Diagnosis Of Pyridoxine-dependent Epilepsy Research Articles

PYRIDOXINE-dependent epilepsy (PDE): An observational study of neonatal cases on the role of pyridoxine in patients treated with standard anti-seizure medications

BackgroundThe main objective of this study was to evaluate the neurological consequences of delayed pyridoxine administration in patients diagnosed with Pyridoxin Dependent Epilepsies (PDE). Materials and MethodsWe reviewed 29 articles, comprising 52 genetically diagnosed PDE cases, ensuring data homogeneity. Three additional cases were included from the General Pediatric Operative Unit of San Marco Hospital. Data collection considered factors like age at the first seizure's onset, EEG reports, genetic analyses, and more. Based on the response to first-line antiseizure medications, patients were categorized into four distinct groups. Follow-up evaluations employed various scales to ascertain neurological, cognitive, and psychomotor developments. ResultsOur study includes 55 patients (28 males and 27 females), among whom 15 were excluded for the lack of follow-up data. 21 patients were categorized as "Responder with Relapse", 11 as "Resistant", 6 as "Pyridoxine First Approach", and 2 as "Responders". The neurological outcome revealed 37,5 % with no neurological effects, 37,5 % showed complications in two developmental areas, 15 % in one, and 10 % in all areas.The statistical analysis highlighted a positive correlation between the time elapsed from the administration of pyridoxine after the first seizure and worse neurological outcomes. On the other hand, a significant association was found between an extended latency period (that is, the time that elapsed between the onset of the first seizure and its recurrence) and worse neurological outcomes in patients who received an unfavorable score on the neurological evaluation noted in a subsequent follow-up. ConclusionsThe study highlights the importance of early recognition and intervention in PDE. Existing medical protocols frequently overlook the timely diagnosis of PDE. Immediate administration of pyridoxine, guided by a swift diagnosis in the presence of typical symptoms, might improve long-term neurological outcomes, and further studies should evaluate the outcome of PDE neonates promptly treated with Pyridoxine.

Inherited Pediatric Neurotransmitter Disorders: Case Studies and Long-Term Outcomes

AbstractPrimary pediatric neurotransmitter disorders include genetic defects of neurotransmitter metabolism that may mimic common neurological conditions in children. Our objective was to evaluate the clinical experience and outcomes of affected patients. Five patients with primary neurotransmitter defects were identified in the neurometabolic database between 2004 and 2022. Two patients with 6-pyruvoyltetrahydropterin synthase deficiency and one with pyridoxine-dependent epilepsy (PDE) presented in the neonatal period. One patient with succinic semialdehyde dehydrogenase (SSADH) deficiency and one with aromatic l-amino acid decarboxylase (AADC) deficiency presented in later life. A diagnosis of cerebral palsy was revised following biochemical confirmation of SSADH deficiency. AADC deficiency was confirmed via exome sequencing and reduced activity on enzyme assay. Late diagnosis in the latter two cases was likely due to a low index of suspicion and lack of access to diagnostic tests in the country of origin. In two children with tetrahydrobiopterin deficiency, newborn screening results and atypical clinical features prompted investigations. An early diagnosis of PDE was established based on presenting features, a high index of suspicion, the presence of an identifiable biochemical marker and molecular genetic testing. Pediatric neurotransmitter disorders can be diagnosed based on a high clinical index of suspicion, availability of biochemical markers, and molecular genetic testing. These disorders, though rare, need to be included in the differential diagnosis of common neurological presentations in children as they may be potentially treatable. Outcomes and influencing factors in the present series are discussed in comparison to published data.

The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy.

