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1.
Clin Genet ; 96(2): 169-175, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31066025

RESUMO

Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5% in our cohort of unrelated patients screened by targeted next-generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders.

2.
Mol Genet Genomic Med ; 6(3): 322-331, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29536651

RESUMO

BACKGROUND: Kabuki syndrome (KS) is a disorder characterized by multiple congenital anomalies affecting development and function of multiple systems. Over the years, researchers have attempted to characterize the neurobehavioral phenotype of KS in cohorts of patients enrolled on the basis of clinical assessment. The availability of molecular testing now allows for recruitment of patients with confirmed KS due to KMT2D and KDM6A. METHODS: The aims of the present study were to investigate the neuropsychological and behavioral profiles of individuals with molecularly confirmed diagnosis of KS, and determine the extent of heterogeneity occurring in these profiles between individuals with clinical diagnosis of KS with and without mutations in KMT2D. We also described performance of our cohort in any neuropsychological domain investigated. RESULTS: We documented a marked variation in the neuropsychological profile of subjects with clinical diagnosis of KS, even though a relatively homogeneous impairment in linguistic domains and motor skills was observed. No significant difference occurred between mutation-positive and mutation-negative groups. Phonological disorders and oromotor dysfunctions were also found, and adaptive functioning was characterized by low performance in daily living and in motor domain. CONCLUSION: The present study allowed identification of a distinctive neurobehavioral profile in a cohort of individuals affected by KS with or without molecularly confirmed diagnosis. These findings are expected to help clinicians define more accurately targeted protocols for individualized intervention.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Face/anormalidades , Doenças Hematológicas/genética , Doenças Hematológicas/fisiopatologia , Doenças Vestibulares/genética , Doenças Vestibulares/fisiopatologia , Adolescente , Criança , Pré-Escolar , Cognição/fisiologia , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Face/fisiopatologia , Feminino , Histona Desmetilases/genética , Histona Desmetilases/fisiologia , Humanos , Masculino , Destreza Motora/fisiologia , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Fenótipo , Adulto Jovem
3.
PLoS One ; 13(1): e0191164, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29338029

RESUMO

This study aimed at comparing implicit sequence learning in individuals affected by Duchenne Muscular Dystrophy without intellectual disability and age-matched typically developing children. A modified version of the Serial Reaction Time task was administered to 32 Duchenne children and 37 controls of comparable chronological age. The Duchenne group showed a reduced rate of implicit learning even if in the absence of global intellectual disability. This finding provides further evidence of the involvement of specific aspects of cognitive function in Duchenne muscular dystrophy and on its possible neurobiological substrate.


Assuntos
Cerebelo/fisiopatologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/psicologia , Transtornos de Aprendizagem/complicações , Transtornos de Aprendizagem/psicologia , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/psicologia , Estudos de Casos e Controles , Criança , Disfunção Cognitiva/fisiopatologia , Humanos , Aprendizagem/fisiologia , Transtornos de Aprendizagem/fisiopatologia , Modelos Logísticos , Masculino , Distrofia Muscular de Duchenne/fisiopatologia , Tempo de Reação/fisiologia
4.
Eur J Paediatr Neurol ; 22(1): 170-177, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29037749

