RARE DISEASE
Pyridoxine-dependent epilepsy
Pyridoxine-dependent epilepsy
Pyridoxine-dependent epilepsy
Synonyms: Antiquitin deficiency, Vitamin B6-dependent seizures
Synonyms: Antiquitin deficiency, Vitamin B6-dependent seizures
Synonyms: Antiquitin deficiency, Vitamin B6-dependent seizures
Drug discovery
1
drug
With orphan designation
Overview
Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive neurometabolic disorder caused by ALDH7A1 mutations, disrupting lysine metabolism and leading to intractable seizures resistant to standard anti-seizure medications. Seizures typically manifest prenatally, neonatally, or postnatally and are exclusively responsive to high-dose pyridoxine (vitamin B6). Despite treatment, most patients experience neurodevelopmental delays, particularly in language and cognition. Diagnosis combines genetic testing, elevated α-aminoadipic semialdehyde biomarkers, and clinical pyridoxine responsiveness [1][6][13].
Burden
Neurodevelopmental: 70–80% develop intellectual disabilities despite seizure control [1][9][17].
Mortality: Untreated cases risk fatal status epilepticus; neonatal deaths reported [9][17].
Economic: Lifelong pyridoxine/diet management, multidisciplinary care, and genetic counseling required [9][16].
Therapies
Pyridoxine: Lifelong supplementation (15–30 mg/kg/day; max 500 mg/day) for seizure control [1][11][16].
Adjunct therapies: Lysine-restricted diets and arginine fortification to reduce toxic metabolites [3][13][16].
Acute management: IV pyridoxine (100–500 mg) during status epilepticus with cardiorespiratory monitoring [8][16].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
222 drug discovery papers about Pyridoxine-dependent epilepsy, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
222 drug discovery papers about Pyridoxine-dependent epilepsy, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-29 | Astrocyte redox imbalance underlies prelimbic neuronal hypoactivity and maladaptive affective behaviors in epilepsy.
A fundamental but unanswered question in neuropsychiatry is whether the psychiatric symptoms of epilepsy are caused by the same or a separate pathophysiology as seizures. To address this question, we investigated a monogenic form of epilepsy (pyridoxine-dependent epilepsy) caused by aldehyde dehydrogenase 7 family member A1 (ALDH7A1) mutations. ALDH7A1 global knockout mice exhibited both seizure-associated and maladaptive affective behavioral phenotypes. However, seizure phenotypes were caused by ALDH7A1 deletion in hepatocytes whereas maladaptive affective behaviors were caused by ALDH7A1 deletion in astrocytes. Deletion in astrocytes disrupted astrocyte redox homeostasis, impairing regulation of extracellular ion concentrations and reducing neuronal activity in the prelimbic cortex. Sulforaphane, which activates the NRF2 antioxidant pathway, restored prelimbic neuronal activity and rescued maladaptive affective behaviors in ALDH7A1 knockout mice but did not prevent seizures. These studies implicate astrocyte redox homeostasis and prelimbic hypoactivity in maladaptive affective behavioral phenotypes in a congenital form of epilepsy, which are mechanistically and therapeutically dissociable from seizure pathophysiology.
2026-05-07 | Synergism of magnesium- and pyridoxine-dependent proteins in nervous system support: systems biological analysis
Background . For magnesium–pyridoxine therapy (original drug Magne B6®), the systems-level proteomic synergy of magnesium and pyridoxine-dependent proteins remains to be not sufficiently characterized in the nervous systems of pregnant women and diverse age groups. Objective : To establish the mechanisms of action of magnesium-dependent proteins on human neurophysiology and to characterize the proteomic synergy of original product components (a fixed combination of magnesium lactate and pyridoxine). Material and methods . In order to compile the most comprehensive list of magnesium- and pyridoxine-dependent proteins, the study applied algorithms for genome/proteome annotation and heterogeneous feature analysis, developed within the topological recognition theory. Subsequent analyses were conducted using data such as annotation keywords, protein tissue distribution, other protein cofactors, roles in the reactom, functional categories, protein interactions with various pharmaceuticals (including other micronutrients and nutraceuticals), and diseases associated with impaired magnesium-dependent protein activity. Results . The study identified a comprehensive set of magnesium- (n=1020) and pyridoxine-dependent (n=99) proteins, with a specific focus on those involved in nervous system function. Among various tissues, the brain exhibits the greatest diversity of magnesiumdependent (n=244) proteins. The synergy between magnesium and pyridoxine is manifested across many levels: cofactor interactions, protein functional categories, interactions with various pharmaceuticals, and associations with diseases. Notably, many pyridoxinedependent proteins interact with the same cofactors as magnesium-dependent proteins. Pyridoxine-dependent proteins generally fall into the same most common functional categories as magnesium-dependent ones, indicating a clear synergism between magnesium and pyridoxine in supporting fundamental physiological processes. At least 172 magnesium-dependent proteins and 20 pyridoxinedependent proteins in the human proteome are involved in the neuroprotective, neurotrophic, and other neurotropic effects of magnesium. These proteins play an important role in maintaining neurotransmitter homeostasis, neuroplasticity, and neuronal survival. Furthermore, a total of 143 drugs (including a number of micronutrients and/or nutraceuticals) are associated with the function/activity of magnesium-dependent proteins; these encompass anesthetics, anxiolytics, hypnotics and sedatives, antidementia drugs, calcium channel blockers, cardiac glycosides, antiarrhythmic agents and other cardiac drugs, antidepressants, antipsychotics, antibiotics, etc. The interaction of magnesium-dependent proteins with these groups of drugs is multidirectional. Analysis of diseases associated with dysfunction of magnesium-dependent proteins in the human proteome revealed at least 80 different diseases associated with magnesium deficiency (seizures; impaired fetal neurological development; myelination of nerves; impaired vision, hearing, and adaptive behavior; cognitive disorders; intellectual deficit). The majority of these pathologies linked to the dysfunction of magnesium-dependent proteins are also associated with the dysfunction of pyridoxine-dependent proteins. An extensive clinical evidence base has been established for the use of Magne B6® in neurology and neuropediatrics. Conclusion . The combination of organic magnesium salts (citrate, lactate, or pyroglutamate) with vitamin B6 in the Magne B6® product line (Magne B6® Forte, Magne B6® tablets, and Magne B6® oral solution) provides synergistic neuroprotective and mood-stabilizing effects. Evidence-based data confirm the pharmacological efficacy of the original drug Magne B6®.
