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1.
BMC Psychiatry ; 24(1): 23, 2024 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-38177999

RESUMEN

BACKGROUND: Many rare genetic neurodevelopmental disorders (RGNDs) are characterized by intellectual disability (ID), severe cognitive and behavioral impairments, potentially diagnosed as a comorbid autism spectrum disorder or attention-deficit hyperactivity disorder. Quality of life is often impaired due to irritability, aggression and self-injurious behavior, generally refractory to standard therapies. There are indications from previous (case) studies and patient reporting that cannabidiol (CBD) may be an effective treatment for severe behavioral manifestations in RGNDs. However, clear evidence is lacking and interventional research is challenging due to the rarity as well as the heterogeneity within and between disease groups and interindividual differences in treatment response. Our objective is to examine the effectiveness of CBD on severe behavioral manifestations in three RGNDs, including Tuberous Sclerosis Complex (TSC), mucopolysaccharidosis type III (MPS III), and Fragile X syndrome (FXS), using an innovative trial design. METHODS: We aim to conduct placebo-controlled, double-blind, block-randomized, multiple crossover N-of-1 studies with oral CBD (twice daily) in 30 patients (aged ≥ 6 years) with confirmed TSC, MPS III or FXS and severe behavioral manifestations. The treatment is oral CBD up to a maximum of 25 mg/kg/day, twice daily. The primary outcome measure is the subscale irritability of the Aberrant Behavior Checklist. Secondary outcome measures include (personalized) patient-reported outcome measures with regard to behavioral and psychiatric outcomes, disease-specific outcome measures, parental stress, seizure frequency, and adverse effects of CBD. Questionnaires will be completed and study medication will be taken at the participants' natural setting. Individual treatment effects will be determined based on summary statistics. A mixed model analysis will be applied for analyzing the effectiveness of the intervention per disorder and across disorders combining data from the individual N-of-1 trials. DISCUSSION: These N-of-1 trials address an unmet medical need and will provide information on the effectiveness of CBD for severe behavioral manifestations in RGNDs, potentially generating generalizable knowledge at an individual-, disorder- and RGND population level. TRIAL REGISTRATION: EudraCT: 2021-003250-23, registered 25 August 2022, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-003250-23/NL .


Asunto(s)
Trastorno del Espectro Autista , Cannabidiol , Síndrome del Cromosoma X Frágil , Mucopolisacaridosis , Esclerosis Tuberosa , Humanos , Cannabidiol/uso terapéutico , Síndrome del Cromosoma X Frágil/complicaciones , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/tratamiento farmacológico , Trastorno del Espectro Autista/tratamiento farmacológico , Calidad de Vida , Resultado del Tratamiento , Mucopolisacaridosis/inducido químicamente , Mucopolisacaridosis/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto
2.
J Intellect Disabil Res ; 68(3): 248-263, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38009976

RESUMEN

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterised by severe intellectual disability, movement disorder, epilepsy, sleeping problems, and behavioural issues. Little is known on child health-related quality of life (HRQoL) in AS. AS family studies have reported elevated parenting stress and a high impact of the child's syndrome on the parent. It is unclear which factors influence child HRQoL and parenting stress/impact in AS. METHODS: We collected data prospectively through standardised clinical assessments of children with AS at the ENCORE Expertise centre for Angelman Syndrome at the Erasmus MC Sophia Children's Hospital. A linear regression analysis was conducted for the following outcome variables: (1) child HRQoL (Infant and Toddler Quality of Life Questionnaire); (2) the impact of the child's syndrome on the parent (Infant and Toddler Quality of Life Questionnaire); and (3) parenting stress (Parenting Stress Index). Predictor variables were child genotype, epilepsy, sleeping problems (Sleep Disturbance Scale for Children), cognitive developmental level (Bayley Cognition Scale), autistic features (Autism Diagnostic Observation Schedule) and emotional/behavioural problems (Child Behaviour Checklist). Covariates were sex, age and socio-economic status. RESULTS: The study sample consisted of 73 children with AS, mean age = 9.1 years, range = 2-18 years. Emotional/behavioural problems were the strongest significant predictor of lowered child HRQoL. Internalising problems were driving this effect. In addition, having the deletion genotype and higher age was related to lower child HRQoL. Sleeping problems were related to a higher impact of the child's syndrome on the parent. Finally, emotional/behavioural problems were associated with higher parenting stress. Cognitive developmental level, autistic features and epilepsy were not a significant predictor of child HRQoL and parenting stress/impact. CONCLUSIONS: These results suggest that interventions aimed at increasing child HRQoL and decreasing parenting stress/impact in AS should focus on child emotional/behavioural problems and sleeping problems, using a family-centred approach.


