Secuestro pulmonar una infrecuente causa de hipertension pulmonar persistente en el recién nacido reporte de un caso

La Hipertensión pulmonar persistente del recién nacido (HPPRN) es una entidad frecuente en las unidades de cuidados intensivos neonatales (UCIN), sin embargo algunas de sus causas, pasan desapercibidas, debido a su baja frecuencia y poca asociación con esta patología. A propósito de un caso en nuestra UCIN, en un neonato a término que presentó HPPRN secundario a una malformación pulmonar, raramente asociada con esta patología en este grupo etareo, ya que se encontró mayor disposición a factores propios del nacimiento, y noxas maternas. El paciente presentó dificultad respiratoria horas después de su nacimiento, con evolución y persistencia de su sintomatología, por lo que se necesitó de diversos medios diagnósticos para establecer su etiología. Es importante destacar, que el primer Ecocardiograma doppler no mostró ninguna alteración anatómica o funcional, reportado normal; con posterior empeoramiento clínico del neonato, por lo que se ordena un control ecocardiográfico, evidenciándose una presión pulmonar estimada de 71 mmHg; continuándose el estudio etiológico con imágenes complementarias, en esta caso, una tomografía de tórax contrastada y finalmente fue corroborado con un cateterismo cardiaco, permitiendo a su vez, manejo terapéutico y corrección de anomalía estructural de vasos pulmonares

NR4A2 Mutations Can Cause Intellectual Disability and Language Impairment With Persistent Dystonia-Parkinsonism

TheNR4A2/NURR1gene (MIM*601828) has recently been associated with autosomal-dominantearly-onset dystonia-parkinsonism with intellectual disability.1NR4A2codifies for a nuclear tran-scription factor and is expressed mainly in the substantia nigra, ventral tegmental area, and limbicareas.2To date, 14 different alterations inNR4A2have been described associated with variousclinical phenotypes, mainly with neurodevelopment disorders (table e-1, links.lww.com/NXG/A371). We describe here an interesting case suffering a persistent dystonia-parkinsonism syndrome(DPS) with motor tics, which expands the clinical phenotype ofNR4A2-associated DPS

Characterization of molecular mechanisms underlying the axonal Charcot-Marie-Tooth neuropathy caused by MORC2 mutations

[EN] Mutations in MORC2 lead to an axonal form of Charcot-Marie-Tooth (CMT) neuropathy type 2Z. To date, 31 families have been described with mutations in MORC2, indicating that this gene is frequently involved in axonal CMT cases. While the genetic data clearly establish the causative role of MORC2 in CMT2Z, the impact of its mutations on neuronal biology and their phenotypic consequences in patients remains to be clarified. We show that the full-length form of MORC2 is highly expressed in both embryonic and adult human neural tissues and that Morc2 expression is dynamically regulated in both the developing and the maturing murine nervous system. To determine the effect of the most common MORC2 mutations, p.S87L and p.R252W, we used several in vitro cell culture paradigms. Both mutations induced transcriptional changes in patient-derived fibroblasts and when expressed in rodent sensory neurons. These changes were more pronounced and accompanied by abnormal axonal morphology, in neurons expressing the MORC2 p.S87L mutation, which is associated with a more severe clinical phenotype. These data provide insight into the neuronal specificity of the mutated MORC2-mediated phenotype and highlight the importance of neuronal cell models to study the pathophysiology of CMT2Z.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 (PI15/00187 to C. E. and PI16/00403 to T. S.), co-funded with FEDER funds; Ramon Areces Foundation (CIVP17A2810 to C. E.); Generalitat Valenciana (PROMETEO/2018/135 to C. E. and T. S.); AFM-Telethon (21500 to C. E. and R. C.); National Health and Medical Research Council of Australia Grant (APP1046680 to M. K.); Czech Health Research Council (AZV16-30206A to P. L.); Swedish StratNeuro program grant; Swedish Research Council (2015-02394 to R. C.). C. E. had a 'Miguel Servet' contract funded by the ISCIII and the Centro de Investigacion Principe Felipe (CPII14/00002). P. S. is the recipient of a FPU-PhD fellowship funded by the Spanish Ministry of Education, Culture and Sport [FPU15/00964]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Sancho, P.; Bartesaghi, L.; Miossec, O.; García-García, F.; Ramírez-Jiménez, L.; Siddell, A.; Ajkesson, E.... (2019). Characterization of molecular mechanisms underlying the axonal Charcot-Marie-Tooth neuropathy caused by MORC2 mutations. Human Molecular Genetics. 28(10):1629-1644. https://doi.org/10.1093/hmg/ddz00616291644281

