Status epilepticus in a neonate treated with pyridoxine because of a familial recurrence risk for antiquitin deficiency: pyridoxine toxicity?

Pyridoxine-dependent epilepsy (PDE) is a treatable inborn error of metabolism with autosomal recessive inheritance. Antenatal and postnatal prophylactic administration of pyridoxine has been recommended to improve the developmental outcome in possible future pregnancies. We report on a male offspring of a second pregnancy at risk for PDE. While on prophylactic treatment with oral pyridoxine, the newborn developed encephalopathy and status epilepticus at age 14 days. Seizures did not respond to parenteral pyridoxine and additional treatment with folinic acid. After treatment was changed to pyridoxal 5'-phosphate, the infant's condition improved. Antiquitin deficiency was excluded by biochemical and molecular genetic testing, and cofactor treatment was stopped on day 26. He has since remained seizure-free with normal psychomotor development. In healthy newborns, high-dose treatment with pyridoxine may result in increased rather than decreased neuroexcitability. Postnatal prophylactic pyridoxine treatment of fetuses and neonates at risk for PDE should be limited to the shortest possible time, by either prenatal diagnosis or immediate postnatal biochemical and genetic testing.

Hartmann H ，Fingerhut M ，Jakobs C ，Plecko B ... -  《-》

Pyridoxine-dependent epilepsy: normal outcome in a patient with late diagnosis after prolonged status epilepticus causing cortical blindness.

Kluger G ，Blank R ，Paul K ，Paschke E ，Jansen E ，Jakobs C ，Wörle H ，Plecko B ... -  《-》

Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene.

Patients with pyridoxine dependent epilepsy (PDE) present with early-onset seizures resistant to common anticonvulsants. According to the benefit of pyridoxine (vitamin B(6)) and recurrence of seizures on pyridoxine withdrawal, patients so far have been classified as having definite, probable, or possible PDE. Recently, PDE has been shown to be caused by a defect of alpha-amino adipic semialdehyde (AASA) dehydrogenase (antiquitin) in the cerebral lysine degradation pathway. The accumulating compound piperideine-6-carboxylic acid (P6C) was shown to inactivate pyridoxalphosphate (PLP) by a Knoevenagel condensation. Pipecolic acid (PA) and AASA are markedly elevated in urine, plasma, and cerebrospinal fluid (CSF) and thus can be used as biomarkers of the disease. We have investigated 18 patients with neonatal seizure onset, who have been classified as having definite (11), probable (four), or possible (three) PDE. All patients had elevated PA and AASA in plasma (and urine) while on treatment with individual dosages of pyridoxine. Within this cohort, molecular analysis identified 10 novel mutations (six missense mutations, one nonsense mutation, two splice site mutations) within highly conserved regions of the antiquitin gene. Seven mutations were located in exonic sequences and two in introns 7 and 17. Furthermore, a novel deletion of exon 7 was identified. Two of the 36 alleles investigated require further investigation. A known mutation (p.Glu399Gln) was found with marked prevalence, accounting for 12 out of 36 alleles (33%) within our cohort. Pyridoxine withdrawal is no longer needed to establish the diagnosis of "definite" PDE. Administration of pyridoxine in PDE may not only correct secondary PLP deficiency, but may also lead to a reduction of AASA (and P6C) as presumably toxic compounds.

Plecko B ，Paul K ，Paschke E ，Stoeckler-Ipsiroglu S ，Struys E ，Jakobs C ，Hartmann H ，Luecke T ，di Capua M ，Korenke C ，Hikel C ，Reutershahn E ，Freilinger M ，Baumeister F ，Bosch F ，Erwa W ... -  《-》

Neonatal vitamin-responsive epileptic encephalopathies.

Gospe SM Jr 《-》

Folinic acid-responsive seizures initially responsive to pyridoxine.

Nicolai J ，van Kranen-Mastenbroek VH ，Wevers RA ，Hurkx WA ，Vles JS ... -  《PEDIATRIC NEUROLOGY》