Sudden unexpected death in epilepsy (SUDEP) has an incidence of 1–2.5 per 1,000 patient-years and accounts for up 30% of deaths in people with epilepsy [1, 2]. Although knowledge about mechanisms for SUDEP still remains largely unknown, it is well known that risk factors for SUDEP include drug-resistant seizures, symptomatic epilepsy, young age, male gender, long duration of epilepsy, and poor compliance with antiepileptic treatment [1, 2]. Khiari and colleagues [3] recently reported an unusual elevated rate of unexpected deaths in a series of patients with Unverricht–Lundborg disease (EPM1), the most common form of progressive myoclonus epilepsy, associated with mutations in the Cystatin B (CSTB) gene. In particular, 6 out of 19 (31.5%) EPM1 subjects died from SUDEP, independent of seizure control and antiepileptic treatment. However, no specific explanation for this association was provided. In the last 10 years, we observed two cases (1 male, 1 female) of SUDEP among six EPM1 followed-up at our Epilepsy Center (Striano P., unpublished data). This percentage (33%) is strikingly similar to that reported by Khiari and colleagues [3]. We hypothesize that a dysfunction of the serotoninergic system may be a potential mechanism explaining the higher risk of SUDEP in EPM1 patients. Several lines of evidence suggest that an abnormal serotoninergic transmission may be responsible for the myoclonic/seizure phenotype in EPM1 [4, 5]. CSTBdeficient mice show constitutively altered concentration of tryptophan, serotonin, and 5-hydroxyindolacetic acid (5HIAA) in the cerebral cortex and cerebellum [4]. In addition, a significant reduction in the levels of tryptophan and its metabolites along serotonin and kynurenine pathways has been found in the serum of both CSTB-deficient mice animal models and EPM1 patients [5]. Experimental and clinical data support that a reduced serotonergic activity is a potential crucial neurochemical change playing a role in animal models of audiogenic seizures (DBA/2 and DBA/1 mice), probably through control of central respiration [6]. Moreover, SUDEP in this animal model may be prevented by the administration of serotonin re-uptake inhibitors (SSRI) ([6], Faingold, personal communication, American Epilepsy Society 2008). Notably, cerebrospinal monoamine metabolites, in particular 5HIAA, have been recently found also decreased in a baboon model of epilepsy and SUDEP [7, 8]. In conclusion, although our hypothesis is merely speculative, data from the literature suggest that the potential link between the serotonergic system and pathophysiology of SUDEP merits to be further investigated by future specific studies. P. Striano (&) F. Zara Muscular and Neurodegenerative Diseases Unit, G. Gaslini Institute, University of Genova, Genova, Italy e-mail: pstriano@email.it