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1.
Hum Mutat ; 41(4): 837-849, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31898846

RESUMEN

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.


Asunto(s)
Mutación con Ganancia de Función , Estudios de Asociación Genética , Genotipo , Helicasa Inducida por Interferón IFIH1/genética , Fenotipo , Alelos , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades Autoinmunes del Sistema Nervioso/genética , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Helicasa Inducida por Interferón IFIH1/química , Masculino , Modelos Moleculares , Malformaciones del Sistema Nervioso/diagnóstico , Malformaciones del Sistema Nervioso/genética , Conformación Proteica , Relación Estructura-Actividad
2.
Clin Genet ; 98(2): 147-154, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32385905

RESUMEN

Variants in the FIG4 gene, which encodes a phosphatidylinositol-3,5-bisphosphatase lead to obstruction of endocytic trafficking, causing accumulation of enlarged vesicles in murine peripheral neurons and fibroblasts. Bi-allelic pathogenic variants in FIG4 are associated with neurological disorders including Charcot-Marie-Tooth disease type-4J (CMT4J) and Yunis-Varón syndrome (YVS). We present four probands from three unrelated families, all homozygous for a recurrent FIG4 missense variant c.506A>C p.(Tyr169Ser), with a novel phenotype involving features of both CMT4J and YVS. Three presented with infant-onset dystonia and one with hypotonia. All have depressed lower limb reflexes and distal muscle weakness, two have nerve conduction studies (NCS) consistent with severe sensorimotor demyelinating peripheral neuropathy and one had NCS showing patchy intermediate/mildly reduced motor conduction velocities. All have cognitive impairment and three have swallowing difficulties. MRI showed cerebellar atrophy and bilateral T2 hyperintense medullary swellings in all patients. These children represent a novel clinicoradiological phenotype and suggest that phenotypes associated with FIG4 missense variants do not neatly fall into previously described diagnoses but can present with variable features. Analysis of this gene should be considered in patients with central and peripheral neurological signs and medullary radiological changes, providing earlier diagnosis and informing reproductive choices.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Displasia Cleidocraneal/genética , Displasia Ectodérmica/genética , Flavoproteínas/genética , Predisposición Genética a la Enfermedad , Deformidades Congénitas de las Extremidades/genética , Micrognatismo/genética , Monoéster Fosfórico Hidrolasas/genética , Edad de Inicio , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/patología , Niño , Preescolar , Displasia Cleidocraneal/complicaciones , Displasia Cleidocraneal/patología , Distonía/complicaciones , Distonía/genética , Distonía/patología , Displasia Ectodérmica/complicaciones , Displasia Ectodérmica/patología , Femenino , Genotipo , Humanos , Deformidades Congénitas de las Extremidades/complicaciones , Deformidades Congénitas de las Extremidades/patología , Masculino , Micrognatismo/complicaciones , Micrognatismo/patología , Hipotonía Muscular/complicaciones , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Mutación/genética , Linaje , Fenotipo
3.
Hum Mutat ; 40(5): 619-630, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30740813

RESUMEN

The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G > A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects in the FIG4 null mouse and the known role of FIG4 in oligodendrocyte maturation. The families described here the expanded clinical spectrum of FIG4 deficiency to include leukoencephalopathy.


Asunto(s)
Alelos , Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/genética , Flavoproteínas/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación , Monoéster Fosfórico Hidrolasas/genética , Niño , Preescolar , Análisis Mutacional de ADN , Enfermedades Desmielinizantes/metabolismo , Fibroblastos/metabolismo , Genotipo , Humanos , Patrón de Herencia , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Linaje , Fenotipo
4.
Cochrane Database Syst Rev ; (6): CD005222, 2015 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-26086765

