Neuromyopathy with congenital cataracts and glaucoma: A distinct syndrome caused by POLG variants

We identified three non-related patients manifesting a childhood-onset progressive neuromyopathy with congenital cataracts, delayed walking, distal weakness and wasting, glaucoma and swallowing difficulties. Electrophysiology and nerve biopsies showed a mixed axonal and demyelinating neuropathy, while muscle biopsy disclosed both neurogenic and myopathic changes with ragged red fibers, and muscle MRI showed consistent features across patients, with a peculiar concentric disto-proximal gradient of fatty replacement. We used targeted next generation sequencing and candidate gene approach to study these families. Compound biallelic heterozygous variants, p.[(Pro648Arg)]; [(His932Tyr)] and p.[(Thr251Ile),(Pro587Leu)]; [(Arg943Cys)], were found in the three patients causing this homogeneous phenotype. Our report on a subset of unrelated patients, that showed a distinct autosomal recessive childhood-onset neuromyopathy with congenital cataracts and glaucoma, expands the clinical spectrum of POLG-related disorders. It also confirms the association between cataracts and neuropathy with variants in POLG. Early onset cataract is otherwise rare in POLG-related disorders and so far reported only in a few patients with the clinical pattern of distal myopathy or neuromyopathy

Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly

Mutations in citron (CIT), leading to loss or inactivation of the citron kinase protein (CITK), cause primary microcephaly in humans and rodents, associated with cytokinesis failure and apoptosis in neural progenitors. We show that CITK loss induces DNA damage accumulation and chromosomal instability in both mammals and Drosophila. CITK-deficient cells display "spontaneous" DNA damage, increased sensitivity to ionizing radiation, and defective recovery from radiation-induced DNA lesions. In CITK-deficient cells, DNA double-strand breaks increase independently of cytokinesis failure. Recruitment of RAD51 to DNA damage foci is compromised by CITK loss, and CITK physically interacts with RAD51, suggesting an involvement of CITK in homologous recombination. Consistent with this scenario, in doubly CitK and Trp53 mutant mice, neural progenitor cell death is dramatically reduced; moreover, clinical and neuroanatomical phenotypes are remarkably improved. Our results underscore a crucial role of CIT in the maintenance of genomic integrity during brain development

Somatic mosaicism represents an underestimated event underlying collagen 6-related disorders

Background: Collagen VI-related disorders (COL6-RD) are a group of heterogenous muscular diseases due to mutations in the COL6A1, COL6A2 and COL6A3 genes, encoding for collagen VI, a critical component of the extracellular matrix. Ullrich congenital muscle disorder and Bethlem myopathy represent the ends of a clinical spectrum that includes intermediate phenotypes of variable severity. UCMD are caused by recessive loss of function mutations or de-novo dominant-negative mutations. The intermediate phenotype and BM are more commonly caused by dominantly acting mutations, and less commonly by recessive mutations. Recently parental mosaicism for dominant mutations in COL6 have been reported in four COL6-RD families and germinal mosaicism has been also identified in a family with recurrence of UCMD in two half-sibs. Methods and results: Here we report three unrelated patients affected by a COL6-RD who carried de novo mosaic mutations in COL6A genes. These mutations, missed by Sanger sequencing, were identified by next generation sequencing. Conclusions: This report highlights the importance of a complete diagnostic workup when clinical and histological finding are consistent with a COL6-RD and strengthen the impression that mosaicisms are underestimated events underlying COL6-RD. (C) 2017 The Authors. Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.Peer reviewe

Advances in Quantitative Imaging of Genetic and Acquired Myopathies: Clinical Applications and Perspectives

In the last years, magnetic resonance imaging (MRI) has become fundamental for the diagnosis and monitoring of myopathies given its ability to show the severity and distribution of pathology, to identify specific patterns of damage distribution and to properly interpret a number of genetic variants. The advances in MR techniques and post-processing software solutions have greatly expanded the potential to assess pathological changes in muscle diseases, and more specifically of myopathies; a number of features can be studied and quantified, ranging from composition, architecture, mechanical properties, perfusion, and function, leading to what is known as quantitative MRI (qMRI). Such techniques can effectively provide a variety of information beyond what can be seen and assessed by conventional MR imaging; their development and application in clinical practice can play an important role in the diagnostic process and in assessing disease course and treatment response. In this review, we briefly discuss the current role of muscle MRI in diagnosing muscle diseases and describe in detail the potential and perspectives of the application of advanced qMRI techniques in this field

Galaxy stellar mass functions of different morphological types in clusters, and their evolution between z=0.8 and z=0

We present the galaxy stellar mass function (MF) and its evolution in clusters from z~0.8 to the current epoch, based on the WIde-field Nearby Galaxy-cluster Survey (WINGS) (0.04<z<0.07), and the ESO Distant Cluster Survey (EDisCS) (0.4<z <0.8). We investigate the total MF and find it evolves noticeably with redshift. The shape at M*>10^11 M' does not evolve, but below M*~10^10.8 M' the MF at high redshift is flat, while in the Local Universe it flattens out at lower masses. The population of M* = 10^10.2 - 10^10.8 M' galaxies must have grown significantly between z=0.8 and z=0. We analyze the MF of different morphological types (ellipticals, S0s and late-types), and find that also each of them evolves with redshift. All types have proportionally more massive galaxies at high- than at low-z, and the strongest evolution occurs among S0 galaxies. Examining the morphology-mass relation (the way the proportion of galaxies of different morphological types changes with galaxy mass), we find it strongly depends on redshift. At both redshifts, ~40% of the stellar mass is in elliptical galaxies. Another ~43% of the mass is in S0 galaxies in local clusters, while it is in spirals in distant clusters. To explain the observed trends, we discuss the importance of those mechanisms that could shape the MF. We conclude that mass growth due to star formation plays a crucial role in driving the evolution. It has to be accompanied by infall of galaxies onto clusters, and the mass distribution of infalling galaxies might be different from that of cluster galaxies. However, comparing with high-z field samples, we do not find conclusive evidence for such an environmental mass segregation. Our results suggest that star formation and infall change directly the MF of late-type galaxies in clusters and, indirectly, that of early-type galaxies through subsequent morphological transformations.Comment: MNRAS in press, 24 pages, 19 figures and 8 table

Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly

Mutations in citron (CIT), leading to loss or inactivation of the citron kinase protein (CITK), cause primary microcephaly in humans and rodents, associated with cytokinesis failure and apoptosis in neural progenitors. We show that CITK loss induces DNA damage accumulation and chromosomal instability in both mammals and Drosophila. CITK-deficient cells display “spontaneous” DNA damage, increased sensitivity to ionizing radiation, and defective recovery from radiation-induced DNA lesions. In CITK-deficient cells, DNA double-strand breaks increase independently of cytokinesis failure. Recruitment of RAD51 to DNA damage foci is compromised by CITK loss, and CITK physically interacts with RAD51, suggesting an involvement of CITK in homologous recombination. Consistent with this scenario, in doubly CitK and Trp53 mutant mice, neural progenitor cell death is dramatically reduced; moreover, clinical and neuroanatomical phenotypes are remarkably improved. Our results underscore a crucial role of CIT in the maintenance of genomic integrity during brain development

VIMOS Ultra-Deep Survey (VUDS): Witnessing the assembly of a massive cluster at z ~ 3.3

International audienceUsing new spectroscopic observations obtained as part of the VIMOS Ultra-Deep Survey (VUDS), we performed a systematic search for overdense environments in the early universe (z> 2) and report here on the discovery of Cl J0227-0421, a massive protocluster at z = 3.29. This protocluster is characterized by both the large overdensity of spectroscopically confirmed members, δgal = 10.5 ± 2.8, and a significant overdensity in photometric redshift members. The halo mass of this protocluster is estimated by a variety of methods to be ~3 × 1014ℳ⊙ at z ~ 3.3, which, evolved to z = 0 results in a halo mass rivaling or exceeding that of the Coma cluster. The properties of 19 spectroscopically confirmed member galaxies are compared with a large sample of VUDS/VVDS galaxies in lower density field environments at similar redshifts. We find tentative evidence for an excess of redder, brighter, and more massive galaxies within the confines of the protocluster relative to the field population, which suggests that we may be observing the beginning ofenvironmentally induced quenching. The properties of these galaxies are investigated, including a discussion of the brightest protocluster galaxy, which appears to be undergoing vigorous coeval nuclear and starburst activity. The remaining member galaxies appear to have characteristics that are largely similar to the field population. Though we find weaker evidence of the suppression of the median star formation rates among and differences in the stacked spectra of member galaxies with respect to the field, we defer any conclusions about these trends to future work with the ensemble of protostructures that are found in the full VUDS sample

Micellar Promoted Multi-Component Synthesis of 1,2,3-Triazoles in Water at Room Temperature

Micellar media in water provide a simple and efficient environment to favor the multi-component synthesis of 1,2,3-triazoles from organic bromides, sodium azide and terminal alkynes in the presence of [Cu(IMes)Cl] 1 catalyst at room temperature within few hours. The micellar medium favors both the in situ formation of the organic azide and its metal promoted cycloaddition with the alkyneMicellar media in water provide a simple and efficient environment favoring the multi-component synthesis of 1,2,3-triazoles from organic bromides, sodium azide and terminal alkynes in the presence of [Cu(IMes)Cl] 1 catalyst at room temperature within a few hours. The micellar medium favors both the in situ formation of the organic azide and its metal promoted cycloaddition with the alkyne

Gradiscutta di Varmo (prov. de Udine)

Bourdin Stéphane, Fontana Alessandro, Tasca Giovanni. Gradiscutta di Varmo (prov. de Udine). In: Mélanges de l'École française de Rome. Antiquité, tome 114, n°1. 2002. Antiquité. pp. 533-541