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1.
Pediatr Infect Dis J ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31634298

RESUMO

Autopsy investigation of a fatal case of rotavirus severe acute gastroenteritis and multiple organ failure in a 16-month boy with previous intrauterine growth retardation showed colocalization of nonstructural and structural rotavirus proteins within viroplasms in nephrons. This case brings new insights into extraintestinal rotavirus infection and new clues to its abilities to bind to human histo-blood group antigens.

2.
Am J Med Genet A ; 179(9): 1756-1763, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31241255

RESUMO

Alpha-mannosidosis (AM) is a very rare (prevalence: 1/500000 births) autosomal recessive lysosomal storage disorder. It is characterized by multi-systemic involvement associated with progressive intellectual disability, hearing loss, skeletal anomalies, and coarse facial features. The spectrum is wide, from very severe and lethal to a milder phenotype that usually progresses slowly. AM is caused by a deficiency of lysosomal alpha-mannosidase. A diagnosis can be established by measuring the activity of lysosomal alpha-mannosidase in leucocytes and screening for abnormal urinary excretion of mannose-rich oligosaccharides. Genetic confirmation is obtained with the identification of MAN2B1 mutations. Enzyme replacement therapy (LAMZEDER ) was approved for use in Europe in August 2018. Here, we describe seven individuals from four families, diagnosed at 3-23 years of age, and who were referred to a clinical geneticist for etiologic exploration of syndromic hearing loss, associated with moderate learning disabilities. Exome sequencing had been used to establish the molecular diagnosis in five cases, including a two-sibling pair. In the remaining two patients, the diagnosis was obtained with screening of urinary oligosaccharides excretion and the association of deafness and hypotonia. These observations emphasize that the clinical diagnosis of AM can be challenging, and that it is likely an underdiagnosed rare cause of syndromic hearing loss. Exome sequencing can contribute significantly to the early diagnosis of these nonspecific mild phenotypes, with advantages for treatment and management.

3.
J Clin Microbiol ; 57(5)2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30814269

RESUMO

Cystic fibrosis (CF) patients are commonly colonized by bacterial pathogens, which can induce persistent lung inflammation and may contribute to clinical deterioration. Colonization of CF patients and cross-transmission by Corynebacterium diphtheriae have not been reported so far. The aim of this article was to investigate the possibility of a cross-transmission of C. diphtheriae biovar Belfanti between four patients of a CF center. C. diphtheriae biovar Belfanti (now formally called C. belfantii) isolates were collected from four patients in a single CF care center over a period of 6 years and analyzed by microbiological methods and whole-genome sequencing. Epidemiological links among patients were investigated. Ten isolates were collected from 4 patients. Whole-genome sequencing of one isolate from each patient showed that a single strain was shared among them. In addition, one patient was found to have the same strain in two consecutive samplings performed 9 months apart. The strain was nontoxigenic and was susceptible to most antimicrobial agents. Ciprofloxacin resistance was observed in one patient. The idea of transmission of the strain among patients was supported by the occurrence of same-day visits to the CF center. This study demonstrated colonization of CF patients by C. diphtheriae biovar Belfanti (C. belfantii), and the data suggest persistence and transmission of a unique strain during at least 6 years in a single CF patient care center.

4.
Am J Hum Genet ; 102(3): 364-374, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29429573

RESUMO

Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.

5.
Mycopathologia ; 183(1): 101-117, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28748285

RESUMO

Fungal respiratory colonization of cystic fibrosis (CF) patients emerges as a new concern; however, the heterogeneity of mycological protocols limits investigations. We first aimed at setting up an efficient standardized protocol for mycological analysis of CF sputa that was assessed during a prospective, multicenter study: "MucoFong" program (PHRC-06/1902). Sputa from 243 CF patients from seven centers in France were collected over a 15-month period and submitted to a standardized protocol based on 6 semi-selective media. After mucolytic pretreatment, sputa were plated in parallel on cycloheximide-enriched (ACT37), erythritol-enriched (ERY37), benomyl dichloran-rose bengal (BENO37) and chromogenic (CAN37) media incubated at 37 °C and on Sabouraud-chloramphenicol (SAB27) and erythritol-enriched (ERY27) media incubated at 20-27 °C. Each plate was checked twice a week during 3 weeks. Fungi were conventionally identified; time for detection of fungal growth was noted for each species. Fungal prevalences and media performances were assessed; an optimal combination of media was determined using the Chi-squared automatic interaction detector method. At least one fungal species was isolated from 81% of sputa. Candida albicans was the most prevalent species (58.8%), followed by Aspergillus fumigatus (35.4%). Cultivation on CAN37, SAB27, ACT37 and ERY27 during 16 days provided an optimal combination, detecting C. albicans, A. fumigatus, Scedosporium apiospermum complex and Exophiala spp. with sensitivities of 96.5, 98.8, 100 and 100%. Combination of these four culture media is recommended to ensure the growth of key fungal pathogens in CF respiratory specimens. The use of such consensual protocol is of major interest for merging results from future epidemiological studies.


