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1.
J Thromb Haemost ; 17(11): 1798-1807, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31271700

RESUMO

BACKGROUND: Congenital disorders of glycosylation are rare inherited diseases affecting many different proteins. The lack of glycosylation notably affects the hemostatic system and leads to deficiencies of both procoagulant and anticoagulant factors. OBJECTIVE: To assess the hemostatic balance in patients with multiple coagulation disorders by using a thrombin generation assay. METHOD: We performed conventional coagulation assays and a thrombin generation assay on samples from patients with congenital disorder of glycosylation. The thrombin generation assay was performed before and after activation of the protein C system by the addition of soluble thrombomodulin. RESULTS: A total of 35 patients were included: 71% and 57% had low antithrombin and factor XI levels, respectively. Protein C and protein S levels were abnormally low in 29% and 26% of the patients, respectively, whereas only 11% displayed low factor IX levels. Under baseline conditions, the thrombin generation assay revealed a significantly higher endogenous thrombin potential and thrombin peak in patients, relative to controls. After spiking with thrombomodulin, we observed impaired involvement of the protein C system. Hence, 54% of patients displayed a hypercoagulant phenotype in vitro. All the patients with a history of stroke-like episodes or thrombosis displayed this hypercoagulant phenotype. CONCLUSION: A thrombin generation assay revealed a hypercoagulant in vitro phenotype under baseline condition; this was accentuated by impaired involvement of the protein C system. This procoagulant phenotype may thus reflect the risk of severe vascular complications. Further research will have to determine whether the thrombin generation assay is predictive of vascular events.

2.
Hum Mutat ; 40(7): 938-951, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067009

RESUMO

ALG3-CDG is one of the very rare types of congenital disorder of glycosylation (CDG) caused by variants in the ER-mannosyltransferase ALG3. Here, we summarize the clinical, biochemical, and genetic data of four new ALG3-CDG patients, who were identified by a type I pattern of serum transferrin and the accumulation of Man5 GlcNAc2 -PP-dolichol in LLO analysis. Additional clinical symptoms observed in our patients comprise sensorineural hearing loss, right-descending aorta, obstructive cardiomyopathy, macroglossia, and muscular hypertonia. We add four new biochemically confirmed variants to the list of ALG3-CDG inducing variants: c.350G>C (p.R117P), c.1263G>A (p.W421*), c.1037A>G (p.N346S), and the intron variant c.296+4A>G. Furthermore, in Patient 1 an additional open-reading frame of 141 bp (AAGRP) in the coding region of ALG3 was identified. Additionally, we show that control cells synthesize, to a minor degree, a hybrid protein composed of the polypeptide AAGRP and ALG3 (AAGRP-ALG3), while in Patient 1 expression of this hybrid protein is significantly increased due to the homozygous variant c.160_196del (g.165C>T). By reviewing the literature and combining our findings with previously published data, we further expand the knowledge of this rare glycosylation defect.

3.
J Inherit Metab Dis ; 42(1): 5-28, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30740725

RESUMO

Phosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2-CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence-based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2-CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2-CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2-CDG patients.

4.
Toxicol Lett ; 305: 94-102, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30716388

RESUMO

Exposure to airborne particulate matter (PM) has significant effects on human health mainly leading to cardio-respiratory diseases. However very few data are available regarding the impact of PM on the skin, so to better understand the impact of fine particle (PM0.3-2.5) on both inflammatory response and epidermal structure, we exposed a reconstructed human epidermis (RHE) to several doses of PM collected in Cotonou (Benin, West Africa). After 24 h of exposure, inflammatory response, histological observations, and gene expression related to oxidative stress, antioxidant defense and structural damages were determined. No PM-linked changes in tissue morphology or membrane integrity were observable. PM was however cytotoxic in a dose dependent manner. An inflammatory response appeared as shown by the increase in IL-1α and IL-8 cytokine productions. PM also induced oxidative stress, leading to an increase in 4-HNE immunostaining and to the up-regulation of HMOX1, MT1G and MT1E. Finally, PM had a negative impact on fundamental skin functions such as tissue anchorage, cell differentiation, cornification / skin desquamation and apoptosis. Our data show that airborne fine particles have an adverse effect on skin integrity, most probably leading to accelerated ageing.