2026-05-04 | Classical and Emerging Biomarkers in Pyridoxine-Dependent Epilepsy (PDE-ALDH7A1): Implications for Early Diagnosis and Therapeutic Development.
Pyridoxine-dependent epilepsy due to ALDH7A1 deficiency (PDE-ALDH7A1) is a rare but treatable epileptic encephalopathy caused by disruption of lysine catabolism and secondary depletion of pyridoxal-5'-phosphate (PLP). Although seizures are often controlled with pyridoxine supplementation, many patients continue to experience neurodevelopmental impairment, underscoring the importance of early diagnosis and improved therapeutic strategies. Central to both diagnosis and pathophysiology is the accumulation of lysine-derived metabolites, most notably α-aminoadipate semialdehyde (α-AASA), its cyclic Schiff base Δ1-piperideine-6-carboxylate (P6C), and pipecolic acid. These metabolites have become the biochemical hallmarks of PDE-ALDH7A1, linking ALDH7A1 pathogenic variants to PLP inactivation and neuronal dysfunction. However, their chemical instability and analytical requirements pose challenges for universal diagnostics and newborn screening. This review summarizes current understanding of lysine catabolism in health and disease, critically evaluates the diagnostic utility and limitations of classical biomarkers, and discusses emerging insights into their pathophysiological roles. We further highlight recent discoveries of novel, chemically stable biomarkers, including 6-oxopiperidine-2-carboxylic acid (6-oxo-PIP), 2-oxopropylpiperidine-2-carboxylic acid (2-OPP), and 6-hydroxy-2-aminocaproic acid (HACA), identified through advanced metabolomics approaches. These metabolites show promise for newborn screening and provide new mechanistic links between metabolic stress, seizure susceptibility, and ongoing neurological morbidity despite pyridoxine treatment. Collectively, advances in biomarker discovery are reshaping diagnostic strategies for PDE-ALDH7A1 and offering new perspectives on disease mechanisms, paving the way for earlier detection and the development of more effective, mechanism-based therapies.
2026-03-06 | A novel therapy for pyridoxine-dependent epilepsy due to biallelic pathogenic variants in ALDH7A1: secondary mitochondrial energy deficiency and improvements of neurodevelopmental outcomes on triheptanoin treatment.
Pyridoxine-dependent epilepsy (PDE) due to biallelic pathogenic variants in ALDH7A1 (PDE-ALDH7A1) is an metabolic disease of lysine catabolism. Current standard treatment includes pyridoxine, arginine, and lysine- or protein-restricted diet. Pyridoxine treats seizures. Arginine and lysine- or protein-restricted diet decrease elevated α-aminoadipic semialdehyde (α-AASA) and Δ1- piperideine-6-carboxylate (P6C) levels to improve neurodevelopmental outcomes. We previously reported abnormalities in tricarboxylic acid (TCA) cycle and electron transport chain in PDE-ALDH7A1. We report a new patient with PDE-ALDH7A1 who did not show any improvements in neurodevelopment on the current standard therapy. We hypothesized that triheptanoin will provide substrate to TCA cycle and improve abnormal energy metabolism leading to improvements in neurodevelopmental outcome. To treat this patient with triheptanoin to improve neurodevelopmental outcome. Due to complex I deficiency and lack of response to the current standard therapy, we applied triheptanoin novel therapy. A 4-year-old male had compound heterozygous variants in ALDH7A1 and markedly elevated urine α-AASA. The goal dose of triheptanoin was 50% of the estimated energy requirement (EER). We assessed efficacy of triheptanoin using neuropsychological assessments. We measured 6-oxopipecolic acid using liquid chromatography tandem mass spectrometry. Triheptanoin was started at 10 mL/day. There was nausea up to 3 weeks after each dose increase, which has improved allowing us to increase triheptanoin gradually. The maximum actual dose of triheptanoin was 40% of EER. Cognitive composite score improved from 16% to 63% on treatment. All chemistry and biochemical investigations were normal. 6-oxopipecolic acid levels did not normalize. Triheptanoin treatment seemed to be safe and tolerated well. Triheptanoin is an anaplerotic agent to provide substrates to the TCA cycle. This novel therapy improved neurodevelopmental outcome in our patient with PDE-ALDH7A1. We think that trihepatonoin should be the part of the current standard therapy to improve neurodevelopmental outcomes in patients with PDE-ALDH7A1.
2026-02-27 | Epileptic encephalopathies in inborn errors of metabolism in young children: focus on pyridoxine-dependent epilepsy
Inborn errors of metabolism (IEM) represent one of the most clinically significant yet underdiagnosed causes of epileptic encephalopathies in young children. The team of the Department of Pediatric Neurology at the State Institution "Ukrainian Center of Maternity and Childhood of the NAMS of Ukraine" has been investigating this problem for over 25 years, which served as the foundation for the preparation of this publication. Particular attention is warranted by pyridoxine-dependent epilepsy (PDE) — a rare autosomal recessive disorder caused by pathogenic variants in the ALDH7A1 gene — as a classical example of a treatable metabolic epileptic encephalopathy. Aim - to systematize current evidence on epileptic encephalopathies in inborn errors of metabolism in young children, and to elucidate the underlying pathogenetic mechanisms, clinical features, and approaches to diagnosis and treatment. A systematic review of the scientific literature was conducted using PubMed/MEDLINE and OMIM databases, with a focus on publications from the past 10 years. A clinical case of a 3-month-old girl with neonatal epilepsy refractory to standard therapy is presented. The diagnostic workup included prolonged video-EEG monitoring, brain MRI, biochemical investigations, and next-generation sequencing (NGS) using the CarrierSeq panel (420 genes). Epileptic seizures associated with IEM are characteristically resistant to standard antiseizure medications and may present as status epilepticus at onset. Age of manifestation serves as a key diagnostic indicator: the neonatal period is most typical for pyridoxine-dependent epilepsy, urea cycle defects, and nonketotic hyperglycinemia, while infancy is more characteristic of GLUT1 deficiency, biotinidase deficiency, and peroxisomal disorders. The diagnostic algorithm encompasses three tiers: a basic biochemical panel (glucose, lactate, pyruvate, ammonia, blood gas analysis, plasma amino acids, urine organic acids, acylcarnitine profile), specialized metabolic tests (α-aminoadipic semialdehyde, pipecolic acid, cerebrospinal fluid pyridoxal phosphate level), and molecular genetic analysis. An empirical therapeutic trial with pyridoxine (30 mg/kg/day for 3 days) is indicated in all neonates with seizures of unknown etiology refractory to conventional therapy. In the presented case, two pathogenic variants in compound heterozygous state were identified in the ALDH7A1 gene, confirming the diagnosis of PDE. Targeted therapy comprising pyridoxine, arginine, folinic acid, and a lysine-restricted diet resulted in sustained seizure remission and normalization of psychomotor development. Conclusions. Early identification and verification of a metabolic defect enables pathogenetically targeted treatment with the potential to fundamentally alter the disease prognosis. Nutritional and vitamin-micronutrient therapy represents an effective therapeutic approach for treatable forms of metabolic epilepsy, particularly in pyridoxine-dependent epilepsies. The authors declare no conflict of interest.
oligonucleotides
2025-11-20 | Potential of AON therapy targeting AASS: A promising molecular therapy for pyridoxine-dependent epilepsy
Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder, associated with pathogenic variants in ALDH7A1 leading to aberrant lysine degradation and accumulation of neurotoxic metabolites. The condition is characterized by epileptic seizures, typically occurring soon after birth, which are unresponsive to standard antiseizure medications (ASMs) and respond only to pyridoxine.1,2 Seizures may respond initially to standard ASM in some patients.3 Despite initiation of early treatment and seizure control, global developmental delay and/or intellectual disability have been reported in 75% of PDE patients.
2025-10-29 | Targeting AASS alleviates neurotoxicity and improves mitochondrial function in astrocyte models for pyridoxine-dependent epilepsy.
Pyridoxine-dependent epilepsy (PDE) is a rare neurometabolic disorder of lysine catabolism caused by bi-allelic variants in ALDH7A1. This enzyme deficiency leads to accumulation of neurotoxic metabolites, pyridoxal-phosphate inactivation, and consequently severe neurological symptoms. Current treatments, including vitamin B6 supplementation and lysine-restricted diets, partially alleviate seizures and intellectual disability but are not curative. To explore underlying mechanisms and potential therapies, we generated patient-derived human induced pluripotent stem cell (hiPSC) lines that were subsequently differentiated into astrocytes, the primary source of ALDH7A1 in the brain and key regulators of metabolic homeostasis. Metabolomic analyses confirmed elevated PDE biomarkers, and RNA sequencing revealed gene expression changes consistent with increased oxidative stress. Oxidative damage was validated by markers of DNA oxidation, increased reactive oxygen species (ROS) levels, and lipid peroxidation. In addition, dysregulated oxygen consumption rates suggested mitochondrial dysfunction in PDE astrocytes. Notably, these pathological phenotypes were alleviated by downregulating alpha-aminoadipic semialdehyde synthase (AASS), the first enzyme of the lysine catabolism, by using CRISPR-Cas9 editing or antisense oligonucleotides (AONs). This demonstrates that lysine catabolism underlies these phenotypes and highlights the therapeutic potential of AON therapy targeting AASS to reduce neurotoxic metabolite accumulation. These findings provide a promising strategy for developing targeted treatments for PDE and other rare neurometabolic disorders.
2025-05-12 | Targeting AASS improves neurotoxicity and mitochondrial function in astrocyte models for pyridoxine dependent epilepsy
Abstract Pyridoxine-dependent epilepsy (PDE) is a rare neurometabolic disorder of lysine catabolism caused by bi-allelic variants in ALDH7A1 . This enzyme deficiency leads to the accumulation of neurotoxic metabolites, pyridoxal-phosphate inactivation and consequently severe neurological symptoms. Current treatments, including vitamin B6 supplementation and lysine-restricted diets, partially alleviate seizures and intellectual disability but are not curative. To explore underlying mechanisms and potential therapies, we generated patient-derived human induced pluripotent stem lines (hiPSC) that were subsequently differentiated into astrocytes, the primary source of ALDH7A1 in the brain and key regulators of metabolic homeostasis. Metabolomic analyses confirmed elevated PDE biomarkers, and RNA sequencing revealed gene expression changes consistent with increased oxidative stress. Oxidative damage was validated by markers of DNA oxidation and lipid peroxidation. In addition, dysregulated oxygen consumption rates suggested mitochondrial dysfunction in PDE astrocytes. Notably, these pathological phenotypes were alleviated by downregulating AASS , the first enzyme of the lysine catabolism, by using CRISPR/Cas9 editing or antisense oligonucleotides (AON). This demonstrates that lysine catabolism underlies these phenotypes and highlights the therapeutic potential of AON therapy targeting AASS to reduce neurotoxic metabolite accumulation. These findings provide a promising strategy for developing targeted treatments for PDE and other rare neurometabolic disorders.
2019-07-29 | Update on the treatment of vitamin B6 dependent epilepsies
Introduction: Vitamin B6 dependent epilepsies are a group of treatable diseases (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinaemia type II and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects) responding to pyridoxine or pyridoxal-5I-phosphate. Areas covered: A critical review was conducted on the therapeutic management of all the reported patients with genetically confirmed diagnoses of diseases affecting vitamin B6 metabolism and presenting with pyridoxine or pyridoxal-5I-phosphate dependent-seizures. Data about safety and efficacy were analyzed as well as the management of supplementation with pyridoxine or pyridoxal-5I-phosphate both in the acute phases and in the maintenance therapies. The authors also analyzed alternative therapeutic strategies for ALDH7A1 deficiency (lysine-restricted diet, arginine supplementation, oligonucleotide antisense therapy, upstream inhibition of aminoadipic semialdehyde synthase). Expert opinion: The administration of pyridoxine or pyridoxal-5I-phosphate should be considered in all intractable seizures also beyond the first year of life. Lysine restricted diet and arginine supplementation should be introduced in all the confirmed ALDH7A1 deficient patients. Pre or post-natal supplementation with pyridoxine should be given in familial cases until an eventual molecular genetic disconfirmation. Minor data about alternative therapies are available for other disorders of vitamin B6 metabolism.
2013-01-25 | Clinical, biochemical, and molecular studies in pyridoxine‐dependent epilepsy. Antisense therapy as possible new therapeutic option
Summary Purpose Pyridoxine‐dependent epilepsy seizure ( PDE ; OMIM 266100) is a disorder associated with severe seizures that can be controlled pharmacologically with pyridoxine. In the majority of patients with PDE , the disorder is caused by the deficient activity of the enzyme α‐aminoadipic semialdehyde dehydrogenase (antiquitin protein), which is encoded by the ALDH7A1 gene. The aim of this work was the clinical, biochemical, and genetic analysis of 12 unrelated patients, mostly from S pain, in an attempt to provide further valuable data regarding the wide clinical, biochemical, and genetic spectrum of the disease. Methods The disease was confirmed based on the presence of α‐aminoadipic semialdehyde (α‐ AASA ) in urine measured by liquid chromatography tandem mass spectrometry (LC‐MS/MS) and pipecolic acid ( PA ) in plasma and/or cerebrospinal fluid ( CSF ) measured by high performance liquid chromatography ( HPLC )/ MS / MS and by sequencing analysis of messenger RNA ( mRNA ) and genomic DNA of ALDH7A1 . Key Findings Most of the patients had seizures in the neonatal period, but they responded to vitamin B 6 administration. Three patients developed late‐onset seizures, and most patients showed mild‐to‐moderate postnatal developmental delay. All patients had elevated PA and α‐ AASA levels, even those who had undergone pyridoxine treatment for several years. The clinical spectrum of our patients is not limited to seizures but many of them show associated neurologic dysfunctions such as muscle tone alterations, irritability, and psychomotor retardation. The mutational spectrum of the present patients included 12 mutations, five already reported (c.500 A > G , c.919 C > T , c.1429 G > C c.1217_1218del AT , and c.1482‐1 G > T ) and seven novel sequence changes (c.75 C > T , c.319 G > T , c.554_555del AA , c.757 C > T , c.787 + 1 G > T , c.1474 T > C , c.1093‐?_1620+?). Only one mutation, p. G 477 R (c.1429 G > C ), was recurrent; this was detected in four different alleles. Transcriptional profile analysis of one patient's lymphoblasts and ex vivo splicing analysis showed the silent nucleotide change c.75 C > T to be a novel splicing mutation creating a new donor splice site inside exon 1. Antisense therapy of the aberrant mRNA splicing in a lymphoblast cell line harboring mutation c.75 C > T was successful. Significance The present results broaden our knowledge of PDE , provide information regarding the genetic background of PDE in S pain, afford data of use when making molecular‐based prenatal diagnosis, and provide a cellular proof‐of concept for antisense therapy application.
gene therapies
2025-05-08 | Targeting Lysine α-Ketoglutarate Reductase to Treat Pyridoxine-Dependent Epilepsy.
