European Journal of Pediatrics

, Volume 168, Issue 6, pp 697–704 | Cite as

Clinical features and the management of pyridoxine-dependent and pyridoxine-responsive seizures: review of 63 North American cases submitted to a patient registry

  • Gregory J. Basura
  • Shawn P. Hagland
  • Anna M. Wiltse
  • Sidney M. GospeJr.
Original Paper

Abstract

To facilitate clinical research on pyridoxine-dependent seizures (PDS), a rare disease registry was established for affected patients in the United States and Canada. From 1999 to 2007, 63 cases, ranging in age from 11 months to 40 years, were registered. All registered cases were diagnosed with PDS by their physicians using clinical criteria. Seventy percent of the cases presented with neonatal seizures, and the mean lag time between presentation and diagnosis was 313 days. Pyridoxine treatment regimens were varied, ranging from 50 to 2,500 mg per day (1.4 to 67.8 mg/kg/day). While 47 of the cases were seizure-free on pyridoxine monotherapy, over time, eight other cases also required the concomitant use of anticonvulsants for effective seizure control, while the remainder continued to have recurrent seizures, despite the use of pyridoxine and multiple anticonvulsants. Our review of this collection of cases suggests that, for some registered individuals, either pyridoxine may be acting as an adjunctive anticonvulsant or the patient may have developed a secondary etiology for seizures. In addition, some of these cases may have pyridoxine-responsive seizures (PRS) rather than pyridoxine-dependency. Four adult and seven school-aged cases were described as developmentally normal, while the other cases had a variety of neurodevelopmental handicaps. Twenty-five percent of the cases required the pharmacologic treatment of behavioral symptoms. Clinicians caring for neonates and other young patients with intractable seizures do not necessarily consider PDS as an etiology; therefore, certain cases may be undiagnosed or diagnosed late in the course of their evaluation and treatment. As the diagnosis of PDS can now be confirmed by genetic and biochemical testing, formal screening protocols for this disorder should be developed. Patients previously diagnosed with PDS by clinical criteria should also receive confirmatory testing.

Keywords

Pyridoxine-dependent seizures Pyridoxine-responsive seizures ALDH7A1 Antiquitin Pipecolic acid α-aminoadipic semialdehyde 

Abbreviations

PDS

Pyridoxine-dependent seizures

PRS

Pyridoxine-responsive seizures

PA

Pipecolic acid

AASA

α-aminoadipic semialdehyde

P5P

Pyridoxal-5-phosphate

OCD

Obsessive compulsive disorder

AD

Autistic disorder

PDD

Pervasive developmental disorder, not otherwise specified

BPSU

British Paediatric Surveillance Unit

Notes

Acknowledgments

The authors wish to thank Mary Voeller, Natalia Oster, Cathy Graubert, and Janna Stults for their assistance with this study, and Dr. Russell Saneto for reviewing the manuscript.

