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Pyridoxine dependent epilepsy

Izabella Agostinho Pena, Lygia Azevedo Marques, Ângelo B A Laranjeira, José A Yunes, Marcos N Eberlin, Alex MacKenzie, Paulo Arruda
Lysine is catabolized in mammals through the saccharopine and pipecolate pathways - the former is mainly hepatic and renal, and the latter is believed to play a role in the cerebral lysine oxidation. Both pathways lead to the formation of aminoadipic semialdehyde (AASA) that is then oxidized to aminoadipate (AAA) by antiquitin (ALDH7A1). Mutations in the ALDH7A1 gene result in the accumulation of AASA and its cyclic form, piperideine-6-carboxylate (P6C), which causes pyridoxine-dependent epilepsy (PDE). P6C reacts with pyridoxal 5'-phosphate (PLP) causing its inactivation...
September 8, 2016: Biochimica et Biophysica Acta
Phillip L Pearl
Vitamin-dependent epilepsies and multiple metabolic epilepsies are amenable to treatment that markedly improves the disease course. Knowledge of these amenably treatable severe pediatric epilepsies allows for early identification, testing, and treatment. These disorders present with various phenotypes, including early onset epileptic encephalopathy (refractory neonatal seizures, early myoclonic encephalopathy, and early infantile epileptic encephalopathy), infantile spasms, or mixed generalized seizure types in infancy, childhood, or even adolescence and adulthood...
May 2016: Seminars in Pediatric Neurology
Svetlana Gataullina, Julia Lauer-Zillhardt, Anna Kaminska, Louise Galmiche-Rolland, Nadia Bahi-Buisson, Clément Pontoizeau, Chris Ottolenghi, Olivier Dulac, Catherine Fallet-Bianco
We report the cases of a brother and a sister of nonconsanguineous parents who developed progressive microcephaly and had tremor, irritability, spasticity, startle reflexes, and permanent erratic myoclonus since birth. Focal clonic seizures, status epilepticus, and infantile spasms appeared later, during the first months of life, while erratic myoclonic jerks persisted. Electroencephalogram initially showed multifocal spikes that evolved into modified hypsarrhythmia and then discontinuous activity, evoking the progressive nature of the condition...
August 14, 2016: Neuropediatrics
J Xue, Z X Yang, H Li, P Qian, Y Wu, Y W Jiang, X Y Liu
OBJECTIVE: To analyze the clinical and genetic characteristics of patients with pyridoxine dependent epilepsy (PDE), and build a method to detect and analyze the concentration of urinary pipecolic acid in PDE patients receiving pyridoxine treatment. METHOD: Twelve patients (8 were male, 4 were female) were diagnosed as PDE in Peking University First Hospital between April 2012 and September 2015. The clinical manifestations, diagnosis and treatment process, video-electroencephalogram, magnetic resonance imaging were retrospectively analyzed...
August 2016: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
Florent Marguet, Hager Barakizou, Abdellah Tebani, Lenaig Abily-Donval, Stéphanie Torre, Fethi Bayoudh, Sami Jebnoun, Marie Brasseur-Daudruy, Stéphane Marret, Annie Laquerriere, Soumeya Bekri
Pyridoxine-dependent epilepsy (PDE) is a pharmacoresistant epileptogenic encephalopathy controlled by pyridoxine supplementation at pharmacological doses. Despite supplementation, the long-term outcome is often poor possibly because of recurrent seizures and developmental structural brain abnormalities. We report on five patients with PDE from three unrelated families. The diagnosis was confirmed by ALDH7A1 sequencing, which allowed for the characterization of two homozygous variations [NM_001182.3:c.1279G > C - p...
July 20, 2016: Metabolic Brain Disease
Déborah Mathis, Lucia Abela, Monique Albersen, Céline Bürer, Lisa Crowther, Karin Beese, Hans Hartmann, Levinus A Bok, Eduard Struys, Sorina M Papuc, Anita Rauch, Martin Hersberger, Nanda M Verhoeven-Duif, Barbara Plecko
BACKGROUND: Recent decades have unravelled the molecular background of a number of inborn errors of metabolism (IEM) causing vitamin B6-dependent epilepsy. As these defects interfere with vitamin B6 metabolism by different mechanisms, the plasma vitamin B6 profile can give important clues for further molecular work-up. This has so far been investigated in only a small number of patients. METHODS: We evaluated the vitamin B6 vitamers pyridoxal 5'-phosphate (PLP), pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN) and the catabolite pyridoxic acid (PA) in the so far largest patient cohort: reference (n = 50); pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency (n = 6); antiquitin (ATQ) deficiency (n = 21); tissue non-specific alkaline phosphatase (TNSALP) deficiency (n = 2) and epileptic encephalopathy (EE) of unknown etiology tested negative for ATQ and PNPO deficiency (n = 64)...
