RESUMEN
BACKGROUND AND AIMS: Glycogen storage disease type I (GSD I) is associated with hyperlipidemia, a known risk factor for premature atherosclerosis. Few studies have addressed endothelial dysfunction in patients with GSD I, and these studies yielded controversial results. METHODS AND RESULTS: We investigated vascular dysfunction in a cohort of 32 patients with GSD I (26 GSD Ia, 6 GSD Ib, mean age 20.7 (4.8-47.5) years) compared to 32 age-, gender-, and BMI-matched healthy controls using non-invasive techniques such as quantification of carotid intima media thickness, retinal vessel analysis and 24 h-blood pressure measurements. In addition, early biomarkers of inflammatory and oxidative endothelial stress were assessed in blood. Although GSD I patients had a clearly proatherogenic lipid profile, increased oxidative stress, higher levels of high sensitivity C-reactive protein and increased lipoprotein associated phospholipase A2 activity, functional and structural parameters including carotid intima media thickness and retinal vessel diameters did not indicate premature atherosclerosis in this patient cohort. Blood pressure values and pulse wave velocity were comparable in patients and healthy controls, while central blood pressure and augmentation index were higher in GSD patients. CONCLUSION: Our data suggest that GSD I is not associated with early vascular dysfunction up to the age of at least 20 years. Further studies are needed to elucidate the possibly protective mechanisms that prevent early atherosclerosis is GSD I. Longer follow-up studies are required to assess the long-term risk of vascular disease with increased oxidative stress being present in GSD I patients.
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Enfermedad del Almacenamiento de Glucógeno Tipo I , Hiperlipidemias , Adolescente , Adulto , Aterosclerosis/epidemiología , Enfermedades Cardiovasculares/epidemiología , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo I/epidemiología , Humanos , Hiperlipidemias/epidemiología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Lysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile. RESULTS: Substantial disease burden at baseline included a very high level of low-density lipoprotein cholesterol (≥190 mg per deciliter) in 38 of 66 patients (58%) and cirrhosis in 10 of 32 patients (31%) who underwent biopsy. A total of 65 of the 66 patients who underwent randomization completed the double-blind portion of the trial and continued with open-label treatment. At 20 weeks, the alanine aminotransferase level was normal in 11 of 36 patients (31%) in the sebelipase alfa group and in 2 of 30 (7%) in the placebo group (P=0.03), with mean changes from baseline of -58 U per liter versus -7 U per liter (P<0.001). With respect to prespecified key secondary efficacy end points, we observed improvements in lipid levels and reduction in hepatic fat content (P<0.001 for all comparisons, except P=0.04 for triglycerides). The number of patients with adverse events was similar in the two groups; most events were mild and were considered by the investigator to be unrelated to treatment. CONCLUSIONS: Sebelipase alfa therapy resulted in a reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency. (Funded by Synageva BioPharma and others; ARISE ClinicalTrials.gov number, NCT01757184.).
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Esterol Esterasa/uso terapéutico , Enfermedad de Wolman/tratamiento farmacológico , Adolescente , Adulto , Anciano , Alanina Transaminasa/sangre , Biopsia , Niño , Preescolar , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Método Doble Ciego , Dislipidemias/tratamiento farmacológico , Dislipidemias/genética , Femenino , Humanos , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Persona de Mediana Edad , Esterol Esterasa/efectos adversos , Esterol Esterasa/farmacología , Enfermedad de Wolman/sangre , Adulto Joven , Enfermedad de WolmanRESUMEN
Percentile-based non-high-density lipoprotein cholesterol levels were analyzed by glycemic control, weight, age, and sex of children with type 1 diabetes (n = 26,358). Ten percent of all children and 25% of overweight adolescent girls require both immediate lipid-lowering medication and lifestyle changes to achieve non-high-density lipoprotein cholesterol levels <120 mg/dL and cardiovascular risk reduction.
