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Pyridoxine-dependent epilepsy

Orpha number ORPHA3006
Synonym(s) Glutamate decarboxylase deficiency
Pyridoxine-responsive seizures
Vitamin B6-responsive seizures
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
ICD-10
  • G40.8
ICD-O -
OMIM
UMLS
  • C1291560
  • C1849508
MeSH
  • C536254
MedDRA -
SNOMED CT
  • 124596009

Summary

Pyridoxine dependent seizures (PDS) is a condition characterized by early onset epilepsy that is unresponsive to any anticonvulsivant therapy except pyridoxine (vitamin B6). The estimated incidence is 1:500.000 live births. The early onset form is the most common, with epileptic seizures occurring in the first days after birth (usually within the first 24 to 48 hours). However, some patients present with later onset, occurring as late as 2 years of age. A wide variety of seizure types may be observed (myoclonic, atonic, partial or generalized seizures, infantile spasms). Abnormal fetal movements have also been reported in association with this condition suggesting intrauterine seizures. Additional clinical signs include variable cognitive impairment and learning difficulties, irritability, abnormal tone and squinting. Brain imaging may demonstrate ventricular dilatation, cortical atrophy, intracerebral hemorrhage, and/or abnormal myelination. The biochemical defect underlying PDS remains unknown. Pyridoxine transport and metabolism in patients appear normal. Anomalies of glutamic acid decarboxylase (GAD), a pyridoxal dependent enzyme, have been suspected. High levels of glutamic acid (substrate of the enzyme) and low levels of GABA (product) have been found in the cerebrospinal fluid and brain of some patients. However, GAD1 and GAD2 gene anomalies have been excluded. Other physiopathological hypotheses include either alteration in the binding of pyridoxal phosphate to GAD or abnormal pyridoxine brain transport. Linkage of the causative gene to 5q31 has been demonstrated in some families but excluded in others, raising the hypothesis of genetic heterogeneity in PDS. The mode of transmission is autosomal recessive. The diagnosis is suspected if intravenous administration of pyridoxine (50-100 mg) results in immediate termination of the seizures. Further supplementation with oral pyridoxine (15 mg/kg/d) should allow definitive withdrawal of all antiepileptic drugs. Recurrence of seizures after discontinuation of pyridoxine confirms the diagnosis, but this test may be difficult to carry out. Some atypical cases with a partial or transient response to conventional antiepileptic drugs have also been described.

Expert reviewer(s)

  • Dr Caroline SEVIN

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Detailed information

Clinical genetics review
  • EN (2014)
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