Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med

University of Freiburg, Freiburg, Baden-Württemberg, Germany
Nature Medicine (Impact Factor: 27.36). 04/2006; 12(3):307-9. DOI: 10.1038/nm1366
Source: PubMed


We show here that children with pyridoxine-dependent seizures (PDS) have mutations in the ALDH7A1 gene, which encodes antiquitin; these mutations abolish the activity of antiquitin as a delta1-piperideine-6-carboxylate (P6C)-alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase. The accumulating P6C inactivates pyridoxal 5'-phosphate (PLP) by forming a Knoevenagel condensation product. Measurement of urinary alpha-AASA provides a simple way of confirming the diagnosis of PDS and ALDH7A1 gene analysis provides a means for prenatal diagnosis.

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    • "Identification of alpha-aminoadipic semialdehyde dehydrogenase deficiency as the cause of PDE, an enzyme within the cerebral lysine degradation pathway, suggested that patients may benefit from dietary limitation of lysine [1] [13]. The impaired lysine metabolism in PDE results in significant accumulation of α-AASA and P6C, which are likely neurotoxic and may contribute to the pathogenesis of PDE. "
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    ABSTRACT: & Objectives: Of patients with pyridoxine-dependent epilepsy (PDE) due to ATQ deficiency, 75% suffer intellectual disability despite adequate seizure control with high dose pyridoxine. We aimed to assess the safety and efficacy of two novel therapeutic strategies to reduce accumulation of toxic intermediates in this cerebral lysine degradation defect. Methods: In two open-label observational studies, seven children with confirmed ATQ deficiency were started on dietary lysine restriction with regular nutritional monitoring, and outcome evaluation pipecolic acid, AASA levels in body fluids; development/cognition via age-appropriate tests and parental observations; epilepsy). Subsequently additional arginine supplementation was initiated to reduce cerebral lysine flux (cation transporter competitive inhibition).. Results: Lysine-restriction was well tolerated and diet is safe, resulted in reduction of lysine intermediates in all body fluids in all patients (up to 80% reduction AASA in cerebrospinal fluid), with beneficial effects on seizure control and psychomotor development. Additional arginine fortification resulted in normalization of biomarkers and dramatic improvement of psychomotor development. Discussion: Triple therapy is effective, especially if implemented early; studies for PDE newborn screening have been initiated. For dissemination and evidence generation, our PDE Consortium published Recommendations, developed a Digital Diet App and established a RedCap study database ( ).
    Preview · Article · May 2015 · The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques
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    • "enzyme in the lysine catabolic pathway were identified in 2006 [2]. α-AASAD enzyme deficiency leads to the accumulation of α-aminoadipic-acid-semialdehyde (α-AASA) and piperidine 6-carboxylic-acid (P6C); the latter inactivates pyridoxal-5-phosphate [2] [3]. Pipecolic acid (PA) elevations in body fluids were reported as a secondary biomarker [4]. "
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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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    • "These mutations result in the excess production of Δ 1 -piperideine-6-carboxylate, a compound which complexes with and depletes pyridoxal-5-phosphate [74]. Pyridoxal-5-phosphate depletion reduces glutamic acid decarboxylase activity, resulting in a reduction in GABA synthesis [74] [76] [77]. Although early-onset intractable tonic–clonic seizures are the usual presentation, late-onset seizures [78] [79] [80] and other seizure types [81] [82] [83] have been described. "
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    ABSTRACT: Autism spectrum disorder (ASD) affects a significant number of individuals in the United States, with the prevalence continuing to grow. A significant proportion of individuals with ASD have comorbid medical conditions such as epilepsy. In fact, treatment-resistant epilepsy appears to have a higher prevalence in children with ASD than in children without ASD, suggesting that current antiepileptic treatments may be suboptimal in controlling seizures in many individuals with ASD. Many individuals with ASD also appear to have underlying metabolic conditions. Metabolic conditions such as mitochondrial disease and dysfunction and abnormalities in cerebral folate metabolism may affect a substantial number of children with ASD, while other metabolic conditions that have been associated with ASD such as disorders of creatine, cholesterol, pyridoxine, biotin, carnitine, γ-aminobutyric acid, purine, pyrimidine, and amino acid metabolism and urea cycle disorders have also been associated with ASD without the prevalence clearly known. Interestingly, all of these metabolic conditions have been associated with epilepsy in children with ASD. The identification and treatment of these disorders could improve the underlying metabolic derangements and potentially improve behavior and seizure frequency and/or severity in these individuals. This paper provides an overview of these metabolic disorders in the context of ASD and discusses their characteristics, diagnostic testing, and treatment with concentration on mitochondrial disorders. To this end, this paper aims to help optimize the diagnosis and treatment of children with ASD and epilepsy. This article is part of a Special Issue entitled "Autism and Epilepsy".
    Full-text · Article · Nov 2014 · Epilepsy & Behavior
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