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Glucemia/metabolismo , Índice de Masa Corporal , Enfermedades Cardiovasculares/sangre , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 1/sangre , Hipoglucemiantes/uso terapéutico , Guías de Práctica Clínica como Asunto , Adolescente , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Niño , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Factores de RiesgoRESUMEN
OBJECTIVE: To facilitate child-specific and diabetes-related cholesterol control, we developed a monitoring algorithm derived from population-based reference values. STUDY DESIGN: Low-density lipoprotein (LDL)-, non-high-density lipoprotein (HDL)-, and HDL cholesterol percentile values were calculated for children with type 1 diabetes (T1D) and their peers without T1D within algorithm-based categories of sex, age: 1-10 vs >10-<18 years, body mass index: <90th vs ≥90th percentile, and hemoglobin A1c <6%, 6%-<7.5%, 7.5%-9%, >9%. Analyses included 26 147 patients sampled from a German/Austrian population-based registry for T1D (Diabetes Documentation and Quality Management System) and 14â057 peers without diabetes participating in the national Health Interview and Examination Survey for Children and Adolescents in Germany. RESULTS: Reference percentile values for cholesterol were derived as a diagnostic algorithm aimed at supporting long-term cholesterol control. Taking account of a patient's sex, age-group, weight-, and hemoglobin A1c-category, the flowcharts of the algorithm developed separately for LDL-, non-HDL-, and HDL cholesterol allow comparing his/her cholesterol levels with population-based reference percentile values of peers without T1D. CONCLUSIONS: The population-based algorithmic approach applied to LDL-, non-HDL-, and HDL cholesterol allows referencing children with T1D with regard to their peers without T1D and, if necessary, suggests corrections of glycemic control to optimize long-term cholesterol levels.
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Algoritmos , Colesterol/sangre , Técnicas de Apoyo para la Decisión , Diabetes Mellitus Tipo 1/complicaciones , Dislipidemias/diagnóstico , Adolescente , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Preescolar , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Estudios Transversales , Bases de Datos Factuales , Diabetes Mellitus Tipo 1/sangre , Dislipidemias/sangre , Femenino , Humanos , Lactante , Masculino , Valores de ReferenciaRESUMEN
Mitochondrial enoyl-CoA isomerase (ECI1) is an auxiliary enzyme involved in unsaturated fatty acid oxidation. In contrast to most of the other enzymes involved in fatty acid oxidation, a deficiency of ECI1 has yet to be identified in humans. We used wild-type (WT) and Eci1-deficient knockout (KO) mice to explore a potential presentation of human ECI1 deficiency. Upon food withdrawal, Eci1-deficient mice displayed normal blood ß-hydroxybutyrate levels (WT 1.09 mM vs. KO 1.10 mM), a trend to lower blood glucose levels (WT 4.58 mM vs. KO 3.87 mM, P=0.09) and elevated blood levels of unsaturated acylcarnitines, in particular C12:1 acylcarnitine (WT 0.03 µM vs. KO 0.09 µM, P<0.01). Feeding an olive oil-rich diet induced an even greater increase in C12:1 acylcarnitine levels (WT 0.01 µM vs. KO 0.04 µM, P<0.01). Overall, the phenotypic presentation of Eci1-deficient mice is mild, possibly caused by the presence of a second enoyl-CoA isomerase (Eci2) in mitochondria. Knockdown of Eci2 in Eci1-deficient fibroblasts caused a more pronounced accumulation of C12:1 acylcarnitine on incubation with unsaturated fatty acids (12-fold, P<0.05). We conclude that Eci2 compensates for Eci1 deficiency explaining the mild phenotype of Eci1-deficient mice. Hypoglycemia and accumulation of C12:1 acylcarnitine might be diagnostic markers to identify ECI1 deficiency in humans.