Assuntos
Fibrose Cística/complicações , Fungos/classificação , Fungos/isolamento & purificação , Pneumopatias Fúngicas/diagnóstico , Técnicas Microbiológicas/métodos , Técnicas Microbiológicas/normas , Escarro/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
6.
Eur J Med Genet ; 60(11): 595-604, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28807864

RESUMO

BACKGROUND AND OBJECTIVE: Whole-exome sequencing (WES) has now entered medical practice with powerful applications in the diagnosis of rare Mendelian disorders. Although the usefulness and cost-effectiveness of WES have been widely demonstrated, it is essential to reduce the diagnostic turnaround time to make WES a first-line procedure. Since 2011, the automation of laboratory procedures and advances in sequencing chemistry have made it possible to carry out diagnostic whole genome sequencing from the blood sample to molecular diagnosis of suspected genetic disorders within 50 h. Taking advantage of these advances, the main objective of the study was to improve turnaround times for sequencing results. METHODS: WES was proposed to 29 patients with severe undiagnosed disorders with developmental abnormalities and faced with medical situations requiring rapid diagnosis. Each family gave consent. The extracted DNA was sequenced on a NextSeq500 (Illumina) instrument. Data were analyzed following standard procedures. Variants were interpreted using in-house software. Each rare variant affecting protein sequences with clinical relevance was tested for familial segregation. RESULTS: The diagnostic rate was 45% (13/29), with a mean turnaround time of 40 days from reception of the specimen to delivery of results to the referring physician. Besides permitting genetic counseling, the rapid diagnosis for positive families led to two pre-natal diagnoses and two inclusions in clinical trials. CONCLUSIONS: This pilot study demonstrated the feasibility of rapid diagnostic WES in our primary genetics center. It reduced the diagnostic odyssey and helped provide support to families.


Assuntos
Exoma , Testes Genéticos/normas , Análise de Sequência de DNA/normas , Adolescente , Adulto , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Testes Genéticos/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Sensibilidade e Especificidade , Análise de Sequência de DNA/métodos , Fatores de Tempo
7.
Acta Paediatr ; 106(7): 1150-1158, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28328065

RESUMO

AIM: We examined the effects on gastrointestinal (GI) tolerance of a novel infant formula that combined specific fermented formula (FERM) with short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS), with a 9:1 ratio and concentration of 0.8 g/100 mL. METHODS: This prospective, double-blind, randomised, controlled trial comprised 432 healthy, term infants aged 0-28 days whose parents decided to not start, or discontinued, breastfeeding. Infant formula with scGOS/lcFOS+50%FERM, scGOS/lcFOS+15%FERM, 50%FERM and scGOS/lcFOS were tested. Parents completed standardised seven-day diaries on GI symptoms, crying, sleeping and stool characteristics each month until the infants were 17 weeks. RESULTS: All the formulas were well tolerated. At four weeks, the overall incidence of infantile colic was significantly lower (8%) with scGOS/lcFOS+50%FERM than scGOS/lcFOS (20%, p = 0.034) or 50%FERM (20%, p = 0.036). Longitudinal modelling showed that scGOS/lcFOS+50%FERM-fed infants also displayed a persistently lower daily crying duration and showed a consistent stool-softening effect than infants who received formula without scGOS/lcFOS. CONCLUSION: The combination of fermented formula with scGOS/lcFOS was well tolerated and showed a lower overall crying time, a lower incidence of infantile colic and a stool-softening effect in healthy term infants. These findings suggest for the first time that a specific infant formula has a preventive effect on infantile colic in formula-fed infants.


