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1.
BMC Med Genet ; 20(1): 88, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31117962

RESUMO

BACKGROUND: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessively-inherited defect of γ-aminobutyric acid (GABA) metabolism. The absence of SSADH, which is encoded by aldehyde dehydrogenase family 5 member A1 (ALDH5A1) gene, leads to the accumulation of GABA and γ-hydroxybutyric acid (GHB). Few cases with SSADH deficiency were reported in China. CASE PRESENTATION: In this study, four Chinese patients were diagnosed with SSADH deficiency in Tianjin Children's Hospital. We conducted a multidimensional analysis with magnetic resonance imaging (MRI) of the head, semi quantitative detection of urine organic acid using gas chromatography-mass spectrometry, and analysis of ALDH5A1 gene mutations. Two of the patients were admitted to the hospital due to convulsions, and all patients were associated with developmental delay. Cerebral MRI showed symmetrical hyperintense signal of bilateral globus pallidus and basal ganglia in patient 1; hyperintensity of bilateral frontal-parietal lobe, widened ventricle and sulci in patient 2; and widened ventricle and sulci in patient 4. Electroencephalogram (EEG) revealed the background activity of epilepsy in patient 1 and the disappearance of sleep spindle in patient 2. Urine organic acid analysis revealed elevated GHB in all the patients. Mutational analysis, which was performed by sequencing the 10 exons and flanking the intronic regions of ALDH5A1 gene for all the patients, revealed mutations at five sites. Two cases had homozygous mutations with c.1529C > T and c.800 T > G respectively, whereas the remaining two had different compound heterozygous mutations including c.527G > A/c.691G > A and c.1344-2delA/c.1529C > T. Although these four mutations have been described previously, the homozygous mutation of c.800 T > G in ALDH5A1 gene is a novel discovery. CONCLUSION: SSADH deficiency is diagnosed based on the elevated GHB and 4, 5DHHA by urinary organic acid analysis. We describe a novel mutation p.V267G (c.800 T > G) located in the NAD binding domain, which is possibly crucial for this disease's severity. Our study expands the mutation spectrum of ALDH5A1 and highlights the importance of molecular genetic evaluation in patients with SSADH deficiency.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Análise Mutacional de DNA/métodos , Deficiências do Desenvolvimento/genética , Mutação , Succinato-Semialdeído Desidrogenase/deficiência , Succinato-Semialdeído Desidrogenase/genética , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico por imagem , Erros Inatos do Metabolismo dos Aminoácidos/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Pré-Escolar , China , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/etnologia , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética/métodos , Masculino , Succinato-Semialdeído Desidrogenase/metabolismo
2.
J Appl Genet ; 60(2): 151-162, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30706430

RESUMO

Autosomal recessive primary microcephaly (MCPH) is a group of rare neurodevelopmental diseases with severe microcephaly at birth. One type of the disorder, MCPH2, is caused by biallelic mutations in the WDR62 gene, which encodes the WD repeat-containing protein 62. Patients with WDR62 mutation may have a wide range of malformations of cortical development in addition to congenital microcephaly. We describe two patients, a boy and a girl, with severe congenital microcephaly, global developmental delay, epilepsy, and failure to thrive. MRI showed hemispherical asymmetry, diffuse pachygyria, thick gray matter, indistinct gray-white matter junction, and corpus callosum and white matter hypoplasia. Whole exome sequencing revealed the same novel homozygous missense mutation, c.668T>C, p.Phe223Ser in exon 6 of the WDR62 gene. The healthy parents were heterozygous for this mutation. The mutation affects a highly conserved region in one of the WD repeats of the WDR62 protein. Haplotype analysis showed genetic relatedness between the families of the patients. Our findings expand the spectrum of mutations randomly distributed in the WDR62 gene. A review is also provided of the brain malformations described in WDR62 mutations in association with congenital microcephaly.


