Genotype-phenotype correlation on 45 individuals with West syndrome.

West syndrome is an epilepsy syndrome characterized by repetitive epileptic spasms (ES) and hypsarrhythmia, typically leading to developmental delay/intellectual disability (DD/ID). It is considered a classic epileptic encephalopathy (EE). We designed a diagnostic sequencing panel targeting 131 genes associated with epilepsy and/or EE and screened a cohort of 45 individuals with clinical diagnosis of West syndrome. We identified disease-causing single nucleotide variants in 11 out of 45 individuals affecting genes commonly associated with West syndrome (such as CDKL5, ARX) but also in genes predominantly linked to other epileptic disorders (such as DEPDC5, SCN1A, WDR45, AARS). Panel analysis revealed copy number variants in two additional cases, comprising a 6,7 Mb Duplication on chromosome 2 including SCN2A and SCN3A and a supernumerary marker chromosome 15 leading to an overall diagnostic yield of 29% (13/45). In our cohort, individuals with a disease-causing variant had significantly more severe phenotypes with respect to DD/ID, therapy resistant epilepsy and cerebral atrophy compared to genetically unclarified cases. In addition to investigating the genotypic spectrum of West syndrome, we compared the phenotypic spectrum of clarified versus unclarified cases. Our study illustrates that West syndrome is an electroclinical syndrome caused by various genetic disorders. Individuals without detectable genetic cause might have less encephalopathy leading to a less severe course.

The prognostic value of sleep spindles in long-term outcome of West Syndrome.

OBJECTIVE: There is a high risk for a profound developmental disorder in West Syndrome. However, a prognostic biomarker for neurodevelopmental outcome does not exist. Hypsarrhythmia disturbs normal EEG sleep patterns and hence sleep spindles, which are thought to be important for memory consolidation and learning. We postulated that the early recurrence of sleep spindles as well as an early resolution of hypsarrhythmic patterns after onset of West Syndrome lead to a favourable long-term outcome. METHOD: 448 sleep EEGs recorded during the first two years of life in 44 patients with newly diagnosed West Syndrome between 1980 and 1989 were reviewed retrospectively. Long-term outcome was assessed in 2015-2016 by the Functional Independence Measurement Score as an indicator for coping with everyday situations. EEG-data were correlated with long-term outcome by Fisher's Exact Probability Test or Kruskal-Wallis H test. RESULTS: There were no statistically noticeable differences between time to cessation of hypsarrhythmia and long-term outcome. In a subgroup analysis of patients with cryptogenic etiology only (n = 13) recurrence of sleep spindles correlated with better long-term outcome (p = 0.038). In this subgroup 11/13 showed recurrence of sleep spindles in childhood, 10 of which had a good or intermediate outcome. Considering the whole patient cohort, recurrence of sleep spindles showed a statistically non-significant better long-term outcome. CONCLUSION: Recurrence of sleep spindles and cessation of hypsarrhythmia cannot be used as a valid prognostic biomarker of neurodevelopmental outcome in non-cryptogenic West Syndrome.