SLC35A2-related congenital disorder of glycosylation : Defining the phenotype

We aim to further delineate the phenotype associated with pathogenic variants in the SLC35A2 gene, and review all published literature to-date. This gene is located on the X chromosome and encodes a UDP-galactose transporter. Pathogenic variants in SLC35A2 cause a congenital disorder of glycosylation. The condition is rare, and less than twenty patients have been reported to-date. The phenotype is complex and has not been fully defined. Here, we present a series of five patients with de novo pathogenic variants in SLC35A2. The patients' phenotype includes developmental and epileptic encephalopathy with hypsarrhythmia, facial dysmorphism, severe intellectual disability, skeletal abnormalities, congenital cardiac disease and cortical visual impairment. Developmental and epileptic encephalopathy with hypsarrhythmia is present in most patients with SLC35A2 variants, and is drug-resistant in the majority of cases. Adrenocorticotropic hormone therapy may achieve partial or complete remission of seizures, but the effect is usually temporary. Isoelectric focusing of transferrins may be normal after infancy, therefore a congenital disorder of glycosylation should still be considered as a diagnosis in the presence of a suggestive phenotype. We also provide evidence that cortical visual impairment is part of the phenotypic spectrum. (C) 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images

Neuroimaging measurements derived from magnetic resonance imaging provide important information required for detecting changes related to the progression of mild cognitive impairment (MCI). Cortical features and changes play a crucial role in revealing unique anatomical patterns of brain regions, and further differentiate MCI patients from normal states. Four cortical features, namely, gray matter volume, cortical thickness, surface area, and mean curvature, were explored for discriminative analysis among three groups including the stable MCI (sMCI), the converted MCI (cMCI), and the normal control (NC) groups. In this study, 158 subjects (72 NC, 46 sMCI, and 40 cMCI) were selected from the Alzheimer's Disease Neuroimaging Initiative. A sparse-constrained regression model based on the l2-1-norm was introduced to reduce the feature dimensionality and retrieve essential features for the discrimination of the three groups by using a support vector machine (SVM). An optimized strategy of feature addition based on the weight of each feature was adopted for the SVM classifier in order to achieve the best classification performance. The baseline cortical features combined with the longitudinal measurements for 2 years of follow-up data yielded prominent classification results. In particular, the cortical thickness produced a classification with 98.84% accuracy, 97.5% sensitivity, and 100% specificity for the sMCI–cMCI comparison; 92.37% accuracy, 84.78% sensitivity, and 97.22% specificity for the cMCI–NC comparison; and 93.75% accuracy, 92.5% sensitivity, and 94.44% specificity for the sMCI–NC comparison. The best performances obtained by the SVM classifier using the essential features were 5–40% more than those using all of the retained features. The feasibility of the cortical features for the recognition of anatomical patterns was certified; thus, the proposed method has the potential to improve the clinical diagnosis of sub-types of MCI and predict the risk of its conversion to Alzheimer's disease

Quantitative 18F-AV1451 Brain Tau PET Imaging in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer's Disease Patients

Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake.Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed.Results:18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p < 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p > 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions.Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Alzheimer disease pathology and longitudinal cognitive performance in the oldest-old with no dementia.

It has been hypothesized that individuals without dementia with Alzheimer disease (AD) neuropathology may be in the preclinical stages of dementia and could be experiencing subtle cognitive decline. The purpose of this study was to compare longitudinal cognitive performance in oldest-old individuals without dementia with and without AD neuropathology.The study included 58 individuals without dementia from The 90+ Autopsy Study, a population-based study of aging and dementia in individuals aged 90 and older. Participants had neurologic and neuropsychological testing every 6 months with an average of 3 years of follow-up. We compared the trajectory of cognitive performance on the Modified Mini-Mental State Examination (3MS) and the California Verbal Learning Test II (CVLT) by level of AD neuropathology. Based on Consortium to Establish a Registry for Alzheimer's Disease plaque staging, individuals were categorized as having low (none or sparse) or high (moderate or frequent) plaques. Based on Braak and Braak staging, participants were classified as having low (stages I-III) or high (IV-VI) tangles.No significant differences were found in 3MS or CVLT cognitive performance over time based on plaque or tangle staging. Both high and low pathology groups showed modest improvements on the 3MS and CVLT consistent with learning effects.AD neuropathology at autopsy is not associated with the trajectory of cognitive performance in the 3 years before death in oldest-old without dementia. Despite the presence of AD neuropathology at death, oldest-old without dementia display learning effects on cognitive tests. Further research is necessary to understand factors other than AD neuropathology that may affect cognition in the oldest-old

Diagnosing dementia in the oldest-old.

