9,007 research outputs found
Legius syndrome in fourteen families
No full textLegius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrom
Legius Syndrome and its Relationship with Neurofibromatosis Type 1
No full textNeurofibromatosis type 1 (NF1) is the most common disorder characterized by multiple café-au-lait macules. Most individuals with this autosomal dominant disorder also have other features, such as skinfold freckling, iris Lisch nodules and benign or malignant peripheral nerve sheath tumours. Legius syndrome is a less frequent autosomal dominant disorder with similar multiple café-au-lait macules and skinfold freckling. Legius syndrome is not characterized by an increased risk of tumours, and a correct diagnosis is important. In young children with a sporadic form of multiple café-au-lait macules with or without freckling and no other manifestations of NF1 these 2 conditions cannot be differentiated based on clinical examination. Molecular analysis of the NF1 and SPRED1 genes is usually needed to differentiate the 2 conditions. Other less frequent conditions with café-au-lait macules are Noonan syndrome with multiple lentigines, constitutional mismatch repair deficiency and McCune-Albright syndrome.status: Publishe
Moleculaire en functionele karakterisatie van een nieuw neuro-cardio-faciaal-cutaan syndroom: Legius syndroom
No full textWe beschreven en karakteriseerden een nieuwe autosomaal dominante aandoening, Legius syndroom, die genetisch verschillend is maar klinisch erg gelijkend op neurofibromatose type 1 (NF1). De klinische kenmerken bestaan uit café-au-lait vlekken met of zonder sproeten, macrocefalie, een relatief kleine gestalte en een verhoogde frequentie van leerproblemen bij kinderen. Sommige patiënten vertonen Noonan-gelijkende dysmorfe karakteristieken en sommige individuen vervullen de klinisch diagnostische NIH criteria voor NF1. Sommige typische NF1-geassocieerde kenmerken zijn systematisch afwezig, zoals Lisch nodules, neurofibromen, NF1-geassocieerde botdefecten en tumoren van het centrale zenuwstelsel. Inactiverende mutaties werden geïdentificeerd in SPRED1, dit gen codeert voor een eiwit dat de RAS-MAPK signaaltransductie cascade negatief reguleert en dit ter hoogte van RAS-RAF interactie. Melanocyten van een café-au-lait vlek van een aangetast individu vertoonden biallelische mutaties in SPRED1 (kiemlijn en somatische SPRED1 mutatie). Deze aandoening is een nieuw lid van de groep van de fenotypisch overlappende neuro-cardio-faciale-cutane (NCFC) syndromen of RASopathieën. Een grote groep van NF1-mutatie negatieve patiënten werd onderzocht en in 1.9% van de patiënten werd een pathogene SPRED1 mutatie geïdentificeerd. In een klein percentage van de gevallen werd een SPRED1 missense mutatie gevonden en functioneel gekarakteriseerd naar pathogeniciteit. We toonden aan dat sommige van deze SPRED1 missense mutaties effectief pathogeen zijn. Omdat leerproblemen gerapporteerd werden bij verscheidene kinderen met Legius syndroom, werd een muis Spred1-/- model gebruikt om zowel hippocampaal afhankelijk leren en geheugen als lange termijn potentiatie te onderzoeken. Spred1-/- muizen vertoonden een verlaagde performantie in de gedragstesten wat leren en geheugen betreft en korte en lange termijn hippocampale synaptische plasticiteitsdefecten werden geobserveerd. We startten een verkennende studie omtrent het Spred Drosophila "loss-of-function" model, omdat dit uiterst geschikt is als screen voor interagerende proteïnen, betrokken celtypes en signaaltransductie cascades. We detecteerden een subtiel groeidefect met een kleinere vleugelgrootte maar met een normaal venenpatroon. We identificeerden verminderde opschrik geïnduceerde locomotie en verminderd agressief gedrag in de Spred "loss-of-function" vliegen. Larvale neuromusculaire juncties vertoonden een verminderd aantal synapsen (boutons) in de Spred-/- vliegen, hoewel de lengte en spier innervatie niet veranderd was. Deze succesvolle initiële verkennende studie in Drosophila toonde verschillende fenotypes aan en laat ons toe om in de toekomst Spred functie en proteïne interacties in dit model te bestuderen.status: Publishe
De NCFC syndromen: klinische, moleculaire en cognitieve aspecten in geselecteerde syndromen
