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Sample records for brachmann-de lange syndrome

  1. Brachmann-de Lange syndrome

    SciTech Connect

    Ackerman, J.; Gilbert-Barness, E.

    1997-01-31

    This report describes an infant with Brachmann-de Lange syndrome and the diagnosis of this disease in utero. It also discusses the future ability to rely on chromosome 9-associated levels of pregnancy-associated plasma protein A (PAPPA) as an indicator of the disease, rather than solely relying on the phenotype of the fetus as determined during ultrasound. 3 refs., 2 figs.

  2. Brachmann-de Lange syndrome: Autosomal dominant inheritance and male-to-male transmission

    SciTech Connect

    McKenney, R.R.; Elder, F.F.B.; Northrup, H.; Garcia, J.

    1996-12-30

    We report on familial occurrence of the Brachmann-de Lange syndrome (BDLS): a mildly affected father and his severely affected son and daughter who have different mothers. Both children are severely affected while the father has a much milder but definite BDLS phenotype. Our report documents the third example of male-to-male transmission and adds to the argument against exclusively maternal transmission in familial cases. In addition, our findings illustrate the occurrence of severe manifestations in cases of familial BDLS. 29 refs., 3 figs.

  3. Identical twin discordance for the Brachmann-de Lange syndrome revisited

    SciTech Connect

    Carakushansky, G.; Goncalves, M.R.; Kahn, E.

    1996-06-14

    The only known twin pair evidently discordantly affected for the BDLS (Brachmann-de Lange syndrome) and who had been considered monozygotic (MZ) based on blood analysis remained a problem because biological zygosity determination needed further typing. In this report we review the clinical findings of this pair of twins at the age of 20. The use of DNA fingerprinting with three multilocus probes, F10, DNT24, and 33.6, allowed us to present evidence of monozygosity with a high degree of certainty. The significance of this confirmation of discordance in determining the cause of BDLS is discussed. Intensive comparative genomic studies of the discordant twin sisters may be useful to unravel the molecular genetics of this enigmatic pattern of malformation. 21 refs., 2 figs.

  4. Multiple mitochondrial DNA deletions and persistent hyperthermia in a patient with Brachmann-de Lange phenotype

    SciTech Connect

    Melegh, B.; Bock, I.; Mehes, K.

    1996-10-02

    In a newborn boy with characteristics of Brachmann-de Lange syndrome (BDLS), high temperatures were observed on the second day after birth and recurred 2-6 times daily during the 7 months of the patient`s life. After, transient hypertonia hypotonia developed. In muscle biopsy specimen taken on the 51st day of life, serious and progressive distortion of mitochondria was observed. In several mitochondria the cristae structure was broken, other mitochondria were shrunken and the damage progressed towards further deterioration in other organelles. At several points between the myofibrils, amorphous material was seen, possibly debris of destroyed mitochondria. Most myofibrils seemed to be intact; however, in some areas myolytic signs were present. Analysis of the mitochondrial DNA (mtDNA) showed multiple deletions in skeletal and heart muscles, liver, lung and kidney. Since the mtDNA encodes several proteins of the respiratory complexes, the deleted mtDNA certainly affected the integrity of the mitochondrial oxidative phosphorylation process by synthesis of abnormal proteins. In the present case the hyperthermia may have been a result of the mtDNA damage. 13 refs.

  5. Cornelia de Lange syndrome with optic disk pit: Novel association and review of literature.

    PubMed

    Shenoy, Bhamy Hariprasad; Gupta, Amit; Sachdeva, Virender; Kekunnaya, Ramesh

    2014-05-01

    Cornelia de Lange syndrome (CdLS), also called Brachmann-de Lange syndrome, is a multiple congenital anomaly syndrome characterized by a distinctive facial appearance, ophthalmological abnormalities, prenatal and postnatal growth deficiency, psychomotor delay, behavioral problems, and malformations of the upper extremities. Most common and consistent ophthalmic features reported are nasolacrimal duct obstruction, long and curly eyelashes, blepharitis, ptosis, synophrys, telecanthus, hypertelorism, microcornea, peripapillary pigment ring, and myopia. In this report we report a case of a 5-year old boy who presented to our institution with complaint of blurring of vision in the right eye since birth. A diagnosis of Cornelia de Lange syndrome was arrived at based on the characteristic external and ophthalmic examination. He was found to have a rare association of optic nerve head coloboma in the right eye and a novel finding of an optic disk pit in the left eye. The association of optic disk pit with CdLS has never been reported earlier. We aim to provide a thorough review of literature of this not so uncommon syndrome. PMID:25136230

  6. Cornelia de Lange Syndrome Foundation

    MedlinePlus

    ... for You Have questions? Need support? The CdLS Foundation staff is here to listen and help. Call ... Site Map The Cornelia de Lange Syndrome (CdLS) Foundation is a family support organization that exists to ...

  7. The Cornelia de Lange Syndrome

    PubMed Central

    Payne, Harold W.; Maeda, William K.

    1965-01-01

    A euploid/aberrant double stem line mosaicism was found in two cases of the de Lange syndrome with severe abnormalities. In both cases the structural heterozygosity of the aberrant stem line involved, apparently, the loss of chromosomal material from a smaller autosome of Group (6-12) X, probably No. 11. Differences in the cultural characteristics of de Lange cells suggest that the aberrant stem line may not proliferate in culture, so that mosaicism may not be detected. Moreover, the mosaicism may not be present in all tissues, resulting in normal cytogenetic findings as noted in a third case studied. Our findings suggest that the de Lange syndrome is the phenotypic expression of chromosomal mosaicism. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8 PMID:5825977

  8. The Jervell and Lange-Nielsen syndrome.

    PubMed

    Komsuoğlu, B; Göldeli, O; Kulan, K; Budak, F; Gedik, Y; Tuncer, C; Komsuoğlu, S S

    1994-12-01

    The association of prolongation of the QT interval with recurrent attacks of syncope, sudden death, and malignant ventricular arrhythmias is known as the long QT syndrome. The syndrome may be familial with or without congenital deafness, or idiopatic. The syndrome with deafness (Jervell and Lange-Nielsen syndrome) is inherited through an autosomal recessive mechanism. In this study, we attempted to identify patients with the Jervell Lange-Nielsen syndrome amongst 154 deaf mute school children. Two patients had a corrected QT interval of 0.52 and congenital sensorineural hearing loss with the other electrocardiographic changes characteristic of the syndrome, such as inverted or bifid T wave. There was no evidence of electrocardiographic (ECG) abnormality in family members, except only one case of parental deafness. This is the first and preliminary report that analyzed the incidence of the Jervell and Lange-Nielsen syndrome amongst 154 deaf mute school children in Turkey. Our study was conducted to identify patients with this syndrome amongst children of another deaf mute school in Turkey. PMID:7721491

  9. ABR Audiometry in Cornelia De Lange Syndrome.

    ERIC Educational Resources Information Center

    Brown, Denice P.

    Eight children (ages 13 days to 5 years) with a diagnosis of Cornelia de Lange syndrome received audiologic evaluation consisting of immittance audiometry and auditory brainstem response audiometry to air and bone conducted "click" stimuli, as behavioral testing was unreliable due to patient age and/or developmental delay. Developmental…

  10. Social Anxiety in Cornelia de Lange Syndrome

    ERIC Educational Resources Information Center

    Richards, Caroline; Moss, Jo; O'Farrell, Laura; Kaur, Gurmeash; Oliver, Chris

    2009-01-01

    In this study we assessed the behavioral presentation of social anxiety in Cornelia de Lange syndrome (CdLS) using a contrast group of Cri du Chat syndrome (CdCS). Behaviors indicative of social anxiety were recorded in twelve children with CdLS (mean age = 11.00; SD = 5.15) and twelve children with CdCS (8.20; SD = 2.86) during social…

  11. De Lange Syndrome: Report of 20 Cases

    PubMed Central

    McArthur, R. G.; Edwards, J. H.

    1967-01-01

    Typus Degenerativus Amstelodamensis or Amsterdam dwarfism, a syndrome of unknown etiology characterized by mental retardation, a distinctive face, characteristic hands and feet, defective growth and other minor malformations, was first described by Cornelia de Lange in 1933. Approximately 69 cases, including nine autopsies, have been reported in the literature. In this paper we present a further 20, with illustrations of the syndrome from infancy to puberty (including de Lange's original three cases). The historical, physical, laboratory and radiographic findings of de Lange's three patients and our 20 are tabulated. Autopsy findings in one of our patients are reported and the literature is briefly reviewed. Although some observers have recently reported chromosome abnormalities in de Lange's syndrome, we feel that the diagnosis is made from the history and physical examination and that there are no definitive laboratory aids which can confirm the diagnosis. Chromosome studies in all 20 of our patients were normal and the genetic implications are discussed. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 9Fig. 11p1197-a PMID:6022788

  12. Case Report: Atypical Cornelia de Lange Syndrome.

    PubMed

    Leanza, Vito; Rubbino, Gabriella; Leanza, Gianluca

    2014-01-01

    Cornelia de Lange Syndrome (CdLS) (also called Bushy Syndrome or Amsterdam dwarfism), is a genetic disorder that can lead to several alterations. This disease affects both physical and neuropsychiatric development. The various abnormalities include facial dysmorphia (arched eyebrows, synophrys, depressed nasal bridge, long philtrum, down-turned angles of the mouth), upper-extremity malformations, hirsutism, cardiac defects, and gastrointestinal alterations. The prevalence of this syndrome is approximately one per 15,000. Ultrasound is not the perfect means to diagnose CdLS, however, many abnormalities can be detected prenatally by scrupulous image observation. We report an atypical CdLS case characterized by increased nuchal translucency in the first trimester, normal karyotype, saddle nose, micrognathia with receding jaw, low set ears, facies senilis, arthrogryposis of the hands, absence of the Aranzio ductus venous, dilatation of gallbladder and bowel, a unique umbilical artery, increased volume of amniotic fluid, and intrauterine growth retardation ending with the interruption of pregnancy. PMID:26834972

  13. Case Report: Atypical Cornelia de Lange Syndrome

    PubMed Central

    Leanza, Vito; Rubbino, Gabriella; Leanza, Gianluca

    2015-01-01

    Cornelia de Lange Syndrome (CdLS) (also called Bushy Syndrome or Amsterdam dwarfism), is a genetic disorder that can lead to several alterations. This disease affects both physical and neuropsychiatric development. The various abnormalities include facial dysmorphia (arched eyebrows, synophrys, depressed nasal bridge, long philtrum, down-turned angles of the mouth), upper-extremity malformations, hirsutism, cardiac defects, and gastrointestinal alterations. The prevalence of this syndrome is approximately one per 15,000. Ultrasound is not the perfect means to diagnose CdLS, however, many abnormalities can be detected prenatally by scrupulous image observation. We report an atypical CdLS case characterized by increased nuchal translucency in the first trimester, normal karyotype, saddle nose, micrognathia with receding jaw, low set ears, facies senilis, arthrogryposis of the hands, absence of the Aranzio ductus venous, dilatation of gallbladder and bowel, a unique umbilical artery, increased volume of amniotic fluid, and intrauterine growth retardation ending with the interruption of pregnancy. PMID:26834972

  14. Social anxiety in Cornelia de Lange syndrome.

    PubMed

    Richards, Caroline; Moss, Jo; O'Farrell, Laura; Kaur, Gurmeash; Oliver, Chris

    2009-08-01

    In this study we assessed the behavioral presentation of social anxiety in Cornelia de Lange syndrome (CdLS) using a contrast group of Cri du Chat syndrome (CdCS). Behaviors indicative of social anxiety were recorded in twelve children with CdLS (mean age = 11.00; SD = 5.15) and twelve children with CdCS (8.20; SD = 2.86) during social interaction. Lag sequential analysis revealed that participants with CdLS were significantly more likely to evidence behavior indicative of anxiety in close temporal proximity to the point at which they maintained eye contact or spoke. Individuals with CdLS demonstrate a heightened probability of anxiety related behavior during social interaction but only at the point at which social demand is high. PMID:19330433

  15. Cornelia de Lange syndrome: a case report.

    PubMed

    Grau Carbó, Joaquim; López Jiménez, Julian; Giménez Prats, Maria José; Sànchez Molins, Meritxell

    2007-10-01

    Cornelia de Lange is a genetic syndrome which affects between 1/10.000 and 1/60.000 neonates, but its genetic bases are still not clear. Its principal clinical characteristics are the delay in growth and development, hirsute, structural anomalies in the limbs and distinctive facial characteristic. Dental problems are frequent and include: ogival palate, micrognathia, dental malalignment, delayed teething, microdontic teeth, periodontal disease and dental erosion produced by gastric reflux. Discussed is the case of a 29 year old patient affected by the syndrome in question, which presents the principal clinical characteristics. The patient's general state of health is acceptable, without cardiac or respiratory alterations. The intraoral exploration shows policaries, periodontal disease, persistence of the temporal teeth and ectopic molars. After completing the necessary pre-operatory preparations, the entire odontological treatment was carried out under general aesthesia, due to the patient's total lack of collaboration. PMID:17909511

  16. Cornelia de Lange syndrome: a case study.

    PubMed

    Kalal, Goud Iravathy; Raina, Vimarsh P; Nayak, Veerabhadra S; Teotia, Pooja; Gupta, Bhushan V

    2009-02-01

    Cornelia de Lange syndrome (CDLS) is a relatively common multiple congenital anomaly/mental retardation disorder with an unknown genetic and molecular pathogenesis. The essential features of this developmental malformation syndrome are retardation in growth, developmental delay, various structural limb abnormalities, and distinctive facial features. Most cases are sporadic and are thought to result from a new dominant mutation. Consequently, hypotheses regarding the pathogenetic mechanisms underlying the two distinct phenotypes, classic and mild, are purely speculative. The recent discovery of molecular techniques and identification of the NIPBL gene has allowed etiologic diagnosis of this disorder. In this article, we describe a patient with CDLS in whom conventional cytogenetics, fluorescence in situ hybridization, and NIPBL gene mutation analysis determined an etiologic diagnosis, providing precise genetic counseling and facilitated the family to make an evidence-based decision for conception and also alleviated the extreme degree of anxiety associated with the thought of having a second child in this set of circumstances. PMID:19309268

  17. Cornelia de Lange Syndrome: Evolution of the Phenotype

    ERIC Educational Resources Information Center

    Passarge, Eberhard; And Others

    1971-01-01

    The medical case history of a 2-year-old girl who developed, during the second year of life, the classical phenotype (typical appearance) indicative of the deLange syndrome, with both mental and physical impairment. (KW)

  18. Cornelia de Lange syndrome, cohesin, and beyond

    PubMed Central

    Liu, J; Krantz, ID

    2010-01-01

    Cornelia de Lange syndrome (CdLS) (OMIM #122470, #300590 and #610759) is a dominant genetic disorder with multiple organ system abnormalities which is classically characterized by typical facial features, growth and mental retardation, upper limb defects, hirsutism, gastrointestinal and other visceral system involvement. Mutations in three cohesin proteins, a key regulator of cohesin, NIPBL, and two structural components of the cohesin ring SMC1A and SMC3, etiologically account for about 65% of individuals with CdLS. Cohesin controls faithful chromosome segregation during the mitotic and meiotic cell cycles. Multiple proteins in the cohesin pathway are also involved in additional fundamental biological events such as double-strand DNA break repair and long-range regulation of transcription. Moreover, chromosome instability was recently associated with defective sister chromatid cohesion in several cancer studies, and an increasing number of human developmental disorders is being reported to result from disruption of this pathway. Here, we will discuss the human disorders caused by alterations of cohesin function (termed ‘cohesinopathies’), with an emphasis on the clinical manifestations of CdLS and mechanistic studies of the CdLS-related proteins. PMID:19793304

  19. Characteristics of Autism Spectrum Disorder in Cornelia de Lange Syndrome

    ERIC Educational Resources Information Center

    Moss, Jo; Howlin, Patricia; Magiati, Iliana; Oliver, Chris

    2012-01-01

    Background: The prevalence of autism spectrum disorder (ASD) symptomatology is comparatively high in Cornelia de Lange syndrome (CdLS). However, the profile and developmental trajectories of these ASD characteristics are potentially different to those observed in individuals with idiopathic ASD. In this study we examine the ASD profile in CdLS in…

  20. Language Acquisition in a Child with Cornelia De Lange Syndrome.

    ERIC Educational Resources Information Center

    Goodban, Marjorie T.

    The paper describes a successful attempt to stimulate expressive language in Becky, a young child with Cornelia de Lange syndrome, a condition characterized by moderate to severe mental retardation, dwarfed stature, and excessive body hair. The child participated in infant stimulation and individual speech therapy and her expressive output has…

  1. Neuropsychological rehabilitation in a case of Cornelia de Lange syndrome.

    PubMed

    Cossu, M C; Nava, I; Leoni, S; Piccardi, L

    2005-05-01

    Cornelia de Lange syndrome is a rare congenital disorder. Symptoms include a characteristic facial structure, pre- and post-natal growth deficiency, hypertrichosis, and visceral and cardiovascular anomalies. Behavioural problems and moderate to severe mental retardation are also present. In this paper, we report a mild case of Cornelia de Lange syndrome. The neuropsychological rehabilitation of this patient is also described. It was structured on the patient's specific areas of strength and weakness in order to facilitate the development of adaptive cognitive abilities. To maximise the learning potential of these children, we recommend specific interventions with a multidimensional neuropsychological approach, which considers developmental abilities and disabilities as related to the global reality of the child. PMID:16353507

  2. Delineating the Profile of Autism Spectrum Disorder Characteristics in Cornelia de Lange and Fragile X Syndromes

    ERIC Educational Resources Information Center

    Moss, Joanna; Oliver, Chris; Nelson, Lisa; Richards, Caroline; Hall, Scott

    2013-01-01

    An atypical presentation of autism spectrum disorder is noted in Cornelia de Lange and Fragile X syndromes, but there are few detailed empirical descriptions. Participants in this study were individuals with Cornelia de Lange syndrome (n = 130, M age = 17.19), Fragile X syndrome (n = 182, M age = 16.94), and autism spectrum disorder (n = 142, M…

  3. Jervell and Lange-Nielsen Syndrome (Long QT Syndrome).

    ERIC Educational Resources Information Center

    Hulbert, T. P.

    1994-01-01

    Clinical features, pathogenetic hypotheses, and symptoms of the cardio-auditory or surdo-cardiac disorder first reported by Jervell and Lange-Nielsen are described, and methods of diagnosis and treatment are presented, to alert teachers and other professionals to potentially life-threatening symptoms they may observe when working with deaf and…

  4. Prevalence of Autism Spectrum Phenomenology in Cornelia de Lange and Cri du Chat Syndromes

    ERIC Educational Resources Information Center

    Moss, Joanna F.; Oliver, Chris; Berg, Katy; Kaur, Gurmeash; Jephcott, Lesley; Cornish, Kim

    2008-01-01

    Autism spectrum disorder characteristics have not been evaluated in Cornelia de Lange and Cri du Chat syndromes using robust assessments. The Autism Diagnostic Observation Schedule and Social Communication Questionnaire were administered to 34 participants with Cornelia de Lange syndrome and a comparison group of 23 participants with Cri du Chat…

  5. The Association Between Environmental Events and Self-Injurious Behaviour in Cornelia de Lange Syndrome

    ERIC Educational Resources Information Center

    Moss, J.; Oliver, C.; Hall, S.; Arron, K.; Sloneem, J.; Petty, J.

    2005-01-01

    There has been limited empirical research into the environmental causes of self-injury in Cornelia de Lange syndrome. The present study examined the variability of self-injurious behaviour in Cornelia de Lange syndrome across environmental setting events. Additionally, the association between setting events and more specific environmental events…

  6. A Boy with a Mild Case of Cornelia de Lange Syndrome with Above Average Intelligence.

    ERIC Educational Resources Information Center

    Lacassie, Yves; Bobadilla, Olga; Cambias, Ron D., Jr.

    1997-01-01

    Describes the characteristics of an 11-year-old boy who represents the only documented case of an individual with Cornelia de Lange syndrome who also has above average cognitive functioning. Major diagnostic criteria for de Lange syndrome and comparisons with other severe and mild cases are discussed. (Author/CR)

  7. Jervell and Lange-Nielson Syndrome masquerading as intractable epilepsy.

    PubMed

    Goyal, Jagdish P; Sethi, Alka; Shah, V B

    2012-04-01

    The long QT syndrome (LQTS) is a cause of syncope and sudden death. Jervell and Lange-Nielson syndrome (JLNS) is an uncommon form of LQTS, having autosomal recessive transmission, and is associated with congenital deafness. We report a case of JLNS in a child who presented to us with refractory epilepsy. The cardiac cause of seizures was suspected as the child was hypotensive and pulseless during the episode of seizures. The child was diagnosed as JLNS based on Schwartz diagnostic criteria for LQTS and congenital sensorineural deafness. The child responded well to β-blocker therapy. Antiepileptic drugs were stopped. The screening of family members with ECG revealed a QT interval more than required for diagnosis of LQTS but they were asymptomatic. All asymptomatic family members were also put on metoprolol. All of them showed great improvement with the reduction of the QT interval on ECG. The patient was doing well on immediate follow-up. PMID:22566733

  8. Thrombocytopenia and Cornelia de Lange syndrome: Still an enigma?

    PubMed

    Cavalleri, Valeria; Bettini, Laura R; Barboni, Chiara; Cereda, Anna; Mariani, Milena; Spinelli, Marco; Gervasini, Cristina; Russo, Silvia; Biondi, Andrea; Jankovic, Momcilo; Selicorni, Angelo

    2016-01-01

    Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder caused by mutations in the cohesion complex and its regulators. The syndrome is characterized by multiple organ system abnormalities, pre- and post-natal growth retardation and typical facial features. Thrombocytopenia is a reduction in platelet count to <150 × 10(9)  L. It can be caused by congenital or acquired decreased production, increased destruction, or sequestration of platelets. In recent years, several papers reported thrombocytopenia and immune thrombocytopenia in patients affected by CdLS. In 2011, Lambert et al. estimated the risk of idiopathic thrombocytopenia purpura in CdLS patients to be 31-633 times greater than in the general population. We describe the incidence of thrombocytopenia in 127 Italian CdLS patients, identifying patients with transient or persistent thrombocytopenia, but a lower incidence of true idiopathic thrombocytopenic purpura (ITP). PMID:26437745

  9. Psychological Well-Being in Parents of Children with Angelman, Cornelia de Lange and Cri du Chat Syndromes

    ERIC Educational Resources Information Center

    Griffith, G. M.; Hastings, R. P.; Oliver, C.; Howlin, P.; Moss, J.; Petty, J.; Tunnicliffe, P.

    2011-01-01

    Background: The current study focuses on mothers and fathers of children with three rare genetic syndromes that are relatively unexplored in terms of family experience: Angelman syndrome, Cornelia de Lange syndrome and Cri du Chat syndrome. Method: Parents of children with Angelman syndrome (n = 15), Cornelia de Lange syndrome (n = 16) and Cri du…

  10. On the Molecular Etiology of Cornelia de Lange Syndrome

    PubMed Central

    Dorsett, Dale; Krantz, Ian D.

    2009-01-01

    Cornelia de Lange syndrome (CdLS) is genetically heterogeneous and is usually sporadic, occurring approximately once per ten thousand births. CdLS individuals display diverse and variable deficits in growth, mental development, limbs and organs. In the past few years it has been shown that CdLS is caused by gene mutations affecting proteins involved in sister chromatid cohesion. Studies in model organisms, and more recently in human cells have revealed, somewhat unexpectedly, that the developmental deficits in CdLS likely arise from changes in gene expression. The mechanisms by which cohesion factors regulate gene expression remain to be elucidated, but current data suggest that they likely regulate transcription in multiple ways. PMID:19154515

  11. Mutation Analysis in Chinese Patients with Cornelia de Lange Syndrome

    PubMed Central

    Zhong, Qiulian; Liang, Desheng; Liu, Jing; Xue, Jinjie

    2012-01-01

    Aims: Cornelia de Lange syndrome (CdLS) is a dominant multisystem developmental disorder and related to mutations of the NIPBL, SMC1A, and SMC3 genes. So far, there has been no report of a mutation analysis in Chinese patients with CdLS, while 12 cases have been clinically described. In the present study, we tried to search for pathogenic mutations of the NIPBL, SMC1A, and SMC3 genes in four patients with CdLS from four unrelated Chinese families. Results: The mutational analysis of the NIPBL, SMC1A, and SMC3 genes by direct sequencing revealed a heterozygous splice-site mutation c.4321G>T(p.V1441L) at exon 20 of NIPBL in proband 2 and a novel heterozygous splice-site mutation c.6589+5G>C at intron 38 of NIPBL in proband 3, which was showed by reverse transcription polymerase chain reaction to generate both the full-length and an alternatively spliced transcript with an exon 38 deletion. Conclusions: This is the first report of the mutation analysis of NIPBL in China and our findings both expand the mutation spectrum of NIPBL and provide data for further understanding of the diverse and variable effects of NIPBL mutations. PMID:22857006

  12. Precocious Sister Chromatid Separation (PSCS) in Cornelia de Lange Syndrome

    PubMed Central

    Kaur, Maninder; DeScipio, Cheryl; McCallum, Jennifer; Yaeger, Dinah; Devoto, Marcella; Jackson, Laird G.; Spinner, Nancy B.; Krantz, Ian D.

    2009-01-01

    The Cornelia de Lange syndrome (CdLS) (OMIM# 122470) is a dominantly inherited multisystem developmental disorder. The phenotype consists of characteristic facial features, hirsutism, abnormalities of the upper extremities ranging from subtle changes in the phalanges and metacarpal bones to oligodactyly and phocomelia, gastroesophageal dysfunction, growth retardation, and neurodevelopmental delay. Prevalence is estimated to be as high as 1 in 10,000. Recently, mutations in NIPBL were identified in sporadic and familial CdLS cases. To date, mutations in this gene have been identified in over 45% of individuals with CdLS. NIPBL is the human homolog of the Drosophila Nipped-B gene. Although its function in mammalian systems has not yet been elucidated, sequence homologs of Nipped-B in yeast (Scc2 and Mis4) are required for sister chromatid cohesion during mitosis, and a similar role was recently demonstrated for Nipped-B in Drosophila. In order to evaluate NIPBL role in sister chromatid cohesion in humans, metaphase spreads on 90 probands (40 NIPBL mutation positive and 50 NIPBL mutation negative) with CdLS were evaluated for evidence of precocious sister chromatid separation (PSCS). We screened 50 metaphases from each proband and found evidence of PSCS in 41% (compared to 9% in control samples). These studies indicate that NIPBL may play a role in sister chromatid cohesion in humans as has been reported for its homologs in Drosophila and yeast. PMID:16100726

  13. Natural history of aging in Cornelia de Lange syndrome.

    PubMed

    Kline, Antonie D; Grados, Marco; Sponseller, Paul; Levy, Howard P; Blagowidow, Natalie; Schoedel, Christianne; Rampolla, Joni; Clemens, Douglas K; Krantz, Ian; Kimball, Amy; Pichard, Carmen; Tuchman, David

    2007-08-15

    Observations about the natural history of aging in Cornelia de Lange syndrome (CdLS) are made, based on 49 patients from a multidisciplinary clinic for adolescents and adults. The mean age was 17 years. Although most patients remain small, obesity may develop. Gastroesophageal reflux persists or worsens, and there are early long-term sequelae, including Barrett esophagus in 10%; other gastrointestinal findings include risk for volvulus, rumination, and chronic constipation. Submucous cleft palate was found in 14%, most undetected before our evaluation. Chronic sinusitis was noted in 39%, often with nasal polyps. Blepharitis improves with age; cataracts and detached retina may occur. Decreased bone density is observed, with occasional fractures. One quarter have leg length discrepancy and 39% scoliosis. Most females have delayed or irregular menses but normal gynecologic exams and pap smears. Benign prostatic hypertrophy occurred in one male prior to 40 years. The phenotype is variable, but there is a distinct pattern of facial changes with aging. Premature gray hair is frequent; two patients had cutis verticis gyrata. Behavioral issues and specific psychiatric diagnoses, including self-injury, anxiety, attention-deficit disorder, autistic features, depression, and obsessive-compulsive behavior, often worsen with age. This work presents some evidence for accelerated aging in CdLS. Of 53% with mutation analysis, 55% demonstrate a detectable mutation in NIPBL or SMC1A. Although no specific genotype-phenotype correlations have been firmly established, individuals with missense mutations in NIPBL and SMC1A appear milder than those with other mutations. Based on these observations, recommendations for clinical management of adults with CdLS are made. PMID:17640042

  14. Infant Attentional Behaviours as Prognostic Indicators in Cornelia-de-Lange Syndrome

    ERIC Educational Resources Information Center

    Sarimski, Klaus

    2007-01-01

    Background: Cornelia-de-Lange syndrome is a rare congenital syndrome with poor social relatedness as one of several characteristics of its behavioural phenotype. Methods: Video observations were collected from seven children in their first year of life and again with age 2-4 years. Data were analysed for distribution of object-related and social…

  15. Facial Expression of Affect in Children with Cornelia de Lange Syndrome

    ERIC Educational Resources Information Center

    Collis, L.; Moss, J.; Jutley, J.; Cornish, K.; Oliver, C.

    2008-01-01

    Background: Individuals with Cornelia de Lange syndrome (CdLS) have been reported to show comparatively high levels of flat and negative affect but there have been no empirical evaluations. In this study, we use an objective measure of facial expression to compare affect in CdLS with that seen in Cri du Chat syndrome (CDC) and a group of…

  16. Analysis of Intentional Communication in Severely Handicapped Children with Cornelia-de-Lange Syndrome.

    ERIC Educational Resources Information Center

    Sarimski, Klaus

    2002-01-01

    Intentional communicative acts were assessed in 13 children (ages 2-8) with Cornelia-de-Lange syndrome with a severe mental disability and compared to children with Down and 5p syndromes. The mean number of intentional communicative acts was significantly lower. Analysis of play behaviors revealed the differences were specific for the…

  17. [Ophthalmological manifestations of Cornelia de Lange syndrome: Case report and review of the literature].

    PubMed

    Avgitidou, G; Cursiefen, C; Heindl, L M

    2015-05-01

    A 2-year-old boy suffering from Cornelia de Lange syndrome, presented with mucopurulent ocular discharge and epiphora since birth. Irrigation and probing of the nasolacrimal system revealed and successfully treated bilateral nasolacrimal duct obstructions. Cornelia de Lange syndrome is characterized not only by typical facial features, visceral and urogenital anomalies but also by ophthalmological manifestations in 99% of cases. The most common ophthalmological disorders are synophrys, blepharitis, epiphora, hypertrichosis of the eyebrows and eyelashes, myopia, ptosis and nasolacrimal duct obstruction. PMID:25566737

  18. Congenital Deafness with Cardiac Arrhythmias: The Jervell and Lange-Nielsen Syndrome.

    ERIC Educational Resources Information Center

    Wahl, Richard A.; Macdonald, Dick, II

    1980-01-01

    The Jervell and Lange-Nielsen syndrome, affecting 0.3 percent of congenitally deaf persons, consists of severe cardiac arrhythmias and sensorineural hearing loss. The authors recommend that every congenitally deaf child with suspicious symptoms receive an electrocardiogram and that professionals who work with deaf children not only inform…

  19. The Behavioural Phenotype of Cornelia de Lange Syndrome: A Study of 56 Individuals

    ERIC Educational Resources Information Center

    Basile, Emanuele; Villa, L.; Selicorni, A.; Molteni, M.

    2007-01-01

    Background: Few studies have investigated functional and behavioural variables of Cornelia de Lange Syndrome (CdLS) in a large sample of individuals. The aim of this study is to provide greater insight into the clinical, behavioural and cognitive characteristics that are associated with CdLS. Methods: In total, 56 individuals with CdLS…

  20. Health and Sleep Problems in Cornelia de Lange Syndrome: A Case Control Study

    ERIC Educational Resources Information Center

    Hall, S. S.; Arron, K.; Sloneem, J.; Oliver, C.

    2008-01-01

    Background: Self-injury, sleep problems and health problems are commonly reported in Cornelia de Lange Syndrome (CdLS) but there are no comparisons with appropriately matched participants. The relationship between these areas and comparison to a control group is warranted. Method: 54 individuals with CdLS were compared with 46 participants with…

  1. Self-Injurious Behavior, Self-Restraint, and Compulsive Behaviors in Cornelia de Lange Syndrome.

    ERIC Educational Resources Information Center

    Hyman, Philippa; Oliver, Chris; Hall, Scott

    2002-01-01

    Analysis of questionnaires completed by caregivers of 77 individuals with Cornelia de Lange syndrome in the United Kingdom found a significant association between self-injurious behaviors and self-restraint, and those displaying both behaviors displayed significantly more compulsions than did those not exhibiting them. Findings extend the…

  2. Self-Injurious Behaviour in Cornelia De Lange Syndrome: 1. Prevalence and Phenomenology

    ERIC Educational Resources Information Center

    Oliver, C.; Sloneem, J.; Hall, S.; Arron, K.

    2009-01-01

    Background: Self-injurious behaviour is frequently identified as part of the behavioural phenotype of Cornelia de Lange syndrome (CdLS). We conducted a case-control study of the prevalence and phenomenology of self-injurious behaviour (SIB) in CdLS. Methods: A total of 54 participants with CdLS were compared with 46 individuals who were comparable…

  3. Genetics Home Reference: Jervell and Lange-Nielsen syndrome

    MedlinePlus

    ... heartbeats increase the risk of fainting (syncope) and sudden death. Related Information What does it mean if a ... list from the University of Kansas Medical Center Sudden Arrhythmia Death Syndromes (SADS) Foundation: Long QT Syndrome GeneReviews (1 ...

  4. Dental Management of Cornelia de Lange Syndrome: A Rare Case Report

    PubMed Central

    Nagpal, Mehak; Gulia, Shweta; Sachdev, Vinod

    2015-01-01

    Cornelia de Lange syndrome (CdLS) is a rare, multiple congenital defect often called as Amsterdam dwarfism. The physical phenotype of CdLS includes low birth body weight, short stature and facio-cranial dysmorphia. The diagnosis of the syndrome is based on clinical grounds as there is no biochemical or chromosomal markers for CDLS that makes its diagnosis more complicated. The purpose of this paper is to present a clinical report of a boy emphasizing the importance of multidisciplinary approach for the diagnosis and treatment of this syndrome. PMID:25859533

  5. Self-Injurious Behaviour in Cornelia De Lange Syndrome: 2. Association with Environmental Events

    ERIC Educational Resources Information Center

    Sloneem, J.; Arron, K.; Hall, S. S.; Oliver, C.

