Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a rare -yet treatable- inherited metabolic disorder. Recent studies have shown an incidence of 1:65 000 to 1:250 000 live births. The disease is characterized by intractable seizures that, in general, do not respond to conventional antiepileptic medications, but are often controlled by daily high doses of vitamin B6 (pyridoxine). However, even with early diagnosis and B6 treatment, outcomes are often poor; 80% of these children still suffer developmental delay and intellectual disability.
Ongoing neurotoxicity despite vitamin B6 treatment may explain these poor outcomes. Antiquitin (ATQ) or the ALDH7A1 gene (see Gene Reviews or OMIM for details), encodes an enzyme in the lysine degradation pathway named α-aminoadipic semi-aldehyde dehydrogenase. Deficiency of this enzyme leads to accumulation of chemical substances -called AASA, P6C and pipecolic acid- that are neurotoxic causing developmental and cognitive deficits.
To overcome these poor outcomes, adjunct lysine reduction therapies (LRT) have been initiated: Lysine restricted diet, as a substrate inhibitor, and arginine supplementation, as a competitive inhibitor. Lysine and arginine compete for transportation over blood-brain barrier, therefore increasing the available amount of arginine lowers the transported lysine into the brain. The combination of these LRT together with vitamin B6 is called ‘Triple Therapy’. Not only was the diet found to be well-tolerated and safe, it also led to a reduction of neurotoxic biomarkers and improved seizure control, behavior and psychomotor development. Addition of arginine showed an additional decrease of neurotoxic metabolites.
The past few years the international PDE consortium has collaborated to achieve several goals in the field of PDE-ALDH7A1, as well as initiate new lines of research.
It’s our mission to:
Diagnosis is made via PDE specific biomarkers and genetic testing.
Diagnostic biomarkers include alpha-AASA, P6C and novel biomarkers 2-OPP and 6-oxoPIP in urine, blood or CSF. Pipecolic Acid (PA) is elevated in urine, blood or CSF in most, but not all patients.
Biallelic mutations in the ALDH7A1 gene are consistent with PDE due to ATQ deficiency, and can be found via molecular or genomic analysis.
Vitamin b6 (pyridoxine) is mainstay for seizure control in PDE
Adjunct lysine reduction therapies (LRT; lysine restricted diet and arginine supplementation) aim on improving neurocognitive outcomes.
Studies have shown lowering of neurotoxic metabolites, however not normalizing, and cognitive improvement in several but not all patients.
Consensus is reached that all newborns should be treated with LRT, and all children, adolescents and adults should be offered these treatments and treated in case of cognitive delay, behavioral difficulties or poor seizure control.
The international PDE registry for patients with pyridoxine-dependent epilepsy was set up in 2014 and includes >130 patients in 2021, and counting. It allows us to:
Guidelines & recommendations
Laura A. Tseng, MD, PhD Student