Researchers at Autonomous University of Madrid, and other centers in Spain studied the clinical, biochemical, and genetic spectrum of pyridoxine-dependent epilepsy (PDE) in 12 patients with the clinically proven diagnosis. Onset of seizures varied from neonatal to first months of life. Seizures were focal or multifocal, clonic or myoclonic, and generalized tonic; 50% had status epilepticus. Seizures were controlled transiently with conventional AEDs for 15 or more days in 8 of 12 patients, leading to a delay in diagnosis. The effective dose of pyridoxine to suppress seizures ranged from 10 to 30 mg/kg/day. Neurologic symptoms in addition to seizures included hypotonia, irritability, and psychomotor retardation. EEG abnormalities were variable and included focal or multifocal discharges, burst-suppression pattern, and generalized slowing. A normal EEG in one patient does not rule out the diagnosis. All EEGs became normal after pyridoxine therapy. MRI abnormalities, mainly posterior fossa, included mega cisterna magna, Dandy Walker syndrome, ventriculomegaly, and corpus callosum dysgenesis. Six patients followed for more than 5 years show cognitive dysfunction and borderline or mildly retarded IQs. Delay in treatment and dysgenesis of the corpus callosum are risk factors for neurodevelopmental delay. Treatment with pyridoxine does not normalize the IQ. Urine levels of a-aminoadipic semialdehyde (a-AASA) and plasma/CSF levels of pipecolic acid (PA) are diagnostic biomarkers. Genetic analysis of these Spanish patients showed 12 mutations, 7 novel, and different from other populations. [1]

COMMENT. PDE should be considered in any infant with intractable seizures, including patients with MRI abnormalities such as corpus callosum dysgenesis or Dandy Walker syndrome. The long-term outcome of PDE was poor in a Dutch PDE cohort of 14 patients [2]. EEG background and epileptiform activity were not correlated with outcome. Delayed initiation of pyridoxine and the association of corpus callosum abnormalities were significantly associated with unfavorable neurodevelopmental outcome, findings similar to the Spanish experience.

PDE with Molybdenum Cofactor Deficiency

PDE with molybdenum cofactor deficiency is reported in 2 siblings. Molecular investigations revealed a homozygous mutation in the MOCS2 gene. Pyridoxine supplementation is recommended in patients diagnosed with molybdenum cofactor or sulfite oxidase deficiencies. [3]