RESUMO

INTRODUCTION: Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, skeletal and haematological/lymphatic defects, distinctive facies, cryptorchidism, and a wide spectrum of congenital heart defects. Recurrent features also include variable cognitive deficits and behavioural problems. Recent research has been focused on the assessment of prevalence, age of onset and characterization of psychiatric features in this disorder. Herein, we evaluated the prevalence of attention deficit and hyperactivity disorder (ADHD), anxiety and depressive symptoms and syndromes in a cohort of individuals with clinical and molecular diagnosis of NS. METHODS: The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS PL) has been used for the assessment of psychiatric disorders according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Multidimensional Anxiety Scale for Children (MASC) and the Children's Depression Inventory (CDI) have been assessed for the evaluation of anxiety and depressive symptoms and syndromes, whereas Conners Teacher and Parent Rating Scales-long version (CRS-R) have been used to evaluate ADHD. RESULTS: The study included 27 individuals (67% males) with an average age of 10.4 years (range 6-18 years) receiving molecular diagnosis of NS or a clinically related condition, evaluated and treated at the Neuropsychiatric Unit of Children's Hospital Bambino Gesù and at the Center for Rare Diseases of Fondazione Policlinico Universitario Agostino Gemelli, in Rome. Twenty individuals showed mutations in PTPN11, five in SOS1 and two in SHOC2. The mean IQ was 94 (Standard Deviation = 17, min = 56, max = 130). Seventy percent of the individuals (n = 19; 95% Confidence Interval = 52-85%) showed ADHD features, with six individuals reaching DSM-IV-TR criteria for ADHD disorder, and thirteen showing subsyndromal traits. Symptoms or syndrome of anxiety were present in 37% of the cohort (n = 10; 95% Confidence Interval = 19-56%), with two individuals showing anxiety disorder and eight cases exhibiting subsyndromal traits. CONCLUSION: Our results show individuals with NS do present a very high risk to develop psychiatric disorders or symptoms during paediatric age. Based on these findings, preschool assessment of inattentive, hyperactivity/impulsivity and anxiety/depressive symptoms is recommended in order to plan a personalized treatment for psychological/psychiatric issues in affected individuals. Dedicated prospective studies are required to confirm the present data and better characterize the psychopathological profile in NS.


Assuntos
Ansiedade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Depressão/epidemiologia , Síndrome de Noonan/epidemiologia , Adolescente , Idade de Início , Criança , Comorbidade , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Itália/epidemiologia , Masculino , Prevalência , Sintomas Prodrômicos , Estudos Prospectivos , Escalas de Graduação Psiquiátrica
5.
Stem Cells Transl Med ; 5(7): 860-9, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27160703

RESUMO

UNLABELLED: : Rho-GTPases have relevant functions in various aspects of neuronal development, such as differentiation, migration, and synaptogenesis. Loss of function of the oligophrenin-1 gene (OPHN1) causes X-linked intellectual disability with cerebellar hypoplasia and leads to hyperactivation of the rho kinase (ROCK) pathway. ROCK mainly acts through phosphorylation of the myosin phosphatase targeting subunit 1, triggering actin-myosin contractility. We show that during in vitro neurogenesis, ROCK activity decreases from day 10 until terminal differentiation, whereas in OPHN1-deficient human induced pluripotent stem cells (h-iPSCs), the levels of ROCK are elevated throughout differentiation. ROCK inhibition favors neuronal-like appearance of h-iPSCs, in parallel with transcriptional upregulation of nuclear receptor NR4A1, which is known to induce neurite outgrowth. This study analyzed the morphological, biochemical, and functional features of OPHN1-deficient h-iPSCs and their rescue by treatment with the ROCK inhibitor fasudil, shedding light on the relevance of the ROCK pathway during neuronal differentiation and providing a neuronal model for human OPHN1 syndrome and its treatment. SIGNIFICANCE: The analysis of the levels of rho kinase (ROCK) activity at different stages of in vitro neurogenesis of human induced pluripotent stem cells reveals that ROCK activity decreases progressively in parallel with the appearance of neuronal-like morphology and upregulation of nuclear receptor NR4A1. These results shed light on the role of the ROCK pathway during early stages of human neurogenesis and provide a neuronal stem cell-based model for the treatment of OPHN1 syndrome and other neurological disorders due to ROCK dysfunction.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Proteínas do Citoesqueleto/genética , Proteínas Ativadoras de GTPase/genética , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Mutação , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Proteínas Nucleares/genética , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Forma Celular/efeitos dos fármacos , Forma Celular/genética , Células Cultivadas , Proteínas do Citoesqueleto/fisiologia , Proteínas Ativadoras de GTPase/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Modelos Biológicos , Mutação/fisiologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Neurogênese/genética , Neurônios/citologia , Neurônios/fisiologia , Proteínas Nucleares/fisiologia , Fenótipo , Síndrome , Quinases Associadas a rho/fisiologia
6.
Hum Mutat ; 36(12): 1155-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26290468

RESUMO

RPL10 encodes ribosomal protein L10 (uL16), a highly conserved multifunctional component of the large ribosomal subunit, involved in ribosome biogenesis and function. Using X-exome resequencing, we identified a novel missense mutation (c.191C>T; p.(A64V)) in the N-terminal domain of the protein, in a family with two affected cousins presenting with X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia (SED). We assessed the impact of the mutation on the translational capacity of the cell using yeast as model system. The mutation generates a functional ribosomal protein, able to complement the translational defects of a conditional lethal mutation of yeast rpl10. However, unlike previously reported mutations, this novel RPL10 missense mutation results in an increase in the actively translating ribosome population. Our results expand the mutational and clinical spectrum of RPL10 identifying a new genetic cause of SED and highlight the emerging role of ribosomal proteins in the pathogenesis of neurodevelopmental disorders.


