Neurofibromin (NF1) is a 2,818aa protein encoded by the very large NF1 tumour suppressor gene located on chromosome 17q11.2. Loss of function mutations and deletions in NF1 underlie Neurofibromatosis type-1 (NF-1) - the most common inherited syndrome of the nervous system in humans with a birth incidence of 1:3,000. The most visible feature of NF-1 is the neoplastic manifestations known as neurofibromas, however, the syndrome is also characterized by pigmentary defects, peripheral motor dysfunction, learning disabilities and several developmental abnormalities. The molecular etiology of many of these non-neoplastic phenotypes remains unknown. Here we demonstrate that the Tubulin Binding Domain (TBD) of NF1 is a binding partner of the Leucine Rich Pentatrico Peptide Repeat motif-Containing protein (LRPPRC) and cytoplasmic Dynein Heavy Chain (DHC). The NF1-LRPPRC interaction is of high significance as it links NF-1 with Leigh’s Syndrome, French Canadian variant (LSFC) – an autosomal recessive neurodegenerative disorder that arises due to mutations in the LRPPRC gene. This interaction occurs as part of an RNA granule complex, and use of transgenic mouse models establishes an important role of NF1 and LRPPRC in peripheral nerve development. The NF1-DHC interaction is of importance in melanocytes where our studies suggest a possible role in melanosome localization, disruptions in which may underlie the abnormal pigmentary features known as café-au-lait macules that are commonly associated with NF-1. The validation of LRPPRC and DHC as novel NF1 interactors reveal new roles of NF1, which open the door to better understanding the molecular mechanisms that underlie the myriad of NF-1 manifestations.

L'autisme et la déficience mentale (DM) sont des pathologies neurodéveloppementales fréquentes qui partagent des facteurs génétiques communs. Afin de mieux comprendre leur étiologie, nous avons étudié les mécanismes moléculaires de la neurofibromatose de type 1 (NF1), qui est souvent associée à l'autisme et à la DM. La neurofibromine, dont le gène est muté dans la NF1 interagit avec LIMK2. Cette protéine fait partie de la voie des Rho-GTPases dont des mutations de plusieurs membres ont été trouvés mutés dans des cas d'autisme et de DM. Chez le rat, nous avons montré que l’expression de Limk2d, une isoforme sans domaine kinase, augmente la croissance des neurites des cellules neuronales NSC-34. Chez l'homme, LIMK2-1 est la seule isoforme qui comporte un domaine inhibiteur de la phosphatase 1 (PP1i). Nous avons montré que l’expression de cette protéine diminue la longueur des neurites des cellules NSC-34 in vitro. Nous avons observé l'association de la variation située dans le domaine PP1i à la DM (p.S668P, rs151191437) (p=0,04, test de Fisher, OR = 3,29). Elle abolit l’effet inhibiteur de croissance des neurites de l'isoforme LIMK2-1 diminue l'interaction de LIMK2-1 avec la neurofibromine. La fréquence de l'autisme est plus élevée chez les patients atteints ayant des délétions de 14 gènes du locus NF1. Nous avons observé une association entre la variation R115K (rs111902263) du gène RNF135 de ce locus et l'autisme (p=0,00014, test de Fisher) ainsi qu’une anomalie du nombre de copies située dans l'intron 2 de ce gène chez un d’entre eux. Ce travail souligne la spécificité de deux isoformes de LIMK2 sur la croissance des neurites. Il renforce l’intérêt d’étudier l’implication du gène RNF135 dans l’autisme. Des études fonctionnelles seront entreprises afin de confirmer le rôle de LIMK2 et de RNF135 dans l'étiologie de l'autisme et de la DM. / Autism and mental deficiency (MD) are two neurodevelopemental diseases which share genetic factors in common. To better understand their etiologies, we studied the molecular mechanisms of neurofibromatosis type 1, a pathology frequently associated with autism and MD. Neurofibromatosis type 1 is due to deletions or mutations of the NF1 gene which encodes neurofibromin. This protein interacts with several proteins such as LIMK2. This protein belongs to the Rho-GTPases pathway in wich mutations of numerous members have been associated with autism and MD. In our study, we showed that LIMK2 