Folinic Acid-responsive Seizures Research Articles

CAD Deficiency—Another Treatable Early Infantile Epileptic Encephalopathy

Early infantile epileptic encephalopathies (EIEEs) are caused by a variety of structural brain abnormalities, genetic defects and inborn errors of metabolism. Although most conditions do not have definitive treatment, a very few of these are treatable like pyridoxine dependency, pyridoxal phosphate–responsive seizures, folinic acid–responsive seizures, biotinidase deficiency, glucose transporter type 1 deficiency syndrome, creatine deficiency, and KCNQ2 and SCN2A encephalopathies.1 We now have another condition in EIEE that is easily treatable, i.e., EIEE-50 caused because of mutations in CAD gene that can be treated with uridine supplementation.

Épilepsies vitamino-sensibles

Inborn error of metabolism may produce a complex clinical picture in which epilepsy is only one of the various neurologic manifestations including developmental delay/regression, mental retardation, and movement disorders. However, metabolic epilepsies may dominate the clinical presentation. A specific diagnosis of metabolic disorders in epileptic patients may provide the possibility of specific treatments that can improve seizures. In a few metabolic diseases such as vitamin-responsive epilepsies, epilepsy responds to specific treatments based on supplementation of cofactors. Certain rare vitamin-responsive inborn errors of metabolism may present as early encephalopathy with anticonvulsant-resistant seizures. These include pyridoxine-dependent seizures, pyridoxal-phosphate-dependent seizures, folinic acid-responsive seizures, and biotinidase deficiency. This review discusses our current understanding of these vitamin-responsive epilepsies.

Treatment of Organic Acidemia

Immidiate ManagementInfants and children with acute metabolic crisis require immediate treatment to prevent further acute deterioration and long-term sequelae.Early and appropriate treatment before confirmation of the diagnosis is life-saving.Eliminate intake of the precursors of possibly toxic metabolites.This applies most often to suspected inborn errors of amino acid or organic acid metabolism. In both cases, dietary or parenteral intake of protein and amino acids should be eliminated immediately an organic acidemia is suspected.Administer glucose a simple source of calories at least 8 mg / kg / min to suppress mobilization of endogenous sources of the metabolites.This is achieved by the intravenous administration of 10% dextrose supplemented by Intralipid.Specific TherapydiseaseNPO: Minimize intake and endogenous productionof toxic metabolites.Hadration: Administer high-calorie, high-carbohydrate intravenousfluids: 10% dextrose in 0.2% NaCl at 1.5 times calculated maintenance, and add KCl .Alkali Therapy: Bicarbonate is generally not indicated unless the plasma bicarbonate is <10 mmol/L; deficits should be only half corrected.Hemo or peritoneal dialysis: If just described measures fail to induce clinical & biochemical improvement ,hemo or peritoneal dialysis is indicated to Accelerate elimination of toxic metabolites. If hyperammonemia exists:1.5 × Maintenance D/W 10 % & intravenous lipids 1 g/kg 24 hSodium benzoate 250 mg/ kg to be added to 20 cc/kg of 10% glucose & infused within 1-2 h (priming dose) Continue infusion of sodium benzoate 250-500 mg / kg / 24 h following the above priming dose & should be added to daily intravenous fluidsInitiate peritoneal dialysis or hemodialysis :if above treatment fails to produce an appropriate decrease in plasma ammonia.Peritoneal dialysis is too slow. Exchange transfusion brings the plasma ammonium down quickly, but rebound hyperammonemia occurs just as quickly.It may be useful in some circumstances as an adjunct to hemodialysis. Cofactors TherapyAdministration of cofactors may be indicated in organic acidemia :Biotin 10 mg / dayCarnitine 100 / mg / kg / day in three divided doses IV or orallyCobalamin (vitamin B12) 1 mg SC or IMB6 100 mg IV or Activated B6 10 mg/kg IV, should be given to neonates with seizures unresponsive to conventional anticonvulsants; if there is no response to B6 and Activated B6 ,folinic acid , should be administered for possible folinic acid responsive seizures.

