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1.
Paediatr Anaesth ; 29(3): 250-257, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30614153

RESUMO

BACKGROUND: In this prospective study, we describe the electroencephalographic (EEG) profiles in children anesthetized with sevoflurane or propofol. METHODS: Seventy-three subjects (11 years, range 5-18) were included and randomly assigned to two groups according to the anesthetic agent. Anesthesia was performed by target-controlled infusion of propofol (group P) or by sevoflurane inhalation (group S). Steady-state periods were performed at a fixed randomized concentration between 2, 3, 4, 5, and 6 µg.ml-1 of propofol in group P and between 1, 2, 3, 4, and 5% of sevoflurane in group S. Remifentanil was continuously administered throughout the study. Clinical data, Bispectral Index (BIS), and raw EEG were continuously recorded. The relationship between BIS and anesthetic concentrations was studied using nonlinear regression. For all steady-state periods, EEG traces were reviewed to assess the presence of epileptoid signs, and spectral analysis of raw EEG was performed. RESULTS: Under propofol, BIS decreased monotonically and EEG slowed down as concentrations increased from 2 to 6 µg.ml-1 . Under sevoflurane, BIS decreased from 0% to 4% and paradoxically rose from 4% to 5% of expired concentration: this increase in BIS was associated with the occurrence of fast oscillations and epileptoid signs on the EEG trace. Propofol was associated with more delta waves and burst suppression periods compared to sevoflurane. CONCLUSION: Under deep anesthesia, the BIS and electroencephalographic profiles differ between propofol and sevoflurane. For high concentrations of sevoflurane, an elevated BIS value may be interpreted as a sign of epileptoid patterns or EEG fast oscillations rather than an insufficient depth of hypnosis.


Assuntos
Anestesia Geral/métodos , Anestésicos Inalatórios/farmacologia , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Propofol/administração & dosagem , Sevoflurano/administração & dosagem , Adolescente , Criança , Pré-Escolar , Humanos , Estudos Prospectivos
2.
Fetal Diagn Ther ; : 1-11, 2018 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-30032153

RESUMO

BACKGROUND: Infection with parvovirus B19 (B19V) during pregnancy may cause severe fetal anemia, hydrops, and fe tal death. Furthermore, neurodevelopmental impairment among survivors may occur despite appropriate prenatal management, including intrauterine transfusion (IUT). OBJECTIVES: Our primary objective was to describe cerebral lesions on MRI in fetuses with severe anemia requiring IUT for B19V infection. Our secondary objective was to search for clinical and biological characteristics associated with the occurrence of such lesions. STUDY DESIGN: We performed a retrospective review of data on fetuses infected with B19V and requiring at least one IUT between 2005 and 2016. Fetuses with abnormal cerebral MRI results in the 3rd trimester were compared to those with normal MRI results. RESULTS: Of 34 transfused fetuses, 26 children were born at full term. Five intrauterine fetal deaths, 1 neonatal death, and 2 terminations of pregnancy occurred. Cerebral anomalies were observed in 7/27 fetuses on MRI, including cerebellar hemorrhage or a small cerebellum. Only viral load in fetal blood appeared to be associated with brain lesions (11.5 log10 copies/mL [10.5-12.5] in case of abnormal MRI results vs. 9.5 log10 copies/mL [7.8-10.0]; p = 0.05). CONCLUSIONS: Among the fetuses transfused for B19V infection, 26% presented with prenatal abnormal cerebral imaging results. In our study, viral load in fetal blood appeared to be the only factor associated with fetal brain lesions.

3.
Genet Med ; 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-29997391

RESUMO

PURPOSE: To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes. METHODS: Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes. RESULTS: We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant. CONCLUSION: Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).

