Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior-Løken syndrome

BACKGROUND: Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that constitutes the most common genetic cause of renal failure in the first three decades of life. Using positional cloning, six genes (NPHP1-6) have been identified as mutated in NPHP. In Joubert syndrome (JBTS), NPHP may be associated with cerebellar vermis aplasia/hypoplasia, retinal degeneration and mental retardation. In Senior-Løken syndrome (SLSN), NPHP is associated with retinal degeneration. Recently, mutations in NPHP6/CEP290 were identified as a new cause of JBTS. METHODS: Mutational analysis was performed on a worldwide cohort of 75 families with SLSN, 99 families with JBTS and 21 families with isolated nephronophthisis. RESULTS: Six novel and six known truncating mutations, one known missense mutation and one novel 3 bp pair in-frame deletion were identified in a total of seven families with JBTS, two families with SLSN and one family with isolated NPHP.

Functional lateralization of the anterior insula during feedback processing

Effective adaptive behavior rests on an appropriate understanding of how much responsibility we have over outcomes in the environment. This attribution of agency to ourselves or to an external event influences our behavioral and affective response to the outcomes. Despite its special importance to understanding human motivation and affect, the neural mechanisms involved in self-attributed rewards and punishments remain unclear. Previous evidence implicates the anterior insula (AI) in evaluating the consequences of our own actions. However, it is unclear if the AI has a general role in feedback evaluation (positive and negative) or plays a specific role during error processing. Using functional magnetic resonance imaging and a motion prediction task, we investigate neural responses to self- and externally attributed monetary gains and losses. We found that attribution effects vary according to the valence of feedback: significant valence × attribution interactions in the right AI, the anterior cingulate cortex (ACC), the midbrain, and the right ventral putamen. Self-attributed losses were associated with increased activity in the midbrain, the ACC and the right AI, and negative BOLD response in the ventral putamen. However, higher BOLD activity to self-attributed feedback (losses and gains) was observed in the left AI, the thalamus, and the cerebellar vermis. These results suggest a functional lateralization of the AI. The right AI, together with the midbrain and the ACC, is mainly involved in processing the salience of the outcome, whereas the left is part of a cerebello-thalamic-cortical pathway involved in cognitive control processes important for subsequent behavioral adaptations.

Cerebellar disorders in childhood: cognitive problems

Over the last decade, increasing evidence of cognitive functions of the cerebellum during development and learning processes could be ascertained. Posterior fossa malformations such as cerebellar hypoplasia or Joubert syndrome are known to be related to developmental problems in a marked to moderate extent. More detailed analyses reveal special deficits in attention, processing speed, visuospatial functions, and language. A study about Dandy Walker syndrome states a relationship of abnormalities in vermis lobulation with developmental problems. Further lobulation or volume abnormalities of the cerebellum and/or vermis can be detected in disorders as fragile X syndrome, Downs's syndrome, William's syndrome, and autism. Neuropsychological studies reveal a relation of dyslexia and attention deficit disorder with cerebellar functions. These functional studies are supported by structural abnormalities in neuroimaging in these disorders. Acquired cerebellar or vermis atrophy was found in groups of children with developmental problems such as prenatal alcohol exposure or extreme prematurity. Also, focal lesions during childhood or adolescence such as cerebellar tumor or stroke are related with neuropsychological abnormalities, which are most pronounced in visuospatial, language, and memory functions. In addition, cerebellar atrophy was shown to be a bad prognostic factor considering cognitive outcome in children after brain trauma and leukemia. In ataxia teleangiectasia, a neurodegenerative disorder affecting primarily the cerebellar cortex, a reduced verbal intelligence quotient and problems of judgment of duration are a hint of the importance of the cerebellum in cognition. In conclusion, the cerebellum seems to play an important role in many higher cognitive functions, especially in learning. There is a suggestion that the earlier the incorrect influence, the more pronounced the problems.

Long-term sequelae after acquired pediatric hemorrhagic cerebellar lesions

The aim of the present study was to assess cognitive, affective, and motor long-term sequelae after acquired focal pediatric cerebellar lesions.

