Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders

\ua9 The Author(s) 2024. Background: Neurodevelopmental disorders (NDDs) and/or associated multiple congenital abnormalities (MCAs) represent a genetically heterogeneous group of conditions with an adverse prognosis for the quality of intellectual and social abilities and common daily functioning. The rapid development of exome sequencing (ES) techniques, together with trio-based analysis, nowadays leads to up to 50% diagnostic yield. Therefore, it is considered as the state-of-the-art approach in these diagnoses. Results: In our study, we present the results of ES in a cohort of 85 families with 90 children with severe NDDs and MCAs. The interconnection of the in-house bioinformatic pipeline and a unique algorithm for variant prioritization resulted in a diagnostic yield of up to 48.9% (44/90), including rare and novel causative variants (41/90) and intragenic copy-number variations (CNVs) (3/90). Of the total number of 47 causative variants, 53.2% (25/47) were novel, highlighting the clinical benefit of ES for unexplained NDDs. Moreover, trio-based ES was verified as a reliable tool for the detection of rare CNVs, ranging from intragenic exon deletions (GRIN2A, ZC4H2 genes) to a 6-Mb duplication. The functional analysis using PANTHER Gene Ontology confirmed the involvement of genes with causative variants in a wide spectrum of developmental processes and molecular pathways, which form essential structural and functional components of the central nervous system. Conclusion: Taken together, we present one of the first ES studies of this scale from the central European region. Based on the high diagnostic yield for paediatric NDDs in this study, 48.9%, we confirm trio-based ES as an effective and reliable first-tier diagnostic test in the genetic evaluation of children with NDDs

Aerobic-Strength Exercise Improves Metabolism and Clinical State in Parkinson's Disease Patients

Regular exercise ameliorates motor symptoms in Parkinson's disease (PD). Here, we aimed to provide evidence that exercise brings additional benefits to the whole-body metabolism and skeletal muscle molecular and functional characteristics, which might help to explain exercise-induced improvements in the clinical state. 3-months supervised endurance/strength training was performed in early/mid-stage PD patients and age/gender-matched individuals (n = 11/11). The effects of exercise on resting energy expenditure (REE), glucose metabolism, adiposity, and muscle energy metabolism (31P-MRS) were evaluated and compared to non-exercising PD patients. Two muscle biopsies were taken to determine intervention-induced changes in fiber type, mitochondrial content, and expression of genes related to muscle energy metabolism, as well as proliferative and regenerative capacity. Exercise improved the clinical disability score (MDS-UPDRS), bradykinesia, balance, walking speed, REE, and glucose metabolism and increased muscle expression of energy sensors (AMPK). However, the exercise-induced increase in muscle mass/strength, mitochondrial content, type II fiber size, and postexercise phosphocreatine (PCr) recovery (31P-MRS) were found only in controls. Nevertheless, MDS-UPDRS was associated with muscle AMPK and mechano-growth factor (MGF) expression. Improvements in fasting glycemia were positively associated with muscle function and the expression of Sirt1 and Cox7a1, and the parameters of fitness/strength were positively associated with the expression of MyHC2, MyHC7, and MGF. Moreover, reduced bradykinesia was associated with better muscle metabolism (maximal oxidative capacity and postexercise PCr recovery; 31P-MRS). Exercise training improved the clinical state in early/mid-stage Parkinson's disease patients, including motor functions and whole-body metabolism. Although the adaptive response to exercise in PD was different from that of controls, exercise-induced improvements in the PD clinical state were associated with specific adaptive changes in muscle functional, metabolic, and molecular characteristics.www.ClinicalTrials.gov, identifier NCT02253732