A PMM2-CDG caused by an A108V mutation associated with a heterozygous 70 kilobases deletion case report.

BACKGROUND: Congenital Disorders of Glycosylation (CDG) are a large group of inborn errors of metabolism with more than 140 different CDG types reported to date (1). The first characterized, PMM2-CDG, with an autosomal recessive transmission, is also the most frequent. The PMM2 gene encodes a phosphomannomutase. Here, a novel genetic variation causing PMM2-CDG is reported.  CASE PRESENTATION: We report the case of a French child, from healthy and unrelated parents, presenting congenital ataxia with hypotonia, hyperlaxity, inverted nipples, as well as altered coagulation parameters and liver function. Transferrin isoelectrofocusing revealed a typical type I CDG profile. Direct Sanger sequencing and quantitative PCR of PMM2 revealed a unique and novel genotype. On one allele, the patient was heterozygote with a known missense variant NM_000303.3(PMM2):c.323C > T, p.Ala108Val in exon 4. On the second allele, whole genome sequencing (WGS) indicated the presence of a novel heterozygous 70 kb deletion. CONCLUSION: We report in the present paper the largest known heterozygous deletion of a PMM2 gene. The observation reveals the impact of a precise diagnostic on genetic counselling: by using WGS, an erroneous conclusion of homozygosity in the case of a relatively rare variant could be avoided, and an index patient with healthy and unrelated parents correctly identified.

Biometry of the Cerebellar Vermis and Brain Stem in Children: MR Imaging Reference Data from Measurements in 718 Children.

BACKGROUND AND PURPOSE: Objective and quantitative data to define cerebellar vermis and/or brain stem hypoplasia in children are lacking. Our aim was to provide MR imaging biometric references for the cerebellar vermis and brain stem from a large cohort of children with normal cerebellums. MATERIALS AND METHODS: The MR imaging data were retrospectively selected from our hospital data base from January 1, 2014, to December 31, 2017. All MR imaging examinations of children between 1 day and 15 years of age, including midline sagittal sections, were included. Children with a clinical history or MR imaging abnormalities that may affect the posterior fossa were excluded. We manually measured four 2D parameters: vermian height, anterior-posterior diameter of the vermis, anterior-posterior diameter of the midbrain-pons junction, and anterior-posterior midpons diameter. The inter- and intraobserver agreement was evaluated. RESULTS: Seven hundred eighteen children were included (372 boys and 346 girls), from 1 day to 15 years of age. Normal values (third to 97th percentiles) were provided for each parameter. The vermis parameters showed a rapid growth phase during the first year, a slower growth until the fifth year, and finally a near-plateau phase. The brain stem parameters showed more progressive growth. The intra- and interobserver agreement was excellent for all parameters. CONCLUSIONS: We provide reference biometric data of the vermis and the brain stem using simple and reproducible measurements that are easy to use in daily practice. The relevance of these 2D measurements should be further validated in diseases associated with cerebellar abnormalities.

The consequences of physical post-treatments (microwave and electron-beam) on food/packaging interactions: A physicochemical and toxicological approach.

The safety of microwave and electron-beam treatments has been demonstrated, in regards to the formation of reaction products that could endanger human health. An integrated approach was used combining the potential toxicity of all the substances likely to migrate to their chemical characterizations. This approach was applied to polypropylene (PP) films prepared with a selection of additives. Components were identified by liquid and gas chromatography using a mass selective detector system. Their potential toxicity was assessed using three in vitro short-term bioassays and their migrations were carried out using a standards-based approach. After the electron-beam treatment some additives decomposed and there was a significant increase in the polyolefin oligomeric saturated hydrocarbons concentration. PP prepared with Irgafos 168 led to a significantly strong cytotoxic effect and PP prepared with Irganox 1076 induced a dose-dependant estrogenic effect in vitro. Migration values were low and below the detection limit of the analytical method applied.

[Lemierre syndrome revealed by torticollis]. / Syndrome de Lemierre révélé par un torticolis.