4.
Brain Struct Funct ; 223(6): 2893-2905, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29687282

RESUMO

The left hemisphere specialization for language is a well-established asymmetry in the human brain. Structural and functional asymmetries are observed as early as the prenatal period suggesting genetically determined differences between both hemispheres. The corpus callosum is a large tract connecting mostly homologous areas; some have proposed that it might participate in an enhancement of the left-hemispheric advantage to process speech. To investigate its role in early development, we compared 13 3-4-month-old infants with an agenesis of the corpus callosum ("AgCC") with 18 typical infants using high-density electroencephalography in an auditory task. We recorded event-related potentials for speech stimuli (syllables and babbling noise), presented binaurally (same syllable in both ears), monaurally (babbling noise in one ear) and dichotically (syllable in one ear and babbling noise in the other ear). In response to these stimuli, both groups developed an anterior positivity synchronous with a posterior negativity, yet the topography significantly differed between groups likely due to the atypical gyration of the medial surface in AgCC. In particular, the anterior positivity was lateral in AgCC infants while it covered the midline in typical infants. We then measured the latencies of the main auditory response (P2 at this age) for the different conditions on the symmetrical left and right clusters. The main difference between groups was a ~ 60 ms delay in typical infants relative to AgCC, for the ipsilateral response (i.e. left hemisphere) to babbling noise presented in the left ear, whereas no difference was observed in the case of right-ear stimulation. We suggest that our results highlight an asymmetrical callosal connectivity favoring the right-to-left hemisphere direction in typical infants. This asymmetry, similar to recent descriptions in adults, might contribute to an enhancement of left lateralization for language processing beyond the initial cortical left-hemisphere advantage.

5.
Fetal Diagn Ther ; 44(4): 247-255, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29161699

RESUMO

OBJECTIVE: To establish which characteristics of fetal ultrasound screening lead to the diagnosis of posterior fossa (PF) anomalies. METHODS: A total of 81 fetuses with PF anomalies diagnosed after dedicated neuroimaging between July 1, 2007, and January 1, 2013, were included. The ultrasound characteristics of the fetal cerebellum categorized according to an anatomical approach to the PF, associated fetal anomalies, gestational age at diagnosis, and the potential benefits from systematic measurement of the transverse cerebellar diameter (TCD) were analyzed. RESULTS: Fifty fetuses (61.7%) presented with a PF malformation responsible for an increased "fluid-filled" space of the PF, 24 fetuses (29.6%) had a malformation associated with a decreased cerebellar biometry, 23 fetuses (28.4%) had an abnormal cerebellar anatomy and/or echogenicity, and 2 fetuses (2.4%) showed an isolated malformation of the brainstem. Forty-seven cases (58%) showed additional cerebral or extracerebral anomalies, which led to the diagnosis of PF anomaly in 55.3% of the cases. Isolated PF anomalies were associated with an increased "fluid-filled" space of the PF in 91.2% of the cases. Twenty-eight fetuses had a TCD measurement considered as pathological. DISCUSSION: Examination of the transcerebellar plane during 2nd- and 3rd-trimester ultrasound screening combined with systematic measurement of the TCD would allow improving the detection of PF anomalies.

6.
Pediatr Radiol ; 48(3): 383-391, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29184973

RESUMO

BACKGROUND: Pericallosal lipomas are often associated with corpus callosum dysgenesis. The diagnosis of lipoma, suggested on ultrasonography, relies on the classic T1 hyperintensity on magnetic resonance imaging (MRI). However, this feature may be absent prenatally. OBJECTIVE: Our objective was to study the changes of T1 intensity in fetal lipomas with comparison to postnatal/postmortem data and to assess the factors influencing the signal variations of pericallosal lipomas on prenatal MRI. MATERIALS AND METHODS: Patients with callosum dysgenesis and interhemispheric hyperechogenicity suggestive of a pericallosal lipoma with available postnatal or postmortem data were included. Gestational age, lipoma size and pattern, corpus callosum size and changes in fetal fat T1 intensity were recorded. Comparison with postmortem neuropathology was available for one fetus. RESULTS: Eleven patients with callosum dysgenesis and pericallosal lipomas (seven curvilinear and four tubulonodular) were included. All MRI scans were performed in the third trimester. Curvilinear lipomas were thinner and six cases were associated with prenatal T1 iso-intensity. Typical T1 hyperintensity appeared on postnatal MRI only. All tubulonodular lipomas were much larger and showed prenatal T1 hyperintensity. In two patients, the lipoma increased in size on postnatal MRI. CONCLUSION: The type and size of a lipoma influence T1 prenatal intensity. Absence of T1 intensity was observed in curvilinear lipomas only. Curvilinear lipomas are much thinner. Changes in T1 intensity may also be related to fat maturation within the lipoma and, subsequently, to gestational age. In the case of callosum dysgenesis, absence of prenatal T1 pericallosal hyperintensity should not exclude the diagnosis of pericallosal lipoma.


