About the Registry

Since the publication of the initial case report in 1954 (1), seizures due to pyridoxine-dependency have been recognized as an uncommon cause of intractable seizures in neonates and infants. In the more than six decades since the first description of pyridoxine-dependent seizures, also known as pyridoxine-dependent epilepsy (PDE), more than 200 cases have been reported, with the majority of these publications appearing over the past 25 years focusing on atypical clinical presentations (2-5), neurodevelopmental features (6-9), electroencephalographic (EEG) characteristics (10-15), and imaging findings (6, 14, 16, 17). The most recent reports have focused on the biochemical abnormality underlying PDE, the associated mutations in the ALDH7A1 gene (8, 18-26), and the use of a lysine-restricted diet in managing patients with the disorder (27,28).

While neonatal seizures due to pyridoxine-dependency are felt to be quite rare, the reports of the late-onset and other atypical presentations (2-5) along with epidemiologic data from Europe (6, 29-31) suggest that this is a more common clinical entity than once thought.

In order to learn more about the variety of clinical presentations of PDE, the response of the disorder to various dosage regimens of pyridoxine, the imaging and EEG characteristics of the disorder, and the long term developmental consequences of PDE, we have developed a PDS Registry. Patients with PDE will be identified to the registry by physicians or parents. After informed consent, clinical and developmental data will be obtained and saved for future analysis and reporting. Other investigators interested in PDE may request to contact registered patients. These investigators will need to have a protocol approved by their institution’s "IRB". However, to protect confidentiality, outside investigators will not be able to directly contact registered patients. Parents who are interested in participating in other studies will be given the names of these researchers and the parents then may contact the investigators.

The Pyridoxine-Dependent Seizures Registry was first developed by the Child Neurology Service at University of California, Davis Medical Center in 1999 and then moved to the Division of Pediatric Neurology at Seattle Children’s Hospital and the University of Washington in Seattle in 2000.  Between 1999-2007, 63 patients were registered and the findings of the initial analysis of this clinical data was published in 2009 (32).

In 2015, an international group of clinical researchers interested in PDE (the PDE Consortium) developed the “International PDE Registry, and information about this project may be found on the Consortium’s website: www.pdeonline.org

Since the 2009 publication (32), additional patients have been added to the Pyridoxine-Dependent Seizures Registry and follow-up information has been requested from previously registered patients. Importantly, during 2015 and 2016 it is planned that existing registry data (with the permission of the patients) will be migrated into the International PDE Registry, and all new patients wishing to be registered will then participate in the International PDE Registry.

References:

1. Hunt AD, Stokes J, McCrory WW, Stroud HH. Pyridoxine dependency: report of a case of intractable convulsions in an infant controlled by pyridoxine. Pediatrics. 1954;13:140-5.

2. Bankier A, Turner M, Hopkins IJ. Pyridoxine dependent seizures--a wider clinical spectrum. Arch Dis Child. 1983;58:415-8.

3. Bass NE, Wyllie E, Cohen B, Joseph SA. Pyridoxine-dependent epilepsy: the need for repeated pyridoxine trials and the risk of severe electrocerebral suppression with intravenous pyridoxine infusion. J Child Neurol. 1996;11:422-4.

4. Coker S. Postneonatal vitamin B6-dependent epilepsy. Pediatrics. 1992;90:221-3.

5. Gutierrez MC, Delgado-Coello BA. Influence of pipecolic acid on the release and uptake of [3H]-GABA from brain slices of mouse cerebral cortex. Neurochem Res. 1989;14:405-8.

6. Baxter P, Griffiths P, Kelly T, Gardner-Medwin D. Pyridoxine-dependent seizures: demographic, clinical, MRI and psychometric features, and effect of dose on intelligence quotient. Dev Med Child Neurol. 1996;38:998-1006.

7. Baynes K, Tomaszewski Farias S, Gospe SM, Jr. Pyridoxine-dependent seizures and cognition in adulthood. Dev Med Child Neurol. 2003;45:782-5.

8. Kluger G, Blank R, Paul K, Paschke E, Jansen E, Jakobs C, et al. Pyridoxine-dependent epilepsy: normal outcome in a patient with late diagnosis after prolonged status epilepticus causing cortical blindness. Neuropediatrics. 2008 Oct;39(5):276-9.

9. Ohtsuka Y, Hattori J, Ishida T, Ogino T, Oka E. Long-term follow-up of an individual with vitamin B6-dependent seizures. Dev Med Child Neurol. 1999;41:203-6.

10. Mikati MA, Trevathan E, Krishnamoorthy KS. Pyridoxine-dependent epilepsy: EEG investigation and long-term follow-up. Electroenceph Clin Neurophys. 1991;78:215-21.

