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BACKGROUND AND PURPOSE: In a subset of patients with inherited peripheral neuropathies the first symptom is atrophy and weakness of the intrinsic muscles of the hands, without involvement of lower limbs until later in the disease course. The exact pathomechanisms of this phenotype are currently unknown. The aim of this study was to characterize the clinical, neurophysiological and genetic features of a group of patients with a clinical diagnosis of upper limb predominant Charcot-Marie-Tooth disease (CMT). METHODS: The clinical, electrophysiology and genetic data of 11 patients with upper limb predominant peripheral neuropathy selected from a single-centre cohort of 461 patients diagnosed with inherited neuropathy were analysed and the clinical, electrophysiological and genetic characteristics of these patients reported. RESULTS: An overlapping phenotype of neuropathy and myopathy was detected in two patients. Four patients carry autosomal dominant mutations in GARS and a single patient had a homozygous mutation in SH3TC2. However, the underlying genetic diagnosis could not be confirmed in six patients by gene panel sequencing. CONCLUSIONS: Upper limb-onset inherited neuropathies are genetically heterogeneous and, in some cases, there is an overlapping myopathy. Autosomal dominant GARS mutations are the most common genetic cause; however, mutations in other CMT genes may also result in this phenotype in individual patients. The majority of these patients cannot be genetically diagnosed by gene panel testing of known CMT and myopathy genes, suggesting further genetic heterogeneity and highlighting the importance of further genetic investigations in these patients and families.
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Enfermedad de Charcot-Marie-Tooth , Neuropatía Hereditaria Motora y Sensorial , Enfermedad de Charcot-Marie-Tooth/genética , Heterogeneidad Genética , Mano , Neuropatía Hereditaria Motora y Sensorial/genética , Humanos , Mutación , FenotipoRESUMEN
BACKGROUND: Psoriatic arthritis (PsA) is a chronic and debilitating disease that can be managed by different clinical specialists. OBJECTIVES: The objective of the LOOP study was to evaluate the impact of clinical specialty setting on the time to diagnosis and treatment of patients with PsA. Clinical disease activity and disease burden were also compared between clinical settings. METHODS: LOOP was a cross-sectional, multicentre, observational study conducted in 17 countries in Western and Eastern Europe, the Middle East, Latin America and Asia. Adult patients (≥18 years) with a suspected or established diagnosis of PsA who were routinely visiting a rheumatologist, dermatologist or non-rheumatology/non-dermatology physician were enrolled. All patients were assessed by both a rheumatologist and a dermatologist. RESULTS: Of 1483 enrolled patients, a total of 1273 had a confirmed diagnosis of PsA. There was no significant difference in the median time from onset of inflammatory musculoskeletal symptoms to PsA diagnosis between patients enrolled by rheumatologists and dermatologists (6.0 vs. 3.9 months). However, the median time from diagnosis to first treatment with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) was significantly shorter in the rheumatology setting compared with the dermatology setting (0 vs. 2.0 months; P < 0.001). In addition, disease activity was significantly higher in the dermatology setting compared with the rheumatology setting. CONCLUSIONS: Differences in the management and clinical status of patients with PsA were observed between the rheumatology and dermatology settings. Importantly, median time from diagnosis to first csDMARD was significantly shorter in the rheumatology setting, and patients in the dermatology setting had higher disease activity. These data show the importance of improved collaboration between rheumatologists and dermatologists.
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Artritis Psoriásica , Dermatología , Psoriasis , Reumatología , Adulto , Artritis Psoriásica/diagnóstico , Artritis Psoriásica/tratamiento farmacológico , Asia , Estudios Transversales , Manejo de la Enfermedad , Europa Oriental , Humanos , Medio OrienteRESUMEN
This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.
