Pipecolic Acid as a Diagnostic Marker of Pyridoxine-Dependent Epilepsy

Abstract

Pyridoxine-dependent epilepsy, although described some decades ago, may still be an underdiagnosed disorder. We have recently described isolated pipecolic acid elevations in the plasma and/or CSF of three patients with pyridoxine-dependent epilepsy with an intriguing inverse correlation to the oral intake of pyridoxine. We have now confirmed these findings in a further 6 unrelated patients with pyridoxine-dependent epilepsy. Pipecolic acid in plasma was 4.3- to 15.3fold elevated compared to the upper normal range before pyridoxine and remained in the mildly elevated range while on pyridoxine. Pipecolic acid was even more markedly elevated in CSF. The extent of pipecolic acid elevation in CSF exceeded that of plasma by a factor of 2.2 to 4.8. This clearly discriminates pyridoxine-dependent epilepsy from other possible defects with elevated pipecolic acid. Determination of pipecolic acid in plasma and/or CSF should be included in the diagnostic work-up of patients with therapy-resistant seizures. It will in addition prevent patients with pyridoxine-dependent epilepsy from experiencing potentially dangerous pyridoxine-withdrawal, which until now has been necessary to prove the diagnosis.

Key words

Pyridoxine - vitamin B₆ - epilepsy - seizures - pipecolic acid - CSF

References

• 1 Bass N E, Wyllie E, Cohen B, Joseph S A. Pyridoxine-dependent epilepsy: the need for repeated pyridoxine trials and the risk of severe electrocerebral suppression with intravenous pyridoxine infusion.  J Child Neurol. 1996;  11 422-424
• 2 Battaglioli G, Rosen D R, Gospe S, Martin D L. Glutamate decarboxylase is not genetically linked to pyridoxine-dependent seizures.  Neurology. 2000;  55 309-311
• 3 Baumeister F A, Gsell W, Shin Y S, Egger J. Glutamate in pyridoxine-dependent epilepsy: neurotoxic glutamate concentration in the cerebrospinal fluid and its normalization by pyridoxine.  Pediatrics. 1994;  94 318-321
• 4 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
• 5 Baxter P. Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK.  Arch Dis Child. 1999;  81 431-433
• 6 Baxter P. Pyridoxine-dependent and pyridoxine-responsive seizures.  Dev Med Child Neurol. 2001;  43 416-4206
• 7 Baxter P. Pyridoxine-dependent seizures: a clinical and biochemical conundrum.  Biochim Biophys Acta. 2003;  1647 36-41
• 8 Cormier-Daire V, Dagoneau N, Nabbout R, Burglen L, Penet C, Soufflet C. et al . A gene for pyridoxine-dependent epilepsy maps to chromosome 5 q31.  Am J Hum Genet. 2000;  67 991-993
• 9 Cox P R, Dancis J. Errors of lysine metabolism. Scriver CR, Beaudet AL, Sly WS, Valle D The Metabolic and Molecular Bases of Inherited Disease. New York; Mc Graw Hill 1995: 1233-1238
• 10 Ebinger M, Schultze C, Konig S. Demographics and diagnosis of pyridoxine-dependent seizures.  J Pediatr. 1999;  134 795-796
• 11 Gospe M. Current perspectives on pyridoxine-dependent seizures.  Pediatrics. 1998;  132 919-923
• 12 Gospe S M. Pyridoxine-dependent seizures: findings from recent studies pose new questions.  Pediatr Neurol. 2002;  26 181-185
• 13 Goutieres F, Aicardi J. Atypical presentations of pyridoxine dependent seizures: a treatable cause of intractable epilepsy in infants.  Ann Neurol. 1985;  17 117-120
• 14 Hindley D, Huyton M. Pyridoxine dependent and pyridoxine responsive seizures.  Arch Dis Child. 2001;  84 91-92
• 15 Kaufman K J, Lederman J N, Wong A M, Tobin A J, Menkes J H. A new method to detect point mutations in the gene for glutamic acid decarboxylase in patients with pyridoxine dependent seizures [abstract].  Ann Neurol. 1987;  22 446-447
• 16 Kelley R I. Quantification of pipecolic acid in plasma and urine by isotope-dilution gas chromatography/mass spectrometry. Hommes FA Techniques in Diagnostic Human Biochemical Genetics. New York; Wiley-Liss 1991: 205-218
• 17 Kure S, Sakata Y, Miyabayashi S, Takahashi K, Shinka T, Matsubara Y. et al . Mutation and polymorphic marker analyses of 65 K- and 67 K - glutamate decarboxylase genes in two families with pypridoxine-dependent seizures.  J Hum Genet. 1998;  43 128-131
• 18 Kok R M, Kaster L, de Long A PJM, Poll-The B T, Saudubray J M, Jakobs C. Stable isotope dilution analysis of pipecolic acid in cerebrospinal fluid, plasma, urine and amniotic fluid using electron capture negative ion mass fragmentography.  Clin Chim Acta. 1987;  168 143-152
• 19 Plecko B, Stöckler-Ipsiroglu S, Paschke E, Erwa W, Struys E, Jakobs C. Pipecolic acid elevation in plasma and cerebrospinal fluid of two patients with pyridoxine-dependent epilepsy.  Ann Neurol. 2000;  48 121-125
• 20 Plecko B, Höger H, Jakobs C, Struys E, Stromberger C, Leschnik M. et al . Pipecolic acid concentrations in brain tissue of nutritional pyridoxine deficient rats.  J Inherit Metab Dis. 2005;  in press
• 21 Struys E A, Jakobs C. Enantiomeric analysis of D- and L- pipecolic acid in plasma using a chiral capillary gas chromatography column and mass fragmentography.  J Inherit Metab Dis. 1999;  22 677-678
• 22 Verhoeven N M, Kulik W, van Heuvel C MM, Jakobs C. Pre- and postnatal diagnosis of peroxisomal disorders using stable isotope dilution gas chromatography-mass spectrometry.  J Inherit Metab Dis. 1995;  18 (Suppl 1) 45-60
• 23 Willemsen M A, Mavinkurve-Groothuis A MC, Wevers R, Rotteveel J J, Jakobs C. Pipecolic acid: a diagnostic marker in Pyridoxine-dependent epilepsy.  Ann Neurol. 2005;  in press (letter to the editor)