheritance, and a variable penetrance of the cerebrovascular phenotype. Diagnostic and evaluation techniques rely on magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) conventional angiography, and cerebral hemodynamics measurements. Revascularization surgery can be indicated, with several techniques. Characteristics of genetic moyamoya syndromes are presented, with a focus on recently reported mutations in BRCC3/MTCP1 and GUCY1A3 genes. Identification of the genes involved in moyamoya disease and several monogenic moyamoya syndromes unraveled different pathways involved in the development of this angiopathy. Studying genes and pathways involved in monogenic moyamoya syndromes may help to give insights into pathophysiological models and discover potential candidates for medical treatment strategies. PMID:25733922

  3. Moyamoya disease and syndromes: from genetics to clinical management

    PubMed Central

    Guey, Stéphanie; Tournier-Lasserve, Elisabeth; Hervé, Dominique; Kossorotoff, Manoelle

    2015-01-01

    Moyamoya angiopathy is characterized by a progressive stenosis of the terminal portion of the internal carotid arteries and the development of a network of abnormal collateral vessels. This chronic cerebral angiopathy is observed in children and adults. It mainly leads to brain ischemic events in children, and to ischemic and hemorrhagic events in adults. This is a rare condition, with a marked prevalence gradient between Asian countries and Western countries. Two main nosological entities are identified. On the one hand, moyamoya disease corresponds to isolated moyamoya angiopathy, defined as being “idiopathic” according to the Guidelines of the Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis. This entity is probably multifactorial and polygenic in most patients. On the other hand, moyamoya syndrome is a moyamoya angiopathy associated with an underlying condition and forms a very heterogeneous group with various clinical presentations, various modes of inheritance, and a variable penetrance of the cerebrovascular phenotype. Diagnostic and evaluation techniques rely on magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) conventional angiography, and cerebral hemodynamics measurements. Revascularization surgery can be indicated, with several techniques. Characteristics of genetic moyamoya syndromes are presented, with a focus on recently reported mutations in BRCC3/MTCP1 and GUCY1A3 genes. Identification of the genes involved in moyamoya disease and several monogenic moyamoya syndromes unraveled different pathways involved in the development of this angiopathy. Studying genes and pathways involved in monogenic moyamoya syndromes may help to give insights into pathophysiological models and discover potential candidates for medical treatment strategies. PMID:25733922

  4. Compartment syndrome after total knee arthroplasty: regarding a clinical case.

    PubMed

    Pinheiro, Ana Alexandra da Costa; Marques, Pedro Miguel Dantas Costa; Sá, Pedro Miguel Gomes; Oliveira, Carolina Fernandes; da Silva, Bruno Pombo Ferreira; de Sousa, Cristina Maria Varino

    2015-01-01

    Although compartment syndrome is a rare complication of total knee arthroplasty, it is one of the most devastating complications. It is defined as a situation of increased pressure within a closed osteofascial space that impairs the circulation and the functioning of the tissues inside this space, thereby leading to ischemia and tissue dysfunction. Here, a clinical case of a patient who was followed up in orthopedic outpatient consultations due to right gonarthrosis is presented. The patient had a history of arthroscopic meniscectomy and presented knee flexion of 10° before the operation, which consisted of total arthroplasty of the right knee. The operation seemed to be free from intercurrences, but the patient evolved with compartment syndrome of the ipsilateral leg after the operation. Since compartment syndrome is a true surgical emergency, early recognition and treatment of this condition through fasciotomy is crucial in order to avoid amputation, limb dysfunction, kidney failure and death. However, it may be difficult to make the diagnosis and cases may not be recognized if the cause of compartment syndrome is unusual or if the patient is under epidural analgesia and/or peripheral nerve block, which thus camouflages the main warning sign, i.e. disproportional pain. In addition, edema of the limb that underwent the intervention is common after total knee arthroplasty operations. This study presents a review of the literature and signals that the possible rarity of cases is probably due to failure to recognize this condition in a timely manner and to placing these patients in other diagnostic groups that are less likely, such as neuropraxia caused by using a tourniquet or peripheral nerve injury.

  5. [The Ehlers-Danlos syndrome: hystory of a clinical hendiadys].

    PubMed

    Brazzaventre, Cristina; Celletti, Claudia; Gobattoni, Paolo; Santilli, Valter; Camerota, Filippo

    2013-01-01

    Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility and tissue fragility, which results in easy bruising and abnormal scarring. The condition shows a phenotypic variance from milder to serious presentations. Complaints related to activity (hypermobility, dislocations, impaired balance), to pain (general pain, headache, jaw and tooth pain) and to skin (bruises, fragility, impaired wound healing) are frequent. It was first noted by Hippocrates in 400 BC in his writing 'Airs Water and Places' that the nomads Scythians had lax joints and multiple scars. Whereas the additional flexibility can give benefits in term of mobility and agility, adverse effects of tissue laxity and fragility can give rise to clinical consequences. We recognize that it is important that, in those hypermobility patients, who develop potentially debilitating symptoms of chronicfatigue or widespread pain, there should be prompt an appropriate intervention. PMID:25807780

  6. Refeeding syndrome in children with different clinical aetiology.

    PubMed

    Lenicek Krleza, J; Misak, Z; Jadresin, O; Skaric, I

    2013-08-01

    Refeeding syndrome (RFS) is a well-described state of the series of metabolic and biochemical changes that can occur during the feeding of malnourished persons. The shifts in fluids and electrolytes can lead to complications during artificial feeding, which if not recognised and untreated can lead to death. Although the physiology and pathophysiology of RFS is well known, the circumstances under which the RFS appears, clinical manifestations and management of these patients are less clear. There are few published studies describing the occurrence of RFS in children. We describe two cases of RFS in children. The first case is a boy with unrecognised coeliac disease and second case is a girl with cerebral palsy. In both cases, the RFS has developed without clinical symptoms and it was shown only through laboratory findings. Electrolyte disturbances have been successfully corrected and treatment of the underlying disease continued.

  7. [The Ehlers-Danlos syndrome: hystory of a clinical hendiadys].

    PubMed

    Brazzaventre, Cristina; Celletti, Claudia; Gobattoni, Paolo; Santilli, Valter; Camerota, Filippo

    2013-01-01

    Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility and tissue fragility, which results in easy bruising and abnormal scarring. The condition shows a phenotypic variance from milder to serious presentations. Complaints related to activity (hypermobility, dislocations, impaired balance), to pain (general pain, headache, jaw and tooth pain) and to skin (bruises, fragility, impaired wound healing) are frequent. It was first noted by Hippocrates in 400 BC in his writing 'Airs Water and Places' that the nomads Scythians had lax joints and multiple scars. Whereas the additional flexibility can give benefits in term of mobility and agility, adverse effects of tissue laxity and fragility can give rise to clinical consequences. We recognize that it is important that, in those hypermobility patients, who develop potentially debilitating symptoms of chronicfatigue or widespread pain, there should be prompt an appropriate intervention.