Assuntos
Agenesia do Corpo Caloso/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Corpo Caloso/diagnóstico por imagem , Lipoma/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Adulto , Agenesia do Corpo Caloso/embriologia , Agenesia do Corpo Caloso/patologia , Autopsia , Neoplasias Encefálicas/embriologia , Neoplasias Encefálicas/patologia , Corpo Caloso/embriologia , Corpo Caloso/patologia , Feminino , Humanos , Lipoma/embriologia , Lipoma/patologia , Gravidez , Estudos Retrospectivos , Ultrassonografia Pré-Natal
7.
Hum Mutat ; 39(1): 23-39, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29068161

RESUMO

The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Genes DCC , Estudos de Associação Genética , Mutação , Fenótipo , Agenesia do Corpo Caloso , Sequência de Aminoácidos , Sítios de Ligação , Sequência Conservada , Bases de Dados Genéticas , Humanos , Imagem por Ressonância Magnética , Modelos Moleculares , Netrina-1/química , Netrina-1/metabolismo , Ligação Proteica , Conformação Proteica , Domínios Proteicos/genética , Síndrome
8.
Nat Genet ; 49(4): 511-514, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28250454

RESUMO

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.


Assuntos
Agenesia do Corpo Caloso/genética , Deficiências do Desenvolvimento/genética , Mutação/genética , Receptores de Superfície Celular/genética , Proteínas Supressoras de Tumor/genética , Anormalidades Múltiplas/genética , Encéfalo/patologia , Corpo Caloso/patologia , Receptor DCC , Família , Feminino , Humanos , Masculino , Malformações do Sistema Nervoso/genética , Células-Tronco Neurais/patologia , Penetrância , Fenótipo
9.
Hum Genet ; 136(4): 463-479, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28283832

RESUMO

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 1 , Ribonucleoproteínas Nucleares Heterogêneas/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Proteínas Repressoras/genética , Humanos
10.
J Pediatr ; 185: 160-166.e1, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28284480

RESUMO

OBJECTIVE: To evaluate the role that chromosomal micro-rearrangements play in patients with both corpus callosum abnormality and intellectual disability, we analyzed copy number variations (CNVs) in patients with corpus callosum abnormality/intellectual disability STUDY DESIGN: We screened 149 patients with corpus callosum abnormality/intellectual disability using Illumina SNP arrays. RESULTS: In 20 patients (13%), we have identified at least 1 CNV that likely contributes to corpus callosum abnormality/intellectual disability phenotype. We confirmed that the most common rearrangement in corpus callosum abnormality/intellectual disability is inverted duplication with terminal deletion of the 8p chromosome (3.2%). In addition to the identification of known recurrent CNVs, such as deletions 6qter, 18q21 (including TCF4), 1q43q44, 17p13.3, 14q12, 3q13, 3p26, and 3q26 (including SOX2), our analysis allowed us to refine the 2 known critical regions associated with 8q21.1 deletion and 19p13.1 duplication relevant for corpus callosum abnormality; report a novel 10p12 deletion including ZEB1 recently implicated in corpus callosum abnormality with corneal dystrophy; and) report a novel pathogenic 7q36 duplication encompassing SHH. In addition, 66 variants of unknown significance were identified in 57 patients encompassed candidate genes. CONCLUSIONS: Our results confirm the relevance of using microarray analysis as first line test in patients with corpus callosum abnormality/intellectual disability.


Assuntos
Agenesia do Corpo Caloso/genética , Variações do Número de Cópias de DNA , Deficiência Intelectual/genética , Adolescente , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Ciclo Celular/genética , Criança , Pré-Escolar , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 7 , Cromossomos Humanos Par 8 , Feminino , Proteínas Hedgehog/genética , Humanos , Masculino , Análise em Microsséries , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Adulto Jovem , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
11.
Pediatrics ; 138(3)2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27581855

RESUMO

CONTEXT: Antenatal counseling in cases of agenesis of the corpus callosum (ACC) is challenging. OBJECTIVES: To ascertain the outcome in fetuses with isolated complete ACC and partial ACC. DATA SOURCES: Medline, Embase, CINAHL, and Cochrane databases. STUDY SELECTION: Studies reporting a prenatal diagnosis of ACC. The outcomes observed were: chromosomal abnormalities at standard karyotype and chromosomal microarray (CMA) analysis, additional anomalies detected only at prenatal MRI and at postnatal imaging or clinical evaluation, concordance between prenatal and postnatal diagnosis and neurodevelopmental outcome. DATA EXTRACTION: Meta-analyses of proportions were used to combine data. RESULTS: Twenty-seven studies were included. In cACC, chromosomal anomalies occurred in 4.81% (95% confidence interval [CI], 2.2-8.4) of the cases. Gross and fine motor control were abnormal in 4.40% (95% CI, 0.6-11.3) and 10.98% (95% CI, 4.1-20.6) of the cases, respectively, whereas 6.80% (95% CI, 1.7-14.9) presented with epilepsy. Abnormal cognitive status occurred in 15.16% (95% CI, 6.9-25.9) of cases. In partial ACC, the rate of chromosomal anomalies was 7.45% (95% CI, 2.0-15.9). Fine motor control was affected in 11.74% (95% CI, 0.9-32.1) of the cases, and 16.11% (95% CI, 2.5-38.2) presented with epilepsy. Cognitive status was affected in 17.25% (95% CI, 3.0-39.7) of cases. LIMITATIONS: Different neurodevelopmental tools and time of follow-up of the included studies. CONCLUSIONS: Children wih a prenatal diagnosis of isolated ACC show several degrees of impairment in motor control, coordination, language, and cognitive status. However, in view of the large heterogeneity in outcomes measures, time at follow-up, and neurodevelopmental tools used, large prospective studies are needed to ascertain the actual occurrence of neuropsychological morbidity of children with isolated ACC.