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

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

Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy

Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6, CPLANE1, and TBCD. The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case added ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presented with pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from mild ataxia with oculomotor apraxia, the de novo novel CLK2 c.1120T>C variant was found. The protein expression of the mutated protein was reduced, which may indicate instability that would affect its kinase activity

Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain

Mutations in the GDAP1 gene can cause Charcot-Marie-Tooth disease. These mutations are quite rare in most Western countries but not so in certain regions of Spain or other Mediterranean countries. This cross-sectional retrospective multicenter study analyzed the clinical and genetic characteristics of patients with GDAP1 mutations across Spain. 99 patients were identified, which were distributed across most of Spain, but especially in the Northwest and Mediterranean regions. The most common genotypes were p.R120W (in 81% of patients with autosomal dominant inheritance) and p.Q163X (in 73% of autosomal recessive patients). Patients with recessively inherited mutations had a more severe phenotype, and certain clinical features, like dysphonia or respiratory dysfunction, were exclusively detected in this group. Dominantly inherited mutations had prominent clinical variability regarding severity, including 29% of patients who were asymptomatic. There were minor clinical differences between patients harboring specific mutations but not when grouped according to localization or type of mutation. This is the largest clinical series to date of patients with GDAP1 mutations, and it contributes to define the genetic distribution and genotype-phenotype correlation in this rare form of CMT

De naguales y culebras. entidades sobrenaturales y “guardianes de los pueblos” en el sur de oaxaca

ResumenEl presente artículo tiene como finalidad analizar una serie de relatos sobre naguales de pueblos zapotecos de la sierra sur de Oaxaca, en la mayoría de los cuales se hace referencia a la culebra de agua como entidad sobrenatural que protege a las comunidades contra los ataques de naguales de otros pueblos, en particular del pueblo huave de San Mateo del Mar, en la región del istmo de Tehuantepec. Estos relatos están insertos en un contexto complejo de relaciones interétnicas de pueblos de diversos grupos etnoligüísticos que han habitado la franja sur del estado –entre ellos zapotecos, chontales, mixes, huaves y zoques–, conformada por las regiones de la sierra sur, la costa y el istmo de Tehuantepec. El análisis se hizo, básicamente, a partir de dos aspectos: el carácter de los naguales como entidades sobrenaturales guardianes de los pueblos; y las historias locales y las relaciones interétnicas entre los pueblos zapotecos del sur y los huaves de San Mateo del Mar.AbstractThis article aims to analyze a series of stories about naguales of the zapotecs from the south of Oaxaca, the most of which refer the water snake as a supernatural protective entity of communities against attacks by naguales of other villages, especially the huave people from San Mateo del Mar, in the region of the Isthmus of Tehuantepec. These stories are integrated in a complex context of interethnic relations among peoples of various groups that have lived in the south fringe of state –among them zapotecs, chontals, mixes, zoques and huaves–, comprising the regions of the Southern Highlands, Coast and the Istmo of Tehuantepec. The analysis was done from two aspects: the character of the naguales as supernaturals entities that protect the villages, and the local stories and ethnic relations among zapotecs villages from south and huaves from San Mateo del Mar

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

Synergy Pattern of Short Cationic Antimicrobial Peptides Against Multidrug-Resistant Pseudomonas aeruginosa

With the rise of various multidrug-resistant (MDR) pathogenic bacteria, worldwide health care is under pressure to respond. Conventional antibiotics are failing and the development of novel classes and alternative strategies is a major priority. Antimicrobial peptides (AMPs) cannot only kill MDR bacteria, but also can be used synergistically with conventional antibiotics. We selected 30 short AMPs from different origins and measured their synergy in combination with polymyxin B, piperacillin, ceftazidime, cefepime, meropenem, imipenem, tetracycline, erythromycin, kanamycin, tobramycin, amikacin, gentamycin, and ciprofloxacin. In total, 403 unique combinations were tested against an MDR Pseudomonas aeruginosa isolate (PA910). As a measure of the synergistic effects, fractional inhibitory concentrations (FICs) were determined using microdilution assays with FICs ranges between 0.25 and 2. A high number of combinations between peptides and polymyxin B, erythromycin, and tetracycline were found to be synergistic. Novel variants of indolicidin also showed a high frequency in synergist interaction. Single amino acid substitutions within the peptides can have a very strong effect on the ability to synergize, making it possible to optimize future drugs toward synergistic interaction