Assuntos
Cólica/prevenção & controle , Produtos Fermentados do Leite , Fórmulas Infantis , Oligossacarídeos/uso terapêutico , Prebióticos , Choro , Método Duplo-Cego , Humanos , Lactente , Recém-Nascido , Estudos Prospectivos
8.
Soins Pediatr Pueric ; 38(295): 12-13, 2017 Mar - Apr.
Artigo em Francês | MEDLINE | ID: mdl-28325378

RESUMO

Incidence of perinatal arterial stroke (ischemic stroke, intracerebral hemorrhage and subarachnoid hemorrhage) occurring between 20 weeks of gestation and postnatal day 28 ranges between 20 and 65 cases per 100,000 living births. In children aged 29 days to 18 years old, the total incidence is 1.3 to 4.3 for 100,000 per year. In France, almost 450 children are hospitalized for a stroke each year, among them approximately half have an intracerebral hemorrhage.


Assuntos
Hemorragia Cerebral/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Hemorragia Subaracnóidea/epidemiologia , Adolescente , Criança , Pré-Escolar , França/epidemiologia , Humanos , Incidência , Lactente , Recém-Nascido , Pediatria
9.
Eur J Hum Genet ; 25(4): 423-431, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28176767

RESUMO

Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5'-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G>A (family 2) and a maternally inherited c.420-8A>G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up.


Assuntos
Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Mutação , Feminino , Síndrome do Cromossomo X Frágil/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Processamento de RNA , Irmãos
10.
Am J Med Genet A ; 173(1): 62-71, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27615324

RESUMO

Neutropenia can be qualified as congenital when of neonatal onset or when associated with extra-hematopoietic manifestations. Overall, 30% of patients with congenital neutropenia (CN) remain without a molecular diagnosis after a multidisciplinary consultation and tedious diagnostic strategy. In the rare situations when neutropenia is identified and associated with intellectual disability (ID), there are few diagnostic hypotheses to test. This retrospective multicenter study reports on a clinically heterogeneous cohort of 10 unrelated patients with CN associated with ID and no molecular diagnosis prior to whole-exome sequencing (WES). WES provided a diagnostic yield of 40% (4/10). The results suggested that in many cases neutropenia and syndromic manifestations could not be assigned to the same molecular alteration. Three sub-groups of patients were highlighted: (i) severe, symptomatic chronic neutropenia, detected early in life, and related to a known mutation in the CN spectrum (ELANE); (ii) mild to moderate benign intermittent neutropenia, detected later, and associated with mutations in genes implicated in neurodevelopmental disorders (CHD2, HUWE1); and (iii) moderate to severe intermittent neutropenia as a probably undiagnosed feature of a newly reported syndrome (KAT6A). Unlike KAT6A, which seems to be associated with a syndromic form of CN, the other reported mutations may not explain the entire clinical picture. Although targeted gene sequencing can be discussed for the primary diagnosis of severe CN, we suggest that performing WES for the diagnosis of disorders associating CN with ID will not only provide the etiological diagnosis but will also pave the way towards personalized care and follow-up. © 2016 Wiley Periodicals, Inc.


Assuntos
Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Neutropenia/congênito , Adolescente , Biomarcadores , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Neutropenia/diagnóstico , Neutropenia/genética , Fenótipo , Estudos Retrospectivos , Síndrome
11.
J Pediatr Gastroenterol Nutr ; 63(4): e43-53, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27472478

RESUMO

OBJECTIVE: Fermented formulae (FERM) and a specific mixture of 90% short-chain galacto-oligosaccharides and 10% long-chain fructo-oligosaccharides (scGOS/lcFOS; 9:1) have a potential beneficial effect on gastrointestinal function and microbiota development in infants. The present study assessed the safety and tolerance of the combination of partly fermented infant milk formulae and scGOS/lcFOS compared with either 1 feature, in healthy term infants. METHODS: Four hundred thirty-two infants were enrolled before 28 days of age and followed up to 17 weeks of age and assigned to 1 of the 4 groups: (i) formula with scGOS/lcFOS, (ii) scGOS/lcFOS + 15% FERM, (iii) scGOS/lcFOS + 50% FERM, or (iv) 50% fermented formula (50% FERM). Primary outcome was daily weight gain during intervention (equivalence criterion: difference in daily weight gain ≤3 g/day). Infants' anthropometrics, formula intake, number, and type of (serious) AEs were monitored monthly. Stool samples were collected at baseline and after 17 weeks for analysis of physiological and microbiological parameters. RESULTS: Equivalence of weight gain per day was demonstrated in both the intention-to-treat and per-protocol population, with a mean weight gain (SD) of 29.7 (6.1), 28.2 (4.8), 28.5 (5.0), and 28.7 (5.9) g/day for the groups i to iv respectively. No differences were observed in other growth parameters, formula intake, and the number or severity of AEs. In all scGOS/lcFOS-containing formulae, a beneficial effect of scGOS/lcFOS was observed, indicated by the lower pH, lower Clostridium difficile levels, and higher secretory immunoglobulin A levels. CONCLUSIONS: The partly fermented infant milk formulae containing the specific mixture scGOS/lcFOS were well-tolerated and resulted in normal growth in healthy infants.