  8. Prevalence and clinical correlates of explosive outbursts in Tourette syndrome.

    PubMed

    Chen, Kevin; Budman, Cathy L; Diego Herrera, Luis; Witkin, Joanna E; Weiss, Nicholas T; Lowe, Thomas L; Freimer, Nelson B; Reus, Victor I; Mathews, Carol A

    2013-02-28

    The aim of this study was to examine the prevalence and clinical correlates of explosive outbursts in two large samples of individuals with Tourette syndrome (TS), including one collected primarily from non-clinical sources. Participants included 218 TS-affected individuals who were part of a genetic study (N=104 from Costa Rica (CR) and N=114 from the US). The relationships between explosive outbursts and comorbid attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), tic severity, and prenatal and perinatal complications were examined using regression analyses. Twenty percent of participants had explosive outbursts, with no significant differences in prevalence between the CR (non-clinical) and the US (primarily clinical) samples. In the overall sample, ADHD, greater tic severity, and lower age of tic onset were strongly associated with explosive outbursts. ADHD, prenatal exposure to tobacco, and male gender were significantly associated with explosive outbursts in the US sample. Lower age of onset and greater severity of tics were significantly associated with explosive outbursts in the CR sample. This study confirms previous studies that suggest that clinically significant explosive outbursts are common in TS and associated with ADHD and tic severity. An additional potential risk factor, prenatal exposure to tobacco, was also identified.

  9. X-linked acrogigantism syndrome: clinical profile and therapeutic responses.

    PubMed

    Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H; Bours, Vincent; Liu, Pengfei; W de Herder, Wouter; Pellegata, Natalia; Lupski, James R; Daly, Adrian F; Stratakis, Constantine A

    2015-06-01

    X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

  10. X-linked acrogigantism syndrome: clinical profile and therapeutic responses.

    PubMed

    Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H; Bours, Vincent; Liu, Pengfei; W de Herder, Wouter; Pellegata, Natalia; Lupski, James R; Daly, Adrian F; Stratakis, Constantine A

    2015-06-01

    X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management. PMID:25712922

  11. Locus Heterogeneity for Waardenburg Syndrome is Predictive of Clinical Subtypes

    PubMed Central

    Farrer, Lindsay A.; Arnos, Kathleen S.; Asher, James H.; Baldwin, Clinton T.; Diehl, Scott R.; Friedman, Thomas B.; Greenberg, Jacquie; Grundfast, Kenneth M.; Hoth, Christopher; Lalwani, Anil K.; Landa, Barbara; Leverton, Kate; Milunsky, Aubrey; Morell, Robert; Nance, Walter E.; Newton, Valerie; Ramesar, Rajkumar; Rao, Valluri S.; Reynolds, Jennifer E.; Agustin, Theresa B. San; Wilcox, Edward R.; Winship, Ingrid; Read, Andrew P.

    1994-01-01

    Waardenburg syndrome (WS) is a dominantly inherited and clinically variable syndrome of deafness, pigmentary changes, and distinctive facial features. Clinically, WS type I (WS1) is differentiated from WS type II (WS2) by the high frequency of dystopia canthorum in the family. In some families, WS is caused by mutations in the PAX3 gene on chromosome 2q. We have typed microsatellite markers within and flanking PAX3 in 41 WS1 kindreds and 26 WS2 kindreds in order to estimate the proportion of families with probable mutations in PAX3 and to study the relationship between phenotypic and genotypic heterogeneity. Evaluation of heterogeneity in location scores obtained by multilocus analysis indicated that WS is linked to PAX3 in 60% of all WS families and in 100% of WS1 families. None of the WS2 families were linked. In those families in which equivocal lod scores (between −2 and +1) were found, PAX3 mutations have been identified in 5 of the 15 WS1 families but in none of the 4 WS2 families. Although preliminary studies do not suggest any association between the phenotype and the molecular pathology in 20 families with known PAX3 mutations and in four patients with chromosomal abnormalities in the vicinity of PAX3, the presence of dystopia in multiple family members is a reliable indicator for identifying families likely to have a defect in PAX3. ImagesFigure 1 PMID:7942851

  12. Clinical and Genetic Aspects of Primary Ciliary Dyskinesia / Kartagener Syndrome

    PubMed Central

    Leigh, Margaret W.; Pittman, Jessica E.; Carson, Johnny L.; Ferkol, Thomas W.; Dell, Sharon D.; Davis, Stephanie D.; Knowles, Michael R.; Zariwala, Maimoona A.

    2013-01-01

    Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder of motile cilia. Most of the disease-causing mutations identified to date involve the heavy (DNAH5) or intermediate (DNAI1) chain dynein genes in ciliary outer dynein arms, although a few mutations have been noted in other genes. Clinical molecular genetic testing for PCD is available for the most common mutations. The respiratory manifestations of PCD (chronic bronchitis leading to bronchiectasis, chronic rhino-sinusitis and chronic otitis media) reflect impaired mucociliary clearance owing to defective axonemal structure. Ciliary ultrastructural analysis in most patients (>80%) reveals defective dynein arms, although defects in other axonemal components have also been observed. Approximately 50% of PCD patients have laterality defects (including situs inversus totalis and, less commonly, heterotaxy and congenital heart disease), reflecting dysfunction of embryological nodal cilia. Male infertility is common and reflects defects in sperm tail axonemes. Most PCD patients have a history of neonatal respiratory distress, suggesting that motile cilia play a role in fluid clearance during the transition from a fetal to neonatal lung. Ciliopathies involving sensory cilia, including autosomal dominant or recessive polycystic kidney disease, Bardet-Biedl syndrome, and Alstrom syndrome, may have chronic respiratory symptoms and even bronchiectasis suggesting clinical overlap with PCD. PMID:19606528

  13. Clinical utility of lenalidomide in the treatment of myelodysplastic syndromes

    PubMed Central

    Abou Zahr, Abdallah; Saad Aldin, Ehab; Komrokji, Rami S; Zeidan, Amer M

    2015-01-01

    Myelodysplastic syndromes (MDS) represent a heterogeneous group of acquired clonal hematopoietic disorders characterized by peripheral blood cytopenias, paradoxical BM hypercellularity, ineffective hematopoiesis, and increased risk of leukemic transformation. Risk stratification, using different prognostic scores and markers, is at the core of MDS management. Deletion 5q [del(5q)] MDS is a distinct class of MDS characterized by the haploinsufficiency of specific genes, microRNAs, and proteins, which has been linked to increased sensitivity to the drug lenalidomide. Phase II and III clinical trials have demonstrated the efficacy of lenalidomide in improving clinical outcomes of patients with del(5q) MDS, including reduction in red blood cell transfusion requirements and improvements in quality of life. Lenalidomide has also demonstrated some activity in non-del(5q) lower-risk MDS as well as higher-risk MDS, especially in combination with other agents. In this paper, we review the pathogenesis of del(5q) MDS, the proposed mechanisms of action of lenalidomide, the major clinical trials that documented the activity of lenalidomide in different MDS populations, potential predictors of benefit from the drug and suggested mechanisms of resistance, and the use of combination strategies to expand the clinical utility of lenalidomide in MDS. PMID:25565910

  14. [Clinical and medicine characteristics of patients with Parkinson's syndrome].