11. Naasan G, Yabroudi M, Rahi A, Mikati MA. Electroencephalographic changes in pyridoxine-dependant epilepsy: new observations. Epileptic Disord. 2009 Dec;11(4):293-300.

12. Nabbout R, Soufflet C, Plouin P, Dulac O. Pyridoxine dependent epilepsy: a suggestive electroclinical pattern. Arch Dis Child Fetal Neonatal Ed. 1999;81:F125-F9.

13. Schmitt B, Baumgartner M, Mills PB, Clayton PT, Jakobs C, Keller E, et al. Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency. Dev Med Child Neurol. 2010 Jul;52(7):e133-42.

14. Shih JJ, Kornblum H, Shewmon DA. Global brain dysfunction in an infant with pyridoxine dependency: evaluation with EEG, evoked potentials, MRI, and PET. Neurology. 1996;47:824-6.

15. Bok LA, Maurits NM, Willemsen MA, Jakobs C, Teune LK, Poll-The BT, et al. The EEG response to pyridoxine-IV neither identifies nor excludes pyridoxine-dependent epilepsy. Epilepsia. 2010 Dec;51(12):2406-11.

16. Gospe SM, Jr., Hecht ST. Longitudinal MRI findings in pyridoxine-dependent seizures. Neurology. 1998;51:74-8.

17. Friedman, SD, Ishak, GE, Poliachik, SL, Poliakov, AV, Otto, RK, Shaw, DW, et al. Callosal alterations in pyridoxine-dependent epilepsy. Dev Med Child Neurol 2014;56:1106-110.

18. Bennett CL, Chen Y, Hahn S, Glass IA, Gospe SM, Jr. Prevalence of ALDH7A1 mutations in 18 North American pyridoxine-dependent seizure (PDS) patients. Epilepsia. 2009;50:1167-75.

19. Bok LA, Struys E, Willemsen MA, Been JV, Jakobs C. Pyridoxine-dependent seizures in Dutch patients: diagnosis by elevated urinary alpha-aminoadipic semialdehyde levels. Arch Dis Child. 2007 Aug;92(8):687-9.

20. Kanno J, Kure S, Narisawa A, Kamada F, Takayanagi M, Yamamoto K, et al. Allelic and non-allelic heterogeneities in pyridoxine dependent seizures revealed by ALDH7A1 mutational analysis. Mol Genet Metab. 2007 Aug;91(4):384-9.

21. Mills PB, Footitt EJ, Mills KA, Tuschl K, Aylett S, Varadkar S, et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain. 2010 Jul;133(Pt 7):2148-59.

22. Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med. 2006 Mar;12(3):307-9.

23. Plecko B, Hikel C, Korenke G-C, Schmitt B, Baumgartner M, Baumeister F, et al. Pipecolic acid as a diagnostic marker of pyridoxine-dependent epilepsy. Neuropediatrics. 2005;36:200-5.

24. Plecko B, Paul K, Paschke E, Stoeckler-Ipsiroglu S, Struys E, Jakobs C, et al. Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene. Hum Mutat. 2007 Jan;28(1):19-26.

25. Salomons GS, Bok LA, Struys EA, Pope LL, Darmin PS, Mills PB, et al. An intriguing "silent" mutation and a founder effect in antiquitin (ALDH7A1). Ann Neurol. 2007 Oct;62(4):414-8.

26. Scharer G, Brocker C, Vasiliou V, Creadon-Swindell G, Gallagher RC, Spector E, et al. The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1. J Inherit Metab Dis. 2010 Oct;33(5):571-81.

27. van Karnebeek, CD, Hartmann, H., Jaggumantri, S, Bok, LA, Cheng, B, Connolly, M, et al. Lysine restricted diet for pyridoxine-dependent epilepsy: first evidence and future trials. Mol Genet Metab 2012;107:335-344.

28. van Karnebeek, CD, Stockler-Ipsiroglu, S, Jaggumantri, S, Assmann, B, Baxter, P, Bok LA, et al. Lysine-restricted diet as adjunct therapy for pyridoxine-dependent epilepsy: The PDE Consortium consensus recommendations. JIMD Rep 2014;15:1-11.

29. Baxter P. Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK. Arch Dis Child. 1999;81:431-3.

30. Been JV, Bok JA, Andriessen P, Renier WO. Epidemiology of pyridoxine-dependent seizures in The Netherlands. Arch Dis Child. 2005;90:1293-6.

31. Ebinger M, Schutze C, Konig S. Demographics and diagnosis of pyridoxine-dependent seizures. J Pediatr. 1999;134:795-6.

32. Basura, GJ, Hagland, SP, Wiltse, AM, Gospe, SM, Jr. Clinical features and the management of pyridoxine-dependent and pyridoxine-responsive seizures: review of 63 north American cases submitted to a patient registry. Eur J Pediatr 2009;168:697-704.