Assuntos
Agenesia do Corpo Caloso/complicações , Agenesia do Corpo Caloso/diagnóstico , Aberrações Cromossômicas , Transtornos Cognitivos/etiologia , Epilepsia/etiologia , Feminino , Humanos , Lactente , Recém-Nascido , Transtornos da Linguagem/etiologia , Imagem por Ressonância Magnética , Transtornos das Habilidades Motoras/etiologia , Testes Neuropsicológicos , Gravidez , Diagnóstico Pré-Natal
13.
Euro Surveill ; 21(13)2016.
Artigo em Inglês | MEDLINE | ID: mdl-27063794

RESUMO

We detected an unusual increase in congenital cerebral malformations and dysfunction in fetuses and newborns in French Polynesia, following an epidemic of Zika virus (ZIKV), from October 2013 to March 2014. A retrospective review identified 19 cases, including eight with major brain lesions and severe microcephaly, six with severe cerebral lesions without microcephaly and five with brainstem dysfunction without visible malformations. Imaging revealed profound neurological lesions (septal and callosal disruption, ventriculomegaly, abnormal neuronal migration, cerebellar hypoplasia, occipital pseudocysts, brain calcifications). Amniotic fluid was drawn from seven cases at gestation weeks 20 to 29. ZIKV RNA was detected by RT-PCR and infectious ZIKV isolates were obtained in four of five microcephalic, but not in two non-microcephalic cases with severe brain lesions. Medical termination of pregnancy was performed in eleven cases; two cases with brainstem dysfunction died in the first months of life; six cases are alive, with severe neurological impairment. The results show that four of seven tested fetuses with major neurological injuries were infected with ZIKV in utero. For other non-microcephalic, congenital abnormalities we were not able to prove or exclude ZIKV infection retrospectively. The unusual occurrence of brain malformations or dysfunction without microcephaly following a ZIKV outbreak needs further studies.


Assuntos
Líquido Amniótico/virologia , Encéfalo/patologia , Feto/anormalidades , Microcefalia/diagnóstico , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/epidemiologia , Zika virus/isolamento & purificação , Adulto , Encéfalo/diagnóstico por imagem , Epidemias , Feminino , Feto/fisiopatologia , Humanos , Recém-Nascido , Imagem por Ressonância Magnética , Microcefalia/complicações , Polinésia/epidemiologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , RNA Viral/genética , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tomografia Computadorizada por Raios X , Infecção por Zika virus/complicações , Infecção por Zika virus/virologia
14.
Epilepsia ; 57(4): 648-59, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26873267

