Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis

© Author(s) (or their employer(s)) 2022. Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0Hereditary transthyretin amyloidosis (ATTRv) is a severe, adult-onset autosomal dominant inherited systemic disease predominantly affecting the peripheral and autonomic nervous system, heart, kidney and the eyes. ATTRv is caused by mutations of the transthyretin (TTR) gene, leading to extracellular deposition of amyloid fibrils in multiple organs including the peripheral nervous system. Typically, the neuropathy associated with ATTRv is characterised by a rapidly progressive and disabling sensorimotor axonal neuropathy with early small-fibre involvement. Carpal tunnel syndrome and cardiac dysfunction frequently coexist as part of the ATTRv phenotype. Although awareness of ATTRv polyneuropathy among neurologists has increased, the rate of misdiagnosis remains high, resulting in significant diagnostic delays and accrued disability. A timely and definitive diagnosis is important, given the emergence of effective therapies which have revolutionised the management of transthyretin amyloidosis. TTR protein stabilisers diflunisal and tafamidis can delay the progression of the disease, if treated early in the course. Additionally, TTR gene silencing medications, patisiran and inotersen, have resulted in up to 80% reduction in TTR production, leading to stabilisation or slight improvement of peripheral neuropathy and cardiac dysfunction, as well as improvement in quality of life and functional outcomes. The considerable therapeutic advances have raised additional challenges, including optimisation of diagnostic techniques and management approaches in ATTRv neuropathy. This review highlights the key advances in the diagnostic techniques, current and emerging management strategies, and biomarker development for disease progression in ATTRv.SV gratefully acknowledges funding support from the National Health and Medical Research Council (NHMRC) of Australia (project grant numbers 510233, 1024915 and 1055778; program grant number 1132524; dementia research team grant number 1095127; and Partnership Project number 1153439) and the Motor Neuron Disease Research Institute of Australia. MCK was supported by a NHMRC Practitioner Fellowship (number 1156093).info:eu-repo/semantics/publishedVersio

A Gradualist Approach to Criminality: Early British Socialists, Utopia and Crime

The attitudes of early British socialists to criminality are a thoroughly under-researched area of historical scholarship. This paper draws on the utopian ideas of Robert Owen, William Morris, H. G. Wells, Robert Blatchford, Edward Carpenter and Ramsay MacDonald as a vehicle for investigating the attitudes of mainstream fin de siècle British socialists to crime, punishment and penal reform. Placing these figures and their utopias along a spectrum that sees radical ‘Arcadian’ socialists on the far left, ‘technological’ socialists on the far right, and moderate socialists occupying the middle ground, it presents two principal findings. First it demonstrates how crime was predicted by most of the left to decrease to a minimum level under socialism. ‘Arcadians’, ‘technological’ and moderate socialists invoked different methods in this pursuit, but each were in essence grappling with the same broader issue of the relationship of the individual to the state under socialism. Secondly, examining the multifaceted ideological heritage of the British left in relation to their approaches to crime, it is argued that, despite the left’s gradualist philosophy, their own attitudes to criminality actually closely reflected utopian conceptions. Examination of these issues offers an important opportunity to re-evaluate the evolution of British socialist thought

A DYNC1H1 mutation in autosomal dominant spinal muscular atrophy shows the potential of pharmacological inhibition of histone deacetylase 6 as a treatment for disease associated cellular phenotypes

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Способы перевода аббревиатур и сокращений в области компьютерных технологий (на примере русского и немецкого языков)

Выпускная квалификационная работа 75 с., 2 главы, 42 источника. Предмет исследования: способы перевода аббревиатур и сокращений в области компьютерных технологий с немецкого языка на русский язык. Объектом исследования: аббревиатуры и сокращения, относящиеся к области компьютерных технологий. Цель работы: выявить эффективные способы перевода аббревиатур и сокращений в области компьютерных технологий с немецкого языка на русский. Результаты исследования: были сформулированы особенности перевода аббревиатур и сокращений в области компьютерных технологий Степень внедрения/апробация работы: Было опубликовано две статьи Область применения: лингвистика, языкознание, переводоведение.Graduation thesis: 75 pg., 2 chapters, 42 resources. Subject of research: translation methods of acronyms and reductions in the field of computer technology from German into Russian. Object of research: Acronyms and reductions in the field of computer technology. Purpose of research: : to identify the translation methods of acronyms and reductions in the field of computer technology from German into Russian. Results of research: The features of the translation of acronyms and reductions in the area of computer technology has been revealed. Degree of implementation /work approbation: two articles were published. Field of application: Linguistic, theory of translatio

Rapid detection of carriers with BRCA1 and BRCA2 mutations using high resolution melting analysis

