Saadet Mercimek-Mahmutoglu1, Dawn Cordeiro2, Vivian Cruz2, Keith Hyland3, Eduard A Struys4, Lianna Kyriakopoulou5, Eva Mamak6. 1. Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada; Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address: saadet.mahmutoglu@sickkids.ca. 2. Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada. 3. Medical Neurogenetics, LLC, Atlanta, GA, USA. 4. Metabolic Laboratory, Department of Clinical Chemistry, VU Medical Centre, Amsterdam, The Netherlands. 5. Biochemical Genetics Laboratory, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. 6. Department of Psychology, The Hospital for Sick Children, Toronto, ON, Canada.
Abstract
BACKGROUND AND HYPOTHESIS: Pyridoxine dependent epilepsy (PDE) due to mutations in the ALDH7A1 gene (PDE-ALDH7A1) is caused by α-aminoadipic-semialdehyde-dehydrogenase enzyme deficiency in the lysine pathway resulting in the accumulation of α-aminoadipic acid semialdehyde (α-AASA). Classical presentation is neonatal intractable seizures with a dramatic response to pyridoxine. Pyridoxine therapy does not prevent developmental delays in the majority of the patients. We hypothesized that L-arginine supplementation will decrease accumulation of α-AASA by competitive inhibition of lysine transport into the central nervous system and improve neurodevelopmental and neurocognitive functions in PDE-ALDH7A1. METHODS: A 12-year-old male with PDE-ALDH7A1 was treated with l-arginine supplementation as an innovative therapy. Treatment outcome was monitored by cerebral-spinal-fluid (CSF) α-AASA measurements at baseline, 6th and 12th months of therapy. Neuropsychological assessments were performed at baseline and 12th months of therapy. RESULTS: L-arginine therapy was well tolerated without side effects. CSF α-AASA was decreased 57% at 12th months of therapy. Neuropsychological assessments revealed improvements in general abilities index from 108 to 116 and improvements in verbal and motor functioning at 12th months of therapy. CONCLUSION: The short-term treatment outcome of this novel L-arginine supplementation therapy for PDE-ALDH7A1 was successful for biochemical and neurocognitive improvements.
BACKGROUND AND HYPOTHESIS: Pyridoxine dependent epilepsy (PDE) due to mutations in the ALDH7A1 gene (PDE-ALDH7A1) is caused by α-aminoadipic-semialdehyde-dehydrogenase enzyme deficiency in the lysine pathway resulting in the accumulation of α-aminoadipic acid semialdehyde (α-AASA). Classical presentation is neonatal intractable seizures with a dramatic response to pyridoxine. Pyridoxine therapy does not prevent developmental delays in the majority of the patients. We hypothesized that L-arginine supplementation will decrease accumulation of α-AASA by competitive inhibition of lysine transport into the central nervous system and improve neurodevelopmental and neurocognitive functions in PDE-ALDH7A1. METHODS: A 12-year-old male with PDE-ALDH7A1 was treated with l-arginine supplementation as an innovative therapy. Treatment outcome was monitored by cerebral-spinal-fluid (CSF) α-AASA measurements at baseline, 6th and 12th months of therapy. Neuropsychological assessments were performed at baseline and 12th months of therapy. RESULTS:L-arginine therapy was well tolerated without side effects. CSF α-AASA was decreased 57% at 12th months of therapy. Neuropsychological assessments revealed improvements in general abilities index from 108 to 116 and improvements in verbal and motor functioning at 12th months of therapy. CONCLUSION: The short-term treatment outcome of this novel L-arginine supplementation therapy for PDE-ALDH7A1 was successful for biochemical and neurocognitive improvements.
Authors: Amal Al Teneiji; Theodora U J Bruun; Dawn Cordeiro; Jaina Patel; Michal Inbar-Feigenberg; Shelly Weiss; Eduard Struys; Saadet Mercimek-Mahmutoglu Journal: Metab Brain Dis Date: 2016-11-23 Impact factor: 3.584
Authors: L A Tseng; L Teela; M C Janssen; L A Bok; M A A P Willemsen; R F Neuteboom; L Haverman; S M Gospe; C R Coughlin; C D M van Karnebeek Journal: Mol Genet Metab Rep Date: 2022-03-04
Authors: Udo Fh Engelke; Rianne E van Outersterp; Jona Merx; Fred Amg van Geenen; Arno van Rooij; Giel Berden; Marleen Cdg Huigen; Leo Aj Kluijtmans; Tessa Ma Peters; Hilal H Al-Shekaili; Blair R Leavitt; Erik de Vrieze; Sanne Broekman; Erwin van Wijk; Laura A Tseng; Purva Kulkarni; Floris Pjt Rutjes; Jasmin Mecinović; Eduard A Struys; Laura A Jansen; Sidney M Gospe; Saadet Mercimek-Andrews; Keith Hyland; Michèl Aap Willemsen; Levinus A Bok; Clara Dm van Karnebeek; Ron A Wevers; Thomas J Boltje; Jos Oomens; Jonathan Martens; Karlien Lm Coene Journal: J Clin Invest Date: 2021-08-02 Impact factor: 14.808
Authors: Hilal H Al-Shekaili; Terri L Petkau; Izabella Pena; Tess C Lengyell; Nanda M Verhoeven-Duif; Jolita Ciapaite; Marjolein Bosma; Martijn van Faassen; Ido P Kema; Gabriella Horvath; Colin Ross; Elizabeth M Simpson; Jan M Friedman; Clara van Karnebeek; Blair R Leavitt Journal: Hum Mol Genet Date: 2020-11-25 Impact factor: 6.150
Authors: Curtis R Coughlin; Michael A Swanson; Elaine Spector; Naomi J L Meeks; Kathryn E Kronquist; Mezhgan Aslamy; Michael F Wempe; Clara D M van Karnebeek; Sidney M Gospe; Verena G Aziz; Becky P Tsai; Hanlin Gao; Peter L Nagy; Keith Hyland; Silvy J M van Dooren; Gajja S Salomons; Johan L K Van Hove Journal: J Inherit Metab Dis Date: 2019-02-22 Impact factor: 4.982
Authors: Izabella A Pena; Yann Roussel; Kate Daniel; Kevin Mongeon; Devon Johnstone; Hellen Weinschutz Mendes; Marjolein Bosma; Vishal Saxena; Nathalie Lepage; Pranesh Chakraborty; David A Dyment; Clara D M van Karnebeek; Nanda Verhoeven-Duif; Tuan Vu Bui; Kym M Boycott; Marc Ekker; Alex MacKenzie Journal: Genetics Date: 2017-10-23 Impact factor: 4.562