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

PubMed

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

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

What are patients with Rett syndrome interested in?

PubMed

Hirano, Daisuke; Taniguchi, Takamichi

2018-02-01

[Purpose] Rett syndrome is a severe neurodevelopmental disease; individuals typically have no verbal skills or purposeful hand movements. In clinical settings, knowledge of their interests would be helpful for therapy. Therefore, we investigated the interests of Rett syndrome patients. [Subjects and Methods] In 2016, we sent a questionnaire regarding the interests of individuals with Rett syndrome to 1,016 directors of schools for special needs education and 204 directors of rehabilitation departments (130 facilities for persons with severe motor and intellectual disabilities, 73 wards for patients with severe motor and intellectual disabilities, and the National Hospital Organization and National Center Hospital, and the National Center of Neurology and Psychiatry) in Japan. We used descriptive statistics and content analysis to examine the answers to the questionnaires. [Results] Information was acquired from 216 individuals (3-53 years old) with Rett syndrome. 92.9% of the individuals were reported to have some interests (e.g., in people, music, things to see, animation, or books). [Conclusion] Individuals with Rett syndrome were observed to be interested in various things despite their having severe motor and intellectual disabilities. These findings suggest that family members and care staff might facilitate various changes or developments of these individuals and discover their hidden strengths by focusing on their interests.

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

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…

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

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.

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

PubMed

Guerrini, Renzo; Parrini, Elena

2012-12-01

Rett syndrome is an X-linked neurodevelopmental disorder that manifests in early childhood with developmental stagnation, and loss of spoken language and hand use, with the development of distinctive hand stereotypies, severe cognitive impairment, and autistic features. About 60% of patients have epilepsy. Seizure onset before the age of 3 years is unlikely, and onset after age 20 is rare. Diagnosis of Rett syndrome is based on key clinical elements that identify "typical" Rett syndrome but also "variant" or "atypical" forms. Diagnostic criteria have been modified only slightly over time, even after discovering that MECP2 gene alterations are present in >90% of patients with typical Rett syndrome but only in 50-70% of atypical cases. Over the last several years, intragenic or genomic alterations of the CDKL5 and FOXG1 genes have been associated with severe cognitive impairment, early onset epilepsy and, often, dyskinetic movement disorders, which have variably been defined as Rett variants. It is now clearly emerging that epilepsy has distinctive characteristics in typical Rett syndrome and in the different syndromes caused by CDKL5 and FOXG1 gene alterations. The progressive parting of CDKL5- and FOXG1-gene-related encephalopathies from the core Rett syndrome is reflected by the effort to produce clearer diagnostic criteria for typical and atypical Rett syndrome. Efforts to characterize the molecular pathology underlying these developmental encephalopathies are pointing to abnormalities of telencephalic development, neuronal morphogenesis, maturation and maintenance, and dendritic arborization. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Rett Syndrome

MedlinePlus

... with movement and coordination, and a loss of social interaction and communication. Stage III: plateau. The third stage usually begins between the ages of 2 and 10 years and can last for many years. ... social functioning Shortened life span — people with Rett syndrome ...

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…

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. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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.…

Speech and motor disturbances in Rett syndrome.

PubMed

Bashina, V M; Simashkova, N V; Grachev, V V; Gorbachevskaya, N L

2002-01-01

Rett syndrome is a severe, genetically determined disease of early childhood which produces a defined clinical phenotype in girls. The main clinical manifestations include lesions affecting speech functions, involving both expressive and receptive speech, as well as motor functions, producing apraxia of the arms and profound abnormalities of gait in the form of ataxia-apraxia. Most investigators note that patients have variability in the severity of derangement to large motor acts and in the damage to fine hand movements and speech functions. The aims of the present work were to study disturbances of speech and motor functions over 2-5 years in 50 girls aged 12 months to 14 years with Rett syndrome and to analyze the correlations between these disturbances. The results of comparing clinical data and EEG traces supported the stepwise involvement of frontal and parietal-temporal cortical structures in the pathological process. The ability to organize speech and motor activity is affected first, with subsequent development of lesions to gnostic functions, which are in turn followed by derangement of subcortical structures and the cerebellum and later by damage to structures in the spinal cord. A clear correlation was found between the severity of lesions to motor and speech functions and neurophysiological data: the higher the level of preservation of elements of speech and motor functions, the smaller were the contributions of theta activity and the greater the contributions of alpha and beta activities to the EEG. The possible pathogenetic mechanisms underlying the motor and speech disturbances in Rett syndrome are discussed.

CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms

PubMed Central

Scala, E; Ariani, F; Mari, F; Caselli, R; Pescucci, C; Longo, I; Meloni, I; Giachino, D; Bruttini, M; Hayek, G; Zappella, M; Renieri, A

2005-01-01

Background: Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterised by a wide spectrum of clinical manifestations. Both the classic form and preserved speech variant of Rett syndrome are due to mutations in the MECP2 gene. Several other variants of Rett syndrome have been described. In 1985, Hanefeld described a variant with the early appearance of convulsions. In this variant, the normal perinatal period is soon followed by the appearance of seizures, usually infantile spasms. We have observed two patients with signs of Rett syndrome showing acquired microcephaly and stereotypic midline hand movements. The disease started with generalised convulsions and myoclonic fits at 1.5 months in the first patient and with spasms at 10 days in the other, suggesting a diagnosis of the Hanefeld variant. In these patients, MECP2 point mutations and gross rearrangements were excluded by denaturing high performance liquid chromatography and real time quantitative PCR. The ARX and CDKL5 genes have been associated with West syndrome (infantile spasms, hypsarrhythmia, and mental retardation). Methods: Based on the clinical overlap between the Hanefeld variant and West syndrome, we analysed ARX and CDKL5 in the two girls. Results: We found frameshift deletions in CDKL5 in both patients; one in exon 5 (c.163_166delGAAA) and the other in exon 18 (c.2635_2636delCT). CDKL5 was then analysed in 19 classic Rett and 15 preserved speech variant patients, all MECP2 negative, but no mutations were found. Conclusion: Our results show that CDKL5 is responsible for a rare variant of Rett syndrome characterised by early development of convulsions, usually of the spasm type. PMID:15689447

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. Copyright © 2011 Elsevier Ltd. All rights reserved.

Brain perfusion abnormalities in Rett syndrome: a qualitative and quantitative SPET study with 99Tc(m)-ECD.

PubMed

Burroni, L; Aucone, A M; Volterrani, D; Hayek, Y; Bertelli, P; Vella, A; Zappella, M; Vattimo, A

1997-06-01

Rett syndrome is a progressive neurological paediatric disorder associated with severe mental deficiency, which affects only girls. The aim of this study was to determine if brain blood flow abnormalities detected with 99Tc(m)-ethyl-cysteinate-dimer (99Tc[m]-ECD) single photon emission tomography (SPET) can explain the clinical manifestation and progression of the disease. Qualitative and quantitative global and regional brain blood flow was evaluated in 12 girls with Rett syndrome and compared with an aged-matched reference group of children. In comparison with the reference group, SPET revealed a considerable global reduction in cerebral perfusion in the groups of girls with Rett syndrome. A large statistical difference was noted, which was more evident when comparing the control group with girls with stage IV Rett syndrome than girls with stage III Rett syndrome. The reduction in cerebral perfusion reflects functional disturbance in the brain of children with Rett syndrome. These data confirm that 99Tc(m)-ECD brain SPET is sensitive in detecting hypoperfused areas in girls with Rett syndrome that may be associated with brain atrophy, even when magnetic resonance imaging appears normal.

Reflex seizures in Rett syndrome.

PubMed

Roche Martínez, Ana; Alonso Colmenero, M Itziar; Gomes Pereira, Andreia; Sanmartí Vilaplana, Francesc X; Armstrong Morón, Judith; Pineda Marfa, Mercé

2011-12-01

Reflex seizures are a rare phenomenon among epileptic patients, in which an epileptic discharge is triggered by various kinds of stimuli (visual, auditory, tactile or gustatory). Epilepsy is common in Rett syndrome patients (up to 70%), but to the authors' knowledge, no pressure or eating-triggered seizures have yet been reported in Rett children. We describe three epileptic Rett patients with reflex seizures, triggered by food intake or proprioception. One patient with congenital Rett Sd. developed infantile epileptic spasms at around seven months and two patients with classic Rett Sd. presented with generalised tonic-clonic seizures at around five years. Reflex seizures appeared when the patients were teenagers. The congenital-Rett patient presented eating-triggered seizures at the beginning of almost every meal, demonstrated by EEG recording. Both classic Rett patients showed self-provoked pressure -triggered attacks, influenced by stress or excitement. Non-triggered seizures were controlled with carbamazepine or valproate, but reflex seizures did not respond to antiepileptic drugs. Risperidone partially improved self-provoked seizures. When reflex seizures are suspected, reproducing the trigger during EEG recording is fundamental; however, self-provoked seizures depend largely on the patient's will. Optimal therapy (though not always possible) consists of avoiding the trigger. Stress modifiers such as risperidone may help control self-provoked seizures.

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.

International Rett Syndrome Foundation

MedlinePlus

... of families and professionals. Sign up Join RettSyndrome.org Join our community to receive updates from the ... 2520 International: 1-513-874-3020 admin@rettsyndrome.org EIN 31-1682518 CFC 11046 Newsroom PSA Press ...

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…

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…

Investigating genotype-phenotype relationships in Rett syndrome using an international data set.

PubMed

Bebbington, A; Anderson, A; Ravine, D; Fyfe, S; Pineda, M; de Klerk, N; Ben-Zeev, B; Yatawara, N; Percy, A; Kaufmann, W E; Leonard, H

2008-03-11

Rett syndrome is an uncommon neurodevelopmental disorder with an incidence of 1:9,000 live female births. The principal genetic cause was first reported in 1999 when the association with mutations in the methyl-CpG-binding protein 2 (or MECP2) gene was identified. This study uses data from a large international database, InterRett, to examine genotype-phenotype relationships and compares these with previous findings in a population-based cohort. The data set for these analyses was derived from a subset of InterRett cases with subject information collected from the family, the clinician, or both. Individual phenotypic characteristics and clinical severity using three scales were compared among those with eight known recurrent pathogenic MECP2 mutations as well as those with C-terminal deletions (n = 272). Overall, p.R270X and p.R255X were the most severe and p.R133C and p.R294X were the mildest mutations. Significant differences by mutation were seen for individual phenotypic characteristics such as hand use, ambulation, and language. This multicenter investigation into the phenotypic correlates of MECP2 mutations in Rett syndrome has provided a greater depth of understanding than hitherto available about the specific phenotypic characteristics associated with commonly occurring mutations. Although the modifying influence of X inactivation on clinical severity could not be included in the analysis, the findings confirm clear genotype-phenotype relationships in Rett syndrome and show the benefits of collaboration crucial to effective research in rare disorders.

A perspective on "cure" for Rett syndrome.

PubMed

Clarke, Angus John; Abdala Sheikh, Ana Paula

2018-04-02

The reversal of the Rett syndrome disease process in the Mecp2 mouse model of Guy et al. (2007) has motivated families and researchers to work on this condition. The reversibility in adult mice suggests that there is potentially much to be gained from rational treatments applied to patients of any age. However, it may be difficult to strike the right balance between enthusiasm on the one hand and realism on the other. One effect of this has been a fragmentation of the "Rett syndrome community" with some groups giving priority to work aimed at a cure while fewer resources are devoted to medical or therapy-based interventions to enhance the quality of life of affected patients or provide support for their families.Several possible therapeutic approaches are under development that, it is claimed and hoped, may lead to a "cure" for patients with Rett syndrome. While all have a rationale, there are potential obstacles to each being both safe and effective. Furthermore, any strategy that succeeded in restoring normal levels of MECP2 gene expression throughout the brain carries potential pitfalls, so that it will be of crucial importance to introduce any clinical trials of such therapies with great care.Expectations of families for a radical, rational treatment should not be inflated beyond a cautious optimism. This is particularly because affected patients with us now may not be able to reap the full benefits of a "cure". Thus, interventions aimed at enhancing the quality of life of affected patients should not be forgone and their importance should not be minimised.

Rett syndrome: revised diagnostic criteria and nomenclature.

PubMed

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

2010-12-01

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 to revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials. 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. 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. 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.

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

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…

Using eye-tracking technology for communication in Rett syndrome: perceptions of impact.

PubMed

Vessoyan, Kelli; Steckle, Gill; Easton, Barb; Nichols, Megan; Mok Siu, Victoria; McDougall, Janette

2018-04-27

Studies have investigated the use of eye-tracking technology to assess cognition in individuals with Rett syndrome, but few have looked at this access method for communication for this group. Loss of speech, decreased hand use, and severe motor apraxia significantly impact functional communication for this population. Eye gaze is one modality that may be used successfully by individuals with Rett syndrome. This multiple case study explored whether using eye-tracking technology, with ongoing support from a team of augmentative and alternative communication (AAC) therapists, could help four participants with Rett syndrome meet individualized communication goals. Two secondary objectives were to examine parents' perspectives on (a) the psychosocial impact of their child's use of the technology, and (b) satisfaction with using the technology. All four participants were rated by the treating therapists to have made improvement on their goals. According to both quantitative findings and descriptive information, eye-tracking technology was viewed by parents as contributing to participants' improved psychosocial functioning. Parents reported being highly satisfied with both the device and the clinical services received. This study provides initial evidence that eye-tracking may be perceived as a worthwhile and potentially satisfactory technology to support individuals with Rett syndrome in communicating. Future, more rigorous research that addresses the limitations of a case study design is required to substantiate study findings.

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.

Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome.

PubMed

Mangatt, Meghana; Wong, Kingsley; Anderson, Barbara; Epstein, Amy; Hodgetts, Stuart; Leonard, Helen; Downs, Jenny

2016-04-14

clinical features occurring in the CDKL5 disorder and in Rett syndrome, reinforcing the concept that CDKL5 is an independent disorder with its own distinctive characteristics.

Rett syndrome from bench to bedside: recent advances

PubMed Central

Ehinger, Yann; Matagne, Valerie; Villard, Laurent; Roux, Jean-Christophe

2018-01-01

Rett Syndrome is a severe neurological disorder mainly due to de novo mutations in the methyl-CpG-binding protein 2 gene ( MECP2). Mecp2 is known to play a role in chromatin organization and transcriptional regulation. In this review, we report the latest advances on the molecular function of Mecp2 and the new animal and cellular models developed to better study Rett syndrome. Finally, we present the latest innovative therapeutic approaches, ranging from classical pharmacology to correct symptoms to more innovative approaches intended to cure the pathology. PMID:29636907

An Exploration of the Use of Eye Gaze and Gestures in Females with Rett Syndrome

ERIC Educational Resources Information Center

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

2016-01-01

Purpose: This study investigated the communicative use of eye gaze and gestures in females with Rett syndrome. Method: Data on 151 females with Rett syndrome participating in the Australian Rett Syndrome Database was used in this study. Items from the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist…

Rett syndrome: an overlooked diagnosis in women with stereotypic hand movements, psychomotor retardation, Parkinsonism, and dystonia?

PubMed

Roze, Emmanuel; Cochen, Valérie; Sangla, Sophie; Bienvenu, Thierry; Roubergue, Anne; Leu-Semenescu, Smaranda; Vidaihet, Marie

2007-02-15

Rett syndrome is an X-linked neurodevelopmental disorder resulting in profound psychomotor retardation. It is usually diagnosed by a pediatrician or pediatric neurologist. Adult neurologists may, therefore, overlook the possibility of Rett syndrome in women with psychomotor retardation of unknown etiology. We report the case of a woman diagnosed with Rett syndrome at age 49 years. This report emphasizes the diagnostic value of movement disorders, including hand stereotypies, Parkinsonism, and dystonia, in adults with Rett syndrome.

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

USDA-ARS?s Scientific Manuscript database

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

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. © 2016 Wiley Periodicals, Inc.

Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers.

PubMed

Knudsen, Gun Peggy S; Neilson, Tracey C S; Pedersen, June; Kerr, Alison; Schwartz, Marianne; Hulten, Maj; Bailey, Mark E S; Orstavik, Karen Helene

2006-11-01

Rett syndrome is a largely sporadic, X-linked neurological disorder with a characteristic phenotype, but which exhibits substantial phenotypic variability. This variability has been partly attributed to an effect of X chromosome inactivation (XCI). There have been conflicting reports regarding incidence of skewed X inactivation in Rett syndrome. In rare familial cases of Rett syndrome, favourably skewed X inactivation has been found in phenotypically normal carrier mothers. We have investigated the X inactivation pattern in DNA from blood and buccal cells of sporadic Rett patients (n=96) and their mothers (n=84). The mean degree of skewing in blood was higher in patients (70.7%) than controls (64.9%). Unexpectedly, the mothers of these patients also had a higher mean degree of skewing in blood (70.8%) than controls. In accordance with these findings, the frequency of skewed (XCI > or =80%) X inactivation in blood was also higher in both patients (25%) and mothers (30%) than in controls (11%). To test whether the Rett patients with skewed X inactivation were daughters of skewed mothers, 49 mother-daughter pairs were analysed. Of 14 patients with skewed X inactivation, only three had a mother with skewed X inactivation. Among patients, mildly affected cases were shown to be more skewed than more severely affected cases, and there was a trend towards preferential inactivation of the paternally inherited X chromosome in skewed cases. These findings, particularly the greater degree of X inactivation skewing in Rett syndrome patients, are of potential significance in the analysis of genotype-phenotype correlations in Rett syndrome.

Variant of Rett syndrome and CDKL5 gene: clinical and autonomic description of 10 cases.

PubMed

Pini, Giorgio; Bigoni, Stefania; Engerström, Ingegerd Witt; Calabrese, Olga; Felloni, Beatrice; Scusa, Maria Flora; Di Marco, Pietro; Borelli, Paolo; Bonuccelli, Ubaldo; Julu, Peter O O; Nielsen, Jytte Bieber; Morin, Bodil; Hansen, Stig; Gobbi, Giuseppe; Visconti, Paola; Pintaudi, Maria; Edvige, Veneselli; Romanelli, Anna; Bianchi, Fabrizio; Casarano, Manuela; Battini, Roberta; Cioni, Giovanni; Ariani, Francesca; Renieri, Alessandra; Benincasa, Alberto; Delamont, Robert S; Zappella, Michele

2012-02-01

Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. In recent years more than 60 patients with mutations in the CDKL5 gene have been described in the literature, but the cardiorespiratory phenotype has not been reported. Our aim is to describe clinical and autonomic features of these girls. 10 girls with CDKL5 mutations and a diagnosis of Hanefeld variant have been evaluated on axiological and clinical aspects. In all subjects an evaluation of the autonomic system was performed using the Neuroscope. Common features were gaze avoidance, repetitive head movements and hand stereotypies. The autonomic evaluation disclosed eight cases with the Forceful breather cardiorespiratory phenotype and two cases with the Apneustic breather phenotype. The clinical picture remains within the RTT spectrum but some symptoms are more pronounced in addition to the very early onset of seizures. The cardiorespiratory phenotype was dominated by Forceful breathers, while Feeble breathers were not found, differently from the general Rett population, suggesting a specific behavioral and cardiorespiratory phenotype of the RTT the Hanefeld variant. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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…

Rett'S syndrome : a case report.

PubMed

Gupta, V

2001-01-01

Rett's syndrome is a rare condition affecting only the girl child. It presents as a pervasive developmental disorder with a remarkable behavioural phenotype. The cause for this remains unknown but genetic factors and brain dysfunction have been implicated. This case report emphasises the importance of being aware of rare yet significant disorders of interest to neuro-developmental psychiatrists.

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.

RETT'S SYNDROME : A CASE REPORT

PubMed Central

Gupta, Vinay

2001-01-01

Rett's syndrome is a rare condition affecting only the girl child. It presents as a pervasive developmental disorder with a remarkable behavioural phenotype. The cause for this remains unknown but genetic factors and brain dysfunction have been implicated. This case report emphasises the importance of being aware of rare yet significant disorders of interest to neuro-developmental psychiatrists. PMID:21407847

What Are the Treatments for Rett Syndrome?

MedlinePlus

... NICHD Research Information Find a Study More Information Cerebral Palsy Condition Information NICHD Research Information Find a Study ... www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002503 United Cerebral Palsy. (2009). Can Rett syndrome be treated? Retrieved June ...

Aerophagia and subcutaneous emphysema in a patient with Rett syndrome.

PubMed

Clark, Christine M; Shah-Becker, Shivani; Mathew, Abraham; Goyal, Neerav

2018-03-01

A patient with Rett syndrome presented to our Emergency Department with extensive subcutaneous emphysema in the cervical region, chest wall, upper extremities, and back. Diagnostic evaluation revealed a mucosal tear in the posterior pharyngeal wall and an abscessed retropharyngeal lymph node, but she had no known history of trauma to account for these findings. This report discusses the occurrence of subcutaneous emphysema in the context of a rare neurodevelopmental disorder and proposes accentuated aerophagia, a sequela of Rett syndrome, as the most likely underlying mechanism.

Rett syndrome: EEG presentation.

PubMed

Robertson, R; Langill, L; Wong, P K; Ho, H H

1988-11-01

Rett syndrome, a degenerative neurological disorder of girls, has a classical presentation and typical EEG findings. The electroencephalograms (EEGs) of 7 girls whose records have been followed from the onset of symptoms to the age of 5 or more are presented. These findings are tabulated with the Clinical Staging System of Hagberg and Witt-Engerström (1986). The records show a progressive deterioration in background rhythms in waking and sleep. The abnormalities of the background activity may only become evident at 4-5 years of age or during stage 2--the Rapid Destructive Stage. The marked contrast between waking and sleep background may not occur until stage 3--the Pseudostationary Stage. In essence EEG changes appear to lag behind clinical symptomatology by 1-3 years. An unexpected, but frequent, abnormality was central spikes seen in 5 of 7 girls. They appeared to be age related and could be evoked by tactile stimulation in 2 patients. We hypothesize that the prominent 'hand washing' mannerism may be self-stimulating and related to the appearance of central spike discharges.

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…

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. © 2016 Wiley Periodicals, Inc.

Assessment and management of nutrition and growth in Rett syndrome

PubMed Central

Leonard, Helen; Ravikumara, Madhur; Baikie, Gordon; Naseem, Nusrat; Ellaway, Carolyn; Percy, Alan; Abraham, Suzanne; Geerts, Suzanne; Lane, Jane; Jones, Mary; Bathgate, Katherine; Downs, Jenny

2014-01-01

Objectives We developed recommendations for the clinical management of poor growth and weight gain in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. Methods Initial draft recommendations were created based upon literature review and 34 open-ended questions where the literature was lacking. Statements and questions were made available to an international, multi-disciplinary panel of clinicians in an online format and a Microsoft Word formatted version of the draft via email. Input was sought using a 2-stage modified Delphi process to reach consensus agreement. Items included clinical assessment of growth, anthropometry, feeding difficulties and management to increase caloric intake, decrease feeding difficulties and consideration of gastrostomy. Results Agreement was achieved on 101/112 statements. A comprehensive approach to the management of poor growth in Rett syndrome is recommended that takes into account factors such as feeding difficulties and nutritional needs. A BMI of approximately the 25th centile can be considered as a reasonable target in clinical practice. Gastrostomy is indicated for very poor growth, if there is risk of aspiration and if feeding times are prolonged. Conclusions These evidence- and consensus-based recommendations have the potential to improve care of nutrition and growth in a rare condition and stimulate research to improve the current limited evidence base. PMID:24084372

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…

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)…

Assessment of Caregiver Inventory for Rett Syndrome

ERIC Educational Resources Information Center

Lane, Jane B.; Salter, Amber R.; Jones, Nancy E.; Cutter, Gary; Horrigan, Joseph; Skinner, Steve A.; Kaufmann, Walter E.; Glaze, Daniel G.; Neul, Jeffrey L.; Percy, Alan K.

2017-01-01

Rett syndrome (RTT) requires total caregiver attention and leads to potential difficulties throughout life. The Caregiver Burden Inventory, designed for Alzheimer disease, was modified to a RTT Caregiver Inventory Assessment (RTT CIA). Reliability and face, construct, and concurrent validity were assessed in caregivers of individuals with RTT. Chi…

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

USDA-ARS?s Scientific Manuscript database

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

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

PubMed Central

Lane, J.B.; Lee, H.-S.; Smith, L.W.; Cheng, P.; Glaze, D.G.; Neul, J.L.; Motil, K.J.; Barrish, J.O.; Skinner, S.A.; Annese, F.; McNair, L.; Graham, J.; Khwaja, O.; Barnes, K.; Krischer, J.P.

2011-01-01

Objective: The clinical features and genetics of Rett syndrome (RTT) have been well studied, but examination of quality of life (QOL) is limited. This study describes the impact of clinical severity on QOL among female children and adolescents with classic RTT. Methods: Cross-sectional and longitudinal analyses were conducted on data collected from an NIH-sponsored RTT natural history study. More than 200 participants from 5 to 18 years of age with classic RTT finished their 2-year follow-up at the time of analysis. Regression models after adjustment for their MECP2 mutation type and age at enrollment were used to examine the association between clinical status and QOL. Results: Severe clinical impairment was highly associated with poor physical QOL, but worse motor function and earlier age at onset of RTT stereotypies were associated with better psychosocial QOL; conversely, better motor function was associated with poorer psychosocial QOL. Conclusions: Standard psychosocial QOL assessment for children and adolescents with RTT differs significantly with regard to their motor function severity. As clinical trials in RTT emerge, the Child Health Questionnaire 50 may represent one of the important outcome measures. PMID:22013176

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…

Parental perspectives on the communication abilities of their daughters with Rett syndrome.

PubMed

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

2016-01-01

This study describes, from the perspective of parents, how females with Rett syndrome communicate in everyday life and the barriers and facilitators to successful communication. Sixteen interviews were conducted with parents with a daughter with Rett syndrome with a pathogenic mutation in the methyl-CpG-binding protein 2 gene. Interviews were recorded and transcribed verbatim. Transcripts were analysed using directed content analysis. All parents reported their daughters were able to express discomfort and pleasure, and make requests and choices using a variety of modalities including vocalisations, body movements and eye gaze. Parents also reported their daughters understood most of what they said and that the level of functional abilities, such as mobility, and environmental factors, such as characteristics of the communication partner, influenced successful communication. The perspectives of parents are integral to the assessment of communication abilities and have the potential to inform communication interventions for girls and women with Rett syndrome.

A qualitative investigation of recovery after femoral fracture in Rett syndrome

PubMed Central

Horne, Thomas; Leonard, Helen; Stannage, Katherine; Downs, Jenny

2016-01-01

BACKGROUND Children with severe disability often develop osteoporosis and have an increased risk of fracture. In Rett syndrome, the prevalence of fracture is four times greater than in the general population and the femur is commonly affected. This study used qualitative methods to investigate the regaining of mobility within 12 months following femoral fracture in Rett syndrome and parent caregiver experiences. METHODS Caregivers (n=14) of cases registered with the Australian Rett Syndrome Database with a daughter with Rett syndrome were recruited if their daughter sustained a femoral fracture between 2009 and 2014. Median (IQR) age at fracture was 11 years 4 months (8 years 8 months to 22 years 3 months). Qualitative methods were used to investigate parent/caregiver experiences and their daughter’s recovery following fracture. Themes in the interview data were identified with thematic analysis. RESULTS Operative management was chosen for those walking independently and non-operative management for most of the remaining. All who walked independently and one of the four who required assistance recovered pre-operative walking skills within 6 months. Themes identified by caregivers related to the complexities of pain recognition, the caregiver emotional journey and later rebuilding of relationships with service providers. CONCLUSIONS Those who walked with assistance were vulnerable to loss of this skill. Difficulties in pain recognition increased time to diagnose fracture and the acute episode was associated with heightened caregiver stress. Service providers can use family-centred practice models to support the strengthening of family functioning following this acute event that is surprisingly common in those with severe disability. PMID:27511284

FOXG1 Is Responsible for the Congenital Variant of Rett Syndrome

PubMed Central

Ariani, Francesca; Hayek, Giuseppe; Rondinella, Dalila; Artuso, Rosangela; Mencarelli, Maria Antonietta; Spanhol-Rosseto, Ariele; Pollazzon, Marzia; Buoni, Sabrina; Spiga, Ottavia; Ricciardi, Sara; Meloni, Ilaria; Longo, Ilaria; Mari, Francesca; Broccoli, Vania; Zappella, Michele; Renieri, Alessandra

2008-01-01

Rett syndrome is a severe neurodevelopmental disease caused by mutations in the X-linked gene encoding for the methyl-CpG-binding protein MeCP2. Here, we report the identification of FOXG1-truncating mutations in two patients affected by the congenital variant of Rett syndrome. FOXG1 encodes a brain-specific transcriptional repressor that is essential for early development of the telencephalon. Molecular analysis revealed that Foxg1 might also share common molecular mechanisms with MeCP2 during neuronal development, exhibiting partially overlapping expression domain in postnatal cortex and neuronal subnuclear localization. PMID:18571142

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…

Community participation for girls and women living with Rett syndrome.

PubMed

Andrews, Jaimi; Leonard, Helen; Hammond, Geoffrey C; Girdler, Sonya; Rajapaksa, Ruwani; Bathgate, Katherine; Downs, Jenny

2014-01-01

To describe the relationships between impairment and contextual factors and community participation for girls and women with Rett syndrome. Data was collected from a questionnaire completed in 2009 by families participating in the Australian Rett Syndrome Database (n = 214). Univariate and multivariate logistic regression were used to analyse relationships between impairment, personal and environmental factors and community participation. The mean age of the girls and women was 17.6 years (SD = 7.95, range 3 to 34 years) with 114 (53.3%) girls still at school and 100 (46.7%) women post school. Frequency of activities was influenced by level of walking, community support and maternal education. For girls living at home, participation in activities was associated with greater functional independence and higher levels of maternal education. Participation in recreational (90.1%), physical/skill-based (67.6%) and/or social (70.3%) activities was commonly reported by families, while self-improvement (17.6%) activities were less reported. Younger girls participated in activities mainly with family members and older girls more frequently participated with carers. Participation for girls and women with Rett syndrome could be enhanced by stronger local community supports. There are also needs for the implementation of policies that ensure resources are available and accessible by those communities most in need.

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

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

PubMed

Krajnc, Natalija

2015-01-01

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

[Role of mitochondrial lesion in pathogenesis of sporadic rett syndrome].

PubMed

Meng, H; Pan, H; Qi, Y

2001-06-10

To investigate the role of mitochondrial lesion in children with Rett syndrome (RTT). The platelets from 6 cases with Rett syndrome and 9 normal controls were fused with mitochondrial DNA-lacking rho degrees cell by polyethylene glycol-mediated fusion technique. The oxygen free radical was evaluated by the polarography with substrates of vitamine C and TMPD (N, N, N', N'-tetramethyl-p-phenlene diamine). The rate of apoptosis was determinated by flow cytometry. The apoptosis was observed by electronic microscope and TUNEL method. The t test between groups was adopted in study. In RTT patients, the anticyano-respiration significantly increased by 23% (t = 4.76, P < 0.01). After 6-hour coincubation with 100 micromol/L H(2)O(2), the rate of apoptosis is (3.6 +/- 1.1) % in normal control, and (9.9 +/- 2.7) % in RTT group with significant difference (t = 6.30, P < 0.01), the existence of apoptosis was confirmed by electronic microscope and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end-labeling (TUNEL). After mitochondrial DNA transfer, the oxygen free radical increased in mitochondrial respiratory chain in cybrids of RTT children. RTT cybrid cell lines demonstrated an increased sensitivity to H(2)O(2)-induced apoptotic cell death as compared to control cybrids. The mitochondrial lesion might play a role in the pathogenesis of Rett syndrome.

The Digestive System and Nutritional Considerations for Individuals with Rett Syndrome

PubMed Central

Lotan, Meir; Zysman, Lilit

2006-01-01

Rett syndrome (RS) is a neurodevelopmental syndrome of genetic origin that mainly affects females. Individuals diagnosed with RS exhibit a variety of functional difficulties that impair their quality of life. One of the affected systems is the digestive system, where 74% of persons with RS have abnormal functioning. The affected digestive system causes this population to present an array of problems, such as gastroesophageal reflux (GER), constipation, and malnutrition, leading to failure to thrive (FTT), which resolves in reduced functional ability. Due to the severe effects of the dysfunctional digestive system of individuals with RS, this article will describe the problems common to this population, as well as propose some clinical suggestions for intervention. . PMID:17195872

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…

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

PubMed

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

2013-03-01

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

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

PubMed

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

2016-11-06

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

Respiratory and sleep disorders in female children with atypical Rett syndrome caused by mutations in the CDKL5 gene.

PubMed

Hagebeuk, Eveline E O; van den Bossche, Renilde A S; de Weerd, Al W

2013-05-01

In female children with drug-resistant seizures and developmental delay from birth, atypical Rett syndrome caused by mutations in the CDKL5 gene should be considered. Several clinical features resemble classic Rett syndrome. Respiratory and sleep abnormalities are frequently present in Rett syndrome, whereas little is known in patients with CDKL5 mutations. In four genetically confirmed female patients with CDKL5 mutations (age range 2-15 y), the presence of breathing and sleep abnormalities was evaluated using the validated Sleep Disturbance Scale for Children and polysomnography (PSG). The Sleep Disturbance Scale for Children indicated disorders of initiating and maintaining sleep, daytime somnolence, and sleep breathing disorders. In one patient, PSG showed central apnoeas during sleep: her total apnoea-hypopnoea index (AHI) was 4.9, of which the central AHI was 3.4/h. When awake, central apnoeas were present in two of the four female children (central AHI 28/h and 41/h respectively), all preceded by hyperventilation. PSG showed low rapid eye movement (REM) sleep (9.7-18.3%), frequent awakenings, and low sleep efficiency (range 59-78%). Episodic hyperventilation followed by central apnoeas was present while awake in two of four patients. This may indicate failure of brainstem respiratory centres. In addition, low REM sleep, frequent arousals (not caused by apnoeas/seizures), and low sleep efficiency were present. Similar to Rett syndrome, in patients with CDKL5 mutations PSG seems warranted to evaluate breathing and sleep disturbances. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.

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.

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

PubMed Central

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.

2015-01-01

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. PMID:26321676

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…

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…

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…

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…

Hand stereotypies distinguish Rett syndrome from autism disorder.

PubMed

Goldman, Sylvie; Temudo, Teresa

2012-07-01

Rett syndrome (RTT) and autism disorder (AD) are 2 neurodevelopmental disorders of early life that share phenotypic features, one being hand stereotypies. Distinguishing RTT from AD often represents a challenge, and given their distinct long-term prognoses, this issue may have far-reaching implications. With the advances in genetic testing, the contribution of clinical manifestations in distinguishing RTT from AD has been overlooked. A comparison of hand stereotypies in 20 children with RTT and 20 with AD was performed using detailed analyses of videotaped standardized observations. Striking differences are observed between RTT and AD children. In RTT, hand stereotypies are predominantly complex, continuous, localized to the body midline, and involving mouthing. Conversely, in AD children, hand stereotypies are simple, bilateral, intermittent, and often involving objects. These results provide important clinical signs useful to the differential diagnosis of RTT versus AD, especially when genetic testing for RTT is not an option. Copyright © 2012 Movement Disorder Society.

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…

Updating the profile of C-terminal MECP2 deletions in Rett syndrome

PubMed Central

Bebbington, A; Percy, A; Christodoulou, J; Ravine, D; Ho, G; Jacoby, P; Anderson, A; Pineda, M; Ben Zeev, B; Bahi-Buisson, N; Smeets, E; Leonard, H

2014-01-01

Objectives This study aimed to compare the phenotype of Rett syndrome cases with C-terminal deletions to that of cases with different MECP2 mutations and to examine the phenotypic variation within C-terminal deletions. Methods Cases were selected from InterRett, an international database and from the population-based Australian Rett Syndrome Database. Cases (n=832) were included if they had a pathogenic MECP2 mutation in which the nature of the amino acid change was known. Three severity scale systems were used, and individual aspects of the phenotype were also compared. Results Lower severity was associated with C-terminal deletions (n=79) compared to all other MECP2 mutations (e.g. Pineda scale C-terminals mean 15.0 (95% CI 14.0–16.0) vs 16.2 (15.9–16.5). Cases with C-terminal deletions were more likely to have a normal head circumference (odds ratio 3.22, 95% CI 1.53 – 6.79) and weight (odds ratio 2.97, 95% CI 1.25–5.76). Onset of stereotypies tended to be later (median age 2.5 years vs 2 years, p<0.001 from survival analysis), and age of learning to walk tended to be earlier (median age 1.6 years vs 2 years, p=0.002 from survival analysis). Those with C-terminal deletions occurring later in the region had lower average severity scores than those occurring earlier in the region. Conclusion In terms of overall severity C-terminal deletion cases would appear to be in the middle of the range. In terms of individual aspects of phenotype growth and ability to ambulate appear to be particular strengths. By pooling data internationally this study has achieved the case numbers to provide a phenotypic profile of C-terminal deletions in Rett syndrome. PMID:19914908

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…

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.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 wasmore » 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.« less

[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).

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. Copyright © 2012 Elsevier Inc. All rights reserved.

Rett syndrome in a 47,XXX patient with a de novo MECP2 mutation.

PubMed

Hammer, Sara; Dorrani, Naghmeh; Hartiala, Jaana; Stein, Stuart; Schanen, N Carolyn

2003-10-15

Rett syndrome is caused by mutation in MECP2, a gene located on Xq28 and subject to X-inactivation. MECP2 encodes methyl CpG-binding protein 2, a widely expressed transcriptional repressor of methylated DNA. Mutations in MECP2 are primarily de novo events in the male germ line and thus lead to an excess of affected females. Here we report the identification of a unique 47,XXX girl with relatively mild atypical Rett syndrome leading initially to a diagnosis of infantile autism with regression. Mutation analysis of the MECP2 gene identified a de novo MECP2 mutation, L100V. Examination of a panel of X-linked microsatellite markers indicated that her supernumerary X chromosome is maternally derived. X-inactivation patterns were determined by analysis of methylation of the androgen receptor locus, and indicated preferential inactivation of her paternal allele. The parental origin of her MECP2 mutation could not be determined because she was uninformative for intronic polymorphisms flanking her mutation. This is the first reported case of sex chromosome trisomy and MECP2 mutation in a female, and it illustrates the importance of allele dosage on the severity of Rett syndrome phenotype. Copyright 2003 Wiley-Liss, Inc.

The Rett syndrome in males.

PubMed

Philippart, M

1990-01-01

Two young males in their thirties are reported with a clinical history and examination indistinguishable from typical females with the Rett syndrome. Both had normal early development. The first patient had a regression by the end of the second year. He was late in walking, had prominent hand-wringing from the age of 4 years, and non-progressive dystonia from the age of 14 years. He is still ambulatory. Seizures which started at the age of 18 months have been easily controlled. The second patient has had a severe seizure disorder since the age of 7 months. In his early teens, he lost ambulation and his height and weight fell below the 2nd percentile. He has severe foot dystonia without spasticity. Both patients have a normal head size and no evidence of atrophy on a CT scan of the brain. Both had kyphoscoliosis in their teens. It is difficult to evaluate the incidence of such cases. Little attention being paid to the normal early development, they hide behind vague diagnoses such as cerebral palsy, static encephalopathy, and behavior disorder. Dystonia is often confused with spasticity, the lack of paralysis is not appreciated, apraxia and hand wringing are assumed to be self-stimulatory behaviors.

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…

Expression profiling of clonal lymphocyte cell cultures from Rett syndrome patients

USDA-ARS?s Scientific Manuscript database

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...

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…

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…

Pinpointing brainstem mechanisms responsible for autonomic dysfunction in Rett syndrome: therapeutic perspectives for 5-HT1A agonists

PubMed Central

Abdala, Ana P.; Bissonnette, John M.; Newman-Tancredi, Adrian

2014-01-01

Rett syndrome is a neurological disorder caused by loss of function of methyl-CpG-binding protein 2 (MeCP2). Reduced function of this ubiquitous transcriptional regulator has a devastating effect on the central nervous system. One of the most severe and life-threatening presentations of this syndrome is brainstem dysfunction, which results in autonomic disturbances such as breathing deficits, typified by episodes of breathing cessation intercalated with episodes of hyperventilation or irregular breathing. Defects in numerous neurotransmitter systems have been observed in Rett syndrome both in animal models and patients. Here we dedicate special attention to serotonin due to its role in promoting regular breathing, increasing vagal tone, regulating mood, alleviating Parkinsonian-like symptoms and potential for therapeutic translation. A promising new symptomatic strategy currently focuses on regulation of serotonergic function using highly selective serotonin type 1A (5-HT1A) “biased agonists.” We address this newly emerging therapy for respiratory brainstem dysfunction and challenges for translation with a holistic perspective of Rett syndrome, considering potential mood and motor effects. PMID:24910619

Management of a severe forceful breather with Rett syndrome using carbogen.

PubMed

Smeets, Eric E J; Julu, Peter O O; van Waardenburg, Dick; Engerström, Ingegerd Witt; Hansen, Stig; Apartopoulos, Flora; Curfs, Leopold M G; Schrander-Stumpel, Connie T R M

2006-11-01

We have used a novel neurophysiological technique in the NeuroScope system in combination with conventional electroencephalography (EEG) to monitor both brainstem and cortical activity simultaneously in real-time in a girl with Rett syndrome. The presenting clinical features in our patient were severe sleep disturbances, irregular breathing in the awake state dominated by Valsalva's type of breathing followed by tachypnoea and very frequent attacks of seizures and vacant spells. Our novel neurophysiological data showed that the patient was a Forceful Breather according to the breathing categories in Rett syndrome. She had frequent abnormal spontaneous brainstem activation (ASBA) preceded by severe attacks of hypocapnoea, which was caused by a combination of Valsalva's type of breathing and tachypnoea and all these together were responsible for the seizures and non-epileptic vacant spells. The ASBA was not detectable in conventional EEG and there were no epileptiform changes in the EEG during the seizures and vacant spells caused by the hypocapnic attacks, therefore these were pseudo-seizures. The record of brainstem activity confirmed that these were autonomic events, a kind of "brainstem epilepsy". We successfully treated the sleep disturbance with Pipamperone, a 5-hydroxytryptophan antagonist of receptor type 2 and we prevented the severe hypocapnoea during Valsalva's type of breathing and during tachypnoea using carbogen (a mixture of 5% carbon dioxide and 95% oxygen), which we gave by inhalation. Our treatment drastically reduced the autonomic events, promoted whole night sleep and significantly improved the quality of life in our patient. She can now participate in normal family activity which was previously impossible before treatment.

Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome.