    2009-01-01

    Background: Self-injurious behaviour is commonly seen in Cornelia de Lange syndrome (CdLS). However, there has been limited research into the aetiology of self-injury in CdLS and whether environmental factors influence the behaviour. Methods: We observed the self-injury of 27 individuals with CdLS and 17 participants who did not have CdLS matched…

  6. A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome.

    PubMed

    Nizon, M; Henry, M; Michot, C; Baumann, C; Bazin, A; Bessières, B; Blesson, S; Cordier-Alex, M-P; David, A; Delahaye-Duriez, A; Delezoïde, A-L; Dieux-Coeslier, A; Doco-Fenzy, M; Faivre, L; Goldenberg, A; Layet, V; Loget, P; Marlin, S; Martinovic, J; Odent, S; Pasquier, L; Plessis, G; Prieur, F; Putoux, A; Rio, M; Testard, H; Bonnefont, J-P; Cormier-Daire, V

    2016-05-01

    Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to a heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: (i) intrauterine growth retardation and postnatal short stature, (ii) feeding difficulties and/or gastro-oesophageal reflux, (iii) microcephaly, (iv) intellectual disability, and (v) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and 3 in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for 20 cases which do not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counselling. PMID:26701315

  7. Behavioral Phenotype and Autism Spectrum Disorders in Cornelia de Lange Syndrome.

    PubMed

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

    2015-09-30

    Cornelia de Lange syndrome (CdLS) is a congenital disorder characterized by distinctive facial features, growth retardation, limb abnormalities, intellectual disability, and behavioral problems. Cornelia de Lange syndrome is associated with abnormalities on chromosomes 5, 10 and X. Heterozygous point mutations in three genes (NIPBL, SMC3 and SMC1A), are responsible for approximately 50-60% of CdLS cases. CdLS is characterized by autistic features, notably excessive repetitive behaviors and expressive language deficits. The prevalence of autism spectrum disorder (ASD) symptomatology is comparatively high in CdLS. However, the profile and developmental trajectories of these ASD characteristics are potentially different to those observed in individuals with idiopathic ASD. A significantly higher prevalence of self-injury are evident in CdLS. Self-injury was associated with repetitive and impulsive behavior. This study describes the behavioral phenotype of four children with Cornelia de Lange syndrome and ASDs and rehabilitative intervention that must be implemented. PMID:26605036

  8. Behavioral Phenotype and Autism Spectrum Disorders in Cornelia de Lange Syndrome

    PubMed Central

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

    2015-01-01

    Cornelia de Lange syndrome (CdLS) is a congenital disorder characterized by distinctive facial features, growth retardation, limb abnormalities, intellectual disability, and behavioral problems. Cornelia de Lange syndrome is associated with abnormalities on chromosomes 5, 10 and X. Heterozygous point mutations in three genes (NIPBL, SMC3 and SMC1A), are responsible for approximately 50-60% of CdLS cases. CdLS is characterized by autistic features, notably excessive repetitive behaviors and expressive language deficits. The prevalence of autism spectrum disorder (ASD) symptomatology is comparatively high in CdLS. However, the profile and developmental trajectories of these ASD characteristics are potentially different to those observed in individuals with idiopathic ASD. A significantly higher prevalence of self-injury are evident in CdLS. Self-injury was associated with repetitive and impulsive behavior. This study describes the behavioral phenotype of four children with Cornelia de Lange syndrome and ASDs and rehabilitative intervention that must be implemented. PMID:26605036

  9. A Longitudinal Follow-Up Study of Affect in Children and Adults with Cornelia de Lange Syndrome

    ERIC Educational Resources Information Center

    Nelson, Lisa; Moss, Jo; Oliver, Chris

    2014-01-01

    Studies of individuals with Cornelia de Lange syndrome (CdLS) have described changes in mood and behavior with age, although no empirical or longitudinal studies have been conducted. Caregivers of individuals with CdLS (N = 67), cri du chat syndrome (CdCS; N = 42), and Fragile X syndrome (FXS; N = 142) completed the Mood, Interest and Pleasure…

  10. Cornelia de Lange and Ehlers-Danlos: comorbidity of two rare syndromes.

    PubMed

    Cravero, Cora; Guinchat, Vincent; Barete, Stéphane; Consoli, Angèle

    2016-01-01

    We present a case of a young adult with both Cornelia de Lange syndrome and Ehlers-Danlos syndrome. The patient showed non-verbal autism, intellectual disability and severe/intractable self-harming behaviours that led to a life-threatening complication (ie, septicaemia). A significant reduction in the self-harming behaviours was attained in a multidisciplinary neurobehavioural inpatient unit after addressing all causes of somatic pains, managing pain using level II and III analgesics, stabilising the patient's mood, limiting the iatrogenic effects of multiple prescriptions and offering a specific psychoeducational approach. PMID:26833951

  11. Jervell and Lange-Nielson Syndrome masquerading as intractable epilepsy

    PubMed Central

    Goyal, Jagdish P.; Sethi, Alka; Shah, V. B.

    2012-01-01

    The long QT syndrome (LQTS) is a cause of syncope and sudden death. Jervell and Lange–Nielson syndrome (JLNS) is an uncommon form of LQTS, having autosomal recessive transmission, and is associated with congenital deafness. We report a case of JLNS in a child who presented to us with refractory epilepsy. The cardiac cause of seizures was suspected as the child was hypotensive and pulseless during the episode of seizures. The child was diagnosed as JLNS based on Schwartz diagnostic criteria for LQTS and congenital sensorineural deafness. The child responded well to β-blocker therapy. Antiepileptic drugs were stopped. The screening of family members with ECG revealed a QT interval more than required for diagnosis of LQTS but they were asymptomatic. All asymptomatic family members were also put on metoprolol. All of them showed great improvement with the reduction of the QT interval on ECG. The patient was doing well on immediate follow-up. PMID:22566733

  12. A Case Report of Cornelia De Lange Syndrome in Northern Iran; A Clinical and Diagnostic Study

    PubMed Central

    Hosseininejad, Seyyed-Mohsen; Bazrafshan, Behnaz

    2016-01-01

    As a rare multisystem congenital anomaly disorder, Cornelia de Lange syndrome (CdLS) is featured by delayed growth and development, distinct facial dimorphism, limb malformations and multiple organ defects. CdLS is a genetic syndrome affecting 1/10000-1/60000 neonates with unknown genetic basis. Delayed growth and development, hirsute, structural anomalies of the limbs and distinct facial dimorphism are considered as its main clinical characteristics. Introducing CdLS cases of different ethnic backgrounds could add distinctions to the phenotypic picture of the syndrome and be useful in diagnosis. Early diagnosis and decreased death rates are achievable through enhanced awareness on this syndrome. We present here a 45-day-old girl, as the first case of Cornelia in Golestan (Northern Iran), referred to our hospital with the symptoms as mentioned above. PMID:27042551

  13. A Case Report of Cornelia De Lange Syndrome in Northern Iran; A Clinical and Diagnostic Study.

    PubMed

    Hosseininejad, Seyyed-Mohsen; Bazrafshan, Behnaz; Alaee, Ehsan

    2016-02-01

    As a rare multisystem congenital anomaly disorder, Cornelia de Lange syndrome (CdLS) is featured by delayed growth and development, distinct facial dimorphism, limb malformations and multiple organ defects. CdLS is a genetic syndrome affecting 1/10000-1/60000 neonates with unknown genetic basis. Delayed growth and development, hirsute, structural anomalies of the limbs and distinct facial dimorphism are considered as its main clinical characteristics. Introducing CdLS cases of different ethnic backgrounds could add distinctions to the phenotypic picture of the syndrome and be useful in diagnosis. Early diagnosis and decreased death rates are achievable through enhanced awareness on this syndrome. We present here a 45-day-old girl, as the first case of Cornelia in Golestan (Northern Iran), referred to our hospital with the symptoms as mentioned above. PMID:27042551

  14. Cornelia de Lange syndrome with NIPBL mutation and mosaic Turner syndrome in the same individual

    PubMed Central

    2012-01-01

    Background Cornelia de Lange syndrome (CdLS) is a dominantly inherited disorder characterized by facial dysmorphism, growth and cognitive impairment, limb malformations and multiple organ involvement. Mutations in NIPBL gene account for about 60% of patients with CdLS. This gene encodes a key regulator of the Cohesin complex, which controls sister chromatid segregation during both mitosis and meiosis. Turner syndrome (TS) results from the partial or complete absence of one of the X chromosomes, usually associated with congenital lymphedema, short stature, and gonadal dysgenesis. Case presentation Here we report a four-year-old female with CdLS due to a frameshift mutation in the NIPBL gene (c.1445_1448delGAGA), who also had a tissue-specific mosaic 45,X/46,XX karyotype. The patient showed a severe form of CdLS with craniofacial dysmorphism, pre- and post-natal growth delay, cardiovascular abnormalities, hirsutism and severe psychomotor retardation with behavioural problems. She also presented with minor clinical features consistent with TS, including peripheral lymphedema and webbed neck. The NIPBL mutation was present in the two tissues analysed from different embryonic origins (peripheral blood lymphocytes and oral mucosa epithelial cells). However, the percentage of cells with monosomy X was low and variable in tissues. These findings indicate that, ontogenically, the NIPBL mutation may have appeared before the mosaic monosomy X. Conclusions The coexistence in several patients of these two rare disorders raises the issue of whether there is indeed a cause-effect association. The detailed clinical descriptions indicate predominant CdLS phenotype, although additional TS manifestations may appear in adolescence. PMID:22676896

  15. Effects of Social Context on Social Interaction and Self-Injurious Behavior in Cornelia de Lange Syndrome

    ERIC Educational Resources Information Center

    Arron, Kate; Oliver, Chris; Hall, Scott; Sloneem, Jenny; Forman, Debbie; McClintock, Karen

    2006-01-01

    Cornelia de Lange syndrome is reported to be associated with self-injurious behavior (SIB) and social avoidance. We used analog methodology to examine the effect of manipulating adult social contact on social communicative behaviors and SIB in 16 children with this syndrome. For 9 participants engagement behavior was related to levels of adult…

  16. Simultaneous Analysis of the Behavioural Phenotype, Physical Factors, and Parenting Stress in People with Cornelia De Lange Syndrome

    ERIC Educational Resources Information Center

    Wulffaert, J.; van Berckelaer-Onnes, I.; Kroonenberg, P.; Scholte, E.; Bhuiyan, Z.; Hennekam, R.

    2009-01-01

    Background: Studies into the phenotype of rare genetic syndromes largely rely on bivariate analysis. The aim of this study was to describe the phenotype of Cornelia de Lange syndrome (CdLS) in depth by examining a large number of variables with varying measurement levels. Virtually the only suitable multivariate technique for this is categorical…

  17. Social Behavior and Characteristics of Autism Spectrum Disorder in Angelman, Cornelia de Lange, and Cri du Chat Syndromes

    ERIC Educational Resources Information Center

    Moss, Joanna; Howlin, Patricia; Hastings, Richard Patrick; Beaumont, Sarah; Griffith, Gemma M.; Petty, Jane; Tunnicliffe, Penny; Yates, Rachel; Villa, Darrelle; Oliver, Chris

    2013-01-01

    We evaluated autism spectrum disorder (ASD) characteristics and social behavior in Angelman (AS; "n" ?=? 19; mean age ?=?10.35 years), Cornelia de Lange (CdLS; "n" ?=? 15; mean age ?=?12.40 years), and Cri du Chat (CdCS, also known as 5 p-syndrome; "n" ?=? 19; mean age ?=? 8.80 years) syndromes. The proportion of…

  18. Cornelia de Lange Syndrome with NIPBL Gene Mutation: A Case Report

    PubMed Central

    Park, Kyung-Hee; Lee, Seung-Tae; Ki, Chang-Seok

    2010-01-01

    Cornelia de Lange Syndrome (CdLS) is a multiple congenital anomaly characterized by distinctive facial features, upper limb malformations, growth and cognitive retardation. The diagnosis of the syndrome is based on the distinctive clinical features. The etiology is still not clear. Mutations in the sister chromatid cohesion factor genes NIPBL, SMC1A (also called SMC1L1) and SMC3 have been suggested as probable cause of this syndrome. We experienced a case of newborn with CdLS showing bushy eyebrows and synophrys, long curly eyelashes, long philtrum, downturned angles of the mouth and thin upper lips, cleft palate, micrognathia, excessive body hair, micromelia of both hands, flexion contracture of elbows and hypertonicity. We detected a NIPBL gene mutation in a present neonate with CdLS, the first report in Korea. PMID:21165303

  19. The Drosophila melanogaster model for Cornelia de Lange syndrome: Implications for etiology and therapeutics.

    PubMed

    Dorsett, Dale

    2016-06-01

    Discovery of genetic alterations that cause human birth defects provide key opportunities to improve the diagnosis, treatment, and family counseling. Frequently, however, these opportunities are limited by the lack of knowledge about the normal functions of the affected genes. In many cases, there is more information about the gene's orthologs in model organisms, including Drosophila melanogaster. Despite almost a billion years of evolutionary divergence, over three-quarters of genes linked to human diseases have Drosophila homologs. With a short generation time, a twenty-fold smaller genome, and unique genetic tools, the conserved functions of genes are often more easily elucidated in Drosophila than in other organisms. Here we present how this applies to Cornelia de Lange syndrome, as a model for how Drosophila can be used to increase understanding of genetic syndromes caused by mutations with broad effects on gene transcription and exploited to develop novel therapies. © 2016 Wiley Periodicals, Inc. PMID:27097273

  20. Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.

    PubMed

    Yuan, Bo; Pehlivan, Davut; Karaca, Ender; Patel, Nisha; Charng, Wu-Lin; Gambin, Tomasz; Gonzaga-Jauregui, Claudia; Sutton, V Reid; Yesil, Gozde; Bozdogan, Sevcan Tug; Tos, Tulay; Koparir, Asuman; Koparir, Erkan; Beck, Christine R; Gu, Shen; Aslan, Huseyin; Yuregir, Ozge Ozalp; Al Rubeaan, Khalid; Alnaqeb, Dhekra; Alshammari, Muneera J; Bayram, Yavuz; Atik, Mehmed M; Aydin, Hatip; Geckinli, B Bilge; Seven, Mehmet; Ulucan, Hakan; Fenercioglu, Elif; Ozen, Mustafa; Jhangiani, Shalini; Muzny, Donna M; Boerwinkle, Eric; Tuysuz, Beyhan; Alkuraya, Fowzan S; Gibbs, Richard A; Lupski, James R

    2015-02-01

    Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" rather than cohesinopathies. PMID:25574841

  1. Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes

    PubMed Central

    Yuan, Bo; Pehlivan, Davut; Karaca, Ender; Patel, Nisha; Charng, Wu-Lin; Gambin, Tomasz; Gonzaga-Jauregui, Claudia; Sutton, V. Reid; Yesil, Gozde; Bozdogan, Sevcan Tug; Tos, Tulay; Koparir, Asuman; Koparir, Erkan; Beck, Christine R.; Gu, Shen; Aslan, Huseyin; Yuregir, Ozge Ozalp; Al Rubeaan, Khalid; Alnaqeb, Dhekra; Alshammari, Muneera J.; Bayram, Yavuz; Atik, Mehmed M.; Aydin, Hatip; Geckinli, B. Bilge; Seven, Mehmet; Ulucan, Hakan; Fenercioglu, Elif; Ozen, Mustafa; Jhangiani, Shalini; Muzny, Donna M.; Boerwinkle, Eric; Tuysuz, Beyhan; Alkuraya, Fowzan S.; Gibbs, Richard A.; Lupski, James R.

    2015-01-01

    Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be “transcriptomopathies” rather than cohesinopathies. PMID:25574841

  2. A new prognostic index of severity of intellectual disabilities in Cornelia de Lange syndrome.

    PubMed

    Cereda, Anna; Mariani, Milena; Rebora, Paola; Sajeva, Anna; Ajmone, Paola Francesca; Gervasini, Cristina; Russo, Silvia; Kullmann, Gaia; Valsecchi, Grazia; Selicorni, Angelo

    2016-06-01

    Cornelia de Lange syndrome is a well-known multiple congenital anomalies/intellectual disability syndrome with genetic heterogeneity and wide clinical variability, regarding the severity of both the intellectual disabilities and the physical features, not completely explained by the genotype-phenotype correlations known to date. The aim of the study was the identification of prognostic features, ascertainable precociously in the patient's life, of a better intellectual outcome and the development of a new prognostic index of severity of intellectual disability in CdLS patients. In 66 italian CdLS patients aged 8 years or more, we evaluated the association of the degree of intellectual disability with various clinical parameters ascertainable before 6 months of life and with the molecular data by the application of cumulative regression logistic model. Based on these results and on the previously known genotype-phenotype correlations, we selected seven parameters to be used in a multivariate cumulative regression logistic model to develop a prognostic index of severity of intellectual disability. The probability of a mild ID increases with the reducing final score less than two, the probability of a severe ID increases with the increasing final score more than three. This prognostic index allows to define, precociously in the life of a baby, the probability of a better or worse intellectual outcome in CdLS patients. © 2016 Wiley Periodicals, Inc. PMID:27148700

  3. Recognition of the Cornelia de Lange syndrome phenotype with facial dysmorphology novel analysis.

    PubMed

    Basel-Vanagaite, L; Wolf, L; Orin, M; Larizza, L; Gervasini, C; Krantz, I D; Deardoff, M A

    2016-05-01

    Facial analysis systems are becoming available to healthcare providers to aid in the recognition of dysmorphic phenotypes associated with a multitude of genetic syndromes. These technologies automatically detect facial points and extract various measurements from images to recognize dysmorphic features and evaluate similarities to known facial patterns (gestalts). To evaluate such systems' usefulness for supporting the clinical practice of healthcare professionals, the recognition accuracy of the Cornelia de Lange syndrome (CdLS) phenotype was examined with FDNA's automated facial dysmorphology novel analysis (FDNA) technology. In the first experiment, 2D facial images of CdLS patients with either an NIPBL or SMC1A gene mutation as well as non-CdLS patients which were assessed by dysmorphologists in a previous study were evaluated by the FDNA technology; the average detection rate of experts was 77% while the system's detection rate was 87%. In the second study, when a new set of NIPBL, SMC1A and non-CdLS patient photos was evaluated, the detection rate increased to 94%. The results from both studies indicated that the system's detection rate was comparable to that of dysmorphology experts. Therefore, utilizing such technologies may be a useful tool in a clinical setting. PMID:26663098

  4. Somatic mosaicism in Cornelia de Lange syndrome: a further contributor to the wide clinical expressivity?

    PubMed

    Castronovo, P; Delahaye-Duriez, A; Gervasini, C; Azzollini, J; Minier, F; Russo, S; Masciadri, M; Selicorni, A; Verloes, A; Larizza, L

    2010-12-01

    Cornelia de Lange syndrome (CdLS) is a rare, congenital syndrome characterized by growth retardation, dysmorphic face, mental retardation and limb reduction defects. Clinical manifestations of CdLS can be extremely variable. Mutations in NIPBL, SMC1A and SMC3 genes, encoding for a regulator and two subunits of the cohesin complex, respectively, are found in 60-65% of CdLS patients. We report on a male with CdLS who is mosaic for the c.2827delA mutation in the NIPBL gene. Allele quantitation by pyrosequencing showed the presence of the mutation in about 10% and 33% of DNA samples from peripheral blood and buccal smears, respectively. The patient shows a complex phenotype: growth and psychomotor retardation are characteristic of the severe forms of CdLS, while the absence of severe limb reduction defects and major malformations are typical of the mild phenotype. He also has depigmentation areas following Blashko lines, an unusual finding in CdLS, which has been associated with mosaicism in other genetic conditions. This case represents the first evidence of somatic mosaicism in CdLS and explains the mild phenotype in the patient as compared to that predicted by a truncating mutation. Besides confirming the clinical and genetic heterogeneity of CdLS, this case also raises the likely underestimated mutation rate of known genes and points to the complexity of addressing genotype-phenotype correlations. PMID:20331678

  5. Human iPS cell models of Jervell and Lange-Nielsen syndrome

    PubMed Central

    Bellin, Milena; Greber, Boris

    2015-01-01

    Recessive mutations in the ion channel-encoding KCNQ1 gene may cause Jervell and Lange-Nielsen syndrome (JLNS), a fatal cardiac disease leading to arrhythmia and sudden cardiac death in young patients. Mutations in KCNQ1 may also cause a milder and dominantly inherited form of the disease, long QT syndrome 1 (LQT1). However, why some mutations cause LQT1 and others cause JLNS can often not be understood a priori. In a recent study,1 we have generated human induced pluripotent stem cell (hiPSC) models of JLNS. Our work mechanistically revealed how distinct classes of JLNS-causing genetic lesions, namely, missense and splice-site mutations, may promote the typical severe features of the disease at the cellular level. Interestingly, the JLNS models also displayed highly sensitive responses to pro-arrhythmic stresses. We hence propose JLNS hiPSCs as a powerful system for evaluating both phenotype-correcting as well as cardiotoxicity-causing drug effects. PMID:26481773

  6. Identification of a novel de novo mutation in the NIPBL gene in an Iranian patient with Cornelia de Lange syndrome: A case report

    PubMed Central

    2011-01-01

    Background Cornelia de Lange syndrome is characterized by dysmorphic facial features, hirsutism, severe growth and developmental delay. Germline mutations in the NIPBL gene with an autosomal dominant pattern and in the SMC1A gene with an X-linked pattern have been identified in Cornelia de Lange syndrome. Case presentation A two-month-old Iranian boy who showed multiple congenital anomalies was referred to the genetic center of a welfare organization in southwest Iran. He was the second child of a non-consanguineous marriage, born after full term with normal delivery. His birth weight was 3110 g, his length was 46 cm and his head circumference was 30 cm. Both parents were clinically asymptomatic, with no positive history of any deformity in their respective families. Conclusions Sequencing of the NIPBL gene from our patient revealed a single-base deletion of thymidine in exon 10 (c.516delT). This mutation presumably results in premature termination at codon 526. We did not observe this mutation in the parents of our patient with Cornelia de Lange syndrome. The results presented here enlarge the spectrum of NIPBL gene mutations associated with Cornelia de Lange syndrome by identifying a novel de novo mutation in an Iranian patient with Cornelia de Lange syndrome and further support the hypothesis that NIPBL mutations are disease-causing mutations leading to Cornelia de Lange syndrome. PMID:21707975

  7. Mutant cohesin affects RNA polymerase II regulation in Cornelia de Lange syndrome

    PubMed Central

    Mannini, Linda; C. Lamaze, Fabien; Cucco, Francesco; Amato, Clelia; Quarantotti, Valentina; Rizzo, Ilaria M; Krantz, Ian D; Bilodeau, Steve; Musio, Antonio

    2015-01-01

    In addition to its role in sister chromatid cohesion, genome stability and integrity, the cohesin complex is involved in gene transcription. Mutations in core cohesin subunits SMC1A, SMC3 and RAD21, or their regulators NIPBL and HDAC8, cause Cornelia de Lange syndrome (CdLS). Recent evidence reveals that gene expression dysregulation could be the underlying mechanism for CdLS. These findings raise intriguing questions regarding the potential role of cohesin-mediated transcriptional control and pathogenesis. Here, we identified numerous dysregulated genes occupied by cohesin by combining the transcriptome of CdLS cell lines carrying mutations in SMC1A gene and ChIP-Seq data. Genome-wide analyses show that genes changing in expression are enriched for cohesin-binding. In addition, our results indicate that mutant cohesin impairs both RNA polymerase II (Pol II) transcription initiation at promoters and elongation in the gene body. These findings highlight the pivotal role of cohesin in transcriptional regulation and provide an explanation for the typical gene dysregulation observed in CdLS patients. PMID:26581180

  8. Two novel NIPBL gene mutations in Chinese patients with Cornelia de Lange syndrome.

    PubMed

    Mei, Libin; Liang, Desheng; Huang, Yanru; Pan, Qian; Wu, Lingqian

    2015-01-25

    Cornelia de Lange syndrome (CdLS) is a dominantly inherited developmental disorder characterized by distinctive facial features, mental retardation, and upper limb defects, with the involvement of multiple organs and systems. To date, mutations have been identified in five genes responsible for CdLS: NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Here, we present a clinical and molecular characterization of five unrelated Chinese patients whose clinical presentation is consistent with that of CdLS. There were no chromosomal abnormalities in the five children. In three patients, DNA sequencing revealed a previously reported frameshift mutation c.2479delA (p.Arg827GlyfsX20), and two novel mutations including a heterozygous mutation c.6272 G>T (p.Cys2091Phe) and a frameshift mutation c.1672delA (p.Thr558LeufsX7) in NIPBL. For the remaining patients, large deletions and/or duplications within the NIPBL gene were excluded as playing a role in the pathogenesis, by Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. These findings broaden the mutation spectrum of NIPBL and further our understanding of the diverse and variable effects of NIPBL mutations on CdLS. PMID:25447906

  9. Mutation Spectrum and Genotype–Phenotype Correlation in Cornelia de Lange Syndrome

    PubMed Central

    Mannini, Linda; Cucco, Francesco; Quarantotti, Valentina; Krantz, Ian D.; Musio, Antonio

    2013-01-01

    Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. Clinical features include growth retardation, intellectual disability, limb defects, typical facial dysmorphism, and other systemic involvement. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of the phenotype. Mutations in five genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8), all regulators or structural components of cohesin, have been identified. Approximately 60% of CdLS cases are due to NIPBL mutations, 5% caused by mutations in SMC1A, RAD21, and HDAC8 and one proband was found to carry a mutation in SMC3. To date, 311 CdLS-causing mutations are known including missense, nonsense, small deletions and insertions, splice site mutations, and genomic rearrangements. Phenotypic variability is seen both intra- and intergenically. This article reviews the spectrum of CdLS mutations with a particular emphasis on their correlation to the clinical phenotype. PMID:24038889

  10. NIPBL rearrangements in Cornelia de Lange syndrome: evidence for replicative mechanism and genotype–phenotype correlation

    PubMed Central

    Pehlivan, Davut; Hullings, Melanie; Carvalho, Claudia M.B.; Gonzaga-Jauregui, Claudia G.; Loy, Elizabeth; Jackson, Laird G.; Krantz, Ian D.; Deardorff, Matthew A.; Lupski, James R.

    2013-01-01

    Purpose Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder characterized by mental retardation, limb abnormalities, distinctive facial features, and hirsutism. Mutations in three genes involved in sister chromatid cohesion, NIPBL, SMC1A, and SMC3, account for ~55% of CdLS cases. The molecular etiology of a significant fraction of CdLS cases remains unknown. We hypothesized that large genomic rearrangements of cohesin complex subunit genes may play a role in the molecular etiology of this disorder. Methods Custom high-resolution oligonucleotide array comparative genomic hybridization analyses interrogating candidate cohesin genes and breakpoint junction sequencing of identified genomic variants were performed. Results Of the 162 patients with CdLS, for whom mutations in known CdLS genes were previously negative by sequencing, deletions containing NIPBL exons were observed in 7 subjects (~5%). Breakpoint sequences in five patients implicated microhomology-mediated replicative mechanisms—such as serial replication slippage and fork stalling and template switching/microhomology-mediated break-induced replication—as a potential predominant contributor to these copy number variations. Most deletions are predicted to result in haploinsuflciency due to heterozygous loss-of-function mutations; such mutations may result in a more severe CdLS phenotype. Conclusion Our findings suggest a potential clinical utility to testing for copy number variations involving NIPBL when clinically diagnosed CdLS cases are mutation-negative by DNA-sequencing studies. PMID:22241092

  11. Nucleotide sequence analysis of NIPBL gene in Indian Cornelia de Lange syndrome cases

    PubMed Central

    Bajaj, Shailesh; Ranade, Suvidya; Gambhir, Prakash

    2013-01-01

    BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder in children. The disorder is caused mainly due to mutations in Nipped-B-like protein. The molecular data for CdLS is available from developed countries, but not available in developing countries like India. In the present study, the hotspot region of NIPBL gene was screened by Polymerase Chain Reaction which includes exon 2, 22, 42, and a biggest exon 10, in six CdLS patients and ten controls. MATERIALS AND METHODS: The method adopted in present study was amplification of the target exon by using polymerase chain reaction, qualitative confirmation of amplicons by Agarose Gel Electrophoresis and use of amplicons for Conformation Sensitive Gel Electrophoresis to find heteroduplex formation followed by sequencing. RESULTS: We report two polymorphisms in the studied region of gene NIPBL. The polymorphisms are in the region of intron 1 and in exon 10. The polymorphism C/A is present in intron 1 region and polymorphism T/G in exon 10. CONCLUSION: The intronic region polymorphism may have a role in intron splicing whereas the polymorphism in exon 10 results in amino acid change (Val to Gly). These polymorphisms are disease associated as these are found in CdLS patients only and not in controls. PMID:23901187

  12. A search for uniparental disomy associated with Cornelia de Lange syndrome and with spontaneous abortion

    SciTech Connect

    Smith, M.J.; Upadhyaya, M.; Clarke, A.

    1994-09-01

    Uniparental disomy (UPD) is the inheritance of a pair of homologous chromosomes from one parent with no corresponding homologue from the other, in an individual with an apparently normal karyotype. Polymorphic DNA markers for the appropriate chromosome will therefore lack alleles from the non-contributing parent. There may be pathological consequences of UPD if an imprinted gene(s) resides on the affected chromosome. A number of human developmental disorders of unknown etiology, including Cornelia de Lange syndrome (CdLS) and spontaneous abortion, may be caused by imprinted genes yet to be discovered. There are a number of reports of chromosome 3q rearrangements associated with CdLS, therefore excluding whole-chromosome 3 UPD as a cause in these patients. We are also examining DNA markers for all autosomes in a series of 42 karyotypically normal spontaneous abortions and their parents. To date, no UPD has been observed for chromosomes 3, 17, 20, 21 and 22. Further work is in progress, both here and using the DNA typing facilities at Geneathon, France.

  13. Adolescents and adults affected by Cornelia de Lange syndrome: A report of 73 Italian patients.

    PubMed

    Mariani, Milena; Decimi, Valentina; Bettini, Laura Rachele; Maitz, Silvia; Gervasini, Cristina; Masciadri, Maura; Ajmone, Paola; Kullman, Gaia; Dinelli, Marco; Panceri, Roberto; Cereda, Anna; Selicorni, Angelo

    2016-06-01

    Cornelia de Lange syndrome (CdLS) is a rare genetic condition related to mutation of various cohesion complex related genes. Its natural history is quite well characterized as regard pediatric age. Relatively little information is available regarding the evolution of the disease in young-adult age. In medical literature, only one specific study has been published on this topic. We report on our experience on 73 Italian CdLS patients (40 males and 33 females) with and age range from 15 to 49 years. Our results confirm the previous study indicating that gastroesophageal reflux disease (GERD) is the main medical problem of these patients in childhood and young-adult age. Other medical features that should be considered in the medical follow-up are tendency to overweight/frank obesity, constipation, discrepancy of limbs' length, epilepsy, hearing, and visual problems. Behavioral problems are particularly frequent as well. For this reason, every source of hidden pain should be actively searched for in evaluating a patient showing such a disorder. Finally, recommendations for medical follow-up in adult age are discussed. © 2016 Wiley Periodicals, Inc. PMID:27164219

  14. Prenatal Profile of Cornelia de Lange Syndrome (CdLS): A Review of 53 Pregnancies

    PubMed Central

    Clark, Dinah M.; Sherer, Ilana; Deardorff, Matthew A.; Byrne, Janice L.B.; Loomes, Kathleen M.; Nowaczyk, Malgorzata J.M.; Jackson, Laird G.; Krantz, Ian D.

    2012-01-01

    Cornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder characterized by growth retardation, cognitive impairment, external and internal structural malformations, and characteristic facial features. Currently, there are no definitive prenatal screening measures that lead to the diagnosis of CdLS. In this study, documented prenatal findings in CdLS syndrome were analyzed towards the development of a prenatal profile predictive of CdLS. We reviewed 53 cases of CdLS (29 previously reported and 24 unreported) in which prenatal observations/findings were available. The review of these cases revealed a pattern of sonographic findings, including obvious associated structural defects, growth restriction, as well as a more subtle, but strikingly characteristic, facial profile, suggestive of a recognizable prenatal ultrasonographic profile for CdLS. In addition the maternal serum marker, PAPP-A, may be reduced and fetal nuchal translucency may be increased in some pregnancies when measured at an appropriate gestational age. In conclusion, CdLS can be prenatally diagnosed or readily ruled out in a family with a known mutation in a CdLS gene. The characteristic ultrasonographic profile may allow for prenatal diagnosis of CdLS in 1) subsequent pregnancies to a couple with a prior child with CdLS in whom a mutation has not been identified or 2) when there are unexplained pregnancy signs of fetal abnormality such as oligo- or polyhydramnios, a low maternal serum PAPP-A level and/or increased nuchal translucency, fetal growth retardation, or structural anomalies consistent with CdLS. PMID:22740382

  15. Cornelia de Lange Syndrome: a case report with clinical review and recommended anticipatory guidance for the general practitioner.

