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Background Individuals with intellectual disabilities (IDs) and neurogenetic conditions (IDNDs) are at greater risk for comorbidities that may increase adverse outcomes for this population when they have coronavirus disease 2019 (COVID-19). The study aims are to examine the population-level odds of hospitalisation and mortality of privately insured individuals with COVID-19 with and without IDNDs IDs, controlling for sociodemographics and comorbid health conditions. Methods This is a retrospective, cross-sectional study of 1174 individuals with IDs and neurogenetic conditions within a population of 752 237 de-identified, privately insured, US patients diagnosed with COVID-19 between February 2020 and September 2020. Odds of hospitalisation and mortality among COVID-19 patients with IDNDs adjusted for demographic characteristics, Health Resources and Services Administration region, states with Affordable Care Act and number of comorbid health conditions were analysed. Results Patients with IDNDs overall had higher rates of COVID-19 hospitalisation than those without IDNDs (35.01% vs. 12.65%, P< .0001) and had higher rates of COVID-19 mortality than those without IDNDs (4.94% vs. .88%, P < .0001). Adjusting for sociodemographic factors only, the odds of being hospitalised for COVID-19 associated with IDNDs was 4.05 [95% confidence interval (CI) 3.56–4.61]. Adjusting for sociodemographic factors and comorbidity count, the odds of hospitalisation for COVID-19 associated with IDNDs was 1.42 (95% CI 1.25–1.61). The odds of mortality from COVID-19 for individuals with IDNDs adjusted for sociodemographic factors only was 4.65 (95% CI 3.47–6.24). The odds of mortality from COVID-19 for patients with IDNDs adjusted for sociodemographic factors and comorbidity count was 2.70 (95% CI 2.03–3.60). A major finding of the study was that even when considering the different demographic structure and generally higher disease burden of patients with IDNDs, having a IDND was an independent risk factor for increased hospitalisation and mortality compared with patients without IDNDs. Conclusions Individuals with IDNDs had significantly higher odds of hospitalisation and mortality after adjusting for sociodemographics. Results remained significant with a slight attenuation after adjusting for sociodemographics and comorbidities. Adjustments for comorbidity count demonstrated a dose–response increase in odds of both hospitalisation and mortality, illustrating the cumulative effect of health concerns on COVID-19 outcomes. Together, findings highlight that individuals with IDNDs experience vulnerability for negative COVID-19 health outcomes with implications for access to comprehensive healthcare. [ABSTRACT FROM AUTHOR]

Aim: Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral neuropathy with autosomal dominant inheritance. Diagnosis can be made from the characteristic abnormalities determined by nerve conduction studies (NCS), including subclinical deficits at physiological compression sites. Heterozygous deletion of the chromosome 17p11.2–p12 region including the peripheral myelin protein 22 gene (PMP22) is the cause in the majority of cases. However, the loss of function of PMP22 due to frameshift‐causing insertion/deletion, missense, nonsense, or splice‐site disrupting variants cause HNPP in some patients. We report a case of a patient diagnosed with HNPP on the basis of clinical features and the results of NCS. No deletions of PMP22 were detected by fluorescence in situ hybridization. Methods: We performed direct nucleotide sequence analysis and identified a heterozygous variant, c.78 + 3G > T, in PMP22. Since this variant is located outside the canonical splice site at the exon 2–intron 2 junction, we investigated whether the variant causes aberrant splicing and leads to the skipping of exon 2 of PMP22 by in vitro minigene splicing assay. Results: We demonstrated that the c.78 + 3G > T variant causes the skipping of exon 2 and leads to loss of function of the mutant allele. Conclusion: Searching for sequence variants located outside the canonical splice sites should also be considered even when deletion of PMP22 is not found in a patient with a clinical diagnosis suggesting HNPP. [ABSTRACT FROM AUTHOR]

