Cerebellum: links between development, developmental disorders and motor learning

The study of the links and interactions between development and motor learning has noticeable implications for the understanding and management of neurodevelopmental disorders. This is particularly relevant for the cerebellum which is critical for sensorimotor learning. The olivocerebellar pathway is a key pathway contributing to learning of motor skills. Its developmental maturation and remodeling are being unraveled. Advances in genetics have led to major improvements in our appraisal of the genes involved in cerebellar development, especially studies in mutant mice. Cerebellar neurogenesis is compartmentalized in relationship with neurotransmitter fate. The Engrailed-2 gene is a major actor of the specification of cerebellar cell types and late embryogenic morphogenesis. Math1, expressed by the rhombic lip, is required for the genesis of glutamatergic neurons. Mutants deficient for the transcription factor Ptf1a display a lack of Purkinje cells and gabaergic interneurons. Rora gene contributes to the developmental signaling between granule cells and Purkinje neurons. The expression profile of sonic hedgehog in postnatal stages determines the final size/shape of the cerebellum. Genes affecting the development impact upon the physiological properties of the cerebellar circuits. For instance, receptors are developmentally regulated and their action interferes directly with developmental processes. Another field of research which is expanding relates to very preterm neonates. They are at risk for cerebellar lesions, which may themselves impair the developmental events. Very preterm neonates often show sensori-motor deficits, highlighting another major link between impaired developments and learning deficiencies. Pathways playing a critical role in cerebellar development are likely to become therapeutical targets for several neurodevelopmental disorders

Ruptured Renal Angiomyolipoma

Teaching Point: This case highlights the importance of extending the medical analysis to other areas with lumbar computed tomography, especially to the kidneys and the retroperitoneum