    PubMed

    Liu, Huan; Xie, Yan-Ming; Yi, Dan-Hui; Wang, Yong-Yan

    2014-09-01

    This study analyze the characteristics and clinical medicine in 17 hospitals all over China, based on hospital information system diagnostic information database, including 4 497 cases of hospitalized patients with Parkinson's syndrome. Results indicate, the most common comorbidities are infarction, hypertension, coronary heart disease, diabetes and lung infections, including cerebral infarction, the combined incidence of hypertension in men reached 33.46% and 30.05%, respectively, it is slightly lower in the females. Men with coronary heart disease are more than women, women with diabetes and bone disease are more than men. Combined incidence of the disease increases with age, vascular factors occupy an important position. The most common combined diseases in patients with 90 years of age or older are coronary heart disease, lung infection, and often accompanied by metabolic disorders and nutritional emergency, critical care. Constipation, depression, anxiety, sleep disorders, cognitive impairment are common non-motor symptoms. The drug categories associated with Parkinson's core symptoms treatment are about 20% to 30% of clinical medicine, the others are associated with the treatment of combined disease, clinical medicine and disease spectrum consistent. Blood circulation topped Chinese agents applied frequency, reaching 44.52%; laxative drugs accounted for 11.66%; detoxification agent representing 9.46%. The first twenty Chinese medicine of the applying frequency reached 56.07% of the total utilization, including 12 kinds of traditional Chinese medicine injections, accounting for 60%. Therefore, in the diagnosis and treatment of Parkinsons syndrome, the treatment of comorbidities is very important, more attentions should be paid to vascular factors of the disease, Chinese medicine should be more concerned to improve the non-motor symptoms, give full play to the pharmaceutical multi-target, the overall regulation of advantages, integrative medicine, and improve

  15. [Clinical and endocrinological findings of bitches with ovarian cyst syndrome].

    PubMed

    Bostedt, H; Jung, C; Wehrend, A; Boryzcko, Z

    2013-10-01

    Aim of this study was to record the clinical findings in bitches with ovarian cyst syndrome (OCS) and to interpret them in connection with the endocrine status in peripheral blood and in cyst liquid. For our investigation 16 bitches of different breeds with an average age of 9.7 years were used. They have been presented to the clinic due to different gynecological symptoms. The leading symptom was in 87.5 % of the cases a chronic vaginal secretion. In addition to a detailed anamnesis a clinical examination was performed including vaginalcytologic, sonographic, hematologic and hormonal findings (progesterone P4, 17β estradiol E2). As basic diagnoses could be made: Cycle aberrations (n = 8), pyometra endometritis complex (n = 4), vaginal tumor (n = 4). In addition 3 patients were presented with alopecia. All patients were ovariohysterectomized without prior conservative treatment and the ovaries histologically examined and classified. Based on sonographic findings before and macroscopic evaluation the ovaries after surgery, the OCS could be divided into an oligocystic and polycystic syndrome. There were predominating (94 %) follicle theca cysts. The formation of cysts on the ovary was in the vast majority (66.7 %) combined with corpora lutea. The endometrium showed mainly (50 %) a glandular cystic hyperplasia (CHE) and the hematologic examination revealed in 31.2 % of the patients a combination of advanced erythropenia and thrombocytopenia. Generally there was no direct relationship between increased P4 and E2 values in the pooled cyst fluid and in the peripheral blood when the oestrous phase was considered. Based on present data the diagnosis of OCS of the bitch by means of peripheral P4 and E2 values is not possible. PMID:24091229

  16. Shapiro's syndrome: Defining the clinical spectrum of the spontaneous paroxysmal hypothermia syndrome.

    PubMed

    Tambasco, Nicola; Belcastro, Vincenzo; Prontera, Paolo; Nigro, Pasquale; Donti, Emilio; Rossi, Aroldo; Calabresi, Paolo

    2014-07-01

    Shapiro Syndrome (SS) is a rare condition of spontaneous periodic hypothermia, corpus callosum agenesis (ACC) and hyperhidrosis which can occur at any age. The variant form refers to the phenotypic SS without ACC. We reported the case of SS variant on a 4-year-old boy who presented from his first year frequent episodes of hypothermia lasting 2-3 h with core rectal temperatures <35 °C. In order to understand the characteristics of this rare syndrome we searched all the cases present in literature. Fifty-two cases of SS were found in literature. Among all clinical signs, paroxysmal hypothermia seems to be the hallmark of both typical and variant SS. ACC is reported only in 40% of cases of SS. Hyperhidrosis, another hallmark of SS, was present in only 42.3% of the cases and mainly in adult onset. The presence of SS in siblings of different genders suggests an autosomal recessive inheritance model, however a gonadic mosaicism responsible for an autosomal de novo mutation cannot be ruled out. From our review of well documented cases of SS, we conclude that only the episodic and spontaneous paroxysmal hypothermia should be considered the defining hallmark of typical and variant SS. This can be important to define the clinical manifestation of SS improving the early diagnosis. PMID:24594427

  17. Myelodysplastic syndromes: pathogenesis, functional abnormalities, and clinical implications.

    PubMed Central

    Jacobs, A

    1985-01-01

    The myelodysplastic syndromes represent a preleukaemic state in which a clonal abnormality of haemopoietic stem cell is characterised by a variety of phenotypic manifestations with varying degrees of ineffective haemopoiesis. This state probably develops as a sequence of events in which the earliest stages may be difficult to detect by conventional pathological techniques. The process is characterised by genetic changes leading to abnormal control of cell proliferation and differentiation. Expansion of an abnormal clone may be related to independence from normal growth factors, insensitivity to normal inhibitory factors, suppression of normal clonal growth, or changes in the immunological or nutritional condition of the host. The haematological picture is of peripheral blood cytopenias: a cellular bone marrow, and functional abnormalities of erythroid, myeloid, and megakaryocytic cells. In most cases marrow cells have an abnormal DNA content, often with disturbances of the cell cycle: an abnormal karyotype is common in premalignant clones. Growth abnormalities of erythroid or granulocyte-macrophage progenitors are common in marrow cultures, and lineage specific surface membrane markers indicate aberrations of differentiation. Progression of the disorder may occur through clonal expansion or through clonal evolution with a greater degree of malignancy. Current attempts to influence abnormal growth and differentiation have had only limited success. Clinical recognition of the syndrome depends on an acute awareness of the signs combined with the identification of clonal and functional abnormalities. PMID:2999194

  18. Primitive reflex evaluation in the clinical assessment of extrapyramidal syndromes.

    PubMed

    Borroni, B; Broli, M; Costanzi, C; Gipponi, S; Gilberti, N; Agosti, C; Padovani, A

    2006-09-01

    The aim of the present study was to evaluate the role of primitive reflexes (PRs) as additional alert sign in routine clinical practice in patients with extrapyramidal syndrome. We considered glabellar, snout, palmomental and grasp reflexes in patients with mild stage of Lewy body dementia (LBD), corticobasal degeneration, progressive supranuclear palsy or Parkinson disease (PD). We also enrolled mild Alzheimer disease (AD) patients, and healthy subjects, as controls. LBD patients showed the highest prevalence of PRs compared with the other groups. The odds ratio of the risk of LBD in PRs > or = 2 was 27.9 (95% CI 2.9-269.0) compared with control group, 14.6 (95% CI 2.7-79.6) compared with mild AD, and 19.7 (95% CI 3.7-104.3) compared with PD. These data suggest that the occurrence of combination of PRs might be an useful additional warning sign of possible diffuse Lewy body pathology more than other causes of extrapyramidal syndrome.