Noncoding RNAs are emerging as potent and multifunctional regulators in all biological processes. In parallel, a rapidly growing number of studies has unravelled associations between aberrant noncoding RNA expression and human diseases. These associations have been extensively reviewed, often with the focus on a particular microRNA (miRNA) (family) or a selected disease/pathology. In this Mini‐Review, we highlight a selection of studies in order to demonstrate the wide‐scale involvement of miRNAs and long noncoding RNAs in the pathophysiology of three types of diseases: cancer, cardiovascular and neurological disorders. This research is opening new avenues to novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Abstract: Statistical genetics is a field involving the analysis of genetic data. With the development of next‐generation sequencing and single‐nucleotide polymorphism microarrays, the amount of genetic data is increasing rapidly. Genome‐wide association studies are one example of the successful application of an approach based on statistical genetics. To shed light on neuroinflammatory diseases, such as multiple sclerosis, >100 000 people have been enrolled in the genome‐wide association study meta‐analysis, and 200 loci associated with multiple sclerosis have been detected. To utilize these genetic data for clinical medicine, development of novel methods of statistical genetics is warranted. Human leukocyte antigen imputation and in silico drug repositioning are good examples of such approaches. [ABSTRACT FROM AUTHOR]

Background Microdeletions of 2q23.1 disrupting MBD5 and loss of function mutations of MBD5 cause MBD5-Associated Neurodevelopmental disorders ( MAND). Nearly all reported patients have been isolated cases of de novo origin. Methods This study investigates three families with inherited MBD5 mutations from three different Regional Genetics Centres in the UK. Results Two of the parents in the study had MBD5 deletions in a mosaic form. The parent with an MBD5 deletion in an apparently nonmosaic form has a psychiatric disorder in the absence of developmental delay or dysmorphism. Conclusions Inherited forms of MBD5 deletions are rare, but do occur, especially in a mosaic form. The phenotypic spectrum of MAND may be wider than previously thought. [ABSTRACT FROM AUTHOR]

The precise genetic cause remains elusive in nearly 50% of patients with presumed neurogenetic disease, representing a significant barrier for clinical care. This is despite significant advances in clinical genetic diagnostics, including the application of whole-exome sequencing and next-generation sequencing-based gene panels. In this study, we identify a deep intronic mutation in the DMD gene in a patient with muscular dystrophy using both conventional and RNAseq-based transcriptome analyses. The implications of our data are that noncoding mutations likely comprise an important source of unresolved genetic disease and that RNAseq is a powerful platform for detecting such mutations. [ABSTRACT FROM AUTHOR]

The article offers information on the 21st International Symposium of the Society for the Study of Behavioural Phenotypes to be held in Melbourne, Australia with topics mentioned including the importance of genetics and genotype within a particular syndrome, treatment uncertainties for particular health conditions such as childhood disability, and the priority outcomes and treatment areas for clinical trials in parents of children with Angelman syndrome.

The article presents the discussion on osteopetrosis encompassing a heterogeneous group of hereditary disorders caused by osteoclast dysfunction. Topics include impairing resorption and remodeling of woven bones and ultimately causing osteosclerosis; and bone marrow failure and neurological deficits secondary to stenosis of neural foramina.

ABCC9 genetic polymorphisms are associated with increased risk for various human diseases including hippocampal sclerosis of aging. The main goals of this study were 1 > to detect the ABCC9 variants and define the specific 3′ untranslated region (3′ UTR) for each variant in human brain, and 2 > to determine whether a polymorphism (rs704180) associated with risk for hippocampal sclerosis of aging pathology is also associated with variation in ABCC9 transcript expression and/or splicing. Rapid amplification of ABCC9 cDNA ends (3′ RACE) provided evidence of novel 3′ UTR portions of ABCC9 in human brain. In silico and experimental studies were performed focusing on the single nucleotide polymorphism, rs704180. Analyses from multiple databases, focusing on rs704180 only, indicated that this risk allele is a local expression quantitative trait locus ( eQTL). Analyses of RNA from human brains showed increased ABCC9 transcript levels in individuals with the risk genotype, corresponding with enrichment for a shorter 3′ UTR which may be more stable than variants with the longer 3′ UTR. Micro RNA transfection experiments yielded results compatible with the hypothesis that miR-30c causes down-regulation of SUR2 transcripts with the longer 3′ UTR. Thus we report evidence of complex ABCC9 genetic regulation in brain, which may be of direct relevance to human disease. [ABSTRACT FROM AUTHOR]

