Lysine restricted diet for pyridoxine-dependent epilepsy: First evidence and future trials

Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada.
Molecular Genetics and Metabolism (Impact Factor: 2.83). 09/2012; 107(3). DOI: 10.1016/j.ymgme.2012.09.006
Source: PubMed

ABSTRACT OBJECTIVE: To evaluate the efficacy and safety of dietary lysine restriction as an adjunct to pyridoxine therapy on biochemical parameters, seizure control, and developmental/cognitive outcomes in children with pyridoxine-dependent epilepsy (PDE) caused by antiquitin (ATQ) deficiency. METHODS: In this observational study, seven children with confirmed ATQ deficiency were started on dietary lysine restriction with regular nutritional monitoring. Biochemical outcomes were evaluated using pipecolic acid and α-aminoadipic semialdehyde (AASA) levels in body fluids; developmental/cognitive outcomes were evaluated using age-appropriate tests and parental observations. RESULTS: Lysine restriction was well tolerated with good compliance; no adverse events were reported. Reduction in biomarker levels (measurement of the last value before and first value after initiation of dietary lysine restriction) ranged from 20 to 67% for plasma pipecolic acid, 13 to 72% for urinary AASA, 45% for plasma AASA and 42% for plasma P6C. For the 1 patient in whom data were available and who showed clinical deterioration upon interruption of diet, cerebrospinal fluid levels decreased by 87.2% for pipecolic acid and 81.7% for AASA. Improvement in age-appropriate skills was observed in 4 out of 5 patients showing pre-diet delays, and seizure control was maintained or improved in 6 out 7 children. CONCLUSIONS: This observational study provides Level 4 evidence that lysine restriction is well tolerated with significant decrease of potentially neurotoxic biomarkers in different body compartments, and with the potential to improve developmental outcomes in children with PDE caused by ATQ deficiency. To generate a strong level of evidence before this potentially burdensome dietary therapy becomes the mainstay treatment, we have established: an international PDE consortium to conduct future studies with an all-inclusive integrated study design; a website containing up-to-date information on PDE; a methodological toolbox; and an online registry to facilitate the participation of interested physicians, scientists, and families in PDE research.

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    ABSTRACT: Background: Seventy-five percent of patients with pyridoxine-dependent epilepsy (PDE) due to Antiquitin (ATQ) deficiency suffer from developmental delay and/or intellectual disability (IQ < 70) despite seizure control. An observational study showed that adjunct treatment with a lysine-restricted diet is safe, results in partial normalization of lysine intermediates in body fluids, and may have beneficial effects on seizure control and psychomotor development. Methods: In analogy to the NICE guideline process, the international PDE Consortium, an open platform uniting scientists and clinicians working in the field of this metabolic epilepsy, during four workshops (2010-2013) developed a recommendation for a lysine-restricted diet in PDE, with the aim of standardizing its implementation and monitoring of patients. Additionally, a proposal for a further observational study is suggested. Results: (1) All patients with confirmed ATQ deficiency are eligible for adjunct treatment with lysine-restricted diet, unless treatment with pyridoxine alone has resulted in complete symptom resolution, including normal behavior and development. (2) Lysine restriction should be started as early as possible; the optimal duration remains undetermined. (3) The diet should be implemented and the patient be monitored according to these recommendations in order to assure best possible quality of care and safety. Discussion: The implementation of this recommendation will provide a unique and a much needed opportunity to gather data with which to refine the recommendation as well as improve our understanding of outcomes of individuals affected by this rare disease. We therefore propose an international observational study that would utilize freely accessible, online data sharing technologies to generate more evidence.
    04/2014; DOI:10.1007/8904_2014_296
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    ABSTRACT: 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.
    European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 07/2014; 18(6). DOI:10.1016/j.ejpn.2014.07.001 · 1.93 Impact Factor
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    ABSTRACT: AimWhile there have been isolated reports of callosal morphology differences in pyridoxine-dependent epilepsy (PDE), a rare autosomal disorder caused by ALDH7A1 gene mutations, no study has systematically evaluated callosal features in a large sample of patients. This study sought to overcome this knowledge gap. Method Spanning a wide age range from birth to 48years, corpus callosum morphology and cross-sectional cerebral area were measured in 30 individuals with PDE (12 males, 18 females, median age 3.92y; 25th centile 0.27, 75th centile 15.25) compared to 30 age-matched comparison individuals (11 males, 19 females, median age 3.85y; 25th centile 0.26, 75th centile 16.00). Individuals with PDE were also divided into age groups to evaluate findings across development. As delay to treatment may modulate clinical severity, groups were stratified by treatment delay (less than or greater than 2wks from birth). ResultsMarkedly reduced callosal area expressed as a ratio of mid-sagittal cerebral area was observed for the entire group with PDE (p<0.001). Stratifying by age (<1y, 1-10y, >10y) demonstrated posterior abnormalities to be a consistent feature, with anterior regions increasingly involved across the developmental trajectory. Splitting the PDE group by treatment lag did not reveal overall or sub-region callosal differences. InterpretationCallosal abnormalities are a common feature of PDE not explained by treatment lag. Future work utilizing tract-based approaches to understand inter- and intra-hemispheric connectivity patterns will help in the better understanding the structural aspects of this disease. What this paper adds Callosal alterations in pyridoxine-dependent epilepsy (PDE) are present in all ages of participants.Older individuals with PDE had area reduction of the posterior callosum and the anterior regions.Findings were not solely related to delaying initial pyridoxine treatment and, by extension, seizure burden'. This article is commented on by Schmitt on pages 1039-1040 of this issue.
    Developmental Medicine & Child Neurology 06/2014; 56(11). DOI:10.1111/dmcn.12511 · 3.29 Impact Factor

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