Assuntos
Fórmulas Infantis , Oligossacarídeos , Ganho de Peso , Clostridium difficile/isolamento & purificação , Método Duplo-Cego , Fezes/microbiologia , Feminino , Seguimentos , Humanos , Lactente , Fórmulas Infantis/efeitos adversos , Recém-Nascido , Masculino , Oligossacarídeos/efeitos adversos , Avaliação de Resultados (Cuidados de Saúde) , Estudos Prospectivos
12.
Am J Med Genet A ; 170(8): 2103-10, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27256868

RESUMO

Using targeted next generation sequencing, we have identified a splicing mutation (c.526-9_526-5del) in the SLC9A6 gene in a 9-year-old boy with mild intellectual disability (ID), microcephaly, and social interaction disabilities. This intronic microdeletion leads to the skipping of exon 3 and to an in-frame deletion of 26 amino acids in the TM4 domain. It segregates with cognitive impairment or learning difficulties in other members of the family. Mutations in SLC9A6 have been reported in X-linked Christianson syndrome associating severe to profound intellectual deficiency and an Angelman-like phenotype with microcephaly, absent speech, ataxia with progressive cerebellar atrophy, ophthalmoplegia, epilepsy, and neurological regression. The proband and his maternal uncle both have an attenuated phenotype with mild ID, attention deficit disorder, speech difficulties, and mild asymptomatic cerebellar atrophy. The proband also have microcephaly. The mutation cosegregated with learning disabilities and speech difficulties in the female carriers (mother and three sisters of the proband). Detailed neuropsychological, speech, and occupational therapy investigations in the female carriers revealed impaired oral and written language acquisition, with dissociation between verbal and performance IQ. An abnormal phenotype, ranging from learning disability with predominant speech difficulties to mild intellectual deficiency, has been described previously in a large proportion of female carriers. Besides broadening the clinical spectrum of SLC9A6 gene mutations, we present an example of a monogenic origin of mild learning disability. © 2016 Wiley Periodicals, Inc.


Assuntos
Ataxia/diagnóstico , Ataxia/genética , Epilepsia/diagnóstico , Epilepsia/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Microcefalia/diagnóstico , Microcefalia/genética , Mutação , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/genética , Fenótipo , Trocadores de Sódio-Hidrogênio/genética , Adolescente , Adulto , Encéfalo/anormalidades , Criança , Análise Mutacional de DNA , Facies , Família , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Imagem por Ressonância Magnética , Masculino , Linhagem , Sítios de Splice de RNA , Deleção de Sequência , Inativação do Cromossomo X
13.
Hum Mutat ; 37(8): 755-64, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27094817

RESUMO

N-terminal acetylation is a common protein modification in eukaryotes associated with numerous cellular processes. Inherited mutations in NAA10, encoding the catalytic subunit of the major N-terminal acetylation complex NatA have been associated with diverse, syndromic X-linked recessive disorders, whereas de novo missense mutations have been reported in one male and one female individual with severe intellectual disability but otherwise unspecific phenotypes. Thus, the full genetic and clinical spectrum of NAA10 deficiency is yet to be delineated. We identified three different novel and one known missense mutation in NAA10, de novo in 11 females, and due to maternal germ line mosaicism in another girl and her more severely affected and deceased brother. In vitro enzymatic assays for the novel, recurrent mutations p.(Arg83Cys) and p.(Phe128Leu) revealed reduced catalytic activity. X-inactivation was random in five females. The core phenotype of X-linked NAA10-related N-terminal-acetyltransferase deficiency in both males and females includes developmental delay, severe intellectual disability, postnatal growth failure with severe microcephaly, and skeletal or cardiac anomalies. Genotype-phenotype correlations within and between both genders are complex and may include various factors such as location and nature of mutations, enzymatic stability and activity, and X-inactivation in females.


