Elo J.M.,Research Programs Unit |
Yadavalli S.S.,Ohio State University |
Euro L.,Research Programs Unit |
Isohanni P.,Research Programs Unit |
And 16 more authors.
Human Molecular Genetics | Year: 2012
Next-generation sequencing has turned out to be a powerful tool to uncover genetic basis of childhood mitochondrial disorders. We utilized whole-exome analysis and discovered novel compound heterozygous mutations in FARS2 (mitochondrial phenylalanyl transfer RNA synthetase), encoding the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) in two patients with fatal epileptic mitochondrial encephalopathy. The mutations affected highly conserved amino acids, p.I329T and p.D391V. Recently, a homozygous FARS2 variant p.Y144C was reported in a Saudi girl with mitochondrial encephalopathy, but the pathogenic role of the variant remained open. Clinical features, including postnatal onset, catastrophic epilepsy, lactic acidemia, early lethality and neuroimaging findings of the patients with FARS2 variants, resembled each other closely, and neuropathology was consistent with Alpers syndrome. Our structural analysis of mtPheRS predicted that p.I329T weakened ATP binding in the aminoacylation domain, and in vitro studies with recombinant mutant protein showed decreased affinity of this variant to ATP. Furthermore, p.D391V and p.Y144C were predicted to disrupt synthetase function by interrupting the rotation of the tRNA anticodon stem-binding domain from a closed to an open form. In vitro characterization indicated reduced affinity of p.D391V mutant protein to phenylalanine, whereas p.Y144C disrupted tRNA binding. The stability of p.I329T and p.D391V mutants in a refolding assay was impaired. Our results imply that the three FARS2 mutations directly impair aminoacylation function and stability of mtPheRS, leading to a decrease in overall tRNA charging capacity. This study establishes a new genetic cause of infantile mitochondrial Alpers encephalopathy and reports a new mitochondrial aminoacyl-tRNA synthetase as a cause of mitochondrial disease. © The Author 2012. Published by Oxford University Press. All rights reserved.
Huppke P.,University of Gottingen |
Rostasy K.,Innsbruck Medical University |
Karenfort M.,Heinrich Heine University Düsseldorf |
Huppke B.,University of Gottingen |
And 4 more authors.
Multiple Sclerosis Journal | Year: 2013
Background: Some pediatric patients with inflammatory demyelinating central nervous system disorders cannot be classified under any of the established disease entities, making their treatment and prognosis difficult. Objective: The objective of this study is to characterize a subgroup of pediatric patients with recurrent demyelinating central nervous system disorders. Methods: This study includes a case series of pediatric patients with monophasic or recurrent acute disseminated encephalomyelitis (ADEM) who later presented with either monophasic or recurrent optic neuritis (ON). Results: We describe seven patients with a median follow-up of six years (five females, two males) who presented at a median age of 6 years (range 4-8 years) with monophasic (n = 4) or recurrent ADEM (two to four attacks) followed by monophasic (n = 3) or recurrent ON (two to nine attacks). Cranial magnetic resonance imaging (MRI) was typical for ADEM (n = 6) with complete or almost complete resolution of lesions on follow-up. Cerebrospinal (CSF) studies at the time of ADEM showed a pleocytosis in six patients and were negative for oligoclonal bands (OCBs) in all. In all patients high titers for serum anti-MOG antibodies were detected. Conclusion: ADEM followed by ON is a rare but distinct clinical phenotype among pediatric patients. Further studies are needed to allow recommendations on treatment or prognosis. © The Author(s) 2012.
Scheuing N.,University of Ulm |
Bartus B.,Olgahospital Stuttgart |
Berger G.,Medical University of Vienna |
Haberland H.,Hospital for Children and Adolescents |
And 6 more authors.
