De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.

GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disability.

Phenotypic and genetic heterogeneity is predominant in autism spectrum disorders (ASD), for which the molecular and pathophysiological bases are still unclear. Significant comorbidity and genetic overlap between ASD and other neurodevelopmental disorders are also well established. However, little is understood regarding the frequent observation of a wide phenotypic spectrum associated with deleterious mutations affecting a single gene even within multiplex families. We performed a clinical, neurophysiological (in vivo electroencephalography-auditory-evoked related potentials) and genetic (whole-exome sequencing) follow-up analysis of two families with known deleterious NLGN4X gene mutations (either truncating or overexpressing) present in individuals with ASD and/or with intellectual disability (ID). Complete phenotypic evaluation of the pedigrees in the ASD individuals showed common specific autistic behavioural features and neurophysiological patterns (abnormal MisMatch Negativity in response to auditory change) that were absent in healthy parents as well as in family members with isolated ID. Whole-exome sequencing in ASD patients from each family identified a second rare inherited genetic variant, affecting either the GLRB or the ANK3 genes encoding NLGN4X interacting proteins expressed in inhibitory or in excitatory synapses, respectively. The GRLB and ANK3 mutations were absent in relatives with ID as well as in control databases. In summary, our findings provide evidence of a double-hit genetic model focused on excitatory/inhibitory synapses in ASD, that is not found in isolated ID, associated with an atypical in vivo neurophysiological pattern linked to predictive coding.

X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Electron Acceleration by Relativistic Surface Plasmons in Laser-Grating Interaction.

The generation of energetic electron bunches by the interaction of a short, ultraintense (I>10(19) W/cm(2)) laser pulse with "grating" targets has been investigated in a regime of ultrahigh pulse-to-prepulse contrast (10(12)). For incidence angles close to the resonant condition for surface plasmon excitation, a strong electron emission was observed within a narrow cone along the target surface, with energy spectra peaking at 5-8 MeV and total charge of ∼100 pC. Both the energy and the number of emitted electrons were strongly enhanced with respect to simple flat targets. The experimental data are closely reproduced by three-dimensional particle-in-cell simulations, which provide evidence for the generation of relativistic surface plasmons and for their role in driving the acceleration process. Besides the possible applications of the scheme as a compact, ultrashort source of MeV electrons, these results are a step forward in the development of high-field plasmonics.

Evidence of resonant surface-wave excitation in the relativistic regime through measurements of proton acceleration from grating targets.

The interaction of laser pulses with thin grating targets, having a periodic groove at the irradiated surface, is experimentally investigated. Ultrahigh contrast (~10(12)) pulses allow us to demonstrate an enhanced laser-target coupling for the first time in the relativistic regime of ultrahigh intensity >10(19) W/cm(2). A maximum increase by a factor of 2.5 of the cutoff energy of protons produced by target normal sheath acceleration is observed with respect to plane targets, around the incidence angle expected for the resonant excitation of surface waves. A significant enhancement is also observed for small angles of incidence, out of resonance.

Xq27 FRAXA locus is a strong candidate for dyslexia: evidence from a genome-wide scan in French families.

Dyslexia is a frequent neurodevelopmental learning disorder. To date, nine susceptibility loci have been identified, one of them being DYX9, located in Xq27. We performed the first French SNP linkage study followed by candidate gene investigation in dyslexia by studying 12 multiplex families (58 subjects) with at least two children affected, according to categorical restrictive criteria for phenotype definition. Significant results emerged on Xq27.3 within DYX9. The maximum multipoint LOD score reached 3,884 between rs12558359 and rs454992. Within this region, seven candidate genes were investigated for mutations in exonic sequences (CXORF1, CXORF51, SLITRK2, FMR1, FMR2, ASFMR1, FMR1NB), all having a role during brain development. We further looked for 5'UTR trinucleotide repeats in FMR1 and FMR2 genes. No mutation or polymorphism co-segregating with dyslexia was found. This finding in French families with Dyslexia showed significant linkage on Xq27.3 enclosing FRAXA, and consequently confirmed the DYX9 region as a robust susceptibility locus. We reduced the previously described interval from 6.8 (DXS1227-DXS8091) to 4 Mb also disclosing a higher LOD score.

Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability.

The nonsense-mediated mRNA decay (NMD) pathway was originally discovered by virtue of its ability to rapidly degrade aberrant mRNAs with premature termination codons. More recently, it was shown that NMD also directly regulates subsets of normal transcripts, suggesting that NMD has roles in normal biological processes. Indeed, several NMD factors have been shown to regulate neurological events (for example, neurogenesis and synaptic plasticity) in numerous vertebrate species. In man, mutations in the NMD factor gene UPF3B, which disrupts a branch of the NMD pathway, cause various forms of intellectual disability (ID). Using Epstein Barr virus-immortalized B cells, also known as lymphoblastoid cell lines (LCLs), from ID patients that have loss-of-function mutations in UPF3B, we investigated the genome-wide consequences of compromised NMD and the role of NMD in neuronal development and function. We found that ~5% of the human transcriptome is impacted in UPF3B patients. The UPF3B paralog, UPF3A, is stabilized in all UPF3B patients, and partially compensates for the loss of UPF3B function. Interestingly, UPF3A protein, but not mRNA, was stabilised in a quantitative manner that inversely correlated with the severity of patients' phenotype. This suggested that the ability to stabilize the UPF3A protein is a crucial modifier of the neurological symptoms due to loss of UPF3B. We also identified ARHGAP24, which encodes a GTPase-activating protein, as a canonical target of NMD, and we provide evidence that deregulation of this gene inhibits axon and dendrite outgrowth and branching. Our results demonstrate that the UPF3B-dependent NMD pathway is a major regulator of the transcriptome and that its targets have important roles in neuronal cells.

Twenty-five novel mutations including duplications in the ATP7A gene.

Twenty-five novel mutations including duplications in the ATP7A gene. Menkes disease (MD) and occipital horn syndrome (OHS) are allelic X-linked recessive copper deficiency disorders resulting from ATP7A gene mutations. MD is a severe condition leading to progressive neurological degeneration and death in early childhood, whereas OHS has a milder phenotype with mainly connective tissue abnormalities. Until now, molecular analyses have revealed only deletions and point mutations in both diseases. This study reports new molecular data in a series of 40 patients referred for either MD or OHS. We describe 23 point mutations (9 missense mutations, 7 splice site variants, 4 nonsense mutations, and 3 small insertions or deletions) and 7 intragenic deletions. Of these, 18 point mutations and 3 deletions are novel. Furthermore, our finding of four whole exon duplications enlarges the mutation spectrum in the ATP7A gene. ATP7A alterations were found in 85% of cases. Of these alterations, two thirds were point mutations and the remaining one third consisted of large rearrangements. We found that 66.6% of point mutations resulted in impaired ATP7A transcript splicing, a phenomenon more frequent than expected. This finding enabled us to confirm the pathogenic role of ATP7A mutations, particularly in missense and splice site variants.

Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism.

Mutations in the UPF3B gene, which encodes a protein involved in nonsense-mediated mRNA decay, have recently been described in four families with specific (Lujan-Fryns and FG syndromes), nonspecific X-linked mental retardation (XLMR) and autism. To further elucidate the contribution of UPF3B to mental retardation (MR), we screened its coding sequence in 397 families collected by the EuroMRX consortium. We identified one nonsense mutation, c.1081C>T/p.Arg361(*), in a family with nonspecific MR (MRX62) and two amino-acid substitutions in two other, unrelated families with MR and/or autism (c.1136G>A/p.Arg379His and c.1103G>A/p.Arg368Gln). Functional studies using lymphoblastoid cell lines from affected patients revealed that c.1081C>T mutation resulted in UPF3B mRNA degradation and consequent absence of the UPF3B protein. We also studied the subcellular localization of the wild-type and mutated UPF3B proteins in mouse primary hippocampal neurons. We did not detect any obvious difference in the localization between the wild-type UPF3B and the proteins carrying the two missense changes identified. However, we show that UPF3B is widely expressed in neurons and also presents in dendritic spines, which are essential structures for proper neurotransmission and thus learning and memory processes. Our results demonstrate that in addition to Lujan-Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. We also identify comorbidity of MR and autism in another family with UPF3B mutation. The neuronal localization pattern of the UPF3B protein and its function in mRNA surveillance suggests a potential function in the regulation of the expression and degradation of various mRNAs present at the synapse.