Pyridoxine dependent epilepsy (PDE) is a treatable epileptic encephalopathy characterized by a positive response to pharmacologic doses of pyridoxine. Despite seizure control, at least 75% of individuals have intellectual disability and developmental delay. Current treatment paradigms have resulted in improved cognitive outcomes emphasizing the importance of an early diagnosis. As genetic testing is increasingly accepted as first tier testing for epileptic encephalopathies, we aimed to provide a comprehensive overview of ALDH7A1 mutations that cause PDE. The genotypes, ethnic origin and reported gender was collected from 185 subjects with a diagnosis of PDE. The population frequency for the variants in this report and the existing literature were reviewed in the Genome Aggregation Database (gnomAD). Novel variants identified in population databases were also evaluated through in silico prediction software and select variants were over-expressed in an E.coli-based expression system to measure α-aminoadipic semialdehyde dehydrogenase activity and production of α-aminoadipic acid. This study adds 47 novel variants to the literature resulting in a total of 165 reported pathogenic variants. Based on this report, in silico predictions, and general population data, we estimate an incidence of approximately 1:64,352 live births. This report provides a comprehensive overview of known ALDH7A1 mutations that cause PDE, and suggests that PDE may be more common than initially estimated. Due to the relative high frequency of the disease, the likelihood of under-diagnosis given the wide clinical spectrum and limited awareness among clinicians as well as the cognitive improvement noted with early treatment, newborn screening for PDE may be warranted.

A case of pyridoxine dependent epilepsy admitted with status epilepticus

Background: Pyridoxine dependent epilepsy (PDE) is a rare autosomal recessive epileptic encephalopathy due to mutations in the ALDH7A1 gene. İntractable seizures is the most seen clinical form in the early infantil period. Patient: 4 months old female admitted our hospital with status epilepticus. Her seizures started in neonatal period and partial response seen to phenobarbital. Seizures could not be controlled although appropriate antiepileptic treatment. After 100 mg pyridoxine intravenously given seizures stopped. Diagnosis of PDE was suspected and ALDH7A1 gene mutation analysis revealed compound homozygous missense amino acid mutation. Before pyridoxine treatment she had developmental delay but after normal mental and motor development seen. Conclusion: PDE causes intractable epilepsy in newborn period and early infancy and untreated cases suffer developmental delay and intellectual disability. In the treatment protocol of status epilepticus and intractable epilepsy pyridoxine should be applied and in case of total or partial pyridoxine response diagnosis of PDE should be considered.

First patient in Serbia with biochemically and genetically diagnosed pyridoxine-dependent epilepsy

Introduction. Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive inborn error of metabolism present with early-onset seizures resistant to common anticonvulsants. PDE has been shown to be caused by a defect of a ?-aminoadipic semialdehyde dehydrogenase (also known as ALDH7A1 or antiquitin) in the cerebral lysine degradation pathway. Its deficiency results in accumulation of ?-aminoadipic semialdehyde (?-AASA), piperideine -6-carboxylate and pipecolic acid, which serve as diagnostic markers in urine, plasma and cerebrospinal fluid of the disease. ?-Aminoadipic semialdehyde dehydrogenase is encoded by the ALDH7A1 or antiquitin gene and definite confirmation of diagnosis of PDE is made by genetic analysis. Case report. We present a first patient in Serbia who was diagnosed clinically, biochemically and genetically. We suspected PDE due to drug-resistant seizures in the seventh day of life when we attempted with pyridoxine. Since that time the patient has taken pyridoxine and the seizures have not recured. Our patient had markedly elevated ?- AASA in urine while on treatment with individual dosages of pyridoxine. Molecular-genetical analysis identified mutations of the ALDH7A1 (antiquitin) gene. Conclusion. ?-AASA is reliable marker to select PDF patient for molecular analysis of the ALDH7A1(antiquitin) gene. Diagnosis is confirmed by molecular- genetical analysis and pyridoxine withdrawal is no longer needed to establish the diagnosis of ?definite? PDE.

A 15-year-old with seizures: late diagnosis of pyridoxine-dependent epilepsy

A 15-year-old with seizures: late diagnosis of pyridoxine-dependent epilepsy

First cases of pyridoxine-dependent epilepsy in Bulgaria: novel mutation in the ALDH7A1 gene.

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder characterized by intractable seizures in neonates and infants. The seizures cannot be controlled with antiepileptic medications but respond both clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). PDE is caused by mutations in the ALDH7A1 gene. Molecular genetic analysis of the ALDH7A1 gene was performed in seven patients, referred with clinical diagnosis of PDE. Mutations were detected in a dizygotic twin pair and a non-related boy with classical form of PDE. Direct sequencing of the ALDH7A1 gene revealed one novel (c.297delG, p.Trp99*) and two already reported (c.328C>T, p.Arg110*; c.584A>G, p.Asn195Ser) mutations. Here, we report the first genetically proven cases of PDE in Bulgaria.

Fetal Onset Ventriculomegaly and Subependymal Cysts in a Pyridoxine Dependent Epilepsy Patient

Pyridoxine dependent epilepsy (PDE) is caused by mutations in the ALDH7A1 gene encoding α-aminoadipic semialdehyde dehydrogenase. The classic clinical presentation is neonatal seizures responsive only to pyridoxine therapy. White matter abnormalities, corpus callosum agenesis or hypoplasia, megacisterna magna, cortical dysplasia, neuronal heterotopias, intracerebral hemorrhage, and hydrocephalus in neuroimaging have been reported in patients with PDE. We report a new patient with asymmetric progressive ventriculomegaly noted on fetal sonography at 22 weeks' gestation. Postnatal brain sonography on day 1 and MRI on day 5 confirmed bilateral asymmetric ventriculomegaly caused by bilateral subependymal cysts. Intractable seizures at age 7 days initially responded to phenobarbital. Markedly elevated urinary α-aminoadipic acid semialdehyde levels and compound heterozygous mutations in the ALDH7A1 gene (c.446C>A/c.919C>T) confirmed the diagnosis of PDE caused by ALDH7A1 genetic defect. Despite the presence of structural brain malformations and subependymal cysts, PDE should always be included in the differential diagnosis of neonatal seizures that are refractory to treatment with antiepileptic drugs.

Early diagnosis of pyridoxine-dependent epilepsy: Video-EEG monitoring and biochemical and genetic investigation

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive metabolic disease. A delay of treatment may affect outcome and early initiation of pyridoxine based on effective diagnosis is crucial to ensure good cognitive outcome in neonates. A consensus for the diagnosis of PDE is based on refractive seizures and responsiveness to pyridoxine, however, a growing body of evidence suggests that additional elements should be considered which include biochemical data, genetic screening, and EEG monitoring. We present a case study of a neonate with PDE, who presented with misleading clinical presentation and a novel mutation in the antiquitin (ALDH7A1) gene (A294V), and highlight important aspects in order to consider the definition of diagnosis and management of PDE in the light of more recent data.