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Biallelic SBF2 mutations cause Charcot-Marie-Tooth disease type 4B2 (CMT4B2), a sensorimotor neuropathy with autosomal recessive inheritance and association with glaucoma. Since the discovery of the gene mutation, only few additional patients have been reported. We identified seven CMT4B2 families with nine different SBF2 mutations. Revisiting genetic and clinical data from our cohort and the literature, SBF2 variants were private mutations, including exon-deletion and de novo variants. The neuropathy typically started in the first decade after normal early motor development, was predominantly motor and had a rather moderate course. Electrophysiology and nerve biopsies indicated demyelination and excess myelin outfoldings constituted a characteristic feature. While neuropathy was >90% penetrant at age 10 years, glaucoma was absent in ~40% of cases but sometimes developed with age. Consequently, SBF2 mutation analysis should not be restricted to individuals with coincident neuropathy and glaucoma, and CMT4B2 patients without glaucoma should be followed for increased intraocular pressure. The presence of exon-deletion and de novo mutations demands comprehensive mutation scanning and family studies to ensure appropriate diagnostic approaches and genetic counseling.
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Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación , Fenotipo , Proteínas Tirosina Fosfatasas no Receptoras/genética , Adolescente , Adulto , Biopsia , Niño , Femenino , Estudios de Asociación Genética/métodos , Humanos , Masculino , Adulto JovenRESUMEN
Mutations in STXBP1 have recently been identified as a cause of infantile epileptic encephalopathy. The underlying mechanism of the disorder remains unclear and, recently, several case reports have described broad and progressive neurological phenotypes in addition to early-onset epilepsy. Herein, we describe a patient with early-onset epilepsy who subsequently developed a progressive neurological phenotype including parkinsonism in her early teens. A de novo mutation in STXBP1 (c.416C>T, p.(Pro139Leu)) was detected with exome sequencing together with profound impairment of complex I of the mitochondrial respiratory chain on muscle biopsy. These findings implicate a secondary impairment of mitochondrial function in the progressive nature of the disease phenotype.
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Complejo I de Transporte de Electrón/deficiencia , Epilepsia/genética , Enfermedades Mitocondriales/genética , Proteínas Munc18/genética , Mutación Missense , Trastornos Parkinsonianos/genética , Encéfalo/fisiopatología , Niño , Progresión de la Enfermedad , Electroencefalografía , Complejo I de Transporte de Electrón/genética , Epilepsia/complicaciones , Exoma , Femenino , Humanos , Enfermedades Mitocondriales/complicaciones , Trastornos Parkinsonianos/complicaciones , FenotipoRESUMEN
Familial Mediterranean fever (FMF) is a well-described monogenic autosomal recessive disorder with highest occurrence in the Mediterranean region. In this article, we describe the experience of a center in the Czech Republic that follows four families with members bearing mutations in MEFV gene without provable ancestry from the Mediterranean region. We also discuss the clinical picture of the heterozygous variants that were present in our cohort. The typical clinical presentation in heterozygotes corresponds to data described in the international literature. The possibility of combination of mutations and/or polymorphisms in different genes and epigenetic or environmental influences on the clinical symptoms are taken into account.
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Proteínas del Citoesqueleto/genética , Fiebre Mediterránea Familiar/genética , Heterocigoto , Mutación , Adulto , República Checa , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , PirinaRESUMEN
Having excluded common structural, inflammatory and vascular causes of a spastic paraparesis, the diagnostic yield of further clinical investigations is low. Here, we show that testing for rare metabolic and genetic causes can have important implications for both the patient and their family.
