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1.
Artigo em Inglês | MEDLINE | ID: mdl-31887391

RESUMO

BACKGROUND: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant. OBJECTIVE: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant. METHOD: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. RESULTS: Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. CONCLUSION: The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.

2.
J Int Med Res ; 46(4): 1339-1348, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29350094

RESUMO

Objective The aim of this study was to determine whether an expanded newborn screening programme, which is not yet available in Slovenia, would have detected the first two patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the country. Two novel ACADM mutations are also described. Methods Both patients were diagnosed clinically; follow-up involved analysis of organic acids in urine, acylcarnitines in dried blood spots, and genetic analysis of ACADM. Cut-off values of acylcarnitines in newborns were established using analysis of 10,000 newborns in a pilot screening study. Results In both patients, analysis of the organic acids in urine showed a possible ß-oxidation defect, while the specific elevation of acylcarnitines confirmed MCAD deficiency. Subsequent genetic analysis confirmed the diagnosis; both patients were compound heterozygotes, each with one novel mutation (c.861 + 2T > C and c.527_533del). The results from a retrospective analysis of newborn screening cards clearly showed major elevations of MCAD-specific acylcarnitines in the patients. Conclusions An expanded newborn screening programme would be beneficial because it would have detected MCAD deficiency in both patients before the development of clinical signs. Our study also provides one of the first descriptions of ACADM mutations in Southeast Europe.


Assuntos
Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/genética , Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/genética , Mutação/genética , Triagem Neonatal , Acil-CoA Desidrogenase/sangue , Acil-CoA Desidrogenase/urina , Ácidos Carboxílicos/urina , Carnitina/análogos & derivados , Carnitina/sangue , Teste em Amostras de Sangue Seco , Feminino , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/urina , Masculino , Estudos Retrospectivos
3.
Orphanet J Rare Dis ; 12(1): 131, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28720148

RESUMO

BACKGROUND: Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency is characterized by primary immunodeficiency and autoimmunity. Cancer may present another feature of LRBA deficiency. We describe a case history of a young adult with LRBA deficiency and two independent malignancies. METHODS: Family-trio whole exome sequencing with unbiased phenotype ontology approach was used for identification of causative mutations of a primary immune deficiency disorder. Additionally, we sought to identify germline mutations in genes known to be associated with two independent malignancies using a targeted approach. A cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in T lymphocytes was determined by flow cytometry. RESULTS: In the patient with clinical signs of LRBA deficiency multifocal gastric carcinoma and malignant melanoma were diagnosed and surgically treated at 19 and 27 years of age, respectively. Despite refusal of any adjuvant chemotherapy or radiotherapy, the patient demonstrated disease free survival for at least 13 years after the first cancer diagnosis. A homozygous frameshift deletion in LRBA gene (p.Glu946Ter) and two common variants in TYR gene were identified. Reduced CTLA4 expression in a subset of regulatory T lymphocytes was identified in the patient and his unaffected mother carrying a heterozygous LRBA mutation as compared to control in a dose-dependent manner. CONCLUSION: This is the first description of gastric cancer and malignant melanoma in a young adult with LRBA deficiency. The role of LRBA gene knockout in cancer development and its prognosis remains to be elucidated.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma/patologia , Síndromes de Imunodeficiência/genética , Neoplasias Gástricas/patologia , Adenocarcinoma/genética , Adulto , Autoimunidade/genética , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Regulação Neoplásica da Expressão Gênica , Mutação em Linhagem Germinativa , Humanos , Masculino , Neoplasias Gástricas/genética , Sequenciamento Completo do Genoma
4.
Diabetes Obes Metab ; 19(4): 553-561, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27981804

RESUMO

AIMS: To evaluate the safety, efficacy and need for remote monitoring of the MD-Logic closed-loop system during short-term overnight use at home. METHODS: Seventy-five patients (38 male; aged 10-54 years; average A1c, 7.8% ± 0.7%, 61.8 ± 7.2 mmol/mol) were enrolled from 3 clinical sites. Patients were randomly assigned to participate in 2 overnight crossover periods, each including 4 consecutive nights, 1 under closed-loop control and 1 under sensor-augmented pump (SAP) therapy in the patient's home. Both study arms were supervised using a remote-monitoring system in a blinded manner. Primary endpoints were time spent with glucose levels below 70 mg/dL and percentage of nights in which mean overnight glucose levels were within 90 to 140 mg/dL. RESULTS: The median [interquartile range] percentage of time spent in hypoglycaemia was significantly lower on nights when MD-Logic was used, compared to SAP therapy (2.07 [0, 4.78] and 2.6 [0, 10.34], respectively; P = .004) and the percentage of individual nights with a mean overnight glucose level in target was significantly greater (75 [42, 75] and 50 [25,75], respectively; P = .008). The time spent in target range was increased by a median of 28% (P = .001), with the same amount of insulin (10.69 [7.28, 13.94] and 10.41[6.9, 14.07], respectively; P = .087). The remote monitoring triggered calls for hypoglycaemia at twice the rate during SAP therapy compared to closed-loop control (62 and 29, respectively; P = .002). CONCLUSIONS: The MD-Logic system demonstrated a safe and efficient profile during overnight use by children, adolescents and adults with type 1 diabetes and, therefore, provides an effective means of mitigating the risk of nocturnal hypoglycaemia.


