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Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger. Exome sequencing from 39 trios were analyzed. We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease. These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.

Background The principal aim of this study was to investigate the long-term outcomes of a large cohort of patients with ornithine transcarbamylase deficiency (OTCD) who were followed up at a single medical center. Methods We analyzed clinical, biochemical and genetic parameters of 90 patients (84 families, 48 males and 42 females) with OTCD between 1971 and 2011. Results Twenty-seven patients (22 boys, 5 girls) had a neonatal presentation; 52 patients had an “intermediate” late-onset form of the disease (21 boys, 31 girls) that was revealed between 1 month and 16 years; and 11 patients (5 boys, 6 girls) presented in adulthood (16 to 55 years). Patients with a neonatal presentation had increased mortality (90% versus 13% in late-onset forms) and peak plasma ammonium (mean value: 960 μmol/L versus 500 μmol/L) and glutamine (mean value: 4110 μmol/L versus 1000 μmol/L) levels at diagnosis. All of the neonatal forms displayed a greater number of acute decompensations (mean value: 6.2/patient versus 2.5 and 1.4 in infants and adults, respectively). In the adult group, some patients even recently died at the time of presentation during their first episode of coma. Molecular analyses identified a deleterious mutation in 59/68 patients investigated. Single base substitutions were detected more frequently than deletions (69% and 12%, respectively), with a recurrent mutation identified in the late-onset groups (pArg40 His; 13% in infants, 57% in adults); inherited mutations represented half of the cases. The neurological score did not differ significantly between the patients who were alive in the neonatal or late-onset groups and did not correlate with the peak ammonia and plasma glutamine concentrations at diagnosis. However, in late-onset forms of the disease, ammonia levels adjusted according to the glutamine/citrulline ratio at diagnosis were borderline predictors of low IQ (p = 0.12 by logistic regression; area under the receiver operating characteristic curve of 76%, p <0.05). Conclusions OTCD remains a severe disease, even in adult-onset patients for whom the prevention of metabolic decompensations is crucial. The combination of biochemical markers warrants further investigations to provide additional prognostic information regarding the neurological outcomes of patients with OTCD.

Background Acute intracranial large vessel occlusion (LVO) is an important cause of morbidity and mortality among children; however, unlike in adults, no clinical trial has investigated the benefit of mechanical thrombectomy (MT) in pediatric LVO. Thus, MT remains an off-label procedure for pediatric stroke. Purpose To investigate the efficacy and safety of MT in pediatric LVO. Methods A systematic literature search was conducted in Ovid MEDLINE, Ovid Embase, Scopus, Web of Science, and Cochrane Central Register of Clinical Trials databases. Studies reporting safety and efficacy outcomes for endovascular treatment of pediatric LVO were included. Data regarding recanalization, functional outcome, symptomatic intracranial hemorrhage (sICH), and mortality were extracted from the included studies. Functional outcome was assessed with the modified Rankin scale (mRS). A fixed or random-effects model was used to calculate pooled event rates and 95% confidence intervals (CI). Results In this study 11 studies comprising 215 patients were included. The successful recanalization rate was 90.3% (95% CIâ¯= 85.77-95.11%), and complete recanalization was achieved in 52.7% (95% CIâ¯= 45.09-61.62%) of the cases. The favorable (mRSâ¯= 0-2) and excellent (mRSâ¯= 0-1) outcome rates were 83.3% (95% CIâ¯= 73.54-94.50%) and 59.5% (95% CIâ¯= 44.24-80.06%), respectively. The overall sICH prevalence was 0.59% (95% CIâ¯= 0-3.30%) and mortality rate was 3.2% (95% CIâ¯= 0.55-7.38%). Conclusion In our meta-analysis, MT demonstrated a promising safety and efficacy profile for pediatric patients, with consistently high efficacy outcomes and low complication rates. Our results support the utilization of MT in pediatric LVOs; however, prospective studies are still needed to further establish the role of pediatric MT as a first-line treatment strategy.