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Transportadoras de Casetes de Unión a ATP/genética , Paraparesia Espástica/genética , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , LinajeRESUMEN
OBJECTIVES: A new method has been developed for detecting genes determining the extended-spectrum beta-lactamase (ESBL) phenotype directly from patients' clinical material. The method enables detection of the bla(CTX-M) gene encoding CTX-M beta-lactamases and the bla(SHV) gene variants with real-time PCR technology using locked nucleic acid oligonucleotides. MATERIAL AND METHODS: In this pilot study, tracheal aspirates obtained from patients with mechanical ventilation hospitalized at Department of Anaesthesiology and Resuscitation of the University Hospital in Olomouc between 1st March and 30th December 2010 period were tested. Each sample was identified with standard microbiological procedures including phenotypic determination of ESBL-positive enterobacteria. At the same time, each sample was analyzed for the presence of nucleic acids (DNA) which encode CTX-M and SHV ESBL using real-time PCR. RESULTS: 150 samples of tracheal aspirates from 71 patients were included into testing. In the set, 13 (8.7%) ESBL-positive samples were identified by culture methods while 27 (18 %) positive samples were identified by the real-time PCR method. Of the 27 PCR-positive samples, 24 were positive for the bla(CTX) gene; in 2 samples, the ESBL bla(SHV) gene was detected, and both genes were present in 1 sample. All culture-positive samples were also PCR-positive for the presence of bla(CTX) and/or bla(SHV) sequences. CONCLUSIONS: The new real-time PCR assay is likely to shorten the time for detection of enterobacteria producing SHV and CTX-M beta-lactamases from 48 to 6 hours. It enables ESBL-positive enterobacteria determination in tracheal aspirates of patients suffered from life-threatening nosocomial pneumonia where the early introduction of adequate antimicrobial treatment plays the important role.
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Infecciones por Enterobacteriaceae/diagnóstico , Enterobacteriaceae/aislamiento & purificación , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , beta-Lactamasas/genética , Infección Hospitalaria , Enterobacteriaceae/enzimología , Enterobacteriaceae/genética , Infecciones por Enterobacteriaceae/microbiología , Humanos , Proyectos Piloto , Ventilación Pulmonar , Respiración Artificial , Tráquea/microbiología , beta-Lactamasas/metabolismoRESUMEN
The glycocalyx is a cell surface sugar layer of most cell types that greatly influences the interaction of cells with their environment. Its components are glycolipids, glycoproteins, and oligosaccharides. Interestingly, cancer cells have a thicker glycocalyx layer compared to healthy cells, but to date, there has been no consensus in the literature on the exact role of cell surface polysaccharides and their derivatives in cellular adhesion and signaling. In our previous work we discovered that specific glycocalyx components of cancer cells regulate the kinetics and strength of adhesion on RGD (arginine-glycine-aspartic acid) peptide-coated surfaces [1]. Depending on the employed enzyme concentration digesting specific components both adhesion strengthening and weakening could be observed by monitoring the averaged behavior of thousands of cells. The enzyme chondroitinase ABC (ChrABC) was used to digest the chondroitin-4-sulfate, chondroitin-6-sulfate, and dermatan sulfate components in the glycocalyx of cancer cells. In the present work, a high spatial resolution label-free optical biosensor was employed to monitor the adhesivity of cancer cells both at the single-cell and population level. Population-level distributions of single-cell adhesivity were first recorded and analyzed when ChrABC was added to the adhering cells. At relatively low and high ChrABC concentrations subpopulations with remarkably large and weak adhesivity were identified. The changes in the adhesivity distribution due to the enzyme treatment were analyzed and the subpopulations most affected by the enzyme treatment were highlighted. The presented results open up new directions in glycocalyx related cell adhesion research and in the development of more meaningful targeted cancer treatments affecting adhesion.
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Combined morphological, immunocytochemical, biochemical and molecular genetic studies were performed on skeletal muscle, heart muscle and liver tissue of a 16-months boy with fatal liver failure. The pathological characterization of the tissues revealed a severe depletion of mtDNA (mitochondrial DNA) that was most pronounced in liver, followed by a less severe, but still significant depletion in skeletal muscle and the heart. The primary cause of the disease was linked to compound heterozygous mutations in the polymerase γ (POLG) gene (DNA polymerase γ; A467T, K1191N). We present evidence, that compound heterozygous POLG mutations lead to tissue selective impairment of mtDNA replication and thus to a mosaic defect pattern even in the severely affected liver. A variable defect pattern was found in liver, muscle and heart tissue as revealed by biochemical, cytochemical, immunocytochemical and in situ hybridization analysis. Functionally, a severe deficiency of cytochrome-c-oxidase (cox) activity was seen in the liver. Although mtDNA depletion was detected in heart and skeletal muscle, there was no cox deficiency in these tissues. Depletion of mtDNA and microdissection of cox-positive or negative areas correlated with the histological pattern in the liver. Interestingly, the mosaic pattern detected for cox-activity and mtDNA copy number fully aligned with the immunohistologically revealed defect pattern using Pol γ, mtSSB- and mtTFA-antibodies, thus substantiating the hypothesis that nuclear encoded proteins located within mitochondria become unstable and are degraded when they are not actively bound to mtDNA. Their disappearance could also aggravate the mtDNA depletion and contribute to the non-homogenous defect pattern.
