Target found for treating rare metabolic disease Inhibiting lysine metabolism reduces toxic substances that damage the brain

8 December 2025

Researchers have identified a starting point for a new therapy against a rare form of epilepsy. By inhibiting the metabolism of amino acid lysine in animal models and human mini brains, they observed a significant reduction in toxic substances that damage brain cells.

Pyridoxine-dependent epilepsy (PDE) is a hereditary metabolic disorder that occurs in about 1 in 65,000 people—roughly thirty individuals in the Netherlands. Patients suffer from severe epileptic seizures and often developmental delays.

The cause is a genetic defect in the ALDH7A1 gene, which disrupts the breakdown of lysine. Lysine cannot be produced by the body but is essential for health, so it must come from food. In people with this genetic defect, excess lysine is not properly broken down but converted into toxic substances that damage brain cells and nerves.

New strategy

Standard epilepsy medications usually do not help with this condition. Reducing lysine intake through diet helps somewhat, but since lysine is important, this can lead to deficiency. In addition, this causes a burden in families as they need to constantly check the lysine intake. Taking extra vitamin B6 prevents seizures in some patients because B6 can neutralize one of the toxic substances. However, since these measures only partially help, there is an urgent need for new therapies.

Researchers from Radboudumc, Amsterdam UMC, and the European research consortium CHARLIE joined forces to find a new strategy to adjust metabolism. 'Fixing the genetic defect itself is difficult', explains Alex Garanto, researcher in genetic therapy for metabolic diseases at Radboudumc. 'But we discovered that we can modify lysine metabolism by inhibiting an enzyme earlier in the lysine breakdown pathway. Blocking this enzyme prevents lysine from being converted into toxic substances that damage the brain.'

Professor of metabolic diseases Clara van Karnebeek, now at Amsterdam UMC, emphasizes the importance for patients: 'They currently live on restrictive diets and are severely limited by epilepsy and other symptoms. These new results offer hope for new treatment options.'

Fewer toxic substances

The findings are described in two publications. In one study, researchers used a mouse model in which the gene for the enzyme AASS was completely knocked out. 'With innovative techniques, we can accurately measure all substances involved in lysine metabolism in this rare disease. We saw that toxic substances were significantly reduced in the brains of mice', says Dirk Lefeber, professor of glycosylation disorders at Radboudumc.

Since completely disabling the enzyme is not feasible in humans, an alternative method was studied. For that, PhD candidate Imke Schuurmans developed so-called mini brains in a dish in a second study. She created these by growing brain cells derived from patients' cells. In these mini brains, she inhibited AASS production using so-called antisense oligonucleotides. This also resulted in fewer toxic substances harmful to brain cells.

'Our results show that this enzyme is a promising therapeutic target', says Garanto. 'Ultimately, we could inhibit the pathway using antisense oligonucleotides. We are already testing similar strategies at Radboudumc for eye diseases and ataxia, and I foresee broad applications for many metabolic disorders.'

 

About the publications

This research was published in: 

• Molecular Therapy – Nucleic Acids: Targeting AASS alleviates neurotoxicity and improves mitochondrial function in astrocyte models for pyridoxine-dependent epilepsy. Imke M.E. Schuurmans, Udo Engelke, Muna Abedrabbo, Sofía Puvogel, Rachel Mijdam, Gijs-Jan Scholten, Sara B. van Katwijk, Astrid Oudakker, Hilal H. Al-Shekaili, Dirk J. Lefeber, Blair R. Leavitt, Clara D.M. van Karnebeek, Nael Nadif Kasri, Alejandro Garanto.

• Brain Communications: New treatment for pyridoxine-dependent epilepsy due to ALDH7A1 deficiency: first proof-of-principle of upstream enzyme inhibition in the mouse. Clara D M van Karnebeek, Valérie Gailus-Durner, Udo F Engelke, Claudia Seisenberger, Susan Marschall, Nathalia R V Dragano, Patricia da Silva-Buttkus, Stefanie Leuchtenberger, Helmut Fuchs, Martin Hrabě de Angelis, Ron A Wevers, Curtis R Coughlin, Dirk J Lefeber.

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