<i>GRIN2A</i>-related disorders:genotype and functional consequence predict phenotype

Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10-6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders

Asthme du jeune enfant: quand évoquer un corps étranger endobronchique?

[Asthma in the young child: when should inhaled foreign body be suspected?] Many young children and infants wheeze during viral infections of the respiratory tract. The differential diagnosis of those children includes the inhalation of a foreign body. This diagnosis is overlooked in about 20% of cases, which leads to subacute and chronic complications. Two clinical observations are reported, involving young children with clinical asthma exacerbations but where the absence of response to usual treatment and/or the absence of evidence for atopy and/or the acute onset brought us to suspect the inhalation of a foreign body. These cases allow us to remind the usual signs and symptoms associated with the inhalation of a foreign body. Amongst these signs, unilateral hypoventilation on chest auscultation associated with localized emphysema on chest x-ray has a very high positive predictive value. Aggressive management in a specialized surrounding is advocated when an inhaled foreign body is suspected. Algorithms based on the level of suspicion have been designed to allow the pediatric respiratory physician to choose between rigid and fiberoptic bronchoscopy. It is only by systematization of these procedures and development of preventive measures that we will be able to reduce the prevalence of complications secondary to the inhalation of a foreign body

Carbon, nitrogen, phosphorus and potassium flows and losses from solid and semi-solid manures produced by beef cattle in deep litter barns and tied stalls

Nutrient losses have to be avoided in agricultural systems for agronomic and environmental reasons. However, they are known to be potentially large and variable. Results from twenty nine trials aiming at quantifying nitrogen (N), phosphorus (P), potassium (K) and carbon (C) flows and losses from barn and manure storage for beef cattle (Belgian Blue double-muscled breed) were synthesized. They included variation in barn type (tied stall and deep litter), leading to contrasted manure types (respectively semi-solid manure and deep litter manure) of small groups (n = 4) of heifers or bulls. Despite uncertainties pointed out by non-zero P or K balances, we established for manure storage, a relation between K losses by flowing out as liquid and rainfalls: K lost (%K stored) = 100*(1–0.99*e(−0.00078*rainfalls (mm)); n = 28). We also emphasized, within the particular set of data treated, the effects of barn type (approached by STRAWr; kg straw kg-1 DM in feed), manure storage duration (d), nitrogen in feed concentration (NFEED; g N kg-1 DM) and storage temperature (°C) on N losses from the whole system (N lost (% N input)=−33.33 + 0.0869*storage duration+1.11*storage temperature+27.9*STRAWr+1.278*NFEED; r² = 0.700; n = 29) such as the strong relation between C and N losses during manure store per day of storage (N lost (% N stored d-1) = 0.038 + 0.617*C lost (% C stored d-1)). We also observed that, even if N and C inputs in the system were higher in deep litter systems due to straw supply, the amounts of N and C remaining in the manure after being stored were very similar, indicating higher losses of these nutrients from deep litter systems compared to tied stalls. These findings will further help in modeling cattle housing systems for nutrient cycling optimization. However, the relations established have to be validated for other tied stall and deep litter systems regarding the diversity in manure management for each barn type. Furthermore, when comparing manure provided under different housing systems, other agronomical (e.g. their sanitization due to heat increase when stored, ease of application to soil after storage) or environmental (e.g. greenhouse gas emissions) aspects have to be considered

Faut-il toujours traiter les convulsions infantiles liées à une mutation de PRRT2 ?

Le développement de nouvelles techniques génétiques a permis de mieux connaître les implications du gène PRTT2 (proline rich transmembrane protein 2) dans divers troubles neurologiques. Des mutations de ce gène sont responsables des dyskinésies paroxystiques kinésigéniques (PKD pour paroxysmal kinesigenic dyskinesia) mais aussi d’épilepsie infantile bénigne familiale (BFIE pour benign familial infantile epilepsy), d’un tableau associant convulsions infantiles et choréo-athétose (ICCA pour infantile convulsions-choreoathetosis), d’une forme de migraine familiale hémiplégiante (FHM de type 4), de torticolis bénins paroxystiques de l’enfance et d’ataxie épisodique. Nous décrivons le cas d’un nourrisson, porteur d’une mutation du gène PRRT2, à la présentation classique. À travers son évolution au cours du temps, nous posons la question du recours au traitement anti-épileptique de manière systématique.[PRRT2 mutation and infantile convulsions] New genetic techniques have made it possible to better understand the implications of the PRRT2 gene (proline rich transmembrane protein 2) in various neurological disorders. Mutations within this gene are responsible for kinesigenic paroxysmal dyskinesias (PKD) as well as for benign familial infantile epilepsy (BFIE), a disease associating infantile convulsions and choreoathetosis (ICCA), a form of familial hemiplegic migraine (FHM type 4), paroxysmal benign torticollis of childhood, and episodic ataxia. We describe the case of an infant, carrying a mutation of the PRRT2 gene, with a classical presentation. Through her progression over time, we raise the question of systematic use of anti-epileptic drugs

A novel RAD21 mutation in a boy with mild Cornelia de Lange presentation: Further delineation of the phenotype.