Asunto(s)
Síndrome de Angelman , Epilepsia , Trastornos del Sueño-Vigilia , Lactante , Humanos , Preescolar , Niño , Adolescente , Responsabilidad Parental , Calidad de Vida , Síndrome de Angelman/complicaciones , Trastornos del Sueño-Vigilia/epidemiología
3.
Ann Vasc Surg ; 76: 330-341, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33905844

RESUMEN

OBJECTIVES: Elective abdominal aortic aneurysm (AAA) repair is performed to prevent rupture. For reasons as yet unknown, the 30-day mortality risk after elective AAA repair is higher in women than in men. We hypothesised that this higher risk might be related to differences in comorbidity. METHODS: Systematic review (PROSPERO CRD42019133314) according to PRISMA guidelines. A search in the EMBASE/MEDLINE/CENTRAL databases identified 1870 studies that included patients who underwent elective AAA repair (final search February 17th, 2021). Ultimately, 28 studies were included and all reported comorbidities were categorised into 17 comorbidity groups. Additionally, 15 groups of clearly defined comorbidities were used for sensitivity analysis. For both groups, meta-analyses of each comorbidity were performed to estimate the difference in pooled prevalence between women and men with a random effects model. RESULTS: When analysing data of all reported comorbidities (17 groups), smoking [risk difference (RD) 11%, 95% confidence interval (CI) 4-18], diabetes (RD 3%, 95% CI 2-4), ischaemic heart disease (RD 12%, 95% CI 8-16), arrhythmia (RD 3%, 95% CI 0.4-5), liver disease (RD 0.1%, 95% CI 0.01-0.2), and cancer (RD 3%, 95% CI 2-4)) were less prevalent in women, whereas, hypertension (RD 4%, 95% CI 3-6) and pulmonary disease (RD 4%, 95% CI 3-5) were more prevalent in women. At the time of surgery women were significantly older than men (74.9 years versus 72.4; mean difference 2.4 years (95% CI 2.1-2.7)). In the sensitivity analysis of 15 comorbidity groups, the same comorbidities remained significantly different between women and men, except smoking and arrhythmia. Women had a higher mortality risk than men (RD 1%, 95% CI 1-2). CONCLUSIONS: Although women undergoing elective AAA repair have fewer baseline comorbidities than men, their 30-day mortality risk is higher. In-depth studies on the cause of death in women after elective AAA repair are needed to explain this discrepancy in mortality.


Asunto(s)
Aneurisma de la Aorta Abdominal/cirugía , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Disparidades en el Estado de Salud , Anciano , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Aneurisma de la Aorta Abdominal/mortalidad , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/mortalidad , Comorbilidad , Procedimientos Quirúrgicos Electivos , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Femenino , Humanos , Masculino , Prevalencia , Medición de Riesgo , Factores de Riesgo , Factores Sexuales , Factores de Tiempo , Resultado del Tratamiento
5.
Prenat Diagn ; 37(12): 1191-1197, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28921563