Tauopathies are clinically, morphologically and biochemically heterogeneous neurodegenerative diseases characterized by the deposition of abnormal tau protein in the brain. The neuropathological phenotypes are distinguished based on the involvement of different anatomical areas, cell types and presence of distinct isoforms of tau in the pathological deposits. The nomenclature of primary tauopathies overlaps with the modern classification of frontotemporal lobar degeneration. Neuropathological phenotypes comprise Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, formerly called also as neurofibrillary tangle-only dementia, and a recently characterized entity called globular glial tauopathy. Mutations in the gene encoding the microtubule-associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17. In addition, further neurodegenerative conditions with diverse aetiologies may be associated with tau pathologies. Thus, the spectrum of tau pathologies and tauopathy entities expands beyond the traditionally discussed disease forms. Detailed multidisciplinary studies are still required to understand their significance. [ABSTRACT FROM AUTHOR]

The article offers information on several articles appeared within the issue on topics including disease-linked dynamin-2 mutations in nervous system disorders, tolerance to the neurochemical and behavioral effects of cocaine, and regulation of the secretogranin II gene.

Microglia are the resident immune cells within the brain and retina, commonly known as the macrophages of the central nervous system (CNS). Microglia survey the surrounding milieu to eliminate invading microbes, clear cellular debris and enforce programmed cell death by removing apoptotic cells. Complementary to their 'house-keeping' role, microglia are capable of releasing brain-derived neurotrophic factor ( BDNF), as well as various anti-inflammatory cytokines that sustain and support neuronal survival., Although microglia are essential for maintaining a healthy CNS, paradoxically they may undergo phenotypic changes to influence numerous neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease. Understanding the underlying mechanisms that determine whether microglia are supportive or toxic could elucidate novel and more effective therapeutic targets to treat an array of neurological and retinal diseases., Although relatively little is known about the influences that evoke phenotypic changes in the microglial population, there is accumulating evidence illustrating an interaction with the renin-angiotensin system ( RAS). The angiotensin AT1 and AT2 receptors may have differential roles in mediating the activity of microglia. Understanding the actions of these angiotensin receptors will be important in defining whether microglia are an important therapeutic target for RAS blockade in brain and ocular diseases. [ABSTRACT FROM AUTHOR]

A major challenge in epilepsy research is to unravel the complex genetic mechanisms underlying both common and rare forms of epilepsy, as well as the genetic determinants of response to treatment. To accelerate progress in this area, the National Institute of Neurological Disorders and Stroke (NINDS) recently offered funding for the creation of a 'Center without Walls' to focus on the genetics of human epilepsy. This article describes Epi4K, the collaborative study supported through this grant mechanism and having the aim of analyzing the genomes of a minimum 4,000 subjects with highly selected and well-characterized epilepsy. [ABSTRACT FROM AUTHOR]

The article focuses on association of Multifocal motor neuropathy (MMN) with genetic variation. Topics discussed include frequencies of single nucleotide polymorphisms (SNPs) in genes such as protein tyrosine phosphatase, determination of SNPs frequencies by using direct sequencing and TaqMan SNP genotyping assay; and role of allelic variation in determining MMN susceptibility.

Recent studies have identified the leucine rich repeat protein LRRTM2 as a post-synaptic ligand of Neurexins. Neurexins also bind the post-synaptic adhesion molecules, Neuroligins. All three families of genes have been implicated in the etiologies of neurodevelopmental disorders, specifically autism spectrum disorders and schizophrenia. Does the binding promiscuity of Neurexins now suggest complex cooperativity or redundancy at the synapse? While recent studies in primary neuronal cultures and also systematic extracellular protein interaction screens suggest summative effects of these systems, we propose that studying these interactions in the developing zebrafish embryo or larvae may shed more light on their functions during synaptogenesis in vivo. These gene families have recently been extensively characterized in zebrafish, demonstrating high sequence conservation with the human genes. The simpler circuitry of the zebrafish, together with the characterization of the expression patterns down to single, identifiable neurons and the ability to knock-down or over-express multiple genes in a rapid way lend themselves to dissecting complex interaction pathways. Furthermore, the capability of performing high-throughput drug screens suggests that these small vertebrates may prove extremely useful in identifying pharmacological approaches to treating autism spectrum disorders. [ABSTRACT FROM AUTHOR]

