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1.
J Child Neurol ; : 883073819870944, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31559893

RESUMO

Aicardi Goutières syndrome is a monogenic interferonopathy caused by abnormalities in the intracellular nucleic acid sensing machinery (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or IFIH1). Most individuals affected by Aicardi Goutières syndrome exhibit some degree of neurologic impairment, from spastic paraparesis with relatively preserved cognition to tetraparesis and severe intellectual disability. Because of this heterogeneity, it is important to fully characterize the developmental trajectory in Aicardi Goutières syndrome. To characterize the clinical presentation in Aicardi Goutières syndrome, early features were collected from an international cohort of children (n = 100) with genetically confirmed Aicardi Goutières syndrome. There was a heterogeneous age of onset, with overlapping clusters of presenting symptoms: altered mental status, systemic inflammatory symptoms, and acute neurologic disability. Next, we created genotype-specific developmental milestone acquisition curves. Individuals with microcephaly or TREX1-related Aicardi Goutières syndrome secondary were the most severely affected and less likely to reach milestones, including head control, sitting, and nonspecific mama/dada. Individuals affected by SAMHD1, IFIH1, and ADAR attained the most advanced milestones, with 44% achieving verbal communication and 31% independently ambulating. Retrospective function scales (Gross Motor Function Classification System, Manual Ability Classification System, and Communication Function Classification System) demonstrated that two-thirds of the Aicardi Goutières syndrome population are severely affected. Our results suggest multifactorial influences on developmental trajectory, including a strong contribution from genotype. Further studies are needed to identify the additional factors that influence overall outcomes to better counsel families and to design clinical trials with appropriate clinical endpoints.

2.
Mol Genet Metab ; 126(4): 489-494, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30826161

RESUMO

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a rare genetic leukoencephalopathy related to inappropriate activation of type I interferon. Neuroradiological findings are typically characterized by white matter abnormalities, cerebral atrophy and cerebral calcification. The disease usually manifests itself during the first year of life in the form of an initial "encephalitic-like" phase followed by a chronic phase of stabilization of the neurological signs. Recently new therapeutic strategies have been proposed aimed at blocking the abnormal activation of the interferon cascade. MATERIALS AND METHODS: We reviewed clinical and MRI findings in three young RNASEH2B-mutated patients studied with serial CT and MRI studies. RESULTS: All three patients presented clinical and MRI features consistent with AGS but, very unexpectedly, an improving neuroradiological course. In patient 1, the MRI improvement was noted some months after treatment with high-dose steroid and IVIg treatment; in patients 2 and 3 it occurred spontaneously. Patient 2 did not show cerebral calcification on CT images. CONCLUSIONS: Our series highlights the possibility of spontaneous neuroradiological improvement in AGS2 patients, as well as the possibility of absence of cerebral calcification in AGS. The study underlines the need for extreme caution when using MRI as an outcome measure in therapeutic trials specific for this disease. MRI follow-up studies in larger series are necessary to describe the natural course of AGS.

3.
Medicine (Baltimore) ; 97(52): e13893, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30593198

RESUMO

Tetraparesis is usually due to cerebral palsy (CP), inborn errors of metabolism, neurogenetic disorders and spinal cord lesions. However, literature data reported that about 10% of children with tetraparesis show a negative/non-specific neuroradiological findings without a specific etiological cause. Aicardi Goutières Syndrome (AGS) is a genetic encephalopathy that may cause tetraparesis. Interferon signature is a reliable biomarker for AGS and could be performed in sine-causa tetraparesis. The aim of the study was to examine the type I interferon signature and AGS related-genes in children with sine causa tetraparesis, to look for misdiagnosed AGS. A secondary aim was to determine which aspects of the patient history, clinical picture and brain imaging best characterize tetraparesis due to an interferonopathy.Seven out of 78 patients affected by tetraparesis, characterized by unremarkable pre-peri-postnatal history and normal/non-specific brain magnetic resonance imaging (MRI) were selected and underwent anamnestic data collection, clinical examination, brain imaging review, peripheral blood interferon signature and AGS-related genes analysis.At our evaluation time (mean age of 11.9 years), all the 7 patients showed spastic-dystonic tetraparesis. At clinical onset brain MRI was normal in 4 and with non-specific abnormalities in 3; at follow-up 3 patients presented with new white-matter lesions, associated with brain calcification in 1 case. Interferon signature was elevated in one subject who presented also a mutation of the IFIH1 gene.AGS should be considered in sine-causa tetraparesis. Core features of interferonopathy-related tetraparesis are: onset during first year of life, psychomotor regression with tetraparesis evolution, brain white-matter lesions with late calcifications. A positive interferon signature may be a helpful marker to select patients with spastic tetraparesis who should undergo genetic analysis for AGS.