    PubMed

    Theile, Anthony R; Gowans, Gordon

    2009-09-01

    Cornelia de Lange Syndrome is a rare congenital malformation syndrome with typical craniofacial abnormalities and can affect the musculoskeletal, cardiovascular, gastrointestinal, genitourinary, and central nervous systems. Not all the patients look alike as the phenotypic appearance is seen on a spectrum. A classic case of CdLS has been reviewed in this article and we have discussed diagnosis, management, and anticipatory guidance. Maintaining consistent health supervision visits and outpatient therapy is vital for these children. Referring the parents to a genetic counselor is recommended if the family desires to have more children. The CdLS foundation Webpage is www.cdlsusa.org. PMID:19813431

  16. Drosophila Nipped-B Mutants Model Cornelia de Lange Syndrome in Growth and Behavior

    PubMed Central

    Xu, Dongbin; Misulovin, Ziva; Schaaf, Cheri A.; Mosarla, Ramya C.; Mannino, Elizabeth; Shannon, Megan; Jones, Emily; Shi, Mi; Chen, Wen-Feng; Katz, Olivia L.; Sehgal, Amita; Jongens, Thomas A.; Krantz, Ian D.; Dorsett, Dale

    2015-01-01

    Individuals with Cornelia de Lange Syndrome (CdLS) display diverse developmental deficits, including slow growth, multiple limb and organ abnormalities, and intellectual disabilities. Severely-affected individuals most often have dominant loss-of-function mutations in the Nipped-B-Like (NIPBL) gene, and milder cases often have missense or in-frame deletion mutations in genes encoding subunits of the cohesin complex. Cohesin mediates sister chromatid cohesion to facilitate accurate chromosome segregation, and NIPBL is required for cohesin to bind to chromosomes. Individuals with CdLS, however, do not display overt cohesion or segregation defects. Rather, studies in human cells and model organisms indicate that modest decreases in NIPBL and cohesin activity alter the transcription of many genes that regulate growth and development. Sister chromatid cohesion factors, including the Nipped-B ortholog of NIPBL, are also critical for gene expression and development in Drosophila melanogaster. Here we describe how a modest reduction in Nipped-B activity alters growth and neurological function in Drosophila. These studies reveal that Nipped-B heterozygous mutant Drosophila show reduced growth, learning, and memory, and altered circadian rhythms. Importantly, the growth deficits are not caused by changes in systemic growth controls, but reductions in cell number and size attributable in part to reduced expression of myc (diminutive) and other growth control genes. The learning, memory and circadian deficits are accompanied by morphological abnormalities in brain structure. These studies confirm that Drosophila Nipped-B mutants provide a useful model for understanding CdLS, and provide new insights into the origins of birth defects. PMID:26544867

  17. Drosophila Nipped-B Mutants Model Cornelia de Lange Syndrome in Growth and Behavior.

    PubMed

    Wu, Yaning; Gause, Maria; Xu, Dongbin; Misulovin, Ziva; Schaaf, Cheri A; Mosarla, Ramya C; Mannino, Elizabeth; Shannon, Megan; Jones, Emily; Shi, Mi; Chen, Wen-Feng; Katz, Olivia L; Sehgal, Amita; Jongens, Thomas A; Krantz, Ian D; Dorsett, Dale

    2015-11-01

    Individuals with Cornelia de Lange Syndrome (CdLS) display diverse developmental deficits, including slow growth, multiple limb and organ abnormalities, and intellectual disabilities. Severely-affected individuals most often have dominant loss-of-function mutations in the Nipped-B-Like (NIPBL) gene, and milder cases often have missense or in-frame deletion mutations in genes encoding subunits of the cohesin complex. Cohesin mediates sister chromatid cohesion to facilitate accurate chromosome segregation, and NIPBL is required for cohesin to bind to chromosomes. Individuals with CdLS, however, do not display overt cohesion or segregation defects. Rather, studies in human cells and model organisms indicate that modest decreases in NIPBL and cohesin activity alter the transcription of many genes that regulate growth and development. Sister chromatid cohesion factors, including the Nipped-B ortholog of NIPBL, are also critical for gene expression and development in Drosophila melanogaster. Here we describe how a modest reduction in Nipped-B activity alters growth and neurological function in Drosophila. These studies reveal that Nipped-B heterozygous mutant Drosophila show reduced growth, learning, and memory, and altered circadian rhythms. Importantly, the growth deficits are not caused by changes in systemic growth controls, but reductions in cell number and size attributable in part to reduced expression of myc (diminutive) and other growth control genes. The learning, memory and circadian deficits are accompanied by morphological abnormalities in brain structure. These studies confirm that Drosophila Nipped-B mutants provide a useful model for understanding CdLS, and provide new insights into the origins of birth defects. PMID:26544867

  18. Biochemical and Structural Characterization of HDAC8 Mutants Associated with Cornelia de Lange Syndrome Spectrum Disorders

    PubMed Central

    2015-01-01

    Cornelia de Lange Syndrome (CdLS) spectrum disorders are characterized by multiple organ system congenital anomalies that result from mutations in genes encoding core cohesin proteins SMC1A, SMC3, and RAD21, or proteins that regulate cohesin function such as NIPBL and HDAC8. HDAC8 is the Zn2+-dependent SMC3 deacetylase required for cohesin recycling during the cell cycle, and 17 different HDAC8 mutants have been identified to date in children diagnosed with CdLS. As part of our continuing studies focusing on aberrant HDAC8 function in CdLS, we now report the preparation and biophysical evaluation of five human HDAC8 mutants: P91L, G117E, H180R, D233G, and G304R. Additionally, the double mutants D233G–Y306F and P91L–Y306F were prepared to enable cocrystallization of intact enzyme–substrate complexes. X-ray crystal structures of G117E, P91L–Y306F, and D233G–Y306F HDAC8 mutants reveal that each CdLS mutation causes structural changes that compromise catalysis and/or thermostability. For example, the D233G mutation disrupts the D233–K202–S276 hydrogen bond network, which stabilizes key tertiary structure interactions, thereby significantly compromising thermostability. Molecular dynamics simulations of H180R and G304R HDAC8 mutants suggest that the bulky arginine side chain of each mutant protrudes into the substrate binding site and also causes active site residue Y306 to fluctuate away from the position required for substrate activation and catalysis. Significantly, the catalytic activities of most mutants can be partially or fully rescued by the activator N-(phenylcarbamothioyl)-benzamide, suggesting that HDAC8 activators may serve as possible leads in the therapeutic management of CdLS. PMID:26463496

  19. Sedation and general anesthesia for patients with Cornelia De Lange syndrome: A case series.

    PubMed

    Moretto, Alessandra; Scaravilli, Vittorio; Ciceri, Valentina; Bosatra, Mariagrazia; Giannatelli, Federica; Ateniese, Bianca; Mariani, Milena; Cereda, Anna; Sosio, Simone; Zanella, Alberto; Pesenti, Antonio; Selicorni, Angelo

    2016-06-01

    Cornelia De Lange syndrome (CdLS) is a rare congenital disease characterized by typical facial dysmorphism, developmental disability, and limb deficiency defects. Various congenital malformations and medical complications have been described with gastroesophageal reflux as the major one. CdLS patients often require multiple high-risk anesthetic procedures. At San Gerardo Hospital (Monza, Italy) the management of CdLS patients is routinely organized through a standard protocol and a dedicated pediatric anesthesia team has been implemented. We report on a retrospective descriptive analysis of the anesthetic records of the CdLS patients admitted to San Gerardo Hospital from January 2010 to December 2015. We retrieved: demographics, genetic profiles, type of procedures, anesthetic approaches, anesthetics usage and complications. Data are reported as median (interquartile range) values. Twenty-seven patients (11 female), with age 12 (7-15) years old, weight 24 (14-35) kg, and severity score of 25 (18-32) were included. NIBPL mutations were the most frequently represented. We analyzed 58 procedures (30 esophagogastroduodenoscopies, 8 evoked auditory potential tests, 5 radiodiagnostics, 5 catheters positioning, 4 bronchoscopies) managed by sedation (36) and general anesthesia (6). Each patient underwent one (1-2) anesthetic procedure. Propofol (59%), sevoflurane (31%), fentanyl (24%), and ketamine (10%) were used. Three out of six endotracheal intubations were difficult. The only documented intraoperative complications were three episodes of desaturation (oxygen saturation <90%) occurring during sedations and were managed without the need for an invasive control of the airways. Implementation of a specific management protocol and a dedicated allowed to provide anesthesia to CdLS patients without the occurrence of major complications. © 2016 Wiley Periodicals, Inc. PMID:27145336

  20. Characterization of limb differences in children with Cornelia de Lange Syndrome.

    PubMed

    Mehta, Devanshi; Vergano, Samantha A Schrier; Deardorff, Matthew; Aggarwal, Sarika; Barot, Akash; Johnson, Drew M; Miller, Nathan F; Noon, Sarah E; Kaur, Maninder; Jackson, Laird; Krantz, Ian D

    2016-06-01

    Cornelia de Lange syndrome (CdLS) is a well-described multisystem developmental disorder characterized by dysmorphic facial features, growth and behavioral deficits, and cardiac, gastrointestinal, and limb anomalies. The limb defects seen in CdLS can be mild, with small feet or hands only, or can be severe, with variable deficiency defects involving primarily the ulnar structures and ranging from mild hypoplasia of the fifth digit to complete absence of the forearm. Interestingly, the upper limbs are typically much more involved than the lower extremities that generally manifest with small feet and 2-3 syndactyly of the toes and shortened fourth metatarsal. The upper limbs often manifest asymmetric involvement. The limb findings in our cohort of 378 individuals with CdLS demonstrate a consistent pattern of laterality and symmetry involvement (with increased severity of right-sided limb in individuals with asymmetric limb defects) and a correlation of more significant limb defects with an increased risk of other structural anomalies, and more severe behavioral outcomes. Additionally, we found that individuals with mutations in NIPBL were most likely to have limb defects compared to mutations in other genes with nonsense, exonic deletion, and frameshift mutations being most prevalent in those with limb defects. Characterization of the limb differences in children with CdLS may provide a tool to assist in genetic counseling and determining prognosis. This paper will review the limb involvement in a large cohort of individuals with CdLS assessing the correlation with molecular etiologies, symmetry, additional structural birth defects, and cognitive outcomes. © 2016 Wiley Periodicals, Inc. PMID:27120260

  1. Cornelia de Lange syndrome: Correlation of brain MRI findings with behavioral assessment.

    PubMed

    Roshan Lal, Tamanna R; Kliewer, Mark A; Lopes, Thelma; Rebsamen, Susan L; O'Connor, Julia; Grados, Marco A; Kimball, Amy; Clemens, Julia; Kline, Antonie D

    2016-06-01

    Neurobehavioral and developmental issues with a broad range of deficits are prominent features of Cornelia de Lange syndrome (CdLS), a disorder due to disruption of the cohesin protein complex. The etiologic relationship of these clinical findings to anatomic abnormalities on neuro-imaging studies has not, however, been established. Anatomic abnormalities in the brain and central nervous system specific to CdLS have been observed, including changes in the white matter, brainstem, and cerebellum. We hypothesize that location and severity of brain abnormalities correlate with clinical phenotype in CdLS, as seen in other developmental disorders. In this study, we retrospectively evaluated brain MRI studies of 15 individuals with CdLS and compared these findings to behavior at the time of the scan. Behavior was assessed using the Aberrant Behavior Checklist (ABC), a validated behavioral assessment tool with several clinical features. Ten of fifteen (67%) of CdLS patients had abnormal findings on brain MRI, including cerebral atrophy, white matter changes, cerebellar hypoplasia, and enlarged ventricles. Other findings included pituitary tumors or cysts, Chiari I malformation and gliosis. Abnormal behavioral scores in more than one behavioral area were seen in all but one patient. All 5 of the 15 (33%) patients with normal structural MRI studies had abnormal ABC scores. All normal ABC scores were noted in only one patient and this was correlated with moderately abnormal MRI changes. Although our cohort is small, our results suggest that abnormal behaviors can exist in individuals with CdLS in the setting of relatively normal structural brain findings. © 2016 Wiley Periodicals, Inc. PMID:27164360

  2. Genetic Enhancement of Limb Defects in a Mouse Model of Cornelia de Lange Syndrome

    PubMed Central

    LOPEZ-BURKS, MARTHA E.; SANTOS, ROSAYSELA; KAWAUCHI, SHIMAKO; CALOF, ANNE L.; LANDER, ARTHUR D.

    2016-01-01

    Cornelia de Lange Syndrome (CdLS) is characterized by a wide variety of structural and functional abnormalities in almost every organ system of the body. CdLS is now known to be caused by mutations that disrupt the function of the cohesin complex or its regulators, and studies of animal models and cell lines tell us that the effect of these mutations is to produce subtle yet pervasive dysregulation of gene expression. With many hundreds of mostly small gene expression changes occurring in every cell type and tissue, identifying the etiology of any particular birth defect is very challenging. Here we focus on limb abnormalities, which are commonly seen in CdLS. In the limb buds of the Nipbl-haploinsufficient mouse (Nipbl+/− mouse), a model for the most common form of CdLS, modest gene expression changes are observed in several candidate pathways whose disruption is known to cause limb abnormalities, yet the limbs of Nipbl+/− mice develop relatively normally. We hypothesized that further impairment of candidate pathways might produce limb defects similar to those seen in CdLS, and performed genetic experiments to test this. Focusing on Sonic hedgehog (Shh), Bone morphogenetic protein (Bmp), and Hox gene pathways, we show that decreasing Bmp or Hox function (but not Shh function) enhances polydactyly in Nipbl+/− mice, and in some cases produces novel skeletal phenotypes. However, frank limb reductions, as are seen in a subset of individuals with CdLS, do not occur, suggesting that additional signaling and/or gene regulatory pathways are involved in producing such dramatic changes. PMID:27120109

  3. Genetic enhancement of limb defects in a mouse model of Cornelia de Lange syndrome.

    PubMed

    Lopez-Burks, Martha E; Santos, Rosaysela; Kawauchi, Shimako; Calof, Anne L; Lander, Arthur D

    2016-06-01

    Cornelia de Lange Syndrome (CdLS) is characterized by a wide variety of structural and functional abnormalities in almost every organ system of the body. CdLS is now known to be caused by mutations that disrupt the function of the cohesin complex or its regulators, and studies of animal models and cell lines tell us that the effect of these mutations is to produce subtle yet pervasive dysregulation of gene expression. With many hundreds of mostly small gene expression changes occurring in every cell type and tissue, identifying the etiology of any particular birth defect is very challenging. Here we focus on limb abnormalities, which are commonly seen in CdLS. In the limb buds of the Nipbl-haploinsufficient mouse (Nipbl(+/-) mouse), a model for the most common form of CdLS, modest gene expression changes are observed in several candidate pathways whose disruption is known to cause limb abnormalities, yet the limbs of Nipbl(+/-) mice develop relatively normally. We hypothesized that further impairment of candidate pathways might produce limb defects similar to those seen in CdLS, and performed genetic experiments to test this. Focusing on Sonic hedgehog (Shh), Bone morphogenetic protein (Bmp), and Hox gene pathways, we show that decreasing Bmp or Hox function (but not Shh function) enhances polydactyly in Nipbl(+/-) mice, and in some cases produces novel skeletal phenotypes. However, frank limb reductions, as are seen in a subset of individuals with CdLS, do not occur, suggesting that additional signaling and/or gene regulatory pathways are involved in producing such dramatic changes. © 2016 Wiley Periodicals, Inc. PMID:27120109

  4. A study of six cases of de Lange Amsterdam dwarf syndrome, with special attention to voice, speech and language characteristics.

    PubMed

    Fraser, W I; Campbell, B M

    1978-04-01

    From a survey of southern Scotland, six severly handicapped subjects (age-range 8 to 22 years) were established by firm criteria as suffering from the de Lange Amsterdam Dwarf syndrome. They showed a high incidence of behaviour disturbance. Language development was retarded and all but one of the subjects were dysphonic. A connection may exist between the glottal "fry" (an unperiodical phonation of the vocal folds in a frequency below the normal pitch register) observed in the cries of the younger non-speaking cases and the hoarseness in the speech of the older subjects. PMID:640263

  5. Dominant Paternal Transmission of Cornelia de Lange Syndrome: A New Case and Review of 25 Previously Reported Familial Recurrences

    PubMed Central

    Russell, Karen L.; Ming, Jeffrey E.; Patel, Ketan; Jukofsky, Lori; Magnusson, Mark; Krantz, Ian D.

    2016-01-01

    The Cornelia de Lange syndrome (CdLS) is an autosomal dominant multisystem disorder characterized by somatic and cognitive retardation, characteristic facial features, limb abnormalities, hearing loss, and other organ system involvement. The vast majority of cases (99%) are sporadic, with rare familial occurrences having been reported. Most individuals with CdLS do not reproduce as a result of the severity of the disorder. Maternal transmission has been well documented, as have several cases of multiple-affected children being born to apparently unaffected parents. Paternal transmission has rarely been reported. A case is reported here of a father with classic features of CdLS with a similarly affected daughter. A review of the reported familial cases of CdLS is summarized. PMID:11754058

  6. Cornelia de Lange syndrome caused by heterozygous deletions of chromosome 8q24: comments on the article by Pereza et al. [2012].

    PubMed

    Pereza, Nina; Severinski, Srećko; Ostojić, Saša; Volk, Marija; Maver, Aleš; Dekanić, Kristina Baraba; Kapović, Miljenko; Peterlin, Borut

    2015-06-01

    In the March issue of the Journal in 2012, we reported on a girl with Langer-Giedion syndrome (LGS) phenotype and a 7.5 Mb interstitial deletion at 8q23.3q24.13, encompassing the EXT1, but not the TRPS1 gene. Recent discoveries have shown that heterozygous intragenic mutations or contiguous gene deletions including the RAD21 gene, which is located downstream of the TRPS1 gene, are the cause of Cornelia de Lange syndrome-4. Considering that the interstitial deletion in our patient included the RAD21 and 30 other RefSeq genes, we would like to suggest a revision of the diagnosis reported in our previous paper and compare our patient to other reported patients with Cornelia de Lange syndrome-4 caused by heterozygous deletions of chromosome 8q24. © 2015 Wiley Periodicals, Inc. PMID:25899858

  7. Cornelia de Lange syndrome: further delineation of phenotype, cohesin biology and educational focus, 5th Biennial Scientific and Educational Symposium abstracts.

    PubMed

    Kline, Antonie D; Calof, Anne L; Schaaf, Cheri A; Krantz, Ian D; Jyonouchi, Soma; Yokomori, Kyoko; Gauze, Maria; Carrico, Cheri S; Woodman, Julie; Gerton, Jennifer L; Vega, Hugo; Levin, Alex V; Shirahige, Katsuhiko; Champion, Michele; Goodban, Marjorie T; O'Connor, Julia T; Pipan, Mary; Horsfield, Julia; Deardorff, Matthew A; Ishman, Stacey L; Dorsett, Dale

    2014-06-01

    Cornelia de Lange syndrome (CdLS) is the prototype for the cohesinopathy disorders that have mutations in genes associated with the cohesin subunit in all cells. Roberts syndrome is the next most common cohesinopathy. In addition to the developmental implications of cohesin biology, there is much translational and basic research, with progress towards potential treatment for these conditions. Clinically, there are many issues in CdLS faced by the individual, parents and caretakers, professionals, and schools. The following abstracts are presentations from the 5th Cornelia de Lange Syndrome Scientific and Educational Symposium on June 20-21, 2012, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting, Lincolnshire, IL. The research committee of the CdLS Foundation organizes the meeting, reviews and accepts abstracts and subsequently disseminates the information to the families. In addition to the basic science and clinical discussions, there were educationally-focused talks related to practical aspects of management at home and in school. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD. PMID:24504889

  8. A 6-year-old boy with Cornelia de Lange syndrome and Coats disease: case report and review of the literature.

    PubMed

    Stacey, Andrew W; Sparagna, Cristina; Borri, Melissa; Rizzo, Stanislao; Hadjistilianou, Theodora

    2015-10-01

    Cornelia de Lange syndrome (CdLS) can result in multiple congenital abnormalities and numerous ocular findings. We report the case of a 6-year-old boy with history of CdLS who presented with Coats disease. The findings in this case are compared to those found in the two previously reported cases of concomitant CdLS and Coats disease. The low incidence of these two disorders makes it highly unlikely that the connection is random in these 3 cases. The number of patients with both Cornelia de Lange syndrome and Coats disease is likely underestimated due to the difficulty in examining the peripheral retina in this patient population. PMID:26486036

  9. Clinical, developmental and molecular update on Cornelia de Lange syndrome and the cohesin complex: abstracts from the 2014 Scientific and Educational Symposium.

    PubMed

    Kline, Antonie D; Calof, Anne L; Lander, Arthur D; Gerton, Jennifer L; Krantz, Ian D; Dorsett, Dale; Deardorff, Matthew A; Blagowidow, Natalie; Yokomori, Kyoko; Shirahige, Katsuhiko; Santos, Rosaysela; Woodman, Julie; Megee, Paul C; O'Connor, Julia T; Egense, Alena; Noon, Sarah; Belote, Maurice; Goodban, Marjorie T; Hansen, Blake D; Timmons, Jenni Glad; Musio, Antonio; Ishman, Stacey L; Bryan, Yvon; Wu, Yaning; Bettini, Laura R; Mehta, Devanshi; Zakari, Musinu; Mills, Jason A; Srivastava, Siddharth; Haaland, Richard E

    2015-06-01

    Cornelia de Lange Syndrome (CdLS) is the most common example of disorders of the cohesin complex, or cohesinopathies. There are a myriad of clinical issues facing individuals with CdLS, particularly in the neurodevelopmental system, which also have implications for the parents and caretakers, involved professionals, therapists, and schools. Basic research in developmental and cell biology on cohesin is showing significant progress, with improved understanding of the mechanisms and the possibility of potential therapeutics. The following abstracts are presentations from the 6th Cornelia de Lange Syndrome Scientific and Educational Symposium, which took place on June 25-26, 2014, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting in Costa Mesa, CA. The Research Committee of the CdLS Foundation organizes the meeting, reviews and accepts abstracts, and subsequently disseminates the information to the families through members of the Clinical Advisory Board. In addition to the scientific and clinical discussions, there were educationally focused talks related to practical aspects of behavior and development. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD. PMID:25899772

  10. Identification and Functional Characterization of Two Intronic NIPBL Mutations in Two Patients with Cornelia de Lange Syndrome.

    PubMed

    Teresa-Rodrigo, María E; Eckhold, Juliane; Puisac, Beatriz; Pozojevic, Jelena; Parenti, Ilaria; Baquero-Montoya, Carolina; Gil-Rodríguez, María C; Braunholz, Diana; Dalski, Andreas; Hernández-Marcos, María; Ayerza, Ariadna; Bernal, María L; Ramos, Feliciano J; Wieczorek, Dagmar; Gillessen-Kaesbach, Gabriele; Pié, Juan; Kaiser, Frank J

    2016-01-01

    Cornelia de Lange syndrome (CdLS) is a rare genetically heterogeneous disorder with a high phenotypic variability including mental retardation, developmental delay, and limb malformations. The genetic causes in about 30% of patients with CdLS are still unknown. We report on the functional characterization of two intronic NIPBL mutations in two patients with CdLS that do not affect a conserved splice-donor or acceptor site. Interestingly, mRNA analyses showed aberrantly spliced transcripts missing exon 28 or 37, suggesting the loss of the branch site by the c.5329-15A>G transition and a disruption of the polypyrimidine by the c.6344del(-13)_(-8) deletion. While the loss of exon 28 retains the reading frame of the NIBPL transcript resulting in a shortened protein, the loss of exon 37 shifts the reading frame with the consequence of a premature stop of translation. Subsequent quantitative PCR analysis demonstrated a 30% decrease of the total NIPBL mRNA levels associated with the frameshift transcript. Consistent with our results, this patient shows a more severe phenotype compared to the patient with the aberrant transcript that retains its reading frame. Thus, intronic variants identified by sequencing analysis in CdLS diagnostics should carefully be examined before excluding them as nonrelevant to disease. PMID:26925417

  11. SMC1A expression and mechanism of pathogenicity in probands with X-Linked Cornelia de Lange syndrome.

    PubMed

    Liu, Jinglan; Feldman, Rachel; Zhang, Zhe; Deardorff, Matthew A; Haverfield, Eden V; Kaur, Maninder; Li, Jennifer R; Clark, Dinah; Kline, Antonie D; Waggoner, Darrel J; Das, Soma; Jackson, Laird G; Krantz, Ian D

    2009-11-01

    Cornelia de Lange Syndrome (CdLS) is a dominantly inherited heterogeneous genetic disorder with multisystem abnormalities. Sixty percent of probands with CdLS have heterozygous mutations in the Nipped-B-like (NIPBL) gene, 5% have mutations in the SMC1A gene, and one proband was found to have a mutation in the SMC3 gene. Cohesin is a multisubunit complex consisting of a SMC1A and SMC3 heterodimer and two non-SMC subunits. SMC1A is located on the human X chromosome and is reported to escape X inactivation. Twenty-nine unrelated CdLS probands with 21 unique SMC1A mutations have been identified including seven males. All mutations identified to date are either missense or small deletions, with all presumably preserving the protein open reading frame. Both wild-type and mutant alleles are expressed. Females quantitatively express twice the amount of SMC1A mRNA compared to males. The transcriptional profiling of 23 selected genes is different in SMC1A mutant probands, controls, and NIPBL mutant probands. These results suggest that mechanistically SMC1A-related CdLS is not due to altered levels of the SMC1A transcript, but rather that the mutant proteins maintain a residual function in males and enact a dominant negative effect in females. PMID:19701948

  12. SMC1A Expression and Mechanism of Pathogenicity in Probands with X-linked Cornelia de Lange Syndrome

    PubMed Central

    Liu, Jinglan; Feldman, Rachel; Zhang, Zhe; Deardorff, Matthew A.; Haverfield, Eden V.; Kaur, Maninder; Li, Jennifer R.; Clark, Dinah; Kline, Antonie D.; Waggoner, Darrel J.; Das, Soma; Jackson, Laird G.; Krantz, Ian D.

    2009-01-01

    Cornelia de Lange Syndrome (CdLS) is a dominantly inherited heterogeneous genetic disorder with multi-system abnormalities. 60% of probands with CdLS have heterozygous mutations in the Nipped-B- like (NIPBL) gene, 5% have mutations in the SMC1A gene, and 1 proband was found to have a mutation in the SMC3 gene. Cohesin is a multi-subunit complex consisting of a SMC1A and SMC3 heterodimer and two non-SMC subunits. SMC1A is located on the human X chromosome and is reported to escape X inactivation. We show that 29 unrelated CdLS probands with 21 unique SMC1A mutations have been identified by our group and others including 7 males. All mutations identified to date are either missense or small deletions with all presumably preserving the protein open reading frame. Both wild type and mutant alleles are expressed. Females quantitatively express twice the amount of SMC1A mRNA as compared to males. The transcriptional profiling of 23 selected genes is different in SMC1A mutant probands, controls and NIPBL mutant probands. These results suggest that mechanistically SMC1A-related CdLS is not due to altered levels of the SMC1A transcript, but rather that the mutant proteins maintain a residual function in males and enact a dominant negative effect in females. PMID:19701948

  13. Multiple Organ System Defects and Transcriptional Dysregulation in the Nipbl+/− Mouse, a Model of Cornelia de Lange Syndrome

    PubMed Central

    Santos, Rosaysela; Lopez-Burks, Martha E.; Young, Clint M.; Hoang, Michelle P.; Chua, Abigail; Lao, Taotao; Lechner, Mark S.; Daniel, Jeremy A.; Nussenzweig, Andre; Kitzes, Leonard; Yokomori, Kyoko; Hallgrimsson, Benedikt; Lander, Arthur D.

    2009-01-01

    Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75–80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only ∼30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/− mice and in individuals with CdLS. PMID:19763162

  14. Incidence and clinical features of X-linked Cornelia de Lange syndrome due to SMC1L1 mutations.

    PubMed

    Borck, Guntram; Zarhrate, Mohamed; Bonnefont, Jean-Paul; Munnich, Arnold; Cormier-Daire, Valérie; Colleaux, Laurence

    2007-02-01

    Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphism, growth and mental retardation, microcephaly, and various malformations. Heterozygous mutations in the NIPBL gene have been detected in approximately 45% of affected individuals. Recently, a second CdLS gene, mapping to the X chromosome, has been identified: SMC1L1 (structural maintenance of chromosomes 1-like 1; or SMC1A). In order to estimate the incidence and refine the clinical presentation of X-linked CdLS, we have screened a series of 11 CdLS boys carrying no NIPBL anomaly. We have identified two novel de novo SMC1L1 missense mutations (c.587G>A [p.Arg196His] and c.3254A>G [p.Tyr1085Cys]). Our results confirm that SMC1L1 mutations cause CdLS and support the view that SMC1L1 accounts for a significant fraction of boys with unexplained CdLS. Furthermore, we suggest that SMC1L1 mutations have milder effects than NIPBL mutations with respect to pre- and postnatal growth retardation and associated malformations. If confirmed, these data may have important implications for directing mutation screening in CdLS. PMID:17221863

  15. Identification and Functional Characterization of Two Intronic NIPBL Mutations in Two Patients with Cornelia de Lange Syndrome

    PubMed Central

    Teresa-Rodrigo, María E.; Eckhold, Juliane; Puisac, Beatriz; Pozojevic, Jelena; Parenti, Ilaria; Baquero-Montoya, Carolina; Gil-Rodríguez, María C.; Braunholz, Diana; Dalski, Andreas; Hernández-Marcos, María; Ayerza, Ariadna; Bernal, María L.; Ramos, Feliciano J.; Wieczorek, Dagmar; Gillessen-Kaesbach, Gabriele; Pié, Juan; Kaiser, Frank J.

    2016-01-01

    Cornelia de Lange syndrome (CdLS) is a rare genetically heterogeneous disorder with a high phenotypic variability including mental retardation, developmental delay, and limb malformations. The genetic causes in about 30% of patients with CdLS are still unknown. We report on the functional characterization of two intronic NIPBL mutations in two patients with CdLS that do not affect a conserved splice-donor or acceptor site. Interestingly, mRNA analyses showed aberrantly spliced transcripts missing exon 28 or 37, suggesting the loss of the branch site by the c.5329-15A>G transition and a disruption of the polypyrimidine by the c.6344del(-13)_(-8) deletion. While the loss of exon 28 retains the reading frame of the NIBPL transcript resulting in a shortened protein, the loss of exon 37 shifts the reading frame with the consequence of a premature stop of translation. Subsequent quantitative PCR analysis demonstrated a 30% decrease of the total NIPBL mRNA levels associated with the frameshift transcript. Consistent with our results, this patient shows a more severe phenotype compared to the patient with the aberrant transcript that retains its reading frame. Thus, intronic variants identified by sequencing analysis in CdLS diagnostics should carefully be examined before excluding them as nonrelevant to disease. PMID:26925417

  16. Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome.

    PubMed

    Kawauchi, Shimako; Calof, Anne L; Santos, Rosaysela; Lopez-Burks, Martha E; Young, Clint M; Hoang, Michelle P; Chua, Abigail; Lao, Taotao; Lechner, Mark S; Daniel, Jeremy A; Nussenzweig, Andre; Kitzes, Leonard; Yokomori, Kyoko; Hallgrimsson, Benedikt; Lander, Arthur D

    2009-09-01

    Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75-80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only approximately 30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/- mice and in individuals with CdLS. PMID:19763162

  17. Regional chromatin decompaction in Cornelia de Lange syndrome associated with NIPBL disruption can be uncoupled from cohesin and CTCF

    PubMed Central

    Nolen, Leisha D.; Boyle, Shelagh; Ansari, Morad; Pritchard, Emily; Bickmore, Wendy A.

    2013-01-01

    Cornelia de Lange syndrome (CdLS) is a developmental disorder caused by mutations in NIPBL, a protein which has functionally been associated with the cohesin complex. Mutations in core cohesin complex components have also been reported in individuals with CdLS-like phenotypes. In addition to its role in sister chromatid cohesion, cohesin is thought to play a role in regulating gene expression during development. The mechanism of this gene regulation remains unclear, but NIPBL and cohesin have been reported to affect long-range chromosomal interactions, both independently and through interactions with CTCF. We used fluorescence in situ hybridization to investigate whether the disruption of NIPBL affects chromosome architecture. We show that cells from CdLS patients exhibit visible chromatin decompaction, that is most pronounced across gene-rich regions of the genome. Cells carrying mutations predicted to have a more severe effect on NIPBL function show more extensive chromatin decompaction than those carrying milder mutations. This cellular phenotype was reproduced in normal cells depleted for NIPBL with siRNA, but was not seen following the knockdown of either the cohesin component SMC3, or CTCF. We conclude that NIPBL has a function in modulating chromatin architecture, particularly for gene-rich areas of the chromosome, that is not dependent on SMC3/cohesin or CTCF, raising the possibility that the aetiology of disorders associated with the mutation of core cohesin components is distinct from that associated with the disruption of NIPBL itself in classical CdLS. PMID:23760082

  18. l-leucine partially rescues translational and developmental defects associated with zebrafish models of Cornelia de Lange syndrome

    PubMed Central

    Xu, Baoshan; Sowa, Nenja; Cardenas, Maria E.; Gerton, Jennifer L.

    2015-01-01

    Cohesinopathies are human genetic disorders that include Cornelia de Lange syndrome (CdLS) and Roberts syndrome (RBS) and are characterized by defects in limb and craniofacial development as well as mental retardation. The developmental phenotypes of CdLS and other cohesinopathies suggest that mutations in the structure and regulation of the cohesin complex during embryogenesis interfere with gene regulation. In a previous project, we showed that RBS was associated with highly fragmented nucleoli and defects in both ribosome biogenesis and protein translation. l-leucine stimulation of the mTOR pathway partially rescued translation in human RBS cells and development in zebrafish models of RBS. In this study, we investigate protein translation in zebrafish models of CdLS. Our results show that phosphorylation of RPS6 as well as 4E-binding protein 1 (4EBP1) was reduced in nipbla/b, rad21 and smc3-morphant embryos, a pattern indicating reduced translation. Moreover, protein biosynthesis and rRNA production were decreased in the cohesin morphant embryo cells. l-leucine partly rescued protein synthesis and rRNA production in the cohesin morphants and partially restored phosphorylation of RPS6 and 4EBP1. Concomitantly, l-leucine treatment partially improved cohesinopathy embryo development including the formation of craniofacial cartilage. Interestingly, we observed that alpha-ketoisocaproate (α-KIC), which is a keto derivative of leucine, also partially rescued the development of rad21 and nipbla/b morphants by boosting mTOR-dependent translation. In summary, our results suggest that cohesinopathies are caused in part by defective protein synthesis, and stimulation of the mTOR pathway through l-leucine or its metabolite α-KIC can partially rescue development in zebrafish models for CdLS. PMID:25378554

  19. L-leucine partially rescues translational and developmental defects associated with zebrafish models of Cornelia de Lange syndrome.

    PubMed

    Xu, Baoshan; Sowa, Nenja; Cardenas, Maria E; Gerton, Jennifer L

    2015-03-15

    Cohesinopathies are human genetic disorders that include Cornelia de Lange syndrome (CdLS) and Roberts syndrome (RBS) and are characterized by defects in limb and craniofacial development as well as mental retardation. The developmental phenotypes of CdLS and other cohesinopathies suggest that mutations in the structure and regulation of the cohesin complex during embryogenesis interfere with gene regulation. In a previous project, we showed that RBS was associated with highly fragmented nucleoli and defects in both ribosome biogenesis and protein translation. l-leucine stimulation of the mTOR pathway partially rescued translation in human RBS cells and development in zebrafish models of RBS. In this study, we investigate protein translation in zebrafish models of CdLS. Our results show that phosphorylation of RPS6 as well as 4E-binding protein 1 (4EBP1) was reduced in nipbla/b, rad21 and smc3-morphant embryos, a pattern indicating reduced translation. Moreover, protein biosynthesis and rRNA production were decreased in the cohesin morphant embryo cells. l-leucine partly rescued protein synthesis and rRNA production in the cohesin morphants and partially restored phosphorylation of RPS6 and 4EBP1. Concomitantly, l-leucine treatment partially improved cohesinopathy embryo development including the formation of craniofacial cartilage. Interestingly, we observed that alpha-ketoisocaproate (α-KIC), which is a keto derivative of leucine, also partially rescued the development of rad21 and nipbla/b morphants by boosting mTOR-dependent translation. In summary, our results suggest that cohesinopathies are caused in part by defective protein synthesis, and stimulation of the mTOR pathway through l-leucine or its metabolite α-KIC can partially rescue development in zebrafish models for CdLS. PMID:25378554

  20. Attitudes about the use of internet support groups and the impact among parents of children with Cornelia de Lange syndrome.

