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1.
Am J Hum Genet ; 104(3): 530-541, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30827496

RESUMO

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

2.
Mol Genet Genomic Med ; 5(6): 758-773, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29178638

RESUMO

BACKGROUND: Individuals with rare diseases may face challenges that are different from those experienced in more common medical conditions. A wide range of different rare conditions has resulted in a myriad of studies investigating the specificities of the diagnosis in focus. The shared psychological experiences of individuals with a rare condition, however, have not been reviewed systematically. METHODS: We performed a systematic review, including qualitative studies on adults, published between 2000 and 2016. Papers including more than one rare genetic or nongenetic diagnosis were included. Studies based on single diagnoses were excluded except for four specific conditions: hemophilia (bleeding disorder), phenylketonuria (metabolic disorder), Fabry disease (lysosomal storage disorder), and epidermolysis bullosa (skin disorder). RESULTS: The review identified 21 studies. Findings were synthesized and categorized according to three main themes: (1) Consequences of living with a rare disorder, (2) Social aspects of living with a rare disorder, and (3) Experiences with the health care system. Findings point to several unique challenges, such as the psychological, medical, and social consequences of a lack of knowledge about the condition in health care and social settings. CONCLUSION: The findings highlight the need for more research on the shared psychological and social impact of living with a rare diagnosis across conditions, in order to identify risk factors and inform clinical practice.


Assuntos
Família/psicologia , Doenças Raras/patologia , Adaptação Psicológica , Assistência à Saúde , Hemofilia A/genética , Hemofilia A/patologia , Humanos , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/patologia , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Pesquisa Qualitativa , Doenças Raras/genética , Dermatopatias/genética , Dermatopatias/patologia , Apoio Social
3.
J Genet Couns ; 26(6): 1324-1332, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28547664

RESUMO

Studies on carriers of genetic disorders mainly focus on the process of genetic testing and reproductive choices, and less on how psychosocial aspects of being a carrier change over time. Our study sought to understand more about the psychosocial aspects of hemophilia carrier status, and thereby improve counseling aiming to advance carriers' quality of life and well-being. We analyzed 16 in-depth interviews from women who were carriers of hemophilia and had a son with hemophilia. Three themes emerged: Guilt and sorrow across generations; the choices and future consequences of genetic testing; and preparing to have a child with hemophilia. Experience with being a hemophilia carrier is a process that changes over time while feelings of guilt and sorrow run across generations. The carrier status may create "mothers-in-waiting" living at risk of having a sick child or not. The women think they are prepared to have a son with hemophilia, but experience more sadness than they expect when a son is diagnosed. Our findings suggest that health professionals, especially clinical geneticists and genetic counselors, carriers, families and patient organizations need to be aware that women's experiences of being a carrier of hemophilia changes during the biographical life course. The women may benefit from several rounds of genetic counseling at different stages of life.


Assuntos
Triagem de Portadores Genéticos , Hemofilia A/psicologia , Mães/psicologia , Qualidade de Vida/psicologia , Adulto , Criança , Feminino , Aconselhamento Genético , Pesar , Hemofilia A/genética , Humanos , Relações Mãe-Filho , Pesquisa Qualitativa
4.
Am J Hum Genet ; 100(5): 737-750, 2017 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-28457472

RESUMO

Keratolytic winter erythema (KWE) is a rare autosomal-dominant skin disorder characterized by recurrent episodes of palmoplantar erythema and epidermal peeling. KWE was previously mapped to 8p23.1-p22 (KWE critical region) in South African families. Using targeted resequencing of the KWE critical region in five South African families and SNP array and whole-genome sequencing in two Norwegian families, we identified two overlapping tandem duplications of 7.67 kb (South Africans) and 15.93 kb (Norwegians). The duplications segregated with the disease and were located upstream of CTSB, a gene encoding cathepsin B, a cysteine protease involved in keratinocyte homeostasis. Included in the 2.62 kb overlapping region of these duplications is an enhancer element that is active in epidermal keratinocytes. The activity of this enhancer correlated with CTSB expression in normal differentiating keratinocytes and other cell lines, but not with FDFT1 or NEIL2 expression. Gene expression (qPCR) analysis and immunohistochemistry of the palmar epidermis demonstrated significantly increased expression of CTSB, as well as stronger staining of cathepsin B in the stratum granulosum of affected individuals than in that of control individuals. Analysis of higher-order chromatin structure data and RNA polymerase II ChIA-PET data from MCF-7 cells did not suggest remote effects of the enhancer. In conclusion, KWE in South African and Norwegian families is caused by tandem duplications in a non-coding genomic region containing an active enhancer element for CTSB, resulting in upregulation of this gene in affected individuals.