Cornelia de Lange syndrome is a rare autosomal dominant or X-linked developmental disorder characterized by characteristic facial dysmorphism, intellectual disability, growth retardation, upper limb and multiorgan anomalies. Causative mutations have been identified in five genes coding for the cohesion complex structure components or regulatory elements. Among them, RAD21 is associated with a milder phenotype. Very few RAD21 intragenic mutations have been identified so far. Thus, any new patient is a valuable tool to delineate the associated phenotype. We discuss a new patient with RAD21 confirmed molecular diagnosis and compare his clinical features to those of previously described patients carrying different RAD21 intragenic mutations

Meningitis with subdural empyema due to non-typhoid Salmonella in a 9-month-old girl

We report a case of a 9-month-old baby admitted to the hospital because of low-grade fever, focal seizures in a context of watery diarrhea for 14 days' duration. The patient workup revealed a mild neutrophilic pleocytosis on cerebrospinal fluid (46 cells/mul), a positive stool culture for Salmonella pomona sensitive to ceftriaxone and ciprofloxacin, and a subdural empyema (SDE) on the cerebral MRI. The child received an intravenous third-generation cephalosporin for 4 weeks which resulted in cure. This case highlights an unusual extra-intestinal complication of non-typhoid salmonella infection. Involvement of the central nervous system with non-typhoidal salmonellosis is an important complication that can result in significant morbidity if not recognized and treated promptly. A focal intra-cranial infection must be considered in the differential diagnosis of any child presenting with focal seizures and gastroenteritis due to Salmonella. Appropriate diagnostic imaging of the head (cerebral CT scan with contrast and/or MRI) is mandatory to exclude the presence of an intra-cranial complication, even in the presence of negative CSF culture for Salmonella. Subfrontal and subtemporal SDE are sometimes missed on axial CT scans and better appreciated on MRI. Non-surgical treatment of small subdural empyemas with prolonged intravenous antibiotic therapy is a therapeutic option

Early skin sensitization to aeroallergens.

BACKGROUND: Early detection of aeroallergen sensitization is important as a prognosis factor but may be more difficult in young children. OBJECTIVE: We sought to demonstrate that skin sensitization to aeroallergens was present in a selected group of 0-2-year-old children and that it was associated with environmental exposure and a family history of allergic disease. METHODS: Data on exposure and history were extracted from the files of 824 children seen in the asthma clinic and who were skin tested to a panel of aero- and food allergens. RESULTS: Forty percent of our children demonstrated atopy, 28% were sensitized to aeroallergens, the majority of which to house dust mite. Higher sensitization rates were found in children with large weals to histamine (P<0.001) and in those who slept with soft toys [odds ratio (OR) 1.45, 95% confidence interval (CI) 1.02-2.08]. With a definition of sensitization including the size of the weal to histamine, there was a negative association with a personal history of eczema only (OR 0.66, 95% CI 0.45-0.99). There was no gender-dependent effect and no association with day-care attendance. CONCLUSION: This is one of the largest studies to evaluate skin testing in a selected population of young children. We found a high prevalence of sensitization to aeroallergens, which was associated with exposure to soft toys. Further follow-up of this population will allow assessment of the predictive value of this sensitization

Biallelic mutations in RTTN are associated with microcephaly, short stature and a wide range of brain malformations.

Biallelic mutations in the RTTN gene have been reported in association with microcephaly, short stature, developmental delay and malformations of cortical development. RTTN mutations have previously shown to link aberrant ciliary function with abnormal development and organization of the human cerebral cortex. We here report three individuals from two unrelated families with novel mutations in the RTTN gene. The phenotype consisted of microcephaly, short stature, pachygyria or polymicrogyria, colpocephaly, hypoplasia of the corpus callosum and superior vermis. These findings provide further confirmation of the phenotype related to pathogenic variants in RTTN

Hypomyelination and congenital cataract: broadening the clinical phenotype.

Our study broadens the clinical spectrum of HCC. The clinical variability ranges from severe early-onset neurologic impairment to a milder phenotype. In contrast to this clinical variability, the peculiar magnetic resonance pattern of hypomyelination combined with increased periventricular white matter water content allows distinction of HCC from other forms of hypomyelinating leukoencephalopathies