RESUMEN
Pathogenic variants in SCN8A are associated with a broad phenotypic spectrum, including Self-Limiting Familial Infantile Epilepsy (SeLFIE), characterized by infancy-onset age-related seizures with normal development and cognition. Movement disorders, particularly paroxysmal kinesigenic dyskinesia typically arising after puberty, may represent another core symptom. We present the case of a 1-year-old girl with a familial disposition to self-limiting focal seizures from the maternal side and early-onset orofacial movement disorders associated with SCN8A-SeLFIE. Brain MRI was normal. Genetic testing revealed a maternally inherited SCN8A variant [c.4447G > A; p.(Glu1483Lys)]. After the introduction of valproic acid, she promptly achieved seizure control as well as complete remission of strabismus and a significant decrease in episodes of tongue deviation. Family history, genetic findings, and epilepsy phenotype are consistent with SCN8A-SeLFIE. Movement disorders are an important part of the SCN8A phenotypic spectrum, and this case highlights the novel early-onset orofacial movement disorders associated with this condition. The episodes of tongue deviation and protrusion suggest focal oromandibular (lingual) dystonia. Additionally, while infantile strabismus or esophoria is a common finding in healthy individuals, our case raises the possibility of an ictal origin of the strabismus. This study underscores the importance of recognizing and addressing movement disorders in SCN8A-SeLFIE patients, particularly the rare early-onset orofacial manifestations. It adds to the growing body of knowledge regarding the diverse clinical presentations of SCN8A-associated disorders and suggests potential avenues for clinical management and further research.
Asunto(s)
Distonía , Trastornos Distónicos , Epilepsia , Síndromes Epilépticos , Trastornos del Movimiento , Estrabismo , Femenino , Humanos , Lactante , Distonía/genética , Trastornos Distónicos/genética , Epilepsia/diagnóstico , Síndromes Epilépticos/genética , Mutación , Canal de Sodio Activado por Voltaje NAV1.6/genética , Convulsiones/genética , Estrabismo/genéticaRESUMEN
BACKGROUND: KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined. METHODS: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature. RESULTS: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones. CONCLUSION: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of ANKRD11 variants in skeletal and brain development.
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Anomalías Múltiples , Enfermedades del Desarrollo Óseo , Discapacidad Intelectual , Anomalías Dentarias , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Enfermedades del Desarrollo Óseo/diagnóstico por imagen , Enfermedades del Desarrollo Óseo/genética , Anomalías Dentarias/diagnóstico por imagen , Anomalías Dentarias/genética , Facies , Fenotipo , Proteínas Represoras/genética , Factores de Transcripción , NeuroimagenRESUMEN
BACKGROUND AND OBJECTIVES: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. METHODS: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details. RESULTS: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. DISCUSSION: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.
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Epilepsia Generalizada , Epilepsia , Canales de Potasio Éter-A-Go-Go , Niño , Humanos , Recién Nacido , Epilepsia/genética , Epilepsia Generalizada/genética , Mutación , Fenotipo , Convulsiones/genética , Canales de Potasio Éter-A-Go-Go/genéticaRESUMEN
BACKGROUND: Acute flaccid myelitis is a serious condition of the spinal cord. More than 80% of patients experience a mild respiratory illness or fever consistent with a viral infection prior to acute flaccid myelitis development. Enterovirus A71 is known to circulate in Denmark, and has previously been associated with severe neurological symptoms. In this case report we describe acute flaccid rhombencephalomyelitis with radiculitis in an infant with an enterovirus infection. CASE PRESENTATION: The 8-month-old male of Asian origin presented with fever and gastrointestinal symptoms, followed by severe neurological deficits such as flaccid paralysis of the neck and upper extremities. An initial magnetic resonance imaging scan of the brain was normal, and the boy was treated for encephalitis. A follow-up magnetic resonance imaging scan of the brain and spinal cord 1 week later showed the development of pathological symmetrical gray matter hyperintensity lesions on T2-weighted images in the brainstem and upper medulla spinalis, and nerve enhancement in the terminal thread of the spinal cord and the cervical roots; findings consistent with rhombencephalomyelitis with radiculitis causing flaccid paralysis. Enterovirus A71 was detected in both nasopharyngeal and fecal specimens. Other differential diagnostic etiologies of viral and bacterial encephalitis, including poliovirus, were excluded. CONCLUSIONS: This is the first case in Denmark of a patient diagnosed with acute flaccid rhombencephalomyelitis strongly linked to an enterovirus A71 infection. This case emphasizes the diagnostic importance of combining a history of respiratory and/or gastrointestinal illness, fever, and delayed onset of varying degrees of paralysis with progressive characteristic spinal and brain lesions. Analysis of respiratory, fecal, and cerebrospinal samples for the presence of enterovirus, and eliminating other differential pathogens, is essential to confirm the diagnosis.