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ADN Mitocondrial/metabolismo , ADN Polimerasa Dirigida por ADN/genética , Fallo Hepático , ADN Polimerasa gamma , Replicación del ADN , Resultado Fatal , Humanos , Lactante , Hígado/metabolismo , Hígado/ultraestructura , Fallo Hepático/genética , Fallo Hepático/metabolismo , Fallo Hepático/patología , Masculino , Mitocondrias/enzimología , Mitocondrias/ultraestructura , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestructura , Mutación , Miocardio/metabolismo , Miocardio/ultraestructuraRESUMEN
Hyper-immunoglobulin (Ig)E syndrome (HIES) is a primary immunodeficiency associated with mutations in STAT3 resulting in impaired development of T helper type 17 (Th17) lymphocytes. HIES patients with a reduced frequency of Th17 cells present with infections caused by Staphylococcus aureus and/or Candida strains. The same spectrum of pathogens is present in patients with chronic granulomatous disease (CGD).We analysed the characteristics of the Th17 compartment in HIES and CGD. HIES patients showed very low numbers of Th17 cells. By contrast, the frequency of Th17 cells and production of Th17-derived cytokines was significantly higher among CGD patients when compared to both control samples and HIES. Naive CD4(+) cells in CGD patients had a normal capacity to differentiate into IL-17-producing cells and the numbers of Th17 cells in the CGD patients normalized following successful bone marrow transplantation. Our findings complement recent data on the importance of Th17 cells for elimination of infections with C. albicans and S. aureus.
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Enfermedad Granulomatosa Crónica/inmunología , Interferón gamma/inmunología , Interleucina-17/inmunología , Síndrome de Job/inmunología , Glicoproteínas de Membrana/inmunología , NADPH Oxidasas/inmunología , Factor de Transcripción STAT3/inmunología , Células Th17/inmunología , Adulto , Candida albicans/crecimiento & desarrollo , Candidiasis/inmunología , Candidiasis/microbiología , Estudios de Casos y Controles , Diferenciación Celular/inmunología , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/metabolismo , Enfermedad Granulomatosa Crónica/patología , Enfermedad Granulomatosa Crónica/terapia , Trasplante de Células Madre Hematopoyéticas , Humanos , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Síndrome de Job/genética , Síndrome de Job/metabolismo , Síndrome de Job/patología , Recuento de Linfocitos , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Mutación , NADPH Oxidasa 2 , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/crecimiento & desarrollo , Células Th17/metabolismo , Células Th17/patología , Trasplante HomólogoRESUMEN
Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.
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Enfermedades del Sistema Nervioso Central/complicaciones , GTP Fosfohidrolasas/genética , Atrofia Óptica Autosómica Dominante/complicaciones , Adolescente , Adulto , Anciano , Enfermedades del Sistema Nervioso Central/genética , Enfermedades del Sistema Nervioso Central/metabolismo , Enfermedades del Sistema Nervioso Central/patología , Niño , Estudios de Cohortes , ADN Mitocondrial/análisis , ADN Mitocondrial/genética , Familia , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Mutación , Atrofia Óptica Autosómica Dominante/genética , Atrofia Óptica Autosómica Dominante/metabolismo , Atrofia Óptica Autosómica Dominante/patología , Fenotipo , Adulto JovenRESUMEN
There are contradictory results on lateralisation and localisation of rhythm processing. Our aim was to test whether there is a hemispheric dissociation of metric and non-metric rhythm processing. We created a non-metric rhythm stimulus without a sense of metre and we measured brain activities during passive rhythm perception. A total of 11 healthy, right-handed, native female Hungarian speakers aged 21.3 ± 1.1 were investigated by functional magnetic resonance imaging (fMRI) using a 3T MR scanner. The experimental acoustic stimulus consisted of comprehensive sentences transformed to Morse code, which represent a non-metric rhythm with irregular perceptual accent structure. Activations were found in the right hemisphere, in the posterior parts of the right-sided superior and middle temporal gyri and temporal pole as well as in the orbital part of the right inferior frontal gyrus. Additional activation appeared in the left-sided superior temporal region. Our study suggests that non-metric rhythm with irregular perceptual accents structure is confined to the right hemisphere. Furthermore, a right-lateralised fronto-temporal network extracts the continuously altering temporal structure of the non-metric rhythm.
