The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy

Abstract

The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant.

Figures

Figure 1

Examples of identified facial, hand and feet features in males and females with the CDKL5 disorder (n=67). (a) Female aged 1 year and 10 months: high/prominent forehead, deep-set eyes, prominent lips, well-defined philtrum, proximal puffy phalanges and tapered fingers. (b) Female aged 2 years: high/prominent forehead, deep-set eyes, prominent lips, well-defined philtrum, tapered fingers, slightly broad hallux, hallux valgus and ‘regular' toes. (c) Female aged 4 years: deep-set eyes, a well-defined philtrum, laterally orientated nasal apertures, prominent lips, slightly tapered fingers, small distal phalanges and a broad hallux. (d) Female aged 3 years and 2 months: prominent forehead, mild synophrys, deep-set eyes, prominent lips, puffy proximal phalanges, tapered fingers, slightly broad hallux and ‘regular' other toes. (e) Female aged 7 years and 11 months: high/prominent forehead, deep-set eyes, everted lower lip, puffy proximal phalanges, prominent proximal IP joints and tapered fingers. (f) Female aged 14 years: broad forehead, deep-set eyes, epicanthic folds, well-defined philtrum, prominent lips, tapered fingers and prominent proximal IP joints. (g) Female aged 24 years and 2 months: high forehead, deep-set eyes, well-defined philtrum and prominent lips. (h) Male aged 4 years 4 months: high/prominent forehead, well-defined philtrum, prominent lips, tapered fingers and ‘regular' toes.

Figure 2

Kaplan–Meier survival curve for the risk of developing seizures by single year of age.

Figure 3

Kaplan–Meier survival curve of the risk of developing hand stereotypies by single year of age.

Figure 4

Kaplan–Meier survival curve for the risk of developing a spinal curvature by single year of age.