Currently no evidence supports pathogenic variants in exons
Currently, no evidence supports pathogenic variants in exons 20, 21, and 22, which are part of transcript isoform hCDKL5_5, or within exon 17, which is part of transcript isoform hCDKL5_2. The pathogenicity of variants in the 5′ untranslated region remain uncertain except for deletions extending to include exons 1 and 2. Deletions and truncating variants appear to nearly universally cause CDD. CDKL5 variants from individuals in the COEs are shown in Fig, on a schematic of the protein and on a three-dimensional model along with population variation.
Individuals with CDKL5 duplications show variable penetrance of macrocephaly and learning disability without epilepsy or magnetic resonance imaging abnormalities. Neighboring genes are rarely affected in these duplications. This contrasts with other genetic developmental encephalopathies for which duplications cause a different disease than deletions (e.g., MECP2 and FOXG1 disorders).28, 36, 37, 38, 39 More comprehensive phenome-genome studies of CDKL5 duplication are needed to determine if these duplications are clinically pathogenic.
Molecular studies in rodent models have identified several signaling pathways that are altered in CDD, including protein kinase B (AKT) and mechanistic target of rapamycin (mTOR), AKT and glycogen synthase kinase-3 beta (GSK-3b), and AACOCF3 receptor derived neurotropic factor and Ras-related C3 botulinum toxin substrate 1 (Rac1) and the netrin G1 ligand and postsynaptic density protein 95 interaction.23, 24, 26, 27, 40, 41 However, these rodent models demonstrate a behavioral phenotype but lack spontaneous seizure activity.41, 42, 43 Dendritic outgrowth and spine development are inconsistently altered in cellular CDD models. Mouse model data suggest that CDKL5 expression modulates postsynaptic localization and composition of N-methyl-D-aspartate receptors. CDKL5 influences MeCP2 activity, possibly explaining overlapping features of CDD with Rett syndrome, although the relevance of this in vitro data remains uncertain. Additional CDKL5 substrates include DNA methyltransferase 1, amphiphysin, netrin G1 ligand, histone deacetylase 4, microtubule associated protein 1S, rho guanine nucleotide exchange factor 2, and microtubule-associated protein RP-EB family member 2 (EB2).45, 46 A recent review summarized the molecular features of CDD.
Epilepsy and treatment Refractory epilepsy severely impacts quality of life and neurodevelopment.14, 34 Median age of epilepsy onset is six weeks with 90% onset by three months.13, 14 Eighty percent of children with CDD have daily seizures and 20% have weekly to monthly seizures. Less than half (43.6%) of caregivers reported >2 month of sustained seizure freedom.14, 34 Among individuals with more than two months of seizure freedom (N = 71 of 163 families reporting information on seizure freedom), in three quarters of families able to provide additional information this honeymoon period had a median duration of six months (range 2.5 months to six years) and median onset of two years. In the COE cohort, 9% of families reported a seizure-free period of one to three months, 12% three to six months, 11% six to 12 months, and 13% >12 months. This honeymoon period typically occurs in the first two years of life, although some have seizure-free periods later in childhood or into their teenage years (Olson et al., unpublished data, 2018). Three proposed epilepsy stages in CDD include (1) early onset, at times pharmacoresponsive, (2) epileptic encephalopathy, and (3) refractory multifocal and myoclonic epilepsy. Infantile spasms are the initial seizure type in 23% and present at any point in 81% of individuals with CDD (Olson et al., unpublished data, 2018). Evolving epilepsy tends to be generalized or mixed focal and generalized with spasms, tonic, and tonic-clonic seizures most common (Olson et al., unpublished data, 2018). Complex seizure semiology with multiple phases per seizure is common (56%) (Olson et al., unpublished data, 2018), including a novel seizure pattern: hypermotor-tonic-spasms sequence.16, 50, 51, 52, 53 Autonomic changes can be seen intermixed with any of these seizure types, including pupillary dilatation, facial flushing, irregular respirations, apneas, or hyperventilation (Olson et al., unpublished data, 2018). Although for many individuals refractory epilepsy continues long term, our experience suggests that rare individuals outgrow their epilepsy in childhood and one individual did not have epilepsy onset until age nine years (de novo c.1675C>T; p.Arg559Ter) (Olson et al., unpublished data, 2018).