Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification

Proceedings of Abstracts Engineering and Computer Science Research Conference 2019

© 2019 The Author(s). This is an open-access work distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. For further details please see https://creativecommons.org/licenses/by/4.0/. Note: Keynote: Fluorescence visualisation to evaluate effectiveness of personal protective equipment for infection control is © 2019 Crown copyright and so is licensed under the Open Government Licence v3.0. Under this licence users are permitted to copy, publish, distribute and transmit the Information; adapt the Information; exploit the Information commercially and non-commercially for example, by combining it with other Information, or by including it in your own product or application. Where you do any of the above you must acknowledge the source of the Information in your product or application by including or linking to any attribution statement specified by the Information Provider(s) and, where possible, provide a link to this licence: http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3/This book is the record of abstracts submitted and accepted for presentation at the Inaugural Engineering and Computer Science Research Conference held 17th April 2019 at the University of Hertfordshire, Hatfield, UK. This conference is a local event aiming at bringing together the research students, staff and eminent external guests to celebrate Engineering and Computer Science Research at the University of Hertfordshire. The ECS Research Conference aims to showcase the broad landscape of research taking place in the School of Engineering and Computer Science. The 2019 conference was articulated around three topical cross-disciplinary themes: Make and Preserve the Future; Connect the People and Cities; and Protect and Care

Dissecting the genetic basis of neurodevelopmental disorders and demyelinating neuropathies

The understanding of the pathophysiology of most rare, complex neurological disorders has been elusive, especially in the case of complex demyelinating neuropathies and neurodevelopmental disorders. In my work, I learnt to employ two main techniques that will help advance the search for better understanding of neurodevelopmental disorders: next generation sequencing and functional validation of rare genetic variants. The main aim of my research was to establish the genetic diagnosis in several patients affected by complex syndromes such as peripheral neuropathy with central nervous system involvement (Chapter 3), neurodevelopmental disorders (Chapter 4) and epilepsy (Chapter 5). The phenotypic and genotypic correlations of identified gene variants were investigated in these chapters and is a profound theme in my project. To achieve this, an integrated approach combining next generation sequencing (NGS) technology, homozygosity mapping, array genotyping, traditional Sanger sequencing and functional experiments was undertaken. Firstly, I describe the work performed in an attempt to identify the causative gene in a cohort of young children presented with an early-onset hereditary form of chronic inflammatory demyelinating polyneuropathy with a central and peripheral involvement. My key findings were that: i) neurofascin is the first gene causally responsible for an inherited disorder that resembles CIDP, ii) this is the largest clinical cohort to date of patients with NFASC mutations with 10 individuals, and iii) the functional evidence implicate the major protein isoforms, which were also shown to be the main targets for the autoantibodies in CIDP pathogenesis. Secondly, I describe the work done on various neurodevelopmental disorder (NDD) genes, with particular focus on a newly identified gene presenting with a complex neurodevelopmental phenotype comprised of developmental delay, epilepsy, and/or a demyelinating neuropathy. My key findings were that: i) NARS1, a cytoplasmic aminoacyl-tRNA synthetase enzyme can be causative for this disorder by either a de-novo heterozygous or a biallelic inheritance mode, ii) functional investigations showed reduced aminoacylation activity in the disease-associated biallelic mutations using fibroblasts and iNPCs transcriptomics, suggesting that the majority of NARS1 mutations cause a loss of function of the protein by reduced expression and disruption of dimer formation suggesting a loss-of-function mechanism, and iii) increased yeast growth in the disease-associated heterozygous mutations showing near normal protein expression are suggestive of a gain-of-function mechanism. Finally, I describe the work done on two relative new genes (PIGS and TARS1) in an attempt to expand the patient phenotypic spectrum, as well as an interesting candidate gene (SLITRK3) linked with epilepsy. I present my understanding for disease-gene discovery that will enable me and other members of the neurogenetics field to identify disease-mechanisms and address important gaps of translational research into rare neurological diseases such as those described in this thesis

Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment

Peer reviewedPublisher PD

Concomitant granule cell neuronopathy in patients with natalizumab-associated PML

