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1.
Mol Genet Metab ; 141(3): 108118, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38244286

RESUMO

Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity.


Assuntos
Falência Hepática Aguda , Neuroblastoma , Anomalia de Pelger-Huët , Humanos , Fenótipo , Anomalia de Pelger-Huët/complicações , Anomalia de Pelger-Huët/genética , Anomalia de Pelger-Huët/patologia , Falência Hepática Aguda/genética , Mutação de Sentido Incorreto , Neuroblastoma/complicações
2.
Pediatr Transplant ; 27(3): e14469, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36617693

RESUMO

BACKGROUND: Kaposi sarcoma (KS) is an endothelial cell tumor, rare in children. It is 200 times more frequent after solid organ transplantation than in the general population. METHODS: We report three cases of pediatric patients who developed KS after liver transplantation (LT). RESULTS: Case 1, a 4-year-old boy undergoing LT due to familial intrahepatic cholestasis. Five months after LT, he presented with fever, dyspnea, and cough with enlarged lymph nodes and splenomegaly, anemia, thrombocytopenia, elevated liver enzymes, and positive EBV viral load. Lymph node biopsy diagnosed KS with an elevated HHV8 viral load. Case 2, a 4-year-old boy who underwent LT due to secondary biliary cirrhosis resulting from extrahepatic biliary atresia. Two years later, graft dysfunction was noticed with positive EBV viral load, thrombocytopenia, massive cervical lymph node enlargement, and splenomegaly. Lymph node biopsy diagnosed KS, Castleman's disease, and plasmablastic lymphoma related to HHV8 infection. Case 3, a 15-month-old girl, who received two LT due to biliary cirrhosis. Six months later, she presented with diarrhea, abdominal distension, anemia, thrombocytopenia, enlarged lymph nodes, splenomegaly, and positive CMV viral load. Axillary lymph node biopsy diagnosed KS and HHV8 infection was confirmed. In all three cases, tacrolimus was discontinued and, after diagnosis, sirolimus was started. All recovered without relapse and have a good graft function. CONCLUSIONS: Kaposi sarcoma is a rare disease post-LT in children. Recognizing keywords and early diagnosis is crucial for timely treatment and survival.


Assuntos
Herpesvirus Humano 8 , Transplante de Fígado , Sarcoma de Kaposi , Trombocitopenia , Masculino , Feminino , Humanos , Criança , Lactente , Pré-Escolar , Sarcoma de Kaposi/diagnóstico , Sarcoma de Kaposi/etiologia , Transplante de Fígado/efeitos adversos , Esplenomegalia/complicações , Recidiva Local de Neoplasia , Fígado/patologia , Trombocitopenia/complicações
3.
BMJ Case Rep ; 20172017 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-29237659

RESUMO

Prognosis of hepatitis-associated aplastic anaemia (HAAA) was improved with haematopoietic stem cell transplantation (HSCT) and immunosuppression, but the long-term outcome remains undefined. Case 1: a girl aged 3 years with acute liver failure (ALF) submitted to orthotopic liver transplantation (OLT) subsequently developed aplastic anaemia and HSCT from a compatible sibling was performed. Post-HSCT, the patient developed post-transplant lymphoproliferative disorder and rituximab was administered with good response. Fifteen years later, both grafts show good outcome. Case 2: a girl aged 10 years submitted to OLT due to ALF, developed pancytopenia 2 months later. Due to the absence of a human leucocyte antigen compatible donor, she was treated with ciclosporin and antithymocyte globulin with very good long-term outcome. These clinical cases suggest that, for patients with HAAA that underwent OLT, aggressive therapy with HSCT or immunosuppression may provide a benign long-term outcome.


