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1.
Am J Med Genet A ; 182(1): 20-24, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31729156

RESUMO

Okur-Chung neurodevelopmental syndrome (OCNS, MIM#617062) is a rare autosomal dominant syndrome related to CSNK2A1 mutations. It is characterized by intellectual disability, hypotonia, feeding and speech difficulties, dysmorphic features, and multisystem involvement. To date, less than 30 patients with OCNS have been described in detail in the literature, primarily in Asian populations. Here, we report a 5-year-old Spanish female with OCNS arising from a novel CSNK2A1 mutation c.149A>G, p.Tyr50Cys. Although her clinical features were compatible with OCNS syndrome, magnetic resonance imaging unexpectedly showed a duplication of the pituitary gland, a clinical finding not previously related to any known genetic condition. Other novel signs were an absence of the olfactory bulbs and multiple duplications of cervical vertebrae. We suggest that the midline abnormalities may be a significant part of this condition and lead to diagnostic suspicion. However, further descriptions are needed.

2.
eNeuro ; 6(4)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31383726

RESUMO

Brain imaging methods have contributed to shed light on the mechanisms of recovery after early brain insult. The assumption that the unaffected right hemisphere can take over language functions after left perinatal stroke is still under debate. Here, we report how patterns of brain structural and functional reorganization were associated with language outcomes in a group of four-year-old children with left perinatal arterial ischemic stroke (PAIS). Specifically, we gathered specific fine-grained developmental measures of receptive and productive aspects of language as well as standardized measures of cognitive development. We also collected structural neuroimaging data as well as functional activations during a passive listening story-telling fMRI task and a resting state session (rs-fMRI). Children with a left perinatal stroke showed larger lateralization indices of both structural and functional connectivity of the dorsal language pathway towards the right hemisphere that, in turn, were associated with better language outcomes. Importantly, the pattern of structural asymmetry was significantly more right-lateralized in children with a left perinatal brain insult than in a group of matched healthy controls. These results strongly suggest that early lesions of the left dorsal pathway and the associated perisylvian regions can induce the interhemispheric transfer of language functions to right homolog regions. This study provides combined evidence of structural and functional brain reorganization of language networks after early stroke with strong implications for neurobiological models of language development.

3.
Pediatr Neurol ; 96: 70-73, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30935719

RESUMO

BACKGROUND: Enterovirus-A71 causes outbreaks of brainstem encephalitis, ranging from self-limited disease to acute flaccid paralysis. The aim of this study was to assess the role of cerebrospinal fluid (CSF) neopterin as a biomarker of disease severity in children with enterovirus-related brainstem encephalitis. METHODS: A descriptive, prospective cohort study was conducted from April 2016 to March 2017 in a tertiary hospital. Pediatric patients with a diagnosis of brainstem encephalitis with or without myelitis due to enterovirus infection were enrolled. The final study group comprised a convenience sample including all patients with sufficient CSF volume for neopterin determination. The major variables considered in estimating the severity were the diagnosis of encephalomyelitis, the presence of lesions and extensive lesions on brain and spinal magnetic resonance imaging (MRI), hospital stay length greater than seven days, and sequelae at day 30. RESULTS: Of 60 patients, CSF neopterin could be measured in 36. Median age was 26 months (interquartile range: 19 to 32). Thirty-three were diagnosed with brainstem encephalitis and three with encephalomyelitis. Enterovirus-A71 was the only identified genotype (25 of 25). CSF neopterin levels were elevated (>61 nmol/L) in 33 of 36 (92%), with a median of 347 nmol/L (interquartile range: 204 to 525). CSF neopterin was useful to distinguish patients with lesions on MRI (area under the receiver operating characteristic curve = 0.76; P = 0.02) and extensive lesions (area under the receiver operating characteristic curve = 0.76; P = 0.04). CONCLUSIONS: This study suggests an association between CSF neopterin levels and the presence of inflammatory lesions on MRI.

4.
Acta Neurochir (Wien) ; 161(2): 351-354, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30617713

RESUMO

Choroid plexus tumors (CPT) can present in the baseline magnetic resonance imaging (MRI) with lesions compatible with leptomeningeal dissemination. Therapeutic strategy in this condition is controversial. We present a case of an infant with CPP and significant diffuse leptomeningeal contrast enhancement at diagnosis, which spontaneously resolved after removal of the primary tumor. In these challenging cases, several aspects, such as histopathological/molecular diagnosis and close radiological follow-up, should be taken into account to avoid unnecessary treatments.


Assuntos
Neoplasias Meníngeas/diagnóstico por imagem , Papiloma do Plexo Corióideo/diagnóstico por imagem , Plexo Corióideo/diagnóstico por imagem , Plexo Corióideo/patologia , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Meninges/diagnóstico por imagem , Meninges/patologia , Papiloma do Plexo Corióideo/patologia , Papiloma do Plexo Corióideo/cirurgia
5.
J Med Genet ; 56(4): 236-245, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30464053

RESUMO

INTRODUCTION: Phosphomannomutase-2 deficiency (PMM2-CDG) is associated with a recognisable facial pattern. There are no early severity predictors for this disorder and no phenotype-genotype correlation. We performed a detailed dysmorphology evaluation to describe facial gestalt and its changes over time, to train digital recognition facial analysis tools and to identify early severity predictors. METHODS: Paediatric PMM2-CDG patients were evaluated and compared with controls. A computer-assisted recognition tool was trained. Through the evaluation of dysmorphic features (DFs), a simple categorisation was created and correlated with clinical and neurological scores, and neuroimaging. RESULTS: Dysmorphology analysis of 31 patients (4-19 years of age) identified eight major DFs (strabismus, upslanted eyes, long fingers, lipodystrophy, wide mouth, inverted nipples, long philtrum and joint laxity) with predictive value using receiver operating characteristic (ROC) curveanalysis (p<0.001). Dysmorphology categorisation using lipodystrophy and inverted nipples was employed to divide patients into three groups that are correlated with global clinical and neurological scores, and neuroimaging (p=0.005, 0.003 and 0.002, respectively). After Face2Gene training, PMM2-CDG patients were correctly identified at different ages. CONCLUSIONS: PMM2-CDG patients' DFs are consistent and inform about clinical severity when no clear phenotype-genotype correlation is known. We propose a classification of DFs into major and minor with diagnostic risk implications. At present, Face2Gene is useful to suggest PMM2-CDG. Regarding the prognostic value of DFs, we elaborated a simple severity dysmorphology categorisation with predictive value, and we identified five major DFs associated with clinical severity. Both dysmorphology and digital analysis may help physicians to diagnose PMM2-CDG sooner.

6.
Parkinsonism Relat Disord ; 61: 179-186, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30340910

RESUMO

INTRODUCTION: PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features. METHODS: Observational clinical study in a cohort of infantile and childhood onset PLAN patients and genetic analysis of the PLA2G6 gene. We analysed chronological evolution in terms of age at onset and disease course through a 66-item questionnaire. We performed qualitative and quantitative assessment of MRI abnormalities and searched for clinical and radiological phenotype and genotype correlations. RESULTS: Sixteen PLAN patients (mean age: 10.2 years, range 3-33) were evaluated, with a median onset (years) of signs/symptoms as follows: neurological regression (1.5), oculomotor abnormalities (1.5), hypotonia (1.8), gait loss (2.2), pyramidal signs (3.0), axonal neuropathy (3.0), dysphagia (4.0), optic atrophy (4.0), psychiatric symptoms (4.0), seizures (5.9), joint contractures (6.0), dystonia (8.0), bladder dysfunction (13.0) and parkinsonism (15.0). MRI assessment identified cerebellar atrophy (19/19), brain iron deposition (10/19), clava hypertrophy (8/19) and T2/FLAIR hyperintensity of the cerebellar cortex (6/19). The mid-sagittal vermis relative diameter (MVRD) correlated with age at onset of clinical variants, meaning that the earlier the onset, the more severe the cerebellar atrophy. All patients harboured missense, nonsense and frameshift mutations in PLA2G6, including four novel variants. CONCLUSIONS: Cerebellar atrophy was a universal radiological sign in infantile and childhood onset PLAN, and correlated with the severity of the phenotype. Iron accumulation within the globus pallidum and substantia nigra was also a common and strikingly uniform feature regardless of the phenotype.

