Folinic Acid-Responsive Seizures Are Identical to Pyridoxine-Dependent Epilepsy

Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado at Denver, CO, USA.
Annals of Neurology (Impact Factor: 9.98). 05/2009; 65(5):550-6. DOI: 10.1002/ana.21568
Source: PubMed


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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    • "The majority of patients are reported to achieve seizure control with pyridoxine alone, although additional antiepileptic drugs may be required in some patients for optimal seizure management [9]. The identification that folinic acidresponsive seizures are also a result of deficiency of α-aminoadipic semialdehyde dehydrogenase has led to concomitant treatment with folinic acid in some individuals [10]. The mechanism of response to folinic acid is not understood, and the benefit of folinic acid in the treatment of PDE has not been established. "
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    ABSTRACT: & Objectives: Of patients with pyridoxine-dependent epilepsy (PDE) due to ATQ deficiency, 75% suffer intellectual disability despite adequate seizure control with high dose pyridoxine. We aimed to assess the safety and efficacy of two novel therapeutic strategies to reduce accumulation of toxic intermediates in this cerebral lysine degradation defect. Methods: In two open-label observational studies, seven children with confirmed ATQ deficiency were started on dietary lysine restriction with regular nutritional monitoring, and outcome evaluation pipecolic acid, AASA levels in body fluids; development/cognition via age-appropriate tests and parental observations; epilepsy). Subsequently additional arginine supplementation was initiated to reduce cerebral lysine flux (cation transporter competitive inhibition).. Results: Lysine-restriction was well tolerated and diet is safe, resulted in reduction of lysine intermediates in all body fluids in all patients (up to 80% reduction AASA in cerebrospinal fluid), with beneficial effects on seizure control and psychomotor development. Additional arginine fortification resulted in normalization of biomarkers and dramatic improvement of psychomotor development. Discussion: Triple therapy is effective, especially if implemented early; studies for PDE newborn screening have been initiated. For dissemination and evidence generation, our PDE Consortium published Recommendations, developed a Digital Diet App and established a RedCap study database ( ).
    The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 05/2015; 42(S1):S13. DOI:10.1017/cjn.2015.83 · 1.53 Impact Factor
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    • "Biallelic mutations in ALDH7A1 have been associated with pyridoxine-dependent epilepsy (PDE) and folinic acid responsive seizures in humans [21], [23]. Although we were not equipped to evaluate seizure activity in our morphants, many of PDE patients also have developmental abnormalities of the CNS, including optic nerve hypoplasia—a phenotype observed in our zebrafish model [20]. "
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    ABSTRACT: Uveal coloboma is a potentially blinding congenital ocular malformation caused by failure of the optic fissure to close during development. Although mutations in numerous genes have been described, these account for a minority of cases, complicating molecular diagnosis and genetic counseling. Here we describe a key role of aldh7a1 as a gene necessary for normal eye development. We show that morpholino knockdown of aldh7a1 in zebrafish causes uveal coloboma and misregulation of nlz1, another known contributor to the coloboma phenotype, as well as skeletal abnormalities. Knockdown of aldh7a1 leads to reduced cell proliferation in the optic cup of zebrafish, delaying the approximation of the edges of the optic fissure. The aldh7a1 morphant phenotype is partially rescued by co-injection of nlz1 mRNA suggesting that nlz1 is functionally downstream of aldh7a1 in regulating cell proliferation in the optic cup. These results support a role of aldh7a1 in ocular development and skeletal abnormalities in zebrafish.
    PLoS ONE 07/2014; 9(7):e101782. DOI:10.1371/journal.pone.0101782 · 3.23 Impact Factor
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    • "Improvement is significant and usually rapidly appreciable on EEG [66]. Variants of the disorder that respond to folinic acid instead of, or in addition to, pyridoxine have also been described, as well as atypical cases with long asymptomatic periods or presenting later in infancy (i.e., weeks or months following birth) [67, 68]. "
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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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