Diabetes Care | Year: 2014
OBJECTIVE To compare clinical characteristics and outcome of type 1 diabetes mellitus (T1DM) between patients with and without a clinically recognized eating disorder (ED). RESEARCH DESIGN AND METHODS A total of 52,215 T1DM patients aged 8 to lt 30 years from the prospective diabetes data acquisition system DPV were analyzed. A total of 467 patients had an additional diagnosis of ED according to DSM-IV criteria (anorexia nervosa [AN], n = 141 [female: 94.3%]; bulimia nervosa [BN], n = 62 [90.3%]; and EDs not otherwise specified, including binge-eating disorder [EDNOS], n = 264 [74.2%]). Groups were compared using multivariable regression. Cox proportional hazard ratios were calculated for the association between ED and retinopathy. RESULTS After adjustment for age, sex, and duration of diabetes, patients with ED revealed higher HbA1c (no ED vs. AN, BN, or EDNOS, respectively: 8.29 ± 0.01% [67.1 ± 0.1 mmol/mol] vs. 8.61 ± 0.15% [70.6 ± 1.6 mmol/mol], 9.11 ± 0.23% [76.1 ± 2.5 mmol/mol], or 9.00 ± 0.11% [74.9 ± 1.2 mmol/mol]) and a higher rate of pathological insulin injection sites (48.4 vs. 64.3, 64.1, or 62.1%). Furthermore, ketoacidosis (5.7±0.1 vs. 12.1±2.1, 18.0±4.1, or 12.9±1.6 events per 100 person-years) and hospitalization (54.9 ± 0.3 vs. 89.3 ± 6.0, 132.0 ± 12.7, or 91.0 ± 4.4 per 100 person-years) were more common, and duration of hospital stay was longer (4.81 ± 0.01 vs. 11.31 ± 0.21, 18.05 ± 0.48, or 8.44 ± 0.13 days per year). All P values were 0.05. Patients with BN and EDNOS had a 2.5-fold (95% CI 1.3-4.8) and a 1.4-fold (0.8-2.3) higher risk for retinopathy, whereas AN patients had no increased risk (0.9 [95% CI 0.4-2.3]). CONCLUSIONS Diabetes health care professionals should be aware of comorbid EDs in pediatric/ young-adult T1DM patients. An ED diagnosis is associated with worse metabolic control and higher rates of diabetes complications. © 2014 by the American Diabetes Association.
Makitalo L.,University of Helsinki |
Kolho K.-L.,Hospital for Children and Adolescents |
Karikoski R.,University of Helsinki |
Anthoni H.,University of Helsinki |
And 2 more authors.
Scandinavian Journal of Gastroenterology | Year: 2010
Objective. The differential diagnosis of chronic colitis in inflammatory bowel disease (IBD) is challenging and a distinction between Crohn's disease (CD) and ulcerative colitis (UC) is not always possible. Matrix metalloproteinases (MMPs) cleave components of the extracellular matrix and their dysregulation leads to damage to the mucosa. They are involved in inflammation in IBD, as well as in eventual tissue repair. We aimed to examine putative differences in the profiles of MMPs and their tissue inhibitors [tissue inhibitors of metalloproteinase (TIMPs)] in pediatric IBD to find better tools for differential diagnosis of various IBD subgroups at the tissue level in the colon. Material and methods. Expression of MMPs -1, -7, -8, -9, -10, -12 and -26 and TIMPs -1 and -3 was studied by immunohistochemistry in colonic tissue samples of 32 pediatric patients with IBD and 11 non-IBD cases. Results. In the colon, expression of MMP-7 in epithelium was greater in CD samples compared to UC samples (1.09 versus 0.33; P = 0.010). Furthermore, epithelial MMP-10 expression was elevated in CD and UC samples compared to non-IBD samples (1.55 versus 1.00; P = 0.041 and 1.58 versus 1.00; P = 0.025, respectively). TIMP-3 expression in the stroma was higher in both the CD and UC groups when compared to non-IBD samples (2.18 versus 1.36; P = 0.026 and 2.50 versus 1.36; P = 0.002, respectively), but differences between UC and CD could not be observed. Conclusions. Increased expression of epithelial MMP-10 and stromal TIMP-3 could serve as histological indicators of IBD etiology. Epithelial MMP-7 expression, on the other hand, could help to differentiate between CD-related colitis and UC. © 2010 Informa UK Ltd.
Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology
Gnekow A.K.,Hospital for Children and Adolescents |
Falkenstein F.,Hospital for Children and Adolescents |
Von Hornstein S.,Hospital for Children and Adolescents |
Zwiener I.,Johannes Gutenberg University Mainz |
And 9 more authors.
Neuro-Oncology | Year: 2012
The Hirntumorstudien (HIT)-LGG-1996 protocol offered a comprehensive treatment strategy for pediatric patients with low-grade glioma (LGG), ie, observation, surgery, adjuvant radiotherapy, and chemotherapy to defer the start of irradiation in young children. In this current study, we sought to determine clinical factors for progression and survival. Between October 1, 1996 and March 31, 2004, 1031 patients were prospectively recruited into an observation arm (n 668) and a nonsurgical arm stratifying 12 months of vincristine- carboplatin chemotherapy (n 216) and conventional radiotherapy/brachytherapy (n 147) in an age-dependent manner. Median patient age was 6.9 years; 28 patients had diencephalic syndrome, 44 had dissemination, and 108 had neurofibromatosis type 1(NF-1). Main tumor location was the supratentorial midline (40.4), and the main histology was pilocytic astrocytoma (67.9). Following a median observation of 9.3 years, 10-year overall survival (OS) was 0.94 and 10-year event-free survival (EFS) was 0.47. Ten-year progression-free survival was 0.62 following radiotherapy and 0.44 following chemotherapy. Sixty-one of 216 chemotherapy patients received radiotherapy 0.38.7 years after initial diagnosis. By multivariate analysis, diencephalic syndrome and incomplete resection were found to be unfavorable factors for OS and EFS, age <11 years for OS, and supratentorial midline location for EFS. Dissemination, age <1 year, and nonpilocytic histology were unfavorable factors for progression following radiotherapy (138 patients); and diencephalic syndrome, dissemination, and age <11 years were unfavorable factors following chemotherapy (210 patients). NF-1 patients and boys experienced prolonged tumor stabilization with chemotherapy. A nationwide multimodal treatment strategy is feasible for pediatric LGG. Extended follow-up yielded results comparable to single-institution series for the treatment groups. Three-quarters of surviving chemotherapy patients have not yet received radiation therapy. Infants with or without diencephalic syndrome and dissemination bear the highest risk for death and progression following diagnosis or treatment. © The Author(s) 2012. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.
Poyhi T.,Helsinki Medical Imaging Center |
Lamminen A.,Helsinki Medical Imaging Center |
Peltonen J.,Hospital for Children and Adolescents |
Willamo P.,University of Helsinki |
Nietosvaara Y.,Hospital for Children and Adolescents
Acta Orthopaedica | Year: 2011
Background Many children with permanent brachial plexus birth injury (BPBI) develop shoulder problems, with subsequent joint deformity without treatment. We assessed the indications and outcome of shoulder operations for BPBI. Patients and methods 31 BPBI patients who had undergone a shoulder operation in our hospital between March 2002 and December 2005 were included in the study. Relocation of the humeral head had been performed in 13 patients, external rotation osteotomy of the humerus in 5 patients, subscapular tendon lengthening in 5 patients, and teres major transposition in 8 patients. Subjective results were registered. Shoulder range of motion was measured, and function assessed according to the Mallet scale. Magnetic resonance imaging (MRI) was performed pre-and postoperatively. Glenoscapular angle (GSA) and percentage of humeral head anterior to the middle of the glenoid fossa (PHHA) were measured. Congruency of the glenohumeral joint (GHJ) was estimated. The mean follow-up time was 3.8 (1.76.8) years. Results At follow-up, the subjective result was satisfactory in 30 of the 31 patients. There were 4 failures, which in retrospect were due to wrong choice of surgical method in 3 of these 4 patients. Mean increase in Mallet score was 5.5 after successful relocation, 1.4 after rotation osteotomy, 2.2 after subscapular tendon lengthening, and 3.1 after teres major transposition. Congruency of the shoulder joint improved in 10 of 13 patients who had undergone a relocation operation, with mean improvement in GSA of 33 and mean increase in PHHA of 25%. There were no substantial changes in congruency of the glenohumeral joint in patients treated with other operation types. Interpretation Restriction of the range of motion and malposition of the glenohumeral joint can be improved surgically in brachial plexus birth injury. Remodeling of the joint takes place after successful relocation of the humeral head in young patients. © 2011 Nordic Orthopaedic Federation.
