AMERICA DEL NORTE. Mapas generales (1879). 1:11883527

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Network for Therapy in Rare Epilepsies (NETRE): Lessons From the Past 15 Years

Background: In 2005, Network for Therapy in Rare Epilepsies (NETRE)\u2014was initiated in order to share treatment experiences among clinicians in patients with rare epilepsies. Here we describe the structure of the rapidly growing NETRE and summarize some of the findings of the last 15 years. Methodology/Structure of NETRE: NETRE is organized in distinct groups (currently >270). Starting point is always a patient with a rare epilepsy/ epileptic disorder. This creates a new group, and next, a medical coordinator is appointed. The exchange of experiences is established using a data entry form, which the coordinator sends to colleagues. The primary aim is to exchange experiences (retrospectively, anonymously, MRI results also non-anonymously) of the epilepsy treatment as well as on clinical presentation and comorbidities NETRE is neither financed nor sponsored. Results: Some of the relevant results: (1) first description of FIRES as a new epilepsy syndrome and its further investigation, (2) in SCN2A, the assignment to gain- vs. loss-of-function mutations has a major impact on clinical decisions to use or avoid treatment with sodium channel blockers, (3) the important aspect of avoiding overtreatment in CDKL5 patients, due to loss of effects of anticonvulsants after 12 months, (4) pathognomonic MRI findings in FOXG1 patients, (5) the first description of pathognomonic chewing-induced seizures in SYNGAP1 patients, and the therapeutic effect of statins as anticonvulsant in these patients, (6) the phenomenon of another reflex epilepsy\u2014bathing epilepsy associated with a SYN1 mutation. Of special interest is also a NETRE group following twins with genetic and/or structural epilepsies [including vanishing-twin-syndrome and twin-twin-transfusion syndrome) [= \u201cEarly Neuroimpaired Twin Entity\u201d (ENITE)]. Discussion and Perspective: NETRE enables clinicians to quickly exchange information on therapeutic experiences in rare diseases with colleagues at an international level. For both parents and clinicians/scientist this international exchange is both reassuring and helpful. In collaboration with other groups, personalized therapeutic approaches are sought, but the present limitations of currently available therapies are also highlighted. Presently, the PATRE Project (PATient based phenotyping and evaluation of therapy for Rare Epilepsies) is commencing, in which information on therapies will be obtained directly from patients and their caregivers

Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans