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Mol Genet Metab. 2015 Sep-Oct;116(1-2):35-43. doi: 10.1016/j.ymgme.2015.05.011. Epub 2015 May 23.

Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: Neurodevelopmental outcome.

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Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, United States.
Division of Biochemical Diseases &Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Department of Medical Genetics, Montreal Children's Hospital, McGill University of Health Centre, Montreal, QC, Canada.
Department of Laboratory Medicine, Seattle Children's Hospital Laboratory, Seattle, WA, United States.
Department of Radiology, University of Colorado, Aurora, CO, United States.
Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, United States. Electronic address:


Pyridoxine-dependent epilepsy (PDE) is an epileptic encephalopathy characterized by response to pharmacologic doses of pyridoxine. PDE is caused by deficiency of α-aminoadipic semialdehyde dehydrogenase resulting in impaired lysine degradation and subsequent accumulation of α-aminoadipic semialdehyde. Despite adequate seizure control with pyridoxine monotherapy, 75% of individuals with PDE have significant developmental delay and intellectual disability. We describe a new combined therapeutic approach to reduce putative toxic metabolites from impaired lysine metabolism. This approach utilizes pyridoxine, a lysine-restricted diet to limit the substrate that leads to neurotoxic metabolite accumulation and L-arginine to compete for brain lysine influx and liver mitochondrial import. We report the developmental and biochemical outcome of six subjects who were treated with this triple therapy. Triple therapy reduced CSF, plasma, and urine biomarkers associated with neurotoxicity in PDE. The addition of arginine supplementation to children already treated with dietary lysine restriction and pyridoxine further reduced toxic metabolites, and in some subjects appeared to improve neurodevelopmental outcome. Dietary lysine restriction was associated with improved seizure control in one subject, and the addition of arginine supplementation increased the objective motor outcome scale in two twin siblings, illustrating the contribution of each component of this treatment combination. Optimal results were noted in the individual treated with triple therapy early in the course of the disease. Residual disease symptoms could be related to early injury suggested by initial MR imaging prior to initiation of treatment or from severe epilepsy prior to diagnosis. This observational study reports the use of triple therapy, which combines three effective components in this rare condition, and suggests that early diagnosis and treatment with this new triple therapy may ameliorate the cognitive impairment in PDE.


Alpha-aminoadipic semialdehyde; Antiquitin; Arginine supplementation; Epileptic encephalopathy; Pyridoxine dependent epilepsy

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