Effect of dietary lysine restriction and arginine supplementation in two patients with pyridoxine-dependent epilepsy
Introduction
Pyridoxine-Dependent Epilepsy (PDE) is a recessive disorder of lysine catabolism caused by impaired function of α-aminoadipic semialdehyde dehydrogenase (AASADH), the enzyme responsible for the oxidation of α-aminoadipic semialdehyde to α-aminoadipic acid [1]. AASADH deficiency leads to accumulation of α-aminoadipic semialdehyde (AASA), its cyclic form Δ1-piperideine-6-carboxylate (P6C), and pipecolic acid in plasma, urine and CSF. The sequestration of the active form of vitamin B6 (pyridoxal 5′-phosphate) by excess P6C is believed to be an underlying cause of intractable seizures in PDE [2], [3] and therefore these patients are treated with high doses of Vitamin B6 (pyridoxine) [2]. Neuronal migration defects and multiple brain malformations, such as hydrocephalus and abnormalities of the corpus callosum, white matter and posterior fossa, have also been reported in association with PDE, suggesting a role of ALDH7A1 gene, encoding AASADH, in neuronal development [4]. Despite seizure control, the majority of PDE patients on pyridoxine monotherapy have intellectual disability and developmental delays [5], [6], possibly due to the accumulation of neurotoxic intermediates in lysine catabolism such as AASA, P6C and pipecolic acid [7], [8], [9]. In fact, lysine restriction significantly decreases the levels of these PDE biomarkers in plasma, urine and CSF, and is associated with noticeable developmental progress in the majority of PDE patients [8]. Improvements in biochemical and neurocognitive outcomes were also achieved in one patient on l-arginine supplementation, possibly through the competitive inhibition of lysine uptake into the central nervous system [10]. Overall, the combination of a lysine-restricted diet with pyridoxine and arginine supplements, known as triple therapy, reduced AASA, P6C and pipecolic acid levels and improved cognitive and motor deficits in > 50% of reported patients with PDE [11]. However, the benefits of dietary therapies were not clear for some PDE patients [11], [12] suggesting that treatment efficiency may depend on genetic and phenotypic variability as well as the degree of developmental structural brain abnormalities prior to therapy [4], [13]. Due to the rarity of this disorder the number of patients on a lysine-restricted therapy and/or arginine supplementation reported in the literature is limited (n = 15). Therefore, additional data are necessary for better evaluation of treatment efficiencies and to correlate dietary interventions with outcome.
Here we report the treatment of two PDE patients with a lysine-restricted diet and arginine supplements in addition to pyridoxine, and show a direct correlation between PDE biomarkers and amino acids in plasma of these patients.
Section snippets
Methods
Patients with PDE included in this study are followed in the Metabolic Clinic at the University of Utah. Demographic, clinical, and laboratory data were collected from patient charts. This retrospective study was reviewed and approved by the Institutional Review Board at the University of Utah.
Clinical outcomes
Patient 1 was diagnosed with PDE at birth and remained seizures-free on pyridoxine monotherapy (20 mg/kg/day) except for one episode of seizures at 33 months of age when unable to tolerate the medication due to a gastrointestinal illness. His somatic growth was adequate; however, by 3 months of age, macrocephaly became apparent, with head circumference consistently above the 99th percentile thereafter. Macrocephaly without hydrocephalus has been previously reported in several other PDE patients
Discussion
In this study we report the effect of lysine/protein restriction and arginine supplementation in two patients with PDE. Pharmacological doses of pyridoxine are usually sufficient to keep seizures under control, but do not prevent developmental and intellectual deficits in the majority of PDE patients [5], [6]. Therefore, the aim of dietary treatments is to improve neurodevelopmental outcomes of these patients, likely by limiting accumulation of neurotoxic compounds such as AASA-P6C and
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Cited by (25)
Cognitive and neurological outcome of patients in the Dutch pyridoxine-dependent epilepsy (PDE-ALDH7A1) cohort, a cross-sectional study
2021, European Journal of Paediatric NeurologyCitation Excerpt :Observational studies of lysine reduction therapies (LRT) in combination with pharmacological doses of pyridoxine have shown variable beneficial effects. These effects include decrease in intermediates pipecolic acid (PA), α-AASA, and P6C; improvement or maintenance of seizure control, subjective developmental improvement, and objective cognitive assessments in many study subjects, but not all [10,12,15–19]. Early initiation of treatment has been postulated beneficial [16].
Disorders of pyridoxine metabolism
2020, Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease: Volume 1Current strategies for the treatment of inborn errors of metabolism
2018, Journal of Genetics and GenomicsCitation Excerpt :Despite seizure control with pyridoxine, intellectual disability still occurs in some PDE patients, which is likely due to the accumulation in the brain of toxic intermediates in the lysine catabolic pathway. Several clinical studies reported that triple therapy in PDE patients decreased the accumulation of PDE biomarkers and reduced the cognitive impairment as well as improved the neurodevelopmental outcome (Coughlin et al., 2015; van Karnebeek and Jaggumantri, 2015; Yuzyuk et al., 2016; Al Teneiji et al., 2017). However, the observed benefits of triple therapy may be confounded by the earlier diagnosis in this cohort of patients.