No full textDe neuro-cardio-facio-cutane (NCFC) syndromen vormen een groep fenotypis ch overlappende aandoeningen die zich presenteren met een variabele graa d van cognitieve beperkingen, hartafwijkingen, gelaatsdysmorfieën en hui dproblemen. De meeste van deze syndromen gaan gepaard met een verhoogd r isico op kanker. De laatste jaren is het duidelijk geworden dat deze syn dromen veroorzaakt worden door mutaties in genen van de RAS-MAPKinase si gnaaltransductiecascade. Deze cascade speelt een rol in celgroei en -dif ferentiatie en is gekend voor zijn rol in kanker en meer recent ook in c ognitie. In deze thesis werd geprobeerd het gekende mutatie- en fenotypisch spect rum van enkele van deze syndromen, namelijk Costello, Noonan en CFC synd room uit te breiden. We beschrijven een nieuwe HRAS mutatie in een pa tiënt met Costello syndroom die geen effect heeft op enzymatische activi teit, maar wel op guanine-nucleotide dissociatie. Ook beschrijven we het fenotype in patiënten met Noonan syndroom en SOS1, RAF1, KRAS en NRAS mutaties en in patiënten met CFC syndroom en BRAF en MEK2 mutaties. Niet eerder gerapporteerde mutaties in SOS1, KRAS, NR AS, BRAF en MEK2 werden gevonden. Daarnaast beschrijven we het fenotype in Legius syndroom, aanvankelijk neurofibromatose type1-achtig syndroom genoemd, een nieuw lid van deze groep van NCFC syndromen. Legius syndroom wordt veroorzaakt door mutatie s in SPRED1, een negatieve regulator van de RAS-MAPKinase cascade, en patiënten presenteren zich met café-au-lait vlekken met of zonder freck ling, doch zonder de andere typische symptomen van neurofibromatose type 1. Leerproblemen werden meermaals gerapporteerd in patiënten met Legius syndroom. We bestudeerden het leergedrag in een Spred1 knockout muiz enmodel en stelden vast dat deze muizen een verrassend gelijkaardig feno type vertonen met Nf1 heterozygote muizen zowel wat betreft leren als synaptische plasticiteit. Tenslotte bestudeerden we de intelligentie en het gedrag in een groep patiënten met Legius syndroom en niet-aangetast e siblings. Patiënten met Legius syndroom hebben een normaal totaal IQ, wat niet verschilt van de siblings, maar wel een lager performaal IQ. In de toekomst willen we proberen de leerproblemen in het Spred1 muiz enmodel om te keren door behandeling met statines, een behandeling die r eeds effectief gebleken is bij het Nf1 muizenmodel. Indien we een pos itief effect van statines op het leergedrag van Spred1 muizen kunnen aantonen, versterkt dit de theoretische basis voor klinische studies met deze medicatie in kinderen met neurofibromatose type 1 en misschien bij uitbreiding de andere NCFC syndromen.status: Publishe
Cognition and Behavior in Neurofibromatosis Type 1 and Legius Syndrome
No full textNeurofibromatosis Type 1 (NF1) is a frequent autosomal dominantgenetic disorder (1/2700 newborns). It is known as a RASopathy, caused by a mutation in the NF1 gene encoding neurofibromin, which is a negative regulator of the RAS (Rat sarcoma) / MAPK (Mitogen Activated Protein Kinase) pathway. This pathway has an important role in the process of cell proliferation and differentiation. However in recent years, accumulating evidence has shown that signaling through this pathway is also important in post‐mitotic neurons for synaptic plasticity and learning and memory. A small but significant proportion of patients has been identified with a milder NF1 phenotype, including pigmentary changes and cognitive and behavioral problems but no neurofibromas, Lisch nodules or optic pathway gliomas. Some of these individuals are diagnosed with Legius Syndrome (LS) . LS is caused by heterozygous loss‐of‐function SPRED1 gene mutations. The SPRED1 protein is another negative regulator of the RAS / MAPK pathway acting at the level of RAS‐RAF interaction and neurofibromin membrane recruitment.The overall objective of this thesis was to further study the consequences of NF1 on cognition (Part 1) and social behavior (Part 2) in daily life. At pediatric age, cognitive impairment is considered to be the most common complication in NF1 children, including an average left shift in IQ and several difficulties concerning visual‐spatial abilities, memory, attention and executive functioning. In Part 1 ‐ Chapter 3 , we characterized all of these cognitive problems in NF1 adults , since literature on this topic was rather limited. When comparing a sample of NF1 adults to a normative reference group, a continuum of neuropsychological deficits to adulthood was observed, except for a deficit in sustained attention. When additionally comparing these adultswith their spouses as an IQ‐matched control group, specific deficits in visualspatial abilities and memory, auditory working and long‐term memory function and several components of EF were observed, while unexpectedly no immediate recall and attention deficits were observed.There has been hope of developing a targeted therapy for cognition and behavioral problems in NF1, especially since their reversibility with statins was demonstrated in a mouse model. In