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3.
Neurology ; 92(8): e852-e865, 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30659139

RESUMO

OBJECTIVE: To genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management. METHODS: Among the 2,697 patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehensive cross-sectional analysis of most relevant qualitative and quantitative variables was performed. RESULTS: We studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cognitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spectrum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce. CONCLUSIONS: The pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (including transition into adulthood) and health policy planning.

4.
Neuromuscul Disord ; 29(2): 114-126, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30598237

RESUMO

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder characterized by progressive motor and respiratory decline during the first year of life. Early and late-onset cases have recently been reported, although not meeting the established diagnostic criteria, these cases have been genotyped. We thus conducted a national multicenter observational retrospective study to determine the prognosis of children with SMARD1 according to their phenotype. We recorded all known French pediatric cases with mutations identified on the immunoglobulin µ-binding protein 2 gene and the presence of respiratory symptoms. Thirty centers provided 22 observations. A diaphragmatic palsy was diagnosed 1.5 months (p = 0.02) after first respiratory symptoms, and hypotonia preceded areflexia by 4 months (p = 0.02). Early onset of symptoms leading to specialist consultation before the age of 3 months was associated with a significantly worse prognosis (p < 0.01). Among the 6 patients who were still alive, all were tracheostomized. Only one case survived beyond 2 years without artificial ventilation. The remaining patients died at a median age of 7 months. Our results may help pediatricians to provide medical information to parents and improve the decision-making process of setting up life support.

5.
Nat Commun ; 9(1): 4619, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30397230

RESUMO

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

6.
Rheumatology (Oxford) ; 57(5): 873-879, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29474663

RESUMO

Objectives: Myositis-specific autoantibodies (MSAs) are increasingly used to delineate distinct subgroups of JDM. The aim of our study was to explore without a priori hypotheses whether MSAs are associated with distinct clinical-pathological changes and severity in a monocentric JDM cohort. Methods: Clinical, biological and histological findings from 23 JDM patients were assessed. Twenty-six histopathological parameters were subjected to multivariate analysis. Results: Autoantibodies included anti-NXP2 (9/23), anti-TIF1γ (4/23), anti-MDA5 (2/23), no MSAs (8/23). Multivariate analysis yielded two histopathological clusters. Cluster 1 (n = 11) showed a more severe and ischaemic pattern than cluster 2 (n = 12) assessed by: total score severity ⩾ 20 (100.0% vs 25.0%); visual analogic score ⩾6 (100.0% vs 25.0%); the vascular domain score >1 (100.0% vs 41.7%); microinfarcts (100% vs 58.3%); ischaemic myofibrillary loss (focal punched-out vacuoles) (90.9 vs 25%); and obvious capillary loss (81.8% vs 16.7). Compared with cluster 2, patients in cluster 1 had strikingly more often anti-NXP2 antibodies (7/11 vs 2/12), more pronounced muscle weakness, more gastrointestinal involvement and required more aggressive treatment. Furthermore, patients with anti-NXP2 antibodies, mostly assigned in the first cluster, also displayed more severe muscular disease, requiring more aggressive treatment and having a lower remission rate during the follow-up period. Conclusion: Marked muscle ischaemic involvement and the presence of anti-NXP2 autoantibodies are associated with more severe forms of JDM.


Assuntos
Adenosina Trifosfatases/imunologia , Autoanticorpos/imunologia , Proteínas de Ligação a DNA/imunologia , Dermatomiosite/complicações , Isquemia/etiologia , Músculo Esquelético/irrigação sanguínea , Adenosina Trifosfatases/metabolismo , Biomarcadores/metabolismo , Biópsia , Proteínas de Ligação a DNA/metabolismo , Dermatomiosite/imunologia , Dermatomiosite/metabolismo , Progressão da Doença , Feminino , Seguimentos , Humanos , Isquemia/diagnóstico , Isquemia/imunologia , Masculino , Músculo Esquelético/diagnóstico por imagem , Índice de Gravidade de Doença
7.
Am J Med Genet A ; 176(1): 151-155, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29130637

RESUMO

A congenital myasthenia was suspected in two unrelated children with very similar phenotypes including several episodes of severe dyspnea. Both children had a 10q11.2 deletion revealed by Single Nucleotide Polymorphisms array or by Next Generation Sequencing analysis. The deletion was inherited from the healthy mother in the first case. These deletions unmasked a recessive mutation at the same locus in both cases, but in two different genes: CHAT and SLC18A3.


Assuntos
Colina O-Acetiltransferase/genética , Deleção Cromossômica , Cromossomos Humanos Par 10 , Genes Recessivos , Mutação , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/genética , Fenótipo , Proteínas Vesiculares de Transporte de Acetilcolina/genética , Sequência de Aminoácidos , Feminino , Estudos de Associação Genética , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único
8.
J Med Genet ; 53(8): 511-22, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26989088

RESUMO

OBJECTIVE: We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations. METHODS: We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed. RESULTS: We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3' and 5' exons. Seizures in patients with mutations in exons 4-5 were more pharmacoresponsive than in patients with mutations in exons 8-15. CONCLUSIONS: SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.