RESUMO

OBJECTIVE: To describe the epileptic phenotype of Tsc1(+/-) mice pups in comparison with age-related seizures in human tuberous sclerosis complex (TSC). METHODS: Tsc1(+/-) and control mice underwent intracranial electroencephalography (EEG) recording at postnatal ages (P)8 to P33, with linear silicon probe implanted in the somatosensory cortex of one or both hemispheres for 8-24 h. Ictal events were classified visually by independent analyzers; distinct EEG patterns were related to age and analyzed to quantify field potential characteristics and signal dynamics between hemispheres. We collected retrospectively 20 infants with prenatally diagnosed TSC and EEG before seizure onset, and analyzed the electroclinical course of epilepsy, taking into account a first-line treatment by vigabatrin. RESULTS: Spontaneous seizures were disclosed in 55% of Tsc1(+/-) mice at P9-18. Three ictal patterns were identified: from P9 to P12 "spike clusters" consisted of recurring large spikes without clinical correlate; "spasm-like" discharges dominated from P13 to P16 consisting of high amplitude large field potential superimposed with or followed by fast activity repeated every 2-10 s for at least 20 s, accompanied by rhythmic limb contractions; from P14 to P18 a "tonic-clonic like" pattern comprised rhythmic spikes of increasing amplitude with tonic-clonic movements. Early onset "spike clusters" were mainly unilateral, whereas "spasm-like" and "tonic-clonic like" patterns were bilateral. Interhemispheric propagation was significantly faster for "tonic-clonic like" than for "spasm-like" events. In infants diagnosed prenatally with TSC, clusters of sharp waves or spikes preceded the first seizure, and vigabatrin prevented the development of seizures. Patients treated after seizure onset developed spasms or focal seizures that were pharmacoresistant in 66.7% of cases. SIGNIFICANCE: Tsc1(+/-) mice pups exhibit an age-dependent seizure pattern sequence mimicking early human TSC epilepsy features. Spike clusters before seizure onset in TSC should be considered as a first stage of epilepsy reinforcing the concept of preventive antiepileptic therapy.


Assuntos
Epilepsia/metabolismo , Esclerose Tuberosa/metabolismo , Proteínas Supressoras de Tumor/biossíntese , Adolescente , Fatores Etários , Animais , Criança , Pré-Escolar , Epilepsia/genética , Epilepsia/patologia , Feminino , Seguimentos , Regulação da Expressão Gênica , Humanos , Lactente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estudos Retrospectivos , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética
15.
Neuropediatrics ; 47(1): 57-60, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26569159

RESUMO

Severe fetal ventriculomegaly is generally associated with poor prognosis in terms of survival and neurodevelopment outcome. As such, many parents opt to terminate the pregnancy independently of a known etiology. We report here the case of a female fetus with severe progressive ventriculomegaly due to the unexpected presence of bilateral nodular periventricular heterotopias visualized on MRI of a fetal brain. Reaching a structural diagnosis was perceived as a relief for the parents and the pregnancy was continued. Neurodevelopment assessment at 3 years of age is normal with no epilepsy.


Assuntos
Ventrículos Cerebrais/patologia , Doenças Fetais/patologia , Heterotopia Nodular Periventricular/diagnóstico , Heterotopia Nodular Periventricular/patologia , Diagnóstico Pré-Natal , Progressão da Doença , Feminino , Feto , Humanos , Imagem por Ressonância Magnética , Gravidez
16.
Genet Med ; 18(1): 49-56, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25790162

RESUMO

PURPOSE: Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. METHODS: We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. RESULTS: We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. CONCLUSION: Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.


Assuntos
RNA Polimerases Dirigidas por DNA/genética , Disostose Mandibulofacial/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Feminino , Estudos de Associação Genética , Humanos , Masculino , Disostose Mandibulofacial/diagnóstico , Microcefalia/genética , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Fatores de Alongamento de Peptídeos/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Deleção de Sequência , Adulto Jovem
17.
Orphanet J Rare Dis ; 10: 123, 2015 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-26410222

RESUMO

BACKGROUND: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. METHODS: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. RESULTS: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. CONCLUSIONS: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trials.


Assuntos
Hemiplegia/genética , Mutação , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Inquéritos Epidemiológicos , Hemiplegia/diagnóstico , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
18.
Proc Natl Acad Sci U S A ; 112(4): 1208-13, 2015 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-25583500

RESUMO

Identifying potentially unique features of the human cerebral cortex is a first step to understanding how evolution has shaped the brain in our species. By analyzing MR images obtained from 177 humans and 73 chimpanzees, we observed a human-specific asymmetry in the superior temporal sulcus at the heart of the communication regions and which we have named the "superior temporal asymmetrical pit" (STAP). This 45-mm-long segment ventral to Heschl's gyrus is deeper in the right hemisphere than in the left in 95% of typical human subjects, from infanthood till adulthood, and is present, irrespective of handedness, language lateralization, and sex although it is greater in males than in females. The STAP also is seen in several groups of atypical subjects including persons with situs inversus, autistic spectrum disorder, Turner syndrome, and corpus callosum agenesis. It is explained in part by the larger number of sulcal interruptions in the left than in the right hemisphere. Its early presence in the infants of this study as well as in fetuses and premature infants suggests a strong genetic influence. Because this asymmetry is barely visible in chimpanzees, we recommend the STAP region during midgestation as an important phenotype to investigate asymmetrical variations of gene expression among the primate lineage. This genetic target may provide important insights regarding the evolution of the crucial cognitive abilities sustained by this sulcus in our species, namely communication and social cognition.