Assuntos
Poluentes Atmosféricos/toxicidade , Epiderme/efeitos dos fármacos , Queratinócitos/fisiologia , Material Particulado/toxicidade , Técnicas de Cultura de Células , Sobrevivência Celular , Epiderme/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Estresse Oxidativo , Tamanho da Partícula , Testes de Toxicidade/métodos
5.
Eur J Hum Genet ; 27(3): 349-352, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30552423

RESUMO

Next-generation sequencing (NGS) gene-panel-based analyses constitute diagnosis strategies which are adapted to the genetic heterogeneity within the field of myopathies, including more than 200 implicated genes to date. Nonetheless, important inter-laboratory diversity of gene panels exists at national and international levels, complicating the exchange of data and the visibility of the diagnostic offers available for referring neurologists. To address this issue, we here describe the initiative of the genetic diagnosis section of the French National Network for Rare Neuromuscular Diseases (Filière Nationale des Maladies Rares Neuromusculaires, FILNEMUS), which led to set up a consensual nationwide diagnostic strategy among the nine French genetic diagnosis laboratories using NGS for myopathies. The strategy is based on the determination of 13 clinical and/or histological entry-diagnosis groups, and consists for each group either in a successive NGS analysis of a "core gene list" followed in case of a negative result by the analysis of an "exhaustive gene list", or in the NGS analysis of a "unique exhaustive gene list".


Assuntos
Consenso , Testes Genéticos/normas , Doenças Neuromusculares/genética , Guias de Prática Clínica como Assunto , Análise de Sequência de DNA/normas , França , Testes Genéticos/métodos , Humanos , Doenças Neuromusculares/diagnóstico , Análise de Sequência de DNA/métodos , Sociedades Médicas
6.
Pediatr Res ; 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420707

RESUMO

BACKGROUND: Congenital disorders of glycosylation (CDG) includes ALG8 deficiency, a protein N-glycosylation defect with a broad clinical spectrum. If most of the 15 previously reported patients present an early-onset multisystem severe disease and early death, three patients including the cas princeps, present long-term survival and less severe symptoms. METHODS: In order to further characterize ALG8-CDG, two new ALG8 patients are described and mRNA analyses of the ALG8-CDG cas princeps were effected. RESULTS: One new patient exhibited a hepato-intestinal and neurological phenotype with two novel variants (c.91A > C p.Thr31Pro; c.139dup p.Thr47Asnfs*12). The other new patient, homozygous for a known variant (c.845C > T p.Ala282Val), presented a neurological phenotype with epilepsy, intellectual disability and retinis pigmentosa. The cas princeps ALG8-CDG patient was reported to have two heterozygous frameshift variants predicted to be without activity. We now described a novel ALG8 transcript variant in this patient and the 3D model of the putative encoded protein reveals no major difference with that of the normal ALG8 protein. CONCLUSION: The description of the two new ALG8 patients affirms that ALG8-CDG is a severe disease. In the cas princeps, as the originally described frameshift variants are degraded, the novel variant is promoted and could explain a milder phenotype.

7.
Genet Med ; 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30293989

RESUMO

PURPOSE: PMM2-CDG is the most common congenital disorder of glycosylation (CDG), which presents with either a neurologic or multisystem phenotype. Little is known about the longitudinal evolution. METHODS: We performed data analysis on PMM2-CDG patients' clinical features according to the Nijmegen CDG severity score and laboratory data. Seventy-five patients (28 males) were followed up from 11.0 ± 6.91 years for an average of 7.4 ± 4.5 years. RESULTS: On a group level, there was no significant evolution in overall clinical severity. There was some improvement in mobility and communication, liver and endocrine function, and strabismus and eye movements. Educational achievement and thyroid function worsened in some patients. Overall, the current clinical function, the system-specific involvement, and the current clinical assessment remained unchanged. On follow-up there was improvement of biochemical variables with (near) normalization of activated partial thromboplastin time (aPTT), factor XI, protein C, antithrombin, thyroid stimulating hormone, and liver transaminases. CONCLUSION: PMM2-CDG patients show a spontaneous biochemical improvement and stable clinical course based on the Nijmegen CDG severity score. This information is crucial for the definition of endpoints in clinical trials.