RESUMEN

OBJECTIVE: Isolated agenesis of the corpus callosum on fetal ultrasound has a varied prognosis. Microarray and exome sequencing (ES) might aid in prenatal counseling. METHOD: This study includes 25 fetuses with apparently isolated complete corpus callosum (cACC) on ultrasound. All cases were offered single nucleotide polymorphism array. Complementary ES was offered postnatally in selected cases. Clinical physical and neurodevelopmental follow-up was collected. RESULTS: Eighteen cases opted for single nucleotide polymorphism array testing, which detected a causal anomaly in 2/18 (11.1%; 95% CI 2.0%-31%). Among ongoing pregnancies without a causal anomaly on microarray, 30% (95% CI 8.5%-60%) showed intellectual disability. Postnatal magnetic resonance imaging and physical examination often (64%; 95% CI 38%-85%, and 64%; 95% CI 38%-85%, respectively) revealed additional physical anomalies in cases without a causal anomaly on microarray. Two cases appeared truly isolated after birth. Postnatal sequencing in 4 of 16 cases without a causal anomaly on microarray but with intellectual disability and/or additional postnatal physical anomalies revealed 2 single-gene disorders. Therefore, the estimated diagnostic yield of ES in chromosomally normal cACC fetuses is between 2/4 (50%; 95% CI 11%-89%) and 2/16 (13.3%; 95% CI 2.4%-36%). CONCLUSION: In accordance with current guidelines, we conclude that microarray should be offered in case of isolated cACC on ultrasound. ES is likely to be informative for prenatal counseling and should be offered if microarray is normal.


Asunto(s)
Agenesia del Cuerpo Calloso/genética , Pruebas Genéticas , Adulto , Agenesia del Cuerpo Calloso/diagnóstico por imagen , Encefalopatías/diagnóstico por imagen , Estudios de Cohortes , Femenino , Asesoramiento Genético , Humanos , Ventrículos Laterales/anomalías , Ventrículos Laterales/diagnóstico por imagen , Imagen por Resonancia Magnética , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Embarazo , Análisis de Secuencia de ADN , Ultrasonografía Prenatal
6.
Eur J Paediatr Neurol ; 21(4): 654-660, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28461111

RESUMEN

OBJECTIVE: To define age-specific reference values for cerebrospinal fluid (CSF) total protein levels for children and validate these values in children with Guillain-Barré syndrome (GBS), acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS). METHODS: Reference values for CSF total protein levels were determined in an extensive cohort of diagnostic samples from children (<18 year) evaluated at Erasmus Medical Center/Sophia Children's Hospital. These reference values were confirmed in children diagnosed with disorders unrelated to raised CSF total protein level and validated in children with GBS, ADEM and MS. RESULTS: The test results of 6145 diagnostic CSF samples from 3623 children were used to define reference values. The reference values based on the upper limit of the 95% CI (i.e. upper limit of normal) were for 6 months-2 years 0.25 g/L, 2-6 years 0.25 g/L, 6-12 years 0.28 g/L, 12-18 years 0.34 g/L. These reference values were confirmed in a subgroup of 378 children diagnosed with disorders that are not typically associated with increased CSF total protein. In addition, the CSF total protein levels in these children in the first 6 months after birth were highly variable (median 0.47 g/L, IQR 0.26-0.65). According to these new reference values, CSF total protein level was elevated in 85% of children with GBS, 66% with ADEM and 23% with MS. CONCLUSION: More accurate age-specific reference values for CSF total protein levels in children were determined. These new reference values are more sensitive than currently used values for diagnosing GBS and ADEM in children.


Asunto(s)
Líquido Cefalorraquídeo/química , Niño , Preescolar , Estudios de Cohortes , Encefalomielitis Aguda Diseminada/líquido cefalorraquídeo , Femenino , Síndrome de Guillain-Barré/líquido cefalorraquídeo , Humanos , Masculino , Valores de Referencia
7.
J Neurol ; 264(1): 161-167, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27878438

RESUMEN

Cognitive development in patients with tuberous sclerosis complex is highly variable. Predictors in the infant years would be valuable to counsel parents and to support development. The aim of this study was to confirm factors that have been reported to be independently correlated with cognitive development. 102 patients included in this study were treated at the ENCORE-TSC expertise center of the Erasmus Medical Center-Sophia Children's Hospital. Data from the first 24 months of life were used, including details on epilepsy, motor development and mutation status. Outcome was defined as cognitive development (intellectual equivalent, IE) as measured using tests appropriate to the patients age and cognitive abilities (median age at testing 8.2 years, IQR 4.7-12.0). Univariable and multivariable regression analyses were used. In a univariable analysis, predictors of lower IE were: the presence of infantile spasms (ß = -18.3, p = 0.000), a larger number of antiepileptic drugs used (ß = -6.3, p = 0.000), vigabatrin not used as first drug (ß = -14.6, p = 0.020), corticosteroid treatment (ß = -33.2, p = 0.005), and a later age at which the child could walk independently (ß = -2.1, p = 0.000). An older age at seizure onset predicted higher IE (ß = 1.7, p = 0.000). In a multivariable analysis, only age at seizure onset was significantly correlated to IE (ß = 1.2, p = 0.005), contributing to 28% of the variation in IE. In our cohort, age at seizure onset was the only variable that independently predicted IE. Factors predicting cognitive development could aid parents and physicians in finding the appropriate support and schooling for these patients.