PubMed

O'Leary, Heather M; Kaufmann, Walter E; Barnes, Katherine V; Rakesh, Kshitiz; Kapur, Kush; Tarquinio, Daniel C; Cantwell, Nicole G; Roche, Katherine J; Rose, Suzanne A; Walco, Alexandra C; Bruck, Natalie M; Bazin, Grace A; Holm, Ingrid A; Alexander, Mark E; Swanson, Lindsay C; Baczewski, Lauren M; Mayor Torres, Juan M; Nelson, Charles A; Sahin, Mustafa

2018-03-01

To measure the efficacy of mecasermin (recombinant human insulin-like growth factor 1, rhIGF-1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double-blind crossover study design. Thirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF-1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28-week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory- and electroencephalography (EEG)-based biomarkers were also analyzed. There were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication. As in the phase 1 trial, rhIGF-1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.

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.…

Correction of respiratory disorders in a mouse model of Rett syndrome

PubMed Central

Abdala, Ana P. L.; Dutschmann, Mathias; Bissonnette, John M.; Paton, Julian F. R.

2010-01-01

Rett syndrome (RTT) is an autism spectrum disorder caused by mutations in the X-linked gene that encodes the transcription factor methyl-CpG-binding protein 2 (MeCP2). A major debilitating phenotype in affected females is frequent apneas, and heterozygous Mecp2-deficient female mice mimic the human respiratory disorder. GABA defects have been demonstrated in the brainstem of Mecp2-deficient mice. Here, using an intact respiratory network, we show that apnea in RTT mice is characterized by excessive excitatory activity in expiratory cranial and spinal nerves. Augmenting GABA markedly improves the respiratory phenotype. In addition, a serotonin 1a receptor agonist that depresses expiratory neuron activity also reduces apnea, corrects the irregular breathing pattern, and prolongs survival in MeCP2 null males. Combining a GABA reuptake blocker with a serotonin 1a agonist in heterozygous females completely corrects their respiratory defects. The results indicate that GABA and serotonin 1a receptor activity are candidates for treatment of the respiratory disorders in Rett syndrome. PMID:20921395

An analogue assessment of repetitive hand behaviours in girls and young women with Rett syndrome.

PubMed

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

2004-10-01

Rett syndrome is a neurodevelopmental disorder that almost exclusively affects females. In addition to neurodevelopmental 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 breath holding. The aim of the study was to investigate the extent to which analogue environmental conditions affected the frequency of repetitive hand behaviour in eight girls and young women with Rett syndrome. The frequency of repetitive hand movements was observed every 10 s for four 4-min sessions under the following conditions: Continuous Adult Attention, Adult Demands, Stimulation and No Stimulation. The frequency of repetitive hand movements was high -- they occurred in above 60% of all intervals in all conditions for all participants and at nearly 100% for some participants in some conditions. For one participant the frequency of repetitive hand movements was somewhat reduced in the Stimulation condition; for another it was relatively increased in the No Stimulation condition. Overall, environmental manipulations had relatively limited effects on repetitive hand behaviours. Repetitive hand behaviour in Rett syndrome may be maintained by automatic reinforcement or neurochemical processes and may not be primarily influenced by contingent reinforcement.

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. Copyright © 2012 Elsevier B.V. All rights reserved.

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

USDA-ARS?s Scientific Manuscript database

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...

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…

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

PubMed

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

2014-03-15

Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by the progressive loss of intellectual functioning, fine and gross motor skills and communicative abilities, deceleration of head growth, and the development of stereotypic hand movements, occurring after a period of normal development. The classic form of RTT involves mutation in MECP2 while the involvement of CDKL5 and FOXG1 genes has been identified in atypical RTT phenotype. FOXG1 gene encodes for a fork-head box protein G1, a transcription factor acting primarily as transcriptional repressor through DNA binding in the embryonic telencephalon as well as a number of other neurodevelopmental processes. In this report we have described the molecular analysis of FOXG1 gene in Indian patients with Rett syndrome. FOXG1 gene mutation analysis was done in a cohort of 34 MECP2/CDKL5 mutation negative RTT patients. We have identified a novel mutation (p. D263VfsX190) in FOXG1 gene in a patient with congenital variant of Rett syndrome. This mutation resulted into a frameshift, thereby causing an alteration in the reading frames of the entire coding sequence downstream of the mutation. The start position of the frameshift (Asp263) and amino acid towards the carboxyl terminal end of the protein was found to be well conserved across species using multiple sequence alignment. Since the mutation is located at forkhead binding domain, the resultant mutation disrupts the secondary structure of the protein making it non-functional. This is the first report from India showing mutation in FOXG1 gene in Rett syndrome. Copyright © 2014 Elsevier B.V. All rights reserved.

Epidemiology of Rett syndrome in Serbia: prevalence, incidence and survival.

PubMed

Sarajlija, Adrijan; Kisic-Tepavcevic, Darija; Nikolic, Zorana; Savic Pavicevic, Dusanka; Obradovic, Slobodan; Djuric, Milena; Pekmezovic, Tatjana

2015-01-01

Rett syndrome (RTT) is a severe neurodevelopmental disorder that represents the second most common cause of mental retardation in females. However, incidence and prevalence of RTT are scarcely reported. A retrospective study included all patients with RTT diagnosed between 1981 and 2012 in Serbia. Estimation of incidence and prevalence was calculated on the basis of vital statistics reported by Statistical Office of Republic of Serbia. From 1981 to 2012, RTT has been diagnosed in 102 girls in Serbia. Incidence of RTT in Serbia is estimated at 0.586:10,000 female live births. We estimated the prevalence of RTT in population of females younger than 19 years at 1:8,439. Death occurred in 19 patients (18.63%), with pneumonia as the most common cause. The lethal outcome by the age of 12 years could be expected for 11% of patients. The mean age at diagnosis was 3.5 years and we have confirmed a significant trend towards earlier dianosis during studied period. Rett syndrome incidence in Serbia is in accordance with reports from other countries. Serbian RTT patients have increased risk for early death when compared to patients in more developed countries, most commonly due to pneumonia. There was significant trend towards early diagnosis of RTT in Serbia over recent decades. © 2015 S. Karger AG, Basel.

Identification of novel genetic causes of Rett syndrome-like phenotypes.

PubMed

Lopes, Fátima; Barbosa, Mafalda; Ameur, Adam; Soares, Gabriela; de Sá, Joaquim; Dias, Ana Isabel; Oliveira, Guiomar; Cabral, Pedro; Temudo, Teresa; Calado, Eulália; Cruz, Isabel Fineza; Vieira, José Pedro; Oliveira, Renata; Esteves, Sofia; Sauer, Sascha; Jonasson, Inger; Syvänen, Ann-Christine; Gyllensten, Ulf; Pinto, Dalila; Maciel, Patrícia

2016-03-01

The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT. Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Parent-reported pain in Rett syndrome.

PubMed

Symons, Frank J; Byiers, Breanne; Tervo, Raymond C; Beisang, Arthur

2013-08-01

Clinical reports suggest that patients with Rett syndrome (RTT) live with significant chronic health issues as well as severe motor and communication impairments. Consequently, patients with RTT may be at risk for living with pain but not having it recognized. The purpose of this preliminary study was to document parent reported estimates of pain frequency, pain communication, and pain source. Caregivers of 44 patients with clinically diagnosed RTT (mean RTT age = 21.5, SD = 13.5) completed a health survey about their daughter that contained a number of items specific to pain from the Non-Communicating Children's Pain Checklist - Revised Among survey responders, 24% reported that their child had experienced pain on 8 or more days (> 1 week) in the previous 30 days. The most frequent form of pain communication was facial expression (85%) and vocalization (82%, eg, moan, cry). The most commonly reported pain source was gastro-intestinal (66%). Pain frequency was significantly (P<0.05) correlated with age (0.41), number of pain sources (0.72), and number of health problems (0.45); and the number pain sources was significantly (P<0.05) correlated with number of health problems (0.67). These preliminary results suggest that pain is a problem for a significant subgroup of patients with RTT. Almost one quarter of respondents indicated their daughters experience over a week of pain per month. The frequent health and communication issues associated with RTT suggest an increased risk that pain may be overlooked or discounted in this vulnerable population.

Assessment of Caregiver Inventory for Rett Syndrome

PubMed Central

Lane, Jane B.; Salter, Amber R.; Jones, Nancy E.; Cutter, Gary; Horrigan, Joseph; Skinner, Steve A.; Kaufmann, Walter E.; Glaze, Daniel G.; Neul, Jeffrey L.; Percy, Alan K.

2017-01-01

Rett syndrome (RTT) requires total caregiver attention and leads to potential difficulties throughout life. The Caregiver Burden Inventory, designed for Alzheimer disease, was modified to a RTT Caregiver Inventory Assessment (RTT CIA). Reliability and face, construct, and concurrent validity were assessed in caregivers of individuals with RTT. Chi-square or Fisher’s exact test for categorical variables and t-tests or Wilcoxon two-sample tests for continuous variables were utilized. Survey completed by 198 caregivers; 70 caregivers completed follow-up assessment. Exploratory factor analysis revealed good agreement for Physical Burden, Emotional Burden, and Social Burden. Internal reliability was high (Cronbach’s alpha: 0.898). RTT CIA represents a reliable and valid measure, providing a needed metric of caregiver burden in this disorder. PMID:28132121

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…

Physical and mental health of mothers caring for a child with Rett syndrome.

PubMed

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

2006-10-01

Our goal was to investigate the physical and mental health of mothers who care for a child with Rett syndrome. 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 syndrome completed the SF-12 measure as part of the Australian Rett Syndrome Study in 2002. The analysis investigated linear relationships between physical and mental health scores and maternal, family, and child characteristics. Mothers ranged in age from 21 to 60 years and their children from 3 to 27 years. Nearly half of these mothers (47.4%) indicated that they worked full-time or part-time outside the home, and 41% had a combined family (gross) income of <40,000 Australian dollars. The resultant model for physical health demonstrated that the following factors were positively associated with better maternal physical health: the mother working full-time or part-time outside the home, having some high school education, having private health insurance, the child not having breathing problems in the last 2 years, the child not having home-based structured therapy, and high scores on the Family Resource Scale (indicating adequacy of time resources for basic and family needs). The resultant model for mental health demonstrated that the following factors were positively associated with better maternal mental health: the mother working full-time or part-time outside the home, the child not having a fracture in the last 2 years, lesser reporting of facial stereotypes and involuntary facial movements, being in a well-adjusted marriage, and having low stress scores. Our study suggests that the most important predictors of maternal physical and emotional health are child behavior, caregiver demands, and family function.

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…

Oral findings in Rett syndrome: a systematic review of the dental literature.

PubMed

Fuertes-González, María-Cristina; Silvestre, Francisco-Javier; Almerich-Silla, José-Manuel

2011-01-01

Rett syndrome (RS) is a chromosome X-linked genetic neurological disorder characterized by developmental regression, particularly in relation to expressive language and use of the hands, together with profound mental retardation, that almost exclusively affects females. The present review describes the 35 cases of RS published in the indexed literature (Medline)--the first corresponding to 1985 and the last to the year 2007. Certain oral manifestations of the disease are derived from the drug treatment prescribed to control the disease, while others are common to other clinical conditions characterized by convulsion activity, difficulties for correct oral hygiene, walking problems and/or an excess of oral/digital-manual habits. In any case, bruxism is the oral habit most frequently associated with RS--the treatment of which remains the subject of controversy.

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)

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…

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

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

PubMed

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

2016-01-01

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

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

PubMed Central

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

2016-01-01

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

Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys.

PubMed

Chen, Yongchang; Yu, Juehua; Niu, Yuyu; Qin, Dongdong; Liu, Hailiang; Li, Gang; Hu, Yingzhou; Wang, Jiaojian; Lu, Yi; Kang, Yu; Jiang, Yong; Wu, Kunhua; Li, Siguang; Wei, Jingkuan; He, Jing; Wang, Junbang; Liu, Xiaojing; Luo, Yuping; Si, Chenyang; Bai, Raoxian; Zhang, Kunshan; Liu, Jie; Huang, Shaoyong; Chen, Zhenzhen; Wang, Shuang; Chen, Xiaoying; Bao, Xinhua; Zhang, Qingping; Li, Fuxing; Geng, Rui; Liang, Aibin; Shen, Dinggang; Jiang, Tianzi; Hu, Xintian; Ma, Yuanye; Ji, Weizhi; Sun, Yi Eve

2017-05-18

Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT. Moreover, blood transcriptome profiling revealed that mutant monkeys resembled RTT patients in immune gene dysregulation. Taken together, the stark similarity in phenotype and/or endophenotype between monkeys and patients suggested that gene-edited RTT founder monkeys would be of value for disease mechanistic studies as well as development of potential therapeutic interventions for RTT. Copyright © 2017 Elsevier Inc. All rights reserved.

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. Copyright © 2015 Elsevier Inc. All rights reserved.

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. Copyright © 2014 Elsevier Ltd. All rights reserved.

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…

Rett syndrome diagnostic criteria: lessons from the Natural History Study.

PubMed

Percy, Alan K; Neul, Jeffrey L; Glaze, Daniel G; Motil, Kathleen J; Skinner, Steven A; Khwaja, Omar; Lee, Hye-Seung; Lane, Jane B; Barrish, Judy O; Annese, Fran; McNair, Lauren; Graham, Joy; Barnes, Katherine

2010-12-01

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

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.…

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. Copyright © 2014 Elsevier Ltd. All rights reserved.

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…

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

USDA-ARS?s Scientific Manuscript database

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...

Dysphagia in Rett Syndrome: A Descriptive Study.

PubMed

Mezzedimi, Chiara; Livi, Walter; De Felice, Claudio; Cocca, Serena

2017-09-01

Rett syndrome (RS) is a neurodevelopmental disorder and the second major cause of mental retardation in females. The aim of this study was to evaluate swallowing problems of RS patients by endoscopic assessment and compile a list of suggestions for managing feeding and preventing complications. The sample consisted of 61 female patients (mean age = 13.6 years, range, 2-33 years) admitted to the Department of Neuropsychiatry, where they had previously been diagnosed with RS. Speech evaluation associated with observation during mealtimes was useful to formulate suggestions for caregivers. Progressive deterioration of feeding was commonly noted by caregivers. Fifty-four patients had a history of recurrent episodes of bronchitis. Oral apraxia, dyskinetic tongue movements, prolonged oral stage, and poor bolus formation were the most common findings in all patients. Dysphagia was primarily limited to oral preparatory phases, while the pharyngeal phase was normal in most patients. The high percentage of dysphagia suggests the need to accurately monitor the feeding capability of RS children. It is critical to correctly inform caregivers about safe swallowing procedures to reduce the incidence of fatal complications.

Altered gut microbiota in Rett syndrome.

PubMed

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

2016-07-30

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

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.…

A novel STXBP1 mutation causes typical Rett syndrome in a Japanese girl.

PubMed

Yuge, Kotaro; Iwama, Kazuhiro; Yonee, Chihiro; Matsufuji, Mayumi; Sano, Nozomi; Saikusa, Tomoko; Yae, Yukako; Yamashita, Yushiro; Mizuguchi, Takeshi; Matsumoto, Naomichi; Matsuishi, Toyojiro

2018-06-01

Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in Methyl-CpG-binding protein 2 (MECP2); however, mutations in various other genes may lead to RTT-like phenotypes. Here, we report the first case of a Japanese girl with RTT caused by a novel syntaxin-binding protein 1 (STXBP1) frameshift mutation (c.60delG, p.Lys21Argfs*16). She showed epilepsy at one year of age, regression of acquired psychomotor abilities thereafter, and exhibited stereotypic hand and limb movements at 3 years of age. Her epilepsy onset was earlier than is typical for RTT patients. However, she fully met the 2010 diagnostic criteria of typical RTT. STXBP1 mutations cause early infantile epileptic encephalopathy (EIEE), various intractable epilepsies, and neurodevelopmental disorders. However, the case described here presented a unique clinical presentation of typical RTT without EIEE and a novel STXBP1 mutation. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Adapting the Mullen Scales of Early Learning for a Standardized Measure of Development in Children with Rett Syndrome

ERIC Educational Resources Information Center

Clarkson, Tessa; LeBlanc, Jocelyn; DeGregorio, Geneva; Vogel-Farley, Vanessa; Barnes, Katherine; Kaufmann, Walter E.; Nelson, Charles A.

2017-01-01

Rett Syndrome (RTT) is characterized by severe impairment in fine motor (FM) and expressive language (EL) function, making accurate evaluations of development difficult with standardized assessments. In this study, the administration and scoring of the Mullen Scales of Early Learning (MSEL) were adapted to eliminate the confounding effects of FM…

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. © 2013 Wiley Periodicals, Inc.

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

[Analysis of the parental origin of MECP2 mutations in patients with Rett syndrome].

PubMed

Zhang, Jing-jing; Bao, Xin-hua; Cao, Guang-na; Jiang, Sheng-ling; Zhu, Xing-wang; Lu, Hong-mei; Jia, Li-fang; Pan, Hong; Wu, Xi-ru

2010-04-01

To identify the parental origin of methyl-CpG-binding protein 2 (MECP2) gene mutations in Chinese patients with Rett syndrome. Single nucleotide polymorphisms (SNPs) in intron 3 of the MECP2 gene were analyzed by PCR and sequencing in 115 patients with Rett syndrome. Then sequencing of the SNP region was performed for the fathers of the patients who had at least one SNP, to determine which allele was from the father. Then allele-specific PCR was performed and the products were sequenced to see whether the allele from father or mother harbored the mutation. Seventy-six of the 115 patients had at least one SNP. Three hot SNPs were found in these patients. They were: IVS3+22C >G, IVS3+266C >T and IVS3+683C>T. Among the 76 cases, 73 had a paternal origin of MECP2 mutations, and the other 3 had a maternal origin. There were multiple types of MECP2 mutation of the paternal origin, including 4 frame shift, 2 deletion and 67 point (56C >T, 6C >G, 2A >G, 2G >T and 1A >T) mutations. The mutation types of the 3 patients with maternal origin included 2 frame shift and 1 point (C >T) mutation. In Chinese RTT patients, the MECP2 mutations are mostly of paternal origin.

A novel CDKL5 mutation in a 47,XXY boy with the early-onset seizure variant of Rett syndrome.

PubMed

Sartori, Stefano; Di Rosa, Gabriella; Polli, Roberta; Bettella, Elisa; Tricomi, Giovanni; Tortorella, Gaetano; Murgia, Alessandra

2009-02-01

Mutations of the cyclin-dependent kinase-like 5 gene (CDKL5), reported almost exclusively in female subjects, have been recently found to be the cause of a phenotype overlapping Rett syndrome with early-onset epileptic encephalopathy. We describe the first CDKL5 mutation detected in a male individual with 47,XXY karyotype. This previously unreported, de novo, mutation truncates the large CDKL5 COOH-terminal region, thought to be crucial for the proper sub-cellular localization of the CDKL5 protein. The resulting phenotype is characterized by a severe early-onset epileptic encephalopathy, global developmental delay, and profound intellectual and motor impairment with features reminiscent of Rett syndrome. In light of the data presented we discuss the possible phenotypic modulatory effects of the supernumerary wild type X allele and pattern of X chromosome inactivation and stress the importance of considering the causal involvement of CDKL5 in developmentally delayed males with early-onset seizures. (c) 2009 Wiley-Liss, Inc.

Novel CDKL5 Mutations in Czech Patients with Phenotypes of Atypical Rett Syndrome and Early-Onset Epileptic Encephalopathy.

PubMed

Záhoráková, D; Langová, M; Brožová, K; Laštůvková, J; Kalina, Z; Rennerová, L; Martásek, P

2016-01-01

The X-linked CDKL5 gene, which encodes cyclin-dependent kinase-like 5 protein, has been implicated in early-onset encephalopathy and atypical Rett syndrome with early-onset seizures. The CDKL5 protein is a kinase required for neuronal development and morphogenesis, but its precise functions are still largely unexplored. Individuals with CDKL5 mutations present with severe global developmental delay, intractable epilepsy, and Rett-like features. A clear genotype-phenotype correlation has not been established due to an insufficient number of reported cases. The aim of this study was to analyse the CDKL5 gene in Czech patients with early-onset seizures and Rett-like features. We performed mutation screening in a cohort of 83 individuals using high-resolution melting analysis, DNA sequencing and multiplex ligation- dependent probe amplification. Molecular analyses revealed heterozygous pathogenic mutations in three girls with severe intellectual disability and intractable epilepsy starting at the age of two months. All three identified mutations, c.637G>A, c.902_977+29del105, and c.1757_1758delCT, are novel, thus significantly extending the growing spectrum of known pathogenic CDKL5 sequence variants. Our results support the importance of genetic testing of the CDKL5 gene in patients with early-onset epileptic encephalopathy and Rett-like features with early-onset seizures. This is the first study referring to molecular defects of CDKL5 in Czech cases.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ellison, K.A.; Fill, C.P.; Terwililger, J.

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 themore » 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.« less

Social-emotional instability in individuals with Rett syndrome: parents' experiences with second stage behaviour.

PubMed

Munde, V; Vlaskamp, C; Ter Haar, A

2016-01-01

While the medical profession often terms behaviours in individuals with Rett syndrome (RTT) in the second stage as 'autistic-like', parents disagree with this description. The present study focuses on a comparison of parents' experiences with the social-emotional behaviour of the child with RTT in the second and subsequent stages. In collaboration with the Dutch Rett Syndrome Organization, 51 parents of children with RTT in the Netherlands took part in the present study. Parents completed an online questionnaire to clarify their experiences of the social-emotional behaviour of their children during and after the second stage of RTT. Both quantitative and qualitative analysis techniques have been used. The results of the paired-samples t-test show that parents see significantly less social-emotional behaviour in the children during the second stage of RTT than in the subsequent stages. Parents reported that their children did not seek as much interaction. From the parents' descriptions, it would seem that the children are willing but unable to interact with their environment. Like previous research, our study leads to doubts about the appropriateness of the label 'autistic-like' for the behaviour of individuals in the second stage of RTT. While behaviours of individuals with autism and individuals with RTT may resemble each other, quality and intentions may differ. Still, future studies are needed for further clarification. © 2015 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Distinguishing response to names in Rett and MECP2 Duplication syndrome: An ERP study of auditory social information processing.

PubMed

Peters, Sarika U; Katzenstein, Ashley; Jones, Dorita; Key, Alexandra P

2017-11-15

Despite significant advances at the level of basic research, the characterization of higher-level processes in Rett and MECP2 Duplication syndrome remains understudied. In this pilot study, we assessed social-emotional information processing by testing whether children (ages 4-12years) with Rett (n=9) and MECP2 Duplication syndrome (n=7) distinguished their own spoken name from other names. We hypothesized that own and familiar names would elicit more positive parietal P300 responses than unknown names, and that the groups would have different neural responses to these stimuli. The MECP2 Duplication group partially mirrored the parietal responses to own name observed in typically developing participants, and better name discrimination correlated with more adaptive behaviors. Conversely, participants with RTT did not resemble the typical group, and showed greater responses to close other names at frontal/central regions. These results may reflect the different consequences of too much (MECP2 Duplication) vs. too little (RTT) MeCP2 protein. Copyright © 2017 Elsevier B.V. All rights reserved.

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

PubMed Central

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

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.

The utility of Next Generation Sequencing for molecular diagnostics in Rett syndrome.

PubMed

Vidal, Silvia; Brandi, Núria; Pacheco, Paola; Gerotina, Edgar; Blasco, Laura; Trotta, Jean-Rémi; Derdak, Sophia; Del Mar O'Callaghan, Maria; Garcia-Cazorla, Àngels; Pineda, Mercè; Armstrong, Judith

2017-09-25

Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that almost exclusively affects girls and is totally disabling. Three genes have been identified that cause RTT: MECP2, CDKL5 and FOXG1. However, the etiology of some of RTT patients still remains unknown. Recently, next generation sequencing (NGS) has promoted genetic diagnoses because of the quickness and affordability of the method. To evaluate the usefulness of NGS in genetic diagnosis, we present the genetic study of RTT-like patients using different techniques based on this technology. We studied 1577 patients with RTT-like clinical diagnoses and reviewed patients who were previously studied and thought to have RTT genes by Sanger sequencing. Genetically, 477 of 1577 patients with a RTT-like suspicion have been diagnosed. Positive results were found in 30% by Sanger sequencing, 23% with a custom panel, 24% with a commercial panel and 32% with whole exome sequencing. A genetic study using NGS allows the study of a larger number of genes associated with RTT-like symptoms simultaneously, providing genetic study of a wider group of patients as well as significantly reducing the response time and cost of the study.

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

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

PubMed

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.

First report of an unusual novel double mutation affecting the transcription repression domain of MeCP2 and causing a severe phenotype of Rett syndrome: Molecular analyses and computational investigation.

PubMed

Ghorbel, Rania; Ghorbel, Raouia; Rouissi, Aida; Fendri-Kriaa, Nourhene; Ben Salah, Ghada; Belguith, Neila; Ammar-Keskes, Leila; Gouider-Khouja, Neziha; Fakhfakh, Faiza

2018-02-26

Rett syndrome is an X-linked neurodevelopmental disorder that develops a profound intellectual and motor disability and affects 1 from 10 000 to 15 000 live female births. This disease is characterized by a period of apparently normal development until 6-18 months of age when motor and communication abilities regress which is caused by mutations occurred in the X-linked MECP2 gene, encoding the methyl-CpG binding protein 2. This research study reports a molecular analysis via an exhaustive gene sequencing which reveals an unusual novel double mutation (c.695 G > T; c.880C > T) located in a highly conserved region in MECP2 gene affecting the transcription repression domain (TRD) of MeCP2 protein and leading for the first time to a severe phenotype of Rett syndrome. Moreover, a computational investigation of MECP2 mutations demonstrates that the novel mutation c.695 G > T is highly deleterious which affects the MeCP2 protein showing also an adverse impact on MECP2 gene expression and resulting in an affected folding and decreased stability of MECP2 structures. Thus, the altered TRD domain engenders a disrupted process of MECP2 functions. Therefore, this is the first study which highlights a novel double mutation among the transcription repression domain (TRD) of MeCP2 protein in Rett patient with a severe clinical phenotype in North Africa region. Copyright © 2018 Elsevier Inc. All rights reserved.

Clinical phenotype of 5 females with a CDKL5 mutation.

PubMed

Stalpers, Xenia L; Spruijt, Liesbeth; Yntema, Helger G; Verrips, Aad

2012-01-01

Mutations in the X-linked cyclin dependent kinase like 5 (CDKL5) gene have been reported in approximately 80 patients since the first description in 2003. The clinical presentation partly corresponds with Rett syndrome, considering clinical features as intellectual disability, hypotonia, and poor visual, language, and motor development. However, these patients do not meet the consensus criteria for Rett syndrome since they lack the clear period of regression. Furthermore, in contrast to Rett syndrome, patients with CDKL5 mutations, have seizures or infantile spasms starting in the first weeks of life. We present clinical phenotype of 5 girls having a mutation in the CDKL5 gene. All mutations are novel and are pathogenic since they either lead to a frameshift in the reading frame or affect a consensus splice site. Four of the mutations are detected de novo in the affected girl.

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. Copyright © 2014 Elsevier Ltd. All rights reserved.

A novel CDKL5 mutation in a Japanese patient with atypical Rett syndrome.

PubMed

Christianto, Antonius; Katayama, Syouichi; Kameshita, Isamu; Inazu, Tetsuya

2016-08-01

Rett syndrome (RTT) is a severe X-linked dominant inheritance disorder with a wide spectrum of clinical manifestations. Mutations in Methyl CpG binding protein 2 (MECP2), Cyclin dependent kinase-like 5 (CDKL5) and Forkhead box G1 (FOXG1) have been associated with classic and/or variant RTT. This study was conducted to identify the responsible gene(s) in atypical RTT patient, and to examine the effect of the mutation on protein function. DNA sequence analysis showed a novel heterozygous mutation in CDKL5 identified as c.530A>G which resulted in an amino acid substitution at position 177, from tyrosine to cysteine. Genotyping analysis indicated that the mutation was not merely a single nucleotide polymorphism (SNP). We also revealed that patient's blood lymphocytes had random X-chromosome inactivation (XCI) pattern. Further examination by bioinformatics analysis demonstrated the mutation caused damage or deleterious in its protein. In addition, we demonstrated in vitro kinase assay of mutant protein showed impairment of its activity. Taken together, the results suggested the mutant CDKL5 was responsible for the disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Rett syndrome: update of a 25 year follow-up investigation in Western Sweden--sociomedical aspects.

PubMed

Berg, M; Hagberg, B

2001-12-01

Through 1998-1999 the Swedish research team have systematically mapped 45 of 54 females with Rett syndrome (RS) aged 5-57 years (Berg M. Uppföljning av flickor med Rett syndrom i Västsverige. Socialmedicinsk kartläggning, Stencilerad rapport, Sahlgrenska universitetssjukhuset, Göteborg, 1999; Läkartidningen (Swedish Medical Journal) 96 (1999) 5488). The emphasis is on the RS females' adjustment to grown-up living. At an adult age the large majority moved over to a Swedish type of small group home. We visited these girls in their group homes and got information about their adaptation to this special home situation. We noted their behaviour and contact with the staff and interviewed their parents. The results showed that the young women usually had adjusted well. The adjustment seemed to depend on the degree of planning before the girls moved from their parents to special group homes. These seem to provide a good environment for the RS females, in respect of both physical and social aspects. Although neuropaediatrics in Sweden today has advanced in RS knowledge, the result from this research shows that in Swedish society there is still a great ignorance of RS, even among medical professionals. In particular there is a gap of knowledge when the medical responsibility had to be transferred over to adult medicine. Many of the parents emphasized the great importance of how they were listened to by professionals in public medical and social services. It is essential that professionals always listen to information from parents and personal assistants.

Rett Syndrome: A Focus on Gut Microbiota

PubMed Central

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

2017-01-01

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

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

Trihexyphenidyl for acute life-threatening episodes due to a dystonic movement disorder in Rett syndrome.

PubMed

Gika, Artemis D; Hughes, Elaine; Goyal, Sushma; Sparkes, Matthew; Lin, Jean-Pierre

2010-02-15

In Rett syndrome (RS), acute life-threatening episodes (ALTEs) are usually attributed to epilepsy or autonomic dysfunction but they can represent a movement disorder (MD). We describe three girls with RS who experienced ALTEs from an early age. These were long considered epileptic until video-EEG in Patients 1 and 3 revealed their non-epileptic nature. A primary dystonic mechanism was suspected and Patients 1 and 2 were treated with Trihexyphenidyl with significantly reduced frequency of the ALTEs. Patient 3 died before Trihexyphenidyl was tried. Trihexyphenidyl in RS patients with similar presentations can modify the dystonia and prevent ALTEs. (c) 2009 Movement Disorder Society.

Development of the Tailored Rett Intervention and Assessment Longitudinal (TRIAL) database and the Rett Evaluation of Symptoms and Treatments (REST) Questionnaire.

PubMed

Santosh, Paramala; Lievesley, Kate; Fiori, Federico; Singh, Jatinder

2017-06-21

Rett syndrome (RTT) is a pervasive neurodevelopmental disorder that presents with deficits in brain functioning leading to language and learning regression, characteristic hand stereotypies and developmental delay. Different mutations in the gene implicated in RTT- methyl-CpG-binding protein 2 ( MECP2 ) establishes RTT as a disorder with divergent symptomatology ranging from individuals with severe to milder phenotypes. A reliable and single multidimensional questionnaire is needed that can embrace all symptoms, and the relationships between them, and can map clinically meaningful data to symptomatology across the lifespan in patients with RTT. As part of the HealthTracker-based Tailored Rett Intervention and Assessment Longitudinal (TRIAL) database, the Rett Evaluation of Symptoms and Treatments (REST) Questionnaire will be able to marry with the physiological aspects of the disease obtained using wearable sensor technology, along with genetic and psychosocial data to stratify patients. Taken together, the web-based TRIAL database will empower clinicians and researchers with the confidence to delineate between different aspects of disorder symptomatology to streamline care pathways for individuals or for those patients entering clinical trials. This protocol describes the anticipated development of the REST questionnaire and the TRIAL database which links with the outcomes of the wearable sensor technology, and will serve as a barometer for longitudinal patient monitoring in patients with RTT. The US Food and Drug Administration Guidance for Patient-Reported Outcome Measures will be used as a template to inform the methodology of the study. It will follow an iterative framework that will include item/concept identification, item/concept elicitation in parent/carer-mediated focus groups, expert clinician feedback, web-based presentation of questionnaires, initial scale development, instrument refinement and instrument validation. The study has received favourable

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

PubMed Central

Kunio, Miyake; 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; Akamatsu, Wado; Ohyama, Manabu; Okano, Hideyuki; 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

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.

Improvement in motor and exploratory behavior in Rett syndrome mice with restricted ketogenic and standard diets.

PubMed

Mantis, John G; Fritz, Christie L; Marsh, Jeremy; Heinrichs, Stephen C; Seyfried, Thomas N

2009-06-01

Rett syndrome (RTT) is a rare X-linked autistic-spectrum neurological disorder associated with impaired energy metabolism, seizure susceptibility, progressive social behavioral regression, and motor impairment primarily in young girls. The objective of this study was to examine the influence of restricted diets, including a ketogenic diet (KD) and a standard rodent chow diet (SD), on behavior in male Mecp2(308/y) mice, a model of RTT. The KD is a high-fat, low-carbohydrate diet that has anticonvulsant efficacy in children with intractable epilepsy and may be therapeutic in children with RTT. Following an 11-day pretrial period, adult wild-type and mutant Rett mice were separated into groups that were fed either an SD in unrestricted or restricted amounts or a ketogenic diet (KetoCal) in restricted amounts for a total of 30 days. The restricted diets were administered to reduce mouse body weight by 20-23% compared to the body weight of each mouse before the initiation of the diet. All mice were subjected to a battery of behavioral tests to determine the influence of the diet on the RTT phenotype. We found that performance in tests of motor behavior and anxiety was significantly worse in male RTT mice compared to wild-type mice and that restriction of either the KD or the SD improved motor behavior and reduced anxiety. We conclude that although both restricted diets increased the tendency of Rett mice to explore a novel environment, the beneficial effects of the KD were due more to calorie restriction than to the composition of the diet. Our findings suggest that calorically restricted diets could be effective in reducing the anxiety and in improving motor behavior in girls with RTT.

Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations.

PubMed

Hadzsiev, Kinga; Polgar, Noemi; Bene, Judit; Komlosi, Katalin; Karteszi, Judit; Hollody, Katalin; Kosztolanyi, Gyorgy; Renieri, Alessandra; Melegh, Bela

2011-03-01

Rett syndrome (RTT) is characterized by a relatively specific clinical phenotype. We screened 152 individuals with RTT phenotype. A total of 22 different known MECP2 mutations were identified in 42 subjects (27.6%). Of the 22 mutations, we identified 7 (31.8%) frameshift-causing deletions, 4 (18.2%) nonsense, 10 (45.5%) missense mutations and one insertion (4.5%). The most frequent pathologic changes were: p.Thr158Met (14.2%) and p.Arg133Cys (11.9%) missense, and p.Arg255Stop (9.5%) and p.Arg294Stop (9.5%) nonsense mutations. We also detected the c.925C >T (p.Arg309Trp) mutation in an affected patient, whose role in RTT pathogenesis is still unknown. Patients without detectable MECP2 defects were screened for mutations of cyclin-dependent kinase-like 5 (CDKL5) gene, responsible for the early-onset variant of RTT. We discovered two novel mutations: c.607G >T resulting in a termination codon at aa203, disrupting the catalytic domain, and c.1708G >T leading to a stop at aa570 of the C terminus. Both patients with CDKL5 mutation presented therapy-resistant epilepsy and a phenotype fitting with the diagnosis of early-onset variant of RTT. No FOXG1 mutation was detected in any of the remaining patients. A total of 110 (72.5%) patients remained without molecular genetic diagnosis that necessitates further search for novel gene mutations in this phenotype. Our results also suggest the need of screening for CDKL5 mutations in patients with Rett phenotype tested negative for MECP2 mutations.

Defining Hand Stereotypies in Rett Syndrome: A Movement Disorders Perspective.

PubMed

Dy, Marisela E; Waugh, Jeff L; Sharma, Nutan; O'Leary, Heather; Kapur, Kush; D'Gama, Alissa M; Sahin, Mustafa; Urion, David K; Kaufmann, Walter E

2017-10-01

Hand stereotypies (HS) are a primary diagnostic criterion for Rett syndrome (RTT) but are difficult to characterize and quantify systematically. We collected video on 27 girls (2-12 years of age) with classic RTT who participated in a mecasermin trial. The present study focused exclusively on video analyses, by reviewing two five-minute windows per subject to identify the two most common HS. Three raters with expertise in movement disorders independently rated the five-minute windows using standardized terminology to determine the level of agreement. We iteratively refined the protocol in three stages to improve descriptive accuracy, categorizing HS as "central" or "peripheral," "simple" or "complex," scoring each hand separately. Inter-rater agreement was analyzed using Kappa statistics. In the initial protocol evaluating HS by video, inter-rater agreement was 20.7%. In the final protocol, inter-rater agreement for the two most frequent HS was higher than the initial protocol at 50%. Phenotypic variability makes standardized evaluation of HS in RTT a challenge; we achieved only 50% level of agreement and only for the most frequent HS. Therefore, objective measures are needed to evaluate HS. Copyright © 2017 Elsevier Inc. All rights reserved.

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

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:…

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

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. Copyright © 2014 the American Physiological Society.

Expression pattern of cdkl5 during zebrafish early development: implications for use as model for atypical Rett syndrome.

PubMed

Vitorino, Marta; Cunha, Nídia; Conceição, Natércia; Cancela, M Leonor

2018-05-11

Atypical Rett syndrome is a child neurodevelopmental disorder induced by mutations in CDKL5 gene and characterized by a progressive regression in development with loss of purposeful use of the hands, slowed brain and head growth, problems with walking, seizures, and intellectual disability. At the moment, there is no cure for this pathology and little information is available concerning animal models capable of mimicking its phenotypes, thus the development of additional animal models should be of interest to gain more knowledge about the disease. Zebrafish has been used successfully as model organism for many human genetic diseases; however, no information is available concerning the spatial and temporal expression of cdkl5 orthologous in this organism. In the present study, we identified the developmental expression patterns of cdkl5 in zebrafish by quantitative PCR and whole-mount in situ hybridization. cdkl5 is expressed maternally at low levels during the first 24 h of development. After that the expression of the gene increases significantly and it starts to be expressed mainly in the nervous system and in several brain structures, such as telencephalon, mesencephalon and diencephalon. The expression patterns of cdkl5 in zebrafish is in accordance with the tissues known to be affected in humans and associated to symptoms and deficits observed in Rett syndrome patients thus providing the first evidence that zebrafish could be an alternative model to study the molecular pathways of this disease as well as to test possible therapeutic approaches capable of rescuing the phenotype.

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…

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. Copyright © 2014. Published by Elsevier Inc.

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

Inflammatory protein response in CDKL5-Rett syndrome: evidence of a subclinical smouldering inflammation.

PubMed

Cortelazzo, Alessio; de Felice, Claudio; Leoncini, Silvia; Signorini, Cinzia; Guerranti, Roberto; Leoncini, Roberto; Armini, Alessandro; Bini, Luca; Ciccoli, Lucia; Hayek, Joussef

2017-03-01

Mutations in the cyclin-dependent kinase-like 5 gene cause a clinical variant of Rett syndrome (CDKL5-RTT). A role for the acute-phase response (APR) is emerging in typical RTT caused by methyl-CpG-binding protein 2 gene mutations (MECP2-RTT). No information is, to date, available on the inflammatory protein response in CDKL5-RTT. We evaluated, for the first time, the APR protein response in CDKL5-RTT. Protein patterns in albumin- and IgG-depleted plasma proteome from CDKL5-RTT patients were evaluated by two-dimensional gel electrophoresis/mass spectrometry. The resulting data were related to circulating cytokines and compared to healthy controls or MECP2-RTT patients. The effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) were evaluated. CDKL5-RTT mutations resulted in a subclinical attenuated inflammation, specifically characterized by an overexpression of the complement component C3 and CD5 antigen-like, both strictly related to the inflammatory response. Cytokine dysregulation featuring a bulk increase of anti-inflammatory cytokines, predominantly IL-10, could explain the unchanged erythrocyte sedimentation rate and atypical features of inflammation in CDKL5-RTT. Omega-3 PUFAs were able to counterbalance the pro-inflammatory status. For the first time, we revealed a subclinical smouldering inflammation pattern in CDKL5-RTT consisting in the coexistence of an atypical APR coupled with a dysregulated cytokine response.

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

PubMed

Dichter, Gabriel S; Damiano, Cara A; Allen, John A

2012-07-06

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.

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

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. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

PubMed Central

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.

2015-01-01

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. PMID:25713300

Early Vocal Development in Autism Spectrum Disorder, Rett Syndrome, and Fragile X Syndrome: Insights from Studies using Retrospective Video Analysis.

PubMed

Roche, Laura; Zhang, Dajie; Bartl-Pokorny, Katrin D; Pokorny, Florian B; Schuller, Björn W; Esposito, Gianluca; Bölte, Sven; Roeyers, Herbert; Poustka, Luise; Gugatschka, Markus; Waddington, Hannah; Vollmann, Ralf; Einspieler, Christa; Marschik, Peter B

2018-03-01

This article provides an overview of studies assessing the early vocalisations of children with autism spectrum disorder (ASD), Rett syndrome (RTT), and fragile X syndrome (FXS) using retrospective video analysis (RVA) during the first two years of life. Electronic databases were systematically searched and a total of 23 studies were selected. These studies were then categorised according to whether children were later diagnosed with ASD (13 studies), RTT (8 studies), or FXS (2 studies), and then described in terms of (a) participant characteristics, (b) control group characteristics, (c) video footage, (d) behaviours analysed, and (e) main findings. This overview supports the use of RVA in analysing the early development of vocalisations in children later diagnosed with ASD, RTT or FXS, and provides an in-depth analysis of vocalisation presentation, complex vocalisation production, and the rate and/or frequency of vocalisation production across the three disorders. Implications are discussed in terms of extending crude vocal analyses to more precise methods that might provide more powerful means by which to discriminate between disorders during early development. A greater understanding of the early manifestation of these disorders may then lead to improvements in earlier detection.

Scoliosis in Rett Syndrome: Progression, Comorbidities, and Predictors.

PubMed

Killian, John T; Lane, Jane B; Lee, Hye-Seung; Skinner, Steve A; Kaufmann, Walter E; Glaze, Daniel G; Neul, Jeffrey L; Percy, Alan K

2017-05-01

Scoliosis is prominent in Rett syndrome (RTT). Following the prior report from the US Natural History Study, the onset and progression of severe scoliosis (≥40° Cobb angle) and surgery were examined regarding functional capabilities and specific genotypes, addressing the hypothesis that abnormal muscle tone, poor oral feeding, puberty, and delays or absence of sitting balance and ambulation may be responsible for greater risk in RTT. The multicenter RTT Natural History Study gathered longitudinal data for classic RTT, including mutation type, scoliosis, muscle tone, sitting, ambulation, hand function, and feeding. Cox regression models were used to examine the association between scoliosis and functional characteristics. All analyses utilized SAS 9.4; two-sided P values of <0.05 were considered significant. A total of 913 females with classic RTT were included. Scoliosis frequency and severity increased with age. Severe scoliosis was found in 251 participants (27%), 113 of whom developed severe scoliosis during the follow-up assessments; 168 (18%) had surgical correction. Severe MECP2 mutations (R106W, R168X, R255X, R270X, and large deletions) showed a higher proportion of scoliosis. Individuals developing severe scoliosis or requiring surgery were less likely to sit, ambulate, or use their hands and were more likely to have begun puberty. Significant differences were absent for epilepsy rates, sleep problems, or constipation. Scoliosis requires vigilance regarding the risk factors noted, particularly specific mutations and the role of puberty and motor abilities. Bracing is recommended for moderate curves and surgery for severe curves in accordance with published guidelines for scoliosis management. Copyright © 2017 Elsevier Inc. All rights reserved.

