Biallelic Variants in PYROXD2 Cause a Severe Infantile Metabolic Disorder Affecting Mitochondrial Function

Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein’s precise biological function. In the present paper, we report biallelic variants in PYROXD2 identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of PYROXD2 in human cells, and suggest that the biallelic PYROXD2 variants are associated with mitochondrial dysfunction, and can plausibly explain the child’s clinical presentation

A systematic evaluation of the neurosurgical application of perioperative and intraoperative diffusion MR tractography in paediatric epilepsy surgery

2015 Dr. Joseph Yuan-Mou YangEpilepsy is a serious health condition affecting children worldwide. In a subset of these children, the epilepsy is refractory despite maximum appropriate medical therapies. Neurosurgical interventions aiming at resecting the seizure generating (epileptogenic) tissue provides the potential for seizure freedom in these children. The principle of epilepsy surgery is to maximally resect the epileptogenic tissues without injuring the eloquent brain regions, which includes both the cortical grey matter (GM) and the subcortical white matter tracts (WMTs). Injuries to these structures can lead to permanent neurological deficits. The surgical success depends on concordant preoperative and intraoperative localisation of both the seizure focus and the eloquent brain through the use of multimodal brain structural and functional neuroimaging techniques. Diffusion MR tractography is an increasingly utilised neuroimaging adjunct in epilepsy surgery that uniquely provides non-invasive virtual reconstructions of the WMT anatomy. Despite the growing popularity, its application in paediatric epilepsy surgery requires judicious evaluation, particularly with respect to its inherent technical limitations relevant to this age group. There is also a paucity of information regarding usefulness of a more sophisticated diffusion model and tractography algorithm in this clinical population. Using a cohort of 20 paediatric epilepsy surgical candidates, this PhD consists of three study experiments addressing both the technical and the clinical aspects of the diffusion MR tractography. Study experiment one (Chapter Five and Six) demonstrates the feasibility of developing a novel tractography methodology by adopting a more sophisticated diffusion model and the tractography algorithm. The study demonstrates highly accurate tractography results when validate against a set of predefined WMT anatomical criteria. Tractography generated in WMTs with distorted anatomy corresponds well with the functional MRI data and the direct brain electrostimulation findings. Study experiment two (Chapter Seven) evaluates the role of diffusion MR tractography to assess the degree of intraoperative WMT shift, and the intraoperative factors impacting on this shift. The study shows WMT shift is dynamic and occurs at both the global hemispheric and the regional WMT-based levels. The durotomy size, the resected lesion size and the presence of brain oedema are significant independent intraoperative variables affecting the WMT shift. Study experiment three (Chapter Eight) evaluates the association between the tractography-derived quantitative metrics and the perioperative functional states of the participants. The incomplete clinical data restricts the analysis to subgroup and case-based observations. The results suggest the adopted quantitative metrics are sensitive but non-specific imaging biomarkers of the underlying WMT microstructure changes, and do not consistently reflect the child’s postoperative function. Further methodological refinements are required to substantiate and to improve on this finding. This PhD provides a reliable technical framework for performing diffusion MR tractography in children. It also highlights the pertinent technical factors that need to be considered when utilising and interpreting diffusion MR tractography results in paediatric epilepsy surgery over both the perioperative and the intraoperative settings. Importantly, this PhD provides the basis for future research while continue searches for a more specific WMT imaging biomarker associating with the child’s postoperative functional state that is of both diagnostic and interventional significance

Individual Differences in Intrinsic Brain Networks Predict Symptom Severity in Autism Spectrum Disorders

The neurobiology of heterogeneous neurodevelopmental disorders such as Autism Spectrum Disorders (ASD) is still unknown. We hypothesized that differences in subject-level properties of intrinsic brain networks were important features that could predict individual variation in ASD symptom severity. We matched cases and controls from a large multicohort ASD dataset (ABIDE-II) on age, sex, IQ, and image acquisition site. Subjects were matched at the individual level (rather than at group level) to improve homogeneity within matched case–control pairs (ASD: n = 100, mean age = 11.43 years, IQ = 110.58; controls: n = 100, mean age = 11.43 years, IQ = 110.70). Using task-free functional magnetic resonance imaging, we extracted intrinsic functional brain networks using projective non-negative matrix factorization. Intrapair differences in strength in subnetworks related to the salience network (SN) and the occipital-temporal face perception network were robustly associated with individual differences in social impairment severity (T = 2.206, P = 0.0301). Findings were further replicated and validated in an independent validation cohort of monozygotic twins (n = 12; 3 pairs concordant and 3 pairs discordant for ASD). Individual differences in the SN and face-perception network are centrally implicated in the neural mechanisms of social deficits related to ASD

