CDKL5 deficiency disorder: progressive brain atrophy may be part of the syndrome

Abstract

The clinical phenotype of Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder (CDD) has been delineated but neuroimaging features have not been systematically analyzed. We studied brain magnetic resonance imaging (MRI) scans in a cohort of CDD patients and reviewed age at seizure onset, seizure semiology, head circumference. Thirty-five brain MRI from 22 unrelated patients were included. The median age at study entry was 13.4 years. In 14/22 patients (85.7%), MRI in the first year of life was unremarkable in all but two. In 11/22, we performed MRI after 24 months of age (range 2.5-23 years). In 8 out of 11 (72.7%), MRI showed supratentorial atrophy and in six cerebellar atrophy. Quantitative analysis detected volumetric reduction of the whole brain (-17.7%, P-value = 0.014), including both white matter (-25.7%, P-value = 0.005) and cortical gray matter (-9.1%, P-value = 0.098), with a reduction of surface area (-18.0%, P-value = 0.032), mainly involving the temporal regions, correlated with the head circumference (ρ = 0.79, P-value = 0.109). Both the qualitative structural assessment and the quantitative analysis detected brain volume reduction involving the gray and white matter. These neuroimaging findings may be related to either progressive changes due to CDD pathogenesis, or to the extreme severity of epilepsy, or both. Larger prospective studies are needed to clarify the bases for the structural changes we observed.

Keywords: CDD; CDKL5; brain atrophy; cerebellar atrophy; developmental and epileptic encephalopathy; genetic epilepsy.

Fig. 1

Schematic representation of the CDKL5 protein (A) and genomic region (B). (A) The linear structure of the CDKL5 protein includes the protein kinase domain (light green), the ATP-binding site (dashed in the light green), the serine–threonine S/T kinase active site (blue), the threonine-Glutammate-tyrosine TEY phosphorylation motif (black), two nuclear localization signal 1 and 2 (red), and the nuclear export signal NES (ochre). The gray filled lollipops show the missense substitutions, whereas the black filled lollipops represent the stopgain and frameshift variants. Red numbers between round brackets correspond to the patients’ identifiers. aa: amino acid. (B) Schematic representation of the CDKL5 genomic region. The vertical black lines show the CDKL5 exonic regions. The 5′—3’ UTR (untranslated regions) and the coding regions are depicted with short and long vertical lines, respectively. Splicing variants and genomic rearrangements are reported above and below the CDKL5 genomic region, respectively. Gray dashed line indicates that the deletion is extended beyond the CDKL5 genomic region. Red numbers between round brackets correspond to the patients’ identifiers. ex: exon; del: deletion.

Fig. 2

MRI findings in CDD population of studied patients. (A) MRI of four CDKL5 patients in the first year of life. Compared with a healthy control (HC on the right), there is mild ventricular and CSF space enlargement more prominent in the frontal regions. Sagittal sequences demonstrate absence of cerebellar atrophy. (B–G) Progressive supratentorial and cerebellar atrophy in CDKL5. MRI performed in subject 7 at 4 (B–D) and 13 (E–G) years of life. There is evidence of progressive enlargement of supratentorial ventricles and CSF spaces (B, E) and widening of the interfolial cerebellar spaces of both cerebellar hemispheres (C, F) and vermis (D, G). (H–M) MRI performed in subject 6 at 3 years of age demonstrates signal alterations in central tegmental tracts (H, arrow) associated with diffusion restriction (I–J) and signal alterations in dentate nuclei bilaterally (K, arrow). There is subtle widening of pericerebellar CSF spaces (L) and of supratentorial ventricle and CSF spaces, more prominent in frontal regions (M).

Fig. 3

(A) Statistical whole-brain group analysis of the cortical volume in CDKL5-related patients compared with healthy controls using the intra-cranial volume as covariate. Z-value maps are superimposed on the pial surfaces of the left and right hemispheres. (B) Plots showing the differences in hippocampus, thalamus, and amygdala between patients and controls. The P-values associated with them are reported in Table 2.