Assuntos
Doenças Autoimunes do Sistema Nervoso/complicações , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Interferon Tipo I/biossíntese , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/diagnóstico , Paresia/etiologia , Adolescente , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes do Sistema Nervoso/genética , Biomarcadores , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Interferon Tipo I/sangue , Interferon Tipo I/genética , Imagem por Ressonância Magnética , Masculino , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Projetos Piloto , Adulto Jovem
4.
Orphanet J Rare Dis ; 13(1): 135, 2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-30111349

RESUMO

BACKGROUND: We present a group of patients affected by a paediatric onset genetic encephalopathy with cerebral calcification of unknown aetiology studied with Next Generation Sequencing (NGS) genetic analyses. METHODS: We collected all clinical and radiological data. DNA samples were tested by means of a customized gene panel including fifty-nine genes associated with known genetic diseases with cerebral calcification. RESULTS: We collected a series of fifty patients. All patients displayed complex and heterogeneous phenotypes mostly including developmental delay and pyramidal signs and less frequently movement disorder and epilepsy. Signs of cerebellar and peripheral nervous system involvement were occasionally present. The most frequent MRI abnormality, beside calcification, was the presence of white matter alterations; calcification was localized in basal ganglia and cerebral white matter in the majority of cases. Sixteen out of fifty patients tested positive for mutations in one of the fifty-nine genes analyzed. In fourteen cases the analyses led to a definite genetic diagnosis while results were controversial in the remaining two. CONCLUSIONS: Genetic encephalopathies with cerebral calcification are usually associated to complex phenotypes. In our series, a molecular diagnosis was achieved in 32% of cases, suggesting that the molecular bases of a large number of disorders are still to be elucidated. Our results confirm that cerebral calcification is a good criterion to collect homogeneous groups of patients to be studied by exome or whole genome sequencing; only a very close collaboration between clinicians, neuroradiologists and geneticists can provide better results from these new generation molecular techniques.

5.
Orphanet J Rare Dis ; 13(1): 45, 2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29615062

RESUMO

BACKGROUND: KARS encodes lysyl- transfer ribonucleic acid (tRNA) synthetase, which catalyzes the aminoacylation of tRNA-Lys in the cytoplasm and mitochondria. Eleven families/sporadic patients and 16 different mutations in KARS have been reported to date. The associated clinical phenotype is heterogeneous ranging from early onset encephalopathy to isolated peripheral neuropathy or nonsyndromic hearing impairment. Recently additional presentations including leukoencephalopathy as predominant cerebral involvement or cardiomyopathy, isolated or associated with muscular and cerebral involvement, have been reported. A progressive Leukoencephalopathy with brainstem and spinal cord calcifications was previously described in a singleton patient and in two siblings, without the identification of the genetic cause. We reported here about a new severe phenotype associated with biallelic KARS mutations and sharing some common points with the other already reported phenotypes, but with a distinct clinical and neuroimaging picture. Review of KARS mutant patients published to date will be also discussed. RESULTS: Herein, we report the clinical, biochemical and molecular findings of 2 unreported Italian patients affected by developmental delay, acquired microcephaly, spastic tetraparesis, epilepsy, sensory-neural hypoacusia, visual impairment, microcytic hypochromic anaemia and signs of hepatic dysfunction. MRI pattern in our patients was characterized by progressive diffuse leukoencephalopathy and calcifications extending in cerebral, brainstem and cerebellar white matter, with spinal cord involvement. Genetic analysis performed on these 2 patients and in one subject previously described with similar MRI pattern revealed the presence of biallelic mutations in KARS in all 3 subjects. CONCLUSIONS: With our report we define the molecular basis of the previously described Leukoencephalopathy with Brainstem and Spinal cord Calcification widening the spectrum of KARS related disorders, particularly in childhood onset disease suggestive for mitochondrial impairment. The review of previous cases does not suggest a strict and univocal genotype/phenotype correlation for this highly heterogeneous entity. Moreover, our cases confirm the usefulness of search for common brain and spine MR imaging pattern and of broad genetic screening, in syndromes clinically resembling mitochondrial disorders in spite of normal biochemical assay.