  19. Clinical findings in obligate carriers of type I Usher syndrome

    SciTech Connect

    Wagenaar, M.; Rahe, B. ter; Aarem, A. van; Huygen, P.; Admiraal, R.

    1995-11-20

    Seventeen obligate carriers from nine families with autosomal recessive Usher syndrome type I underwent otological, audiological, vestibular, and ophthalmological examination in order to identify possible manifestations of heterozygosity. Linkage studies were performed and six families showed linkage to chromosome region 11q13.5 while 3 families have so far failed to show linkage to the candidate regions. Eight obligate carriers had an abnormal puretone audiogram. Two different audiometric patterns could be distinguished when hearing loss was corrected for age and sex. Four carriers (24%) had significant sensorineural hearing loss (SNHL) which increased at higher frequencies. The other 13 carriers had SNHL of about 10 dB at 0.25 and 0.5 kHz, but less at higher frequencies. Vestibular findings were generally normal. Electrooculography demonstrated a significant lower mean light peak/dark trough ratio in Usher type I carriers compared to normal control individuals. The methods used in this study were found not to be specific enough to clinically identify carriers of Usher type I syndrome. Nevertheless it is remarkable that a number of obligate carriers showed significant audiological and ophthalmological abnormalities. 29 refs., 1 fig., 3 tabs.

  20. Clinical manifestations and oral findings in Fraser syndrome.

    PubMed

    Diniz, Michele Baffi; Lima, Luciana Monti; Sacono, Nancy Tomoko; de Paula, Andréia Bolzan; dos Santos-Pinto, Lourdes

    2007-01-01

    This article is the first known case report of Fraser syndrome in the dental literature. Its purpose was to present the clinical manifestations, oral findings, and dental treatment of a 14-year, 10-month-old female patient. Fraser syndrome is a rare recessive autosomal genetic disorder characterized by multisystemic malformation, usually comprising cryptophthalmos, syndactyly, and renal defects. The child presented with: (1) hydrocephaly; (2) face asymmetry; (3) low-inserted ears; (4) flat nose bridge; (5) cryptophthalmos; (6) bilateral absence of eyeballs; (7) hypertelorism; (8) syndactyly on the left fingers and toes; (9) skeletal defects; and (10) lower limb asymmetry. The intraoral examination revealed: (1) complete primary denture; (2) malocclusion; (3) tooth crowding; (4) ogival palate; (5) normal labial frena; (6) absence of lingual frenum (not compromising the tongue movements); (7) parched lips; (8) supragingival calculus adhered to all tooth surfaces; and (9) moderate gingivitis. The dental treatment consisted of periodic monitoring of the patient's oral health status and supragingival scaling associated with topical applications of 0.12% chlorhexidine digluconate gel at 2-week intervals to reduce gingivitis.

  1. [Clinical practice guideline 'Complex regional pain syndrome type I'].

    PubMed

    Perez, R S G M; Zollinger, P E; Dijkstra, P U; Thomassen-Hilgersom, I L; Zuurmond, W W A; Rosenbrand, C J G M; Geertzen, J H B

    2007-07-28

    The development and treatment ofthe complex regional pain syndrome type I (CRPS-I) are a subject of much discussion. Using the method for the development ofevidence-based guidelines, a multidisciplinary guideline for the diagnosis and treatment of this syndrome has been drawn up. The diagnosis of CRPS-I is based on the clinical observation of signs and symptoms. For pain treatment, the WHO analgesic ladder is advised up to step z. In case of pain ofa neuropathic nature, anticonvulsants and tricyclic antidepressants may be considered. For the treatment ofinflammatory symptoms, free-radical scavengers (dimethylsulphoxide or acetylcysteine) are advised. In order to enhance peripheral blood flow, vasodilatory medication may be considered. Percutaneous sympathetic blockades may be used for a cold extremity ifvasodilatory medication produces insufficient effect. To decrease functional limitations, standardised physiotherapy and occupational therapy are advised. To prevent the occurrence of CRPS-I after wrist fractures, the use of vitamin C is recommended. Adequate perioperative analgesia, limitation of operation time and limited use of bloodlessness are advised for the secondary prevention of CRPS-I. Use of regional anaesthetic techniques can also be considered in this connection.

  2. Cytogenetic evaluation of patients with clinical spectrum of Turner syndrome

    PubMed Central

    Moka, Rajasekhar; Sreelakshmi, Kodandapani; Gopinath, Puthiya Mundyat; Satyamoorthy, Kapettu

    2013-01-01

    AIM: The objective of this study was to correlate the genotype, of female patients, withshort stature and primary amenorrhea. MATERIALS AND METHODS: One hundred and forty-six subjects were recruited during 2005-2012. Microscopic and automated karyotyping analyses were done by using chromosomes isolated from the lymphocytes using Giemsa banding (GTG) to identify chromosome abnormalities. RESULTS: A total of 146 clinically suspected Turner syndrome (TS) subjects were recruited for the study, of which, 61 patients were identified to have chromosome abnormalities. The chromosomal abnormalities detected were as follows: Monosomy X (n = 19, 13.01%), triple X syndrome (n = 4, 2.7%), mosaic TS (n = 12, 8.21%), XY gonadal dysgenesis (n = 13, 8.9%), and structural abnormalities including X chromosome (n = 15, 10.27%) and one patient each with autosomal changes involving 9qh inversion and translocation of chromosomes 12 and 14. CONCLUSION: Karyotype abnormalities accounting for 46% in this study emphasize the need for karyotype testing in cases of short stature with primary amenorrhea. PMID:24082654