Assuntos
Deficiências do Desenvolvimento/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Haplótipos , Homozigoto , Humanos , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/fisiopatologia , Mutação de Sentido Incorreto/genética , Linhagem , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
3.
J Neurosurg Anesthesiol ; 31(1): 115-118, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30767933

RESUMO

An important element of designing research studies is the selection of appropriate outcome measures to ensure that the question posed is properly answered given the evidence. The selection of outcome measures is especially important when tackling complex, interdisciplinary problems, where appropriate outcome measures may not be as simple as a blood test or a laboratory value. One such area of study is the research into neurodevelopmental outcomes after early exposure to anesthetic agents. Concern has arisen recently that certain anesthetic agents may be toxic to the developing brain; a public-private partnership, SmartTots, was formed in conjunction with the Food and Drug Administration and various stakeholders to develop safe anesthetic regimens for neonates and infants who require surgery. However, as research has progressed, questions have arisen regarding the best outcome measures to use in order to detect a true effect, as well as the optimal window in which to measure. These issues were discussed in a round table meeting during the SmartTots meeting in September 2017, and a summary of the discussion is presented here.


Assuntos
Anestesia/efeitos adversos , Anestésicos/efeitos adversos , Deficiências do Desenvolvimento/induzido quimicamente , Adolescente , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/diagnóstico por imagem , Humanos , Hipnóticos e Sedativos/efeitos adversos , Lactente , Recém-Nascido , Neuroimagem , Avaliação de Resultados (Cuidados de Saúde)
4.
J Neurosurg Anesthesiol ; 31(1): 163-165, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30767942

RESUMO

The potential for long-term neurotoxic effects of anesthetics on the developing human brain has led to intensified research in this area. To date, the human evidence has been inconclusive, but a large body of animal evidence continues to demonstrate cause for concern. On April 14 and 15, 2018 the sixth biennial Pediatric Anesthesia and Neurodevelopmental Assessment (PANDA) study symposium was held at Morgan Stanley Children's Hospital of New York. This symposium brought together clinicians and researchers and served as a platform to review preclinical and clinical data related to anesthesia and neurotoxicity in developing brains. The program participants included many active investigators in the field of anesthesia neurotoxicity as well as stakeholders from different backgrounds with the common interest of potential anesthetic neurotoxicity in children. The moderated poster session included presentations of preclinical animal research studies. These studies focused on defining the anesthetic-induced neurotoxicity phenotype, understanding the mechanism of injury and discovering potential inhibitors of neurotoxic effects.


Assuntos
Anestesia/efeitos adversos , Anestésicos/efeitos adversos , Deficiências do Desenvolvimento/induzido quimicamente , Adolescente , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Humanos , Lactente , Recém-Nascido , Síndromes Neurotóxicas/etiologia
5.
J Neurosurg Anesthesiol ; 31(1): 166-169, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30767943

RESUMO

Clinical researchers studying the long-term neurocognitive effects of anesthetic and sedative agents on children continue to struggle with identifying a phenotype for anesthetic neurotoxicity, the window of vulnerability, and the toxicity threshold in terms of concentration and duration. The Sixth Biennial Pediatric Anesthesia Neurodevelopment Assessment (PANDA) symposium at Columbia University included a moderated poster presentation session where 4 investigators presented their latest contributions to the landscape of clinical anesthetic neurotoxicity research. A lack of standardization in the design of clinical studies in terms of age at exposure, duration and type of exposure, and outcome measures assessed were highlighted by all the investigators. Suggestions for the future direction of clinical trials included the implementation of more consistent study parameters and the employment of standardized neurocognitive testing and imaging before and after exposure to general anesthesia. Presentations covered a broad range of topics including the valid translation of preclinical studies to human subjects, the quantification of real-world exposures to anesthetic and sedative medications, and possible alternatives to these exposures.