Classical Lemierre syndrome is a rare and severe disease with thrombosis of the internal jugular vein and metastatic infections. We report on a case of Lemierre-like syndrome secondary to mastoiditis, with a favorable outcome, in a healthy infant presenting with torticollis. Early diagnosis and treatment with antibiotics are necessary to decrease mortality.

The emerging role of Twist proteins in hematopoietic cells and hematological malignancies.

Twist1 and Twist2 (Twist1-2) are two transcription factors, members of the basic helix-loop-helix family, that have been well established as master transcriptional regulators of embryogenesis and developmental programs of mesenchymal cell lineages. Their role in oncogenesis in epithelium-derived cancer and in epithelial-to-mesenchymal transition has also been thoroughly characterized. Recently, emerging evidence also suggests a key role for Twist1-2 in the function and development of hematopoietic cells, as well as in survival and development of numerous hematological malignancies. In this review, we summarize the latest data that depict the role of Twist1-2 in monocytes, T cells and B lymphocyte activation, and in associated hematological malignancies.

[Characteristics of tuberous sclerosis in children]. / Spécificités de la sclérose tubéreuse de Bourneville chez l'enfant.

Tuberous sclerosis complex is a genetic multisystem disease characterized by hamartic development of many organs, most notably the brain, heart, kidneys, lungs, and skin. This autosomic dominant disorder results from mutations in one of two genes, TSC1 and TSC2, coding for hamartin and tuberin, respectively. The hamartin-tuberin complex inhibits the mammalian target of rapamycin pathway, which controls cell growth and proliferation. The clinical presentation is highly variable and most features of tuberous sclerosis become evident only in childhood after the child is several years of age, limiting their usefulness for early diagnosis. The aim of this article is to define the pediatric clinical manifestations of tuberous sclerosis in correlation with patient age. Sometimes, a prenatal diagnosis can be made based on fetal ultrasound and MRI, which show cardiac and brain lesions. However, newborns are most often asymptomatic. In the 1st year, seizures are the most common symptoms, with a high incidence of infantile spasms. In children between 2 and 10 years of age, neurological symptoms are the most frequent with epilepsy, mental retardation, and autism, but extraneurological manifestations can be diagnosed. In adolescents, most features of tuberous sclerosis become evident and renal and pulmonary manifestations must be sought. The knowledge of age-dependent clinical features of tuberous sclerosis can provide an earlier diagnosis and improve the management of these patients with a special role for multidisciplinary consultation.

Rotation sequence is an important factor in shoulder kinematics. Application to the elite players' flat serves.

The aim of this study was to test three different rotation sequences (YXY, ZXY, and XZY) on the shoulder kinematics (rotations of the humerus relative to the thorax) during an original movement such as the tennis flat serve (FS). Nine elite male and female players performed a minimum of five flat serves. An optoelectronic motion analysis system was used to record the movements. Segment kinematics during each FS was reconstructed from the spatial trajectories of the markers according to ISB recommendations. For each rotation sequence, three angles were reported for the shoulder joint, each corresponding to a rotation component around a defined axis. The occurrence of gimbal lock (GL) and angle amplitude coherences were examined. From these three rotation sequences tested, it appears that the XZY sequence was the only decomposition not to suffer from GL. Moreover, the rotation sequence XZY was found to be coherent for all rotation components. Thus, these results show that the best rotation sequence, from both GL and amplitude coherence points of view, is XZY to describe the shoulder kinematics during the tennis serve.

Segment-interaction in sprint start: Analysis of 3D angular velocity and kinetic energy in elite sprinters.