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Isomerasas de Doble Vínculo Carbono-Carbono/metabolismo , Ácidos Grasos Insaturados/metabolismo , Mitocondrias/enzimología , Animales , Glucemia/metabolismo , Isomerasas de Doble Vínculo Carbono-Carbono/genética , Carnitina/análogos & derivados , Carnitina/sangre , Células Cultivadas , Cromatografía Líquida de Alta Presión , Dodecenoil-CoA Isomerasa , Immunoblotting , Espectrometría de Masas , Ratones , Ratones Noqueados , Oxidación-Reducción , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: Metabolic control and dietary management of patients with phenylketonuria (PKU) are based on single blood samples obtained at variable intervals. Sampling conditions are often not well-specified and intermittent variation of phenylalanine concentrations between two measurements remains unknown. We determined phenylalanine and tyrosine concentrations in blood over 24 hours. Additionally, the impact of food intake and physical exercise on phenylalanine and tyrosine concentrations was examined. Subcutaneous microdialysis was evaluated as a tool for monitoring phenylalanine and tyrosine concentrations in PKU patients. METHODS: Phenylalanine and tyrosine concentrations of eight adult patients with PKU were determined at 60 minute intervals in serum, dried blood and subcutaneous microdialysate and additionally every 30 minutes postprandially in subcutaneous microdialysate. During the study period of 24 hours individually tailored meals with defined phenylalanine and tyrosine contents were served at fixed times and 20 min bicycle-ergometry was performed. RESULTS: Serum phenylalanine concentrations showed only minor variations while tyrosine concentrations varied significantly more over the 24-hour period. Food intake within the patients' individual diet had no consistent effect on the mean phenylalanine concentration but the tyrosine concentration increased up to 300% individually. Mean phenylalanine concentration remained stable after short-term bicycle-exercise whereas mean tyrosine concentration declined significantly. Phenylalanine and tyrosine concentrations in dried blood were significantly lower than serum concentrations. No close correlation has been found between serum and microdialysis fluid for phenylalanine and tyrosine concentrations. CONCLUSIONS: Slight diurnal variation of phenylalanine concentrations in serum implicates that a single blood sample does reliably reflect the metabolic control in this group of adult patients. Phenylalanine concentrations determined by subcutaneous microdialysis do not correlate with the patients' phenylalanine concentrations in serum/blood.
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Ritmo Circadiano , Microdiálisis/métodos , Fenilalanina/sangre , Fenilcetonurias/sangre , Tejido Subcutáneo/química , Tirosina/sangre , Administración Oral , Adulto , Dieta , Femenino , Humanos , Masculino , Comidas , Actividad Motora , Fenilalanina/administración & dosificación , Fenilcetonurias/dietoterapia , Tirosina/administración & dosificación , Adulto JovenRESUMEN
OBJECTIVES: To improve screening and quantification of subclinical atherosclerosis in children and adolescents with type 1 diabetes (T1D), we investigated the distribution of cardiovascular risk factors (cRFs) and carotid intima-media thickness (cIMT) percentiles with regard to sex-specific differences. METHODS: This cross-sectional analysis included clinical parameters, blood lipids, and B-mode ultrasound examination of the bilateral mean cIMT using an automatic contour identification procedure combined with computerized analysis. RESULTS: A total of 270 patients were eligible for evaluation (126 females, mean age 13.7 yr; 144 males, mean age 13.8 yr). In the total group, cIMT was significantly related to sex and diabetes duration but not to age. In males, cIMT was significantly higher than in females and sex-specific cIMT percentiles were calculated. Both pulse pressure and diabetes duration in boys and low-density lipoprotein (LDL)-cholesterol, hemoglobin A1c (HbA1c), and diabetes duration in girls showed a significant association with cIMT. CONCLUSIONS: On the basis of sex differences of cRFs and cIMT in pediatric T1D, the assessment of sex-specific IMT percentiles facilitates a differentiated interpretation of subclinical atherosclerosis. The underlying diabetes and additional cRFs seem to be more important determinants of intima-media thickening than age. To improve the comparability of IMT measurements of relevant studies, the international harmonization of IMT measurements should be aimed for.