7.
Pediatr. catalan ; 78(3): 107-110, jul.-sept. 2018. tab, graf
Artigo em Catalão | IBECS | ID: ibc-174674

RESUMO

Fonament: La cel·lulitis orbitària (CO) és un diagnòstic de sospita clínica que requereix confirmació radiològica. És habitual l'ingrés amb tractament antibiòtic a l'espera de la confirmació diagnòstica. Objecti: Avaluar el possible impacte de la realització d'una tomografia computada (TC) en el maneig a Urgències del pacient amb sospita de CO. Mètode: Estudi retrospectiu, descriptiu-observacional. Es van revisar les històries clíniques dels pacients atesos a Urgències entre 2011 i 2014 amb diagnòstic de cel·lulitis periorbitària/orbitària. Es van incloure els casos amb sospita de CO. Es van excloure els pacients sense TC. Es defineix CO com la cel•lulitis que afecta més enllà del septe orbitari. Es van considerar criteris d'ingrés: edat <1 any, immunosupressió, vacunació incompleta, triangle d'avaluació pediàtrica (TAP) alterat, mala resposta antibiòtica i presència d'algun dels símptomes o signes oculars següents: dolor amb els moviments oculars, oftalmoplegia, disminució de l'agudesa visual, alteració dels reflexos pupil•lars, edema conjuntival i proptosi. Resultats: Es van incloure 85 pacients. Tots van ser immuno-competents, ben vacunats i presentaven un TAP normal. Vint (23,5%) presentaven un o més signes o símptomes oculars. Vint-i-set (31,8%) tenien un o més criteris d'ingrés. Dels 58 sense criteris d'ingrés, en 38 (65,5%) no es va confirmar CO. A 18 (31%) d'aquests pacients se'ls va fer TC a Urgències; en 13 casos es va indicar maneig ambulatori, ja que l'afectació era només preseptal. Es va confirmar CO en 34 pacients (concordança diagnòstica 40%).Conclusions: En més de la meitat dels pacients amb sospita de CO, aquesta no es confirma radiològicament. Fer una TC a Urgències, en els pacients que no tenen criteris d'ingrés, evitaria hospitalitzacions innecessàries en un nombre significatiu


Fundamento: La celulitis orbitaria (CO) es un diagnóstico de sospecha clínica que requiere confirmación radiológica. Es habitual el ingreso con tratamiento antibiótico a la espera de la confirmación diagnóstica. Objetivo: Evaluar el posible impacto de la realización de una tomografía computadorizada (TC) en el manejo en urgencias del paciente con sospecha de CO. Método: Estudio retrospectivo, descriptivo-observacional. Se revisaron las historias clínicas de los pacientes atendidos en Urgencias entre 2011 y 2014 con el diagnóstico de celulitis periorbitaria/orbitaria. Se incluyeron aquellos con sospecha de CO. Se excluyeron los pacientes sin TC. Se define CO como la celulitis que afecta más allá del septo orbitario. Se consideraron criterios de ingreso: edad <1 año, inmunosupresión, vacunación incompleta, triángulo de evaluación pediátrica (TEP) alterado, mala respuesta antibiótica y presencia de alguno de los siguientes síntomas o signos oculares: dolor con los movimientos oculares, oftalmoplejía, disminución de la agudeza visual, alteración de los reflejos pupilares, edema conjuntival y proptosis. Resultados: Se incluyeron 85 pacientes. Todos fueron inmunocompetentes, bien vacunados y presentaron un TEP normal. Veinte (23,5%) presentaron uno o más signos o síntomas oculares. Veintisiete (31,8%) tenían uno o más de los criterios de ingreso. De los 58 sin criterios de ingreso, en 38 (65,5%) no se confirma CO. A 18 (31%) de estos pacientes se realizó TC en urgencias; en 13 casos se indicó manejo ambulatorio, dado que la afectación era sólo preseptal. Se confirmó CO en 34 pacientes (concordancia diagnóstica 40%) Conclusiones: En más de la mitad de los pacientes con sospecha de CO, ésta no se confirma radiológicamente. La realización de TC en urgencias, en los pacientes que no tienen criterios de ingreso, evitaría hospitalizaciones innecesarias en un número significativo


