A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Mise en concordance d'images sous cadre stéréotaxique (applications neurochirurgicales)

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUP (751062107) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

La stimulation cérébrale profonde dans le traitement des syndromes dystono-dyskinétiques (modélisation tridimensionnelle de la distribution des paramètres électriques appliquée au globus pallidus interne)

MONTPELLIER-BU Médecine UPM (341722108) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Dentate Nucleus as Target for Deep Brain Stimulation in Dystono-Dyskinetic Syndromes

International audiencePurpose: To discuss the potential of deep brain stimulation (DBS) of the dentate nucleus as a treatment for dystono-dyskinetic syndromes.Methods: An extensive literature review covered the anatomy and physiology of the dentate nucleus and the experimental evidence for its involvement in the pathophysiology of dystonia and dyskinesia.Results: Evidence from animal models and from functional imaging in humans is strongly in favor of involvement of the dentate nucleus in dystono-dyskinetic syndromes. Results from previous surgical series of dentate nucleus stimulation were promising but precise description of movement disorders being treated were lacking and outcome measures were generally not well defined.Conclusions: In the light of new evidence regarding the involvement of the dentate nucleus in dystono-dyskinetic syndromes, we present a review of the current literature and discuss why the question of dentate nucleus stimulation deserves to be revisited

A target-specific electrode and lead design for internal globus pallidus deep brain stimulation.

In nearly all deep brain stimulation (DBS) applications, the same quadripolar electrode design is used for different anatomical targets even if shape and volume differences exist between nuclei. Taking into account the electrode location within the internal globus pallidus (GPi) and the size of the GPi, 2 electrodes were designed in order to improve the therapeutic benefit, to minimize side effects from DBS and to obtain a more homogeneous electric field distribution. The electrodes were evaluated numerically by using a stereotactic model measuring the correlation between the electric field and the GPi. The model was applied to 26 dystonodyskinetic patients who underwent surgery for a bilateral lead implantation into the posteroventral part of the GPi. The designed electrodes produced a more homogeneous distribution of the electric field than the quadripolar electrode

Can emotional stress trigger the onset of epilepsy?

International audienc

Deep Brain Stimulation and Hypoxemic Perinatal Encephalopathy: State of Art and Perspectives

Cerebral palsy (CP) is a heterogeneous group of non-progressive syndromes with lots of clinical variations due to the extent of brain damages and etiologies. CP is majorly defined by dystonia and spasticity. The treatment of acquired dystonia in CP is very difficult. Many pharmacological treatments have been tried and surgical treatment consists of deep brain stimulation (continuous electrical neuromodulation) of internal globus pallidus (GPi). A peculiar cause of CP is neonatal encephalopathy due to an anoxic event in the perinatal period. Many studies showed an improvement of dystonia in CP patients with bilateral GPi DBS. However, it remains a variability in the range of 1% to 50%. Published case-series concerned mainly small population with a majority of adult patients. Selection of patients according to the clinical pattern, to the brain lesions observed on classical imaging and to DTI is the key of a high success rate of DBS in children with perinatal hypoxemic encephalopathy. Only a large retrospective study with a high number of patients in a homogeneous pediatric population with a long-term follow-up or a prospective multicenter trial investigation could answer with a high degree of certitude of the real interest of this therapeutic in children with hypoxemic perinatal encephalopathy

Prognostic value of globus pallidus internus volume in primary dystonia treated by deep brain stimulation.

OBJECT: Given that improvement is variable from one patient to another, the authors analyzed the impact of globus pallidus internus (GPi) volume on the result of deep brain stimulation (DBS) by comparing highly and less improved patients with primary dystonodyskinetic syndromes. METHODS: A stereotactic model was developed to visualize and quantify the relationship between the isofield lines generated by the DBS lead and GPi target. The model was used in 30 right-handed selected patients with primary dystonodyskinetic syndromes who had been treated using bilateral stimulation of the sensorimotor GPi. Ten healthy control individuals were also included in the study. First, the authors compared the GPi volumes between patients and healthy controls. Second, the stimulated GPi volumes, that is, the intersection between the volume of each isofield value and the GPi volumes, were compared between less improved and highly improved patients. RESULTS: Improvement in the Burke-Fahn-Marsden Dystonia Rating Scale's motor score was rated > 90% in 20 patients (97 +/- 4.6%) and < 60% in 10 patients (56.9 +/- 6%). The mean volume of the right (461.8 +/- 81.8 mm(3)) and left (406.6 +/- 113.2 mm(3)) GPi in patients showing less response to DBS was significantly smaller than the GPi volume of patients who responded well (right 539.9 +/- 86.6 mm(3), left 510.6 +/- 88.7 mm(3)) and healthy controls (right 557.8 +/- 109.1 mm(3), left 525.1 +/- 40.8 mm(3)). CONCLUSIONS: On the left side, the mean stimulated volumes (isofield line range 0.2-1 V/mm) were significantly larger in highly improved than in less improved patients. In this model, the threshold for functional effect was calculated at 0.2 V/mm