The p.R1109X mutation in SH3TC2 gene is predominant in Spanish Gypsies with Charcot-Marie-Tooth disease type 4

[EN] Charcot-Marie-Tooth (CMT) disease type 4 (CMT4) is the name given to autosomal recessive forms of hereditary motor and sensory neuropathy (HMSN). When we began this study, three genes or loci associated with inherited peripheral neuropathies had already been identified in the European Gypsy population: HMSN-Lom (MIM 601455), HMSN-Russe (MIM 605285) and the congenital cataracts facial dysmorphism neuropathy syndrome (MIM 604168). We have carried out genetic analyses in a series of 20 Spanish Gypsy families diagnosed with a demyelinating CMT disease compatible with an autosomal recessive trait. We found the p.R148X mutation in the N-myc downstream-regulated gene 1 gene to be responsible for the HMSN-Lom in four families and also possible linkage to the HMSN-Russe locus in three others. We have also studied the CMT4C locus because of the clinical similarities and showed that in 10 families, the disease is caused by mutations located on the SH3 domain and tetratricopeptide repeats 2 (SH3TC2) gene: p.R1109X in 20 out of 21 chromosomes and p.C737_P738delinsX in only one chromosome. Moreover, the SH3TC2 p.R1109X mutation is associated with a conserved haplotype and, therefore, may be a private founder mutation for the Gypsy population. Estimation of the allelic age revealed that the SH3TC2 p.R1109X mutation may have arisen about 225 years ago, probably as the consequence of a bottleneck.We are grateful for the kind collaboration of patients and families. This work was supported by the Fondo de Investigacio¿n Sanitaria (grant PI040932) and the Spanish Network on Cerebellar Ataxias of the Instituto de Salud Carlos III (grant G03/56). English text was revised by F Barraclough.Claramunt, R.; Sevilla, T.; Lupo, V.; Cuesta, A.; Millán, J.; Vilchez, JJ.; Palau, F.... (2007). The p.R1109X mutation in SH3TC2 gene is predominant in Spanish Gypsies with Charcot-Marie-Tooth disease type 4. Clinical Genetics. 71(4):343-349. https://doi.org/10.1111/j.1399-0004.2007.00774.x34334971

Vocal cord paresis and diaphragmatic dysfunction are severe and frequent symptoms of GDAP1-associated neuropathy

[EN] Cranial nerve involvement in Charcot-Marie-Tooth disease (CMT) is rare, though there are a number of CMT syndromes in which vocal cord paralysis is a characteristic feature. CMT disease due to mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) has been reported to be associated with vocal cord and diaphragmatic palsy. In order to address the prevalence of these complications in patients with GDAP1 mutations we evaluated vocal cord and respiratory function in nine patients from eight unrelated families with this disorder. Hoarseness of the voice and inability to speak loudly were reported by eight patients and one had associated symptoms of respiratory insufficiency. Patients were investigated by means of peripheral and phrenic nerve conduction studies, flexible laryngoscopy, pulmonary function studies and polysomnography. Nerve conduction velocities and pathological studies were compatible with axonal CMT (CMT2). Flexible laryngoscopy showed left vocal cord palsy in four cases, bilateral cord palsies in four cases and was normal in one case. Restrictive respiratory dysfunction was seen in the eight patients with vocal cord paresis who were all chair-bound. These eight had confirmed phrenic nerve dysfunction on neurophysiology evaluation. The patient with normal vocal cord and pulmonary function had a less severe clinical course.This study shows that CMT patients with GDAP1 mutations develop severe disability due to weakness of limb muscles and that laryngeal and respiratory muscle involvement occurs late in the disease process when significant proximal upper limb weakness has developed. The early and predominant involvement of the left vocal cord innervated by the longer left recurrent laryngeal nerve suggests a length dependent pattern of nerve degeneration. In GDAP1 neuropathy, respiratory function should be thoroughly investigated because life expectancy can be compromised due to respiratory failure.Fondo de Investigacion Sanitaria (PI/05/1572); CIBERNED; CIBERER; Instituto de Salud Carlos III.Sevilla, T.; Jaijo, T.; Nauffal, D.; Collado, D.; Chumillas, MJ.; Vilchez, JJ.; Muelas, N.... (2008). Vocal cord paresis and diaphragmatic dysfunction are severe and frequent symptoms of GDAP1-associated neuropathy. Brain. 131:3051-3061. https://doi.org/10.1093/brain/awn2283051306113