Sistonen S.,Hospital for Children and Adolescents |
Sistonen S.,Paijat Hame Central Hospital |
Malmberg P.,University of Helsinki |
Malmstrom K.,University of Helsinki |
And 4 more authors.
European Respiratory Journal | Year: 2010
Although after oesophageal atresia (OA) repair in infancy, respiratory problems are common, their natural history remains unclear. We assessed morbidity, pulmonary function (PF), and bronchial hyperresponsiveness (BHR) in adults with repaired OA respiratory. 588 patients who underwent surgery for OA during 1947-1985 were identified and those 262 who were alive and had their native oesophagus were included. Respiratory symptoms and respiratory symptom-related quality of life (RSRQoL) were assessed by questionnaire and interview, and the patients underwent spirometry, a histamine challenge test, and an exhaled nitric oxide test. For the questionnaires, we added 287 carefully matched general population-derived controls. Among the 101 (58 male) patients, median age 36 yrs (range 22-56 yrs), respiratory morbidity was significantly increased compared to controls. Patients had more respiratory symptoms and infections, as well as asthma and allergies, and more often impaired RSRQoL (p<0.001 for all). PF tests revealed restrictive ventilatory defect in 21 (21%) patients, obstructive ventilatroy defect in 21 (21%) patients, and both in 36 (36%) patients. A total of 41 (41%) had BHR, and in 15 (15%), it was consistent with asthma. The most significant risk factors for restrictive ventilatory defect were thoracotomy-induced rib fusions (OR 3.4, 95% CI 1.3-8.7; p=0.01) and oesophageal epithelial metaplasia (OR 3.0, 95% CI 1.0-8.9; p=0.05). After repair of OA, respiratory-related morbidity, restrictive ventilatory defect and BHR extended into adulthood. Nearly half the patients had BHR and over half had a restrictive ventilatory defect. Thoracotomy-induced rib fusions and gastro-oesophageal reflux-associated oesophageal epithelial metaplasia were the strongest risk factors for restrictive ventilatory defect. Copyright©ERS 2010.
Sandini U.,Hospital for Children and Adolescents |
Kukkonen A.K.,University of Helsinki |
Poussa T.,Nokia Inc. |
Sandini L.,Hospital for Children and Adolescents |
And 2 more authors.
International Archives of Allergy and Immunology | Year: 2011
Background: Environmental and lifestyle factors such as breast-feeding and pets seem to affect atopic disease prevalence. We identified risk factors for allergic diseases. Methods: We prospectively followed until the age of 5 years a cohort of 1,223 children born into allergic families, who participated in a randomized placebo-controlled trial of probiotics as preventive against allergic disease. We evaluated the cumulative incidence of allergic diseases with questionnaires and examined all children at the ages of 2 and 5 years. Results: Compared to allergy in one parent only, allergy in both parents conferred an increased risk of allergic disease at the ages of 2 (OR 1.64; 95% CI 1.11-2.42, p = 0.013) and 5 (OR 1.83; 95% CI 1.24-2.70, p = 0.002) and at the age of 2 for eczema (OR 1.74; 95% CI 1.17-2.58, p = 0.006). Exclusive breast-feeding over 2 months elevated the risk of eczema at the ages of 2 (OR 1.73; 95% CI 1.15-2.61, p = 0.009) and 5 (OR 1.51; 95% CI 1.03-2.23, p = 0.036). Cat or dog exposure at 0-2 years and at 0-5 years protected against IgE sensitization until 5 years of age (OR 0.60; 95% CI 0.37-1.00, p = 0.048, and OR 0.61; 95% CI 0.39-0.96, p = 0.033), and exposure at the ages of 0-5 years protected against allergic rhinitis until the age of 5 (OR 0.46; 95% CI 0.25-0.85, p = 0.013) in the probiotic group. Conclusions: Allergy in both parents is an independent predictor of eczema and of allergic disease until the ages of 2 and 5. Long, exclusive breast-feeding was associated with increased eczema at the ages of 2 and 5, and cat or dog exposure was associated with decreased IgE sensitization and allergic rhinitis in the probiotic group. Copyright © 2011 S. Karger AG, Basel.