RESUMEN

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 1, 2007.Epilepsy is a disorder with recurrent epileptic seizures. Corticosteroids have been used in the treatment of children with epilepsy and have significant adverse effects. Their efficacy and tolerability have not been clearly established. OBJECTIVES: To determine the efficacy, in terms of seizure control, improvements in cognition and in quality of life and tolerability of steroids compared to placebo or other antiepileptic drugs in children with epilepsy, excluding epileptic spasms. SEARCH METHODS: We searched the following databases: The Cochrane Epilepsy Group Specialized Register (1 August 2014); CENTRAL, (The Cochrane Library Issue 7, July 2014); MEDLINE (1946 to 1 August 2014); EMBASE (1966 to December 2004); Database of Abstracts of Reviews of Effectiveness (DARE; Issue 3 of the database published in The Cochrane Library Issue 7, July 2014); ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform ICTRP (1 August 2014).We checked the reference lists of retrieved studies for additional reports of relevant studies. SELECTION CRITERIA: All randomised controlled trials of administration of corticosteroids to children (less than 16 years) with epilepsy. DATA COLLECTION AND ANALYSIS: For this update two review authors independently selected trials for inclusion and extracted data. Outcomes included cessation of seizures, reduction in seizure frequency, improvement in cognition, quality of life and adverse effects of steroids. MAIN RESULTS: A single RCT was included that recruited five children in a double blind cross-over trial. One child was withdrawn prematurely from the study and another had infantile spasms and hence was excluded from further analysis. Adrenocorticotrophin hormone (ACTH 4-9) was administered. Of the three children analysed, one showed a reduction in seizures of 25% to 50% at both the low and higher doses of corticosteroids compared to placebo; one child showed a reduction in seizures at the higher dose only and one child showed no reduction in seizures at either dose. No adverse effects were reported. AUTHORS' CONCLUSIONS: Since the last version of this review no new evidence has been found for the efficacy of corticosteroids in treating childhood epilepsies. Clinicians using steroids in childhood epilepsies, other than for epileptic spasms, should take this into account before using these agents.


Asunto(s)
Corticoesteroides/uso terapéutico , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Hormona Adrenocorticotrópica/uso terapéutico , Niño , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto
5.
Childs Nerv Syst ; 31(6): 931-9, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25896219

RESUMEN

PURPOSE: The demand for paediatric epilepsy surgery in the UK greatly exceeds the number of operations performed. Hence, Children's Epilepsy Surgery Service (CESS) was commenced in 2012. This study is aimed to characterise the changes in service delivery in the North East of England Paediatric Neuroscience Network and nationally. METHODS: A retrospective cohort study of paediatric epilepsy surgery in Leeds between 2005 and 2012 is presented followed by analysis of British Paediatric Neurosurgical Group (BPNG) data before and after CESS commissioning. RESULTS: During the study period, 42 children underwent epilepsy surgery in Leeds. The commonest aetiologies were neoplasm (33%), focal cortical dysplasia (19%) and mesial temporal sclerosis (19%). Seizure outcome was 71 % EngelI and 83% EngelI+II. Complications included one infection (2%), two temporary (5%) and one permanent (2%) motor deficits, three new/worsened visual field deficits (7%). There were six re-craniotomies (14%). The BPNG data show a 48% increase in paediatric epilepsy surgery in England between 2009 (90 cases) and 2012 (133 cases), and a 20% fall in 2013 (106 cases)--the first calendar year for CESS. On average, 64% of all operations were performed in London. CONCLUSIONS: The number of children receiving surgery for epilepsy in England had increased annually up to, and declined after, the establishment of CESS centres. The yearly caseload in neurosurgical units outside of London is small. The outcomes from Leeds are comparable to those published elsewhere. Other UK units are encouraged to publish outcomes to facilitate patient, commissioner and provider decision making.


Asunto(s)
Epilepsia/cirugía , Auditoría Administrativa/métodos , Auditoría Administrativa/tendencias , Monitorización Neurofisiológica/métodos , Procedimientos Neuroquirúrgicos/métodos , Niño , Preescolar , Estudios de Cohortes , Electroencefalografía , Inglaterra/epidemiología , Femenino , Humanos , Masculino , Valores de Referencia , Resultado del Tratamiento
6.
Front Neurol ; 13: 918022, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35911904

