The phenotype caused by recessive variations in SLC25A22: Report of a new case and literature review.

We describe the clinical, electroencephalography (EEG), and developmental features of a patient with developmental and epileptic encephalopathy due to a homozygous pathogenic variation of mitochondrial glutamate/H+ symporter SLC25A22. Epilepsy began during the first week of life with focal onset seizures. Interictal EEG revealed a suppression-burst pattern with extensive periods of non-activity. The prospective follow-up confirmed developmental encephalopathy as well as ongoing active epilepsy and almost no sign of development at 8 years of age. We confirm in the following paper that SLC25A22 recessive variations may cause a severe developmental and epileptic encephalopathy characterized by a suppression-burst pattern. On the basis of an in-depth literature review, we also provide an overview of this rare genetic cause of neonatal onset epilepsy.

Severe neonatal seizures: From molecular diagnosis to precision therapy?

Early onset epileptic encephalopathies (EOEE) are heterogeneous group of severe epilepsies that still need to be better defined and characterized. On a genetic point of view, several dozen of genes have been associated with EOEE, and to date, it is difficult to find a common mechanism to explain EOEE. In this short review, we show that two mains genes are involved in EOEE: STXBP1 and KCNQ2. Focusing on KCNQ2 related EOEE, we show that a relatively similar phenotype can be related to various consequences of mutations on a single gene. This will probably challenge the treatment of EOEE patients.

Tokamak magnetohydrodynamic equilibrium states with axisymmetric boundary and a 3D helical core.

Magnetohydrodynamic (MHD) equilibrium states with imposed axisymmetric boundary are computed in which a spontaneous bifurcation develops to produce an internal three-dimensional (3D) configuration with a helical structure in addition to the standard axisymmetric system. Equilibrium states with similar MHD energy levels are shown to develop very different geometric structures. The helical equilibrium states resemble saturated internal kink mode structures.

System size effects on gyrokinetic turbulence.

The scaling of turbulence-driven heat transport with system size in magnetically confined plasmas is reexamined using first-principles based numerical simulations. Two very different numerical methods are applied to this problem, in order to resolve a long-standing quantitative disagreement, which may have arisen due to inconsistencies in the geometrical approximation. System size effects are further explored by modifying the width of the strong gradient region at fixed system size. The finite width of the strong gradient region in gyroradius units, rather than the finite overall system size, is found to induce the diffusivity reduction seen in global gyrokinetic simulations.

Novel FOXG1 mutations associated with the congenital variant of Rett syndrome.

BACKGROUND: Rett syndrome is a severe neurodevelopmental disorder representing one of the most common genetic causes of mental retardation in girls. The classic form is caused by MECP2 mutations. In two patients affected by the congenital variant of Rett we have recently identified mutations in the FOXG1 gene encoding a brain specific transcriptional repressor, essential for early development of the telencephalon. METHODS: 60 MECP2/CDKL5 mutation negative European Rett patients (classic and variants), 43 patients with encephalopathy with early onset seizures, and four atypical Rett patients were analysed for mutations in FOXG1. RESULTS AND CONCLUSIONS: Mutations have been identified in four patients, independently classified as congenital Rett variants from France, Spain and Latvia. Clinical data have been compared with the two previously reported patients with mutations in FOXG1. In all cases hypotonia, irresponsiveness and irritability were present in the neonatal period. At birth, head circumference was normal while a deceleration of growth was recognised soon afterwards, leading to severe microcephaly. Motor development was severely impaired and voluntary hand use was absent. In contrast with classic Rett, patients showed poor eye contact. Typical stereotypic hand movements with hand washing and hand mouthing activities were present continuously. Some patients showed abnormal movements of the tongue and jerky movements of the limbs. Brain magnetic resonance imaging showed corpus callosum hypoplasia in most cases, while epilepsy was a variable sign. Scoliosis was present and severe in the older patients. Neurovegetative symptoms typical of Rett were frequently present.

Bilateral periventricular nodular heterotopia in France: frequency of mutations in FLNA, phenotypic heterogeneity and spectrum of mutations.