Assuntos
Anestesia/efeitos adversos , Anestésicos/efeitos adversos , Deficiências do Desenvolvimento/induzido quimicamente , Adolescente , Anestesiologia , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Humanos , Lactente , Recém-Nascido , Síndromes Neurotóxicas
6.
Medicina (Kaunas) ; 55(2)2019 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-30781564

RESUMO

Magnetic resonance imaging (MRI) is used as a clarifying technique after a high-resolution ultrasound examination during pregnancy. Combining ultrasound with MRI, additional diagnostic information is obtained or ultrasound diagnosis is frequently corrected. High spatial resolution provides accurate radiological imaging of internal organs and widens possibilities for detecting perinatal development disorders. The safety of MRI and the use of intravenous contrast agent gadolinium are discussed in this article. There is no currently available evidence that MRI is harmful to the fetus, although not enough research has been carried out to prove enduring safety. MRI should be performed when the benefit outweighs the potential side effects. The narrative review includes several clinical cases of fetal MRI performed in Vilnius University Hospital Santaros Clinics.


Assuntos
Abdome/anormalidades , Abdome/diagnóstico por imagem , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Deficiências do Desenvolvimento/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Ultrassonografia Pré-Natal/métodos , Adulto , Meios de Contraste/efeitos adversos , Feminino , Gadolínio/efeitos adversos , Hospitais Universitários , Humanos , Lituânia , Imagem por Ressonância Magnética/efeitos adversos , Gravidez , Ultrassonografia Pré-Natal/efeitos adversos
7.
Pediatrics ; 143(2)2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30635350

RESUMO

: media-1vid110.1542/5972296741001PEDS-VA_2018-2373Video Abstract BACKGROUND: Studies have revealed an association between positional plagiocephaly and/or brachycephaly (PPB) and development, although little is known about long-term outcomes. We examined cognition and academic achievement in children with and without PPB, testing the hypothesis that children who had PPB as infants would score lower than controls. METHODS: We enrolled 187 school-aged children with a history of PPB and 149 controls. Exposures were the presence or absence and severity of infancy PPB (mild, moderate to severe). Cognitive and academic outcomes were assessed by using the Differential Ability Scales, Second Edition and Wechsler Individual Achievement Test, Third Edition, respectively. RESULTS: Children with PPB scored lower than controls on most scales of the Differential Ability Scales, Second Edition (standardized effect sizes [ESs] = -0.38 to -0.20) and the Wechsler Individual Achievement Test, Third Edition (ESs = -0.22 to -0.17). Analyses by PPB severity revealed meaningful differences among children with moderate to severe PPB (ESs = -0.47 to -0.23 for 8 of 9 outcomes), but few differences in children with mild PPB (ESs = -0.28 to 0.14). CONCLUSIONS: School-aged children with moderate to severe PPB scored lower than controls on cognitive and academic measures; associations were negligible among children with mild PPB. The findings do not necessarily imply that these associations are causal; rather, PPB may serve as a marker of developmental risk. Our findings suggest a role for assessing PPB severity in clinical practice: providing developmental assessment and intervention for infants with more severe deformation and reassurance and anticipatory guidance for patients with mild deformation.


Assuntos
Cognição/fisiologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/epidemiologia , Plagiocefalia não Sinostótica/diagnóstico por imagem , Plagiocefalia não Sinostótica/epidemiologia , Decúbito Dorsal , Estudos de Casos e Controles , Criança , Estudos de Coortes , Deficiências do Desenvolvimento/psicologia , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Plagiocefalia não Sinostótica/psicologia , Estudos Prospectivos , Decúbito Dorsal/fisiologia
8.
J Hum Genet ; 64(4): 291-296, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30692598

RESUMO

A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.


Assuntos
Sistema Nervoso Central/fisiopatologia , Deficiência Intelectual/genética , Osteogênese Imperfeita/genética , Proteína Wnt1/genética , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/fisiopatologia , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/fisiopatologia , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Pamidronato/administração & dosagem , Pamidronato/efeitos adversos
9.
Neurology ; 92(2): e96-e107, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30541864

RESUMO

OBJECTIVE: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. METHODS: Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. RESULTS: We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%). CONCLUSIONS: SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.