Assuntos
Cerebelo/anormalidades , Genes Ligados ao Cromossomo X , Deficiência Intelectual/genética , Mutação , Malformações do Sistema Nervoso/genética , Osteocondrodisplasias/genética , Proteínas Ribossômicas/genética , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico , Imagem por Ressonância Magnética , Masculino , Malformações do Sistema Nervoso/diagnóstico , Neuroimagem , Osteocondrodisplasias/diagnóstico , Fenótipo , Proteínas Ribossômicas/metabolismo , Análise de Sequência de DNA , Inativação do Cromossomo X
7.
Res Dev Disabil ; 36C: 55-61, 2015 01.
Artigo em Inglês | MEDLINE | ID: mdl-25462465

RESUMO

Children with Duchenne muscular dystrophy (DMD) present a specific deficit of voluntary attention but to date there has been no clear characterization of their attentional skills. The present study investigated the hypothesis that DMD patients present deficits of both voluntary and automatic visuospatial attention systems and that their performance could be equivalent to that of younger healthy males. Twenty males (mean age 10 years) with diagnosis of DMD, 20 age-matched healthy males (10 years 3 months) and 20 healthy younger males (7 years 6 months) were required to perform two visuospatial attention tasks: voluntary and automatic. In the voluntary task, the performance of the DMD group was significantly worse than that of the age-matched group, and equal to that of the younger controls. In the automatic attention task also, the performance of the DMD patients was less efficient than that of the age-matched controls and equal to that of the younger children. This study supports the previous report of voluntary attention deficit in DMD and extends the evidence to include also an automatic attention system deficit. The development level of attention in DMD patients is below that expected for their age and corresponds to a delay of about three years.

8.
Am J Med Genet B Neuropsychiatr Genet ; 168B(1): 66-71, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25367099

RESUMO

Costello syndrome (CS) is a rare genetic disorder caused, in the majority of cases, by germline missense HRAS mutations affecting Gly(12) promoting enhanced signaling through the MAPK and PI3K-AKT signaling cascades. In general, the cognitive profile in CS is characterized by intellectual disability ranging from mild to severe impairment. The first published descriptions of behavior in CS children underlined the presence of irritability and shyness at younger ages with sociable personality and good empathic skills after 4-5 years of age, however some recent studies have reported autistic traits. We report on a 7-year-old boy heterozygous for a rare duplication of codon 37 (p.E37dup) in HRAS, manifesting impaired social interaction and non-verbal communication and with circumscribed interests. These additional features improve phenotype delineation in individuals with rare HRAS mutations, facilitating the development of specific behavioral treatments which could lead to improvement in cases of autism spectrum disorder.


Assuntos
Transtornos do Comportamento Infantil/genética , Síndrome de Costello/genética , Síndrome de Costello/psicologia , Comunicação não Verbal/psicologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/psicologia , Criança , Transtornos do Comportamento Infantil/psicologia , Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/psicologia , Humanos , Masculino
9.
Am J Med Genet A ; 164A(4): 934-42, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24458522

RESUMO

Here, we describe neurobehavioral features in patients with RASopathies (i.e., Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome), developmental disorders caused by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade. Parents of 70 individuals with a RASopathy were asked to fill out the following questionnaires: Child Behavior Checklist (CBCL), Social Communication Questionnaire version lifetime (SCQ-L), and Modified Checklist for Autism in toddlers (M-CHAT). Data analysis indicated high rates of internalizing (37%) and externalizing problems (31%) on CBCL. Scores over the cut-off were documented in 64% of patients with cardiofaciocutaneous syndrome, 44% with Costello syndrome, and 12% with Noonan syndrome on SCQ-L/M-CHAT. Our findings indicate that mutations promoting dysregulation of the RAS-MAPK cascade mark an increased psychopathological risk and highlight that autistic-like behavior could be underdiagnosed in patients with RASopathies.