Assuntos
Anemia Aplástica/diagnóstico , Hepatite/diagnóstico , Falência Hepática Aguda , Transplante de Fígado , Aciclovir/administração & dosagem , Aciclovir/uso terapêutico , Anemia Aplástica/complicações , Anemia Aplástica/tratamento farmacológico , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Hepatite/complicações , Hepatite/tratamento farmacológico , Humanos , Complicações Pós-Operatórias/diagnóstico
4.
J Exp Med ; 214(12): 3707-3729, 2017 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-29127204

RESUMO

The biogenesis of the multi-subunit vacuolar-type H+-ATPase (V-ATPase) is initiated in the endoplasmic reticulum with the assembly of the proton pore V0, which is controlled by a group of assembly factors. Here, we identify two hemizygous missense mutations in the extracellular domain of the accessory V-ATPase subunit ATP6AP2 (also known as the [pro]renin receptor) responsible for a glycosylation disorder with liver disease, immunodeficiency, cutis laxa, and psychomotor impairment. We show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. The introduction of one of the missense mutations into Drosophila led to reduced survival and altered lipid metabolism. We further demonstrate that in the liver-like fat body, the autophagic dysregulation was associated with defects in lysosomal acidification and mammalian target of rapamycin (mTOR) signaling. Finally, both ATP6AP2 mutations impaired protein stability and the interaction with ATP6AP1, a member of the V0 assembly complex. Collectively, our data suggest that the missense mutations in ATP6AP2 lead to impaired V-ATPase assembly and subsequent defects in glycosylation and autophagy.


Assuntos
Autofagia , Proteínas de Drosophila/genética , Genes Ligados ao Cromossomo X , Proteínas de Membrana/genética , Mutação/genética , ATPases Translocadoras de Prótons/genética , Receptores de Superfície Celular/genética , ATPases Vacuolares Próton-Translocadoras/genética , Adolescente , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas Sanguíneas/metabolismo , Encéfalo/embriologia , Encéfalo/patologia , Cútis Laxa/complicações , Cútis Laxa/patologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Degradação Associada com o Retículo Endoplasmático , Fibroblastos/patologia , Glicosilação , Humanos , Lactente , Lipídeos/química , Fígado/patologia , Hepatopatias/complicações , Hepatopatias/patologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Ligação Proteica , Processamento de Proteína Pós-Traducional , ATPases Translocadoras de Prótons/deficiência , ATPases Translocadoras de Prótons/metabolismo , Transtornos Psicomotores/complicações , Transtornos Psicomotores/patologia , Receptores de Superfície Celular/química , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/metabolismo , ATPases Vacuolares Próton-Translocadoras/química , ATPases Vacuolares Próton-Translocadoras/deficiência , Adulto Jovem
5.
J Pediatr Gastroenterol Nutr ; 58(3): 382-6, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24164902

RESUMO

OBJECTIVES: Fibrosis, related to several causes, can be diagnosed in children and adolescents' liver grafts that are >1 year old. At present, liver biopsy is the gold standard for assessing liver damage in the posttransplant setting. We aimed to evaluate the accuracy of noninvasive biomarkers of fibrosis, namely, acoustic radiation force impulse (ARFI), aspartate-to-platelet ratio index, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio index, either alone or in combination, for predicting fibrosis in pediatric patients submitted to liver transplantation. METHODS: We prospectively assessed liver fibrosis in 30 children/adolescents with liver transplant through biopsy (liver transplant follow-up during 12 months). ARFI with Virtual Touch Software (Acuson 2000) was performed, and blood samples were taken to determine liver function and platelet count. Two groups were analyzed according to the histopathologic stage of fibrosis, namely, none/mild (F0-F1) versus significant fibrosis (F2-4). RESULTS: The mean age of the 30 patients was 11 years (3-18 years), with a mean posttransplant period of assessment of 6.5 years. Twenty-four patients (80%) presented stage F0-F1 fibrosis and 6 patients (20%) presented stage F2-4. The area under the curve using receiver operating characteristic analysis for ARFI, aspartate-to-platelet ratio index, and AST/ALT ratio index for significant fibrosis was 0.76 (P = 0.052), 0.74 (P = 0.066), and 0.69 (P = 0.162), respectively. Through multivariate logistic regression analysis, the only independent predictor of significant fibrosis was ARFI (odds ratio 10.7, 95% confidence interval 1.2-95.7; P = 0.045). The combination of ARFI and AST/ALT ratio index presented a good diagnostic accuracy of fibrosis (area under the curve of 0.83; P = 0.013). CONCLUSIONS: ARFI may serve as a potential method for assessing significant fibrosis in pediatric patients with liver transplant, particularly in combination with AST/ALT ratio index.