Assuntos
Deficiências do Desenvolvimento/genética , Mutação/genética , Espasmos Infantis/genética , Proteínas Ativadoras de ras GTPase/genética , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Encéfalo/diagnóstico por imagem , Encefalopatias/complicações , Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/diagnóstico por imagem , Eletroencefalografia , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Espasmos Infantis/complicações , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/tratamento farmacológico , Adulto Jovem
11.
Semin Pediatr Neurol ; 26: 88-91, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29961530

RESUMO

Cytomegalovirus (CMV) is the most common congenital virus passed from mother to fetus in the United States, and the most common acquired cause of sensorineural hearing loss. Neuroimaging in patients with symptomatic congenital CMV demonstrates abnormalities frequently, but many providers are unaware of the extent of these findings. We present a case of a 15-month-old girl with progressive sensorineural hearing loss and developmental delays. Magnetic resonance imaging of her brain was done by her otolaryngologist as part of a routine cochlear implant evaluation where it was found to be drastically abnormal and reported as a likely leukodystrophy. It was subsequently found to be related to congenital CMV on further evaluation. Congenital CMV should be considered in the differential of white matter hyperintensities, especially in the setting of sensorineural hearing loss, developmental delays, or both, and given how common CMV is around the world.


Assuntos
Infecções por Citomegalovirus/congênito , Deficiências do Desenvolvimento/etiologia , Perda Auditiva Neurossensorial/etiologia , Encéfalo/diagnóstico por imagem , Infecções por Citomegalovirus/diagnóstico por imagem , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/virologia , Diagnóstico Diferencial , Feminino , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/reabilitação , Perda Auditiva Neurossensorial/virologia , Humanos , Lactente
12.
Handb Clin Neurol ; 155: 49-59, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891076

RESUMO

Although preterm birth is best known to result in adverse neurodevelopmental outcomes through injury of the supratentorial structures, including intraventricular hemorrhage and periventricular leukomalacia, the cerebellum has become increasingly recognized as an important target for injury and adverse motor and cognitive outcomes. Undergoing the most dramatic growth during the preterm period, the cerebellum is vulnerable to large and small hemorrhages, as well as hypoplasia resulting from a number of potentially modifiable risk factors. These factors include contact with intraventricular blood, crossed cerebrocerebellar diaschisis, postnatal glucocorticoid exposure, pain and opioid exposure, nutrition and somatic growth, cardiorespiratory factors, and socioeconomic status. Strategies targeting these factors may result in prevention of the motor and cognitive deficits seen after cerebellar hemorrhage or hypoplasia.


Assuntos
Doenças Cerebelares/complicações , Cerebelo/anormalidades , Transtornos Cognitivos/etiologia , Deficiências do Desenvolvimento/etiologia , Doenças do Prematuro/fisiopatologia , Doenças Cerebelares/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Hemorragia Cerebral , Deficiências do Desenvolvimento/diagnóstico por imagem , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro
13.
Brain Dev ; 40(9): 813-818, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29858110

RESUMO

Microdeletions in the 1q44 region encompassing the HNRNPU gene have been associated with infantile spasms and hemiconvulsion-hemiplegia-epilepsy syndrome. Recent studies have revealed that heterozygous HNRNPU variants resulted in early onset epilepsy and severe intellectual disability. A de novo frameshift mutation in HNRNPU was identified in a 5-year-old boy with developmental delay associated with Rett-like features including stereotypic hand movements and respiratory abnormalities with episode of apnea and hyperpnea followed by falling. He also showed an episode of acute encephalopathy with biphasic seizures and late reduced diffusion followed by hemiplegia and intractable epilepsy. Unique and variable clinical features are related to loss-of-function or haploinsufficiency of HNRNPU.