Assuntos
Mutação em Linhagem Germinativa , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Acetiltransferase N-Terminal A/deficiência , Acetiltransferase N-Terminal E/deficiência , Acetilação , Feminino , Genes Ligados ao Cromossomo X , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Modelos Moleculares , Mosaicismo , Acetiltransferase N-Terminal A/química , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/química , Acetiltransferase N-Terminal E/genética , Linhagem
14.
Eur J Hum Genet ; 24(6): 830-7, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26395556

RESUMO

The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneous-mucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.


Assuntos
Deleção Cromossômica , Anormalidades Craniofaciais/genética , Endoglina/genética , Epilepsia/genética , Deficiência Intelectual/genética , Proteínas com Homeodomínio LIM/genética , Proteínas Munc18/genética , Fatores de Transcrição/genética , Adolescente , Criança , Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/diagnóstico , Epilepsia/diagnóstico , Feminino , Haploinsuficiência , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo , Síndrome
15.
Eur J Hum Genet ; 24(6): 911-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26486473

RESUMO

Learning disabilities (LDs) are a clinically and genetically heterogeneous group of diseases. Array-CGH and high-throughput sequencing have dramatically expanded the number of genes implicated in isolated intellectual disabilities and LDs, highlighting the implication of neuron-specific post-mitotic transcription factors and synaptic proteins as candidate genes. We report a unique family diagnosed with autosomal dominant learning disability and a 6p21 microdeletion segregating in three patients. The 870 kb microdeletion encompassed the brain-expressed gene LRFN2, which encodes for a synaptic cell adhesion molecule. Neuropsychological assessment identified selective working memory deficits, with borderline intellectual functioning. Further investigations identified a defect in executive function, and auditory-verbal processes. These data were consistent with brain MRI and FDG-PET functional brain imaging, which, when compared with controls, revealed abnormal brain volume and hypometabolism of gray matter structures implicated in working memory. We performed electron microscopy immunogold labeling demonstrating the localization of LRFN2 at synapses of cerebellar and hippocampal rat neurons, often associated with the NR1 subunit of N-methyl-D-aspartate receptors (NMDARs). Altogether, the combined approaches imply a role for LRFN2 in LD, specifically for working memory processes and executive function. In conclusion, the identification of familial cases of clinically homogeneous endophenotypes of LD might help in both the management of patients and genetic counseling for families.


Assuntos
Deleção de Genes , Transtornos de Aprendizagem/genética , Proteínas de Membrana/genética , Transtornos da Memória/genética , Memória de Curto Prazo , Adulto , Animais , Encéfalo/diagnóstico por imagem , Células Cultivadas , Criança , Feminino , Fluordesoxiglucose F18 , Heterozigoto , Humanos , Transtornos de Aprendizagem/complicações , Transtornos de Aprendizagem/diagnóstico , Imagem por Ressonância Magnética , Masculino , Proteínas de Membrana/metabolismo , Transtornos da Memória/complicações , Transtornos da Memória/diagnóstico , Linhagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Sinapses/ultraestrutura
16.
Eur Neurol ; 73(1-2): 119-25, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25472600

RESUMO

BACKGROUND: This study aimed to evaluate the clinical symptoms of Angelman syndrome (AS) in adults and to identify the neurological pathways affected in this disease. AS is a neurogenetic disorder resulting due to the deletion or inactivation of the ubiquitin-protein-ligase E3A gene on maternal chromosome 15. SUMMARY: A retrospective analysis of data from six adults patients with clinical, electroencephalographic and genetic confirmation of AS was performed. Movement disorders of the hands and mouth, laughing spells, severe expressive speech disorders, a happy nature, hyposomnia and anxiety are the major neurological characteristics of AS in adulthood. Cerebellar ataxia, muscle hypotonia and tremor, though constant in childhood, tend to be attenuated in adulthood. Epilepsy, one of the most frequent symptoms in childhood and in adulthood, is characterised by specific electroencephalographic patterns. Key Messages: These clinical characteristics are important to improve the clinical awareness and genetic diagnosis of AS. Clinicians must be better informed concerning the adult phenotype as it is not well described in the literature. We stress the importance of AS as one of the main causes of intractable epilepsy. The authors suggest frontal and cerebellar dysfunction. Further functional cerebral imaging studies are necessary.