References

  1. 1.
    Alkan A, Kutlu R, Aslan M, Sigirci A, Orkan I, Yakinci C (2004) Pyridoxine-dependent seizures: magnetic resonance spectroscopy findings. J Child Neurol 19:75–78. doi:10.1177/08830738040190010712 PubMedCrossRefGoogle Scholar
  2. 2.
    Bass NE, Wyllie E, Cohen B, Joseph SA (1996) Pyridoxine-dependent epilepsy: the need for repeated pyridoxine trials and the risk of severe electrocerebral suppression with intravenous pyridoxine infusion. J Child Neurol 11:422–424PubMedCrossRefGoogle Scholar
  3. 3.
    Baxter P (1999) Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK. Arch Dis Child 81:431–433PubMedCrossRefGoogle Scholar
  4. 4.
    Baxter P (2001) Pyridoxine dependent and pyridoxine responsive seizures. In: Baxter P (ed) Vitamin responsive conditions in paediatric neurology. Mac Keith Press, London, pp 109–165Google Scholar
  5. 5.
    Baxter P, Griffiths P, Kelly T, Gardner-Medwin D (1996) Pyridoxine-dependent seizures: demographic, clinical, MRI and psychometric features, and effect of dose on intelligence quotient. Dev Med Child Neurol 38:998–1006PubMedCrossRefGoogle Scholar
  6. 6.
    Baynes K, Farias ST, Gospe SM Jr (2003) Pyridoxine-dependent seizures and cognition in adulthood. Dev Med Child Neurol 45:782–785. doi:10.1017/S0012162203001440 PubMedCrossRefGoogle Scholar
  7. 7.
    Been JV, Bok LA, Andriessen P, Renier WO (2005) Epidemiology of pyridoxine dependent seizures in the Netherlands. Arch Dis Child 90:1293–1296. doi:10.1136/adc.2005.075069 PubMedCrossRefGoogle Scholar
  8. 8.
    Berger AR, Schaumburg HH, Schroeder C, Apfel S, Reynolds R (1992) Dose response, coasting, and differential fiber vulnerability in human toxic neuropathy: a prospective study of pyridoxine neurotoxicity. Neurology 42:1367–1370PubMedGoogle Scholar
  9. 9.
    Bok LA, Struys E, Willemsen MA, Been JV, Jakobs C (2007) Pyridoxine-dependent seizures in Dutch patients: diagnosis by elevated urinary alpha-aminoadipic semialdehyde levels. Arch Dis Child 92:687–689. doi:10.1136/adc.2006.103192 PubMedCrossRefGoogle Scholar
  10. 10.
    Chou ML, Wang HS, Hung PC, Sun PC, Huang SC (1995) Late-onset pyridoxine-dependent seizures: report of two cases. Acta Paediatr Sin 36:434–437PubMedGoogle Scholar
  11. 11.
    Coker SB (1992) Postneonatal vitamin B6-dependent epilepsy. Pediatrics 90:221–223PubMedGoogle Scholar
  12. 12.
    Ebinger M, Schultze C, König S (1999) Demographics and diagnosis of pyridoxine-dependent seizures. J Pediatr 134:795–796PubMedGoogle Scholar
  13. 13.
    Frye RE, Donner E, Golja A, Rooney CM (2003) Folinic acid-responsive seizures presenting as breakthrough seizures in a 3-month-old boy. J Child Neurol 18:562–569. doi:10.1177/08830738030180081001 PubMedCrossRefGoogle Scholar
  14. 14.
    Gospe SM Jr (2006) Pyridoxine-dependent seizures: new genetic and biochemical clues to help with diagnosis and treatment. Curr Opin Neurol 19:148–153. doi:10.1097/01.wco.0000218230.81301.12 PubMedCrossRefGoogle Scholar
  15. 15.
    Gospe SM Jr, Hecht ST (1998) Longitudinal MRI findings in pyridoxine-dependent seizures. Neurology 51:74–78PubMedGoogle Scholar
  16. 16.
    Goutières F, Aicardi J (1985) Atypical presentations of pyridoxine-dependent seizures: a treatable cause of intractable epilepsy in infants. Ann Neurol 17:117–120. doi:10.1002/ana.410170203 PubMedCrossRefGoogle Scholar
  17. 17.
    Grillo E, da Silva RJM, Barbato JH Jr (2001) Pyridoxine-dependent seizures responding to extremely low-dose pyridoxine. Dev Med Child Neurol 43:413–415. doi:10.1017/S0012162201000767 PubMedCrossRefGoogle Scholar
  18. 18.
    Haenggeli C-A, Girardin E, Paunier L (1991) Pyridoxine-dependent seizures, clinical and therapeutic aspects. Eur J Pediatr 150:452–455. doi:10.1007/BF01958419 PubMedCrossRefGoogle Scholar
  19. 19.
    Hoffmann GF, Schmitt B, Windfuhr M, Wagner N, Strehl H, Bagci S et al (2007) Pyridoxal 5′-phosphate may be curative in early-onset epileptic encephalopathy. J Inherit Metab Dis 30:96–99. doi:10.1007/s10545-006-0508-4 PubMedCrossRefGoogle Scholar
  20. 20.
    Hunt AD Jr, Stokes J Jr, McCrory WW, Stroud HH (1954) Pyridoxine dependency: report of a case of intractable convulsions in an infant controlled by pyridoxine. Pediatrics 13:140–145PubMedGoogle Scholar
  21. 21.
    Hyland K, Buist NR, Powell BR, Hoffman GF, Rating D, McGrath J et al (1995) Folinic acid responsive seizures: a new syndrome? J Inherit Metab Dis 18:177–181. doi:10.1007/BF00711760 PubMedCrossRefGoogle Scholar
  22. 22.
    Kanno J, Kure S, Narisawa A, Kamada F, Takayanagi M, Yamamoto K et al (2007) Allelic and non-allelic heterogeneities in pyridoxine dependent seizures revealed by ALDH7A1 mutational analysis. Mol Genet Metab 91:384–389. doi:10.1016/j.ymgme.2007.02.010 PubMedCrossRefGoogle Scholar
  23. 23.
