Biomedical subjects

David Grabli

Publications and source records attributed to David Grabli.

5 recordsLinked to original sources

PubMed2025

Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies.

Variants in spliceosomal small nuclear RNA (snRNA) genes RNU4-2 (ReNU syndrome), RNU5B-1, and RNU2-2 have recently been linked to dominant neurodevelopmental disorders (NDDs), revealing a major, previously overlooked role for noncoding snRNAs in human disease. Here, we systematically analysed 200 potentially functional snRNA genes in a French cohort comprising 26,911 individuals with rare disorders and through international collaborations. We identify de novo and biallelic variants in RNU2-2 associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive RNU2-2 NDD is at least twice as frequent as the dominant NDD caused by n.4G>A and n.35A>G, and often arises from a de novo variant in trans with an inherited allele, reflecting the high mutability of snRNA genes. Dominant and recessive RNU2-2-NDDs share overlapping clinical features with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our findings support a gradient-of-impact model and a continuum between dominant and recessive inheritance, establishing RNU2-2 variants as a frequent cause of NDDs, nearly as prevalent as ReNU syndrome.

Journal Article↗

PubMed2004

Behavioural disorders induced by external globus pallidus dysfunction in primates: I. Behavioural study.

The current model of basal ganglia organization postulates the existence of a functional partitioning into sensorimotor, associative and limbic territories, implicated in motor, cognitive and emotional aspects of behaviour, respectively. This organization was proposed initially on the basis of the cortico-striatal projections and was extended to the various structures of the basal ganglia. While there is a considerable body of experimental evidence in support of an involvement of the basal ganglia sensorimotor territory in basic control of movements, evidence for the functional relevance of the non-motor territories has had to be based on a growing number of clinical observations due to the paucity of relevant animal studies. Previous studies in monkeys have, however, shown that a reversible and focal dysfunction induced by microinjections of bicuculline in the sensorimotor territory of the external globus pallidus (GPe) can generate abnormal movements. We therefore hypothesized that the same approach applied to the associative and limbic territories of the GPe would induce behavioural disorders rather than abnormal movements. To address this hypothesis, we performed microinjections of bicuculline, using the same concentration in each of the sensorimotor, associative and limbic territories of the GPe, as defined by striato-pallidal projections. Spontaneous behaviour and performance of a simple food-retrieving task during the effects of these microinjections were compared with data obtained in control conditions in the same monkeys. We found that bicuculline microinjections induced stereotypy when performed in the limbic part of the GPe, and attention deficit and/or hyperactivity when performed in the associative part. No movement disorders were observed during these behavioural disturbances. As previously described, abnormal movements were observed when bicuculline was injected into the sensorimotor territory of the GPe. The relationship between the localization of microinjection sites and the type of behavioural effect was similar for the three monkeys. Control microinjections of bicuculline into surrounding structures (striatum and internal globus pallidus) and saline injections into the GPe failed to induce any observable effect. These results support the hypotheses of functional diversity and territorial specificity in the GPe, in agreement with the parallel circuits organizational model of the basal ganglia. Furthermore, the behavioural effects shared similar features with symptoms observed in Tourette's syndrome, attention deficit/hyperactivity and compulsive disorders. Thus, our study provides experimental evidence for the involvement of the associative and limbic parts of the basal ganglia in these pathologies. These results may provide the basis for a primate model of these disorders.

Animals↗

PubMed2004

Behavioural disorders induced by external globus pallidus dysfunction in primates II. Anatomical study.

