ANO3 as a Cause of Early‐Onset Chorea Combined with Dystonia: Illustration of Phenotypic Evolution

Here, we signpost a case of a childhood-onset chorea-dominant phenotype later evolved into a dystonia-dominant phenotype during adulthood, in a subject carrying a missense pathogenic variant (c.1528 G > A; p.Glu510Lys)1 in the anoctamin 3 protein-coding gene (ANO3, DYT24, OMIM 610110).

The Italian TREETALKER NETWORK (ITT-Net): continuous large scale monitoring of tree functional traits and vulnerabilities to climate change

20openItalian coauthor/editorThe Italian TREETALKER NETWORK (ITT-Net) aims to respond to one of the grand societal challenges: the impact of climate changes on forests ecosystem services and forest dieback. The comprehension of the link between these phenomena requires to complement the most classical approaches with a new monitoring paradigm based on large scale, single tree, high frequency and long-term monitoring tree physiology, which, at present, is limited by the still elevated costs of multi-sensor devices, their energy demand and maintenance not always suitable for monitoring in remote areas. The ITT-Net network will be a unique and unprecedented worldwide example of real time, large scale, high frequency and long-term monitoring of tree physiological parameters. By spring 2020, as part of a national funded project (PRIN) the network will have set 37 sites from the north-east Alps to Sicily where a new low cost, multisensor technology “the TreeTalker®” equipped to measure tree radial growth, sap flow, transmitted light spectral components related to foliage dieback and physiology and plant stability (developed by Nature 4.0), will monitor over 600 individual trees. A radio LoRa protocol for data transmission and access to cloud services will allow to transmit in real time high frequency data on the WEB cloud with a unique IoT identifier to a common database where big data analysis will be performed to explore the causal dependency of climate events and environmental disturbances with tree functionality and resilience. With this new network, we aim to create a new knowledge, introducing a massive data observation and analysis, about the frequency, intensity and dynamical patterns of climate anomalies perturbation on plant physiological response dynamics in order to: 1) characterize the space of “normal or safe tree operation mode” during average climatic conditions; 2) identify the non-linear tree responses beyond the safe operation mode, induced by extreme events, and the tipping points; 3) test the possibility to use a high frequency continuous monitoring system to identify early warning signals of tree stress which might allow to follow tree dynamics under climate change in real time at a resolution and accuracy that cannot always be provided through forest inventories or remote sensing technologies.openCastaldi, S.; Antonucci, S.; Asgharina, S.; Battipaglia, G.; Belelli Marchesini, L.; Cavagna, M.; Chini, I.; Cocozza, C.; Gianelle, D.; La Mantia, T.; Motisi, A.; Niccoli, F.; Pacheco Solana, A.; Sala, G.; Santopuoli, G.; Tonon, G.; Tognetti, R.; Zampedri, R.; Zorzi, I.; Valentini, R.Castaldi, S.; Antonucci, S.; Asgharina, S.; Battipaglia, G.; Belelli Marchesini, L.; Cavagna, M.; Chini, I.; Cocozza, C.; Gianelle, D.; La Mantia, T.; Motisi, A.; Niccoli, F.; Pacheco Solana, A.; Sala, G.; Santopuoli, G.; Tonon, G.; Tognetti, R.; Zampedri, R.; Zorzi, I.; Valentini, R

Characteristics of people living in Italy after a cancer diagnosis in 2010 and projections to 2020

BACKGROUND: Estimates of cancer prevalence are widely based on limited duration, often including patients living after a cancer diagnosis made in the previous 5 years and less frequently on complete prevalence (i.e., including all patients regardless of the time elapsed since diagnosis). This study aims to provide estimates of complete cancer prevalence in Italy by sex, age, and time since diagnosis for all cancers combined, and for selected cancer types. Projections were made up to 2020, overall and by time since diagnosis. METHODS: Data were from 27 Italian population-based cancer registries, covering 32% of the Italian population, able to provide at least 7 years of registration as of December 2009 and follow-up of vital status as of December 2013. The data were used to compute the limited-duration prevalence, in order to estimate the complete prevalence by means of the COMPREV software. RESULTS: In 2010, 2,637,975 persons were estimated to live in Italy after a cancer diagnosis, 1.2 million men and 1.4 million women, or 4.6% of the Italian population. A quarter of male prevalent cases had prostate cancer (n\u2009=\u2009305,044), while 42% of prevalent women had breast cancer (n\u2009=\u2009604,841). More than 1.5 million people (2.7% of Italians) were alive since 5 or more years after diagnosis and 20% since 6515 years. It is projected that, in 2020 in Italy, there will be 3.6 million prevalent cancer cases (+\u200937% vs 2010). The largest 10-year increases are foreseen for prostate (+\u200985%) and for thyroid cancers (+\u200979%), and for long-term survivors diagnosed since 20 or more years (+\u200945%). Among the population aged 6575 years, 22% will have had a previous cancer diagnosis. CONCLUSIONS: The number of persons living after a cancer diagnosis is estimated to rise of approximately 3% per year in Italy. The availability of detailed estimates and projections of the complete prevalence are intended to help the implementation of guidelines aimed to enhance the long-term follow-up of cancer survivors and to contribute their rehabilitation need