Asunto(s)
Infecciones por Enterovirus , Enterovirus , Mielitis , Radiculopatía , Niño , Dinamarca , Infecciones por Enterovirus/complicaciones , Infecciones por Enterovirus/diagnóstico , Humanos , Lactante , Masculino , Mielitis/diagnósticoRESUMEN
Coffin-Siris syndrome (CSS) is a rare congenital malformation syndrome, caused by mutations in the ARID1B gene in over half of the cases. While the clinical characteristics of the syndrome have been increasingly described, a detailed evaluation of the epileptic phenotype in patients with ARID1B alterations and CSS has not been approached yet. We report seven patients with ARID1B-related CSS, focusing on epilepsy and its electroclinical features. The evolution of epilepsy and EEG findings of children with CSS are described and compared with patients previously reported in the literature. The patients described here reveal common features, consistent with those of patients previously described in the literature. The epilepsy phenotype of CSS due to ARID1B pathogenic variants may be described as focal epilepsy with seizures, variable in frequency, arising from motor areas, with onset in the first years of life and susceptibility to fever, and interictal perisylvian (centrotemporal) epileptiform abnormalities that are enhanced during sleep with possible evolution to an EEG pattern of continuous spike and wave during sleep (without documented developmental regression). Additional information emerging from other patients is needed to confirm this definition.
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Anomalías Múltiples , Proteínas de Unión al ADN/genética , Epilepsia , Cara/anomalías , Deformidades Congénitas de la Mano , Discapacidad Intelectual , Micrognatismo , Cuello/anomalías , Factores de Transcripción/genética , Anomalías Múltiples/genética , Epilepsia/genética , Deformidades Congénitas de la Mano/complicaciones , Deformidades Congénitas de la Mano/genética , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Micrognatismo/complicaciones , Micrognatismo/genéticaRESUMEN
ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine published individuals, plus detailed case history of two children. New individuals were identified through GeneMatcher, ClinVar and the European Network for Therapies in Rare Epilepsy (NETRE). Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria. Individuals with ZMYND11 associated epilepsy fell into three groups: (i) atypical benign partial epilepsy or idiopathic focal epilepsy (n = 8); (ii) generalised epilepsies/infantile epileptic encephalopathy (n = 4); (iii) unclassified (n = 8). Seizure prognosis ranged from spontaneous remission to drug resistant. Neurodevelopmental deficits were invariable. Dysmorphic features were variable. Variants were distributed across the gene and mostly de novo with no precise genotype-phenotype correlation. ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE. More detailed epilepsy descriptions of larger cohorts and functional studies might reveal genotype-phenotype correlation. The epileptogenic mechanism may be linked to interaction with histone H3.3.
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Proteínas de Ciclo Celular/genética , Proteínas Co-Represoras/genética , Proteínas de Unión al ADN/genética , Epilepsia/diagnóstico , Epilepsia/genética , Variación Genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Fenotipo , Adolescente , Adulto , Alelos , Sustitución de Aminoácidos , Niño , Preescolar , Bases de Datos Factuales , Electroencefalografía , Epilepsia/terapia , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Adulto JovenRESUMEN
Xia-Gibbs syndrome (XGS) is a neurodevelopmental disorder characterized by intellectual disability, developmental delay, seizures, hypotonia, obstructive sleep apnoea and mild facial dysmorphism. Heterozygosity for loss-of-function variants in AHDC1, encoding the AT-hook DNA binding motif containing protein 1, were discovered in 2014 as the likely genetic cause of Xia-Gibbs syndrome. We present five patients with Xia-Gibbs syndrome caused by previously unreported variants in AHDC1. Two of the patients share a frameshift variant: c.2849del (p.(Pro950Argfs*192)) in AHDC1. Despite sharing this variant, the two patients show remarkable phenotypic differences underscoring the clinical heterogeneity of Xia-Gibbs syndrome. In addition, we present a case of Xia-Gibbs syndrome caused by mosaicism for an AHDC1 variant.
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Anomalías Craneofaciales/genética , Proteínas de Unión al ADN/genética , Discapacidades del Desarrollo/genética , Deformidades del Pie/genética , Hipotonía Muscular/genética , Fenotipo , Adolescente , Adulto , Anomalías Craneofaciales/patología , Discapacidades del Desarrollo/patología , Femenino , Deformidades del Pie/patología , Mutación del Sistema de Lectura , Humanos , Masculino , Hipotonía Muscular/patología , Síndrome , Adulto JovenRESUMEN
α-L-Arabinofuranosidases from glycoside hydrolase family 51 use a stereochemically retaining hydrolytic mechanism to liberate nonreducing terminal α-L-arabinofuranose residues from plant polysaccharides such as arabinoxylan and arabinan. To date, more than ten fungal GH51 α-L-arabinofuranosidases have been functionally characterized, yet no structure of a fungal GH51 enzyme has been solved. In contrast, seven bacterial GH51 enzyme structures, with low sequence similarity to the fungal GH51 enzymes, have been determined. Here, the crystallization and structural characterization of MgGH51, an industrially relevant GH51 α-L-arabinofuranosidase cloned from Meripilus giganteus, are reported. Three crystal forms were grown in different crystallization conditions. The unliganded structure was solved using sulfur SAD data collected from a single crystal using the I23 in vacuo diffraction beamline at Diamond Light Source. Crystal soaks with arabinose, 1,4-dideoxy-1,4-imino-L-arabinitol and two cyclophellitol-derived arabinose mimics reveal a conserved catalytic site and conformational itinerary between fungal and bacterial GH51 α-L-arabinofuranosidases.
Asunto(s)
Glicósido Hidrolasas/química , Polyporales/enzimología , Arabinosa/química , Dominio Catalítico , Iminofuranosas/química , Ligandos , Modelos Moleculares , Unión Proteica , Alcoholes del Azúcar/químicaRESUMEN
BACKGROUND: Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children. RESULTS: In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build. CONCLUSIONS: These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.
Asunto(s)
Enfermedad de Hirschsprung , Discapacidad Intelectual , Microcefalia , Niño , Facies , Femenino , Gráficos de Crecimiento , Enfermedad de Hirschsprung/genética , Proteínas de Homeodominio , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/genética , Italia , Masculino , Microcefalia/genética , Proteínas Represoras , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genéticaRESUMEN
In this case report, a 14-year-old male presented with episodes of migraine-like headaches preceded by unilateral hemiparaesthesia, hemiparesis, confusion, and dysphasia with the last two lasting more than four hours. The cerebrospinal fluid (CSF) showed lymphocytosis with no detectable aetiology, neuroimaging was normal, and an electroencephalogram showed diffuse slowing. The patient was diagnosed with headache associated with neurologic deficits and CSF lymphocytosis, i.e. syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis. The condition is a rare disorder, especially in children. Normally, a complete remission takes place within few weeks to months without treatment.
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Linfocitosis , Trastornos Migrañosos , Enfermedades del Sistema Nervioso , Adolescente , Niño , Cefalea/etiología , Humanos , Linfocitosis/complicaciones , Linfocitosis/diagnóstico , Masculino , Trastornos Migrañosos/complicaciones , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/tratamiento farmacológico , Enfermedades del Sistema Nervioso/complicaciones , Enfermedades del Sistema Nervioso/diagnóstico , SíndromeRESUMEN
This case report describes a seven-year-old girl with autism and nightly "anxiety" attacks. A diagnosis of Alice in Wonderland syndrome (AIWS) presumably associated to migraine was made, and the girl was successfully treated with lamotrigine. Effective treatment of the AIWS depends on correct diagnosis. Symptoms are bizarre and affect the senses of vision, sensation, touch and hearing, as well as one's own body image. AIWS is associated with epilepsy, migraine, certain infectious diseases and rarely cerebral tumours.
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Síndrome de Alicia en el País de las Maravillas , Trastornos de Ansiedad , Síndrome de Alicia en el País de las Maravillas/diagnóstico , Ansiedad , Trastornos de Ansiedad/diagnóstico , Niño , Femenino , Humanos , Trastornos MigrañososRESUMEN
We have characterized the structure and dynamics of the carbohydrate-modifying enzyme Paenibacillus nanensis xanthan lyase (PXL) involved in the degradation of xanthan by X-ray crystallography, small-angle X-ray scattering, and hydrogen/deuterium exchange mass spectrometry. Unlike other xanthan lyases, PXL is specific for both unmodified mannose and pyruvylated mannose, which we find is correlated with structural differences in the substrate binding groove. The structure of the full-length enzyme reveals two additional C-terminal modules, one of which belongs to a new non-catalytic carbohydrate binding module family. Ca2+ are critical for the activity and conformation of PXL, and we show that their removal by chelating agents results in localized destabilization/unfolding of particularly the C-terminal modules. We use the structure and the revealed impact of Ca2+ coordination on conformational dynamics to guide the engineering of PXL variants with increased activity and stability in a chelating environment, thus expanding the possibilities for industrial applications of PXL.
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Proteínas Bacterianas/metabolismo , Liasas de Carbono-Oxígeno/metabolismo , Paenibacillus/enzimología , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Calcio/química , Calcio/metabolismo , Liasas de Carbono-Oxígeno/química , Liasas de Carbono-Oxígeno/genética , Dominio Catalítico , Cristalografía por Rayos X , Cinética , Mutagénesis Sitio-Dirigida , Estabilidad Proteica , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Dispersión del Ángulo Pequeño , Difracción de Rayos XRESUMEN
PURPOSE: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS. METHODS: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. RESULTS: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. CONCLUSION: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.
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Enfermedad de Hirschsprung/diagnóstico , Enfermedad de Hirschsprung/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Microcefalia/diagnóstico , Microcefalia/genética , Anomalías Múltiples/genética , Adolescente , Adulto , Niño , Preescolar , Facies , Femenino , Estudios de Asociación Genética/métodos , Genotipo , Humanos , Lactante , Masculino , Mutación , Fenotipo , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genéticaRESUMEN
The Adaptive Poisson-Boltzmann Solver (APBS) software was developed to solve the equations of continuum electrostatics for large biomolecular assemblages that have provided impact in the study of a broad range of chemical, biological, and biomedical applications. APBS addresses the three key technology challenges for understanding solvation and electrostatics in biomedical applications: accurate and efficient models for biomolecular solvation and electrostatics, robust and scalable software for applying those theories to biomolecular systems, and mechanisms for sharing and analyzing biomolecular electrostatics data in the scientific community. To address new research applications and advancing computational capabilities, we have continually updated APBS and its suite of accompanying software since its release in 2001. In this article, we discuss the models and capabilities that have recently been implemented within the APBS software package including a Poisson-Boltzmann analytical and a semi-analytical solver, an optimized boundary element solver, a geometry-based geometric flow solvation model, a graph theory-based algorithm for determining pKa values, and an improved web-based visualization tool for viewing electrostatics.