Assuntos
Epilepsia Resistente a Medicamentos/genética , Mutação da Fase de Leitura , Hemiplegia/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/genética , Convulsões/genética , Encéfalo/diagnóstico por imagem , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/fisiopatologia , Hemiplegia/diagnóstico por imagem , Hemiplegia/fisiopatologia , Humanos , Masculino , Fenótipo , Convulsões/diagnóstico por imagem , Convulsões/fisiopatologia
14.
Brain Dev ; 40(8): 678-684, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29752200

RESUMO

BACKGROUND: Germline mutations of the PTEN gene are responsible for several PTEN hamartoma tumor syndromes. They are also implicated as a cause of macrocephaly and mild to severe developmental delay, regardless of the presence or absence of hamartomas in childhood. Nevertheless, because of limited information, the clinical features present during childhood in patients with a PTEN mutation are yet to be elucidated. METHODS: PTEN mutations were investigated by multiplex targeted sequencing of genomic DNA from 33 children with increased head circumference (>+2 SD) and developmental delay. The clinical features of all the patients with a PTEN mutation were abstracted by dysmorphologists. RESULTS: We have identified six children with a PTEN mutation. Clinical dissection of these six patients, in addition to patient reports in the literature, revealed distinctive facial features that included frontal bossing, dolichocephaly, horizontal eyebrows, and a depressed nasal bridge. Macrocephaly (+3.2 to +6.0 SD) was noticeable compared to their height (-0.8 to +2.1 SD), and the difference in the SD value of head circumference and height was more than 3 SD in all patients. CONCLUSION: The presence of distinctive facies, extreme macrocephaly with normal to mildly high stature, and developmental delay may be useful for identifying patients with a PTEN mutation in childhood. Early identification of patients with a PTEN mutation would help uncover the natural course of tumor development in this group of individuals who have a possible predisposition to cancer, and be important for the development of an optimal surveillance strategy.


Assuntos
Deficiências do Desenvolvimento/genética , Face/anormalidades , Megalencefalia/genética , Mutação , PTEN Fosfo-Hidrolase/genética , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Feminino , Humanos , Masculino , Megalencefalia/diagnóstico por imagem , Fenótipo
15.
J Obstet Gynaecol Res ; 44(6): 1031-1035, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29517144

RESUMO

AIM: This study was aimed to determine reference ranges for fetal cerebellar hemisphere biometry, including the transverse cerebellar diameter (TCD), anteroposterior cerebellar diameter (APCD) and APCD/TCD ratio in normal fetuses. In addition, we investigated which parameter would be useful for cerebellar hypoplasia in trisomy 18. METHODS: This retrospective study included 340 normal singleton pregnancies and 15 cases of trisomy 18, in all of which fetal cerebellar biometry was performed between 14 and 40 weeks of gestational age (GA). The TCD, APCD and APCD/TCD ratio were assessed ultrasonographically. RESULTS: In normal fetuses, the TCD (rs = 0.876, P < 0.001) and APCD (rs = 0.791, P < 0.001) were strongly correlated with GA. However, the APCD/TCD ratio was not correlated with GA (rs = 0.058, P = 0.289), with median values of 0.52. Low TCD, APCD and APCD/TCD ratio values were detected in 53%, 100% and 100% of trisomy 18 cases, respectively. The median APCD/TCD ratio for trisomy 18 was 0.39 (range, 0.30-0.43), which was significantly lower than that of normal fetuses (P < 0.001). A cut-off APCD/TCD ratio of 0.44 served as a good predictor for trisomy 18 (sensitivity 100%, specificity 95.3% and negative predictive value 100%). CONCLUSION: This study shows that TCD and APCD are correlated with GA, while the APCD/TCD ratio is a fixed value throughout gestation. Using the APCD/TCD ratio to assess cerebellar hypoplasia in trisomy 18 is useful because it does not require the individual evaluation of the TCD and APCD.


Assuntos
Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Síndrome da Trissomía do Cromossomo 18/diagnóstico por imagem , Ultrassonografia Pré-Natal/normas , Cerebelo/patologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Malformações do Sistema Nervoso/etiologia , Malformações do Sistema Nervoso/patologia , Gravidez , Sensibilidade e Especificidade , Síndrome da Trissomía do Cromossomo 18/complicações , Síndrome da Trissomía do Cromossomo 18/patologia
16.
World Neurosurg ; 114: e976-e981, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29588243