Asunto(s)
Cognición , Inteligencia , Esclerosis Tuberosa/diagnóstico , Esclerosis Tuberosa/psicología , Edad de Inicio , Niño , Desarrollo Infantil , Preescolar , Epilepsia/diagnóstico , Epilepsia/epidemiología , Epilepsia/psicología , Epilepsia/terapia , Femenino , Estudios de Seguimiento , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/genética , Pruebas de Inteligencia , Masculino , Análisis Multivariante , Pronóstico , Psicología Infantil , Análisis de Regresión , Estudios Retrospectivos , Esclerosis Tuberosa/epidemiología , Esclerosis Tuberosa/terapia
8.
Ultrasound Obstet Gynecol ; 49(3): 342-348, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27102944

RESUMEN

OBJECTIVE: To assess phenotypic and genotypic characteristics of small-for-gestational-age (SGA) fetuses without structural anomalies at 18-24 weeks' gestation. METHODS: This retrospective study included structurally normal singleton fetuses with an abdominal circumference ≤ 5th percentile on detailed ultrasound examination between 18 and 24 weeks' gestation. Cases were stratified according to the absence or presence of other abnormal ultrasound findings, such as abnormal amniotic fluid or soft markers. All patients were offered invasive prenatal testing with rapid aneuploidy detection by qualitative fluorescence polymerase chain reaction (QF-PCR) and, if normal, consecutive single nucleotide polymorphism (SNP) array was also offered. Detailed postnatal follow-up (≥ 5 months) was performed. In cases in which a syndromic phenotype became apparent within 5 months after birth and SNP array had not been performed prenatally, it was performed postnatally. RESULTS: A total of 211 pregnancies were eligible for inclusion. Of the 158 cases with isolated SGA on ultrasound, 36 opted for invasive prenatal testing. One case of trisomy 21 and one case of a submicroscopic abnormality (a susceptibility locus for neurodevelopmental disease) were detected. Postnatal follow-up showed a postnatal apparent syndromic phenotype in 10 cases. In one case this was due to trisomy 21 and the other nine (5.8%; 95% CI, 2.8-10.0%) cases had normal SNP array results. In 32/53 cases with SGA and associated ultrasound abnormalities, parents opted for invasive testing. One case of trisomy 21 and one of triploidy were found. In 11 cases a syndromic phenotype became apparent after birth. One was due to trisomy 21 and in one case a submicroscopic anomaly (a susceptibility locus) was found. The remaining syndromic cases (17.3%; 95% CI, 8.7-29.0%) had normal SNP array results. CONCLUSION: Testing for chromosomal anomalies should be offered in cases of SGA between 18 and 24 weeks' gestation. Whole chromosome anomalies occur in 1.3% (95% CI, 0.2-3.9%) of isolated SGA and 5.8% (95% CI, 1.5-14.0%) of associated SGA. In 0.6% (95% CI, 0.1-2.8%) and 1.9% (95% CI, 0.2-8.2%), respectively, SNP array detected a susceptibility locus for neurodevelopmental disease that would not be detected by karyotyping, QF-PCR or non-invasive prenatal testing. Therefore, and because the genetic causes of SGA are diverse, we suggest SNP array testing in cases of SGA. Thorough postnatal examination and follow-up of infants that presented with reduced fetal growth is important because chromosomally normal syndromic phenotypes occur frequently in SGA fetuses. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.