The course of awake breathing disturbances across the lifespan in Rett syndrome.

PubMed

Tarquinio, Daniel C; Hou, Wei; Neul, Jeffrey L; Berkmen, Gamze Kilic; Drummond, Jana; Aronoff, Elizabeth; Harris, Jennifer; Lane, Jane B; Kaufmann, Walter E; Motil, Kathleen J; Glaze, Daniel G; Skinner, Steven A; Percy, Alan K

2018-04-12

Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, is associated with a peculiar breathing disturbance exclusively during wakefulness that is distressing, and can even prompt emergency resuscitation. Through the RTT Natural History Study, we characterized cross sectional and longitudinal characteristics of awake breathing abnormalities in RTT and identified associated clinical features. Participants were recruited from 2006 to 2015, and cumulative lifetime prevalence of breathing dysfunction was determined using the Kaplan-Meier estimator. Risk factors were assessed using logistic regression. Of 1205 participants, 1185 had sufficient data for analysis, including 922 females with classic RTT, 778 of whom were followed longitudinally for up to 9.0 years, for a total of 3944 person-years. Participants with classic or atypical severe RTT were more likely to have breathing dysfunction (nearly 100% over the lifespan) compared to those with atypical mild RTT (60-70%). Remission was common, lasting 1 year on average, with 15% ending the study in terminal remission. Factors associated with higher odds of severe breathing dysfunction included poor gross and fine motor function, frequency of stereotypical hand movements, seizure frequency, prolonged corrected QT interval on EKG, and two quality of life metrics: caregiver concern about physical health and contracting illness. Factors associated with lower prevalence of severe breathing dysfunction included higher body mass index and head circumference Z-scores, advanced age, and severe scoliosis or contractures. Awake breathing dysfunction is common in RTT, more so than seizures, and is associated with function, quality of life and risk for cardiac dysrhythmia. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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

PubMed

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

2016-11-01

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

Unconventional Transcriptional Response to Environmental Enrichment in a Mouse Model of Rett Syndrome

PubMed Central

Kerr, Bredford; Silva, Pamela A.; Walz, Katherina; Young, Juan I.

2010-01-01

Background Rett syndrome (RTT) is an X-linked postnatal neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2) and one of the leading causes of mental retardation in females. RTT is characterized by psychomotor retardation, purposeless hand movements, autistic-like behavior and abnormal gait. We studied the effects of environmental enrichment (EE) on the phenotypic manifestations of a RTT mouse model that lacks MeCP2 (Mecp2 −/y). Principal Findings We found that EE delayed and attenuated some neurological alterations presented by Mecp2 −/y mice and prevented the development of motor discoordination and anxiety-related abnormalities. To define the molecular correlate of this beneficial effect of EE, we analyzed the expression of several synaptic marker genes whose expression is increased by EE in several mouse models. Conclusions/Significance We found that EE induced downregulation of several synaptic markers, suggesting that the partial prevention of RTT-associated phenotypes is achieved through a non-conventional transcriptional program. PMID:20634955

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.

Rett syndrome treatment in mouse models: searching for effective targets and strategies.

PubMed

Ricceri, Laura; De Filippis, Bianca; Laviola, Giovanni

2013-05-01

Rett syndrome (RTT) is a pervasive developmental disorder, primarily affecting girls with a prevalence of 1 in every 10,000 births; it represents the second most common cause of intellectual disability in females. Mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2) have been identified as clear etiological factors in more than 90% of classical RTT cases. Whereas the mechanisms leading to the severe, progressive and specific neurological dysfunctions when this gene is mutated still remain to be elucidated, a series of different mouse models have been generated, bearing different Mecp2 mutation. Neurobehavioural analysis in these mouse lines have been carried out and phenotyping analysis can be now utilised to preclinically evaluate the effects of potential RTT treatments. This review summarizes the different results achieved in this research field taking into account different key targets identified to ameliorate RTT phenotype in mouse models, including those not directly downstream of MeCP2 and those limited to the early phases of postnatal development. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

PubMed

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

2015-05-01

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

Direct Observation of the Behaviour of Females with Rett Syndrome.

PubMed

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

The aim was to observe the behaviour of a sample of females with RTT and explore how it was organized in relation to environmental events. Ten participants, all with a less severe form of classic ( n  = 9) or atypical ( n  = 1) Rett syndrome (RTT), were filmed at home and at school or day centre. Analysis used real-time data capture software. Observational categories distinguished engagement in social and non-social pursuits, hand stereotypies, self-injury and the receipt of attention from a parent, teacher or carer. Associations between participant behaviour and intake variables and receipt of attention were explored. Concurrent and lagged conditional probabilities between behavioural categories and receipt of attention were calculated. Receipt of adult attention was high. Engagement in activity using the hands was associated with a less severe condition and greater developmental age. Engagement in activity, whether using the hands or not, and social engagement were positively associated with receipt of support. The extent of hand stereotypies varied greatly across participants but was independent of environmental events. Six participants self-injured. There was some evidence that self-injury was related to adult attention. Participants appeared to experience a carer and attention rich environment and their levels of engagement seemed high as a result. As in the more general literature, engagement in activity was related to personal development and to social support. Self-injury contrasted with hand stereotypies in having possible environmental function.

Vitamin D Deficiency is Prevalent in Females with Rett Syndrome

PubMed Central

Motil, Kathleen J.; Barrish, Judy O.; Lane, Jane; Geerts, Suzanne P.; Annese, Fran; McNair, Lauren; Percy, Alan K.; Skinner, Steven A; Neul, Jeffrey L.; Glaze, Daniel G.

2013-01-01

Objectives 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 females with Rett syndrome (RTT). Study design Retrospective review of the medical records of 284 females with RTT to determine serum 25(OH)D and parathyroid hormone levels, nutritional status, dietary sources of vitamin D, exposure to anticonvulsants, degree of mobility, and MECP2 status. Results Twenty percent of females who were tested (n=157) had 25(OH)D levels <50 nmol/L. Multivitamin supplements, vitamin D fortified milk, and commercial formulas were consumed by 40%, 52%, and 54%. Anticonvulsants were used by 57% and 39% ambulated independently. Median 25(OH)D levels were lower in individuals who did not receive multivitamin supplements (p<0.05) or commercial formulas (p<0.001) than in those who did. Median 25(OH)D levels differed (p<0.01) among racial and ethnic groups, but the number in some groups was small. Nutritional status, use of anticonvulsants, degree of mobility, and MECP2 status did not influence 25(OH)D levels. Conclusion Vitamin D deficiency is prevalent in females with RTT. The use of multivitamin supplements or commercial formulas is associated with improved vitamin D levels. Attention to vitamin D may enhance bone mineral deposition and reduce the frequency of bone fractures in these individuals. PMID:21637127

Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders

USDA-ARS?s Scientific Manuscript database

Many postnatal onset neurological disorders such as autism spectrum disorders (ASDs) and intellectual disability are thought to arise largely from disruption of excitatory/inhibitory homeostasis. Although mouse models of Rett syndrome (RTT), a postnatal neurological disorder caused by loss-of-functi...

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

Novel therapeutic approaches: Rett syndrome and human induced pluripotent stem cell technology

PubMed Central

Gomathi, Mohan

2017-01-01

Recent advances in induced pluripotent stem cell (iPSC) technology target screening and discovering of therapeutic agents for the possible cure of human diseases. Human induced pluripotent stem cells (hiPSC) are the right kind of platform for testing potency of specific active compounds. Ayurveda, the Indian traditional system of medicine developed between 2,500 and 500 BC, is a science involving the intelligent formulations of herbs and minerals. It can serve as a “goldmine” for novel neuroprotective agents used for centuries to treat neurological disorders. This review discusses limitations in screening drugs for neurological disorders and the advantages offered by hiPSC integrated with Indian traditional system of medicine. We begin by describing the current state of hiPSC technology in research on Rett syndrome (RTT) followed by the current controversies in RTT research combined with the emergence of patient-specific hiPSC that indicate an urgent need for researchers to understand the etiology and drug mechanism. We conclude by offering recommendations to reinforce the screening of active compounds present in the ayurvedic medicines using the human induced pluripotent neural model system for research involving drug discovery for RTT. This integrative approach will fill the current knowledge gap in the traditional medicines and drug discovery. PMID:28447035

A Mutation in the Rett Syndrome Gene, MECP2, Causes X-Linked Mental Retardation and Progressive Spasticity in Males

PubMed Central

Meloni, Ilaria; Bruttini, Mirella; Longo, Ilaria; Mari, Francesca; Rizzolio, Flavio; D’Adamo, Patrizia; Denvriendt, Koenraad; Fryns, Jean-Pierre; Toniolo, Daniela; Renieri, Alessandra

2000-01-01

Heterozygous mutations in the X-linked MECP2 gene cause Rett syndrome, a severe neurodevelopmental disorder of young females. Only one male presenting an MECP2 mutation has been reported; he survived only to age 1 year, suggesting that mutations in MECP2 are male lethal. Here we report a three-generation family in which two affected males showed severe mental retardation and progressive spasticity, previously mapped in Xq27.2-qter. Two obligate carrier females showed either normal or borderline intelligence, simulating an X-linked recessive trait. The two males and the two obligate carrier females presented a mutation in the MECP2 gene, demonstrating that, in males, MECP2 can be responsible for severe mental retardation associated with neurological disorders. PMID:10986043

MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression.

PubMed

Makedonski, Kirill; Abuhatzira, Liron; Kaufman, Yotam; Razin, Aharon; Shemer, Ruth

2005-04-15

Rett syndrome (RS) is a severe and progressive neurodevelopmental disorder caused by heterozygous mutations in the X-linked methyl CpG binding protein 2 (MeCP2) gene. MeCP2 is a nuclear protein that binds specifically to methylated DNA and functions as a general transcription repressor in the context of chromatin remodeling complexes. RS shares clinical features with those of Angelman syndrome (AS), an imprinting neurodevelopmental disorder. In AS patients, the maternally expressed copy of UBE3A that codes for the ubiquitin protein ligase 3A (E6-AP) is repressed. The similar phenotype of these two syndromes led us to hypothesize that part of the RS phenotype is due to MeCP2-associated silencing of UBE3A. Indeed, UBE3A mRNA and protein are shown here to be significantly reduced in human and mouse MECP2 deficient brains. This reduced UBE3A level was associated with biallelic production of the UBE3A antisense RNA. In addition, MeCP2 deficiency resulted in elevated histone H3 acetylation and H3(K4) methylation and reduced H3(K9) methylation at the PWS/AS imprinting center, with no effect on DNA methylation or SNRPN expression. We conclude, therefore, that MeCP2 deficiency causes epigenetic aberrations at the PWS imprinting center. These changes in histone modifications result in loss of imprinting of the UBE3A antisense gene in the brain, increase in UBE3A antisense RNA level and, consequently reduction in UBE3A production.

The short-time structural plasticity of dendritic spines is altered in a model of Rett syndrome.

PubMed

Landi, Silvia; Putignano, Elena; Boggio, Elena Maria; Giustetto, Maurizio; Pizzorusso, Tommaso; Ratto, Gian Michele

2011-01-01

The maturation of excitatory transmission comes about through a developmental period in which dendritic spines are highly motile and their number, form and size are rapidly changing. Surprisingly, although these processes are crucial for the formation of cortical circuitry, little is known about possible alterations of these processes in brain disease. By means of acute in vivo 2-photon imaging we show that the dynamic properties of dendritic spines of layer V cortical neurons are deeply affected in a mouse model of Rett syndrome (RTT) at a time around P25 when the neuronal phenotype of the disease is still mild. Then, we show that 24h after a subcutaneous injection of IGF-1 spine dynamics is restored. Our study demonstrates that spine dynamics in RTT mice is severely impaired early during development and suggest that treatments for RTT should be started very early in order to reestablish a normal period of spine plasticity.

Longitudinal brain MRI study in a mouse model of Rett Syndrome and the effects of choline.

PubMed

Ward, B C; Agarwal, S; Wang, K; Berger-Sweeney, J; Kolodny, N H

2008-07-01

Rett Syndrome (RTT), the second most common cause of mental retardation in girls, is associated with mutations of an X-linked gene encoding the transcriptional repressor protein MeCP2. Mecp2(1lox) mutant mice express no functional MeCP2 protein and exhibit behavioral abnormalities similar to those seen in RTT patients. Here we monitor the development of both whole brain and regional volumes between 21 and 42 days of age in this model of RTT using MRI. We see decreases in whole brain volumes in both male and female mutant mice. Cerebellar and ventricular volumes are also decreased in RTT males. Previous work has suggested that perinatal choline supplementation alleviates some of the behavioral deficits in both male and female Mecp2(1lox) mutant mice. Here we show that perinatal choline supplementation also positively affects whole brain volume in heterozygous females, and cerebellar volume in male RTT mice.

Paradoxical physiological responses to propranolol in a Rett syndrome patient: a case report.

PubMed

Santosh, P J; Bell, L; Lievesley, K; Singh, J; Fiori, F

2016-11-29

Rett Syndrome (RTT), caused by a loss-of-function in the epigenetic modulator: X-linked methyl-CpG binding protein 2 (MeCP2), is a pervasive neurological disorder characterized by compromised brain functions, anxiety, severe mental retardation, language and learning disabilities, repetitive stereotyped hand movements and developmental regression. An imbalance in the sympathetic and the parasympathetic nervous system (dysautonomia) and the resulting autonomic storms is a frequent occurrence in patients with RTT. The prototypical beta blocker propranolol has been used to manage sympathetic hyperactivity in patients with RTT. A 13 year old girl with RTT was referred to the Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust. Her clinical picture included disordered breathing with concomitant hyperventilation and apnoea, epilepsy, scoliosis, no QT prolongation (QT/QTc [372/467 ms on automated electrocardiogram [ECG], but manually calculated to be 440 ms]), no cardiac abnormalities (PR interval: 104 ms, QRS duration: 78 ms), and generalised anxiety disorder (ICD-10-CM Diagnosis Code F41.1). She was also constipated and was fed via percutaneous endoscopic gastrostomy (PEG). To manage the dysautonomia, propranolol was given (5 mg and 10 mg) and in parallel her physiological parameters, including heart rate, skin temperature and skin transpiration, were monitored continuously for 24 h as she went about her activities of daily living. Whilst her skin temperature increased and skin transpiration decreased, unexpectedly there was a significant paradoxical increase in the patient's average heart rate following propranolol treatment. Here, we present a unique case of a paradoxical increase in heart rate response following propranolol treatment for managing dysautonomia in a child with RTT. Further studies are warranted to better understand the underlying dysautonomia in patients with RTT and

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

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

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. Copyright © 2014 Elsevier Ltd. All rights reserved.

Rett Syndrome: Overview

MedlinePlus

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A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation.

PubMed

Saitsu, Hirotomo; Tohyama, Jun; Walsh, Tom; Kato, Mitsuhiro; Kobayashi, Yu; Lee, Ming; Tsurusaki, Yoshinori; Miyake, Noriko; Goto, Yu-Ichi; Nishino, Ichizo; Ohtake, Akira; King, Mary-Claire; Matsumoto, Naomichi

2014-10-01

Recently, de novo mutations in TBL1XR1 were found in two patients with autism spectrum disorders. Here, we report on a Japanese girl presenting with West syndrome, Rett syndrome-like and autistic features. Her initial development was normal until she developed a series of spasms at 5 months of age. Electroencephalogram at 7 months showed a pattern of hypsarrhythmia, which led to a diagnosis of West syndrome. Stereotypic hand movements appeared at 8 months of age, and autistic features such as deficits in communication, hyperactivity and excitability were observed later, at 4 years and 9 months. Whole exome sequencing of the patient and her parents revealed a de novo TBL1XR1 mutation [c.209 G>A (p.Gly70Asp)] occurring at an evolutionarily conserved amino acid in an F-box-like domain. Our report expands the clinical spectrum of TBL1XR1 mutations to West syndrome with Rett-like features, together with autistic features.

MECP2 variation in Rett syndrome-An overview of current coverage of genetic and phenotype data within existing databases.

PubMed

Townend, Gillian S; Ehrhart, Friederike; van Kranen, Henk J; Wilkinson, Mark; Jacobsen, Annika; Roos, Marco; Willighagen, Egon L; van Enckevort, David; Evelo, Chris T; Curfs, Leopold M G

2018-04-27

Rett syndrome (RTT) is a monogenic rare disorder that causes severe neurological problems. In most cases, it results from a loss-of-function mutation in the gene encoding methyl-CPG-binding protein 2 (MECP2). Currently, about 900 unique MECP2 variations (benign and pathogenic) have been identified and it is suspected that the different mutations contribute to different levels of disease severity. For researchers and clinicians, it is important that genotype-phenotype information is available to identify disease-causing mutations for diagnosis, to aid in clinical management of the disorder, and to provide counseling for parents. In this study, 13 genotype-phenotype databases were surveyed for their general functionality and availability of RTT-specific MECP2 variation data. For each database, we investigated findability and interoperability alongside practical user functionality, and type and amount of genetic and phenotype data. The main conclusions are that, as well as being challenging to find these databases and specific MECP2 variants held within, interoperability is as yet poorly developed and requires effort to search across databases. Nevertheless, we found several thousand online database entries for MECP2 variations and their associated phenotypes, diagnosis, or predicted variant effects, which is a good starting point for researchers and clinicians who want to provide, annotate, and use the data. © 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.

CDKL5 gene status in female patients with epilepsy and Rett-like features: two new mutations in the catalytic domain

PubMed Central

2012-01-01

Background Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) located in the Xp22 region have been shown to cause a subset of atypical Rett syndrome with infantile spasms or early seizures starting in the first postnatal months. Methods We performed mutation screening of CDKL5 in 60 female patients who had been identified as negative for the methyl CpG-binding protein 2 gene (MECP2) mutations, but who had current or past epilepsy, regardless of the age of onset, type, and severity. All the exons in the CDKL5 gene and their neighbouring sequences were examined, and CDKL5 rearrangements were studied by multiplex ligation-dependent probe amplification (MLPA). Results Six previously unidentified DNA changes were detected, two of which were disease-causing mutations in the catalytic domain: a frameshift mutation (c.509_510insGT; p.Glu170GlyfsX36) and a complete deletion of exon 10. Both were found in patients with seizures that started in the first month of life. Conclusions This study demonstrated the importance of CDKL5 mutations as etiological factors in neurodevelopmental disorders, and indicated that a thorough analysis of the CDKL5 gene sequence and its rearrangements should be considered in females with Rett syndrome-like phenotypes, severe encephalopathy and epilepsy with onset before 5 months of age. This study also confirmed the usefulness of MLPA as a diagnostic screening method for use in clinical practice. PMID:22867051

CDKL5 gene status in female patients with epilepsy and Rett-like features: two new mutations in the catalytic domain.

PubMed

Maortua, Hiart; Martínez-Bouzas, Cristina; Calvo, María-Teresa; Domingo, Maria-Rosario; Ramos, Feliciano; García-Ribes, Ainhoa; Martínez, María-Jesús; López-Aríztegui, María-Asunción; Puente, Nerea; Rubio, Izaskun; Tejada, María-Isabel

2012-08-06

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) located in the Xp22 region have been shown to cause a subset of atypical Rett syndrome with infantile spasms or early seizures starting in the first postnatal months. We performed mutation screening of CDKL5 in 60 female patients who had been identified as negative for the methyl CpG-binding protein 2 gene (MECP2) mutations, but who had current or past epilepsy, regardless of the age of onset, type, and severity. All the exons in the CDKL5 gene and their neighbouring sequences were examined, and CDKL5 rearrangements were studied by multiplex ligation-dependent probe amplification (MLPA). Six previously unidentified DNA changes were detected, two of which were disease-causing mutations in the catalytic domain: a frameshift mutation (c.509_510insGT; p.Glu170GlyfsX36) and a complete deletion of exon 10. Both were found in patients with seizures that started in the first month of life. This study demonstrated the importance of CDKL5 mutations as etiological factors in neurodevelopmental disorders, and indicated that a thorough analysis of the CDKL5 gene sequence and its rearrangements should be considered in females with Rett syndrome-like phenotypes, severe encephalopathy and epilepsy with onset before 5 months of age. This study also confirmed the usefulness of MLPA as a diagnostic screening method for use in clinical practice.

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

PubMed Central

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

2016-01-01

Mouse models of the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) have advanced our understanding of Rett syndrome (RTT). RTT is a ‘prototypical’ neurodevelopmental disorder with many clinical features overlapping with other intellectual and developmental disabilities (IDD). Therapeutic interventions for RTT may therefore have broader applications. However, the reliance on the laboratory mouse to identify viable therapies for the human condition may present challenges in translating findings from the bench to the clinic. In addition, the need to identify outcome measures in well-chosen animal models is critical for preclinical trials. Here, we report that a novel Mecp2 rat model displays high face validity for modelling psychomotor regression of a learned skill, a deficit that has not been shown in Mecp2 mice. Juvenile play, a behavioural feature that is uniquely present in rats and not mice, is also impaired in female Mecp2 rats. Finally, we demonstrate that evaluating the molecular consequences of the loss of MeCP2 in both mouse and rat may result in higher predictive validity with respect to transcriptional changes in the human RTT brain. These data underscore the similarities and differences caused by the loss of MeCP2 among divergent rodent species which may have important implications for the treatment of individuals with disease-causing MECP2 mutations. Taken together, these findings demonstrate that the Mecp2 rat model is a complementary tool with unique features for the study of RTT and highlight the potential benefit of cross-species analyses in identifying potential disease-relevant preclinical outcome measures. PMID:27365498

Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome.

PubMed

Moretti, Paolo; Bouwknecht, J Adriaan; Teague, Ryan; Paylor, Richard; Zoghbi, Huda Y

2005-01-15

Rett syndrome (RTT) is an autistic spectrum disorder with a known genetic basis. RTT is caused by loss of function mutations in the X-linked gene MECP2 and is characterized by loss of acquired motor, social and language skills in females beginning at 6-18 months of age. MECP2 mutations also cause non-syndromic mental retardation in males and females, and abnormalities of MeCP2 expression in the brain have been found in autistic spectrum disorders. We studied home-cage behavior and social interactions in a mouse model of RTT (Mecp2(308/Y)) carrying a mutation similar to common RTT causing alleles. Young adult mutant mice showed abnormal home-cage diurnal activity in the absence of motor skill deficits. Nesting, a phenotype related to social behavior, and social interactions were both impaired in these animals. Mecp2(308/Y) mice showed deficits in nest building and decreased nest use. Although there were no differences in aggression or exploration of novel inanimate stimuli, mutant mice took less initiative and were less decisive approaching unfamiliar males and spent less time in close vicinity to them in several social interaction paradigms. The abnormalities of diurnal activity and social behavior in Mecp2(308/Y) mice are reminiscent of the sleep/wake dysfunction and autistic features of RTT. These data suggest that MECP2 regulates the expression and/or function of genes involved in social behavior. The study of Mecp2(308/Y) mice will allow the identification of the molecular basis of social impairment in RTT and related autistic spectrum disorders.

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

PubMed

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

2014-08-01

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

Severe changes in colon epithelium in the Mecp2-null mouse model of Rett syndrome.

PubMed

Millar-Büchner, Pamela; Philp, Amber R; Gutierrez, Noemí; Villanueva, Sandra; Kerr, Bredford; Flores, Carlos A

2016-12-01

Rett syndrome is best known due to its severe and devastating symptoms in the central nervous system. It is produced by mutations affecting the Mecp2 gene that codes for a transcription factor. Nevertheless, evidence for MECP2 activity has been reported for tissues other than those of the central nervous system. Patients affected by Rett presented with intestinal affections whose origin is still not known. We have observed that the Mecp2-null mice presented with episodes of diarrhea, and decided to study the intestinal phenotype in these mice. Mecp2-null mice or bearing the conditional intestinal deletion of MECP2 were used. Morphometirc and histologic analysis of intestine, and RT-PCR, western blot and immunodetection were perfomed on intestinal samples of the animals. Electrical parameters of the intestine were determined by Ussing chamber experiments in freshly isolated colon samples. First we determined that MECP2 protein is mainly expressed in cells of the lower part of the colonic crypts and not in the small intestine. The colon of the Mecp2-null mice was shorter than that of the wild-type. Histological analysis showed that epithelial cells of the surface have abnormal localization of key membrane proteins like ClC-2 and NHE-3 that participate in the electroneutral NaCl absorption; nevertheless, electrogenic secretion and absorption remain unaltered. We also detected an increase in a proliferation marker in the crypts of the colon samples of the Mecp2-null mice, but the specific silencing of Mecp2 from intestinal epithelium was not able to recapitulate the intestinal phenotype of the Mecp2-null mice. In summary, we showed that the colon is severely affected by Mecp2 silencing in mice. Changes in colon length and epithelial histology are similar to those observed in colitis. Changes in the localization of proteins that participate in fluid absorption can explain watery stools, but the exclusive deletion of Mecp2 from the intestine did not reproduce colon

Low Bone Mineral Mass Is Associated with Decreased Bone Formation and Diet in Females with Rett Syndrome

PubMed Central

Motil, Kathleen J.; Barrish, Judy O.; Neul, Jeffrey L.; Glaze, Daniel G.

2014-01-01

Objective To characterize biomarkers of bone turnover and their relation with bone mineral mass in a cross-sectional cohort of females with Rett syndrome (RTT) and to examine the role of dietary, biochemical, hormonal, and inflammatory factors on bone mineral mass and bone biomarkers in this disorder. Methods Total body bone mineral content (BMC) and density (BMD) were determined by dual-energy x-ray absorptiometry. Dietary nutrient intakes were determined from 3-day food records. Biomarkers of bone turnover, bone metabolites, vitamin D metabolites, hormones, and inflammatory markers were measured by standard clinical laboratory methods. Results Serum osteocalcin, bone alkaline phosphatase, and C-telopeptide showed significant inverse relations with age in the RTT cohort. Mean osteocalcin concentrations were significantly lower and mean bone alkaline phosphatase concentrations were significantly higher for individual age groups in the RTT cohort than mean values for their respective age ranges in the reference population. Significant inverse associations were identified between urinary calcium losses, expressed as calcium:creatinine ratios, and total body BMC and BMD z-scores. Dietary protein, calcium, and phosphorus intakes, expressed as a proportion of Dietary Reference Intakes for age and gender, showed significant positive associations with total body BMD z-scores. Conclusion This study suggests decreased bone formation rather than increased bone resorption may explain in part the deficits in bone mineral mass in RTT and that attention to the adequacy of dietary protein, calcium and phosphorus intakes may offer an opportunity to improve bone health in RTT. PMID:25144778

Low bone mineral mass is associated with decreased bone formation and diet in girls with Rett syndrome.

PubMed

Motil, Kathleen J; Barrish, Judy O; Neul, Jeffrey L; Glaze, Daniel G

2014-09-01

The aim of the present study was to characterize biomarkers of bone turnover and their relation with bone mineral mass in a cross-sectional cohort of girls with Rett syndrome (RTT) and to examine the role of dietary, biochemical, hormonal, and inflammatory factors on bone mineral mass and bone biomarkers in this disorder. Total body bone mineral content (BMC) and bone mineral density (BMD) were determined by dual-energy x-ray absorptiometry. Dietary nutrient intakes were determined from 3-day food records. Biomarkers of bone turnover, bone metabolites, vitamin D metabolites, hormones, and inflammatory markers were measured by standard clinical laboratory methods. Serum osteocalcin, bone alkaline phosphatase, and C-telopeptide showed significant inverse relations with age in the RTT cohort. Mean osteocalcin concentrations were significantly lower and mean bone alkaline phosphatase concentrations were significantly higher for individual age groups in the RTT cohort than mean values for their respective age ranges in the reference population. Significant inverse associations were identified between urinary calcium losses, expressed as calcium:creatinine ratios, and total body BMC and BMD z scores. Dietary protein, calcium, and phosphorus intakes, expressed as a proportion of Dietary Reference Intakes for age and sex, showed significant positive associations with total body BMD z scores. The present study suggests decreased bone formation instead of increased bone resorption may explain in part the deficits in bone mineral mass in RTT and that attention to the adequacy of dietary protein, calcium, and phosphorus intakes may offer an opportunity to improve bone health in RTT.

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. © 2015 Wiley Periodicals, Inc.

Rett Syndrome Mutation MeCP2 T158A Disrupts DNA Binding, Protein Stability and ERP Responses

PubMed Central

Goffin, Darren; Allen, Megan; Zhang, Le; Amorim, Maria; Wang, I-Ting Judy; Reyes, Arith-Ruth S.; Mercado-Berton, Amy; Ong, Caroline; Cohen, Sonia; Hu, Linda; Blendy, Julie A.; Carlson, Gregory C.; Siegel, Steve J.; Greenberg, Michael E.; Zhou, Zhaolan (Joe)

2011-01-01

Mutations in the MECP2 gene cause the autism spectrum disorder Rett Syndrome (RTT). One of the most common mutations associated with RTT occurs at MeCP2 Threonine 158 converting it to Methionine (T158M) or Alanine (T158A). To understand the role of T158 mutation in the pathogenesis of RTT, we generated knockin mice recapitulating MeCP2 T158A mutation. Here we show a causal role for T158A mutation in the development of RTT-like phenotypes including developmental regression, motor dysfunction, and learning and memory deficits. These phenotypes resemble those in Mecp2-null mice and manifest through a reduction in MeCP2 binding to methylated DNA and a decrease in MeCP2 protein stability. Importantly, the age-dependent development of event-related neuronal responses are disrupted by MeCP2 mutation, suggesting that impaired neuronal circuitry underlies the pathogenesis of RTT and that assessment of event-related potentials may serve as a biomarker for RTT and treatment evaluation. PMID:22119903

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. Copyright © 2016 Elsevier Ltd. All rights reserved.

Assessing cognitive functioning in females with Rett syndrome by eye-tracking methodology.

PubMed

Ahonniska-Assa, Jaana; Polack, Orli; Saraf, Einat; Wine, Judy; Silberg, Tamar; Nissenkorn, Andreea; Ben-Zeev, Bruria

2018-01-01

While many individuals with severe developmental impairments learn to communicate with augmentative and alternative communication (AAC) devices, a significant number of individuals show major difficulties in the effective use of AAC. Recent technological innovations, i.e., eye-tracking technology (ETT), aim to improve the transparency of communication and may also enable a more valid cognitive assessment. To investigate whether ETT in forced-choice tasks can enable children with very severe motor and speech impairments to respond consistently, allowing a more reliable evaluation of their language comprehension. Participants were 17 girls with Rett syndrome (M = 6:06 years). Their ability to respond by eye gaze was first practiced with computer games using ETT. Afterwards, their receptive vocabulary was assessed using the Peabody Picture Vocabulary Test-4 (PPVT-4). Target words were orally presented and participants responded by focusing their eyes on the preferred picture. Remarkable differences between the participants in receptive vocabulary were demonstrated using ETT. The verbal comprehension abilities of 32% of the participants ranged from low-average to mild cognitive impairment, and the other 68% of the participants showed moderate to severe impairment. Young age at the time of assessment was positively correlated with higher receptive vocabulary. The use of ETT seems to make the communicational signals of children with severe motor and communication impairments more easily understood. Early practice of ETT may improve the quality of communication and enable more reliable conclusions in learning and assessment sessions. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice.

PubMed

Jorge-Torres, Olga C; Szczesna, Karolina; Roa, Laura; Casal, Carme; Gonzalez-Somermeyer, Louisa; Soler, Marta; Velasco, Cecilia D; Martínez-San Segundo, Pablo; Petazzi, Paolo; Sáez, Mauricio A; Delgado-Morales, Raúl; Fourcade, Stephane; Pujol, Aurora; Huertas, Dori; Llobet, Artur; Guil, Sonia; Esteller, Manel

2018-05-08

Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG-binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

A novel mutation R190H in the AT-hook 1 domain of MeCP2 identified in an atypical Rett syndrome.

PubMed

Zhou, Xiao; Liao, Yuangao; Xu, Miaojing; Ji, Zhong; Xu, Yunqi; Zhou, Liang; Wei, Xiaoming; Hu, Peiqian; Han, Peng; Yang, Fanghan; Pan, Suyue; Hu, Yafang

2017-10-10

Mutations in Methyl-CpG binding protein 2 ( MECP2 ) have been identified as the disease-causing mutations in Rett Syndrome (RTT). However, no mutation in the AT-hook 1 domain of MECP2 has been reported in RTT yet. The function of AT-hook 1 domain of MECP2 has not been described either. The clinical and radiological features of a girl with progressive hyperactivity and loss of acquired linguistic and motor functions were presented. Next generation sequencing was used to screen the causative gene. Effect of the mutant protein on histone 3 methylation was assessed in vitro experiment. The patient was diagnosed with an atypical RTT at the age of nine. Magnetic resonance imaging revealed a loss of whole-brain volume and abnormal myelination. Genetic analysis identified a de novo novel missense mutation of MECP2 (NM_004992, c.570G->A, p.Arg190His). This mutation is located in the AT-hook 1 domain of MeCP2 protein. Overexpression of the mutant MeCP2 in cultured neuroblastoma cells SH-SY5Y revealed increased level of dimethylated histone 3 lysine 9, a transcriptional repressor marker. A novel missense mutation in AT-hook 1 domain of MeCP2 was identified in a patient with atypical RTT. Clinical data and in vitro experiment result imply that R190H mutation in AT-hook1 may cause dysfunction of MeCP2 and be a pathogenic variant.

Developmental profile of speech-language and communicative functions in an individual with the Preserved Speech Variant of Rett syndrome

PubMed Central

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

2018-01-01

Objective We assessed various aspects of speech-language and communicative functions of an individual with the preserved speech variant (PSV) of Rett syndrome (RTT) to describe her developmental profile over a period of 11 years. Methods For this study we incorporated the following data resources and methods to assess speech-language and communicative functions during pre-, peri- and post-regressional development: retrospective video analyses, medical history data, parental checklists and diaries, standardized tests on vocabulary and grammar, spontaneous speech samples, and picture stories to elicit narrative competences. Results Despite achieving speech-language milestones, atypical behaviours were present at all times. We observed a unique developmental speech-language trajectory (including the RTT typical regression) affecting all linguistic and socio-communicative sub-domains in the receptive as well as the expressive modality. Conclusion Future research should take into consideration a potentially considerable discordance between formal and functional language use by interpreting communicative acts on a more cautionary note. PMID:23870013

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

What does the nature of the MECP2 mutation tell us about parental origin and recurrence risk in Rett syndrome?

PubMed

Zhang, J; Bao, X; Cao, G; Jiang, S; Zhu, X; Lu, H; Jia, L; Pan, H; Fehr, S; Davis, M; Leonard, H; Ravine, D; Wu, X

2012-12-01

The MECP2 mutations occurring in the severe neurological disorder Rett syndrome are predominantly de novo, with rare familial cases. The aims of this study were to provide a precise estimate of the parental origin of MECP2 mutations using a large Chinese sample and to assess whether parental origin varied by mutation type. The parental origin was paternal in 84/88 [95.5%, (95% confidence interval 88.77-98.75)] of sporadic Chinese cases. However, in a pooled sample including data from the literature the spectrum of mutations occurring on maternally and paternally derived chromosomes differed significantly. The excess we found of 'single base pair gains or losses' on maternally derived MECP2 gene alleles suggests that this mutational category is associated with an elevated risk of gonadal mosaicism, which has implications for genetic counseling. © 2011 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

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

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…

Systemic Delivery of MeCP2 Rescues Behavioral and Cellular Deficits in Female Mouse Models of Rett Syndrome

PubMed Central

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

2013-01-01

De novo mutations in the X-linked gene encoding the transcription factor methyl-CpG binding protein 2 (MECP2) are the most frequent cause of the neurological disorder Rett syndrome (RTT). Hemizygous males usually die of neonatal encephalopathy. Heterozygous females survive into adulthood but exhibit severe symptoms including microcephaly, loss of purposeful hand motions and speech, and motor abnormalities, which appear after a period of apparently normal development. Most studies have focused on male mouse models because of the shorter latency to and severity in symptoms, yet how well these mice mimic the disease in affected females is not clear. Very few therapeutic treatments have been proposed for females, the more gender-appropriate model. Here, we show that self-complementary AAV9, bearing MeCP2 cDNA under control of a fragment of its own promoter (scAAV9/MeCP2), is capable of significantly stabilizing or reversing symptoms when administered systemically into female RTT mice. To our knowledge, this is the first potential gene therapy for females afflicted with RTT. PMID:23966684

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

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…

A rare male patient with classic Rett syndrome caused by MeCP2_e1 mutation.

PubMed

Tokaji, Narumi; Ito, Hiromichi; Kohmoto, Tomohiro; Naruto, Takuya; Takahashi, Rizu; Goji, Aya; Mori, Tatsuo; Toda, Yoshihiro; Saito, Masako; Tange, Shoichiro; Masuda, Kiyoshi; Kagami, Shoji; Imoto, Issei

2018-03-01

Rett syndrome (RTT) is a severe neurodevelopmental disorder typically affecting females. It is mainly caused by loss-of-function mutations that affect the coding sequence of exon 3 or 4 of methyl-CpG-binding protein 2 (MECP2). Severe neonatal encephalopathy resulting in death before the age of 2 years is the most common phenotype observed in males affected by a pathogenic MECP2 variant. Mutations in MECP2 exon 1 affecting the MeCP2_e1 isoform are relatively rare causes of RTT in females, and only one case of a male patient with MECP2-related severe neonatal encephalopathy caused by a mutation in MECP2 exon 1 has been reported. This is the first reported case of a male with classic RTT caused by a 5-bp duplication in the open-reading frame of MECP2 exon 1 (NM_001110792.1:c.23_27dup) that introduced a premature stop codon [p.(Ser10Argfs*36)] in the MeCP2_e1 isoform, which has been reported in one female patient with classic RTT. Therefore, both males and females displaying at least some type of MeCP2_e1 mutation may exhibit the classic RTT phenotype. © 2018 Wiley Periodicals, Inc.

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. (c) 2009 Movement Disorder Society.

Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease.

PubMed

Allou, L; Julia, S; Amsallem, D; El Chehadeh, S; Lambert, L; Thevenon, J; Duffourd, Y; Saunier, A; Bouquet, P; Pere, S; Moustaïne, A; Ruaud, L; Roth, V; Jonveaux, P; Philippe, C

2017-03-01

Several genes have been implicated in Rett syndrome (RTT) in its typical and variant forms. We applied next-generation sequencing (NGS) to evaluate for mutations in known or new candidate genes in patients with variant forms of Rett or Rett-like phenotypes of unknown molecular aetiology. In the first step, we used NGS with a custom panel including MECP2, CDKL5, FOXG1, MEF2C and IQSEC2. In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free. This missense was maternally inherited with opposite allele expression ratios in the proband and her mother. In the asymptomatic mother, the mutated copy of the CDKL5 gene was inactivated in 90% of blood cells. We also identified a premature stop codon (p.Arg926*) in IQSEC2 in a patient with a Rett-like phenotype. Finally, exome sequencing enabled us to characterize a heterozygous de novo missense (p.Val408Ala) in KCNA2 encoding the potassium channel Kv 1.2 in a girl with infantile-onset seizures variant of RTT. Our study expands the genetic heterogeneity of RTT and RTT-like phenotypes. Moreover, we report the first familial case of CDKL5-related disease. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Variations of stereotypies in individuals with Rett syndrome: A nationwide cross-sectional study in Taiwan.

PubMed

Chin Wong, Lee; Hung, Pi-Lien; Jan, Tz-Yun; Lee, Wang-Tso

2017-07-01

Individuals with Rett syndrome (RTT) can have variable manifestations of stereotypies. In this nation-wide cross-sectional study, we recruited all individuals with RTT in Taiwan diagnosed as RTT by neurologists based on genetic findings and diagnostic criteria. The data were collected using questionnaire. A total 43 cases of typical RTT and 15 cases of atypical RTT, aged from 2.1 to 40.1 years, were enrolled. They included 3 (5.2%) in stage II, 42 (72.4%) in stage III, and 13 (22.4%) in stage IV. All individuals presented with at least one stereotypy. Individuals with atypical RTT had more varied stereotypies (mean: 14 ± 6) compared to those with typical RTT (mean: 9 ± 5) (P = 0.003). Flapping (73.3%) and wringing (58.1%) were the most common hand stereotypies in atypical and typical RTT, respectively. Compared with typical RTT, hair pulling, bruxism, retropulsion, and protrusion of lips were more common in atypical RTT (P = 0.003, P = 0.006, P = 0.003 and <0.001, respectively). The number of stereotypies did not differ among different stages, clinical severities, and hand functions. Although there were no age-related changes in stereotypies in atypical RTT, flapping (P = 0.012), clapping (P = 0.044), and mouthing with single hand (P = 0.009) were significantly more prevalent in individuals aged <10 years with typical RTT, and they decreased after 10 years. In conclusion, our study showed that the stereotypical movements varied in typical and atypical RTT, implying the heterogeneous nature of the disease and the pathogenic mechanisms of RTT with atypical features. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1204-1214. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Effect of Sarizotan, a 5-HT1a and D2-like receptor agonist, on respiration in three mouse models of Rett syndrome.

PubMed

Abdala, Ana P; Lioy, Daniel T; Garg, Saurabh K; Knopp, Sharon J; Paton, Julian F R; Bissonnette, John M

2014-06-01

Disturbances in respiration are common and debilitating features of Rett syndrome (RTT). A previous study showed that the 5-HT1a receptor agonist (R)-(+)-8-hydroxy-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT) significantly reduced the incidence of apnea and the irregular breathing pattern in a mouse model of the disorder. 8-OH-DPAT, however, is not available for clinical practice. Sarizotan, a full 5-HT1a agonist and a dopamine D2-like agonist/partial agonist, has been used in clinical trials for the treatment of l-dopa-induced dyskinesia. The purpose of this study was to evaluate the effects of sarizotan on respiration and locomotion in mouse models of RTT. Studies were performed in Bird and Jaenisch strains of methyl-CpG-binding protein 2--deficient heterozygous female and Jaenisch strain Mecp2 null male mice and in knock-in heterozygous female mice of a common nonsense mutation (R168X). Respiratory pattern was determined with body plethysmography, and locomotion was determined with open-field recording. Sarizotan or vehicle was administered 20 minutes before a 30-minute recording of respiratory pattern or motor behavior. In separate studies, a crossover design was used to administer the drug for 7 and for 14 days. Sarizotan reduced the incidence of apnea in all three RTT mouse models to approximately 15% of their pretreatment levels. The irregular breathing pattern was corrected to that of wild-type littermates. When administered for 7 or 14 days, apnea decreased to 25 to 33% of the incidence seen with vehicle. This study indicates that the clinically approved drug sarizotan is an effective treatment for respiratory disorders in mouse models of RTT.