cooperation with the Erasmus Medical Center of Rotterdam, we participated in a randomized, placebo‐controlled, double blind clinical trial in NF1 children, resulting in an adequate sample size of 84 NF1 children in combination with a low attrition rate and high medication compliance. However, no long‐term effect of Simvastatin treatment (dose: 12y: 40mg) on cognition and behavioral dysfunctioning in the daily life of NF1 children was observed (Part 1 ‐ Chapter 4 ).While considerable work has focused on cognitive functioning in NF1, several research groups also observed difficulties in general and social behavior (Part 2). Literature over the last 10 years has frequently described social and communication deficits within NF1 but without integrating this within a broader ASD syndromic framework. Therefore, our objective was to specifically screen for increased ASD symptoms and clinical ASD diagnosis in NF1 children visiting the NF1 outpatient clinic of the University Hospital of Leuven (Part 2 ‐ Chapter 5 ). We showed that NF1 is often accompanied by ASDsymptomatically, with 63% being at risk of clinically significant symptoms. Multidisciplinary child psychiatric assessment shows a minimum prevalence estimate of 26% clinical ASD co‐occurrence. Nonetheless, detailed characterization of the ASD behavioural phenotype was still lacking. However, based on in‐depth analyses of two gold standard instruments, a distinctive phenotypic profile was found with NF1+ASD children displaying overall better eye contact, better language skills and less stereotyped behavior when compared to IQ‐matched children with autism/ASD (Part 2 ‐ Chapter 6 ).Although several studies have shown Executive Functioning (EF) deficits in NF1 children, findings remain inconsistent and incomplete. In a large NF1 sample, we observed deficits on five EF domains, namely inhibition, cognitive flexibility, generativity, working memory and planning. Most of these deficits were not solely attributable to theirlower average IQ and/or elevated Autism Spectrum Disorder (ASD) characteristics (Part 2 ‐ Chapter 7). Taking a step back from a clinical to preclinical point of view, we focused on characterizing and rescuing ASD core symptoms, while also assessing motor and attention problems in the Spred1 ‐/‐ mouse model for LS (Part 3 ‐ Chapter 8 ). Experiments showed social and flexibility dysfunctions associated with ASD, which could be rescued with MEK inhibitor treatment. Other findings support a motor deficit in Spred1 knock‐out mice.To conclude, NF1 and LS are two single‐gene disorders, which can be seen as excellent experimental platforms to identify the relationshipbetween specific human phenotypes and particular molecular and cellularmechanisms. Clearly characterizing and understanding the cognitive and behavioral difficulties of these disorders is critical to guide clinicalcare and offer multidisciplinary support in development and functioning. In a next step, assembling preclinical observations on these difficulties within a small‐animal (e.g. mouse) model is crucial to get insight into the pathogenesis of these problems and generate efficient translational research. The convergence of multidisciplinary andclinical support with targeted treatment(s) will be essential as we move forward into a time period of personalized care .status: Publishe
Mechanotransduction and NF1 Loss—Partner in Crime: New Hints for Neurofibroma Genesis
No full textThe mechanical properties of the microenvironment have been increasingly accepted as potent modulators of cell behavior and function in physiological and pathological conditions. In tumors, tissue rigidity has been recognized as a potent driver of both neoplastic initiation from healthy tissue and progression toward malignancy. Several benign or malignant tumors are fibrotic and characterized by increased deposition, turnover, and posttranslational modifications of the extracellular matrix (ECM) that progressively stiffens the stroma. Likewise, neurofibromas are complex tumors composed of transformed Schwann cells, immersed in a heterogeneous fibrotic matrix. The molecular crosstalks that govern neurofibroma onset, growth, invasiveness, and progression toward malignancy remain poorly understood. In this chapter we propose that neurofibroma development requires the integration of potent pro-tumorigenic circuitries, such as those mastered by hyperactive Ras, and altered mechanosignaling axes conveyed by a stiff ECM, and that these pathways could be orchestrated by a pro-inflammatory extracellular milieu
Review and update of SPRED1 mutations causing legius syndrome
