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1.
Genet Med ; 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30918357

RESUMO

PURPOSE: Exome sequencing (ES) is an efficient tool to diagnose genetic disorders postnatally. Recent studies show that it may have a considerable diagnostic yield in fetuses with structural anomalies on ultrasound. We report on the clinical impact of the implementation of prenatal ES (pES) for ongoing pregnancies in routine care. METHODS: We retrospectively analyzed the impact of pES on pregnancy outcome and pre- or perinatal management in the first 22 patients counseled for pES because of one or more structural anomalies on fetal ultrasound. RESULTS: In two cases, a diagnosis was made by chromosomal microarray analysis after ES counseling. The remaining 20 cases were divided in three groups: (1) pES to aid parental decision making (n = 12), (2) pES in the context of late pregnancy termination requests (n = 5), and (3) pES to guide pre- or perinatal management (n = 3). pES had a clinical impact in 75% (9/12), 40% (2/5), and 100% (3/3) respectively, showing an overall clinical impact of pES of 70% (14/20). CONCLUSION: We show that clinical implementation of pES is feasible and affects parental decision making or pre- and perinatal management supporting further implementation of ES in the prenatal setting.

3.
Am J Hum Genet ; 104(1): 139-156, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595372

RESUMO

Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.

5.
Genet Med ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30287924

RESUMO

PURPOSE: Several studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population. METHODS: We retrospectively evaluated all genetic NICU consultations in a 2-year period. RESULTS: In 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients. CONCLUSIONS: Our study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.

6.
Front Neurol ; 9: 258, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29725319

RESUMO

Background: Hypoxic-ischemic encephalopathy following perinatal asphyxia is a leading cause of neonatal death and disability worldwide. Treatment with therapeutic hypothermia reduced adverse outcomes from 60 to 45%. Additional strategies are urgently needed to further improve the outcome for these neonates. Inhibition of nitric oxide synthase (NOS) is a potential neuroprotective target. This article reviews the evidence of neuroprotection by nitric oxide (NO) synthesis inhibition in animal models. Methods: Literature search using the EMBASE, Medline, Cochrane, and PubMed databases. Studies comparing NOS inhibition to placebo, with neuroprotective outcome measures, in relevant animal models were included. Methodologic quality of the included studies was assessed. Results: 26 studies were included using non-selective or selective NOS inhibition in rat, piglet, sheep, or rabbit animal models. A large variety in outcome measures was reported. Outcome measures were grouped as histological, biological, or neurobehavioral. Both non-selective and selective inhibitors show neuroprotective properties in one or more outcome measures. Methodologic quality was either low or moderate for all studies. Conclusion: Inhibition of NO synthesis is a promising strategy for additional neuroprotection. In humans, intervention can only take place after the onset of the hypoxic-ischemic event. Therefore, combined inhibition of neuronal and inducible NOS seems the most likely candidate for human clinical trials. Future studies should determine its safety and effectiveness in neonates, as well as a potential sex-specific neuroprotective effect. Researchers should strive to improve methodologic quality of animal intervention studies by using a systematic approach in conducting and reporting of these studies.

8.
Prenat Diagn ; 36(7): 601-13, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27187181

RESUMO

Congenital heart defects (CHDs) are associated with neurodevelopmental (ND) delay. This study aims to assess evidence for impaired prenatal brain development, in fetuses with CHD. A systematical search was performed, and 34 studies evaluating the fetal brain [magnetic resonance imaging (MRI) or ultrasound] in isolated CHD were included (1990-2015). Data regarding cerebral abnormalities, head circumference growth and middle cerebral artery flow were extracted. Prenatal MRI was studied in ten articles (445 fetuses), resulting in a pooled prevalence of 18% (95%CI -6%; 42%) for combined structural and acquired cerebral abnormalities. Prenatal head circumference was studied in 13 articles (753 fetuses), resulting in a pooled z-score of -0.51 (95%CI -0.84; -0.18). Doppler was studied in 21 articles (1412 fetuses), resulting in a lower middle cerebral artery pulsatility index (z-score -0.70 95%CI -0.99; -0.41) in left-sided CHD only. We conclude that prenatal MRI and ultrasound demonstrate brain abnormalities, delay in head growth and brainsparing in subgroups of CHD. However, large MRI studies are scarce, and ultrasound data are biased towards severe and left-sided CHD. Long-term follow-up studies correlating prenatal findings with postnatal ND outcome are limited, and data are lacking to support counseling families regarding ND outcome based on prenatal findings suggestive of altered brain development. © 2016 John Wiley & Sons, Ltd.