A case of a Tunisian Rett patient with a novel double-mutation of the MECP2 gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fendri-Kriaa, Nourhene, E-mail: nourhene.fendri@gmail.com; Hsairi, Ines; Kifagi, Chamseddine

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 monthsmore » 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.« less

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

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. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Clinical and neurophysiological aspects of severe forms of autism in children].

PubMed

Simashkova, N V; Iakupova, L P; Bashina, V M

2006-01-01

The aim of the study was to elucidate fundamentals for the phenomenon of universality of childhood autism by comparison of clinical and neurophysiological features of its severest forms--children endogenous autism (CEA) and Rett's syndrome (RS). Each group included 20 patients. Both groups were similar by age-at-disease-onset, clinical appearances during the disease course and dynamics of psychopathological syndromes. The theta-rhythm is common for CEA and RS at the disease stage with marked signs of disease acuity, autism, regress and, therefore, may be regarded as a marker of severity and development delay. The universality of autism phenomenon in its severe forms was confirmed both at the clinical and neurophysiological levels.

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

PubMed

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

2012-01-01

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

Cell cloning-based transcriptome analysis in Rett patients: relevance to the pathogenesis of Rett syndrome of new human MeCP2 target genes.

PubMed

Nectoux, J; Fichou, Y; Rosas-Vargas, H; Cagnard, N; Bahi-Buisson, N; Nusbaum, P; Letourneur, F; Chelly, J; Bienvenu, T

2010-07-01

More than 90% of Rett syndrome (RTT) patients have heterozygous mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene that encodes the methyl-CpG-binding protein 2, a transcriptional modulator. Because MECP2 is subjected to X chromosome inactivation (XCI), girls with RTT either express the wild-type or mutant allele in each individual cell. To test the consequences of MECP2 mutations resulting from a genome-wide transcriptional dysregulation and to identify its target genes in a system that circumvents the functional mosaicism resulting from XCI, we carried out gene expression profiling of clonal populations derived from fibroblast primary cultures expressing exclusively either the wild-type or the mutant MECP2 allele. Clonal cultures were obtained from skin biopsy of three RTT patients carrying either a non-sense or a frameshift MECP2 mutation. For each patient, gene expression profiles of wild-type and mutant clones were compared by oligonucleotide expression microarray analysis. Firstly, clustering analysis classified the RTT patients according to their genetic background and MECP2 mutation. Secondly, expression profiling by microarray analysis and quantitative RT-PCR indicated four up-regulated genes and five down-regulated genes significantly dysregulated in all our statistical analysis, including excellent potential candidate genes for the understanding of the pathophysiology of this neurodevelopmental disease. Thirdly, chromatin immunoprecipitation analysis confirmed MeCP2 binding to respective CpG islands in three out of four up-regulated candidate genes and sequencing of bisulphite-converted DNA indicated that MeCP2 preferentially binds to methylated-DNA sequences. Most importantly, the finding that at least two of these genes (BMCC1 and RNF182) were shown to be involved in cell survival and/or apoptosis may suggest that impaired MeCP2 function could alter the survival of neurons thus compromising brain function without inducing cell death.

Effect of Sarizotan, a 5-HT1a and D2-Like Receptor Agonist, on Respiration in Three Mouse Models of Rett Syndrome

PubMed Central

Abdala, Ana P.; Lioy, Daniel T.; Garg, Saurabh K.; Knopp, Sharon J.; Paton, Julian F. R.

2014-01-01

Disturbances in respiration are common and debilitating features of Rett syndrome (RTT). A previous study showed that the 5-HT1a receptor agonist (R)-(+)-8-hydroxy-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT) significantly reduced the incidence of apnea and the irregular breathing pattern in a mouse model of the disorder. 8-OH-DPAT, however, is not available for clinical practice. Sarizotan, a full 5-HT1a agonist and a dopamine D2–like agonist/partial agonist, has been used in clinical trials for the treatment of l-dopa–induced dyskinesia. The purpose of this study was to evaluate the effects of sarizotan on respiration and locomotion in mouse models of RTT. Studies were performed in Bird and Jaenisch strains of methyl-CpG–binding protein 2-–deficient heterozygous female and Jaenisch strain Mecp2 null male mice and in knock-in heterozygous female mice of a common nonsense mutation (R168X). Respiratory pattern was determined with body plethysmography, and locomotion was determined with open-field recording. Sarizotan or vehicle was administered 20 minutes before a 30-minute recording of respiratory pattern or motor behavior. In separate studies, a crossover design was used to administer the drug for 7 and for 14 days. Sarizotan reduced the incidence of apnea in all three RTT mouse models to approximately 15% of their pretreatment levels. The irregular breathing pattern was corrected to that of wild-type littermates. When administered for 7 or 14 days, apnea decreased to 25 to 33% of the incidence seen with vehicle. This study indicates that the clinically approved drug sarizotan is an effective treatment for respiratory disorders in mouse models of RTT. PMID:24351104

Finding patients using similarity measures in a rare diseases-oriented clinical data warehouse: Dr. Warehouse and the needle in the needle stack.

PubMed

Garcelon, Nicolas; Neuraz, Antoine; Benoit, Vincent; Salomon, Rémi; Kracker, Sven; Suarez, Felipe; Bahi-Buisson, Nadia; Hadj-Rabia, Smail; Fischer, Alain; Munnich, Arnold; Burgun, Anita

2017-09-01

In the context of rare diseases, it may be helpful to detect patients with similar medical histories, diagnoses and outcomes from a large number of cases with automated methods. To reduce the time to find new cases, we developed a method to find similar patients given an index case leveraging data from the electronic health records. We used the clinical data warehouse of a children academic hospital in Paris, France (Necker-Enfants Malades), containing about 400,000 patients. Our model was based on a vector space model (VSM) to compute the similarity distance between an index patient and all the patients of the data warehouse. The dimensions of the VSM were built upon Unified Medical Language System concepts extracted from clinical narratives stored in the clinical data warehouse. The VSM was enhanced using three parameters: a pertinence score (TF-IDF of the concepts), the polarity of the concept (negated/not negated) and the minimum number of concepts in common. We evaluated this model by displaying the most similar patients for five different rare diseases: Lowe Syndrome (LOWE), Dystrophic Epidermolysis Bullosa (DEB), Activated PI3K delta Syndrome (APDS), Rett Syndrome (RETT) and Dowling Meara (EBS-DM), from the clinical data warehouse representing 18, 103, 21, 84 and 7 patients respectively. The percentages of index patients returning at least one true positive similar patient in the Top30 similar patients were 94% for LOWE, 97% for DEB, 86% for APDS, 71% for EBS-DM and 99% for RETT. The mean number of patients with the exact same genetic diseases among the 30 returned patients was 51%. This tool offers new perspectives in a translational context to identify patients for genetic research. Moreover, when new molecular bases are discovered, our strategy will help to identify additional eligible patients for genetic screening. Copyright © 2017. Published by Elsevier Inc.

CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling.

PubMed

Chen, Qian; Zhu, Yong-Chuan; Yu, Jing; Miao, Sheng; Zheng, Jing; Xu, Li; Zhou, Yang; Li, Dan; Zhang, Chi; Tao, Jiong; Xiong, Zhi-Qi

2010-09-22

Mutations in cyclin-dependent kinase-like 5 (CDKL5), also known as serine/threonine kinase 9 (STK9), have been identified in patients with Rett syndrome (RTT) and X-linked infantile spasm. However, the function of CDKL5 in the brain remains unknown. Here, we report that CDKL5 is a critical regulator of neuronal morphogenesis. We identified a neuron-specific splicing variant of CDKL5 whose expression was markedly induced during postnatal development of the rat brain. Downregulating CDKL5 by RNA interference (RNAi) in cultured cortical neurons inhibited neurite growth and dendritic arborization, whereas overexpressing CDKL5 had opposite effects. Furthermore, knocking down CDKL5 in the rat brain by in utero electroporation resulted in delayed neuronal migration, and severely impaired dendritic arborization. In contrast to its proposed function in the nucleus, we found that CDKL5 regulated dendrite development through a cytoplasmic mechanism. In fibroblasts and in neurons, CDKL5 colocalized and formed a protein complex with Rac1, a critical regulator of actin remodeling and neuronal morphogenesis. Overexpression of Rac1 prevented the inhibition of dendrite growth caused by CDKL5 knockdown, and the growth-promoting effect of ectopically expressed CDKL5 on dendrites was abolished by coexpressing a dominant-negative form of Rac1. Moreover, CDKL5 was required for brain-derived neurotrophic factor (BDNF)-induced activation of Rac1. Together, these results demonstrate a critical role of CDKL5 in neuronal morphogenesis and identify a Rho GTPase signaling pathway which may contribute to CDKL5-related disorders.

mGlu5 positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett syndrome

PubMed Central

Gogliotti, Rocco G.; Senter, Rebecca K.; Rook, Jerri M.; Ghoshal, Ayan; Zamorano, Rocio; Malosh, Chrysa; Stauffer, Shaun R.; Bridges, Thomas M.; Bartolome, Jose M.; Daniels, J. Scott; Jones, Carrie K.; Lindsley, Craig W.; Conn, P. Jeffrey; Niswender, Colleen M.

2016-01-01

Rett syndrome (RS) is a neurodevelopmental disorder that shares many symptomatic and pathological commonalities with idiopathic autism. Alterations in protein synthesis-dependent synaptic plasticity (PSDSP) are a hallmark of a number of syndromic forms of autism; in the present work, we explore the consequences of disruption and rescue of PSDSP in a mouse model of RS. We report that expression of a key regulator of synaptic protein synthesis, the metabotropic glutamate receptor 5 (mGlu5) protein, is significantly reduced in both the brains of RS model mice and in the motor cortex of human RS autopsy samples. Furthermore, we demonstrate that reduced mGlu5 expression correlates with attenuated DHPG-induced long-term depression in the hippocampus of RS model mice, and that administration of a novel mGlu5 positive allosteric modulator (PAM), termed VU0462807, can rescue synaptic plasticity defects. Additionally, treatment of Mecp2-deficient mice with VU0462807 improves motor performance (open-field behavior and gait dynamics), corrects repetitive clasping behavior, as well as normalizes cued fear-conditioning defects. Importantly, due to the rationale drug discovery approach used in its development, our novel mGlu5 PAM improves RS phenotypes and synaptic plasticity defects without evoking the overt adverse effects commonly associated with potentiation of mGlu5 signaling (i.e. seizures), or affecting cardiorespiratory defects in RS model mice. These findings provide strong support for the continued development of mGlu5 PAMs as potential therapeutic agents for use in RS, and, more broadly, for utility in idiopathic autism. PMID:26936821

Analysis of the parental origin of de novo MECP2 mutations and X chromosome inactivation in 24 sporadic patients with Rett syndrome in China.

PubMed

Zhu, Xingwang; Li, Meirong; Pan, Hong; Bao, Xinhua; Zhang, Jingjing; Wu, Xiru

2010-07-01

Rett syndrome is an X-linked neurodevelopmental disorder that predominantly affects females. It is caused by mutations in methyl-CpG-binding protein 2 gene. Due to the sex-limited expression, it has been suggested that de novo X-linked mutations may exclusively occur in male germ cells and thus only females are affected. In this study, the authors have analyzed the parental origin of mutations and the X-chromosome inactivation status in 24 sporadic patients with identified methyl-CpG-binding protein 2 gene mutations. The results showed that 22 of 24 patients have a paternal origin. Only 2 patients have a maternal origin. Except for 2 cases which were homozygotic at the androgen receptor gene locus, of the remaining 22 cases, 16 cases have a random X-chromosome inactivation pattern; the other 6 cases have a skewed X-chromosome inactivation and they favor expression of the wild allele. The relationship between X-chromosome inactivation and phenotype may need more cases to explore.

The disruption of central CO2 chemosensitivity in a mouse model of Rett syndrome

PubMed Central

Zhang, Xiaoli; Su, Junda; Cui, Ningren; Gai, Hongyu; Wu, Zhongying

2011-01-01

People with Rett syndrome (RTT) have breathing instability in addition to other neuropathological manifestations. The breathing disturbances contribute to the high incidence of unexplained death and abnormal brain development. However, the cellular mechanisms underlying the breathing abnormalities remain unclear. To test the hypothesis that the central CO2 chemoreception in these people is disrupted, we studied the CO2 chemosensitivity in a mouse model of RTT. The Mecp2-null mice showed a selective loss of their respiratory response to 1–3% CO2 (mild hypercapnia), whereas they displayed more regular breathing in response to 6–9% CO2 (severe hypercapnia). The defect was alleviated with the NE uptake blocker desipramine (10 mg·kg−1·day−1 ip, for 5–7 days). Consistent with the in vivo observations, in vitro studies in brain slices indicated that CO2 chemosensitivity of locus coeruleus (LC) neurons was impaired in Mecp2-null mice. Two major neuronal pH-sensitive Kir currents that resembled homomeric Kir4.1 and heteromeric Ki4.1/Kir5.1 channels were identified in the LC neurons. The screening of Kir channels with real-time PCR indicated the overexpression of Kir4.1 in the LC region of Mecp2-null mice. In a heterologous expression system, an overexpression of Kir4.1 resulted in a reduction in the pH sensitivity of the heteromeric Kir4.1-Kir5.1 channels. Given that Kir4.1 and Kir5.1 subunits are also expressed in brain stem respiration-related areas, the Kir4.1 overexpression may not allow CO2 to be detected until hypercapnia becomes severe, leading to periodical hyper- and hypoventilation in Mecp2-null mice and, perhaps, in people with RTT as well. PMID:21307341

Spinal fusion for scoliosis in Rett syndrome with an emphasis on early postoperative complications.

PubMed

Gabos, Peter G; Inan, Muharrem; Thacker, Mihir; Borkhu, Buttugs

2012-01-15

Retrospective case-control study. To examine the postoperative complications of posterior spinal fusion in a population of patients with Rett syndrome (RS). Scoliosis is a common feature of RS, a progressive neurologic disorder affecting almost exclusively females. Despite this, there is little published information regarding the surgical treatment of scoliosis in this disorder. Sixteen consecutive female patients with RS treated by posterior spinal fusion and unit rod instrumentation for progressive scoliosis between 1995 and 2003 were evaluated. Only patients with a minimum of 2-year follow-up were included. Preoperative medical conditions and postoperative complications were recorded. As a control group, we randomly selected 32 spastic quadriplegic patients who underwent the identical procedure during the same time period, selected from our database and matched according to age, level of neurologic impairment, and medical complexity. There was a high rate of early medical complications in the RS patients, with 28 major and 37 minor complications. Only 1 patient did not have a major medical complication, and every patient had at least 1 minor gastrointestinal and/or respiratory complication. Major respiratory complications occurred in 10 patients (63%) and comprised 61% of all major complications. Major gastrointestinal complications occurred in 6 patients (37%) and comprised 21% of all major complications. Other major complications included disseminated intravascular coagulopathy (1 patient), subacute bacterial endocarditis (1 patient), sacral decubiti requiring surgical debridement (2 patients), and extensive bilateral heterotopic ossification of the hips (1 patient). There were no cases of instrumentation failure, pseudarthrosis, deep infection, or need for rod revision. Postoperative complication scores were similar to those in patients with spastic quadriplegic pattern cerebral palsy. Spinal fusion for scoliosis in RS can give a satisfactory technical result

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

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

PubMed Central

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

2013-01-01

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. PMID:24150225

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.

Increased Mitochondrial Mass and Cytosolic Redox Imbalance in Hippocampal Astrocytes of a Mouse Model of Rett Syndrome: Subcellular Changes Revealed by Ratiometric Imaging of JC-1 and roGFP1 Fluorescence

PubMed Central

Bebensee, Dörthe F.

2017-01-01

Rett syndrome (RTT) is a neurodevelopmental disorder with mutations in the MECP2 gene. Mostly girls are affected, and an apparently normal development is followed by cognitive impairment, motor dysfunction, epilepsy, and irregular breathing. Various indications suggest mitochondrial dysfunction. In Rett mice, brain ATP levels are reduced, mitochondria are leaking protons, and respiratory complexes are dysregulated. Furthermore, we found in MeCP2-deficient mouse (Mecp2−/y) hippocampus an intensified mitochondrial metabolism and ROS generation. We now used emission ratiometric 2-photon imaging to assess mitochondrial morphology, mass, and membrane potential (ΔΨm) in Mecp2−/y hippocampal astrocytes. Cultured astrocytes were labeled with the ΔΨm marker JC-1, and semiautomated analyses yielded the number of mitochondria per cell, their morphology, and ΔΨm. Mecp2−/y astrocytes contained more mitochondria than wild-type (WT) cells and were more oxidized. Mitochondrial size, ΔΨm, and vulnerability to pharmacological challenge did not differ. The antioxidant Trolox opposed the oxidative burden and decreased the mitochondrial mass, thereby dampening the differences among WT and Mecp2−/y astrocytes; mitochondrial size and ΔΨm were not markedly affected. In conclusion, mitochondrial alterations and redox imbalance in RTT also involve astrocytes. Mitochondria are more numerous in Mecp2−/y than in WT astrocytes. As this genotypic difference is abolished by Trolox, it seems linked to the oxidative stress in RTT. PMID:28894505

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

NASA Astrophysics Data System (ADS)

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

2017-02-01

Rett Syndrome (RTT) is a pervasive, X-linked neurodevelopmental disorder that predominantly affects girls. It is mostly caused by a sporadic mutation in the gene encoding methyl CpG-binding protein 2 (MeCP2).The clinical features of RTT are most commonly reported to emerge between the ages of 6-18 months and implicating RTT as a disorder of postnatal development. However, a variety of recent evidence from our lab and others demonstrates that RTT phenotypes are present at the earliest stages of brain development including neurogenesis, migration, and patterning in addition to stages of synaptic and circuit development and plasticity. We have used RTT patient-derived induced pluripotent stem cells to generate 3D human cerebral organoids that can serve as a model for human neurogenesis in vitro. We aim to expand on our existing findings in order to determine aberrancies at individual stages of neurogenesis by performing structural and immunocytochemical staining in isogenic control and MeCP2-deficient organoids. In addition, we aim to use Third Harmonic Generation (THG) microscopy as a label-free, nondestructive 3D tissue visualization method in order to gain a complete understanding of the structural complexity that underlies human neurogenesis. As a proof of concept, we have performed THG imaging in healthy intact human cerebral organoids cleared with SWITCH. We acquired an intrinsic THG signal with the following laser configurations: 400 kHz repetition rate, 65 fs pulse width laser at 1350 nm wavelength. In these THG images, nuclei are clearly delineated and cross sections demonstrate the depth penetration capacity (< 1mm) that extends throughout the organoid. Imaging control and MeCP2-deficient human cerebral organoids in 2D sections reveals structural and protein expression-based alterations that we expect will be clearly elucidated via both THG and three-photon fluorescence microscopy.

Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms.

PubMed

Zahorakova, Daniela; Rosipal, Robert; Hadac, Jan; Zumrova, Alena; Bzduch, Vladimir; Misovicova, Nadezda; Baxova, Alice; Zeman, Jiri; Martasek, Pavel

2007-01-01

Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder in females, is caused mainly by de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). Here we report mutation analysis of the MECP2 gene in 87 patients with RTT from the Czech and Slovak Republics, and Ukraine. The patients, all girls, with classical RTT were investigated for mutations using bi-directional DNA sequencing and conformation sensitive gel electrophoresis analysis of the coding sequence and exon/intron boundaries of the MECP2 gene. Restriction fragment length polymorphism analysis was performed to confirm the mutations that cause the creation or abolition of the restriction site. Mutation-negative cases were subsequently examined by multiple ligation-dependent probe amplification (MLPA) to identify large deletions. Mutation screening revealed 31 different mutations in 68 patients and 12 non-pathogenic polymorphisms. Six mutations have not been previously published: two point mutations (323T>A, 904C>T), three deletions (189_190delGA, 816_832del17, 1069delAGC) and one deletion/inversion (1063_1236del174;1189_1231inv43). MLPA analysis revealed large deletions in two patients. The detection rate was 78.16%. Our results confirm the high frequency of MECP2 mutations in females with RTT and provide data concerning the mutation heterogeneity in the Slavic population.

Seizures and EEG features in 74 patients with genetic-dysmorphic syndromes.

PubMed

Alfei, Enrico; Raviglione, Federico; Franceschetti, Silvana; D'Arrigo, Stefano; Milani, Donatella; Selicorni, Angelo; Riva, Daria; Zuffardi, Orsetta; Pantaleoni, Chiara; Binelli, Simona

2014-12-01

Epilepsy is one of the most common findings in chromosome aberrations. Types of seizures and severity may significantly vary both between different conditions and within the same aberration. Hitherto specific seizures and EEG patterns are identified for only few syndromes. We studied 74 patients with defined genetic-dysmorphic syndromes with and without epilepsy in order to assess clinical and electroencephalographic features, to compare our observation with already described electro-clinical phenotypes, and to identify putative electroencephalographic and/or seizure characteristics useful to address the diagnosis. In our population, 10 patients had chromosomal disorders, 19 microdeletion or microduplication syndromes, and 32 monogenic syndromes. In the remaining 13, syndrome diagnosis was assessed on clinical grounds. Our study confirmed the high incidence of epilepsy in genetic-dysmorphic syndromes. Moreover, febrile seizures and neonatal seizures had a higher incidence compared to general population. In addition, more than one third of epileptic patients had drug-resistant epilepsy. EEG study revealed poor background organization in 42 patients, an excess of diffuse rhythmic activities in beta, alpha or theta frequency bands in 34, and epileptiform patterns in 36. EEG was completely normal only in 20 patients. No specific electro-clinical pattern was identified, except for inv-dup15, Angelman, and Rett syndromes. Nevertheless some specific conditions are described in detail, because of notable differences from what previously reported. Regarding the diagnostic role of EEG, we found that--even without any epileptiform pattern--the generation of excessive rhythmic activities in different frequency bandwidths might support the diagnosis of a genetic syndrome. © 2014 Wiley Periodicals, Inc.

The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy.

PubMed

Fehr, Stephanie; Wilson, Meredith; Downs, Jenny; Williams, Simon; Murgia, Alessandra; Sartori, Stefano; Vecchi, Marilena; Ho, Gladys; Polli, Roberta; Psoni, Stavroula; Bao, Xinhua; de Klerk, Nick; Leonard, Helen; Christodoulou, John

2013-03-01

The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant.

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

Selective preservation of cholinergic MeCP2 rescues specific Rett-syndrome-like phenotypes in MeCP2stop mice.

PubMed

Zhou, Huanhuan; Wu, Wei; Zhang, Ying; He, Haiyang; Yuan, Zhefeng; Zhu, Zhiwei; Zhao, Zhengyan

2017-03-30

RTT is a neurodevelopmental disorder characterized by growth regression, motor dysfunction, stereotypic hand movements, and autism features. Typical Rett syndrome (RTT) is predominantly caused by mutations in X-linked MeCP2 gene which encodes methyl-CpG-binding protein 2 (MeCP2). The brain-abundant MeCP2 protein mainly functions as a transcriptional regulator for neurodevelopment-associated genes. Specific functions of MeCP2 in certain neuron types remain to be known. Although cholinergic system is an important modulating system in brain, how MeCP2 in cholinergic neurons contribute to RTT has not been clearly understood. Here we use a mouse model with selectively activated endogenous MeCP2 in cholinergic neurons in otherwise MeCP2 stop mice to determine the cholinergic MeCP2 effects on rescuing the RTT-like phenotypes. We found cholinergic MeCP2 preservation could reverse some aspects of the RTT-like phenotypes in mice including hypolocomotion and increased anxiety level, and delay the onset of underweight, instead of improving the hypersocial abnormality and the poor general conditions such as short lifespan, low brain weight, and increasing severity score. Our findings suggest that selective activation of cholinergic MeCP2 is sufficient to reverse the locomotor impairment and increased anxiety-like behaviors at least in early symptomatic stage, supporting future development of RTT therapies associated with cholinergic system. Copyright © 2017 Elsevier B.V. All rights reserved.

The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy

PubMed Central

Fehr, Stephanie; Wilson, Meredith; Downs, Jenny; Williams, Simon; Murgia, Alessandra; Sartori, Stefano; Vecchi, Marilena; Ho, Gladys; Polli, Roberta; Psoni, Stavroula; Bao, Xinhua; de Klerk, Nick; Leonard, Helen; Christodoulou, John

2013-01-01

The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant. PMID:22872100

How Do Health Care Providers Diagnose Rett Syndrome?

MedlinePlus

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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

Characterization of the Pathological and Biochemical Markers that Correlate to the Clinical Features of Autism

DTIC Science & Technology

2009-10-01

Specified (PDD-NOS), Asperger disorder, Childhood Disintegrative Disorder (CDD) and Rett syndrome . According to the Centers for Disease Control (CDC), 1 in...induced epilepsy (Fernandes et al., 1996; Reime et al., 2007), and in Crush syndrome (Desai and Desai, 2007). In chronic fatigue syndrome , the...the gene encoding the L-type voltage-gated Ca2+channel CaV1.2 (CACNA1C) cause Timothy syndrome , a multisystem disorder that includes cardiac

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.

Comparing Parental Well-Being and Its Determinants across Three Different Genetic Disorders Causing Intellectual Disability

ERIC Educational Resources Information Center

Mori, Yuka; Downs, Jenny; Wong, Kingsley; Heyworth, Jane; Leonard, Helen

2018-01-01

Using the Short Form 12 Health Survey this cross-sectional study examined parental well-being in caregivers of children with one of three genetic disorders associated with intellectual disability; Down syndrome, Rett syndrome and the CDKL5 disorder. Data were sourced from the Western Australian Down Syndrome (n = 291), Australian Rett Syndrome (n…

Comparing Parental Well-Being and Its Determinants Across Three Different Genetic Disorders Causing Intellectual Disability.

PubMed

Mori, Yuka; Downs, Jenny; Wong, Kingsley; Heyworth, Jane; Leonard, Helen

2018-05-01

Using the Short Form 12 Health Survey this cross-sectional study examined parental well-being in caregivers of children with one of three genetic disorders associated with intellectual disability; Down syndrome, Rett syndrome and the CDKL5 disorder. Data were sourced from the Western Australian Down Syndrome (n = 291), Australian Rett Syndrome (n = 187) and International CDKL5 Disorder (n = 168) Databases. Among 596 mothers (median age, years 43.7; 24.6-72.2), emotional well-being was poorer than general female populations across age groups. Multivariate linear regression identified the poorest well-being in parents of children with the CDKL5 disorder, a rare but severe and complex encephalopathy, and negative associations with increased clinical severity irrespective of diagnosis. These findings are important for those providing healthcare and social services for these populations.

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

Horner syndrome: clinical perspectives

PubMed Central

Kanagalingam, Sivashakthi; Miller, Neil R

2015-01-01

Horner syndrome consists of unilateral ptosis, an ipsilateral miotic but normally reactive pupil, and in some cases, ipsilateral facial anhidrosis, all resulting from damage to the ipsilateral oculosympathetic pathway. Herein, we review the clinical signs and symptoms that can aid in the diagnosis and localization of a Horner syndrome as well as the causes of the condition. We emphasize that pharmacologic testing can confirm its presence and direct further testing and management. PMID:28539793

Marfan Syndrome: A Clinical Update.

PubMed

Bitterman, Adam D; Sponseller, Paul D

2017-09-01

Marfan syndrome is a connective tissue disorder that can affect many organ systems. Affected patients present with orthopaedic manifestations of the syndrome during all phases of life. Pain caused by musculoskeletal abnormalities often requires definitive orthopaedic treatment. Orthopaedic surgeons must understand the phenotypes of Marfan syndrome so they can recognize when screening is warranted and can appropriately address the skeletal manifestations. Through medical advancements, patients with Marfan syndrome are living longer and more active lives. Knowledge of the latest diagnostic criteria for the disorder, as well as of advances in understanding the skeletal phenotype, clinical trials of medication therapy, and lifestyle considerations is important for orthopaedic surgeons who treat these patients because these clinicians often are the first to suspect Marfan syndrome and recommend screening.

Secondary Dystonia-Clinical Clues and Syndromic Associations

PubMed Central

Schneider, Susanne A; Bhatia, Kailash P

2009-01-01

Background: Dystonia is a hyperkinetic movement disorder defined by involuntary sustained muscle spasms and unusual postures. Etiologically, dystonic syndromes can be broadly divided into primary and secondary forms, dystonia-plus syndromes and heredodegenerative forms. In particular, diagnosis of secondary dystonic syndromes can be challenging in view of the variety of causes. Purpose: The purpose of this article is to highlight some clinical clues and syndromic associations as well as investigational findings which may be helpful in the approach to a patient with suspected secondary dystonia. Methods: We outline characteristic clinical and neuroimaging findings which may be directive in the diagnostic process of dystonia patients and facilitate making the correct diagnosis, thus allowing initiating the best treatment. Results: Secondary causes of dystonia include, among others, strategic brain lesions of various origins, metabolic disease, neurodegenerative conditions, and previous exposure to drugs or toxins. Presence of clinical signs including prominent oromandibular involvement, eye movement disorders, retinitis pigmentosa, deafness, peripheral neuropathy, parkinsonism or progressive dementia should alert the clinician to consider a secondary cause. Strategic lesions within the basal ganglia, but also within the brainstem, cerebellum or cortical areas may underlie dystonia and should thus be excluded. Conclusions: When thorough clinical examination reveals features atypical of primary dystonia, syndromic associations may help the clinician to narrow down the list of differential diagnosis. Directive investigations like neuroimaging may confirm the clinical suspicion. PMID:24868358

Marfan Syndrome: Clinical, Surgical, and Anesthetic Considerations.

PubMed

Castellano, José M; Silvay, George; Castillo, Javier G

2014-09-01

Marfan syndrome is a multisystem connective tissue disorder, with primary involvement of the cardiovascular, ocular, and skeletal systems. This autosomal heritable disease is mainly attributable to a defect in the FBN1 gene. Clinical diagnosis of Marfan syndrome has been based on the Ghent criteria since 1996. In 2010, these criteria were updated, and the revised guidelines place more emphasis on aortic root dilation, ectopia lentis, and FBN1 mutation testing in the diagnostic assessment of Marfan syndrome. Among its many different clinical manifestations, cardiovascular involvement deserves special consideration, owing to its impact on prognosis. Recent molecular, surgical, and clinical research has yielded profound new insights into the pathological mechanisms that ultimately lead to tissue degradation and weakening of the aortic wall, which has led to exciting new treatment strategies. Furthermore, with the increasing life expectancy of patients with Marfan syndrome, there has been a subtle shift in the spectrum of medical problems. Consequently, this article focuses on recent advances to highlight their potential impact on future concepts of patient care from a clinical, surgical, and anesthetic perspective. © The Author(s) 2013.

CLINICAL AND IMAGING FEATURES OF OTHELLO'S SYNDROME

PubMed Central

Graff-Radford, Jonathan; Whitwell, Jennifer L.; Geda, Yonas E.; Josephs, Keith A.

2011-01-01

Background Our objective was to document the clinical and imaging features of Othello's syndrome (delusional jealousy). Methods The study design was a retrospective case series of 105 patients with Othello's syndrome that were identified by using the Electronic Medical Record system of Mayo Clinic. Results The average age at onset of Othello's syndrome was 68 (25–94) years with 61.9% of patients being male. Othello's syndrome was most commonly associated with a neurological disorder (73/105) compared with psychiatric disorders (32/105). Of the patients with a neurological disorder, 76.7% had a neurodegenerative disorder. Seven of eight patients with a structural lesion associated with Othello's syndrome had right frontal lobe pathology. Voxel-based morphometry showed greater grey matter loss predominantly in the dorsolateral frontal lobes in the neurodegenerative patients with Othello's compared to matched patients with neurodegenerative disorders without Othello's syndrome. Treatment success was notable for patients with dopamine agonist induced Othello's syndrome in which all six patients had improvement in symptoms following decrease in medication. Conclusions This study demonstrates that Othello's syndrome occurs most frequently with neurological disorders. This delusion appears to be associated with dysfunction of the frontal lobes, especially right frontal lobe. PMID:21518145

Overview of Social Cognitive Dysfunctions in Rare Developmental Syndromes With Psychiatric Phenotype

PubMed Central

Morel, Aurore; Peyroux, Elodie; Leleu, Arnaud; Favre, Emilie; Franck, Nicolas; Demily, Caroline

2018-01-01

Rare neurodevelopmental syndromes often present social cognitive deficits that may underlie difficulties in social interactions and increase the risk of psychosis or autism spectrum disorders. However, little is known regarding the specificities of social cognitive impairment across syndromes while it remains a major challenge for the care. Our review provides an overview of social cognitive dysfunctions in rare diseases associated with psychiatric symptoms (with a prevalence estimated between 1 in 1,200 and 1 in 25,000 live births: 22q11.2 deletion syndrome, Angelman syndrome, Fragile X syndrome, Klinefelter syndrome, Prader–Willi syndrome, Rett syndrome, Smith–Magenis syndrome, Turner syndrome, and Williams syndrome) and shed some light on the specific mechanisms that may underlie these skills in each clinical presentation. We first detail the different processes included in the generic expression “social cognition” before summarizing the genotype, psychiatric phenotype, and non-social cognitive profile in each syndrome. Then, we offer a systematic review of the social cognitive abilities and the disturbed mechanisms they are likely associated with. We followed the PRISMA process, including the definition of the relevant search terms, the selection of studies based on clear inclusion, and exclusion criteria and the quality appraisal of papers. We finally provide insights that may have considerable influence on the development of adapted therapeutic interventions such as social cognitive training (SCT) therapies specifically designed to target the psychiatric phenotype. The results of this review suggest that social cognition impairments share some similarities across syndromes. We propose that social cognitive impairments are strongly involved in behavioral symptoms regardless of the overall cognitive level measured by intelligence quotient. Better understanding the mechanisms underlying impaired social cognition may lead to adapt therapeutic

Rett syndrome

MedlinePlus

... and height. Weight gain may improve alertness and social interaction. Medicines may be used to treat seizures. Supplements ... Bethesda, MD 20894 U.S. Department of Health and Human Services National Institutes of Health Page last updated: ...

The impact of having a sibling with an intellectual disability: parental perspectives in two disorders.

PubMed

Mulroy, S; Robertson, L; Aiberti, K; Leonard, H; Bower, C

2008-03-01

The potential effects on other children when there is a child with intellectual disability (ID) in the family are being increasingly recognized. This study describes the impact of having a sibling with Down syndrome or Rett syndrome using a questionnaire completed by parents. The parents of 186 Western Australian children with Down syndrome and 141 Australian girls and women with Rett syndrome participated in the study. Patterns of reporting disadvantages and/or benefits were compared across a number of child and family variables (age, functional ability and birth order of the affected child, number of siblings and number of parents in the family home) and by socio-economic status as measured by the index of relative socio-economic disadvantage and by area of residence. Parents' responses to open-ended questions about the benefits and/or disadvantages for siblings of their child were analysed for themes. The majority of parents in the Rett syndrome and Down syndrome groups reported both disadvantages and benefits for siblings. In the Rett syndrome group, families from outer regional areas were the least likely to mention disadvantages and those with a smaller family more likely to note disadvantages. In both groups, more socio-economically advantaged families were more likely to report disadvantages. In the Down syndrome group, benefits were also more commonly reported by parents who were socio-economically advantaged, and by larger and two-parent families. Major disadvantages for siblings centred around parental and personal time constraints, relationships and socializing, restrictions, parental emotion and burden of helping. Major benefits were related to personality characteristics. Parents identified both benefits and disadvantages to the siblings of their child with either Rett syndrome or Down syndrome. It is important that these findings are incorporated into any discussion around the impact on the family of a child diagnosed with an ID.

CSF B-Endorphin Levels in Patients with Infantile Autism.

ERIC Educational Resources Information Center

Nagamitsu, Shinichiro; And Others

1997-01-01

A Japanese study measured CSF (cerebrospinal fluid) levels of beta-endorphin in 19 children (ages 4-6) with infantile autism and in 3 children (ages 10-14) with Rett syndrome. In infantile autism, levels did not differ significantly from control participants (n=23). However, levels were significantly higher in those with Rett syndrome. (Author/CR)

Metabolic syndrome pathophysiology and clinical presentation.

PubMed

Handelsman, Yehuda

2009-01-01

Metabolic syndrome is a relatively new definition, designed to help the health care practitioner to easily identify people at risk for the development of cardiovascular disease and diabetes. With the obesity epidemic, we are witnessing an epidemic of multiple-risk patients. Insulin resistance is the perceived pathophysiology of metabolic syndrome and defines its clinical presentation. Hypertension, dyslipedemia, polycystic ovarian syndrome, fatty liver disease, pre-diabetes, sleep and breathing disorder, certain cancers, and cognitive impairment are many of the presentations of the syndrome; patients with any of these conditions are at a high risk of developing cardiovascular disease and diabetes. The metabolic syndrome helps identify people at risk to allow early intervention for prevention. Lifestyle modification is the most important part of the management of people with the syndrome. Lately medications--though none approved by the U.S. Food and Drug Administration (FDA)--have been recommended by major medical societies when lifestyle modification is not enough or when it fails.

An oral clinical approach to Gorlin-Goltz syndrome.

PubMed

Abreu, Lucas Guimaraes; Paiva, Saul Martins; Pretti, Henrique; Bastos Lages, Elizabeth Maria; Castro, Wagner Henriques

2015-01-01

Gorlin-Goltz syndrome is a rare hereditary disease that can have negative effects on one's quality of life. The main clinical features are multiple nevoid basal cell carcinomas, odontogenic keratocysts, congenital skeletal abnormalities, calcification of the falx cerebri, facial dysmorphism, and skin depressions (pits) on the palms and soles. Diagnosis is based on major and minor clinical and radiological criteria and can be confirmed by DNA analysis. This article describes the case of a child with Gorlin-Goltz syndrome and outlines the clinical manifestations of the disease.

What Are the Symptoms of Rett Syndrome?

MedlinePlus

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Mecp2 truncation in male mice promotes affiliative social behavior

PubMed Central

Pearson, B.L.; Defensor, E.B.; Pobbe, R.L.H.; Yamamoto, L.H.L.; Bolivar, V.J.; Blanchard, D.C.; Blanchard, R.J.

2018-01-01

Mouse models of Rett syndrome, with targeted mutations in the Mecp2 gene, show a high degree of phenotypic consistency with the clinical syndrome. In addition to severe and age-specific regression in motor and cognitive abilities, a variety of studies have demonstrated that Mecp2 mutant mice display impaired social behavior. Conversely, other studies indicate complex enhancements of social behavior in Mecp2 mutant mice. Since social behavior is a complicated accumulation of constructs, we performed a series of classic and refined social behavior tasks and revealed a relatively consistent pattern of enhanced pro-social behavior in hypomorphic Mecp2308/Y mutant mice. Analyses of repetitive motor acts, and cognitive stereotypy did not reveal any profound differences due to genotype. Taken together, these results suggest that the mutations associated with Rett syndrome are not necessarily associated with autism-relevant social impairment in mice. However, this gene may be a valuable candidate for revealing basic mechanisms of affiliative behavior. PMID:21909962

[Clinical analysis of 6 cases of Bartter syndrome].

PubMed

Yin, Fang-mei; Zheng, Fang-qiu; Zhang, Xin; Wu, Mei-jun; Wei, Hong-yan; Ma, Zhong-shu; Lu, Biao; Qiu, Ming-cai

2011-03-01

To summarize the clinical characteristics of Bartter syndrome and investigate its pathogenesis. The clinical data of 6 cases of Bartter syndrome at our hospital from November 2006 to May 2010 were analyzed retrospectively. The onset age of Bartter syndrome was 13-35 years old. The main symptoms included weakness (6/6), paralysis (1/6), numbness (5/6) and tetany (4/6). All patients had normal blood pressure. The biochemical tests showed persistent hypokalemia, metabolic alkalosis (6/6) and hyperreninemia. The pathological examination of deltoid muscle biopsy showed the swelling, degeneration and necrosis of myocytes and the deposition of immunocomplex in myolemma. And the pathological examination of renal biopsy showed the hyperplasia of juxtaglomerular apparatus (5/6) and the deposition of immunocomplex. All symptoms were relieved after a therapy of potassium supplementation or a combination of indomethacin, spironolactone and immunosuppressant. When such clinical features as weakness, paralysis, tetany, hypokalemic alkalosis and normotension are encountered, Bartter syndrome should be suspected. Serum electrolytes, blood gas analysis and activation of the renin-angiotensin-aldosterone system should be examined for a definite diagnosis. The treatment of choice includes potassium and magnesium supplementation or in combination with prostaglandin synthetase inhibitor, aldosterone antagonist and immunosuppressant. Immunologic mechanism may participate in the course of Bartter syndrome.

The SAPHO syndrome: a clinical and imaging study.

PubMed

Sallés, Meritxell; Olivé, Alejandro; Perez-Andres, Ricard; Holgado, Susana; Mateo, Lourdes; Riera, Elena; Tena, Xavier

2011-02-01

The purpose of this study is to describe the clinical and radiological manifestations of patients with the synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. Retrospective study (1984-2007) was performed in a single center. All patients with the SAPHO syndrome were included. Fifty-two patients were included: 26 male, mean age at diagnosis is 42±12 years. Ostearticular involvement was present before cutaneous involvement in 59.6% of patients and concomitantly in 23.5%. Anterior chest pain was the commonest clinical manifestation, it was present in 38 patients (73%), followed by peripheral arthritis in 17 patients (32%), and sacroliliac pain in 14 patients (26.9%). Cutaneous involvement was present in 33 patients (63.5%). HLA B27 antigen was present in eight patients (17.7%). Bone scintigraphy showed an increased uptake in 42 patients (93.3%). The location of the uptake was mainly in sternoclavicular and manubriosternal joints. CT scan was performed in all "hot joints" showing sclerosis, erosions, hyperostosis, and soft tissue involvement. Refractory patients were treated mainly with pamidronate. Although SAPHO syndrome is an entity that share features that fit into a variety of established disease categories, the present study has a homogenous clinical and radiological pattern that gives support to believe that the SAPHO syndrome is an isolated clinical entity.

[Clinical and pathological features of Alport syndrome in children].