RESUMO

INTRODUCTION: Hydrocephalus due to congenital aqueductal stenosis (CAS) has significant long-term clinical implications. Previous reports on outcomes after treatment of congenital hydrocephalus are heterogenous and lack specificity for the subgroup of patients with isolated aqueductal stenosis. METHODS: An institutional surgical database was queried for the time period of 2005-2013 for patients with the diagnosis of isolated CAS and >2 years of clinical follow-up. Medical history and neurodevelopmental outcomes were recorded. RESULTS: The institutional cohort consisted of 41 patients with isolated CAS who underwent cerebrospinal fluid diversion. At a mean follow-up of 5.9 years, 48.8% carried a diagnosis of epilepsy and 68% were developmentally delayed. Four patients were diagnosed with cerebral palsy (9.8%). In total, 78% of patients were shunt-dependent, and the remainder had patent third ventriculostomies. Only 32% of patients in our cohort were neurologically normal after long-term follow-up despite contemporary management. CONCLUSIONS: Regardless of the initial treatment strategy, the age at diagnosis, or the timing of cerebrospinal fluid diversion after birth, patients with aqueductal stenosis have high rates of epilepsy, neurodevelopmental delay, and educational difficulties, and few are neurologically normal despite contemporary management. Investigation into in utero identification and correction of hydrocephalus may result in improved outcomes and warrants further investigation.


Assuntos
Hidrocefalia/diagnóstico por imagem , Hidrocefalia/cirurgia , Derivação Ventriculoperitoneal/tendências , Ventriculostomia/tendências , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/epidemiologia , Epilepsia/diagnóstico por imagem , Epilepsia/epidemiologia , Feminino , Seguimentos , Humanos , Hidrocefalia/epidemiologia , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Terceiro Ventrículo/diagnóstico por imagem , Terceiro Ventrículo/cirurgia , Resultado do Tratamento
17.
Epilepsia ; 59(1): e5-e13, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29171013

RESUMO

Heterozygous de novo variants in the autophagy gene, WDR45, are found in beta-propeller protein-associated neurodegeneration (BPAN). BPAN is characterized by adolescent onset dementia and dystonia; 66% patients have seizures. We asked whether WDR45 was associated with developmental and epileptic encephalopathy (DEE). We performed next generation sequencing of WDR45 in 655 patients with developmental and epileptic encephalopathies. We identified 3/655 patients with DEE plus 4 additional patients with de novo WDR45 pathogenic variants (6 truncations, 1 missense); all were female. Six presented with DEE and 1 with early onset focal seizures and profound regression. Median seizure onset was 12 months, 6 had multiple seizure types, and 5/7 had focal seizures. Three patients had magnetic resonance susceptibility-weighted imaging; blooming was noted in the globus pallidi and substantia nigra in the 2 older children aged 4 and 9 years, consistent with iron accumulation. We show that de novo pathogenic variants are associated with a range of developmental and epileptic encephalopathies with profound developmental consequences.


Assuntos
Proteínas de Transporte/genética , Deficiências do Desenvolvimento/genética , Mutação/genética , Espasmos Infantis/complicações , Espasmos Infantis/genética , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Espasmos Infantis/diagnóstico por imagem
18.
Congenit Anom (Kyoto) ; 58(1): 33-35, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28220539

RESUMO

Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostotic disorder characterized by coronal synostosis, facial asymmetry, ptosis, and limb abnormalities. Haploinsufficiency of TWIST1, a basic helix-loop-helix transcription factor is responsible for SCS. Here, we report a 15-month-old male patient with typical clinical features of SCS in addition to developmental delay, which is a rare complication in SCS. He showed a de novo 0.9-Mb microdeletion in 7p21, in which TWIST1, NPMIP13, FERD3L, TWISTNB, and HDAC9 were included. In comparison with previously reported patients, HDAC9 was suggested to contribute to developmental delay in SCS patients with 7p21 mirodeletions.