Ylanen K.,University of Tampere |
Poutanen T.,University of Tampere |
Hiippala A.,Hospital for Children and Adolescents |
Swan H.,University of Helsinki |
Korppi M.,University of Tampere
European Journal of Pediatrics | Year: 2010
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder that causes syncopal episodes related with stress or emotion and even sudden cardiac deaths. Signs and symptoms usually begin in childhood. A suspicion of CPVT should be kept in mind when a child or an adolescent suddenly loses consciousness, particularly if this happens upon physical exercise or sudden mental stress. During the past decade, the knowledge of CPVT genetics and physiology has increased. Exercise testing is essential when suspecting arrhythmogenic origin of syncope, and in the case of CPVT, it may be even more sensitive than Holter monitoring. Beta-antiadrenergic medication can substantially decrease the mortality associated with CPVT. Asymptomatic patients with known CPVT gene defects should also be treated because sudden cardiac death may be the first manifestation of the disease. An implantable cardioverter-defibrillator may also be required in the most severe CPVT cases. In this review, we summarise the current knowledge on the clinical characteristics, diagnostic, genetic and prognostic features of CPVT in children. In all, 133 publications covering 60 years were checked, and those written in English and containing ten or more, mainly paediatric CPVT cases, were included. In addition, a CPVT family with three members and delayed diagnoses until late childhood and adulthood is presented. © 2010 Springer-Verlag.
Kapellen T.,University of Leipzig |
Vogel C.,Hospital for Children and Adolescents |
Telleis D.,University of Leipzig |
Siekmeyer M.,University of Leipzig |
Kiess W.,University of Leipzig
Experimental and Clinical Endocrinology and Diabetes | Year: 2012
Aims: Diabetic ketoacidosis (DKA) is still the most dangerous acute complication in type 1 diabetes. The aim of this study was to compare treatment of DKA with a regimen of a low insulin dose (0.025 units/kg/h) vs. a standard insulin dose (0.1 units/kg/h). Methods: We retrospectively analysed all cases of children and adolescents (age 0-18 years) with type 1 diabetes and DKA who needed treatment in the ICU in the time period of 1998-2005 in 2 pediatric diabetes centers. In a chart review of the first 48 h after onset of DKA the following parameters where evaluated: pH, blood glucose, sodium, potassium, and ketones in urine. Consciousness, neurological status and complications such as cerebral edema, hypoglycaemia or hypokalemia were also recorded. Results: 23 children were treated in center A (low insulin dose) whereas 41 where treated in center B (standard insulin dose). Mean age of the patients was 8.9 (range 1.58-17.7) and 13.5 years (1.25-17.7) respectively (p=0.134). Mean pH was 7.1 and HCO3 was 9.05 and 7.79 respectively (p=0.122). Initial blood glucose was 26 mmol/l (no difference between the 2 centres). Treatment with the standard insulin dose resulted in a slightly shorter duration of acidosis (8 h in center A, 6.5 h in center B) and a significantly faster normalization of blood glucose (18 h in A, vs. 10.5 h in B) (p<0.005). During the first day we found similar and very low rates of hypoglycaemia. In center B one case of suspected cerebral edema and cerebral infarction occurred. Conclusions: Low dose insulin substitution is as safe as the recommended standard dose in respect to the occurrence of acute complications. Acidosis is broken slightly earlier with the standard dose. Implications of this earlier normalisation of pH remain unclear. © Georg Thieme Verlag KG Stuttgart · New York.