isoforms do not only have important structural differencies but have also functional specificities. Limk2d, which lacks the kinase domain, promotes neurite outgrowth of NSC-34 cells. On the contrary, LIMK2-1, which is primate specific and has a C-terminal PP1i domain, inhibits neurite outgrowth. Analysis of the LIMK2-1 coding sequence, revealed the association between MD and a variation located in the PP1i domain, S668P (rs151191437) (p=0.04, Fisher test, OR = 3.29). This variation abrogated the LIMK2-1 effect on neurite outgrowth and inhibited LIMK2-1 interaction with neurofibromin. Deletions occuring in neurofibromatosis type 1 which include the NF1 gene and 13 others are associated with a higher frequency of autism. Mutations of one of them, RNF135, have been identified in patients with MD and overgrowth syndrome. Two of these patients also presented autistic features. By analysing RNF135 gene in autistic patients, we showed the association of the variation R115K (rs111902263) with autism. We also identified a duplication of a region located in RNF135 gene intron 2 in one patient presenting autism and MD. Our results highlight the importance and specificity of LIMK2 isoforms on neurite outgrowth and strengthen the importance to analyze both the sequence and copy-number of RNF135 gene. Further functional experiments will be undertaken to confirm the implication of LIMK2 and RNF135 in autism and MD etiology.

LIMK1 et LIMK2 sont des sérines/thréonine kinases capables de phosphoryler et d’inactiver la cofiline, un facteur de dépolymérisation de l’actine. Elles sont régulées négativement par la neurofibromine, responsable de la neurofibromatose de type 1, et pourraient être impliquées à la fois dans les aspects tumoraux et cognitifs de cette maladie par leur rôle dans la dynamique de l’actine. Nous avons étudié l’isoforme LIMK2‐1 de LIMK2, spécifique des hominidés et précédemment associée à la déficience intellectuelle. Cette isoforme possède un domaine kinase tronqué et un domaine inhibiteur de la phosphatase 1 (PP1i) en C‐terminal. Nos résultats montrent, d’une part, que LIMK2‐1 existe sous forme de protéine et qu’elle est exprimée dans le système nerveux central chez l’homme, en particulier au cours du neurodéveloppement. D’autre part, il apparaît que cette isoforme favorise la polymérisation de l’actine. Cette action semble indépendant de l’activité kinase puisque LIMK2‐1 ne phosphoryle pas la cofiline. Nous avons également montré que le domaine PP1i interagissait spécifiquement avec la phosphatase 1 et des résultats complémentaires suggèrent un rôle de ce domaine dans l’inhibition de la dépolymérisation de l’actine. Ces données mettent en évidence un mécanisme moléculaire nouveau pour une protéine de la famille des LIMK et soulignent l’intérêt d’étudier ces protéines afin de mieux comprendre leur implication dans les troubles cognitifs et dans la neurofibromatose de type 1. / LIMK1 and LIMK2 are serine/threonine kinases that phosphorylate and subsequently inactivate cofilin, an actin-depolymerizing factor. Neurofibromin, the protein responsible for neurofibromatosis type 1, negatively regulates these proteins that may be involved in tumoral and cognitive aspects of the disease through their role in actin dynamics. We studied LIMK2-1, a hominidae-specific isoform previously involved in intellectual disability. This isoform possesses a truncated kinase domain and a protein phosphatase 1 inhibitory (PP1i) domain at its C-terminal extremity. Our results showed that LIMK2-1 exists at a protein level and that it is expressed in human central nervous system, especially during neurodevelopment. Moreover, LIMK2-1 promotes actin polymerization independently from a kinase activity, since this isoform does not phosphorylate cofiline. We also highlighted an interaction between the PP1i domain and protein phosphatase 1 and complementary results suggest a role of this domain in the inhibition of actin depolymerization. These data highlight a new molecular mechanism for a LIMK protein and emphasize the interest of studying these proteins to understand their involvement in cognitive disorders and in neurofibromatosis type 1.

