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Shorvon S.D.,University College London | Andermann F.,McGill University | Andermann F.,Montreal Neurological Institute | Guerrini R.,University of Florence | Guerrini R.,Pediatric Neurology Unit and Laboratories
The Causes of Epilepsy: Common and Uncommon Causes in Adults and Children | Year: 2011

Causation is an aspect of epilepsy neglected in the scientific literature and in the conceptualization of epilepsy at a clinical and experimental level. It was to remedy this deficiency that this book was conceived. The book opens with a draft etiological classification that goes some way to filling the nosological void. The book is divided into four etiological categories: idiopathic, symptomatic, cryptogenic, and provoked epilepsies. Each chapter considers topics in a consistent fashion, dealing with the phenomenon of epilepsy in each etiology, including its epidemiology, clinical features and prognosis, and any specific aspects of treatment. The book is a comprehensive reference work, a catalogue of all important causes of epilepsy, and a clinical tool for all clinicians dealing with patients who have epilepsy. It is aimed at epileptologists and neurologists and provides a distillation of knowledge in a form that is helpful in the clinical setting. © Cambridge University Press 2011. Source

Bartolini E.,Pediatric Neurology Unit and Laboratories | Bartolini E.,Epilepsy Unit | Falchi M.,Pediatric Neurology Unit and Laboratories | Zellini F.,Pediatric Neurology Unit and Laboratories | And 12 more authors.
Neurology | Year: 2016

Objective: We explored the long-term follow-up of continuous spike-and-wave complexes during sleep (CSWS) in polymicrogyria and the anatomic volumetric variables that influence the risk of developing this age-related epileptic encephalopathy. Methods: We performed prospective follow-up of 27 patients with polymicrogyria/CSWS (mean follow-up 14.3 years; range 2-31 years) and comparative volumetric analysis of the polymicrogyric hemispheres and ipsilateral thalami vs 3 subgroups featuring polymicrogyria without CSWS, benign rolandic epilepsy (BRE), and headache. Receiver operator characteristic analysis of the power of volumetric values was determined to predict CSWS. Results: CSWS peaked between 5 and 7 years (mean age at onset 4.7 years). Remission occurred within 2 years from onset in 21%, within 4 years in 50%, and by age 13 years in 100%. We found smaller thalamic and hemispheric volumes in polymicrogyria/CSWS with respect to polymicrogyria without CSWS (p 0.0021 for hemispheres; p 0.0003 for thalami), BRE, and controls with headache (p < 0.0001). Volumes of the malformed hemispheres and ipsilateral thalami reliably identified the risk of incurring CSWS, with a 68-fold increased risk for values lower than optimal diagnostic cutoffs (436,150 mm 3 for malformed hemispheres or 4,616 mm 3 for ipsilateral thalami; sensitivity 92.54%; specificity 84.62%). The risk increased by 2% for every 1,000 mm 3 reduction of the polymicrogyric hemispheres and by 15% for every 100 mm 3 reduction of ipsilateral thalami. Conclusions: The polymicrogyria/CSWS syndrome is likely caused by a cortico-thalamic malformation complex and is characterized by remission of epilepsy within early adolescence. Early assessment of hemispheric and thalamic volumes in children with polymicrogyria and epilepsy can reliably predict CSWS. © 2016 American Academy of Neurology. Source

Morrone A.,Pediatric Neurology Unit and Laboratories | Morrone A.,University of Florence | Caciotti A.,Pediatric Neurology Unit and Laboratories | Atwood R.,The Buck Institute for Research on Aging | And 10 more authors.
Human Mutation | Year: 2014