Clinical Spectrum in Children With Pyridoxine-Dependent Epilepsy

Research Article| May 01 2013 Clinical Spectrum in Children With Pyridoxine-Dependent Epilepsy AAP Grand Rounds (2013) 29 (5): 55. https://doi.org/10.1542/gr.29-5-55 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Clinical Spectrum in Children With Pyridoxine-Dependent Epilepsy. AAP Grand Rounds May 2013; 29 (5): 55. https://doi.org/10.1542/gr.29-5-55 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: epilepsy, pyridoxine dependency syndrome, seizures, pyridoxine Source: Perez B, Gutierrez-Solana LG, Verdu A, et al. Clinical, biochemical, and molecular studies in pyridoxine-dependent epilepsy: antisense therapy as possible new therapeutic option. Epilepsia. 2013; 54(2): 239– 248; doi: https://doi.org/10.1111/epi.12083Google Scholar Researchers in Spain and India studied the clinical, biochemical, and genetic spectrum in children with pyridoxine-dependent epilepsy (PDE). The disease was confirmed based on the presence of α-aminoadipic semialdehyde (α-AASA) in urine and pipecolic acid (PA) in plasma and/or cerebrospinal fluid, and by DNA analysis. A total of 12 children were included in the case series. Onset of seizures varied from the neonatal period to the first months of life. Seizures were focal or multifocal, clonic or myoclonic, and generalized tonic; 50% of study patients had status epilepticus. Seizures were controlled transiently with conventional antiepileptic drugs (AED) for 15 or more days in 8 of 12 patients, leading to a delay in diagnosis. The effective dose of pyridoxine (vitamin B6) to suppress seizures ranged from 10 to 30 mg/kg per day. Refractory neonatal seizures were the main indications for suspecting and starting treatment for PDE. Neurologic symptoms in addition to seizures included hypotonia, irritability, and psychomotor retardation. EEG abnormalities were variable in the study children; the EEG was normal in 1 patient. All EEGs became normal after pyridoxine therapy. MRI abnormalities included mega cisterna magna, Dandy Walker syndrome, ventriculomegaly, and corpus callosum dysgenesis. Six study children, followed for more than 5 years, had evidence of cognitive dysfunction. Delay in treatment and dysgenesis of the corpus callosum were risk factors for neurodevelopmental delay. Treatment with pyridoxine failed to normalize IQ. The authors conclude that, despite pyridoxine therapy, there remains a need to reduce persistent neurologic damage in PDE, and that the diagnosis of PDE should be considered in infants with intractable or poorly controlled seizures. Dr Millichap has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. PDE is an autosomal recessive inherited disorder caused by mutations in the ALDH7A1 gene, which encodes antiquitin protein. The clinical spectrum of antiquitin deficiency extends from ventriculomegaly detected on fetal ultrasound, through abnormal fetal movements, to the onset of seizures after birth.1 Clinical diagnosis of PDE can be challenging, because (1) there may be some response to AEDs, (2) response to pyridoxine may not be instantaneous, and (3) structural brain abnormalities may coexist.1 PDE should be considered in the differential diagnosis of any infant with intractable seizures, including patients with MRI abnormalities such as corpus callosum dysgenesis or Dandy Walker syndrome. In suspected cases of PDE, the use of biochemical and DNA tests for antiquitin deficiency is recommended together with a clinical trial of pyridoxine.1 The long-term outcome of PDE is often poor. In a Dutch PDE cohort of 14 patients,2 mental development was delayed in the majority of children, with a median IQ of 72; only 5 walked at 2... You do not currently have access to this content.

Epilepsy due to 20q13.33 subtelomere deletion masquerading as pyridoxine‐dependent epilepsy

A cause of antiepileptic medication resistant seizures presenting in neonates and young infants is pyridoxine-dependent epilepsy (PDE), an organic aciduria, which is due to recessive mutations in the ALDH7A1 gene, resulting in deficiency of antiquitin. Since the discovery of molecular basis of this disorder, a few patients have been reported with a similar clinical phenotype but without evidence of antiqutin dysfunction. We report on a patient who had carried a clinical diagnosis of PDE for 7 years, but who was than shown to have normal ALDH7A1 sequencing and the absence of biomarkers characteristic of this familial epilepsy. Array comparative genomic hybridization (CGH) demonstrated a 1.5-Mb terminal deletion of the long arm of chromosome 20, which included deletion of the KCNQ2 and CHRNA4 genes, both of which have been associated with specific epilepsy syndromes. We suggest that this boy's neonatal epilepsy and neurodevelopmental disabilities are secondary to this deletion and that his clinical response to pyridoxine was coincidental. This patient's history emphasizes the utility of array CGH in the evaluation of children with epilepsy of unknown etiology.

Variability of Phenotype in Two Sisters with Pyridoxine Dependent Epilepsy

Pyridoxine dependent epilepsy (PDE) is characterized by neonatal epileptic encepahalopathy responsive to pharmacological doses of vitamin B6. Recently an autosomal recessive deficiency in Antiquitin (ALDH7A1), a gene involved in the catabolism of lysine has been identified as the underlying cause. In 21 and 23 year-old sisters, who had presented with neonatal / early infantile onset seizures, PDE was confirmed by elevated urinary alpha aminoadipic- 6- semialdehyde (α-AASA) excretion and compound heterozygosity for two known ALDH7A1 missense mutations. Although epilepsy was well controlled upon treatment with pyridoxine, thiamine, phenytoin and carbamazepine since early infancy, both had developmental delay with prominent speech delay as children. As adults, despite the same genetic background and early treatment with pyridoxine, their degree of intellectual disability (ID) differed widely. While the older sister's cognitive functions were in the moderate ID range and she was not able to live unattended, the younger sister had only mild ID and was able to live independently. Although seizures are a defining feature of PDE, other disease manifestations can vary widely even within the same family. Adult neurologists should be aware that the diagnosis of PDE can be delayed and PDE should be considered in the differential diagnosis of adults with seizure disorders dating from childhood.

Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of l-α-aminoadipic semialdehyde/l-Δ1-piperideine 6-carboxylate. However, whilst this is a highly treatable disorder, there is general uncertainty about when to consider this diagnosis and how to test for it. This study aimed to evaluate the use of measurement of urine l-α-aminoadipic semialdehyde/creatinine ratio and mutation analysis of ALDH7A1 (antiquitin) in investigation of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary l-α-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on foetal ultrasound, through abnormal foetal movements and a multisystem neonatal disorder, to the onset of seizures and autistic features after the first year of life. Our relatively large series suggested that clinical diagnosis of pyridoxine dependent epilepsy can be challenging because: (i) there may be some response to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive to pyridoxine. These findings support the use of biochemical and DNA tests for antiquitin deficiency and a clinical trial of pyridoxine in infants and children with epilepsy across a broad range of clinical scenarios.

Electroencephalographic changes in pyridoxine‐dependant epilepsy: new observations

Pyridoxine-dependent epilepsy (PDE) is a rare disease, of which the EEG manifestations are only partially characterised. We report our observations of EEG recordings in four patients with PDE. EEG tracings from four patients fulfilling the clinical criteria for PDE were reviewed. Relative to the time of treatment with pyridoxine, EEG recordings were available before treatment in two patients (at ages four and 10 months), immediately after treatment in two patients and during long-term follow-up with treatment in all four patients. Pre-pyridoxine interictal EEG findings included: diffuse slowing, bilateral independent multifocal epileptiform discharges, generalized bursts of polyspike slow waves and focal or generalized sharp waves. In addition, the EEG was often asymmetrical and included: generalized semi-rhythmic sharp and slow waves, a burst suppression pattern and continuous generalized spike and slow waves. In one patient, who was followed subsequently, a decrease in multifocal spikes and sharp waves and permanent cessation of clinical seizures, within 10 minutes of concurrent reduction of spikes in the pre-existing generalized spike slow wave pattern, was observed immediately after pyridoxine treatment. However, despite the clinical response in this patient we observed persistent generalized burst suppression for four days, and fluctuation of the EEG with diffuse slowing on day four and transient exacerbation of discharges with continuous spike slow waves on day 22. This was followed by intermittent sharp waves at eight and 20 months, mild slowing at 31 months and normal EEG at 43 months. Long-term EEG findings in the other three patients receiving pyridoxine ranged between normal and intermittent multifocal sharp waves. Our data confirm previous observations and provide the following new findings: (1) the presence of burst suppression pattern after cessation of seizures can occur for up to five days after initiation of pyridoxine and should not exclude the diagnosis of PDE, (2) possible fluctuation and even transient worsening of electrographic discharges were observed for up to three weeks after initiation of pyridoxine and (3) the abnormal EEG can persist for up to 43 months before normalizing (range 1-43 months) and in other cases in which it continues to be abnormal it may still improve after increasing the dose of pyridoxine.

Pipecolic acid elevation in plasma and cerebrospinal fluid of two patients with pyridoxine-dependent epilepsy

Diagnosis of pyridoxine-dependent epilepsy is based on the clinical response to high-dosage application of pyridoxine. Here, we report on 2 patients with pyridoxine-dependent epilepsy with significant elevation of pipecolic acid concentrations in plasma and cerebrospinal fluid (CSF) and further increase of pipecolic acid in CSF during a 72-hour pyridoxine withdrawal in 1 of them. Patients with non-pyridoxine-dependent epilepsy had normal pipecolic acid concentrations in plasma and significantly lower concentrations in CSF. High plasma and CSF pipecolic acid concentrations might provide a diagnostic marker in pyridoxine-dependent epilepsy.