Bilateral periventricular nodular heterotopia (BPNH) is the most common form of periventricular heterotopia. Mutations in FLNA, encoding filamin A, are responsible for the X linked dominant form of BPNH (FLNA-BPNH). Recently, atypical phenotypes including BPNH with Ehlers-Danlos syndrome (BPNH-EDS) have been recognised. A total of 44 FLNA mutations have so far been reported in this phenotype. Most of these mutations lead to a truncated protein, but few missense mutations have also been described. Here, the results of a mutation screening conducted in a series of 32 BPNH patients with the identification of 12 novel point mutations in 15 patients are reported. Nine mutations were truncating, while three were missense. Three additional patients with BPNH-EDS and a mutation in FLNA are described. No phenotype-genotype correlations could be established, but these clinical data sustain the importance of cardiovascular monitoring in FLNA-BPNH patients.

Role of plasma elongation on turbulent transport in magnetically confined plasmas.

The theoretical study of plasma turbulence is of central importance to fusion research. Experimental evidence indicates that the confinement time results mainly from the turbulent transport of energy, the magnitude of which depends on the turbulent state resulting from nonlinear saturation mechanisms, in particular, the self-generation of coherent macroscopic structures and large scale flows. Plasma geometry has a strong impact on the structure and magnitude of these flows and also modifies the mode linear growth rates. Nonlinear global gyrokinetic simulations in realistic tokamak magnetohydrodynamic equilibria show how plasma shape can control the turbulent transport. Results are best described in terms of an effective temperature gradient. With increasing plasma elongation, the nonlinear critical effective gradient is not modified while the stiffness of transport is decreasing.

Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion.

BACKGROUND: Periventricular heterotopia (PH) is an etiologically heterogeneous disorder characterized by nodules of neurons ectopically placed along the lateral ventricles. Most affected patients have seizures and their cognitive level varies from normal to severely impaired. At present, two genes have been identified to cause PH when mutated. Mutations in FLNA (Xq28) and ARFGEF2 (20q13) are responsible for X-linked bilateral PH and a rare autosomal recessive form of PH with microcephaly. Chromosomal rearrangements involving the 1p36, 5p15, and 7q11 regions have also been reported in association with PH but the genes implicated remain unknown. Fourteen additional distinct anatomoclinical PH syndromes have been described, but no genetic insights into their causes have been gleaned. METHODS: We report the clinical and imaging features of three unrelated patients with epilepsy, mental retardation, and bilateral PH in the walls of the temporal horns of the lateral ventricles, associated with a de novo deletion of the 5q14.3-15 region. We used microarray-based comparative genomic hybridization to define the boundaries of the deletions. RESULTS: The three patients shared a common deleted region spanning 5.8 Mb and containing 14 candidate genes. CONCLUSION: We identified a new syndrome featuring bilateral periventricular heterotopia (PH), mental retardation, and epilepsy, mapping to chromosome 5q14.3-q15. This observation reinforces the extreme clinical and genetic heterogeneity of PH. Array comparative genomic hybridization is a powerful diagnostic tool for characterizing causative chromosomal rearrangements of limited size, identifying potential candidate genes for, and improving genetic counseling in, malformations of cortical development.

Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations.

OBJECTIVE: We have recently shown that de novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders. To better define the range of these abnormalities, we searched for additional mutations in a cohort of 100 patients with lissencephaly spectrum for whom no mutation was identified in DCX, LIS1 and ARX genes and compared these data to five previously described patients with TUBA1A mutations. RESULTS: We detected de novo TUBA1A mutations in six patients and highlight the existence of a prominent form of TUBA1A related lissencephaly. In four patients, the mutations identified, c.1190T>C (p.L397P), c.1265G>A (p.R422H), c.1264C>T (p.R422C), c.1306G>T (p.G436R), have not been reported before and in two others, the mutation corresponds to a recurrent missense mutation, c.790C>T (p.R264C), likely to be a hot spot of mutation. All together, it emerges that the TUBA1A related lissencephaly spectrum ranges from perisylvian pachygyria, in the less severe form, to posteriorly predominant pachygyria in the most severe, associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. When compared with a large series of lissencephaly of other origins (ILS17, ILSX or unknown origin), these features appear to be specific to TUBA1A related lissencephaly. In addition, TUBA1A mutated patients share a common clinical phenotype that consists of congenital microcephaly, mental retardation and diplegia/tetraplegia. CONCLUSIONS: Our data highlight the presence of consistent and specific abnormalities that should allow the differentiation of TUBA1A related lissencephalies from those related to LIS1, DCX and ARX genes.

