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1.
Genet Med ; 21(3): 553-563, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29997391

RESUMO

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


Assuntos
Ataxia/genética , Ataxia Cerebelar/genética , Espasmos Infantis/genética , Adolescente , Ataxia/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Exoma/genética , Feminino , França , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Mutação/genética , Fenótipo , Sequenciamento do Exoma/métodos , Adulto Jovem
2.
J Neurol Neurosurg Psychiatry ; 83(10): 956-62, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22832740

RESUMO

BACKGROUND: Benign hereditary chorea (BHC) is a rare autosomal dominant disorder characterised by childhood onset that tends to improve in adulthood. The associated gene, NKX2-1 (previously called TITF1), is essential for organogenesis of the basal ganglia, thyroid and lungs. The aim of the study was to refine the movement disorders phenotype. We also studied disease course and response to therapy in a large series of genetically proven patients. METHODS: We analysed clinical, genetic findings and follow-up data in 28 NKX2-1 mutated BHC patients from 13 families. RESULTS: All patients had private mutations, including seven new mutations, three previously reported mutations and three sporadic deletions encompassing the NKX2-1 gene. Hypotonia and chorea were present in early infancy, with delayed walking ability (25/28); dystonia, myoclonus and tics were often associated. Attention deficit hyperactivity disorder (ADHD) was present in seven. Among the 14 patients followed-up until adulthood, nine had persistent mild chorea, two had near total resolution of chorea but persistent disabling prominent myoclonus and three recovered completely. Learning difficulties were observed in 20/28 patients, and three had mental retardation. Various combinations of BHC, thyroid (67%) and lung (46%) features were noted. We found no genotype-phenotype correlation. A rapid and sustained beneficial effect on chorea was obtained in 5/8 patients treated with tetrabenazine. CONCLUSION: Early onset chorea preceded by hypotonia is suggestive of BHC. Associated thyroid or respiratory disorders further support the diagnosis and call for genetic studies. Tetrabenazine may be an interesting option to treat disabling chorea.


Assuntos
Inibidores da Captação Adrenérgica/uso terapêutico , Coreia , Transtornos Cromossômicos , Mutação , Proteínas Nucleares/genética , Tetrabenazina/uso terapêutico , Fatores de Transcrição/genética , Inibidores da Captação Adrenérgica/administração & dosagem , Inibidores da Captação Adrenérgica/efeitos adversos , Adulto , Idade de Início , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Pré-Escolar , Coreia/diagnóstico , Coreia/tratamento farmacológico , Coreia/genética , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/tratamento farmacológico , Transtornos Cromossômicos/genética , Transtornos Cognitivos/genética , Hipotireoidismo Congênito/genética , Análise Mutacional de DNA , Feminino , Seguimentos , França , Genes Dominantes , Humanos , Lactente , Masculino , Testes Neuropsicológicos , Fenótipo , Prognóstico , Análise Serial de Proteínas , Doenças Respiratórias/genética , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Fator Nuclear 1 de Tireoide , Resultado do Tratamento
3.
J Child Neurol ; 36(8): 625-634, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33507832

RESUMO

Attention span, which has been shown to have an impact on reading quality in many other conditions, is one of the main cognitive disorders of neurofibromatosis type 1 (NF1). The aim of this work is to observe the impact of attention on reading comprehension, in NF1 and non-NF1 children. A multicenter, cross-sectional study was conducted on 150 children (8-12 years old) with or without NF1 (75 NF1 vs 75 non-NF1; 72 female, 78 male), matched for age, sex, handedness, and reading level, thus forming a continuum from good to poor readers in both NF1 and non-NF1 groups. Children with intellectual deficiency or neurologic or psychiatric disorder were excluded. Attentional skills were assessed by combining a parent questionnaire (Child Behavior CheckList) and a performance-based assessment (Conner's Continuous Performance Test-Second Edition). Reading comprehension was assessed through a standardized reading comprehension test (ORLEC Lobrot). The performance-based attention scores were associated with text and sentence comprehension ability (P = .0235 and P = .0164, respectively), while indirect questionnaire attention scores were only associated with sentence comprehension (P = .0263). For both groups, the correlations between questionnaire and performance-based measures were low. We have shown that reading comprehension is greatly influenced by attention in NF1 and non-NF1, even if predictors of good reading comprehension also include IQ score and reading accuracy. Indirect observer-rated questionnaires and direct performance-based measures of attention do not assess the same variables, are linked to different components of reading skills, and are not interchangeable assessments of attention difficulties. Both assessments are complementary and must be used simultaneously, leading to recommendations that support multimodal assessment of attention.