Cerebellar dysplasias : structural functional correlations

La dysplasie cérébelleuse est une anomalie du développement tissulaire intéressant principalement le cervelet et résultant en une anomalie focale ou diffuse de son architecture macroscopique et microscopique. Plusieurs travaux antérieurs ont bien documenté sa caractérisation morphologique à l'imagerie par résonance magnétique (IRM). Cependant, le retentissement de cette malformation, parfois associée à d'autres anomalies développementales du système nerveux central (SNC), sur le développement et le fonctionnement cognitifs est mal connu et peu documenté. Dans le but d'étudier les corrélations anatomo-fonctionnelles de cette pathologie constitutionnelle du cervelet, par le biais de l'approche des altérations neuropsychologiques, génétiques et, fonctionnelles associées, ainsi que par l'approche neuroanatomique, nous avons dirigé nos travaux dans quatre axes principaux et sur trois types de population distinctes. Le premier axe a concerné l'évaluation du profil neuropsychologique et du suivi chez dix enfants porteurs d'une dysplasie cérébelleuse isolée (DCI). Nous avons pu observer chez ces enfants une grande diversité de l'expression neuropsychologique de la DCI, depuis l'efficience normale jusqu'au retard mental sévère, sans corrélation avec le degré de dysplasie. D'autre part, au cours du suivi de ces enfants, nous avons observé une hétérogénéité d'évolution à caractère imprédictible, avec l'émergence des certaines fonctions dans l'axe du langage notamment. Le deuxième axe a porté sur l'investigation fonctionnelle du SNC par l'étude de la consommation cérébrale du fluorodeoxyglucose par Tomographie à émission de positons (TEP-FDG) chez six enfants porteurs d'une DCI. Les résultats ont montré, au sein du cervelet, un aspect normal dans les dysplasies mineures (limitées au vermis), un hypométabolisme des zones dysplasiques (corrélé à l'extension anatomique), et un isométabolisme au cortex dans les hétérotopies. Toutefois, ces anomalies de captation du glucose n'étaient pas corrélées au dysfonctionnement cognitif. Le troisième axe était d'approcher les corrélations génétiques, dans l'hypothèse d'un lien physiopathologique embryologique entre le cerveau et le cervelet, dans les dysplasies cérébelleuses associées (DCA) aux Lissencéphalies (cerveaux lisses). La caractérisation génétique relativement bien définie des Lissencéphalies nous a permis d'identifier des gènes de la migration neuronale et axonale (RELN et VLDRL) comme étant significativement associés aux dysplasies cérébelleuses, en dehors des dystrophies musculaires congénitales impliquant les gènes de la O-glycosylation. Le quatrième axe a été de rechercher chez des volontaires sains les marqueurs neuroanatomiques potentiels des altérations cognitives dans les dysplasies cérébelleuses, partant de l'hypothèse selon laquelle, une malformation isolée du cervelet induirait des anomalies anatomiques détectables en imagerie par tenseur de diffusion (DTI), sur les voies de projections cérébello-corticales, vraisemblablement impliquées dans la contribution du cervelet au développement et à l'exécution des fonctions supérieures. Ce travail nous a permis d'individualiser et de quantifier les projections cérébello-corticales préfrontales et pariétales chez tous les sujets sains.Cerebellar dysplasia is a developmental anomaly involving mainly the cerebellum, resulting in a focal or diffuse macroscopic and microscopic disruption of the tissue architecture. Previous studies have well documented the magnetic resonance imaging (MRI) features of this malformation. However, the impact of cerebellar dysplasia, which may be associated with other developmental anomalies of the central nervous system (CNS), on the cognitive development and function, is ill known and poorly documented. We aimed to study the structural functional correlations in this cerebellar malformation, by investigating the neuropsychological, genetic and, functional disturbances associated as well as the neuroanatomical approach. Our work was conducted in 4 directions including 3 different populations. First, we assessed the neuropsychological profile and the follow-up of children with isolated cerebellar dysplasia (ICD). We observed I this population a wide range of neuropsychological expression of ICD, from normal efficiency to severe mental retardation, without no correlation with the degree of dysplasia. Moreover, during the follow-up of these children, we noticed the unpredictable heterogeneity of the cognitive evolution with the emergence in some cases of certain function such as language. Secondly, we investigated the CNS function using fluorodeoxyglucose positron emission tomography (FDG-PET) in six children with ICD. The results showed within the cerebellum a normal aspect in patients with minor dysplasia (restricted to the vermis), a hypometabolism in dysplastic zones (correlating with the anatomical extent), and a metabolism similar to that of the cortex in heterotopias. Nevertheless, these functional disturbances were not correlated with neuropsychological impairement. Thirdly, we attempted to investigate the genetic abnormalities leading to the embryology physiopathology basis of cerebellar dysplasias associated (CDA) with Lissencephalies (smooth brain). The quite well characterized genetics of human brain lissencephalies have allowed us to identify some genes involved in the neuronal and axonal migration process (RELN and VLDLR) to be significantly associated with cerebellar dysplasia, not including CDA in muscular dystrophy syndromes related to O-glycosylation defects. Fourthly, we aimed to find in normal volunteers the neuroanatomical potential markers of cognitive disturbances associated with cerebellar dysplasia, on the hypothesis that an isolated cerebellar malformation could induce some anomalies on the pathways of cerebello-cortical projections, detectable by diffusion tensor imaging (DTI). These pathways are presumably involved in the cerebellar implication in higher functions. This work has allowed us to visualize and quantify selectively the cerebello-cortical projections to the prefrontal and parietal cortices in the normal human brain. Thus, our overall results have permitted: (i) to clearly assess the neuropsychological disturbances associated with ICD and their heterogeneity, both at the time of diagnosis and at the follow-up, (ii) to correlate the cerebellar dysplasia to brain glucose uptake differences and subsequently to brain dysfunction, (iii) to suggest some precise genetic analyses in neuronal and axonal migration pathways, and eventually, (iv) to obtain some anatomical markers which we can apply to dysplastic patients in order to assess the putative disruption of cerebello-cortical projections. Thereby, our results have opened numerous perspectives in applying advanced anatomical and functional neuroimaging techniques to the cerebellar dysplastic patients

Intérêt du scanner et de l'IRM dans les pathologies neurologiques

CT and MRI are the main imaging techniques used for diagnosis and follow-up of neurological disorders. These techniques are complementary but differ from each other by availability and accessibility, and the radiation effect of the first one, let alone the cost. Writing a state of the art regarding this topic means to highlight the interest of each technique in emergency imaging as well as in the late assessment. The applications of both techniques are discussed according to the context and in addition, the current development and future perspectives are mentioned.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Les dysplasies cérébelleuses : corrélations anatomo-fonctionnelles