Pyridoxine-dependent epilepsy (PDE), a rare autosomal recessively inherited metabolic disease, results from mutations in ALDH7A1, a gene crucial for lysine metabolism. Although early high-dose pyridoxine treatment can control seizures, ∼75% of PDE patients still have intellectual disabilities. In this study, we test the hypothesis of substrate reduction therapy for PDE by genetically perturbing lysine α-ketoglutarate reductase (LKR), an enzyme upstream of the defective ALDH7A1, in male and female laboratory mice. A homozygous mutation in LKR completely abolishes the accumulation of toxic lysine catabolism intermediates (α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate), ends the epileptic state, and restores the defective brain development and cognitive impairments in ALDH7A1-deficient mice. Therefore, these genetic data prove the concept of the effectiveness of substrate reduction therapy for PDE via LKR inhibition.
small molecules
2026-07-29 | Astrocyte redox imbalance underlies prelimbic neuronal hypoactivity and maladaptive affective behaviors in epilepsy.
A fundamental but unanswered question in neuropsychiatry is whether the psychiatric symptoms of epilepsy are caused by the same or a separate pathophysiology as seizures. To address this question, we investigated a monogenic form of epilepsy (pyridoxine-dependent epilepsy) caused by aldehyde dehydrogenase 7 family member A1 (ALDH7A1) mutations. ALDH7A1 global knockout mice exhibited both seizure-associated and maladaptive affective behavioral phenotypes. However, seizure phenotypes were caused by ALDH7A1 deletion in hepatocytes whereas maladaptive affective behaviors were caused by ALDH7A1 deletion in astrocytes. Deletion in astrocytes disrupted astrocyte redox homeostasis, impairing regulation of extracellular ion concentrations and reducing neuronal activity in the prelimbic cortex. Sulforaphane, which activates the NRF2 antioxidant pathway, restored prelimbic neuronal activity and rescued maladaptive affective behaviors in ALDH7A1 knockout mice but did not prevent seizures. These studies implicate astrocyte redox homeostasis and prelimbic hypoactivity in maladaptive affective behavioral phenotypes in a congenital form of epilepsy, which are mechanistically and therapeutically dissociable from seizure pathophysiology.
2026-05-07 | Synergism of magnesium- and pyridoxine-dependent proteins in nervous system support: systems biological analysis
Background . For magnesium–pyridoxine therapy (original drug Magne B6®), the systems-level proteomic synergy of magnesium and pyridoxine-dependent proteins remains to be not sufficiently characterized in the nervous systems of pregnant women and diverse age groups. Objective : To establish the mechanisms of action of magnesium-dependent proteins on human neurophysiology and to characterize the proteomic synergy of original product components (a fixed combination of magnesium lactate and pyridoxine). Material and methods . In order to compile the most comprehensive list of magnesium- and pyridoxine-dependent proteins, the study applied algorithms for genome/proteome annotation and heterogeneous feature analysis, developed within the topological recognition theory. Subsequent analyses were conducted using data such as annotation keywords, protein tissue distribution, other protein cofactors, roles in the reactom, functional categories, protein interactions with various pharmaceuticals (including other micronutrients and nutraceuticals), and diseases associated with impaired magnesium-dependent protein activity. Results . The study identified a comprehensive set of magnesium- (n=1020) and pyridoxine-dependent (n=99) proteins, with a specific focus on those involved in nervous system function. Among various tissues, the brain exhibits the greatest diversity of magnesiumdependent (n=244) proteins. The synergy between magnesium and pyridoxine is manifested across many levels: cofactor interactions, protein functional categories, interactions with various pharmaceuticals, and associations with diseases. Notably, many pyridoxinedependent proteins interact with the same cofactors as magnesium-dependent proteins. Pyridoxine-dependent proteins generally fall into the same most common functional categories as magnesium-dependent ones, indicating a clear synergism between magnesium and pyridoxine in supporting fundamental physiological processes. At least 172 magnesium-dependent proteins and 20 pyridoxinedependent proteins in the human proteome are involved in the neuroprotective, neurotrophic, and other neurotropic effects of magnesium. These proteins play an important role in maintaining neurotransmitter homeostasis, neuroplasticity, and neuronal survival. Furthermore, a total of 143 drugs (including a number of micronutrients and/or nutraceuticals) are associated with the function/activity of magnesium-dependent proteins; these encompass anesthetics, anxiolytics, hypnotics and sedatives, antidementia drugs, calcium channel blockers, cardiac glycosides, antiarrhythmic agents and other cardiac drugs, antidepressants, antipsychotics, antibiotics, etc. The interaction of magnesium-dependent proteins with these groups of drugs is multidirectional. Analysis of diseases associated with dysfunction of magnesium-dependent proteins in the human proteome revealed at least 80 different diseases associated with magnesium deficiency (seizures; impaired fetal neurological development; myelination of nerves; impaired vision, hearing, and adaptive behavior; cognitive disorders; intellectual deficit). The majority of these pathologies linked to the dysfunction of magnesium-dependent proteins are also associated with the dysfunction of pyridoxine-dependent proteins. An extensive clinical evidence base has been established for the use of Magne B6® in neurology and neuropediatrics. Conclusion . The combination of organic magnesium salts (citrate, lactate, or pyroglutamate) with vitamin B6 in the Magne B6® product line (Magne B6® Forte, Magne B6® tablets, and Magne B6® oral solution) provides synergistic neuroprotective and mood-stabilizing effects. Evidence-based data confirm the pharmacological efficacy of the original drug Magne B6®.