Exercise as therapy for neurodevelopmental and cognitive dysfunction in people with a Fontan circulation : A narrative review

People with a Fontan circulation are at risk of neurodevelopmental delay and disability, and cognitive dysfunction, that has significant implications for academic and occupational attainment, psychosocial functioning, and overall quality of life. Interventions for improving these outcomes are lacking. This review article discusses current intervention practices and explores the evidence supporting exercise as a potential intervention for improving cognitive functioning in people living with a Fontan circulation. Proposed pathophysiological mechanisms underpinning these associations are discussed in the context of Fontan physiology and avenues for future research are recommended.peerReviewe

Association of Acute Infarct Topography With Development of Cerebral Palsy and Neurological Impairment in Neonates With Stroke.

OBJECTIVES Research investigating neonatal arterial ischemic stroke (NAIS) outcomes have shown that combined cortical and basal ganglia infarction or involvement of the corticospinal tract predict cerebral palsy (CP). The research question was whether voxel-based lesion-symptom mapping (VLSM) on acute MRI can identify brain regions associated with CP and neurodevelopmental impairments in neonatal arterial ischemic stroke (NAIS). METHODS Newborns were recruited from prospective Australian and Swiss pediatric stroke registries. CP diagnosis was based on clinical examination. Language and cognitive-behavioral impairments were assessed using the Pediatric Stroke Outcome Measure, dichotomized to good (0-0.5) or poor (≥ 1), at ≥18 months of age. Infarcts were manually segmented using diffusion-weighted imaging, registered to a neonatal-specific brain template. VLSM was conducted using MATLAB SPM12 toolbox. A general linear model was used to correlate lesion masks with motor, language and cognitive-behavioral outcomes. Voxel-wise t-test statistics were calculated, correcting for multiple comparisons using family-wise error rate (FWE). RESULTS Eighty-five newborns met inclusion criteria. Infarct lateralization was left hemisphere (62%), right (8%) and bilateral (30%). At median age 2.1 years (IQR 1.9-2.6), 33% developed CP and 42% had neurological impairments. 54 grey and white matter regions correlated with CP (t>4.33; FWE <0.05), including primary motor pathway regions, such as the precentral gyrus, and cerebral peduncle, and regions functionally connected to the primary motor pathway, such as the pallidum, and corpus callosum motor segment. No significant correlations were found for language or cognitive-behavioral outcomes. CONCLUSIONS CP following NAIS correlates with infarct regions directly involved in motor control and, or in functionally connected regions. Areas associated with language or cognitive-behavioral impairment are less clear

PEG/Dextran Double Layer Influences Fe Ion Release and Colloidal Stability of Iron Oxide Nanoparticles

Abstract Despite preliminary confidence on biosafety of polymer coated iron oxide nanoparticles (SPIONs), toxicity concerns have hampered their clinical translation. SPIONs toxicity is known to be due to catalytic activity of their surface and release of toxic Fe ions originating from the core biodegradation, leading to the generation of reactive oxygen species (ROS). Here, we hypothesized that a double-layer polymeric corona comprising of dextran as an interior, and polyethylene glycol (PEG) as an exterior layer better shields the core SPIONs. We found that ROS generation was cell specific and depended on SPIONs concentration, although it was reduced by sufficient PEG immobilization or 100 µM deferoxamine. 24 h following injection, PEGylated samples showed reduction of biodistribution in liver, heterogenous biodistribution profile in spleen, and no influence on NPs blood retention. Sufficient surface masking or administration of deferoxamine could be beneficial strategies in designing and clinical translation of future biomedical SPIONs