Cerebellar dysplasia is a developmental anomaly involving mainly the cerebellum, resulting in a focal or diffuse macroscopic and microscopic disruption of the tissue architecture. Previous studies have well documented the magnetic resonance imaging (MRI) features of this malformation. However, the impact of cerebellar dysplasia, which may be associated with other developmental anomalies of the central nervous system (CNS), on the cognitive development and function, is ill known and poorly documented. We aimed to study the structural functional correlations in this cerebellar malformation, by investigating the neuropsychological, genetic and, functional disturbances associated as well as the neuroanatomical approach. Our work was conducted in 4 directions including 3 different populations. First, we assessed the neuropsychological profile and the follow-up of children with isolated cerebellar dysplasia (ICD). We observed I this population a wide range of neuropsychological expression of ICD, from normal efficiency to severe mental retardation, without no correlation with the degree of dysplasia. Moreover, during the follow-up of these children, we noticed the unpredictable heterogeneity of the cognitive evolution with the emergence in some cases of certain function such as language. Secondly, we investigated the CNS function using fluorodeoxyglucose positron emission tomography (FDG-PET) in six children with ICD. The results showed within the cerebellum a normal aspect in patients with minor dysplasia (restricted to the vermis), a hypometabolism in dysplastic zones (correlating with the anatomical extent), and a metabolism similar to that of the cortex in heterotopias. Nevertheless, these functional disturbances were not correlated with neuropsychological impairement. Thirdly, we attempted to investigate the genetic abnormalities leading to the embryology physiopathology basis of cerebellar dysplasias associated (CDA) with Lissencephalies (smooth brain). The quite well characterized genetics of human brain lissencephalies have allowed us to identify some genes involved in the neuronal and axonal migration process (RELN and VLDLR) to be significantly associated with cerebellar dysplasia, not including CDA in muscular dystrophy syndromes related to O-glycosylation defects. Fourthly, we aimed to find in normal volunteers the neuroanatomical potential markers of cognitive disturbances associated with cerebellar dysplasia, on the hypothesis that an isolated cerebellar malformation could induce some anomalies on the pathways of cerebello-cortical projections, detectable by diffusion tensor imaging (DTI). These pathways are presumably involved in the cerebellar implication in higher functions. This work has allowed us to visualize and quantify selectively the cerebello-cortical projections to the prefrontal and parietal cortices in the normal human brain. Thus, our overall results have permitted: (i) to clearly assess the neuropsychological disturbances associated with ICD and their heterogeneity, both at the time of diagnosis and at the follow-up, (ii) to correlate the cerebellar dysplasia to brain glucose uptake differences and subsequently to brain dysfunction, (iii) to suggest some precise genetic analyses in neuronal and axonal migration pathways, and eventually, (iv) to obtain some anatomical markers which we can apply to dysplastic patients in order to assess the putative disruption of cerebello-cortical projections. Thereby, our results have opened numerous perspectives in applying advanced anatomical and functional neuroimaging techniques to the cerebellar dysplastic patients.La dysplasie cérébelleuse est une anomalie du développement tissulaire intéressant principalement le cervelet et résultant en une anomalie focale ou diffuse de son architecture macroscopique et microscopique. Plusieurs travaux antérieurs ont bien documenté sa caractérisation morphologique à l'imagerie par résonance magnétique (IRM). Cependant, le retentissement de cette malformation, parfois associée à d'autres anomalies développementales du système nerveux central (SNC), sur le développement et le fonctionnement cognitifs est mal connu et peu documenté. Dans le but d'étudier les corrélations anatomo-fonctionnelles de cette pathologie constitutionnelle du cervelet, par le biais de l'approche des altérations neuropsychologiques, génétiques et, fonctionnelles associées, ainsi que par l'approche neuroanatomique, nous avons dirigé nos travaux dans quatre axes principaux et sur trois types de population distinctes. Le premier axe a concerné l'évaluation du profil neuropsychologique et du suivi chez dix enfants porteurs d'une dysplasie cérébelleuse isolée (DCI). Nous avons pu observer chez ces enfants une grande diversité de l'expression neuropsychologique de la DCI, depuis l'efficience normale jusqu'au retard mental sévère, sans corrélation avec le degré de dysplasie. D'autre part, au cours du suivi de ces enfants, nous avons observé une hétérogénéité d'évolution à caractère imprédictible, avec l'émergence des certaines fonctions dans l'axe du langage notamment. Le deuxième axe a porté sur l'investigation fonctionnelle du SNC par l'étude de la consommation cérébrale du fluorodeoxyglucose par Tomographie à émission de positons (TEP-FDG) chez six enfants porteurs d'une DCI. Les résultats ont montré, au sein du cervelet, un aspect normal dans les dysplasies mineures (limitées au vermis), un hypométabolisme des zones dysplasiques (corrélé à l'extension anatomique), et un isométabolisme au cortex dans les hétérotopies. Toutefois, ces anomalies de captation du glucose n'étaient pas corrélées au dysfonctionnement cognitif. Le troisième axe était d'approcher les corrélations génétiques, dans l'hypothèse d'un lien physiopathologique embryologique entre le cerveau et le cervelet, dans les dysplasies cérébelleuses associées (DCA) aux Lissencéphalies (cerveaux lisses). La caractérisation génétique relativement bien définie des Lissencéphalies nous a permis d'identifier des gènes de la migration neuronale et axonale (RELN et VLDRL) comme étant significativement associés aux dysplasies cérébelleuses, en dehors des dystrophies musculaires congénitales impliquant les gènes de la O-glycosylation. Le quatrième axe a été de rechercher chez des volontaires sains les marqueurs neuroanatomiques potentiels des altérations cognitives dans les dysplasies cérébelleuses, partant de l'hypothèse selon laquelle, une malformation isolée du cervelet induirait des anomalies anatomiques détectables en imagerie par tenseur de diffusion (DTI), sur les voies de projections cérébello-corticales, vraisemblablement impliquées dans la contribution du cervelet au développement et à l'exécution des fonctions supérieures. Ce travail nous a permis d'individualiser et de quantifier les projections cérébello-corticales préfrontales et pariétales chez tous les sujets sains