Development of a morphometric magnetic resonance image parameter suitable for distinguishing between normal dogs and dogs with cerebellar atrophy

Neurodegenerative diseases affect the cerebellum of numerous dog breeds. Although subjective, magnetic resonance (MR) imaging has been used to detect cerebellar atrophy in these diseases, but there are few data available on the normal size range of the cerebellum relative to other brain regions. The purpose of this study was to determine whether the size of the cerebellum maintains a consistent ratio with other brain regions in different ages and breeds of normal dogs and to define a measurement that can be used to identify cerebellar atrophy on MR images. Images from 52 normal and 13 dogs with cerebellar degenerative diseases were obtained. Volume and mid-sagittal cross-sectional area of the forebrain, brainstem, and cerebellum were calculated for each normal dog and compared between different breeds and ages as absolute and relative values. The ratio of the cerebellum to total brain and of the brainstem to cerebellum mid-sagittal cross-sectional area was compared between normal and affected dogs and the sensitivity and specificity of these ratios at distinguishing normal from affected dogs was calculated. The percentage of the brain occupied by the cerebellum in diverse dog breeds between 1 and 5 years of age was not significantly different, and cerebellar size did not change with increasing age. Using a cut off of 89%, the ratio between the brainstem and cerebellum mid-sagittal cross-sectional area could be used successfully to differentiate affected from unaffected dogs with a sensitivity and specificity of 100%, making this ratio an effective tool for identifying cerebellar atrophy on MR images.

Cerebellar cortical degeneration with selective granule cell loss in Bavarian mountain dogs

Three Bavarian mountain dogs aged between 18 and 20 months, not related to each other, were presented with chronic signs of cerebellar dysfunction. On sagittal T2-weighted magnetic resonance imaging brain images, the tentative diagnosis of cerebellar hypoplasia was established based on an enlarged cerebrospinal fluid space around the cerebellum and an increased cerebrospinal fluid signal between the folia. Post-mortem examination was performed in one dog and did show an overall reduction of cerebellar size. On histopathologic examination, a selective loss of cerebellar granule cells with sparing of Purkinje cells was evident. Therefore, the Bavarian mountain dog is a breed where cerebellar cortical degeneration caused by the rather exceptional selective granule cell loss can be seen as cause of chronic, slowly progressive cerebellar dysfunction starting at an age of several months.

Cerebellar cleft: a form of prenatal cerebellar disruption

In contrast to malformations, cerebellar disruptions have attracted little interest in the literature. We draw attention for the first time to the hypothesis that cerebellar clefts are residual changes following a prenatal cerebellar insult, and represent disruptions. We reviewed the clinical records and MR findings of six patients with a cerebellar cleft, two of whom also had prenatal MRI at 24 weeks of gestation. The clefts were located in the left cerebellar hemisphere in five cases, in the right in one patient. Other typical findings included disorderly alignment of the cerebellar folia and fissures, irregular gray/white matter junction, and abnormal arborization of the white matter in all patients. The cerebellar cleft extended into the fourth ventricle in three cases, and in two children cystic cortical lesions were seen. Supratentorial schizencephaly was found in two patients. In two patients there was a documented fetal cerebellar hemorrhage at 24 weeks of gestation. We conclude that cerebellar clefts are residual changes resulting from a prenatal cerebellar insult and consequently represent disruptions rather than primary malformations. The supratentorial findings are also in agreement with an acquired lesion. The outcome in these children was variable, mainly depending of the presence of supratentorial lesions.

Rosette-forming glioneuronal tumor of the cerebellum in statu nascendi: an incidentally detected diminutive example indicates derivation from the internal granule cell layer

Rosette-forming glioneuronal tumor (RGNT) is a recently introduced, indolent neoplasm composed of diminutive circular aggregates of neurocytic-like cells on a noninfiltrative astrocytic background, typically located in the cerebellar midline The traded concept of RGNT being derived from site-specific periventricular precursors may be questioned in the face of extracerebellar examples as well as ones occurring in combination with other representatives of the glioneuronal family. We describe a hitherto not documented example of asymptomatic RGNT discovered during autopsy of a 74-year-old male. Located in the tuberal vermis, this lesion of 6 mm diameter consisted of several microscopic nests of what were felt to represent nascent stages of RGNT, all of them centered on the internal granular layer, and ranging from mucoid dehiscences thereof to fully evolved - if small - tumor foci. Molecular genetic analysis revealed a missense mutation in Exon 20 of the PIK3CA gene involving an A→G transition at Nucleotide 3140. On the other hand, neither codeletion of chromosomes 1p/19q nor pathogenic mutations of IDH1/2 were detected. By analogy with in situ paradigms in other organs, we propose that this tumor is likely to have arisen from the internal granular layer, rather than the plate of the 4th ventricle. A suggestive departure from the wholesale argument of "undifferentiated precursors", this finding also indirectly indicates that a subset of non-classical RGNTs - in particular extracerebellar examples, whose origin cannot be mechanistically accounted for by either of the above structures - may possibly reflect an instance of phenotypic convergence, rather than a lineage-restricted entity.