8.
Nat Commun ; 9(1): 3087, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30082715

RESUMO

Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7-/- mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7-/- mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development.

10.
Electrophoresis ; 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29869806

RESUMO

Congenital disorders of glycosylation (CDG) are rare autosomal genetic diseases affecting the glycosylation of proteins and lipids. Since CDG-related clinical symptoms are classically extremely variable and nonspecific, a combination of electrophoretic, mass spectrometric, and gene sequencing techniques is often mandatory for obtaining a definitive CDG diagnosis, as well as identifying causative gene mutations and deciphering the underlying biochemical mechanisms. Here, we illustrate the potential of integrating data from capillary electrophoresis of transferrin, two-dimensional electrophoresis of N- and O-glycoproteins, mass spectrometry analyses of total serum N-linked glycans and mucin core1 O-glycosylated apolipoprotein C-III for the determination of various culprit CDG gene mutations. "Step-by-step" diagnosis pathways of four particular and new CDG cases, including MGAT2-CDG, ATP6V0A2-CDG, SLC35A2-CDG, and SLC35A3-CDG, are described as illustrative examples.

11.
Mol Genet Metab ; 124(3): 228-235, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29759592

RESUMO

Congenital disorders of glycosylation (CDG) linked to defects in Golgi apparatus homeostasis constitute an increasing part of these rare inherited diseases. Among them, COG-CDG, ATP6V0A2-CDG, TMEM199-CDG and CCDC115-CDG have been shown to disturb Golgi vesicular trafficking and/or lumen pH acidification. Here, we report 3 new unrelated cases of CCDC115-CDG with emphasis on diagnosis difficulties related to strong phenotypic similarities with mitochondriopathies, Niemann-Pick disease C and Wilson Disease. Indeed, while two individuals clinically presented with early and severe liver fibrosis and cirrhosis associated with neurological symptoms, the other one "only" showed isolated and late severe liver involvement. Biological results were similar to previously described patients, including hypercholesterolemia, elevated alkaline phosphatases and defects in copper metabolism. CDG screening and glycosylation study finally led to the molecular diagnosis of CCDC115-CDG. Besides pointing to the importance of CDG screening in patients with unexplained and severe liver disease, these reports expand the clinical and molecular phenotypes of CCDC115-CDG. The hepatic involvement is particularly addressed. Furthermore, hypothesis concerning the pathogenesis of the liver disease and of major biological abnormalities are proposed.

12.
Eur J Med Genet ; 61(11): 643-663, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29079546

RESUMO

The survey summarizes in its first part the current status of knowledge on the Congenital Disorders of Glycosylation (CDG) with regard to their phenotypic spectrum, diagnostic and therapeutic strategies, and pathophysiology. It documents the clinical and basic research activities, and efforts to involve patients and their families. In the second part, it tries to look into the future of CDG. More specific biomarkers are needed for fast CDG diagnosis and treatment monitoring. Whole genome sequencing will play an increasingly important role in the molecular diagnosis of unsolved CDG. Epigenetic defects are expected to join the rapidly expanding genetic and allelic heterogeneity of the CDG family. Novel treatments are urgently needed particularly for PMM2-CDG, the most prevalent CDG. Patient services such as apps should be developed e.g. to document the natural history and monitor treatment. Networking (EURO-CDG, the European Reference Networks (MetabERN)) is an efficient tool to disseminate knowledge and boost collaboration at all levels. The final goal is of course to improve the quality of life of the patients and their families.