PubMed

Zhu, Chun-Hua; Huang, Song-Ming; Wu, Hong-Mei; Bao, Hua-Ying; Chen, Ying; Han, Yuan; Zhao, Fei; Zhang, Ai-Hua; Zhang, Wei-Zhen

2010-03-01

To study the clinical and pathological features of Alport syndrome in children. The clinical and histopathological data of 10 hospitalized children with Alport syndrome from February 2007 to February 2009 were retrospectively reviewed. There were 7 males and 3 females, with the age ranging from 2 years to 6 years and 7 months (mean 3 years and 2 months). Five of 10 cases had positive family history. X-linked dominant inheritance Alport syndrome was diagnosed in 8 cases, and autosomal recessive inheritance Alport syndrome in 2 cases. Recurrent gross hematuria was found in 5 cases, hematuria and proteinuria in 3 cases, massive proteinuria in 1 case, and nephritic syndrome in 1 case. Under the light microscope, 8 cases presented with mesangial proliferation glomerulonephritis, and 2 cases with focal segmental glomerulosclerosis. Immunofluorescence assay showed that all cases had IgM deposition in glomerulus. Only 1 case showed typical glomerular basement membrane (GBM) pathological changes. All cases showed abnormal alpha-chain distribution in renal collagen IV. The children with Alport syndrome have diverse clinical manifestations. Characteristic histopathological presentations could not be found under a light microscope, mesangial proliferation glomerulonephritis is the dominant pathological change, and IgM deposition in glomerulus is common. The GBM pathological change in children is not common. Immunofluorescence assay of alpha-chain in collagen IV is needed for the diagnosis of Alport syndrome.

Temporomandibular joint dysfunction syndrome. A clinical report.

PubMed

Passero, P L; Wyman, B S; Bell, J W; Hirschey, S A; Schlosser, W S

1985-08-01

We have presented two clinical case reports of patients with TMJ dysfunction syndrome as an example of coordinated treatments between dentists and physical therapists. The clinical profiles of these patients with craniocervical pain were compiled from comprehensive physical therapy and dental-orthopedic evaluations. The significance of the relationship between the rest position of the mandible and forward head posture has been shown by the changes observed after correction of the postural deviations and vertical resting dimensions by dental treatments and physical therapy. Additional research is necessary to determine long-term effects of this combined approach in TMJ dysfunction syndrome.

Prevention, clinical, and pathophysiological research on vibration syndrome.

PubMed

Yamada, S; Sakakibara, H; Harada, N; Matsumoto, T

1993-11-01

In the 1950s, introduction of portable power tools into the production process of many industries began on a large scale around the world and resulted in many cases of occupational vibration syndrome after the 1960s. There was an urgent need to undertake preventive steps, medical assessment and therapy throughout the world. At the end of 1964, our investigation began in Japanese national forests, and then in mining and stone quarries. Our research and efforts resulted in a comprehensive system for prevention of vibration syndrome in the Japanese national forest industry. It has presented a good model of prevention for other industries in Japan. Clinical and pathophysiological research on vibration syndrome in the 1960s and 1970s clarified disturbances of the peripheral circulatory, nervous, and musculoskeletal systems. From the mid-1970s, neurophysiological, neurochemical, and clinical research on vibration syndrome in relation to the autonomic nervous system developed. Our studies contributed to the advancement of research in this field. More in-depth study is needed to determine the role of the autonomic nervous system in vibration syndrome.

A novel mutation in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene associated with a severe Rett phenotype.

PubMed

Sprovieri, T; Conforti, F L; Fiumara, A; Mazzei, R; Ungaro, C; Citrigno, L; Muglia, M; Arena, A; Quattrone, A

2009-02-15

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have recently been reported in patients with severe neurodevelopmental disorder characterized by early-onset seizures, infantile spasms, severe psychomotor impairment and very recently, in patients with Rett syndrome (RTT)-like phenotype. Although the involvement of CDKL5 in specific biological pathways and its neurodevelopmental role have not been completely elucidated, the CDKL5 appears to be physiologically related to the MECP2 gene. Here we report on the clinical and CDKL5 molecular investigation in a very unusual RTT case, with severe, early-neurological involvement in which we have shown in a previous report, a novel P388S MECP2 mutation [Conforti et al. (2003); Am J Med Genet A 117A: 184-187]. The patient has had severe psychomotor delay since the first month of life and infantile spasms since age 5 months. Moreover, at age 5 years the patient suddenly presented with renal failure. The severe pattern of symptoms in our patient, similar to a CDKL5 phenotype, prompted us to perform an analysis of the CDKL5, which revealed a novel missense mutation never previously described. The X-inactivation assay was non-informative. In conclusion, this report reinforces the observation that the CDKL5 phenotype overlaps with RTT and that CDKL5 analysis is recommended in patients with a seizure disorder commencing during the first months of life.

[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.

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,…

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

Cauda equina syndrome: evaluation of the clinical outcome.

PubMed

Tamburrelli, F C; Genitiempo, M; Bochicchio, M; Donisi, L; Ratto, C

2014-01-01

Cauda equina syndrome is a rare but highly impairing syndrome involving lower limbs as well as urinary, defecatory and sexual function. In the literature the most investigated sphincter dysfunction is the urinary. Bowel and sexual function are often overlooked since they become more relevant after the acute phase. Eight consecutive male patients affected by cauda equina syndrome with sphincter dysfunction due to herniated disc disease of lumbar spine were treated between 2007 and 2009. Five patients were followed-up for at least two years. Sexual function was evaluated by IIEF-5 questionnaire; bowel function was investigated by means of clinical and instrumental investigation and manometry. Although little clinical improved, patients still complained severe symptoms at first year follow-up while all but one improved significantly in the following year. At two years follow-up only the patient whose cauda equina syndrome was misdiagnosed and surgically treated late respect to the onset of the syndrome, complained a persistent severe sexual and bowel dysfunction. Our results show that a long-term follow-up is mandatory to evaluate the real outcome of surgical managed cauda equine syndrome because short-term evaluation could be misleading about the residual capacity of late neurologic improving. Despite the relatively low number of cases evaluated, our results confirm that early diagnosing and treating the syndrome are relevant for the final outcome.

Clinical manifestations of trisomy 4p syndrome.

PubMed

Patel, S V; Dagnew, H; Parekh, A J; Koenig, E; Conte, R A; Macera, M J; Verma, R S

1995-06-01

Trisomy 4p syndrome is a distinct clinical entity which was noted almost a quarter century ago by Wilson et al. [71] and later was delineated by Gonzalez and colleagues [29]. The variation in the length of duplicated segment usually associated with monosomy of other genetic material which has resulted in confusion and as a result a so-called 4p syndrome could not be recognized without cytogenetic analysis. We wish to draw the attention of clinicians to this subject by presenting the description of over 75 cases including one from our clinic and stress the point that molecular approaches are imperative to characterize this anomaly. After extensive review, it appears that patients retaining at least the distal two-thirds to the entire short arm share an overlapping phenotypic expression that constitutes pure trisomy 4p syndrome which includes prominent glabella, bulbous nose with flat or depressed nasal bridge, retrognathia, pointed chin, short neck with low hairline, enlarged ears with abnormal helix and antihelix, rocker-bottom feet with prominent heel. Arachnodactyly and camptodactyly. Molecular characterization of 4p is imperative. We have also included an extensive bibliography for clinicians who may find it useful as a single reference source for evaluating their future cases. The 4p-syndrome is a distinct entity but without cytogenetic evaluation, the syndrome can not be recognized.

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

PubMed Central

Kron, Miriam; Lang, Min; Adams, Ian T.; Sceniak, Michael; Longo, Frank; Katz, David M.

2014-01-01

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

Cognitive impairment, clinical severity and MRI changes in MELAS syndrome.

PubMed

Kraya, Torsten; Neumann, Lena; Paelecke-Habermann, Yvonne; Deschauer, Marcus; Stoevesandt, Dietrich; Zierz, Stephan; Watzke, Stefan

2017-12-29

To examine clinical severity, cognitive impairment, and MRI changes in patients with MELAS syndrome. Cognitive-mnestic functions, brain MRI (lesion load, cella media index) and clinical severity of ten patients with MELAS syndrome were examined. All patients carried the m.3243A>G mutation. The detailed neuropsychological assessment revealed cognitive deficits in attention, executive function, visuoperception, and -construction. There were significant correlations between these cognitive changes, lesion load in MRI, disturbances in everyday life (clinical scale), and high scores in NMDAS. Patients with MELAS syndrome showed no global neuropsychological deficit, but rather distinct cognitive deficits. Copyright © 2018 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

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…

MECP2 gene study in a large cohort: testing of 240 female patients and 861 healthy controls (519 females and 342 males).

PubMed

Maortua, Hiart; Martínez-Bouzas, Cristina; García-Ribes, Ainhoa; Martínez, María-Jesus; Guillen, Encarna; Domingo, María-Rosario; Calvo, María-Teresa; Guitart, Miriam; Gabau, Elisabeth; Botella, María-Pilar; Gener, Blanca; Rubio, Izaskun; López-Aríztegui, María-Asunción; Tejada, María-Isabel

2013-09-01

The MECP2 gene located on Xq28 is one of the most important genes contributing to the spectrum of neurodevelopmental disorders. Therefore, we present our experience in the molecular study of this gene. MECP2 was thoroughly tested for the presence of mutations (sequencing of four exons and rearrangements) in 120 female patients: 28 with classic Rett syndrome, five with atypical Rett syndrome, and 87 with heterogeneous phenotypes with some Rett-like features. Another 120 female patients with intellectual disability of unknown origin were also studied, but in these cases we only tested exons 3 and 4. Finally, 861 healthy controls (519 females and 342 males) were also studied for exon 3 and 4. Eighteen different pathological mutations were found, five of them previously undescribed, and four large deletions detected by multiplex ligation-dependent probe amplification. All were de novo mutations not present in the parents. In conclusion, i) MECP2 is one of the most important genes in the diagnosis of genetic intellectual disability in females; ii) MECP2 must be studied not only in patients with classical/atypical Rett syndrome but also in patients with other phenotypes related to Rett syndrome; and iii) for the new variants, it is important to perform complementary studies, including the analysis of large populations of healthy individuals and the use of in silico programs. Copyright © 2013 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Tyr120Asp mutation alters domain flexibility and dynamics of MeCP2 DNA binding domain leading to impaired DNA interaction: Atomistic characterization of a Rett syndrome causing mutation.

PubMed

D'Annessa, Ilda; Gandaglia, Anna; Brivio, Elena; Stefanelli, Gilda; Frasca, Angelisa; Landsberger, Nicoletta; Di Marino, Daniele

2018-05-01

Mutations in the X-linked MECP2 gene represent the main origin of Rett syndrome, causing a profound intellectual disability in females. MeCP2 is an epigenetic transcriptional regulator containing two main functional domains: a methyl-CpG binding domain (MBD) and a transcription repression domain (TRD). Over 600 pathogenic mutations were reported to affect the whole protein; almost half of missense mutations affect the MBD. Understanding the impact of these mutations on the MBD structure and interaction with DNA will foster the comprehension of their pathogenicity and possibly genotype/phenotype correlation studies. Herein, we use molecular dynamics simulations to obtain a detailed view of the dynamics of WT and mutated MBD in the presence and absence of DNA. The pathogenic mutation Y120D is used as paradigm for our studies. Further, since the Y120 residue was previously found to be a phosphorylation site, we characterize the dynamic profile of the MBD also in the presence of Y120 phosphorylation (pY120). We found that addition of a phosphate group to Y120 or mutation in aspartic acid affect domain mobility that samples an alternative conformational space with respect to the WT, leading to impaired ability to interact with DNA. Experimental assays showing a significant reduction in the binding affinity between the mutated MBD and the DNA confirmed our predictions. Copyright © 2018 Elsevier B.V. All rights reserved.

Pathophysiology and Japanese clinical characteristics in Marfan syndrome.

PubMed

Fujita, Daishi; Takeda, Norifumi; Imai, Yasushi; Inuzuka, Ryo; Komuro, Issei; Hirata, Yasunobu

2014-08-01

Marfan syndrome is an autosomal dominant heritable disorder of the connective tissue, caused by mutations of the gene FBN1, which encodes fibrillin-1, a major component of the microfibrils of the extracellular matrix. Fibrillin-1 interacts with transforming growth factor-β (TGF-β), and dysregulated TGF-β signaling plays a major role in the development of connective tissue disease and familial aortic aneurysm and dissection, including Marfan syndrome. Losartan, an angiotensin II blocker, has the potential to reduce TGF-β signaling and is expected to be an additional therapeutic option. Clinical diagnosis is made using the Ghent nosology, which requires comprehensive patient assessment and has been proven to work well, but evaluation of some of the diagnostic criteria by a single physician is difficult and time-consuming. A Marfan clinic was established at the University of Tokyo Hospital in 2005, together with cardiologists, cardiac surgeons, pediatricians, orthopedists, and ophthalmologists in one place, for the purpose of speedy and accurate evaluation and diagnosis of Marfan syndrome. In this review, we discuss the recent progress in diagnosis and treatment of Marfan syndrome, and the characteristics of Japanese patients with Marfan syndrome. © 2014 Japan Pediatric Society.

Clinical presentation of Churg–Strauss syndrome in children

PubMed Central

Razenberg, Femke G.E.M.; Heynens, Jan W.C.M.; Jan de Vries, Geeuwke; Duijts, Liesbeth; de Jongste, Johan C.; de Blic, Jacques; Rosias, Philippe P.R.

2012-01-01

Churg–Strauss syndrome is an uncommon multisystem disorder characterized by asthma, eosinophilia and vasculitis. We report on a 12-year-old boy with asthma and deterioration of his general condition, who was eventually diagnosed with an ANCA-negative Churg–Strauss syndrome. The propositus included, 50 cases of childhood Churg–Strauss syndrome have been reported. The patient characteristics and clinical characteristics of these children are summarized. The respiratory tract is most frequently involved with pulmonary infiltrates, asthma and sinusitis. Early recognition of childhood Churg–Strauss syndrome is important as delayed diagnosis can lead to severe organ involvement, and possible fatal outcome. PMID:26029598

Single and Multiple Clinical Syndromes in Incarcerated Offenders: Associations With Dissociative Experiences and Emotionality

PubMed Central

Garofalo, Carlo; Velotti, Patrizia; Crocamo, Cristina; Carrà, Giuseppe

2017-01-01

The present study examined the prevalence and correlates of clinical syndromes in a large group (N = 438) of incarcerated violent offenders, looking at differences between inmates with one and those with more than one clinical syndromes. More than a half of the sample (57%) reported clinically relevant symptoms for at least one clinical syndrome (n = 252), and the majority of them (38%) reported more syndromes in comorbidity (n = 169). Increased severity of clinical conditions (none, one, more than one syndrome) corresponded with significantly greater levels of personality disorder traits, psychological symptoms, dissociation, and negative emotionality, with large effect sizes. After controlling for co-occurrence of personality disorder traits and other symptoms, the presence of more than one comorbid syndrome significantly predicted unique variance in dissociation (positively) and positive emotionality (negatively). The presence of one clinical syndrome significantly and positively predicted negative emotionality. Findings support the possibility that the complexity, and not just the presence, of psychopathology could identify different groups of inmates. PMID:27913716

Single and Multiple Clinical Syndromes in Incarcerated Offenders: Associations With Dissociative Experiences and Emotionality.

PubMed

Garofalo, Carlo; Velotti, Patrizia; Crocamo, Cristina; Carrà, Giuseppe

2018-04-01

The present study examined the prevalence and correlates of clinical syndromes in a large group ( N = 438) of incarcerated violent offenders, looking at differences between inmates with one and those with more than one clinical syndromes. More than a half of the sample (57%) reported clinically relevant symptoms for at least one clinical syndrome ( n = 252), and the majority of them (38%) reported more syndromes in comorbidity ( n = 169). Increased severity of clinical conditions (none, one, more than one syndrome) corresponded with significantly greater levels of personality disorder traits, psychological symptoms, dissociation, and negative emotionality, with large effect sizes. After controlling for co-occurrence of personality disorder traits and other symptoms, the presence of more than one comorbid syndrome significantly predicted unique variance in dissociation (positively) and positive emotionality (negatively). The presence of one clinical syndrome significantly and positively predicted negative emotionality. Findings support the possibility that the complexity, and not just the presence, of psychopathology could identify different groups of inmates.

[Clinical features of a Chinese pedigree with Waardenburg syndrome type 2].

PubMed

Yang, Shu-zhi; Yuan, Hui-jun; Bai, Lin-na; Cao, Ju-yang; Xu, Ye; Shen, Wei-dong; Ji, Fei; Yang, Wei-yan

2005-10-12

To investigate detailed clinical features of a Chinese pedigree with Waardenburg syndrome type 2. Members of this pedigree were interviewed to identify personal or family medical histories of hearing loss, the use of aminoglycosides, and other clinical abnormalities by filling questionnaire. The audiological and other clinical evaluations of the proband and other members of this family were conducted, including pure-tone audiometry, immittance and auditory brain-stem response and ophthalmological, dermatologic, hair, temporal bone CT examinations. This family is categorized as Waardenburg syndrome type 2 according to its clinical features. It's an autosomal dominant disorder with incomplete penetrance. The clinical features varied greatly among family members and characterized by sensorineural hearing loss, heterochromia irides, freckle on the face and premature gray hair. Hearing loss can be unilateral or bilateral, congenital or late onset in this family. This Chinese family has some unique clinical features comparing with the international diagnostic criteria for Waardenburg syndrome. This study may provide some evidences to amend the diagnostic criteria for Waardenburg syndrome in Chinese population.

[Usher syndrome: clinical features, diagnostic options, and therapeutic prospects].

PubMed

Seeliger, M W; Fischer, M D; Pfister, M

2009-06-01

Usher syndrome denotes a clinically and genetically heterogeneous combination of retinitis pigmentosa and sensorineural deafness. The division into subtypes I, II, and III is based on the degree of hearing loss: Type I is characterized by deafness from birth together with ataxia and retarded motor development, type II by a stationary deafness of a moderate degree, and type III by a progressive deafness with adult onset. In Germany, Usher syndrome currently bears particular relevance because in January 2009 a new compulsory screening of auditory function in newborn infants was introduced. Consequently, it can be expected that a higher number of patients with Usher syndrome will be identified in early childhood and referred to ophthalmologists. The focus of this work is to introduce the typical clinical picture of Usher syndrome, summarize diagnostic options, and give an overview of therapeutic strategies.

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. © 2013 Wiley Periodicals, Inc.

Kindler syndrome: a case report and proposal for clinical diagnostic criteria.

PubMed

Fischer, Irena Angelova; Kazandjieva, Jana; Vassileva, Snejina; Dourmishev, Assen

2005-06-01

Kindler syndrome is a rare hereditary disorder characterized by acral blister formation in infancy and childhood, progressive poikiloderma, cutaneous atrophy and increased photosensitivity. Since it was first described in 1954, less than 100 cases have been reported worldwide. Recently it has been reported that Kindler syndrome is the first genodermatosis caused by a defect in the actin-extracellular matrix linkage, and the gene was mapped to chromosome 20p12.3. The clinical features of the syndrome have been annotated by different authors but the definite of criteria to confirm the diagnosis have not yet been generally accepted. We report a case of Kindler syndrome that presents a full spectrum of clinical manifestations, and we propose a set of clinical criteria for diagnosis.

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

Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement.

PubMed

Soto, David; Olivella, Mireia; Grau, Cristina; Armstrong, Judith; Alcon, Clara; Gasull, Xavier; Gómez de Salazar, Macarena; Gratacòs-Batlle, Esther; Ramos-Vicente, David; Fernández-Dueñas, Víctor; Ciruela, Francisco; Bayés, Àlex; Sindreu, Carlos; López-Sala, Anna; García-Cazorla, Àngels; Altafaj, Xavier

2018-01-15

N-Methyl-D-aspartate receptors (NMDARs) play pivotal roles in synaptic development, plasticity, neural survival, and cognition. Despite recent reports describing the genetic association between de novo mutations of NMDAR subunits and severe psychiatric diseases, little is known about their pathogenic mechanisms and potential therapeutic interventions. Here we report a case study of a 4-year-old Rett-like patient with severe encephalopathy carrying a missense de novo mutation in GRIN2B(p.P553T) coding for the GluN2B subunit of NMDAR. We generated a dynamic molecular model of mutant GluN2B-containing NMDARs. We expressed the mutation in cell lines and primary cultures, and we evaluated the putative morphological, electrophysiological, and synaptic plasticity alterations. Finally, we evaluated D-serine administration as a therapeutic strategy and translated it to the clinical practice. Structural molecular modeling predicted a reduced pore size of mutant NMDARs. Electrophysiological recordings confirmed this prediction and also showed gating alterations, a reduced glutamate affinity associated with a strong decrease of NMDA-evoked currents. Moreover, GluN2B(P553T)-expressing neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of GluA1 at stimulated synapses. Notably, the naturally occurring coagonist D-serine was able to attenuate hypofunction of GluN2B(p.P553T)-containing NMDARs. Hence, D-serine dietary supplementation was initiated. Importantly, the patient has shown remarkable motor, cognitive, and communication improvements after 17 months of D-serine dietary supplementation. Our data suggest that hypofunctional NMDARs containing GluN2B(p.P553T) can contribute to Rett-like encephalopathy and that their potentiation by D-serine treatment may underlie the associated clinical improvement. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

RS3PE syndrome: a clinical and immunogenetical study.

PubMed

Queiro, Rubén

2004-03-01

This study analyses the clinical, radiological, evolutive, and immunogenetical characteristics of a series of patients diagnosed with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. Reviewed were the clinical charts and human leukocyte antigen (HLA) profiles of all patients treated at a single teaching hospital fulfilling the features of this syndrome according to the definition of McCarty. Twelve cases were detected in ten men and two women aged from 62 to 85 years. Rheumatoid factor was negative in all cases, and antinuclear antibodies (ANA) were positive in two. All patients achieved complete resolution of their condition within 1 year with glucocorticoid (GC) use. Two relapsed after remission but responded again to low doses of GC. Four patients showed clinical and electrodiagnostic studies consistent with carpal tunnel syndrome. No specific HLA association could be found in this report. To date, none of these patients has developed definite rheumatic diseases, infections, or malignant diseases. Although the real nature of the syndrome is still a matter of debate, at least in our context, RS3PE remains a definite condition with an excellent prognosis.

[From "deadly quartet" to "metabolic syndrome". An analysis of its clinical relevance].

PubMed

Vancheri, Federico; Burgio, Antonio; Dovico, Rossana

2007-03-01

The metabolic syndrome denotes a clustering of specific risk factors for both cardiovascular disease and type 2 diabetes, whose underlying pathophysiology is believed to include insulin resistance. It has been widely reported that the syndrome is a simple clinical tool to identify people at high long term risk of cardiovascular disease and diabetes. However, its clinical importance is under debate. There are substantial uncertainties about the clinical definition of the syndrome, as to whether the risk factors clustering indicates a single unifying disorder, whether the risk conferred by the condition as a whole is higher risk than its individual components, and whether its predictive value of future cardiovascular events or diabetes is greater than established predicting models such as the Framingham Risk Score and the Diabetes Risk Score. We undertook an extensive review of the literature. Our analysis indicates that current definitions of the syndrome are incomplete or ambiguous, more than one pathophysiological process underlies the syndrome, although the combination of insulin resistance and hyperinsulinemia are related to most cases; the risk associated with the syndrome is no greater than that explained by the presence of its components, and the syndrome is less effective in predicting the future development of cardiovascular events and diabetes than established predicting models. Although the syndrome has some importance in understanding the pathophysiology of cardiovascular and diabetes risk factors clustering, its use as a clinical syndrome is not justified by current data.

Epileptic encephalopathy in a girl with an interstitial deletion of Xp22 comprising promoter and exon 1 of the CDKL5 gene.

PubMed

Bahi-Buisson, Nadia; Girard, Benoit; Gautier, Agnes; Nectoux, Juliette; Fichou, Yann; Saillour, Yoann; Poirier, Karine; Chelly, Jamel; Bienvenu, Thierry

2010-01-05

We report a 2-year-old girl with early onset seizures variant of Rett syndrome with a deletion at Xp22 detected by multiplex ligation-dependent probe amplification (MLPA) technique. This patient presented with tonic seizures at 7 days of life. Subsequently, she developed infantile spasms at three months and finally refractory myoclonic epilepsy. She demonstrated severe encephalopathy with hypotonia, deceleration of head growth, with eye gaze but limited eye pursuit, no language, limited hand use, and intermittent hand stereotypies. This combination of clinical features, suggestive of early onset variant of Rett syndrome led us to screen the CDKL5 gene. In a first step, screening of the whole coding sequence of the CDKL5 gene revealed no point mutations. In a second step, we searched gross rearrangements by MLPA and identified a microdeletion affecting both the promoter and exon 1 in CDKL5. Subsequent analysis on a Nimblegen HD2 microarray confirmed a deletion of approximately 300 kb at Xp22, including the BEND2, SCML2, and CDKL5 genes. In conclusion, our report suggests that searching for large rearrangements in CDKL5 should be considered in girls with early onset seizures and Rett-like features. (c) 2009 Wiley-Liss, Inc.

[Free radicals in the origin and clinical manifestation of Down's syndrome].

PubMed

Arbuzova, S B

1996-01-01

The high level of free radicals and antioxidant protection disbalancing cause the chromosome nondisjunction in meiosis, appearance of trisomy 21 and fetuses with Down's syndrome, age-dependent pathology, of parent's mosaic clone, clinical manifestations of the syndrome, diseases in relatives, recurrent cases of trisomy 21. The comparative analysis of clinical traits of Down's syndrome and pathological changes in families with after-effects of radiation exposure was carried out. The factors causing an increase in the level of free radicals were considered.

[Autoimmune/inflammatory syndrome induced by adjuvants. A new clinical entity?

PubMed

Ferrer-Cosme, Belkis; Téllez-Martínez, Damiana; Batista-Duharte, Alexander

2017-01-01

Recently Shoenfeld and Agmon-Levin proposed a new clinical entity called autoimmune/inflammatory syndrome induced by adjuvants (ASIA), which includes four clinical entities called: 1) siliconosis, 2) Gulf War syndrome, 3) macrophage myofasciitis) and 4) post-vaccination phenomenon associated with adjuvants. They all have a common denominator: a prior exposure to immunoadjuvants, and, in addition, they also share several clinical criteria associated to chronic inflammation and autoimmune reactions. This proposal still needs to be validated by the scientific community, but nowadays is a topic of hot discussion in the literature and in various international conferences. In this revision article, we analyze the characteristics of this syndrome, the current mechanisms possibly involved in the pathogenesis, and the more recent reports regarding ASIA associated to vaccine and some foreign substances.

[Magnetic Resonance Imaging Conversion Predictors of Clinically Isolated Syndrome to Multiple Sclerosis].

PubMed

Peixoto, Sara; Abreu, Pedro

2016-11-01

Clinically isolated syndrome may be the first manifestation of multiple sclerosis, a chronic demyelinating disease of the central nervous system, and it is defined by a single clinical episode suggestive of demyelination. However, patients with this syndrome, even with long term follow up, may not develop new symptoms or demyelinating lesions that fulfils multiple sclerosis diagnostic criteria. We reviewed, in clinically isolated syndrome, what are the best magnetic resonance imaging findings that may predict its conversion to multiple sclerosis. A search was made in the PubMed database for papers published between January 2010 and June 2015 using the following terms: 'clinically isolated syndrome', 'cis', 'multiple sclerosis', 'magnetic resonance imaging', 'magnetic resonance' and 'mri'. In this review, the following conventional magnetic resonance imaging abnormalities found in literature were included: lesion load, lesion location, Barkhof's criteria and brain atrophy related features. The non conventional magnetic resonance imaging techniques studied were double inversion recovery, magnetization transfer imaging, spectroscopy and diffusion tensor imaging. The number and location of demyelinating lesions have a clear role in predicting clinically isolated syndrome conversion to multiple sclerosis. On the other hand, more data are needed to confirm the ability to predict this disease development of non conventional techniques and remaining neuroimaging abnormalities. In forthcoming years, in addition to the established predictive value of the above mentioned neuroimaging abnormalities, different clinically isolated syndrome neuroradiological findings may be considered in multiple sclerosis diagnostic criteria and/or change its treatment recommendations.

Prediction of polycystic ovarian syndrome based on ultrasound findings and clinical parameters.

PubMed

Moschos, Elysia; Twickler, Diane M

2015-03-01

To determine the accuracy of sonographic-diagnosed polycystic ovaries and clinical parameters in predicting polycystic ovarian syndrome. Medical records and ultrasounds of 151 women with sonographically diagnosed polycystic ovaries were reviewed. Sonographic criteria for polycystic ovaries were based on 2003 Rotterdam European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine guidelines: at least one ovary with 12 or more follicles measuring 2-9 mm and/or increased ovarian volume >10 cm(3) . Clinical variables of age, gravidity, ethnicity, body mass index, and sonographic indication were collected. One hundred thirty-five patients had final outcomes (presence/absence of polycystic ovarian syndrome). Polycystic ovarian syndrome was diagnosed if a patient had at least one other of the following two criteria: oligo/chronic anovulation and/or clinical/biochemical hyperandrogenism. A logistic regression model was constructed using stepwise selection to identify variables significantly associated with polycystic ovarian syndrome (p < .05). The validity of the model was assessed using receiver operating characteristics and Hosmer-Lemeshow χ(2) analyses. One hundred twenty-eight patients met official sonographic criteria for polycystic ovaries and 115 (89.8%) had polycystic ovarian syndrome (p = .009). Lower gravidity, abnormal bleeding, and body mass index >33 were significant in predicting polycystic ovarian syndrome (receiver operating characteristics curve, c = 0.86). Pain decreased the likelihood of polycystic ovarian syndrome. Polycystic ovaries on ultrasound were sensitive in predicting polycystic ovarian syndrome. Ultrasound, combined with clinical parameters, can be used to generate a predictive index for polycystic ovarian syndrome. © 2014 Wiley Periodicals, Inc.

Hot Tub Folliculitis: A Clinical Syndrome

PubMed Central

Zacherle, Barry J.; Silver, Diane S.

1982-01-01

With the increasing use of hot tubs, patients are being seen with a distinct clinical syndrome that appears several hours or days after hot tub exposure. It consists of a maculovesicular, often pruritic rash, and commonly occurring associated symptoms including fever, upper respiratory tract complaints, axillary adenopathy and breast tenderness. Cultures in the cases described here grew out Pseudomonas aeruginosa, giving a diagnosis of Pseudomonas folliculitis. The illness clears spontaneously without any treatment. Proper attention to hot tub chlorination and use are probably important in preventing this problem, and awareness of the syndrome by physicians may prevent unnecessary and costly diagnostic studies and treatment programs. PMID:7147933

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.

[Clinical implications of polycystic ovary syndrome].

PubMed

Dravecká, Ingrid

Polycystic ovary syndrome (PCOS) is a heterogeneous and complex endocrine disease which among the female population belongs to the most widespread endocrinopathies and it is the most frequent cause of hyperthyroidism, anticoagulation and infertility. Insulin resistance is one of the important diabetology factors impacting hyperglycaemia in a majority of women with PCOS (60-80 %). Clinical expressions of PCOS include reproduction disorders, metabolic characteristics and psychological implications. Reproduction disorders include hyperthyroidism, menstruation cycle disorders, infertility and pregnancy complications as well as early abortions, gestational diabetes and pregnancy induced hypertension. Long-term metabolic risks of PCOS include type 2 diabetes mellitus, dyslipidemia, arterial hypertension and endothelial dysfunction. The available data confirms higher incidence of cardiovascular diseases in women with PCOS. In particular among obese women PCOS is more frequently associated with non-alcoholic hepatic steatosis, sleep apnoea syndrome and endometrial cancer. The literature includes some controversial data about the relationship between PCOS and autoimmunity. Women with PCOS are more prone to suffer from insufficient confidence with higher incidence of anxiety, depression, bipolar disorder and eating disorders. autoimmunity - diabetes mellitus - pregnancy - insulin resistance - metabolic syndrome - menstrual disorders - polycystic ovary syndrome.

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features.

PubMed

Zhou, Yaoyao; Zhang, Junfeng

2014-09-20

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare but fatal autosomal recessive multisystem disorder caused by mutations in the VPS33B or VIPAR gene. The classical presentation of ARC includes congenital joint contractures, renal tubular dysfunction, and cholestasis. Additional features include ichthyosis, central nervous system malformation, platelet anomalies, and severe failure to thrive. Diagnosis of ARC syndrome relies on clinical features, organ biopsy, and mutational analysis. However, no specific treatment currently exists for this syndrome. This is an overview of the latest knowledge regarding the genetic features and clinical manifestations of ARC syndrome. Greater awareness and understanding of this syndrome should allow more timely intervention with potential for improving long-term outcome.

[Kindler syndrome: clinical and ultra-structural particularities, a propos of three cases].

PubMed

El Fekih, Nadia; Mahfoudh, Anis; Zekri, Samy; Kharfi, Monia; Fazaa, Bécima; Jaafoura, Mohamed Habib; Kamoun, Mohamed Ridha

2011-08-01

Kindler's syndrome is a rare type of genetic skin condition belonging to the class of bullous poikilodermia. We report three new sibling cases of this rare syndrome. The condition was seen in three sisters aged 12, 16 and 20 years, born of a first-degree consanguineous marriage with no family history of Kindler's syndrome. The three patients presented spontaneously regressive bullous eruptions, poikilodermia of gradual onset, major cutaneous atrophy on the back of the hands and the feet, photosensitivity and gingival hypertrophy. Electron microscopy examination of poikilodermic skin showed normal anchoring filaments and intraepidermal cleavage. Diagnosis of Kindler's syndrome is based upon clinical evidence. Kidler's syndrome is a well defined clinical entity. Ultra-structural studies show intraepidermal, junctional, and dermal cleavage. This syndrome must be differentiated from congenital epidermolysis bullosa, Weary's syndrome, and other bullous hereditary poikilodermas. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Outcome Measures for Clinical Trials in Down Syndrome

PubMed Central

Esbensen, Anna J.; Hooper, Stephen R.; Fidler, Deborah; Hartley, Sigan; Edgin, Jamie; d’Ardhuy, Xavier Liogier; Capone, George; Conners, Frances; Mervis, Carolyn B.; Abbeduto, Leonard; Rafii, Michael; Krinsky-McHale, Sharon J.; Urv, Tiina

2017-01-01

Increasingly individuals with intellectual and developmental disabilities, including Down syndrome, are being targeted for clinical trials. However, a challenge exists in effectively evaluating the outcomes of these new pharmacological interventions. Few empirically evaluated, psychometrically sound outcome measures appropriate for use in clinical trials with individuals with Down syndrome have been identified. To address this challenge, the NIH assembled leading clinicians and scientists to review existing measures and identify those that currently are appropriate for trials; those that may be appropriate after expansion of age range addition of easier items, and/or downward extension of psychometric norms; and areas where new measures need to be developed. This paper focuses on measures in the areas of cognition and behavior. PMID:28452584

Iridocorneal endothelial syndrome: clinical perspectives

PubMed Central

Walkden, Andrew; Au, Leon

2018-01-01

This article aims to review the clinical management strategies available for the rare iridocorneal endothelial syndrome. The different clinical variations as well as the imaging techniques available to aid diagnosis are discussed. We then present the evidence available to help the reader to understand how the condition can be managed medically and also the important surgical aspects of treatment. This involves raised intraocular pressure management in addition to the visual management options of partial or full thickness keratoplasty. We hope that this review provides an exhaustive but also succinct review of the literature available on what is a rare and difficult condition to treat. PMID:29670326

Clinical characteristics of childhood guillain-barré syndrome.

PubMed

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

2008-07-01

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. 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. 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. 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.

Increased PK11195-PET binding in normal-appearing white matter in clinically isolated syndrome

PubMed Central

Politis, Marios; Su, Paul; Turkheimer, Federico E.; Malik, Omar; Keihaninejad, Shiva; Wu, Kit; Waldman, Adam; Reynolds, Richard; Nicholas, Richard; Piccini, Paola

2015-01-01

The most accurate predictor of the subsequent development of multiple sclerosis in clinically isolated syndrome is the presence of lesions at magnetic resonance imaging. We used in vivo positron emission tomography with 11C-(R)-PK11195, a biomarker of activated microglia, to investigate the normal-appearing white matter and grey matter of subjects with clinically isolated syndrome to explore its role in the development of multiple sclerosis. Eighteen clinically isolated syndrome and eight healthy control subjects were recruited. Baseline assessment included: history, neurological examination, expanded disability status scale, magnetic resonance imaging and PK11195-positron emission tomography scans. All assessments except the PK11195-positron emission tomography scan were repeated over 2 years. SUPERPK methodology was used to measure the binding potential relative to the non-specific volume, BPND. We show a global increase of normal-appearing white matter PK11195 BPND in clinically isolated syndrome subjects compared with healthy controls (P = 0.014). Clinically isolated syndrome subjects with T2 magnetic resonance imaging lesions had higher PK11195 BPND in normal-appearing white matter (P = 0.009) and their normal-appearing white matter PK11195 BPND correlated with the Expanded Disability Status Scale (P = 0.007; r = 0.672). At 2 years those who developed dissemination in space or multiple sclerosis, had higher PK11195 BPND in normal-appearing white matter at baseline (P = 0.007 and P = 0.048, respectively). Central grey matter PK11195 BPND was increased in subjects with clinically isolated syndrome compared to healthy controls but no difference was found in cortical grey matter PK11195 BPND. Microglial activation in clinically isolated syndrome normal-appearing white matter is diffusely increased compared with healthy control subjects and is further increased in those who have magnetic resonance imaging lesions. Furthermore microglial activation in clinically

Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome

PubMed Central

Kamiyoshi, Naohiro; Fu, Xue Jun; Morisada, Naoya; Nozu, Yoshimi; Ye, Ming Juan; Imafuku, Aya; Miura, Kenichiro; Yamamura, Tomohiko; Minamikawa, Shogo; Shono, Akemi; Ninchoji, Takeshi; Morioka, Ichiro; Nakanishi, Koichi; Yoshikawa, Norishige; Kaito, Hiroshi; Iijima, Kazumoto

2016-01-01

Background and objectives Alport syndrome comprises a group of inherited heterogeneous disorders involving CKD, hearing loss, and ocular abnormalities. Autosomal dominant Alport syndrome caused by heterozygous mutations in collagen 4A3 and/or collagen 4A4 accounts for <5% of patients. However, the clinical, genetic, and pathologic backgrounds of patients with autosomal dominant Alport syndrome remain unclear. Design, setting, participants, & measurements We conducted a retrospective analysis of 25 patients with genetically proven autosomal dominant Alport syndrome and their family members (a total of 72 patients) from 16 unrelated families. Patients with suspected Alport syndrome after pathologic examination who were referred from anywhere in Japan for genetic analysis from 2006 to 2015 were included in this study. Clinical, laboratory, and pathologic data were collected from medical records at the point of registration for genetic diagnosis. Genetic analysis was performed by targeted resequencing of 27 podocyte-related genes, including Alport–related collagen genes, to make a diagnosis of autosomal dominant Alport syndrome and identify modifier genes or double mutations. Clinical data were obtained from medical records. Results The median renal survival time was 70 years, and the median age at first detection of proteinuria was 17 years old. There was one patient with hearing loss and one patient with ocular lesion. Among 16 patients who underwent kidney biopsy, three showed FSGS, and seven showed thinning without lamellation of the glomerular basement membrane. Five of 13 detected mutations were reported to be causative mutations for autosomal recessive Alport syndrome in previous studies. Two families possessed double mutations in both collagen 4A3 and collagen 4A4, but no modifier genes were detected among the other podocyte–related genes. Conclusions The renal phenotype of autosomal dominant Alport syndrome was much milder than that of autosomal recessive

Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome.

PubMed

Kamiyoshi, Naohiro; Nozu, Kandai; Fu, Xue Jun; Morisada, Naoya; Nozu, Yoshimi; Ye, Ming Juan; Imafuku, Aya; Miura, Kenichiro; Yamamura, Tomohiko; Minamikawa, Shogo; Shono, Akemi; Ninchoji, Takeshi; Morioka, Ichiro; Nakanishi, Koichi; Yoshikawa, Norishige; Kaito, Hiroshi; Iijima, Kazumoto

2016-08-08

Alport syndrome comprises a group of inherited heterogeneous disorders involving CKD, hearing loss, and ocular abnormalities. Autosomal dominant Alport syndrome caused by heterozygous mutations in collagen 4A3 and/or collagen 4A4 accounts for <5% of patients. However, the clinical, genetic, and pathologic backgrounds of patients with autosomal dominant Alport syndrome remain unclear. We conducted a retrospective analysis of 25 patients with genetically proven autosomal dominant Alport syndrome and their family members (a total of 72 patients) from 16 unrelated families. Patients with suspected Alport syndrome after pathologic examination who were referred from anywhere in Japan for genetic analysis from 2006 to 2015 were included in this study. Clinical, laboratory, and pathologic data were collected from medical records at the point of registration for genetic diagnosis. Genetic analysis was performed by targeted resequencing of 27 podocyte-related genes, including Alport-related collagen genes, to make a diagnosis of autosomal dominant Alport syndrome and identify modifier genes or double mutations. Clinical data were obtained from medical records. The median renal survival time was 70 years, and the median age at first detection of proteinuria was 17 years old. There was one patient with hearing loss and one patient with ocular lesion. Among 16 patients who underwent kidney biopsy, three showed FSGS, and seven showed thinning without lamellation of the glomerular basement membrane. Five of 13 detected mutations were reported to be causative mutations for autosomal recessive Alport syndrome in previous studies. Two families possessed double mutations in both collagen 4A3 and collagen 4A4, but no modifier genes were detected among the other podocyte-related genes. The renal phenotype of autosomal dominant Alport syndrome was much milder than that of autosomal recessive Alport syndrome or X-linked Alport syndrome in men. It may, thus, be difficult to make an

[Clinical study of area of Jiangsu province of polycystic ovarian syndrome correlation distribution of traditional Chinese medicine syndrome type and improper diet].

PubMed

Feng, Yu; Gao, Yue-Ping

2014-05-01

Polycystic ovary syndrome (PCOS) is one of the most popular diseases in obstetrics and gynecology research at internal and abroad at present, traditional Chinese medicine(TCM)in the clinical treatment of the disease have the advantage. Clinical epidemiological study of descriptive research method this research adopts investigation, observation of TCM syndromes and improper diet through 401 cases in Jiangsu Province confirmed PCOS patients, to explore the relationship between TCM syndrome type distribution and improper diet factors, and to provide the clinical basis for further etiology of this disease research. TCM syndrome type distribution of the disease is kidney deficiency, phlegm stagnation syndrome, qi stagnation and blood stasis syndrome, syndrome of dampness heat of liver channel and is composed of 4 basic syndromes and formed complex syndrome, and the composite and syndrome type (60.85%); combined with the analysis of traditional Chinese medicine dialectical, Pure empirical syndrome this disease (46.88%), followed by the actual card (45.39%), pure deficiency is rare. Improper diet factors associated with the disease, in which improper diet with different TCM syndrome type distribution significantly related. Stagnation of phlegm dampness syndrome is the main syndrome of the disease type, improper diet factors and every syndrome PCOS type distribution is as follows: the partial eclipse fatness greasy with basic syndromes of phlegm dampness stagnation of kidney deficiency syndrome, the nephrasthenia syndrome is less; eating spicy stimulation by basic syndromes of stagnation of Qi and blood stasis; eating cold people the basic certificate type of qi stagnation and blood stasis; The diet of patients are more prone to stagnation of phlegm dampness syndrome.