Assuntos
Atenção/fisiologia , Transtornos Cognitivos/diagnóstico , Compreensão/fisiologia , Neurofibromatose 1/fisiopatologia , Testes Neuropsicológicos/estatística & dados numéricos , Leitura , Criança , Transtornos Cognitivos/complicações , Transtornos Cognitivos/fisiopatologia , Estudos Transversais , Feminino , Humanos , Masculino , Neurofibromatose 1/complicações
4.
J Exp Med ; 218(11)2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34546337

RESUMO

Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenic mechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, loss of which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomic studies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels as putative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We also confirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disrupts mitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in our mouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.


Assuntos
Família 2 do Citocromo P450/genética , Família 2 do Citocromo P450/metabolismo , Deficiência de Ácido Fólico/genética , Deficiência de Ácido Fólico/metabolismo , Ácido Fólico/farmacologia , Animais , Biomarcadores/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mutação/genética , Fenótipo , Proteômica/métodos
5.
Mov Disord ; 25(11): 1605-11, 2010 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-20629163

RESUMO

Speech disturbances are frequent and potentially disabling in patients with dystonia or chorea due to neurometabolic disorders (DCND), but their precise characteristics are poorly documented. We prospectively studied 29 consecutive patients with DCND. A detailed description of their speech patterns was obtained by using the Frenchay dysarthria assessment test and the apraxia of speech evaluation test of Wertz. Gross motor function and intelligibility were each scored on 5-point scales to identify a possible correlation between the severity of the speech and motor disorders. All the patients were found to have complex speech alterations with combined features of hyperkinetic dysarthria and speech apraxia. We also noted a correlation between the severity of the speech disorders and the motor disorders. These findings have important implications for speech rehabilitation, and may provide new insights into the pathophysiology of dystonia due to neurometabolic disorders.


Assuntos
Encefalopatias Metabólicas/complicações , Coreia/complicações , Coreia/etiologia , Distonia/complicações , Distonia/etiologia , Distúrbios da Fala/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Saúde da Família , Feminino , Humanos , Masculino , Exame Neurológico/métodos , Adulto Jovem
6.
J Atten Disord ; 24(13): 1807-1823, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-28587546

RESUMO

Objective: To compare children with Neurofibromatosis type 1 and associated ADHD symptomatology (NF1 + ADHD) with children having received a diagnosis of ADHD without NF1. The idea was that performance differences in tasks of attention between these two groups would be attributable not to the ADHD symptomatology, but to NF1 alone. Method: One group of children with NF1 + ADHD (N = 32), one group of children with ADHD (N = 31), and one group of healthy controls (N = 40) participated in a set of computerized tasks assessing intensive, selective, and executive aspects of attention. Results: Differences were found between the two groups of patients in respect of several aspects of attention. Children with NF1 + ADHD did not always perform worse than children with ADHD. Several double dissociations can be established between the two groups of patients. Conclusion: ADHD symptomatology in NF1 does not contribute to all attention deficits, and ADHD cannot account for all attention impairments in NF1.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Neurofibromatose 1 , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Humanos , Neurofibromatose 1/complicações , Testes Neuropsicológicos
7.
Case Rep Psychiatry ; 2019: 4764031, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32089936

RESUMO

Introduction. Cognitive and behavioural problems associated with Neurofibromatosis type 1 (NF1) are common sources of distress and the reasons behind seeking help. Here we describe patients with NF1 or NF1-like phenotypes referred to a Tier 3 Child and Adolescent Psychiatry Department and highlight the benefits of a multidisciplinary assessment. METHODS: Prospective data were gathered from NF1 patients aged 7-15 years, referred by the NF1 Referral Centre due to additional difficulties either in management or diagnosis. For the selected cases, we performed a psychiatric assessment, a tailored neuropsychological evaluation based on clinical demands and history, broad speech and motor skills evaluations if there were concerns regarding language, motor abilities and/or learning difficulties and autism specific evaluations, if clinically relevant. No exclusion criteria were applied. RESULTS: Complex NF1 cases represented only 5% of the patients (11/224). Assessments revealed the complexity of NF1 phenotype and a variety of problems including learning difficulties, emotional problems and autism spectrum disorders. Specific evaluations of language, motor, attentional and neurovisual domains were essential to guide tailored intervention strategies. CONCLUSIONS: In terms of clinical implications, the heterogeneity of NF1 phenotypical manifestations needs to be considered when developing assessment and remediation approaches for children with complex NF1.