September 2016: Journal of Inherited Metabolic Disease
Tatiana Yuzyuk, Amanda Thomas, Krista Viau, Aiping Liu, Irene De Biase, Lorenzo D Botto, Marzia Pasquali, Nicola Longo
Pyridoxine-Dependent Epilepsy (PDE) is a recessive disorder caused by deficiency of α-aminoadipic semialdehyde dehydrogenase in the catabolic pathway of lysine. It is characterized by intractable seizures controlled by the administration of pharmacological doses of vitamin B6. Despite seizure control with pyridoxine, intellectual disability and developmental delays are still observed in some patients with PDE, likely due to the accumulation of toxic intermediates in the lysine catabolic pathway: alpha-aminoadipic semialdehyde (AASA), delta-1-piperideine-6-carboxylate (P6C), and pipecolic acid...
July 2016: Molecular Genetics and Metabolism
Richard E Frye, Manuel F Casanova, S Hossein Fatemi, Timothy D Folsom, Teri J Reutiman, Gregory L Brown, Stephen M Edelson, John C Slattery, James B Adams
This manuscript reviews biological abnormalities shared by autism spectrum disorder (ASD) and epilepsy. Two neuropathological findings are shared by ASD and epilepsy: abnormalities in minicolumn architecture and γ-aminobutyric acid (GABA) neurotransmission. The peripheral neuropil, which is the region that contains the inhibition circuits of the minicolumns, has been found to be decreased in the post-mortem ASD brain. ASD and epilepsy are associated with inhibitory GABA neurotransmission abnormalities including reduced GABAA and GABAB subunit expression...
2016: Frontiers in Neuroscience
Muhammad Mahajnah, Dawn Corderio, Valerie Austin, Sarah Herd, Carly Mutch, Melissa Carter, Eduard Struys, Saadet Mercimek-Mahmutoglu
BACKGROUND: Pyridoxine-dependent epilepsy (PDE) is caused by mutations in ALDH7A1 (PDE-ALDH7A1), which encodes α-aminoadipic semialdehyde dehydrogenase in the lysine catabolic pathway, resulting in accumulation of α-aminoadipic-acid-semialdehyde. PATIENT DESCRIPTION AND RESULTS: We present a three-year treatment outcome of a child with PDE-ALDH7A1 on pyridoxine (started at age three weeks of age), lysine-restricted diet (started at age seven months), and arginine supplementation therapy (started at age 26 months)...
July 2016: Pediatric Neurology
Gülen Gül-Mert, Faruk İncecik, M Özlem Hergüner, Serdar Ceylaner, Şakir Altunbaşak
Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive enzyme defect in the vitamin B6 metabolism characterized by intractable seizures which are usually resistant to all antiepileptic drugs but respond to pharmacological doses of pyridoxine. We present the clinical and molecular genetic findings of two patients with c.1597_1597delG mutations in ALDH7A1 gene. There are different clinical phenotypes in PDE: patients with complete seizure control with pyridoxine and normal development (group 1), patients with complete seizure control with pyridoxine and development delay (group 2), and patients with persistent seizures despite pyridoxine treatment and with development delay (group 3)...
July 2015: Turkish Journal of Pediatrics
Izabella A Pena, Lygia A Marques, Angelo B A Laranjeira, José A Yunes, Marcos N Eberlin, Paulo Arruda
Detection and quantification of lysine degradation metabolites in plasma is necessary for the diagnosis and follow-up of diseases such as pyridoxine-dependent epilepsy. The principal metabolites involved in the disease are related to the first steps of lysine oxidation, either through the saccharopine or the pipecolate pathways. Currently, there are three different analytical methods used to assess the content of these metabolites in urine and plasma, but they require different sample preparations and analytical equipment...
2016: SpringerPlus
Clara D M van Karnebeek, Sylvia A Tiebout, Jikkemien Niermeijer, Bwee Tien Poll-The, Aisha Ghani, Curtis R Coughlin, Johan L K Van Hove, Jost Wigand Richter, Hans Juergen Christen, Renata Gallagher, Hans Hartmann, Sylvia Stockler-Ipsiroglu
BACKGROUND: Pyridoxine-dependent epilepsy is a rare autosomal recessive epileptic encephalopathy caused by antiquitin (ALDH7A1) deficiency. In spite of adequate seizure control, 75% of patients suffer intellectual developmental disability. Antiquitin deficiency affects lysine catabolism resulting in accumulation of α-aminoadipic semialdehyde/pyrroline 6' carboxylate and pipecolic acid. Beside neonatal refractory epileptic encephalopathy, numerous neurological manifestations and metabolic/biochemical findings have been reported...
