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 15.3 fold 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.

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

“…We could confirm our previous findings, that PA levels in plasma are elevated 4-to 15-fold prior to treatment and remain in the mildly elevated range (1.5-to 3-fold) while on treatment with pyridoxine [Plecko et al, 2005]. AASA concentrations in plasma and CSF prior to treatment with pyridoxine have not been reported so far.…”

“…The observed decrease of PA [Plecko et al, 2005] and lower AASA concentrations following pyridoxine administration points toward elimination pathways of the products formed by the Knoevenagel condensation. The fate of the two different PLP-P6C products, complex A and B [Mills et al, 2006], has not been studied so far (E. Struys, personal communication).…”

“…Clinical description and data on PA elevation in Patients 2,6,7,8,9,11,and 14 have been included in previous publications [Plecko et al, 2000[Plecko et al, , 2005 and data on AASA and molecular analysis of the antiquitin gene has been published on Patients 8 and 11 [Mills et al, 2006]. Patient samples and parents' EDTAtreated blood were collected from seven different centers after parental written informed consent.…”

“…Until recently, a definite diagnosis of PDE had been established upon a successful therapeutic trial with pyridoxine and further proof of pyridoxine after a controlled withdrawal with recurrence of seizures [Baxter, 2001;Gospe, 1998Gospe, , 2002. Following the description of elevated pipecolic acid (PA) in plasma and cerebrospinal fluid (CSF) of patients with PDE [Plecko et al, 2000[Plecko et al, , 2005Willemsen et al, 2005], the underlying enzyme defect was shown to be located at the level of alpha-aminoadipic semialdehyde (AASA) dehydrogenase (antiquitin) in the cerebral lysine degradation pathway ( Fig. 1) [Mills et al, 2006].…”

Molecular Defects of Vitamin B6 Metabolism Associated with Neonatal Epileptic Encephalopathy

“…It should be noted that, if there is no improvement with pyridoxine administration, the patient should be promptly treated with PLP. Screening for PN-dependent seizures is also possible via determination of plasma pipecolic acid and by measuring urinary or plasma αAASA and P6C levels [77,78]. Diagnosis is also confirmed by mutational analysis of the antiquitin gene.…”