The anatomical organization of the basal ganglia supports their involvement in movement and behavioural disorders. Thus dyskinesia, attention deficit with or without hyperactivity, and stereotyped behaviour can be induced by microinjections of bicuculline, a GABAergic antagonist, into different parts of the external globus pallidus (GPe) in monkeys. The aim of the present study was to determine the anatomo-functional circuits inside the basal ganglia which are specifically related to each of these behavioural changes. For that, axonal tracers were injected in the same pallidal sites where abnormal behaviours have previously been obtained by bicuculline microinjections. The labelling was mapped in the different basal ganglia and matched with the topography of the cortico-striato-pallidal projections already reported in the literature and with the distribution of calbindin immunoreactivity. Our results first show that the pallidal sites related to dyskinesia, attention deficit with or without hyperactivity, and stereotyped behaviour, were respectively in motor, associative and limbic territories, defined as weak, moderate and intensive calbindin immunoreactivity. The same relationship was observed between the distribution of the labelling in the different basal ganglia after tracer injections performed in these different pallidal sites and the anatomo-functional territories. Thus regarding the origin of the circuits within the striatum, tracer injections performed in the dyskinesia site labelled neurons located in the posterior sensorimotor putamen, those performed in the hyperactivity and/or attention deficit labelled neurons in the laterodorsal putamen and caudate nucleus, regions corresponding to associative and anterior motor territories, while those performed in the stereotyped behaviour site labelled neurons in the ventral limbic striatum. Regarding the GPe output on the basal ganglia, the different circuits also appeared underlined by different anatomo-functional territories, even if a partial overlap exists. Each of these anatomical circuits systematically involves both the internal globus pallidus (GPi) and the substantia nigra pars reticulata (SNr) but, whereas movement circuit is mainly related to the GPi, stereotyped behaviour is mainly related to the SNr. Additionally, subregions of the subthalamic nucleus were also systematically involved, depending on the movement or behavioural disorder produced. These results demonstrate that distinct circuits involving different anatomo-functional territories of the basal ganglia, with partial overlap, participate in different behavioural disorders in monkeys. It seems likely that these neuronal circuits are involved in pathologies like Tourette's syndrome, attention deficit/hyperactivity disorders and obsessional compulsive troubles. This study provides the basis for further researches with a therapeutical viewpoint.

Animals↗

PubMed2003

Cerebral sinus venous thrombosis in two patients with spontaneous intracranial hypotension.

We report 2 patients who had clinical and neuroimaging signs of spontaneous intracranial hypotension and who developed cerebral sinus venous thrombosis. This sequence of events -- known after dural puncture but not in spontaneous intracranial hypotension -- was suggested by the change in the pattern of headache, from a postural to a permanent and increasing one. The diagnostic and therapeutic difficulties that this complication raises are discussed.

Adult↗

PubMed2002

Association between influenza vaccination and reduced risk of brain infarction.

BACKGROUND AND PURPOSE: Because infections subsequent to influenza may play a role in promoting the complications of atherosclerotic disease and may also induce hypercoagulation, we hypothesized that influenza vaccination may protect against brain infarction. METHODS: During the influenza epidemic period we studied 270 subjects, including 90 consecutive patients older than 60 years admitted to the hospital for brain infarction and 180 population-based controls, matched for age, sex, and district of residency in Paris. We conducted a structured interview on whether they had been vaccinated during the last influenza vaccination campaign or every year during the 5 last years. RESULTS: We found significantly fewer vaccinated subjects during the last vaccination campaign among patients with brain infarction than among controls (46.7% versus 59.4%; P=0.036) and fewer patients vaccinated every year during the last 5 years (41.1% versus 56.1%; P=0.017). After adjustment for age, traditional risk factors, and recent use of antibiotics, the risk of stroke was reduced in the subjects vaccinated during the year of the study and in those vaccinated during the last 5 years, with an odds ratio of 0.50 (95% CI, 0.26 to 0.94; P=0.033) and 0.42 (95% CI, 0.21 to 0.81; P=0.009), respectively. Similar associations were observed in cases and controls free of previous cardiovascular history. Subjects younger than 75 years and subjects free of risk factors or in high social class were significantly less often vaccinated than controls. CONCLUSIONS: Influenza vaccination may protect against brain infarction by reducing infections or may identify a subgroup of patients at low risk for stroke because of a better lifestyle. These results give rise to a new hypothesis for research into stroke prevention.

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