Serological and molecular comparison of Mannheimia haemolytica and Pasteurella trehalosi strains isolated from wild and domestic ruminants in the French Alps.

Over a period of 17 years, 84 bacterial isolates identified as Mannheimia haemolytica or M. glucosida, and 52 isolates identified as Pasteurella trehalosi were detected in the lungs of domestic and wild ruminants in the French Alps. The isolates were serotyped according to their surface capsular antigens, and those sharing common antigens were further characterized by pulsed field gel electrophoresis. The results showed that the bacterial isolates included in the study clustered according to the host species from which they were isolated. These findings indicate that the transmission of serotypes of M. haemolytica, M. glucosida or P. trehalosi from an animal host in which they are common to another species sharing the same geographical space may be a rare epidemiological event.

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.

Delineation of the clinical phenotype associated with OPHN1 mutations based on the clinical and neuropsychological evaluation of three families.

Recent reports have demonstrated that mutations in the OPHN1 gene were responsible for a syndromic rather than non-specific mental retardation. Abnormalities of the posterior fossa with cerebellar hypoplasia have been demonstrated in all male patients reported to date. We report here a new family with X-linked mental retardation due to mutation in OPHN1 and present unpublished data about two families previously reported, concerning the facial and psychological phenotype of affected males and carrier females. Our study confirms that cerebellar hypoplasia is a hallmark of this syndrome. In addition, affected males display facial similarities that can help the diagnosis. Most carrier females have mild mental retardation and subtle facial changes.

[Epigenetic study of Rett's syndrome as an adequate model for autistic disorders].

Rett's syndrome (RTT) is a severe hereditary disorder of the nervous system. MECP2 gene mutations are considered as a primary cause of the disease. In the present study, we have found MECP2 mutations in 33 (84.6%) out of 39 RTT females. We have also studied X-inactivation patterns in 70 girls with RTT. A frequency of skewed X-inactivation was 37% (26 patients), being significantly higher (p < 0.001) than that in the controls. The investigation of inactivated X chromosome origin revealed that about 33% pairs had preferentially the inactivated maternal X chromosome. An abnormal type of chromosome X inactivation was observed in all RTT females. Thus, we conclude that skewed X-inactivation may be considered as a common feature of RTT. There is unambiguous evidence that epigenetic alterations in RTT are associated with MECP2 mutations. MeCP2 protein also appears to be involved in transcriptional regulation of chromosome X genes. RTT in females without MECP2 mutations is related to the epigenetic alterations. We suggest X chromosome inactivation study in RTT females and their mothers to be informative for investigation of genetic processes in RTT girls, even in case MECP2 mutations have not been found. RTT could be considered as an appropriate model for studying epigenetic abnormalities in relation to autistic spectrum disorders.

Pulsed-field gel electrophoresis profiles of aeromonads isolated from healthy and diseased Helix aspersa from French snail farms.

The XbaI digestion patterns of chromosomal DNA of 42 aeromonads isolated from French breeding snails during a new epizootic disease, which rapidly progressed to death during the summer of 1994, were analyzed by pulsed-field gel electrophoresis. Biochemical identification to species level was also performed. Interestingly, we found that 76% of the aeromonads isolated from diseased snails clustered into a unique pulsotype (P1) whatever their geographic origin, and were assessed to belong to Aeromonas hydrophila. Other strains belonged to Aeromonas caviae or remained unspecified. Our results provide retrospective supplementary epidemiological evidence for implication of A. hydrophila strains in the snail summer disease.