Assuntos
Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Técnicas de Imagem por Elasticidade/métodos , Cirrose Hepática , Transplante de Fígado , Fígado , Adolescente , Área Sob a Curva , Biomarcadores/sangue , Biópsia , Criança , Pré-Escolar , Feminino , Humanos , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Modelos Logísticos , Masculino , Contagem de Plaquetas , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos Testes , Índice de Gravidade de Doença
6.
Acta Med Port ; 24(3): 413-8, 2011.
Artigo em Português | MEDLINE | ID: mdl-22015028

RESUMO

BACKGROUND: Adolescents usually have risky sexual behaviors which can result in an unwanted pregnancy and/or in transmission of sexually transmitted infections (STIs). Medical consultation can provide adequate and early sexual information. Medical surveillance and pelvic examination are essential for a healthy sexual life. Despite the availability of two vaccines against the major oncogenic types of human papilloma virus, the main agent of cervical cancer, performance of cytology is still needed. The purpose of this study was to characterize the group of adolescents/young adults who made their first cytology during 2005 and 2006 and determine the results of gynecological observation and first cytology. METHODS: This is a retrospective study of users of Centro de Atendimento a Jovens (CAJ) of Centro de Saúde de Celas de Coimbra, who made their first cytology in 2005 and 2006. Clinical data were analyzed to determine the following parameters: demographic data, habits, sexual parameters, gynecological observation, symptoms, first and subsequent cytology results and consultations dropout rate until January 2009. RESULTS: During these two years, 172 first cytologies were performed. At first consultation in CAJ, the average age was 19 years old (15-24). At first intercourse, which occurred on average at 17,5 years old (13-21), 75,6% of girls used condom, 4,6% only pill and 16,3% did not use any contraceptive method. The mean number of sexual partners at first consultation was 1,6. The majority needed to take emergency pill (43/54). Gynecological observation was abnormal in 50,6% of cases, but only 10% reported symptoms. First cytology was performed, on average, three years after first intercourse, and was normal in 149 cases, unsatisfactory for evaluation in one case and abnormal in 22 (eight bacterial vaginosis, six with signs of inflammation, six candidiasis and two low grade intraepithelial lesions). Fifty nine per cent of adolescents made, at least, once more cytology. Three more cases of low grade intraepithelial lesions were detected. Dropout rate of consultations was 17%. CONCLUSIONS: In adolescence, isolated pill use increases the risk of transmission of STIs. Not using any contraceptive method may be related to the increasing use of emergency contraceptive pills. Abnormal gynecological examination may be present in asymptomatic girls. Dysplastic lesions (which are increasing in adolescence) have the same course of adulthood, supporting the need for screening and continuity of follow-up in young people.


Assuntos
Promoção da Saúde/métodos , Sexualidade , Esfregaço Vaginal , Adolescente , Feminino , Humanos , Portugal , Estudos Retrospectivos , Esfregaço Vaginal/estatística & dados numéricos , Adulto Jovem
7.
BMJ Case Rep ; 20112011 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-22687675

RESUMO

An 11-year-old boy was treated since 6-years-old with methylphenidate for combined attention deficit and hyperactivity disorder. At age nine his behaviour had worsened and he started to have phobias. One year later persistent hypertransaminasemia was found. Physical examination showed a dysdiadocokinesia. Laboratory investigation revealed a low caeruloplasmin and augmented basal urinary copper with a positive postpenicillamine test. Liver biopsy showed high liver copper (853 µg/g) and brain MRI was normal. D-penicillamine and zinc acetate were started without side effects. ATP7B gene mutation was confirmed after treatment initiation.


Assuntos
Degeneração Hepatolenticular/complicações , Transtornos Mentais/etiologia , Criança , Humanos , Masculino
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