Base teórica: A qualidade de vida é uma variável amplamente estudada nas ciências da saúde e tem se tornado, cada vez mais, um indicativo importante na avaliação dos estados e desfechos de saúde. As doenças crônicas se caracterizam por curso prolongado, por vezes acompanhando o portador por toda sua vida, o que pode influenciar a percepção que o indivíduo tem de si mesmo e de sua vida. A Neurofibromatose tipo 1 (NF1) é uma doença crônica, genética, que atinge cerca de 1:3500 nascimentos. Além de ser uma doença que acarreta uma maior predisposição ao desenvolvimento de tumores, a NF1 possui sintomas físicos de fácil identificação. Objetivo: O presente estudo visa estudar a qualidade de vida e algumas variáveis emocionais de pessoas com neurofibromatose tipo 1. Método: Trata-se de um estudo transversal. Foram avaliadas as variáveis de qualidade de vida genérica (WHOQOL-bref e SF-36), qualidade de vida específica para pessoas com problemas de pele (DLQI-bra), sintomas depressivos (BDI), sintomas de ansiedade(BAI), percepção de suporte familiar (IPSF) e estratégias de enfrentamento (Inventário de Estratégias de Coping de Folkman e Lazarus). Os participantes deste estudo também foram avaliados quanto à gravidade (Escala de Riccardi) e visibilidade dos sintomas da doença (Ablon). Resultados: Foram coletados dados de 71 pacientes adultos com NF1. Do total 60,0% da amostra foram pessoas do sexo feminino, a média de idade foi de ± 40,36 anos. Dos 52 pacientes avaliados pela escala de Riccardi, 11,3% apresentou gravidade leve, 40,4% gravidade moderada, 42% sintomas graves de gravidade e 6,5% sintomas muito graves da doença. Com relação a visibilidade dos sintomas medidos pela escala de Ablon, 36,5% apresentam visibilidade leve de sintomas, 30,8% visibilidade moderada e 32.7% visibilidade severa dos sintomas. Conclusão: Os resultados da avaliação de qualidade de vida de pessoas com NF1, ao serem comparados com os dados normativos para amostra, não apresentou diferença estatisticamente significativa. A análise dos sintomas depressivos indicou que grande parte dos entrevistados apresentam sintomas leves de depressão e os dados da escala BAI referente aos sintomas de ansiedade constatou que a média dos entrevistados apresentam sintomas graves de ansiedade, podendo sugerir que a ansiedade seja uma característica importante dessa população. As estratégias de enfrentamento mais utilizadas por esta população foram a reavaliação e o suporte social. Com relação aos resultados da percepção de suporte familiar, podemos perceber que os dados da amostra não apresentaram diferença significativa ao serem comparados com os dados normativos da escala. / Theoretical basis: Quality of life is an important studied variable in health sciences and has become an important indicator in assessing states and health outcome. Chronic diseases are characterized by a prolonged course, sometimes accompanying the carrier all his life, which can influence the perception that the individual has of himself and of his life. The neurofibromatosis type 1 (NF1) is a chronic and genetics condition that affects about 1: 3500 births. Besides being a disease that leads to a greater predisposition to develop tumors, NF1 has physical symptoms of easy identification. Objective: This project aims to study the quality of life and emotional variables of people with neurofibromatosis type 1. Method: This is an observational study. The overall quality of life variables were evaluated (WHOQOL-bref and SF-36), specific quality of life for people with skin problems (DLQI-bra), depressive symptoms (BDI), anxiety symptoms (BAI), perception of family supports (IPSF) and coping strategies (coping strategies Inventory of Folkman and Lazarus). The participants were also evaluated for the severity (Riccardi Scale) and visibility of disease symptoms (Ablon). Results: Were collected data from 71 adults patients with NF1. From all sample 60% were female. The mean age was ± 40.36 years . Of the 52 patients evaluated for Riccardi scale , 11.3 % had mild severity , 40.4 % moderate severity , 42% Severity of symptoms and 6.5 % symptoms very severe. The data of the visibility of the symptoms were measure by Ablon scale , 36.5 % have mild symptoms visibility , 30.8 % moderate and 32.7 % severe visibility of symptoms. Conclusion: The results of the quality of life of people with NF1, when compared with the normative data for sample, indicate no statistically significant difference. The analysis of depressive symptoms indicated that the majority of respondents have mild symptoms of depression and the BAI scale data related to symptoms of anxiety found that the average of respondents have severe anxiety symptoms and may suggest that anxiety can be an important feature of this population. Coping strategies most used by this population were the re-evaluation and social support. Regarding the results of the perception of family support, we can see that the sample data showed no significant difference when compared with the normative data range.