8.
Child Neuropsychol ; 24(4): 558-574, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28393676

RESUMO

Learning disabilities are one of the most frequent complications of neurofibromatosis type 1 (NF1) in children. Studies of the effects of the neurocognitive deficit on academic performance are relatively rare, owing to the small size of the populations concerned. However, research is needed to develop effective rehabilitation programs. In the present study, we explored the impact of a possible phonological deficit on the reading abilities of children with NF1. A multicenter, cross-sectional study was conducted in France on two groups of 75 children with or without NF1 aged 8-12 years, matched for age, sex, handedness, and reading level. All participants underwent a neuropsychological evaluation to assess their general cognitive level, reading skills, phonological processes, visuoperceptual abilities, and attentional capacity. Phonological skills were assessed by means of two phonological awareness tasks and one short-term memory task. In the group of children with NF1, 41% had reading difficulties. Phonological processes were impaired in this group, compared with the children without NF1. Similar differences were found for a phoneme deletion task after adjustment for reading difficulties, IQ level, and visuoperceptual abilities. Phonological awareness, but not phonological short-term memory, was impaired in children with NF1, and not just those whose reading was impaired. Results suggest that children with NF1 have a phonological awareness deficit, whatever their reading level. Identification of reduced phonological skills may warrant the implementation of a specific rehabilitation program before early reading difficulties emerge.


Assuntos
Neurofibromatose 1/psicologia , Testes Neuropsicológicos/normas , Fonética , Criança , Estudos Transversais , Feminino , Humanos , Deficiências da Aprendizagem , Masculino , Neurofibromatose 1/patologia
9.
Eur J Paediatr Neurol ; 20(2): 275-281, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26774135

RESUMO

BACKGROUND/PURPOSE: Optic pathway glioma (OPG) is the most common central nervous system tumor in children with neurofibromatosis type 1 (NF1), affecting 15-20% of patients. We reviewed the medical records of children systematically screened by ophthalmologic and MRI examinations to determine the influence of screening on the therapeutic management of children with OPG. METHODS: Data were collected on 306 newly diagnosed cases screened with systematic MRI from January 2001 to July 2007. In the OPG group, we distinguished the asymptomatic or symptomatic groups according to their initial status. RESULTS: Forty-five patients had confirmed OPG (14.7%). Thirty-six patients (80%) were asymptomatic and nine (20%) were symptomatic at the time of diagnosis with visual symptoms in six cases. The average age at OPG diagnosis was 3.4 years with six patients (13%) over six years old. Average follow-up was 7.7 years. Progression was observed in 16 cases (35%). Most patient conditions were managed conservatively (87%). Six children (13%) were treated with chemotherapy due to worsening visual function. All of these children had severe or mild visual impairment at the end of follow-up. CONCLUSION: Our study does not support a clear benefit of systematic MRI screening in NF1 children under six years old. Systematic neuroimaging in our study did not influence therapeutic management. Although OPG diagnosis was made early, treatment with chemotherapy did not improve the final visual outcome. If MRI remains the best tool for the diagnosis of cerebral and spinal pathologies in the NF1 population, our current study questions the usefulness of systematic MRI screening for OPG diagnosis. Conversely, this study suggests that the indication of neuroimaging should be dictated by the results of annual clinical and ophthalmological assessments.