    PubMed

    Cacioppo, Cara N; Conway, Laura J; Mehta, Devanshi; Krantz, Ian D; Noon, Sarah E

    2016-06-01

    There is an abundance of information in the literature on patient experiences with Internet support groups (ISGs). However, studies exploring these experiences in a rare disease population are scarce, even though these families are often at a disadvantage for resources, reliable information, and support. The aim of the current study was to explore the experiences with ISGs for parents of children with Cornelia de Lange syndrome (CdLS), a rare genetic diagnosis, in order to better understand the impact on emotional support and their child's medical care. Focus groups were conducted to inform the design of a large-scale internet survey. The survey asked parents closed- and open-ended questions regarding experiences with ISGs, with a focus on the psychosocial, medical, and logistical aspects. The survey found that 141/170 (82.6%) respondents have visited an Internet-based support group to find support or information about their child's CdLS diagnosis. The majority of respondents (71.7%) reported that ISGs have been helpful in finding emotional support, with the most common areas impacted as a result of ISG participation being behavior toward their children and family dynamic. Regarding medical care, most respondents (63.9%) reported that ISGs have been helpful in finding medical information and support, with the most commonly impacted areas of their child's care including day-to-day management, diet, therapy interventions, and healthcare providers. These findings provide a greater understanding of the role of Internet networking in healthcare and may inform future approaches to medical care and psychosocial support for rare, complex genetic diagnoses. © 2016 Wiley Periodicals, Inc. PMID:27163126

  1. Benefits and limitations of a multidisciplinary approach to individualized management of Cornelia de Lange syndrome and related diagnoses.

    PubMed

    January, Kathleen; Conway, Laura J; Deardorff, Matthew; Harrington, Ann; Krantz, Ian D; Loomes, Kathleen; Pipan, Mary; Noon, Sarah E

    2016-06-01

    Given the clinical complexities of Cornelia de Lange Syndrome (CdLS), the Center for CdLS and Related Diagnoses at The Children's Hospital of Philadelphia (CHOP) and The Multidisciplinary Clinic for Adolescents and Adults at Greater Baltimore Medical Center (GBMC) were established to develop a comprehensive approach to clinical management and research issues relevant to CdLS. Little work has been done to evaluate the general utility of a multispecialty approach to patient care. Previous research demonstrates several advantages and disadvantages of multispecialty care. This research aims to better understand the benefits and limitations of a multidisciplinary clinic setting for individuals with CdLS and related diagnoses. Parents of children with CdLS and related diagnoses who have visited a multidisciplinary clinic (N = 52) and who have not visited a multidisciplinary clinic (N = 69) were surveyed to investigate their attitudes. About 90.0% of multispecialty clinic attendees indicated a preference for multidisciplinary care. However, some respondents cited a need for additional clinic services including more opportunity to meet with other specialists (N = 20), such as behavioral health, and increased information about research studies (N = 15). Travel distance and expenses often prevented families' multidisciplinary clinic attendance (N = 41 and N = 35, respectively). Despite identified limitations, these findings contribute to the evidence demonstrating the utility of a multispecialty approach to patient care. This approach ultimately has the potential to not just improve healthcare for individuals with CdLS but for those with medically complex diagnoses in general. © 2016 Wiley Periodicals, Inc. PMID:27145433

  2. Using Mouse and Zebrafish Models to Understand the Etiology of Developmental Defects in Cornelia de Lange Syndrome

    PubMed Central

    KAWAUCHI, SHIMAKO; SANTOS, ROSAYSELA; MUTO, AKIHIKO; LOPEZ-BURKS, MARTHA E.; SCHILLING, THOMAS F.; LANDER, ARTHUR D.; CALOF, ANNE L.

    2016-01-01

    Cornelia de Lange Syndrome (CdLS) is a multisystem birth defects disorder that affects every tissue and organ system in the body. Understanding the factors that contribute to the origins, prevalence, and severity of these developmental defects provides the most direct approach for developing screens and potential treatments for individuals with CdLS. Since the majority of cases of CdLS are caused by haploinsufficiency for NIPBL (Nipped-B-like, which encodes a cohesin-associated protein), we have developed mouse and zebrafish models of CdLS by using molecular genetic tools to create Nipbl-deficient mice and zebrafish (Nipbl+/− mice, zebrafish nipbl morphants). Studies of these vertebrate animal models have yielded novel insights into the developmental etiology and genes/gene pathways that contribute to CdLS-associated birth defects, particularly defects of the gut, heart, craniofacial structures, nervous system, and limbs. Studies of these mouse and zebrafish CdLS models have helped clarify how deficiency for NIPBL, a protein that associates with cohesin and other transcriptional regulators in the nucleus, affects processes important to the emergence of the structural and physiological birth defects observed in CdLS: NIPBL exerts chromosome position-specific effects on gene expression; it influences long-range interactions between different regulatory elements of genes; and it regulates combinatorial and synergistic actions of genes in developing tissues. Our current understanding is that CdLS should be considered as not only a cohesinopathy, but also a “transcriptomopathy,” that is, a disease whose underlying etiology is the global dysregulation of gene expression throughout the organism. PMID:27120001

  3. Using mouse and zebrafish models to understand the etiology of developmental defects in Cornelia de Lange Syndrome.

    PubMed

    Kawauchi, Shimako; Santos, Rosaysela; Muto, Akihiko; Lopez-Burks, Martha E; Schilling, Thomas F; Lander, Arthur D; Calof, Anne L

    2016-06-01

    Cornelia de Lange Syndrome (CdLS) is a multisystem birth defects disorder that affects every tissue and organ system in the body. Understanding the factors that contribute to the origins, prevalence, and severity of these developmental defects provides the most direct approach for developing screens and potential treatments for individuals with CdLS. Since the majority of cases of CdLS are caused by haploinsufficiency for NIPBL (Nipped-B-like, which encodes a cohesin-associated protein), we have developed mouse and zebrafish models of CdLS by using molecular genetic tools to create Nipbl-deficient mice and zebrafish (Nipbl(+/-) mice, zebrafish nipbl morphants). Studies of these vertebrate animal models have yielded novel insights into the developmental etiology and genes/gene pathways that contribute to CdLS-associated birth defects, particularly defects of the gut, heart, craniofacial structures, nervous system, and limbs. Studies of these mouse and zebrafish CdLS models have helped clarify how deficiency for NIPBL, a protein that associates with cohesin and other transcriptional regulators in the nucleus, affects processes important to the emergence of the structural and physiological birth defects observed in CdLS: NIPBL exerts chromosome position-specific effects on gene expression; it influences long-range interactions between different regulatory elements of genes; and it regulates combinatorial and synergistic actions of genes in developing tissues. Our current understanding is that CdLS should be considered as not only a cohesinopathy, but also a "transcriptomopathy," that is, a disease whose underlying etiology is the global dysregulation of gene expression throughout the organism. © 2016 Wiley Periodicals, Inc. PMID:27120001

  4. Multifactorial Origins of Heart and Gut Defects in nipbl-Deficient Zebrafish, a Model of Cornelia de Lange Syndrome

    PubMed Central

    Muto, Akihiko; Calof, Anne L.

    2011-01-01

    Cornelia de Lange Syndrome (CdLS) is the founding member of a class of multi-organ system birth defect syndromes termed cohesinopathies, named for the chromatin-associated protein complex cohesin, which mediates sister chromatid cohesion. Most cases of CdLS are caused by haploinsufficiency for Nipped-B-like (Nipbl), a highly conserved protein that facilitates cohesin loading. Consistent with recent evidence implicating cohesin and Nipbl in transcriptional regulation, both CdLS cell lines and tissues of Nipbl-deficient mice show changes in the expression of hundreds of genes. Nearly all such changes are modest, however—usually less than 1.5-fold—raising the intriguing possibility that, in CdLS, severe developmental defects result from the collective action of many otherwise innocuous perturbations. As a step toward testing this hypothesis, we developed a model of nipbl-deficiency in zebrafish, an organism in which we can quantitatively investigate the combinatorial effects of gene expression changes. After characterizing the structure and embryonic expression of the two zebrafish nipbl genes, we showed that morpholino knockdown of these genes produces a spectrum of specific heart and gut/visceral organ defects with similarities to those in CdLS. Analysis of nipbl morphants further revealed that, as early as gastrulation, expression of genes involved in endodermal differentiation (sox32, sox17, foxa2, and gata5) and left-right patterning (spaw, lefty2, and dnah9) is altered. Experimental manipulation of the levels of several such genes—using RNA injection or morpholino knockdown—implicated both additive and synergistic interactions in causing observed developmental defects. These findings support the view that birth defects in CdLS arise from collective effects of quantitative changes in gene expression. Interestingly, both the phenotypes and gene expression changes in nipbl morphants differed from those in mutants or morphants for genes encoding cohesin

  5. KCNQ1 mutations associated with Jervell and Lange-Nielsen syndrome and autosomal recessive Romano-Ward syndrome in India-expanding the spectrum of long QT syndrome type 1.

    PubMed

    Vyas, Bijal; Puri, Ratna D; Namboodiri, Narayanan; Nair, Mohan; Sharma, Deepak; Movva, Sireesha; Saxena, Renu; Bohora, Shomu; Aggarwal, Neeraj; Vora, Amit; Kumar, Jatinder; Singh, Tarandeep; Verma, Ishwar C

    2016-06-01

    Long QT syndrome type 1 (LQT1) is the most common type of all Long QT syndromes (LQTS) and occurs due to mutations in KCNQ1. Biallelic mutations with deafness is called Jervell and Lange-Nielsen syndrome (JLNS) and without deafness is autosomal recessive Romano-Ward syndrome (AR RWS). In this prospective study, we report biallelic mutations in KCNQ1 in Indian patients with LQT1 syndrome. Forty patients with a clinical diagnosis of LQT1 syndrome were referred for molecular testing. Of these, 18 were excluded from the analysis as they did not fulfill the inclusion criteria of broad T wave ECG pattern of the study. Direct sequencing of KCNQ1 was performed in 22 unrelated probands, parents and at-risk family members. Mutations were identified in 17 patients, of which seven had heterozygous mutations and were excluded in this analysis. Biallelic mutations were identified in 10 patients. Five of 10 patients did not have deafness and were categorized as AR RWS, the rest being JLNS. Eight mutations identified in this study have not been reported in the literature and predicted to be pathogenic by in silico analysis. We hypothesize that the homozygous biallelic mutations identified in 67% of families was due to endogamous marriages in the absence of consanguinity. This study presents biallelic gene mutations in KCNQ1 in Asian Indian patients with AR JLNS and RWS. It adds to the scant worldwide literature of mutation studies in AR RWS. © 2016 Wiley Periodicals, Inc. PMID:27041150

  6. Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange-Nielsen deafness syndrome.

    PubMed

    Chang, Qing; Wang, Jianjun; Li, Qi; Kim, Yeunjung; Zhou, Binfei; Wang, Yunfeng; Li, Huawei; Lin, Xi

    2015-08-01

    Mutations in the potassium channel subunit KCNQ1 cause the human severe congenital deafness Jervell and Lange-Nielsen (JLN) syndrome. We applied a gene therapy approach in a mouse model of JLN syndrome (Kcnq1(-/-) mice) to prevent the development of deafness in the adult stage. A modified adeno-associated virus construct carrying a Kcnq1 expression cassette was injected postnatally (P0-P2) into the endolymph, which resulted in Kcnq1 expression in most cochlear marginal cells where native Kcnq1 is exclusively expressed. We also found that extensive ectopic virally mediated Kcnq1 transgene expression did not affect normal cochlear functions. Examination of cochlear morphology showed that the collapse of the Reissner's membrane and degeneration of hair cells (HCs) and cells in the spiral ganglia were corrected in Kcnq1(-/-) mice. Electrophysiological tests showed normal endocochlear potential in treated ears. In addition, auditory brainstem responses showed significant hearing preservation in the injected ears, ranging from 20 dB improvement to complete correction of the deafness phenotype. Our results demonstrate the first successful gene therapy treatment for gene defects specifically affecting the function of the stria vascularis, which is a major site affected by genetic mutations in inherited hearing loss. PMID:26084842

  7. Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange-Nielsen deafness syndrome

    PubMed Central

    Chang, Qing; Wang, Jianjun; Li, Qi; Kim, Yeunjung; Zhou, Binfei; Wang, Yunfeng; Li, Huawei; Lin, Xi

    2015-01-01

    Mutations in the potassium channel subunit KCNQ1 cause the human severe congenital deafness Jervell and Lange-Nielsen (JLN) syndrome. We applied a gene therapy approach in a mouse model of JLN syndrome (Kcnq1−/− mice) to prevent the development of deafness in the adult stage. A modified adeno-associated virus construct carrying a Kcnq1 expression cassette was injected postnatally (P0–P2) into the endolymph, which resulted in Kcnq1 expression in most cochlear marginal cells where native Kcnq1 is exclusively expressed. We also found that extensive ectopic virally mediated Kcnq1 transgene expression did not affect normal cochlear functions. Examination of cochlear morphology showed that the collapse of the Reissner’s membrane and degeneration of hair cells (HCs) and cells in the spiral ganglia were corrected in Kcnq1−/− mice. Electrophysiological tests showed normal endocochlear potential in treated ears. In addition, auditory brainstem responses showed significant hearing preservation in the injected ears, ranging from 20 dB improvement to complete correction of the deafness phenotype. Our results demonstrate the first successful gene therapy treatment for gene defects specifically affecting the function of the stria vascularis, which is a major site affected by genetic mutations in inherited hearing loss. PMID:26084842

  8. Exclusion of Linkage to the CDL1 Gene Region on Chromosome 3q26.3 in Some Familial Cases of Cornelia de Lange Syndrome

    PubMed Central

    Krantz, Ian D.; Tonkin, Emma; Smith, Melanie; Devoto, Marcella; Bottani, Armand; Simpson, Claire; Hofreiter, Mary; Abraham, Vinod; Jukofsky, Lori; Conti, Brian P.; Strachan, Tom; Jackson, Laird

    2016-01-01

    Cornelia de Lange Syndrome (CdLS) is a complex developmental disorder consisting of characteristic facial features, limb abnormalities, hirsutism, ophthalmologic involvement, gastroesophageal dysfunction, hearing loss, as well as growth and neuro-developmental retardation. Most cases of CdLS appear to be sporadic. Familial cases are rare and indicate autosomal dominant inheritance. Several individuals with CdLS have been reported with chromosomal abnormalities, suggesting candidate genomic regions within which the causative gene(s) may lie. A CdLS gene location (CDL1) has been assigned to 3q26.3 based on phenotypic overlap with the duplication 3q syndrome (critical region 3q26.2-q27) and the report of a CdLS individual with a balanced de novo t(3;17)(q26.3;q23.1). It has been postulated that a gene within the dup3q critical region results in the CdLS when deleted or mutated. We have performed a linkage analysis to the minimal critical region for the dup3q syndrome (that encompasses the translocation breakpoint) on chromosome 3q in 10 rare familial cases of CdLS. Nineteen markers spanning a region of approximately 40 Mb (37 cM) were used. Results of a multipoint linkage analysis demonstrated total lod-scores that were negative across the chromosome 3q26-q27 region. In 4/10 families, lod-scores were less than −2 in the 2 cM region encompassing the translocation, while in the remaining 6/10 families, lod-scores could not exclude linkage to this region. These studies indicate that in some multicase families, the disease gene does not map to the CDL1 region at 3q26.3. PMID:11391654

  9. Exome sequencing identifies a novel EP300 frame shift mutation in a patient with features that overlap Cornelia de Lange syndrome.

    PubMed

    Woods, Susan A; Robinson, Haynes B; Kohler, Lisa J; Agamanolis, Dimitris; Sterbenz, George; Khalifa, Mohamed

    2014-01-01

    Rubinstein-Taybi syndrome (RTS) and Cornelia de Lange syndrome (CdLS) are genetically heterogeneous multiple anomalies syndromes, each having a distinctive facial gestalt. Two genes (CREBBP and EP300) are known to cause RTS, and five (NIPBL, SMC1A, SMC3, RAD21, and HDAC8) have been associated with CdLS. A diagnosis of RTS or CdLS is molecularly confirmed in only 65% of clinically identified cases, suggesting that additional causative genes exist for both conditions. In addition, although EP300 and CREBBP encode homologous proteins and perform similar functions, only eight EP300 positive RTS patients have been reported, suggesting that patients with EP300 mutations might be escaping clinical recognition. We report on a child with multiple congenital abnormalities and intellectual disability whose facial features and complex phenotype resemble CdLS. However, no mutations in CdLS-related genes were identified. Rather, a novel EP300 mutation was found on whole exome sequencing. Possible links between EP300 and genes causing CdLS are evident in the literature. Both EP300 and HDAC8 are involved in the regulation of TP53 transcriptional activity. In addition, p300 and other chromatin associated proteins, including NIPBL, SMCA1, and SMC3, have been found at enhancer regions in different cell types. It is therefore possible that EP300 and CdLS-related genes are involved in additional shared pathways, producing overlapping phenotypes. As whole exome sequencing becomes more widely utilized, the diverse phenotypes associated with EP300 mutations should be better understood. In the meantime, testing for EP300 mutations in those with features of CdLS may be warranted. PMID:24352918

  10. Novel Pathogenic Variant (c.3178G>A) in the SMC1A Gene in a Family With Cornelia de Lange Syndrome Identified by Exome Sequencing

    PubMed Central

    Jang, Mi-Ae; Lee, Chang-Woo

    2015-01-01

    Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous congenital anomaly. Mutations in the NIPBL gene account for a half of the affected individuals. We describe a family with CdLS carrying a novel pathogenic variant of the SMC1A gene identified by exome sequencing. The proband was a 3-yr-old boy presenting with a developmental delay. He had distinctive facial features without major structural anomalies and tested negative for the NIPBL gene. His younger sister, mother, and maternal grandmother presented with mild mental retardation. By exome sequencing of the proband, a novel SMC1A variant, c.3178G>A, was identified, which was expected to cause an amino acid substitution (p.Glu1060Lys) in the highly conserved coiled-coil domain of the SMC1A protein. Sanger sequencing confirmed that the three female relatives with mental retardation also carry this variant. Our results reveal that SMC1A gene defects are associated with milder phenotypes of CdLS. Furthermore, we showed that exome sequencing could be a useful tool to identify pathogenic variants in patients with CdLS. PMID:26354354

  11. Proteomic Profile Identifies Dysregulated Pathways in Cornelia de Lange Syndrome Cells With Distinct Mutations in SMC1A and SMC3 Genes

    PubMed Central

    Gimigliano, Anna; Mannini, Linda; Bianchi, Laura; Puglia, Michele; Deardorff, Matthew A.; Menga, Stefania; Krantz, Ian D; Musio, Antonio; Bini, Luca

    2012-01-01

    Mutations in cohesin genes have been identified in Cornelia de Lange syndrome (CdLS), but its etiopathogenetic mechanisms are still poorly understood. To define biochemical pathways that are affected in CdLS we analyzed the proteomic profile of CdLS cell lines carrying mutations in the core cohesin genes, SMC1A and SMC3. Dysregulated protein expression was found in CdLS probands compared to controls. The proteomics analysis was able to discriminate between probands harboring mutations in the different domains of the SMC proteins. In particular, proteins involved in the response to oxidative stress were specifically down-regulated in hinge mutated probands. In addition, the finding that CdLS cell lines show an increase in global oxidative stress argues that it could contribute to some CdLS phenotypic features such as premature physiological aging and genome instability. Finally, the c-MYC gene represents a convergent hub lying at the center of dysregulated pathways, and is down-regulated in CdLS. This study allowed us to highlight, for the first time, specific biochemical pathways that are affected in CdLS, providing plausible causal evidence for some of the phenotypic features seen in CdLS. PMID:23106691

  12. Novel pathogenic variant (c.3178G>A) in the SMC1A gene in a family with Cornelia de Lange syndrome identified by exome sequencing.

    PubMed

    Jang, Mi Ae; Lee, Chang Woo; Kim, Jin Kyung; Ki, Chang Seok

    2015-11-01

    Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous congenital anomaly. Mutations in the NIPBL gene account for a half of the affected individuals. We describe a family with CdLS carrying a novel pathogenic variant of the SMC1A gene identified by exome sequencing. The proband was a 3-yr-old boy presenting with a developmental delay. He had distinctive facial features without major structural anomalies and tested negative for the NIPBL gene. His younger sister, mother, and maternal grandmother presented with mild mental retardation. By exome sequencing of the proband, a novel SMC1A variant, c.3178G>A, was identified, which was expected to cause an amino acid substitution (p.Glu1060Lys) in the highly conserved coiled-coil domain of the SMC1A protein. Sanger sequencing confirmed that the three female relatives with mental retardation also carry this variant. Our results reveal that SMC1A gene defects are associated with milder phenotypes of CdLS. Furthermore, we showed that exome sequencing could be a useful tool to identify pathogenic variants in patients with CdLS. PMID:26354354

  13. Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism

    PubMed Central

    Ansari, Morad; Poke, Gemma; Ferry, Quentin; Williamson, Kathleen; Aldridge, Roland; Meynert, Alison M; Bengani, Hemant; Chan, Cheng Yee; Kayserili, Hülya; Avci, Şahin; Hennekam, Raoul C M; Lampe, Anne K; Redeker, Egbert; Homfray, Tessa; Ross, Alison; Falkenberg Smeland, Marie; Mansour, Sahar; Parker, Michael J; Cook, Jacqueline A; Splitt, Miranda; Fisher, Richard B; Fryer, Alan; Magee, Alex C; Wilkie, Andrew; Barnicoat, Angela; Brady, Angela F; Cooper, Nicola S; Mercer, Catherine; Deshpande, Charu; Bennett, Christopher P; Pilz, Daniela T; Ruddy, Deborah; Cilliers, Deirdre; Johnson, Diana S; Josifova, Dragana; Rosser, Elisabeth; Thompson, Elizabeth M; Wakeling, Emma; Kinning, Esther; Stewart, Fiona; Flinter, Frances; Girisha, Katta M; Cox, Helen; Firth, Helen V; Kingston, Helen; Wee, Jamie S; Hurst, Jane A; Clayton-Smith, Jill; Tolmie, John; Vogt, Julie; Tatton–Brown, Katrina; Chandler, Kate; Prescott, Katrina; Wilson, Louise; Behnam, Mahdiyeh; McEntagart, Meriel; Davidson, Rosemarie; Lynch, Sally-Ann; Sisodiya, Sanjay; Mehta, Sarju G; McKee, Shane A; Mohammed, Shehla; Holden, Simon; Park, Soo-Mi; Holder, Susan E; Harrison, Victoria; McConnell, Vivienne; Lam, Wayne K; Green, Andrew J; Donnai, Dian; Bitner-Glindzicz, Maria; Donnelly, Deirdre E; Nellåker, Christoffer; Taylor, Martin S; FitzPatrick, David R

    2014-01-01

    Background Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. Methods We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. Results Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases. Conclusions Future diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues. PMID:25125236

  14. Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue.

    PubMed

    Zhang, Miao; D'Aniello, Cristina; Verkerk, Arie O; Wrobel, Eva; Frank, Stefan; Ward-van Oostwaard, Dorien; Piccini, Ilaria; Freund, Christian; Rao, Jyoti; Seebohm, Guiscard; Atsma, Douwe E; Schulze-Bahr, Eric; Mummery, Christine L; Greber, Boris; Bellin, Milena

    2014-12-16

    Jervell and Lange-Nielsen syndrome (JLNS) is one of the most severe life-threatening cardiac arrhythmias. Patients display delayed cardiac repolarization, associated high risk of sudden death due to ventricular tachycardia, and congenital bilateral deafness. In contrast to the autosomal dominant forms of long QT syndrome, JLNS is a recessive trait, resulting from homozygous (or compound heterozygous) mutations in KCNQ1 or KCNE1. These genes encode the α and β subunits, respectively, of the ion channel conducting the slow component of the delayed rectifier K(+) current, IKs. We used complementary approaches, reprogramming patient cells and genetic engineering, to generate human induced pluripotent stem cell (hiPSC) models of JLNS, covering splice site (c.478-2A>T) and missense (c.1781G>A) mutations, the two major classes of JLNS-causing defects in KCNQ1. Electrophysiological comparison of hiPSC-derived cardiomyocytes (CMs) from homozygous JLNS, heterozygous, and wild-type lines recapitulated the typical and severe features of JLNS, including pronounced action and field potential prolongation and severe reduction or absence of IKs. We show that this phenotype had distinct underlying molecular mechanisms in the two sets of cell lines: the previously unidentified c.478-2A>T mutation was amorphic and gave rise to a strictly recessive phenotype in JLNS-CMs, whereas the missense c.1781G>A lesion caused a gene dosage-dependent channel reduction at the cell membrane. Moreover, adrenergic stimulation caused action potential prolongation specifically in JLNS-CMs. Furthermore, sensitivity to proarrhythmic drugs was strongly enhanced in JLNS-CMs but could be pharmacologically corrected. Our data provide mechanistic insight into distinct classes of JLNS-causing mutations and demonstrate the potential of hiPSC-CMs in drug evaluation. PMID:25453094

  15. Anaesthesia management of a case of Jervell and Lange-Nielsen syndrome for minimally invasive bilateral thoracoscopic cervicothoracic sympathectomy

    PubMed Central

    Roy, Preety Mittal; Khanna, Sangeeta; Mehta, Yatin; Khan, Ali Z

    2016-01-01

    Long QT syndrome (LQTS) is an arrhythmogenic cardiac disorder resulting from the malfunction of cardiac ion channels. Patient with LQTS may present with syncope, seizures or sudden cardiac death secondary to polymorphic ventricular tachycardia (VT) or torsades de pointes. Patient may be asymptomatic in the pre-operative period but may develop VT for the first time in operation theatre. We are reporting anaesthetic management of a child with LQTS planned for bilateral thoracoscopic cervicothoracic sympathectomy. PMID:27330206

  16. Anaesthesia management of a case of Jervell and Lange-Nielsen syndrome for minimally invasive bilateral thoracoscopic cervicothoracic sympathectomy.

    PubMed

    Roy, Preety Mittal; Khanna, Sangeeta; Mehta, Yatin; Khan, Ali Z

    2016-06-01

    Long QT syndrome (LQTS) is an arrhythmogenic cardiac disorder resulting from the malfunction of cardiac ion channels. Patient with LQTS may present with syncope, seizures or sudden cardiac death secondary to polymorphic ventricular tachycardia (VT) or torsades de pointes. Patient may be asymptomatic in the pre-operative period but may develop VT for the first time in operation theatre. We are reporting anaesthetic management of a child with LQTS planned for bilateral thoracoscopic cervicothoracic sympathectomy. PMID:27330206

  17. Overall and allele-specific expression of the SMC1A gene in female Cornelia de Lange syndrome patients and healthy controls

    PubMed Central

    Parenti, Ilaria; Rovina, Davide; Masciadri, Maura; Cereda, Anna; Azzollini, Jacopo; Picinelli, Chiara; Limongelli, Giuseppe; Finelli, Palma; Selicorni, Angelo; Russo, Silvia; Gervasini, Cristina; Larizza, Lidia

    2014-01-01

    Cornelia de Lange syndrome (CdLS) is a rare multisystem disorder characterized by facial dysmorphisms, limb anomalies, and growth and cognitive deficits. Mutations in genes encoding subunits (SMC1A, SMC3, RAD21) or regulators (NIPBL, HDAC8) of the cohesin complex account for approximately 65% of clinically diagnosed CdLS cases. The SMC1A gene (Xp11.22), responsible for 5% of CdLS cases, partially escapes X chromosome inactivation in humans and the allele on the inactive X chromosome is variably expressed. In this study, we evaluated overall and allele-specific SMC1A expression. Real-time PCR analysis conducted on 17 controls showed that SMC1A expression in females is 50% higher than in males. Immunoblotting experiments confirmed a 44% higher protein level in healthy females than in males, and showed no significant differences in SMC1A protein levels between controls and patients. Pyrosequencing was used to assess the reciprocal level of allelic expression in six female carriers of different SMC1A mutations and 15 controls who were heterozygous at a polymorphic transcribed SMC1A locus. The two alleles were expressed at a 1:1 ratio in the control group and at a 2:1 ratio in favor of the wild type allele in the test group. Since a dominant negative effect is considered the pathogenic mechanism in SMC1A-defective female patients, the level of allelic preferential expression might be one of the factors contributing to the wide phenotypic variability observed in these patients. An extension of this study to a larger cohort containing mild to borderline cases could enhance our understanding of the clinical spectrum of SMC1A-linked CdLS. PMID:24756084

  18. Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.

    PubMed

    Kaiser, Frank J; Ansari, Morad; Braunholz, Diana; Concepción Gil-Rodríguez, María; Decroos, Christophe; Wilde, Jonathan J; Fincher, Christopher T; Kaur, Maninder; Bando, Masashige; Amor, David J; Atwal, Paldeep S; Bahlo, Melanie; Bowman, Christine M; Bradley, Jacquelyn J; Brunner, Han G; Clark, Dinah; Del Campo, Miguel; Di Donato, Nataliya; Diakumis, Peter; Dubbs, Holly; Dyment, David A; Eckhold, Juliane; Ernst, Sarah; Ferreira, Jose C; Francey, Lauren J; Gehlken, Ulrike; Guillén-Navarro, Encarna; Gyftodimou, Yolanda; Hall, Bryan D; Hennekam, Raoul; Hudgins, Louanne; Hullings, Melanie; Hunter, Jennifer M; Yntema, Helger; Innes, A Micheil; Kline, Antonie D; Krumina, Zita; Lee, Hane; Leppig, Kathleen; Lynch, Sally Ann; Mallozzi, Mark B; Mannini, Linda; McKee, Shane; Mehta, Sarju G; Micule, Ieva; Mohammed, Shehla; Moran, Ellen; Mortier, Geert R; Moser, Joe-Ann S; Noon, Sarah E; Nozaki, Naohito; Nunes, Luis; Pappas, John G; Penney, Lynette S; Pérez-Aytés, Antonio; Petersen, Michael B; Puisac, Beatriz; Revencu, Nicole; Roeder, Elizabeth; Saitta, Sulagna; Scheuerle, Angela E; Schindeler, Karen L; Siu, Victoria M; Stark, Zornitza; Strom, Samuel P; Thiese, Heidi; Vater, Inga; Willems, Patrick; Williamson, Kathleen; Wilson, Louise C; Hakonarson, Hakon; Quintero-Rivera, Fabiola; Wierzba, Jolanta; Musio, Antonio; Gillessen-Kaesbach, Gabriele; Ramos, Feliciano J; Jackson, Laird G; Shirahige, Katsuhiko; Pié, Juan; Christianson, David W; Krantz, Ian D; Fitzpatrick, David R; Deardorff, Matthew A

    2014-06-01

    Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS. PMID:24403048

  19. Causes of Death and Autopsy Findings in a Large Study Cohort of Individuals with Cornelia de Lange Syndrome and Review of the Literature

    PubMed Central

    Schrier, Samantha A.; Sherer, Ilana; Deardorff, Matthew A.; Clark, Dinah; Audette, Lynn; Gillis, Lynette; Kline, Antonie D.; Ernst, Linda; Loomes, Kathy; Krantz, Ian D.; Jackson, Laird G.

    2011-01-01

    To identify causes of death (COD) in propositi with Cornelia de Lange syndrome (CdLS) at various ages, and to develop guidelines to improve management and avoid morbidity and mortality, we retrospectively reviewed a total of 426 propositi with confirmed clinical diagnoses of CdLS in our database who died in a 41-year period between 1966–2007. Of these, 295 had an identifiable COD reported to us. Clinical, laboratory and complete autopsy data were completed on 41, of which 38 were obtainable, an additional 19 had autopsies that only documented the COD, and 45 propositi had surgical, imaging, or terminal event clinical documentation of their COD. Proband ages ranged from fetuses (21 to 40 weeks gestation) to 61 years. A literature review was undertaken to identify all reported causes of death in CdLS individuals. In our cohort of 295 propositi with a known COD, respiratory causes including aspiration/reflux and pneumonias were the most common primary causes (31%), followed by gastrointestinal disease, including obstruction/volvulus (19%). Congenital anomalies accounted for 15% of deaths and included congenital diaphragmatic hernia and congenital heart defects. Acquired cardiac disease accounted for 3% of deaths. Neurological causes and accidents each accounted for 8%, sepsis for 4%, cancer for 2%, renal disease for 1.7%, and other causes, 9% of deaths. We also present 21 representative clinical cases for illustration. This comprehensive review has identified important etiologies contributing to the morbidity and mortality in this population that will provide for an improved understanding of clinical complications, and management for children and adults with CdLS. PMID:22069164

  20. Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

    PubMed Central

    Kaiser, Frank J.; Ansari, Morad; Braunholz, Diana; Concepción Gil-Rodríguez, María; Decroos, Christophe; Wilde, Jonathan J.; Fincher, Christopher T.; Kaur, Maninder; Bando, Masashige; Amor, David J.; Atwal, Paldeep S.; Bahlo, Melanie; Bowman, Christine M.; Bradley, Jacquelyn J.; Brunner, Han G.; Clark, Dinah; Del Campo, Miguel; Di Donato, Nataliya; Diakumis, Peter; Dubbs, Holly; Dyment, David A.; Eckhold, Juliane; Ernst, Sarah; Ferreira, Jose C.; Francey, Lauren J.; Gehlken, Ulrike; Guillén-Navarro, Encarna; Gyftodimou, Yolanda; Hall, Bryan D.; Hennekam, Raoul; Hudgins, Louanne; Hullings, Melanie; Hunter, Jennifer M.; Yntema, Helger; Innes, A. Micheil; Kline, Antonie D.; Krumina, Zita; Lee, Hane; Leppig, Kathleen; Lynch, Sally Ann; Mallozzi, Mark B.; Mannini, Linda; Mckee, Shane; Mehta, Sarju G.; Micule, Ieva; Mohammed, Shehla; Moran, Ellen; Mortier, Geert R.; Moser, Joe-Ann S.; Noon, Sarah E.; Nozaki, Naohito; Nunes, Luis; Pappas, John G.; Penney, Lynette S.; Pérez-Aytés, Antonio; Petersen, Michael B.; Puisac, Beatriz; Revencu, Nicole; Roeder, Elizabeth; Saitta, Sulagna; Scheuerle, Angela E.; Schindeler, Karen L.; Siu, Victoria M.; Stark, Zornitza; Strom, Samuel P.; Thiese, Heidi; Vater, Inga; Willems, Patrick; Williamson, Kathleen; Wilson, Louise C.; Hakonarson, Hakon; Quintero-Rivera, Fabiola; Wierzba, Jolanta; Musio, Antonio; Gillessen-Kaesbach, Gabriele; Ramos, Feliciano J.; Jackson, Laird G.; Shirahige, Katsuhiko; Pié, Juan; Christianson, David W.; Krantz, Ian D.; Fitzpatrick, David R.; Deardorff, Matthew A.