2026-05-04 | Classical and Emerging Biomarkers in Pyridoxine-Dependent Epilepsy (PDE-ALDH7A1): Implications for Early Diagnosis and Therapeutic Development.
Pyridoxine-dependent epilepsy due to ALDH7A1 deficiency (PDE-ALDH7A1) is a rare but treatable epileptic encephalopathy caused by disruption of lysine catabolism and secondary depletion of pyridoxal-5'-phosphate (PLP). Although seizures are often controlled with pyridoxine supplementation, many patients continue to experience neurodevelopmental impairment, underscoring the importance of early diagnosis and improved therapeutic strategies. Central to both diagnosis and pathophysiology is the accumulation of lysine-derived metabolites, most notably α-aminoadipate semialdehyde (α-AASA), its cyclic Schiff base Δ1-piperideine-6-carboxylate (P6C), and pipecolic acid. These metabolites have become the biochemical hallmarks of PDE-ALDH7A1, linking ALDH7A1 pathogenic variants to PLP inactivation and neuronal dysfunction. However, their chemical instability and analytical requirements pose challenges for universal diagnostics and newborn screening. This review summarizes current understanding of lysine catabolism in health and disease, critically evaluates the diagnostic utility and limitations of classical biomarkers, and discusses emerging insights into their pathophysiological roles. We further highlight recent discoveries of novel, chemically stable biomarkers, including 6-oxopiperidine-2-carboxylic acid (6-oxo-PIP), 2-oxopropylpiperidine-2-carboxylic acid (2-OPP), and 6-hydroxy-2-aminocaproic acid (HACA), identified through advanced metabolomics approaches. These metabolites show promise for newborn screening and provide new mechanistic links between metabolic stress, seizure susceptibility, and ongoing neurological morbidity despite pyridoxine treatment. Collectively, advances in biomarker discovery are reshaping diagnostic strategies for PDE-ALDH7A1 and offering new perspectives on disease mechanisms, paving the way for earlier detection and the development of more effective, mechanism-based therapies.
2026-03-06 | A novel therapy for pyridoxine-dependent epilepsy due to biallelic pathogenic variants in ALDH7A1: secondary mitochondrial energy deficiency and improvements of neurodevelopmental outcomes on triheptanoin treatment.
Pyridoxine-dependent epilepsy (PDE) due to biallelic pathogenic variants in ALDH7A1 (PDE-ALDH7A1) is an metabolic disease of lysine catabolism. Current standard treatment includes pyridoxine, arginine, and lysine- or protein-restricted diet. Pyridoxine treats seizures. Arginine and lysine- or protein-restricted diet decrease elevated α-aminoadipic semialdehyde (α-AASA) and Δ1- piperideine-6-carboxylate (P6C) levels to improve neurodevelopmental outcomes. We previously reported abnormalities in tricarboxylic acid (TCA) cycle and electron transport chain in PDE-ALDH7A1. We report a new patient with PDE-ALDH7A1 who did not show any improvements in neurodevelopment on the current standard therapy. We hypothesized that triheptanoin will provide substrate to TCA cycle and improve abnormal energy metabolism leading to improvements in neurodevelopmental outcome. To treat this patient with triheptanoin to improve neurodevelopmental outcome. Due to complex I deficiency and lack of response to the current standard therapy, we applied triheptanoin novel therapy. A 4-year-old male had compound heterozygous variants in ALDH7A1 and markedly elevated urine α-AASA. The goal dose of triheptanoin was 50% of the estimated energy requirement (EER). We assessed efficacy of triheptanoin using neuropsychological assessments. We measured 6-oxopipecolic acid using liquid chromatography tandem mass spectrometry. Triheptanoin was started at 10 mL/day. There was nausea up to 3 weeks after each dose increase, which has improved allowing us to increase triheptanoin gradually. The maximum actual dose of triheptanoin was 40% of EER. Cognitive composite score improved from 16% to 63% on treatment. All chemistry and biochemical investigations were normal. 6-oxopipecolic acid levels did not normalize. Triheptanoin treatment seemed to be safe and tolerated well. Triheptanoin is an anaplerotic agent to provide substrates to the TCA cycle. This novel therapy improved neurodevelopmental outcome in our patient with PDE-ALDH7A1. We think that trihepatonoin should be the part of the current standard therapy to improve neurodevelopmental outcomes in patients with PDE-ALDH7A1.
