Abstracts

Rationale: The cyclin-dependent kinase-like 5 (CDKL5) gene is a known cause of early onset epileptic encephalopathy and an atypical Rett-like phenotype. Despite expanding knowledge in this area of neurogenetics there are limited studies of genotype-phenotype correlation. Recently, genotype phenotype study by Fehr et al did reveal some segregation of developmental outcome based on mutation type, but it did not account for the role of variation in epilepsy phenotypes.Methods: Nineteen patients with CDKL5 related encephalopathy seen in our comprehensive Rett clinic were reviewed for the presences of infantile spasms, hypsarrhythmia, and developmental milestones. These phenotypic findings were then correlated with mutation type, based on the mutation classification used by Fehr et al. Group A was defined as a complete loss of the gene or early truncation in the first part of the kinase region. Group B is limited to missense and in-frame mutations within the kinase region. Group C is a truncation or frame shift mutation in the second half of the kinase region through the majority of the C-terminus up to the second nuclear localization signal. Group D was limited to truncation or frame shift mutations in the final portion of the C-terminus after amino acid 781 (See Figure 1). Mutations effecting only exons 19, 20, or 21 were not included as these are of questionable clinical significance.Results: Nineteen patients with an average age of 7 years (ranging from 1-23 years) were analyzed. Five of the 19 patients were males; one male was mosaic for the mutation (patient # 6) and another had XXY cytogenetic make up in the blood samples analyzed (patient # 19). There were nine patients in Group A, six in Group B, three in Group C and one in Group D (see Table 1). The limited sample size of this rare disease limits the use of statistical analysis, but overall 42% (9/19) of our cohort had a history of hypsarrhythmia and 63% (12/19) had a history of epileptic spasms in infancy. Three (of 12) patients had a history of epileptic spasms without EEG capture of hypsarrhythmia. Interestingly, all of the patients in Group C (only 3 patients) had hypsarrhythmia and epileptic spasms whereas only 17% of patients in Group B had hypsarrhythmia and only 44% in Group A. Group A overall seems to attain fewer developmental milestones which supports the findings by Fehr et al. However, there does not seem to be a clear relationship between developmental outcome and a history of hypsarrhythmia or epileptic spasms. However, of the five patients who achieved at least single words with or without walking (6,7,13,18,19) only one had a history of hypsarrhythmia. This may suggest an additive effect of the mutation type and the early epileptic history. A larger sample size is needed to assess these trends.Conclusions: This preliminary study suggests that early life epilepsy phenotype, including hypsarrhythmia and epileptic spasms, impacts developmental outcome in patients with CDKL5 encephalopathy. Larger studies are necessary to determine the relationship between genotypes and early life epilepsy.