13.
J Med Genet ; 54(12): 843-851, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28954837

RESUMO

BACKGROUND: Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism. OBJECTIVES: To better characterise the natural history of PMM2-CDG. METHODS: Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed. Data on clinical, laboratory and molecular parameters at diagnosis were analysed. Follow-up data at last examination were reported for 25 patients. RESULTS: The patients were born between 1963 and 2011. Diagnosis of PMM2-CDG was made at a mean (SD) age of 6.8 (8.5) years. The presenting signs were mostly neurological (hypotonia, intellectual disability, cerebellar syndrome) and observed in almost all the patients. A total of 38 patients (14 males, 24 females) exhibited, in addition to neurological signs, visceral features including at least one of these: feeding difficulty requiring a nutritional support (n=23), cardiac features (n=20; pericarditis: 14, cardiac malformation: 9, cardiomyopathy: 2), hepato-gastrointestinal features (n=12; chronic diarrhoea: 7, protein-losing enteropathy: 1, ascites: 3, liver failure: 1, portal hypertension: 1), kidney features (n=4; nephrotic syndrome: 2, tubulopathy: 2) and hydrops fetalis (n=1). Twelve patients died at a mean age of 3.8 years (especially from pericarditis and other cardiac issues). Laboratory abnormalities mostly included elevated transaminases and abnormal coagulation parameters. High thyreostimulin levels, hypocholesterolemia, hypoalbuminemia and elevated transaminases were associated with the visceral phenotype. Besides the common Arg141His PMM2 variant harboured by half of the patients, 45 different variants were observed. CONCLUSIONS: PMM2-CDG clinical phenotype is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.


Assuntos
Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Estudos de Associação Genética , Fosfotransferases (Fosfomutases)/genética , Adolescente , Alelos , Substituição de Aminoácidos , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/mortalidade , Feminino , Seguimentos , Humanos , Lactente , Masculino , Mutação , Fenótipo , Fosfotransferases (Fosfomutases)/metabolismo
14.
Toxins (Basel) ; 9(7)2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28640227

RESUMO

Exposure to molds and mycotoxins not only contributes to the onset of respiratory disease, it also affects the ocular surface. Very few published studies concern the evaluation of the effect of mycotoxin exposure on ocular cells. The present study investigates the effects of aflatoxin B1 (AFB1) and gliotoxin, two mycotoxins secreted by Aspergillus molds, on the biological activity of the human corneal epithelial (HCE) cells. After 24, 48, and 72 h of exposure, cellular viability and inflammatory response were assessed. Both endpoint cell viability colorimetric assays and continuous cell impedance measurements, providing noninvasive real-time assessment of the effect on cells, were performed. Cytokine gene expression and interleukin-8 release were quantified. Gliotoxin appeared more cytotoxic than AFB1 but, at the same time, led to a lower increase of the inflammatory response reflecting its immunosuppressive properties. Real-time cell impedance measurement showed a distinct profile of cytotoxicity for both mycotoxins. HCE cells appeared to be a well-suited in vitro model to study ocular surface reactivity following biological contaminant exposure. Low, but persistent inflammation, caused by environmental factors, such as fungal toxins, leads to irritation and sensitization, and could be responsible for allergic manifestations which, in turn, could lead to mucosal hyper-reactivity.


Assuntos
Aflatoxina B1/toxicidade , Células Epiteliais/efeitos dos fármacos , Gliotoxina/toxicidade , Inflamação/induzido quimicamente , Aspergillus/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Córnea/citologia , Citocinas/genética , Células Epiteliais/metabolismo , Expressão Gênica , Humanos , Inflamação/genética
15.
Clin Chim Acta ; 470: 70-74, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28457853

RESUMO

Congenital disorders of glycosylation (CDGs) are rare inherited disorders affecting glycosylation of proteins and lipids and sharing very heterogeneous multivisceral symptoms. The biochemical screening of these diseases is currently limited to electrophoresis or HPLC separation/quantification of serum transferrin glycoforms and is relatively frequently hampered by genetic polymorphism. Further, it has been shown that transferrin glycosylation can be very poorly affected in confirmed CDGs. We developed a fast and simple two-dimensional (2-DE) Western-blot analysis applied to the simultaneous detection of various serum glycoproteins, i.e. haptoglobin, α1-anti-trypsin, transferrin and α1-acid glycoprotein, and applied it to a large cohort of CDGs and secondary glycosylation disorders. When separated using 2-DE, haptoglobin ß glycoforms showed clear abnormalities in all interpretable CDG type I and CDG type II patterns. Although secondary glycosylation defects such as alcoholism, untreated fructosemia and bacterial neuraminidase remain to be excluded, we showed that 2-DE pattern of haptoglobin ß glycoforms thus constitute a very reliable additional biomarker of all types of CDGs. Coupled with common screening techniques and glycans mass spectrometry, it can orientate and facilitate the way towards CDG molecular diagnostic.