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Enfermedades Cardiovasculares/etiología , Grosor Intima-Media Carotídeo , Diabetes Mellitus Tipo 1/complicaciones , Adolescente , Presión Sanguínea , Arterias Carótidas/diagnóstico por imagen , Niño , Estudios Transversales , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Riesgo , Factores Sexuales , Rigidez VascularRESUMEN
BACKGROUND: To provide estimates of the nationwide prevalence of type 1 diabetes (T1D) and type 2 diabetes (T2D) in individuals younger than 20 years of age in Germany from 2002 to 2020 and to identify trends. METHODS: Data were obtained from the electronic health record "Diabetes Prospective Follow-up Registry (DPV)" specific to diabetes care. Prevalence was estimated based on prevalent cases at the end of each year for the years 2002, 2008, 2014, and 2020 per 100 000 persons assuming a Poisson distribution and directly age- and/or sex-standardized to the population in 2020. Individuals younger than 20 years of age with a clinical diagnosis of T1D or 10-19-year-olds with T2D were eligible for inclusion in the study. RESULTS: The standardized T1D prevalence per 100 000 persons was 138.9 (95% CI: 137.1; 140.6) in 2002 and 245.6 (243.1; 248.0) in 2020. The standardized T2D prevalence per 100 000 persons was 3.4 (3.1; 3.8) in 2002 and 10.8 (10.1; 11.5) in 2020. The annual percent change (APC) in prevalence declined over the three periods 2002-2008/2008-2014/2014-2020 (T1D: 6.3% [3.6%; 9.0%]/3.1% [0.7%; 5.5%]/0.5% [-1.7%; 2.85], T2D: 12.3% [5.3%; 20.8%]/4.7% [-0.6%; 10.3%]/3.0% [-1.8%; 8.0%]). From 2014 to 2020, the highest APCs were observed among 15-19-year-olds (T1D: 2.5% [1.3%; 3.6%], T2D: 3.4% [-0.5%; 7.5%]). CONCLUSIONS: The increase in diabetes prevalence has slowed, but medical care should be prepared for an increase in adolescents with diabetes.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Niño , Humanos , Adolescente , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 1/epidemiología , Prevalencia , Registros Electrónicos de Salud , Estudios Prospectivos , Alemania/epidemiología , Sistema de RegistrosRESUMEN
Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and catalyses the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine. To date, only 11 individuals have been reported suffering from a complete DHP deficiency. Here, we report on the clinical, biochemical and molecular findings of 17 newly identified DHP deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological and gastrointestinal abnormalities and markedly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in plasma, cerebrospinal fluid and urine. Analysis of DPYS, encoding DHP, showed nine missense mutations, two nonsense mutations, two deletions and one splice-site mutation. Seventy-one percent of the mutations were located at exons 5-8, representing 41% of the coding sequence. Heterologous expression of 11 mutant enzymes in Escherichia coli showed that all but two missense mutations yielded mutant DHP proteins without significant activity. Only DHP enzymes containing the mutations p.R302Q and p.T343A possessed a residual activity of 3.9% and 49%, respectively. The crystal structure of human DHP indicated that the point mutations p.R490C, p.R302Q and p.V364M affect the oligomerization of the enzyme. In contrast, p.M70T, p.D81G, p.L337P and p.T343A affect regions near the di-zinc centre and the substrate binding site. The p.S379R and p.L7V mutations were likely to cause structural destabilization and protein misfolding. Four mutations were identified in multiple unrelated DHP patients, indicating that DHP deficiency may be more common than anticipated.
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Amidohidrolasas/química , Amidohidrolasas/genética , Enfermedades Metabólicas/genética , Adolescente , Adulto , Amidohidrolasas/deficiencia , Amidohidrolasas/metabolismo , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Enfermedades Metabólicas/enzimología , Modelos Biológicos , Modelos Moleculares , Fenotipo , Estabilidad Proteica , Estructura Secundaria de Proteína , Relación Estructura-Actividad , Adulto JovenRESUMEN
OBJECTIVES: Characterization of children with type 1 diabetes (T1DM) regarding number and gender distribution of cardiovascular risk factors (cvRF) and of total cholesterol/high-density lipoprotein cholesterol ratio (TC/HDL-C ratio) for risk assessment. METHODS: 33488 patients
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Aterosclerosis/epidemiología , Diabetes Mellitus Tipo 1/epidemiología , Adolescente , Edad de Inicio , Aterosclerosis/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiología , Niño , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Estudios Transversales , Diabetes Mellitus Tipo 1/sangre , Dislipidemias/sangre , Dislipidemias/epidemiología , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipertensión/sangre , Hipertensión/epidemiología , Estudios Longitudinales , Masculino , Obesidad/sangre , Obesidad/epidemiología , Estudios Prospectivos , Factores de Riesgo , Factores Sexuales , Fumar/efectos adversos , Fumar/epidemiologíaRESUMEN
AIM: Moebius sequence is a rare condition usually defined as congenital facial paralysis with congenital impairment of ocular abduction. At present, there is little information on behavioural problems, parental stress and possible relationships between these factors. To fill this gap, this study investigated these aspects relevant for counselling. METHODS: Parents of 4-17 year old subjects known to the German Möbius syndrome foundation were anonymously asked to fill out several questionnaires, for example, the Child Behavior Checklist (CBCL)4-18. RESULTS: The primary care givers of 41/58 subjects (70.7%) sent back filled-out questionnaires. Ten subjects did not meet the inclusion criteria; 15 males and 16 females (4; 7-17; 0 years, median age: 10; 7 years) were included. Ten out of 31 subjects were rated as clinical on at least one CBCL scale; three had a total problem score in the clinical range. Social problems were the most important problems with rates of 12-17-year old subjects being about five times as high as those of younger subjects. Compared with the general population, but not with other parents of mentally and/or physically handicapped children, the primary care givers experienced higher levels of stress, which were correlated to anxious/depressed behaviour, aggressive behaviour, externalising problems and total problem score of the children. The older a child the higher the primary care giver's life satisfaction was. CONCLUSIONS: Social problems seem to be frequent among 4-17-year old subjects with Moebius sequence, and primary care givers show increased strain. Therefore, families with an affected child need early and adequate support.