Ultrashort high energy electron bunches from tunable surface plasma waves driven with laser wavefront rotation.

We propose to use ultrahigh intensity laser pulses with wave-front rotation (WFR) to produce short, ultraintense surface plasma waves (SPW) on grating targets for electron acceleration. Combining a smart grating design with optimal WFR conditions identified through simple analytical modeling and particle-in-cell simulation allows us to decrease the SPW duration (down to a few optical cycles) and increase its peak amplitude. In the relativistic regime, for Iλ_{0}^{2}=3.4×10^{19}W/cm^{2}µm^{2}, such SPW are found to accelerate high charge (few 10 s of pC), high energy (up to 70 MeV), and ultrashort (few fs) electron bunches.

Novel missense mutations in the ubiquitination-related gene UBE2A cause a recognizable X-linked mental retardation syndrome.

Recently, a truncating mutation of the UBE2A gene has been observed in a family with X-linked mental retardation (XLMR) (1). The three affected males had similar phenotypes, including seizures, obesity, marked hirsutism and a characteristic facial appearance. Here, we report on two families with a total of seven patients and a clinically very similar syndromic form of XLMR. Linkage analysis was performed in the larger of these families, and screening several positional candidate genes revealed a G23R missense mutation in the UBE2A gene. Subsequent UBE2A screening of a phenotypically similar second family revealed another missense mutation, R11Q, again affecting an evolutionarily conserved amino acid close to the N-terminus of the protein. SIFT and PolyPhen analyses suggest that both mutations are pathogenic, which is supported by their absence in 168 healthy controls. Thus, both missense and truncating mutations can give rise to a specific, syndromic form of XLMR which is identifiable in a clinical setting.

Excitation of surface plasma waves and fast electron generation in relativistic laser-plasma interaction.

The excitation of surface plasma waves (SPW) by an intense short laser pulse is a useful tool to enhance the laser absorption and the electron heating in the target. In this work, the influence of the transverse laser profile and the pulse duration used to excited SPW is investigated from Fluid and 2D Particle-in-Cell simulations. We show the existence of a lobe of surface plasma wave modes. Our results highlight surface plasma waves excitation mechanism and define the laser parameters to optimise the SPW excitation and the kinetic energy of the associated electron trapped in the wave. It opens the door to monitor the spectral mode distribution and temporal shape of the excited surface waves in the high relativistic regime. The most important result of the study is that-at least in 2D-the charge and the energy of the electron bunches depend essentially on the laser energy rather than on temporal or spatial shape of the laser pulse.

Phenotype and genotype in females with POU3F4 mutations.

X-linked deafness is a rare cause of hereditary isolated hearing impairment estimated as at least 1% or 2% of the non-syndromic hearing loss. To date, four loci for DFN have been identified and only one gene, POU3F4 responsible for DFN3, has been cloned. In males, DFN3 is characterized by a progressive deafness associated with perilymphatic gusher at stapes surgery and with a characteristic inner ear malformation. The phenotype of eight independent females carrying POU3F4 anomalies is defined, and a late-onset hearing loss is found in three patients. Only one has an inner ear malformation. No genotype/phenotype correlation is identified.

Tracing of dissolved organic matter from the Sepetiba Bay (Brazil) by PARAFAC analysis of total luminescence matrices.

Fluorescent excitation-emission matrices (FEEM) of the fluorescent dissolved organic matter (FDOM) are widely used for DOM characterization and tracing. In this work, a set of FEEM from sampling campaigns in the Sepetiba Bay (Brazil) was decomposed into independent components using the parallel factor analysis (PARAFAC) algorithm. Four independent components were extracted describing the total fluorescence of the FDOM. The well described peaks A, C, M, B and T were found, and a new peak, A', linked to the C peak, was detected. Relative contribution of each of four components to the total fluorescence confirms that the coastal water has DOM of terrestrial origin, except for the 275Ex/400-500Em range (nm), which primarily occurs in marine waters.

