Folinic Acid-Responsive Seizures Are Identical to Pyridoxine-Dependent Epilepsy
ABSTRACT Folinic acid-responsive seizures and pyridoxine-dependent epilepsy are two treatable causes of neonatal epileptic encephalopathy. The former is diagnosed by characteristic peaks on cerebrospinal fluid (CSF) monoamine metabolite analysis; its genetic basis has remained elusive. The latter is due to alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase deficiency, associated with pathogenic mutations in the ALDH7A1 (antiquitin) gene. We report two patients whose CSF showed the marker of folinic acid-responsive seizures, but who responded clinically to pyridoxine. We performed genetic and biochemical testing of samples from these patients, and seven others, to determine the relation between these two disorders.
CSF samples were analyzed for the presence of alpha-AASA and pipecolic acid. DNA sequencing of the ALDH7A1 gene was performed.
Both patients reported here had increased CSF alpha-AASA, CSF pipecolic acid, and known or likely pathogenic mutations in the ALDH7A1 gene, consistent with alpha-AASA dehydrogenase deficiency. Analysis of CSF samples from seven other anonymous individuals diagnosed with folinic acid-responsive seizures showed similar results.
These results demonstrate that folinic acid-responsive seizures are due to alpha-AASA dehydrogenase deficiency and mutations in the ALDH7A1 gene. Thus, folinic acid-responsive seizures are identical to the major form of pyridoxine-dependent epilepsy. We recommend consideration of treatment with both pyridoxine and folinic acid for patients with alpha-AASA dehydrogenase deficiency, and consideration of a lysine restricted diet. The evaluation of patients with neonatal epileptic encephalopathy, as well as those with later-onset seizures, should include a measurement of alpha-AASA in urine to identify this likely underdiagnosed and treatable disorder.
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ABSTRACT: Bei therapieresistenten Anfällen müssen, unabhängig vom jeweiligen Lebensalter, angeborene Stoffwechselerkrankungen erwogen werden. Nur selten liegen hierbei erkennbare Epilepsiesyndrome mit typischem EEG-Muster (EEG: Elektroenzephalographie) oder wegweisende Begleitbefunde in Klinik oder kranialer Bildgebung vor. Für zahlreiche metabolisch bedingte Epilepsien existiert ein kausaler Therapieansatz, z. B. durch gezielte Substitution von Vitaminen, Aminosäuren oder alternativen Energieträgern. Dabei entscheidet ein früher Therapiebeginn wesentlich über das Langzeit-Outcome. Der vorliegende Beitrag soll durch die Beschreibung des klinischen Phänotyps, der Anfallssemiologie sowie der diagnostischen Biomarker und Enzymdefekte einen Leitfaden für die Früherkennung behandelbarer metabolischer Epilepsien im Klinikalltag bieten. Abstract In the presence of therapy-resistant seizures of any age, genetic metabolic diseases have to be considered. Rarely they present with recognizable epileptic syndromes, typical EEG features or clinical and radiologic hallmarks. For many metabolic epilepsies, there is causal treatment available, e.g., pharmacologic doses of selected vitamins, amino acid substitution or by providing alternate energy substrates. Early recognition and initiation of specific treatment is crucial to prevent irreversible brain damage. This article aims to provide a detailed description of selected clinical phenotypes, seizure semiology, diagnostic biomarkers, and enzyme defects in order to enable early recognition of treatable metabolic epilepsies in daily clinical practice.Monatsschrift Kinderheilkunde 08/2012; 160(8):723-733. DOI:10.1007/s00112-012-2684-7 · 0.28 Impact Factor
Article: Recent Advances in Neonatal Seizures[Show abstract] [Hide abstract]
ABSTRACT: Neonatal seizures are the most important indicators of underlying brain injury. Seizures in a neonate are different from seizures in older children in many aspects including clinical presentation and etiology. The neonatal brain is immature and tends to have a decreased seizure threshold. Neonatal seizures are classified, based on their presentation as, clinical seizures, electroclinical seizures and electroencephalographic seizures; based on the pathophysiology as epileptic and nonepileptic seizures; and also on the basis of the etiology. Hypoxic ischemic encephalopathy is the leading cause of neonatal seizures, followed by intracranial hemorrhage, metabolic causes such as hypoglycemia and hypocalcemia, intracranial infections and strokes. Neonatal epilepsy syndromes are rare. Electroencephalography (EEG) is the gold standard for diagnosis. Amplitude integrated EEG (aEEG) is also used for continuous monitoring. The approach to management consists of initial stabilization of the neonate followed by treatment of potentially correctable injurious processes such as hypocalcemia, hypoglycemia and electrolyte disturbances, etiology specific therapies and antiepileptic drug (AED) therapy. Phenobarbital remains the first line AED therapy. Pharmacokinetic data on newer drugs is limited. Prognosis depends on the etiology, seizure type, neurological examination at discharge and EEG. Long term neurodevelopmental follow up is essential for babies with neonatal seizures.The Indian Journal of Pediatrics 08/2014; 81(9). DOI:10.1007/s12098-014-1540-2 · 0.92 Impact Factor
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ABSTRACT: Pyridoxine dependent epilepsy (PDE) due to mutations in the ALDH7A1 gene (PDE-ALDH7A1) is caused by α-aminoadipic-semialdehyde-dehydrogenase enzyme deficiency in the lysine pathway resulting in the accumulation of α-aminoadipic acid semialdehyde (α-AASA). Classical presentation is neonatal intractable seizures with a dramatic response to pyridoxine. Pyridoxine therapy does not prevent developmental delays in the majority of the patients. We hypothesized that l-arginine supplementation will decrease accumulation of α-AASA by competitive inhibition of lysine transport into the central nervous system and improve neurodevelopmental and neurocognitive functions in PDE-ALDH7A1.European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 07/2014; 18(6). DOI:10.1016/j.ejpn.2014.07.001 · 1.93 Impact Factor