  3. Linking Doses with Clinical Scores of Hematopoietic Acute Radiation Syndrome.

    PubMed

    Hu, Shaowen

    2016-10-01

    In radiation accidents, determining the radiation dose the victim received is a key step for medical decision making and patient prognosis. To reconstruct and evaluate the absorbed dose, researchers have developed many physical devices and biological techniques during the last decades. However, using the physical parameter "absorbed dose" alone is not sufficient to predict the clinical development of the various organs injured in an individual patient. In operational situations for radiation accidents, medical responders need more urgently to classify the severity of the radiation injury based on the signs and symptoms of the patient. In this work, the author uses a unified hematopoietic model to describe dose-dependent dynamics of granulocytes, lymphocytes, and platelets, and the corresponding clinical grading of hematopoietic acute radiation syndrome. This approach not only visualizes the time course of the patient's probable outcome in the form of graphs but also indirectly gives information of the remaining stem and progenitor cells, which are responsible for the autologous recovery of the hematopoietic system. Because critical information on the patient's clinical evolution can be provided within a short time after exposure and only peripheral cell counts are required for the simulation, these modeling tools will be useful to assess radiation exposure and injury in human-involved radiation accident/incident scenarios. PMID:27575346

  4. Irritable bowel syndrome: diagnostic approaches in clinical practice

    PubMed Central

    Burbige, Eugene J

    2010-01-01

    Background: Irritable bowel syndrome (IBS), a functional gastrointestinal disorder long considered a diagnosis of exclusion, has chronic symptoms that vary over time and overlap with those of non-IBS disorders. Traditional symptom-based criteria effectively identify IBS patients but are not easily applied in clinical practice, leaving >40% of patients to experience symptoms up to 5 years before diagnosis. Objective: To review the diagnostic evaluation of patients with suspected IBS, strengths and weaknesses of current methodologies, and newer diagnostic tools that can augment current symptom-based criteria. Methods: The peer-reviewed literature (PubMed) was searched for primary reports and reviews using the limiters of date (1999–2009) and English language and the search terms irritable bowel syndrome, diagnosis, gastrointestinal disease, symptom-based criteria, outcome, serology, and fecal markers. Abstracts from Digestive Disease Week 2008–2009 and reference lists of identified articles were reviewed. Results: A disconnect is apparent between practice guidelines and clinical practice. The American Gastroenterological Association and American College of Gastroenterology recommend diagnosing IBS in patients without alarm features of organic disease using symptom-based criteria (eg, Rome). However, physicians report confidence in a symptom-based diagnosis without further testing only up to 42% of the time; many order laboratory tests and perform sigmoidoscopies or colonoscopies despite good evidence showing no utility for this work-up in uncomplicated cases. In the absence of diagnostic criteria easily usable in a busy practice, newer diagnostic methods, such as stool-form examination, fecal inflammatory markers, and serum biomarkers, have been proposed as adjunctive tools to aid in an IBS diagnosis by increasing physicians’ confidence and changing the diagnostic paradigm to one of inclusion rather than exclusion. Conclusion: New adjunctive testing for IBS can

  5. Monogenic Autoinflammatory Syndromes: State of the Art on Genetic, Clinical, and Therapeutic Issues

    PubMed Central

    Costa, Luisa; Atteno, Mariangela; Compagnone, Adele; Caso, Paolo; Frediani, Bruno; Galeazzi, Mauro; Punzi, Leonardo

    2013-01-01

    Monogenic autoinflammatory syndromes (MAISs) are caused by innate immune system dysregulation leading to aberrant inflammasome activation and episodes of fever and involvement of skin, serous membranes, eyes, joints, gastrointestinal tract, and nervous system, predominantly with a childhood onset. To date, there are twelve known MAISs: familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, familial cold urticaria syndrome, Muckle-Wells syndrome, CINCA syndrome, mevalonate kinase deficiency, NLRP12-associated autoinflammatory disorder, Blau syndrome, early-onset sarcoidosis, PAPA syndrome, Majeed syndrome, and deficiency of the interleukin-1 receptor antagonist. Each of these conditions may manifest itself with more or less severe inflammatory symptoms of variable duration and frequency, associated with findings of increased inflammatory parameters in laboratory investigation. The purpose of this paper is to describe the main genetic, clinical, and therapeutic aspects of MAISs and their most recent classification with the ultimate goal of increasing awareness of autoinflammation among various internal medicine specialists. PMID:24282415

  6. Evidence-based clinical practice guidelines for irritable bowel syndrome.

    PubMed

    Fukudo, Shin; Kaneko, Hiroshi; Akiho, Hirotada; Inamori, Masahiko; Endo, Yuka; Okumura, Toshikatsu; Kanazawa, Motoyori; Kamiya, Takeshi; Sato, Ken; Chiba, Toshimi; Furuta, Kenji; Yamato, Shigeru; Arakawa, Tetsuo; Fujiyama, Yoshihide; Azuma, Takeshi; Fujimoto, Kazuma; Mine, Tetsuya; Miura, Soichiro; Kinoshita, Yoshikazu; Sugano, Kentaro; Shimosegawa, Tooru

    2015-01-01

    New strategies for the care of irritable bowel syndrome (IBS) are developing and several novel treatments have been globally produced. New methods of care should be customized geographically because each country has a specific medical system, life style, eating habit, gut microbiota, genes and so on. Several clinical guidelines for IBS have been proposed and the Japanese Society of Gastroenterology (JSGE) subsequently developed evidence-based clinical practice guidelines for IBS. Sixty-two clinical questions (CQs) comprising 1 definition, 6 epidemiology, 6 pathophysiology, 10 diagnosis, 30 treatment, 4 prognosis, and 5 complications were proposed and statements were made to answer to CQs. A diagnosis algorithm and a three-step treatment was provided for patients with chronic abdominal pain or abdominal discomfort and/or abnormal bowel movement. If more than one alarm symptom/sign, risk factor and/or routine examination is positive, colonoscopy is indicated. If all of them, or the subsequent colonoscopy, are/is negative, Rome III or compatible criteria is applied. After IBS diagnosis, step 1 therapy consisting of diet therapy, behavioral modification and gut-targeted pharmacotherapy is indicated for four weeks. Non-responders to step 1 therapy proceed to the second step that includes psychopharmacological agents and simple psychotherapy for four weeks. In the third step, for patients non-responsive to step 2 therapy, a combination of gut-targeted pharmacotherapy, psychopharmacological treatments and/or specific psychotherapy is/are indicated. Clinical guidelines and consensus for IBS treatment in Japan are well suited for Japanese IBS patients; as such, they may provide useful insight for IBS treatment in other countries around the world. PMID:25500976