Morquio A syndrome (mucopolysaccharidosis IVA) is an autosomal recessive disorder that results from deficient activity of the enzyme N-acetylgalactosamine-6-sulfatase (GALNS) due to alterations in the GALNS gene, which causes major skeletal and connective tissue abnormalities and effects on multiple organ systems. The GALNS alterations associated with Morquio A are numerous and heterogeneous, and new alterations are continuously identified. To aid detection and interpretation of GALNS alterations, from previously published research, we provide a comprehensive and up-to-date listing of 277 unique GALNS alterations associated with Morquio A identified from 1,091 published GALNS alleles. In agreement with previous findings, most reported GALNS alterations are missense changes and even the most frequent alterations are relatively uncommon. We found that 48% of patients are assessed as homozygous for a GALNS alteration, 39% are assessed as heterozygous for two identified GALNS alterations, and in 13% of patients only one GALNS alteration is detected. We report here the creation of a locus-specific database for the GALNS gene (http://galns.mutdb.org/) that catalogs all reported alterations in GALNS to date. We highlight the challenges both in alteration detection and genotype-phenotype interpretation caused in part by the heterogeneity of GALNS alterations and provide recommendations for molecular testing of GALNS. © 2014 The Authors. Source

Morrone A.,Pediatric Neurology Unit and Laboratories | Morrone A.,University of Florence | Tylee K.L.,University of Manchester | Al-Sayed M.,King Faisal Specialist Hospital And Research Center | And 12 more authors.
Molecular Genetics and Metabolism | Year: 2014

Morquio A (Mucopolysaccharidosis IVA; MPS IVA) is an autosomal recessive lysosomal storage disorder caused by partial or total deficiency of the enzyme galactosamine-6-sulfate sulfatase (GALNS; also known as N-acetylgalactosamine-6-sulfate sulfatase) encoded by the GALNS gene. Patients who inherit two mutated GALNS gene alleles have a decreased ability to degrade the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate, thereby causing GAG accumulation within lysosomes and consequently pleiotropic disease. GALNS mutations occur throughout the gene and many mutations are identified only in single patients or families, causing difficulties both in mutation detection and interpretation. In this study, molecular analysis of 163 patients with Morquio A identified 99 unique mutations in the GALNS gene believed to negatively impact GALNS protein function, of which 39 are previously unpublished, together with 26 single-nucleotide polymorphisms. Recommendations for the molecular testing of patients, clear reporting of sequence findings, and interpretation of sequencing data are provided. © 2014 Elsevier Inc. Source

Cavicchi C.,Molecular and Cell Biology Laboratory | Donati M.A.,Metabolic and Muscular Unit | Parini R.,Rare Metabolic Diseases Unit | Rigoldi M.,Rare Metabolic Diseases Unit | And 14 more authors.
Orphanet Journal of Rare Diseases | Year: 2014

Background: X-linked Ornithine Transcarbamylase deficiency (OTCD) is often unrecognized in adults, as clinical manifestations are non-specific, often episodic and unmasked by precipitants, and laboratory findings can be normal outside the acute phase. It may thus be associated with significant mortality if not promptly recognized and treated. The aim of this study was to provide clues for recognition of OTCD in adults and analyze the environmental factors that, interacting with OTC gene mutations, might have triggered acute clinical manifestations. Methods. We carried out a clinical, biochemical and molecular study on five unrelated adult patients (one female and four males) with late onset OTCD, who presented to the Emergency Department (ED) with initial fatal encephalopathy. The molecular study consisted of OTC gene sequencing in the probands and family members and in silico characterization of the newly detected mutations. Results: We identified two new, c.119G>T (p.Arg40Leu) and c.314G>A (p.Gly105Glu), and three known OTC mutations. Both new mutations were predicted to cause a structural destabilization, correlating with late onset OTCD. We also identified, among the family members, 8 heterozygous females and 2 hemizygous asymptomatic males. Patients' histories revealed potential environmental triggering factors, including steroid treatment, chemotherapy, diet changes and hormone therapy for in vitro fertilization. Conclusions: This report raises awareness of the ED medical staff in considering OTCD in the differential diagnosis of sudden neurological and behavioural disorders associated with hyperammonemia at any age and in both genders. It also widens the knowledge about combined effect of genetic and environmental factors in determining the phenotypic expression of OTCD. © 2014 Cavicchi et al.; licensee BioMed Central Ltd. Source

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