CDKL5-Related Disorders: From Clinical Description to Molecular Genetics

Abstract

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in girls with Rett-like features and early-onset epileptic encephalopathy including infantile spasms. To date, with more than 80 reported cases, the phenotype of CDKL5-related encephalopathy is better defined. The main features consist of early-onset seizures starting before 5 months of age, severe mental retardation with absent speech and Rett-like features such as hand stereotypies and deceleration of head growth. On the other hand, neuro-vegetative signs and developmental regression are rare in CDKL5 mutation patients. The CDKL5 gene encodes a serine threonine kinase protein which is characterized by a catalytic domain and a long C-terminal extension involved in the regulation of the catalytic activity of CDKL5 and in the sub-nuclear localization of the protein. To our knowledge, more than 70 different point mutations have been described including missense mutations within the catalytic domain, nonsense mutations causing the premature termination of the protein distributed in the entire open reading frame, splice variants, and frameshift mutations. Additionally, CDKL5 mutations have recently been described in 7 males with a more severe epileptic encephalopathy and a worse outcome compared to female patients. Finally, about 23 male and female patients have been identified with gross rearrangements encompassing all or part of the CDKL5 gene, with a phenotype reminiscent of CDKL5-related encephalopathy combined with dysmorphic features. Even if recent data clearly indicate that CDKL5 plays an important role in brain function, the protein remains largely uncharacterized. Phenotype-genotype correlation is additionally hampered by the relatively small number of patients described.

Fig. 1

Brain MRI findings for patients with CDKL5 point mutations. a Nonspecific hyperintensities in both temporal lobes (T2 FLAIR coronal section) in a 12-year-old CDKL5 mutation patient. b Nonspecific periventricular hyperintensities (T2 axial section) in a 3-year-old CDKL5 mutation patient. c Nonspecific periventricular hyperintensities (T2 FLAIR axial section) in a 9-month-old CDKL5 mutation patient. Arrows show the location of the main abnormalities in each figure.

Fig. 2

Schematic illustration of CDKL5. Full-length human CDKL5 is 1,030 aa long and contains the ATP-binding site, the serine-threonine (ST) kinase active site and the conserved Thr-Xaa-Tyr (T-X-Y) motif within the catalytic domain. A putative signal peptidase I serine active site, 2 supposed nuclear localization signals and one supposed nuclear export signal are indicated. The number at the top refers to the amino acid positions.

Fig. 3

Schematic representation of the CDKL5 gene. The 3 noncoding exons (1, 1a, and 1b) are in mauve, exons corresponding to the ATP-binding site are in yellow, and exons corresponding to the serine/threonine kinase active site are in red. The new recently described exon 16b is in grey. The positions of reported point mutations, and translocations involving CDKL5 gene identified in female patients are illustrated.

Fig. 4

Gene structure of human CDKL5. The gene consists of 23 exons (21 coding exons 2 to 21). This figure does not include the novel exon 18 including the first 170 nucleotides of intron 18 [Williamson et al., 2011]. The location of the mutations identified in male patients are indicated by arrows at the top. Exons and introns are indicated by open boxes and horizontal lines.