Background: Orbital cellulitis (OC) is a diagnos hospitalization with intravenous antibiotic therapy until the diagnosis is confirmed. Objective: To evaluate the impact of performing a computerized tomography (CT) in the emergency department when orbital ellulitis is suspected on the initial management of the patient. Method: Descriptive observational retrospective study. Clinical records of patients who were attended in the emergency department with the diagnosis of periorbital/orbital cellulitis between 2011 and 2014 were reviewed. Patients with suspected OC were included, and those without T were excluded. OC was defined as postseptal when there was inflammatory extension posterior to the orbital septum. Criteria for hospitalization were: age < 1 year-old, immunosuppression, incomplete vaccinations, altered pediatric assessment triangle PAT), inadequate antibiotic response, and the presence of any of the following: painful ocular movements, ophthalmoplegia, decline of visual acuity, altered pupillary response, conjunctival edema, and proptosis. Results: Eighty-five patients were included. All of hem were immunocompetent, correctly vaccinated, and had normal PAT. Twenty patients (23.5%) presented > 1 ocular signs-symptoms, and 27 (31.8%) had > 1 riteria for hospitalization. In 38 of the 58 pa-tients (65.5%) without hospitalization criteria, C as not confirmed. In 18 (31%) of them, CT was performed in the Emergency Department; in 3 of them the affected area was only preseptal, and ambulatory management was indicated. he diagnosis of OC was confirmed in 34 cases (diagnostic concordance: 40%).Conclusions: in more than half of the patients with clinical suspicion of OC there is not radiological confirmation. Performing a CT in the Emergency Department in patients without hospitalization criteria would avoid unnecessary hospitalizations in a significant proportion of patients.is of clinical suspicion that requires radiologic confirmation. Performing a CT in the Emergency Department in patients without hospitalization criteria would avoid unnecessary hospitalizations in a significant proportion of patients


Assuntos
Humanos , Masculino , Feminino , Lactente , Tomografia Computadorizada por Raios X/métodos , Celulite Orbitária/diagnóstico por imagem , Blefaroptose/epidemiologia , Oftalmoplegia/epidemiologia , Conjuntivite/epidemiologia , Estudos Retrospectivos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Tratamento de Emergência/métodos , Diagnóstico Diferencial
8.
Environ Int ; 120: 1-10, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30053755

RESUMO

BACKGROUND: CT scan is a life-saving medical diagnostic tool, entailing higher levels of ionising radiation exposure than conventional radiography, which may result in an increase in cancer risk, particularly in children. Information about the use and potential health effects of CT scan imaging among young people in Spain is scarce. OBJECTIVE: This paper aims to estimate the number of radiation-related cancer cases which can be expected due to the use of CT scanning in Spanish children and young adults in a single year (2013). METHODS: The 2013 distribution of number and types of CT scans performed in young people was obtained for Catalonia and extrapolated to the whole Spain. Organ doses were estimated based on the technical characteristics of 17,406 CT examinations extracted from radiology records. Age and sex-specific data on cancer incidence and life tables were obtained for the Spanish population. Age and sex-specific risk models developed by the Committee on Health Risks of Exposure to Low Levels of Ionizing Radiations (BEIR VII) and Berrington de Gonzalez were used, together, with the dose estimates to derive the lifetime attributable risks of cancer in Spain due to one year of CT scanning and project the number of future cancer cases to be expected. RESULTS: In 2013, 105,802 CT scans were estimated to have been performed in people younger than age 21. It was estimated that a total of 168.6 cancer cases (95% CrI: 30.1-421.1) will arise over life due to the ionising radiation exposure received during these CTs. Lifetime attributable risks per 100,000 exposed patients were highest for breast and lung cancer. The largest proportion of CTs was to the head and neck and hence the highest numbers of projected cancer cases were of thyroid and oral cavity/pharynx. CONCLUSIONS: Despite the undeniable medical effectiveness of CT scans, this risk assessment suggests a small excess in cancer cases which underlines the need for justification and optimisation in paediatric scanning. Given the intrinsic uncertainties of these risk projection exercises, care should be taken when interpreting the predicted risks.