Clinical and electrographic features of sunflower syndrome.

PubMed

Baumer, Fiona M; Porter, Brenda E

2018-05-01

Sunflower Syndrome describes reflex seizures - typically eyelid myoclonia with or without absence seizures - triggered when patients wave their hands in front of the sun. While valproate has been recognized as the best treatment for photosensitive epilepsy, many clinicians now initially treat with newer medications; the efficacy of these medications in Sunflower Syndrome has not been investigated. We reviewed all cases of Sunflower Syndrome seen at our institution over 15 years to describe the clinical course, electroencephalogram (EEG), and treatment response in these patients. Search of the electronic medical record and EEG database, as well as survey of epilepsy providers at our institution, yielded 13 cases of Sunflower Syndrome between 2002 and 2017. We reviewed the records and EEG tracings. Patients were mostly young females, with an average age of onset of 5.5 years. Seven had intellectual, attentional or academic problems. Self-induced seizures were predominantly eyelid myoclonia ± absences and 6 subjects also had spontaneous seizures. EEG demonstrated a normal background with 3-4 Hz spike waves ± polyspike waves as well as a photoparoxysmal response. Based on both clinical and EEG response, valproate was the most effective treatment for reducing or eliminating seizures and improving the EEG; 9 patients tried valproate and 66% had significant improvement or resolution of seizures. None of the nine patients on levetiracetam or seven patients on lamotrigine monotherapy achieved seizure control, though three patients had improvement with polypharmacy. Valproate monotherapy continues to be the most effective treatment for Sunflower Syndrome and should be considered early. For patients who cannot tolerate valproate, higher doses of lamotrigine or polypharmacy should be considered. Levetiracetam monotherapy, even at high doses, is unlikely to be effective. Copyright © 2018 Elsevier B.V. All rights reserved.

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.…

Clinical Spectrum of Autoerythrocyte Sensitization Syndrome: A Series of Five Cases

PubMed Central

Thokchom, Nandakishore Singh; Pradeepa, D.; Hafi, N. A. Bishurul; Verma, Kapila

2018-01-01

Autoerythrocyte sensitization syndrome (Gardner Diamond syndrome or GDS) is a rare syndrome characterized by painful and spontaneous purpura commonly affecting adult women, and is mostly associated with psychiatric illness. Diagnosis is mainly based on clinical presentation, exclusion of other simulating diseases, and psychiatric evaluation. Only few cases have been reported till date. We report five cases of spontaneous purpura with a normal investigation profile, except for iron deficiency anemia in 1 patient, of which three had associated underlying psychiatric illness. Autoerythrocyte sensitization test was positive in all our cases. Patients presenting with painful bruises without significant medical history such as underlying bleeding disorder or drug history or history of trauma should be considered for autoerythrocyte sensitization syndrome, and managed accordingly. The present study is a case series of patients with characteristic features of autoerythrocyte sensitization syndrome, considering the rarity of the reports on its clinical spectra. PMID:29644197

Next generation phenotyping using narrative reports in a rare disease clinical data warehouse.

PubMed

Garcelon, Nicolas; Neuraz, Antoine; Salomon, Rémi; Bahi-Buisson, Nadia; Amiel, Jeanne; Picard, Capucine; Mahlaoui, Nizar; Benoit, Vincent; Burgun, Anita; Rance, Bastien

2018-05-31

Secondary use of data collected in Electronic Health Records opens perspectives for increasing our knowledge of rare diseases. The clinical data warehouse (named Dr. Warehouse) at the Necker-Enfants Malades Children's Hospital contains data collected during normal care for thousands of patients. Dr. Warehouse is oriented toward the exploration of clinical narratives. In this study, we present our method to find phenotypes associated with diseases of interest. We leveraged the frequency and TF-IDF to explore the association between clinical phenotypes and rare diseases. We applied our method in six use cases: phenotypes associated with the Rett, Lowe, Silver Russell, Bardet-Biedl syndromes, DOCK8 deficiency and Activated PI3-kinase Delta Syndrome (APDS). We asked domain experts to evaluate the relevance of the top-50 (for frequency and TF-IDF) phenotypes identified by Dr. Warehouse and computed the average precision and mean average precision. Experts concluded that between 16 and 39 phenotypes could be considered as relevant in the top-50 phenotypes ranked by descending frequency discovered by Dr. Warehouse (resp. between 11 and 41 for TF-IDF). Average precision ranges from 0.55 to 0.91 for frequency and 0.52 to 0.95 for TF-IDF. Mean average precision was 0.79. Our study suggests that phenotypes identified in clinical narratives stored in Electronic Health Record can provide rare disease specialists with candidate phenotypes that can be used in addition to the literature. Clinical Data Warehouses can be used to perform Next Generation Phenotyping, especially in the context of rare diseases. We have developed a method to detect phenotypes associated with a group of patients using medical concepts extracted from free-text clinical narratives.

Prevalence and clinical correlates of metabolic syndrome in Nigerians living with human immunodeficiency virus/acquired immunodeficiency syndrome.

PubMed

Ayodele, Olugbenga Edward; Akinboro, Adeolu Oludayo; Akinyemi, Suliat Omolola; Adepeju, Akinlawon Adetiloye; Akinremi, Oluwaseun Akinsanmi; Alao, Christiana Adeola; Popoola, Adetoun Adedayo

2012-10-01

Sub-Saharan Africa bears an inordinate burden of human immunodeficiency virus (HIV) infection/acquired immune deficiency syndrome (AIDS). Reports have shown increased prevalence of clustering of cardiovascular risk factors referred to as metabolic syndrome in treatment-naïve patients and patients on highly active antiretroviral therapy (HAART). In view of the fact that metabolic syndrome is a heterogeneous disorder with substantial variability in the prevalence and component traits within and across populations and the dearth of publications on the prevalence and clinical correlates of metabolic syndrome in people living with HIV/AIDS (PLWHA) in Nigeria, this study was carried out to determine the prevalence and clinical correlates of metabolic syndrome among an HIV-infected outpatient population using the National Cholesterol Education Adult Treatment Panel III (NCEP ATP III), the International Diabetes Federation (IDF), and the Joint Interim Statement (JIS) definitions. We also sought to determine if HAART use and CD4 count level were associated with metabolic syndrome. This cross-sectional study involved 291 (95 men, 196 women) consecutive PLWHA. Anthropometry, blood pressure, fasting plasma glucose, and lipid profile values were determined. The prevalence rates of metabolic syndrome according to the ATP III, IDF, and JIS criteria were 12.7%, 17.2%, and 21.0%, respectively. Metabolic syndrome was significantly associated with female gender (all definitions), body mass index (all definitions), increasing age, and CD4 count (IDF definition). There was no significant association between metabolic syndrome and HAART. The concordance [kappa coefficient (κ)] between the definitions of metabolic syndrome varied between 0.583 and 0.878. The prevalence of metabolic syndrome varied with the criteria used and metabolic syndrome correlates with traditional cardiovascular risk factors rather than HAART-related factors.

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.

Outcome Measures for Clinical Trials in Down Syndrome.

PubMed

Esbensen, Anna J; Hooper, Stephen R; Fidler, Deborah; Hartley, Sigan L; Edgin, Jamie; d'Ardhuy, Xavier Liogier; Capone, George; Conners, Frances A; Mervis, Carolyn B; Abbeduto, Leonard; Rafii, Michael; Krinsky-McHale, Sharon J; Urv, Tiina

2017-05-01

Increasingly individuals with intellectual and developmental disabilities, including Down syndrome, are being targeted for clinical trials. However, a challenge exists in effectively evaluating the outcomes of these new pharmacological interventions. Few empirically evaluated, psychometrically sound outcome measures appropriate for use in clinical trials with individuals with Down syndrome have been identified. To address this challenge, the National Institutes of Health (NIH) assembled leading clinicians and scientists to review existing measures and identify those that currently are appropriate for trials; those that may be appropriate after expansion of age range addition of easier items, and/or downward extension of psychometric norms; and areas where new measures need to be developed. This article focuses on measures in the areas of cognition and behavior.

Alström Syndrome: Genetics and Clinical Overview

PubMed Central

Marshall, Jan D; Maffei, Pietro; Collin, Gayle B; Naggert, Jürgen K

2011-01-01

Alström syndrome is a rare autosomal recessive genetic disorder characterized by cone-rod dystrophy, hearing loss, childhood truncal obesity, insulin resistance and hyperinsulinemia, type 2 diabetes, hypertriglyceridemia, short stature in adulthood, cardiomyopathy, and progressive pulmonary, hepatic, and renal dysfunction. Symptoms first appear in infancy and progressive development of multi-organ pathology leads to a reduced life expectancy. Variability in age of onset and severity of clinical symptoms, even within families, is likely due to genetic background. Alström syndrome is caused by mutations in ALMS1, a large gene comprised of 23 exons and coding for a protein of 4,169 amino acids. In general, ALMS1 gene defects include insertions, deletions, and nonsense mutations leading to protein truncations and found primarily in exons 8, 10 and 16. Multiple alternate splice forms exist. ALMS1 protein is found in centrosomes, basal bodies, and cytosol of all tissues affected by the disease. The identification of ALMS1 as a ciliary protein explains the range of observed phenotypes and their similarity to those of other ciliopathies such as Bardet-Biedl syndrome. Studies involving murine and cellular models of Alström syndrome have provided insight into the pathogenic mechanisms underlying obesity and type 2 diabetes, and other clinical problems. Ultimately, research into the pathogenesis of Alström syndrome should lead to better management and treatments for individuals, and have potentially important ramifications for other rare ciliopathies, as well as more common causes of obesity and diabetes, and other conditions common in the general population. PMID:22043170

Prevalence of burnout syndrome in clinical nurses at a hospital of excellence.

PubMed

Ribeiro, Vivian F; Filho, Celso Ferreira; Valenti, Vitor E; Ferreira, Marcelo; de Abreu, Luiz Carlos; de Carvalho, Tatiana Dias; Xavier, Valdelias; de Oliveira Filho, JapyAngeli; Gregory, Pedro; Leão, Eliseth Ribeiro; Francisco, Natascha G; Ferreira, Celso

2014-01-01

Burnout syndrome can be defined as long-term work stress resulting from the interaction between constant emotional pressure associated with intense interpersonal involvement for long periods of time and personal characteristics. We investigated the prevalence/propensity of Burnout syndrome in clinical nurses, and the factors related to Burnout syndrome-associated such as socio-demographic characteristics, work load, social and family life, leisure activities, extra work activities, physical activities, and work-related health problems. We conducted a cross-sectional, quantitative, prospective epidemiological study with 188 surgical clinic nurses. We used the Maslach Burnout Inventory (MBI), which is a socio-demographic questionnaire and the most widely used instrument to assess Burnout syndrome (three basic dimensions: emotional exhaustion, despersonalization and professional underachievement). The socio-demographic profile questionnaire wascomposed of questions regarding identification, training, time at work, work characteristics and personal circumstances. The prevalence of Burnout syndrome was higher (10.1%) and 55, 4% of subjects had a propensity to develop this syndrome. The analysis of the socio-demographic profile of the nurse sample studied showed that most nurses were childless married women, over 35 years of age, working the day shift for 36 hours weekly on average, with 2-6 years of post-graduation experience, and without extra employments. Factors such as marital status, work load, emotion and work related stress aggravated the onset of the syndrome. The prevalence and propensity of Burnout syndrome were high. Some factors identified can be useful for the adoption of preventive actions in order to decrease the prevalence of the clinical nurses Burnout syndrome.

Prevalence of burnout syndrome in clinical nurses at a hospital of excellence

PubMed Central

2014-01-01

Background Burnout syndrome can be defined as long-term work stress resulting from the interaction between constant emotional pressure associated with intense interpersonal involvement for long periods of time and personal characteristics. We investigated the prevalence/propensity of Burnout syndrome in clinical nurses, and the factors related to Burnout syndrome-associated such as socio-demographic characteristics, work load, social and family life, leisure activities, extra work activities, physical activities, and work-related health problems. Method We conducted a cross-sectional, quantitative, prospective epidemiological study with 188 surgical clinic nurses. We used the Maslach Burnout Inventory (MBI), which is a socio-demographic questionnaire and the most widely used instrument to assess Burnout syndrome (three basic dimensions: emotional exhaustion, despersonalization and professional underachievement). The socio-demographic profile questionnaire wascomposed of questions regarding identification, training, time at work, work characteristics and personal circumstances. Results The prevalence of Burnout syndrome was higher (10.1%) and 55, 4% of subjects had a propensity to develop this syndrome. The analysis of the socio-demographic profile of the nurse sample studied showed that most nurses were childless married women, over 35 years of age, working the day shift for 36 hours weekly on average, with 2-6 years of post-graduation experience, and without extra employments. Factors such as marital status, work load, emotion and work related stress aggravated the onset of the syndrome. Conclusion The prevalence and propensity of Burnout syndrome were high. Some factors identified can be useful for the adoption of preventive actions in order to decrease the prevalence of the clinical nurses Burnout syndrome. PMID:24860618

Hereditary Nonpolyposis Colorectal Cancer and Cancer Syndromes: Recent Basic and Clinical Discoveries

PubMed Central

Chen, Erbao; Xu, Xiaojing

2018-01-01

Approximately one-third of individuals diagnosed with colorectal cancer have a family history of cancer, suggesting that CRCs may result from a heritable component. Despite the availability of current gene-identification techniques, only 5% of all CRCs emerge from well-identifiable inherited causes for predisposition, including polyposis and nonpolyposis syndromes. Hereditary nonpolyposis colorectal cancer represents a large proportion of cases, and robustly affected patients are at increased risk for early onset, synchronous, and metachronous colorectal malignancies and extracolonic malignancies. HNPCC encompasses several cancer syndromes, such as Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X, which have remarkable clinical presentations and overlapping genetic profiles that make clinical diagnosis a challenging task. Therefore, distinguishing between the HNPCC disorders is crucial for physicians as an approach to tailor different recommendations for patients and their at-risk family members according to the risks for colonic and extracolonic cancer associated with each syndrome. Identification of these potential patients through epidemiological characteristics and new genetic testing can estimate the individual risk, which informs appropriate cancer screening, surveillance, and/or treatment strategies. In the past three years, many appealing and important advances have been made in our understanding of the relationship between HNPCC and CRC-associated syndromes. The knowledge from the genetic profile of cancer syndromes and unique genotype-phenotype profiles in the different syndromes has changed our cognition. Therefore, this review presents and discusses HNPCC and several common nonpolyposis syndromes with respect to molecular phenotype, histopathologic features, and clinical presentation. PMID:29849630

Clinical aspects of the fragile X syndrome.

PubMed

Brown, W Ted

2012-01-01

Fragile X syndrome patients express a wide array of cognitive and other gender-specific phenotypic features. These manifestations result not only from molecular mechanisms that are altered as a result of the expansion of a CGG-repeat region in the FMR1 promoter, but also genetic factors such as founder effects and mosaicism. In this chapter, I will summarize the many and varied features of fragile X syndrome as they present themselves in a clinical setting and describe the procedures that are used to diagnose patients. Finally, I will briefly touch on recent developments that will affect patient screening in the future.

Increased PK11195-PET binding in normal-appearing white matter in clinically isolated syndrome.

PubMed

Giannetti, Paolo; Politis, Marios; Su, Paul; Turkheimer, Federico E; Malik, Omar; Keihaninejad, Shiva; Wu, Kit; Waldman, Adam; Reynolds, Richard; Nicholas, Richard; Piccini, Paola

2015-01-01

The most accurate predictor of the subsequent development of multiple sclerosis in clinically isolated syndrome is the presence of lesions at magnetic resonance imaging. We used in vivo positron emission tomography with (11)C-(R)-PK11195, a biomarker of activated microglia, to investigate the normal-appearing white matter and grey matter of subjects with clinically isolated syndrome to explore its role in the development of multiple sclerosis. Eighteen clinically isolated syndrome and eight healthy control subjects were recruited. Baseline assessment included: history, neurological examination, expanded disability status scale, magnetic resonance imaging and PK11195-positron emission tomography scans. All assessments except the PK11195-positron emission tomography scan were repeated over 2 years. SUPERPK methodology was used to measure the binding potential relative to the non-specific volume, BPND. We show a global increase of normal-appearing white matter PK11195 BPND in clinically isolated syndrome subjects compared with healthy controls (P = 0.014). Clinically isolated syndrome subjects with T2 magnetic resonance imaging lesions had higher PK11195 BPND in normal-appearing white matter (P = 0.009) and their normal-appearing white matter PK11195 BPND correlated with the Expanded Disability Status Scale (P = 0.007; r = 0.672). At 2 years those who developed dissemination in space or multiple sclerosis, had higher PK11195 BPND in normal-appearing white matter at baseline (P = 0.007 and P = 0.048, respectively). Central grey matter PK11195 BPND was increased in subjects with clinically isolated syndrome compared to healthy controls but no difference was found in cortical grey matter PK11195 BPND. Microglial activation in clinically isolated syndrome normal-appearing white matter is diffusely increased compared with healthy control subjects and is further increased in those who have magnetic resonance imaging lesions. Furthermore microglial activation in clinically

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

What Health Issues or Conditions Are Specific to Women Only?

MedlinePlus

... Research Information Find a Study Resources and Publications Turner Syndrome Condition Information NICHD Research Information Find a Study ... disorders and conditions that affect only women include Turner syndrome , Rett syndrome , and ovarian and cervical cancers. Issues ...

Refeeding syndrome: clinical and nutritional relevance.

PubMed

Viana, Larissa de Andrade; Burgos, Maria Goretti Pessoa de Araújo; Silva, Rafaella de Andrade

2012-01-01

Feedback syndrome is characterized clinically by neurological alterations, respiratory symptoms, arrhythmias and heart failure few days after refeeding. It happens due to severe electrolyte changes, such as hypophosphatemia, hypomagnesemia and hypokalemia associated with metabolic abnormalities that may occur as a result of nutritional support (oral, enteral or parenteral) in severely malnourished patients. To evaluate its causes and the preventive dietary measures aiming to reduce the morbimortality. Was conducted literature review in SciELO, LILACS, Medline / PUBMED, Cochrane Library and government websites in Portuguese, English and Spanish. The survey was about the last 15 years, selecting the headings: refeeding syndrome, malnutrition, hypophosphatemia, hypokalemia, hypomagnesemia. The monitoring of metabolic parameters and electrolyte levels before starting nutritional support and periodically during feeding should be based on protocols and the duration of therapy. Patients at high risk and other metabolic complications should be followed closely, and depletion of minerals and electrolytes should be replaced before starting the diet. A multidisciplinary team of nutrition therapy can guide and educate other health professionals in prevention, diagnosis and treatment of the syndrome.

[Clinical manifestation and cytogenetic analysis of 607 patients with Turner syndrome].

PubMed

Zheng, Jiemei; Liu, Zhiying; Xia, Pei; Lai, Yi; Wei, Yangjun; Liu, Yanyan; Chen, Jiurong; Qin, Li; Xie, Liangyu; Wang, He

2017-02-10

To explore the correlation between cytogenetic findings and clinical manifestations of Turner syndrome. 607 cases of cytogenetically diagnosed Turner syndrome, including those with a major manifestation of Turner syndrome, were analyzed with conventional G-banding. Correlation between the karyotypes and clinical features were analyzed. Among the 607 cases, there were 154 cases with monosomy X (25.37%). Mosaicism monosomy X was found in 240 patients (39.54%), which included 194 (80.83%) with a low proportion of 45,X (3 ≤ the number of 45, X ≤5, while the normal cells ≥ 30). Structural X chromosome abnormalities were found in 173 patients (28.50%). A supernumerary marker chromosome was found in 40 cases (6.59%). Most patients with typical manifestations of Turner syndrome were under 11 years of age and whose karyotypes were mainly 45,X. The karyotype of patients between 11 and 18 years old was mainly 45,X, 46,X,i(X)(q10) and mos45,X/46,X,i(X)(q10), which all had primary amenorrhea in addition to the typical clinical manifestations. The karyotype of patients over 18 years of age were mainly mosaicism with a low proportion of 45,X, whom all had primary infertility. 53 patients had a history of pregnancy, which included 48 with non-structural abnormalities of X chromosome and 5 with abnormal structure of X chromosome. Generally, the higher proportion of cells with an abnormal karyotype, the more severe were the clinical symptoms and the earlier clinical recognition. Karyotyping analysis can provide guidance for the early diagnosis of Turner syndrome, especially those with a low proportion of 45,X.

Xeroderma pigmentosum and Cockayne syndrome: overlapping clinical and biochemical phenotypes.

PubMed Central

Greenhaw, G A; Hebert, A; Duke-Woodside, M E; Butler, I J; Hecht, J T; Cleaver, J E; Thomas, G H; Horton, W A

1992-01-01

Two siblings are described whose clinical presentation of cutaneous photosensitivity and central nervous system dysfunction is strongly reminiscent of the DeSanctis-Cacchione syndrome (DCS) variant of xeroderma pigmentosum. An extensive clinical evaluation supported a diagnosis of DCS and documented previously unreported findings. In vitro fibroblast studies showed UV sensitivity that was two to three times that of normal controls. However, neither a post-UV-irradiation DNA excision-repair defect indicative of XP nor a semiconservative DNA replication defect indicative of XP variant was found. Rather, a failure of RNA synthesis to recover to normal levels after UV exposure was observed, a biochemical abnormality seen in Cockayne syndrome (CS), one of the premature-aging syndromes with clinical UV sensitivity. These patients, therefore, clinically have XP, but their biochemical characteristics suggest CS. The reason(s) for the severe neurologic disease, in light of the relatively mild cutaneous abnormalities, is unclear. Other cases with unusual fibroblast responses to irradiation have been noted in the literature and, along with the data from our patients, reinforce the notion of the complexity of DNA maintenance and repair. Images Figure 1 Figure 1 Figure 2 Figure 3 PMID:1372469

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. © 2016 Wiley Periodicals, Inc.

The Rare Painful Phenomena - Chronic Paroxysmal Hemicrania-tic Syndrome as a Clinically Isolated Syndrome of the Central Nervous System.

PubMed

Ljubisavljevic, Srdjan; Prazic, Ana; Lazarevic, Miodrag; Stojanov, Dragan; Savic, Dejan; Vojinovic, Slobadan

2017-02-01

The association of paroxysmal hemicrania with trigeminal neuralgia (TN) has been described and called paroxysmal hemicrania-tic syndrome (PH-tic). We report the case of a patient diagnosed as having chronic PH-tic (CPH-tic) syndrome as a clinically isolated syndrome of the central nervous system (CNS) (CIS).A forty year old woman was admitted to our hospital suffering from right facial pain for the last 2 years. The attacks were paroxysmal, neuralgiform, consisting of throb-like sensations, which developed spontaneously or were triggered by different stimuli in right facial (maxilar and mandibular) areas. Parallel with those, she felt a throbbing orbital and frontal pain with homolateral autonomic symptoms such as conjunctival injection, lacrimation, and the feeling that the ear on the same side was full. This pain lasted most often between 15 and 20 minutes. Beyond hemifacial hypoesthesia in the region of right maxilar and mandibular nerve, the other neurological finding was normal. Magnetic resonance imaging (MRI) study showed a T2-weighted multiple hyperintense paraventricular lesion and hyperintense lesion in the right trigeminal main sensory nucleus and root inlet, all of them being hypointense on T1-weighted image. All of these lesions were hypointense in gadolinium-enhanced T1-weighted images. Neurophysiological studies of trigeminal nerve (somatosensory evoked potentials and blink reflex) correlated with MRI described lesions. The patient's pain bouts were improved immediately after treatment with indomethacin, and were completely relieved with lamotrigine for a longer period. According to the actual McDonald's criteria, clinical state was defined as CIS which was clinically presented by CPH-tic syndrome.Even though it is a clinical rarity and its etiology is usually idiopathic, CPH-tic syndrome can also be symptomatic. When dealing with symptomatic cases, like the one described here, when causal therapy is not possible due to the nature of the primary

Targeted molecular investigation in patients within the clinical spectrum of Auriculocondylar syndrome.

PubMed

Romanelli Tavares, Vanessa L; Zechi-Ceide, Roseli M; Bertola, Debora R; Gordon, Christopher T; Ferreira, Simone G; Hsia, Gabriella S P; Yamamoto, Guilherme L; Ezquina, Suzana A M; Kokitsu-Nakata, Nancy M; Vendramini-Pittoli, Siulan; Freitas, Renato S; Souza, Josiane; Raposo-Amaral, Cesar A; Zatz, Mayana; Amiel, Jeanne; Guion-Almeida, Maria L; Passos-Bueno, Maria Rita

2017-04-01

Auriculocondylar syndrome, mainly characterized by micrognathia, small mandibular condyle, and question mark ears, is a rare disease segregating in an autosomal dominant pattern in the majority of the families reported in the literature. So far, pathogenic variants in PLCB4, GNAI3, and EDN1 have been associated with this syndrome. It is caused by a developmental abnormality of the first and second pharyngeal arches and it is associated with great inter- and intra-familial clinical variability, with some patients not presenting the typical phenotype of the syndrome. Moreover, only a few patients of each molecular subtype of Auriculocondylar syndrome have been reported and sequenced. Therefore, the spectrum of clinical and genetic variability is still not defined. In order to address these questions, we searched for alterations in PLCB4, GNAI3, and EDN1 in patients with typical Auriculocondylar syndrome (n = 3), Pierre Robin sequence-plus (n = 3), micrognathia with additional craniofacial malformations (n = 4), or non-specific auricular dysplasia (n = 1), which could represent subtypes of Auriculocondylar syndrome. We found novel pathogenic variants in PLCB4 only in two of three index patients with typical Auriculocondylar syndrome. We also performed a detailed comparative analysis of the patients presented in this study with those previously published, which showed that the pattern of auricular abnormality and full cheeks were associated with molecularly characterized individuals with Auriculocondylar syndrome. Finally, our data contribute to a better definition of a set of parameters for clinical classification that may be used as a guidance for geneticists ordering molecular testing for Auriculocondylar syndrome. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

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

The Korsakoff syndrome: clinical aspects, psychology and treatment.

PubMed

Kopelman, Michael D; Thomson, Allan D; Guerrini, Irene; Marshall, E Jane

2009-01-01

The Korsakoff syndrome is a preventable memory disorder that usually emerges (although not always) in the aftermath of an episode of Wernicke's encephalopathy. The present paper reviews the clinical and scientific literature on this disorder. A systematic review of the clinical and scientific literature on Wernicke's encephalopathy and the alcoholic Korsakoff syndrome. The Korsakoff syndrome is most commonly associated with chronic alcohol misuse, and some heavy drinkers may have a genetic predisposition to developing the syndrome. The characteristic neuropathology includes neuronal loss, micro-haemorrhages and gliosis in the paraventricular and peri-aqueductal grey matter. Lesions in the mammillary bodies, the mammillo-thalamic tract and the anterior thalamus may be more important to memory dysfunction than lesions in the medial dorsal nucleus of the thalamus. Episodic memory is severely affected in the Korsakoff syndrome, and the learning of new semantic memories is variably affected. 'Implicit' aspects of memory are preserved. These patients are often first encountered in general hospital settings where they can occupy acute medical beds for lengthy periods. Abstinence is the cornerstone of any rehabilitation programme. Korsakoff patients are capable of new learning, particularly if they live in a calm and well-structured environment and if new information is cued. There are few long-term follow-up studies, but these patients are reported to have a normal life expectancy if they remain abstinent from alcohol. Although we now have substantial knowledge about the nature of this disorder, scientific questions (e.g. regarding the underlying genetics) remain. More particularly, there is a dearth of appropriate long-term care facilities for these patients, given that empirical research has shown that good practice has beneficial effects.

Ellis-van Creveld syndrome in adulthood: extending the clinical spectrum

PubMed Central

Pérez-Andreu, Joaquín; Ray, Victor Glenn; Arribas, José María; Sánchez, Sergio Juan

2015-01-01

Ellis-van Creveld (EvC) syndrome is a rare autosomal recessive malformation disorder. Cardiac defects are observed in about 50% of EvC cases. Surgical data is lacking on the prognosis and life expectancy of EvC patients. Herein, we report the case of a 38-year-old man with EvC syndrome who underwent two surgical corrections for cardiac anomalies. This report supplements the available information on the clinical course of EvC syndrome in older patients. PMID:26106249

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

Exome analysis in clinical practice: expanding the phenotype of Bartsocas-Papas syndrome.

PubMed

Gripp, Karen W; Ennis, Sara; Napoli, Joseph

2013-05-01

Exome analysis has had a dramatic impact on genetic research. We present the application of such newly generated information to patient care. The patient was a female, born with normal growth parameters to nonconsanguineous parents after an uneventful pregnancy. She had bilateral cleft lip/palate and ankyloblepharon. Sparse hair, dysplastic nails and hypohidrosis were subsequently noted. With exception of speech related issues, her development was normal. A clinical diagnosis of ankyloblepharon-ectodermal defects-cleft lip/palate or Hay-Wells syndrome resulted in TP63 sequence analysis. TP63 sequence and deletion/duplication analysis of all coding exons had a normal result, as did chromosome and SNP array analysis. Diagnostic exome analysis revealed a heterozygous nonsense mutation in KRT83 categorized as deleterious and associated with monilethrix. In addition, a homozygous missense variant of unknown clinical significance was reported in RIPK4. Using research based exome analysis, RIPK4 had just a few months prior been identified as pathogenic for Bartsocas-Papas syndrome. While the clinical diagnostic report implied the KRT83 mutation as a more likely cause for the patient's phenotype, clinical correlation, literature review and use of computerized mutation analysis programs allowed us to identify the homozygous RIPK4 (c.488G > A; p.Gly163Asp) mutation as the underlying pathogenic change. Consequently, we expand the phenotype of Bartsocas-Papas syndrome to an attenuated presentation resembling Hay-Wells syndrome, lacking lethality and pterygia. In contrast to the autosomal dominant Hay-Wells syndrome, Bartsocas-Papas syndrome is autosomal recessive, implying a 25% recurrence risk. Copyright © 2013 Wiley Periodicals, Inc.

[Poland'syndrome and hand's malformations: about a clinic series of 37 patients].

PubMed

Foucras, L; Grolleau, J L; Chavoin, J P

2005-04-01

Poland's syndrome is a rare malformation which associates thoracic anomalies and anomalies of homolateral upper end. We wish to know the frequency of hand's malformations in this syndrome in our clinical experience. We have revised 37 patients who were seen initially for a thoracomammary anomaly. This clinical series from plastic surgery service of Toulouse has been revised to know the importance of hand's malformations. Hand's malformations in Poland's syndrome are rare in your study, they touch only 12% patients. We find only 4 malformations in 33 patients, four were lost. They were only females, we find three brachymesophalangies and a major form. Hand's malformations in Poland's syndrome are less frequent than classically. There is no parallelism between gravity of thoracic malformation and that one of upper end. In this series, we find only one case with syndactyly; originally, Poland's syndrome was named < Poland's syndactyly >. Finally, we think that we can talk about Poland's syndrome without anomaly of homolateral upper end, the major element is musculary agenesia of sternocostal pectoralis major. The search of homolateral upper end has to be systematic in front of suspicious of Poland's syndrome.

Genetic and Medical Considerations of Autism: A Literature Review.

ERIC Educational Resources Information Center

Silver, Kathi O.

This literature review, from 1990 to the present, discusses the characteristics of autism and the comorbidity of mental retardation and autism. Specific medical syndromes that complement the heterogeneity concept are described, including epilepsy, fragile X syndrome, Rett syndrome, tuberous sclerosis, and Asperger syndrome. The paper presents some…

Effects of early-life exposure to THIP on brainstem neuronal excitability in the Mecp2-null mouse model of Rett syndrome before and after drug withdrawal.

PubMed

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

2017-01-01

Rett syndrome (RTT) is mostly caused by mutations of the X-linked MECP2 gene. Although the causal neuronal mechanisms are still unclear, accumulating experimental evidence obtained from Mecp2 -/Y mice suggests that imbalanced excitation/inhibition in central neurons plays a major role. Several approaches may help to rebalance the excitation/inhibition, including agonists of GABA A receptors (GABA A R). Indeed, our previous studies have shown that early-life exposure of Mecp2-null mice to the extrasynaptic GABA A R agonist THIP alleviates several RTT-like symptoms including breathing disorders, motor dysfunction, social behaviors, and lifespan. However, how the chronic THIP affects the Mecp2 -/Y mice at the cellular level remains elusive. Here, we show that the THIP exposure in early lives markedly alleviated hyperexcitability of two types of brainstem neurons in Mecp2 -/Y mice. In neurons of the locus coeruleus (LC), known to be involved in breathing regulation, the hyperexcitability showed clear age-dependence, which was associated with age-dependent deterioration of the RTT-like breathing irregularities. Both the neuronal hyperexcitability and the breathing disorders were relieved with early THIP treatment. In neurons of the mesencephalic trigeminal nucleus (Me5), both the neuronal hyperexcitability and the changes in intrinsic membrane properties were alleviated with the THIP treatment in Mecp2-null mice. The effects of THIP on both LC and Me5 neuronal excitability remained 1 week after withdrawal. Persistent alleviation of breathing abnormalities in Mecp2 -/Y mice was also observed a week after THIP withdrawal. These results suggest that early-life exposure to THIP, a potential therapeutic medicine, appears capable of controlling neuronal hyperexcitability in Mecp2 -/Y mice, which occurs in the absence of THIP in the recording solution, lasts at least 1 week after withdrawal, and may contribute to the RTT-like symptom mitigation. © 2017 The Authors

Clinical practice guidelines for the management of acute limb compartment syndrome following trauma.

PubMed

Wall, Christopher J; Lynch, Joan; Harris, Ian A; Richardson, Martin D; Brand, Caroline; Lowe, Adrian J; Sugrue, Michael

2010-03-01

Acute compartment syndrome is a serious and not uncommon complication of limb trauma. The condition is a surgical emergency, and is associated with significant morbidity if not managed appropriately. There is variation in management of acute limb compartment syndrome in Australia. Clinical practice guidelines for the management of acute limb compartment syndrome following trauma were developed in accordance with Australian National Health and Medical Research Council recommendations. The guidelines were based on critically appraised literature evidence and the consensus opinion of a multidisciplinary team involved in trauma management who met in a nominal panel process. Recommendations were developed for key decision nodes in the patient care pathway, including methods of diagnosis in alert and unconscious patients, appropriate assessment of compartment pressure, timing and technique of fasciotomy, fasciotomy wound management, and prevention of compartment syndrome in patients with limb injuries. The recommendations were largely consensus based in the absence of well-designed clinical trial evidence. Clinical practice guidelines for the management of acute limb compartment syndrome following trauma have been developed that will support consistency in management and optimize patient health outcomes.

Recent Clinical Drug Trials Evidence in Marfan Syndrome and Clinical Implications.

PubMed

Singh, Michael N; Lacro, Ronald V

2016-01-01

Marfan syndrome is a genetic disorder of connective tissue with principal manifestations in the cardiovascular, ocular, and skeletal systems. Cardiovascular disease, mainly progressive aortic root dilation and aortic dissection, is the leading cause of morbidity and mortality. The primary aims of this report were to examine the evidence related to medical therapy for Marfan syndrome, including recently completed randomized clinical trials on the efficacy of β-blockers and angiotensin II receptor blockers for the prophylactic treatment of aortic enlargement in Marfan syndrome, and to provide recommendations for medical therapy on the basis of available evidence. Medical therapy for Marfan syndrome should be individualized according to patient tolerance and risk factors such as age, aortic size, and family history of aortic dissection. The Pediatric Heart Network trial showed that atenolol and losartan each reduced the rate of aortic dilation. All patients with known or suspected Marfan syndrome and aortic root dilation should receive medical therapy with adequate doses of either β-blocker or angiotensin receptor blocker. The Pediatric Heart Network trial also showed that atenolol and losartan are more effective at reduction of aortic root z score in younger subjects, which suggests that medical therapy should be prescribed even in the youngest children with aortic dilation. For patients with Marfan syndrome without aortic dilation, the available evidence is less clear. If aortic dilation is severe and/or progressive, therapy with a combination of β-blocker and angiotensin receptor blocker should be considered, although trial results are mixed with respect to the efficacy of combination therapy vs monotherapy. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

[Clinical study of 12 cases with obstetric mirror syndrome].

PubMed

Wu, Lin-lin; Wang, Chen-hong; Li, Zhi-quan

2012-03-01

To discuss the clinical features, management, pregnancy outcome and prognosis of obstetric mirror syndrome. The clinical data of 12 cases with obstetric mirror syndrome at Shenzhen Maternity and Child Healthcare Hospital from April 2008 to December 2010 were collected to retrospectively analyze the clinical features, management, pregnancy outcome and prognosis. (1) ETIOLOGY: 12 cases with obstetric mirror syndrome included 9 cases of Bart's hydrops fetalis, 2 cases with fetal complicated congenital cardiac anomalies, and 1 case of unknown etiology. (2) Gestational age at diagnosis and at delivery: gestational age at diagnosis ranged from 28 to 36 weeks [mean (31.5 ± 4.7) weeks], and gestational age at delivery ranged from 28(+3) to 38 weeks [mean (32.9 ± 2.9) weeks]. There were no significant differences between the gestational age at diagnosis and at delivery in consistence with severe preeclampsia group and mild preeclampsia group [(31.8 ± 2.3) weeks vs. (30.9 ± 7.2) weeks, (32.5 ± 2.3) weeks vs. (33.5 ± 3.9) weeks, P > 0.05]. (3) The patients with obstetric mirror syndrome can present a preeclampsia-like syndrome: maternal extremity edema in 12 cases, headache and visual disturbance in 1 case, proteinuria in 11 cases, elevated blood pressure in 5 cases, elevated uric acid in 9 cases, hypoproteinemia in 12 cases, elevated creatinine in 3 case, elevated liver enzyme in 1 case, thrombocytopenia in 2 cases. The major complications included 1 case of HELLP syndrome, acute pulmonary edema, placental abruption, amnionic fluid embolism, DIC respectively, 3 cases of acute kidney failure and 6 cases of postpartum hemorrhage. (4) Sonographic findings: 1) Hydrops fetalis: fetal ultrasound revealed pleural fluid, fetal ascites, skin edema, scalp edema, encephalocolele enlargement, hydropericardium and increased cardio-chest ratio. 2) Placenta megaly: the placental pathological examination revealed edematous and large in 12 cases. Placental thickness was beyond 4 cm in

Differential diagnosis of Bartter syndrome, Gitelman syndrome, and pseudo-Bartter/Gitelman syndrome based on clinical characteristics.

PubMed

Matsunoshita, Natsuki; Nozu, Kandai; Shono, Akemi; Nozu, Yoshimi; Fu, Xue Jun; Morisada, Naoya; Kamiyoshi, Naohiro; Ohtsubo, Hiromi; Ninchoji, Takeshi; Minamikawa, Shogo; Yamamura, Tomohiko; Nakanishi, Koichi; Yoshikawa, Norishige; Shima, Yuko; Kaito, Hiroshi; Iijima, Kazumoto

2016-02-01

Phenotypic overlap exists among type III Bartter syndrome (BS), Gitelman syndrome (GS), and pseudo-BS/GS (p-BS/GS), which are clinically difficult to distinguish. We aimed to clarify the differences between these diseases, allowing accurate diagnosis based on their clinical features. A total of 163 patients with genetically defined type III BS (n = 30), GS (n = 90), and p-BS/GS (n = 43) were included. Age at diagnosis, sex, body mass index, estimated glomerular filtration rate, and serum and urine electrolyte concentrations were determined. Patients with p-BS/GS were significantly older at diagnosis than those with type III BS and GS. Patients with p-BS/GS included a significantly higher percentage of women and had a lower body mass index and estimated glomerular filtration rate than did patients with GS. Although hypomagnesemia and hypocalciuria were predominant biochemical findings in patients with GS, 17 and 23% of patients with type III BS and p-BS/GS, respectively, also showed these abnormalities. Of patients with type III BS, GS, and p-BS/GS, 40, 12, and 63%, respectively, presented with chronic kidney disease. This study clarified the clinical differences between BS, GS, and p-BS/GS for the first time, which will help clinicians establish differential diagnoses for these three conditions.

[Noonan syndrome can be diagnosed clinically and through molecular genetic analyses].

PubMed

Henningsen, Marie Krab; Jelsig, Anne Marie; Andersen, Helle; Brusgaard, Klaus; Ousager, Lilian Bomme; Hertz, Jens Michael

2015-08-03

Noonan syndrome is part of the group of RASopathies caused by germ line mutations in genes involved in the RAS/MAPK pathway. There is substantial phenotypic overlap among the RASopathies. Diagnosis of Noonan syndrome is often based on clinical features including dysmorphic facial features, short stature and congenital heart disease. Rapid advances in sequencing technology have made molecular genetic analyses a helpful tool in diagnosing and distinguishing Noonan syndrome from other RASopathies.

Clinical and microbiologic study of periodontitis associated with Kindler syndrome.

PubMed

Wiebe, Colin B; Penagos, Homero; Luong, Nancy; Slots, Jørgen; Epstein, Ervin; Siegel, Dawn; Häkkinen, Lari; Putnins, Edward E; Larjava, Hannu S

2003-01-01

Little is known about the onset and prevalence of periodontal disease in patients with the rare Kindler syndrome, a genodermatological disorder. This study investigated the level of clinical periodontal attachment in relation to age and presence of putative periodontopathogenic bacteria in individuals with Kindler syndrome. Eighteen individuals diagnosed with Kindler syndrome and 13 control subjects, aged 4 to 37 years, from rural Panama received a limited clinical periodontal examination. Subgingival samples were collected for identification of putative periodontal pathogens by polymerase chain reaction. Mild to severe gingivitis was a common finding in all adults of the study population. Seventy-two percent (13/18) of the Kindler patients and 46% (6/13) of the control subjects showed mild to severe periodontal disease (P = 0.001, chi-square test). The onset of periodontitis was earlier and the progression occurred at a faster rate in the Kindler group. There was a strong correlation (r = 0.83) between the level of attachment loss and age in the Kindler group and a weaker correlation (r = 0.66) in the control group. The appearance of gingival tissues suggested atypical periodontitis with spontaneous bleeding and fragile, often desquamative, gingiva. In periodontitis patients, Porphyromonas gingivallis and Diallster pneumosintes tended to occur more frequently in control individuals compared to those with Kindler syndrome. In the Kindler group, periodontitis had an onset in early teenage years and progressed more rapidly compared to non-Kindler individuals of the same geographic and ethnic group. Clinical and microbiological findings suggest atypical periodontitis in Kindler patients. We propose to include Kindler syndrome in the category of medical disorders predisposing to destructive periodontal disease.