    2014-01-01

    Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS. PMID:24403048

  1. Genetics Home Reference: Cornelia de Lange syndrome

    MedlinePlus

    ... L, Mortier GR, Nozaki N, Petersen MB, Seimiya H, Siu VM, Suzuki Y, Takagaki K, Wilde JJ, ... Xu W, Gil-Rodríguez MC, Clark D, Hakonarson H, Halbach S, Michelis LD, Rampuria A, Rossier E, Spranger S, ...

  2. Obituary: Andrew Lange (1957-2010)

    NASA Astrophysics Data System (ADS)

    Kamionkowski, Marc

    2011-12-01

    The worlds of physics and astrophysics were stunned to learn on 22 January 2010 that Andrew Lange, the Marvin L. Goldberger Professor of Physics at Caltech, had taken his own life the night before. He had succumbed to the severe depression that he had suffered from for many years, unbeknownst to even his closest colleagues. Lange will perhaps be best remembered as the co-leader of Boomerang, the balloon-borne experiment that provided the first high-angular-resolution map of the cosmic microwave background (CMB). And while this was certainly his most notable achievement, Andrew amassed a record of accomplishment as an instrumentalist, leader, mentor, and communicator that extended much further. Andrew was born in Urbana, Illinois on July 23, 1957, the son of an architect and a librarian, and raised primarily in Connecticut. His family and early friends remember him as a serious and extremely intelligent child and young man. Andrew Lange's lifelong interest in the CMB was nurtured as an undergraduate at Princeton University by David Wilkinson, and he recalled fondly a summer spent working with John Mather at Goddard Space Flight Center. Andrew Lange went to graduate school in physics at Berkeley where he worked in Paul Richards' group. Although his thesis project, the Berkeley-Nagoya rocket experiment, showed an anomalous sub-millimeter excess in the CMB spectrum that was shortly thereafter shown by a later flight of the same rocket and COBE-FIRAS to be incorrect, Lange's talents were recognized by the physics department at Berkeley who appointed him shortly after his PhD (1987) to their faculty. While on the Berkeley faculty, Andrew obtained early detections of the Sunyaev-Zeldovich effect, upper limits to small-angle CMB fluctuations, and important infrared constraints to the interstellar medium. He also led a pioneering instrument operating 300 mK detectors for a small infrared satellite experiment. This early work showed high ambition and daring, and it pioneered

  3. Obituary: Andrew Lange (1957-2010)

    NASA Astrophysics Data System (ADS)

    Kamionkowski, Marc

    2011-12-01

    The worlds of physics and astrophysics were stunned to learn on 22 January 2010 that Andrew Lange, the Marvin L. Goldberger Professor of Physics at Caltech, had taken his own life the night before. He had succumbed to the severe depression that he had suffered from for many years, unbeknownst to even his closest colleagues. Lange will perhaps be best remembered as the co-leader of Boomerang, the balloon-borne experiment that provided the first high-angular-resolution map of the cosmic microwave background (CMB). And while this was certainly his most notable achievement, Andrew amassed a record of accomplishment as an instrumentalist, leader, mentor, and communicator that extended much further. Andrew was born in Urbana, Illinois on July 23, 1957, the son of an architect and a librarian, and raised primarily in Connecticut. His family and early friends remember him as a serious and extremely intelligent child and young man. Andrew Lange's lifelong interest in the CMB was nurtured as an undergraduate at Princeton University by David Wilkinson, and he recalled fondly a summer spent working with John Mather at Goddard Space Flight Center. Andrew Lange went to graduate school in physics at Berkeley where he worked in Paul Richards' group. Although his thesis project, the Berkeley-Nagoya rocket experiment, showed an anomalous sub-millimeter excess in the CMB spectrum that was shortly thereafter shown by a later flight of the same rocket and COBE-FIRAS to be incorrect, Lange's talents were recognized by the physics department at Berkeley who appointed him shortly after his PhD (1987) to their faculty. While on the Berkeley faculty, Andrew obtained early detections of the Sunyaev-Zeldovich effect, upper limits to small-angle CMB fluctuations, and important infrared constraints to the interstellar medium. He also led a pioneering instrument operating 300 mK detectors for a small infrared satellite experiment. This early work showed high ambition and daring, and it pioneered

  4. Chromosome Rearrangements in Cornelia de Lange Syndrome (CdLS): Report of a der(3)t(3;12)(p25.3;p13.3) in Two Half Sibs With Features of CdLS and Review of Reported CdLS Cases With Chromosome Rearrangements

    PubMed Central

    DeScipio, Cheryl; Kaur, Maninder; Yaeger, Dinah; Innis, Jeffrey W.; Spinner, Nancy B.; Jackson, Laird G.; Krantz, Ian D.

    2016-01-01

    Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited disorder characterized by multisystem involvement, cognitive delay, limb defects, and characteristic facial features. Recently, mutations in NIPBL have been found in ~50% of individuals with CdLS. Numerous chromosomal rearrangements have been reported in individuals with CdLS. These rearrangements may be causative of a CdLS phenotype, result in a phenocopy, or be unrelated to the observed phenotype. We describe two half siblings with a der(3)t(3;12)(p25.3;p13.3) chromosomal rearrangement, clinical features resembling CdLS, and phenotypic overlap with the del(3)(p25) phenotype. Region-specific BAC probes were used to fine-map the breakpoint region by fluorescence in situ hybridization (FISH). FISH analysis places the chromosome 3 breakpoint distal to RP11-115G3 on 3p25.3; the chromosome 12 breakpoint is distal to BAC RP11-88D16 on 12p13.3. A review of published cases of terminal 3p deletions and terminal 12p duplications indicates that the findings in these siblings are consistent with the del(3)(p25) phenotype. Given the phenotypic overlap with CdLS, we have reviewed the reported cases of chromosomal rearrangements involved in CdLS to better elucidate other potential loci that could harbor additional CdLS genes. Additionally, to identify chromosome rearrangements, genome-wide array comparative genomic hybridization (CGH) was performed on eight individuals with typical CdLS and without identifiable deletion or mutation of NIPBL. No pathologic rearrangements were identified. PMID:16075459

  5. SuperMacLang: Development of an Authoring System.

    ERIC Educational Resources Information Center

    Frommer, Judith; Foelsche, Otmar K. E.

    1999-01-01

    Describes the development of "SuperMacLang, the 1990s version of the MacLang authoring system. An analysis of various features of the program explains the ways in which certain aspects of collaboration and funding affected developer and programming decisions. (Author/VWL)

  6. Characteristics of CdLS (Cornelia de Lange Syndrome)

    MedlinePlus

    ... Highlighted Events Cornelia's Garden Dress Down for CdLS Golf Tournaments Grandparents Tea Phantom Runner Team CdLS Team ... with the degree ranging from mild to severe. Learning disabilities and severe language delays are often present. ...

  7. Rare Diseases Leading to Childhood Glaucoma: Epidemiology, Pathophysiogenesis, and Management.

    PubMed

    Abdolrahimzadeh, Solmaz; Fameli, Valeria; Mollo, Roberto; Contestabile, Maria Teresa; Perdicchi, Andrea; Recupero, Santi Maria

    2015-01-01

    Noteworthy heterogeneity exists in the rare diseases associated with childhood glaucoma. Primary congenital glaucoma is mostly sporadic; however, 10% to 40% of cases are familial. CYP1B1 gene mutations seem to account for 87% of familial cases and 27% of sporadic cases. Childhood glaucoma is classified in primary and secondary congenital glaucoma, further divided as glaucoma arising in dysgenesis associated with neural crest anomalies, phakomatoses, metabolic disorders, mitotic diseases, congenital disorders, and acquired conditions. Neural crest alterations lead to the wide spectrum of iridocorneal trabeculodysgenesis. Systemic diseases associated with childhood glaucoma include the heterogenous group of phakomatoses where glaucoma is frequently encountered in the Sturge-Weber syndrome and its variants, in phakomatosis pigmentovascularis associated with oculodermal melanocytosis, and more rarely in neurofibromatosis type 1. Childhood glaucoma is also described in systemic disorders of mitotic and metabolic activity. Acquired secondary glaucoma has been associated with uveitis, trauma, drugs, and neoplastic diseases. A database research revealed reports of childhood glaucoma in rare diseases, which do not include glaucoma in their manifestation. These are otopalatodigital syndrome, complete androgen insensitivity, pseudotrisomy 13, Brachmann-de Lange syndrome, acrofrontofacionasal dysostosis, caudal regression syndrome, and Wolf-Hirschhorn syndrome. PMID:26451378

  8. Rare Diseases Leading to Childhood Glaucoma: Epidemiology, Pathophysiogenesis, and Management

    PubMed Central

    Abdolrahimzadeh, Solmaz; Fameli, Valeria; Mollo, Roberto; Contestabile, Maria Teresa; Perdicchi, Andrea; Recupero, Santi Maria

    2015-01-01

    Noteworthy heterogeneity exists in the rare diseases associated with childhood glaucoma. Primary congenital glaucoma is mostly sporadic; however, 10% to 40% of cases are familial. CYP1B1 gene mutations seem to account for 87% of familial cases and 27% of sporadic cases. Childhood glaucoma is classified in primary and secondary congenital glaucoma, further divided as glaucoma arising in dysgenesis associated with neural crest anomalies, phakomatoses, metabolic disorders, mitotic diseases, congenital disorders, and acquired conditions. Neural crest alterations lead to the wide spectrum of iridocorneal trabeculodysgenesis. Systemic diseases associated with childhood glaucoma include the heterogenous group of phakomatoses where glaucoma is frequently encountered in the Sturge-Weber syndrome and its variants, in phakomatosis pigmentovascularis associated with oculodermal melanocytosis, and more rarely in neurofibromatosis type 1. Childhood glaucoma is also described in systemic disorders of mitotic and metabolic activity. Acquired secondary glaucoma has been associated with uveitis, trauma, drugs, and neoplastic diseases. A database research revealed reports of childhood glaucoma in rare diseases, which do not include glaucoma in their manifestation. These are otopalatodigital syndrome, complete androgen insensitivity, pseudotrisomy 13, Brachmann-de Lange syndrome, acrofrontofacionasal dysostosis, caudal regression syndrome, and Wolf-Hirschhorn syndrome. PMID:26451378

  9. Kaj Ulrik Linderstrøm-Lang (1896-1959).

    PubMed Central

    Schellman, J. A.; Schellman, C. G.

    1997-01-01

    The Carlsberg Laboratory in Copenhagen has had a long tradition of outstanding science. At the time covered by this discussion, Kjeldahl, Sørensen, and Linderstrøm-Lang had been consecutive directors of the Chemical Laboratory for 83 years. Lang's inspired leadership began in the 1930s with a number of innovations (study of metabolism in single cells, titrations in non-aqueous solvents, relation of proteolysis to structure) but it was not until the early 1950s that Denmark had sufficiently recovered from the war for the laboratory to enter world science again. During World War II, Lang had been active in the Danish resistance movement. After the war, a number of major advances were being made that would revolutionize the field of protein chemistry (Pauling and Corey's H-bonded structures, Sanger's sequencing techniques, chromatography, Watson and Crick structures, modern instrumentation). The time for the new field of the physical biochemistry of proteins had arrived. Lang, with his broad experience, adventurous spirit, and genius for innovation, created an environment that was ideal for the convergence of these disconnected advances into a uniform science. The emphasis was to be on quantitative measurements on proteins in solution with interpretations based on molecular structures. During an all-too-brief period of time, Lang's laboratory attracted a large fraction of those who were destined to be the leaders of the next generation of protein chemists. At this time, the Carlsberg Laboratory was probably the most scientifically exciting environment for a protein chemist. The methods developed at that time-hydrogen exchange, limited proteolysis, optical rotatory dispersion, volume changes accompanying protein reactions, automatic titrations-are still all in common use and many of the visitors to the laboratory in that period and their students are still playing major roles in protein research. Lang's other qualities should not be ignored. He was not only a great

  10. Arc Magma Genesis from Melting of Mélange Diapirs

    NASA Astrophysics Data System (ADS)

    Cruz-Uribe, A. M.; Marschall, H.; Gaetani, G. A.

    2015-12-01

    Alkaline basalts occur in many subduction-related volcanic settings, including the Sunda, Izu-Bonin, Honshu, Aeolian, and Aleutian arcs, yet their origin continues to be debated. Recent studies have suggested that buoyant material (mélange) from the slab-wedge interface may rise into the hot corner of the mantle wedge as low-density plumes or diapirs, where it will melt or induce mantle melting due to dehydration. High-pressure mélange rocks represent a mixture of mafic, ultramafic, and sedimentary components, and are often dominated by chlorite. Mélange rocks are also enriched in accessory phases such as monazite, zircon, and rutile, which host a variety of trace elements. We present results from experimental melting of chlorite-rich mélange material at mantle wedge conditions that reproduce many of the compositional features of subduction-related lavas. Piston cylinder experiments were performed at conditions appropriate for mantle wedge diapirs (1030-1280 °C, 1.5-2.5 GPa) using natural mélange rocks from Syros, Greece. Experimental melts derived from omphacite-epidote-phengite bearing chlorite schists range in composition from basaltic trachyandesites to trachydacites to more alkaline melt compositions (50.7-60.73 wt% SiO2, 7.48-12.93 wt% Na2O+K2O). All of the experimental melts are characterized by high alumina contents (16.79-21.36 wt% Al2O3). Minerals coexisting with these melts include clinopyroxene, amphibole (at lower T) or olivine (at higher T), garnet (at higher P), ilmenite and/or rutile, and zircon. Trace element patterns in our experimentally produced melts are similar to those from arc volcanoes worldwide. Experimental melts are enriched in large ion lithophile elements (Cs, Rb, Ba, K, Pb, Sr) and depleted in high field strength elements (Nb, Ta, and Ti). Zirconium and Hf are enriched relative to the rare earth elements (REE), which show flat to heavy REE depleted patterns depending on the presence of residual garnet. Thorium is fractionated

  11. Genes and Syndromic Hearing Loss.

    ERIC Educational Resources Information Center

    Keats, Bronya J. B.

    2002-01-01

    This article provides a description of the human genome and patterns of inheritance and discusses genes that are associated with some of the syndromes for which hearing loss is a common finding, including: Waardenburg, Stickler, Jervell and Lange-Neilsen, Usher, Alport, mitochondrial encephalomyopathy, and sensorineural hearing loss. (Contains…

  12. Discrete Lange-Newell criterion for dissipative systems.

    PubMed

    Ndzana, Fabien I I; Mohamadou, Alidou; Kofané, Timoleon Crépin

    2009-05-01

    We report on the derivation of the discrete complex Ginzburg-Landau equation with first- and second-neighbor couplings using a nonlinear electrical network. Furthermore, we discuss theoretically and numerically modulational instability of plane carrier waves launched through the line. It is pointed out that the underlying analysis not only spells out the discrete Lange-Newell criterion by the means of the linear stability analysis at which the modulational instability occurs for the generation of a train of ultrashort pulses, but also characterizes the long-time dynamical behavior of the system when the instability grows. PMID:19518586

  13. Tectonic Emplacement of the Ophiolitic Mélange in the West Junggar, NW China: Comment on the Plate Boundary Significance of Ophiolitic Mélange Belt

    NASA Astrophysics Data System (ADS)

    Wang, G.; Xu, Y.; Xiao, L.; Chen, C.

    2014-12-01

    Many ophiolitic mélanges distribute in the West Junggar, NW China. They are fault-contacted with Carboniferous turbidites with mostly NE trend and some NS trend with ages mostly Ordovician-Silurian and some Late Devonian. The boundary faults and the foliation inside the mélanges are of high-angle or nearly vertical. The NE trend ophiolitic mélange belts were structurally emplaced into the Carboniferous strata mainly by dextral transpressive deformation, but the NS trend ophiolitic mélange belts mainly by lateral extrusion deformation or pure shearing, suggesting a uniform stress field of nearly EW compression controlled the emplacements. The tectonic relationship between the ophiolitic mélanges and the Carboniferous turbidites imply that the ophiolitic mélanges are the main components of the basement of the Carboniferous strata. The geophysical data also reveal that high gravity, high magnetic and medium resistivity exist under the Carboniferous strata, matching well to the distribution of the ophiolitic mélanges on the surface. The neodymium model ages (TDM) of widely distributed Late Carboniferous-Permian granites are mostly between 0.352-0.923Ga and concentrate in 0.45-0.6Ga with positive eNd(t) mostly between 5~10, suggesting the Early Paleozoic rocks as the main magma source, consistent with the age of the ophiolitic mélanges, also coinciding with the conclusion of the ophiolitic mélanges as the basement of the Carboniferous strata. The Carboniferous turbidites primarily formed in residual basin. Early Permian terrestrial coarse molasses deposits unconformitily cover on the Carboniferous turbidites, suggesting the residual basin closed in Late Carboniferous. The accretionary complex or residual oceanic crust emplaced into the overlying Carboniferous turbidites through the dextral transpression or lateral extrusion due to EW convergent when the residual basin closed. The tectonic juxtaposition relationship between the ophiolitic mélanges and the

  14. Roberts syndrome

    PubMed Central

    Xu, Baoshan; Lu, Shuai; Gerton, Jennifer L

    2014-01-01

    All living organisms must go through cycles of replicating their genetic information and then dividing the copies between two new cells. This cyclical process, in cells from bacteria and human alike, requires a protein complex known as cohesin. Cohesin is a structural maintenance of chromosomes (SMC) complex. While bacteria have one form of this complex, yeast have several SMC complexes, and humans have at least a dozen cohesin complexes alone. Therefore the ancient structure and function of SMC complexes has been both conserved and specialized over the course of evolution. These complexes play roles in replication, repair, organization, and segregation of the genome. Mutations in the genes that encode cohesin and its regulatory factors are associated with developmental disorders such as Roberts syndrome, Cornelia de Lange syndrome, and cancer. In this review, we focus on how acetylation of cohesin contributes to its function. In Roberts syndrome, the lack of cohesin acetylation contributes to nucleolar defects and translational inhibition. An understanding of basic SMC complex function will be essential to unraveling the molecular etiology of human diseases associated with defective SMC function. PMID:25054091

  15. The origin of mélanges: Cautionary tales from Indonesia

    NASA Astrophysics Data System (ADS)

    Barber, A. J.

    2013-10-01

    The origin of block-in-matrix mélanges has been the subject of intense speculation by structural and tectonic geologists working in accretionary complexes since their first recognition in the early twentieth century. Because of their enigmatic nature, a number of important international meetings and a large number of publications have been devoted to the problem of the origin of mélanges. As mélanges show the effects of the disruption of lithological units to form separate blocks, and also apparently show the effects shearing in the scaly fabric of the matrix, a tectonic origin has often been preferred. Then it was suggested that the disruption to form the blocks in mélanges could also occur in a sedimentary environment due to the collapse of submarine fault scarps to form olistostromes, upon which deformation could be superimposed tectonically. Subsequently it has proposed that some mélanges have originated by overpressured clays rising buoyantly towards the surface, incorporating blocks of the overlying rocks in mud or shale diapirs and mud volcanoes. Two well-known examples of mélanges from the Banda and Sunda arcs are described, to which tectonic and sedimentary origins were confidently ascribed, which proved on subsequent examination to have been formed due to mud diapirism, in a dynamically active environment, as the result of tectonism only indirectly. Evidence from the Australian continental Shelf to the south of Sumba shows that large quantities of diapiric mélange were generated before the diapirs were incorporated in the accretionary complex. Comparable diapirs can be recognised in Timor accreted at an earlier stage. Evidence from both Timor and Nias shows that diapiric mélange can be generated well after the initial accretion process was completed. The problem is: Why, when diapirism is so abundantly found in present convergent margins, is it so rarely reported from older orogenic belts? Many occurrences of mélanges throughout the world to

  16. Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients

    PubMed Central

    Russo, Silvia; Masciadri, Maura; Gervasini, Cristina; Azzollini, Jacopo; Cereda, Anna; Zampino, Giuseppe; Haas, Oskar; Scarano, Gioacchino; Di Rocco, Maja; Finelli, Palma; Tenconi, Romano; Selicorni, Angelo; Larizza, Lidia

    2012-01-01

    Cornelia de Lange syndrome (CdLS) is a rare multisystemic congenital anomaly disorder that is characterised by intellectual disability and growth retardation, congenital heart defects, intestinal anomalies, facial dysmorphism (including synophyris and high arched eyebrows) and limb reduction defects. Mutations in three cohesin-associated genes encoding a key regulator (NIPBL, chr 5p13.2) and one structural component of the cohesin ring (SMC1A, chr Xp11) occur in about 65% of CdLS patients. NIPBL is the major causative gene, and accounts for 40–60% of CdLS patients as shown by a number of mutational screening studies that indicate a wide mutational repertoire of mainly small deletions and point mutations. Only a few data are available concerning the occurrence of large NIPBL rearrangements or intragenic deletions or duplications involving whole exons. We used multiplex ligation-dependent probe amplification (MLPA) to study 132 CdLS patients negative to the standard mutation NIPBL test out of a cohort of 200 CdLS patients. A total of 7 out of 132 patients were found to carry NIPBL alterations, including two large gene deletions extending beyond the gene, four intragenic multi- or single-exon deletions and one single-exon duplication. These findings show that MLPA leads to a 5.3% increase in the detection of mutations when used in addition to the standard NIPBL scan, and contributes per se to the molecular diagnosis of 3.5% (7/200) of clinically diagnosed CdLS patients. It is recommended that MLPA be included in the CdLS diagnostic flow chart. PMID:22353942

  17. Delineation of Behavioral Phenotypes in Genetic Syndromes: Characteristics of Autism Spectrum Disorder, Affect and Hyperactivity

    ERIC Educational Resources Information Center

    Oliver, Chris; Berg, Katy; Moss, Jo; Arron, Kate; Burbidge, Cheryl

    2011-01-01

    We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n = 104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in…

  18. Mechanisms and processes of stratal disruption and mixing in the development of mélanges and broken formations: Redefining and classifying mélanges

    NASA Astrophysics Data System (ADS)

    Festa, A.; Dilek, Y.; Pini, G. A.; Codegone, G.; Ogata, K.

    2012-09-01

    The terms mélange and broken formation have been used in different ways in the literature. The lack of agreement on their definition often leads to confusion and misinterpretations. An evaluation of the various uses of these terms allows us to consider several types of chaotic rock bodies originated by tectonic, sedimentary and diapiric processes in different tectonic settings. Our review of stratal disruption and mixing processes shows that there exists a continuum of deformation structures and processes in the generation of mélanges and broken formations. This continuum is directly controlled by the increase of the degree of consolidation with burial. In tectonically active environments, at the shallow structural levels, the occurrence of poorly consolidated sediments favors gravitational deformation. At deeper structural levels, the deformation related to tectonic forces becomes gradually more significant with depth. Sedimentary (and diapiric) mélanges and broken formations represent the products of punctuated stratal disruption mechanisms recording the instantaneous physical conditions in the geological environment at the time of their formation. The different kinematics, the composition and lithification degree of sediments, the geometry and morphology of the basins, and the mode of failure propagation control the transition between different types of mass-transported chaotic bodies, the style of stratal disruption, and the amount of rock mixing. Tectonically broken formations and mélanges record a continuum of deformation that occurs through time and different degrees of lithification during a progressive increase of the degree of consolidation and of the diagenetic and metamorphic mineral transformation. Systematic documentation of the mechanisms and processes of the formation of different broken formations and mélanges and their interplay in time and space are highly important to increase the understanding of the evolutionary history of accretionary

  19. The Prevalence and Phenomenology of Repetitive Behavior in Genetic Syndromes

    ERIC Educational Resources Information Center

    Moss, Joanna; Oliver, Chris; Arron, Kate; Burbidge, Cheryl; Berg, Katy

    2009-01-01

    We investigated the prevalence and phenomenology of repetitive behavior in genetic syndromes to detail profiles of behavior. The Repetitive Behaviour Questionnaire (RBQ) provides fine-grained identification of repetitive behaviors. The RBQ was employed to examine repetitive behavior in Angelman (N = 104), Cornelia de Lange (N = 101), Cri-du-Chat…

  20. Development of tectono-sedimentary mélanges in accretionary wedges: Insights from analog modeling

    NASA Astrophysics Data System (ADS)

    Genti, M.; Malavieille, J.; Molli, G.; Dominguez, S.; Taboada, A.; Vitale-Brovarone, A.

    2012-04-01

    Orogenic wedges locally present chaotic tectonostratigraphic units that contain exotic blocks of various size, origin, age and lithology, embedded in a sedimentary matrix. The occurrence of ophiolitic blocks, sometimes huge, in such "mélanges" raises questions on i) the mechanisms responsible for the incorporation of oceanic basement rocks into an accretionary wedge and ii) the mechanisms allowing exhumation and possibly redeposition of these exotic elements in "mélanges" during wedge growth. The tectonic evolution of the back part of doubly vergent accretionary wedges is mainly controled by backthrusting. The retrowedge is characterized by steep slopes that are prone to gravitational instabilities. We assume that these steep slopes trigger submarine landslides playing a major erosional role and therefore inducing huge mass transfers. This erosion allows exhumation of the ophiolitic fragments formerly accreted at the base of the wedge and then reworked as tectono-sedimentary "mélanges" redeposited in proximal basins located at the base of the retrowedge slope. These basin deposits are then continuously involved in backthrusting-induced deformation. In this study, we present the results of a series of analog experiments performed to characterize the processes and parameters responsible for accretion, exhumation and final tectonosedimentary reworking of oceanic basement lithosphere fragments in an accretionary wedge. The experimental setup is designed to simulate the interaction between tectonics, erosion and sedimentation. Different configurations are applied to study the impact of various parameters, such as irregular oceanic floor due to structural inheritance, or the presence of layers with contrasted rheology that can affect deformation partitioning in the wedge (frontal accretion vs basal accretion) influencing its growth. The experimental results are then compared with observations on ophiolite-bearing mélanges in the Taïwan (Lichi mélange) and northern

  1. Carer-Reported Contemporary Health Problems in People with Severe and Profound Intellectual Disability and Genetic Syndromes

    ERIC Educational Resources Information Center

    Berg, Katy; Arron, Kate; Burbidge, Cheryl; Moss, Joanna; Oliver, Chris

    2007-01-01

    Identifying health problems in people with severe and profound disabilities and genetic syndromes can be problematic, and unidentified or unmanaged health problems may adversely impact an individual's quality of life. The authors studied carer-reported contemporary health problems in three genetic syndromes (Angelman, Cornelia de Lange, and Cri du…

  2. Mechanisms of mélange formation: Examples from SW Japan and southern Scotland

    NASA Astrophysics Data System (ADS)

    Needham, D. T.

    1995-07-01

    The formation of synthetic Riedel shears either as discrete faults or ductile shear-zones is important in the fragmentation of layers to form mélanges. The magnitude of longitudinal and shear strain necessary for this fragmentation has been assessed using a simple rigid-domino model for layer-parallel shear. The strain required for layer fragmentation is a function of block aspect ratio and initial fracture dip relative to layering. Layer stretching can occur during simple shear if folds are developed but a component of extension parallel to the shear zones reduces the strain required for fragmentation. Simple models of this type break down when there is a component of dilation across the mélange block bounding fractures allowing shale matrix infill or mineral vein growth. Some mélanges show evidence, in the form of symmetrical structures, of a more coaxial deformation history and this may in part reflect deformation partitioning between sandstone and shale layers. Other mechanisms of mélange formation include the development of out-of-sequence thrusts cutting through already dipping beds. The causes of strike-parallel extension are tentatively related to large-scale evidence of arc-parallel forearc stretching.

  3. From Tappan to Lange: Evolution of the Public Junior College Idea.

    ERIC Educational Resources Information Center

    Gallagher, Edward Arthur

    This study is a historical analysis of the public junior college idea and its emergence. The thoughts and actions of Henry P. Tappan, William W. Folwell, William R. Harper, David S. Jordan, and Alexis Lange contributed most to its origin and development. These men, products of the late nineteenth and early twentieth centuries, were strongly…

  4. The Varieties of Emotional Experience: A Meditation on James-Lange Theory.

    ERIC Educational Resources Information Center

    Lang, Peter J.

    1994-01-01

    This article traces the origin of the James-Lange theory of emotion, considers differences in their thinking, and assesses early criticisms and debate. Research on physiological patterns in emotion is reviewed. New paths for emotion research are outlined and homage is paid to the inspiration of William James. (SLD)

  5. Friedrich Albert Lange on neo-Kantianism, socialist Darwinism, and a psychology without a soul.

    PubMed

    Teo, Thomas

    2002-01-01

    Friedrich Albert Lange was a German philosopher, political theorist, educator, and psychologist who outlined an objective psychology in the 1860s. This article shows how some of the most important worldviews of the nineteenth century (Kantianism, Marxism, and Darwinism) were combined creatively in his thought system. He was crucial in the development of neo-Kantianism and incorporated psycho-physiological research on sensation and perception in order to defend Kant's epistemological idealism. Based on a critique of phrenology and philosophical psychology of his time, Lange developed a program of a psychology without a soul. He suggested that only those phenomena that can be observed and controlled should be studied, that psychology should focus on actions and speech, and that for each psychological event the corresponding physical or physiological processes should be identified. Lange opposed introspection and subjective accounts and promoted experiments and statistics. He also promoted Darwinism for psychology while developing a socialist progressive-democratic reading of Darwin in his social theory. The implications of socialist Darwinism on Lange's conceptualization of race are discussed and his prominence in nineteenth century philosophy and psychology is summarized. PMID:12115788

  6. lange as a Plate Boundary Rock and its Seismogenic Roof Thrust - An Example From the Shimanto Belt, Japan

    NASA Astrophysics Data System (ADS)

    Kitamura, Y.; Sato, K.; Ikesawa, E.; Kimura, G.; Kondo, H.; Ujiie, K.; Onishi, C. T.; Kawabata, K.; Hashimoto, Y.; Mukoyoshi, H.; Masago, H.

    2003-12-01

    A tectonic mélange of the ancient accretionary prism of the Shimanto Belt, Japan is investigated to understand a plate boundary process, especially of seismogenic zone in subduction zone. We analyzed deformation fabric, magnetic fabrics, deformation mechanisms and their thermal condition by using vitrinite reflectance. The investigated Mugi mélange is located in western Shikoku. In the Mugi mélange, systematic fabrics such as Y-P-R fabric formed by micro shear and pressure solution mechanisms are penetrated throughout the mélange pile. Magnetic ellipsoids obtained from the anisotropy of magnetic susceptibility (AMS) are highly oblate. Maximum and minimum axes of the ellipsoids are in accordance with shear orientation of mélange and mean pole of foliation, respectively. These facts suggest that the Mugi mélange was formed as a result of underthrusting of trench filling sediments. Vitrinite reflectance ranges from 2.52% to 3.08%, which correlates to the maximum paleo-temperature of ca. 240 §C to 260 §C. Pseudotachylite of the most reliable seismogenic rock was found from the upper boundary roof fault of the Mugi mélange. The fault is composed of about 1 m thick cataclastic zone injected by many veins. The overlying Hiwasa formation is sandstone-dominated and folded coherent piles. The finding of the pseudotachylite in this study area is another example from the ancient accretionary complex after the first one from the Okitsu mélange in western Shikoku Island. The setting of the pseudotachylite from the boundary fault between tectonic mélange and overlying folded coherent pile is quite similar to that of the first one. There is no thermal gap between the mélange and coherent piles but temperature obtained from vitrinite reflectance gradually rises in descending from the coherent piles to the mélange beyond the boundary fault. Such setting suggests that paleo-isotherm was parallel to the orientation of the boundary fault. The isotherm in the seismogenic

  7. Effects of herbicides on Behr's metalmark butterfly, a surrogate species for the endangered butterfly, Lange's metalmark.

    PubMed

    Stark, John D; Chen, Xue Dong; Johnson, Catherine S

    2012-05-01

    Lange's metalmark butterfly, Apodemia mormo langei Comstock, is in danger of extinction due to loss of habitat caused by invasive exotic plants which are eliminating its food, naked stem buckwheat. Herbicides are being used to remove invasive weeds from the dunes; however, little is known about the potential effects of herbicides on butterflies. To address this concern we evaluated potential toxic effects of three herbicides on Behr's metalmark, a close relative of Lange's metalmark. First instars were exposed to recommended field rates of triclopyr, sethoxydim, and imazapyr. Life history parameters were recorded after exposure. These herbicides reduced the number of adults that emerged from pupation (24-36%). Each herbicide has a different mode of action. Therefore, we speculate that effects are due to inert ingredients or indirect effects on food plant quality. If these herbicides act the same in A. mormo langei, they may contribute to the decline of this species. PMID:22310058

  8. Toxicity of phosphor esters: Willy Lange (1900-1976) and Gerda von Krueger (1907-after 1970).

    PubMed

    Petroianu, G A

    2010-10-01

    In 1851 Williamson serendipitously discovered a new and efficient way to produce ethers using ethyl iodide and potassium salts. Based on this new synthetic approach, the Frenchman Philippe de Clermont and the Muscovite Wladimir Moschnin, both élèves of Adolphe Wurtz in his Paris School of Chemistry, achieved the synthesis of the first ester of pyrophosphoric acid (TEPP). de Clermont "tasted" the new compound and although TEPP is a potent cholinesterase inhibitor he failed to recognize its toxicity. Almost a century later, in 1932, Willy Lange (1900-1976) and his graduate student Gerda v. Krueger (1907-after 1970) described the toxicity of organophosphonates. While the classic paper of the two "Uber Ester der Monofluorphosphorsäure." is cited by almost everybody working in the field, little is known about Lange and almost nothing about v. Krueger. This brief communication attempts to shed some light on the life of both. PMID:21105582

  9. Unmetamorphosed sedimentary mélange with high-pressure metamorphic blocks in a nascent forearc basin setting

    NASA Astrophysics Data System (ADS)

    Hitz, Brian; Wakabayashi, John

    2012-09-01

    langes crop out within unmetamorphosed basal Great Valley Group (GVG) forearc basin strata and between GVG and the underlying Coast Range Ophiolite (CRO) in the San Francisco Bay region of coastal California. These mélanges include high-pressure (HP) metamorphic blocks of the Franciscan subduction complex that structurally underlies the unmetamorphosed CRO as well as blocks of GVG and CRO. The matrix consists of foliated shale and serpentinite, locally interleaved at centimeter scale. The mélanges strike and dip parallel to bounding GVG sandstones and conglomerates. The matrix locally consists of sedimentary breccia and conglomerate made up of clasts of serpentinite and shale. GVG sandstones within and bounding the mélanges have detrital serpentinite clasts. The field relationships indicate a sedimentary origin of the mélanges as olistostromal deposits within latest Jurassic to earliest Cretaceous basal GVG. The mélanges correlate to units along the eastern margin of the northern Coast Ranges, about 250 km to the north with restoration of post-subduction dextral faulting, and differ from the latter in the higher proportion of shale, stronger matrix foliation, and common occurrence of HP blocks. Similar units may have mistakenly been assigned to the Franciscan owing to the foliated nature of the matrix and occurrence of HP blocks. This and the broad distribution of localities indicate that these deposits are more widespread than previously believed. Exhumation rates of coarse-grained HP mélange blocks may have been 2 to 10 mm/yr or higher based on the ages of similar blocks in the Coast Ranges, burial depth of the blocks, and depositional age of the enclosing strata. Exhumation and deposition of Franciscan blocks in these GVG mélanges predates preserved accretion of similar materials in the adjacent Franciscan by at least 30 m.y., suggesting subduction erosion of previously accreted material, or exhumation of the blocks in forearc serpentinite

  10. Modelling the impact of submarine frontal melting and ice mélange on glacier dynamics

    NASA Astrophysics Data System (ADS)

    Krug, J.; Durand, G.; Gagliardini, O.; Weiss, J.

