Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of epilepsy-related premature death. Despite increasing awareness of SUDEP, the underlying causes remain elusive. Cardiac death has been implicated because of the occurrence of ictal cardiac arrhythmias, however, the recent MORTEMUS study suggested central apnoea may be the key mechanism. Congenital central hypoventilation syndrome (CCHS) is a potentially fatal autonomic nervous system disorder characterized by hypoventilation with an impaired response to hypercapnia and hypoxaemia. It is caused by expansion of an alanine repeat in the homeobox gene PHOX2B. We hypothesized that genetic variation in PHOX2B may increase the risk of SUDEP and we sequenced this gene in a large cohort of SUDEP cases. Methods: Patients who died of SUDEP were identified in two major Australian cohorts, the Epilepsy Genetics research program in Melbourne and post-mortem cases from the Department of Forensic Medicine in Sydney. Coding exons of the PHOX2B gene were Sanger sequenced and a fluorescent sizing assay was used to measure the PHOX2B polyalanine repeat sequence. A segment spanning the PHOX2B polyalanine repeat sequence was PCR amplified with a fluorescently labelled reverse primer, and sized on an ABI3730xl DNA analyser with PeakScannerTM software. Results: 68 cases of SUDEP underwent sequencing of PHOX2B. In one case, a 15 nucleotide deletion in the PHOX2B polyalanine repeat region was identified. This was in a 16 year old adolescent who had focal dyscognitive seizures from 5 years and mild intellectual disability. This deletion was verified using a fluorescent sizing assay but its functional significance remains uncertain. Two synonymous variants were identified in four cases, but no PHOX2B polyalanine repeat expansion alleles or point mutations were found. Conclusions: The absence of PHOX2B polyalanine repeat expansion alleles or point mutations in 68 Australian cases of SUDEP, with one deletion of uncertain significance, shows that PHOX2B mutations are not a common risk factor for SUDEP.