  7. Clinical and molecular phenotype of Aicardi-Goutieres syndrome.

    PubMed

    Rice, Gillian; Patrick, Teresa; Parmar, Rekha; Taylor, Claire F; Aeby, Alec; Aicardi, Jean; Artuch, Rafael; Montalto, Simon Attard; Bacino, Carlos A; Barroso, Bruno; Baxter, Peter; Benko, Willam S; Bergmann, Carsten; Bertini, Enrico; Biancheri, Roberta; Blair, Edward M; Blau, Nenad; Bonthron, David T; Briggs, Tracy; Brueton, Louise A; Brunner, Han G; Burke, Christopher J; Carr, Ian M; Carvalho, Daniel R; Chandler, Kate E; Christen, Hans-Jurgen; Corry, Peter C; Cowan, Frances M; Cox, Helen; D'Arrigo, Stefano; Dean, John; De Laet, Corinne; De Praeter, Claudine; Dery, Catherine; Ferrie, Colin D; Flintoff, Kim; Frints, Suzanna G M; Garcia-Cazorla, Angels; Gener, Blanca; Goizet, Cyril; Goutieres, Francoise; Green, Andrew J; Guet, Agnes; Hamel, Ben C J; Hayward, Bruce E; Heiberg, Arvid; Hennekam, Raoul C; Husson, Marie; Jackson, Andrew P; Jayatunga, Rasieka; Jiang, Yong-Hui; Kant, Sarina G; Kao, Amy; King, Mary D; Kingston, Helen M; Klepper, Joerg; van der Knaap, Marjo S; Kornberg, Andrew J; Kotzot, Dieter; Kratzer, Wilfried; Lacombe, Didier; Lagae, Lieven; Landrieu, Pierre Georges; Lanzi, Giovanni; Leitch, Andrea; Lim, Ming J; Livingston, John H; Lourenco, Charles M; Lyall, E G Hermione; Lynch, Sally A; Lyons, Michael J; Marom, Daphna; McClure, John P; McWilliam, Robert; Melancon, Serge B; Mewasingh, Leena D; Moutard, Marie-Laure; Nischal, Ken K; Ostergaard, John R; Prendiville, Julie; Rasmussen, Magnhild; Rogers, R Curtis; Roland, Dominique; Rosser, Elisabeth M; Rostasy, Kevin; Roubertie, Agathe; Sanchis, Amparo; Schiffmann, Raphael; Scholl-Burgi, Sabine; Seal, Sunita; Shalev, Stavit A; Corcoles, C Sierra; Sinha, Gyan P; Soler, Doriette; Spiegel, Ronen; Stephenson, John B P; Tacke, Uta; Tan, Tiong Yang; Till, Marianne; Tolmie, John L; Tomlin, Pam; Vagnarelli, Federica; Valente, Enza Maria; Van Coster, Rudy N A; Van der Aa, Nathalie; Vanderver, Adeline; Vles, Johannes S H; Voit, Thomas; Wassmer, Evangeline; Weschke, Bernhard; Whiteford, Margo L; Willemsen, Michel A A; Zankl, Andreas; Zuberi, Sameer M; Orcesi, Simona; Fazzi, Elisa; Lebon, Pierre; Crow, Yanick J

    2007-10-01

    Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

  8. A case of a Tunisian Rett patient with a novel double-mutation of the MECP2 gene.

    PubMed

    Fendri-Kriaa, Nourhene; Hsairi, Ines; Kifagi, Chamseddine; Ellouze, Emna; Mkaouar-Rebai, Emna; Triki, Chahnez; Fakhfakh, Faiza

    2011-06-01

    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. PMID:21575601

  9. Neuroleptic Malignant Syndrome: A Review from a Clinically Oriented Perspective.

    PubMed

    Tse, Lurdes; Barr, Alasdair M; Scarapicchia, Vanessa; Vila-Rodriguez, Fidel

    2015-01-01

    Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening side-effect that can occur in response to treatment with antipsychotic drugs. Symptoms commonly include hyperpyrexia, muscle rigidity, autonomic dysfunction and altered mental status. In the current review we provide an overview on past and current developments in understanding the causes and treatment of NMS. Studies on the epidemiological incidence of NMS are evaluated, and we provide new data from the Canada Vigilance Adverse Reaction Online database to elaborate on drug-specific and antipsychotic drug polypharmacy instances of NMS reported between 1965 and 2012. Established risk factors are summarized with an emphasis on pharmacological and environmental causes. Leading theories about the etiopathology of NMS are discussed, including the potential contribution of the impact of dopamine receptor blockade and musculoskeletal fiber toxicity. A clinical perspective is provided whereby the clinical presentation and phenomenology of NMS is detailed, while the diagnosis of NMS and its differential is expounded. Current therapeutic strategies are outlined and the role for both pharmacological and non-pharmacological treatment strategies in alleviating the symptoms of NMS are discussed.

  10. Neuroleptic Malignant Syndrome: A Review from a Clinically Oriented Perspective

    PubMed Central

    Tse, Lurdes; Barr, Alasdair M.; Scarapicchia, Vanessa; Vila-Rodriguez, Fidel

    2015-01-01

    Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening sideeffect that can occur in response to treatment with antipsychotic drugs. Symptoms commonly include hyperpyrexia, muscle rigidity, autonomic dysfunction and altered mental status. In the current review we provide an overview on past and current developments in understanding the causes and treatment of NMS. Studies on the epidemiological incidence of NMS are evaluated, and we provide new data from the Canada Vigilance Adverse Reaction Online database to elaborate on drug-specific and antipsychotic drug polypharmacy instances of NMS reported between 1965 and 2012. Established risk factors are summarized with an emphasis on pharmacological and environmental causes. Leading theories about the etiopathology of NMS are discussed, including the potential contribution of the impact of dopamine receptor blockade and musculoskeletal fiber toxicity. A clinical perspective is provided whereby the clinical presentation and phenomenology of NMS is detailed, while the diagnosis of NMS and its differential is expounded. Current therapeutic strategies are outlined and the role for both pharmacological and non-pharmacological treatment strategies in alleviating the symptoms of NMS are discussed. PMID:26411967

  11. Irritable bowel syndrome and chronic pelvic pain: A singular or two different clinical syndrome?

    PubMed Central

    Matheis, Anna; Martens, Ute; Kruse, Johannes; Enck, Paul

    2007-01-01

    Irritable bowel syndrome (IBS) and chronic pelvic pain (CPP) are both somatoform disorders with a high prevalence within the population in general. The objective was to compare both entities, to find the differences and the similarities related to epidemiology and psychosocial aspects like stressful life events, physical and sexual abuse, illness behaviour and comorbidity. The technical literature was reviewed systematically from 1971 to 2006 and compared. According to literature, IBS and CPP seem to be one rather than two different entities with the same localisation of pain. Both syndromes also are similar concerning prevalence, the coexistence of mental and somatoform disorders, the common history of sexual and physical abuse in the past and their health care utilization. It could be shown that there were many similarities between IBS and CPP. Nevertheless both are traded as different clinical pictures as far. Therefore it seems to be reasonable and necessary to generate a common diagnosis algorithm and to bring gynaecologists and gastroenterologists into dialogue. PMID:17659691

  12. 3q29 Microdeletion Syndrome: Clinical and Molecular Characterization of a New Syndrome