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Percepción Auditiva/fisiología , Cerebro/fisiología , Dominancia Cerebral/fisiología , Lateralidad Funcional/fisiología , Periodicidad , Percepción del Tiempo/fisiología , Estimulación Acústica/métodos , Mapeo Encefálico/métodos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Adulto JovenRESUMEN
A 39-year-old woman presented to the neurology clinic with an abnormal gait. Subsequent investigations confirmed a rare neurodegenerative disease. This case highlights the key clinical features and diagnostic approach to neuroferritinopathy, and describes the discovery of the disease in a family from Cumbria in the north west of England.
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Enfermedades de los Ganglios Basales/diagnóstico , Distonía/etiología , Trastornos Neurológicos de la Marcha/etiología , Trastornos del Metabolismo del Hierro/diagnóstico , Adulto , Enfermedades de los Ganglios Basales/complicaciones , Enfermedades de los Ganglios Basales/genética , Enfermedades de los Ganglios Basales/patología , Distonía/genética , Distonía/patología , Femenino , Trastornos Neurológicos de la Marcha/genética , Trastornos Neurológicos de la Marcha/patología , Humanos , Trastornos del Metabolismo del Hierro/complicaciones , Trastornos del Metabolismo del Hierro/genética , Trastornos del Metabolismo del Hierro/patología , Distrofias Neuroaxonales/complicaciones , Distrofias Neuroaxonales/diagnóstico , Distrofias Neuroaxonales/genética , Distrofias Neuroaxonales/patologíaRESUMEN
Dominant mutations in ubiquitously expressed transfer RNA (tRNA) synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic evidence in mouse and Drosophila models suggests a gain-of-function mechanism. In this study, we used in vivo, cell typespecific transcriptional and translational profiling to show that mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2 (general control nonderepressible 2). The chronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of Gcn2 alleviated the peripheral neuropathy. The activation of GCN2 suggests that the aberrant activity of the mutant tRNA synthetases is still related to translation and that inhibiting GCN2 or the ISR may represent a therapeutic strategy in CMT.
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Enfermedad de Charcot-Marie-Tooth/metabolismo , Glicina-ARNt Ligasa/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Estrés Fisiológico , Tirosina-ARNt Ligasa/metabolismo , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Animales , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Modelos Animales de Enfermedad , Femenino , Eliminación de Gen , Genes Dominantes , Glicina-ARNt Ligasa/genética , Masculino , Ratones , Ratones Mutantes , Neuronas Motoras/fisiología , Biosíntesis de Proteínas , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Médula Espinal/fisiopatología , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/genética , Estrés Fisiológico/fisiología , Transcriptoma , Tirosina-ARNt Ligasa/genéticaRESUMEN
These tables list both published and a number of unpublished mutations in genes associated with early onset defects in mitochondrial DNA (mtDNA) maintenance including C10orf2, SUCLG1, SUCLA2, TYMP, RRM2B, MPV17, DGUOK and TK2. The list should not be taken as evidence that any particular mutation is pathogenic. We have included genes known to cause mtDNA depletion, excluding POLG1, because of the existing database (http://tools.niehs.nih.gov/polg/). We have also excluded mutations in C10orf2 associated with dominant adult onset disorders.