Assuntos
Sistema de Sinalização das MAP Quinases/genética , Transtornos Mentais/enzimologia , Transtornos Mentais/genética , Proteínas ras/genética , Adolescente , Adulto , Transtorno Autístico/enzimologia , Transtorno Autístico/genética , Criança , Pré-Escolar , Síndrome de Costello/enzimologia , Síndrome de Costello/genética , Deficiências do Desenvolvimento/enzimologia , Deficiências do Desenvolvimento/genética , Displasia Ectodérmica/enzimologia , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento/enzimologia , Insuficiência de Crescimento/genética , Feminino , Cardiopatias Congênitas/enzimologia , Cardiopatias Congênitas/genética , Humanos , Síndrome LEOPARD/enzimologia , Síndrome LEOPARD/genética , Masculino , Mutação/genética , Síndrome de Noonan/enzimologia , Síndrome de Noonan/genética , Adulto Jovem
10.
J Pediatr ; 161(4): 705-9.e1, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22560791

RESUMO

OBJECTIVES: To assess attention deficit hyperactivity disorder (ADHD) in boys affected by Duchenne muscular dystrophy (DMD) and to explore the relationship with cognitive abilities and genetic findings. STUDY DESIGN: Boys with DMD (n = 103; 4-17 years of age, mean: 12.6) were assessed using a cognitive test (Wechsler scales). Assessment of ADHD was based on the Diagnostic Statistical Manual, Fourth Edition, Text Revision criteria and on the long version of the Conners Parents and Teachers Rating Scales. RESULTS: ADHD was found in 33 of the 103 boys with DMD. Attention problems together with hyperactivity (17/33) or in isolation (15/33) were more frequent than hyperactivity alone, which was found in 1 patient. Intellectual disability (ID) was found in 27/103 (24.6%). Sixty-two of the 103 boys had no ID and no ADHD, 9 had ID but no ADHD, 14 had ADHD but no ID, and 18 had both. ADHD occurred more frequently in association with mutations predicted to affect Dp140 expression (exon 45-55) and in those with mutations predicted to affect all dystrophin product, including Dp71 (ie, those that have promoter region and specific first exon between exons 62 and 63 but were also relatively frequent). CONCLUSIONS: Our results suggest that ADHD is a frequent feature in DMD. The risk of ADHD appears to be higher in patients carrying mutations predicted to affect dystrophin isoforms expressed in the brain and are known to be associated with higher risk of cognitive impairment.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Cognição , Distrofia Muscular de Duchenne/epidemiologia , Adolescente , Criança , Pré-Escolar , Transtornos Cognitivos/epidemiologia , Comorbidade , Distrofina/genética , Genótipo , Humanos , Masculino , Distrofia Muscular de Duchenne/genética , Mutação , Fenótipo , Estudos Prospectivos , Isoformas de Proteínas
11.
Behav Genet ; 41(3): 423-9, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21274610

RESUMO

In the present study we evaluated long term memory in twenty individuals with molecularly confirmed diagnosis of Noonan syndrome and LEOPARD syndrome, two disorders caused by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade. The profile of explicit long term memory abilities was investigated using PROMEA, which includes a battery of tests specifically developed to assess memory and learning in verbal, visual and spatial domains. Ten individuals (50%) had impaired (≤5th percentile) or below average (≤15th percentile) performance on a delayed verbal free recall memory task, four (20%) on a delayed visual recognition memory task, and only one (5%) on a delayed spatial recognition memory task. Our data suggest that dysregulation of the RAS-MAPK cascade may be associated with a pattern of reduced verbal recall memory performance but relative sparing of visual and spatial recognition memory.


Assuntos
Síndrome LEOPARD/genética , Transtornos de Aprendizagem/genética , Sistema de Sinalização das MAP Quinases/genética , Transtornos da Memória/genética , Memória de Longo Prazo , Proteínas Quinases Ativadas por Mitógeno/genética , Síndrome de Noonan/genética , Proteínas ras/genética , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Síndrome LEOPARD/diagnóstico , Transtornos de Aprendizagem/diagnóstico , Masculino , Transtornos da Memória/diagnóstico , Testes Neuropsicológicos , Síndrome de Noonan/diagnóstico , Fenótipo
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