Reduced serotonin and 3-hydroxyanthranilic acid levels in serum of cystatin B-deficient mice, a model system for progressive myoclonus epilepsy

Summary: Purpose: To evaluate the levels of tryptophan and its metabolites along serotonin (5-HT) and kynurenine (KYN) pathways in serum of progressive myoclonus epilepsy (EPM1) patients and cystatin B (CSTB)-deficient mice, a model system for EPM1. Methods: Tryptophan and its metabolites along serotonin (5HT) and KYN pathways were determined in serum of EPM1 patients and CSTB-deficient mice by reverse-phase high-pressure liquid chromatography (HPLC) with electrochemical detection. Results: Reduced levels of 5-HT and KYN intermediate metabolite 3-hydroxyanthranilic acid were found in serum of CSTB-deficient mice. A similar trend was found in EPM1 patients. Although tryptophan concentration was reduced in serum of EPM1 patients, no such decrease was observed in CSTBdeficient mice. Conclusions: The present study demonstrates that tryptophan metabolism along 5-HT and KYN pathways are disrupted in EPM1. Further studies are needed to elucidate the role of KYN pathway in pathogenesis of EPM1. Key Words: Progressive myoclonus epilepsy—Cystatin B-deficient mice—Kynurenines—Serotonin—Tryptophan. Progressive myoclonus epilepsy of the UnverrichtLundborg type (EPM1) is a recessively inherited neurodegenerative disease caused by loss of function mutations in the gene encoding cystatin B (CSTB), a cysteine protease inhibitor of the cathepsin family of proteases (1). The disease has an onset of 6‐15 years of age and is characterized by stimulus-sensitive myoclonus, clonic‐tonic seizures, ataxia, and slow decline in the cognitive functions. Previous clinical investigations in patients with EPM1 have demonstrated reduced 5-hydroxyindoleacetic acid (5-HIAA), suggesting a disrupted serotonin metabolism (2). Furthermore, the concentrations of 5HIAA seemed to correlate to the severity of the EPM1 (3). Also, it was found that administration of L-tryptophan, a precursor of serotonin, improved ambulation, myoclonic jerks, and the general condition in six of seven EPM1 patients. The quantitative EEG revealed