6.
Eur J Paediatr Neurol ; 22(2): 336-339, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29396177

RESUMO

FOXG1-related syndrome is a developmental encephalopathy with a high phenotypic variability. A movement disorder presenting at onset is one of the main features, along with microcephaly and severe psychomotor delay without regression. Specific brain MRI findings facilitate the diagnosis. We report three cases of FOXG1-related syndrome, focusing on clinical onset, brain MRI and evolution over time in order to identify common features despite the three different underlying genotypes (14q12 deletion including the FOXG1 gene, FOXG1 intragenic mutation, 14q12 deletion including PRKD1 and a region regulating FOXG1 expression). In conclusion, we stress the importance of considering genetic syndromes in the differential diagnosis of early-onset movement disorders.


Assuntos
Encefalopatias/genética , Encefalopatias/patologia , Fatores de Transcrição Forkhead/genética , Transtornos dos Movimentos/genética , Proteínas do Tecido Nervoso/genética , Cromossomos Humanos Par 14 , Feminino , Genótipo , Humanos , Masculino , Transtornos dos Movimentos/patologia , Mutação , Deleção de Sequência
7.
Mol Genet Metab ; 122(3): 134-139, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28739201

RESUMO

BACKGROUND: Aicardi Goutières Syndrome (AGS) is a heritable interferonopathy associated with systemic autoinflammation causing interferon (IFN) elevation, central nervous system calcifications, leukodystrophy and severe neurologic sequelae. An infant with TREX1 mutations was recently found to have abnormal C26:0 lysophosphatidylcholine (C26:0 Lyso-PC) in a newborn screening platform for X-linked adrenoleukodystrophy, prompting analysis of this analyte in retrospectively collected samples from individuals affected by AGS. METHODS: In this study, we explored C26:0 Lyso-PC levels and IFN signatures in newborn blood spots and post-natal blood samples in 19 children with a molecular and clinical diagnosis of AGS and in the blood spots of 22 healthy newborns. We used Nanostring nCounter™ for IFN-induced gene analysis and a high-performance liquid chromatography with tandem mass spectrometry (HPLC MS/MS) newborn screening platform for C26:0 Lyso-PC analysis. RESULTS: Newborn screening cards from patients across six AGS associated genes were collected, with a median disease presentation of 2months. Thirteen out of 19 (68%) children with AGS had elevations of first tier C26:0 Lyso-PC (>0.4µM), that would have resulted in a second screen being performed in a two tier screening system for X-linked adrenoleukodystrophy (X-ALD). The median (95%CI) of first tier C26:0 Lyso-PC values in AGS individuals (0.43µM [0.37-0.48]) was higher than that seen in controls (0.21µM [0.21-0.21]), but lower than X-ALD individuals (0.72µM [0.59-0.84])(p<0.001). Fourteen of 19 children had elevated expression of IFN signaling on blood cards relative to controls (Sensitivity 73.7%, 95%CI 51-88%, Specificity 95%, 95% CI 78-99%) including an individual with delayed disease presentation (36months of age). All five AGS patients with negative IFN signature at birth had RNASEH2B mutations. Consistency of agreement between IFN signature in neonatal and post-natal samples was high (0.85). CONCLUSION: This suggests that inflammatory markers in AGS can be identified in the newborn period, before symptom onset. Additionally, since C26:0 Lyso-PC screening is currently used in X-ALD newborn screening panels, clinicians should be alert to the fact that AGS infants may present as false positives during X-ALD screening.


