α-Aminoadipic Semialdehyde and 6-Oxo-pipecolic Acid

Lysine is an essential amino acid in humans that undergo catabolism in the mitochondria via the saccharopine pathway and in the peroxisomes via the pipecolic acid pathway. One enzyme in both catabolic pathways, α-aminoadipic semialdehyde dehydrogenase (ALDH7A1), catalyses the conversion of α-aminoadipic semialdehyde (AASA) to α-aminoadipic acid. A deficiency in this enzyme leads to accumulation of AASA and its cyclic form piperideine-6-carboxylic acid (P6C) which in turn binds to pyridoxal phosphate (vitamin B6) and reduces its bioavailability. This results in neonatal seizures that are responsive to treatment with vitamin B6 supplementation but which do not respond, or only partially respond, to administration of general anti-convulsants, hence the disorder name Pyridoxine-Dependent Epilepsy–ALDH7A1 (PDE–ALDH7A1). In addition to supplementation of the patients with vitamin B6, a lysine restricted diet and/or arginine supplementation is recommended to reduce lysine degradation and AASA/P6C accumulation. The gold standard for biochemical diagnosis of PDE-ALDH7A1 is a measurement of the urinary excretion of AASA by liquid chromatography-mass spectrometry. This biomarker is highly elevated in newborns with PDE-ALDH7A1 and can be reduced to normal levels following lysine restriction. However, AASA is unstable at room temperature with substantial degradation occurring within hours. Another biomarker for PDE-ALDH7A1 is 6-oxo-pipecolic acid derived from the intermediate metabolite 6-hydroxypipecolate, between P6C and AASA. Preliminary data indicates that this biomarker may be elevated in patients, however, more work needs to be done to validate the utility of this as a clinical assay.