Assuntos
Encéfalo/diagnóstico por imagem , Feto/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico por imagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Encéfalo/embriologia , Feminino , Cardiopatias Congênitas/complicações , Humanos , Imagem por Ressonância Magnética , Artéria Cerebral Média/diagnóstico por imagem , Malformações do Sistema Nervoso/complicações , Transtornos do Neurodesenvolvimento/complicações , Neuroimagem , Gravidez , Fluxo Pulsátil , Ultrassonografia Pré-Natal
9.
Clin Case Rep ; 4(4): 425-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27099744

RESUMO

Severe recessive mitochondrial myopathy caused by FBXL4 gene mutations may present prenatally with polyhydramnios and cerebellar hypoplasia. Characteristic dysmorphic features are: high and arched eyebrows, triangular face, a slight upslant of palpebral fissures, and a prominent pointed chin. Metabolic investigations invariably show increased serum lactate and pyruvate levels.

10.
Eur J Hum Genet ; 24(8): 1145-53, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26757981

RESUMO

Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Transporte/genética , Anormalidades Craniofaciais/genética , Proteínas de Drosophila/genética , Deficiência Intelectual/genética , Transtornos de Aprendizagem/genética , Mutação , Adolescente , Animais , Proteínas de Transporte/metabolismo , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Drosophila/genética , Drosophila/fisiologia , Proteínas de Drosophila/metabolismo , Feminino , Habituação Psicofisiológica , Humanos , Deficiência Intelectual/diagnóstico , Aprendizagem , Transtornos de Aprendizagem/diagnóstico , Masculino , Fenótipo , Síndrome , Adulto Jovem
11.
Am J Med Genet A ; 167A(8): 1884-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25900458

RESUMO

Copy number variations (CNVs) on the short arm of chromosome 19 are relatively rare. We present a patient with a tandem de novo 3.9 Mb duplication of 19p13.12p13.2 and an adjacent 288 kb deletion of 19p13.12. The CNVs were detected by genome wide SNP-array and confirmed by fluorescence in situ hybridization. Mate-pair sequencing revealed two breakpoint junctions leading to a germline tandem inverted duplication and an adjacent deletion. The patient had a major congenital heart defect and refractory edema leading to metabolic and endocrinological disturbances. Further complications occurred due to refractory chylothorax, severe inflammatory response syndrome, and repeating sepsis. After 2 months, the child died due to intractable respiratory failure. The phenotype of this patient was compared with reported patients with overlapping deletions or duplications. We conclude that the congenital heart defect, respiratory insufficiency, and abnormal neurologic examination are most likely due the contiguous gene deletion/duplication.


Assuntos
Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 19 , Humanos , Recém-Nascido , Masculino
12.
Am J Med Genet A ; 161A(5): 973-6, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23494849

RESUMO

Chudley-McCullough syndrome (CMS) is characterized by profound sensorineural hearing loss and brain anomalies. Variants in GPSM2 have recently been reported as a cause of CMS by Doherty et al. In this study we have performed exome sequencing of three CMS patients from two unrelated families from the same Dutch village. We identified one homozygous frameshift GPSM2 variants c.1473delG in all patients. We show that this variant arises from a shared, rare haplotype. Since the c.1473delG variant was found in Mennonite settlers, it likely originated in Europe. To support DNA diagnostics, we established an LOVD database for GPSM2 containing all variants thus far described.


Assuntos
Agenesia do Corpo Caloso/genética , Cistos Aracnóideos/genética , Exoma/genética , Perda Auditiva Neurossensorial/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Adolescente , Adulto , Pré-Escolar , Europa (Continente) , Feminino , Efeito Fundador , Humanos , Lactente , Masculino , Mutação , Países Baixos , América do Norte , Linhagem , Análise de Sequência de DNA
13.
Stroke ; 44(3): 809-11, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23362078

RESUMO

BACKGROUND AND PURPOSE: To determine the optimal dose of 2-iminobiotin (2-IB) for the treatment of moderate to severe asphyxia in a neonatal piglet model of hypoxia-ischemia. METHODS: Newborn piglets were subjected to a 30-minute hypoxia-ischemia insult and randomly treated with vehicle or 2-IB (0.1 mg/kg, 0.2 mg/kg, or 1.0 mg/kg). aEEG background and seizure activity were scored after hypoxia-ischemia every 4 h until 24 h and at 48 h and neurobehavioral scores were obtained. Brain tissue was collected and processed for analysis of caspase-3 activity, histology, and tyrosine nitration. RESULTS: A dose range of 0.1 to 1.0 mg/kg/dose of 2-IB improved short-term outcome as demonstrated by an increased survival with a normal aEEG and decreased nitrotyrosine staining in the 2-IB-treated animals, indicating decreased cellular damage. Neurobehavior, caspase-3 activity in thalamus, and histology scores were not significantly different. CONCLUSIONS: Based on survival with a normal aEEG, 0.2 mg/kg 2-IB is likely to be the most appropriate dose for use in future clinical trials in neonates with perinatal hypoxia-ischemia.