Assuntos
Doenças Autoimunes do Sistema Nervoso/sangue , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Interferons/sangue , Lisofosfatidilcolinas/sangue , Triagem Neonatal/métodos , Malformações do Sistema Nervoso/sangue , Malformações do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Teste em Amostras de Sangue Seco/métodos , Exodesoxirribonucleases/genética , Feminino , Humanos , Lactente , Recém-Nascido , Inflamação/sangue , Inflamação/genética , Interferons/genética , Masculino , Mutação , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Fosfoproteínas/genética , Estudos Retrospectivos , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem , Transcriptoma/imunologia
8.
Neuropediatrics ; 48(3): 166-184, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28561207

RESUMO

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.


Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Interferon Tipo I/metabolismo , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/imunologia , Proteínas de Ligação a RNA/genética , Adolescente , Adulto , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Biomarcadores/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Fenótipo , Adulto Jovem
9.
J Autism Dev Disord ; 47(5): 1490-1495, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28258350

RESUMO

The aim of this retrospective study, with prospective data collection, was to correlate congenital cytomegalovirus (CMV) infection with autism spectrum disorder (ASD) and to define its prevalence. Seventy proven congenitally-infected infants, born between 2007 and 2012, were referred to our centre for CMV diagnosis and follow-up, which consisted of a consolidated protocol allowing an early evaluation of autism. We considered four children 2-year old, two of whom, at the age of 3, were diagnosed with ASD demonstrating a 2-3 fold higher prevalence (2.86%), than that in general Italian population (0.66-1.36%).Our protocol enabled us to make the earliest diagnosis and highlight the role of the virus among other causes of autism, which may be a long term sequela of congenital CMV.


Assuntos
Transtorno do Espectro Autista/virologia , Infecções por Citomegalovirus/complicações , Transtorno do Espectro Autista/epidemiologia , Pré-Escolar , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/psicologia , Feminino , Humanos , Lactente , Recém-Nascido , Itália/epidemiologia , Masculino , Prevalência , Estudos Prospectivos , Estudos Retrospectivos
10.
Am J Perinatol ; 33(11): 1093-8, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27603543

RESUMO

Objective We aimed at assessing the association between superior vena cava flow (SVCf), regional (cerebral) tissue oxygen saturation (rSO2), and cerebral fractional oxygen extraction (CFOE) during the first 48 hours of life and 2-years neurodevelopmental outcome of very low-birth-weight infants (VLBW). Methods We prospectively studied 60 VLBW infants admitted to our neonatal intensive care unit; rSO2 was continuously monitored with near-infrared spectroscopy during the first 48 hours of life, SVCf was measured at 4 to 6, 12, 24, and 48 hours, and CFOE was calculated. Neurodevelopmental outcome was assessed at 24 months corrected age. Results The mean gestational age at birth was 27.9 weeks (standard deviation: 2.4); 8 infants died in the first 3 months of life, 6 were lost to follow-up, 46 survived and were followed up. At 24 months, 6 (13%) and 7 (15.2%) infants developed minor and major sequelae, respectively. Infants who died had higher CFOE (p < 0.001) and lower SVCf (p < 0.001) than infants surviving with sequelae. In turn, these had higher SVCf between 24 and 48 hours than those without sequelae (p < 0.001). Conclusion SVCf, rSO2, and CFOE patterns in the first days of life suggest cerebral hyperperfusion, related to loss of autoregulation and/or use of inotropic drugs, as a potential mechanism of cerebral injury.


