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Heng H.S.,Evelina Childrens Hospital | Heng H.S.,Institute of Paediatrics | Lim M.,Evelina Childrens Hospital | Absoud M.,Evelina Childrens Hospital | And 7 more authors.
Neuromuscular Disorders

Most evidence supporting the benefit of thymectomy in juvenile myasthenia gravis (JMG) is extrapolated from adult studies, with only little data concerning paediatric populations. Here we evaluate the outcome of children with generalized JMG who underwent thymectomy between 1996 and 2010 at 2 tertiary paediatric neurology referral centres in the United Kingdom. Twenty patients (15 female, 5 male), aged 13. months to 15.5. years (median 10.4. years) at disease onset, were identified. Prior to thymectomy, disease severity was graded as IIb in 3, III in 11, and IV in 6 patients according to the Osserman classification. All demonstrated positive anti-acetylcholine receptor (AChR) antibody titres. All patients received pyridostigmine and 14 received additional steroid therapy. Transternal thymectomy was performed at the age of 2.7-16.6. years (median 11.1. years). At the last follow-up (10. months to 10.9. years, median 2.7. years, after thymectomy), the majority of children demonstrated substantial improvement, although some had required additional immune-modulatory therapies. About one third achieved complete remission. The postoperative morbidity was low. No benefit was observed in one patient with thymoma. We conclude that thymectomy should be considered as a treatment option early in the course of generalised AChR antibody-positive JMG. © 2013 Elsevier B.V. Source

Wijlaars L.P.M.M.,University College London | Hardelid P.,University College London | Woodman J.,University College London | Allister J.,Clinical Innovation and Research | And 2 more authors.
Archives of Disease in Childhood

Objective To examine the contribution of recurrent admissions to the high rate of emergency admissions among children and young people (CYP) in England, and to what extent readmissions are accounted for by patients with chronic conditions. Design All hospital admissions to the National Health Service (NHS) in England using hospital episode statistics (HES) from 2009 to 2011 for CYP aged 0-24 years. We followed CYP for 2 years from discharge of their first emergency admission in 2009. We determined the number of subsequent emergency admissions, time to next admission, length of stay and the proportion of injury and chronic condition admissions measured by diagnostic codes in all following admissions. Results 869 895 children had an index emergency admission in 2009, resulting in a further 939 710 admissions (of which 600 322, or 64%, were emergency admissions) over the next 2 years. After discharge from the index admission, 32% of 274,986 (32%) children were readmitted within 2 years, 26% of these readmissions occurring within 30 days of discharge. Recurrent emergency admission accounted for 41% of all emergency admissions in the 2-year cohort and 66% of inpatient days. 41% of index admissions, but 76% of the recurrent emergency admissions, were in children with a chronic condition. Conclusions Recurrent admissions contribute substantially to total emergency admissions. They often occur soon after discharge, and disproportionately affect CYP with chronic conditions. Policies aiming to discourage readmissions should consider whether they could undermine necessary inpatient care for children with chronic conditions. Source

Voermans N.C.,Radboud University Nijmegen | Jungbluth H.,Evelinas Children Hospital | Aronica E.,Academic Medical Center Amsterdam | Monnier N.,Grenoble University Hospital Center | And 3 more authors.
Neuromuscular Disorders

In 1977 Wijngaarden et al. reported a Dutch family with a congenital myopathy characterized by external ophthalmoplegia and a remarkable histological feature, focal loss of cross-striations. A small number of other families with similar clinical and pathological features led to the consideration of this congenital myopathy as a distinct entity. Here we present more than 30. years of follow-up from the Dutch family and report recently identified compound heterozygous mutations in the skeletal muscle ryanodine receptor (RYR1) gene, c.10627-2A>G and p.Arg3539His (c.10616G>A). Focal loss of cross-striations on muscle biopsy is another histopathological feature that should raise the possibility of RYR1 involvement. © 2012 Elsevier B.V. Source

Ebrahimi-Fakhari D.,University of Heidelberg | Saffari A.,University of Heidelberg | Wahlster L.,Heidelberg University | Lu J.,Harvard University | And 4 more authors.
Brain : a journal of neurology

Single gene disorders of the autophagy pathway are an emerging, novel and diverse group of multisystem diseases in children. Clinically, these disorders prominently affect the central nervous system at various stages of development, leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration, among others. Frequent early and severe involvement of the central nervous system puts the paediatric neurologist, neurogeneticist, and neurometabolic specialist at the forefront of recognizing and treating these rare conditions. On a molecular level, mutations in key autophagy genes map to different stages of this highly conserved pathway and thus lead to impairment in isolation membrane (or phagophore) and autophagosome formation, maturation, or autophagosome-lysosome fusion. Here we discuss 'congenital disorders of autophagy' as an emerging subclass of inborn errors of metabolism by using the examples of six recently identified monogenic diseases: EPG5-related Vici syndrome, beta-propeller protein-associated neurodegeneration due to mutations in WDR45, SNX14-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome, and three forms of hereditary spastic paraplegia, SPG11, SPG15 and SPG49 caused by SPG11, ZFYVE26 and TECPR2 mutations, respectively. We also highlight associations between defective autophagy and other inborn errors of metabolism such as lysosomal storage diseases and neurodevelopmental diseases associated with the mTOR pathway, which may be included in the wider spectrum of autophagy-related diseases from a pathobiological point of view. By exploring these emerging themes in disease pathogenesis and underlying pathophysiological mechanisms, we discuss how congenital disorders of autophagy inform our understanding of the importance of this fascinating cellular pathway for central nervous system biology and disease. Finally, we review the concept of modulating autophagy as a therapeutic target and argue that congenital disorders of autophagy provide a unique genetic perspective on the possibilities and challenges of pathway-specific drug development. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com. Source

Dafsari H.S.,Evelinas Children Hospital | Byrne S.,Evelinas Children Hospital | Lin J.-P.,Evelinas Children Hospital | Pitt M.,Great Ormond Street Hospital for Children | And 4 more authors.
American Journal of Medical Genetics, Part A

Goldberg-Shprintzen megacolon syndrome (GOSHS) (OMIM 609460) is characterized by a combination of learning difficulties, characteristic dysmorphic features and Hirschsprung's disease. Variable clinical features include iris coloboma, congenital heart defects and central nervous system abnormalities, in particular polymicrogyria. GOSHS has been attributed to recessive mutations in KIAA1279, encoding kinesin family member (KIF)-binding protein (KBP) with a crucial role in neuronal microtubule dynamics. Here we report on a 7-year-old girl with GOSHS as a result of a homozygous deletion of exons 5 and 6 of the KIAA1279 gene. She had been referred with the suspicion of an underlying neuromuscular disorder before the genetic diagnosis was established, prompted by the findings of motor developmental delay, hypotonia, ptosis and absent reflexes. Neurophysiological studies revealed unequivocal evidence of a peripheral axonal sensory motor neuropathy. We hypothesize that an axonal sensory motor neuropathy may be part of the phenotypical spectrum of KIAA1279-related GOSHS, probably reflecting the effects of reduced KBP protein expression on peripheral neuronal function. © 2015 Wiley Periodicals, Inc. Source

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