Authors :
Presenting Author: Isabel Haviland, MD – Boston Children's Hospital
Judith Weisenberg, MD – Washington University in Saint Louis; Holly Dubbs, MS, CGC – Children's Hospital of Philadelphia; Eric Marsh, MD, PhD – Children's Hospital of Philadelphia; Rajsekar Rajaraman, MD – UCLA Mattel Children's Hospital; Scott Demarest, MD, MSCS – Children's Hospital Colorado; Timothy Benke, MD, PhD – Children's Hospital Colorado; Dana Price, MD – NYU Langone Health; Helen Leonard, MBChB, MPH – University of Western Australia; Heather Olson, MD, MS – Boston Children's Hospital
Rationale:
CDKL5 deficiency disorder (CDD) is an X-linked developmental and epileptic encephalopathy associated with severe disability, leading to significant limitations in mobility, functional hand use, and communication in most individuals reported to date. Of around 400 individuals with CDD described in the literature, fewer than 10 have been reported to have independent functional abilities. Understanding the phenotype and genetic features of this cohort could improve understanding of prognosis and inform therapeutic development for the broader CDD population.
Methods:
We describe phenotypic and genotypic characteristics for twenty individuals (fourteen unpublished, six previously published with updated information) with CDD and independent functional abilities, based on retrospective review of medical records and clinical research databases. Minimum inclusion criteria were as follows (all three required): independent walking, pincer grasp, and expressive communication five consistent words or signs). Individuals participate in Institutional Review Board-approved protocols at five clinical CDKL5 Centers of Excellence in the United States, and in the International CDKL5 Disorder Database, approved by the University of Western Australia Human Research Ethics Committee.
Results:
Individuals (fifteen female, five male) range in age from 2.5 to 34 years. Eight individuals are reported to have gross motor skills similar to peers of the same age. Nineteen of twenty speak at least in phrases of two or more words, with some using full sentences and over 30 consistent words. One individual is non-vocal but uses over 50 consistent signs for communication. Four individuals have never had epilepsy and six have been seizure-free for more than a year; epilepsy characteristics and seizure frequency are variable in the others. Eleven individuals report behavioral issues, including irritability, aggression, anxiety, hyperactivity, and impulsivity; co-morbid neuropsychiatric diagnoses include autism spectrum disorder and attention-deficit/hyperactivity disorder. Somatic mosaicism is reported in four individuals. Six individuals have missense variants in the catalytic domain; remaining variants are truncating/likely truncating or lead to no functional protein. See Tables 1 and 2 for detailed information.
Conclusions:
Though underrepresented in the literature, a subset of individuals with CDD achieves independent functional abilities. Behavioral dysregulation is an important co-morbidity in this group. The presence of somatic mosaicism may explain the achievement of independent functional abilities for some individuals, but additional mechanisms warrant exploration, including skewed X-inactivation, alternative splicing, and variability in mRNA and protein expression/activity. Prospective studies should further explore genotype-phenotype correlations in this group of individuals.
Funding:
National Institute of Neurological Disorders and Stroke (U01NS114312-03, 5K23NS107646-05, 3K23NS107646-05S1), National Institute of Mental Health (2T32MH112510).