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

Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients

PubMed Central

2014-01-01

Background Mutations in the cyclin-dependent kinase-like 5 (CDKL5) (NM_003159.2) gene have been associated with early-onset epileptic encephalopathies or Hanefeld variants of RTT(Rett syndrome). In order to clarify the CDKL5 genotype-phenotype correlations in Chinese patients, CDKL5 mutational screening in cases with early-onset epileptic encephalopathies and RTT without MECP2 mutation were performed. Methods The detailed clinical information including clinical manifestation, electroencephalogram (EEG), magnetic resonance imaging (MRI), blood, urine amino acid and organic acid screening of 102 Chinese patients with early-onset epileptic encephalopathies and RTT were collected. CDKL5 gene mutations were analyzed by PCR, direct sequencing and multiplex ligation-dependent probe amplification (MLPA). The patterns of X-chromosome inactivation (XCI) were studied in the female patients with CDKL5 gene mutation. Results De novo CDKL5 gene mutations were found in ten patients including one missense mutation (c.533G > A, p.R178Q) which had been reported, two splicing mutations (ISV6 + 1A > G, ISV13 + 1A > G), three micro-deletions (c.1111delC, c.2360delA, c.234delA), two insertions (c.1791 ins G, c.891_892 ins TT in a pair of twins) and one nonsense mutation (c.1375C > T, p.Q459X). Out of ten patients, 7 of 9 females with Hanefeld variants of RTT and the remaining 2 females with early onset epileptic encephalopathy, were detected while only one male with infantile spasms was detected. The common features of all female patients with CDKL5 gene mutations included refractory seizures starting before 4 months of age, severe psychomotor retardation, Rett-like features such as hand stereotypies, deceleration of head growth after birth and poor prognosis. In contrast, the only one male patient with CDKL5 mutation showed no obvious Rett-like features as females in our cohort. The X-chromosome inactivation patterns of all the female patients were random. Conclusions Mutations in CDKL

Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients.

PubMed

Zhao, Ying; Zhang, Xiaoying; Bao, Xinhua; Zhang, Qingping; Zhang, Jingjing; Cao, Guangna; Zhang, Jie; Li, Jiarui; Wei, Liping; Pan, Hong; Wu, Xiru

2014-02-25

Mutations in the cyclin-dependent kinase-like 5 (CDKL5) (NM_003159.2) gene have been associated with early-onset epileptic encephalopathies or Hanefeld variants of RTT(Rett syndrome). In order to clarify the CDKL5 genotype-phenotype correlations in Chinese patients, CDKL5 mutational screening in cases with early-onset epileptic encephalopathies and RTT without MECP2 mutation were performed. The detailed clinical information including clinical manifestation, electroencephalogram (EEG), magnetic resonance imaging (MRI), blood, urine amino acid and organic acid screening of 102 Chinese patients with early-onset epileptic encephalopathies and RTT were collected. CDKL5 gene mutations were analyzed by PCR, direct sequencing and multiplex ligation-dependent probe amplification (MLPA). The patterns of X-chromosome inactivation (XCI) were studied in the female patients with CDKL5 gene mutation. De novo CDKL5 gene mutations were found in ten patients including one missense mutation (c.533G > A, p.R178Q) which had been reported, two splicing mutations (ISV6 + 1A > G, ISV13 + 1A > G), three micro-deletions (c.1111delC, c.2360delA, c.234delA), two insertions (c.1791 ins G, c.891_892 ins TT in a pair of twins) and one nonsense mutation (c.1375C > T, p.Q459X). Out of ten patients, 7 of 9 females with Hanefeld variants of RTT and the remaining 2 females with early onset epileptic encephalopathy, were detected while only one male with infantile spasms was detected. The common features of all female patients with CDKL5 gene mutations included refractory seizures starting before 4 months of age, severe psychomotor retardation, Rett-like features such as hand stereotypies, deceleration of head growth after birth and poor prognosis. In contrast, the only one male patient with CDKL5 mutation showed no obvious Rett-like features as females in our cohort. The X-chromosome inactivation patterns of all the female patients were random. Mutations in CDKL5 gene are responsible for 7 with

Noonan syndrome: clinical features, diagnosis, and management guidelines.

PubMed

Romano, Alicia A; Allanson, Judith E; Dahlgren, Jovanna; Gelb, Bruce D; Hall, Bryan; Pierpont, Mary Ella; Roberts, Amy E; Robinson, Wanda; Takemoto, Clifford M; Noonan, Jacqueline A

2010-10-01

Noonan syndrome (NS) is a common, clinically and genetically heterogeneous condition characterized by distinctive facial features, short stature, chest deformity, congenital heart disease, and other comorbidities. Gene mutations identified in individuals with the NS phenotype are involved in the Ras/MAPK (mitogen-activated protein kinase) signal transduction pathway and currently explain ∼61% of NS cases. Thus, NS frequently remains a clinical diagnosis. Because of the variability in presentation and the need for multidisciplinary care, it is essential that the condition be identified and managed comprehensively. The Noonan Syndrome Support Group (NSSG) is a nonprofit organization committed to providing support, current information, and understanding to those affected by NS. The NSSG convened a conference of health care providers, all involved in various aspects of NS, to develop these guidelines for use by pediatricians in the diagnosis and management of individuals with NS and to provide updated genetic findings.

[Cardiofaciocutaneous syndrome, a Noonan syndrome related disorder: clinical and molecular findings in 11 patients].

PubMed

Carcavilla, Atilano; García-Miñaúr, Sixto; Pérez-Aytés, Antonio; Vendrell, Teresa; Pinto, Isabel; Guillén-Navarro, Encarna; González-Meneses, Antonio; Aoki, Yoko; Grinberg, Daniel; Ezquieta, Begoña

2015-01-20

To describe 11 patients with cardiofaciocutaneous syndrome (CFC) and compare them with 130 patients with other RAS-MAPK syndromes (111 Noonan syndrome patients [NS] and 19 patients with LEOPARD syndrome). Clinical data from patients submitted for genetic analysis were collected. Bidirectional sequencing analysis of PTPN11, SOS1, RAF1, BRAF, and MAP2K1 focused on exons carrying recurrent mutations, and of all KRAS exons were performed. Six different mutations in BRAF were identified in 9 patients, as well as 2 MAP2K1 mutations. Short stature, developmental delay, language difficulties and ectodermal anomalies were more frequent in CFC patients when compared with other neuro-cardio-faciocutaneous syndromes (P<.05). In at least 2 cases molecular testing helped reconsider the diagnosis. CFC patients showed a rather severe phenotype but at least one patient with BRAF mutation showed no developmental delay, which illustrates the variability of the phenotypic spectrum caused by BRAF mutations. Molecular genetic testing is a valuable tool for differential diagnosis of CFC and NS related disorders. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis, and Management Guidelines

PubMed Central

Magoulas, Pilar L.; Adi, Saleh; Kavamura, Maria Ines; Neri, Giovanni; Noonan, Jacqueline; Pierpont, Elizabeth I.; Reinker, Kent; Roberts, Amy E.; Shankar, Suma; Sullivan, Joseph; Wolford, Melinda; Conger, Brenda; Santa Cruz, Molly; Rauen, Katherine A.

2014-01-01

Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies that bears many clinical features in common with the other syndromes in this group, most notably Noonan syndrome and Costello syndrome. CFC is genetically heterogeneous and caused by gene mutations in the Ras/mitogen-activated protein kinase pathway. The major features of CFC include characteristic craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. It is essential that this condition be differentiated from other RASopathies, as a correct diagnosis is important for appropriate medical management and determining recurrence risk. Children and adults with CFC require multidisciplinary care from specialists, and the need for comprehensive management has been apparent to families and health care professionals caring for affected individuals. To address this need, CFC International, a nonprofit family support organization that provides a forum for information, support, and facilitation of research in basic medical and social issues affecting individuals with CFC, organized a consensus conference. Experts in multiple medical specialties provided clinical management guidelines for pediatricians and other care providers. These guidelines will assist in an accurate diagnosis of individuals with CFC, provide best practice recommendations, and facilitate long-term medical care. PMID:25180280

Metabolic syndrome and its characteristics among obese patients attending an obesity clinic.

PubMed

Termizy, H M; Mafauzy, M

2009-04-01

The increased prevalence of metabolic syndrome worldwide is closely related to the rising obesity epidemic. The objectives of the study were to determine the prevalence and identify the associated and prognostic factors that influence the risk of metabolic syndrome among obese patients attending the Obesity Clinic at Hospital Universiti Sains Malaysia. A study was conducted involving 102 obese persons who attended the Obesity Clinic from January 1 to December 31, 2005. Metabolic syndrome was defined according to the International Diabetes Federation criteria. The overall prevalence of metabolic syndrome among obese patients was 40.2 percent. The prevalence was higher in females (43.7 percent) than in males (32.3 percent). The prevalence of metabolic syndrome was noted to increase with increasing body mass index class, from class 1 to class 2. However, the prevalence was lower in obesity class 3. The prevalence of metabolic comorbidities of raised blood pressure, reduced high density lipoprotein, high triglyceride and raised fasting blood glucose was 42, 40, 36 and 17 percent, respectively. A quarter of obese patients in this study had no other comorbidity. Based on logistic regression multivariable analysis, age was the only significant associated factor that influenced the risk of having metabolic syndrome. The prevalence of metabolic syndrome was high and the highest comorbidity was high blood pressure. Age was the only significant risk factor of having this syndrome.

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. © 2015 Japanese Teratology Society.

Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome Type III and Ehlers-Danlos syndrome hypermobility type): Clinical description and natural history.

PubMed

Tinkle, Brad; Castori, Marco; Berglund, Britta; Cohen, Helen; Grahame, Rodney; Kazkaz, Hanadi; Levy, Howard

2017-03-01

The hypermobile type of Ehlers-Danlos syndrome (hEDS) is likely the most common hereditary disorder of connective tissue. It has been described largely in those with musculoskeletal complaints including joint hypermobility, joint subluxations/dislocations, as well as skin and soft tissue manifestations. Many patients report activity-related pain and some go on to have daily pain. Two undifferentiated syndromes have been used to describe these manifestations-joint hypermobility syndrome and hEDS. Both are clinical diagnoses in the absence of other causation. Current medical literature further complicates differentiation and describes multiple associated symptoms and disorders. The current EDS nosology combines these two entities into the hypermobile type of EDS. Herein, we review and summarize the literature as a better clinical description of this type of connective tissue disorder. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

National data elements for the clinical management of acute coronary syndromes.

PubMed

Chew, Derek P B; Allan, Roger M; Aroney, Constantine N; Sheerin, Noella J

2005-05-02

Patients with acute coronary syndromes represent a clinically diverse group and their care remains heterogeneous. These patients account for a significant burden of morbidity and mortality in Australia. Optimal patient outcomes depend on rapid diagnosis, accurate risk stratification and the effective implementation of proven therapies, as advocated by clinical guidelines. The challenge is in effectively applying evidence in clinical practice. Objectivity and standardised quantification of clinical practice are essential in understanding the evidence-practice gap. Observational registries are key to understanding the link between evidence-based medicine, clinical practice and patient outcome. Data elements for monitoring clinical management of patients with acute coronary syndromes have been adapted from internationally accepted definitions and incorporated into the National Health Data Dictionary, the national standard for health data definitions in Australia. Widespread use of these data elements will assist in the local development of "quality-of-care" initiatives and performance indicators, facilitate collaboration in cardiovascular outcomes research, and aid in the development of electronic data collection methods.

Clinical picture and treatment implication in a child with Capgras syndrome: a case report

PubMed Central

2012-01-01

Introduction Capgras syndrome is a delusional misidentification syndrome characterized by the patient’s belief that his or her relatives have been replaced by impostors. Case presentation Here we describe the clinical picture and the therapeutic approach to an 11-year-old Caucasian girl with Capgras syndrome. A complete psychopathological assessment was conducted during the acute phase, at one month, two months and six months since diagnosis. Conclusion Subsequent follow-up evaluations in this patient allowed us to detect improvements in the psychotic symptoms following treatment with risperidone and selective serotonin reuptake inhibitors, suggesting that this combined therapy may significantly improve the clinical outcome in patients who have Capgras syndrome. PMID:23186382

Clinical picture and treatment implication in a child with Capgras syndrome: a case report.

PubMed

Mazzone, Luigi; Armando, Marco; De Crescenzo, Franco; Demaria, Francesco; Valeri, Giovanni; Vicari, Stefano

2012-11-27

Capgras syndrome is a delusional misidentification syndrome characterized by the patient's belief that his or her relatives have been replaced by impostors. Here we describe the clinical picture and the therapeutic approach to an 11-year-old Caucasian girl with Capgras syndrome. A complete psychopathological assessment was conducted during the acute phase, at one month, two months and six months since diagnosis. Subsequent follow-up evaluations in this patient allowed us to detect improvements in the psychotic symptoms following treatment with risperidone and selective serotonin reuptake inhibitors, suggesting that this combined therapy may significantly improve the clinical outcome in patients who have Capgras syndrome.

Gorlin-Goltz syndrome in a child: case report and clinical review.

PubMed

Snoeckx, A; Vanhoenacker, F M; Verhaert, K; Chappelle, K; Parizel, P M

2008-01-01

Gorlin-Goltz syndrome is a rare autosomal dominant disorder that involves multiple organ systems, including the skin, skeleton and jaws. We report the case of a mild mentally retarded 7-year-old boy who was referred with a swelling of his left mandible. Imaging studies showed a unilocular well-defined lytic mandibular lesion, calcifications of the falx, bifid ribs and fusion anomalies of the ribs. The mandibular lesion was treated with surgical decompression and proved to represent a keratocyst on histological examination. Further clinical examination revealed cutaneous lesions, Sprengel deformity, pectus excavatum and facial dysmorphism. Based on the combination of imaging and clinical findings the diagnosis of Gorlin-Goltz syndrome was made. This was confirmed by genetic tests. During three-year follow-up the boy presented with recurrent and multiple odontogenic keratocysts. The occurrence of multiple and recurrent keratocysts at young age, should alert the radiologist to the potential diagnosis of an underlying Gorlin-Goltz syndrome. This paper reviews the imaging findings in Gorlin-Goltz syndrome, with emphasis on maxillofacial imaging.

Insufficient sleep syndrome: An unrecognized but important clinical entity.

PubMed

Kohyama, Jun; Anzai, Yuki; Ono, Makoto; Kishino, Ai; Tamanuki, Keita; Takada, Kazuma; Inoue, Kento; Horiuchi, Maho; Hatai, Yoshiho

2018-04-01

A sleep clinic for adults and children was established in the Tokyo Bay Urayasu Ichikawa Medical Centre, in August 2012. Given that few sleep clinics are available in Japan specifically for children, this clinic provides the opportunity to provide data on child patients with sleep problems. Records of patients who visited the sleep clinic at the Tokyo Bay Urayasu Ichikawa Medical Centre aged ≤20 years at the first visit were retrospectively examined, along with the initial and final diagnoses. Of 2,157 patients who visited the sleep clinic at Tokyo Bay Urayasu Ichikawa Medical Centre between August 2012 and March 2017, 181 were ≤20 years old. In these 181 patients, the most frequent final diagnosis was insufficient sleep syndrome (ISS), n = 56, followed by circadian rhythm sleep-wake disorder, n = 28; insomnia, n = 28; and sleep-related movement disorder, n = 15. Insufficient sleep produces various brain dysfunctions in both adults and children, and is associated with behavioral, cognitive and physical problems, as well as with atypical early development. Insufficient sleep has also been reported to cause obesity. Insufficient sleep-induced obesity is often associated with the occurrence of metabolic syndrome. More effort is needed to ensure that children are receiving sufficient sleep. © 2018 Japan Pediatric Society.

Rett Syndrome Fact Sheet

MedlinePlus

... management of symptoms — and supportive, requiring a multidisciplinary approach. Medication may be needed for breathing irregularities and motor difficulties, and anticonvulsant drugs may be used to control seizures. There should be regular monitoring for scoliosis ...

Breath holding spell

MedlinePlus

... such as Riley-Day syndrome or Rett syndrome Iron deficiency anemia A family history of breath holding spells ( ... tests may be done to check for an iron deficiency. Other tests that may be done include: EKG ...

Psychologists' Clinical Practices in Assessing Dementia in Individuals with Down Syndrome

ERIC Educational Resources Information Center

Auty, Ellen; Scior, Katrina

2008-01-01

There are now ample guidelines for the assessment and diagnosis of possible dementia in individuals with intellectual disabilities (ID) and Down syndrome. However, little is known about their implementation in clinical practice. This study set out to examine the clinical practice of one key professional group, namely clinical psychologists. A…

[Secondary cardiovascular prevention after acute coronary syndrome in clinical practice].

PubMed

Colivicchi, Furio; Di Roma, Angelo; Uguccioni, Massimo; Scotti, Emilio; Ammirati, Fabrizio; Arcas, Marcello; Avallone, Aniello; Bonaccorso, Orazio; Germanò, Giuseppe; Letizia, Claudio; Manfellotto, Dario; Minardi, Giovanni; Pristipino, Christian; D'Amore, Francesco; Di Veroli, Claudio; Fierro, Aldo; Pastorellio, Ruggero; Tozzi, Quinto; Tubaro, Marco; Santini, Massimo; Angelico, Francesco; Azzolini, Paolo; Bellasi, Antonio; Brocco, Paola; Calò, Leonardo; Cerquetani, Elena; De Biase, Luciano; Di Napoli, Mauro; Galati, Alfonso; Gallieni, Maurizio; Jesi, Anna Patrizia; Lombardo, Antonella; Loricchio, Vincenzo; Menghini, Fabio; Mezzanotte, Roberto; Minutolos, Roberto; Mocini, David; Patti, Giuseppe; Patrizi, Roberto; Pajes, Giuseppe; Pulignano, Giovanni; Ricci, Renato Pietro; Ricci, Roberto; Sardella, Gennaro; Strano, Stefano; Terracina, David; Testa, Marco; Tomai, Fabrizio; Volpes, Roberto; Volterrani, Maurizio

2010-05-01

Secondary prevention after acute coronary syndromes should be aimed at reducing the risk of further adverse cardiovascular events, thereby improving quality of life, and lengthening survival. Despite compelling evidence from large randomized controlled trials, secondary prevention is not fully implemented in most cases after hospitalization for acute coronary syndrome. The Lazio Region (Italy) has about 5.3 million inhabitants (9% of the entire Italian population). Every year about 11 000 patients are admitted for acute coronary syndrome in hospitals of the Lazio Region. Most of these patients receive state-of-the art acute medical and interventional care during hospitalization. However, observational data suggest that after discharge acute coronary syndrome patients are neither properly followed nor receive all evidence-based treatments. This consensus document has been developed by 11 Scientific Societies of Cardiovascular and Internal Medicine in order develop a sustainable and effective clinical approach for secondary cardiovascular prevention after acute coronary syndrome in the local scenario of the Lazio Region. An evidence-based simplified decalogue for secondary cardiovascular prevention is proposed as the cornerstone of clinical intervention, taking into account regional laws and relative shortage of resources. The following appropriate interventions should be consistently applied: smoking cessation, blood pressure control (blood pressure < 130/80 mmHg), optimal lipid management (LDL cholesterol < 80 mmHg), weight and diabetes management, promotion of physical activity and rehabilitation, correct use of antiplatelet agents, beta-blockers, renin-angiotensin-aldosterone system blockers.

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

Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD).

PubMed

Ornoy, Asher; Weinstein-Fudim, Liza; Ergaz, Zivanit

2016-01-01

Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal, and postnatal etiologies. In addition, ASD is often an important clinical presentation of some well-known genetic syndromes in human. We discuss these syndromes as well as the role of the more important prenatal factors affecting the fetus throughout pregnancy which may also be associated with ASD. Among the genetic disorders we find Fragile X, Rett syndrome, tuberous sclerosis, Timothy syndrome, Phelan-McDermid syndrome, Hamartoma tumor syndrome, Prader-Willi and Angelman syndromes, and a few others. Among the maternal diseases in pregnancy associated with ASD are diabetes mellitus (PGDM and/or GDM), some maternal autoimmune diseases like antiphospholipid syndrome (APLS) with anti-β2GP1 IgG antibodies and thyroid disease with anti-thyroid peroxidase (TPO) antibodies, preeclampsia and some other autoimmune diseases with IgG antibodies that might affect fetal brain development. Other related factors are maternal infections (rubella and CMV with fetal brain injuries, and possibly Influenza with fever), prolonged fever and maternal inflammation, especially with changes in a variety of inflammatory cytokines and antibodies that cross the placenta and affect the fetal brain. Among the drugs are valproic acid, thalidomide, misoprostol, and possibly SSRIs. β2-adrenergic receptor agonists and paracetamol have also lately been associated with increased rate of ASD but the data is too preliminary and inconclusive. Associations were also described with ethanol, cocaine, and possibly heavy metals, heavy smoking, and folic acid deficiency. Recent studies show that heavy exposure to pesticides and air pollution, especially particulate matter < 2.5 and 10 μm in diameter (PM2.5 and PM10) during pregnancy is also associated with ASD. Finally, we have to remember that many of the associations mentioned in this review are

Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD)

PubMed Central

Ornoy, Asher; Weinstein- Fudim, Liza; Ergaz, Zivanit

2016-01-01

Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal, and postnatal etiologies. In addition, ASD is often an important clinical presentation of some well-known genetic syndromes in human. We discuss these syndromes as well as the role of the more important prenatal factors affecting the fetus throughout pregnancy which may also be associated with ASD. Among the genetic disorders we find Fragile X, Rett syndrome, tuberous sclerosis, Timothy syndrome, Phelan–McDermid syndrome, Hamartoma tumor syndrome, Prader-Willi and Angelman syndromes, and a few others. Among the maternal diseases in pregnancy associated with ASD are diabetes mellitus (PGDM and/or GDM), some maternal autoimmune diseases like antiphospholipid syndrome (APLS) with anti-β2GP1 IgG antibodies and thyroid disease with anti-thyroid peroxidase (TPO) antibodies, preeclampsia and some other autoimmune diseases with IgG antibodies that might affect fetal brain development. Other related factors are maternal infections (rubella and CMV with fetal brain injuries, and possibly Influenza with fever), prolonged fever and maternal inflammation, especially with changes in a variety of inflammatory cytokines and antibodies that cross the placenta and affect the fetal brain. Among the drugs are valproic acid, thalidomide, misoprostol, and possibly SSRIs. β2-adrenergic receptor agonists and paracetamol have also lately been associated with increased rate of ASD but the data is too preliminary and inconclusive. Associations were also described with ethanol, cocaine, and possibly heavy metals, heavy smoking, and folic acid deficiency. Recent studies show that heavy exposure to pesticides and air pollution, especially particulate matter < 2.5 and 10 μm in diameter (PM2.5 and PM10) during pregnancy is also associated with ASD. Finally, we have to remember that many of the associations mentioned in this review are

Clinical management of a child with Prader-Willi Syndrome from maternal uniparental disomy (UPD) genetic inheritance.

PubMed

Bellon-Harn, Monica L

2005-01-01

Prader-Willi Syndrome (PWS) is reported in 1 in 10,000-15,000 individuals. Unfortunately, many cases are missed due to clinicians' lack of familiarity with the syndrome as well as clinical and laboratory diagnostic criteria. Although common clinical characteristics are reported, variety exists in the nature and severity of dysfunction associated with PWS. Case studies can provide information to understand relationships between phenotypic characteristics and genetic inheritance, which can in turn lead to effective clinical management. The purpose of this case study was to describe the characteristics of a child with PWS due to maternal uniparental disomy inheritance pattern and to describe clinical management and treatment outcomes. The reader will obtain information about: (1) the genetic inheritance patterns and clinical characteristics of Prader-Willi Syndrome, (2) genotypic/phenotypic relationships specific to Prader-Willi Syndrome, and (3) clinical implications, management, and outcomes in a case description of a child with PWS due to maternal uniparental disomy inheritance pattern.

Clinical presentation of Churg-Strauss syndrome in children: A 12-year-old-boy with ANCA-negative Churg-Strauss syndrome.

PubMed

Razenberg, Femke G E M; Heynens, Jan W C M; Jan de Vries, Geeuwke; Duijts, Liesbeth; de Jongste, Johan C; de Blic, Jacques; Rosias, Philippe P R

2012-01-01

Churg-Strauss syndrome is an uncommon multisystem disorder characterized by asthma, eosinophilia and vasculitis. We report on a 12-year-old boy with asthma and deterioration of his general condition, who was eventually diagnosed with an ANCA-negative Churg-Strauss syndrome. The propositus included, 50 cases of childhood Churg-Strauss syndrome have been reported. The patient characteristics and clinical characteristics of these children are summarized. The respiratory tract is most frequently involved with pulmonary infiltrates, asthma and sinusitis. Early recognition of childhood Churg-Strauss syndrome is important as delayed diagnosis can lead to severe organ involvement, and possible fatal outcome.

'Refeeding syndrome' in a Kuwaiti child: clinical diagnosis and management.

PubMed

Al Sharkawy, Ibrahim; Ramadan, Dina; El-Tantawy, Amira

2010-01-01

To report a case of refeeding syndrome in a Kuwaiti child, its clinical presentation and management. A 13-month-old Kuwaiti boy presented with acute severe malnutrition in the form of marasmic kwashiorkor. On admission, blood sugar and serum electrolytes were normal but on the 3rd day he developed typical biochemical features of refeeding syndrome in the form of hyperglycemia, severe hypophosphatemia, hypokalemia, hypocalcemia and hypomagnesemia. The child then received treatment appropriate for refeeding syndrome in the form of lower calorie intake with gradual increase, as well as supplementation of electrolytes, thiamine and vitamins and he eventually made a safe recovery. This case showed that during rehabilitation of a malnourished child, a severe potentially lethal electrolyte disturbance (refeeding syndrome) can occur. Careful monitoring of electrolytes before and during the refeeding phase was needed and helped to detect this syndrome early. We suggest that slow and gradual calorie increase in the 'at-risk' patient can help prevent its occurrence. Copyright (c) 2010 S. Karger AG, Basel.

Clinical and laboratory survey of 65 Chinese patients with Leigh syndrome.

PubMed

Yang, Yan-ling; Sun, Fang; Zhang, Yao; Qian, Ning; Yuan, Yun; Wang, Zhao-xia; Qi, Yu; Xiao, Jiang-xi; Wang, Xiao-ying; Qi, Zhao-yue; Zhang, Yue-hua; Jiang, Yu-wu; Bao, Xin-hua; Qin, Jiong; Wu, Xi-ru

2006-03-05

Leigh syndrome is an inherited neurodegenerative disease that emerges in infancy and childhood and presents with a clinically heterogeneous variety of neuromuscular and non-neuromuscular disorders. It can result from the inheritance of mutations in either nuclear or mitochondrial DNA. In the current study, we performed a retrospective study in 65 patients in order to investigate the clinical and genetic characteristics of Leigh syndrome in Chinese patients. Sixty-five unrelated cases (35 men and 30 women) who were hospitalized in the past 12 years were reviewed. Diagnosis was based on both the clinical presentation and the characteristic neuropathologic findings of bilateral symmetric necrotizing lesions in the basal ganglia and brain stem as detected using cranial computed tomography (CT) scan or magnetic resonance imaging (MRI). The differential diagnosis of organic acidurias and fatty acid beta-oxidation defects were performed. Specific point mutations and deletions in mitochondrial DNA (T8993G, T8993C, T9176C, A8344G, A3243G) were screened by PCR-restriction analysis and Southern blot. The SURF1 gene was sequenced. Skeletal muscle biopsies were performed in 17 (26.2%) of the patients. The diagnosis was confirmed by autopsy in 6 (9.2%) patients. The patients had various forms of metabolic encephalomyopathy. Fifty-nine (90.8%) of the patients had the typical neuroradiological features of Leigh syndrome, including symmetrical necrotizing lesions scattered within the basal ganglia, thalamus and brain stem. Twenty (30.8%) patients were confirmed by genetic, biochemical analysis and autopsy. Specific point mutations in mitochondrial DNA were found in 5 cases (7.7%). Of these, the A8344G mutation was detected in 2 patients. The T8993G, T8993C, and A3243G point mutations were identified in 3 other patients, respectively. SURF1 mutations associated with cytochrome c oxidase deficiency were identified in 8 (12.3%) families by DNA sequencing. A G604C mutation was

TARGETED TREATMENTS IN AUTISM AND FRAGILE X SYNDROME

PubMed Central

Gürkan, C. Kağan; Hagerman, Randi J.

2012-01-01

Autism is a neurodevelopmental disorder consisting of a constellation of symptoms that sometimes occur as part of a complex disorder characterized by impairments in social interaction, communication and behavioral domains. It is a highly disabling disorder and there is a need for treatment targeting the core symptoms. Although autism is accepted as highly heritable, there is no genetic cure at this time. Autism is shown to be linked to several genes and is a feature of some complex genetic disorders, including fragile X syndrome (FXS), fragile X premutation involvement, tuberous sclerosis and Rett syndrome. The term autism spectrum disorders (ASDs) covers autism, Asperger syndrome and pervasive developmental disorders (PDD-NOS) and the etiologies are heterogeneous. In recent years, targeted treatments have been developed for several disorders that have a known specific genetic cause leading to autism. Since there are significant molecular and neurobiological overlaps among disorders, targeted treatments developed for a specific disorder may be helpful in ASD of unknown etiology. Examples of this are two drug classes developed to treat FXS, Arbaclofen, a GABAB agonist, and mGluR5 antagonists, and both may be helpful in autism without FXS. The mGluR5 antagonists are also likely to have a benefit in the aging problems of fragile X premutation carriers, the fragile X –associated tremor ataxia syndrome (FXTAS) and the Parkinsonism that can occur in aging patients with fragile X syndrome. Targeted treatments in FXS which has a well known genetic etiology may lead to new targeted treatments in autism. PMID:23162607

Alport syndrome--insights from basic and clinical research.

PubMed

Kruegel, Jenny; Rubel, Diana; Gross, Oliver

2013-03-01

In 1927, Arthur C. Alport first published his description of a triad of symptoms in a family with hereditary congenital haemorrhagic nephritis, deafness and ocular changes. A few years after his death, this group of symptoms was renamed Alport syndrome. To this day, Alport syndrome still inevitably leads to end-stage renal disease and the need for renal replacement therapy, starting in young adulthood. During the past two decades, research into this rare disease has focused on the effects of mutations in collagen type IV and the role of changes in podocytes and the glomerular basement membrane that lead to early kidney fibrosis. Animal models of Alport syndrome also demonstrate the pathogenetic importance of interactions between podocytes and the extracellular matrix. Such models might also help researchers to answer basic questions about podocyte function and the development of fibrosis, and to develop new therapeutic approaches that might be of use in other kidney diseases. In this Review, we discuss the latest basic and clinical research on Alport syndrome, focusing on the roles of podocyte pathology and the extracellular matrix. We also highlight early diagnosis and treatment options for young patients with this disorder.

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

Reclassification of clinical sleep disorders using traditional models of syndromic, neuroanatomic, pathophysiological and etiological diagnosis.

PubMed

Spitzer, A Robert

2014-09-01

Existing classifications of central nervous system sleep disorders do not often provide tools to diagnose the majority of patients complaining of sleep-related symptoms, nor always guide effective treatment. I present a novel classification system that completely separates clinical syndromes from anatomical localization, pathophysiology, and etiology. The clinical syndrome I present can describe the majority of patients, but can be fractionated into individual subgroups for further study. By then separating the anatomy and physiology from the symptoms, an avenue of research becomes available to study the different possible structures that regulate sleep, that may be damaged and cause syndromes of sleep dysfunction. Some of these may produce symptoms that overlap with narcolepsy and some may be distinct. Because the clinical syndrome should be distinguished from anatomy or physiology, I have proposed the term narcoleptiform syndrome for the clinical syndrome. The model also clearly separates etiology from anatomy in a classical neurological manner. This allows etiology, localization and symptoms to be studied separately. It is likely that different etiologies may produce damage in areas that produce similar syndromes. For example, in this model, different causes of damage to the orexin nucleus would result in the same clinical syndrome. This reinforces the concept of studying anatomy, symptoms and etiology separately. By studying the relationship of syndromes or symptoms to anatomic localization and pathophysiology, it should be possible to test novel approaches to treatment based on different underlying structure or function. For example, patients with lesions in the ventrolateral preoptic nucleus or the thalamic intralaminar nuclei may both present with insomnia symptoms but need different treatment; or they might present with symptoms overlapping narcolepsy (a narcoleptiform syndrome) yet need different treatment. In some cases, a single treatment may cross over

[Network clusters of symptoms as elementary syndromes of psychopathology: implications for clinical practice].

PubMed

Goekoop, R; Goekoop, J G

2016-01-01

In a recent publication we reported the existence of around 11 (to 15) 'elementary syndromes' that may combine in various ways, rather like 'building blocks', to explain the wide range of psychiatric symptoms. 'Bridge symptoms' seem to be responsible both for combining large sets of symptoms into elementary syndromes and for combining the various elementary syndromes to form one globally connected network structure. To discuss the implication of these findings for clinical practice. We performed a network analysis of symptom scores. Elementary syndromes provide a massive simplification of the description of psychiatric disease. Instead of the more than 300 categories in DSM-5, we now need to consider only a handful of elementary syndromes and personality domains. This modular representation of psychiatric illnesses allows us to make a complete, systematic and efficient assessment of patients and a systematic review of treatment options. Clinicians, patients, managerial staff and insurance companies can verify whether symptom reduction is taking place in the most important domains of psychopathology. Unlike classic multidimensional methods of disease description, network models of psychopathology can be used to explain comorbidity patterns, predict the clinical course of psychopathology and to designate primary targets for therapeutic interventions. A network view on psychopathology could significantly improve everyday clinical practice.

Drug-induced Brugada syndrome: Clinical characteristics and risk factors.

PubMed

Konigstein, Maayan; Rosso, Raphael; Topaz, Guy; Postema, Pieter G; Friedensohn, Limor; Heller, Karin; Zeltser, David; Belhassen, Bernard; Adler, Arnon; Viskin, Sami

2016-05-01

Cardiac arrest may result from seemingly innocuous medications that do not necessarily have cardiac indications. The best-known example is the drug-induced long QT syndrome. A less known but not necessarily less important form of drug-induced proarrhythmia is the drug-induced Brugada syndrome. The purpose of this study was to identify clinical and ECG risk markers for drug-induced Brugada syndrome. Reports of drug-induced Brugada syndrome recounted by an international database (http://www.brugadadrugs.org) were reviewed to define characteristics that identify patients prone to developing this complication. For each patient with drug-induced Brugada syndrome who had an ECG recorded in the absence of drugs, we included 5 healthy controls matched by gender and age. All ECGs were evaluated for Brugada-like abnormalities. Seventy-four cases of drug-induced Brugada syndrome from noncardiac medications were identified: 77% were male, and drug toxicity was involved in 46%. Drug-induced Brugada syndrome from oral medications generally occurred weeks after the initiation of therapy. Mortality was 13%. By definition, all cases had a type I Brugada pattern during drug therapy. Nevertheless, their ECG in the absence of drugs was more frequently abnormal than the ECG of controls (56% vs 33%, P = .04). Drug-induced Brugada syndrome from noncardiac drugs occurs predominantly in adult males, is frequently due to drug toxicity, and occurs late after the onset of therapy. Minor changes are frequently noticeable on baseline ECG, but screening is impractical because of a prohibitive false-positive rate. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Treatment of autistic spectrum disorder with insulin-like growth factors.

PubMed

Riikonen, Raili

2016-11-01

There are no treatments for the core symptoms of autistic spectrum disorder (ASD), but there is now more knowledge on emerging mechanisms and on mechanism-based therapies. In autism there are altered synapses: genes affected are commonly related to synaptic and immune function. Dysregulation of activity-dependent signaling networks may have a key role the etiology of autism. There is an over-activation of IGF-AKT-mTor in autism spectrum disorders. Morphological and electro-physiological defects of the cerebellum are linked to system-wide ASD-like behavior defects. The molecular basis for a cerebellar contribution has been demonstrated in a mouse model. These have led to a potential mechanism-based use of drug targets and mouse models. Neurotrophic factors are potential candidates for the treatment. Insulin-like growth factor-1 (IGF-1) is altered in autism. It reduces neuro-inflammation: by causing changes of cytokines such as IL-6 and microglial function. IGF-1 reduces the defects in the synapse. It alleviates NMDA-induced neurotoxicity via the IGF-AKT-mTor pathway in microglia. IGF-1 may rescue function in Rett syndrome and ASD caused by changes of the SCHANK3 gene. There are recently pilot studies of the treatment of Rett syndrome and of SCHANK3 gene deficiency syndromes. The FDA has granted Orphan drug designations for Fragile X syndrome, SCHANK3 gene deficiency syndrome and Rett syndrome. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

An overview of clinical tools used to assess neonatal abstinence syndrome.

PubMed

Orlando, Susan

2014-01-01

Several clinical tools have been developed to quantify the severity of withdrawal signs and symptoms exhibited by infants born to substance-using mothers. Scores from the systematic assessments are used to guide treatment of infants with moderate to severe clinical signs. This article provides an overview of published assessment tools developed for infants with neonatal abstinence syndrome. Nurses caring for infants at risk for neonatal abstinence syndrome should be knowledgeable about the tools used to evaluate these infants and guide their treatment. The ideal assessment tool should be published and include item definitions and a protocol for administering the tool. Nurses need education and training to achieve competency and interobserver reliability in the use of a selected tool. Tool-specific materials should be used to standardize training and improve accuracy in assessments. Competent and knowledgeable nurses play a critical role in improving outcomes for infants with neonatal abstinence syndrome.

Portal vascular anomalies in Down syndrome: spectrum of clinical presentation and management approach.

PubMed

Golewale, Nazar; Paltiel, Harriet J; Fishman, Steven J; Alomari, Ahmad I

2010-08-01

The occurrence of portal vascular anomalies in Down syndrome has been sporadically reported in the literature. These rare disorders have a wide spectrum of anatomical and clinical presentations. The aim of this communication was to describe the clinical course, imaging features, and management approaches in patients with this association. We conducted a comprehensive search of the databases of the Vascular Anomalies Center and the Department of Radiology at Children's Hospital Boston for patients with Down syndrome and portal vascular anomalies. Medical records and imaging studies of varying modalities were reviewed. Three children with Down syndrome and portal anomalies (portosystemic shunt, simple arterioportal shunt, complex arterioportal shunt) were managed at our institution. The portosystemic shunt was clinically insignificant and resolved without any intervention. The simple arterioportal shunt was successfully treated with embolization. The complex arterioportal shunt was associated with major congenital cardiac defects and the child ultimately expired despite a decrease in the arterioportal shunting after embolization. Three is a wide spectrum of clinical and anatomical features of portal vascular shunts in Down syndrome. The management approach should be tailored based on the severity of symptoms. Percutaneous embolization can offer a safe, effective, and minimally invasive alternative to the surgical approach in selective cases. Copyright 2010 Elsevier Inc. All rights reserved.

A molecular and clinical study of Larsen syndrome caused by mutations in FLNB.

PubMed

Bicknell, Louise S; Farrington-Rock, Claire; Shafeghati, Yousef; Rump, Patrick; Alanay, Yasemin; Alembik, Yves; Al-Madani, Navid; Firth, Helen; Karimi-Nejad, Mohammad Hassan; Kim, Chong Ae; Leask, Kathryn; Maisenbacher, Melissa; Moran, Ellen; Pappas, John G; Prontera, Paolo; de Ravel, Thomy; Fryns, Jean-Pierre; Sweeney, Elizabeth; Fryer, Alan; Unger, Sheila; Wilson, L C; Lachman, Ralph S; Rimoin, David L; Cohn, Daniel H; Krakow, Deborah; Robertson, Stephen P

2007-02-01

Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied. Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated. The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G-->A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB.

Hemizygosity at the elastin locus and clinical features of Williams syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morimoto, Y; Kuwano, A.; Kuwajima, K.

1994-09-01

Williams syndrome is a recognizable syndrome characterized by distinctive facial appearance, gregarious personality, mental retardation, congenital heart defect, particularly supravalvular aortic stenosis (SVAS), and joint limitation. SVAS is an autosomal vascular disorder and the elastin gene was disrupted in patients with SVAS. Ewat et al. reported that hemizygosity at the elastin locus was detected in four familial and five sporadic cases of Williams syndrome. However, three patients did not have SVAS. We reconfirmed hemizygosity at the elastin locus in five patients with typical clinical features of Williams syndrome. Hemizygosity was detected in four cases with SVAS. However, one patient withmore » distinctive facial appearance and typical Williams syndrome personality had two alleles of the elastin gene, but he did not have the congenital heart anomaly. Williams syndrome is thought to be a contiguous gene disorder. Thus, our data suggest that the elastin gene is responsible for the vascular defect in patients with Williams syndrome, and flanking genes are responsible for characteristic facial appearance and personality.« less

Sweet's syndrome mimicking alkali burn: a clinical conundrum.

PubMed

O'Halloran, E; Stewart, N; Vetrichevvel, T P; Rea, S; Wood, F

2013-06-01

Sweet's syndrome or acute febrile neutrophilic dermatosis presents most commonly on the hands, upper extremities and face. The disease is of clinical relevance to surgeons as it could mimic an infective aetiology but debridement negates such wounds. A 34-year-old man was referred from a peripheral hospital with suspected infected alkali burn to the hands. A builder by profession, he had been working outdoors with possible exposure to cement-concrete mix, 5 days previously. At presentation, the dorsal aspect of the thenar eminence appeared erythematous and oedematous, with pustules and blisters with central ulcerations. Haematological investigation revealed a neutrophilic leucocytosis and raised CRP. On the second day of admission the patient became febrile. He was treated with analgesia, IV Tazocin (Pipperacillin and Tazobactam) and the wounds were surgically debrided and covered using autologous cell therapy via the Recell kit. Two days following surgery, microbiology of wound swabs, tissue samples and blood cultures yielded no growth. The wound was noted to be extending beyond the zone of injury and a new area of erythema was evident on the neck. A diagnosis of idiopathic acral Sweet's syndrome was confirmed when histopathological investigation showed a moderate inflammatory cell infiltrate in the dermis. A rapid response to oral corticosteroids was clinically evident after 48 h and the lesions were completely healed at 4 weeks follow-up. We recommend thorough clinical history and examination, systematic wound review, tissue biopsy and culture in conjunction with dermatology opinion in cases of suspected Sweet's syndrome. Surgical debridement should be avoided as it has the potential to negate such wounds secondary to pathergy phenomenon. Copyright © 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

A pragmatic evidence-based clinical management algorithm for burning mouth syndrome.

PubMed

Kim, Yohanan; Yoo, Timothy; Han, Peter; Liu, Yuan; Inman, Jared C

2018-04-01

Burning mouth syndrome is a poorly understood disease process with no current standard of treatment. The goal of this article is to provide an evidence-based, practical, clinical algorithm as a guideline for the treatment of burning mouth syndrome. Using available evidence and clinical experience, a multi-step management algorithm was developed. A retrospective cohort study was then performed, following STROBE statement guidelines, comparing outcomes of patients who were managed using the algorithm and those who were managed without. Forty-seven patients were included in the study, with 21 (45%) managed using the algorithm and 26 (55%) managed without. The mean age overall was 60.4 ±16.5 years, and most patients (39, 83%) were female. Cohorts showed no statistical difference in age, sex, overall follow-up time, dysgeusia, geographic tongue, or psychiatric disorder; xerostomia, however, was significantly different, skewed toward the algorithm group. Significantly more non-algorithm patients did not continue care (69% vs. 29%, p =0.001). The odds ratio of not continuing care for the non-algorithm group compared to the algorithm group was 5.6 [1.6, 19.8]. Improvement in pain was significantly more likely in the algorithm group ( p =0.001), with an odds ratio of 27.5 [3.1, 242.0]. We present a basic clinical management algorithm for burning mouth syndrome which may increase the likelihood of pain improvement and patient follow-up. Key words: Burning mouth syndrome, burning tongue, glossodynia, oral pain, oral burning, therapy, treatment.