[Hypermobile snapping medial meniscus: features on flexion-extension MRI]. / Hypermobilité du ménisque médial avec ressaut: IRM en extension et en flexion.

We report 3 cases of snapping medial meniscus due to hypermobility confirmed on extension and flexion MR imaging. The anterior horn of the medial meniscus was anteriorly subluxed during extension with reduction during flexion. Analysis of our imaging data and a review of the literature confirm that this relates to hypermobile medial meniscus, an anatomical variant.

Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update.

Mutations in the MECP2 (Methyl-CpG-binding protein) gene have been reported to cause Rett syndrome (RTT), an X-linked progressive encephalopathy. Recent studies have identified large gene rearrangements that escape the common PCR-based mutation screening strategy and mutations in a novel MeCP2 isoform (named MECP2B). We have collected the results of MECP2 mutational analysis concerning 424 RTT patients conducted in eight laboratories in France. In total, 121 different MECP2 mutations were identified. R168X (11.5%) is the most common of MECP2 mutations, followed by R270X (9%), R255X (8.7%), T158 M (8.3%) and R306C (6.8%). Only eight mutations had relative frequency>3%. Large and complex rearrangements not previously detected using only a PCR-based strategy represent 5.8% of MECP2 mutations. On the contrary, mutation in exon 1 appears to be rare (less than 0.5%). These data demonstrate the high allelic heterogeneity of RTT in France and suggest that routine mutation screening in MECP2 should include quantitative analysis of the MECP2 gene. This study represents an important instrument for molecular diagnosis strategy and genetic counseling in RTT families.

[Non traumatic high flow priapism: arterial embolization treatment]. / Priapisme à haut débit non traumatique: traitement par embolisation artérielle.

PURPOSE: To report cases of non traumatic high flow priapism treated by arterial embolization. MATERIAL AND METHODS: Six men presented with non traumatic high flow priapism, the diagnosis was based on colour Doppler ultrasound, cavernous blood gas analysis with arterial blood saturation levels and failed medical or surgical therapy. Four patients had sickle cell disease. The embolization was performed with Gelfoam and was unilateral in one case, bilateral in the other cases. RESULTS: Detumescence occurred in a few hours in all cases. One patient had recurrent priapism two years after and was treated by embolization. Transient erectile dysfunction was observed in five cases, permanent in one case. CONCLUSION: Arterial embolization is the treatment of choice in high flow priapism with low rate of permanent erectile dysfunction.

Enhanced photoemission from laser-excited plasmonic nano-objects in periodic arrays.

The process of photoelectron emission from gold surfaces covered with nano-objects that are organized in the form of a periodic array is addressed in the short laser pulse regime ([Formula: see text] fs) at moderate intensities [Formula: see text] W cm(-2) and for various laser wavelengths. The emission spectrum from a gold single crystal measured under the same conditions is used for reference. The comparison of the photo-emission yield and the energy of the ejected electrons with their counterparts from the (more simple) reference system shows that the periodic conditions imposed on the target surface drastically enhance both quantities. In addition to the standard mechanism of Coulomb explosion, a second mechanism comes into play, driven by surface plasmon excitation. This can be clearly demonstrated by varying the laser wavelength. This interpretation of the experimental data is supported by predictions from model calculations that account both for the primary quantum electron emission and for the subsequent surface-plasmon-driven acceleration in the vacuum. Despite the fact that the incident laser intensity is as low as [Formula: see text] W cm(-2), such a structured target permits generating electrons with energies as high as 300 eV. Experiments with two incident laser beams of different wavelengths with an adjustable delay, have also been carried out. The results show that there exist various channels for the decay of the photo-emission signal, depending on the target type. These observations are shedding light on the various relaxation mechanisms that take place on different timescales.