Critical Role of Oxygen in Silver-Catalyzed Glaser-Hay Coupling on Ag(100) under Vacuum and in Solution on Ag Particles

The essential role of oxygen in enabling heterogeneously catalyzed Glaser-Hay coupling of phenylacetylene on Ag(100) was elucidated by STM, laboratory and synchrotron photoemission, and DFT calculations. In the absence of coadsorbed oxygen, phenylacetylene formed well-ordered dense overlayers which, with increasing temperature, desorbed without reaction. In striking contrast, even at 120 K, the presence of oxygen led to immediate and complete disruption of the organic layer due to abstraction of acetylenic hydrogen with formation of a disordered mixed layer containing immobile adsorbed phenylacetylide. At higher temperatures phenylacetylide underwent Glaser-Hay coupling to form highly ordered domains of diphenyldiacetylene that eventually desorbed without decomposition, leaving the bare metal surface. DFT calculations showed that, while acetylenic H abstraction was otherwise an endothermic process, oxygen adatoms triggered a reaction-initiating exothermic pathway leading to OH(a) + phenylacetylide, consistent with the experimental observations. Moreover, it was found that, with a solution of phenylacetylene in nonane and in the presence of O, Ag particles catalyzed Glaser-Hay coupling with high selectivity. Rigorous exclusion of oxygen from the reactor strongly suppressed the catalytic reaction. Interestingly, too much oxygen lowers the selectivity toward diphenyldiacetylene. Thus, vacuum studies and theoretical calculations revealed the key role of oxygen in the reaction mechanism, subsequently borne out by catalytic studies with Ag particles that confirmed the presence of oxygen as a necessary and sufficient condition for the coupling reaction to occur. The direct relevance of model studies to a mechanistic understanding of coupling reactions under conditions of practical catalysis was reaffirmed.Support from the European Union FEDER Program and MINECO under projects MAT2013-40852-R and 201560E055 is acknowledged. Computational resources were provided by the Spanish Ministerio de Economía y Competitividad, grant CTQ2015-64669-P, and the EU FEDER Program

Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease

[EN] Mutations in the ganglioside-induced-differentiation-associated protein 1 gene (GDAP1) can cause Charcot-Marie-Tooth (CMT) disease with demyelinating (CMT4A) or axonal forms (CMT2K and ARCMT2K). Most of these mutations present a recessive inheritance, but few autosomal dominant GDAP1 mutations have also been reported. We performed a GDAP1 gene screening in a clinically well-characterized series of 81 index cases with axonal CMT neuropathy, identifying 17 patients belonging to 4 unrelated families in whom the heterozygous p.R120W was found to be the only disease-causing mutation. The main objective was to fully characterize the neuropathy caused by this mutation. The clinical picture included a mild-moderate phenotype with onset around adolescence, but great variability. Consistently, ankle dorsiflexion and plantar flexion were impaired to a similar degree. Nerve conduction studies revealed an axonal neuropathy. Muscle magnetic resonance imaging studies demonstrated selective involvement of intrinsic foot muscles in all patients and a uniform pattern of fatty infiltration in the calf, with distal and superficial posterior predominance. Pathological abnormalities included depletion of myelinated fibers, regenerative clusters and features of axonal degeneration with mitochondrial aggregates. Our findings highlight the relevance of dominantly transmitted p.R120W GDAP1 gene mutations which can cause an axonal CMT with a wide clinical profile.We are grateful to the propositi and their relatives for their kind collaboration. We also want to thank I. Llopis and M. Escutia for their help with sample management. This work was supported by the Instituto de Salud Carlos III [PI08/90857, PI08/0889, CP08/00053 and PS09/00095], the Fundacion para la Investigacion del Hospital Universitari La Fe [CM06/00154], the Spanish Ministry Science and Innovation [grant number SAF2006-01047], and the Generalitat Valenciana [grant no. Prometeo/2009/05]. Dr. C. Espinos has a "Miguel Servet'' contract funded by the Fondo de Investigacion Sanitaria. Both Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER) and Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED) are initiatives from the Instituto de Salud Carlos III.Sivera, R.; Espinós-Armero, CÁ.; Vílchez, JJ.; Mas, F.; Martínez-Rubio, D.; Chumillas, MJ.; Mayordomo, F.... (2010). Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease. Journal of the Peripheral Nervous System. 15(4):334-344. https://doi.org/10.1111/j.1529-8027.2010.00286.x33434415

Enhanced stability of perovskite solar cells incorporating dopant-free Crystalline spiro-OMeTAD layers by vacuum sublimation

The main handicap still hindering the eventual exploitation of organometal halide perovskite-based solar cells is their poor stability under prolonged illumination, ambient conditions, and increased temperatures. This article shows for the first time the vacuum processing of the most widely used solid-state hole conductor (SSHC), i.e., the Spiro-OMeTAD [2,2′,7,7′-tetrakis (N,N-di-p-methoxyphenyl-amine) 9,9′-spirobifluorene], and how its dopant-free crystalline formation unprecedently improves perovskite solar cell (PSC) stability under continuous illumination by about two orders of magnitude with respect to the solution-processed reference and after annealing in air up to 200 °C. It is demonstrated that the control over the temperature of the samples during the vacuum deposition enhances the crystallinity of the SSHC, obtaining a preferential orientation along the π–π stacking direction. These results may represent a milestone toward the full vacuum processing of hybrid organic halide PSCs as well as light-emitting diodes, with promising impacts on the development of durable devices. The microstructure, purity, and crystallinity of the vacuum sublimated Spiro-OMeTAD layers are fully elucidated by applying an unparalleled set of complementary characterization techniques, including scanning electron microscopy, X-ray diffraction, grazing-incidence small-angle X-ray scattering and grazing-incidence wide-angle X-ray scattering, X-ray photoelectron spectroscopy, and Rutherford backscattering spectroscopy.The authors thank the “Agencia Estatal de Investigación”, “Consejería de Economía y Conocimiento de la Junta de Andalucía” (US‐1263142), “Ministerio de Economía y Competitividad” (MAT2016‐79866‐R, MAT2013‐42900‐P, FPA2016‐77689‐C2‐1‐R, and MAT2016‐76892‐C3‐2‐R) and the European Union (EU) through cohesion fund and FEDER 2014‐2020 programs for financial support. J.R.S.‐V. and A.B. acknowledge the EU project PlasmaPerovSol and funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement ID 661480. J.R.S.‐V‐ and M.C.L.‐S. thank the University of Seville through the VI “Plan Propio de Investigación y Transferencia de la US” (VI PPIT‐US). This research has received funding from the EU‐H2020 research and innovation programme under Grant Agreement No. 654360 having benefitted from the access provided by Technische Universität Graz at Elettra—TUG in Trieste (IT) within the framework on the NFFA (Nanoscience Foundries & Fine Analysis) Europe Transnational Access Activity. F.J.A. and J.R.S.‐V. acknowledge the “Juan de la Cierva” and “Ramon y Cajal” national programs, respectively

Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease

[EN] Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p. R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p. R190W mutation and another patient that harboured a MORC2 p. S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.This collaborative joint project is awarded by IRDiRC and funded by the Instituto de Salud Carlos III (ISCIII) - Subdireccion General de Evaluacion y Fomento de la Investigacion within the framework of the National R+D+I Plan (IR11/TREAT-CMT to T.S., S.I.P.P., F.P. and C.E.; PI12/00453 to C.E.; and PI12/0946 to T.S.), co-funded with FEDER funds. Additional support was provided by the Ramon Areces Foundation and by the ISCIII and the Centro de Investigacion Principe Felipe (CPII14/00002) to C.E.Sevilla, T.; Lupo, V.; Martínez-Rubio, D.; Sancho, P.; Sivera, R.; Chumillas, MJ.; García-Romero, M.... (2016). Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease. Brain. 139:62-72. https://doi.org/10.1093/brain/awv311627213

Characterizing the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations

[EN] Background Mutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME. Methods We screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members. Results We found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease. Conclusion MME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling.The authors thank the patients and healthy relatives for having participated in this project. We are grateful to the Eurobiobank CIBERER and the Biobank La Fe for their participation in the collection and processing of patient samples. We also thank the technicians at the Department of Genomics and Translational Genetics (CIPF) who participated in the quality control and processing of DNA samples (Virginia Rejas and Laura Ramírez), and the Bachelor¿s thesis student Andrea Ballester who helped with some clinical data collection. This project was funded by the Instituto de Salud Carlos III (ISCIII), FEDER (Grants no. PI12/00946 and PI16/00403 to TS, PI15/00187 to CE). MF holds a grant funded by the IIS La Fe (Grant no. 2015/0085). AS-M holds a grant funded by the Fundació Per Amor a l'Art (FPAA). JFV-C holds a ' Rio Hortega' contract funded by the ISCIII.Lupo, V.; Frasquet, M.; Sánchez-Monteagudo, A.; Pelayo-Negro, A.; García-Sobrino, T.; Sedano, MJ.; Pardo, J.... (2018). Characterizing the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations. Journal of Medical Genetics. 55(12):814-823. https://doi.org/10.1136/jmedgenet-2018-105650814823551

Deep learning for MRI-based CT synthesis: a comparison of MRI sequences and neural network architectures

[Otros] Synthetic computed tomography (CT) images derived from magnetic resonance images (MRI) are of interest for radiotherapy planning and positron emission tomography (PET) attenuation correction. In recent years, deep learning implementations have demonstrated improvement over atlasbased and segmentation-based methods. Nevertheless, several open questions remain to be addressed, such as which is the best of MRI sequences and neural network architectures. In this work, we compared the performance of different combinations of two common MRI sequences (T1- and T2-weighted), and three state-of-the-art neural networks designed for medical image processing (Vnet, HighRes3dNet and ScaleNet). The experiments were conducted on brain datasets from a public database. Our results suggest that T1 images perform better than T2, but the results further improve when combining both sequences. The lowest mean average error over the entire head (MAE = 101.76 ± 10.4 HU) was achieved combining T1 and T2 scans with HighRes3dNet. All tested deep learning models achieved significantly lower MAE (p < 0.01) than a well-known atlas-based method.This work was supported by the Spanish Government grants TEC2016-79884-C2 and RTC-2016-5186-1, and by the European Union through the European Regional Development Fund (ERDF)Larroza, A.; Moliner, L.; Álvarez-Gómez, JM.; Oliver-Gil, S.; Espinós-Morató, H.; Vergara-Díaz, M.; Rodríguez-Álvarez, MJ. (2019). Deep learning for MRI-based CT synthesis: a comparison of MRI sequences and neural network architectures. IEEE. 1-4. https://doi.org/10.1109/NSS/MIC42101.2019.9060051S1

Dietary and/or physical activity interventions in women with overweight or obesity prior to fertility treatment : protocol for a systematic review and individual participant data meta-analysis

Funding Information: This project is partly supported by the Centre for Research Excellence in Women's Health in Reproductive Life (app1171592) through a project support grant. RW is supported by a National Health and Medical Research Council (NHRMC) Investigator grant (2009767). LM is supported by a Heart Foundation Future Leader Fellowship. Funding Information: AH reports consultancy for Ferring with respect to the development of a lifestyle app. BWM is supported by an NHMRC Investigator grant (GNT1176437). BWM reports personal fees from ObsEva and Merck, and travel support from Merck, outside the submitted work. RW reports grants from the NHMRC. TM is supported by a Future Leader in Diabetes Award from the European Foundation for the Study of Diabetes/Novo Nordisk Foundation (NNF19SA058975) and grants from the regional health authority in Central Norway. ATK reports personal fees from Merck for lectures. The other authors do not have competing interest to declare. Funding Information: This project is partly supported by the Centre for Research Excellence in Women’s Health in Reproductive Life (app1171592) through a project support grant. RW is supported by a National Health and Medical Research Council (NHRMC) Investigator grant (2009767). LM is supported by a Heart Foundation Future Leader Fellowship. Publisher Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Peer reviewedPublisher PD