9.
Prenat Diagn ; 32(3): 277-83, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22430728

RESUMO

BACKGROUND: Corpus callosum agenesis (CCA) is generally diagnosed in utero. Outcome appears to be better if the malformation is isolated. The aim of this study, which is the first one with a long (10 years) and standardized follow up, was to report cognitive abilities of children with isolated CCA diagnosed prenatally. METHODS: We prospectively evaluated 17 children. Clinical examinations, neuropsychological tests were performed each year. School achievement and personal and familial data were collected. RESULTS: Twelve children completed the entire follow up. One child was finally considered to have associated CCA, because signs of fetal alcohol syndrome had become obvious. Of the 11 other children, three (27%) had borderline intelligence whereas the intelligence levels of eight (73%) were in the normal range, although half of these children experienced some difficulties in scholastic achievement. Neither epilepsy nor intellectual deficiency was noted and intellectual quotient scores correlated strongly with the mother's education level. CONCLUSION: Although prenatal diagnosis of isolated CCA is reliable, false postnatal diagnoses remain possible (10-20%) even with complete prenatal screening. Outcome is mostly favorable because intelligence is within the normal range for nearly 3/4 of the children. However, they frequently have mild learning difficulties.


Assuntos
Agenesia do Corpo Caloso/diagnóstico por imagem , Desenvolvimento Infantil/fisiologia , Ultrassonografia Pré-Natal , Fatores Etários , Agenesia do Corpo Caloso/complicações , Agenesia do Corpo Caloso/epidemiologia , Agenesia do Corpo Caloso/fisiopatologia , Criança , Escolaridade , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/etiologia , Inteligência , Masculino , Destreza Motora/fisiologia , Testes Neuropsicológicos , Gravidez , Ultrassonografia Pré-Natal/métodos
10.
J Inherit Metab Dis ; 33 Suppl 3: S477-80, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21103936

RESUMO

Patients with type I glycogen storage disease (GSD) have poor tolerance to fasting, sometimes less than 3 hours during infancy. Even though most patients are able, as they get older, to tolerate a longer fasting period, they are at permanent risk for fast-induced hypoglycaemia, even in adulthood. Klüver Bucy syndrome, is characterized by psychic blindness (inability to recognize familiar objects), hypermetamorphosis (strong tendency to react to visual stimulus), increased oral exploration, placidity, indiscriminate hyper-sexuality and change in dietary habits. In this case report, we describe the development of Klüver Bucy syndrome in a 28-year-old man with type Ib GSD, following prolonged and severe hypoglycaemia triggered by a common respiratory infection.


Assuntos
Coma/etiologia , Doença de Depósito de Glicogênio Tipo I/complicações , Hipoglicemia/etiologia , Síndrome de Kluver-Bucy/etiologia , Infecções Respiratórias/complicações , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Coma/diagnóstico , Jejum/sangue , Doença de Depósito de Glicogênio Tipo I/diagnóstico , Doença de Depósito de Glicogênio Tipo I/terapia , Humanos , Hipoglicemia/sangue , Hipoglicemia/diagnóstico , Hipoglicemia/terapia , Síndrome de Kluver-Bucy/diagnóstico , Síndrome de Kluver-Bucy/psicologia , Síndrome de Kluver-Bucy/terapia , Imagem por Ressonância Magnética , Masculino , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/terapia , Índice de Gravidade de Doença , Resultado do Tratamento
11.
Pediatr Nephrol ; 25(5): 965-9, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20091056

RESUMO

Tacrolimus is known to potentially lead to adverse events in recipients with diarrhoea and/or calcium channel blocker (CCB) co-administration. We report a renal transplant recipient who suffered from severe nephrotoxicity related to a toxic tacrolimus trough concentration in both conditions, diarrhoea and CCB co-administration, and with genotyped CYP3A system and P-glycoprotein (P-gp) polymorphisms. To our knowledge, this is the first case to be investigated for such polymorphisms. Clinicians should be reminded of the possibility of highly increased levels of tacrolimus in situations of diarrhoea and/or co-administration of CCBs. It also highlights the key role in tacrolimus pharmacokinetics of the CYP3A system and P-gp polymorphisms, and their influence in high-risk situations when enzyme activity is already affected by enterocyte damage due to diarrhoea and CCB competition.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Lesão Renal Aguda/induzido quimicamente , Bloqueadores dos Canais de Cálcio/efeitos adversos , Sistema Enzimático do Citocromo P-450/genética , Diarreia/complicações , Imunossupressores/efeitos adversos , Transplante de Rim , Tacrolimo/efeitos adversos , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Lesão Renal Aguda/enzimologia , Lesão Renal Aguda/genética , Adolescente , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Interações de Medicamentos , Monitoramento de Medicamentos , Predisposição Genética para Doença , Humanos , Imunossupressores/farmacocinética , Masculino , Farmacogenética , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Tacrolimo/farmacocinética
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