Granule cell neuronopathy (GCN) is a rare JC virus infection of the cerebellar granule cell neurons in immunocompromised patients. On brain imaging, GCN is characterized by cerebellar atrophy which can be accompanied by infratentorial white matter lesions. The objective of this study is to investigate the prevalence of MRI findings suggestive of GCN in a large natalizumab-associated progressive multifocal leukoencephalopathy (PML) cohort. MRI scans from before, at the time of, and during follow-up after diagnosis of PML in 44 natalizumab-treated MS patients, and a control group of 25 natalizumab-treated non-PML MS patients were retrospectively reviewed for imaging findings suggestive of GCN. To assess and quantify the degree of cerebellar atrophy, we used a 4 grade rating scale. Three patients in the PML group showed imaging findings suggestive of GCN and none in the control group. In two of these PML patients, cerebellar atrophy progressed from grade 0 at the time of diagnosis of isolated supratentorial PML to grade 1 and 2 after 2.5 and 3 months, respectively, in the absence of infratentorial white mater lesions. The third patient had grade 1 cerebellar atrophy before diagnosis of infra- and supratentorial PML, and showed progression of cerebellar atrophy to grade 2 in the 3 months following PML diagnosis. None of the other eight patients with infratentorial PML lesions developed cerebellar atrophy suggestive of GCN. Three cases with imaging findings suggestive of GCN were detected among 44 natalizumab-associated PML patients. GCN may, therefore, be more common than previously considered in natalizumab-associated PML patients

DHTKD1 Mutations Cause 2-Aminoadipic and 2-Oxoadipic Aciduria

Abnormalities in metabolite profiles are valuable indicators of underlying pathologic conditions at the molecular level. However, their interpretation relies on detailed knowledge of the pathways, enzymes, and genes involved. Identification and characterization of their physiological function are therefore crucial for our understanding of human disease: they can provide guidance for therapeutic intervention and help us to identify suitable biomarkers for monitoring associated disorders. We studied two individuals with 2-aminoadipic and 2-oxoadipic aciduria, a metabolic condition that is still unresolved at the molecular level. This disorder has been associated with varying neurological symptoms. Exome sequencing of a single affected individual revealed compound heterozygosity for an initiating methionine mutation (c.1A>G) and a missense mutation (c.2185G>A [p.Gly729Arg]) in DHTKD1. This gene codes for dehydrogenase E1 and transketolase domain-containing protein 1, which is part of a 2-oxoglutarate-dehydrogenase-complex-like protein. Sequence analysis of a second individual identified the same missense mutation together with a nonsense mutation (c.1228C>T [p.Arg410∗]) in DHTKD1. Increased levels of 2-oxoadipate in individual-derived fibroblasts normalized upon lentiviral expression of the wild-type DHTKD1 mRNA. Moreover, investigation of L-lysine metabolism showed an accumulation of deuterium-labeled 2-oxoadipate only in noncomplemented cells, demonstrating that DHTKD1 codes for the enzyme mediating the last unresolved step in the L-lysine-degradation pathway. All together, our results establish mutations in DHTKD1 as a cause of human 2-aminoadipic and 2-oxoadipic aciduria via impaired turnover of decarboxylation 2-oxoadipate to glutaryl-CoA

On the Impact of Voice Anonymization on Speech-Based COVID-19 Detection

With advances seen in deep learning, voice-based applications are burgeoning, ranging from personal assistants, affective computing, to remote disease diagnostics. As the voice contains both linguistic and paralinguistic information (e.g., vocal pitch, intonation, speech rate, loudness), there is growing interest in voice anonymization to preserve speaker privacy and identity. Voice privacy challenges have emerged over the last few years and focus has been placed on removing speaker identity while keeping linguistic content intact. For affective computing and disease monitoring applications, however, the paralinguistic content may be more critical. Unfortunately, the effects that anonymization may have on these systems are still largely unknown. In this paper, we fill this gap and focus on one particular health monitoring application: speech-based COVID-19 diagnosis. We test two popular anonymization methods and their impact on five different state-of-the-art COVID-19 diagnostic systems using three public datasets. We validate the effectiveness of the anonymization methods, compare their computational complexity, and quantify the impact across different testing scenarios for both within- and across-dataset conditions. Lastly, we show the benefits of anonymization as a data augmentation tool to help recover some of the COVID-19 diagnostic accuracy loss seen with anonymized data.Comment: 11 pages, 10 figure