Assuntos
Automonitorização da Glicemia/instrumentação , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Sistemas de Infusão de Insulina , Insulina/administração & dosagem , Adolescente , Adulto , Glicemia/análise , Criança , Estudos Cross-Over , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Cronoterapia Farmacológica , Feminino , Humanos , Hipoglicemia/sangue , Hipoglicemia/tratamento farmacológico , Hipoglicemia/etiologia , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Telemetria/métodos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
5.
Horm Res Paediatr ; 84(3): 153-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26111865

RESUMO

BACKGROUND/AIMS: The HESX1 gene is essential in forebrain development and pituitary organogenesis, and its mutations are the most commonly identified genetic cause of septo-optic dysplasia (SOD). The PROP1 gene is involved in anterior pituitary cell lineage specification and is commonly implicated in non-syndromic combined pituitary hormone deficiency (CPHD). We aimed to assess the involvement of HESX1 and PROP1 mutations in a cohort of patients with SOD and CPHD. METHODS: Six patients with sporadic SOD and 16 patients with CPHD from 14 pedigrees were screened for mutations in HESX1 and PROP1 genes by exon sequencing. Half of the CPHD patients had variable associated clinical characteristics, such as hearing loss, orofacial cleft, kidney disorder or developmental delay. Novel variants were evaluated in silico and verified in SNP databases. RESULTS: A novel heterozygous p.Glu102Gly mutation in the HESX1 gene and a novel homozygous p.Arg121Thr mutation in the PROP1 gene were detected in 2 pedigrees with CPHD. A small previously reported deletion in PROP1 c.301_302delAG was detected in a separate patient with CPHD, in heterozygous state. No mutations were identified in patients with SOD. CONCLUSIONS: Our results expand the spectrum of mutations implicated in CPHD. The frequency of 15% of the PROP1 mutations in CPHD was low, likely due to the clinical heterogeneity of the cohort.


Assuntos
Proteínas de Homeodomínio/genética , Hipopituitarismo/genética , Displasia Septo-Óptica/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , DNA/genética , Éxons , Feminino , Frequência do Gene , Heterozigoto , Humanos , Hipopituitarismo/patologia , Masculino , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único , Displasia Septo-Óptica/patologia , Adulto Jovem
6.
Zdr Varst ; 54(2): 112-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27646917

RESUMO

INTRODUCTION: Autoimmune polyglandular syndrome type 1 (APS-1) is an autosomal recessive disorder, caused by mutations in the AIRE gene. The major components of APS-1 are chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP) and Addison's disease (AD). Clinical, genetic and immunological characteristics of Slovenian paediatric APS-1 patients were investigated. METHODS: Existing medical records of 15 APS-1 patients were rewieved, when necessary, additional clinical and laboratory investigations were issued. AIRE gene analysis was performed to identify causative mutations, and autoantibodies against type I interferons were measured by luminescence immunoprecipitation system. RESULTS: Patients had one to eight different manifestations of the disease. CMC was present in all, HP in 12/15 (80 %) and AD in 8/15 (53 %) patients. Growth retardation, due to hyposomatotropism, growth hormone resistance, autoimmune thyroiditis, corticosteroid treatment, malabsorption or secretory failure of exocrine pancreas, was observed in altogether 7 (46 %) patients. Six different AIRE gene mutations were detected and p.R257X mutation was present in 63.3 % of pathological alleles. Antibodies against type I interferons were detected in all patients. CONCLUSION: APS-1 is a rare disorder with a broad spectrum of clinical manifestations, which, if unrecognized or inadequately treated may be fatal. AIRE gene mutational analysis and autoantibodies against type I interferons are important in early identification of the disease. The aetiology of growth retardation was shown to be extremely diverse, frequently caused by less characteristic manifestations. APS-1 may affect patients' quality of life in numerous ways, and may cause great psychosocial burden leading to depression and suicidal thoughts even in paediatric patients.