Asunto(s)
Aberraciones Cromosómicas/estadística & datos numéricos , Peso Fetal/genética , Diagnóstico Prenatal/métodos , Ultrasonografía/métodos , Adolescente , Adulto , Aneuploidia , Tamaño Corporal , Femenino , Humanos , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Edad Materna , Fenotipo , Atención Posnatal , Embarazo , Segundo Trimestre del Embarazo , Estudios Retrospectivos , Ultrasonografía Prenatal/métodos , Adulto Joven
10.
Ultrasound Obstet Gynecol ; 43(2): 139-46, 2014 02.
Artículo en Inglés | MEDLINE | ID: mdl-23897843

RESUMEN

OBJECTIVE: To establish the prevalence of submicroscopic genetic copy number variants (CNVs) in fetuses with a structural ultrasound anomaly (restricted to one anatomical system) and a normal karyotype. The aim was to determine the diagnostic and prognostic value of genomic array testing in these pregnancies. METHODS: Embase and PubMed databases were systematically searched for all relevant articles on prevalence of pathogenic submicroscopic CNVs in fetuses with ultrasound anomalies. Reported cases were sorted into groups according to anatomical site of the detected ultrasound anomaly. The prevalence of causative submicroscopic CNVs was calculated for each group. RESULTS: Combined data of the reviewed studies (n = 18) indicated that fetuses with an ultrasound anomaly restricted to one anatomical system (n = 2220) had a 3.1-7.9% chance of carrying a causative submicroscopic CNV, depending on the anatomical system affected. This chance increased to 9.1% for fetuses with multiple ultrasound anomalies (n = 1139). CONCLUSION: This review indicates that 3.1-7.9% of fetuses with a structural ultrasound anomaly restricted to one anatomical system and a normal karyotype will show a submicroscopic CNV, which explains its phenotype and provides information for fetal prognosis. Therefore, we conclude that microarray has considerable diagnostic and prognostic value in these pregnancies.


Asunto(s)
Variaciones en el Número de Copia de ADN , Enfermedades Fetales , Análisis de Secuencia por Matrices de Oligonucleótidos , Diagnóstico Prenatal , Femenino , Enfermedades Fetales/diagnóstico por imagen , Enfermedades Fetales/genética , Genómica , Humanos , Cariotipificación , Embarazo , Pronóstico , Ultrasonografía Prenatal
11.
Neurology ; 76(9): 807-10, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21357832

RESUMEN

OBJECTIVE: To determine whether recognition of Guillain-Barré syndrome (GBS) is delayed in preschool children, what causes this delay, and if the clinical presentation differs from older children. METHODS: In a retrospective cohort study, standardized data from all children with GBS seen at the Erasmus MC Sophia Children's University Hospital in Rotterdam from 1987 to 2009 were collected regarding clinical presentation, patient's delay, initial diagnosis, and doctor's delay to the diagnosis. We compared preschool children (<6 years old) with older children (6-18 years old). RESULTS: GBS was diagnosed in 23 preschool children and in 32 older children. Fifteen (68%) of the preschool children were initially misdiagnosed compared to 6 (21%) of the older children (p = 0.001). Median patient delay to consult a pediatrician in both age groups was the same (5.0 days). The median doctor's delay to diagnose possible GBS in preschool children was significantly longer than in older children (3 days vs 0 days). In one-quarter of preschool children, this doctor's delay was more than 1 week, up to 22 days. In preschool children, refusal to walk and pain in the legs were the most frequent presenting symptoms (65%), while older children presented with more classic symptoms of weakness and paresthesias. The preschool children were initially misdiagnosed with myopathy, tonsillitis, meningitis, rheumatoid disorders, coxitis, or discitis. CONCLUSION: The diagnosis of GBS in preschool children is delayed compared to older children. This delay is partly explained by the nonspecific clinical presentation, challenging neurologic examination, and alternative diagnoses in preschool children.