Assuntos
Agenesia do Corpo Caloso , Transtornos Globais do Desenvolvimento Infantil , Cognição , Situs Inversus , Lobo Temporal , Síndrome de Turner , Adulto , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/fisiopatologia , Animais , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico por imagem , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Pan troglodytes , Radiografia , Situs Inversus/diagnóstico por imagem , Situs Inversus/fisiopatologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/fisiopatologia , Síndrome de Turner/diagnóstico por imagem , Síndrome de Turner/fisiopatologia
19.
J Med Genet ; 52(1): 61-70, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25411445

RESUMO

BACKGROUND: Homozygous mutations in WWOX were reported in eight individuals of two families with autosomal recessive spinocerebellar ataxia type 12 and in two siblings with infantile epileptic encephalopathy (IEE), including one who deceased prior to DNA sampling. METHODS: By combining array comparative genomic hybridisation, targeted Sanger sequencing and next generation sequencing, we identified five further patients from four families with IEE due to biallelic alterations of WWOX. RESULTS: We identified eight deleterious WWOX alleles consisting in four deletions, a four base-pair frameshifting deletion, one missense and two nonsense mutations. Genotype-phenotype correlation emerges from the seven reported families. The phenotype in four patients carrying two predicted null alleles was characterised by (1) little if any psychomotor acquisitions, poor spontaneous motility and absent eye contact from birth, (2) pharmacoresistant epilepsy starting in the 1st weeks of life, (3) possible retinal degeneration, acquired microcephaly and premature death. This contrasted with the less severe autosomal recessive spinocerebellar ataxia type 12 phenotype due to hypomorphic alleles. In line with this correlation, the phenotype in two siblings carrying a null allele and a missense mutation was intermediate. CONCLUSIONS: Our results obtained by a combination of different molecular techniques undoubtedly incriminate WWOX as a gene for recessive IEE and illustrate the usefulness of high throughput data mining for the identification of genes for rare autosomal recessive disorders. The structure of the WWOX locus encompassing the FRA16D fragile site might explain why constitutive deletions are recurrently reported in genetic databases, suggesting that WWOX-related encephalopathies, although likely rare, may not be exceptional.


Assuntos
Oxirredutases/genética , Fenótipo , Espasmos Infantis/genética , Ataxias Espinocerebelares/genética , Proteínas Supressoras de Tumor/genética , Códon sem Sentido/genética , Hibridização Genômica Comparativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação de Sentido Incorreto/genética , Espasmos Infantis/patologia , Ataxias Espinocerebelares/patologia , Oxidorredutase com Domínios WW
20.
Prenat Diagn ; 35(4): 337-41, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25475607

RESUMO

OBJECTIVE: The association of periventricular nodular heterotopia (PVNH) with posterior fossa cyst (PFC) is documented after birth. We report this association in a series of fetuses. METHODS: Eleven cases (7 females) of PVNH and PFC diagnosed at prenatal imaging were collected in this retrospective multicenter study. The patients were referred to tertiary centers for targeted ultrasonography (US) and Magnetic Resonance Imaging (MRI) following detection of PFC on routine US. Mutations of the filamin A gene (FLNA) were searched for (n = 6). Maternal brain MRI was performed (n = 8). Post-mortem or postnatal data were recorded. RESULTS: Targeted US was performed at a mean gestational age of 29 (range; 23-35) weeks and identified PVNH in 4 cases. At MRI, performed at a mean gestational age of 31 (range; 29-35) weeks, PVNH and PFC were visible in all cases. Those findings were confirmed by postnatal MRI (n = 3), autopsy (n = 7) and/or post-mortem MRI (n = 2) or US (n = 1). Maternal brain MRI showed PVNH in one case. A de novo FLNA mutation was found in four cases. CONCLUSION: We describe a series of PVNH and PFC in fetuses, which underlines the importance of searching for PVNH when PFC is identified at prenatal US. © 2014 John Wiley & Sons, Ltd.


Assuntos
Neoplasias Infratentoriais/diagnóstico , Imagem por Ressonância Magnética/métodos , Heterotopia Nodular Periventricular/diagnóstico , Ultrassonografia Pré-Natal/métodos , Cistos , Feminino , Humanos , Neoplasias Infratentoriais/complicações , Masculino , Mutação , Heterotopia Nodular Periventricular/complicações , Gravidez , Estudos Retrospectivos
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