<p>Abstract</p> <p>Background</p> <p>Germline inactivating mutations in <it>BRCA1 </it>and <it>BRCA2 </it>underlie a major proportion of the inherited predisposition to breast and ovarian cancer. These mutations are usually detected by DNA sequencing. Cost-effective and rapid methods to screen for these mutations would enable the extension of mutation testing to a broader population. High resolution melting (HRM) analysis is a rapid screening methodology with very low false negative rates. We therefore evaluated the use of HRM as a mutation scanning tool using, as a proof of principle, the three recurrent BRCA1 and BRCA2 founder mutations in the Ashkenazi Jewish population in addition to other mutations that occur in the same regions.</p> <p>Methods</p> <p>We designed PCR amplicons for HRM scanning of <it>BRCA1 </it>exons 2 and 20 (carrying the founder mutations185delAG and 5382insC respectively) and the part of the <it>BRCA2 </it>exon 11 carrying the 6174delT founder mutation. The analysis was performed on an HRM-enabled real time PCR machine.</p> <p>Results</p> <p>We tested DNA from the peripheral blood of 29 individuals heterozygous for known mutations. All the Ashkenazi founder mutations were readily identified. Other mutations in each region that were also readily detected included the recently identified Greek founder mutation 5331G>A in exon 20 of <it>BRCA1</it>. Each mutation had a reproducible melting profile.</p> <p>Conclusion</p> <p>HRM is a simple and rapid scanning method for known and unknown <it>BRCA1 </it>and <it>BRCA2 </it>germline mutations that can dramatically reduce the amount of sequencing required and reduce the turnaround time for mutation screening and testing. In some cases, such as tracking mutations through pedigrees, sequencing may only be necessary to confirm positive results. This methodology will allow for the economical screening of founder mutations not only in people of Ashkenazi Jewish ancestry but also in other populations with founder mutations such as Central and Eastern Europeans (<it>BRCA1 </it>5382insC) and Greek Europeans (<it>BRCA1 </it>5331G>A).</p

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing

More than 50 neurological and neuromuscular diseases are caused by short tandem repeat (STR) expansions, with 37 different genes implicated to date. We describe the use of programmable targeted long-read sequencing with Oxford Nanopore's ReadUntil function for parallel genotyping of all known neuropathogenic STRs in a single assay. Our approach enables accurate, haplotype-resolved assembly and DNA methylation profiling of STR sites, from a list of predetermined candidates. This correctly diagnoses all individuals in a small cohort (n = 37) including patients with various neurogenetic diseases (n = 25). Targeted long-read sequencing solves large and complex STR expansions that confound established molecular tests and short-read sequencing and identifies noncanonical STR motif conformations and internal sequence interruptions. We observe a diversity of STR alleles of known and unknown pathogenicity, suggesting that long-read sequencing will redefine the genetic landscape of repeat disorders. Last, we show how the inclusion of pharmacogenomic genes as secondary ReadUntil targets can further inform patient care

Missense mutations in the copper transporter gene ATP7A cause X-Linked distal hereditary motor neuropathy

Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporter's known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor-neuron maintenance and function

A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes

Detection of mutations by DNA sequencing can be facilitated by scanning methods to identify amplicons which may have mutations. Current scanning methods used for the detection of germline sequence variants are laborious as they require post-PCR manipulation. High resolution melting (HRM) is a cost-effective rapid screening strategy, which readily detects heterozygous variants by melting curve analysis of PCR products. It is well suited to screening genes such as BRCA1 and BRCA2 as germline pathogenic mutations in these genes are always heterozygous. Assays for the analysis of all coding regions and intron-exon boundaries of BRCA1 and BRCA2 were designed, and optimised. A final set of 94 assays which ran under identical amplification conditions were chosen for BRCA1 (36) and BRCA2 (58). Significant attention was placed on primer design to enable reproducible detection of mutations within the amplicon while minimising unnecessary detection of polymorphisms. Deoxyinosine residues were incorporated into primers that overlay intronic polymorphisms. Multiple 384 well plates were used to facilitate high throughput. 169 BRCA1 and 239 BRCA2 known sequence variants were used to test the amplicons. We also performed an extensive blinded validation of the protocol with 384 separate patient DNAs. All heterozygous variants were detected with the optimised assays. This is the first HRM approach to screen the entire coding region of the BRCA1 and BRCA2 genes using one set of reaction conditions in a multi plate 384 well format using specifically designed primers. The parallel screening of a relatively large number of samples enables better detection of sequence variants. HRM has the advantages of decreasing the necessary sequencing by more than 90%. This markedly reduced cost of sequencing will result in BRCA1 and BRCA2 mutation testing becoming accessible to individuals who currently do not undergo mutation testing because of the significant costs involved