Information on the papers discussed at a conference of the Nutritionists in Industry (NII) held at King's College London in London, England in November 2010 is presented. Topics include the Association for Nutrition (AfN) membership benefits, iron fortification and supplementation, and a panel discussion on best practices and continuing professional education. The symposium featured several nutritionists and dietitians including Richard Denyer, Jonathan Powell, and Louis Levy.

One of the fundamental goals in human genetics is to link gene function to phenotype, yet the function of the majority of the genes in the human body is still poorly understood. This is especially true for the developing human brain. The study of human phenotypes that result from inherited, mutated alleles is the most direct evidence for the requirement of a gene in human physiology. Thus, the study of Mendelian central nervous system (CNS) diseases can be an extremely powerful approach to elucidate such phenotypic/genotypic links and to increase our understanding of the key components required for development of the human brain. In this review, we highlight examples of how the study of inherited neurodevelopmental disorders contributes to our knowledge of both the 'normal' and diseased human brain, as well as elaborate on the future of this type of research. Mendelian disease research has been, and will continue to be, key to understanding the molecular mechanisms that underlie human brain function, and will ultimately form a basis for the design of intelligent, mechanism-specific treatments for nervous system disorders. [ABSTRACT FROM AUTHOR]

The article describes the case of de novo NALCN mutation in a 33-year-old Japanese woman presented with cerebellar ataxia associated with intellectual disability and arthrogryposis. Topics discussed include clinical signs of mutations in NALCN gene, findings from the neurological examination and whole-exome sequencing performed on the patient, and the four reasons that confirmed the role of de novo NALCN mutation in the patient's disease.

Abstract: Niemann-Pick type C (NP-C) disease is a fatal, autosomal recessive disorder of cholesterol metabolism that results in progressive central nervous system deterioration and premature death. Recently, a gene mutated in NP-C disease (NPC1) was identified in both human patients and in the npcnih mouse model. Although the function of the NPC1 gene is at present unknown, determining the pattern of its expression in the brain may facilitate identification of the mechanisms underlying the neuropathology of this disease and in identifying relevant targets for any potential therapeutic intervention. We have used in situ hybridization techniques to characterize the pattern of Npc1 mRNA expression in both the wild-type and the npcnih mutant mouse brain. In adult animals of both genotypes, the Npc1 mRNA was detected in the majority of neurons in nearly all regions, but at significantly higher levels in the cerebellum and in specific pontine nuclei. Analysis of Npc1 mRNA levels during development in the wild-type mouse indicated that this transcript was expressed in neurons as early as embryonic day 15 and that a significant region-specific pattern of expression was established by postnatal day 7. Our data suggest that whereas the NPC1 gene is widely expressed in neurons of the brain, the higher levels of expression in the cerebellum and pontine structures established by early postnatal ages may make these regions more susceptible to neuronal dysfunction in NP-C disease. [ABSTRACT FROM AUTHOR]

Links between the microbiome and psychiatric and neurological disease have been the focus of much attention in recent years and may add to our understanding of the complexities of these diseases in tandem with our developing knowledge of the genome's role. However, a third domain ‐ the so‐called exposome ‐ may also need consideration if we are to gain deeper insights into the complex nature of psychiatric and neurological disease. [ABSTRACT FROM AUTHOR]

The author discusses the important relationship betweem academic and clinical neurology. Topics include how academic papers in neurology provide detailed cases of children with neurological problems, the evolution of academic research due to the emergence of new genetic technologies and advancement in molecular medicine, and the academic perspective to child neurology to be discussed at the British Paediatric Neurology Association (BPNA) Annual Conference 2018.