    2015-01-01

    Two mechanisms are generally proposed to explain seasonal variations in the calving front of tidewater glaciers: submarine melting of the calving face and the mechanical back-force applied by the ice mélange. However, the way these processes affect the calving rate and the glacier dynamics remains uncertain. In this study, we used the finite element model Elmer/Ice to simulate the impact of these forcings on more than 200 two dimensional theoretical flowline glacier configurations. The model, which includes calving processes, suggests that frontal melting affects the position of the terminus only slightly (< a few hundred meters) and does not affect the pluriannual glacier mass balance at all. However, the ice mélange has a greater impact on the advance and retreat cycles of the glacier front (more than several 1000 m) and its consequences for the mass balance are not completely negligible, stressing the need for better characterization of forcing properties. We also show that ice mélange forcing against the calving face can mechanically prevent crevasse propagation at sea level and hence prevent calving. Results also revealed different behaviors in grounded and floating glaciers: in the case of a floating extension, the heaviest forcings can disrupt the glacier equilibrium by modifying its buttressing and ice flux at the grounding line.

  11. Lawsonite Blueschists in Recycled Mélange Involved in K-Rich Orogenic Magmatism

    NASA Astrophysics Data System (ADS)

    Wang, Y.; Prelevic, D.; Foley, S. F.; Buhre, S.; Galer, S. J. G.

    2014-12-01

    The origin of K-rich orogenic magmatism in the Alpine-Himalayan belt and its relationship to the large-scale elevations in several massifs of the orogen is controversial, particularly the significance of the widespread presence of a geochemical signal typical for recycled continental crust. Two competing scenarios invoke direct melting of continental crust during deep intercontinental subduction and removal of heavily metasomatised mantle lithosphere by delamination into the convecting mantle. Here we investigate the coupling of high Th/La ratio with crustal isotopic signatures in K-rich orogenic lavas that does not occur in volcanic rocks from other collisional environments to distinguish between these two models. High-pressure experimental results on a phyllite representing upper crustal composition and a detailed mineral and geochemical study of blueschists from Tavşanlı mélange, Turkey, indicate that this geochemical fingerprint originates by melting of subducted mélange. Melting of crust at the top of the subducted continental lithosphere cannot produce observed fingerprint, whereas lawsonites, especially those with terrigenous sediment origin from blueschists with high Th/La can. Lawsonites that grow in various components of a subduction mélange inherit the geochemical characteristics of either oceanic or continental protoliths. It is currently uncertain whether those carrying the high Th/La signature originate by direct melting of continental blocks in the mélange or by the introduction of supercritical fluids from lawsonite blueschist of continental origin that infiltrate oceanic sediment blocks. Either way, the high Th/La is later released into subsequently formed melts. This confirms the supposition that lawsonite is the main progenitor of the high Th/La and Sm/La ratio. However, lawsonite must break down completely to impart this unique feature to subsequent magmas. The source regions of the potassic volcanic rocks consist of blueschist facies mélanges

  12. Subducted sedimentary serpentinite mélanges: Record of multiple burial-exhumation cycles and subduction erosion

    NASA Astrophysics Data System (ADS)

    Wakabayashi, John

    2012-09-01

    Serpentinite matrix mélanges give insight into large-scale convergent plate margin processes, particularly because of the derivation of the serpentinite from oceanic mantle. Similar to shale-matrix mélanges, a field geologist may easily recognize the sedimentary origins of little-deformed serpentinite matrix mélanges, but mélanges within accretionary prisms have undergone significant deformation and recrystallization of matrix. Serpentinite mélanges of the Franciscan subduction complex of California have a seemingly intact and foliated matrix. Such exposures contrast sharply with the granular undeformed sedimentary serpentinite mélanges of the coeval Great Valley Group (GVG) forearc basin deposits that depositionally overlie Coast Range Ophiolite (that structurally overlies the Franciscan). Nonetheless, Franciscan serpentinite mélanges display evidence of sedimentary origins, including sedimentary breccia composed of exotic block material (Tolay Ridge), sedimentary serpentinite breccia (Panoche Pass Road), basal serpentinite conglomerate with exotic clasts (Sunol Regional Wilderness), and serpentinite sandstones and conglomerates, including a basal conglomerate overlying coherent metagraywacke (Tiburon Peninsula). These examples record two burial-exhumation cycles to blueschist facies depths. In addition, a mélange/breccia in the Panoche Pass area may have components that record three burial-exhumation cycles to blueschist (or greater) depth. Exhumation rates for various cycles ranged from about 1.2 to 10 mm/year. The Tiburon Peninsula serpentinite mélange occupies the structurally highest horizon in the Franciscan of the San Francisco Bay area, and regional field relationships indicate deposition at ca. 100 Ma. Apparently, about 65 Ma of subduction erosion/non accretion followed initiation of Franciscan subduction in this region. The oldest Franciscan serpentinite mélanges are at least 35 Ma younger than sedimentary serpentinites of the GVG. Subduction

  13. The long Q-T syndromes.

    PubMed

    Gordon, N

    1994-01-01

    Loss of consciousness in childhood may be due to cardiovascular causes, and the Long Q-T syndromes can present with seizures. The Romano-Ward syndrome is of autosomal dominant inheritance, and the Jervell and Lange-Nielson syndrome, with associated deafness, of autosomal recessive inheritance. The diagnosis is often delayed, but a careful history can avoid this. The syndromes can appear to be due to an imbalance in the sympathetic nerve to the ventricular myocardium, and precipitating causes such as stress suggest a CNS influence on this. The electrocardiogram can confirm the prolonged Q-T interval, but this is not always present, at least without an exercise test. Treatment with beta-blockers is often successful. If a wrong diagnosis of epilepsy is made a chance may be missed of avoiding sudden death, quite apart from all the medical, and social consequences that can result from such a diagnosis. PMID:8048706

  14. Sedimentary Origins Of The Block-In-Matrix Fabric Of A Mélange Between Coherent Nappes Of A Subduction Complex: Localization Of The Paleosubduction Megathrust Along The Upper Mélange Contact

    NASA Astrophysics Data System (ADS)

    Wakabayashi, J.

    2011-12-01

    The Franciscan subduction complex of California comprises coherent nappes and intervening mélanges. The difference in metamorphic grade and/or accretionary age of adjacent coherent nappes suggests localization of paleosubduction megathrust horizons between them. One of the best examples of a mélange between coherent nappes crops out in an inactive quarry in El Cerrito in the eastern San Francisco Bay area. The upper coherent nappe consists of foliated, jadeite-bearing, blueschist facies metagraywacke, whereas the lower coherent nappe comprises prehnite-pumpellyite facies graywacke with little or no penetrative fabric makes. Detrital zircon geochronology indicates maximum depositional ages of 102 and 100 Ma, respectively, for these units. The foliation or bedding of the graywackes and their contacts strike northwest and dip northeast. C-s fabrics, shear bands, and asymmetric porphyroclasts show a consistent tops-to-the-southwest shear sense in the upper coherent unit, and this fabric developed with syntectonic growth of glaucophane, lawsonite, and jadeite. The intervening mélange has a matrix made up primarily of dark gray shale, with blocks of mostly graywacke, chert, and basalt. The mélange consists of mostly or entirely prehnite-pumpellyite facies material except for the upper 5-10 meters that features metamorphic growth of lawsonite, glaucophane, and jadeite. Thus, the metamorphic contrast between the two nappes, equivalent to at least 10 km in differential burial depth and greater amount of fault displacement, occurs within this narrow zone. The upper half of the mélange (~50 meters of structural thickness) exhibits a pronounced foliation oriented parallel to the bounding contacts. The foliation deflects into shear bands and c-surfaces and this fabric shows a consistent tops-to-the-southwest shear sense. Strain appears to increase structurally upward within the mélange. The structurally lowest part of the mélange displays virtually no strain, with

  15. Insights on deep, accretionary subduction processes from the Sistan ophiolitic "mélange" (Eastern Iran)

    NASA Astrophysics Data System (ADS)

    Angiboust, S.; Agard, P.; De Hoog, J. C. M.; Omrani, J.; Plunder, A.

    2013-01-01

    The Sistan ophiolitic belt, formed by the closure of the N-S trending Sistan Ocean during late Cretaceous times, comprises several branches and basins across a 100 × 700 km area along the Iran-Afghanistan border. One of these, the Ratuk complex, exposes disrupted HP ophiolitic blocks from a paleo-subduction complex generally interpreted as a tectonic "mélange". In order to better understand its overall structure and evaluate the degree of mixing within this mélange, an extensive set of serpentinized peridotites, mafic rocks and metasediments was collected in the Sulabest area (Ratuk complex). A detailed geological and structural map of the Sulabest area is herein provided, in which three main units (the Western, Upper and Eclogitic Units) separated by relatively sharp tectonic contacts were identified. The latter two of these slices exhibit metamorphic evidence for burial along the same HP-LT gradient (up to blueschist and eclogite facies, respectively). Sharp differences in peak metamorphic conditions and retrograde parageneses nevertheless suggest that they followed two distinct P-T trajectories. Geochemical signatures of ultramafic rocks indicate an abyssal origin for the non-metamorphic Western Unit while the presence of mantle wedge serpentinites is inferred for some samples from the high-pressure units. The differences in peak temperatures (between 520 and 650 °C) and the geochemical heterogeneity of mafic rocks suggest that tectonic mixing occurred (only) within the high-pressure units, possibly within the hydrated mantle wedge. Our results show that this portion of the Sistan ophiolitic belt did not form, as earlier proposed, by chaotic tectonic "mélange" (i.e. where small tectonic blocks with distinct P-T histories are mixed in a mechanically weak matrix). We instead propose that this segment of the ophiolitic belt formed via accretionary processes deep in the subduction zone, whereby distinct slices with different P-T histories were tectonically

  16. Controls on accretion of flysch and mélange belts at convergent margins: Evidence from the Chugach Bay thrust and Iceworm mélange, Chugach accretionary wedge, Alaska

    NASA Astrophysics Data System (ADS)

    Kusky, Timothy M.; Bradley, Dwight C.; Haeussler, Peter J.; Karl, Sue

    1997-12-01

    Controls on accretion of flysch and mélange terranes at convergent margins are poorly understood. Southern Alaska's Chugach terrane forms the outboard accretionary margin of the Wrangellia composite terrane, and consists of two major lithotectonic units, including Triassic-Cretaceous mélange of the McHugh Complex and Late Cretaceous flysch of the Valdez Group. The contact between the McHugh Complex and the Valdez Group on the Kenai Peninsula is a tectonic boundary between chaotically deformed melange of argillite, chert, greenstone, and graywacke of the McHugh Complex and a less chaotically deformed mélange of argillite and graywacke of the Valdez Group. We assign the latter to a new, informal unit of formational rank, the Iceworm mélange, and interpret it as a contractional fault zone (Chugach Bay thrust) along which the Valdez Group was emplaced beneath the McHugh Complex. The McHugh Complex had already been deformed and metamorphosed to prehnite-pumpellyite facies prior to formation of the Iceworm mélange. The Chugach Bay thrust formed between 75 and 55 Ma, as shown by Campanian-Maastrichtian depositional ages of the Valdez Group, and fault-related fabrics in the Iceworm mélange that are cut by Paleocene dikes. Motion along the Chugach Bay thrust thus followed Middle to Late Cretaceous collision (circa 90-100 Ma) of the Wrangellia composite terrane with North America. Collision related uplift and erosion of mountains in British Columbia formed a submarine fan on the Farallon plate, and we suggest that attempted subduction of this fan dramatically changed the subduction/accretion style within the Chugach accretionary wedge. We propose a model in which subduction of thinly sedimented plates concentrates shear strains in a narrow zone, generating mélanges like the McHugh in accretionary complexes. Subduction of thickly sedimented plates allows wider distribution of shear strains to accommodate plate convergence, generating a more coherent accretionary style

  17. The Casanova Complex of the Northern Apennines: A mélange formed on a distal passive continental margin

    NASA Astrophysics Data System (ADS)

    Naylor, Michaél A.

    1982-01-01

    The Cretaceous-Palaeocene Casanova Complex occurs in two thrust sheets of the eugeosynclinal Ligurids of the Northern Apennines. It is a sedimentary mélange with ophiolitic and quartzose turbidites or limestone-shale olistostrome (submarine debris flows) as matrix. Exotic blocks of ophiolite and granite, serpentinite breccias and lenticular ophiolitic breccias and olistostromes contribute to the mélange character of the complex. Deformational structures include soft-sediment slump folds (indicating a SW-dipping palaeoslope) and boudins, a gradational slumped top to the mélange, small-scale faults in chert blocks and deformation associated with the emplacement of the exotic slide blocks. The blocks were shed as rotational slides from submarine fault scarps and are surrounded by haloes of debris created by submarine weathering. The stacking pattern of the blocks, with the originally stratigraphically highest ophiolite lithologies lowest in the pile of blocks, is explained by a diverticulation model with progressively deeper erosion. Mechanical analysis shows that the blocks were stable when partly exposed resting on a soft sediment substratum. Criteria which distinguish the Casanova Complex from a tectonic mélange, and which may be of value in other mélanges, are discussed. Previous interpretations of the complex as a precursor olistostrome to northeastward nappe emplacement (the Bracco ridge model) are rejected. The mélange is believed to have formed on ocean crust as a result of turbidite and debris flow sedimentation, soft sediment deformation, block faulting, gravity sliding and submarine erosion at the distal edge of a uniformly SW-dipping continental margin.

  18. Biomarkers in Tertiary mélange, western Olympic Peninsula, Washington, U.S.A.

    USGS Publications Warehouse

    Kvenvolden, Keith A.; Hostettler, Frances D.; Rapp, John B.; Snavely, Parke D., Jr.

    1991-01-01

    Middle Eocene to middle Miocene mélange and broken formations are exposed in the coastal outcrops along the west side of the Olympic Peninsula, Washington. A petroleum geochemical assessment of these geologic units has included the investigation of biomarker compounds. A comparison was made of biomarkers in an oil sample from a middle Miocene reservoir penetrated in the Medina No. 1 well with biomarkers in extracts from two samples of middle Eocene Ozette mélange (one sample having a strong petroliferous odor, and the other sample lacking this characteristic odor). Distribution patterns of n-alkanes, tricyclic terpanes, pentacyclic triterpanes, steranes, and diasteranes are remarkably similar in the oil and rock extracts. Biomarker maturity parameters indicate higher maturity in the oil relative to the extracts. The presence of 17α(H)-23,28-bisnorlupane, 18α(H)- and 18β(H)-oleanane, and de-A-lupane and an odd-carbon-number dominance of the n-alkanes in the oil and extracts seems to tie the hydrocarbons to a common source that has a significant terrigenous component.

  19. Structural analysis and shape-preferred orientation determination of the mélange facies in the Chañaral mélange, Las Tórtolas Formation, Coastal Cordillera, northern Chile

    NASA Astrophysics Data System (ADS)

    Fuentes, Paulina; Díaz-Alvarado, Juan; Fernández, Carlos; Díaz-Azpiroz, Manuel; Rodríguez, Natalia

    2016-04-01

    This study sheds light on the tectonic and structural knowledge of the mélange facies located to the south of Chañaral city, Chile. The Chañaral mélange has been related to an accretionary prism at the western active continental margin of Gondwana. Based on the fossil content, the original turbidite sequence would have been deposited during Devonian to Carboniferous times. The Chañaral mélange is included in the Las Tórtolas Formation, which corresponds to the Paleozoic metasedimentary basement located in the Coastal Range in northern Chile. It consists of a monotonous sequence of more than 90% of interbedded sandstones and shales, with a few limestones, pelagic chert, conglomerates and basic volcanic rocks, metamorphosed to the greenschist facies. In the study area, the Las Tórtolas Formation is divided into two structural domains separated by a major reverse dextral structure, called here the Infieles fault. To the east, the Las Tórtolas Formation is characterized by a brittle-ductile deformation, defined by the original sedimentary contacts in the turbiditic sequence. Besides, thrust faults and associated thrust propagation folds promotes a penetrative axial plane foliation. Mélange facies are located to the west of the Infieles fault. Although lithologies comprising this domain are similar to the rest of the Las Tórtolas Formation, mélange facies (ductile domain) are characterized by the complete disruption of the original architecture of the turbidite succession. The most significant structures in the mélange are the ubiquitous boudinage and pinch and swell structures, asymmetric objects, S-C structures and tight to isoclinal folds. This deformation is partitioned in the Chañaral mélange between linear fabric domains (L), characterized by quartzite blocks with prolate shape in a phyllite matrix with pencil structures, and linear-planar fabric domains (L-S), where quartzite objects show oblate shape and phyllites present a penetrative foliation

  20. A giant novel gene undergoing extensive alternative splicing is severed by a Cornelia de Lange-associated translocation breakpoint at 3q26.3

    PubMed Central

    Tonkin, Emma T.; Smith, Melanie; Eichhorn, Piet; Jones, Sandie; Imamwerdi, Burhan; Lindsay, Susan; Jackson, Mike; Wang, Tzu-Jou; Ireland, Maggie; Burn, John; Krantz, Ian D.; Carr, Philippa

    2016-01-01

    Cornelia de Lange syndrome (CdLS) is a rare developmental malformation syndrome characterised by mental handicap, growth retardation, distinctive facial features and limb reduction defects. The vast majority of CdLS cases are sporadic. We carried out a high density bacterial artificial chromosome (BAC) microarray comparative genome hybridisation screen but no evidence was found for a consistent pattern of microdeletion/micro-duplication. As an alternative, we focused on identifying chromosomal regions spanning associated translocation breakpoints. We prioritised the distal 3q region because of the occurrence, in a classical CdLS patient, of a de novo balanced translocation with a breakpoint at 3q26.3 and of reports of phenotypic overlap between cases of mild CdLS and individuals trisomic for the 3q26-q27 region. We show that the 3q26.3 breakpoint severs a previously uncharacterised giant gene, NAALADL2, containing at least 32 exons spanning 1.37 Mb. Northern blot analysis identified up to six different transcripts in the 1–10 kb range with strongest expression in kidney and placenta; embryonic expression was largely confined to duodenal and stomach endoderm, mesonephros, metanephros and pancreas. Transcript analysis identified extensive alternative splicing leading to multiple 5′ and 3′ untranslated regions and variable coding sequences. Multiple protein isoforms were defined by different N-terminal regions (with at least four alternative initiating methionine codons), and by differential protein truncation/use of alternative C-terminal sequences attributable to alternative splicing/polyadenylation. Outside the N-terminal regions, the predicted proteins showed significant homology to N-acetylated alpha-linked acidic dipeptidase and transferrin receptors. Mutation screening of NAALADL2 in a panel of CdLS patient DNA samples failed to identify patient-specific mutations. We discuss the possibility that the 3q26.3 translocation could nevertheless contribute to

  1. Low-frequency fluctuations in vertical cavity lasers: Experiments versus Lang-Kobayashi dynamics

    SciTech Connect

    Torcini, Alessandro; Barland, Stephane; Giacomelli, Giovanni; Marin, Francesco

    2006-12-15

    The limits of applicability of the Lang-Kobayashi (LK) model for a semiconductor laser with optical feedback are analyzed. The model equations, equipped with realistic values of the parameters, are investigated below the solitary laser threshold where low-frequency fluctuations (LFF's) are usually observed. The numerical findings are compared with experimental data obtained for the selected polarization mode from a vertical cavity surface emitting laser (VCSEL) subject to polarization selective external feedback. The comparison reveals the bounds within which the dynamics of the LK model can be considered as realistic. In particular, it clearly demonstrates that the deterministic LK model, for realistic values of the linewidth enhancement factor {alpha}, reproduces the LFF's only as a transient dynamics towards one of the stationary modes with maximal gain. A reasonable reproduction of real data from VCSEL's can be obtained only by considering the noisy LK or alternatively deterministic LK model for extremely high {alpha} values.

  2. Malabsorption Syndromes

    MedlinePlus

    ... syndrome, your small intestine cannot absorb nutrients from foods. Causes of malabsorption syndromes include Celiac disease Lactose intolerance Short bowel syndrome. This happens after surgery to ...

  3. Ophiolitic mélanges in crustal-scale fault zones: Implications for the Late Palaeozoic tectonic evolution in West Junggar, China

    NASA Astrophysics Data System (ADS)

    Chen, Shi; Pe-Piper, Georgia; Piper, David J. W.; Guo, Zhaojie

    2014-12-01

    The Baijiantan and Darbut ophiolites in West Junggar are exposed in steep fault zones (>70°) containing serpentinite mélange, in contact on either side with regionally distributed Upper Devonian-Lower Carboniferous ocean floor peperitic basalts and overlying sedimentary successions. The ophiolitic mélanges show classic structural features created by strike-slip faulting and consistent shear sense indicators of left-slip kinematics. Sandstone blocks within the mélanges resemble the surrounding sediments in lithology and age, indicating that the ophiolitic mélanges consist of locally derived rocks. The ophiolitic mélanges therefore originated from left-slip fault zones within a remnant basin and are not plate boundaries nor subduction suture zones. Sandstone is the youngest lithology involved in the mélange and provides a maximum age for the mélange of 322 Ma, whereas stitching plutons are younger than 302 Ma. Multiple clusters in zircon ages from single gabbro blocks in the mélange at ~375, ~360, ~354, and ~340 Ma are inconsistent with accretionary incorporation of subducting ocean crust but rather suggest that episodic movement of the faults provided pathways for magma from the mantle into magma chambers. Late Paleozoic tectonic evolution of West Junggar involved Late Devonian to Carboniferous relative motion between the Junggar block and West Junggar ocean basin, which triggered the left-slip fault zones within a remnant ocean basin, along which the oceanic crust was disrupted to form linear ophiolitic mélanges. Final filling of this remnant ocean basin and its dismemberment by strike-slip faulting occurred in the late Carboniferous, followed by crustal thickening by juvenile granites at the Carboniferous-Permian boundary.

  4. Isaac's Syndrome

    MedlinePlus

    ... syndrome (also known as neuromyotonia, Isaacs-Mertens syndrome, continuous muscle fiber activity syndrome, and quantal squander syndrome) is a rare neuromuscular disorder caused by hyperexcitability and continuous firing of ... which include progressive muscle stiffness, continuously contracting ...

  5. Petrological and geochemical characterization of Proterozoic ophiolitic mélange, Nellore-Khammam schist belt, SE India

    NASA Astrophysics Data System (ADS)

    Dharma Rao, C. V.; Reddy, U. V. B.

    2009-10-01

    The ophiolitic mélange occurs close to a major fault within the metavolcanics of Kanigiri area in the western margin of the Khammam-Nellore schist belt, Andhra Pradesh, India. The unique feature of Kanigiri mélange is the occurrence of ophiolitic bodies of various sizes, most of which display petrological and geochemical characteristics typical of supra-subduction zone oceanic crust. The ophiolitic mélange is composed mainly of blocks of variably deformed and metamorphosed pillow basalts, serpentinized ultramafic rocks, meta-gabbros, cherts and pelagic sediments in a pervasive scaly argillite matrix. The mélange has a tectonic contact with a granite intrusion and numerous thrust faults cut across the mélange exposures. Primary magmatic features such as drainage cavities in pillow basalts, magmatic layering in gabbros, and clinopyroxene cumulates in ultramafic rocks are well preserved in low-strain domains. Mafic components enclosed in the mélange are characterized by low pressure secondary mineral assemblages retrograded from amphibolite down to greenschist facies as commonly observed in subducted and exhumed orogens. All amphiboles in the studied fragments are calcic and cluster in the range from winchite, actinolite to hornblende. Amphibole compositions are characterized by Al 2O 3 (2.4-13.8%), FeO (5-13%), K 2O (0.04-0.7%) and X Mg (0.67-0.77). The metabasalt and wherlite samples exhibit light rare earth element (LREE) - enriched patterns and negative high field strength element (HFSE: Zr and Ti) consistent with a suprasubduction zone geodynamic setting. A notable feature of both metabasalt and wherlite samples is their pronounced negative Ce anomaly and a positive Eu anomaly as observed in a number of modern island arc suites. As the petrological features and the geochemical characteristics of the remnant fragments we analyzed in this study are reminiscent of their Phanerozoic ophiolite counterparts, we suggest that these rocks were derived from a

  6. Understanding Mechanisms of Rind Formation in Mélange Zones using Highly Siderophile Elements

    NASA Astrophysics Data System (ADS)

    Gorman, J. K.; Penniston-Dorland, S. C.; Walker, R. J.; Marschall, H. R.

    2012-12-01

    Two mechanisms have previously been proposed for the formation of reaction zones found between mafic and ultramafic rocks in mélange zones. These mechanisms are fluid-assisted metasomatism (transport by fluid flow or by diffusion through an intergranular fluid) and tectonic mixing. We are currently studying the highly siderophile element (HSE) compositions of mafic and ultramafic rocks and reaction zones from several different high P/T metamorphic complexes, including the Catalina Schist (Santa Catalina Island, CA), the Cycladic Complex (Syros, Greece), the Samana Metamorphic Complex (Dominican Republic), and the Franciscan Complex (CA). The mafic rocks in all localities have high 187Os/188Os and low Os, Ir and Ru concentrations, consistent with basaltic protoliths. The more mantle-like rocks (serpentinite, mélange matrix) and the reaction zones have lower 187Os/188Os, and higher Os, Ir and Ru concentrations. Here we report data from traverses across two reaction features: one from the Catalina Schist, the other from the Cycladic complex. The Catalina traverse consists of twelve samples along 30cm between an amphibolite-grade mafic block and its reaction rind (actinolite-chlorite schist) adjacent to ultramafic-rich matrix. The traverse from Syros consists of five samples along 165cm between blueschist-grade metamorphosed volcaniclastic (basaltic to intermediate) tuffs and a >50 m serpentinite lens between which there is a 1-2m thick reaction blackwall zone dominantly consisting of chlorite schist. Samples of the Catalina rind are enriched in whole-rock SiO2, K2O, Rb, Ba, MgO, Cr, Ni, Os, Ir, and Ru relative to samples of the block core, and are depleted in FeO, Al2O3, TiO2, CaO, and Zr. 187Os/188Os ratios are distinctly lower in the rind (0.13 to 0.18) compared to the block (0.43 to 2.23). The Syros blackwall has elevated MgO, CaO, Cr and Ni relative to the non-metasomatised assemblage, while there is depletion of Rb, Ba, and K2O. The HSE concentrations are

  7. ModeLang: A New Approach for Experts-Friendly Viral Infections Modeling

    PubMed Central

    Blazewicz, Jacek

    2013-01-01

    Computational modeling is an important element of systems biology. One of its important applications is modeling complex, dynamical, and biological systems, including viral infections. This type of modeling usually requires close cooperation between biologists and mathematicians. However, such cooperation often faces communication problems because biologists do not have sufficient knowledge to understand mathematical description of the models, and mathematicians do not have sufficient knowledge to define and verify these models. In many areas of systems biology, this problem has already been solved; however, in some of these areas there are still certain problematic aspects. The goal of the presented research was to facilitate this cooperation by designing seminatural formal language for describing viral infection models that will be easy to understand for biologists and easy to use by mathematicians and computer scientists. The ModeLang language was designed in cooperation with biologists and its computer implementation was prepared. Tests proved that it can be successfully used to describe commonly used viral infection models and then to simulate and verify them. As a result, it can make cooperation between biologists and mathematicians modeling viral infections much easier, speeding up computational verification of formulated hypotheses. PMID:24454531

  8. Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange

    PubMed Central

    Yan, Jiong; Zhang, Feng; Brundage, Ellen; Scheuerle, Angela; Lanpher, Brendan; Erickson, Robert P.; Powis, Zoe; Robinson, Haynes B.; Trapane, Pamela L.; Stachiw-Hietpas, Danuta; Keppler-Noreuil, Kim M.; Lalani, Seema R.; Sahoo, Trilochan; Chinault, A. Craig; Patel, Ankita; Cheung, Sau Wai; Lupski, James R.

    2009-01-01

    Cornelia de Lange Syndrome (CdLS) is a multisystem congenital anomaly disorder. Heterozygous point mutations in three genes (NIPBL, SMC3 and SMC1A), encoding components of the sister chromatid cohesion apparatus, are responsible for ∼ 50-60% of CdLS cases. Recent studies have revealed a high degree of genomic rearrangements (e.g. deletions and duplications) in the human genome, which result in gene copy number variations (CNV). CNVs have been associated with a wide range of both Mendelian and complex traits including disease phenotypes such as Charcot-Marie-Tooth type 1A, Pelizaeus-Merzbacher, Parkinson, Alzheimer, autism and schizophrenia. Increased versus decreased copy number of the same gene can potentially cause either similar or different clinical features. We identified duplications on chromosomes 5 or X using genome wide array Comparative Genomic Hybridization (aCGH). The duplicated regions contain either the NIPBL or the SMC1A genes. Junction sequences analyses revealed the involvement of three genomic rearrangement mechanisms. The patients share some common features including mental retardation, developmental delay, sleep abnormalities, and crainofacial and limb defects. The systems affected are the same as in CdLS, but clinical manifestations are distinct from CdLS; particularly the absence of the CdLS facial gestalt. Our results confirm the notion that duplication CNV of genes can be a common mechanism for human genetic diseases. Defining the clinical consequences for a specific gene dosage alteration represents a new “reverse genomics” trend in medical genetics that is reciprocal to the traditional approach of delineation of the common clinical phenotype preceding the discovery of the genetic etiology. PMID:19052029

  9. Shear Veins Under High Pore Pressure Condition Along Subduction Interface: Yokonami Mélange, Cretaceous Shimanto Belt, Shikoku, Southwest Japan

    NASA Astrophysics Data System (ADS)

    Hashimoto, Y.; Eida, M.

    2013-12-01

    Fluid pressure along subdcution interface is a key parameter to understand the fault strength, wedge geometry and seismogenic behavior. In this study, we focused on shear veins pervasively observed in exhumed accretionary complex, Yokonami mélange, Cretaceous Shiamanto Belt, Southwest Japan to examine paleo-stress, effective friction coefficient, fluid pressure ratio and fluid pressure along subduction interface. Lithology of the Yokonami mélange is mainly sandstones surrounded by foliated black shales with minor components of basalts, cherts, tuffs, and limestones, representing tectonic mélange textures. Shear veins cutting mélange foliations are pervasively observed. Shear veins are composed of quartz and calcite. Slicken lines and slicken steps are always observed on the surfaces of shear veins. Pressure-temperature conditions for shear veins are about 180MPa and about 200 degree C on the basis of fluid inclusion analysis. Since the distribution of shear veins are related to packages of ocean floor stratigraphy, formation of shear vein can be before underplating and after mélange formation along subduction interface. We conducted multiple inversion method using slip data of shear veins to examine paleo-stress. In the result, we obtained maximum shear stress horizontal to foliations with 0.3 of stress ratio that is defined as (sigma2-sigma3)/(sigma1-sigma3). Effective friction coefficient was estimated as about 0.10-0.22 by the lowest value of ratio of normal and shear stresses in the normalized Mohr's circle on each plane of shear vein. If we put friction coefficient under dry condition as 0.7 because shear veins cut lithified mélange through out, fluid pressure ratio is equivalent to 0.68-0.86. This is very high fluid pressure ratio along subduction plate interface. On the basis of this fluid pressure ratio and P-T conditions of shear veins from fluid inclusion analysis, 7-12km of depth and 20-30 degree C of geothermal gradient were estimated. The age of

  10. Cushing syndrome

    MedlinePlus

    ... Cushing disease Cushing syndrome due to adrenal tumor Diabetes Ectopic Cushing syndrome Exogenous Cushing syndrome Kidney stones Pituitary tumor Rheumatoid arthritis Tumor Update Date 10/28/2015 Updated by: ...

  11. Brown Syndrome

    MedlinePlus

    ... Does Brown syndrome cause eye problems besides abnormal eye movements? Some children with Brown syndrome have poor binocular ... In the congenital form of Brown syndrome, the eye movement problem is usually constant and unlikely to resolve ...

  12. Fahr's Syndrome

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Fahr's Syndrome Information Page Synonym(s): Familial Idiopathic Basal Ganglia ... is being done? Clinical Trials Organizations What is Fahr's Syndrome? Fahr's Syndrome is a rare, genetically dominant, ...

  13. Dravet Syndrome

    MedlinePlus

    ... NINDS Dravet Syndrome Information Page Synonym(s): Severe Myoclonic Epilepsy of Infancy (SMEI) Table of Contents (click to ... Dravet Syndrome? Dravet syndrome, also called severe myoclonic epilepsy of infancy (SMEI), is a severe form of ...

  14. Williams syndrome

    MedlinePlus

    Williams-Beuren syndrome ... Williams syndrome is a rare condition caused by missing a copy of several genes. Parents may not have ... history of the condition. However, a person with Williams syndrome has a 50% chance of passing the disorder ...