2026-02-27 | Epileptic encephalopathies in inborn errors of metabolism in young children: focus on pyridoxine-dependent epilepsy
Inborn errors of metabolism (IEM) represent one of the most clinically significant yet underdiagnosed causes of epileptic encephalopathies in young children. The team of the Department of Pediatric Neurology at the State Institution "Ukrainian Center of Maternity and Childhood of the NAMS of Ukraine" has been investigating this problem for over 25 years, which served as the foundation for the preparation of this publication. Particular attention is warranted by pyridoxine-dependent epilepsy (PDE) — a rare autosomal recessive disorder caused by pathogenic variants in the ALDH7A1 gene — as a classical example of a treatable metabolic epileptic encephalopathy. Aim - to systematize current evidence on epileptic encephalopathies in inborn errors of metabolism in young children, and to elucidate the underlying pathogenetic mechanisms, clinical features, and approaches to diagnosis and treatment. A systematic review of the scientific literature was conducted using PubMed/MEDLINE and OMIM databases, with a focus on publications from the past 10 years. A clinical case of a 3-month-old girl with neonatal epilepsy refractory to standard therapy is presented. The diagnostic workup included prolonged video-EEG monitoring, brain MRI, biochemical investigations, and next-generation sequencing (NGS) using the CarrierSeq panel (420 genes). Epileptic seizures associated with IEM are characteristically resistant to standard antiseizure medications and may present as status epilepticus at onset. Age of manifestation serves as a key diagnostic indicator: the neonatal period is most typical for pyridoxine-dependent epilepsy, urea cycle defects, and nonketotic hyperglycinemia, while infancy is more characteristic of GLUT1 deficiency, biotinidase deficiency, and peroxisomal disorders. The diagnostic algorithm encompasses three tiers: a basic biochemical panel (glucose, lactate, pyruvate, ammonia, blood gas analysis, plasma amino acids, urine organic acids, acylcarnitine profile), specialized metabolic tests (α-aminoadipic semialdehyde, pipecolic acid, cerebrospinal fluid pyridoxal phosphate level), and molecular genetic analysis. An empirical therapeutic trial with pyridoxine (30 mg/kg/day for 3 days) is indicated in all neonates with seizures of unknown etiology refractory to conventional therapy. In the presented case, two pathogenic variants in compound heterozygous state were identified in the ALDH7A1 gene, confirming the diagnosis of PDE. Targeted therapy comprising pyridoxine, arginine, folinic acid, and a lysine-restricted diet resulted in sustained seizure remission and normalization of psychomotor development. Conclusions. Early identification and verification of a metabolic defect enables pathogenetically targeted treatment with the potential to fundamentally alter the disease prognosis. Nutritional and vitamin-micronutrient therapy represents an effective therapeutic approach for treatable forms of metabolic epilepsy, particularly in pyridoxine-dependent epilepsies. The authors declare no conflict of interest.
oligonucleotides
2025-11-20 | Potential of AON therapy targeting AASS: A promising molecular therapy for pyridoxine-dependent epilepsy
Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder, associated with pathogenic variants in ALDH7A1 leading to aberrant lysine degradation and accumulation of neurotoxic metabolites. The condition is characterized by epileptic seizures, typically occurring soon after birth, which are unresponsive to standard antiseizure medications (ASMs) and respond only to pyridoxine.1,2 Seizures may respond initially to standard ASM in some patients.3 Despite initiation of early treatment and seizure control, global developmental delay and/or intellectual disability have been reported in 75% of PDE patients.
2025-10-29 | Targeting AASS alleviates neurotoxicity and improves mitochondrial function in astrocyte models for pyridoxine-dependent epilepsy.
Pyridoxine-dependent epilepsy (PDE) is a rare neurometabolic disorder of lysine catabolism caused by bi-allelic variants in ALDH7A1. This enzyme deficiency leads to accumulation of neurotoxic metabolites, pyridoxal-phosphate inactivation, and consequently severe neurological symptoms. Current treatments, including vitamin B6 supplementation and lysine-restricted diets, partially alleviate seizures and intellectual disability but are not curative. To explore underlying mechanisms and potential therapies, we generated patient-derived human induced pluripotent stem cell (hiPSC) lines that were subsequently differentiated into astrocytes, the primary source of ALDH7A1 in the brain and key regulators of metabolic homeostasis. Metabolomic analyses confirmed elevated PDE biomarkers, and RNA sequencing revealed gene expression changes consistent with increased oxidative stress. Oxidative damage was validated by markers of DNA oxidation, increased reactive oxygen species (ROS) levels, and lipid peroxidation. In addition, dysregulated oxygen consumption rates suggested mitochondrial dysfunction in PDE astrocytes. Notably, these pathological phenotypes were alleviated by downregulating alpha-aminoadipic semialdehyde synthase (AASS), the first enzyme of the lysine catabolism, by using CRISPR-Cas9 editing or antisense oligonucleotides (AONs). This demonstrates that lysine catabolism underlies these phenotypes and highlights the therapeutic potential of AON therapy targeting AASS to reduce neurotoxic metabolite accumulation. These findings provide a promising strategy for developing targeted treatments for PDE and other rare neurometabolic disorders.
2025-05-12 | Targeting AASS improves neurotoxicity and mitochondrial function in astrocyte models for pyridoxine dependent epilepsy
Abstract Pyridoxine-dependent epilepsy (PDE) is a rare neurometabolic disorder of lysine catabolism caused by bi-allelic variants in ALDH7A1 . This enzyme deficiency leads to the accumulation of neurotoxic metabolites, pyridoxal-phosphate inactivation and consequently severe neurological symptoms. Current treatments, including vitamin B6 supplementation and lysine-restricted diets, partially alleviate seizures and intellectual disability but are not curative. To explore underlying mechanisms and potential therapies, we generated patient-derived human induced pluripotent stem lines (hiPSC) that were subsequently differentiated into astrocytes, the primary source of ALDH7A1 in the brain and key regulators of metabolic homeostasis. Metabolomic analyses confirmed elevated PDE biomarkers, and RNA sequencing revealed gene expression changes consistent with increased oxidative stress. Oxidative damage was validated by markers of DNA oxidation and lipid peroxidation. In addition, dysregulated oxygen consumption rates suggested mitochondrial dysfunction in PDE astrocytes. Notably, these pathological phenotypes were alleviated by downregulating AASS , the first enzyme of the lysine catabolism, by using CRISPR/Cas9 editing or antisense oligonucleotides (AON). This demonstrates that lysine catabolism underlies these phenotypes and highlights the therapeutic potential of AON therapy targeting AASS to reduce neurotoxic metabolite accumulation. These findings provide a promising strategy for developing targeted treatments for PDE and other rare neurometabolic disorders.