Assuntos
Encéfalo/diagnóstico por imagem , Recém-Nascido de muito Baixo Peso/crescimento & desenvolvimento , Monitorização Fisiológica/métodos , Espectroscopia de Luz Próxima ao Infravermelho , Veia Cava Superior/diagnóstico por imagem , Encéfalo/irrigação sanguínea , Pré-Escolar , Feminino , Seguimentos , Idade Gestacional , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Itália , Masculino , Oxigênio/metabolismo , Estudos Prospectivos , Análise de Regressão
11.
J Clin Immunol ; 36(7): 693-9, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27539236

RESUMO

PURPOSE: The purpose of this study was to explore the presence of autoimmune manifestations and characterize the autoantibody production in a cohort of patients with Aicardi-Goutières syndrome (AGS). METHODS: Seventeen patients with a genetically-confirmed diagnosis of AGS were recruited. At the time of enrollment, past medical and family history was reviewed, looking for possible signs or symptoms of autoimmune disorders. Blood samples were taken, for the detection of a panel of autoantibodies: anti-nuclear, anti-double-stranded-DNA, anti-nucleosome, anti-extractable nuclear antigens, anti-cardiolipin IgG/IgM, anti-ß2glycoprotein I IgG/IgM, and anti-neutrophil cytoplasmic. We also measured complement levels determined as C3 and C4 quantification and total complement activity, measured as CH50. RESULTS: Nine of seventeen patients presented with at least one first- or second-degree relative with a history of autoimmune diseases (the childrens' mother or grand-mother in the majority of cases). A specific autoimmune disease was present in only one AGS patient, namely an autoimmune thyroiditis. Autoantibodies were present in 9/17 patients, with different patterns of positivity. Complement levels were normal in all the patients. There was no correlation between auto-antibody production and personal or family history of autoimmune diseases. CONCLUSIONS: Definite autoimmune diseases are not common in patients with AGS. Autoantibodies are mainly directed towards nucleic acids-containing elements but seem not to be pathogenic and, rather, may represent an epiphenomenon of the enhanced interferon production.


Assuntos
Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Autoimunidade/genética , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/imunologia , Alelos , Autoanticorpos/sangue , Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Biomarcadores , Criança , Pré-Escolar , Estudos de Coortes , Suscetibilidade a Doenças , Feminino , Testes Genéticos/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Malformações do Sistema Nervoso/diagnóstico , Fenótipo
12.
Dev Med Child Neurol ; 58(9): 957-64, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27061508

RESUMO

AIM: This study was conducted to develop and validate a new self-report questionnaire for measuring quality of life (QoL), at school age, in children with a very low birthweight (VLBW). METHOD: Through a focus group approach, children were involved directly in defining the questionnaire items, which were presented as illustrations rather than written questions. This preliminary validation of the questionnaire was conducted in 152 participants with VLBW (aged 7-11y) randomly selected from the five participating Italian centres. The questionnaire was completed by children and parents separately; data on children's demographic and medical history, and intellectual, adaptive, and behavioural functioning were collected using standardized scales. All the children also completed the Paediatric Quality of Life Inventory (PedsQL), another Italian-language measure of QoL in children. RESULTS: Our questionnaire was readily accepted and understood, and quick to complete. The Cronbach's alpha value showed it to be a reliable instrument. The child-compiled version correlated well with the PedsQL, whereas no correlations emerged with the other scales used, IQ, or degree of impairment. Conversely, these variables correlated significantly with the parent-compiled version. Children's and parents' answers were divergent on practically all the items. INTERPRETATION: The results confirm the validity of the new instrument and highlight a poor overlap between parents' and children's perspectives.


Assuntos
Recém-Nascido de muito Baixo Peso/psicologia , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida/psicologia , Autoavaliação , Inquéritos e Questionários , Criança , Feminino , Humanos , Masculino , Psicometria , Reprodutibilidade dos Testes
13.
Eur J Paediatr Neurol ; 20(4): 604-10, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27091087

