Differences in renal hemodynamics and renin secretion between patients with unifocal and multifocal fibromuscular dysplasia

Objective: Fibromuscular dysplasia (FMD) can be classified in a multifocal and a unifocal subtype. As unifocal FMD generally leads to more severe hypertension at younger age, we hypothesized that renal hemodynamics are more disturbed in unifocal renal artery FMD as compared with multifocal FMD, leading to increased renin secretion. Methods: We measured renal blood flow ((133)Xenon washout method), renin secretion, and glomerular filtration rate per kidney in 101 patients with FMD (26 unifocal and 75 multifocal), all off medication and prior to balloon angioplasty. Results: We found that renal blood flow and glomerular filtration were substantially lower in kidneys with unifocal FMD as compared with multifocal FMD. In the affected kidney from patients with unilateral FMD for example, mean renal blood flow was 173 +/- 77 in unifocal vs. 244 +/- 79 ml/100 g kidney/min in multifocal FMD (P=0.013). Moreover, lateralization in renin secretion was only observed in a subset of patients with unifocal FMD, but not in any of the patients with multifocal FMD. Conclusion: These findings suggest that the impact of unifocal FMD lesions on the kidney is more severe, resulting in a classical pattern of renovascular hypertension. In multifocal FMD, however, renal blood flow is more preserved, local renin secretion is not increased, and the association between renin levels and blood pressure is inverse. These differences may explain the often more severe clinical presentation and higher success rate of revascularization in unifocal FMD, but also suggest that the pathophysiological mechanisms leading to hypertension may differ between these two disease entities

Executive functioning in preschoolers with 22q11.2 deletion syndrome and the impact of congenital heart defects

Background: Executive functioning (EF) is an umbrella term for various cognitive functions that play a role in monitoring and planning to effectuate goal-directed behavior. The 22q11.2 deletion syndrome (22q11DS), the most common microdeletion syndrome, is associated with a multitude of both somatic and cognitive symptoms, including EF impairments in school-age and adolescence. However, results vary across different EF domains and studies with preschool children are scarce. As EF is critically associated with later psychopathology and adaptive functioning, our first aim was to study EF in preschool children with 22q11DS. Our second aim was to explore the effect of a congenital heart defects (CHD) on EF abilities, as CHD are common in 22q11DS and have been implicated in EF impairment in individuals with CHD without a syndromic origin. Methods: All children with 22q11DS (n = 44) and typically developing (TD) children (n = 81) were 3.0 to 6.5 years old and participated in a larger prospective study. We administered tasks measuring visual selective attention, visual working memory, and a task gauging broad EF abilities. The presence of CHD was determined by a pediatric cardiologist based on medical records. Results: Analyses showed that children with 22q11DS were outperformed by TD peers on the selective attention task and the working memory task. As many children were unable to complete the broad EF task, we did not run statistical analyses, but provide a qualitative description of the results. There were no differences in EF abilities between children with 22q11DS with and without CHDs. Conclusion: To our knowledge, this is the first study measuring EF in a relatively large sample of young children with 22q11DS. Our results show that EF impairments are already present in early childhood in children with 22q11DS. In line with previous studies with older children with 22q11DS, CHDs do not appear to have an effect on EF performance. These findings might have important implications for early intervention and support the improvement of prognostic accuracy

Executive functioning in preschoolers with 22q11.2 deletion syndrome and the impact of congenital heart defects

BACKGROUND: Executive functioning (EF) is an umbrella term for various cognitive functions that play a role in monitoring and planning to effectuate goal-directed behavior. The 22q11.2 deletion syndrome (22q11DS), the most common microdeletion syndrome, is associated with a multitude of both somatic and cognitive symptoms, including EF impairments in school-age and adolescence. However, results vary across different EF domains and studies with preschool children are scarce. As EF is critically associated with later psychopathology and adaptive functioning, our first aim was to study EF in preschool children with 22q11DS. Our second aim was to explore the effect of a congenital heart defects (CHD) on EF abilities, as CHD are common in 22q11DS and have been implicated in EF impairment in individuals with CHD without a syndromic origin. METHODS: All children with 22q11DS (n = 44) and typically developing (TD) children (n = 81) were 3.0 to 6.5 years old and participated in a larger prospective study. We administered tasks measuring visual selective attention, visual working memory, and a task gauging broad EF abilities. The presence of CHD was determined by a pediatric cardiologist based on medical records. RESULTS: Analyses showed that children with 22q11DS were outperformed by TD peers on the selective attention task and the working memory task. As many children were unable to complete the broad EF task, we did not run statistical analyses, but provide a qualitative description of the results. There were no differences in EF abilities between children with 22q11DS with and without CHDs. CONCLUSION: To our knowledge, this is the first study measuring EF in a relatively large sample of young children with 22q11DS. Our results show that EF impairments are already present in early childhood in children with 22q11DS. In line with previous studies with older children with 22q11DS, CHDs do not appear to have an effect on EF performance. These findings might have important implications for early intervention and support the improvement of prognostic accuracy

Identification of a pathogenic deep intronic variant in ATRX ends a diagnostic odyssey

Variation in the non-coding genome is being increasingly recognized to be involved in monogenic disease etiology. However, the interpretation of non-coding variation is complicated by a lack of understanding of how non-coding genetic elements function. Additional lines of evidence are therefore needed to recognize non-coding variants as pathogenic. We here present a case where a collective body of evidence resulted in the identification and conclusive classification of a pathogenic deep intronic variant in ATRX. This report demonstrates the utility of a multi-platform approach in aiding the identification of pathogenic variants outside coding regions. Furthermore, it marks the first reported instance of a deep intronic pathogenic variant in ATRX

Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration

Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132—requiring upregulation of neddylation to restore proteasomal function and proteasomal stress—led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature—delayed closure of the ischiopubic rami—correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects.</p