Base teórica: A qualidade de vida é uma variável amplamente estudada nas ciências da saúde e tem se tornado, cada vez mais, um indicativo importante na avaliação dos estados e desfechos de saúde. As doenças crônicas se caracterizam por curso prolongado, por vezes acompanhando o portador por toda sua vida, o que pode influenciar a percepção que o indivíduo tem de si mesmo e de sua vida. A Neurofibromatose tipo 1 (NF1) é uma doença crônica, genética, que atinge cerca de 1:3500 nascimentos. Além de ser uma doença que acarreta uma maior predisposição ao desenvolvimento de tumores, a NF1 possui sintomas físicos de fácil identificação. Objetivo: O presente estudo visa estudar a qualidade de vida e algumas variáveis emocionais de pessoas com neurofibromatose tipo 1. Método: Trata-se de um estudo transversal. Foram avaliadas as variáveis de qualidade de vida genérica (WHOQOL-bref e SF-36), qualidade de vida específica para pessoas com problemas de pele (DLQI-bra), sintomas depressivos (BDI), sintomas de ansiedade(BAI), percepção de suporte familiar (IPSF) e estratégias de enfrentamento (Inventário de Estratégias de Coping de Folkman e Lazarus). Os participantes deste estudo também foram avaliados quanto à gravidade (Escala de Riccardi) e visibilidade dos sintomas da doença (Ablon). Resultados: Foram coletados dados de 71 pacientes adultos com NF1. Do total 60,0% da amostra foram pessoas do sexo feminino, a média de idade foi de ± 40,36 anos. Dos 52 pacientes avaliados pela escala de Riccardi, 11,3% apresentou gravidade leve, 40,4% gravidade moderada, 42% sintomas graves de gravidade e 6,5% sintomas muito graves da doença. Com relação a visibilidade dos sintomas medidos pela escala de Ablon, 36,5% apresentam visibilidade leve de sintomas, 30,8% visibilidade moderada e 32.7% visibilidade severa dos sintomas. Conclusão: Os resultados da avaliação de qualidade de vida de pessoas com NF1, ao serem comparados com os dados normativos para amostra, não apresentou diferença estatisticamente significativa. A análise dos sintomas depressivos indicou que grande parte dos entrevistados apresentam sintomas leves de depressão e os dados da escala BAI referente aos sintomas de ansiedade constatou que a média dos entrevistados apresentam sintomas graves de ansiedade, podendo sugerir que a ansiedade seja uma característica importante dessa população. As estratégias de enfrentamento mais utilizadas por esta população foram a reavaliação e o suporte social. Com relação aos resultados da percepção de suporte familiar, podemos perceber que os dados da amostra não apresentaram diferença significativa ao serem comparados com os dados normativos da escala. / Theoretical basis: Quality of life is an important studied variable in health sciences and has become an important indicator in assessing states and health outcome. Chronic diseases are characterized by a prolonged course, sometimes accompanying the carrier all his life, which can influence the perception that the individual has of himself and of his life. The neurofibromatosis type 1 (NF1) is a chronic and genetics condition that affects about 1: 3500 births. Besides being a disease that leads to a greater predisposition to develop tumors, NF1 has physical symptoms of easy identification. Objective: This project aims to study the quality of life and emotional variables of people with neurofibromatosis type 1. Method: This is an observational study. The overall quality of life variables were evaluated (WHOQOL-bref and SF-36), specific quality of life for people with skin problems (DLQI-bra), depressive symptoms (BDI), anxiety symptoms (BAI), perception of family supports (IPSF) and coping strategies (coping strategies Inventory of Folkman and Lazarus). The