Assuntos
Detecção Precoce de Câncer/métodos , Imageamento por Ressonância Magnética/métodos , Neurofibromatose 1/complicações , Glioma do Nervo Óptico/diagnóstico , Criança , Pré-Escolar , Estudos de Coortes , Feminino , França , Humanos , Masculino , Neurofibromatose 1/diagnóstico , Neuroimagem , Glioma do Nervo Óptico/genética
10.
Orphanet J Rare Dis ; 9: 142, 2014 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-25205361

RESUMO

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an estimated prevalence of about 1/3000, independent of ethnicity, race, or gender. Attention Deficit Hyperactivity like Disorder (ADHD)-like characteristics are often reported in patients with NF1. We hypothesised that learning disabilities in NF1 children were related to ADHD symptoms. Treatment with methylphenidate (MPD) has improved learning disabilities in ADHD by acting on neurotransmitters. Our objective was to evaluate its efficacy on ADHD-like symptoms in neurofibromatosis type 1 children (7-12 years). METHODS: This was a randomised, double blind, placebo controlled, and crossover trial comparing 0.5 to 0.8 mg/kg/d of MPD as it is indicated for ADHD to placebo in NF1 children with ADHD-like symptoms. Children aged 7 to 12 years were eligible when their IQ was between 80 and 120. The total follow-up was 9 weeks including 4 weeks for each period and 1 week wash out. Fifty subjects (25 for each period) were required for testing the primary study hypothesis. The main outcome was an improvement in scores on the simplified Conners' Parent Rating Scale. RESULTS: Thirty-nine patients were included between April 2004 and December 2010. Twenty participants received MPD and 19 placebo during the first period. They all completed the trial. MPD decreased the simplified Conners by 3.9 points (±1.1, p = 0. 0003). CONCLUSIONS: This is the first randomised controlled trial showing the short-term benefit of MPD on simplified Conners scores in NF1 children. TRIAL REGISTRATION: ClinicalTrials.gov NCT00169611.


Assuntos
Metilfenidato/uso terapêutico , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/tratamento farmacológico , Criança , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Neurofibromatose 1/psicologia , Resultado do Tratamento
11.
Orphanet J Rare Dis ; 6: 18, 2011 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-21542925

RESUMO

BACKGROUND: Neurofibromatosis 1 (NF1), a common autosomal dominant disorder, was shown in one study to be associated with a 15-year decrease in life expectancy. However, data on mortality in NF1 are limited. Our aim was to evaluate mortality in a large retrospective cohort of NF1 patients seen in France between 1980 and 2006. METHODS: Consecutive NF1 patients referred to the National French Referral Center for Neurofibromatoses were included. The standardized mortality ratio (SMR) with its 95% confidence interval (CI) was calculated as the ratio of observed over expected numbers of deaths. We studied factors associated with death and causes of death. RESULTS: Between 1980 and 2006, 1895 NF1 patients were seen. Median follow-up was 6.8 years (range, 0.4-20.6). Vital status was available for 1226 (65%) patients, of whom 1159 (94.5%) survived and 67 (5.5%) died. Overall mortality was significantly increased in the NF1 cohort (SMR, 2.02; CI, 1.6-2.6; P < 10-4). The excess mortality occurred among patients aged 10 to 20 years (SMR, 5.2; CI, 2.6-9.3; P < 10-4) and 20 to 40 years (SMR, 4.1; 2.8-5.8; P < 10-4). Significant excess mortality was found in both males and females. In the 10-20 year age group, females had a significant increase in mortality compared to males (SMR, 12.6; CI, 5.7-23.9; and SMR, 1.8; CI, 0.2-6.4; respectively). The cause of death was available for 58 (86.6%) patients; malignant nerve sheath tumor was the main cause of death (60%). CONCLUSIONS: We found significantly increased SMRs indicating excess mortality in NF1 patients compared to the general population. The definitive diagnosis of NF1 in all patients is a strength of our study, and the high rate of death related to malignant transformation is consistent with previous work. The retrospective design and hospital-based recruitment are limitations of our study. Mortality was significantly increased in NF1 patients aged 10 to 40 years and tended to be higher in females than in males.


Assuntos
Neoplasias de Bainha Neural/mortalidade , Neurofibromatose 1/complicações , Neurofibromatose 1/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Criança , Pré-Escolar , Estudos de Coortes , Feminino , França/epidemiologia , Genes da Neurofibromatose 1 , Humanos , Expectativa de Vida , Masculino , Pessoa de Meia-Idade , Neoplasias de Bainha Neural/complicações , Neurofibromatose 1/genética , Fatores de Risco , Adulto Jovem
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