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: 2.63). 09/2012; 107(3). DOI: 10.1016/j.ymgme.2012.09.006
Source: PubMed


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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Available from: Sidney M Gospe, Jr
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    • "Pyridoxine supplementation alone does not normalize the accumulation of α-AASA and PA levels in the central nervous system (CNS), which might be the likely cause of developmental delays, necessitating new treatment modalities to improve neurodevelopmental outcomes. Lysine-restricted diet has been recently reported as an observational study with some evidence of improvements in biochemical and neurodevelopmental outcomes [6]. Here, we report a patient with PDE-ALDH7A1 and his one-year treatment outcome on lysine-restricted diet as a case study. "
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    ABSTRACT: Pyridoxine dependent epilepsy (PDE) is caused by mutations in the ALDH7A1 gene (PDE-ALDH7A1) encoding α-aminoadipic-semialdehyde-dehydrogenase enzyme in the lysine catabolic pathway resulting in an accumulation of α-aminoadipic-acid-semialdehyde (α-AASA). We present the one-year treatment outcome of a patient on a lysine-restricted diet. Serial cerebral-spinal-fluid (CSF) α-AASA and CSF pipecolic-acid levels showed decreased levels but did not normalize. He had a normal neurodevelopmental outcome on a lysine-restricted diet. Despite normal CSF and plasma tryptophan levels and normal tryptophan intake, he developed mild CSF serotonin deficiency at one year of therapy. Stricter lysine restriction would be necessary to normalize CSF α-AASA levels, but might increase the risks associated with the diet. Patients are at risk of cerebral serotonin deficiency and should be monitored by CSF neurotransmitter measurements.
    Full-text · Article · Dec 2014 · Molecular Genetics and Metabolism Reports
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    • "Peripheral neuropathy and dorsal root ganglionopathy have been reported as a side effect of high-dose pyridoxine therapy [31] [32]. In addition to pyridoxine, a lysine-restricted diet might be of beneficial effect in improving the long term developmental outcomes of children with PDE [33]. Although early diagnosis and treatment are very important , a wide variety of neurodevelopmental disabilities have been noted in patients with PDE irrespective of timing of initiation of treatment, indicating an underlying multifactorial etiology for developmental outcome. "
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    ABSTRACT: Untreated epileptic encephalopathies in children may potentially have disastrous outcomes. Treatment with antiepileptic drugs (AEDs) often may not control the seizures, and even if they do, this measure is only symptomatic and not specific. It is especially valuable to identify potential underlying conditions that have specific treatments. Only a few conditions have definitive treatments that can potentially modify the natural course of disease. In this paper, we discuss the few such conditions that are responsive to vitamin or vitamin derivatives.
    Full-text · Article · Jul 2013
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    ABSTRACT: Autosomal recessive disorders affecting pyridoxine (vitamin B6) metabolism are a rare but well-recognized cause of neonatal seizures. Antiquitin deficiency, caused by mutations in ALDH7A1, is a disorder of the lysine degradation pathway causing accumulation of an intermediate that complexes with pyridoxal phosphate. Reports of long-term follow-up of neonatal pyridoxine-dependent seizures (PDS) remain scarce and prognostic information is varied. We report a case of PDS in a 47-year-old lady who originally presented shortly after birth in 1964. Pyridoxine replacement was successful and diagnostic confirmation was obtained later in life, initially by biochemical analysis of serum pipecolic acid. Subsequently we organized genetic analysis of ALDH7A1, which revealed compound heterozygous mutations. To our knowledge, this represents the longest duration of follow-up published to date.
    No preview · Article · Feb 2013
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