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1.
Clin Genet ; 99(2): 325-329, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33174625

RESUMEN

Human multiple synostoses syndrome 3 is an autosomal dominant disorder caused by pathogenic variants in FGF9. Only two variants have been described in FGF9 in humans so far, and one in mice. Here we report a novel missense variant c.566C > G, p.(Pro189Arg) in FGF9. Functional studies showed this variant impairs FGF9 homodimerization, but not FGFR3c binding. We also review the findings of cases reported previously and report on additional features not described previously.


Asunto(s)
Factor 9 de Crecimiento de Fibroblastos/genética , Mutación Missense , Sinostosis/genética , Anomalías Múltiples/genética , Adolescente , Factor 9 de Crecimiento de Fibroblastos/metabolismo , Heterocigoto , Humanos , Masculino , Fenotipo , Unión Proteica , Radiografía , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Sinostosis/diagnóstico por imagen , Sinostosis/patología
2.
Diabetes Metab Res Rev ; 37(7): e3440, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33486892

RESUMEN

AIM: We aimed to study the feasibility and tolerability of a combination therapy consisting of glutamic acid decarboxylase (GAD-alum), Etanercept and vitamin D in children and adolescents with newly diagnosed with type 1 diabetes (T1D), and evaluate preservation of beta cell function. MATERIAL AND METHODS: Etanercept Diamyd Combination Regimen is an open-labelled multi-centre study pilot trial which enrolled 20 GAD antibodies positive T1D patients (7 girls and 13 boys), aged (mean ±SD): 12.4 ± 2.3 (8.3-16.1) years, with a diabetes duration of 81.4 ± 22.1 days. Baseline fasting C-peptide was 0.24 ± 0.1 (0.10-0.35) nmol/l. The patients received Day 1-450 Vitamin D (Calciferol) 2000 U/d per os, Etanercept sc Day 1-90 0.8 mg/kg once a week and GAD-alum sc injections (20 µg, Diamyd™) Day 30 and 60. They were followed for 30 months. RESULTS: No treatment related serious adverse events were observed. After 6 months 90-min stimulated C-peptide had improved in 8/20 patients and C-peptide area under the curve (AUC) after Mixed Meal Tolerance Test in 5 patients, but declined thereafter, while HbA1c and insulin requirement remained close to baseline. Administration of Etanercept did not reduce tumour necrosis factor (TNF) spontaneous secretion from peripheral blood mononuclear cells, but rather GAD65-induced TNF-α increased. Spontaneous interleukin-17a secretion increased after the administration of Etanercept, and GAD65-induced cytokines and chemokines were also enhanced following 1 month of Etanercept administration. CONCLUSIONS: Combination therapy with parallel treatment with GAD-alum, Etanercept and vitamin D in children and adolescents with type 1 diabetes was feasible and tolerable but had no beneficial effects on the autoimmune process or beta cell function.


Asunto(s)
Diabetes Mellitus Tipo 1 , Adolescente , Anciano , Compuestos de Alumbre , Niño , Etanercept/uso terapéutico , Femenino , Glutamato Descarboxilasa/uso terapéutico , Humanos , Insulina/metabolismo , Leucocitos Mononucleares/metabolismo , Masculino , Proyectos Piloto , Vitamina D
3.
Pediatr Diabetes ; 22(3): 417-424, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33259121

RESUMEN

OBJECTIVES: Children with type 1 diabetes (T1D) are not included in guidelines regarding diagnosis criteria for celiac disease (CD) without a diagnostic biopsy, due to lack of data. We explored whether tissue transglutaminase antibodies (anti-tTG) that were ≥ 10 times the upper limit of normal (10× ULN) predicted CD in T1D. METHODS: Data from the Swedish prospective Better Diabetes Diagnosis study was used, and 2035 children and adolescents with T1D diagnosed between 2005-2010 were included. Of these, 32 had been diagnosed with CD before T1D. The children without CD were repeatedly screened for CD using anti-tTG antibodies of immunoglobulin type A. In addition, their human leukocyte antigen (HLA) were genotyped. All children with positive anti-tTG were advised to undergo biopsy. Biopsies were performed on 119 children and graded using the Marsh-Oberhüber classification. RESULTS: All of the 60 children with anti-tTG ≥10x ULN had CD verified by biopsies. The degree of mucosal damage correlated with anti-tTG levels. Among 2003 screened children, 6.9% had positive anti-tTG and 5.6% were confirmed CD. The overall CD prevalence, when including the 32 children with CD before T1D, was 7.0% (145/2035). All but one of the children diagnosed with CD had HLA-DQ2 and/or DQ8. CONCLUSIONS: As all screened children and adolescents with T1D with tissue transglutaminase antibodies above 10 times the positive value 10x ULN had CD, we propose that the guidelines for diagnosing CD in screened children, when biopsies can be omitted, should also apply to children and adolescents with T1D as a noninvasive method.


Asunto(s)
Autoanticuerpos/sangre , Enfermedad Celíaca/sangre , Enfermedad Celíaca/diagnóstico , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Transglutaminasas/inmunología , Adolescente , Factores de Edad , Enfermedad Celíaca/etiología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Valor Predictivo de las Pruebas , Suecia
4.
N Engl J Med ; 366(5): 433-42, 2012 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-22296077

RESUMEN

BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).


Asunto(s)
Péptido C/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Glutamato Descarboxilasa/uso terapéutico , Adolescente , Autoanticuerpos/sangre , Niño , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/inmunología , Femenino , Glutamato Descarboxilasa/efectos adversos , Glutamato Descarboxilasa/inmunología , Humanos , Masculino , Isoformas de Proteínas , Adulto Joven
5.
Horm Res Paediatr ; 91(3): 195-202, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31096231

RESUMEN

BACKGROUND: We found an increase in the incidence rate (IR) of childhood thyrotoxicosis (CT) during the 1990s in central Sweden. The optimal treatment method for CT is a subject that is still debated upon. OBJECTIVES: To investigate whether the increase in IR of CT in Sweden persists and to study the treatment outcome. METHOD: Children <16 years of age diagnosed with CT during 2000-2009 and living in 1 of 5 counties in central Sweden were identified retrospectively using hospital registers. Data on clinical and biochemical characteristics and outcomes of treatment were collected from medical records. The corresponding data from 1990 to 1999 were pooled with the new data. RESULTS: In total, 113 children were diagnosed with CT during 1990-2009 in the study area. The overall IR was 2.2/100,000 person-years (95% CI 1.2-2.5/100,000 person-years). The IR was significantly higher during 2000-2009 than during 1990-1999 (2.8/100,000 [2.2-3.6] vs. 1.6/100,000 person-years [1.2-2.2], p = 0.006). The increase was significant for both sexes. Seventy percent of the patients who completed the planned initial treatment with antithyroid drugs (ATDs) and were not lost to follow-up relapsed within 3 years. Boys tended to relapse earlier than girls (6.0 months after drug withdrawal [95% CI 1.9-10.0] vs. 12.0 months [95% CI 6.8-17.3], p = 0.074). CONCLUSIONS: The IR of CT is increasing in both girls and boys. Relapse rate after withdrawal of ATD treatment is 70%. Boys tend to relapse earlier than girls, and this needs to be further investigated.


Asunto(s)
Antitiroideos/administración & dosificación , Sistema de Registros , Tirotoxicosis , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Masculino , Estudios Retrospectivos , Suecia , Tirotoxicosis/diagnóstico , Tirotoxicosis/tratamiento farmacológico , Tirotoxicosis/epidemiología
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