Late-onset folinic acid-responsive seizures

Folinic acid-responsive seizures are rare a cause of treatable neonatal epilepsy. Patients present with multifocal, tonic or myoclonic seizures that are unresponsive to antiepileptic medication but respond to folinic acid. It has recently been shown that some patients with folinic acid-responsive seizures have an alpha-AASA deficiency due to mutations in the ALDH7A1 gene and are thus identical to pyridoxine-dependent epilepsy. We describe a 7 month old boy who presented with multifocal and tonic seizures. Prior development had been normal. EEG showed beginning hypsarrythmia that did not respond to escalating treatment with pyridoxine. After treatment with folinic acid and phenobarbital seizures stopped and the EEG improved. When folinic acid treatment was stopped after three days, seizures started again and the EEG deteriorated. Upon retreatment with folinic acid, the child became seizure free again and the EEG showed a normal pattern. Analysis of biogenic amine metabolites was not typical of folinic acid-responsive seizures and pipecolic acid and alpha-AASA in CSF was of normal range. The MRI scan showed a normal pattern without white matter loss. Genetic analysis is being performed.

Aldehyde dehydrogenase 7A1 (ALDH7A1) attenuates reactive aldehyde and oxidative stress induced cytotoxicity

Mammalian aldehyde dehydrogenase 7A1 (ALDH7A1) is homologous to plant ALDH7B1 which protects against various forms of stress such as increased salinity, dehydration and treatment with oxidants or pesticides. Deleterious mutations in human ALDH7A1 are responsible for pyridoxine-dependent and folinic acid-responsive seizures. In previous studies, we have shown that human ALDH7A1 protects against hyperosmotic stress presumably through the generation of betaine, an important cellular osmolyte, formed from betaine aldehyde. Hyperosmotic stress is coupled to an increase in oxidative stress and lipid peroxidation (LPO). In this study, cell viability assays revealed that stable expression of mitochondrial ALDH7A1 in Chinese hamster ovary (CHO) cells provides significant protection against treatment with the LPO-derived aldehydes hexanal and 4-hydroxy-2-nonenal (4HNE) implicating a protective function for the enzyme during oxidative stress. A significant increase in cell survival was also observed in CHO cells expressing either mitochondrial or cytosolic ALDH7A1 treated with increasing concentrations of hydrogen peroxide (H 2O 2) or 4HNE, providing further evidence for anti-oxidant activity. In vitro enzyme activity assays indicate that human ALDH7A1 is sensitive to oxidation and that efficiency can be at least partially restored by incubating recombinant protein with the thiol reducing agent β-mercaptoethanol (BME). We also show that after reactivation with BME, recombinant ALDH7A1 is capable of metabolizing the reactive aldehyde 4HNE. In conclusion, ALDH7A1 mechanistically appears to provide cells protection through multiple pathways including the removal of toxic LPO-derived aldehydes in addition to osmolyte generation.

Simultaneous determination of alpha-aminoadipic semialdehyde, piperideine-6-carboxylate and pipecolic acid by LC–MS/MS for pyridoxine-dependent seizures and folinic acid-responsive seizures

Pyridoxine-dependent seizures (PDS) is an autosomal recessive disorder characterized by seizures presenting in neonates or infants up to 3 years of age which respond to pharmacological doses of pyridoxine. Alpha-aminoadipic semialdehyde dehydrogenase (antiquitin) deficiency was identified as an underlying defect in PDS characterized by accumulation of alpha-aminoadipic semialdehyde (α-AASA) as a specific marker and recently folinic acid-responsive seizures (FRS) were found to be allelic to PDS as the putative mutations were identified in the antiquitin gene ( ALDH7A1). α-AASA is known to be in reversible equilibrium with its cyclic Shiff base, δ 1-piperideine-6-carboxylate (P6C). Pipecolic acid (PA) is another biomarker often elevated but is not specific to PDS. Here, we developed the liquid chromatography–mass spectrometry (LC–MS/MS) method to determine the analytes of α-AASA, P6C and PA simultaneously in plasma and validated the assay using samples from confirmed cases. This approach eliminates the extra time and expense of running multiple assays and provides valuable information for the rapid diagnosis and treatment of patients with PDS and FRS which potentially could lead to a better outcome with improved quality of life. The stability study showed that α-AASA and P6C were unstable even at −20 °C. A careful sample handling with immediate freezing and testing is required for reliable result.