Assuntos
Defeitos Congênitos da Glicosilação/metabolismo , Eletroforese em Gel Bidimensional , Haptoglobinas/metabolismo , Biomarcadores/metabolismo , Glicosilação , Haptoglobinas/isolamento & purificação , Humanos , Transferrina/metabolismo
16.
Int J Hyg Environ Health ; 219(8): 792-800, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27649627

RESUMO

BACKGROUND: Allergic sensitisation is poorly documented in infants. This study aims to provide new insights into allergic sensitisation patterns and related factors in infancy. METHODS: This study concerns 1860 infants involved in the Pollution and Asthma Risk: an Infant Study (PARIS) population-based birth cohort who had a standardised health examination when 18 months old, from 2004 to 2008. Sensitisation was assessed by measurements of serum specific IgE to 12 food and 4 inhalant allergens and defined by IgE≥0.35kUA/L. Information regarding lifestyle and environment were obtained from questionnaires prospectively administered. RESULTS: Prevalence of allergic sensitisation to any allergen, to food allergens, and to aeroallergens was 13.8%, 12.3%, and 2.3%, respectively. Multiple sensitisation (to at least two allergens) concerned 6.2% of toddlers. Intrinsic factors such as male gender, family history of allergy, and high birth weight increased the risk of food allergen sensitisation and multiple sensitisation. Caesarean section was also positively associated with multiple sensitisation. Day-care attendance was negatively related to food allergen, aeroallergen, and multiple sensitisation. A cat entering the baby's room in early life was strongly associated with aeroallergen sensitisation (ORa 3.21, 95%CI: 1.29-8.01). An introduction of meat in infant's diet after 6 months of age was negatively related to food allergen sensitisation (ORa 0.46, 95%CI: 0.24-0.91). CONCLUSION: Our results suggest that intrinsic factors and indicators of exposure to microorganisms such as caesarean section and day-care attendance may be associated with inhalant as well as food allergen sensitisation in infancy. For example, male gender, family history of allergy, high birth weight, and caesarean section could be positively related whereas day-care attendance could be negatively related to both aeroallergen and food allergen sensitisation. Conversely, early life exposure to inhalant allergens or food allergens may be specifically linked to either aeroallergen sensitisation or food allergen sensitisation, respectively.


Assuntos
Hipersensibilidade/epidemiologia , Alérgenos/imunologia , Animais , Peso ao Nascer , Gatos , Cesárea , Estudos de Coortes , Hospital Dia , Feminino , Alimentos , Humanos , Imunoglobulina E/sangue , Lactente , Masculino , Anamnese , Prevalência , Fatores de Risco
18.
Toxicol Lett ; 259: 60-68, 2016 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-27480279

RESUMO

More than a barrier against environmental agents, skin reflects individual health and is a visible sign of ageing with the progressive loss of skin integrity. In order to evaluate the consequences of an environmental complex mixture, with tobacco smoke (TS) as model, on cellular and morphological changes, a 3D skin model was used. Morphologically, tissue integrity was intact after one TS-exposure while the superficial layers were drastically reduced after two TS-exposures. However, TS modified epidermal organisation at the molecular level after just one exposure. A decrease in loricrin protein staining was showed in the epidermis, while production of inflammatory cytokines (IL-8, IL-1α, IL-18) and metalloproteinase (MMP-1, MMP-3) were stimulated. Oxidative stress was also illustrated with an increase in 4-HNE protein staining. Moreover, terminal differentiation, cell-cell junction and anchorage gene expression was down-regulated in our model after one TS-exposure. In conclusion, tobacco smoke impacted the fundamental functions of skin, namely tissue anchorage, cornification and skin desquamation. Oxidative stress resulted in skin ageing. The tissue was even reactive with the inflammatory pathways, after one TS-exposure. The 3D-RHE model is appropriate for evaluating the impact of environmental pollutants on skin ageing.