participants were also evaluated for the severity (Riccardi Scale) and visibility of disease symptoms (Ablon). Results: Were collected data from 71 adults patients with NF1. From all sample 60% were female. The mean age was ± 40.36 years . Of the 52 patients evaluated for Riccardi scale , 11.3 % had mild severity , 40.4 % moderate severity , 42% Severity of symptoms and 6.5 % symptoms very severe. The data of the visibility of the symptoms were measure by Ablon scale , 36.5 % have mild symptoms visibility , 30.8 % moderate and 32.7 % severe visibility of symptoms. Conclusion: The results of the quality of life of people with NF1, when compared with the normative data for sample, indicate no statistically significant difference. The analysis of depressive symptoms indicated that the majority of respondents have mild symptoms of depression and the BAI scale data related to symptoms of anxiety found that the average of respondents have severe anxiety symptoms and may suggest that anxiety can be an important feature of this population. Coping strategies most used by this population were the re-evaluation and social support. Regarding the results of the perception of family support, we can see that the sample data showed no significant difference when compared with the normative data range.

Abstract The stem cell is a primitive cell that is capable of dividing to reproduce itself and can give rise to a selection of differentiated progeny. Stem cells are thought to be involved in or even main factors in many diseases. In postnatal humans, mesenchymal tissues have the capacity to regenerate from stem cells called mesenchymal stem cells (MSC). It is currently thought that these cells will become the basis of therapy for many diseases. In the present study, a novel in vitro method was developed to examine human bone marrow derived MSC differentiation into osteoblast lineage, and to study the role of MSC in a variety of mesenchymal diseases. The ability of MSCs to differentiate into osteoblasts was investigated during aging. In addition, the interindividual variability in the osteogenesis of MSCs and in the osteoblastic response of MSC to estrogen and testosterone was studied. Furthermore, an ex vivo model using a human aortic valve microenvironment was developed to explore whether the extracellular matrix influences the osteoblastic differentiation of the MSC. Finally, the role of MSC in neurofibromatosis type 1 (NF1) related congenital pseudarthrosis of the tibia (CPT) was studied. It was found that after menopause the osteogenic potential of MSCs does not decrease. It was also found that estrogen receptor (ER) alpha genotype confers interindividual variability of response to estrogen and testosterone in MSC derived osteoblasts. In addition, it was found that the non-calcified valves with living valve cells inhibited osteogenesis of co-cultured MSCs, whereas the calcified and devitalised valves promoted differentiation towards an osteoblastic lineage. Finally, MSCs from NF1-related pseudarthrosis showed altered NF1 gene expression, poor osteoblastic differentiation and bone formation. In conclusion, MSC can be easily isolated from the bone marrow and MSC has the capacity to regenerate tissue even at later stages of life. These results could help explain the contradictory effects of 17β-estradiol (E2) on osteoblasts in vitro and might also provide new insights into understanding the differences in responses to hormone replacement therapy. It seems that adult stem cells from bone marrow undergo milieu-dependent differentiation to express phenotypes that are similar to cells in the local microenvironment. Finally, the NF1 gene was shown to have a role in bone development and remodelling.