Spinocerebellar Atrophy

Triplet repeat expansions in the human genome, discovered in 1991, cause a heterogeneous group of disorders which may affect at various degrees the cerebellum, brain stem, and spinal tracts. The pathogenic mechanisms involve either loss of protein function or gain of function at the protein or RNA level. Triplets disorders with spinocerebellar symptoms include autosomal dominant spinocerebellar ataxias (SCAs); fragile X tremor ataxia syndrome (FXTAS), caused by an expansion in the. FMR1 X-linked gene; and the recessive Friedreich ataxia. One main feature of triplet expansion disorders is anticipation, a pattern in which new generations show an increased frequency and severity of the disorder. The phenotypic anticipation is associated with increases in repeat length due to the instability of expanded alleles until a full expansion mutation is transmitted in a classical Mendelian fashion. Clinically, patients usually exhibit a slowly evolving cerebellar syndrome with various combinations of oculomotor disorders, dysarthria, dysmetria/kinetic tremor, and/or ataxic gait. They can also show pigmentary retinopathy, extrapyramidal movement disorders, pyramidal deficits, cortical symptoms, signs of spinal cord involvement, and peripheral neuropathy. Expansions of CAG repeats are found in SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17, dentatorubral-pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA). SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, DRPLA, and SBMA are also classified as polyglutamine expansion disorders. Expansions of CTG repeats occur in SCA8. A pentanucleotide repeat expansion (ATTCT) is associated with SCA10. Missense mutations have been found in SCA14 and fibroblast growth factor (FGF)14. FXTAS syndrome is due to expansions of CGG repeats with a premutation, whereas the full mutation causes fragile X syndrome. Friedreich ataxia results from a triplet expansion (GAA) in an intron, causing a deficiency of frataxin, a mitochondrial protein that plays a role in iron homeostasis. It is estimated that extensive genetic testing leads to the identification of the causative gene in approximately 70-75% of cases. There is currently an intense effort to develop relevant cellular and animal models of triplet repeat expansion disorders. Effective therapies are expected in the coming decade. © 2009 Elsevier Ltd All rights reserved.SCOPUS: ch.binfo:eu-repo/semantics/publishe

Brain imaging in cerebellar ataxia associated with autoimmune polyglandular syndrome type 2.

Autoimmune polyglandular syndrome (APS) type 2 (Schmidt syndrome) is a disorder characterized by a combination of autoimmune adrenal insufficiency, autoimmune thyroid disease, and type 1 autoimmune diabetes mellitus. We describe the first case of subacute cerebellar syndrome associated with APS type 2. Brain magnetic resonance imaging showed atrophy of the cerebellum and the vermis, as well as of the anterior pituitary gland. Magnetic resonance spectroscopy showed decreased N-acetylaspartate/creatine ratio in the cerebellum and in the pons. Our findings expand the spectrum of neurological deficits in APS type 2 and underlines that cerebellar pathways may be a main target of the disorder.Journal ArticleFLWINSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Etude de l'épaisseur, de la complexité corticales et du gradient dans l'épilepsie partielle réfractaire associée à une dysplasie corticale focale

AMIENS-BU Santé (800212102) / SudocSudocFranceF

Valeur latéralisatrice de la spectroscopie dans l'épilespsie temporale cryptogénique

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Diagnostic différentiel des lésions à coefficient apparent de diffusion abaissé, à l'exception de l'accident vasculaire cérébral ischémique

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF