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The first-tier genetic testing for developmental and epileptic encephalopathies (DEE) is now increasingly used in routine clinical practice. Antiquitin deficiency, also referred to as pyridoxine-dependent epilepsy (PDE-ALDH7A1), represents an inherited metabolic disorder with the phenotype of an early infantile DEE. In addition to the fact that biochemical biomarkers of PDE-ALDH7A1, including a-aminoadipic semialdehyde dehydrogenase, pipecolic acid (PA), 1-piperideine-6-carboxylate, and 6-oxopipecolate (6-oxo-PIP), are well-characterized, and their analysis and usefulness have some limitations. Here, we describe the case of a newborn presenting with seizures from the first hours of life, who was resistant to standard antiepileptic drugs and was found to be a biallelic compound heterozygote of two clearly pathogenic variants in the ALDH7A1 gene based on targeted next-generation sequencing (NGS). The diagnostic process of PDE-ALDH7A1 was limited by the possibility to determine only urinary PA and 6-oxo-PIP (urinary organic acid profile using the GC-MS method), and the exogenous peak of levetiracetam, due to the fact that it has a similar retention time as 6-oxo-PIP, masked the detection of 6-oxo-PIP. [ABSTRACT FROM AUTHOR]

Abstract Background Pyridoxine-dependent epilepsy is primarily characterized by early-onset refractory seizures. This condition can be caused by alpha-aminoadipic semialdehyde dehydrogenase deficiency due to a mutation in the ALDH7A1 gene, leading to the accumulation of certain substances that impact the production of various brain neurotransmitters and enzymes. Case presentation Our report presents the first documented case of pyridoxine dependency in Syria. The female infant, born to consanguineous parents, exhibited seizures on the second day of life. Despite the administration of multiple antiepileptic medications, seizures persisted. A comprehensive assessment, including metabolic evaluation, electroencephalography, and phenotypic characteristics of seizures, prompted genetic testing for pyridoxine-dependent epilepsy, which identified a homozygous likely pathogenic variant in the ALDH7A1 gene, confirming the diagnosis of this condition. Subsequently, the baby was put on oral pyridoxine, resulting in complete cessation of seizures. Conclusions Due to its rarity, this condition was initially overlooked and led to an inappropriate therapeutic approach. Pyridoxine dependency should be considered after the manifestation of refractory seizures, as increased awareness can enable early diagnosis, appropriate treatment, and avoid unnecessary use of antiepileptic drugs. However, predicting the long-term outcome remains challenging.

The first-tier genetic testing for developmental and epileptic encephalopathies (DEE) is now increasingly used in routine clinical practice. Antiquitin deficiency, also referred to as pyridoxine-dependent epilepsy (PDE-ALDH7A1), represents an inherited metabolic disorder with the phenotype of an early infantile DEE. In addition to the fact that biochemical biomarkers of PDE-ALDH7A1, including α-aminoadipic semialdehyde dehydrogenase, pipecolic acid (PA), Δ1-piperideine-6-carboxylate, and 6-oxopipecolate (6-oxo-PIP), are well-characterized, and their analysis and usefulness have some limitations. Here, we describe the case of a newborn presenting with seizures from the first hours of life, who was resistant to standard antiepileptic drugs and was found to be a biallelic compound heterozygote of two clearly pathogenic variants in the ALDH7A1 gene based on targeted next-generation sequencing (NGS). The diagnostic process of PDE-ALDH7A1 was limited by the possibility to determine only urinary PA and 6-oxo-PIP (urinary organic acid profile using the GC–MS method), and the exogenous peak of levetiracetam, due to the fact that it has a similar retention time as 6-oxo-PIP, masked the detection of 6-oxo-PIP.

Abstract Pyridoxine‐dependent epilepsy (PDE‐ALDH7A1) is a neurometabolic disorder in the lysine metabolism pathway. In 2014 and 2021, the International PDE consortium published consensus guidelines about diagnosis and management. In this follow‐on, a literature review was performed and nutrition management was evaluated through an international dietary questionnaire with 40 respondents. This manuscript discusses consensus dietary statements and the practical provision of lysine reduction therapies. Results from the questionnaire, statements from the PDE consensus guidelines, new data from the literature, as well as clinical practice experience of the metabolic dietitian group form the basis of these updated practical diet recommendations. These dietary management recommendations can support dietitians, nutritionists, and physicians in initiation and monitoring of lysine reduction therapies for PDE‐ALDH7A1 patients and families.

Although a rare cause of neonatal seizures, inborn errors of metabolism (IEMs) remain an essential component of a comprehensive differential diagnosis for poorly controlled neonatal epilepsy. Diagnosing neonatal-onset metabolic conditions proves a difficult task for clinicians; however, routine state newborn screening panels now include many IEMs. Three in particular—pyridoxine-dependent epilepsy, maple syrup urine disease, and Zellweger spectrum disorders—are highly associated with neonatal epilepsy and neurocognitive injury yet are often misdiagnosed. As research surrounding biomarkers for these conditions is emerging and gene sequencing technologies are advancing, clinicians are beginning to better establish early identification strategies for these diseases. In this literature review, the authors aim to present clinicians with an innovative clinical guide highlighting IEMs associated with neonatal-onset seizures, with the goal of promoting quality care and safety. [ABSTRACT FROM AUTHOR]

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive developmental and epileptic encephalopathy caused by pathogenic variants in the ALDH7A1 gene (PDE-ALDH7A1), which mainly has its onset in neonates and infants. Early diagnosis and treatment are crucial to prevent severe neurological sequelae or death. Sensitive, specific, and stable biomarkers for diagnostic evaluations and follow-up examinations are essential to optimize outcomes. However, most of the known biomarkers for PDE lack these criteria. Additionally, there is little discussion regarding the interdependence of biomarkers in the PDE-ALDH7A1 metabolite profile. Therefore, the aim of this study was to understand the underlying mechanisms in PDE-ALDH7A1 and to discover new biomarkers in the plasma of patients using global metabolomics. Plasma samples from 9 patients with genetically confirmed PDE-ALDH7A1 and 22 carefully selected control individuals were analyzed by ultra high performance liquid chromatography–high-resolution mass spectrometry (UHPLC-HRMS). Two novel and reliable pyridoxine-independent diagnostic markers, 6-hydroxy-2-aminocaproic acid (HACA) and an isomer of C9H11NO4, were identified. Furthermore, a possible reaction mechanism is proposed for HACA. This study demonstrates the capability of global metabolomics in disease screening to detect established and novel biomarkers. [ABSTRACT FROM AUTHOR]

Objective: To analyze the clinical diagnosis, treatment, and prognosis of the patients with pyridoxine-dependent epilepsy (PDE) characterized by infantile epileptic spasm syndrome (IESS)., Methods: A total of 75 PDE patients with ALDH7A1 variants were diagnosed at the Department of Pediatrics of Peking University First Hospital and Peking University People's Hospital from July 2012 to June 2024, and five PDE patients with the phenotype of IESS were selected. The clinical manifestations, treatment, blood biochemistry, metabolic screening, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and gene testing results of the five PDE patients were analyzed., Results: Among the five patients diagnosed with PDE, three were female and two were male, and the phenotype was consistent with IESS. The age at the last follow-up was from one year and 3 months to 11 years and 9 months. All the five cases were delivered at term. Two cases had anoxia and asphyxia at birth, and three cases had normal birth history. The onset age of seizure ranged from one day to 4 months after birth. One case presented with epileptic spasms (ES), and three cases presented with focal seizure and ES. The other patient was started with ES, followed by multiple seizure types, including focal seizure and generalized tonic-clonic seizure, and developed epileptic status which caused secondary brain injury. The interictal EEG results showed hypsarrhythmia in three cases, generalized and multifocal discharges in one cases, and multifocal discharges in one case. No abnormalities were found in brain MRI in three cases, and secondary cerebral atrophy and hydrocephalus were observed in two cases during the course of the disease. Gene analysis confirmed that the five patients carried compound heterozygous variants of ALDH7A1 , and two of them carried exon deletion variants. High dose pyridoxine treatment started at the end of 2 days, 4 years, 3 years, 4 days. and 2 months after the onset of the disease. Up to the last follow-up, seizures of four cases were controlled, followed by normal EEG. One patient with brain atrophy had uncontrolled seizures and EEG remained abnormal. The neurodevelopment of the three patients were severely delayed, and two were mildly delayed., Conclusion: IESS could be a rare phenotype of PDE. High doses of pyridoxine can control or reduce the frequency of seizures. Delayed diagnosis and treatment, secondary brain injury, and the genotype, especially deletions variants, were associated with poor prognosis.

Pyridoxine-dependent epilepsy is a rare autosomal recessive disease usually associated with neonatal seizures that do not respond to common antiseizure medications but are controlled by pyridoxine administration. Because the symptoms can mimic common neonatal disorders, the diagnosis can be initially missed or delayed. We report a fatal case of a boy who was initially diagnosed with respiratory distress, birth asphyxia, and persistent pulmonary hypertension and whose condition rapidly deteriorated during the first day of life.

Objective: To analyze the clinical feature, treatment, and prognosis of epileptic spasms (ES) in vitamin B6–dependent epilepsy, including patients with pyridoxine-dependent epilepsy (PDE) caused by ALDH7A1 mutation, pyridox(am)ine-5′-phosphate oxidase (PNPO) deficiency, and PLPBP deficiency. Methods: We analyzed data from a cohort of 54 cases with PDE, 13 cases with PNPO deficiency, and 2 cases with PLPBP deficiency and looked for the presentation of ES among them. Results: A total of 11 patients with the seizure presentation of ES have been collected. Among them, four patients carried mutations in ALDH7A1 , six carried mutations in PNPO , and the remaining one carried mutation in PLPBP. The analysis of this cohort identified nine cases presenting as infantile spasms distributed in the three diseases and two cases presenting as Ohtahara syndrome diagnosed with PDE and PNPO deficiency, respectively. In the PDE and PLPBP deficiency groups, seizures were controlled by pyridoxine monotherapy, and the remaining one had refractory seizures due to secondary brain atrophy. In the groups with PNPO deficiency, one patient showed seizure-free when treated by PLP combined with valproic acid, three still had infrequent seizures treated by PLP monotherapy or pyridoxine or PLP combined with other antiseizure medications, and two died. In two cases presenting as Ohtahara syndrome, after regular treatment, one showed seizure-free, the others showed a marked decrease in seizure frequency, and they both showed an improvement in EEG. Significance: ES might be a common form of seizures in PNPO deficiency, and EEG presented as hypsarrhythmia or a burst suppression pattern. It is difficult for pyridoxine to control frequent seizures caused by secondary brain injury. In our PNPO deficiency cohort, patients with infantile spasms did not respond better to PLP than pyridoxine. Timely and correct treatment could prevent the transformation of the child's disease from Ohtahara syndrome and infantile spasms to subsequent epileptic encephalopathy or refractory epilepsy. [ABSTRACT FROM AUTHOR]

Seventy-five percent of patients with pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function. This retrospective, multi-center cohort study evaluated the effect of timing of pyridoxine monotherapy and pyridoxine with adjunct LRT on neurodevelopmental outcome. Patients with confirmed PDE-ALDH7A1 with at least one sibling with PDE-ALDH7A1 and a difference in age at treatment initiation were eligible and identified via the international PDE registry, resulting in thirty-seven patients of 18 families. Treatment regimen was pyridoxine monotherapy in ten families and pyridoxine with adjunct LRT in the other eight. Primary endpoints were standardized and clinically assessed neurodevelopmental outcomes. Clinical neurodevelopmental status was subjectively assessed over seven domains: overall neurodevelopment, speech/language, cognition, fine and gross motor skills, activities of daily living and behavioral/psychiatric abnormalities. The majority of early treated siblings on pyridoxine monotherapy performed better than their late treated siblings on the clinically assessed domain of fine motor skills. For siblings on pyridoxine and adjunct LRT, the majority of early treated siblings performed better on clinically assessed overall neurodevelopment, cognition, and behavior/psychiatry. Fourteen percent of the total cohort was assessed as normal on all domains. Early treatment with pyridoxine and adjunct LRT may be beneficial for neurodevelopmental outcome. When evaluating a more extensive neurodevelopmental assessment, the actual impairment rate may be higher than the 75% reported in literature. Early initiation of lysine reduction therapies adjunct to pyridoxine treatment in patients with PDE-ALDH7A1 may result in an improved neurodevelopmental outcome. [ABSTRACT FROM AUTHOR]

Pediatric seizures are a common reason for emergency department visits. The highest risk of seizures in children is during the neonatal period. A low index of suspicion is important to facilitate the early assessment, workup, and treatment of inborn errors of metabolism to optimize developmental outcomes. We present the rare case of a 9-day-old with seizures refractory to multiple anticonvulsant medications who was diagnosed with pyridoxine-dependent epilepsy. We review differences in the management of neonatal seizures from older patients, the utility of a trial of pyridoxine in refractory neonatal seizures, and the importance of preparing for emergent airway management given pyridoxine’s ability to cause apnea and central nervous system depression. [ABSTRACT FROM AUTHOR]

Objective: To analyze the clinical feature, treatment, and prognosis of epileptic spasms (ES) in vitamin B6–dependent epilepsy, including patients with pyridoxine-dependent epilepsy (PDE) caused by ALDH7A1 mutation, pyridox(am)ine-5′-phosphate oxidase (PNPO) deficiency, and PLPBP deficiency.Methods: We analyzed data from a cohort of 54 cases with PDE, 13 cases with PNPO deficiency, and 2 cases with PLPBP deficiency and looked for the presentation of ES among them.Results: A total of 11 patients with the seizure presentation of ES have been collected. Among them, four patients carried mutations in ALDH7A1, six carried mutations in PNPO, and the remaining one carried mutation in PLPBP. The analysis of this cohort identified nine cases presenting as infantile spasms distributed in the three diseases and two cases presenting as Ohtahara syndrome diagnosed with PDE and PNPO deficiency, respectively. In the PDE and PLPBP deficiency groups, seizures were controlled by pyridoxine monotherapy, and the remaining one had refractory seizures due to secondary brain atrophy. In the groups with PNPO deficiency, one patient showed seizure-free when treated by PLP combined with valproic acid, three still had infrequent seizures treated by PLP monotherapy or pyridoxine or PLP combined with other antiseizure medications, and two died. In two cases presenting as Ohtahara syndrome, after regular treatment, one showed seizure-free, the others showed a marked decrease in seizure frequency, and they both showed an improvement in EEG.Significance: ES might be a common form of seizures in PNPO deficiency, and EEG presented as hypsarrhythmia or a burst suppression pattern. It is difficult for pyridoxine to control frequent seizures caused by secondary brain injury. In our PNPO deficiency cohort, patients with infantile spasms did not respond better to PLP than pyridoxine. Timely and correct treatment could prevent the transformation of the child’s disease from Ohtahara syndrome and infantile spasms to subsequent epileptic encephalopathy or refractory epilepsy.

Abstract Pyridoxine‐dependent epilepsy (PDE) is a potentially treatable vitamin‐responsive epileptic encephalopathy. The most prevalent form of PDE is due to an underlying genetic defect in ALDH7A1 encoding Antiquitin (ATQ), an enzyme with α‐aminoadipic semialdehyde dehydrogenase (AASADH) activity which facilitates cerebral lysine degradation. Devastating outcomes including intellectual disability and significant developmental delays are still observed in 75% to 80% of pyridoxine responsive individuals with good seizure control, potentially attributable to the accumulation of toxic intermediates α‐aminoadipic semialdehyde (AASA) and its cyclic form Δ1‐piperideine‐6‐carboxylate (P6C) in plasma, urine and CSF. Thus, adjunct treatment strategies incorporating lysine restriction and arginine supplementation, separately or in combination with pyridoxine have been attempted to enhance seizure control and improve cognitive function. We describe a 4 year old girl with classical PDE who demonstrated significant improvements in clinical, neurological and developmental outcomes including absence of clinical seizures and cessation of antiepileptic medications since age 3 months, normalisation of EEG, significant improvement in the white matter signal throughout the cerebrum on neuroimaging and significant reduction in urine P6C and pipecolic acid levels post‐ combined therapy with lysine restricted diet in conjunction with pyridoxine and folinic acid. Lysine restriction was well tolerated with impressive compliance and plasma lysine levels remained within the lower reference ranges; mean level 70 μmol/L (ref range 52‐196 μmol/L). This case further emphasizes the benefit of early dietary intervention as an effective adjunct in the management of PDE.

ALDH7A1 deficiency is an epileptic encephalopathy whose seizures respond to treatment with supraphysiological doses of pyridoxine. It arises as a result of damaging variants in ALDH7A1, a gene in the lysine catabolism pathway. α-Aminoadipic semialdehyde (α-AASA) and Δ 1 -piperideine-6-carboxylate (P6C), which accumulate because of the block in the lysine pathway, are diagnostic biomarkers for this disorder. Recently, it has been reported that 6-oxo-pipecolic acid (6-oxo-PIP) also accumulates in the urine, CSF and plasma of ALDH7A1-deficient individuals and that, given its improved stability, it may be a more suitable biomarker for this disorder. This study measured 6-oxo-PIP in urine from a cohort of 30 patients where α-AASA was elevated and showed that it was above the normal range in all those above 6 months of age. However, 6-oxo-PIP levels were within the normal range in 33% of the patients below 6 months of age. Levels increased with age and correlated with a decrease in α-AASA levels. Longitudinal analysis of urine samples from ALDH7A1-deficient patients who were on a lysine restricted diet whilst receiving supraphysiological doses of pyridoxine showed that levels of 6-oxo-PIP remained elevated whilst α-AASA decreased. Similar to α-AASA, we found that elevated urinary excretion of 6-oxo-PIP can also occur in individuals with molybdenum cofactor deficiency. This study demonstrates that urinary 6-oxo-PIP may not be a suitable biomarker for ALDH7A1 deficiency in neonates. However, further studies are needed to understand the biochemistry leading to its accumulation and its potential long-term side effects., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive developmental and epileptic encephalopathy that is responsive to pharmacologic doses of vitamin B6. The deficiency of antiquitin, an enzyme involved in the catabolism of lysine, is believed to be its key molecular basis. Research to date has tended to focus on two known catabolic pathways of lysine, namely, saccharopine and pipecolic acid. However, the occurrence of oxidative stress and the presence of its metabolites have been only briefly highlighted in the literature. Owing to the importance of the topic and its potential for future diagnosis, prognosis and therapy, this paper reviews the suggested mechanisms of oxidative stress in antiquitin deficiency along with the proposed reactions and intermediates, and finally, discusses the challenges and opportunities. [ABSTRACT FROM AUTHOR]

Pyridoxine monotherapy in PDE-ALDH7A1 often results in adequate seizure control, but neurodevelopmental outcome varies. Detailed long-term neurological outcome is unknown. Here we present the cognitive and neurological features of the Dutch PDE-ALDH7A1 cohort. Neurological outcome was assessed in 24 patients (age 1–26 years); classified as normal, complex minor neurological dysfunction (complex MND) or abnormal. Intelligence quotient (IQ) was derived from standardized IQ tests with five severity levels of intellectual disability (ID). MRI's and treatments were assessed. Ten patients (42%) showed unremarkable neurological examination, 11 (46%) complex MND, and 3 (12%) cerebral palsy (CP). Minor coordination problems were identified in 17 (71%), fine motor disability in 11 (46%), posture/muscle tone deviancies in 11 (46%) and abnormal reflexes in 8 (33%). Six patients (25%) had an IQ > 85, 7 (29%) borderline, 7 (29%) mild, 3 (13%) moderate, and 1 severe ID. Cerebral ventriculomegaly on MRI was progressive in 11. Three patients showed normal neurologic exam, IQ, and MRI. Eleven patients were treated with pyridoxine only and 13 by additional lysine reduction therapy (LRT). LRT started at age <3 years demonstrated beneficial effect on IQ results in 3 patients. Complex MND and CP occurred more frequently in PDE-ALDH7A1 (46% and 12%) than in general population (7% and 0.2%, Peters et al., 2011, Schaefer et al., 2008). Twenty-five percent had a normal IQ. Although LRT shows potential to improve outcomes, data are heterogeneous in small patient numbers. More research with longer follow-up via the International PDE Registry (www.pdeonline.org) is needed. • Complex MND/CP was more frequent in PDE- ALDH7A1 compared to Dutch population. • PDE- ALDH7A1 patients predominantly showed minor problems with coordination. • ID occurred in 75%, MRI abnormalities in 83%, both in accordance with literature. • Early B6 therapy correlated with better outcomes. • LRT had a positive effect on cognitive outcomes in a small subset of patients. [ABSTRACT FROM AUTHOR]

Pyridoxine-dependent epilepsy (PDE- ALDH7A1) is a rare autosomal recessive disorder due to a deficiency of α-aminoadipic semialdehyde dehydrogenase. This study aimed to systematically explore genotypic and phenotypic features and prognostic factors of neonatal-onset PDE. A literature search covering PubMed, Elsevier, and Web of Science was conducted from January 2006 to August 2023. We identified 56 eligible studies involving 169 patients and 334 alleles. The c.1279 G>C variant was the most common variant of neonatal-onset PDE (25.7 %). All patients were treated with pyridoxine; forty patients received dietary intervention therapy. 63.9 % of the patients were completely seizure-free; however, 68.6 % of the patients had neurodevelopmental delays. Additionally, homozygous c.1279 G>C variants were significantly associated with ventriculomegaly, abnormal white matter signal, and cysts (P<0.05). In contrast, homozygous c.1364 T>C was associated with clonic seizure (P=0.031). Pyridoxine used immediately at seizure onset was an independent protective factor for developmental delay (P=0.035; odds ratio [OR]: 3.14). Besides, pyridoxine used early in the neonatal period was a protective factor for language delay (P=0.044; OR: 4.59). In contrast, neonatal respiratory distress (P=0.001; OR: 127.44) and abnormal brain magnetic resonance imaging (P=0.049; OR: 3.64) were risk factors. Prenatal movement abnormality (P=0.041; OR: 20.56) and abnormal white matter signal (P=0.012; OR: 24.30) were risk factors for motor delay. Myoclonic seizure (P=0.023; OR: 7.13) and status epilepticus (P=0.000; OR: 9.93) were risk factors for breakthrough seizures. In conclusion, our study indicated that pyridoxine should be started immediately when unexplained neonatal seizures occur and not later than the neonatal period to prevent poor neurodevelopmental outcomes. • Genotypic and phenotypic features and prognostic factors of neonatal-onset PDE were studied. • The c.1279G>C (p.E427Q) variant was the most common variant of neonatal-onset PDE (25.7 %). • Forty patients received dietary intervention therapy. 63.9 % of the patients were completely seizure-free. • Pyridoxine used immediately at seizure onset was an independent protective factor for developmental delay. • Neonatal respiratory distress was a risk factor for language delay. [ABSTRACT FROM AUTHOR]

ObjectiveTo describe the clinical characteristics of 12 patients from six families with pyridoxine-dependent epilepsy (PDE) carrying ALDH7A1 mutations, and analyze the impact of early diagnosis and treatment, as well as possible genotype–phenotype relationship.MethodsClinical and genetics data of 12 patients were collected.ResultsFamily 1–3 presented with symptoms in the neonatal period, while family 4-6 presented during early infancy. In the same family, the age of onset was similar. The focal motor seizure appeared in all patients. The affected identical twins from family 4 were diagnosed with infantile spasms. Mutation analysis identified nine different ALDH7A1 mutations among six families. The neurodevelopment of siblings in family 1 was mild delay and normal separately due to the minor difference of delayed diagnosis time. Siblings in family 2 showed severely delayed and normal development respectively due to the significant difference of a delayed diagnosis for 4 years. In family 5, although the difference of the delayed diagnosis time is up to 7 years, the nearly normal psychomotor development in both patients might be due to infrequent seizures before the delayed diagnosis. A severe phenotype exhibited in family 3, 4, and 6. The survived affected patients presented with severe developmental delay or refractory seizures and their twins or older sisters presented a similar clinical history and died in the early days of life. Mutation analysis showed D511N and IVS11 + 1G > A in family 3, V188A and exon1 deletion in family 4, and Y354C and exon 8–13 deletion in family 6.ConclusionPatients from the same family often have the same phenotype, including onset age and seizure type. Early treatment with pyridoxine and infrequent seizures showed positive relationship with prognosis. The deletion of exon 1 and exon 8–13 might be associated with the severe phenotype.

Certain mutations in the ALDH7A1 gene cause pyridoxine-dependent epilepsy (PDE), an autosomal recessive metabolic disease characterized by seizures, and in some cases, intellectual disability. The mutational spectrum of PDE is vast and includes over 70 missense mutations. This review summarizes the current state of biochemical and biophysical research on the impact of PDE missense mutations on the structure and catalytic activity of ALDH7A1. Paradoxically, some mutations that target active site residues have a relatively modest impact on structure and function, while those remote from the active site can have profound effects. For example, missense mutations targeting remote residues in oligomer interfaces tend to strongly impact catalytic function by inhibiting formation of the active tetramer. These results shows that it remains very difficult to predict the impact of missense mutations, even when the structure of the wild-type enzyme is known. Additional biophysical analyses of many more disease-causing mutations are needed to develop the rules for predicting the impact of genetic mutations on enzyme structure and catalytic function. [Display omitted] • Certain mutations in the ALDH7A1 gene cause pyridoxine-dependent epilepsy. • The impact of missense mutations on enzyme function is very challenging to predict. • Biophysical analysis of enzyme variants yields deep insight into disease pathology. • 3D protein structure analysis is an enabling technology of personalized medicine. [ABSTRACT FROM AUTHOR]

Objective: To describe the clinical characteristics of 12 patients from six families with pyridoxine-dependent epilepsy (PDE) carrying ALDH7A1 mutations, and analyze the impact of early diagnosis and treatment, as well as possible genotype–phenotype relationship. Methods: Clinical and genetics data of 12 patients were collected. Results: Family 1–3 presented with symptoms in the neonatal period, while family 4-6 presented during early infancy. In the same family, the age of onset was similar. The focal motor seizure appeared in all patients. The affected identical twins from family 4 were diagnosed with infantile spasms. Mutation analysis identified nine different ALDH7A1 mutations among six families. The neurodevelopment of siblings in family 1 was mild delay and normal separately due to the minor difference of delayed diagnosis time. Siblings in family 2 showed severely delayed and normal development respectively due to the significant difference of a delayed diagnosis for 4 years. In family 5, although the difference of the delayed diagnosis time is up to 7 years, the nearly normal psychomotor development in both patients might be due to infrequent seizures before the delayed diagnosis. A severe phenotype exhibited in family 3, 4, and 6. The survived affected patients presented with severe developmental delay or refractory seizures and their twins or older sisters presented a similar clinical history and died in the early days of life. Mutation analysis showed D511N and IVS11 + 1G > A in family 3, V188A and exon1 deletion in family 4, and Y354C and exon 8–13 deletion in family 6. Conclusion: Patients from the same family often have the same phenotype, including onset age and seizure type. Early treatment with pyridoxine and infrequent seizures showed positive relationship with prognosis. The deletion of exon 1 and exon 8–13 might be associated with the severe phenotype. [ABSTRACT FROM AUTHOR]

Pyridoxine‐dependent epilepsy (PDE‐ALDH7A1) is an autosomal recessive condition due to a deficiency of α‐aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE‐ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE‐ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine‐restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine‐reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re‐evaluate and update the two previously published recommendations for diagnosis, treatment, and follow‐up of patients with PDE‐ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus‐based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE‐ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE‐ALDH7A1 are provided. [ABSTRACT FROM AUTHOR]

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a neurometabolic disorder in the lysine metabolism pathway. In 2014 and 2021, the International PDE consortium published consensus guidelines about diagnosis and management. In this follow-on, a literature review was performed and nutrition management was evaluated through an international dietary questionnaire with 40 respondents. This manuscript discusses consensus dietary statements and the practical provision of lysine reduction therapies. Results from the questionnaire, statements from the PDE consensus guidelines, new data from the literature, as well as clinical practice experience of the metabolic dietitian group form the basis of these updated practical diet recommendations. These dietary management recommendations can support dietitians, nutritionists, and physicians in initiation and monitoring of lysine reduction therapies for PDE-ALDH7A1 patients and families., Competing Interests: Annemiek M. J. van Wegberg has received a research grant from Nutricia, travel support from Nutricia and Vitaflo and participated in nutritional product research evaluation studies for Vitaflo International Ltd UK. Marjorie Dixon has received honoraria, travel support from Danone Nutricia and Vitaflo International Ltd and participated in nutritional product research evaluation studies for Vitaflo International Ltd and Nutricia, UK. Clara D. M. van Karnebeek was the principal investigator in nutritional product research evaluation studies for Vitaflo International Ltd. Chloe Millington participated in nutritional product research evaluation studies for Vitaflo International Ltd. Sommer Gaughan received an honorarium from Nutricia North America for PDE case write up. The other authors (Laurie Bernstein, Curtis R. Coughlin II, Morgan Drumm) declare no conflict of interest., (© 2024 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: We aimed to demonstrate the biochemical characteristics of vitamin B6-dependent epilepsy, with a particular focus on pyridoxal 5'-phosphate and pyridoxal in the cerebrospinal fluid.Methods: Using our laboratory database, we identified patients with vitamin B6-dependent epilepsy and extracted their data on the concentrations of pyridoxal 5'-phosphate, pyridoxal, pipecolic acid, α-aminoadipic semialdehyde, and monoamine neurotransmitters. We compared the biochemical characteristics of these patients with those of other epilepsy patients with low pyridoxal 5'-phosphate concentrations.Results: We identified seven patients with pyridoxine-dependent epilepsy caused by an ALDH7A1 gene abnormality, two patients with pyridoxal 5'-phosphate homeostasis protein deficiency, and 28 patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Cerebrospinal fluid pyridoxal and pyridoxal 5'-phosphate concentrations were low in patients with vitamin B6-dependent epilepsy but cerebrospinal fluid pyridoxal concentrations were not reduced in most patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Increase in 3-O-methyldopa and 5-hydroxytryptophan was demonstrated in some patients with vitamin B6-dependent epilepsy, suggestive of pyridoxal 5'-phosphate deficiency in the brain.Conclusions: Low cerebrospinal fluid pyridoxal concentrations may be a better indicator of pyridoxal 5'-phosphate deficiency in the brain in vitamin B6-dependent epilepsy than low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. This finding is especially helpful in individuals with suspected pyridoxal 5'-phosphate homeostasis protein deficiency, which does not have known biomarkers. [ABSTRACT FROM AUTHOR]

Pyridoxine-dependent epilepsy (PDE) is an autosomal recessive neurometabolic disorder due to a deficiency of α-aminoadipic semialdehyde dehydrogenase (mutation in ALDH7A1 gene), more commonly known as antiquitin (ATQ). ATQ is one of the enzymes involved in lysine oxidation; thus, its deficiency leads to the accumulation of toxic metabolites in body fluids. PDE is characterized by persistent, recurrent neonatal seizures that cannot be well controlled by antiepileptic drugs but are responsive clinically and electrographically to daily pyridoxine (vitamin B6) supplementation. Although the phenotypic spectrum distinguishes between typical and atypical, pyridoxine-dependent is true for each. Diagnosis may pose a challenge mainly due to the rarity of the disorder and the fact that seizures may not occur until childhood or even late adolescence. Moreover, patients may not demonstrate an obvious clinical or electroencephalography response to the initial dose of pyridoxine. Effective treatment requires lifelong pharmacologic supplements of pyridoxine, and dietary lysine restriction and arginine enrichment should improve prognosis and avoid developmental delay and intellectual disability. The purpose of this review is to summarize briefly the latest reports on the etiology, clinical symptoms, diagnosis, and management of patients suffering from pyridoxine-dependent epilepsy.

Objective: Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder that typically presents with refractory seizures in infancy or early childhood. Seizures are resistant to conventional antiepileptic treatments and responsive to pharmacologic doses of pyridoxine. In this study, we aimed to present the clinical and genetic features of six patients followed up in our clinic with PDE diagnosis. Material and Methods: Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder that typically presents with refractory seizures in infancy or early childhood. Seizures are resistant to conventional antiepileptic treatments and responsive to pharmacologic doses of pyridoxine. In this study, we aimed to present the clinical and genetic features of six patients followed up in our clinic with PDE diagnosis. Results: Among six patients five were male and one was female. Mean age was 6.83 ± 3.71 years. The mean age of onset for seizures was 22.33 ± 31.77 (3-90 days). Seizures had started in the newborn period in all patients except one patient (n: 4). Three patients had focal motor seizures, 2 patients had generalized motor seizures and 1 patient had epileptic spasms. Vitamin B6 therapy was started in the early period except one patient. Mental retardation, stereotypic movements and autistic findings were observed in the all patients except one patient who had received early treatment. Molecular genetic analysis revealed 5 different mutations [homozygous c.1597delG (p.Ala533ProfsTer18) in 2 cases, homozygous c.781 A> G (p.Met261Val) in 1 case, compound heterozygous c.328C> T (p.Arg110Ter) / c.1566- 1G>T, 1 case heterozygous c.328C> T (p.Arg110Ter) and 1 case heterozygous c.1356 A> C (p.Lys452Asn)] . Conclusion: Pyridoxine-dependent epilepsy is a treatable cause of epilepsy and should come to mind in infants with unexplained refractory seizures. Treatment with a therapeutic dose of pyridoxine should be started promptly. [ABSTRACT FROM AUTHOR]

Antiquitin (ATQ) deficiency leads to tissue, plasma, and urinary accumulation of alpha‐aminoadipic semialdehyde (AASA) and its Schiff base delta‐1‐piperideine‐6‐carboxylate (P6C). Although genetic testing of ALDH7A1 is the most definitive diagnostic method, quantifications of pathognomonic metabolites are important for the diagnosis and evaluation of therapeutic and dietary interventions. Current metabolite quantification methods use laborious, technically highly complex, and expensive liquid chromatography‐tandem mass spectro‐metry, which is available only in selected laboratories worldwide. Incubation of ortho‐aminobenzaldehyde (oABA) with P6C leads to the formation of a triple aromatic ring structure with characteristic absorption and fluorescence properties. The mean concentration of P6C in nine urine samples from seven ATQ‐deficient patients under standard treatment protocols was statistically highly significantly different (P <.001) compared to the mean of 74 healthy controls aged between 2 months and 57 years. Using this limited data set the specificity and sensitivity is 100% for all tested age groups using a P6C cut‐off of 2.11 μmol/mmol creatinine, which represents the 99% prediction interval of the P6C concentrations in 17 control urine samples from children below 6 years of age. Plasma P6C concentrations were only elevated in one ATQ subject, possibly because P6C is trapped by pyridoxal‐5‐phosphate (PLP) blocking fusing with oABA. Nevertheless, both urine and plasma samples were amenable to the quantification of exogenous P6C with high response rates. The P6C quantification method using fusion of oABA with P6C is fast, simple, and inexpensive and might be readily implemented into routine clinical diagnostic laboratories for the early diagnosis of neonatal pyridoxine‐dependent epilepsy. [ABSTRACT FROM AUTHOR]

The aim of this study was to describe the electroclinical variability of four Taiwanese patients with pyridoxine-dependent epilepsy (PDE) caused by ALDH7A1 gene mutations. Demographic data, case histories, clinical seizure patterns, EEG features, neuroimaging findings, ALDH7A1 gene mutations, treatments, and neurodevelopmental outcomes of the four patients were collected and analyzed. The four patients exhibited the first symptom between the ages of 6 days and 11 months. The age of diagnosis was between 2 months and 13 years 8 months. Patient 1 exhibited classical phenotype of PDE, neonatal onset epileptic encephalopathy. Patient 2 showed atypical phenotypes of intractable epilepsy with additional neurological and abdominal symptoms. Patients 3 and 4, who had normal neurodevelopment, had familial epilepsy with fever sensitivity. Patients 2, 3, and 4 had atypical phenotypes and showed seizure exacerbation during febrile infections. EEG features of patient 1 revealed alternating rhythmic discharges followed by electrodecremental episodes; while those of patients 2, 3, and 4 disclosed nonspecific findings or normal results. Administration of oral pyridoxine hydrochloride resulted in seizure cessation in patients 1, 3, and 4, and they achieved normal neurodevelopmental outcomes, but intractable epilepsy and profound mental retardation occurred in patient 2 as he was not diagnosed until he was 13 years and 8 months old. Electroclinical features of PDE vary widely, including patients with normal neurodevelopment and normal or nonspecific EEG findings. To avoid delay in treatment, a therapeutic trial with pyridoxine hydrochloride should be performed in all cases of neonatal, infantile, and childhood refractory epilepsy until ALDH7A1 gene mutation-related PDE has been excluded. Pyridoxine treatment may show clinical effectiveness even in a relatively late stage, i.e., age older than one year. [ABSTRACT FROM AUTHOR]

Certain loss‐of‐function mutations in the gene encoding the lysine catabolic enzyme aldehyde dehydrogenase 7A1 (ALDH7A1) cause pyridoxine‐dependent epilepsy (PDE). Missense mutations of Glu427, especially Glu427Gln, account for ~30% of the mutated alleles in PDE patients, and thus Glu427 has been referred to as a mutation hot spot of PDE. Glu427 is invariant in the ALDH superfamily and forms ionic hydrogen bonds with the nicotinamide ribose of the NAD+ cofactor. Here we report the first crystal structures of ALDH7A1 containing pathogenic mutations targeting Glu427. The mutant enzymes E427Q, Glu427Asp, and Glu427Gly were expressed in Escherichia coli and purified. The recombinant enzymes displayed negligible catalytic activity compared to the wild‐type enzyme. The crystal structures of the mutant enzymes complexed with NAD+ were determined to understand how the mutations impact NAD+ binding. In the E427Q and E427G structures, the nicotinamide mononucleotide is highly flexible and lacks a defined binding pose. In E427D, the bound NAD+ adopts a "retracted" conformation in which the nicotinamide ring is too far from the catalytic Cys residue for hydride transfer. Thus, the structures revealed a shared mechanism for loss of function: none of the variants are able to stabilise the nicotinamide of NAD+ in the pose required for catalysis. We also show that these mutations reduce the amount of active tetrameric ALDH7A1 at the concentration of NAD+ tested. Altogether, our results provide the three‐dimensional molecular structural basis of the most common pathogenic variants of PDE and implicate strong (ionic) hydrogen bonds in the aetiology of a human disease. [ABSTRACT FROM AUTHOR]

In humans, certain mutations in the gene encoding aldehyde dehydrogenase 7A1 are associated with pyridoxine‐dependent epilepsy (PDE). Understanding the impact of PDE‐causing mutations on the structure and activity of ALDH7A1 could allow for the prediction of symptom‐severity and aid the development of patient‐specific medical treatments. Herein, we investigate the biochemical and structural consequences of PDE missense mutations targeting residues in the aldehyde substrate binding site: N167S, P169S, A171V, G174V, and W175G. All but G174V could be purified for biochemical and X‐ray crystallographic analysis. W175G has a relatively mild kinetic defect, exhibiting a fivefold decrease in kcat with no change in Km. P169S and N167S have moderate defects, characterized by catalytic efficiencies of 20‐ and 100‐times lower than wild‐type, respectively. A171V has a profound functional defect, with catalytic efficiency 2000‐times lower than wild‐type. The crystal structures of the variants are the first for any PDE‐associated mutant of ALDH7A1. The structures show that missense mutations that decrease the steric bulk of the side chain tend to create a cavity in the active site. The protein responds by relaxing into the vacant space, and this structural perturbation appears to cause misalignment of the aldehyde substrate in W175G and N167S. The P169S structure is nearly identical to that of the wild‐type enzyme; however, analysis of B‐factors suggests the catalytic defect may result from altered protein dynamics. The A171V structure suggests that the potential for steric clash with Val171 prevents Glu121 from ion pairing with the amino group of the aldehyde substrate. Enzymes: Aldehyde dehydrogenase 7A1 (EC1.2.1.31). Databases: Coordinates have been deposited in the Protein Data Bank under the following accession codes: 6O4B, 6O4C, 6O4D, 6O4E, 6O4F, 6O4G, 6O4H. [ABSTRACT FROM AUTHOR]

In recent years, the clinical spectrum of pyridoxine phosphate oxidase (PNPO) deficiency has broadened. There are a growing number of patients with a transient or lasting response to pyridoxine in addition to cases that respond more traditionally to pyridoxal-phosphate. However, among pyridoxine-responsive patients with PNPO gene mutation, there are only a few reports on electroencephalogram (EEG) ictal/interictal patterns, and data regarding the outcomes are inconsistent. We describe a case of neonatal onset epilepsy with missense mutation c(674G>A) p(R225 H) in PNPO gene and pyridoxine responsiveness. Comparing this patient with 24 cases of previously described pyridoxine-responsive pyridoxine phosphate oxidase deficiency epilepsy, we found that patients carrying the missense mutation c(674G>A) p(R225 H) of the PNPO gene might have a more severe epileptic phenotype, possibly because of their lower residual PNPO activity. Indeed, pyridoxine-responsive pyridoxine phosphate oxidase deficiency epilepsy remains a challenge, with neurodevelopmental disabilities occurring in about half of the cases. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effects of a single oral dose of pyridoxine on lysine metabolites including α-aminoadipic semialdehyde (a-AASA), piperideine-6-carboxylate (P6C), the sum of AASA and P6C (AASA-P6C), pipecolic acid (PA), and α-aminoadipic acid (α-AAA) in PDE patients.Methods: The lysine metabolites of 15 patients with molecularly confirmed PDE were detected before and 4 h after taking a single oral dose of pyridoxine, respectively, using liquid chromatography-mass spectrometry (LC-MS/MS) method. Five types of samples were freshly prepared, including plasma, serum, dried blood spots (DBS), urine, and dried urine spots (DUS).Results: All the patients had been treated with long-term oral pyridoxine for several months to years, with doses of 30–360 mg/d. The concentrations of a-AASA, P6C, AASA-P6C, PA, and a-AAA before and after taking a single oral dose of pyridoxine for the same analyte detected in the same type of sample varied among patients. The mean concentrations increased in almost all the metabolites after taking an oral dose of pyridoxine, with or without statistical significance. Whereas, the metabolites concentrations might increase or decrease among different patients, or in different samples of the same patient, without a regular tendency. There was no statistical correlation between the concentrations before and after taking pyridoxine in the same type of sample for most metabolites.Conclusions: No obvious relationship between the metabolite levels or concentration differences and the age, pyridoxine dose (a single oral dose and long-term maintenance dose), duration of treatment, or neurodevelopmental phenotype was found at present study. The large individual differences among patients, probably affected by various genotypes, leading to quite different effects of pyridoxine on the change degree of metabolites concentrations. Our study suggested that long-term pyridoxine treatment could control seizures rather than getting toxic lysine metabolites such as a-AASA and P6C back to normal. In the future, more therapies should be focused to alleviate the metabolites accumulation and further improve the prognosis of PDE.

Objective Pyridoxine responsive seizures (PDRs) are characterized by early-onset seizures and epileptic encephalopathy (neonates and infants) which respond to pyridoxine. Any type of seizures can be the first presentation of PDRs in these children. The aim of this 20-year retrospective study was to report the profile of 35 children with PDRs. Materials and Methods Neonatal and infantile seizures responding to pyridoxine were analyzed retrospectively from 1998 to 2018. Depending on the clinical features, laboratory results, and genetic study, they were divided into following four groups: (A) responders with α-aminoadipic semialdehyde dehydrogenase 7A1 (ALDH7A1) mutation, (B) responders with pyridoxal phosphate homeostasis protein (PLPHP) mutation, (C) responders with none of these two known mutations, (D) and responders in combination with antiepileptic medications. Results Sixteen of 35 children had genetic mutation, 4 with ALDH7A1 mutation, and 12 with PLPHP mutation recently described. Nineteen of 35 children had no genetic positivity. Conclusion A large number of children with pyridoxine response do not have known genetic confirmation. Over time, new genes, responsible for pyridoxine dependency, may be identified or an unknown metabolic disorder may be seen in these children. [ABSTRACT FROM AUTHOR]

Pyridoxine‐dependent epilepsy (PDE) is often characterized as an early onset epileptic encephalopathy with dramatic clinical improvement following pyridoxine supplementation. Unfortunately, not all patients present with classic neonatal seizures or respond to an initial pyridoxine trial, which can result in the under diagnosis of this treatable disorder. Restriction of lysine intake and transport is associated with improved neurologic outcomes, although treatment should be started in the first year of life to be effective. Because of the documented diagnostic delay and benefit of early treatment, we aimed to develop a newborn screening method for PDE. Previous studies have demonstrated the accumulation of Δ1‐piperideine‐6‐carboxylate and α‐aminoadipic semialdehyde in individuals with PDE, although these metabolites are unstable at room temperature (RT) limiting their utility for newborn screening. As a result, we sought to identify a biomarker that could be applied to current newborn screening paradigms. We identified a novel metabolite, 6‐oxo‐pipecolate (6‐oxo‐PIP), which accumulates in substantial amounts in blood, plasma, urine, and cerebral spinal fluid of individuals with PDE. Using a stable isotope‐labeled internal standard, we developed a nonderivatized liquid chromatography tandem mass spectrometry‐based method to quantify 6‐oxo‐PIP. This method replicates the analytical techniques used in many laboratories and could be used with few modifications in newborn screening programs. Furthermore, 6‐oxo‐PIP was measurable in urine for 4 months even when stored at RT. Herein, we report a novel biomarker for PDE that is stable at RT and can be quantified using current newborn screening techniques. [ABSTRACT FROM AUTHOR]

Lysine, as an essential amino acid, predominantly undergoes metabolic processes through the saccharopine pathway, whereas a smaller fraction follows the pipecolic acid pathway. Although the liver is considered the primary organ for lysine metabolism, it is worth noting that lysine catabolism also takes place in other tissues and organs throughout the body, including the brain. Enzyme deficiency caused by pathogenic variants in its metabolic pathway may lead to a series of neurometabolic diseases, among which glutaric aciduria type 1 and pyridoxine-dependent epilepsy have the most significant clinical manifestations. At present, through research, we have a deeper understanding of the multiple pathophysiological mechanisms related to these diseases, including intracerebral accumulation of neurotoxic metabolites, imbalance between GABAergic and glutamatergic neurotransmission, energy deprivation due to metabolites, and the dysfunction of antiquitin. Because of the complexity of these diseases, their clinical manifestations are also diverse. The early implementation of lysine-restricted diets and supplementation with arginine and carnitine has reported positive impacts on the neurodevelopmental outcomes of patients. Presently, there is more robust evidence supporting the effectiveness of these treatments in glutaric aciduria type 1 compared with pyridoxine-dependent epilepsy. [ABSTRACT FROM AUTHOR]

To investigate which genetic epilepsies should be prioritized for newborn screening research and development, we interviewed 17 US academic pediatric epileptologists and followed up these interviews with an electronic survey of members of the Pediatric Epilepsy Research Consortium (also all US academic pediatric epilepsy specialists). Interviewees were enthusiastic about the idea of screening newborns for epilepsy, but many expressed reservations regarding the paucity of disease-modifying therapies. We further evaluated how well these epilepsies meet established newborn screening criteria including incidence, suitable biomarkers, and availability of disease-modifying therapies (Table). Despite these limitations, it is important to prioritize newborn screening research for specific monogenic epilepsy syndromes in anticipation of future therapies. [Extracted from the article]