RESUMEN

We report the genetic analysis of two consanguineous pedigrees of Pakistani ancestry in which two siblings in each family exhibited developmental delay, epilepsy, intellectual disability and aggressive behavior. Whole-genome sequencing was performed in Family 1, and we identified ~80,000 variants located in regions of homozygosity. Of these, 615 variants had a minor allele frequency ≤ 0.001, and 21 variants had CADD scores ≥ 15. Four homozygous exonic variants were identified in both affected siblings: PDZD7 (c.1348_1350delGAG, p.Glu450del), ALG6 (c.1033G>C, p.Glu345Gln), RBM20 (c.1587C>G, p.Ser529Arg), and CNTNAP2 (c.785G>A, p.Gly228Arg). Sanger sequencing revealed co-segregation of the PDZD7, RBM20, and CNTNAP2 variants with disease in Family 1. Pathogenic variants in PDZD7 and RBM20 are associated with autosomal recessive non-syndromic hearing loss and autosomal dominant dilated cardiomyopathy, respectively, suggesting that these variants are unlikely likely to contribute to the clinical presentation. Gene panel analysis was performed on the two affected siblings in Family 2, and they were found to also be homozygous for the p.Gly228Arg CNTNAP2 variant. Together these families provide a LOD score 2.9 toward p.Gly228Arg CNTNAP2 being a completely penetrant recessive cause of this disease. The clinical presentation of the affected siblings in both families is also consistent with previous reports from individuals with homozygous CNTNAP2 variants where at least one allele was a nonsense variant, frameshift or small deletion. Our data suggests that homozygous CNTNAP2 missense variants can also contribute to disease, thereby expanding the genetic landscape of CNTNAP2 dysfunction.

7.
Epilepsy Res ; 154: 116-123, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31125839

RESUMEN

PURPOSE: RCTs are the gold standard in determining intervention efficacy with journal impact factor assumed to index research quality. Flint et al's (2017) systematic review examined neurocognitive outcomes following paediatric temporal lobe epilepsy surgery. Retrieved evidence was restricted to non-RCTs, which pose greater risk of bias and thus diminish research quality. The current study evaluated risk of bias in sources retrieved by Flint et al. and explored whether impact factor related to research quality within this selected field. METHODS: Methodological and reporting bias was evaluated using categories of bias specified by Cochrane. The relationship between the identified number of biases and journal impact factors of retrieved sources was examined. RESULTS: All studies carried substantial risk for bias. Methodology bias included low sample size (76.71%; 56/73), risk of confounding cognitive outcomes due to failure to report pre-surgery neurocognitive data (21.92%; 16/73) and to determine whether patients were prescribed antiepileptic drugs at follow-up (53.42%; 39/73). Reporting bias included overstating claims based on findings (53.42%; 39/73), failure to report individual patient characteristics (66%; 33/50) and omitting the nature of surgical interventions (15.07%; 11/73). The number of sources of common bias within studies was not associated significantly with journal impact factor (p = .878). CONCLUSION: This evaluation highlights risk of bias when sources are predominantly uncontrolled non-RCTs and provides evidence that journal impact factor is not a reliable indicator of quality within this field. Authors should limit bias in their methods and reporting of results, to ensure the highest quality evidence possible is used to inform treatment decisions and prognosis.


Asunto(s)
Epilepsia del Lóbulo Temporal/diagnóstico , Epilepsia del Lóbulo Temporal/cirugía , Pruebas de Estado Mental y Demencia/normas , Trastornos Neurocognitivos/diagnóstico , Psicocirugía/normas , Investigación Cualitativa , Niño , Estudios Transversales , Epilepsia del Lóbulo Temporal/psicología , Humanos , Trastornos Neurocognitivos/etiología , Trastornos Neurocognitivos/psicología , Psicocirugía/efectos adversos , Psicocirugía/psicología , Estudios Retrospectivos , Lóbulo Temporal/cirugía , Resultado del Tratamiento
8.
Seizure ; 52: 89-116, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29032016

RESUMEN

OBJECTIVE: The systematic review aimed to assess the neuropsychological outcomes of temporal lobe resections for epilepsy in children. Additional objectives included determining whether earlier age at surgery leads to better neuropsychological outcomes; the relationships between and predictors of these outcomes. METHODS: Using advanced search terms, a systematic review of electronic databases was conducted, comprising MEDLINE, Embase, PsycINFO, Global Health, Web of Science and CINAHL. Included studies reported on outcome following neurosurgical treatment for epilepsy. Specifically, studies were included if they reported neuropsychological outcomes and were concerned only with temporal lobe resection. RESULTS: 73 studies met inclusion criteria. For reported neuropsychological outcomes, the majority of participants remained stable after surgery; some declined and some improved. There was some evidence for increased material-specific memory deficits after temporal lobe surgery based on resection side, and more positive cognitive outcome for those with lower pre-surgical ability level. SIGNIFICANCE: Retrieved evidence highlights the need for improvements to quality of methodology and reporting. Appropriately designed prospective multicentre trials should be conducted with adequate follow-up for long-term outcomes to be measured. Core outcome measures should be agreed between centres. This would permit higher quality evidence so that clinicians, young people and their families may make better informed decisions about whether or not to proceed with surgery and likely post-operative profile.