β1-Class Integrins Regulate the Development of Laminae and Folia in the Cerebral and Cerebellar Cortex

Mice that lack all beta1-class integrins in neurons and glia die prematurely after birth with severe brain malformations. Cortical hemispheres and cerebellar folia fuse, and cortical laminae are perturbed. These defects result from disorganization of the cortical marginal zone, where beta1-class integrins regulate glial endfeet anchorage, meningeal basement membrane remodeling, and formation of the Cajal-Retzius cell layer. Surprisingly, beta1-class integrins are not essential for neuron-glia interactions and neuronal migration during corticogenesis. The phenotype of the beta1-deficient mice resembles pathological changes observed in human cortical dysplasias, suggesting that defective integrin-mediated signal transduction contributes to the development of some of these diseases.

Neuropsychological long-term sequelae after posterior fossa tumour resection during childhood

The importance of the cerebellum for non‐motor functions is becoming more and more evident. The influence on cognitive functions from acquired cerebellar lesions during childhood, however, is not well known. We present follow‐up data from 24 patients, who were operated upon during childhood for benign cerebellar tumours. The benign histology of these tumours required neither radiotherapy nor chemotherapy. Post‐operatively, these children were of normal intelligence with a mean IQ of 99.1, performance intelligence quotient (PIQ) of 101.3 and verbal intelligence quotient (VIQ) of 96.8. However, 57% of patients showed abnormalities in subtesting. In addition, more extensive neuropsychological testing revealed significant problems for attention, memory, processing speed and interference. Visuo‐constructive problems were marked for copying the Rey figure, but less pronounced for recall of the figure. Verbal fluency was more affected than design fluency. Behavioural deficits could be detected in 33% of patients. Attention deficit problems were marked in 12.5%, whereas others demonstrated psychiatric symptoms such as mutism, addiction problems, anorexia, uncontrolled temper tantrums and phobia. Age at tumour operation and size of tumour had no influence on outcome. Vermis involvement was related to an increase in neuropsychological and psychiatric problems. The observation that patients with left‐sided cerebellar tumours were more affected than patients with right‐sided tumours is probably also influenced by a more pronounced vermian involvement in the former group. In summary, this study confirms the importance of the cerebellum for cognitive development and points to the necessity of careful follow‐up for these children to provide them with the necessary help to achieve full integration into professional life.

Intracranial meningiomas associated with cervical syringohydromyelia in a cat

Eine dreizehnjährige, weibliche, nicht kastrierte Hauskatze wurde zur chirurgischen Therapie eines multiplen Meningeoms in der Kleintierklinik des Tierspital Bern vorgestellt. Eine leichtgradige generalisierte Ataxie wurde beobachtet, die Propriozeption war generalisiert herabgesetzt und der Drohreflex war beidseitig reduziert. Es wurden eine prä- und eine postoperative Magnetrezonanztomographie durchgeführt. Drei supratentoriale extra-axiale Raumforderungen wurden diagnostiziert. Eine vierte Masse wurde infratentorial extra-axial über der linken zerebellären Hemisphere lokalisiert. Eine Herniation des kaudoventralen Kleinhirn (Vermis) von ungefähr einem Zentimeter Länge durch das Foramen magnum wurde beobachtet. Eine zervikale Syringohydromyelie wurde als Zufallsbefund diagnostiziert. Die Meningeome wurden durch 3 Kraniotomiestellen entfernt. Zwei Jahre nach der Operation ist die Katze normal. Anhand der vorhandenen Literatur wird die tumor-assoziierte Syringohydromyelie besprochen. Die Therapie der Syringohydromyelie sollte gegen den kausalen pathologischen Prozess (z.B. intrakranieller Tumor) für die Liquorzirkulationsstörung gerichtet sein.