    PubMed Central

    Willatt, Lionel ; Cox, James ; Barber, John ; Cabanas, Elisabet Dachs ; Collins, Amanda ; Donnai, Dian ; FitzPatrick, David R. ; Maher, Eddy ; Martin, Howard ; Parnau, Josep ; Pindar, Lesley ; Ramsay, Jacqueline ; Shaw-Smith, Charles ; Sistermans, Erik A. ; Tettenborn, Michael ; Trump, Dorothy ; de Vries, Bert B. A. ; Walker, Kate ; Raymond, F. Lucy 

    2005-01-01

    We report the identification of six patients with 3q29 microdeletion syndrome. The clinical phenotype is variable despite an almost identical deletion size. The phenotype includes mild-to-moderate mental retardation, with only slightly dysmorphic facial features that are similar in most patients: a long and narrow face, short philtrum, and high nasal bridge. Autism, gait ataxia, chest-wall deformity, and long and tapering fingers were noted in at least two of six patients. Additional features—including microcephaly, cleft lip and palate, horseshoe kidney and hypospadias, ligamentous laxity, recurrent middle ear infections, and abnormal pigmentation—were observed, but each feature was only found once, in a single patient. The microdeletion is ∼1.5 Mb in length, with molecular boundaries mapping within the same or adjacent bacterial artificial chromosome (BAC) clones at either end of the deletion in all patients. The deletion encompasses 22 genes, including PAK2 and DLG1, which are autosomal homologues of two known X-linked mental retardation genes, PAK3 and DLG3. The presence of two nearly identical low-copy repeat sequences in BAC clones on each side of the deletion breakpoint suggests that nonallelic homologous recombination is the likely mechanism of disease causation in this syndrome. PMID:15918153

  13. 3q29 microdeletion syndrome: clinical and molecular characterization of a new syndrome.

    PubMed

    Willatt, Lionel; Cox, James; Barber, John; Cabanas, Elisabet Dachs; Collins, Amanda; Donnai, Dian; FitzPatrick, David R; Maher, Eddy; Martin, Howard; Parnau, Josep; Pindar, Lesley; Ramsay, Jacqueline; Shaw-Smith, Charles; Sistermans, Erik A; Tettenborn, Michael; Trump, Dorothy; de Vries, Bert B A; Walker, Kate; Raymond, F Lucy

    2005-07-01

    We report the identification of six patients with 3q29 microdeletion syndrome. The clinical phenotype is variable despite an almost identical deletion size. The phenotype includes mild-to-moderate mental retardation, with only slightly dysmorphic facial features that are similar in most patients: a long and narrow face, short philtrum, and high nasal bridge. Autism, gait ataxia, chest-wall deformity, and long and tapering fingers were noted in at least two of six patients. Additional features--including microcephaly, cleft lip and palate, horseshoe kidney and hypospadias, ligamentous laxity, recurrent middle ear infections, and abnormal pigmentation--were observed, but each feature was only found once, in a single patient. The microdeletion is approximately 1.5 Mb in length, with molecular boundaries mapping within the same or adjacent bacterial artificial chromosome (BAC) clones at either end of the deletion in all patients. The deletion encompasses 22 genes, including PAK2 and DLG1, which are autosomal homologues of two known X-linked mental retardation genes, PAK3 and DLG3. The presence of two nearly identical low-copy repeat sequences in BAC clones on each side of the deletion breakpoint suggests that nonallelic homologous recombination is the likely mechanism of disease causation in this syndrome.

  14. Rapp-Hodgkin ectodermal dysplasia syndrome: the clinical and molecular overlap with Hay-Wells syndrome.

    PubMed

    Kannu, Peter; Savarirayan, Ravi; Ozoemena, Linda; White, Susan M; McGrath, John A

    2006-04-15

    We report on the clinical and molecular abnormalities in a 7-month-old girl and her mother with an ectodermal dysplasia disorder that most closely resembles Rapp-Hodgkin syndrome (RHS). At birth, the child had bilateral cleft palate, a narrow pinched nose, small chin, and hypoplastic nipples, and suffered from respiratory distress, feeding difficulties, and poor weight gain, although developmental progress was normal. Her mother had a cleft palate, sparse hair, high forehead, dental anomalies, a narrow nose, dysplastic nails, and reduced sweating. Sequencing of the p63 gene in genomic DNA from both individuals revealed a heterozygous frameshift mutation, 1721delC, in exon 14. This mutation has not been described previously and is the seventh report of a pathogenic p63 gene mutation in RHS. The frameshift results in changes to the tail of p63 with the addition of 90 missense amino acids downstream and a delayed termination codon that extends the protein by 21 amino acids. This mutation is predicted to disrupt the normal repressive function of the transactivation inhibitory domain leading to gain-of-function for at least two isoforms of the p63 transcription factor. The expanding p63 mutation database demonstrates that there is considerable overlap between the molecular pathology of RHS and Hay-Wells syndrome, with identical mutations in some cases, and that these two disorders may in fact be synonymous.

  15. A case of a Tunisian Rett patient with a novel double-mutation of the MECP2 gene

    SciTech Connect

    Fendri-Kriaa, Nourhene; Hsairi, Ines; Kifagi, Chamseddine; Ellouze, Emna; Mkaouar-Rebai, Emna; Triki, Chahnez; Fakhfakh, Faiza

    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.

  16. Clinical Presentation of Klinefelter's Syndrome: Differences According to Age.

    PubMed

    Pacenza, Néstor; Pasqualini, Titania; Gottlieb, Silvia; Knoblovits, Pablo; Costanzo, Pablo R; Stewart Usher, Jorge; Rey, Rodolfo A; Martínez, María P; Aszpis, Sergio

    2012-01-01

    The aim of the study was to establish the characteristics of presentation of 94 patients with Kinelfelter's syndrome (KS) referred to the endocrinologist at different ages. The diagnosis of KS was more frequent in the age group between 11 and 20 years (46.8%). Most of the patients (83.7%) showed the classic 47,XXY karyotype and 7.1% showed a 47,XXY/46,XY mosaicism. Half of the patients younger than 18 years presented mild neurodevelopmental disorders. The most frequent clinical findings were cryptorchidism in prepubertal patients, and small testes, cryptorchidism, and gynecomastia in pubertal patients. FSH, LH, AMH, and inhibin B levels were normal in prepubertal patients and became abnormal from midpuberty. Most adults were referred for small testes, infertility, and gynecomastia; 43.6% had sexual dysfunction. Testosterone levels were low in 45%. Mean stature was above the 50th percentile, and 62.5% had BMI ≥25.0 kg/m(2). In conclusion, the diagnosis of Klinefelter syndrome seems to be made earlier nowadays probably because pediatricians are more aware that boys and adolescents with neuro-developmental disorders and cryptorchidism are at increased risk. The increasing use of prenatal diagnosis has also decreased the mean age at diagnosis and allowed to get insight into the evolution of previously undiagnosed cases, which probably represent the mildest forms. In adults average height and weight are slightly higher than those in the normal population. Bone mineral density is mildly affected, more at the spine than at the femoral neck level, in less than half of cases. PMID:22291701

  17. Clinical Presentation of Klinefelter's Syndrome: Differences According to Age.

    PubMed

    Pacenza, Néstor; Pasqualini, Titania; Gottlieb, Silvia; Knoblovits, Pablo; Costanzo, Pablo R; Stewart Usher, Jorge; Rey, Rodolfo A; Martínez, María P; Aszpis, Sergio

    2012-01-01

    The aim of the study was to establish the characteristics of presentation of 94 patients with Kinelfelter's syndrome (KS) referred to the endocrinologist at different ages. The diagnosis of KS was more frequent in the age group between 11 and 20 years (46.8%). Most of the patients (83.7%) showed the classic 47,XXY karyotype and 7.1% showed a 47,XXY/46,XY mosaicism. Half of the patients younger than 18 years presented mild neurodevelopmental disorders. The most frequent clinical findings were cryptorchidism in prepubertal patients, and small testes, cryptorchidism, and gynecomastia in pubertal patients. FSH, LH, AMH, and inhibin B levels were normal in prepubertal patients and became abnormal from midpuberty. Most adults were referred for small testes, infertility, and gynecomastia; 43.6% had sexual dysfunction. Testosterone levels were low in 45%. Mean stature was above the 50th percentile, and 62.5% had BMI ≥25.0 kg/m(2). In conclusion, the diagnosis of Klinefelter syndrome seems to be made earlier nowadays probably because pediatricians are more aware that boys and adolescents with neuro-developmental disorders and cryptorchidism are at increased risk. The increasing use of prenatal diagnosis has also decreased the mean age at diagnosis and allowed to get insight into the evolution of previously undiagnosed cases, which probably represent the mildest forms. In adults average height and weight are slightly higher than those in the normal population. Bone mineral density is mildly affected, more at the spine than at the femoral neck level, in less than half of cases.

  18. Clinical Presentation of Klinefelter's Syndrome: Differences According to Age

    PubMed Central

    Pacenza, Néstor; Pasqualini, Titania; Gottlieb, Silvia; Knoblovits, Pablo; Costanzo, Pablo R.; Stewart Usher, Jorge; Rey, Rodolfo A.; Martínez, María P.; Aszpis, Sergio

    2012-01-01

    The aim of the study was to establish the characteristics of presentation of 94 patients with Kinelfelter's syndrome (KS) referred to the endocrinologist at different ages. The diagnosis of KS was more frequent in the age group between 11 and 20 years (46.8%). Most of the patients (83.7%) showed the classic 47,XXY karyotype and 7.1% showed a 47,XXY/46,XY mosaicism. Half of the patients younger than 18 years presented mild neurodevelopmental disorders. The most frequent clinical findings were cryptorchidism in prepubertal patients, and small testes, cryptorchidism, and gynecomastia in pubertal patients. FSH, LH, AMH, and inhibin B levels were normal in prepubertal patients and became abnormal from midpuberty. Most adults were referred for small testes, infertility, and gynecomastia; 43.6% had sexual dysfunction. Testosterone levels were low in 45%. Mean stature was above the 50th percentile, and 62.5% had BMI ≥25.0 kg/m2. In conclusion, the diagnosis of Klinefelter syndrome seems to be made earlier nowadays probably because pediatricians are more aware that boys and adolescents with neuro-developmental disorders and cryptorchidism are at increased risk. The increasing use of prenatal diagnosis has also decreased the mean age at diagnosis and allowed to get insight into the evolution of previously undiagnosed cases, which probably represent the mildest forms. In adults average height and weight are slightly higher than those in the normal population. Bone mineral density is mildly affected, more at the spine than at the femoral neck level, in less than half of cases. PMID:22291701

  19. The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis

    PubMed Central

    Muftuoglu, Meltem; Oshima, Junko; von Kobbe, Cayetano; Cheng, Wen-Hsing; Leistritz, Dru F.; Bohr, Vilhelm A.

    2015-01-01

    Werner syndrome (WS) is an adult onset segmental progeroid syndrome caused by mutations in the WRN gene. The WRN gene encodes a 180 kDa nuclear protein that possesses helicase and exonuclease activities. The absence of WRN protein leads to abnormalities in various DNA metabolic pathways such as DNA repair, replication and telomere maintenance. Individuals with WS generally develop normally until the third decade of life, when premature aging phenotypes and a series of age-related disorders begin to manifest. In Japan, where a founder effect has been described, the frequency of Werner heterozygotes appears to be as high as 1/180 in the general population. Due to the relatively non-specific nature of the symptoms and the lack of awareness of the condition, this disease may be under-diagnosed in other parts of the world. Genetic counseling of WS patients follows the path of other autosomal recessive disorders, with special attention needed for cancer surveillance in relatives. Molecular diagnosis of WS is made by nucleotide sequencing and, in some cases, protein analysis. It is also of potential interest to measure WRN activities in WS patients. More than 50 different disease-causing mutations in the WRN gene have been identified in WS patients from all over the world. All but one of these cases has mutations that result in the premature termination of the protein. Here we describe the clinical, molecular and biochemical characteristics of WS for use by medical professionals in a health care setting. Additional information is available through the International Registry of WS (http://www.wernersyndrome.org). PMID:18810497

  20. Prediction of clinical manifestations of transurethral resection syndrome by preoperative ultrasonographic estimation of prostate weight

    PubMed Central

    2014-01-01

    Background This study aimed to investigate the relationship between preoperative estimated prostate weight on ultrasonography and clinical manifestations of transurethral resection (TUR) syndrome. Methods The records of patients who underwent TUR of the prostate under regional anesthesia over a 6-year period were retrospectively reviewed. TUR syndrome is usually defined as a serum sodium level of < 125 mmol/l combined with clinical cardiovascular or neurological manifestations. This study focused on the clinical manifestations only, and recorded specific central nervous system and cardiovascular abnormalities according to the checklist proposed by Hahn. Patients with and without clinical manifestations of TUR syndrome were compared to determine the factors associated with TUR syndrome. Receiver operating characteristic curve analysis was used to determine the optimal cutoff value of estimated prostate weight for the prediction of clinical manifestations of TUR syndrome. Results This study included 167 patients, of which 42 developed clinical manifestations of TUR syndrome. There were significant differences in preoperative estimated prostate weight, operation time, resected prostate weight, intravenous fluid infusion volume, blood transfusion volume, and drainage of the suprapubic irrigation fluid between patients with and without clinical manifestations of TUR syndrome. The preoperative estimated prostate weight was correlated with the resected prostate weight (Spearman’s correlation coefficient, 0.749). Receiver operator characteristic curve analysis showed that the optimal cutoff value of estimated prostate weight for the prediction of clinical manifestations of TUR syndrome was 75 g (sensitivity, 0.70; specificity, 0.69; area under the curve, 0.73). Conclusions Preoperative estimation of prostate weight by ultrasonography can predict the development of clinical manifestations of TUR syndrome. Particular care should be taken when the estimated prostate