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Cuidadores/psicología , Trastornos de la Conducta Infantil/psicología , Síndrome de Mobius/psicología , Padres/psicología , Trastorno de la Conducta Social/psicología , Adolescente , Niño , Preescolar , Femenino , Alemania , Humanos , Masculino , Encuestas y CuestionariosRESUMEN
OBJECTIVE: We investigated influences of a 12-h fast, age, gender, body mass index (BMI), hemoglobin A1c (HbA1c) on total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) to provide reference percentiles for TC, LDL-C, and HDL-C of patients with good diabetes control (HbA1c < 7.5%) and normal weight (BMI < 90th percentile). METHOD: A cross-sectional analysis of the diabetes documentation and quality management system using the diabetes data acquisition system for prospective surveillance (DPV) software included 29 979 patients with type 1 diabetes mellitus (T1DM) aged 1-20 yr (52.4% male) from 253 diabetes centers in Germany and Austria. RESULTS: Fasting had no relevant influence on TC, LDL-C, and HDL-C. Multivariate regression analysis revealed strongest dependences of cholesterol on gender and HbA1c followed by BMI and age. Reference cholesterol percentiles of well-controlled and normal weight patients showed TC >or=4.40 mmol/L (170 mg/dL) corresponding to the 50th percentile in females and the 75th percentile in males. LDL-C >or=2.59 mmol/L (100 mg/dL) corresponded to the 50th-75th percentile in females and the 75th percentile in males. CONCLUSIONS: (i) Fasting is no precondition for the determination of TC, LDL-C, and HDL-C; (ii) TC, LDL-C, and HDL-C are strongest associated with gender and HbA1c followed by BMI and age; (iii) Gender- and age-adjusted cholesterol percentiles of well-controlled and normal weight patients with T1DM may serve as reference values and are similar to healthy German children; and (iv) Single target values for TC, LDL-C, and HDL-C based on healthy individuals' data do not sufficiently characterize abnormal cholesterol levels in young patients with T1DM.
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Índice de Masa Corporal , Colesterol/sangre , Diabetes Mellitus Tipo 1/sangre , Ingestión de Energía , Hemoglobina Glucada/metabolismo , Adolescente , Niño , Preescolar , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 1/fisiopatología , Documentación , Ayuno , Femenino , Alemania , Humanos , Lactante , Masculino , Valores de Referencia , Caracteres Sexuales , Adulto JovenRESUMEN
Moebius sequence is a rare congenital disorder usually defined as a combination of facial weakness with impairment of ocular abduction. A strong association of Moebius sequence with autism spectrum disorders (ASDs) has been suggested in earlier studies with heterogenous age groups. The primary caregivers of all children and adolescents with Moebius sequence aged 6-17 years known to the German Moebius foundation were anonymously asked to complete two screening measures of ASD [Behavior and Communication Questionnaire (VSK); Marburger Asperger's Syndrome Rating Scale (MBAS)]. For those who reached the cut-off for ASD, well standardized diagnostic instruments (Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, WISC-III, and Kinder-DIPS) should be administered. Minimal diagnostic criteria for Moebius sequence were congenital facial weakness (uni- or bilateral) and impairment of ocular abduction (uni- or bilateral). Familiar cases should be excluded. The primary caregivers of 35/46 children and adolescents (18 males, 17 females, mean age 11.5 years) sent back completed questionnaires, but only 27 subjects met inclusion criteria. According to the primary caregivers, none of these subjects showed mental retardation. Two probands (both males 9 and 16 years old) reached the cut-off of the MBAS whereas the results of the VSK did not indicate ASDs in any of the patients. The 9 year old boy could be examined personally and did not meet diagnostic criteria of ASD. ASDs might be not as frequent as reported in previous studies on patients with Moebius sequence, at least not in patients without mental retardation.