Folinic acid–responsive seizures are identical to pyridoxine‐dependent epilepsy

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.

Folate-Responsive Neurologic Diseases

Folate is a water-soluble vitamin of the B complex group, and is required for optimal health, growth, and development. In humans, it cannot be synthesized de novo. As a cofactor or coenzyme, folate plays key biological roles in a variety of physiologic processes: maintenance and repair of the genome, regulation of gene expression, amino-acid metabolism, neurotransmitter synthesis, and the formation of myelin. Dietary folates must undergo multiple, tightly regulated absorption and metabolic processes before their cellular utilization occurs. Clinical conditions associated with abnormal body folate status are very diverse. They range from genetic syndromes defined prior to conception, to malformations that develop during embryogenesis (neural tube defects), to disorders that are postnatally acquired and progressive (e.g., cerebral folate deficiency, or folinic acid-responsive seizures). Central nervous system folate deficiency or impaired availability can occur in the settings of normal or decreased systemic folate levels. Because the majority of patients respond to treatment with folinic acid, pediatric neurologists should remain vigilant to the possibility of deficiencies of folate in patients with unexplained neurologic disorders. The deleterious outcomes of untreated patients underscore the importance of making an early diagnosis.

Folinic Acid–Responsive Seizures Initially Responsive to Pyridoxine

This report presents a male who developed clonic seizures on the day he was born. The next day, the diagnosis of pyridoxine-dependent seizures was made. However, contradictory to this diagnosis, seizures reappeared despite treatment with pyridoxine. Seizures ceased after folinic acid was initiated. The clinical and biochemical characteristics of folinic acid-responsive seizures are reviewed. Treatment with folinic acid should be considered in neonatal seizures of unknown origin that do not respond to pyridoxine, or manifest a transient response to pyridoxine.

Clinical approach to inherited metabolic disorders in neonates: an overview

There are almost one hundred inborn errors of metabolism which can start in the neonatal period, but less than 20 are amenable to treatment. In general, an extremely evocative clinical setting is the course of a full-term baby born after normal pregnancy and delivery who, after an initial symptom-free period deteriorates relentlessly for no apparent reason and does not respond to symptomatic therapy. Investigations routinely performed in all sick neonates yield normal results. Emergency treatment must be undertaken in parallel with investigations. Five main presentations can be observed: a neurologic deterioration ‘intoxication’ type mostly suggests maple syrup urine disease, methylmalonic, propionic, isovaleric acidaemias and urea cycle disorders. Isolated seizures is the revealing symptom of pyridoxine-responsive and folinic acid responsive seizures. A jaundice or a liver failure suggest galactosaemia, fructosaemia, tyrosinaemia type I (after 3 weeks), phosphomannoisomerase deficiency or bile acid synthesis defects. Cardiac failure and heartbeat disorders should first suggest mitochondrial fatty acid oxidation (FAO) disorders. Persistent hypoglycaemia is the presenting sign of glyco/ gluconeogeneis defects, hyperinsulinism and FAO disorders. The first line investigation relies upon the collection at the same time of a few samples including blood gases electrolytes, prothrombin time, transaminases, ammonia and lactic acid, and the search for ketonuria. The storage of plasma, urine and blood (on filter paper) is an important element in the diagnosis. The utilization of these samples should be carefully planned after taking advice from specialists in inborn errors.