Abstracts

Rationale: The cyclin-dependent kinase-like 5 (CDKL5) gene is a known cause of early onset epileptic encephalopathy. This study seeks to extends the number of reported patients, clarify the clinical phenotypic features of CDKL5 deficiency syndrome (CDD), and determine if these features are correlated with genotype. Methods: We collected 93 patients with CDKL5 deficiency syndrome from the 3 CDKL5 Centers of Excellence (Children’s Hospital Colorado, Cleveland Clinic and Boston Children’s Hospital). Phenotypic features were captured through structured interviews, physical exam and collection of medical results. These phenotypic findings were then correlated with mutation type based on the mutation classification used by Fehr et al: type A means there is presumably no functional protein as there is a complete deletion or very early truncation, type B is a missense mutation in the kinase domain, type C is a truncation or frameshift between amino acid 172 and 781, and type D is a truncation or frameshift between amino acid 781 and 905. Results: Of the 93 patients with CDD 26 (28%) were type A, 24 (26%) type B, 32 (34%) type C, and 11 (12%) type D. 81% were female. Most common initial seizure types included tonic seizures (31%), generalized tonic clonic (GTCs, 23%) and epileptic spasms (23%). Hypermotor tonic spasms sequence (HTSS, 9%), myoclonic (6%) and clonic (9%) were less common. 22% of the time the initial seizure type included focal features. 81% of patients developed epileptic spasms but only 39% had hypsarrhythmia. Classically described HTSS was seen in only 24% of patients but 56% of patients had a multiple seizure types (often tonic and spasms) that clustered together or HTSS seizures.  Epileptic spasms (81%) and tonic seizures (63%) were the most common seizure type overall. 22% of those with tonic seizure experienced asymmetric tonic seizures. Myoclonic (39%), GTCs (33%), clonic (11%), atonic (9%) and absence (2%) seizures were less common. 30% of patient had either pure focal seizures or focal features to these other seizure types. Half of all patients had 4 or more seizure types and only 15% had only one seizure type. 45% of patients experienced a seizure free period (1-3 months 9%, 3-6 months 12%, 6-12 months 11%, >12 months 13%) at some point, but only 6% were still seizure free at the last visit. Cortical visual impairment was present in 75% of all CDD patients. None of these clinical features were associated with genotype group. Conclusions: There is variability in the presentation and evolution of patients with CDKL5 Deficiency Syndrome, but the majority experience epileptic spasms (often without hypsarrhythmia) and tonic which frequently cluster together. Most patients have cortical visual impairment. While many patients have a period of seizure freedom it is rarely maintained. Funding: This research is supported by funding from the International Foundation for CDKL5 Research.