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ADN Mitocondrial/genética , Genes Mitocondriales/genética , Enfermedades Mitocondriales/genética , Mutación/genética , Humanos , SíndromeRESUMEN
In the last decade, there has been a rapid development in the use of molecular genetics methods in clinical microbiology. Novel technologies bring new knowledge and approaches to various disciplines of microbiology--taxonomy, identification of microbes, clinical diagnosis, epidemiology of infectious diseases and antibiotic resistance. This article summarizes the conclusions from the workshop of the Molecular Microbiology Working Group TIDE held during the Second Annual Meeting of the Society for Medical Microbiology of the J. E. Purkyne Czech Medical Association.
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Técnicas Microbiológicas , Biología Molecular , Técnicas de Diagnóstico Molecular , Bacterias , ADN Bacteriano/análisis , Humanos , Infecciones/diagnósticoRESUMEN
BACKGROUND: Congenital disorders of glycosylation (CDG) is a heterogeneous group of congenital metabolic diseases with multisystem clinical involvement. ALG3-CDG is a very rare subtype with only 24 cases reported so far. CASE: Here, we report two siblings with dysmorphic features, growth retardation, microcephaly, intractable epilepsy, and hemangioma in the frontal, occipital and lumbosacral regions. RESULTS: We studied two siblings by whole exome sequencing. A pathogenic variant in ALG3 (NM_005787.6: c.165C > T; p.Gly55=) that had been previously associated with congenital glycolysis defect type 1d was identified. Their intractable seizures were controlled by ketogenic diet. CONCLUSION: Although prominent findings of growth retardation and microcephaly seen in our patients have been extensively reported before, presence of hemangioma is a novel finding that may be used as an indication for ALG3-CDG diagnosis. Our patients are the first reported cases whose intractable seizures were controlled with ketogenic diet. This report adds ketogenic diet as an option for treatment of intractable epilepsy in ALG3-CDG.
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Trastornos Congénitos de Glicosilación/complicaciones , Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/genética , Dieta Cetogénica , Epilepsia Refractaria/dietoterapia , Manosiltransferasas/genética , Neoplasias del Sistema Nervioso Central/etiología , Anomalías Craneofaciales/etiología , Discapacidades del Desarrollo/etiología , Epilepsia Refractaria/diagnóstico , Epilepsia Refractaria/etiología , Femenino , Hemangioma/etiología , Humanos , Lactante , Masculino , Gemelos , Secuenciación del ExomaRESUMEN
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently characterized adult onset neurodegenerative disorder affecting both male and female (male>female) carriers of premutation CGG repeat expansions of the FMR1 gene. Onset typically occurs after the age of 50 years with a lifetime risk of FXTAS in males of about 1 in 3,000-6,000. Core features include progressive gait ataxia and cerebellar tremor with associated features of cognitive deficits, peripheral neuropathy and dysautonomia. The diagnosis of FXTAS is established based on clinical presentation, cerebral imaging and genetic testing. Due to the still low level of awareness of FXTAS and its variable clinical picture FXTAS is substantially underdiagnosed. However, confirming the diagnosis is essential for genetic counseling of the patients as the offspring are at risk for fragile X syndrome, premature ovarian insufficiency (POI) or FXTAS. Furthermore, many features of FXTAS can be treated symptomatically.
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Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/genética , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/genética , Asesoramiento Genético/tendencias , Predisposición Genética a la Enfermedad/genética , Temblor/diagnóstico , Temblor/genética , Ataxia Cerebelosa/epidemiología , Comorbilidad , Femenino , Síndrome del Cromosoma X Frágil/epidemiología , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Medición de Riesgo , Temblor/epidemiologíaRESUMEN
Two types of metal-clad waveguide biosensors, so-called dip-type and peak-type, are analyzed and tested. Their performances are benchmarked against the well-known surface-plasmon resonance biosensor, showing improved probe characteristics for adlayer thicknesses above 150-200 nm. The dip-type metal-clad waveguide sensor is shown to be the best all-round alternative to the surface-plasmon resonance biosensor. Both metal-clad waveguides are tested experimentally for cell detection, showing a detection limit of 8-9 cells/mm2.