Abstract Background The ALDH7A1 gene is known to be responsible for autosomal recessive pyridoxine-dependent epilepsy (OMIM 266100). The phenotypic spectrum of ALDH7A1 mutations is very heterogeneous ranging from refractory epilepsy and neurodevelopmental delay, to multisystem neonatal disorder. Aim The present study aims at describing the phenotype associated with a novel homozygous ALDH7A1 mutation and the spectrum of brain malformations associated with pyridoxine-dependent epilepsy. Methods We conducted a literature review on the Internet database Pubmed (up to November 2017) searching for ALDH7A1 mutations associated with brain malformations and brain MRI findings. Results We present the case of two siblings, children of related parents. The proband presented neonatal focal seizures not responding to conventional antiepileptic drugs. Electroencephalography showed a suppression burst pattern and several multifocal ictal patterns, responsive to pyridoxine. Brain MRI was normal. Molecular analysis by targeted next-generation sequencing panel for epileptic encephalopathy disclosed a homozygous missense mutation of ALDH7A1. The same mutation was then found in a stored sample of DNA from peripheral blood of an older sister dead 3 years earlier. This girl presented a complex brain malformation diagnosed with a foetal MRI and had neonatal refractory seizures with suppression burst pattern. She died at 6 months of age. Literature review The brain abnormalities most frequently reported in pyridoxine-dependent epilepsy include: agenesia/hypoplasia of the corpus callosum, not specific white matter abnormalities, large cisterna magna, ventriculomegaly, haemorrhages, cerebellum hypoplasia/dysplasia, and, more rarely, dysplasia of the brainstem and hydrocephalus. Discussion and conclusions ALDH7A1 mutations have been associated to different brain abnormalities, documented by MRI only in few cases. The study cases expand the clinical spectrum of ALDH7A1 associated conditions, suggesting to look for ALDH7A1 mutations not only in classical phenotypes but also in patients with brain malformations, mainly if there is a response to a pyridoxine trial. Highlights • We describe a novel mutation of ALDH7A1 gene associated with brain malformations. • We highlight the possibility to look for ALDH7A1 mutations in patients with brain anomalies. • We report a literature review on ALDH7A1 mutations associated to brain abnormalities. [ABSTRACT FROM AUTHOR]

Introduction Pyridoxine-dependent epilepsy (PDE) is a rare disorder of the lysine metabolism, characterized by a pharmacoresistant epileptic encephalopathy that usually begins in the neonatal period. However, its phenotypic spectrum is wide and not limited to seizures. We report a new case of PDE who developed hydrocephalus, along with an exhaustive review of the literature. Case report Our patient presented with seizures at 13 h of life. Antiepileptic drugs, vitamins and cofactors were required to achieve seizure control. Laboratory tests were congruent with PDE. She remained seizure-free until age five months, when seizures reappeared in the context of increasing head size and irritability. A cranial ultrasound showed hydrocephalus, for which she underwent ventriculoperitoneal shunting. Discussion Seven other patients with same features have been previously reported. Seizure onset occurred within the first 7 days in all patients. Most of the children developed hydrocephalus at 6–7 months of age. In 4 out of 7 a genetic mutation was identified, despite the accurate etiology of hydrocephalus was unknown in most of them. The case we report behaved similarly to the others previously described. We postulate that the pathogenesis of this complication could be related to the high expression of antiquitin in choroid plexus epithelium, where the cerebrospinal fluid is produced. Conclusions patients with PDE should be closely monitored, since they may present severe complications. We highlight the development of hydrocephalus, an uncommon but potentially life-threatening problem reported in 8 patients up to present time. [ABSTRACT FROM AUTHOR]

Pyridoxine-dependent epilepsy (PDE) is a rare disease characterized by mutations in the lysine degradation gene ALDH7A1 leading to recurrent neonatal seizures, which are uniquely alleviated by high doses of pyridoxine or pyridoxal 59-phosphate (vitamin B6 vitamers). Despite treatment, neurodevelopmental disabilities are still observed in most PDE patients underlining the need for adjunct therapies. Over 60 years after the initial description of PDE, we report the first animal model for this disease: an aldh7a1-null zebrafish (Danio rerio) displaying deficient lysine metabolism and spontaneous and recurrent seizures in the larval stage (10 days postfertilization). Epileptiform electrographic activity was observed uniquely in mutants as a series of population bursts in tectal recordings. Remarkably, as is the case in human PDE, the seizures show an almost immediate sensitivity to pyridoxine and pyridoxal 59-phosphate, with a resulting extension of the life span. Lysine supplementation aggravates the phenotype, inducing earlier seizure onset and death. By using mass spectrometry techniques, we further explored the metabolic effect of aldh7a1 knockout. Impaired lysine degradation with accumulation of PDE biomarkers, B6 deficiency, and low g-aminobutyric acid levels were observed in the aldh7a12/2 larvae, which may play a significant role in the seizure phenotype and PDE pathogenesis. This novel model provides valuable insights into PDE pathophysiology; further research may offer new opportunities for drug discovery to control seizure activity and improve neurodevelopmental outcomes for PDE. [ABSTRACT FROM AUTHOR]

Aldehyde dehydrogenase 7A1 (ALDH7A1) is involved in lysine catabolism, catalyzing the oxidation of α-aminoadipate semialdehyde to α-aminoadipate. Certain mutations in the ALDH7A1 gene, which are presumed to reduce catalytic activity, cause an autosomal recessive seizure disorder known as pyridoxine-dependent epilepsy (PDE). Although the genetic association between ALDH7A1 and PDE is well established, little is known about the impact of PDE-mutations on the structure and catalytic function of the enzyme. Herein we report the first study of the molecular consequences of PDE mutations using purified ALDH7A1 variants. Eight variants, with mutations in the oligomer interfaces, were expressed in Escherichia coli : P78L, G83E, A129P, G137V, G138V, A149E, G255D, and G263E. All but P78L and G83E were soluble and could be purified. All six soluble mutants were catalytically inactive. The impact of the mutations on oligomerization was assessed by analytical ultracentrifugation. Wild-type ALDH7A1 is shown to exist in a dimer-tetramer equilibrium with a dissociation constant of 16 μM. In contrast to the wild-type enzyme, the variants reside in monomer-dimer equilibria and are apparently incapable of forming a tetrameric species, even at high enzyme concentration. The available evidence suggests that they are misfolded assemblies lacking the three-dimensional structure required for catalysis. [ABSTRACT FROM AUTHOR]

Pyridoxine-dependent epilepsy is a rare autosomal recessive hereditary disorder causing severe intractable epileptic seizures presenting typically in prenatal and neonatal period, rarely in early infancy (age up to 3 years). Pyridoxine-dependent epilepsy, caused by metabolic disturbance of pyridoxine, is associated with mutations in the ALDH7A1 or ALDH4A1 gene. Pyridoxine-dependent epilepsy is successfully treatable using high doses of pyridoxine. The diagnosis is based on biochemical and genetic examinations. Three case reports of patients with a typical clinical course of pyridoxine-dependent epilepsy and genetically detected mutation in the ALDH7A1 gene are presented. [ABSTRACT FROM AUTHOR]