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      Pyridoxine responsive epilepsy caused by a novel homozygous PNPO mutation ☆

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          Abstract

          We report a patient with anti-epileptic treatment refractory neonatal seizures responsive to pyridoxine. Biochemical analysis revealed normal markers for antiquitin deficiency and also mutation analysis of the ALDH7A1 ( Antiquitin) gene was negative. Mutation analysis of the PNPO gene revealed a novel, homozygous, presumed pathogenic mutation (c.481C > T; p.(Arg161Cys)). Measurements of B 6 vitamers in a CSF sample after pyridoxine administration revealed elevated pyridoxamine as the only metabolic marker for PNPO deficiency. With pyridoxine monotherapy the patient is seizure free and neurodevelopmental outcome at the age of 14 months is normal.

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          Mutations in antiquitin in individuals with pyridoxine-dependent seizures.

          Birgit Uhlenberg, Peter Baxter, Barbara Plecko … (2006)
          We show here that children with pyridoxine-dependent seizures (PDS) have mutations in the ALDH7A1 gene, which encodes antiquitin; these mutations abolish the activity of antiquitin as a delta1-piperideine-6-carboxylate (P6C)-alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase. The accumulating P6C inactivates pyridoxal 5'-phosphate (PLP) by forming a Knoevenagel condensation product. Measurement of urinary alpha-AASA provides a simple way of confirming the diagnosis of PDS and ALDH7A1 gene analysis provides a means for prenatal diagnosis.
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            Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up.

            Sylvia Stockler, Barbara Plecko, Sidney M. Gospe … (2016)
            Antiquitin (ATQ) deficiency is the main cause of pyridoxine dependent epilepsy characterized by early onset epileptic encephalopathy responsive to large dosages of pyridoxine. Despite seizure control most patients have intellectual disability. Folinic acid responsive seizures (FARS) are genetically identical to ATQ deficiency. ATQ functions as an aldehyde dehydrogenase (ALDH7A1) in the lysine degradation pathway. Its deficiency results in accumulation of α-aminoadipic semialdehyde (AASA), piperideine-6-carboxylate (P6C) and pipecolic acid, which serve as diagnostic markers in urine, plasma, and CSF. To interrupt seizures a dose of 100 mg of pyridoxine-HCl is given intravenously, or orally/enterally with 30 mg/kg/day. First administration may result in respiratory arrest in responders, and thus treatment should be performed with support of respiratory management. To make sure that late and masked response is not missed, treatment with oral/enteral pyridoxine should be continued until ATQ deficiency is excluded by negative biochemical or genetic testing. Long-term treatment dosages vary between 15 and 30 mg/kg/day in infants or up to 200 mg/day in neonates, and 500 mg/day in adults. Oral or enteral pyridoxal phosphate (PLP), up to 30 mg/kg/day can be given alternatively. Prenatal treatment with maternal pyridoxine supplementation possibly improves outcome. PDE is an organic aciduria caused by a deficiency in the catabolic breakdown of lysine. A lysine restricted diet might address the potential toxicity of accumulating αAASA, P6C and pipecolic acid. A multicenter study on long term outcomes is needed to document potential benefits of this additional treatment. The differential diagnosis of pyridoxine or PLP responsive seizure disorders includes PLP-responsive epileptic encephalopathy due to PNPO deficiency, neonatal/infantile hypophosphatasia (TNSALP deficiency), familial hyperphosphatasia (PIGV deficiency), as well as yet unidentified conditions and nutritional vitamin B6 deficiency. Commencing treatment with PLP will not delay treatment in patients with pyridox(am)ine phosphate oxidase (PNPO) deficiency who are responsive to PLP only. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

              Philippa B. Mills, Emma J. Footitt, Kevin A. Mills … (2010)
              Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of l-α-aminoadipic semialdehyde/l-Δ1-piperideine 6-carboxylate. However, whilst this is a highly treatable disorder, there is general uncertainty about when to consider this diagnosis and how to test for it. This study aimed to evaluate the use of measurement of urine l-α-aminoadipic semialdehyde/creatinine ratio and mutation analysis of ALDH7A1 (antiquitin) in investigation of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary l-α-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on foetal ultrasound, through abnormal foetal movements and a multisystem neonatal disorder, to the onset of seizures and autistic features after the first year of life. Our relatively large series suggested that clinical diagnosis of pyridoxine dependent epilepsy can be challenging because: (i) there may be some response to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive to pyridoxine. These findings support the use of biochemical and DNA tests for antiquitin deficiency and a clinical trial of pyridoxine in infants and children with epilepsy across a broad range of clinical scenarios.
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                Author and article information

                Contributors
                B. Jaeger
                N.G. Abeling
                G.S. Salomons
                E.A. Struys
                M. Simas-Mendes
                V.G. Geukers
                B.T. Poll-The
                Journal
                Journal ID (nlm-ta): Mol Genet Metab Rep
                Journal ID (iso-abbrev): Mol Genet Metab Rep
                Title: Molecular Genetics and Metabolism Reports
                Publisher: Elsevier
                ISSN (Electronic): 2214-4269
                Publication date PMC-release: 10 February 2016
                Publication date Collection: March 2016
                Publication date (Electronic): 10 February 2016
                Volume: 6
                Pages: 60-63
                Affiliations
                [a ]Department of Pediatric Neurology, Academic Medical Center, Amsterdam, The Netherlands
                [b ]Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands
                [c ]Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands
                [d ]Pediatric Intensive Care Department, Academic Medical Center, Amsterdam, The Netherlands
                Author notes
                [* ]Corresponding author at: Dept. of Pediatric Neurology, Room H7-228, Emma Children's Hospital, Academic Medical Center, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands.Dept. of Pediatric NeurologyEmma Children's HospitalAcademic Medical CenterRoom H7-228P.O. Box 22660Amsterdam1100 DDThe Netherlands b.jaeger@ 123456amc.uva.nl
                Article
                Publisher ID: S2214-4269(16)30004-0
                DOI: 10.1016/j.ymgmr.2016.01.004
                PMC ID: 4789384
                PubMed ID: 27014579
                SO-VID: 3d5c8779-952b-4451-84d9-ed67705f439f
                Copyright © © 2016 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 8 November 2015
                Date revision received : 26 January 2016
                Date accepted : 26 January 2016
                Categories
                Subject: Short Communication

                Keywords: csf, cerebrospinal fluid,pde, (classic) pyridoxine dependent epilepsy,plp, pyridoxal-5′-phosphate,plp-de, pyridoxal-phosphate dependent epilepsy,pnpo, pyridox(am)ine-5′-phosphate oxidase,α-aasa, alpha-aminoadipic semialdehyde dehydrogenase,pnpo,pyridoxine,neonatal,epilepsy,pyridoxal-phosphate,antiquitin
                Data availability:
                Keywords: csf, cerebrospinal fluid, pde, (classic) pyridoxine dependent epilepsy, plp, pyridoxal-5′-phosphate, plp-de, pyridoxal-phosphate dependent epilepsy, pnpo, pyridox(am)ine-5′-phosphate oxidase, α-aasa, alpha-aminoadipic semialdehyde dehydrogenase, pnpo, pyridoxine, neonatal, epilepsy, pyridoxal-phosphate, antiquitin

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