Assuntos
Síndrome de Angelman/complicações , Síndrome de Angelman/fisiopatologia , Adolescente , Adulto , Eletroencefalografia/métodos , Feminino , Humanos , Masculino , Estudos Retrospectivos
17.
J Cyst Fibros ; 14(1): 97-103, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25107684

RESUMO

BACKGROUND AND AIMS: Catheter venous thrombosis may result in life-threatening embolic complications. Recently, a thrombophilic tendency was described in cystic fibrosis (CF), the significance of which remains unclear. The aims of this study were to (1) document the frequency of catheter venous thrombosis detected by colour-Doppler-ultrasound (Doppler-US), (2) assess genetic and acquired thrombophilia risk factors for catheter venous thrombosis and hypercoagulability status and (3) provide recommendations on laboratory screening when considering insertion of a totally implantable vascular access device (TIVAD) in CF patients. METHODS: We designed a multicentre prospective study in patients selected at the time of catheter insertion. Doppler-US was scheduled at 1 and 6months after insertion and before insertion in case of a previous central line. Blood samplings were drawn at insertion and at 1 and 6months later. RESULTS: One-hundred patients received a TIVAD and 90 completed the 6-month study. Prevalence of thrombophilia abnormalities and hypercoagulability was found in 50% of the cohorts. Conversely, catheter venous thrombosis frequency was low (6.6%). CONCLUSION: Our data do not support biological screening at the time of a TIVAD insertion. We emphasise the contribution of a medical history of venous thromboembolism and prospective Doppler-US for identifying asymptomatic catheter venous thrombosis to select patients who may benefit from biological screening and possible anticoagulant therapy.


Assuntos
Cateteres de Demora/efeitos adversos , Fibrose Cística/epidemiologia , Trombofilia/epidemiologia , Trombose Venosa/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Criança , Estudos de Coortes , Comorbidade , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Feminino , Humanos , Masculino , Prevalência , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Distribuição por Sexo , Trombofilia/sangue , Ultrassonografia Doppler/métodos , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/etiologia , Adulto Jovem
18.
Am J Med Genet A ; 164A(12): 3027-34, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25258245

RESUMO

Distal limb contractures (DLC) represent a heterogeneous clinical and genetic condition. Overall, 20-25% of the DLC are caused by mutations in genes encoding the muscle contractile apparatus. Large interstitial deletions of the 3p have already been diagnosed by standard chromosomal analysis, but not associated with a specific phenotype. We report on four patients with syndromic DLC presenting with a de novo 3p14.1p13 microdeletion. The clinical features associated multiple contractures, feeding problems, developmental delay, and intellectual disability. Facial dysmorphism was constant with low-set posteriorly rotated ears and blepharophimosis. Review of previously reported cases with a precise mapping of the deletions, documented a 250 kb smallest region of overlap (SRO) necessary for DLC. This region contained one gene, EIF4E3, the first three exons of the FOXP1 gene, and an intronic enhancer of FOXP1 named hs1149. Sanger sequencing and locus quantification of hs1149, EIF4E3, and FOXP1 in a cohort of 11 French patients affected by DLC appeared normal. In conclusion, we delineate a new microdeletion syndrome involving the 3p14.1p13 locus and associated with DLC and severe developmental delay.


Assuntos
Artrogripose/epidemiologia , Aberrações Cromossômicas , Cromossomos Humanos Par 3/genética , Contratura/epidemiologia , Contratura/genética , Extremidades/patologia , Animais , Proteínas de Transporte/genética , Hibridização Genômica Comparativa , Contratura/patologia , Feminino , Fatores de Transcrição Forkhead/genética , França/epidemiologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Proteínas Repressoras/genética , Síndrome
19.
Nat Genet ; 46(8): 905-11, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24997988

RESUMO

Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia. How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth, whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation. Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages. Because C2CD3 overexpression triggers centriole hyperelongation and OFD1 antagonizes this activity, we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3. Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies.


Assuntos
Centríolos/genética , Proteínas Associadas aos Microtúbulos/genética , Síndromes Orofaciodigitais/genética , Linhagem Celular , Pré-Escolar , Predisposição Genética para Doença , Células HEK293 , Humanos , Masculino , Microcefalia/genética , Proteínas/genética
20.
Am J Hum Genet ; 95(1): 113-20, 2014 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-24995870

RESUMO

Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.


Assuntos
Encefalopatias/genética , Genes Recessivos , Mutação , Convulsões/genética , Simportadores/genética , Encefalopatias/complicações , Feminino , Humanos , Masculino , Linhagem , Convulsões/etiologia
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