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Trastornos Generalizados del Desarrollo Infantil/complicaciones , Trastornos Generalizados del Desarrollo Infantil/diagnóstico , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico , Síndrome de Mobius/complicaciones , Adolescente , Niño , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Selección de Paciente , Escalas de Valoración Psiquiátrica , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To investigate handicap-related problems of children and adolescents with 22q11.2 deletion syndrome and their primary caregivers' coping strategies. METHOD: Primary caregivers of 153 subjects aged 2-16 years were anonymously asked to fill out questionnaires, e.g., the Handicap Related Problems for Parents Inventory. RESULTS: Primary caregivers of 96 subjects (53 males, 43 females; mean age: 7;0 [2;1-16;11] years) sent back questionnaires. Patient's behaviour and discipline were the most important handicap-related problems. Significant correlations could be found between the patient's age and his/her relationship with the primary caregiver (rho=0.228; p=.029) and other family members (rho=0.293; p=.004). Compared to other parents of physically handicapped children or those with multiple handicaps, these parents did not experience increased stress. The more the coping strategies "self-fulfillment" and "intensification of partnership" were used, the lower parental stress was (p=.012, p=.025, respectively). "Focusing on the handicapped child" was positively correlated with high parental stress (p=.000). CONCLUSIONS: With regard to parental stress and coping strategies, primary caregivers of children and adolescents with 22q11.2 deletion do not significantly differ from other parents of physically handicapped children. As handicap-related family problems increase with the patient's age, a growing need for counseling, especially for aspects of parenting and discipline, and for treatment can be presumed.
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Anomalías Múltiples/genética , Adaptación Psicológica , Cuidadores/psicología , Trastornos de la Conducta Infantil/genética , Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Costo de Enfermedad , Niños con Discapacidad/psicología , Anomalías Múltiples/psicología , Adolescente , Niño , Trastornos de la Conducta Infantil/diagnóstico , Trastornos de la Conducta Infantil/psicología , Preescolar , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/psicología , Femenino , Humanos , Masculino , Determinación de la Personalidad/estadística & datos numéricos , Fenotipo , Psicometría , Calidad de Vida/psicología , Grupos de Autoayuda , Ajuste SocialRESUMEN
BACKGROUND: 22q11.2 deletion syndrome can be associated with a variety of somatic symptoms, developmental delays and psychiatric disorders. At present, there is little information on behaviour problems, parental stress and possible relations between these factors. Therefore, this study investigates behaviour problems of children and adolescents with 22q11.2DS, and their primary caregivers' stress. METHODS: Parents of 4-17 year old subjects known to the German 22q11.2 deletion syndrome foundation were anonymously asked to fill out several questionnaires, e.g. the Child Behavior Checklist 4-18 (CBCL/4-18). RESULTS: The primary caregivers of 77/126 children [43 males, 34 females, mean age: 8;0 (4;0-16;11) years] sent back filled-out questionnaires. Forty-six of 76 subjects were rated as clinical on at least one of the CBCL-scales. Males had significantly higher scores on the total problems scale and the internalizing problems scale than females. The patients' age correlated with several CBCL-scales. Eleven of 49 subjects were suspicious of an autism spectrum disorder. Compared with the general population, but not with other parents of mentally and/or physically handicapped children, the primary caregivers experienced higher levels of stress, but showed normal life satisfaction. CONCLUSIONS: In spite of high rates of clinical behaviour problems among children and adolescents with 22q11.2DS and despite increased parental stress, most primary caregivers seem to have effective coping strategies, e.g. partnership support, to sustain normal levels of life satisfaction.