    McLachlan RS, Brown WF (1995) Pyridoxine dependent epilepsy with iatrogenic sensory neuronopathy. Can J Neurol Sci 22:50–51PubMedGoogle Scholar
  24. 24.
    Mikati MA, Trevathan E, Krishnamoorthy KS, Lombroso CT (1991) Pyridoxine-dependent epilepsy: EEG investigations and long-term follow-up. Electroencephalogr Clin Neurophysiol 78:215–221. doi:10.1016/0013-4694(91)90035-3 PubMedCrossRefGoogle Scholar
  25. 25.
    Mills PB, Surtees RAH, Champion MP, Beesley CE, Dalton N, Scambler PJ et al (2005) Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5′-phosphate oxidase. Hum Mol Genet 14:1077–1086. doi:10.1093/hmg/ddi120 PubMedCrossRefGoogle Scholar
  26. 26.
    Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M et al (2006) Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med 12:307–309. doi:10.1038/nm1366 PubMedCrossRefGoogle Scholar
  27. 27.
    Nabbout R, Soufflet C, Plouin P, Dulac O (1999) Pyridoxine dependent epilepsy: a suggestive electroclinical pattern. Arch Dis Child Fetal Neonatal Ed 81:F125–F129PubMedCrossRefGoogle Scholar
  28. 28.
    Ohtahara S, Ohtsuka Y, Yamatogi Y, Oka E, Yoshinaga H, Sato M (1993) Prenatal etiologies of West syndrome. Epilepsia 34:716–722. doi:10.1111/j.1528-1157.1993.tb00451.x PubMedCrossRefGoogle Scholar
  29. 29.
    Pearl PL, Gospe SM (2007) Pyridoxal phosphate dependency, a newly recognized treatable catastrophic epileptic encephalopathy. J Inherit Metab Dis 30:2–4. doi:10.1007/S10545-008-9974-1 PubMedCrossRefGoogle Scholar
  30. 30.
    Plecko B, Stöckler-Ipsiroglu S, Paschke E, Erwa W, Struys EA, Jakobs C (2000) Pipecolic acid elevation in plasma and cerebrospinal fluid of two patients with pyridoxine-dependent epilepsy. Ann Neurol 48:121–125. doi:10.1002/1531-8249(200007)48:1<121::AID-ANA20>3.0.CO;2-V PubMedCrossRefGoogle Scholar
  31. 31.
    Plecko B, Hikel C, Korenke G-C, Schmitt B, Baumgartner M, Baumeister F et al (2005) Pipecolic acid as a diagnostic marker of pyridoxine-dependent epilepsy. Neuropediatrics 36:200–205. doi:10.1055/s-2005-865727 PubMedCrossRefGoogle Scholar
  32. 32.
    Plecko B, Paul K, Paschke E, Stoeckler-Ipsiroglu S, Struys E, Jakobs C et al (2007) Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene. Hum Mutat 28:19–26. doi:10.1002/humu.20433 PubMedCrossRefGoogle Scholar
  33. 33.
    Rankin PM, Harrison S, Chong WK, Boyd S, Aylett SE (2007) Pyridoxine-dependent seizures: a family phenotype that leads to severe cognitive deficits, regardless of treatment regime. Dev Med Child Neurol 49:300–305PubMedCrossRefGoogle Scholar
  34. 34.
    Salomons GS, Bok LA, Struys EA, Pope LL, Darmin PS, Mills PB et al (2007) An intriguing “silent” mutation and a founder effect in antiquitin (ALDH7A1). Ann Neurol 62:414–418. doi:10.1002/ana.21206 PubMedCrossRefGoogle Scholar
  35. 35.
    Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus S, Pleasure D et al (1983) Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med 309:445–448PubMedGoogle Scholar
  36. 36.
    Shih JJ, Kornblum H, Shewmon DA (1996) Global brain dysfunction in an infant with pyridoxine dependency: evaluation with EEG, evoked potentials, MRI, and PET. Neurology 47:824–826PubMedGoogle Scholar
  37. 37.
    Struys EA, Jakobs C (2007) Alpha-aminoadipic semialdehyde is the biomarker for pyridoxine dependent epilepsy caused by alpha-aminoadipic semialdehyde dehydrogenase deficiency. Mol Genet Metab 91:405. doi:10.1016/j.ymgme.2007.04.016 PubMedCrossRefGoogle Scholar
  38. 38.
    Wang H-S, Kuo M-F, Chou M-L, Hung P-C, Lin K-L, Hsieh M-Y et al (2005) Pyridoxal phosphate is better than pyridoxine for controlling idiopathic intractable epilepsy. Arch Dis Child 90:512–515. doi:10.1136/adc.2003.045963 PubMedCrossRefGoogle Scholar
  39. 39.
    Yoshii A, Takeoka M, Kelly PJ, Krishnamoorthy KS (2005) Focal status epilepticus as atypical presentation of pyridoxine-dependent epilepsy. J Child Neurol 20:696–698. doi:10.1177/08830738050200081301 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Gregory J. Basura
    • 1
    • 6
  • Shawn P. Hagland
    • 2
    • 7
  • Anna M. Wiltse
    • 3
    • 8
  • Sidney M. GospeJr.
    • 2
    • 3
    • 4
    • 5
  1. 1.School of MedicineUniversity of WashingtonSeattleUSA
  2. 2.Seattle Children’s Hospital Research InstituteSeattleUSA
  3. 3.Departments of Neurology and PediatricsUniversity of CaliforniaDavisUSA
  4. 4.Departments of Neurology and Pediatrics, Center on Human Development and Disability, Center for Neurogenetics and NeurotherapeuticsUniversity of WashingtonSeattleUSA
  5. 5.California Department of Mental HealthVacavilleUSA
  6. 6.Children’s Hospital and Regional Medical CenterSeattleUSA
  7. 7.Department of Otolaryngology, Head and Neck SurgeryUniversity of North CarolinaChapel HillUSA
  8. 8.School of PharmacyUniversity of WashingtonSeattleUSA

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