Assuntos
Pele/efeitos dos fármacos , Poluição por Fumaça de Tabaco/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Biológicos , Técnicas de Cultura de Tecidos
19.
Pediatr Allergy Immunol ; 27(8): 831-837, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27501330

RESUMO

BACKGROUND: Profiles of allergic sensitization are poorly documented in infancy. Relations between early sensitization and allergic morbidity need to be clarified. METHODS: This study dealt with children involved in the Pollution and Asthma Risk: an Infant Study (PARIS), a population-based prospective birth cohort. Allergic sensitization to twelve food and four inhalant allergens was assessed at 18 months and defined by a specific immunoglobulin E (IgE) level ≥0.35 kUA /l. Health data were collected by standardized questionnaires at 2 and 6 years. Early allergic profiles were identified by an unsupervised cluster analysis based on health data at 2 years and IgE measurements. Profiles were compared with regard to allergic morbidity and multimorbidity at 6 years. RESULTS: Sensitization to any allergen concerned 13.6% of infants. By cluster analysis, 1525 infants were grouped into three profiles: 89.2% not or rarely sensitized (only 3.7% of sensitized), 9.2% mainly sensitized to one or few allergens (45.2% of monosensitized and 45.9% of paucisensitized) and 1.6% all polysensitized. The prevalence of doctor-diagnosed asthma, rhinitis, eczema, food allergy and multimorbidity at 2 years increased from profile one to profile three (p-trend <0.001). At 6 years, symptoms of current asthma, rhinitis, eczema and multimorbidity were significantly more frequent in the last two profiles. CONCLUSIONS: This study highlights, as early as 18 months of age, three profiles of increasing severity with regard to allergic sensitization and diseases. These profiles also differ in terms of allergic morbidity at 6 years. Early sensitization can predict allergic multimorbidity in childhood, and in the case of early polysensitization, multimorbidity is more frequent as soon as infancy.


Assuntos
Alérgenos/imunologia , Hipersensibilidade/epidemiologia , Imunização , Pré-Escolar , Estudos de Coortes , Reações Cruzadas , Feminino , Seguimentos , Alimentos , Humanos , Hipersensibilidade/diagnóstico , Imunoglobulina E/sangue , Lactente , Masculino , Grupos Populacionais , Prevalência , Prognóstico , Estudos Prospectivos
20.
J Inherit Metab Dis ; 39(5): 713-723, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27287710

RESUMO

INTRODUCTION: Alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital disorder of glycosylation. The original patients were described with hypotonia, developmental disability, epilepsy, and increased bleeding tendency. METHODS: Based on Euroglycan database registration, we approached referring clinicians and collected comprehensive data on 41 patients. RESULTS: We found hypotonia and developmental delay in all ALG6-CDG patients and epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in <50 % of cases, without spontaneous bleedings. Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly. Cyclic behavioral change, with autistic features and depressive episodes, was one of the most significant complaints. Eleven children died before the age of 4 years due to protein losing enteropathy (PLE), sepsis, or seizures. The oldest patient was a 40 year-old Dutch woman. The most common pathogenic protein alterations were p.A333V and p.I299Del, without any clear genotype-phenotype correlation. DISCUSSION: ALG6-CDG has been now described in 89 patients, making it the second most common type of CDG. It has a recognizable phenotype and a primary neurologic presentation.


Assuntos
Ataxia/patologia , Defeitos Congênitos da Glicosilação/patologia , Epilepsia/patologia , Glucosiltransferases/genética , Deformidades Congênitas dos Membros/patologia , Proteínas de Membrana/genética , Transtornos Mentais/patologia , Debilidade Muscular/patologia , Adolescente , Adulto , Ataxia/genética , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/genética , Epilepsia/genética , Feminino , Estudos de Associação Genética/métodos , Glicosilação , Humanos , Lactente , Recém-Nascido , Deformidades Congênitas dos Membros/genética , Masculino , Transtornos Mentais/genética , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Debilidade Muscular/genética , Fenótipo , Estudos Retrospectivos , Convulsões/genética , Convulsões/patologia , Adulto Jovem
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