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: Epileptic encephalopathy can be induced by inborn metabolic defects that may be rare individually but in aggregate represent a substantial clinical portion of child neurology. These may present with various epilepsy phenotypes including refractory neonatal seizures, early myoclonic encephalopathy, early infantile epileptic encephalopathy, infantile spasms, and generalized epilepsies which in particular include myoclonic seizures. There are varying degrees of treatability, but the outcome if untreated can often be catastrophic. The importance of early recognition cannot be overemphasized. This paper provides an overview of inborn metabolic errors associated with persistent brain disturbances due to highly active clinical or electrographic ictal activity. Selected diseases are organized by the defective molecule or mechanism and categorized as small molecule disorders (involving amino and organic acids, fatty acids, neurotransmitters, urea cycle, vitamers and cofactors, and mitochondria) and large molecule disorders (including lysosomal storage disorders, peroxisomal disorders, glycosylation disorders, and leukodystrophies). Details including key clinical features, salient electrophysiological and neuroradiological findings, biochemical findings, and treatment options are summarized for prominent disorders in each category.05/2013; 2013:124934. DOI:10.1155/2013/124934
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ABSTRACT: Introduction: Inherited metabolic epilepsies are rare disorders that in aggregate represent significant morbidity. Emphasis is given here to entities in which early recognition and treatment are crucial. Methodology: Review based on Literature Search (PubMed: Inherited metabolic epilepsies), Clinical Experience, Expert Opinion. Results: Biopterin synthesis/recycling disorders can be misdiagnosed as atypical phenylketonuria. Cerebral folate deficiency, treatable with folinic acid, is associated with decreased CSF 5-methyltetrahydrofolate. Seizures may be the sole manifestation of biotinidase deficiency. Serine biosynthesis disorders are treatable with serine and glycine but otherwise result in microcephaly and epilepsy. Creatine synthesis disorders are amenable to creatine supplementation and other dietary modalities. A neonate presenting with seizures and diabetes may have a potassium channelopathy, DEND, responsive to oral hypoglycemics. Congenital hyperinsulinism with hyperammonemia (HI/HA) is associated with generalized epilepsy and treated with diazoxide, protein restriction, and antiepileptics. Glucose transporter-1 deficiency has an enlarging phenotype and is treatable with the ketogenic diet. Pyridoxine dependency is associated with antiquitin deficiency and is allelic to folinic acid dependency; PNPO (pyridoxamine 5′-phosphate oxidase) deficiency requires pyridoxal-5′-phosphate therapy. Urea cycle disorders precipitate severe neonatal hyperammonemia and are controlled with dialysis, protein-restriction, and nitrogen-scavenging drugs. Hyperekplexia, an epilepsy mimic involving glycine receptors or transporters, is manageable with benzodiazepine. Expert opinion: Diagnostic and therapeutic recommendations are presented for these challenging conditions having potential catastrophic consequences but inherent treatability.01/2013; 1(2). DOI:10.1517/21678707.2013.758580
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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