June 2016: Pediatric Neurology
Tatiana Yuzyuk, Aiping Liu, Amanda Thomas, JoDell E Wilson, Irene De Biase, Nicola Longo, Marzia Pasquali
OBJECTIVES: Elevated levels of pipecolic acid (PA), α-aminoadipic semialdehyde (AASA) and its cyclic form Δ1-piperideine-6-carboxylate (P6C) are characteristic of pyridoxine dependent epilepsy (PDE), a rare disorder of inborn error of metabolism. Recent studies showed the effectiveness of dietary therapy in PDE patients and emphasized the importance of the assessment of these metabolites for monitoring treatment efficacy. The objective of this study was to develop a robust and sensitive method for simultaneous quantification of AASA-P6C and PA in plasma and urine...
April 1, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Debopam Samanta
No abstract text is available yet for this article.
March 4, 2016: Acta Neurologica Belgica
John J Tanner
Enzymes of the aldehyde dehydrogenase (ALDH) superfamily catalyze the nicotinamide adenine dinucleotide-dependent oxidation of aldehydes to carboxylic acids. ALDHs are important in detoxification of aldehydes, amino acid metabolism, embryogenesis and development, neurotransmission, oxidative stress, and cancer. Mutations in genes encoding ALDHs cause metabolic disorders, including alcohol flush reaction (ALDH2), Sjögren-Larsson syndrome (ALDH3A2), hyperprolinemia type II (ALDH4A1), γ-hydroxybutyric aciduria (ALDH5A1), methylmalonic aciduria (ALDH6A1), pyridoxine dependent epilepsy (ALDH7A1), and hyperammonemia (ALDH18A1)...
December 2015: Data in Brief
Nicole A Hawkins, Jennifer A Kearney
Mutations in voltage-gated sodium channel genes cause several types of human epilepsies. Often, individuals with the same sodium channel mutation exhibit diverse phenotypes. This suggests that factors beyond the primary mutation influence disease severity, including genetic modifiers. Mouse epilepsy models with voltage-gated sodium channel mutations exhibit strain-dependent phenotype variability, supporting a contribution of genetic modifiers in epilepsy. The Scn2a(Q54) (Q54) mouse model has a strain-dependent epilepsy phenotype...
January 2016: Epilepsy Research
Jiao Xue, Ping Qian, Hui Li, Ye Wu, Xiaoyan Liu, Zhixian Yang
PURPOSE: Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder caused by mutations of the ALDH7A1 gene. We aimed to analyze the relations between the clinical diagnosis and treatment of PDE and ALDH7A1 gene mutations in Chinese PDE patients. METHODS: The clinical manifestations, diagnosis and treatment were observed in a cohort of PDE patients with early onset of seizure. Video-electroencephalogram (VEEG) and magnetic resonance imaging (MRI) were performed...
December 2015: Epilepsy Research
Sandra L Poliachik, Seth D Friedman, Andrew V Poliakov, Christopher B Budech, Gisele E Ishak, Dennis W W Shaw, Sidney M Gospe
BACKGROUND: In this observational study, white matter structure, functional magnetic resonance imaging (fMRI) task-based responses, and functional connectivity were assessed in four subjects with high functioning pyridoxine-dependent epilepsy and age-matched control subjects. METHODS: Four male subjects with pyridoxine-dependent epilepsy (mean age 31 years 8 months, standard deviation 12 years 3 months) and age-matched control subjects (32 years 4 months, standard deviation 13 years) were recruited to participate in the study...
January 2016: Pediatric Neurology
R Riikonen, K Mankinen, E Gaily
BACKGROUND: Dose regimens of pyridoxine (vitamin B6) for treatment of infantile spasms have varied from 200 mg/d to 300 mg/kg/d. Only two long-term outcome studies of the treated patients are available. METHODS: We asked all pediatric neurologists treating pediatric epilepsy in Finland if they had seen patients with pyridoxine-responsive infantile epilepsy. Five children with infantile spasms and hypsarrhythmia and one with focal epilepsy were reported as pyridoxine responders...
November 2015: European Journal of Paediatric Neurology: EJPN
Min Luo, John J Tanner
Aldehyde dehydrogenase 7A1 (ALDH7A1) is part of lysine catabolism and catalyzes the NAD(+)-dependent oxidation of α-aminoadipate semialdehyde to α-aminoadipate. Herein, we describe a structural study of human ALDH7A1 focused on substrate recognition. Five crystal structures and small-angle X-ray scattering data are reported, including the first crystal structure of any ALDH7 family member complexed with α-aminoadipate. The product binds with the ε-carboxylate in the oxyanion hole, the aliphatic chain packed into an aromatic box, and the distal end of the product anchored by electrostatic interactions with five conserved residues...
September 8, 2015: Biochemistry
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