Abstract
We report treatment outcome of eleven patients with pyridoxine-dependent epilepsy caused by pathogenic variants in ALDH7A1 (PDE-ALDH7A1). We developed a clinical severity score to compare phenotype with biochemical features, genotype and delays in the initiation of pyridoxine. Clinical severity score included 1) global developmental delay/ intellectual disability; 2) age of seizure onset prior to pyridoxine; 3) current seizures on treatment. Phenotype scored 1–3 = mild; 4–6 = moderate; and 7–9 = severe. Five patients had mild, four patients had moderate, and two patients had severe phenotype. Phenotype ranged from mild to severe in eight patients (no lysine-restricted diet in the infantile period) with more than 10-fold elevated urine or plasma α-AASA levels. Phenotype ranged from mild to moderate in patients with homozygous truncating variants and from moderate to severe in patients with homozygous missense variants. There was no correlation between severity of the phenotype and the degree of α-AASA elevation in urine or genotype. All patients were on pyridoxine, nine patients were on arginine and five patients were on the lysine-restricted diet. 73% of the patients became seizure free on pyridoxine. 25% of the patients had a mild phenotype on pyridoxine monotherapy. Whereas, 100% of the patients, on the lysine-restricted diet initiated within their first 7 months of life, had a mild phenotype. Early initiation of lysine-restricted diet and/or arginine therapy likely improved neurodevelopmental outcome in young patients with PDE-ALDH7A1.
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Acknowledgements
We would like to thank to parents and patients. We would like to thank to Mrs. L. Nagy, metabolic dietician and Mrs. S. Herd, metabolic dietician for the application of lysine-restricted diet. We would like to thank to Dr. G. Salomons for performing mutation analysis of ALDH7A1. We would like to thank to Dr. Siriwardena, Dr. Donner, Dr. Raiman and Dr. Peter Humphreys referring their patients. We would like to thank to Stacy Hewson for genetic counseling of families for molecular genetic test results.
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Supplemental Figure 1
Clinical severity score compared to the X-fold elevated in the upper limit of normal urine and plasma α-AASA levels in eight patients with no lysine-restricted diet initiated within their first 7 months of life (except patient ID# 5, 8 and 11) with PDE-ALDH7A1. *Values for these patients are from plasma α-AASA level. (JPEG 46 kb)
Supplemental Table 1
Neuropsychological assessment results on treatment in patients with PDE-ALDH7A1. (DOCX 30 kb)
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Al Teneiji, A., Bruun, T.U.J., Cordeiro, D. et al. Phenotype, biochemical features, genotype and treatment outcome of pyridoxine-dependent epilepsy. Metab Brain Dis 32, 443–451 (2017). https://doi.org/10.1007/s11011-016-9933-8
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DOI: https://doi.org/10.1007/s11011-016-9933-8