The "oldest-old" comprise the fastest growing segment of the population in much of the world. Rates of dementia are extremely high in this age group and will present a major public health burden as the numbers of these individuals quadruple by the middle of the century. Studies in this age group are rare and frequently have small numbers of participants. In research studies and the clinic, the diagnosis of dementia and determination of the etiology of the disorder are challenging. In this review, we include some of our experiences in a population-based longitudinal investigation, The 90+ Study. Oldest-old individuals are more likely to suffer from medical comorbidities and have high rates of sensory loss, psychoactive medication usage, frailty and fatigue. Moreover, social and cultural expectations affect the reporting and interpretation of behavioral changes. These and other factors make it difficult to determine the relative contributions of cognitive losses and non-cognitive losses in the development of functional disability. Contributing further to the complexities of diagnosis, current research suggests that dementia in the oldest-old, compared to younger people, is more likely to be related to mixed disease pathologies. Frequent cerebral neuropathologies include Alzheimer's disease neurodegeneration, small and large vessel vascular disease, and hippocampal sclerosis. More research is necessary in the oldest-old to better understand the etiologies of dementia in this age group, and factors that may affect the expression of disease as we age

Alzheimer disease pathology and longitudinal cognitive performance in the oldest-old with no dementia.

It has been hypothesized that individuals without dementia with Alzheimer disease (AD) neuropathology may be in the preclinical stages of dementia and could be experiencing subtle cognitive decline. The purpose of this study was to compare longitudinal cognitive performance in oldest-old individuals without dementia with and without AD neuropathology.The study included 58 individuals without dementia from The 90+ Autopsy Study, a population-based study of aging and dementia in individuals aged 90 and older. Participants had neurologic and neuropsychological testing every 6 months with an average of 3 years of follow-up. We compared the trajectory of cognitive performance on the Modified Mini-Mental State Examination (3MS) and the California Verbal Learning Test II (CVLT) by level of AD neuropathology. Based on Consortium to Establish a Registry for Alzheimer's Disease plaque staging, individuals were categorized as having low (none or sparse) or high (moderate or frequent) plaques. Based on Braak and Braak staging, participants were classified as having low (stages I-III) or high (IV-VI) tangles.No significant differences were found in 3MS or CVLT cognitive performance over time based on plaque or tangle staging. Both high and low pathology groups showed modest improvements on the 3MS and CVLT consistent with learning effects.AD neuropathology at autopsy is not associated with the trajectory of cognitive performance in the 3 years before death in oldest-old without dementia. Despite the presence of AD neuropathology at death, oldest-old without dementia display learning effects on cognitive tests. Further research is necessary to understand factors other than AD neuropathology that may affect cognition in the oldest-old

Acute liver injury induced by low dose dimethylnitrosamine alters mediators of hepatic vascular flow

Alterations in liver vascular tone play an important role in chronic liver disease. The hepatic stellate cell (HSC) and mediators such as nitric oxide (NO) and hydrogen sulfide (H2S) have been implicated in regulation of vascular tone and intra-hepatic pressure. Though these have been studied in chronic liver damage, changes in response to acute liver injury induced by hepatotoxins such as dimethyl nitrosamine are not well understood. Liver injury was induced in mice by a single intra-peritoneal injection of dimethylnitrosamine (DMN), following which animals were sacrificed at 24, 48 and 72 h. Changes in vascular mediators such as NO and H2S as well as stellate cell activation was then examined. It was found that a single low dose of DMN in mice is sufficient to induce activation of hepatic stellate cells within 24 h, accompanied by oxidative stress, compromised metabolism of H2S and decreased levels of the von Willebrand factor (vWF) cleaving protease; a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), which functions in intravascular thrombosis. A suppression of hepatic NO levels is also initiated at this time point, which progresses further and is sustained up to 72 h, at which point the HSC activation is still present. Compromised levels of ADAMTS13 and H2S metabolism however, begin to recover by 48 h and are almost similar to control by 72 h. In conclusion, these data suggest that even moderate acute insults in the liver can have far reaching consequences on a number of mediators of vascular flow in the liver