Asunto(s)
Errores Diagnósticos , Síndrome de Guillain-Barré/diagnóstico , Adolescente , Factores de Edad , Niño , Preescolar , Estudios de Cohortes , Resultado Fatal , Femenino , Síndrome de Guillain-Barré/sangre , Humanos , Lactante , Masculino , Estudios Retrospectivos , Factores de Tiempo
12.
Eur J Med Genet ; 54(3): 299-300, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21194575

RESUMEN

Recently in this journal, Masurel-Paulet et al. reported the association between pulmonary disease and a mutation in X-linked FLNA in a male patient. We confirm this association in a female patient, showing that this complication is not sex-specific. Our patient has a FLNA missense mutation (c.220G > A) and presented with cerebral periventricular nodular heterotopia, cardiovascular abnormalities, and pulmonary disease consisting of lobar emphysema of the right middle pulmonary lobe with severe malacia of the right sided bronchus intermedius. Surgical resection of the right middle lobe was necessary and she had long-term oxygen dependency. Symptoms improved with age.


Asunto(s)
Anomalías Múltiples/genética , Proteínas Contráctiles/genética , Enfermedades Pulmonares/patología , Proteínas de Microfilamentos/genética , Mutación Missense , Anomalías Múltiples/patología , Anomalías Cardiovasculares/patología , Preescolar , Femenino , Filaminas , Humanos , Lactante , Heterotopia Nodular Periventricular/patología
13.
Mol Syndromol ; 1(3): 113-120, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21031080

RESUMEN

Partial monosomy 21 has been reported, but the phenotypes described are variable with location and size of the deletion. We present 2 patients with a partially overlapping microdeletion of 21q22 and a striking phenotypic resemblance. They both presented with severe psychomotor delay, behavioral problems, no speech, microcephaly, feeding problems with frequent regurgitation, idiopathic thrombocytopenia, obesity, deep set eyes, down turned corners of the mouth, dysplastic ears, and small chin. Brain MRI showed cerebral atrophy mostly evident in frontal and temporal lobes, widened ventricles and thin corpus callosum in both cases, and in one patient evidence of a migration disorder. The first patient also presented with epilepsy and a ventricular septum defect. The second patient had a unilateral Peters anomaly. Microarray analysis showed a partially overlapping microdeletion spanning about 2.5 Mb in the 21q22.1-q22.2 region including the DYRK1A gene and excluding RUNX1. These patients present with a recognizable phenotype specific for this 21q22.1-q22.2 locus. We searched the literature for patients with overlapping deletions including the DYRK1A gene, in order to define other genes responsible for this presentation.

14.
Seizure ; 19(7): 450-2, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20637656

RESUMEN

We report a case of a girl who presented with typical absence seizures at age of 4.5 years. EEG showed absence seizures of sudden onset with 3 Hz spike-and-waves that also correlated with the clinical absences. The seizure semiology included subtle deviation of the eyes which prompted MRI investigation of the brain. This showed a periventricular nodular heterotopia in the mid to anterior horn of the right lateral ventricle. Although possibly coincidental, periventricular heterotopia are considered to be epileptogenic and this association has been reported once before. Migration disorders, such as in the periventricular heterotopia of our patient, may influence the formation and excitability of the striato-thalamo-cortical network involved in the generation of 3 Hz spike-waves.


Asunto(s)
Epilepsia Tipo Ausencia/etiología , Epilepsia Tipo Ausencia/patología , Heterotopia Nodular Periventricular/complicaciones , Heterotopia Nodular Periventricular/patología , Anticonvulsivantes/uso terapéutico , Preescolar , Quimioterapia Combinada , Electroencefalografía , Epilepsia Tipo Ausencia/tratamiento farmacológico , Femenino , Humanos , Lamotrigina , Imagen por Resonancia Magnética , Triazinas/administración & dosificación , Ácido Valproico/administración & dosificación
15.
Neurogenetics ; 10(4): 333-6, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19384555

RESUMEN

We report a child with a severe choreadystonic movement disorder, bilateral periventricular nodular heterotopia (BPNH), and secondary microcephaly based on compound heterozygosity for two new ARFGEF2 mutations (c.2031_2038dup and c.3798_3802del), changing the limited knowledge about the phenotype. The brain MRI shows bilateral hyperintensity of the putamen, BPNH, and generalized atrophy. Loss of ARFGEF2 function affects vesicle trafficking, proliferation/apoptosis, and neurotransmitter receptor function. This can explain BPNH and microcephaly. We hypothesize that the movement disorder and the preferential damage to the basal ganglia, specifically to the putamen, may be caused by an increased sensitivity to degeneration, a dynamic dysfunction due to neurotransmitter receptor mislocalization or a combination of both.