Asunto(s)
Modelos Moleculares , Programas Informáticos , Electricidad EstáticaRESUMEN
GH-18 chitinases are chitinolytic enzymes, primarily responsible for the recycling of insoluble chitin biomaterials. These enzymes contain three invariant acidic active-site residues within a DXDXE motif, which play a synergistic role in the catalytic cycle of chitin degradation. We employed a pKa calculation approach to approximate the protonation states of residues D1, D2, and E in the DXDXE motif of 75 GH-18 chitinases. Theoretical pH-activity profiles of these enzymes were subsequently constructed and compared with the experimentally determined pH-activity profiles. Theoretical pKa data indicate that in the majority of chitinases the D1 side-chain is in the "up" and the E side-chain in the "down" position, while the position of the D2 side-chain is versatile and depends on the state of the enzyme. The pKa values in 75 GH-18 chitinases were predicted to be <0 for D1, 8-13 for D2, and 6-9 for E, indicating that the D1-D2 pair holds exactly one net negative charge. On the other hand, the catalytic acid E is protonated over the active pH-range, agreeing with the pH-activity curves reported previously for most chitinases. The results obtained from this study help to elucidate the mechanistic details of the concerted participation of D1, D2, and E in the catalytic cycle of chitin hydrolysis by GH-18 chitinases.
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Fenómenos Químicos , Quitinasas/química , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Quitinasas/metabolismo , Bases de Datos de Proteínas , Concentración de Iones de Hidrógeno , Modelos Moleculares , Alineación de SecuenciaRESUMEN
Selective internal radiation therapy (SIRT) of hepatocellular carcinoma has been introduced at Aarhus University Hospital. 90Y-microspheres are implanted in the tumour by catheterization of the tumour feeding liver artery. Pretreatment angiography and test treatment using 99mTc-labelled particles followed by scintigraphy ensure a feasible and effective treatment. Post-treatment imaging of radiation from 90Y visualize the localization of microspheres. Currently, SIRT is also applied for liver metastases of neuroendocrine tumours. Future indications may include other liver tumours and metastases.
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Neoplasias Hepáticas/radioterapia , Radiofármacos/uso terapéutico , Agregado de Albúmina Marcado con Tecnecio Tc 99m , Radioisótopos de Itrio/uso terapéutico , Angiografía , Carcinoma Hepatocelular/radioterapia , Embolización Terapéutica/métodos , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Microesferas , Cintigrafía , Radiofármacos/administración & dosificación , Tomografía Computarizada de Emisión de Fotón Único , Radioisótopos de Itrio/administración & dosificaciónRESUMEN
BACKGROUND: Recent studies have shown that the combination of radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC) may offer a survival advantage compared to monotherapy. PURPOSE: To study the effectiveness of combination therapy with RFA and TACE compared to that of TACE alone in a Scandinavian tertiary liver cancer center. MATERIAL AND METHODS: A retrospective study of the patients treated with combination therapy vis-à-vis TACE alone from June 2007 to November 2012 was performed. Eighteen patients were treated with a combination of RFA and TACE with an interval of 1-4 days between the treatments. For comparison, a group of 18 patients treated with TACE as monotherapy in the same time period was matched with the combination group by demographic data, tumor characteristics, biochemical and clinical parameters, and performance status (PS). RESULTS: Each group consisted of 14 patients with cirrhosis and four without. There were no significant differences between the groups regarding age, gender, tumor characteristics, causes of cirrhosis, levels of bilirubin, creatinine, prothrombin time, Child Pugh score, or World Health Organization (WHO) performance status. The median survival of patients in the RFA + TACE combination group was 586 days compared to 296 days in the control group. The difference was not statistically significant (P = 0.26). However, when we stratified the data for cirrhosis and WHO performance status, patients in the combination group had significantly better survival (P = 0.024). CONCLUSION: Combination therapy with RFA and TACE for unresectable HCC, compared to TACE alone, may offer a survival benefit for a selected group of patients with HCC.