Asunto(s)
Trastornos de la Conducta Infantil/psicología , Síndrome de DiGeorge/psicología , Relaciones Padres-Hijo , Estrés Psicológico/etiología , Adaptación Psicológica , Adolescente , Cuidadores/psicología , Niño , Trastornos de la Conducta Infantil/epidemiología , Preescolar , Síndrome de DiGeorge/epidemiología , Femenino , Alemania/epidemiología , Humanos , Masculino , Padres/psicología , Satisfacción Personal , Estrés Psicológico/epidemiología , Encuestas y CuestionariosRESUMEN
Selenium-binding protein 1 (SELENBP1) has been associated with several cancers, although its exact role is unknown. We show that SELENBP1 is a methanethiol oxidase (MTO), related to the MTO in methylotrophic bacteria, that converts methanethiol to H2O2, formaldehyde, and H2S, an activity not previously known to exist in humans. We identified mutations in SELENBP1 in five patients with cabbage-like breath odor. The malodor was attributable to high levels of methanethiol and dimethylsulfide, the main odorous compounds in their breath. Elevated urinary excretion of dimethylsulfoxide was associated with MTO deficiency. Patient fibroblasts had low SELENBP1 protein levels and were deficient in MTO enzymatic activity; these effects were reversed by lentivirus-mediated expression of wild-type SELENBP1. Selenbp1-knockout mice showed biochemical characteristics similar to those in humans. Our data reveal a potentially frequent inborn error of metabolism that results from MTO deficiency and leads to a malodor syndrome.
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Halitosis/genética , Oxidorreductasas/genética , Proteínas de Unión al Selenio/genética , Animales , Pruebas Respiratorias , Línea Celular , Células Cultivadas , Dimetilsulfóxido/sangre , Dimetilsulfóxido/líquido cefalorraquídeo , Dimetilsulfóxido/orina , Halitosis/enzimología , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Proteínas de Unión al Selenio/deficiencia , Proteínas de Unión al Selenio/metabolismoRESUMEN
OBJECTIVE: The aim of this data analysis was to ascertain the type and prevalence rate as well as age and sex distribution of cardiovascular risk factors in type 1 diabetic patients up to 26 years of age. RESEARCH DESIGN AND METHODS: Cardiovascular risk factors such as obesity, hypertension, dyslipidemia, poor glycemic control, and smoking were analyzed in 27,358 patients who were divided into three groups (prepubertal, pubertal, and adult) using specifically designed diabetes software for prospective disease documentation. RESULTS: More than half of the patients per age-group had at least one cardiovascular risk factor. Two risk factors were age dependently found in 6.2-21.7% and three or four risk factors in 0.5-4.7%. Elevated values of HbA(1c), total cholesterol, and BMI were found most frequently. Hypertension, smoking, and HDL cholesterol were observed more frequently in males, and elevated BMI, total cholesterol, and LDL cholesterol more often in females. Although 28.6% of the patients had dyslipidemia, merely 0.4% of them received medical treatment, and of the 8.1% of the patients with hypertension, only 2.1% of them were given antihypertensive medication. CONCLUSIONS: With increasing age, a greater number of patients with cardiovascular risk factors were observed. Significant sex differences were seen in the majority of risk factors. Despite the high prevalence of risk factors, only a small minority of patients received antihypertensive or lipid-lowering treatment. Early identification, prevention, and treatment of additional risk factors seem to be necessary, particularly in light of the high incidence of future cardiovascular disease.