Abnormal hepatic biochemistries and clinical liver disease in patients with primary Sjögren's syndrome.

PubMed

Montaño-Loza, Aldo J; Crispín-Acuña, José Carlos; Remes-Troche, José María; Uribe, Misael

2007-01-01

Patients with primary Sjögren's syndrome may present liver involvement. Our goals were to establish the prevalence of abnormal hepatic biochemistries and clinical liver disease in patients with primary Sjögren's syndrome and correlate their presence with other clinical and laboratory features. Ninety-five patients with diagnosis of primary Sjögren's syndrome were studied. Data on gender, age, clinical features, liver biochemistries, tests of inflammation and autoimmunity, and concomitant diseases were collected. Forty-two patients (44%) had abnormal hepatic biochemistries, and of these 19 patients (20%) had clinical liver disease. Patients with abnormal hepatic biochemistries had higher frequency of autoimmune hypotiroidism, arthritis, vasculitis, Raynaud's phenomenon, higher sedimentation rate,and higher frequency of antinuclear and antimitochondrial antibodies than patients with normal liver biochemistries (P < 0.05 for each). Patients with clinical liver disease had higher frequency of arthritis, vasculitis, and higher frequency of antimitochondrial antibodies than patients without clinical liver disease (P < 0.05 for each). Twenty-one patients had diagnosis of a specific liver disease, such as hepatitis C virus infection (n = 11), autoimmune hepatitis (n = 2), primary biliary cirrhosis (n =5),nonalcoholic fatty liver disease (n = 2), and hepatitis B virus infection (n = 1). In half of patients with liver involvement a definitive cause could not be identified. Liver involvement is frequently found in patients with primary Sjögren's syndrome, and its presence is associated with clinical features of systemic disease, and markers of autoimmunity and inflammation. There may be a subgroup of patients with liver involvement secondary to primary Sjögren's syndrome.

Clinical and molecular features of Joubert syndrome and related disorders

PubMed Central

Parisi, Melissa A.

2009-01-01

Joubert syndrome (JBTS; OMIM 213300) is a rare, autosomal recessive disorder characterized by a specific congenital malformation of the hindbrain and a broad spectrum of other phenotypic findings that is now known to be caused by defects in the structure and/or function of the primary cilium. The complex hindbrain malformation that is characteristic of JBTS can be identified on axial magnetic resonance imaging and is known as the molar tooth sign (MTS); other diagnostic criteria include intellectual disability, hypotonia, and often, abnormal respiratory pattern and/or abnormal eye movements. In addition, a broad spectrum of other anomalies characterize Joubert syndrome and related disorders (JSRD), and may include retinal dystrophy, ocular coloboma, oral frenulae and tongue tumors, polydactyly, cystic renal disease (including cystic dysplasia or juvenile nephronophthisis), and congenital hepatic fibrosis. The clinical course can be variable, but most children with this condition survive infancy to reach adulthood. At least 8 genes cause JSRD, with some genotype-phenotype correlations emerging, including the association between mutations in the MKS3 gene and hepatic fibrosis characteristic of the JSRD subtype known as COACH syndrome. Several of the causative genes for JSRD are implicated in other ciliary disorders, such as juvenile nephronophthisis and Meckel syndrome, illustrating the close association between these conditions and their overlapping clinical features that reflect a shared etiology involving the primary cilium. PMID:19876931

Syndromic autism spectrum disorders: moving from a clinically defined to a molecularly defined approach

PubMed Central

Fernandez, Bridget A.; Scherer, Stephen W.

2017-01-01

Autism spectrum disorder (ASD) encompasses a group of neurodevelopmental conditions diagnosed solely on the basis of behavioral assessments that reveal social deficits. Progress has been made in understanding its genetic underpinnings, but most ASD-associated genetic variants, which include copy number variants (CNVs) and mutations in ASD-risk genes, account for no more than 1 % of ASD cases. This high level of genetic heterogeneity leads to challenges obtaining and interpreting genetic testing in clinical settings. The traditional definition of syndromic ASD is a disorder with a clinically defined pattern of somatic abnormalities and a neurobehavioral phenotype that may include ASD. Most have a known genetic cause. Examples include fragile X syndrome and tuberous sclerosis complex. We propose dividing syndromic autism into the following two groups: (i) ASD that occurs in the context of a clinically defined syndrome-recognizing these disorders depends on the familiarity of the clinician with the features of the syndrome, and the diagnosis is typically confirmed by targeted genetic testing (eg, mutation screening of FMR1); (ii) ASD that occurs as a feature of a molecularly defined syndrome-for this group of patients, ASD-associated variants are identified by genome-wide testing that is not hypothesis driven (eg, microarray, whole exome sequencing). These ASD groups cannot be easily clinically defined because patients with a given variant have variable somatic abnormalities (dysmorphism and birth defects). In this article, we review common diagnoses from the above categories and suggest a testing strategy for patients, guided by determining whether the individual has essential or complex ASD; patients in the latter group have multiple morphologic anomalies on physical examination. Finally, we recommend that the syndromic versus nonsyndromic designation ultimately be replaced by classification of ASD according to its genetic etiology, which will inform about the

Fat embolism syndrome: Case report of a clinical conundrum

PubMed Central

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

2014-01-01

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

Late whiplash syndrome: a clinical science approach to evidence-based diagnosis and management.

PubMed

Poorbaugh, Keith; Brismée, Jean-Michel; Phelps, Valerie; Sizer, Phillip S

2008-01-01

The purpose of this article is to narrow the gap that exists in the clinical application of scientific research and empiric evidence for the evaluation and management of late whiplash. Considering that 14% to 42% of patients are left with chronic symptoms following whiplash injury, it is unlikely that only minor self-limiting injuries result from the typical rear-end impact. As psychosocial issues play a role in the development of persistent whiplash symptoms, discerning the organic conditions from the biopsychosocial factors remains a challenge to clinicians. The term "whiplash" represents the multiple factors associated with the event, injury, and clinical syndrome that are the end-result of a sudden acceleration-deceleration trauma to the head and neck. However, contentions surround the nature of soft-tissue injuries that occur with most motor vehicle accidents and whether these injuries are significant enough to result in chronic pain and limitations. The stark contrast in litigation for whiplash that exists among industrialized nations and less developed countries suggests another factor that could influence one's interpretation of symptoms' chronicity associated with Late Whiplash Syndrome. There are no gold standard tests or imaging techniques that can objectify whiplash-associated disorders. A lack of supporting evidence and disparity in medico-legal issues have created distinct camps in the scientific interpretations and clinical management of late whiplash. It is likely that efforts in research and/or clinical practice will begin to explain the disparity between acute and chronic whiplash syndrome. Recent evidence suggests that Late Whiplash Syndrome should be considered from a different context. The purpose of this article is to expound on several of the significant findings in the literature and offer clinical applications for evaluation and management of Late Whiplash Syndrome.

Systematization of clinical trials related to treatment of metabolic syndrome, 1980-2015.

PubMed

Cardona Velásquez, Santiago; Guzmán Vivares, Laura; Cardona-Arias, Jaiberth Antonio

2017-02-01

Despite the clinical, epidemiological, and economic significance of metabolic syndrome, the profile of clinical trials on this disease is unknown. To characterize the clinical trials related to treatment of metabolic syndrome during the 1980-2015 period. Systematic review of the literature using an ex ante search protocol which followed the phases of the guide Preferred Reporting Items for Systematic Reviews and Meta-Analyses in four multidisciplinary databases with seven search strategies. Reproducibility and methodological quality of the studies were assessed. One hundred and six trials were included, most from the United States, Italy, and Spain, of which 63.2% evaluated interventions effective for several components of the syndrome such as diet (40.6%) or physical activity (22.6%). Other studies assessed drugs for a single factor such as hypertension (7.5%), hypertriglyceridemia (11.3%), or hyperglycemia (9.4%). Placebo was used as control in 54.7% of trials, and outcome measures included triglycerides (52.8%), HDL (48.1%), glucose (29.2%), BMI (33.0%), blood pressure (27.4%), waist circumference (26.4%), glycated hemoglobin (11.3%), and hip circumference (7.5%). It was shown that studies ob efficacy of treatment for metabolic syndrome are scarce and have mainly been conducted in the last five years and in high-income countries. Trials on interventions that affect three or more factors and assess several outcome measures are few, and lifestyle interventions (diet and physical activity) are highlighted as most important to impact on this multifactorial syndrome. Copyright © 2017 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

Spine deformities in rare congenital syndromes: clinical issues.

PubMed

Campbell, Robert M

2009-08-01

early onset scoliosis that is very rigid and requires early intervention. Cervical kyphosis and subluxation may be lethal in these patients and screening radiographs are important. Upper airway abnormalities are an anesthesia concern. Jarcho-Levin syndrome is a thoracic volume depletion deformity due to shortness of the thorax, either a spondylocostal dysostosis variant or spondylothoracic dysplasia. The former has a chaotic congenital scoliosis with varied combination of missing and fused ribs. Although spondylocostal dysostosis has a benign reputation in the literature for respiratory complications, respiratory insufficiency is nevertheless common and 1 death is known from respiratory failure. Spondylothoracic dysplasia seldom has significant scoliosis, but has a mortality rate approaching 50% from respiratory complications due to thoracic insufficiency syndrome. In spite of severe restrictive respiratory disease, adult survivors of spondylothoracic dysplasia appear to do well clinically for unknown reasons. Cerebrocostomandibular syndrome has scoliosis, micrognathia, and thoracic insufficiency syndrome, due to an "implosion" deformity of the thorax from congenital pseudarthrosis of the posterior ribs. For optimal patient care, it is necessary to have a clear understanding of exotic congenital syndromes and how they may impact on both the presentation of spinal deformity and the response to treatment, as well as how they may introduce additional morbidity into standard treatment plans. It is clear that with this understanding that preoperative strategies can be employed to enhance the safety of spinal treatment for these unique children.

Severe hypertension and hypokalemia as first clinical manifestations in ectopic Cushing's syndrome.

PubMed

Fernández-Rodríguez, Eva; Villar-Taibo, Rocío; Pinal-Osorio, Iria; Cabezas-Agrícola, José Manuel; Anido-Herranz, Urbano; Prieto, Alma; Casanueva, Felipe F; Araujo-Vilar, David

2008-08-01

Ectopic ACTH production occurs in about 10% of all cases of Cushing's syndrome, and about 25% of cases of ACTH-dependent Cushing's syndrome. Diverse tumor types are able to produce ACTH ectopically, including small cell lung carcinoma. Ectopic ACTH secretion by malignant neoplasm has been reported to have earlier and more aggressive metabolic effects. We report a 59-year-old male patient with severe hypertension, metabolic alkalosis and hypokalemia as the first clinical manifestations of an ACTH-secreting small cell lung carcinoma, although the typical phenotypic features of Cushing's syndrome were not present. Ectopic Cushing's syndrome should always be ruled out in patients with severe hypertension and hypokalemia.

A girl with early-onset epileptic encephalopathy associated with microdeletion involving CDKL5.

PubMed

Saitsu, Hirotomo; Osaka, Hitoshi; Nishiyama, Kiyomi; Tsurusaki, Yoshinori; Doi, Hiroshi; Miyake, Noriko; Matsumoto, Naomichi

2012-05-01

Recent studies have shown that aberrations of CDKL5 in female patients cause early-onset intractable seizures, severe developmental delay or regression, and Rett syndrome-like features. We report on a Japanese girl with early-onset epileptic encephalopathy, hypotonia, developmental regression, and Rett syndrome-like features. The patient showed generalized tonic seizures, and later, massive myoclonus induced by phone and light stimuli. Brain magnetic resonance imaging showed no structural brain anomalies but cerebral atrophy. Electroencephalogram showed frontal dominant diffuse poly spikes and waves. Through copy number analysis by genomic microarray, we found a microdeletion at Xp22.13. A de novo 137-kb deletion, involving exons 5-21 of CDKL5, RS1, and part of PPEF1 gene, was confirmed by quantitative PCR and breakpoint specific PCR analyses. Our report suggests that the clinical features associated with CDKL5 deletions could be implicated in Japanese patients, and that genetic testing of CDKL5, including both sequencing and deletion analyses, should be considered in girls with early-onset epileptic encephalopathy and RTT-like features. Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Twenty-one years to the right diagnosis - clinical overlap of Simpson-Golabi-Behmel and Beckwith-Wiedemann syndrome.

PubMed

Knopp, C; Rudnik-Schöneborn, S; Zerres, K; Gencik, M; Spengler, S; Eggermann, T

2015-01-01

Clinical overlap makes the diagnosis of overgrowth syndromes challenging. Clinical overlap exists between Simpson-Golabi-Behmel syndrome (SGBS) and Beckwith-Wiedemann syndrome (BWS) which share pre- and postnatal overgrowth, macroglossia, umbilical hernia, organomegaly, ear lobe creases, and occurrence of embryonal tumors as characteristic features. Based on the clinical history of a patient, who was diagnosed with BWS shortly after birth and reassessed and rediagnosed with SGBS at age 21 years, particular attention should be paid to developing facial dysmorphia. In addition, we delineate further clinical findings that may allow differentiation between both conditions. © 2014 Wiley Periodicals, Inc.

Genetic syndrome suspicion: examples of clinical approach in the neonatal unit.

PubMed

Giuffrè, M; De Sanctis, L

2010-06-01

Overgrowth syndromes: the practical clinical approach. Excessive growth can be present in a variety of medical conditions as result of abnormal fetal metabolism (i.e., maternal gestational diabetes) or of an overgrowth syndrome. Within this latter group of diseases, a LGA newborn requires a complex differential diagnosis encompassing several syndromes, such as Beckwith-Wiedemman, Sotos, Weaver, Simpson-Golabi-Behmel, Perlman, and Bannayan-Riley-Ruvalcaba. Partial or global overgrowth, other dysmorphisms, abdominal organs anomalies, as well as benign and malignant tumors are the common issues to examine for the diagnosis and the monitoring of all these disorders. The molecular bases of these conditions, even if partially known so far, can help in explaining the clinical features and prognosis. The diagnostic course, the genetic investigations and the follow-up of a LGA patient will be presented during the seminar. A wide clinical spectrum from esophageal atresia to VACTERL association. Oesophageal atresia (OA) occurs approximately in 1 in 3000 live births. It can be clinically divided into isolated and syndromic, when associated with other features. The aetiology is largely unknown and is likely to be multifactorial, however, various clues have been uncovered in animal experiments particularly defects in the expression of the gene Sonic hedgehog (Shh). The vast majority of cases are sporadic and the recurrence risk for siblings is 1%. Survival is directly related to birth weight and to the presence of a major cardiac defect. The VACTERL association refers to anomalies of the bony spinal column (V), atresias in the gastrointestinal tract (A), congenital heart lesions (C), tracheoesophageal defects (TE), renal and distal urinary tract anomalies (R) and limb lesions (L). The overall phenotype of a series of newborn patients we observed may vary widely, reflecting the aetiologic heterogeneity of this group of conditions. Therefore, possible additional defects must be

[Gorlin-Goltz syndrome: review of the neuroradiological and maxillofacial features illustrated with two clinical cases].

PubMed

Safronova, Marta Maia; Arantes, Mavilde; Lima, Iva; Domingues, Sara; Almeida, Marta; Moniz, Pedro

2010-01-01

Gorlin-Goltz syndrome or nevoid basal cell carcinoma syndrome is a rare hereditary autosomal-dominant disorder characterized by multiple basal cell carcinomas in young patients, odontogenic keratocysts, palmar or plantar pits, calcification of the falx cerebri and skeletal malformations. This syndrome is due to mutations in PTCH1 (patched homolog 1 da Drosophila), a tumor suppressor gene. Diagnostic criteria were defined by Evans, revised by Kimonis and include major and minor criteria. The authors review in particular the neuroradiological and maxillofacial characteristics of the syndrome. The authors describe the clinical presentation of two children with Gorlin-Goltz syndrome without affected first degree relatives. In both the clinical suspicion of the syndrome is raised by the presence of multiple odontogenic cysts surgically removed. Histopathological exam revealed keratocysts. None of the patients has basal cell carcinomas but both present with skeletal anomalies, namely marked pectus deformity. The absence of major diagnostic criteria like basal cell carcinomas or palmar or plantar pits in young patients delay the early diagnosis and the correct screening for medulloblastoma, basal cell carcinomas and cardiac fibromas. Odontogenic keratocysts are the most consistent clinical finding in Gorlin-Goltz syndrome in the first one or two decades of life. These patients are very sensitive to ionizing radiation, being able to develop basal cell carcinomas and meningiomas. Treatment should accomplish the complete resection of the tumors.

Progressive Changes in a Distributed Neural Circuit Underlie Breathing Abnormalities in Mice Lacking MeCP2.

PubMed

Huang, Teng-Wei; Kochukov, Mikhail Y; Ward, Christopher S; Merritt, Jonathan; Thomas, Kaitlin; Nguyen, Tiffani; Arenkiel, Benjamin R; Neul, Jeffrey L

2016-05-18

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Severe breathing abnormalities are common in RTT and are reproduced in mouse models of RTT. Previously, we found that removing MeCP2 from the brainstem and spinal cord in mice caused early lethality and abnormal breathing. To determine whether loss of MeCP2 in functional components of the respiratory network causes specific breathing disorders, we used the Cre/LoxP system to differentially manipulate MeCP2 expression throughout the brainstem respiratory network, specifically within HoxA4-derived tissues, which include breathing control circuitry within the nucleus tractus solitarius and the caudal part of ventral respiratory column but do not include more rostral parts of the breathing control circuitry. To determine whether respiratory phenotypes manifested in animals with MeCP2 removed from specific pons medullary respiratory circuits, we performed whole-body plethysmography and electrophysiological recordings from in vitro brainstem slices from mice lacking MeCP2 in different circuits. Our results indicate that MeCP2 expression in the medullary respiratory network is sufficient for normal respiratory rhythm and preventing apnea. However, MeCP2 expression within components of the breathing circuitry rostral to the HoxA4 domain are neither sufficient to prevent the hyperventilation nor abnormal hypoxic ventilatory response. Surprisingly, we found that MeCP2 expression in the HoxA4 domain alone is critical for survival. Our study reveals that MeCP2 is differentially required in select respiratory components for different aspects of respiratory functions, and collectively for the integrity of this network functions to maintain proper respiration. Breathing abnormalities are a significant clinical feature in Rett syndrome and are robustly reproduced in the mouse models of this disease. Previous work has established that alterations in the function of Me

Clinical characteristics of abnormal savda syndrome type in human immunodeficiency virus infection and acquired immune deficiency syndrome patients: A cross-sectional investigation in Xinjiang, China.

PubMed

Peierdun, Mi-ji-ti; Liu, Wen-xian; Renaguli, Ai-ze-zi; Nurmuhammat, Amat; Li, Xiao-chun; Gulibaier, Ka-ha-er; Ainivaer, Wu-la-mu; Halmurat, Upur

2015-12-01

To investigate the distribution of abnormal hilit syndromes in traditional Uighur medicine (TUM) among human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) patients, and to find out the clinical characteristics of abnormal savda syndrome type HIV/AIDS patients. Between June and July in 2012, 307 eligible HIV/AIDS patients from in-patient department and out-patient clinics of Xinjiang Uighur Autonomous Region the Sixth People's Hospital in Urumqi were investigated. TUM syndrome differentiation was performed by a senior TUM physician. Each participant completed a Sign and Symptom Check-List for Persons Living with HIV/AIDS (SSC-HIV) questionnaire. Depression was evaluated by using Hamilton Rating Scale for Depression Questionnaire. Blood specimen was collected from each participant to test the levels of blood chemicals. Of 307 HIV/AIDS patients, 189 (61.6%) were abnormal savda syndrome type, 118 (38.4%) were non-abnormal-savda syndrome type. Mean CD4 counts of abnormal savda syndrome type patients was (227.61±192.93) cells/µL, and the prevalence of anemia, thrombocytopenia, and elevated cystatin C were 49.7%, 28.6%, and 44.7%, which were significantly higher than those in the non-abnormal-savda syndrome type patients (26.3%, 16.0% and 25.0%,P<0.05). In addition, depression (79.9%) and HIV/AIDS-related symptoms such as fatigue (42.3%), back aches (40.7%), lack of appetite (33.9%), night sweats (31.7%) were more common among abnormal savda syndrome patients (P<0.05). Abnormal savda syndrome is the dominant syndrome among HIV/AIDS patients, and they present a more sever clinical manifestation.

Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein–Taybi and Filippi syndromes

PubMed Central

de Vries, Tamar I; R Monroe, Glen; van Belzen, Martine J; van der Lans, Christian A; Savelberg, Sanne MC; Newman, William G; van Haaften, Gijs; Nievelstein, Rutger A; van Haelst, Mieke M

2016-01-01

Rubinstein–Taybi syndrome (RTS, OMIM 180849) and Filippi syndrome (FLPIS, OMIM 272440) are both rare syndromes, with multiple congenital anomalies and intellectual deficit (MCA/ID). We present a patient with intellectual deficit, short stature, bilateral syndactyly of hands and feet, broad thumbs, ocular abnormalities, and dysmorphic facial features. These clinical features suggest both RTS and FLPIS. Initial DNA analysis of DNA isolated from blood did not identify variants to confirm either of these syndrome diagnoses. Whole-exome sequencing identified a homozygous variant in C9orf173, which was novel at the time of analysis. Further Sanger sequencing analysis of FLPIS cases tested negative for CKAP2L variants did not, however, reveal any further variants. Subsequent analysis using DNA isolated from buccal mucosa revealed a mosaic variant in CREBBP. This report highlights the importance of excluding mosaic variants in patients with a strong but atypical clinical presentation of a MCA/ID syndrome if no disease-causing variants can be detected in DNA isolated from blood samples. As the striking syndactyly observed in the present case is typical for FLPIS, we suggest CREBBP analysis in saliva samples for FLPIS syndrome cases in which no causal CKAP2L variant is detected. PMID:26956253

Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein-Taybi and Filippi syndromes.

PubMed

de Vries, Tamar I; Monroe, Glen R; van Belzen, Martine J; van der Lans, Christian A; Savelberg, Sanne Mc; Newman, William G; van Haaften, Gijs; Nievelstein, Rutger A; van Haelst, Mieke M

2016-08-01

Rubinstein-Taybi syndrome (RTS, OMIM 180849) and Filippi syndrome (FLPIS, OMIM 272440) are both rare syndromes, with multiple congenital anomalies and intellectual deficit (MCA/ID). We present a patient with intellectual deficit, short stature, bilateral syndactyly of hands and feet, broad thumbs, ocular abnormalities, and dysmorphic facial features. These clinical features suggest both RTS and FLPIS. Initial DNA analysis of DNA isolated from blood did not identify variants to confirm either of these syndrome diagnoses. Whole-exome sequencing identified a homozygous variant in C9orf173, which was novel at the time of analysis. Further Sanger sequencing analysis of FLPIS cases tested negative for CKAP2L variants did not, however, reveal any further variants. Subsequent analysis using DNA isolated from buccal mucosa revealed a mosaic variant in CREBBP. This report highlights the importance of excluding mosaic variants in patients with a strong but atypical clinical presentation of a MCA/ID syndrome if no disease-causing variants can be detected in DNA isolated from blood samples. As the striking syndactyly observed in the present case is typical for FLPIS, we suggest CREBBP analysis in saliva samples for FLPIS syndrome cases in which no causal CKAP2L variant is detected.

[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.

A pragmatic evidence-based clinical management algorithm for burning mouth syndrome

PubMed Central

Yoo, Timothy; Han, Peter; Liu, Yuan; Inman, Jared C.

2018-01-01

Background Burning mouth syndrome is a poorly understood disease process with no current standard of treatment. The goal of this article is to provide an evidence-based, practical, clinical algorithm as a guideline for the treatment of burning mouth syndrome. Material and Methods Using available evidence and clinical experience, a multi-step management algorithm was developed. A retrospective cohort study was then performed, following STROBE statement guidelines, comparing outcomes of patients who were managed using the algorithm and those who were managed without. Results Forty-seven patients were included in the study, with 21 (45%) managed using the algorithm and 26 (55%) managed without. The mean age overall was 60.4 ±16.5 years, and most patients (39, 83%) were female. Cohorts showed no statistical difference in age, sex, overall follow-up time, dysgeusia, geographic tongue, or psychiatric disorder; xerostomia, however, was significantly different, skewed toward the algorithm group. Significantly more non-algorithm patients did not continue care (69% vs. 29%, p=0.001). The odds ratio of not continuing care for the non-algorithm group compared to the algorithm group was 5.6 [1.6, 19.8]. Improvement in pain was significantly more likely in the algorithm group (p=0.001), with an odds ratio of 27.5 [3.1, 242.0]. Conclusions We present a basic clinical management algorithm for burning mouth syndrome which may increase the likelihood of pain improvement and patient follow-up. Key words:Burning mouth syndrome, burning tongue, glossodynia, oral pain, oral burning, therapy, treatment. PMID:29750091

Clinical characteristics of a sample of patients with cat eye syndrome.

PubMed

Rosa, Rafael Fabiano Machado; Mombach, Rômulo; Zen, Paulo Ricardo Gazzola; Graziadio, Carla; Paskulin, Giorgio Adriano

2010-01-01

Cat eye syndrome is considered a rare chromosome disease with a highly variable phenotype. The objective of this paper was to describe the clinical characteristics of a sample of patients with cat eye syndrome who were seen at our service. This is a retrospective analysis of a sample of six patients with diagnoses of cat eye syndrome. All of these patients’ karyotypes exhibited the presence of an additional marker chromosome, inv dup(22)(pter->q11.2::q11.2->pter). One patient also exhibited mosaicism with a lineage that had a normal chromosomal constitution. Clinical and follow-up data were collected from the patients’ medical records. Fisher’s exact test was used to compare the frequencies observed in our study with figures given in the literature (P<0.05). The main abnormalities observed were preauricular tags and/or pits and anal atresia (both observed in 83% of cases). Coloboma of the iris, an important finding with this syndrome, was observed in two cases (33%). Congenital heart disease was detected in four patients (67%) and the main defect found was interatrial communication (75%). Uncommon findings included hemifacial microsomia combined with unilateral microtia and biliary atresia. Just one of these patients died, from chylothorax and sepsis. The phenotype observed in cat eye syndrome is highly variable and may be superimposed on the phenotype of the oculo-auriculo-vertebral spectrum. Although these patients usually have good prognosis, including from a neurological point of view, we believe that all patients with the syndrome should be assessed very early on for the presence of cardiac, biliary and anorectal malformations, which may avoid possible complications in the future, including patient deaths.

Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects

PubMed Central

Weemaes, Corry MR; van Tol, Maarten JD; Wang, Jun; van Ostaijen-ten Dam, Monique M; van Eggermond, Marja CJA; Thijssen, Peter E; Aytekin, Caner; Brunetti-Pierri, Nicola; van der Burg, Mirjam; Graham Davies, E; Ferster, Alina; Furthner, Dieter; Gimelli, Giorgio; Gennery, Andy; Kloeckener-Gruissem, Barbara; Meyn, Stephan; Powell, Cynthia; Reisli, Ismail; Schuetz, Catharina; Schulz, Ansgar; Shugar, Andrea; van den Elsen, Peter J; van der Maarel, Silvère M

2013-01-01

Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype–phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling. PMID:23486536

Clinical aspects, neuroimaging, and electroencephalography of 35 cases of hemiconvulsion-hemiplegia syndrome.

PubMed

Albakaye, Mohamed; Belaïdi, Halima; Lahjouji, Fatiha; Errguig, Leila; Kuate, Callixte; Maiga, Youssoufa; Diallo, Seybou Hassane; Kissani, Najib; Ouazzani, Reda

2018-03-01

The hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is a rare consequence of febrile seizures during childhood. It is characterized by the presence of prolonged unilateral clonic seizures occurring during febrile illness in a child less than 4years of age. Then, a flaccid unilateral hemiplegia with variable duration occurs. The objective of the study was to describe the clinical, electroencephalogram (EEG), and neuroimaging treatment and outcome of series of cases of HHE syndrome followed for 10years in our clinical neurophysiology department of the specialty hospital of Rabat. We report a retrospective study of 35 patients followed up for HHE syndrome from January 2005 to December 2015. All patients included in the study met the definition criteria for HHE syndrome. The age of onset ranged from 1 to 10years. Hemiplegia or spastic hemiparesis of the ipsilateral side to the convulsion was present in all patients. Abnormal brain magnetic resonance imaging (MRI) was found in all patients. All patients developed drug-resistant focal epilepsy during the course of the disease. The management of HHE syndrome constitutes a real public health problem in developing countries like Morocco. The neurological morbidity and the severe sequels are of high impact in these young kids. On the one hand, authors highlight the need for improving emergency care of status epilepticus. On the other hand, in our context, the prophylaxis of febrile seizures seems to be the corner stone of the prevention of HHE Syndrome. Copyright © 2018 Elsevier Inc. All rights reserved.

Phenotypic and Molecular Convergence of 2q23.1 Deletion Syndrome with Other Neurodevelopmental Syndromes Associated with Autism Spectrum Disorder

PubMed Central

Mullegama, Sureni V.; Alaimo, Joseph T.; Chen, Li; Elsea, Sarah H.

2015-01-01

Roughly 20% of autism spectrum disorders (ASD) are syndromic with a well-established genetic cause. Studying the genes involved can provide insight into the molecular and cellular mechanisms of ASD. 2q23.1 deletion syndrome (causative gene, MBD5) is a recently identified genetic neurodevelopmental disorder associated with ASD. Mutations in MBD5 have been found in ASD cohorts. In this study, we provide a phenotypic update on the prevalent features of 2q23.1 deletion syndrome, which include severe intellectual disability, seizures, significant speech impairment, sleep disturbance, and autistic-like behavioral problems. Next, we examined the phenotypic, molecular, and network/pathway relationships between nine neurodevelopmental disorders associated with ASD: 2q23.1 deletion Rett, Angelman, Pitt-Hopkins, 2q23.1 duplication, 5q14.3 deletion, Kleefstra, Kabuki make-up, and Smith-Magenis syndromes. We show phenotypic overlaps consisting of intellectual disability, speech delay, seizures, sleep disturbance, hypotonia, and autistic-like behaviors. Molecularly, MBD5 possibly regulates the expression of UBE3A, TCF4, MEF2C, EHMT1 and RAI1. Network analysis reveals that there could be indirect protein interactions, further implicating function for these genes in common pathways. Further, we show that when MBD5 and RAI1 are haploinsufficient, they perturb several common pathways that are linked to neuronal and behavioral development. These findings support further investigations into the molecular and pathway relationships among genes linked to neurodevelopmental disorders and ASD, which will hopefully lead to common points of regulation that may be targeted toward therapeutic intervention. PMID:25853262

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.

Does This Older Adult With Lower Extremity Pain Have the Clinical Syndrome of Lumbar Spinal Stenosis?

PubMed Central

Suri, Pradeep; Rainville, James; Kalichman, Leonid; Katz, Jeffrey N.

2012-01-01

Context The clinical syndrome of lumbar spinal stenosis (LSS) is a common diagnosis in older adults presenting with lower extremity pain. Objective To systematically review the accuracy of the clinical examination for the diagnosis of the clinical syndrome of LSS. Data Sources MEDLINE, EMBASE, and CINAHL searches of articles published from January 1966 to September 2010. Study Selection Studies were included if they contained adequate data on the accuracy of the history and physical examination for diagnosing the clinical syndrome of LSS, using a reference standard of expert opinion with radiographic or anatomic confirmation. Data Extraction Two authors independently reviewed each study to determine eligibility, extract data, and appraise levels of evidence. Data Synthesis Four studies evaluating 741 patients were identified. Among patients with lower extremity pain, the likelihood of the clinical syndrome of LSS was increased for individuals older than 70 years (likelihood ratio [LR], 2.0; 95% confidence interval [CI], 1.6–2.5), and was decreased for those younger than 60 years (LR, 0.40; 95% CI, 0.29–0.57). The most useful symptoms for increasing the likelihood of the clinical syndrome of LSS were having no pain when seated (LR, 7.4; 95% CI, 1.9–30), improvement of symptoms when bending forward (LR, 6.4; 95% CI, 4.1–9.9), the presence of bilateral buttock or leg pain (LR, 6.3; 95% CI, 3.1–13), and neurogenic claudication (LR, 3.7; 95% CI, 2.9–4.8). Absence of neurogenic claudication (LR, 0.23; 95% CI, 0.17–0.31) decreased the likelihood of the diagnosis. A wide-based gait (LR, 13; 95% CI, 1.9–95) and abnormal Romberg test result (LR, 4.2; 95% CI, 1.4–13) increased the likelihood of the clinical syndrome of LSS. A score of 7 or higher on a diagnostic support tool including history and examination findings increased the likelihood of the clinical syndrome of LSS (LR, 3.3; 95% CI, 2.7–4.0), while a score lower than 7 made the diagnosis much less

The clinical phenotype of Lynch syndrome due to germline PMS2 mutations

PubMed Central

Senter, Leigha; Clendenning, Mark; Sotamaa, Kaisa; Hampel, Heather; Green, Jane; Potter, John D.; Lindblom, Annika; Lagerstedt, Kristina; Thibodeau, Stephen N.; Lindor, Noralane M.; Young, Joanne; Winship, Ingrid; Dowty, James G.; White, Darren M.; Hopper, John L.; Baglietto, Laura; Jenkins, Mark A.; de la Chapelle, Albert

2009-01-01

Background and Aims Although the clinical phenotype of Lynch syndrome (also known as Hereditary Nonpolyposis Colorectal Cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. Methods We performed PMS2 mutation analysis using long range PCR and MLPA for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Results Germline PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2 fold higher and the incidence of endometrial cancer was 7.5 fold higher. In North America, this translates to a cumulative cancer risk to age 70 of 15–20% for colorectal cancer, 15% for endometrial cancer, and 25–32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. Conclusions PMS2 mutations contribute significantly to Lynch syndrome but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed. PMID:18602922

Clinics in diagnostic imaging (178). Wünderlich syndrome and pseudoaneurysm.

PubMed

Chung, Raymond; Chawla, Ashish; Peh, Wilfred Cg

2017-06-01

Wünderlich syndrome is a rare entity characterised by spontaneous retroperitoneal haemorrhage with renal origin. We present a case of Wünderlich syndrome secondary to clotting dyscrasia in a 64-year-old woman. The patient experienced a second Wünderlich haemorrhagic event with metachronous pseudoaneurysm formation, which was likely secondary to the large subcapsular haematoma stripping the renal capsule and tearing the cortical arteries. Selective pseudoaneurysm embolisations were successfully performed on both occasions. This clinical entity, its imaging differential diagnoses and management are discussed. Copyright: © Singapore Medical Association.

Metabolic syndrome in patients with hypertension attending a family practice clinic in Jordan.

PubMed

Yasein, N; Ahmad, M; Matrook, F; Nasir, L; Froelicher, E S

2010-04-01

Metabolic syndrome is being reported more frequently in the Eastern Mediterranean region. Patients with hypertension attending family practice clinics in the University of Jordan Hospital between February and July 2006 were assessed for the frequency of metabolic syndrome and its individual components. Of 345 patients studied, 65% had metabolic syndrome. Females were more likely to meet Adult Treatment Panel-III criteria for the diagnosis. Diabetes mellitus was the most frequent component of metabolic syndrome in males, while low serum high-density lipoprotein cholesterol and high waist circumference ranked first and second in females. Primary care providers should be alert to the importance of screening patients with hypertension for metabolic syndrome to prevent and manage these combined conditions.

Comparative responsiveness and minimal clinically important differences for idiopathic ulnar impaction syndrome.

PubMed

Kim, Jae Kwang; Park, Eun Soo

2013-05-01

Patient-reported questionnaires have been widely used to predict symptom severity and functional disability in musculoskeletal disease. Importantly, questionnaires can detect clinical changes in patients; however, this impact has not been determined for ulnar impaction syndrome. We asked (1) which of Patient-Rated Wrist Evaluation (PRWE), DASH, and other physical measures was more responsive to clinical improvements, and (2) what was the minimal clinically important difference for the PRWE and DASH after ulnar shortening osteotomy for idiopathic ulnar impaction syndrome. All patients who underwent ulnar shortening osteotomy between March 2008 and February 2011 for idiopathic ulnar impaction syndrome were enrolled in this study. All patients completed the PRWE and DASH questionnaires, and all were evaluated for grip strength and wrist ROM, preoperatively and 12 months postoperatively. We compared the effect sizes observed by each of these instruments. Effect size is calculated by dividing the mean change in a score of each instrument during a specified interval by the standard deviation of the baseline score. In addition, patient-perceived overall improvement was used as the anchor to determine the minimal clinically important differences on the PRWE and DASH 12 months after surgery. The average score of each item except for wrist flexion and supination improved after surgery. The PRWE was more sensitive than the DASH or than physical measurements in detecting clinical changes. The effect sizes and standardized response means of the outcome measures were as follows: PRWE (1.51, 1.64), DASH (1.12, 1.24), grip strength (0.59, 0.68), wrist pronation (0.33, 0.41), and wrist extension (0.28, 0.36). Patient-perceived overall improvement and score changes of the PRWE and DASH correlated significantly. Minimal clinically important differences were 17 points (of a possible 100) for the PRWE and 13.5 for the DASH (also of 100), and minimal detectable changes were 7.7 points

Sneddon syndrome: rare disease or under diagnosed clinical entity? Review of the literature related to a clinical case.

PubMed

Orac, Amalia; Artenie, Anca; Toader, Mihaela Paula; Harnagea, Raluca; Dinu-Mitrofan, Diana; Grigorovici, Mirela; Ungureanu, G

2014-01-01

Sneddon syndrome is defined by the association of livedo racemosa and recurrent cerebrovascular ischemic lesions. The annual incidence is 4/1,000,000. This syndrome particularly affects young women, some reports suggesting a family predisposition. It is a chronic, progressive, arterio-occlusive disease of unknown etiology that involves small and medium-sized arteries. It is usually associated with antiphospholipid antibodies. We report the case of a female patient with Sneddon syndrome with significant family history, personal history of stroke, epilepsy, migraine, cardiovascular involvement, three miscarriages, cognitive decline, noncompliant to therapy, in the absence of antiphospholipid antibodies. This paper aims to analyze the main characteristic features and management of Sneddon syndrome by conducting a literature review related to a clinical case.

HAEMORRHAGIC SYNDROME IN THE CLINICAL PICTURE OF RADIATION SICKNESS IN DOGS AFFECTED BY POLONIUM (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mikhailovich, S.M.

Subcutaneous introduction of polonium to dogs brings about development of radiation sickness with appearance of haemorrhagic syndrome, which is characterized by disturbed process of blood coagulation, thrombocytopenia, decreased prothrombin value of the blood, increased permeability of capillaries. The clinical picture of the usually developed affection corresponds to the well known symptomatology, described in literature. Indicators of the haemorrhagic syndrome (blood coagulation, prothrombin value, permeabillty and stability of capillaries) appear in animals earlier than the clinical manifestations of this syndrome. (tr-auth)

Autism Spectrum Disorders (Pervasive Developmental Disorders)

ERIC Educational Resources Information Center

Strock, Margaret

2007-01-01

This booklet focuses on classic autism, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger syndrome, with brief descriptions of Rett syndrome and childhood disintegrative disorder. The booklet describes possible indicators of autism spectrum disorders (ASD), their diagnosis, available aids, treatment options, adults…

The prevalence and clinical impact of obesity in adults with Marfan syndrome

PubMed Central

Yetman, Anji T; McCrindle, Brian W

2010-01-01

BACKGROUND: Patients with Marfan syndrome characteristically have an asthenic body habitus and are considered to be exempt from the obesity epidemic. OBJECTIVE: To examine the prevalence and clinical impact of obesity in a cohort of adults with Marfan syndrome. METHODS: Fifty outpatients (30 female) with a mean (± SD) age of 38±13 years were studied. Demographic variables including previously identified risk factors for aortic dissection were recorded. Body mass index (BMI) was determined and patients were classified as normal (BMI less than 25 kg/m2), overweight (BMI 25 kg/m2 to 29.9 kg/m2) or obese (BMI 30 kg/m2 or greater). Other cardiovascular risk factors were examined. An adverse clinical outcome was defined as either the attainment of surgical criteria for aortic root replacement or the presence of aortic dissection. RESULTS: A family history of aortic dissection was present in 13 (26%) patients. In 23 (46%) patients, there was no known family history of Marfan syndrome. Mean BMI was 25.4±7.4 kg/m2, with 18 (36%) patients having an elevated BMI. Positive smoking status was present in 15 (30%), hypertension in 13 (26%) and hyperlipidemia in 19 (38%) patients. Adverse clinical outcome was present in 27 (54%) patients. Logistic regression analysis revealed only index case (OR 44; P<0.001) and higher BMI (OR 1.2; P=0.04) to be significantly and independently associated with increased risk of adverse clinical outcome. CONCLUSIONS: Obesity is common in adults with Marfan syndrome and is associated with an increased risk of aortic complications. PMID:20386774

Burning mouth syndrome: Clinical description, pathophysiological approach, and a new therapeutic option.

PubMed

Cárcamo Fonfría, A; Gómez-Vicente, L; Pedraza, M I; Cuadrado-Pérez, M L; Guerrero Peral, A L; Porta-Etessam, J

2017-05-01

Burning mouth syndrome is defined as scorching sensation in the mouth in the absence of any local lesions or systemic disease that would explain that complaint. The condition responds poorly to commonly used treatments and it may become very disabling. We prospectively analysed the clinical and demographic characteristics and response to treatment in 6 cases of burning mouth syndrome, diagnosed at 2 tertiary hospital headache units. Six female patients between the ages of 34 and 82 years reported symptoms compatible with burning mouth syndrome. In 5 of them, burning worsened at the end of the day; 4 reported symptom relief with tongue movements. Neurological examinations and laboratory findings were normal in all patients and their dental examinations revealed no buccal lesions. Each patient had previously received conventional treatments without amelioration. Pramipexol was initiated in doses between 0.36mg and 1.05mg per day, resulting in clear improvement of symptoms in all cases, a situation which continues after a 4-year follow up period. Burning mouth syndrome is a condition of unknown aetiology that shares certain clinical patterns and treatment responses with restless leg syndrome. Dopamine agonists should be regarded as first line treatment for this entity. Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches.

PubMed

Butler, Merlin G; Manzardo, Ann M; Forster, Janice L