Assuntos
Acrocefalossindactilia/genética , Deleção Cromossômica , Cromossomos Humanos Par 7 , Deficiências do Desenvolvimento/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Nucleares/genética , Proteína 1 Relacionada a Twist/genética , Acrocefalossindactilia/diagnóstico por imagem , Acrocefalossindactilia/patologia , Tomografia Computadorizada de Feixe Cônico , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/patologia , Genes Dominantes , Haploinsuficiência , Histona Desacetilases/deficiência , Histona Desacetilases/genética , Humanos , Lactente , Masculino , Fatores de Regulação Miogênica/genética , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/patologia , Proteínas Nucleares/deficiência , Proteínas/genética , Proteínas/metabolismo , Proteínas Repressoras/deficiência , Proteínas Repressoras/genética , Proteína 1 Relacionada a Twist/deficiência
19.
Brain Dev ; 40(2): 134-139, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28893434

RESUMO

Mutations in SZT2 were first reported in 2013 as a cause of early-onset epileptic encephalopathy. Because only five reports have been published to date, the clinical features associated with SZT2 remain unclear. We herein report an additional patient with biallelic mutations in SZT2. The proband, a four-year-old girl, showed developmental delay and seizures from two years of age. Her seizures were not intractable and readily controlled by valproate. She showed mildly dysmorphic facies with macrocephaly, high forehead, and hypertelorism, and also had pectus carinatum. An EEG showed epileptic discharges which rarely occurred. A brain MRI revealed a short and thick corpus callosum. Whole-exome sequencing detected compound heterozygous biallelic mutations (c.8596dup (p.Tyr2866Leufs∗42) and c.2930-17_2930-3delinsCTCGTG) in SZT2, both of which were novel and predicted to be truncating. This case suggested a broad phenotypic spectrum arises from SZT2 mutations, forming a continuum from epileptic encephalopathy and severe developmental delay to mild intellectual disability without epilepsy. The characteristic thick and short corpus callosum observed in 7/8 cases with epilepsy, including the proband, but not in three non-syndromic cases, appears to be specific, and thus useful for indicating the possibility of SZT2 mutations. This feature has the potential to make loss of SZT2 a clinically discernible disorder despite a wide clinical spectrum.


Assuntos
Agenesia do Corpo Caloso/genética , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Megalencefalia/genética , Mutação , Proteínas do Tecido Nervoso/genética , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/fisiopatologia , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Epilepsia/diagnóstico por imagem , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Feminino , Humanos , Megalencefalia/diagnóstico por imagem , Megalencefalia/fisiopatologia , Fenótipo
20.
Georgian Med News ; (285): 41-46, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30702068

RESUMO

The aim of the research was to determine the diagnostic significance of Brain-derived neurotrophic factor (BDNF) in preterm infants with gestational age less than 34 weeks. The study group included 30 preterm infants with average birth weight 1373.5±66.0 g and gestational age 29.3±0.5 weeks. The catamnestic observation was conducted over this category of infants until reaching the corrected age of 18 months. The relationship between BDNF levels and antenatal factors, postnatal results and remote effects were determined. Premature infants who were diagnosed with disability at the corrected age of 18 months, had the lowest BDNF concentrations at 5-7 days of life (142.1±64.7 pg/ml, р<0.05). BDNF concentrations were still low at the 4th weeks of life - 166.7±69.5 pg/ml, р<0.01. The above data correlates with fertility problems of the mothers (r=-0.74, р<0.05). BDNF concentrations at the 5-7 days of life also correlated with the development of retinopathy of prematurity (r=0.58, р<0.05). Insufficient activity of neurotrophic factors (BDNF) that enable the functional activity of neurons during hypoxia, causes low MDI and CDI (less than 69) at the corrected age of 18 months (r=0.63, r=0.78 respectively, р<0.01). The paper shows the changes in BDNF concentrations during the neonatal period of preterm newborns with gestational age less than 34 weeks.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Encéfalo/crescimento & desenvolvimento , Desenvolvimento Infantil/fisiologia , Deficiências do Desenvolvimento/sangue , Recém-Nascido Prematuro/sangue , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Deficiências do Desenvolvimento/diagnóstico por imagem , Crianças com Deficiência , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Imagem por Ressonância Magnética , Valor Preditivo dos Testes , Estudos Retrospectivos , Ultrassonografia Doppler Transcraniana
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