Asunto(s)
Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 1/epidemiología , Dislipidemias/complicaciones , Hipertensión/complicaciones , Obesidad/complicaciones , Fumar/epidemiología , Adolescente , Adulto , Distribución por Edad , Austria/epidemiología , Índice de Masa Corporal , Enfermedades Cardiovasculares/etiología , Niño , Preescolar , Colesterol/sangre , Estudios Transversales , Dislipidemias/epidemiología , Femenino , Alemania/epidemiología , Hemoglobina Glucada , Humanos , Hipertensión/epidemiología , Lactante , Estudios Longitudinales , Masculino , Análisis Multivariante , Obesidad/epidemiología , Vigilancia de la Población , Prevalencia , Sistema de Registros , Factores de RiesgoRESUMEN
Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle defect. The clinical presentation in female manifesting carriers varies both in onset and severity. We report on a female with insulin dependent diabetes mellitus and recurrent episodes of hyperammonemia. Since OTC activity measured in a liver biopsy sample was within normal limits, OTC deficiency was initially excluded from the differential diagnoses of hyperammonemia. Due to moderately elevated homocitrulline excretion, hyperornithinemia-hyperammonemia-homocitrullinuria-syndrome was suggested, but further assays in fibroblasts showed normal ornithine utilization. Later, when mutation analysis of the OTC gene became available, a known pathogenic missense mutation (c.533C>T) in exon 5 leading to an exchange of threonine-178 by methionine (p.Thr178Met) was detected. Skewed X-inactivation was demonstrated in leukocyte DNA. In the further clinical course the girl developed marked obesity. By initiating physical activities twice a week, therapeutic control of both diabetes and OTC deficiency improved, but obesity persisted. In conclusion, our case confirms that normal hepatic OTC enzyme activity measured in a single liver biopsy sample does not exclude a clinical relevant mosaic of OTC deficiency because of skewed X-inactivation. Mutation analysis of the OTC gene in whole blood may be a simple way to establish the diagnosis of OTC deficiency. The joint occurrence of OTC deficiency and diabetes in a patient has not been reported before.
RESUMEN
BACKGROUND: Despite its first description over 40 years ago, knowledge of the clinical course of isovaleric acidemia (IVA), a disorder predisposing to severe acidotic episodes during catabolic stress, is still anecdotal. We aimed to investigate the phenotypic presentation and factors determining the neurological and neurocognitive outcomes of patients diagnosed with IVA following clinical manifestation. METHODS: Retrospective data on 21 children and adults with symptomatic IVA diagnosed from 1976 to 1999 were analyzed for outcome determinants including age at diagnosis and number of catabolic episodes. Sixteen of 21 patients were evaluated cross-sectionally focusing on the neurological and neurocognitive status. Additionally, 155 cases of patients with IVA published in the international literature were reviewed and analyzed for outcome parameters including mortality. RESULTS: 57% of study patients (12/21) were diagnosed within the first weeks of life and 43% (9/21) in childhood. An acute metabolic attack was the main cause of diagnostic work-up. 44% of investigated study patients (7/16) showed mild motor dysfunction and only 19% (3/16) had cognitive deficits. No other organ complications were found. The patients' intelligence quotient was not related to the number of catabolic episodes but was inversely related to age at diagnosis. In published cases, mortality was high (33%) if associated with neonatal diagnosis, following manifestation at an average age of 7 days. CONCLUSIONS: Within the group of "classical" organic acidurias, IVA appears to be exceptional considering its milder neuropathologic implications. The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening.
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Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/patología , Trastornos Psicomotores/complicaciones , Adolescente , Adulto , Envejecimiento , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual , Isovaleril-CoA Deshidrogenasa/deficiencia , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine metabolism caused by mutations in MCCC1 or MCCC2 encoding the α and ß subunit of MCC, respectively. The phenotype is highly variable ranging from acute neonatal onset with fatal outcome to asymptomatic adults. METHODS: We report clinical, biochemical, enzymatic and mutation data of 88 MCC deficient individuals, 53 identified by newborn screening, 26 diagnosed due to clinical symptoms or positive family history and 9 mothers, identified following the positive newborn screening result of their baby. RESULTS: Fifty-seven percent of patients were asymptomatic while 43% showed clinical symptoms, many of which were probably not related to MCC deficiency but due to ascertainment bias. However, 12 patients (5 of 53 identified by newborn screening) presented with acute metabolic decompensations. We identified 15 novel MCCC1 and 16 novel MCCC2 mutant alleles. Additionally, we report expression studies on 3 MCCC1 and 8 MCCC2 mutations and show an overview of all 132 MCCC1 and MCCC2 variants known to date. CONCLUSIONS: Our data confirm that MCC deficiency, despite low penetrance, may lead to a severe clinical phenotype resembling classical organic acidurias. However, neither the genotype nor the biochemical phenotype is helpful in predicting the clinical course.