The aim of the present study was to measure during a sprint start the joint angular velocity and the kinetic energy of the different segments in elite sprinters. This was performed using a 3D kinematic analysis of the whole body. Eight elite sprinters (10.30+/-0.14s 100 m time), equipped with 63 passive reflective markers, realised four maximal 10 m sprints start on an indoor track. An opto-electronic Motion Analysis system consisting of 12 digital cameras (250 Hz) was used to collect the 3D marker trajectories. During the pushing phase on the blocks, the 3D angular velocity vector and its norm were calculated for each joint. The kinetic energy of 16 segments of the lower and upper limbs and of the total body was calculated. The 3D kinematic analysis of the whole body demonstrated that joints such as shoulders, thoracic or hips did not reach their maximal angular velocity with a movement of flexion-extension, but with a combination of flexion-extension, abduction-adduction and internal-external rotation. The maximal kinetic energy of the total body was reached before clearing block (respectively, 537+/-59.3 J vs. 514.9+/-66.0 J; p< or =0.01). These results suggested that a better synchronization between the upper and lower limbs could increase the efficiency of pushing phase on the blocks. Besides, to understand low interindividual variances in the sprint start performance in elite athletes, a 3D complete body kinematic analysis shall be used.

[Antiepileptic drugs in pediatric migraine]. / Les antiépileptiques dans le traitement préventif de la migraine de l'enfant.

According to the criteria of the International Headache Society, migraine occurs in approximately 5 to 10% of children. As many as 30% of young patients with migraine experience such frequent and disabling attacks, or have unsatisfactory results and/or experience adverse effects with pharmacologic treatment of acute migraine attack, that daily preventive medications are required. Many studies have investigated the use of antiepileptic drugs in this indication but there is a paucity of placebo-controlled studies. So far, in the setting of migraine with and without aura, only flunarizine and topiramate have proved their efficacy in more than one placebo-controlled study. Uncontrolled studies suggest the possible efficacy of valproic acid, gabapentin, levetiracetam, zonisamide, and magnesium in preventive therapy of childhood periodic syndromes. Most of antiepileptic drugs used in pediatric preventive therapy are well tolerated. The most common adverse events are asthenia and somnolence.

Tailoring fatty food simulants made from solvent mixtures (2): determining the equivalent migration behaviour of olive oil and of solvents in the case of polyolefins.

It is suggested that solvent mixtures consisting of an ester and of an inert solvent can be used as fatty food simulants capable of having the same migration behaviour as olive oil with plastics. Migration tests carried out with low-density polyethylene for 20 and 48 h in an 8 and 5% mixture of tert-butyl acetate in ethanol respectively gave results equivalent to those obtained with olive oil after 10 days at 40 degrees C. The use of solvent mixtures facilitated the analysis and improved detection limits, giving good repeatability. Furthermore, the more rapid migration in solvent mixtures can be particularly useful for industrial controls as alternative test methods.

Safety and quality of food contact materials. Part 1: evaluation of analytical strategies to introduce migration testing into good manufacturing practice.

The results of a research project (EU AIR Research Programme CT94-1025) aimed to introduce control of migration into good manufacturing practice and into enforcement work are reported. Representative polymer classes were defined on the basis of chemical structure, technological function, migration behaviour and market share. These classes were characterized by analytical methods. Analytical techniques were investigated for identification of potential migrants. High-temperature gas chromatography was shown to be a powerful method and 1H-magnetic resonance provided a convenient fingerprint of plastic materials. Volatile compounds were characterized by headspace techniques, where it was shown to be essential to differentiate volatile compounds desorbed from those generated during the thermal desorption itself. For metal trace analysis, microwave mineralization followed by atomic absorption was employed. These different techniques were introduced into a systematic testing scheme that is envisaged as being suitable both for industrial control and for enforcement laboratories. Guidelines will be proposed in the second part of this paper.

Tailoring fatty food simulants made from solvent mixtures (1): comparison of methanol, ethanol and isopropanol behaviour with polystyrene.

To investigate the use of solvent mixtures as test media replacing olive oil in migration tests, the interaction of polystyrene with mixtures composed of various amounts of tert.butyl acetate (mimicking the ester functions of oil) and of a low molecular weight alcohol (methanol, ethanol and isopropanol as inert co-solvent) was studied, using FTIR. Isopropanol, which has a lesser tendency to form hydrogen bonds in the plastic, can be used as main component of alternative fatty test media, its aggressiveness to polystyrene being tailored by adjusting the concentration of tert.butyl acetate. Concentrations below 20% seem useful on the basis of the mechanism of displacement of the alcohols.