Assuntos
Neoplasias Induzidas por Radiação/epidemiologia , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Medição de Risco , Espanha/epidemiologia , Tomografia Computadorizada por Raios X/efeitos adversos , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Adulto Jovem
9.
J Neurosurg Pediatr ; 22(4): 416-425, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30028274

RESUMO

OBJECTIVE: The purpose of this study was to verify the safety and accuracy of the Neuromate stereotactic robot for use in deep brain stimulation (DBS) electrode implantation for the treatment of hyperkinetic movement disorders in childhood and describe the authors' initial clinical results. METHODS: A prospective evaluation of pediatric patients with dystonia and other hyperkinetic movement disorders was carried out during the 1st year after the start-up of a pediatric DBS unit in Barcelona. Electrodes were implanted bilaterally in the globus pallidus internus (GPi) using the Neuromate robot without the stereotactic frame. The authors calculated the distances between the electrodes and their respective planned trajectories, merging the postoperative CT with the preoperative plan using VoXim software. Clinical outcome was monitored using validated scales for dystonia and myoclonus preoperatively and at 1 month and 6 months postoperatively and by means of a quality-of-life questionnaire for children, administered before surgery and at 6 months' follow-up. We also recorded complications derived from the implantation technique, "hardware," and stimulation. RESULTS: Six patients aged 7 to 16 years and diagnosed with isolated dystonia ( DYT1 negative) (3 patients), choreo-dystonia related to PDE2A mutation (1 patient), or myoclonus-dystonia syndrome SGCE mutations (2 patients) were evaluated during a period of 6 to 19 months. The average accuracy in the placement of the electrodes was 1.24 mm at the target point. At the 6-month follow-up, patients showed an improvement in the motor (65%) and functional (48%) components of the Burke-Fahn-Marsden Dystonia Rating Scale. Patients with myoclonus and SGCE mutations also showed an improvement in action myoclonus (95%-100%) and in functional tests (50%-75%) according to the Unified Motor-Rating Scale. The Neuro-QOL score revealed inconsistent results, with improvement in motor function and social relationships but worsening in anxiety, cognitive function, and pain. The only surgical complication was medial displacement of the first electrode, which limited intensity of stimulation in the lower contacts, in one case. CONCLUSIONS: The Neuromate stereotactic robot is an accurate and safe tool for the placement of GPi electrodes in children with hyperkinetic movement disorders.


Assuntos
Estimulação Encefálica Profunda/instrumentação , Estimulação Encefálica Profunda/métodos , Transtornos dos Movimentos/terapia , Procedimentos Cirúrgicos Robóticos/instrumentação , Procedimentos Cirúrgicos Robóticos/métodos , Adolescente , Criança , Feminino , Globo Pálido/fisiopatologia , Globo Pálido/cirurgia , Humanos , Masculino , Estudos Prospectivos , Resultado do Tratamento
10.
Lancet Neurol ; 17(9): 760-772, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30049614

RESUMO

BACKGROUND: Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication. METHODS: We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis. FINDINGS: Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001). INTERPRETATION: The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy. FUNDING: Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.


Assuntos
Encefalite por Herpes Simples/complicações , Encefalite por Herpes Simples/epidemiologia , Encefalite/epidemiologia , Encefalite/etiologia , Doença de Hashimoto/epidemiologia , Doença de Hashimoto/etiologia , Adolescente , Adulto , Idoso , Animais , Autoanticorpos/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Encefalite/líquido cefalorraquidiano , Encefalite/diagnóstico por imagem , Encefalite por Herpes Simples/líquido cefalorraquidiano , Encefalite por Herpes Simples/diagnóstico por imagem , Feminino , Glutamato Descarboxilase/metabolismo , Doença de Hashimoto/líquido cefalorraquidiano , Doença de Hashimoto/diagnóstico por imagem , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Ratos , Receptores de N-Metil-D-Aspartato/imunologia , Fatores de Risco , Estatísticas não Paramétricas , Adulto Jovem
11.
Int J Mol Sci ; 19(2)2018 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-29470411

RESUMO

Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in CACNA1A (encoding CaV2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, N-glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients' group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α2α) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic CACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at α1A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α2δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.


Assuntos
Doenças Cerebelares/complicações , Canalopatias/complicações , Fosfotransferases (Fosfomutases)/deficiência , Acidente Vascular Cerebral/complicações , Adolescente , Sequência de Aminoácidos , Canais de Cálcio/genética , Doenças Cerebelares/diagnóstico por imagem , Canalopatias/diagnóstico por imagem , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Glicosilação , Células HEK293 , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Imagem por Ressonância Magnética , Masculino , Mutação/genética , Fosfotransferases (Fosfomutases)/química , Fosfotransferases (Fosfomutases)/metabolismo , Acidente Vascular Cerebral/diagnóstico por imagem , Tunicamicina/farmacologia
12.
Rev. neurol. (Ed. impr.) ; 65(3): 112-116, 1 ago., 2017. ilus
Artigo em Espanhol | IBECS | ID: ibc-165554

