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2.
Am J Hum Genet ; 102(5): 995-1007, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656858

RESUMO

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.

3.
Clin Case Rep ; 3(10): 862-5, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26509025

RESUMO

Hemolytic anemia due to GPI deficiency can be severe and life threatening during fetal life. When parents decline invasive testing, ultrasound monitoring of fetuses at risk is feasible. Intrauterine transfusion can be effective for the treatment of severe fetal anemia due to GPI deficiency.

4.
Thromb Haemost ; 109(1): 16-23, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23138324

RESUMO

Cardiovascular disease (CVD) mortality is reported to be decreased in haemophilia patients, but reports on the prevalence of CVD risk factors are conflicting. A cross-sectional assessment of CVD risk profiles was performed in a large cohort of haemophilia patients. Baseline data on CVD risk factors of 709 Dutch and UK haemophilia patients aged ≥30 years were analysed and compared with the general age-matched male population. CVD risk profiles were assessed using the QRISK®2-2011 and SCORE algorithms. Although QRISK® 2 was only validated in the UK, comparison with SCORE indicated similar properties of QRISK®2 in both Dutch and UK patients (correlation 0.86). Mean age was 49.8 years. Hypertension was more common in haemophilia patients than in the general population (49% vs. 40%), while the prevalences of obesity and hypercholesterolaemia were lower (15 vs. 20% and 44 vs. 68%, respectively), and those of diabetes and smoking were similar. The predicted 10-year QRISK®2 risk was significantly higher in haemophilia patients than in the general population (8.9 vs. 6.7%), indicating more unfavourable cardiovascular disease risk profiles. This increased risk became apparent after the age of 40 years. Our results indicate an increased prevalence of hypertension and overall more unfavourable CVD risk profiles in haemophilia patients compared with the general age-matched male population.


Assuntos
Doenças Cardiovasculares/epidemiologia , Hemofilia A/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Doenças Cardiovasculares/diagnóstico , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus/epidemiologia , Hemofilia A/diagnóstico , Humanos , Hipercolesterolemia/epidemiologia , Hipertensão/epidemiologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Países Baixos/epidemiologia , Obesidade/epidemiologia , Prevalência , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Fatores de Tempo , Reino Unido/epidemiologia
5.
Thromb Haemost ; 108(4): 750-5, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22955860

RESUMO

An increased prevalence of hypertension is reported in haemophilia patients, but data from large, unbiased studies are lacking. The aim of our study was to cross-sectionally assess the prevalence of hypertension in a large cohort of 701 haemophilia patients. Blood pressure (BP) measurements performed in 386 Dutch and 315 UK haemophilia patients aged 30 years or older were analysed and compared with the general age-matched male population. Mean values of up to three BP measurements were used when available. Hypertension was defined as BP over 140/90 mmHg and/or the use of antihypertensive medication. A total of 49% of patients had severe haemophilia. Mean age was 49.8 years. The prevalence of hypertension was significantly higher in haemophilia patients (49%, 95% confidence interval [CI] 45-53) than in the general population (40%, 95% CI 37-43). The prevalence of hypertension was higher in patients with severe haemophilia than in those with non-severe disease, but similar across haemophilia types and in Dutch and UK patients. Multiple BP measurements were available for 70%.The prevalence of hypertension was similar in patients with multiple BP measurements and the complete cohort. Hypertension was not significantly associated with renal function, a history of renal bleeding or with infection with hepatitis C or HIV, but it was associated with overweight/obesity and age. In conclusion, the prevalence of hypertension is higher in haemophilia patients than in the general population. The cause of this increased prevalence is unknown. Blood pressure measurements should be part of standard care in haemophilia patients aged 30 years or older.


Assuntos
Hemofilia A/epidemiologia , Hipertensão/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Estudos Transversais , Hemofilia A/complicações , Hemofilia A/fisiopatologia , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prevalência , Estudos Prospectivos , Fatores de Risco , Reino Unido/epidemiologia
6.
Eur J Haematol ; 89(4): 336-9, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22775476

RESUMO

OBJECTIVE: Cardiovascular disease (CVD) mortality is reported to be lower in haemophilia patients than in the general population, but information on the occurrence of non-fatal CVD is lacking. The aim of our study was to assess CVD history in a cohort of living haemophilia patients. METHODS: Retrospective data on the occurrence of myocardial infarction, angina pectoris, ischaemic stroke and intracranial bleeding in 709 living Dutch and British haemophilia patients aged 30 yr or older were analysed and compared with the general age-matched male population. RESULTS: There was a trend towards a lower cumulative incidence of myocardial infarction (1.7% vs. 4.0%) and ischaemic stroke (0% vs. 1.5%) in patients with severe haemophilia than in the general population, while the occurrence of angina pectoris was similar (3.2 vs. 3.7%). As expected, the cumulative incidence of intracranial bleeding was, on the other hand, significantly increased in haemophilia patients (1.6% vs. 0.4% in the general population). CONCLUSION: Our results suggest a protective effect of severe haemophilia against acute ischaemic CVD.


Assuntos
Doenças Cardiovasculares/complicações , Hemofilia A/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Reino Unido
7.
Thromb Res ; 130(2): 157-62, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22209337

RESUMO

INTRODUCTION: With increasing life expectancy, more haemophilia patients will be confronted with age-related problems. To ensure optimal care, it is important to know the occurrence of both fatal and non-fatal cardiovascular disease, malignancies and other types of co-morbidity in these patients. Our aim was to retrospectively assess the occurrence of co-morbidity and causes of death in a substantial birth-cohort of haemophilia patients. METHODS: Data on all types of co-morbidity were collected from medical records of 408 haemophilia patients (204 severe, 204 non-severe) born before 1971, and compared with the Dutch age-matched general male population. RESULTS: Ten patients had 11 myocardial infarctions, none of which were fatal. The cumulative incidence of non-fatal myocardial infarction was significantly lower in patients with severe haemophilia than in the general population (0.5% versus 4.8%), but was not decreased in patients with non-severe haemophilia (4.4%). Intracranial bleeding occurred significantly more often in haemophilia patients. The occurrence of non-virus related malignancies, and other non-virus related co-morbidities was similar in haemophilia patients and the general population. HIV infection was present in 12% of patients, and hepatitis C infection in 56%. Seventy-eight patients (19%) were deceased. Main causes of death were malignancies, AIDS, hepatitis C, and intracranial bleeding. CONCLUSIONS: Our results showed a decreased occurrence of myocardial infarction in patients with severe haemophilia, suggesting a protective effect of very low clotting factor levels on thrombotic cardiac events. No differences were found between haemophilia patients and the general population in the occurrence of any other type of non-virus related co-morbidity.


Assuntos
Doenças Cardiovasculares/epidemiologia , Hemofilia A/epidemiologia , Neoplasias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Comorbidade , Feminino , Infecções por HIV/epidemiologia , Hepatite C/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Estudos Retrospectivos , Adulto Jovem
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