Safety evaluation of an ionized multilayer plastic film used for vacuum cooking and meat preservation.

The main concern in safety evaluation of ionized plastic food packaging materials is the possible formation of unsuspected potential migrants. Solvent extracts and migrates of a polypropylene-based multilayer film, beta-irradiated at 80 kGy and widely used for vacuum cooking of packaged meat were studied, using complementary analytical techniques. 1H-NMR and HPLC showed that 96% of the initial phenolic stabilizer was not found after irradiation. A phosphite stabilizer and its reaction products, identified by GC-MS, accounted for 35% of the initial amount. The sum of all potential migrants derived from the additives accounted for less than 1% of global migration. This global migration was mainly due to oligomers. By comparison our results with literature work done with the same film, but at lower doses, it was suggested that larger electron beam doses reduce the possibility of migration and enhance the consumer's safety.

Food and packaging interactions: determination of the kinetic parameters of olive oil diffusion in polypropylene using concentration profiles.

The penetration of olive oil into polypropylene was studied in order to allow a complete modellization of food and packaging interactions. Oil concentration profiles through polypropylene food trays were determined by FTIR-microscopy measurements along the thickness at various times. Calculations of the relevant parameters characterizing Fickian diffusion, namely constant diffusivity, coefficient of convective mass transport on the surface and concentration at equilibrium were carried out. This way of working has proven to be considerably shorter and more accurate than the method consisting of recording the global absorbance of the substance absorbed, especially when the amount of diffusing fat is low. Major conclusions are: that absorption of olive oil is strongly influenced by convection; the diffusion coefficient of olive oil in polypropylene is constant. Possible consequences to simplify global migration testing are discussed.

Quick methods to control compliance of plastic materials with food packaging regulations.

A general strategy is presented, aiming to provide plastics manufacturers, food industries and enforcement laboratories with quick methods to check whether migration from materials for food contact will be acceptable during the time of use. The strategy involves several steps, with increasing time demand and cost. Monitoring extraction kinetics allows both the optimization of the extraction time, and the selection of conditions where extraction is more severe than migration. The influence of the extracting solvent is discussed. It may give rise to specific non-extraction of some migrants, which may change the conclusions when the solvent is used in replacement of a fatty food simulant. Factors ruling this effect at a given temperature are identified: the affinity to the solvent with the migrant (selectivity), its ability to reach molecules entangled in the polymeric network (accessibility) and its interaction with the polymer (penetration). The kinetic parameters of the penetration of olive oil into polypropylene have been determined by the determination of profiles of concentration.

Food and packaging interactions: tailoring fatty food simulants.

Migration of paramagnetic probes from rigid PVC within 24 h at 50 degrees C depends on the simulant to a considerable extent. With a strongly swelling simulant like tert.butyl acetate, the rate of diffusion is governed by the rate of penetration of the medium into the polymeric network. Isooctane has a very weak interaction with rigid PVC. With a mixture of tert.butyl acetate and isooctane it is possible to adjust the aggressivity of the medium and to tailor an alternative simulant that interacts with the polymer in the same fashion as the EU's official fatty food simulants. Particular responses of polar probes underline the importance of the interaction between simulant and additives in the choice of alternative fatty food simulants for rigid PVC.

Guidelines of the Commission of the European Communities: a challenge for the control of packaging.

Questions arising from the Commission of the European Communities Directives and guidelines regulating packaging materials are discussed in relation to whether compliance ensures safety in use and the consequent analytical problems. Difficulties may arise from interactions between food contact materials and food involving mass transfer (migration, off-odours, 'scalping', loss of aroma) or mass transfer and chemical interactions and the implications for safety assurance and regulation are addressed. The criteria for suitable low molecular weight fatty food simulants and conditions for migration testing are presented. In food surveillance, the usefulness of various methods of analysis differs for monomers and for additives. For monomers, IR spectroscopy can identify the polymer type and which specific monomers need controlling; for unknown mixtures of additives, preliminary functional group identification by techniques such as 1H-NMR is useful.