Asunto(s)
Trastornos del Conocimiento/etiología , Epilepsia/cirugía , Procedimientos Neuroquirúrgicos/efectos adversos , Complicaciones Posoperatorias/etiología , Lóbulo Temporal/cirugía , Niño , Trastornos del Conocimiento/diagnóstico , Bases de Datos Factuales , Humanos , Pruebas Neuropsicológicas , Complicaciones Posoperatorias/diagnóstico
9.
Seizure ; 52: 136-146, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29055867

RESUMEN

PURPOSE: A review of all published evidence for mapping eloquent (motor, language and memory) cortex using advanced functional neuroimaging (functional magnetic resonance imaging [fMRI] and magnetoencephalography [MEG]) for paediatric epilepsy surgery candidates has not been conducted previously. Research in this area has predominantly been in adult populations and applicability of these techniques to paediatric populations is less established. METHODS: A review was performed using an advanced systematic search and retrieval of all published papers examining the use of functional neuroimaging for paediatric epilepsy surgery candidates. RESULTS: Of the 2724 papers retrieved, 34 met the inclusion criteria. Total paediatric participants identified were 353 with an age range of 5 months-19 years. Sample sizes and comparisons with alternative investigations to validate techniques are small and variable paradigms are used. Sensitivity 0.72 (95% CI 0.52-0.86) and specificity 0.60 (95% CI 0.35-0.92) values with a Positive Predictive Value of 74% (95% CI 61-87) and a Negative Predictive Value of 65% (95% CI 52-78) for fMRI language lateralisation with validation, were obtained. Retrieved studies indicate evidence that both fMRI and MEG are able to provide information lateralising and localising motor and language functions. CONCLUSIONS: A striking finding of the review is the paucity of studies (n=34) focusing on the paediatric epilepsy surgery population. For children, it remains unclear which language and memory paradigms produce optimal activation and how these should be quantified in a statistically robust manner. Consensus needs to be achieved for statistical analyses and the uniformity and yield of language, motor and memory paradigms. Larger scale studies are required to produce patient series data which clinicians may refer to interpret results objectively. If functional imaging techniques are to be the viable alternative for pre-surgical mapping of eloquent cortex for children, paradigms and analyses demonstrating concordance with independent measures must be developed.


Asunto(s)
Corteza Cerebral/diagnóstico por imagen , Epilepsia/diagnóstico por imagen , Imagen por Resonancia Magnética , Pediatría , Adolescente , Mapeo Encefálico , Corteza Cerebral/cirugía , Niño , Bases de Datos Factuales , Epilepsia/cirugía , Humanos , Magnetoencefalografía
10.
Neurol Genet ; 3(2): e143, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28357411

RESUMEN

OBJECTIVE: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. METHODS: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. RESULTS: Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. CONCLUSIONS: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.

11.
Eur J Paediatr Neurol ; 20(4): 560-5, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27140808

RESUMEN

OBJECTIVE: To establish the efficacy and tolerability of inhaled 5% carbon dioxide/95% oxygen as a treatment for paediatric non-convulsive status epilepticus (NCSE). METHODS: In an open label clinical trial, children in NCSE were given high flow inhaled 5% carbon dioxide/95% oxygen by face mask for 120 s under EEG control. RESULTS: Six children (five male; ages 3-13; all with severe underlying epilepsy and disability) were recruited. Inhalation was well tolerated in all cases. Capillary blood gasses showed no significant derangements at the end of the inhalation. Effects on EEG normalisation were limited and transient, and no clinical improvements were noted. No adverse effects occurred. CONCLUSION: Inhaled 5% carbon dioxide/95% oxygen has been suggested as a potent, well tolerated anticonvulsant. An anticonvulsant without sedating and respiration-depressing effects would be particularly welcome in the management of NCSE where the justification for aggressive anticonvulsant therapy is often uncertain, however it appears that 5% carbon dioxide is of limited efficacy in this context.


Asunto(s)
Dióxido de Carbono/uso terapéutico , Estado Epiléptico/tratamiento farmacológico , Adolescente , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Análisis de los Gases de la Sangre , Dióxido de Carbono/administración & dosificación , Dióxido de Carbono/efectos adversos , Niño , Preescolar , Electroencefalografía/efectos de los fármacos , Femenino , Humanos , Masculino
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