Assuntos
Asfixia/tratamento farmacológico , Asfixia/etiologia , Biotina/análogos & derivados , Hipóxia-Isquemia Encefálica/complicações , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Biotina/uso terapêutico , Encéfalo/metabolismo , Encéfalo/patologia , Caspase 3/metabolismo , Relação Dose-Resposta a Droga , Eletroencefalografia , Modelos Animais , Suínos , Fatores de Tempo , Resultado do Tratamento
15.
Amino Acids ; 43(1): 355-63, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21947661

RESUMO

Worldwide, perinatal asphyxia is an important cause of morbidity and mortality among term-born children. Overactivation of the N-methyl-D-aspartate receptor (NMDAr) plays a central role in the pathogenesis of cerebral hypoxia-ischemia, but the role of both endogenous NMDAr co-agonists D-serine and glycine remains largely elusive. We investigated D-serine and glycine concentration changes in rat glioma cells, subjected to oxygen and glucose deprivation (OGD) and CSF from piglets exposed to hypoxia-ischemia by occlusion of both carotid arteries and hypoxia. We illustrated these findings with analyses of cerebrospinal fluid (CSF) from human newborns affected by perinatal asphyxia. Extracellular concentrations of glycine and D-serine were markedly increased in rat glioma cells exposed to OGD, presumably through increased synthesis from L-serine. Upon reperfusion glycine concentrations normalized and D-serine concentrations were significantly lowered. The in vivo studies corroborated the finding of initially elevated and then normalizing concentrations of glycine and decreased D-serine concentrations upon reperfusion These significant increases of both endogenous NMDAr co-agonists in combination with elevated glutamate concentrations, as induced by global cerebral ischemia, are bound to lead to massive NMDAr activation, excitotoxicity and neuronal damage. Influencing these NMDAr co-agonist concentrations provides an interesting treatment target for this common, devastating and currently poorly treatable condition.


Assuntos
Asfixia Neonatal/líquido cefalorraquidiano , Glicina/análise , Hipóxia-Isquemia Encefálica/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Reperfusão , Serina/análise , Animais , Animais Recém-Nascidos , Asfixia Neonatal/metabolismo , Linhagem Celular Tumoral , Humanos , Hipóxia , Hipóxia-Isquemia Encefálica/líquido cefalorraquidiano , Recém-Nascido , Neurônios/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Síndrome do Desconforto Respiratório do Recém-Nascido/líquido cefalorraquidiano , Síndrome do Desconforto Respiratório do Recém-Nascido/metabolismo , Suínos
16.
J Inherit Metab Dis ; 33 Suppl 3: S401-7, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20865336

RESUMO

Molybdenum cofactor (Moco) deficiency is a rare neurometabolic disorder, characterized by neurological impairment and refractive seizures, due to toxic accumulation of sulfite in the brain. Earlier it was suggested that in Moco-deficient humans maternal clearance of neurotoxic metabolites prevents prenatal brain damage. However, limited data are available about the time profile in which neurophysiologic deterioration occurs after birth. The amplitude-integrated electroencephalography (aEEG) is a bedside method in neonates to monitor cerebral recovery after hypoxic-ischemic insults, detect epileptic activity, and evaluate antiepileptic drug treatment. We describe a chronological series of changes in aEEG tracings in a neonate with Moco deficiency. He presented with myoclonic spasms and hypertonicity a few hours after birth, however, the aEEG pattern was still normal. Within 2 days, the aEEG rapidly changed into a burst suppression pattern with repetitive seizures. After antiepileptic treatment, the aEEG remained abnormal. In this patient, the normal aEEG pattern at birth may have been due to maternal clearance of sulfite in utero. After birth, accumulation of sulfite causes progressive brain damage, reflected by the progressive depression of the aEEG tracings. This is in agreement with the results from a Moco-deficient mouse model, suggesting that maternal sulfite clearance suppresses prenatal brain damage. To our knowledge, this is the first case report describing the chronological changes in the aEEG pattern in a Moco-deficient patient. Insight into the time profile in which neurologic deterioration in Moco-deficient humans occurs is essential, especially when potential treatment strategies are being evaluated.


