Authors :
Presenting Author: Katheryn Mansour, BS – Boston Children's Hospital
Itay Tokatly Latzer, MD – Boston Children's Hospital
Isabel Haviland, MD – Children’s Hospital of Los Angeles
Zoë Frazier, MS, CGC – Boston Children's Hospital
Nancy Aly, MD – Boston Children's Hospital
Eorna Maguire-Lobos, BA – Boston Children's Hospital
Jenny Downs, PhD – The Kids Research Institute Australia; Curtin School of Allied Health
Nadia Bahi-Buisson, MD, PhD – Département de Pédiatrie, Service de Neurologie Pédiatrique, Hopital Necker Enfants Malades
Bo Zhang, PhD – Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Eric Marsh, MD PhD – Children's Hospital of Philadelphia
Scott Demarest, MD – Children's Hospital Colorado
Tim Benke, MD – Children’s Hospital Colorado
Tim Yu, MD, PhD – Harvard Medical School
Helen Leonard, MBChB – The Kids Research Institute Australia
Maya Chopra, MBBS, FRACP – Boston Children's Hospital
Heather Olson, MD, MS – Boston Children's Hospital
Rationale:
CDKL5 deficiency disorder (CDD) is a severe X-linked developmental and epileptic encephalopathy. A minority of individuals with CDD achieve independent motor and communication skills and/or seizure freedom. This study aims to characterize the variant spectrum and phenotypic features of individuals belonging to this subgroup.
Methods:
Participants were recruited from existing research studies and family foundations. We included participants ≥ 18 months of age with a CDKL5 variant thought to explain their neurological phenotype. Genetic variants were internally classified according to the American College of Medical Genetics and CDKL5 specifications. Additional inclusion criteria consisted of independent walking, pincer grasp, and expressive communication skills (Group A), and/or seizure-freedom for ≥ 5 years (Group B). Prior to a semi-structured qualitative interview, designed to capture additional challenges, strengths, and coping strategies, caregivers completed questionnaires evaluating developmental abilities, adaptive behavior, social communication, and quality of life.
Results:
We evaluated 16 individuals with CDD (13 female, 3 male) between 3.2 and 40.5 years old (median 9.5 y/o). Of the 16 subjects, 12 belong to Group A (advanced developmental skills) and 3 to Group B (seizure free), one participant belongs to both Groups A and B. Variant types included missense variants in the catalytic domain (4), truncating variants (11), and splice variants (1). Variants in 2 males were mosaic (blood). All were internally classified as likely pathogenic/pathogenic (one missense variant was classified as VUS). For Group A, the total score of the caregiver CDKL5 Clinical Severity Assessment (100-point scale) was low, median 17.6 (IQR 9.7 - 26). The median total score of the Social Communication Questionnaire, for Group A was 11.5 (IQR 9-12), below the cutoff for high risk of autism spectrum disorder. 94% of caregivers report overall adequate psychosocial well-being, according to the Child and Family Quality of Life form. In Group A, 9 families noted that they don’t participate in family groups because their child presents differently than other families. Themes identified across all qualitative interviews (Groups A and B) include descriptions of behavioral challenges; feelings of caregiver isolation, guilt, and fears associated with the future.Conclusions:
This study demonstrates a broader spectrum of CDD than previously identified. Independent motor skills are frequently accompanied by behavioral challenges. Despite social communication and behavioral challenges, few patients were in the high-risk range. Families are hesitant to engage with CDD support groups and thus may be under-represented in larger research studies. The spectrum of genetic variants is not unique. Milder symptoms could be explained by mosaicism or incomplete impact of splicing. Further studies of x-inactivation and RNA sequencing may provide additional insights.Funding:
LouLou Foundation, NINDS (T32, Haviland)