Assuntos
Catepsina B/metabolismo , Elementos Facilitadores Genéticos , Eritema/genética , Duplicação Gênica , Regulação da Expressão Gênica , Ceratose/genética , Dermatopatias Genéticas/genética , Estudos de Casos e Controles , Catepsina B/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 8/genética , Variações do Número de Cópias de DNA , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Epiderme/metabolismo , Epigenômica , Eritema/epidemiologia , Feminino , Marcadores Genéticos , Humanos , Queratinócitos/metabolismo , Ceratose/epidemiologia , Células MCF-7 , Masculino , Noruega/epidemiologia , Linhagem , Dermatopatias Genéticas/epidemiologia , África do Sul/epidemiologia
5.
Pediatr Blood Cancer ; 64(1): 121-127, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27472376

RESUMO

BACKGROUND: In Norway, boys with hemophilia usually begin treatment after their first bleeding episode. Boys with severe hemophilia usually start prophylactic treatment around 18-24 months. Health professionals administer factor concentrate initially, but when boys are around 4 years old most parents start treating their children at home. There is a lack of research on how parents, and especially how carrier mothers, experience the medical treatment for their sons' hemophilia. Our aim was to investigate how carrier mothers experience this treatment in the hospital setting and at home. METHODS: In this qualitative study, we interviewed 16 mothers of boys or men with hemophilia A or B. Data were collected via semistructured interviews and analyzed using an inductive thematic analytical approach. RESULTS: Mothers experienced both practical and emotional challenges in relation to their sons' treatment, and repeated venipuncture was especially difficult emotionally. Parents preferred home treatment to hospital treatment because it was less time-consuming, less disruptive to family life, and provided a greater sense of control. Encountering healthcare professionals who were unfamiliar with hemophilia was a second major stress factor, especially when parents felt that health professionals lacked competence and were unwilling to seek advice. CONCLUSION: While home treatment for hemophilia enables freedom, flexibility, and autonomy for the boys as well as for the family, mothers may experience treatment of hemophilia as a burden. Health professionals should provide tailored practical and emotional support to parents by probing into their experiences with treating their sons' hemophilia.


Assuntos
Adaptação Psicológica , Hemofilia A/terapia , Mães/psicologia , Pais/psicologia , Adulto , Idoso , Aconselhamento , Emoções , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Pesquisa Qualitativa
6.
J Genet Couns ; 25(5): 1085-92, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26948256

RESUMO

Little is known about the experiences of women with Fabry disease. The aim of this study was to explore women's experiences of being heterozygous for Fabry disease. We used an explorative qualitative study design and selected ten Norwegian women who were known heterozygous for Fabry disease to participate. We conducted in-depth semi-structured interviews and analyzed the interviews using inductive thematic analysis. We found that learning about one's heterozygous status may be devastating for some. However, for most of the participants, heterozygous status, as well as doctors' acceptance of symptoms in women heterozygous for Fabry disease, provided an explanation and relief. Although many women did not consider themselves ill, they wished to be acknowledged as more than "just carriers." The participants were grateful for enzyme replacement therapy, although it had its burdens regarding time, planning, and absences from school or work. Women with Fabry disease felt that the lack of knowledge among healthcare professionals about Fabry disease was frustrating and worrisome. These findings suggest that healthcare professionals should acknowledge the different ways women react to their diagnosis, and be aware of the personal costs of receiving treatment.