RESUMO

Introducción. La trisomía 9 es una cromosomopatía inusual en pacientes nacidos vivos, que frecuentemente se acompaña de anomalías funcionales y estructurales del sistema nervioso central. Entre otras muchas alteraciones, varios trabajos en la bibliografía anglosajona demuestran una asociación entre cromosomopatía 9 y patología de los plexos coroideos. Caso clínico. Varón de 4 meses de vida con mosaicismo de trisomía 9 asociado a hidrocefalia secundaria a hiperplasia de los plexos coroideos, que fue remitido por clínica de hipertensión intracraneal. El procedimiento derivativo de líquido cefalorraquídeo por el que optamos inicialmente provocó una ascitis masiva debida a la producción desmesurada de líquido cefalorraquídeo, y desembocó en una cascada de múltiples intervenciones quirúrgicas, entre las que se incluyeron procedimientos endoscópicos y derivativos. Conclusiones. Se trata de un ejemplo más de asociación entre patología de los plexos coroideos y cromosomopatía 9. Debido a su escasa incidencia, es difícil establecer el diagnóstico de hidrocefalia secundaria a hiperplasia de los plexos y, por tanto, el tratamiento más adecuado. En este tipo de hidrocefalia existe un doble mecanismo fisiopatológico, que implica un aumento de producción de líquido cefalorraquídeo y una disminución de su reabsorción. A pesar de tener en cuenta dicha consideración, el tratamiento de la hidrocefalia secundaria a hiperplasia de los plexos supone un verdadero reto que habitualmente pasa por múltiples procedimientos quirúrgicos, desde la plexectomía o coagulación de los plexos coroideos hasta la implantación de dispositivos de derivación de líquido cefalorraquídeo (AU)


Introduction. Trisomy 9 is an unusual chromosome abnormality in live-born patients, which is frequently accompanied by functional and structural anomalies of the central nervous system. Among many other alterations, several studies have been published in the English-speaking literature that show an association between chromosome 9 abnormality and pathologies affecting the choroid plexuses. Case report. We report the case of a 4-month-old male with trisomy 9 mosaicism associated to hydrocephalus secondary to choroid plexus hyperplasia, who was referred due to a clinical picture of intracranial hypertension. The cerebrospinal fluid (CSF) drainage procedure that was initially chosen caused massive ascites due to an excessive production of CSF, and led to a cascade of multiple surgical interventions, which included endoscopic and drainage procedures. Conclusions. This is another example of an association between choroid plexus pathologies and chromosome 9 abnormality. Due to its scarce incidence, diagnosis of hydrocephalus secondary to plexus hyperplasia is difficult, as is selecting its most suitable treatment. In this type of hydrocephalus there is a double pathophysiological mechanism, which involves an increase in CSF production and a decrease in its reabsorption. Despite taking these considerations into account, the treatment of hydrocephalus secondary to plexus hyperplasia is a real challenge that usually leads to multiple surgical interventions ranging from plexectomy or coagulation of the choroid plexuses to the implantation of CSF drainage devices (AU)


Assuntos
Humanos , Masculino , Lactente , Hidrocefalia/etiologia , Neoplasias do Plexo Corióideo/complicações , Trissomia/genética , Derivações do Líquido Cefalorraquidiano/métodos , Mosaicismo , Procedimentos Neurocirúrgicos/métodos
14.
J Inherit Metab Dis ; 40(5): 709-713, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28341975

RESUMO

OBJECTIVE: We aim to delineate the progression of cerebellar atrophy (the primary neuroimaging finding) in children with phosphomannomutase-deficiency (PMM2-CDG) by analyzing longitudinal MRI studies and performing cerebellar volumetric analysis and a 2D cerebellar measurement. METHODS: Statistical analysis was used to compare MRI measurements [midsagittal vermis relative diameter (MVRD) and volume] of children with PMM2-CDG and sex- and age-matched controls, and to determine the rate of progression of cerebellar atrophy at different ages. RESULTS: Fifty MRI studies of 33 PMM2-CDG patients were used for 2D evaluation, and 19 MRI studies were available for volumetric analysis. Results from a linear regression model showed that patients have a significantly lower MVRD and cerebellar volume compared to controls (p < 0.001 and p < 0.001 respectively). There was a significant negative correlation between age and MVRD for patients (p = 0.014). The rate of cerebellar atrophy measured by the loss of MVRD and cerebellar volume per year was higher at early ages (r = -0.578, p = 0.012 and r = -0.323, p = 0.48 respectively), particularly in patients under 11 years (p = 0.004). There was a significant positive correlation between MVRD and cerebellar volume in PMM2-CDG patients (r = 0.669, p = 0.001). CONCLUSIONS: Our study quantifies a progression of cerebellar atrophy in PMM2-CDG patients, particularly during the first decade of life, and suggests a simple and reliable measure, the MVRD, to monitor cerebellar atrophy. Quantitative measurement of MVRD and cerebellar volume are essential for correlation with phenotype and outcome, natural follow-up, and monitoring in view of potential therapies in children with PMM2-CDG.


