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Eur J Paediatr Neurol. 2014 Nov;18(6):741-6. doi: 10.1016/j.ejpn.2014.07.001. Epub 2014 Jul 27.

Novel therapy for pyridoxine dependent epilepsy due to ALDH7A1 genetic defect: L-arginine supplementation alternative to lysine-restricted diet.

Author information

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.

KEYWORDS:

ALDH7A1 gene; Alpha-amino adipic acid semialdehyde; Lysine catabolism; Pyridoxine dependent epilepsy; l-arginine

PMID:
25127453
DOI:
10.1016/j.ejpn.2014.07.001
[Indexed for MEDLINE]

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