Assuntos
Doença de Fabry/psicologia , Heterozigoto , Adulto , Idoso , Doença de Fabry/genética , Feminino , Aconselhamento Genético , Humanos , Pessoa de Meia-Idade , Noruega , Pesquisa Qualitativa , Inquéritos e Questionários , Adulto Jovem
7.
Tidsskr Nor Laegeforen ; 134(11): 1151-4, 2014 Jun 17.
Artigo em Inglês, Norueguês | MEDLINE | ID: mdl-24939783

RESUMO

Gorlin syndrome is a rare genetic condition in which patients may develop medulloblastomas, jaw cysts and basal cell carcinomas and show congenital skeletal malformations. If left undiagnosed, Gorlin syndrome can have a number of negative consequences. Early diagnosis and good follow-up is important for all patients with rare disorders. We wish to make doctors and dentists aware of Gorlin syndrome so that, whenever the syndrome is suspected or a patient has been diagnosed, the patient is referred for assessment, treatment and follow-up by specialists who know the disorder well. Dermatology departments at university hospitals and departments of medical genetics have a key role to play in assessment and follow-up. A national support group for Gorlin syndrome has been established, consisting of a dermatologist, oncologist, geneticist, paediatrician, specialist dentist, ophthalmologist, orthopaedic surgeon, plastic surgeon, oral and maxillofacial surgeon and counsellors. Patients, relatives and health professionals can contact the Centre for Rare Disorders directly for information about Gorlin syndrome, or to be put in touch with members of the group.


Assuntos
Síndrome do Nevo Basocelular/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adulto , Síndrome do Nevo Basocelular/complicações , Síndrome do Nevo Basocelular/patologia , Humanos , Transtornos de Aprendizagem/etiologia , Masculino , Megalencefalia/etiologia , Cistos Odontogênicos/diagnóstico por imagem , Cistos Odontogênicos/etiologia , Radiografia , Doenças Raras/complicações , Doenças Raras/diagnóstico , Doenças Raras/patologia , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologia
8.
Amyotroph Lateral Scler ; 11(5): 478-80, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20192886

RESUMO

We describe a patient with apparently sporadic amyotrophic lateral sclerosis (SALS) with a novel g > c point mutation at position 382 in the SOD1 gene, leading to a substitution of glycine for arginine in amino acid position 127 (G127R). The disease presented with flaccid leg paresis, and progressed rapidly with generalized paresis resulting in respiratory failure after seven months. In addition to a predominating lower motor neuron syndrome, the phenotype was characterized by a severe lower back and leg pain syndrome which was treated successfully with spinal anaesthesia.


Assuntos
Esclerose Amiotrófica Lateral , Dor , Mutação Puntual , Superóxido Dismutase/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/fisiopatologia , Sequência de Bases , Análise Mutacional de DNA , Progressão da Doença , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Dor/genética , Dor/fisiopatologia , Superóxido Dismutase-1 , Síndrome
9.
Tidsskr Nor Laegeforen ; 129(22): 2358-61, 2009 Nov 19.
Artigo em Norueguês | MEDLINE | ID: mdl-19935936

RESUMO

BACKGROUND: Mutations in genes of the mitogen-activated protein kinase (MAPK) cascade have recently been shown to cause several syndromes characterized by dysmorphic facial features, growth retardation, cognitive impairment, heart disease and cutaneous abnormalities. This signalling pathway involves RAS and RAF proteins, and is central in the regulation of normal growth and the development of cancer. MATERIAL AND METHODS: We have studied 23 Norwegian patients for whom there was a clinical suspicion of Costello, Noonan or cardio-facio-cutaneous syndrome. Patients suspected of having Noonan syndrome had previously tested negative for mutations in the tyrosine phosphatase gene PTPN11. The material was examined for mutations in the HRAS, KRAS, RAF1 and BRAF genes. Two patients are described to illustrate diagnostic challenges and the usefulness of genetic testing. RESULTS: Ten of 23 patients (43 %) had mutations affecting the RAS/MAPK signalling pathway. Mutations in HRAS were most common (five cases), while three patients had mutations in KRAS and two in RAF1. Spontaneous mutations were demonstrated in eight cases. Our data indicate an annual incidence of 1-2 new cases of congenital RAS/RAF mutations in Norway. INTERPRETATION: Upon clinical suspicion of syndromes of the RAS/MAPK signalling pathway, molecular genetic analyses may be essential for a correct diagnosis. Certain mutations are associated with an increased cancer risk, exemplifying that results of genetic laboratory testing may influence medical management.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Sistema de Sinalização das MAP Quinases/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Proteínas ras/genética , Adolescente , Adulto , Pré-Escolar , Síndrome de Costello/genética , Genes ras/genética , Técnicas Genéticas , Humanos , Lactente , Síndrome LEOPARD/genética , Masculino , Síndrome de Noonan/genética , Proteínas Proto-Oncogênicas A-raf/genética , Proteínas Proto-Oncogênicas B-raf/genética , Síndrome
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