RESUMO

BACKGROUND: Cystic leukoencephalopathy without megalencephaly is a disorder related in some cases to RNASET2 mutations and characterized by bilateral anterior temporal subcortical cysts and multifocal lobar white matter lesions with sparing of central white matter structures. This phenotype significantly overlaps with the sequelae of in utero cytomegalovirus (CMV) infection, including the presence of intracranial calcification in some cases. Aicardi-Goutières syndrome (AGS) is another inherited leukodystrophy with cerebral calcification mimicking congenital infection. Clinical, radiological and biochemical criteria for the diagnosis of AGS have been established, although the breadth of phenotype associated with mutations in the AGS-related genes is much greater than previously envisaged. PATIENTS AND METHODS: We describe the clinical, biochemical and radiological findings of five patients demonstrating a phenotype reminiscent of AGS. RESULTS: All patients were found to carry biallelic mutations of RNASET2. CONCLUSIONS: Our patients illustrate the clinical and radiological overlap that can be seen between RNASET2-related leukodystrophy and AGS in some cases. Our data highlight the need to include both disorders in the same differential diagnosis, and hint at possible shared pathomechanisms related to auto-inflammation which are worthy of further investigation.


Assuntos
Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Encéfalo/fisiopatologia , Cistos/fisiopatologia , Leucoencefalopatias/fisiopatologia , Malformações do Sistema Nervoso/fisiopatologia , Adolescente , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes do Sistema Nervoso/genética , Encéfalo/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Criança , Pré-Escolar , Cistos/diagnóstico por imagem , Cistos/genética , Infecções por Citomegalovirus/congênito , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Masculino , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Fenótipo , Ribonucleases/genética , Tomografia Computadorizada por Raios X , Proteínas Supressoras de Tumor/genética , Adulto Jovem
14.
J Matern Fetal Neonatal Med ; 29(5): 771-6, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25747945

RESUMO

OBJECTIVE: To clarify the links between parents' prenatal attachment and psychosocial perinatal factors such as maternal depression, anxiety and social support. METHODS: Cross-sectional study including 43 couples with high-risk pregnancy (RP) and 37 with physiologic pregnancy (PP). Self-report measures (depression, anxiety, social support and prenatal attachment) are completed by mothers, prenatal attachment questionnaire by fathers. RESULTS: Depression (p < 0.001) and state anxiety (p < 0.001) are higher in RP. Both, maternal and paternal antenatal attachment is significantly lower in RP (p < 0.001; p < 0.005) but not related to depression or anxiety. Paternal antenatal attachment is strictly related to the maternal attachment scale in both groups (PP: r < 0.034; RP: r < 0.004) and paternal antenatal scores in RP have a negative significant correlation with mothers' depression (r < 0.095). CONCLUSION: Hospitalized expecting parents at risk of preterm delivery develop less attachment to the fetus and higher levels of anxiety and depression compared to the physiologic pregnancy group. Maternal antenatal attachment is an independent variable related to the diagnosis of a possible preterm delivery. The promotion of prenatal psychological well-being and attachment for future mothers and fathers may serve to improve maternal health practices, perinatal health and neonatal outcome.


Assuntos
Pai/psicologia , Mães/psicologia , Apego ao Objeto , Gravidez de Alto Risco/psicologia , Nascimento Prematuro/psicologia , Adulto , Ansiedade/epidemiologia , Ansiedade/psicologia , Estudos Transversais , Depressão/epidemiologia , Depressão/psicologia , Feminino , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Pais/psicologia , Gravidez , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Fatores de Risco , Apoio Social , Inquéritos e Questionários , Adulto Jovem
15.
Neurology ; 86(1): 28-35, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26581299

RESUMO

OBJECTIVE: To perform an updated characterization of the neuroradiologic features of Aicardi-Goutières syndrome (AGS). METHODS: The neuroradiologic data of 121 subjects with AGS were collected. The CT and MRI data were analyzed with a systematic approach. Moreover, we evaluated if an association exists between the neuroradiologic findings, clinical features, and genotype. RESULTS: Brain calcifications were present in 110 subjects (90.9%). Severe calcification was associated with TREX1 mutations and early age at onset. Cerebral atrophy was documented in 111 subjects (91.8%). Leukoencephalopathy was present in 120 children (99.2%), with 3 main patterns: frontotemporal, diffuse, and periventricular. White matter rarefaction was found in 54 subjects (50.0%), strongly associated with mutations in TREX1 and an early age at onset. Other novel radiologic features were identified: deep white matter cysts, associated with TREX1 mutations, and delayed myelination, associated with RNASEH2B mutations and early age at onset. CONCLUSIONS: We demonstrate that the AGS neuroradiologic phenotype is expanding by adding new patterns and findings to the classic criteria. The heterogeneity of neuroradiologic patterns is partly explained by the timing of the disease onset and reflects the complexity of the pathogenic mechanisms.


Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes do Sistema Nervoso/genética , Imagem por Ressonância Magnética , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Tomografia Computadorizada por Raios X , Substância Branca/diagnóstico por imagem , Adolescente , Criança , Pré-Escolar , Exodesoxirribonucleases/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fosfoproteínas/genética , Adulto Jovem
16.
Eur J Paediatr Neurol ; 20(2): 323-330, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26643067

RESUMO

BACKGROUND: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) was first described in 2002. After the recent identification of TUBB4A mutation as the genetic basis of the disease, the clinical and neuroimaging phenotype related to TUBB4A mutations expanded, ranging from primary dystonia type 4 with normal MRI to severe H-ABC cases. PATIENTS AND METHODS: The study included patients referred to us for an unclassified hypomyelinating leukodystrophy. We selected patients with deleterious heterozygous TUBB4A mutations. Molecular analysis of TUBB4A was performed on genomic DNA extracted from peripheral blood. RESULTS: The series included 12 patients (5 females and 7 males). Five patients carried the common mutation c.745G > A (p.Asp249Asn), while the remaining harbored different mutations. Three new mutations were found in 5 patients. Clinical and neuroimaging observations are described. A clear correlation between the clinical presentation and the genotype seems to be absent in our group of 12 patients. CONCLUSIONS: TUBB4A-mutated patients manifest a comparable clinical and neuroimaging picture but they can differ from each other in terms of rate of disease progression. Extrapyramidal signs can be absent in the first stages of the disease, and a careful evaluation of MRI is fundamental to obtain the final diagnosis. From a therapeutic perspective a trial with l-dopa should be considered in all patients presenting extrapyramidal symptoms.


Assuntos
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Tubulina (Proteína)/genética , Adulto , Progressão da Doença , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Neuroimagem , Fenótipo
17.
Dev Med Child Neurol ; 57(11): 1035-41, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26239047

RESUMO

AIM: To assess the time trends of neonatal survival and infant neurodevelopmental outcome in very-low-birthweight children at 24 months corrected age over a 20-year period. METHOD: The study cohort comprised 857 infants (439 males and 418 females) weighing less than 1500g at birth or delivered before 32 weeks gestational age in the period 1989 to 2008. Neurological examination and cognitive assessment of the infants (Bayley Scales of Infant Development and Griffiths Mental Developmental Scale) were performed at 24 months corrected age. RESULTS: The prevalence of neonatal survival with normal neurodevelopmental outcome increased from 55.3% (104/188) in 1989 to 1993, to 61.4% in 1994-1998 (116/189), 68.3% in 1999 to 2003 (138/202), and 84.5% in 2004 to 2008 (235/278) (annual increase=1%, 95% CI 2.1-4.1; p<0.001). In logistic models, the increase in the rate of normal neurodevelopmental outcome during the periods studied was consistent across the categories of birthweight (≤1000g as opposed to >1000g), gestational age (≤28wks as opposed to >28wks), and clinical characteristics (pre-eclampsia/growth restriction as opposed to spontaneous prematurity/rupture of membranes). INTERPRETATION: The increased rate of normal neurodevelopmental outcome at 2 years among very-low-birthweight infants is independent of obstetric risk factors.


