Neuropediatrics 2012; 43 - PS11_11
DOI: 10.1055/s-0032-1307078

The role of vitamin B6 deficiency in infantile epilepsies of unknown etiology

A Baumgart 1, M van Kempen 2, N Verhoeven 2, R Møller 3, R Boor 4, H Muhle 1, J Albers 1, L Klitten 3, H Hjalgrim 3, D Lindhout 2, U Stephani 1, I Helbig 1, S von Spiczak 1
  • 1Klinik für Neuropädiatrie, Universitätsklinikum Schleswig-Holstein, Kiel, Germany
  • 2Department of Medical Genetics, UMC Utrecht, EA Utrecht, The Netherlands
  • 3Danish Epilepsy Centre, Dianalund, Denmark
  • 4Norddeutsches Epilepsiezentrum Raisdorf, Schwentinental, Germany

Aims: Pyridoxine dependent epilepsy (PDE) and pyridoxal-5'-phosphate deficiency are rare autosomal recessive enzyme defects in vitamin B6 metabolism due to mutations in the ALDH7A1 and PNPO gene. These disorders are typically characterized by severe, neonatal seizures that are resistant to anticonvulsant drugs but can be controlled by pyridoxine/pyridoxal phosphate. Recently, the phenotypic variability has been shown to be broader than previously assumed. The aim of this study was to further characterize the phenotypic spectrum of vitamin B6 dependent epilepsies.

Methods: A cohort of 113 patients with unclear epilepsy syndromes starting in the first year of life was screened for mutations in ALDH7A1 and PNPO. Mutation analysis of the entire coding region of both genes including adjacent splice sites was performed. Pathogenicity of identified variants was verified using SIFT and PolyPhen2.

Results: Sequence analysis of ALDH7A1 identified one patient as compound heterozygous for both a novel, likely pathogenic c.1468A>G; p.Arg490Gly variant and a known mutation c.1195G>C; p.Glu399Gln. Phenotypic characteristics of the patient comprised onset on postnatal day 5, various seizure types as well as focal and generalized EEG abnormalities, mental retardation and hypotonic cerebral palsy. At birth, perinatal distress was suspected. Partial response to antiepileptic drugs was observed; he never received treatment with pyridoxine. In adulthood seizures occurred in clusters with long seizure-free periods. The patient died at age 31 from epileptic status prior to genetic diagnosis. No pathogenic mutations in PNPO were found.

Conclusion: Diagnosis of PDE should be considered in all infants with severe epilepsy irrespective of atypical phenotypes. Medical history suggestive of birth asphyxia and partial response to anticonvulsive drugs may co-exist. Seizure types and EEG patterns were confirmed to be non-specific. Variable outcome with seizure-free periods in adulthood is possible.

PNPO deficiency seems to be very rare in unclear epilepsy syndromes during first year of life.

Vitamin B6 - ALDH7A1 - PNPO