Incontinentia pigmenti (IP) is a multisystemic disorder in which pulmonary arterial hypertension (PAH) is a severe and rarely reported association. The prognosis has been poor in reported cases. In our patient, IP was diagnosed during the neonatal period with a combination of cutaneous, ophthalmic, and neurological symptoms. The infant experienced severe collapse with bradycardia during general anesthesia to treat retinal telangiectasia. Echocardiography after resuscitation revealed suprasystemic pulmonary hypertension (PH). Right heart catheterization (RHC) confirmed precapillary PAH not responding to acute vasodilatation test. Lung biopsy was performed to exclude alveolo-capillary dysplasia. Upfront triple therapy with endothelin receptor antagonist, PDE5 inhibitors, and prostacyclin was started. Due to a potential inflammatory mechanism of this acute PAH in the setting of IP, TNF-alpha blockers and steroids were associated. The evolution was favorable with progressive normalization of the pulmonary artery pressure confirmed by RHC after six months. Doses of PAH drugs were tapered down, and finally all PAH treatments could be stopped after 18 months. Subsequent controls including physical exams and echocardiograms did not show signs of PH. This unusual reversible case of pediatric PAH without associated congenital heart disease or portal hypertension highlights the potential reversibility of pediatric PH when an inflammatory mechanism can be suspected. This is the first reported case of non-fatal isolated PAH associated with IP.

Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING-finger and two AAA+ domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-finger domain of RNF213 (P<10 ). This association was even stronger when restricting the analysis to childhood-onset and familial cases (OR=4.54, 95% CI=(1.80-11.34), P=1.1 × 10 ). All clinically affected relatives who were genotyped were carriers. However, the need for additional factors to develop MMA is strongly suggested by the fact that only 25% of mutation carrier relatives were clinically affected.

Moyamoya angiopathy is characterized by a progressive stenosis of the terminal portion of the internal carotid arteries and the development of a network of abnormal collateral vessels. This chronic cerebral angiopathy is observed in children and adults. It mainly leads to brain ischemic events in children, and to ischemic and hemorrhagic events in adults. This is a rare condition, with a marked prevalence gradient between Asian countries and Western countries. Two main nosological entities are identified. On the one hand, moyamoya disease corresponds to isolated moyamoya angiopathy, defined as being \"idiopathic\" according to the Guidelines of the Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis. This entity is probably multifactorial and polygenic in most patients. On the other hand, moyamoya syndrome is a moyamoya angiopathy associated with an underlying condition and forms a very heterogeneous group with various clinical presentations, various modes of inheritance, and a variable penetrance of the cerebrovascular phenotype. Diagnostic and evaluation techniques rely on magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) conventional angiography, and cerebral hemodynamics measurements. Revascularization surgery can be indicated, with several techniques. Characteristics of genetic moyamoya syndromes are presented, with a focus on recently reported mutations in BRCC3/MTCP1 and GUCY1A3 genes. Identification of the genes involved in moyamoya disease and several monogenic moyamoya syndromes unraveled different pathways involved in the development of this angiopathy. Studying genes and pathways involved in monogenic moyamoya syndromes may help to give insights into pathophysiological models and discover potential candidates for medical treatment strategies.

Background Acute brain injury (ABI) is a frequent complication of pediatric extracorporeal membrane oxygenation (ECMO) that could be detected by continuous neuromonitoring. Cerebral near-infrared spectroscopy (NIRS) allows monitoring of cerebral oxygenation. Objective To assess whether an impaired cerebral oxygenation was associated with short-term outcome during pediatric ECMO. Methods We conducted a single-center retrospective study in a pediatric intensive care unit. Children under 18 years old were included if receiving veno-venous or veno-arterial ECMO with concurrent NIRS monitoring. Cerebral saturation impairment was defined as rScO2 under 50% or 20% from the baseline for desaturation, and above 80%. Cerebral imaging (magnetic resonance imaging or CT scan) was performed in case of neurological concern. A radiologist blinded for patient history identified ABI as any hemorragic or ischemic lesion, then classified as major or minor. Primary endpoint was the outcome at hospital discharge. Poor outcome was defined as death or survival with a pediatric cerebral performance category scale (PCPC) score ≥ 3 and/or a major ABI. Good outcome was defined as survival with a PCPC score ≤ 2 and/or a minor or no ABI. Secondary endpoint was mortality before PICU discharge. Results Sixty-three patients met inclusion criteria; 48 (76%) had veno-arterial ECMO. Mortality rate was 51%. Forty-eight of sixty-three patients (76%) evolved with a poor outcome, including 20 major ABI. Mean rScO2 in the right/left hemisphere was 73 ± 9%/75 ± 9%. Cerebral desaturation and decline of rScO 2 below 20% from the baseline, regardless of side, were each associated with poor outcome (multivariable-adjusted odds ratio (OR), 4 [95%CI 1.2; 15.1], p  = 0.03, and 3.9 [95%CI 1.1; 14.9], p  = 0.04, respectively), as well as a mean right rScO 2  < 70% during the ECMO course (adjusted OR, 5.6 [95%CI 1.3; 34], p  = 0.04). Left rSCO 2  ≥ 80% was inversely correlated with hospital mortality (adjusted OR of 0.14 [95%CI 0.02; 0.8], p  = 0.04). Conclusions Cerebral desaturation attested by NIRS was associated with a poor short-term outcome in children of all ages undergoing ECMO, and rScO2 > 80% seemed to be protective. NIRS monitoring might be included within multimodal neuromonitoring to assess the risk of the brain injury related to pediatric ECMO.