Assuntos
Atrofia/metabolismo , Atrofia/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Fosfotransferases (Fosfomutases)/deficiência , Fosfotransferases (Fosfomutases)/metabolismo , Criança , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética/métodos , Masculino
17.
Mitochondrion ; 28: 73-8, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27079373

RESUMO

The genetic causes of Leigh syndrome are heterogeneous, with a poor correlation between the phenotype and genotype. Here, we present a patient with an NDUFS4 mutation to expand the clinical and biochemical spectrum of the disease. A combined defect in the CoQ, PDH and RCC activities in our patient was due to an inappropriate assembly of the RCC complex I (CI), which was confirmed using Blue-Native polyacrylamide gel electrophoresis (BN-PAGE) analysis. Targeted exome sequencing analysis allowed for the genetic diagnosis of this patient. We reviewed 198 patients with 24 different genetic defects causing RCC I deficiency and compared them to 22 NDUFS4 patients. We concluded that NDUFS4-related Leigh syndrome is invariably linked to an early onset severe phenotype that results in early death. Some data, including the clinical phenotype, neuroimaging and biochemical findings, can guide the genetic study in patients with RCC I deficiency.


Assuntos
Doença de Leigh/diagnóstico , NADH Desidrogenase/deficiência , Eletroforese em Gel de Poliacrilamida , Feminino , Humanos , Recém-Nascido , Ubiquinona/deficiência
18.
Cortex ; 77: 95-118, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26922507

RESUMO

Brain imaging methods have contributed to shed light on the possible mechanisms of recovery and cortical reorganization after early brain insult. The idea that a functional left hemisphere is crucial for achieving a normalized pattern of language development after left perinatal stroke is still under debate. We report the case of a 3.5-year-old boy born at term with a perinatal ischemic stroke of the left middle cerebral artery, affecting mainly the supramarginal gyrus, superior parietal and insular cortex extending to the precentral and postcentral gyri. Neurocognitive development was assessed at 25 and 42 months of age. Language outcomes were more extensively evaluated at the latter age with measures on receptive vocabulary, phonological whole-word production and linguistic complexity in spontaneous speech. Word learning abilities were assessed using a fast-mapping task to assess immediate and delayed recall of newly mapped words. Functional and structural imaging data as well as a measure of intrinsic connectivity were also acquired. While cognitive, motor and language levels from the Bayley Scales fell within the average range at 25 months, language scores were below at 42 months. Receptive vocabulary fell within normal limits but whole word production was delayed and the child had limited spontaneous speech. Critically, the child showed clear difficulties in both the immediate and delayed recall of the novel words, significantly differing from an age-matched control group. Neuroimaging data revealed spared classical cortical language areas but an affected left dorsal white-matter pathway together with right lateralized functional activations. In the framework of the model for Social Communication and Language Development, these data confirm the important role of the left arcuate fasciculus in understanding and producing morpho-syntactic elements in sentences beyond two word combinations and, most importantly, in learning novel word-referent associations, a building block of language acquisition.


