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

Abstract

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.

• Authors: Barbara Plecko, Karl Paul, Eduard Paschke, Sylvia Stoeckler-Ipsiroglu, Eduard Struys, Cornelis Jakobs, Hans Hartmann, Thomas Luecke, Matteo di Capua, Christoph Korenke, Christiane Hikel, Elke Reutershahn, Michael Freilinger, Fritz Baumeister, Friedrich Bosch, Wolfgang Erwa
• Journal: Human mutation (Hum Mutat) Vol. 28 Issue 1 Pg. 19-26 (Jan 2007) ISSN: 1098-1004 [Electronic] United States
• PMID: 17068770 (Publication Type: Journal Article)
• Copyright: (c) 2006 Wiley-Liss, Inc.

Chemical References

• Pyridoxal Phosphate
• ALDH7A1 protein, human
• Aldehyde Dehydrogenase
• Pyridoxine

Topics

• Aldehyde Dehydrogenase (genetics)
• Amino Acid Sequence
• DNA Mutational Analysis
• Epilepsy (drug therapy, genetics)
• Female
• Humans
• Infant, Newborn
• Male
• Models, Biological
• Mutation
• Pyridoxal Phosphate (deficiency)
• Pyridoxine (therapeutic use)
• Sequence Homology, Amino Acid
• Vitamin B 6 Deficiency (genetics)