  15. Interpretation of tracer tests performed in fractured rock of the Lange Bramke basin, Germany

    NASA Astrophysics Data System (ADS)

    Maloszewski, Piotr; Herrmann, Andreas; Zuber, Andrzej

    Two multitracer tests performed in one of the major cross-fault zones of the Lange Bramke basin (Harz Mountains, Germany) confirm the dominant role of the fault zone in groundwater flow and solute transport. Tracers having different coefficients of molecular diffusion (deuterium, bromide, uranine, and eosine) yielded breakthrough curves that can only be explained by a model that couples the advective-dispersive transport in the fractures with the molecular diffusion exchange in the matrix. For the scale of the tests (maximum distance of 225m), an approximation was used in which the influence of adjacent fractures is neglected. That model yielded nearly the same rock and transport parameters for each tracer, which means that the single-fracture approximation is acceptable and that matrix diffusion plays an important role. The hydraulic conductivity of the fault zone obtained from the tracer tests is about 1.5×10-2m/s, whereas the regional hydraulic conductivity of the fractured rock mass is about 3×10-7m/s, as estimated from the tritium age and the matrix porosity of about 2%. These values show that the hydraulic conductivity along the fault is several orders of magnitude larger than that of the remaining fractured part of the aquifer, which confirms the dominant role of the fault zones as collectors of water and conductors of fast flow. Résumé Deux multitraçages ont été réalisés dans l'une des zones principales de failles du bassin de Lange Bramke (massif du Harz, Allemagne); les résultats confirment le rôle prédominant de la zone de failles pour l'écoulement souterrain et le transport de soluté. Les traceurs, possédant des coefficients de diffusion différents (deutérium, bromure, uranine et éosine), ont fourni des courbes de restitution qui ne peuvent être expliquées que par un modèle qui associe un transport advectif-dispersif dans les fractures à un échange par diffusion moléculaire dans la matrice. A l'échelle des expériences (distance

  16. Interpretation of tracer tests performed in fractured rock of the Lange Bramke basin, Germany

    NASA Astrophysics Data System (ADS)

    Maloszewski, Piotr; Herrmann, Andreas; Zuber, Andrzej

    Two multitracer tests performed in one of the major cross-fault zones of the Lange Bramke basin (Harz Mountains, Germany) confirm the dominant role of the fault zone in groundwater flow and solute transport. Tracers having different coefficients of molecular diffusion (deuterium, bromide, uranine, and eosine) yielded breakthrough curves that can only be explained by a model that couples the advective-dispersive transport in the fractures with the molecular diffusion exchange in the matrix. For the scale of the tests (maximum distance of 225m), an approximation was used in which the influence of adjacent fractures is neglected. That model yielded nearly the same rock and transport parameters for each tracer, which means that the single-fracture approximation is acceptable and that matrix diffusion plays an important role. The hydraulic conductivity of the fault zone obtained from the tracer tests is about 1.5×10-2m/s, whereas the regional hydraulic conductivity of the fractured rock mass is about 3×10-7m/s, as estimated from the tritium age and the matrix porosity of about 2%. These values show that the hydraulic conductivity along the fault is several orders of magnitude larger than that of the remaining fractured part of the aquifer, which confirms the dominant role of the fault zones as collectors of water and conductors of fast flow. Résumé Deux multitraçages ont été réalisés dans l'une des zones principales de failles du bassin de Lange Bramke (massif du Harz, Allemagne); les résultats confirment le rôle prédominant de la zone de failles pour l'écoulement souterrain et le transport de soluté. Les traceurs, possédant des coefficients de diffusion différents (deutérium, bromure, uranine et éosine), ont fourni des courbes de restitution qui ne peuvent être expliquées que par un modèle qui associe un transport advectif-dispersif dans les fractures à un échange par diffusion moléculaire dans la matrice. A l'échelle des expériences (distance

  17. Geochemistry and geochronology of HP mélanges from Tinos and Andros, cycladic blueschist belt, Greece

    NASA Astrophysics Data System (ADS)

    Bulle, Florian; Bröcker, Michael; Gärtner, Claudia; Keasling, Alan

    2010-06-01

    U-Pb zircon geochronology, Sr-Nd isotope and bulk-rock geochemistry have been applied to meta-igneous and meta-sedimentary rocks from high-pressure metamorphic mélanges exposed on the Cycladic islands of Tinos, Syros and Andros. Ion microprobe (SHRIMP) U-Pb zircon dating of 7 samples representing meta-igneous blocks (Tinos), a blackwall zone (Tinos) and chlorite-talc schists from block-matrix contacts (Syros and Tinos) yielded Cretaceous ages of c. 80 Ma. Many of the criteria commonly used to distinguish between magmatic or metamorphic zircon genesis (internal structure, Th/U ratio, REE characteristics, Ti-in zircon thermometry, enclosed mineral phases) do not provide unambiguous constraints for the mode of formation. However, a magmatic origin for Cretaceous zircon of meta-gabbros and eclogites is considered likely. Supporting evidence for a previously suggested metamorphic origin for c. 80 Ma zircon in eclogite has not been found. Zircon of the same age occurring in chlorite-talc schists is presumably related to non-magmatic processes. Well-defined Cretaceous age groups clustering at c. 79 Ma also occur in the detrital zircon populations of 2 quartz mica schists representing the mélange matrix on Tinos, and suggest a much later time for sediment accumulation than previously assumed. The importance of c. 57 Ma zircon ages remains unclear, but may record either HP metamorphic processes or a post-57 Ma depositional age. The youngest age group in a third quartz mica schist from Tinos, collected outside the main mélange occurrences, clusters at c. 226-238 Ma. In all clastic metasediments from Tinos, most data points plot along the concordia between c. 300 and 900 Ma; single data points indicate concordant ages of c. 2.5 Ga, 2.3 Ga and 1 Ga, respectively. The youngest 206Pb/ 238U age group that has been recognized in a felsic paragneiss from Andros indicates an age of 163.1 ± 3.9 Ma, and mostly represents overgrowths around zircon with ages in the range from ˜ 272

  18. Tectonic mélanges and the exhumation of HP ophiolites: a case-study from the Ligurian Alps

    NASA Astrophysics Data System (ADS)

    Federico, Laura; Crispini, Laura; Scambelluri, Marco; Capponi, Giovanni; Malatesta, Cristina

    2010-05-01

    langes form in a variety of geodynamic settings and can be related to either sedimentary, tectonic or diapiric processes, or a combination of them. We studied in detail a 100 m-scale tectonic mélange formed in the context of the alpine subduction/collision and we tested if the local-scale pattern could be applicable at larger scale in the Ligurian Western Alps. The studied mélange crops out inside metamorphic serpentinites belonging to the high-pressure (HP), meta-ophiolitic Voltri Massif (southern end of the Western Alps). It is made up of a foliated chlorite-actinolite greenschist matrix enclosing 10m-scale lenses of metabasites and metasediments. These blocks appear to be exotic because similar rocks do not outcrop in the surrounding HP-units. The matrix records three sets of superposed folds from blueschist to greenschist-facies conditions. The metabasite lenses preserve internal HP schistosities forming high angles with the greenschist matrix foliation. The lenses equilibrated at different peak metamorphic conditions (ranging from eclogite- to blueschist-facies). The matrix is widely retrogressed in greenschist facies, but it contains rare relics of Na-amphibole. Individual lenses display different segments of typical subduction PT paths which apparently converge in the blueschist facies. Moreover, geochronological data for the different HP blocks show that two undistinguishable blueschist samples display distinct peak ages of 43 and 40 Ma. One blueschist age is contemporaneous with the eclogitic equilibration of another block (43.2 ± 0.5 Ma) (Federico et al., 2007). The described structural, metamorphic and geochronological features suggest that this mélange formed at depth in a subduction channel and was active at least from blueschist- to greenschist-facies conditions, but possibly also at higher pressures. The subduction channel formed between the overriding and the subducting plates, as a consequence of progressive hydration of the mantle wedge by

  19. Kinematic analysis of mélange fabrics: examples and applications from the McHugh Complex, Kenai Peninsula, Alaska

    NASA Astrophysics Data System (ADS)

    Kusky, Timothy M.; Bradley, Dwight C.

    1999-12-01

    Permian to Cretaceous mélange of the McHugh Complex on the Kenai Peninsula, south-central Alaska includes blocks and belts of graywacke, argillite, limestone, chert, basalt, gabbro, and ultramafic rocks, intruded by a variety of igneous rocks. An oceanic plate stratigraphy is repeated hundreds of times across the map area, but most structures at the outcrop scale extend lithological layering. Strong rheological units occur as blocks within a matrix that flowed around the competent blocks during deformation, forming broken formation and mélange. Deformation was noncoaxial, and disruption of primary layering was a consequence of general strain driven by plate convergence in a relatively narrow zone between the overriding accretionary wedge and the downgoing, generally thinly sedimented oceanic plate. Soft-sediment deformation processes do not appear to have played a major role in the formation of the mélange. A model for deformation at the toe of the wedge is proposed in which layers oriented at low angles to σ1 are contracted in both the brittle and ductile regimes, layers at 30-45° to σ1 are extended in the brittle regime and contracted in the ductile regime, and layers at angles greater than 45° to σ1 are extended in both the brittle and ductile regimes. Imbrication in thrust duplexes occurs at deeper levels within the wedge. Many structures within mélange of the McHugh Complex are asymmetric and record kinematic information consistent with the inferred structural setting in an accretionary wedge. A displacement field for the McHugh Complex on the lower Kenai Peninsula includes three belts: an inboard belt of Late Triassic rocks records west-to-east-directed slip of hanging walls, a central belt of predominantly Early Jurassic rocks records north-south directed displacements, and Early Cretaceous rocks in an outboard belt preserve southwest-northeast directed slip vectors. Although precise ages of accretion are unknown, slip directions are compatible with

  20. Incrementally Developed `Dilational Hydro-Shears' Forming at High Angles to σ1 in Foliated Mélange Matrix

    NASA Astrophysics Data System (ADS)

    Fagereng, A.; Remitti, F.; Sibson, R. H.

    2009-12-01

    The Chrystalls Beach accretionary mélange, New Zealand, contains an extensive fault-fracture mesh, in which mutually cross-cutting, incrementally developed, subhorizontal slickenfibre shear veins and subvertical extension veins intersect at an oblique angle of ~80° (Fig. 1). Slickenfibre shear veins commonly have multiple internal stylolitic slip surfaces subparallel to ubiquitous cleavage in pelitic mélange matrix, macroscopic `crack-seal' textures, and dissolution selvages along the vein margins. Stylolites, internal slip surfaces, and the long axes of elongate crystals within slickenfibre shear veins are inclined at a low angle (<15°) to the vein margin. Where shear and extension veins intersect, crystal fibres within the extension vein are parallel to elongate crystals within slickenfibres. The two kinematic vein types therefore had the same crystal-growth direction and are inferred to have formed contemporaneously in the same stress field. Thus field and microstructural observations suggest that slickenfibre-coated shear surfaces in the Chrystalls Beach mélange were active at ~80° to σ1, despite the constraint from Coulomb mechanics that new-forming faults, in cohesive, low porosity rocks, should lie at an angle θi = 45° - φ/2 to σ1. The slickenfibres appear to have formed by reactivation of subhorizontal weak planes (e.g. stylolites parallel to cleavage) which act as micro-transforms linking subvertical extension fractures opening parallel to σ3. This requires Pf > σ3 and low differential stress depending on the frictional resistance on the stylolites, and allows for shear failure at high angle to σ1 in fluid overpressured heterogeneous shear zones. The reshear conditions are similar to the extensional hydrofracture criterion, but low tensile strength, low intrinsic cohesion, and localised elevated shear strain controlled by material heterogeneities and anisotropy, create a situation where shear occurs essentially by extension under local

  1. Concomitant Posterior Hip Dislocation, Ipsilateral Intertrochanteric- and Proximal Tibial- Fractures with Popliteal Artery Injury: A Challenging Trauma Mélange

    PubMed Central

    Chotai, Pranit N.; Hart, Ryan; Wassef, Andrew

    2015-01-01

    Constellation of ipsilateral posterior hip dislocation, intertrochanteric- and proximal tibial fracture with popliteal artery injury is rare. Management of this presentation is challenging. A motor vehicle accident victim presented with these injuries, but without any initial signs of vascular compromise. Popliteal artery injury was diagnosed intra-operatively and repaired. This was followed by external fixation of tibial fracture, open reduction of dislocated hip and internal fixation of intertrochanteric fracture. Patient regained bilateral complete weight bearing and returned to pre-accident activity level. Apt surgical management including early repair of vascular injury in such a trauma mélange allows for a positive postoperative outcome. PMID:26918095

  2. Formation of diamondiferous kyanite-eclogite in a subduction mélange

    NASA Astrophysics Data System (ADS)

    Aulbach, S.; Gerdes, A.; Viljoen, K. S.

    2016-04-01

    interaction reconciles evidence for both low- and high-pressure igneous processes in some aluminous eclogites. We suggest that a subduction mélange is a favourable setting for the transfer of a sediment-derived signature into oceanic crust, leading to formation of diamondiferous kyanite-eclogites from bimineralic eclogites. Diapirism, fluxed by the presence of partial melt, may have facilitated dispersal of the eclogites in the lithosphere column, consistent with their widely varying equilibration pressures ranging from ∼5 to 8 GPa.

  3. Congenital long QT syndrome

    PubMed Central

    Crotti, Lia; Celano, Giuseppe; Dagradi, Federica; Schwartz, Peter J

    2008-01-01

    disease is usually good in patients that are correctly diagnosed and treated. However, there are a few exceptions: patients with Timothy syndrome, patients with Jervell Lange-Nielsen syndrome carrying KCNQ1 mutations and LQT3 patients with 2:1 atrio-ventricular block and very early occurrence of cardiac arrhythmias. PMID:18606002

  4. Provenance of the Indus-Yarlung Suture Mélange and the Location of the India-Asia Suture, Southern Tibet

    NASA Astrophysics Data System (ADS)

    Metcalf, K.; Kapp, P. A.; Orme, D. A.; Laskowski, A. K.

    2013-12-01

    The Indus-Yarlung Suture Zone (IYSZ) is the boundary between rocks of Indian and Asian affinity. From north to south in southern Tibet, it exposes the preserved Asian forearc, ophiolitic rocks, tectonic mélanges, and Tethyan Himalayan strata of Indian affinity. The mélange has long been considered the accretionary prism corresponding to the ophiolite to the north which obducted onto the Indian margin prior to India-Asia collision. An outstanding issue is whether the ophiolitic rocks and mélanges were (1) obducted onto the northern margin of India or (2) associated with the Cordilleran-style southern margin of Asia, prior to India - Asia collision. Resolving this issue is fundamental to understanding the precollisional tectonic framework of the Neo-Tethyan realm, interpreting the timing of initial continental collision from detrital records, and locating the suture. We conducted geologic mapping and U/Pb detrital zircon provenance studies of the blocks and matrix of the mélanges and of Tethyan Himalayan units to the south at two localities: near Lhatse, which is ~140 km north of Mt. Everest and near Lopu Kangri, ~300 km along strike to the west. Near Lhatse the mélange is composed of a mudstone matrix with blocks of basalt, chert, mudstone, metabasite, limestone, and sandstone. The majority of the blocks are deep-water facies or consistent with oceanic crust, supporting the interpretation that the mélange is an accretionary complex formed by oceanic subduction. A south-dipping fault ~9 km north of Lhatse separates the mélange to the north from a continuous sequence of sandstone, shale, and minor limestone to the south. Previous work along strike suggests that this sequence, which has been previously identified as Tethyan affinity, contains Asian affinity detrital zircon populations. Near Lopu Kangri, the mélange is similar to that exposed in Lhatse. Over a distance of ~10 km to the southwest, blocks gradually increase in size to encompass ~2 km x ~10 km

  5. Fluid-metapelite interaction in an ultramafic mélange: implications for mass transfer along the slab-mantle interface in subduction zones

    NASA Astrophysics Data System (ADS)

    Mori, Yasushi; Shigeno, Miki; Nishiyama, Tadao

    2014-12-01

    The slab-mantle interface in subduction zones is a site of tectonic mixing of crustal and mantle rocks. It is the interface for fluid flow of slab-derived components into the mantle wedge. To assess the fluid-rock interaction along the slab-mantle interface, we studied the bleaching of pelitic schist in an ultramafic mélange. The Nishisonogi metamorphic rocks in Kyushu, Japan, comprise ultramafic mélanges intercalated with epidote-blueschist facies schists. The ultramafic mélange consists of tectonic blocks of various lithologies and a matrix of chlorite-actinolite schist and serpentinite. Along the contact with the mélange matrix, pelitic schist blocks are bleached mainly due to the modal increase of albite and the consumption of carbonaceous material. The bleaching is probably attributed to infiltration of Na-rich external fluid from the mélange matrix. Mass balance analysis indicates losses of C, Rb, K2O, Ba, Pb, and SiO2 from the bleached pelitic schist, although Al2O3, TiO2, Sc, Y, Zr, Nb, La, Ce, and Nd remain immobile. This suggests fractionation of large-ion lithophile elements (LILE) and Pb from the high-field-strength elements and rare earth elements during the bleaching. If this ultramafic mélange is analogous to the slab-mantle interface, similar infiltration metasomatism will promote liberation of C, Si, LILE, and Pb from subducting metapelites and enhance metasomatism of the mantle wedge.

  6. The Beimarang mélange (southern Tibet) brings additional constraints in assessing the origin, metamorphic evolution and obduction processes of the Yarlung Zangbo ophiolite

    NASA Astrophysics Data System (ADS)

    Huot, François; Hébert, Réjean; Varfalvy, Véronika; Beaudoin, Georges; Wang, Chengshan; Liu, Zhifei; Cotten, Jo; Dostal, Jaroslav

    2002-12-01

    The Beimarang massif is one of many ophiolitic remnants which crop out discontinuously along the Yarlung Zangbo suture zone in southern Tibet. The southern contact of these remnants is marked by a highly sheared serpentinite mélange made up of blocks of serpentinites, diabases, gabbros and composite blocks of serpentinites and mafic injections. The Beimarang mélange has been investigated in order to bring additional constraints on the origin, metamorphic evolution and obduction processes of the Yarlung Zangbo ophiolite. Petrography and geochemical data suggest that the ultramafic components are similar to moderately depleted upper mantle peridotites. They may represent the already cooled and serpentinized Tethyan upper mantle which was trapped in a mantle wedge at the onset of a north-dipping Early Cretaceous intra-oceanic subduction zone located south of the Gangdese arc. These peridotites were then intruded by back-arc-like mafic magmas whose moderately depleted mantle source was affected by a subduction component. Ultramafic and mafic secondary mineral assemblages suggest that early low-( P/ T) metamorphic intra-oceanic conditions reached the amphibolite facies (>550 °C) before being retrograded down to the pumpellyite-prehnite facies (<280 °C). The Beimarang mélange, interpreted as an obduction mélange formed near a spreading ridge, was subjected to metamorphic conditions in the pumpellyite-prehnite facies which favored re-serpentinization of the peridotites and partial rodingitization of the mafic rocks. Unlike subduction-related mélanges and their associated lithological units found in the Ladakh area, we found no evidence of high-( P/ T) conditions in lithologies from the Beimarang mélange.

  7. In Vitro Antioxidant Activities and in Vivo Anti-Hypoxic Activity of the Edible Mushroom Agaricus bisporus (Lange) Sing. Chaidam.

    PubMed

    Li, Hong-Ji; Chen, Hai-Yan; Fan, Lin-Lin; Jiao, Zhi-Hua; Chen, Qi-He; Jiao, Ying-Chun

    2015-01-01

    With the rising awareness of a healthy lifestyle, natural functional foods have gained much interest as promising alternatives to synthetic functional drugs. Recently, wild Agaricus bisporus (Lange) Sing. Chaidam has been found and artificially cultivated for its thick fresh body and excellent taste, with its antioxidant and anti-hypoxic abilities unknown. In this work, the antioxidant potential of its methanolic, 55% ethanolic, aqueous extracts and crude polysaccharide was evaluated in different systems. The results showed that polysaccharide was the most effective in scavenging ability on 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radicals, metal chelating activity and reducing power, with EC50 values of 0.02, 2.79, 1.29, and 1.82 mg/mL, respectively. Therefore, we further studied the anti-hypoxic activity of crude polysaccharide. The results turned out that polysaccharide (300 mg/kg) prolonged the survival time, decreased the blood urea nitrogen and lactic acid content as well as increased the liver glycogen significantly, compared with the blank control and the commercialized product Hongjingtian (p < 0.05). With such excellent activities, we purified the polysaccharide and analyzed its molecular weight (120 kDa) as well as monosaccharide components (glucose, fructose and mannose). This study indicated that wild Agaricus bisporus (Lange) Sing. Chaidam had strong potential to be exploited as an effective natural functional food to relieve oxidative and hypoxia stresses. PMID:26404217

  8. Bill Lang's contributions to acoustics at the International Business Machines Corp. (IBM) and to IBM in general

    NASA Astrophysics Data System (ADS)

    Nobile, Matthew A.; Chu, Richard C.

    2005-09-01

    Although Bill Lang's accomplishments and key roles in national and international standards and in the formation of INCE are widely recognized, sometimes it has to be remembered that for nearly 35 years he also had a ``day job'' at the IBM Corporation. His achievements at IBM were no less significant and enduring than those in external standards and professional societies. This paper will highlight some of the accomplishments and activities of Bill Lang as an IBM noise control engineer, the creator of the IBM Acoustics Lab in Poughkeepsie, the founder of the global Acoustics program at IBM, and his many other IBM leadership roles. Bill was also a long-serving IBM manager, with the full set of personnel issues to deal with, so his people-management skills were often called into play. Bill ended his long and fruitful IBM career at a high point. In 1988, he took an original idea of his to the top of IBM executive management, which led directly to the formation of the IBM Academy of Technology, today the preeminent body of IBM top technical leaders from around the world.

  9. Sedimentary environment of a halite-mudrock mélange (Haselgebirge Formation, Eastern Alps)

    NASA Astrophysics Data System (ADS)

    Leitner, Christoph; Köster, Mathias H.; Neubauer, Franz

    2015-04-01

    During Variscan orogeny in Carboniferous times, Gondwana and Europe collided to form Pangea (Stampfli et al., 2013). The succeeding Permian was a time of continental consolidation and erosion of the uplifted Vaiscan mountain belt but also its destruction by rifting processes forming the Tethys Sea (in its initial definition). During late Permian (c. 255-250 Ma), when the later Eastern Alps were located around north of the equator, evaporites of the Haselgebirge Formation (now exposed in Northern Calcareous Alps) were deposited. The location of the deposits was at around 10° north of the equator, which would be at the transition from a tropical climate to a moderate to semi-aride climate nowadays (Blakey, 2008), but on the other side the average temperature can be assumed higher than today (Berner, 1998). In salt mines, the Haselgebirge Fm. consists of a two-component tectonite of c. 50 % halite and 50 % sedimentary clastic and other evaporite rocks (Schauberger, 1986; Spötl 1998). Most of the clastic rocks are mud- to siltstones ("mudrock"). Its present appearance as a tectonic mélange is a result of the superimposed stages of Alpine orogenic events during Jurassic, Cretaceous and Cenocoic times. During the present study, we investigated the sedimentary/ diagenetic development of the evaporite rocks by field work in underground salt mines (Hallstatt, Berchtesgaden, Bad Dürrnberg, Altaussee), thin section analysis, SEM, RDX and EMPA. Mudrock needs a quiet or non-turbulent environment to settle down. Higher water energy leads to non-horizontal structures like ripples, re-sedimentation of clasts and a larger grain size. Therefore, water depth was in general deeper than 5 m, but the question remains unanswered how deep the basin could become in its deepest parts. Massive anhydrite rock precipitated from sea water (layered, black), while nodular/mosaic anhydrite (red) crystallized within the sediment (earlier or coevally). The transition gypsum  anhydrite

  10. Angelman Syndrome

    MedlinePlus

    ... causes developmental delay and neurological problems. The physician Harry Angelman first delineated the syndrome in 1965, when ... 202-534-3731 Prader-Willi Syndrome Association 8588 Potter Park Drive Suite 500 Sarasota, FL 34238 national@ ...

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    MedlinePlus

    ... Glycogen Storage Disease, Type 1A Joubert Syndrome Maple Syrup Urine Disease and DLD Mucolipidosis IV (MLIV) Nemaline ... Glycogen Storage Disease, Type 1A Joubert Syndrome Maple Syrup Urine Disease and DLD Mucolipidosis IV (MLIV) Nemaline ...

  12. Turner Syndrome

    MedlinePlus

    Turner syndrome is a genetic disorder that affects a girl's development. The cause is a missing or ... t work properly. Other physical features typical of Turner syndrome are Short, "webbed" neck with folds of ...

  13. Premenstrual syndrome

    MedlinePlus

    ... syndrome. Cochrane Database Syst Rev. 2009;2:CD001396. Lentz GM. Primary and secondary dysmenorrhea, premenstrual syndrome, and premenstrual dysphoric disorder: etiology, diagnosis, management. In: Lentz GM, Lobo RA, Gershenson DM, Katz VL, eds. ...

  14. Cushing syndrome

    MedlinePlus

    ... Cushing syndrome is called exogenous Cushing syndrome . Prednisone, dexamethasone, and prednisolone are examples of this type of ... Blood cortisol levels Blood sugar Saliva cortisol levels Dexamethasone suppression test 24-hour urine for cortisol and ...

  15. Asperger syndrome

    MedlinePlus

    Asperger syndrome is often considered a high functioning form of autism. It can lead to difficulty interacting socially, repeat behaviors, and clumsiness. Asperger syndrome is a part of the larger developmental disorder ...

  16. Pseudoaminopterin syndrome.

    PubMed

    Kraoua, Lilia; Capri, Yline; Perrin, Laurence; Benmansour, Abdelmajjid; Verloes, Alain

    2012-09-01

    Pseudoaminopterin syndrome or aminopterin syndrome-like sine aminopterin (ASSA syndrome--OMIM 600325] is a rare autosomal recessive syndrome defined by characteristic dysmorphic features, skeletal defects, limb anomalies, cryptorchidism, and growth retardation. The syndrome owes its name to the fact that patients resemble the children exposed to aminopterin or to methotrexate, two dihydrofolate reductase inhibitors used for chemotherapy, or as an abortificient in early pregnancy. Ten patients have been described with pseudoaminopterin syndrome. Their phenotype is variable, and differs from the phenotype resulting from folic acid deprivation, leading to the notion that the pathogenesis may be more complex than simple vitamin deficiency. We report on an Algerian patient with pseudoaminopterin syndrome, review the previously reported cases and confirm that pseudoaminopterin syndrome does not result from a detectable contiguous gene imbalance as high resolution CGH array was normal in this child. PMID:22811276

  17. Usher Syndrome

    MedlinePlus

    Usher syndrome is an inherited disease that causes serious hearing loss and retinitis pigmentosa, an eye disorder ... hearing and vision. There are three types of Usher syndrome: People with type I are deaf from ...

  18. Morquio syndrome

    MedlinePlus

    ... to have children and who have a family history of Morquio syndrome. Counseling is also recommended for families who have a child with Morquio syndrome to help them understand the condition and possible treatments. Prenatal testing is available.

  19. Asperger syndrome

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001549.htm Asperger syndrome To use the sharing features on this page, please enable JavaScript. Asperger syndrome is often considered a high functioning form ...

  20. Piriformis syndrome

    MedlinePlus

    ... sciatica; Hip socket neuropathy; Pelvic outlet syndrome; Low back pain - piriformis References Joseph RL, Alleva JT, Hudgins TH. Piriformis syndrome. In: Frontera: Essentials of Physical Medicine and Rehabilitation . 3rd ed. Philadelphia, PA: Elsevier Saunders; 2014:chap ...

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    MedlinePlus

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  2. Hurler syndrome

    MedlinePlus

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    MedlinePlus

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    MedlinePlus

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  5. Unraveling the polymetamorphic history of garnet-bearing metabasites: Insights from the North Motagua Mélange (Guatemala Suture Zone)

    NASA Astrophysics Data System (ADS)

    Bonnet, G.; Flores, K. E.; Martin, C.; Harlow, G. E.

    2014-12-01

    The Guatemala Suture Zone is the fault-bound region in central Guatemala that contains the present North American-Caribbean plate boundary. This major composite geotectonic unit contains a variety of ophiolites, serpentinite mélanges, and metavolcano-sedimentary sequences along with high-grade schists, gneisses, low-grade metasediments and metagranites thrusted north and south of the active Motagua fault system (MFS). The North Motagua Mélange (NMM) outcrops north of the MFS and testifies the emplacement of exhumed subduction assemblages along a collisional tectonic setting. The NMM is composed of a serpentinite-matrix mélange that contains blocks of metabasites (subgreenschist facies metabasalt, grt-blueschist, eclogite, grt-amphibolite), vein-related rocks (jadeitite, omphacitite, albitite, mica-rock), and metatrondhjemites. Our new detailed petrographic and thermobarometric study on the garnet-bearing metabasites reveals a complex polymetamorphic history with multiple tectonic events. Eclogites show a classical clockwise PT path composed of (a) prograde blueschist/eclogite facies within garnet cores, (b) eclogite facies metamorphic peak at ~1.7 GPa and 620°C, (c) post-peak blueschist facies, (d) amphibolite facies overprint, and (e) late stage greenschist facies. Two types of garnet amphibolite blocks can be found, the first consist of (a) a relict eclogite facies peak at ~1.3 GPa and 550°C only preserved within anhedral garnet cores, and (b) surrounded by a post-peak amphibolite facies. In contrast, the second type displays a prograde amphibolite facies at 0.6-1.1 GPa and 400-650°C. The eclogites metamorphic peak suggests formation in a normal subduction zone at ~60 km depth, a subsequent exhumation to the middle section of the subduction channel (~35 km), and a later metamorphic reworking at lower P and higher T before its final exhumation. The first type of garnet amphibolite shows a similar trajectory as the eclogites but at warmer conditions. In

  6. Jurassic-Paleogene intra-oceanic magmatic evolution of the Ankara Mélange, North-Central Anatolia, Turkey

    NASA Astrophysics Data System (ADS)

    Sarifakioglu, E.; Dilek, Y.; Sevin, M.

    2013-11-01

    Oceanic rocks in the Ankara Mélange along the Izmir-Ankara-Erzincan suture zone (IAESZ) in North-Central Anatolia include locally coherent ophiolite complexes (~179 Ma and ~80 Ma), seamount or oceanic plateau volcanic units with pelagic and reefal limestones (96.6 ± 1.8 Ma), metamorphic rocks with ages of 187.4 ± 3.7 Ma, 158.4 ± 4.2 Ma, and 83.5 ± 1.2 Ma, and subalkaline to alkaline volcanic and plutonic rocks of an island arc origin (~67-63 Ma). All but the arc rocks occur in a shaly-graywacke and/or serpentinite matrix, and are deformed by south-vergent thrust faults and folds that developed in the Middle to Late Eocene due to continental collisions in the region. Ophiolitic volcanic rocks have mid-ocean ridge (MORB) and island arc tholeiite (IAT) affinities showing moderate to significant LILE enrichment and depletion in Nb, Hf, Ti, Y and Yb, which indicate the influence of subduction-derived fluids in their melt evolution. Seamount/oceanic plateau basalts show ocean island basalt (OIB) affinities. The arc-related volcanic rocks, lamprophyric dikes and syeno-dioritic plutons exhibit high-K shoshonitic to medium-to high-K calc-alkaline compositions with strong enrichment in LILE, REE and Pb, and initial ϵNd values between +1.3 and +1.7. Subalkaline arc volcanic units occur in the northern part of the mélange, whereas the younger alkaline volcanic rocks and intrusions (lamprophyre dikes and syeno-dioritic plutons) in the southern part. The Early to Late Jurassic and Late Cretaceous epidote-actinolite, epidote-chlorite and epidote-glaucophane schists represent the metamorphic units formed in a subduction channel in the Northern Neotethys. The Middle to Upper Triassic neritic limestones spatially associated with the seamount volcanic rocks indicate that the Northern Neotethys was an open ocean with its MORB-type oceanic lithosphere by the Early Triassic. The Latest Cretaceous-Early Paleocene island arc volcanic, dike and plutonic rocks with

  7. Jurassic-Paleogene intraoceanic magmatic evolution of the Ankara Mélange, north-central Anatolia, Turkey

    NASA Astrophysics Data System (ADS)

    Sarifakioglu, E.; Dilek, Y.; Sevin, M.

    2014-02-01

    Oceanic rocks in the Ankara Mélange along the Izmir-Ankara-Erzincan suture zone (IAESZ) in north-central Anatolia include locally coherent ophiolite complexes (∼ 179 Ma and ∼ 80 Ma), seamount or oceanic plateau volcanic units with pelagic and reefal limestones (96.6 ± 1.8 Ma), metamorphic rocks with ages of 256.9 ± 8.0 Ma, 187.4 ± 3.7 Ma, 158.4 ± 4.2 Ma, and 83.5 ± 1.2 Ma indicating northern Tethys during the late Paleozoic through Cretaceous, and subalkaline to alkaline volcanic and plutonic rocks of an island arc origin (∼ 67-63 Ma). All but the arc rocks occur in a shale-graywacke and/or serpentinite matrix, and are deformed by south-vergent thrust faults and folds that developed in the middle to late Eocene due to continental collisions in the region. Ophiolitic volcanic rocks have mid-ocean ridge (MORB) and island arc tholeiite (IAT) affinities showing moderate to significant large ion lithophile elements (LILE) enrichment and depletion in Nb, Hf, Ti, Y and Yb, which indicate the influence of subduction-derived fluids in their melt evolution. Seamount/oceanic plateau basalts show ocean island basalt (OIB) affinities. The arc-related volcanic rocks, lamprophyric dikes and syenodioritic plutons exhibit high-K shoshonitic to medium- to high-K calc-alkaline compositions with strong enrichment in LILE, rare earth elements (REE) and Pb, and initial ɛNd values between +1.3 and +1.7. Subalkaline arc volcanic units occur in the northern part of the mélange, whereas the younger alkaline volcanic rocks and intrusions (lamprophyre dikes and syenodioritic plutons) in the southern part. The late Permian, Early to Late Jurassic, and Late Cretaceous amphibole-epidote schist, epidote-actinolite, epidote-chlorite and epidote-glaucophane schists represent the metamorphic units formed in a subduction channel in the northern Neotethys. The Middle to Upper Triassic neritic limestones spatially associated with the seamount volcanic rocks indicate that the northern

  8. Dumping Syndrome

    MedlinePlus

    ... Disease Organizations​​ (PDF, 341 KB)​​​​​ Alternate Language URL Dumping Syndrome Page Content On this page: What is ... Nutrition Points to Remember Clinical Trials What is dumping syndrome? Dumping syndrome occurs when food, especially sugar, ...

  9. Down syndrome

    MedlinePlus

    Down syndrome is a genetic condition in which a person has 47 chromosomes instead of the usual 46. ... In most cases, Down syndrome occurs when there is an extra copy of chromosome 21. This form of Down syndrome is called trisomy 21. ...

  10. Velocardiofacial Syndrome

    ERIC Educational Resources Information Center

    Gothelf, Doron; Frisch, Amos; Michaelovsky, Elena; Weizman, Abraham; Shprintzen, Robert J.

    2009-01-01

    Velocardiofacial syndrome (VCFS), also known as DiGeorge, conotruncal anomaly face, and Cayler syndromes, is caused by a microdeletion in the long arm of Chromosome 22. We review the history of the syndrome from the first clinical reports almost half a century ago to the current intriguing molecular findings associating genes from the…

  11. Oculocerebral hypopigmentation syndrome (Cross syndrome).

    PubMed

    Ozkan, H; Unsal, E; Köse, G

    1991-01-01

    A typical case of Cross syndrome with hypopigmentation, mental and psychomotor retardation, spasticity, bilateral optic atrophy and dental defects in a three-year-old boy is presented. The clinical features of this rare syndrome are discussed. PMID:1814043

  12. [The province of East Prussia and "euthanasia" during national socialism: the SS-"Aktion Lange" and "Aktion T4"].