Abstract Type 1 neurofibromatosis (NF1) syndrome is caused by a mutation of the NF1 gene. NF1 protein (neurofibromin) contains a domain which is related to the GTPase activating protein (GAP) and accelerates the switch of active Ras-GTP to inactive Ras-GDP. The clinical symptoms of NF1 patients include e.g. the formation of benign neurofibroma tumors and hyperpigmented lesions of the skin. The NF1 protein has been referred to as a tumor suppressor since cells of malignant schwannomas of NF1 patients may display loss of heterozygosity of the NF1 gene. In the present study, the expression of the NF1 gene was investigated during tissue repair in human skin. Elevated NF1 protein levels were seen in a fibroblastic cell population of healing wounds. In vitro studies were designed to investigate NF1 expression in dermal fibroblasts under the influence of growth factors that are operative during wound healing. Platelet-derived growth factor (PDGF) isoforms AB and BB and transforming growth factor β1 (TGFβ1) elevated NF1 mRNA levels in cultured dermal fibroblasts. In further studies, histological examination on apparently healthy skin of NF1 patients revealed frequently small masses of neurofibromatous tissue at the vicinity of hair follicles. Thus, action of the NF1 gene appears to be an integral part of normal tissue repair. Enhanced NF1 tumor suppressor expression may serve to limit excessive fibrosis in wound healing. As Ras proteins play a role in the regulation of cell differentiation and formation of cell junctions, the functional expression of NF1 protein was elucidated using differentiating keratinocytes as an in vitro model system. The results demonstrate that an intense NF1 tumor suppressor signal on intermediate filaments was temporally limited to the period in which the formation of desmosomes takes place. In analogy to NF1 protein, a rapid elevation of NF1 mRNA level was detected following initiation of differentiation. Interestingly, NF1 mRNA hybridization signal polarized towards cell-cell contact zones. This finding recognizes a potential way for post-transcriptional modification of NF1 expression and targeting of translation to subplasmalemmal location. The results demonstrate that the function of NF1 protein is associated with the formation of cell junctions, and thus to cellular communication.

Abstract This study examined the role of tumor suppressor neurofibromin and Protein kinase C (PKC) in urinary bladder cancer, and the effect of PKC inhibitors on cancer cell behaviour. Tumor suppressor protein neurofibromin is a product of the NF1 gene, a mutation of which causes the most common hereditary tumor syndrome, type 1 neurofibromatosis. NF1 gene mutations and changes in expression have been demonstrated in malignancies, unrelated to type 1 neurofibromatosis. The best known function of neurofibromin is its Ras GTPase accelerating function. Thus, it functions as a Ras inactivator. This study demonstrated for the first time that the NF1 gene is expressed in normal and malignant urinary bladder epithelium and in cultured bladder carcinoma cells in mRNA and at the protein level. Furthermore, neurofibromin expression is decreased during bladder carcinogenesis. It can be speculated that this may lead to increased Ras activity in urinary bladder cancer. The PKC family is composed of several different isoenzymes which are responsible for a number of important intracellular events and cellular functions. Many of these are also important in cancer development and progression. The results demonstrate changes in expression of PKC α and βI isoenzymes in urinary bladder carcinoma. Furthermore, the results relate the increased expression of isoenzymes to increased PKC enzyme activity and the high proliferation rate of the cancer cells. In addition, this study utilizes small molecular inhibitors of PKC isoenzymes in order to study the effect of the inhibition of these isoenzymes on cancer cell behaviour in vitro and in vivo. The study mainly focuses on the function of PKC α and βI isoenzymes and on the effects of inhibition of these by using Go6976. The results show that Go6976 inhibits cancer cell growth, migration and invasion in vitro, and tumor growth in a mouse model. The use of Go6976 induces changes in desmosomes and adherens junctions, and in focal adhesions and hemidesmosomes. The results also show that Go6976 functions as a cell cycle checkpoint abrogator and increases the cytotoxicity of two classical chemotherapeutic agents, doxorubicin and paclitaxel. In the future, it may be possible that Go6976 or related drugs could be used in clinical cancer treatments.