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Carcinoma Hepatocelular/terapia , Ablación por Catéter/métodos , Quimioembolización Terapéutica/métodos , Neoplasias Hepáticas/terapia , Anciano , Anciano de 80 o más Años , Antibióticos Antineoplásicos/uso terapéutico , Terapia Combinada , Dinamarca , Doxorrubicina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Selección de Paciente , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: SCN8A encodes the sodium channel voltage-gated α8-subunit (Nav1.6). SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. We aimed to delineate the phenotype associated with SCN8A mutations. METHODS: We used high-throughput sequence analysis of the SCN8A gene in 683 patients with a range of epileptic encephalopathies. In addition, we ascertained cases with SCN8A mutations from other centers. A detailed clinical history was obtained together with a review of EEG and imaging data. RESULTS: Seventeen patients with de novo heterozygous mutations of SCN8A were studied. Seizure onset occurred at a mean age of 5 months (range: 1 day to 18 months); in general, seizures were not triggered by fever. Fifteen of 17 patients had multiple seizure types including focal, tonic, clonic, myoclonic and absence seizures, and epileptic spasms; seizures were refractory to antiepileptic therapy. Development was normal in 12 patients and slowed after seizure onset, often with regression; 5 patients had delayed development from birth. All patients developed intellectual disability, ranging from mild to severe. Motor manifestations were prominent including hypotonia, dystonia, hyperreflexia, and ataxia. EEG findings comprised moderate to severe background slowing with focal or multifocal epileptiform discharges. CONCLUSION: SCN8A encephalopathy presents in infancy with multiple seizure types including focal seizures and spasms in some cases. Outcome is often poor and includes hypotonia and movement disorders. The majority of mutations arise de novo, although we observed a single case of somatic mosaicism in an unaffected parent.
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Encefalopatías/genética , Epilepsia/genética , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.6/genética , Fenotipo , Adolescente , Encefalopatías/diagnóstico , Encefalopatías/fisiopatología , Niño , Preescolar , Electroencefalografía/métodos , Epilepsia/diagnóstico , Epilepsia/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Internacionalidad , MasculinoRESUMEN
Understanding the connection between protein structure and function requires a quantitative understanding of electrostatic effects. Structure-based electrostatic calculations are essential for this purpose, but their use has been limited by a long-standing discussion on which value to use for the dielectric constants (ε(eff) and ε(p)) required in Coulombic and Poisson-Boltzmann models. The currently used values for ε(eff) and ε(p) are essentially empirical parameters calibrated against thermodynamic properties that are indirect measurements of protein electric fields. We determine optimal values for ε(eff) and ε(p) by measuring protein electric fields in solution using direct detection of NMR chemical shift perturbations (CSPs). We measured CSPs in 14 proteins to get a broad and general characterization of electric fields. Coulomb's law reproduces the measured CSPs optimally with a protein dielectric constant (ε(eff)) from 3 to 13, with an optimal value across all proteins of 6.5. However, when the water-protein interface is treated with finite difference Poisson-Boltzmann calculations, the optimal protein dielectric constant (ε(p)) ranged from 2 to 5 with an optimum of 3. It is striking how similar this value is to the dielectric constant of 2-4 measured for protein powders and how different it is from the ε(p) of 6-20 used in models based on the Poisson-Boltzmann equation when calculating thermodynamic parameters. Because the value of ε(p) = 3 is obtained by analysis of NMR chemical shift perturbations instead of thermodynamic parameters such as pK(a) values, it is likely to describe only the electric field and thus represent a more general, intrinsic, and transferable ε(p) common to most folded proteins.