Asunto(s)
Movimiento Celular/fisiología , Factores de Intercambio de Guanina Nucleótido/genética , Trastornos del Movimiento/genética , Mutación , Neuronas/fisiología , Heterotopia Nodular Periventricular/genética , Anomalías Múltiples/genética , Secuencia de Bases , Encéfalo/citología , Encéfalo/patología , Niño , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Microcefalia/genética , Microcefalia/patología , Datos de Secuencia Molecular , Trastornos del Movimiento/patología , Trastornos del Movimiento/fisiopatología , Heterotopia Nodular Periventricular/patología , Heterotopia Nodular Periventricular/fisiopatología , Fenotipo
16.
J Neurol Neurosurg Psychiatry ; 80(4): 426-8, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19289478

RESUMEN

Filamin A is an important gene involved in the development of the brain, heart, connective tissue and blood vessels. A case is presented illustrating the challenge in recognising patients with filamin A mutations. The patient, a 71-year-old woman, was known to have heart valve disease and bilateral periventricular nodular heterotopia when she died of a subarachnoid haemorrhage. Autopsy showed typical cerebral bilateral periventricular heterotopia and vascular abnormalities. Postmortally, the diagnosis of a filamin A mutation was confirmed. Recognition during life may prevent cardiovascular problems and provide possibilities for genetic counselling.


Asunto(s)
Proteínas Contráctiles/genética , Cardiopatías Congénitas/etiología , Cardiopatías Congénitas/genética , Aneurisma Intracraneal/etiología , Aneurisma Intracraneal/genética , Proteínas de Microfilamentos/genética , Mutación/genética , Mutación/fisiología , Heterotopia Nodular Periventricular/etiología , Heterotopia Nodular Periventricular/genética , Anciano , Encéfalo/patología , Angiografía Cerebral , ADN/genética , Exones/genética , Resultado Fatal , Femenino , Filaminas , Cardiopatías Congénitas/patología , Humanos , Aneurisma Intracraneal/patología , Angiografía por Resonancia Magnética , Heterotopia Nodular Periventricular/patología , Tomografía Computarizada por Rayos X
17.
Neurogenetics ; 7(4): 259-63, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16972080

RESUMEN

Two families are presented with a child suffering from microcephaly with a simplified gyral pattern of the brain (SGP) and early onset insulin dependent diabetes mellitus (IDDM). The first patient was diagnosed postmortally with Wolcott-Rallison syndrome, after her younger brother developed IDDM, and a homozygous mutation in the eukaryotic translation initiation factor 2-alpha kinase 3 was found. The younger brother did not undergo magnetic resonance imaging (MRI). The patient from the second family has no EIF2AK3 mutation. SGP is considered to arise from decreased neuronal proliferation or increased apoptosis at an early stage of embryonal development, but insight into the pathways involved is minimal. EIF2AK3 is involved in translation initiation. It has been proposed that loss of function mutations reduce the ability of the cell to respond to endoplasmic reticulum stress, resulting in apoptosis of pancreatic Langerhans cells. Our findings suggest that in some cases, early onset IDDM and SGP can arise from common mechanisms leading to increased apoptosis.


Asunto(s)
Corteza Cerebral/anomalías , Diabetes Mellitus Tipo 1/complicaciones , Microcefalia/complicaciones , Microcefalia/patología , Edad de Inicio , Corteza Cerebral/patología , Femenino , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Osteocondrodisplasias/diagnóstico por imagen , Osteoporosis/diagnóstico por imagen , Radiografía
18.
Mol Genet Metab ; 87(2): 102-6, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16275149

RESUMEN

Malonyl-CoA decarboxylase (MCD) deficiency is an extremely rare inborn error of metabolism that presents with metabolic acidosis, hypoglycemia, and/or cardiomyopathy. Patients also show neurological signs and symptoms that have been infrequently reported. We describe a girl with MCD deficiency, whose brain MRI shows white matter abnormalities and additionally diffuse pachygyria and periventricular heterotopia, consistent with a malformation of cortical development. MLYCD-gene sequence analysis shows normal genomic sequence but no messenger product, suggesting an abnormality of transcription regulation. Our patient has strikingly low appetite, which is interesting in the light of the proposed role of malonyl-CoA in the regulation of feeding control, but this remains to be confirmed in other patients. Considering the incomplete understanding of the role of metabolic pathways in brain development, patients with MCD deficiency should be evaluated with brain MRI and unexplained malformations of cortical development should be reason for metabolic screening.