No full textLegius syndrome presents as a mild neurofibromatosis type 1 (NF1) phenotype. Multiple café-au-lait spots and macrocephaly are present with or without axillary or inguinal freckling. Other typical NF1-associated features (Lisch nodules, bone abnormalities, neurofibromas, optic pathway gliomas, and malignant peripheral nerve sheath tumors) are systematically absent. Legius syndrome is caused by germline loss-of-function SPRED1 mutations, resulting in overactivation of the RAS-MAPK signal transduction cascade. The first families were identified in 2007. Here, we review all identified SPRED1 mutations and summarize molecular, clinical, and functional data. All mutations have been deposited in a database created using the Leiden Open Variation Database software and accessible at http://www.lovd.nl/SPRED1. At present, the database contains 89 different mutations identified in 146 unrelated probands, including 16 new variants described for the first time. The database contains a spectrum of mutations: 29 missense, 28 frameshift, 19 nonsense, eight copy number changes, two splicing, one silent, one in-frame deletion and a mutation affecting the initiation codon. Sixty-three mutations and deletions are definitely pathogenic or most likely pathogenic, eight SPRED1 mutations are probably benign rare variants, and 17 SPRED1 missense mutations are still unclassified and need further family and functional studies to help with the interpretation.sponsorship: Contract grant sponsors: The European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 200754: The GEN2PHEN project (construction of the LOVD database); Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (G.0578.06) (to E.L.); the cancer foundation "Stichting tegen Kanker' (C.0011-204-208) (to E.L.); and a Concerted Action Grant (GOA/11/010) from the KULeuven. (European Community|200754, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen|G.0578.06, cancer foundation "Stichting tegen Kanker'|C.0011-204-208, KULeuven|GOA/11/010)status: Publishe
Observations on intelligence and behavior in 15 patients with Legius syndrome
No full textLegius syndrome is a RAS-MAPK syndrome characterized by pigmentary findings similar to neurofibromatosis type 1 (NF1), but without tumor complications. Learning difficulties and behavioral problems have been reported to be associated with Legius syndrome, but have not been studied systematically. We investigated intelligence and behavior in 15 patients with Legius syndrome and 7 unaffected family members. We report a mean full-scale IQ of 101.57 in patients with Legius syndrome, which does not differ from the control group. We find a significantly lower Performance IQ in children with Legius syndrome compared to their unaffected family members. Few behavioral problems are present as assessed by the Child Behavior Checklist (CBCL) questionnaire. Our observations suggest that, akin to the milder somatic phenotype, the cognitive phenotype in Legius syndrome is less severe than that of NF1. © 2011 Wiley-Liss, Inc.sponsorship: Grant sponsor: Fonds voor Wetenschappelijk Onderzoek Vlaanderen; Grant numbers: G.0578.06, G.O551.08; Grant sponsor: Interuniversity Attraction Poles (IAP); Federal Office for Scientific, Technical and Cultural Affairs, Belgium (2007-2011); Grant number: P6/05; Grant sponsor: Concerted Action Grant; K.U. Leuven; Grant sponsor: Division of Intramural Research of the National Human Genome Research Institute, National Institute of Mental Health.E.D. is predoctoral researcher of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen; This work is supported by research grants from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (G.0578.06 and G.O551.08 to E.L.); the Interuniversity Attraction Poles (IAP) granted by the Federal Office for Scientific, Technical and Cultural Affairs, Belgium (2007-2011; P6/05) (E.L.), and by a Concerted Action Grant from the K.U. Leuven (E.L.). The work was supported in part by the Division of Intramural Research of the National Human Genome Research Institute and the National Institute of Mental Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. (Fonds voor Wetenschappelijk Onderzoek Vlaanderen|G.0578.06, Fonds voor Wetenschappelijk Onderzoek Vlaanderen|G.O551.08, Federal Office for Scientific, Technical and Cultural Affairs, Belgium|P6/05, K.U. Leuven, Division of Intramural Research of the National Human Genome Research Institute, National Institute of Mental Health)status: Publishe
ROSENTHAL, Eric Inventory of documents
No full textCOVERAGE 1904; 1 File; 011 metre.Private papers of Eric Rosenthal, author, journalist and broadcaster
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