Assuntos
Ondas Encefálicas , Encéfalo/fisiopatologia , Coenzimas/deficiência , Eletroencefalografia , Epilepsia/diagnóstico , Erros Inatos do Metabolismo dos Metais/diagnóstico , Metaloproteínas/deficiência , Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Ondas Encefálicas/efeitos dos fármacos , Coenzimas/genética , Imagem de Difusão por Ressonância Magnética , Epilepsia/tratamento farmacológico , Epilepsia/enzimologia , Epilepsia/fisiopatologia , Humanos , Recém-Nascido , Masculino , Erros Inatos do Metabolismo dos Metais/enzimologia , Erros Inatos do Metabolismo dos Metais/genética , Erros Inatos do Metabolismo dos Metais/fisiopatologia , Metaloproteínas/genética , Molibdoferredoxina/genética , Valor Preditivo dos Testes , Pteridinas , Sulfitos/metabolismo , Fatores de Tempo , Resultado do Tratamento
17.
J Cereb Blood Flow Metab ; 25(1): 67-74, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15678113

RESUMO

The short- and long-term neuroprotective effects of 2-iminobiotin, a selective inhibitor of neuronal and inducible nitric oxide synthase, were studied in 12-day-old rats following hypoxia-ischemia. Hypoxia-ischemia was induced by occlusion of the right carotid artery followed by 90 minutes of hypoxia (FiO2 0.08). Immediately on reoxygenation, 12 and 24 hours later the rats were treated with vehicle or 2-iminobiotin at a dose of 5.5, 10, 30, or 60 mg/kg per day. Histologic analysis of brain damage was performed at 6 weeks after hypoxia-ischemia. To assess early changes of cerebral tissue, levels of HSP70, nitrotyrosine, and cytochrome c were determined 24 hours after reoxygenation. Significant neuroprotection was obtained using a dose of 30 mg/kg per day of 2-iminobiotin. Levels of HSP70 were increased in the ipsilateral hemisphere in both groups (P<0.05), but the increase was significantly (P<0.05) less in the rats receiving the optimal dose of 2-iminobiotin (30 mg/kg per day). Hypoxia-ischemia did not lead to increased levels of nitrotyrosine, nor did 2-iminobiotin influence levels of nitrotyrosine. In contrast, hypoxia-ischemia induced an increase in cytochrome c level that was prevented by 2-iminobiotin. In conclusion, 2-iminobiotin administered after hypoxia-ischemia provides long-term neuroprotection. This neuroprotection is obtained by mechanisms other than a reduction of nitrotyrosine formation in proteins.


Assuntos
Biotina/análogos & derivados , Biotina/administração & dosagem , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Tirosina/análogos & derivados , Animais , Animais Recém-Nascidos , Química Encefálica/efeitos dos fármacos , Citocromos c/metabolismo , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Masculino , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , Tirosina/metabolismo
18.
Dev Neurosci ; 24(5): 389-95, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12640177

RESUMO

In this study, we tested the hypothesis that combined inhibition of nNOS and iNOS will reduce neuronal damage and the inflammatory response induced by perinatal hypoxia-ischaemia (HI). In 12-day-old rats, HI was induced by right carotid artery occlusion followed by 90 min of 8% O2. Immediately upon reoxygenation, the rats were treated with NOS inhibitors (n = 24) or placebo (n = 24). Neuropathology was scored at 6 weeks after HI on a 4-point scale (n = 12 per group). The expression of heat shock protein 70 (HSP70) and mRNA expression for cytokines were measured 12 h after HI (n = 12 per group). Histopathological analysis showed that the ipsilateral hemisphere in the NOS inhibition group was less damaged than in the placebo group (p < 0.05). HI induced a significant increase in HSP70 levels (p < 0.05) in the ipsilateral hemispheres, which tended to be lower in the NOS inhibition group (p = 0.07). HI induced an increase in mRNA expression for IL-1beta, TNF-alpha and TNF-beta, but there was no difference between the ipsi- and contralateral hemispheres. Combined inhibition of nNOS and iNOS did not induce any change in cytokine expression. We conclude that the long-term neuroprotective effects of combined nNOS and iNOS inhibition were not achieved by an altered cytokine response.


Assuntos
Inibidores Enzimáticos/farmacologia , Hipóxia-Isquemia Encefálica/enzimologia , Indazóis/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Western Blotting , Citocinas/biossíntese , Feminino , Lateralidade Funcional , Guanidinas/farmacologia , Proteínas de Choque Térmico HSP70/biossíntese , Hipóxia-Isquemia Encefálica/fisiopatologia , Masculino , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo II , RNA Mensageiro/análise , Ratos , Ratos Wistar
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