Assuntos
Ruptura Prematura de Membranas Fetais/epidemiologia , Ruptura Prematura de Membranas Fetais/mortalidade , Recém-Nascido de muito Baixo Peso , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/mortalidade , Complicações do Trabalho de Parto/epidemiologia , Pré-Escolar , Estudos de Coortes , Feminino , Idade Gestacional , Humanos , Modelos Logísticos , Masculino , Idade Materna , Doenças do Sistema Nervoso/etiologia , Gravidez , Fatores de Risco , Estatísticas não Paramétricas
18.
Ann Clin Transl Neurol ; 2(6): 648-61, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26125040

RESUMO

OBJECTIVE: The objective of this study was to investigate the genetic etiology of the X-linked disorder "Hypomyelination of Early Myelinating Structures" (HEMS). METHODS: We included 16 patients from 10 families diagnosed with HEMS by brain MRI criteria. Exome sequencing was used to search for causal mutations. In silico analysis of effects of the mutations on splicing and RNA folding was performed. In vitro gene splicing was examined in RNA from patients' fibroblasts and an immortalized immature oligodendrocyte cell line after transfection with mutant minigene splicing constructs. RESULTS: All patients had unusual hemizygous mutations of PLP1 located in exon 3B (one deletion, one missense and two silent), which is spliced out in isoform DM20, or in intron 3 (five mutations). The deletion led to truncation of PLP1, but not DM20. Four mutations were predicted to affect PLP1/DM20 alternative splicing by creating exonic splicing silencer motifs or new splice donor sites or by affecting the local RNA structure of the PLP1 splice donor site. Four deep intronic mutations were predicted to destabilize a long-distance interaction structure in the secondary PLP1 RNA fragment involved in regulating PLP1/DM20 alternative splicing. Splicing studies in fibroblasts and transfected cells confirmed a decreased PLP1/DM20 ratio. INTERPRETATION: Brain structures that normally myelinate early are poorly myelinated in HEMS, while they are the best myelinated structures in Pelizaeus-Merzbacher disease, also caused by PLP1 alterations. Our data extend the phenotypic spectrum of PLP1-related disorders indicating that normal PLP1/DM20 alternative splicing is essential for early myelination and support the need to include intron 3 in diagnostic sequencing.

19.
Am J Med Genet A ; 167A(4): 810-5, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25706114

RESUMO

COL4A1 is located in humans on chromosome13q34 and it encodes the alpha 1 chain of type IV collagen, a component of basal membrane. It is expressed mainly in the brain, muscles, kidneys and eyes. Different COL4A1 mutations have been reported in many patients who present a very wide spectrum of clinical symptoms. They typically show a multisystemic phenotype. Here we report on the case of a patient carrying a novel de novo splicing mutation of COL4A1 associated with a distinctive clinical picture characterized by onset in infancy and an unusual evolution of the neuroradiological features. At three months of age, the child was diagnosed with a congenital cataract, while his brain MRI was normal. Over the following years, the patient developed focal epilepsy, mild diplegia, asymptomatic microhematuria, raised creatine kinase levels, MRI white matter abnormalities and brain calcification on CT. During the neuroradiological follow-up the extension and intensity of the brain lesions progressively decreased. The significance of a second variant in COL4A1 carried by the child and inherited from his father remains to be clarified. In conclusion, our patient shows new aspects of this collagenopathy and possibly a COL4A1 compound heterozygosity.


Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Paralisia Cerebral/diagnóstico , Colágeno Tipo IV/genética , Anormalidades Múltiplas/genética , Sequência de Bases , Paralisia Cerebral/genética , Criança , Análise Mutacional de DNA , Estudos de Associação Genética , Humanos , Masculino , Mutação , Radiografia , Substância Branca/anormalidades , Substância Branca/diagnóstico por imagem
20.
Hum Genome Var ; 2: 15051, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27081556

RESUMO

The SPRED1 gene encodes a protein involved in the Ras/MAPK (mitogen-activated protein kinase) signaling pathway. Mutations in SPRED1 have been reported to cause Legius Syndrome, a rare developmental disorder that shares some clinical features with Neurofibromatosis-1. Direct sequencing was used to define SPRED1 mutations. We present two previously undescribed mutations: a frameshift mutation causing a stop codon, which was identified in an Italian family (p.Ile60Tyrfs*18) and a missense variation, which was identified in one sporadic Italian case (p.Pro422Arg). Our results led us to hypothesize that these modifications may contribute to the Legius Syndrome phenotype. Further studies will be needed to determine the roles of these mutations in the mechanisms of Legius Syndrome.

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