OBJECTIVES: Models for the development of new treatment options in vestibular schwannoma (VS) treatment are lacking. The purpose of this study is to establish a quantifiable human VS xenograft model in mice. STUDY DESIGN AND METHODS: Both rat malignant schwannoma cells (KE-F11 and RT4) and human malignant schwannoma (HMS-97) cells were implanted near the sciatic nerve in the thigh of severe combined immunodeficiency (SCID) mice. Additionally, human benign VS specimens were implanted in another set of SCID mice. Three-dimensional tumor volumes were calculated from magnetic resonance images over the next 6 months. RESULTS: Mice implanted with malignant schwannoma cells developed visible tumors within 2 weeks. Imaging using a 4.7-tesla magnetic resonance imaging and immunohistopathologic examination identified solid tumors in all KE-F11 and HMS-97 xenografts, whereas RT4 xenografts consistently developed cystic schwannomas. VS xenografts demonstrated variability in their growth rates similar to human VS. The majority of VS xenografts did not grow but persisted throughout the study, whereas two of 15 xenografts grew significantly. Histopathologic examination and immunohistochemistry confirmed that VS xenografts retained their original microscopic and immunohistochemical characteristics after prolonged implantation. CONCLUSIONS: This study describes the first animal model for cystic schwannomas. Also, we demonstrate the use of high-field magnetic resonance imaging to quantify VS xenograft growth over time. The VS xenografts represent a model complimentary to Nf2 transgenic and knockout mice for translational VS research.

Les données de la littérature concernant les difficultés cognitives et comportementales dans la Neurofibromatose de type 1 (NF1) sont nombreuses avec des résultats parfois contradictoires. Après une revue de la littérature, ce travail de recherche : (i) décrit les difficultés comportementales, cognitives et motrices chez 78 patients atteints de NF1, âgés de 5 à 18 ans, au moyen de questionnaires aux parents (qualité de vie, impact de la maladie, difficultés des parents eux-mêmes, Conners, BRIEF, CBCL), et d'une évaluation de l'efficience intellectuelle et neuropsychologique détaillée ; (ii) analyse les relations entre les aspects cliniques, comportementaux, neuropsychologiques et l'imagerie (présence ou non d'« Objets Brillants Non Identifiés » caractéristiques de la NF1). Les difficultés d'apprentissage, malgré une qualité de vie plutôt bonne et un faible impact de la maladie, les troubles attentionnels et l'anxiété de l'enfant constituaient les principales sources d'inquiétude des parents. Les questionnaires étaient corrélés entre eux, mais ils étaient peu liés aux tests neuropsychologiques. La présence de difficultés cognitives spécifiques, en particulier visuo-spatiales et en motricité fine, a été confirmée. Aucune relation n'a pu être établie entre la neuropsychologie et l'imagerie. Les difficultés neuropsychologiques étaient plus sévères dans les formes familiales que sporadiques. / Cognitive and behavioral difficulties are common in children with Neurofibromatosis type 1 (NF1), however findings concerning the specific neuropsychological and behavioral profile as well as the association of these difficulties with clinical manifestations and brain imagery abnormalities are often contradictory. After a literature review, the present study: (i) describes behavioral, cognitive, and motor difficulties in 78 patients with NF1, aged 5 to 18 years, using parental questionnaires (quality of life, impact of illness, parental difficulties, Conners, BRIEF, CBCL), and tests of intellectual efficiency and specific neuropsychological functions; (ii) examines the relationships between clinical, behavioral, neuropsychological and imaging findings (presence or absence of "Unidentified Bright Objects" UBOs, characteristic feature of NF1). Learning disabilities, despite relatively good report of quality of life, attention disorders and child anxiety were the main parental concerns. All parental questionnaires were strongly inter-correlated, and associated with an overall positive or negative parental attitude during the interview with the psychologist. Parental concerns were only weakly related to neuropsychological tests. The presence of specific cognitive difficulties, particularly in visuospatial and fine motor skills, was confirmed. Imaging data were not associated with neuropsychological scores. Cognitive difficulties were more important in familial than sporadic forms.