2019-07-29 | Update on the treatment of vitamin B6 dependent epilepsies
Introduction: Vitamin B6 dependent epilepsies are a group of treatable diseases (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinaemia type II and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects) responding to pyridoxine or pyridoxal-5I-phosphate. Areas covered: A critical review was conducted on the therapeutic management of all the reported patients with genetically confirmed diagnoses of diseases affecting vitamin B6 metabolism and presenting with pyridoxine or pyridoxal-5I-phosphate dependent-seizures. Data about safety and efficacy were analyzed as well as the management of supplementation with pyridoxine or pyridoxal-5I-phosphate both in the acute phases and in the maintenance therapies. The authors also analyzed alternative therapeutic strategies for ALDH7A1 deficiency (lysine-restricted diet, arginine supplementation, oligonucleotide antisense therapy, upstream inhibition of aminoadipic semialdehyde synthase). Expert opinion: The administration of pyridoxine or pyridoxal-5I-phosphate should be considered in all intractable seizures also beyond the first year of life. Lysine restricted diet and arginine supplementation should be introduced in all the confirmed ALDH7A1 deficient patients. Pre or post-natal supplementation with pyridoxine should be given in familial cases until an eventual molecular genetic disconfirmation. Minor data about alternative therapies are available for other disorders of vitamin B6 metabolism.
2013-01-25 | Clinical, biochemical, and molecular studies in pyridoxine‐dependent epilepsy. Antisense therapy as possible new therapeutic option
Summary Purpose Pyridoxine‐dependent epilepsy seizure ( PDE ; OMIM 266100) is a disorder associated with severe seizures that can be controlled pharmacologically with pyridoxine. In the majority of patients with PDE , the disorder is caused by the deficient activity of the enzyme α‐aminoadipic semialdehyde dehydrogenase (antiquitin protein), which is encoded by the ALDH7A1 gene. The aim of this work was the clinical, biochemical, and genetic analysis of 12 unrelated patients, mostly from S pain, in an attempt to provide further valuable data regarding the wide clinical, biochemical, and genetic spectrum of the disease. Methods The disease was confirmed based on the presence of α‐aminoadipic semialdehyde (α‐ AASA ) in urine measured by liquid chromatography tandem mass spectrometry (LC‐MS/MS) and pipecolic acid ( PA ) in plasma and/or cerebrospinal fluid ( CSF ) measured by high performance liquid chromatography ( HPLC )/ MS / MS and by sequencing analysis of messenger RNA ( mRNA ) and genomic DNA of ALDH7A1 . Key Findings Most of the patients had seizures in the neonatal period, but they responded to vitamin B 6 administration. Three patients developed late‐onset seizures, and most patients showed mild‐to‐moderate postnatal developmental delay. All patients had elevated PA and α‐ AASA levels, even those who had undergone pyridoxine treatment for several years. The clinical spectrum of our patients is not limited to seizures but many of them show associated neurologic dysfunctions such as muscle tone alterations, irritability, and psychomotor retardation. The mutational spectrum of the present patients included 12 mutations, five already reported (c.500 A > G , c.919 C > T , c.1429 G > C c.1217_1218del AT , and c.1482‐1 G > T ) and seven novel sequence changes (c.75 C > T , c.319 G > T , c.554_555del AA , c.757 C > T , c.787 + 1 G > T , c.1474 T > C , c.1093‐?_1620+?). Only one mutation, p. G 477 R (c.1429 G > C ), was recurrent; this was detected in four different alleles. Transcriptional profile analysis of one patient's lymphoblasts and ex vivo splicing analysis showed the silent nucleotide change c.75 C > T to be a novel splicing mutation creating a new donor splice site inside exon 1. Antisense therapy of the aberrant mRNA splicing in a lymphoblast cell line harboring mutation c.75 C > T was successful. Significance The present results broaden our knowledge of PDE , provide information regarding the genetic background of PDE in S pain, afford data of use when making molecular‐based prenatal diagnosis, and provide a cellular proof‐of concept for antisense therapy application.
gene therapies
2025-05-08 | Targeting Lysine α-Ketoglutarate Reductase to Treat Pyridoxine-Dependent Epilepsy.
Pyridoxine-dependent epilepsy (PDE), a rare autosomal recessively inherited metabolic disease, results from mutations in ALDH7A1, a gene crucial for lysine metabolism. Although early high-dose pyridoxine treatment can control seizures, ∼75% of PDE patients still have intellectual disabilities. In this study, we test the hypothesis of substrate reduction therapy for PDE by genetically perturbing lysine α-ketoglutarate reductase (LKR), an enzyme upstream of the defective ALDH7A1, in male and female laboratory mice. A homozygous mutation in LKR completely abolishes the accumulation of toxic lysine catabolism intermediates (α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate), ends the epileptic state, and restores the defective brain development and cognitive impairments in ALDH7A1-deficient mice. Therefore, these genetic data prove the concept of the effectiveness of substrate reduction therapy for PDE via LKR inhibition.
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Drug Discovery Landscape
1 orphan drug designation for Pyridoxine-dependent epilepsy.
1 orphan drug designation for Pyridoxine-dependent epilepsy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
pyridoxine; vitamin B6 | small molecules | FDA | 2011-03-03 | — | NBI Pharmaceuticals, Inc. |
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