7.
Zdr Varst ; 54(2): 119-25, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27646918

RESUMO

INTRODUCTION: Osteogenesis imperfecta (OI) is etiologically heterogeneous disorder characterized by childhood osteoporosis. A subtype OI type V is caused by the same c.-14C>T mutation in the IFITM5 gene. Nevertheless, there is a marked interindividual phenotypic variability in clinical presentation; however, response to bisphosphonates is reported to be good. METHODS: Two individuals with OI type V had multiple recurrent fractures with hypertrophic calluses, scoliosis and ossifications of the forearm interosseous membranes. Sequencing of IFITM5, genotyping of variants rs2297480 in farnesyl diphosphate synthase gene (FDPS), and rs3840452 in geranylgeranyl diphosphate synthase 1 gene (GGPS1), both involved in bisphosphonate metabolism, was performed. RESULTS: In patient 1 BMD reached normal values during bisphosphonate treatment and remained normal four years after the treatment discontinuation. In patient 2 no increase in BMD after five years of bisphosphonate treatment was observed and callus formation continued. The c.-14C>T IFITM5 mutation in heterozygous state was detected in both individuals. Additionally, both patients carried FDPS variant rs2297480 in homozygous state, and were heterozygous for GGPS 1 variant rs3840452. CONCLUSIONS: The paper presents a short overview of childhood osteoporosis with a special emphasis on OI type V by presenting two cases. Both OI type V patients had identical disease-causing mutation, but marked interindividual phenotypic variability. The striking failure in response to bisphosphonate treatment in one of the patients could not be explained by the variants in genes involved in bisphosphonate metabolism.

8.
Eur J Endocrinol ; 170(2): 293-300, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24225029

RESUMO

BACKGROUND: Overweight/obesity in children is a worldwide public health problem. Together with hypercholesterolaemia they are associated with early atherosclerotic complications. OBJECTIVES: In this study, we aimed to investigate the anthropometric characteristics and total cholesterol (TC) levels in a population of 5-year-old children, to determine trends in the prevalence of overweight/obesity and hypercholesterolaemia in 5-year-old children over a period of 8 years (2001-2009) and to assess the impact of modified national nutritional guidelines for kindergartens implemented in 2005. DESIGN: Cross-sectional studies of overweight/obesity prevalence in the years 2001, 2003-2005 and 2009, and hypercholesterolaemia in years 2001 and 2009, in 5-year-old children. SUBJECTS: Altogether, 12 832 (6308 girls/6524 boys) children were included. METHODS: Overweight/obesity was defined by IOTF criteria. Hypercholesterolaemia was defined by TC level >5 mmol/l. Multivariable logistic regression models were used. RESULTS: NO CORRELATION BETWEEN BMI VALUES AND TC LEVELS WAS FOUND. OVERWEIGHT AND OBESITY PREVALENCE WERE STABILISED FROM 2001 TO 2009 (ODDS RATIO (OR) (95% CI): 1.13 (0.99-1.3) and 1.13 (0.89-1.42) respectively). Girls were more frequently overweight/obese than boys (OR (95% CI): 0.71 (0.65-0.79) and 0.75 (0.64-0.89) respectively). Prevalence of hypercholesterolaemia significantly decreased from 2001 to 2009 (OR (95% CI): 0.47 (0.41-0.55)). It was less frequent in boys than in girls (OR (95% CI): O.7 (0.61-0.8)). CONCLUSIONS: This is the first study to describe a negative trend in the prevalence of hypercholesterolaemia in pre-pubertal children. In addition, the prevalence of overweight/obesity in these children has been stabilised. Nationwide changes in public health policies could have influenced these observations.


Assuntos
Hipercolesterolemia/epidemiologia , Obesidade/epidemiologia , Sobrepeso/epidemiologia , Índice de Massa Corporal , Pré-Escolar , Estudos Transversais , Feminino , Política de Saúde , Humanos , Masculino , Programas de Rastreamento , Razão de Chances , Prevalência , Eslovênia/epidemiologia
9.
Hum Mol Genet ; 21(19): 4314-24, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22773735

RESUMO

Congenital gonadotropin-releasing hormone (GnRH) deficiency manifests as absent or incomplete sexual maturation and infertility. Although the disease exhibits marked locus and allelic heterogeneity, with the causal mutations being both rare and private, one causal mutation in the prokineticin receptor, PROKR2 L173R, appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins. To track the genetic ancestry of PROKR2 L173R, haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives. The mutation's age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same ~123 kb haplotype whose population frequency is ≤10%. Thus, PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years. Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers, influenced by additional mutations in the other PROKR2 allele (recessive inheritance) or another gene (digenicity). The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection, including potential selective advantages of mutation carriers in genes affecting reproduction.


Assuntos
Efeito Fundador , Mutação de Sentido Incorreto , Receptores Acoplados a Proteínas-G/genética , Receptores de Peptídeos/genética , Reprodução , Grupos de Populações Continentais/genética , Evolução Molecular , Feminino , Hormônio Liberador de Gonadotropina/deficiência , Haplótipos , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Peptídeos/metabolismo
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