Disruption of a new X linked gene highly expressed in brain in a family with two mentally retarded males.

BACKGROUND: Mental retardation (MR) affects 2-3% of the human population and some of these cases are genetically determined. Although several genes responsible for MR have been identified, many cases have still not been explained. METHODS: We have identified a pericentric inversion of the X chromosome inv(X)(p22.3;q13.2) segregating in a family where two male carriers have severe MR while female carriers are not affected. RESULTS: The molecular characterisation of this inversion led us to identify two new genes which are disrupted by the breakpoints: KIAA2022 in Xq13.2 and P2RY8 in Xp22.3. These genes were not previously fully characterised in humans. KIAA2022 encodes a protein which lacks significant homology to any other known protein and is highly expressed in the brain. P2RY8 is a member of the purine nucleotide G-protein coupled receptor gene family. It is located in the pseudo-autosomal region of the X chromosome and is not expressed in brain. CONCLUSIONS: Because the haploinsufficiency of P2RY8 in carrier mothers does not have a phenotypic consequence, we propose that the severe MR of the affected males in this family is due to the absence of the KIAA2022 gene product. However, screening 20 probands from X linked MR families did not reveal mutations in KIAA2022. Nonetheless, the high expression of this gene in fetal brain and in the adult cerebral cortex could be consistent with a role in brain development and/or cognitive function.

Partial androgen insensitivity syndrome and t(X;5): are there upstream regulatory elements of the androgen receptor gene?

BACKGROUND/AIMS: Two half-brothers with similar malformed genitals, who both inherited a maternally derived t(X;5)(q13;p15) translocation, have a phenotype consistent with partial androgen sensitivity syndrome. The aim was to identify the gene disrupted by the X chromosome breakpoint. METHODS: The breakpoint was localized using fluorescence in situ hybridization to metaphase spreads of the translocation. RESULTS: The breakpoint on the X chromosome of the X;5 translocation was localized to a 30-kb region. This region does not contain any identified genes or transcripts. However, the breakpoint is approximately 134 kb from the 5' end of the androgen receptor (AR) gene. CONCLUSIONS: Genetic defects of the AR gene are collectively called androgen insensitivity syndrome and include a range of phenotypes from normal males, often with associated sterility, to XY females. The phenotype seen in the males with the t(X;5) is consistent with this syndrome. The analysis of the chromosomal abnormality suggests that this translocation may remove one or more upstream regulatory elements of the AR gene that are essential for its normal expression and its role in typical external masculinization.

Tokamak equilibria with reversed current density.

Observations of nearly zero toroidal current in the central region of tokamaks (the "current hole") raises the question of the existence of toroidal equilibria with very low or reversed current in the core. The solutions of the Grad-Shafranov equilibrium equation with hollow toroidal current density profile including negative current density in the plasma center are investigated. Solutions of the corresponding eigenvalue problem provide simple examples of such equilibrium configurations. More realistic equilibria with toroidal current density reversal are computed using a new equilibrium problem formulation and computational algorithm which do not assume nested magnetic surfaces.

[Genotype-phenotype correlations in Rett syndrome: the study of Russian cohort of patients]. / Kliniko-geneticheskie korreliatsii pri sindrome Retta: izuchenie rossiiskoi kogorty bol'nykh.

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein 2 gene (MECP2). We carried out a mutations analysis in Russian cohort of patients with RTT. MECP2 mutations were found in 23 of 28 RTT girls and one boy (82%). Thirteen different types of mutations have been identified: 6 nonsense, 5 missense and 2 deletions in MECP2 gene. In typical RTT form, most frequent mutations were R255X (5 cases) and T158M (4 cases). A boy with classical clinical picture of RTT had R270X mutation. Skewed inactivation of chromosome x has been found in 2 of 27 RTT girls with classical RTT form and "forme fruste". The data obtained imply possible correlations between genotype and phenotype in RTT.