    PubMed

    Topp, Sascha; Fuchs, Petra; Hohendorf, Gerrit; Richter, Paul; Rotzoll, Maike

    2008-01-01

    During World War II, psychiatric patients hospitalized in asylums in Eastern Prussia became victims of two separate killing programmes: first, by the SS-special command Lange, second by the centrally (in Berlin) organized "euthanasia"-"Aktion T4". By an analysis of the patient files of the victims, the present paper shows that the historical actors responsible for the killings were communicating with each other. It is now also possible to reconstruct the exact dynamic in time and space of the killings. A comparative analysis of the selection criteria within the total population of the asylums documents that in both programs, the responsible historical actors included physicians and provincial administrative personnel; it further shows that under the conditions of war, only patients who were able to contribute to the asylum work and economy, and were behaviourally adapted could survive. PMID:18664012

  13. Metasomatic Evolution in Tectonically Mixed Zones (Mélange) and Significance for Geochemical Evolution of the Slab-Mantle Interface

    NASA Astrophysics Data System (ADS)

    Bebout, G. E.; King, R. L.

    2012-12-01

    Fluid flow focused in highly deformed zones (shear zones), and the physical juxtaposition of chemically disparate rocks (via mechanical mixing) in such zones, can lead to extensive metasomatism, including volume strain, and result in rocks with hybridized compositions little resembling the compositions of the incorporated rock types [1-5]. In the Catalina Schist (California), lawsonite-albite, lawsonite-blueschist, and amphibolite-facies units contain shear zones at scales of meters to kilometers, each containing "blocks" (with more spherical or more tabular dimensions) co-facial in grade with the "matrix" surrounding these blocks [1-3]. Oxygen isotope data for these "mélange" units, and adjacent more "coherent" expanses, indicate enhanced fluid flow in the more strongly deforming mélange zones while fluid flow in coherent domains was dominantly fracture-controlled and episodic. The amphibolite-facies mélange unit shows evidence for km-scale equilibration of varying mineral assemblages with H2O-rich fluids with uniform O and H isotope compositions consistent with a lower-grade metasedimentary source. This unit is believed to have formed largely by mechanical mixing of mafic and ultramafic compositions, partly because of the scarcity of sedimentary blocks. However, the mélange matrix in this unit preserves a number of sedimentary chemical/isotopic characteristics (e.g., Pb isotope compositions [3]) that could reflect the incorporation of sedimentary rocks, with or without fluid-related fractionation, and possibly fluid-mediated additions. Tectonically mixed zones such as these, if volumetrically significant at the slab-mantle interface, could exert disproportionate control on the compositions of hydrous fluids or silicate melts emanating from subducting slabs and entering the forearc to backarc mantle wedge, including those contributing to arc magmatism [1-5]. Geochemical studies of arc lavas should consider the possibility that the "fluids" contributed from

  14. Relationships between seep-carbonates, mud volcanism and basin geometry in the Late Miocene of the northern Apennines of Italy: the Montardone mélange

    NASA Astrophysics Data System (ADS)

    Conti, Stefano; Fontana, Daniela; Lucente, Claudio Corrado; Pini, Gian Andrea

    2014-01-01

    The Montardone mélange (Mm) is a chaotic, block-in-matrix unit outcropping in the Montebaranzone syncline in the northern Apennines. The Mm occurs in the uppermost part of the Termina Fm, the Middle-Late Miocene interval of a succession deposited in a wedge-top slope basin (Epiligurian succession). The Mm is closely associated with bodies of authigenic carbonates, characterized by negative values of δ13C (from -18.22 to -39.05 ‰ PDB) and chemosynthetic benthic fauna (lucinid and vesicomyid bivalves). In this paper, we propose that the Mm is a mud volcano originated by the post-depositional reactivation and rising of a stratigraphically lower mud-rich mass transport body (Canossa-Val Tiepido sedimentary mélange or olistostrome) triggered by fluid overpressure. We base our conclusion on (1) the Mm pierces the entire Termina Fm and older Epiligurian units and represents the direct continuation of the underlying Canossa-Val Tiepido mélange; (2) the geometry and facies distribution of the Montebaranzone sandstone body, which are compatible with a confined basin controlled by the rising of the Mm; (3) the systematic presence of large-scale (lateral extension 300-400 m) seep-carbonates associated with the mélange, suggesting a persistent gas-enriched fluid vent from the ascending overpressured mud; (4) blocks and clasts sourced from the Mm, hosted by the authigenic carbonates, conveyed by ascending mud and gas-enriched fluids. The Mm represents one of the few fossil examples of reactivation of a basin-scale sedimentary mélange (olistostrome); a three-stage model showing mechanisms of Mm raising is proposed.

  15. Overgrowth Syndromes.

    PubMed

    Edmondson, Andrew C; Kalish, Jennifer M

    2015-09-01

    Numerous multiple malformation syndromes associated with pathologic overgrowth have been described and, for many, their molecular bases elucidated. This review describes the characteristic features of these overgrowth syndromes, as well as the current understanding of their molecular bases, intellectual outcomes, and cancer predispositions. We review syndromes such as Sotos, Malan, Marshall-Smith, Weaver, Simpson-Golabi-Behmel, Perlman, Bannayan-Riley-Ruvalcaba, PI3K-related, Proteus, Beckwith-Wiedemann, fibrous dysplasia, Klippel-Trenaunay-Weber, and Maffucci. PMID:27617124

  16. Lutembacher's syndrome

    PubMed Central

    Kulkarni, Sandhya S.; Sakaria, Amit K.; Mahajan, Sanket K.; Shah, Kuldeep B.

    2012-01-01

    The definition of Lutembacher's syndrome has undergone many changes. It refers to combination of congenital Atrial Septal Defect with acquired mitral stenosis. Lutembacher's syndrome is a very rare disease and in the past, it has been either overdiagnosed or misdiagnosed. Here, we will discuss a case of a pregnant lady who developed breathlessness during her third trimester of pregnancy and on detailed examination and investigation, she was found to be having Lutembacher's syndrome. PMID:22629045

  17. Sheehan syndrome

    MedlinePlus

    Postpartum hypopituitarism; Postpartum pituitary insufficiency; Hypopituitarism Syndrome ... Malee MP. Pituitary and adrenal disorders in pregnancy. In: Gabbe ... Problem Pregnancies . 6th ed. Philadelphia, PA: Elsevier Mosby; ...

  18. Sanfilippo syndrome

    MedlinePlus

    ... for families who have a child with Sanfilippo syndrome, to help them understand the condition and possible treatments. Prenatal testing is available. Alternative Names MPS III References Pyeritz ...

  19. "High-grade burial metamorphism of sedimentary mélange, Shoo Fly Complex, central Sierra Nevada, California"

    NASA Astrophysics Data System (ADS)

    Mendoza, Y.; Wakabayashi, J.

    2013-12-01

    blocks are present within sub to lower greenschist facies phyllites. This relationship suggests that much of this unit is a sedimentary mélange. Given the similarity of protoliths, such an origin is probable for the higher-grade rocks but the high-grade metamorphism has obscured obvious differences in metamorphic grade between block and matrix there. This study indicates that the Shoo Fly Complex in this region comprises a subduction complex made up of typical oceanic and trench fill lithologies, with a significant proportion consisting of submarine debris flow deposits (sedimentary mélange). Burial metamorphism reaching upper amphibolite/granulite facies has affected these rocks. Whether this metamorphism resulted from collision/slab breakoff, ridge subduction, or other mechanisms is not clear at this time, but these rocks clearly experienced different a different tectonothermal history than their lower grade equivalents in the northern Sierra.

  20. Sandstone provenance and tectonic evolution of the Xiukang Mélange from Neotethyan subduction to India-Asia collision (Yarlung-Zangbo suture, south Tibet)

    NASA Astrophysics Data System (ADS)

    An, Wei; Hu, Xiumian; Garzanti, Eduardo

    2016-04-01

    The Xiukang Mélange of the Yarlung-Zangbo suture zone in south Tibet documents low efficiency of accretion along the southern active margin of Asia during Cretaceous Neotethyan subduction, followed by final development during the early Paleogene stages of the India-Asia collision. Here we investigate four transverses in the Xigaze area (Jiding, Cuola Pass, Riwuqi and Saga), inquiry the composition in each transverse, and present integrated petrologic, U-Pb detrital-zircon geochronology and Hf isotope data on sandstone blocks. In fault contact with the Yarlung-Zangbo Ophiolite to the north and the Tethyan Himalaya to the south, the Xiukang mélange can be divided into three types: serpentinite-matrix mélange composed by broken Yarlung-Zangbo Ophiolite, thrust-sheets consisting mainly chert, quartzose or limestone sheets(>100m) with little intervening marix, and mudstone-matrix mélange displaying typical blocks-in-matrix texture. While serpentinite-matrix mélange is exposed adjacent to the ophiolite, distributions of thrust-sheets and blocks in mudstone-matrix mélange show along-strike diversities. For example, Jiding transverse is dominant by chert sheets and basalt blocks with scarcely sandstone blocks, while Cuola Pass and Saga transverses expose large amounts of limestone/quartzarenite sheets in the north and volcaniclastic blocks in the south. However, turbidite sheets and volcaniclastic blocks are outcropped in the north Riwuqi transverse with quartzarenite blocks preserved in the south. Three groups of sandstone blocks/sheets with different provenance and depositional setting are distinguished by their petrographic, geochronological and isotopic fingerprints. Sheets of turbiditic quartzarenite originally sourced from the Indian continent were deposited in pre-Cretaceous time on the northernmost edge of the Indian passive margin and eventually involved into the mélange at the early stage of the India-Asia collision. Two distinct groups of volcaniclastic

  1. Marfan Syndrome

    MedlinePlus

    ... thin, and loose jointed. Most people with Marfan syndrome have heart and blood vessel problems, such as a weakness in the aorta or heart valves that leak. They may also have problems with ... diagnose Marfan syndrome. Your doctor may use your medical history, family ...

  2. Turner syndrome

    MedlinePlus

    ... at birth is often smaller than average. A child with Turner syndrome is much shorter than children who are the ... Growth hormone may help a child with Turner syndrome grow taller. ... started when the girl is 12 or 13 years old. These help trigger ...

  3. Marfan Syndrome

    MedlinePlus

    ... Connective tissue helps support all parts of your body. It also helps control how your body grows and develops. Marfan syndrome most often affects ... A mutation, or change, in the gene that controls how the body makes fibrillin causes Marfan syndrome. Fibrillin is a ...

  4. Tourette Syndrome.

    ERIC Educational Resources Information Center

    Look, Kathy

    Tourette Syndrome has a history of being misdiagnosed or undiagnosed due to its unusual and complex symptoms. This paper describes: the symptoms of Tourette Syndrome; its etiology; age of onset; therapeutic methods, such as drug therapy, psychotherapy, diet control, and hypnosis; educational implications; and employment prospects. Several…

  5. Emplacement of serpentinites in the Chohar Gonbad-Gugher-Baft ophiolitic mélange, southeast Iran: examination of the mineral-chemical, petrologic, and structural features

    NASA Astrophysics Data System (ADS)

    Mohammadi, N.; Ahmadipour, H.; Lentz, D. R.; Shafaii Moghadam, H.

    2016-03-01

    The Chohar Gonbad-Gugher-Baft ophiolite mélange, located along the major Baft and Shahr-e-Babak fault zones, southeast Iran, represents remnants of Neo-Tethyan oceanic lithosphere. This mélange contains blocks of harzburgite, dunite, lherzolite, basalt, and other ophiolite-related lithologies tectonically mixed with and embedded in a serpentinite matrix. Field, petrographic, and geochemical data show that peridotites in this mélange belong to the upper mantle. They seem to have undergone up to ~20 % partial melting in a supra-subduction zone setting, based on their spinel Cr# values (0.21-0.53). Chemical compositions and textures in the serpentinites indicate that they were partially hydrated during emplacement and further mobilized diapirically to the surface. The different deformation stages occurred in an accretionary wedge environment. Petrographic evidence shows that the first serpentinization event produced mesh-textured serpentinites formed under static conditions in an ocean floor environment (Nain-Baft ocean crust), where the initial lizardite, bastite, and chrysotile veins formed. Plastic deformation occurred due to the subduction of Nain-Baft oceanic lithospheric beneath the central Iranian microcontinent, with antigorite-bearing flare-textured serpentinites produced. During progressive exhumation of the Nain-Baft ophiolite mélange, the serpentinites were affected by ductile, ductile-brittle, and brittle deformation, respectively. Accretion and resultant diapirism are the most important processes in the emplacement of serpentinite, which is a consequence of hydration of the ocean crust. In this example, late-stage emplacement via thrusting occurred along the northern extent of the southern Sanandaj-Sirjan zone (S-SZ).

  6. Accessory minerals and subduction zone metasomatism: a geochemical comparison of two mélanges (Washington and California, U.S.A.)

    USGS Publications Warehouse

    Sorensen, Sorena S.; Grossman, Jeffrey N.

    1993-01-01

    Data from the Gee Point and Catalina mélanges suggest that the accessory minerals titanite, rutile, apatite, zircon and REE-rich epidote play a significant role in the enrichment of trace elements in both mafic and ultramafic rocks during subduction-related fluid-rock interaction. Mobilization of incompatible elements, and deposition of such elements in the accessory minerals of mafic and ultramafic rocks may be fairly common in fluid-rich metamorphic environments in subduction zones.

  7. Neotethyan rifting-related ore occurrences: study of an accretionary mélange complex (Darnó Unit, NE Hungary)

    NASA Astrophysics Data System (ADS)

    Kiss, Gabriella B.; Oláh, Erika; Zaccarini, Federica; Szakáll, Sándor

    2016-02-01

    The geology of the NE Hungarian Darnó Unit is rather complicated, as it is composed mostly of a Jurassic accretionary mélange complex, according to the most recent investigations. The magmatic and sedimentary rock blocks of the mélange represent products of different evolutionary stages of the Neotethys; including Permian and Triassic sedimentary rocks of marine rifting related origin, Triassic pillow basalt of advanced rifting related origin and Jurassic pillow basalt originated in back-arc-basin environment. This small unit contains a copper-gold occurrence in the Permian marly-clayey limestone, an iron enrichment in the Triassic sedimentary succession, a copper-silver ore occurrence in Triassic pillow basalts and a copper ore indication, occurring both in the Triassic and Jurassic pillow basalts. The present study deals with the Cu(-Ag) occurrence in the Triassic basalt and the Fe occurrence in the Triassic sedimentary succession. The former shows significant similarities with the Michigan-type mineralizations, while the latter has typical characteristics of the Fe-SEDEX deposits. All the above localities fit well into the new geological model of the investigated area. The mineralizations represent the different evolutionary stages of the Neotethyan rifting and an epigenetic, Alpine metamorphism-related process and their recent, spatially close position is the result of the accretionary mélange formation. Thus, the Darnó Unit represents a perfect natural laboratory for studying and understanding the characteristic features of several different rifting related ore forming processes.

  8. Deformation process and kinematics of mélange in the Early Cretaceous accretionary complex of the Mino-Tamba Belt, eastern southwest Japan

    NASA Astrophysics Data System (ADS)

    Fukui, Akiko; Kano, Ken-Ichi

    2007-04-01

    The Kanayama unit of the Mesozoic Mino-Tamba accretionary complex in eastern southwest Japan is a thick mélange unit composed mainly of abundant muddy matrix and variously sized clasts of chert, hemipelagic siliceous mudstone, and sandstone. Two episodes of deformation formed the mélange fabrics: the first involved fragmentation of sandstone layers in response to mud injections; the second involved layer-parallel, noncoaxial shear that resulted in the mixing of pelagic to terrigenous clasts and the formation of S-C-like asymmetric fabrics with scaly foliation. The S-C fabrics exhibit a predominantly sinistral shear sense in plan view. After fold and tilt corrections, the restored slip motion inferred from the S-C fabrics indicates a bulk top-to-the-south shear. Combining the unit's terminal fossil age and radiometric age with a regional plate reconstruction model, these data suggest that the Kanayama mélange formed along a décollement during oblique subduction of the Izanagi plate in the Early Cretaceous.

  9. Lang and Goulet Hardiness Scale: development and testing on bereaved parents following the death of their fetus/infant.

    PubMed

    Lang, Ariella; Goulet, Celine; Amsel, Rhonda

    2003-12-01

    The process of development and testing of the Lang and Goulet Hardiness Scale (LGHS), a self-report instrument designed to measure hardiness in bereaved parents following the death of their fetus/infant, is presented. Hardiness is a personal resource, composed of 3 interdependent components that are characterized by a sense of personal control over the outcome of life events and hardships such as the death of a fetus/infant, an active orientation toward meeting the challenges brought on by the loss, and a belief in the ability to make sense of one's own existence following such a tragedy. The concept of hardiness has been studied by various disciplines and in a multitude of settings to understand its ability to lessen potentially negative effects of life stress. However, it has never been studied within the context of parental bereavement. The LGHS was developed systematically, originating from a concept analysis. A panel of 15 experts was used to establish content validity.A pretest was conducted on 73 bereaved individuals to assess convergent and discriminant validity of the LGHS. Subsequently, a validation study on 220 bereaved parents who had experienced the death of their fetus/infant 2 months previously was conducted including a retest 6 months after the loss with 192 of the remaining participants. Analyses reveal that the LGHS is a valid and reliable instrument for measuring hardiness and that it is sensitive enough to detect changes in the construct over time. PMID:14610777

  10. Craniofacial Syndrome Descriptions

    MedlinePlus

    ... with this syndrome do not have a smile). Miller syndrome Miller Syndrome is very rare condition characterized by downward ... dysplasia • Hemangioma • Hemifacial Microsomia / Goldenhar syndrome • Microtia/Atresia • Miller syndrome • Moebius syndrome • Nager syndrome • Pierre Robin Sequence • ...

  11. Kounis syndrome.

    PubMed

    Ntuli, P M; Makambwa, E

    2015-10-01

    Kounis syndrome is characterised by a group of symptoms that manifest as unstable vasospastic or non-vasospastic angina secondary to a hypersensitivity reaction. It was first described by Kounis and Zavras in 1991 as the concurrence of an allergic response with an anaphylactoid or anaphylactic reaction and coronary artery spasm or even myocardial infarction. Since then, this condition has evolved to include a number of mast cell activation disorders associated with acute coronary syndrome. There are many triggering factors, including reactions to multiple medications, exposure to radiological contrast media, poison ivy, bee stings, shellfish and coronary stents. In addition to coronary arterial involvement, Kounis syndrome comprises other arterial systems with similar physiologies, such as mesenteric and cerebral circulation resulting in ischaemia/infarction of the vital organs. The incidence of this condition is difficult to establish owing to the number of potential instigating factors and its relatively infrequent documentation in the literature.We report the case of an HIV-negative 39-year-old man with no coronary risk factors or family history of premature coronary artery disease, who developed Kounis syndrome after the administration of fluoroquinolone for dysuria. However, to the best of our knowledge,no data on the incidence and prevalence of Kounis syndrome in South Africa have ever been reported in the literature. The recent understanding of Kounis syndrome has led to the condition being classified into three syndrome variants. PMID:26636160

  12. Neurocutaneous syndromes.

    PubMed

    Klar, Nitasha; Cohen, Bernard; Lin, Doris D M

    2016-01-01

    Neurocutaneous syndromes (or phakomatoses) are a diverse group of congenital disorders that encompass abnormalities of neuroectodermal and, sometimes, mesodermal development, hence commonly involving the skin, eye, and central nervous system. These are often inherited conditions and typically present in early childhood or adolescence. Some of the abnormalities and clinical symptoms may, however, be progressive, and there is an increased risk of neoplastic formation in many of the syndromes. As a group, neurocutaneous syndromes are characterized by distinctive cutaneous stigmata and neurologic symptomology, the latter often representing the most devastating and debilitating features of these diseases. Many of these syndromes are markedly heterogeneous in nature as they affect many organ systems. Given the incurable nature of these conditions and the broad spectrum of pathologies they comprise, treatments vary on a case-by-case basis and tend to be palliative rather than curative. With the advances in molecular genetics, however, greater understanding of biologic functions of the gene products and the correlative phenotypic expression is being attained, and this knowledge may guide future therapeutic developments. This chapter focuses on the cutaneous and neurologic pathology with emphasis on neuroimaging of selective neurocutaneous syndromes, including tuberous sclerosis, Sturge-Weber syndrome, Klippel-Trenaunay syndrome, ataxia-telangiectasia, and incontinentia pigmenti. PMID:27432683

  13. Structural and metamorphic evolution of an ocean-continent transition (OCT) zone mélange deformed under HP conditions during Alpine subduction (Western Italian Alps)

    NASA Astrophysics Data System (ADS)

    Gosso, G.; Benciolini, L.; Dilek, Y.; Festa, A.; Spalla, M.; Tartarotti, P.

    2011-12-01

    We report on the structural architecture and metamorphic evolution of a mélange, developed originally in an ocean-continent transition (OCT) zone along the boundary between the continental crust of the Sesia-Lanzo (SLZ) and the oceanic Piemonte Zones (PZ) in the axial part of the Western Alps. All these units were deformed together under high-pressure conditions. The mélange consists of thin layers of calcschist, fine-grained gneiss, quartzite, minor metabasic rocks and serpentinite, and occurs all along the western margin of southern SLZ, extending from Santanel klippe to Lanzo Massif, over a distance of 50 km (Spalla et al., 1983; Battiston et al., 1984). Calcschist rocks range from phyllites to carbonatic schists and marbles; fine-grained gneisses of continental origin (very similar to those of SLZ) include phengitic white mica, chlorite, ± garnet ± albite and relict allanite. Thinly layered quartzites are white mica- and garnet-bearing. Metabasic rocks consist of metagabbros and metabasalts with minor mylonitic serpentinites. All these lithologies of the mélange unit and the rocks of SLZ and PZ together underwent four episodes of deformation, giving rise to a complex regional tectonostratigraphy. The earliest deformational structures are represented by up to ten meter-scale isoclinal rootless folds. The metamorphic mineral assemblages marking successive foliations indicate that all rock units in the mélange, SLZ and PZ (Spalla et al., 1983; Benciolini et al., 1984) experienced an early eclogite facies imprint, followed by re-equilibration under blueschist facies conditions, and that they were finally widely retrogressed under greenschist facies conditions during the last two deformational episodes (D3 and D4 structures). The strong synmetamorphic deformation of this mélange prevents an unequivocal interpretation of its origin; hence, we envisage two possible scenarios: i) the present day configuration of these thin, intermingled layers, including

  14. Remnants of a hyperextended passive margin in a Caledonian mélange unit below the Jotun nappe, B\\overdalen, Central-south Norway

    NASA Astrophysics Data System (ADS)

    Alsaif, Manar; Jakob, Johannes; Andersen, Torgeir; Corfu, Fernando

    2015-04-01

    The Scandinavian Caledonides have been long studied, yet their ever unfolding complexity renders them far from being fully understood. It has been recognized that the Caledonian Allochthons have neither a linear nor straightforward along-strike relationship (Corfu et al. 2014). A mélange unit has been recently identified as a separate tectonic unit (Andersen et al. 2012). This unit is structurally positioned below crystalline nappes previously assigned to the Middle Allochthon. The mélange comprises meta-sediments and minor meta-basalt/gabbro, but most intriguingly, numerous solitary meta-peridotites. These occur as 'Alpine type' meta-peridotites, serpentinites, soapstones and detrital serpentinites. We present results of a field study of the mélange in the B\\overdalen area, structurally below the Jotun nappe, and suggest that this provides further evidence that the regional mélange unit was formed in a hyperextended passive margin. The meta-peridotites represent exhumed serpentinized mantle and are intimately associated with meta-sediments. The sediments are garnetiferous chlorite-muscovite schists, graphitic schists, phyllites, amphibolites, meta-sandstones as well as quartzite-pebble dominated conglomerates. It is suggested that this highly heterogeneous unit formed during the early stages of rifting and hyperextension along the Baltican passive margin. Characteristics of the detrital peridotites suggests that serpentinite-talc protrusions may have formed islands. The processes involved are observed on modern margins where the best-studied example is the Iberia-Newfoundland passive margin. Work in present-day margins (mostly seismic reflection data) elucidate the large-scale structure of hyperextended margins, while studies of ancient exposed examples in mountain belts provide insight into the lithology, geochemistry and details of these margins. The widespread distribution of hyperextended margins in modern margins and the increasing number of recognizable

  15. Magmatic origin of low-T mafic blueschist and greenstone blocks from the Franciscan mélange, San Simeon, California

    NASA Astrophysics Data System (ADS)

    Ukar, Estibalitz; Cloos, Mark

    2015-08-01

    The Franciscan mélange exposure near San Simeon contains abundant greenstone and minor blueschist blocks that were tectonically boudinaged while encased in the shale-matrix. Tectonic deformation of the blueschists is evident from variable amounts of cataclastic flow along their margins and in pinched tails. Major, trace, and rare earth elemental analyses indicate that blueschist and greenstone blocks in this area of the mélange were derived from sources with MORB-like composition along with some having trace element and REE patterns similar to OIB compositions. Most blocks are low LREE basalts that probably formed in an open ocean ridge setting, but some blocks have high LREE contents similar to off-axis seamounts. Linear trends of incompatible elements for both blueschist and greenstone blocks indicate that both lithologies were probably derived from a similar, variably fractionated, tholeiitic magma. Blueschist blocks with sodic amphibole + lawsonite ± epidote were pervasively recrystallized at 300-350 °C and foliated during ductile deformation that included folding. Their protolith can only be identified as mafic. A few blocks contain very small amounts of metasedimentary materials indicating some were probably seafloor basalts, but some may have been diabase or even gabbro. Where interlayered sediment was present, the mafic protolith was enriched in K, Rb, and Na. Greenstones, on the other hand, contain abundant pseudomorphic evidence of magmatic textures. Alteration to albite, chlorite and pumpellyite at temperatures of 100-200 °C is intense, especially in cataclastic margins and pinched tails. Some of the basaltic greenstones have attached radiolarian chert, and a few have relict diabasic textures. The mafic blueschists and greenstones in the mélange near San Simeon are probably fragments from the uppermost part of the Farallon plate. The blueschists may be mostly mafic slabs uprooted from the subducting crust, underplated to the base of the North

  16. [Aarskog's syndrome].

    PubMed

    Hromádková, L; Frána, L

    1991-05-01

    The authors described the rare Aarskog syndrome in a 6-year-old boy, associated with left-sided Brown's syndrome. Another 4-year-old boy came from an affected family where the brother suffered also from Aarskog's syndrome and in the mother some microsymptoms were detected. The authors recommend that patients who on examination of a refraction defect or strabism display uncommon features in the face or other parts of the body should be always subjected to a general examination incl. genetic examination. PMID:1913912

  17. Hubris syndrome.

    PubMed

    Owen, David

    2008-08-01

    Hubris syndrome is associated with power, more likely to manifest itself the longer the person exercises power and the greater the power they exercise. A syndrome not to be applied to anyone with existing mental illness or brain damage. Usually symptoms abate when the person no longer exercises power. It is less likely to develop in people who retain a personal modesty, remain open to criticism, have a degree of cynicism or well developed sense of humour. Four heads of government in the last 100 years are singled out as having developed hubris syndrome: David Lloyd George, Margaret Thatcher, George W Bush and Tony Blair. PMID:18724614

  18. LEOPARD Syndrome.

    PubMed

    Ghosh, Sudip Kumar; Majumdar, Biswajit; Rudra, Olympia; Chakraborty, Sougat

    2015-10-01

    LEOPARD syndrome (LS) is an autosomal dominantly inherited or sporadic disorder of variable penetrance and expressivity. The acronym LEOPARD stands for its cardinal clinical features including Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and Deafness. We present herein a patient with LEOPARD syndrome and distinctive features. It was noteworthy that our patient presented with the concern of generalized lentiginosis and subsequent evaluation revealed that the patient had LEOPARD syndrome. In this report we would like to highlight the importance of detailed clinical examination and appropriate imaging in patients with multiple lentigines. PMID:26632807

  19. [DRESS syndrome].

    PubMed

    Adamcová, Monika; Šturdík, Igor; Koller, Tomáš; Payer, Juraj

    2016-04-01

    DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms) is severe drug-induced allergic-type reaction which occurs few days to weeks after taking a drug in a predisposed patient. Organ damage, eosinophilia and skin rash are typical at presentation. Corticotherapy is often necessary in severe cases. In this report we describe a case of 56-year old female with fever, elevated liver tests and skin rash. DRESS syndrome was diagnosed and allopurinol was indentified as a causative drug. Due to possible fatal outcome, DRESS syndrome should be considered in a differential diagnosis of all patients presenting with similar signs and symptoms. PMID:27250614

  20. Velocardiofacial syndrome.

    PubMed Central

    Pike, A. C.; Super, M.

    1997-01-01

    Velocardiofacial syndrome is a syndrome of multiple anomalies that include cleft palate, cardiac defects, learning difficulties, speech disorder and characteristic facial features. It has an estimated incidence of 1 in 5000. The majority of cases have a microdeletion of chromosome 22q11.2. The phenotype of this condition shows considerable variation, not all the principal features are present in each case. Identification of the syndrome can be difficult as many of the anomalies are minor and present in the general population. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:9497944

  1. Zircon ages of metamorphic and magmatic rocks within peridotite-bearing mélanges: Crucial time constraints on early Carboniferous extensional tectonics in the Chinese Tianshan

    NASA Astrophysics Data System (ADS)

    Jian, Ping; Kröner, Alfred; Jahn, Bor-ming; Liu, Dunyi; Zhang, Wei; Shi, Yuruo; Ma, Huadong

    2013-07-01

    We dated and geochemically characterized peridotite-bearing mélanges in the Chinese South Tianshan and within the Main Tianshan Shear Zone. The Yushugou-Tonghuashan mélange in the Chinese South Tianshan exposes a tectonic juxtaposition of a diapirically emplaced metaperidotite (predominantly lherzolite) massif with a high-grade metamorphic terrane (ca. 10 km long; protolith age ≥ ca. 445-466 Ma). Metamorphic zircons of a mafic granulite (εNd(t) = 5.0) yielded a weighted mean 206Pb/238U age of 341 ± 8 Ma that we interpret as the time of granulite-facies metamorphism. The youngest zircon rims of an intermediate granulite (εNd(t) = - 4.3) have a mean age of 332 ± 13 Ma that records a retrogressive metamorphic event. These ages determine the timing (ca. 341-332 Ma) of mantle diapirism through continental crust. A dolerite dike (εNd(t) = 2.3) emplaced into metaperidote has a crystallization age of 335 ± 5 Ma, that, on the basis of geochemistry, we interpret as representing E-MORB-OIB magmatism that accompanied mantle diapirism. An undeformed pink granite (εNd(t) = - 3.6) intrudes the mélange matrix and has an emplacement age of 324 ± 5 Ma, thus providing an upper time limit for a tectonic movement that led to mélange formation. The older time limit of deformation (ca. 362-352 Ma) is constrained by the youngest ages of thermo-tectonically modified zircons in a mylonitized metagabbro and a foliated meta-andesite. Magmatic zircons in the meta-andesite (εNd(t) = - 3.3) and a dacite (εNd(t) = - 5.6) have eruption ages of 433 ± 4 Ma and 435 ± 3 Ma that date formation of the mélange matrix. A microgabbro dike (εNd(t) = 10.0) cutting metasediments (i.e. mélange matrix) has an emplacement age of 279 ± 3 Ma and contains abundant zircon xenocrysts ranging in age from Archean to late Paleozoic. Similarly, a dolerite dike, a meta-andesite, an intermediate granulite, and a metagabbro all contain inherited Precambrian to Paleozoic zircons. We accordingly conclude

  2. HELLP syndrome

    MedlinePlus

    ... out of 1,000 pregnancies. In women with preeclampsia or eclampsia , the condition develops in 10 to ... have high blood pressure and are diagnosed with preeclampsia before they develop HELLP syndrome. In some cases, ...

  3. Down syndrome

    MedlinePlus

    ... their limitations, they may also feel frustration and anger. Many different medical conditions are seen in people ... syndrome and their families deal with the frustration, anger, and compulsive behavior that often occur. Parents and ...

  4. Behcet's Syndrome

    MedlinePlus

    Behcet's syndrome is a disease that involves vasculitis, which is inflammation of the blood vessels. It causes problems in many parts of the body. The ... National Institute of Arthritis and Musculoskeletal and Skin Diseases

  5. Marfan Syndrome

    MedlinePlus

    Marfan syndrome is a disorder that affects connective tissue. Connective tissues are proteins that support skin, bones, blood vessels, and other organs. One of these proteins is fibrillin. A problem with the ...

  6. Paraneoplastic Syndromes

    MedlinePlus

    ... used to determine effective treatment strategies. NIH Patient Recruitment for Paraneoplastic Syndromes Clinical Trials At NIH Clinical Center Throughout the U.S. and Worldwide NINDS Clinical Trials Organizations Column1 Column2 American Autoimmune Related Diseases Association 22100 ...

  7. Paraneoplastic Syndromes

    PubMed Central

    Stolinsky, David C.

    1980-01-01

    Neoplasms can produce a variety of remote effects on the host; these are referred to as paraneoplastic syndromes. The syndromes may affect any of the systems of the body, may precede or follow the diagnosis of the underlying neoplasm, and may or may not parallel the course of the neoplasm in severity. The diagnosis of and therapy for these syndromes can be challenging to a physician, but successful therapy may bring about worthwhile relief for the patient. In addition, the syndromes and the substances that cause them are sometimes useful in diagnosing and in following the course of certain neoplasms. Perhaps of greater importance, study of these remote effects of neoplasia may shed light on the nature of the neoplastic process itself. PMID:6990627

  8. Hunter syndrome

    MedlinePlus

    Hunter syndrome is a disease in which long chains of sugar molecules (glycosaminoglycans, formerly called mucopolysaccharides ) are ... of the enzyme iduronate sulfatase. Without this enzyme, chains of sugar molecules build up in various body ...

  9. Malabsorption Syndromes

    MedlinePlus

    ... They often include chronic diarrhea, abnormal stools, weight loss, and gas. Your doctor may use lab, imaging, or other tests to make a diagnosis. Treatment of malabsorption syndromes depends on the cause.

  10. Compartment syndrome

    MedlinePlus

    ... caused by repetitive activities, such as running. The pressure in a compartment only increases during that activity. Compartment syndrome is most common in the lower leg and forearm. It can also occur in the hand, foot, thigh, and upper arm.