Background Moyamoya angiopathy (MMA) is a rare cerebrovascular condition leading to stroke. Mutations in 15 genes have been identified in Mendelian forms of MMA, but they explain only a very small proportion of cases. Our aim was to investigate the genetic basis of MMA in consanguineous patients having unaffected parents in order to identify genes involved in autosomal recessive MMA. Methods Exome sequencing (ES) was performed in 6 consecutive consanguineous probands having MMA of unknown etiology. Functional consequences of variants were assessed using western blot and protein 3D structure analyses. Results Causative homozygous variants of NOS3 , the gene encoding the endothelial nitric oxide synthase (eNOS), and GUCY1A3 , the gene encoding the alpha1 subunit of the soluble guanylate cyclase (sGC) which is the major nitric oxide (NO) receptor in the vascular wall, were identified in 3 of the 6 probands. One NOS3 variant (c.1502 + 1G > C) involves a splice donor site causing a premature termination codon and leads to a total lack of eNOS in endothelial progenitor cells of the affected proband. The other NOS3 variant (c.1942 T > C) is a missense variant located into the flavodoxine reductase domain; it is predicted to be destabilizing and shown to be associated with a reduction of eNOS expression. The GUCY1A3 missense variant (c.1778G > A), located in the catalytic domain of the sGC, is predicted to disrupt the tridimensional structure of this domain and to lead to a loss of function of the enzyme. Both NOS3 mutated probands suffered from an infant-onset and severe MMA associated with posterior cerebral artery steno-occlusive lesions. The GUCY1A3 mutated proband presented an adult-onset MMA associated with an early-onset arterial hypertension and a stenosis of the superior mesenteric artery. None of the 3 probands had achalasia. Conclusions We show for the first time that biallelic loss of function variants in NOS3 is responsible for MMA and that mutations in NOS3 and GUCY1A3 are causing fifty per cent of MMA in consanguineous patients. These data pinpoint the essential role of the NO pathway in MMA pathophysiology.

The BCAP31 gene, located at Xq28, encodes BAP31, which plays a role in ER-to-Golgi anterograde transport. To date, BCAP31 pathogenic variants have been reported in 12 male cases from seven families (six loss of function (LoF) and one missense). Patients had severe intellectual disability (ID), dystonia, deafness, and central hypomyelination, delineating a so-called deafness, dystonia and cerebral hypomyelination syndrome (DDCH). Female carriers are mostly asymptomatic but may present with deafness. BCAP31 is flanked by the SLC6A8 and ABCD1 genes. Contiguous deletions of BCAP31 and ABCD1 and/or SLC6A8 have been described in 12 patients. Patients with deletions including BCAP31 and SLC6A8 have the same phenotype as BCAP31 patients. Patients with deletions of BCAP31 and ABCD1 have contiguous ABCD1 and DXS1375E/BCAP31 deletion syndrome (CADDS), and demonstrate a more severe neurological phenotype with cholestatic liver disease and early death. We report 17 novel families, 14 with intragenic BCAP31 variants (LoF and missense) and three with a deletion of BCAP31 and adjacent genes (comprising two CADDS patients, one male and one symptomatic female). Our study confirms the phenotype reported in males with intragenic LoF variants and shows that males with missense variants exhibit a milder phenotype. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation. We further demonstrate that carrier females (n = 10) may have a phenotype comprising LD, ID, and/or deafness. The male with CADDS had a severe neurological phenotype, but no cholestatic liver disease, and the symptomatic female had moderate ID and cholestatic liver disease.