Asunto(s)
Encefalopatías Metabólicas/genética , Encéfalo/anomalías , Carboxiliasas/deficiencia , Agenesia del Cuerpo Calloso , Encefalopatías Metabólicas/enzimología , Tronco Encefálico/anomalías , Carboxiliasas/genética , Células Cultivadas , Cerebelo/anomalías , Corteza Cerebral/anomalías , Preescolar , Análisis Mutacional de ADN , Ingestión de Alimentos/genética , Femenino , Fibroblastos/enzimología , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Persona de Mediana Edad , Piel/citología , Piel/enzimología
19.
Neurology ; 63(3): 535-7, 2004 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-15304589

RESUMEN

To determine the frequency of progressive MRI lesions shortly after radiotherapy for glioma with spontaneous improvement or stabilization, the authors studied a cohort of patients treated within two prospective phase III trials with radiotherapy only. In 9 out of 32 patients, the first post-radiotherapy MRI showed progressive enhancement. In 3 of these 9 the MRI improved or stabilized for 6 months without additional treatment. The authors conclude that patients with progressive lesions within 3 months after radiotherapy should not be eligible for phase II trials on recurrent glioma.


Asunto(s)
Artefactos , Edema Encefálico/etiología , Neoplasias Encefálicas/radioterapia , Irradiación Craneana , Dacarbazina/análogos & derivados , Glioma/radioterapia , Imagen por Resonancia Magnética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/tratamiento farmacológico , Astrocitoma/patología , Astrocitoma/radioterapia , Astrocitoma/cirugía , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Quimioterapia Adyuvante , Ensayos Clínicos Fase III como Asunto/normas , Estudios de Cohortes , Terapia Combinada , Medios de Contraste , Dacarbazina/administración & dosificación , Dexametasona/uso terapéutico , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Gadolinio , Glioma/tratamiento farmacológico , Glioma/patología , Humanos , Lomustina/administración & dosificación , Masculino , Persona de Mediana Edad , Selección de Paciente , Procarbazina/administración & dosificación , Temozolomida , Vincristina/administración & dosificación
20.
Pediatr Pulmonol ; 29(6): 434-7, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10821724

RESUMEN

The single-breath maneuver used to measure nitric oxide (NO) in adults cannot be performed by young children. We, therefore, developed a method of measuring NO in mixed exhaled gas collected during tidal breathing. NO was measured in mixed exhaled gas during 5 min of tidal breathing in 113 children 4-14 years of age: 22 nonasthmatics, 21 asthmatic children not taking inhaled corticosteroids, and 70 asthmatic children using inhaled corticosteroids. Exhaled NO levels (median, range) were significantly lower in nonasthmatic controls (median, range: 7, 2-10 ppb) than in asthmatic children on inhaled corticosteroids (8, 3-25 ppb; 95% CI for difference in medians with those of controls, 0-4 ppb), and in those not on inhaled corticosteroids (13, 6-37, ppb; 95% CI for difference in medians, 5-17 ppb). Asthmatic children not using inhaled corticosteroids had significantly higher exhaled NO levels than asthmatic children using inhaled corticosteroids (95% CI for difference in medians, 3-10 ppb). The tidal breathing method is a useful and practical way of measuring exhaled NO levels in children regardless of their age.


Asunto(s)
Asma/fisiopatología , Óxido Nítrico/análisis , Respiración , Administración por Inhalación , Adolescente , Corticoesteroides/administración & dosificación , Pruebas Respiratorias/métodos , Niño , Preescolar , Femenino , Humanos , Masculino , Sensibilidad y Especificidad , Volumen de Ventilación Pulmonar
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