Assuntos
Mapeamento Encefálico , Encéfalo/fisiologia , Lateralidade Funcional/fisiologia , Desenvolvimento da Linguagem , Fala/fisiologia , Vocabulário , Pré-Escolar , Compreensão/fisiologia , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Masculino , Testes Neuropsicológicos
19.
Pediatr Radiol ; 46(1): 119-29, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26276264

RESUMO

BACKGROUND: Although there are undeniable diagnostic benefits of CT scanning, its increasing use in paediatric radiology has become a topic of concern regarding patient radioprotection. OBJECTIVE: To assess the rate of CT scanning in Catalonia, Spain, among patients younger than 21 years old at the scan time. MATERIALS AND METHODS: This is a sub-study of a larger international cohort study (EPI-CT, the International pediatric CT scan study). Data were retrieved from the radiological information systems (RIS) of eight hospitals in Catalonia since the implementation of digital registration (between 1991 and 2010) until 2013. RESULTS: The absolute number of CT scans annually increased 4.5% between 1991 and 2013, which was less accentuated when RIS was implemented in most hospitals. Because the population attending the hospitals also increased, however, the rate of scanned patients changed little (8.3 to 9.4 per 1,000 population). The proportions of patients with more than one CT and more than three CTs showed a 1.51- and 2.7-fold increase, respectively, over the 23 years. CONCLUSION: Gradual increases in numbers of examinations and scanned patients were observed in Catalonia, potentially explained by new CT scanning indications and increases in the availability of scanners, the number of scans per patient and the size of the attended population.


Assuntos
Padrões de Prática Médica/estatística & dados numéricos , Padrões de Prática Médica/tendências , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Tomografia Computadorizada por Raios X/tendências , Adolescente , Adulto , Distribuição por Idade , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Espanha/epidemiologia , Adulto Jovem
20.
Orphanet J Rare Dis ; 10: 138, 2015 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-26502900

RESUMO

BACKGROUND: Phosphomannomutase deficiency (PMM2-CDG) is the most frequent congenital disorder of glycosylation. The cerebellum is nearly always affected in PMM2-CDG patients, a cerebellar atrophy progression is observed, and cerebellar dysfunction is their main daily functional limitation. Different therapeutic agents are under development, and clinical evaluation of drug candidates will require a standardized score of cerebellar dysfunction. We aim to assess the validity of the International Cooperative Ataxia Rating Scale (ICARS) in children and adolescents with genetically confirmed PMM2-CDG deficiency. We compare ICARS results with the Nijmegen Pediatric CDG Rating Scale (NPCRS), neuroimaging, intelligence quotient (IQ) and molecular data. METHODS: Our observational study included 13 PMM2-CDG patients and 21 control subjects. Ethical permissions and informed consents were obtained. Three independent child neurologists rated PMM2-CDG patients and control subjects using the ICARS. A single clinician administered the NPCRS. All patients underwent brain MRI, and the relative diameter of the midsagittal vermis was measured. Psychometric evaluations were available in six patients. The Mann-Whitney U test was used to compare ICARS between patients and controls. To evaluate inter-observer agreement in patients' ICARS ratings, intraclass correlation coefficients (ICC) were calculated. ICARS internal consistency was evaluated using Cronbach's alpha. Spearman's rank correlation coefficient test was used to correlate ICARS with NPCRS, midsagittal vermis relative diameter and IQ. RESULTS: ICARS and ICARS subscores differed between patients and controls (p < 0.001). Interobserver agreement of ICARS was "almost perfect" (ICC = 0.99), with a "good" internal reliability (Cronbach's alpha = 0.72). ICARS was significantly correlated with the total NPCRS score (rs 0.90, p < 0.001). However, there was no agreement regarding categories of severity. Regarding neuroimaging, inverse correlations between ICARS and midsagittal vermis relative diameter (rs -0.85, p = 0.003) and IQ (rs -0.94, p = 0.005) were found. Patients bearing p.E93A, p.C241S or p.R162W mutations presented a milder phenotype. CONCLUSIONS: ICARS is a reliable instrument for assessment of PMM2-CDG patients, without significant inter-rater variability. Despite our limited sample size, the results show a good correlation between functional cerebellar assessment, IQ and neuroimaging. For the first a correlation between ICARS, neuroimaging and IQ in PMM2-CDG patients has been demonstrated.


Assuntos
Ataxia Cerebelar/diagnóstico , Cerebelo/patologia , Defeitos Congênitos da Glicosilação/diagnóstico , Fosfotransferases (Fosfomutases)/deficiência , Índice de Gravidade de Doença , Adolescente , Ataxia Cerebelar/enzimologia , Ataxia Cerebelar/genética , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/enzimologia , Defeitos Congênitos da Glicosilação/genética , Feminino , Humanos , Masculino , Fosfotransferases (Fosfomutases)/genética
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