The CACNA1B R1389H variant is not associated with myoclonus-dystonia in a large European multicentric cohort.

Myoclonus-dystonia (M-D) is a very rare movement disorder, caused in ∼30-50% of cases by mutations in SGCE. The CACNA1B variant c.4166G>A; (p.R1389H) was recently reported as the likely causative mutation in a single 3-generation Dutch pedigree with five subjects affected by a unique dominant M-D syndrome and cardiac arrhythmias. In an attempt to replicate this finding, we assessed by direct sequencing the frequency of CACNA1B c.4166G>A; (p.R1389H) in a cohort of 520 M-D cases, in which SGCE mutations had been previously excluded. A total of 146 cases (28%) had a positive family history of M-D. The frequency of the variant was also assessed in 489 neurologically healthy controls and in publicly available data sets of genetic variation (1000 Genomes, Exome Variant Server and Exome Aggregation Consortium). The variant was detected in a single sporadic case with M-D, but in none of the 146 probands with familial M-D. Overall, the variant was present at comparable frequencies in M-D cases (1 out of 520; 0.19%) and healthy controls (1 out of 489; 0.2%). A similar frequency of the variant was also reported in all publicly available databases. These results do not support a causal association between the CACNA1B c.4166G>A; (p.R1389H) variant and M-D

Digital Breast Tomosynthesis with Synthesized Two-Dimensional Images versus Full-Field Digital Mammography for Population Screening: Outcomes from the Verona Screening Program.

The purpose of this study was to examine the outcomes of a breast cancer screening program based on digital breast tomosynthesis (DBT) plus synthesized two-dimensional (2D) mammography compared with those after full-field digital mammography (FFDM). This prospective study included 16 666 asymptomatic women aged 50–69 years who were recruited in April 2015 through March 2016 for DBT plus synthetic 2D screening in the Verona screening program. A comparison cohort of women screened with FFDM (n = 14 423) in the previous year was included. Screening detection measures for the two groups were compared by calculating the proportions associated with each outcome, and the relative rates (RRs) were estimated with multivariate logistic regression

Variants in ATP5F1B are associated with dominantly inherited dystonia

Nasca et al. identify a new candidate gene for dystonia, ATP5F1B, encoding a subunit of the mitochondrial ATP synthase (complex V). Likely pathogenic variants in ATP5F1B were associated with early-onset isolated dystonia in two independent families, both with an autosomal dominant mode of inheritance and incomplete penetrance. ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C;p.Thr334Pro and c.1445T>C;p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism

Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile

Background: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28). Since 2016, more than one hundred rare KMT2B variants have been reported, including frameshift, nonsense, splice site, missense and other in-frame changes, many having an uncertain clinical impact. Results: We characterize the genome-wide peripheral blood DNA methylation profiles of a cohort of 18 patients with pathogenic and unclassified KMT2B variants. We resolve the “episignature” associated with KMT2B haploinsufficiency, proving that this approach is robust in diagnosing clinically unsolved cases, properly classifying them with respect to other partially overlapping dystonic phenotypes, other rare neurodevelopmental disorders and healthy controls. Notably, defective KMT2B function in DYT28 causes a non-random DNA hypermethylation across the genome, selectively involving promoters and other regulatory regions positively controlling gene expression. Conclusions: We demonstrate a distinctive DNA hypermethylation pattern associated with DYT28, provide an epigenetic signature for this disorder enabling accurate diagnosis and reclassification of ambiguous genetic findings and suggest potential therapeutic approaches

Clinical rating scale for pantothenate kinase-associated neurodegeneration: A pilot study

Pantothenate kinase-associated neurodegeneration is a progressive neurological disorder occurring in both childhood and adulthood. The objective of this study was to design and pilot-test a disease-specific clinical rating scale for the assessment of patients with pantothenate kinase-associated neurodegeneration.info:eu-repo/semantics/publishedVersio

De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy, and movement disorder. We evaluated a large cohort of patients (n=25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor, and ataxia. Later in the disease course they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration, and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibers and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders