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. 2023 Feb;31(2):169-178.
doi: 10.1038/s41431-022-01163-1. Epub 2022 Aug 18.

Factors influencing the attainment of major motor milestones in CDKL5 deficiency disorder

Kingsley Wong  1 , Mohammed Junaid  1 , Scott Demarest  2 , Jacinta Saldaris  1 , Tim A Benke  2 , Eric D Marsh  3 , Jenny Downs  1 , Helen Leonard  4
Affiliations

Factors influencing the attainment of major motor milestones in CDKL5 deficiency disorder

Kingsley Wong et al. Eur J Hum Genet. 2023 Feb.

Erratum in

Abstract

This study investigated the influence of factors at birth and in infancy on the likelihood of achieving major motor milestones in CDKL5 Deficiency Disorder (CDD). Data on 350 individuals with a pathogenic CDKL5 variant was sourced from the International CDKL5 Disorder Database. A first model included factors available at birth (e.g., sex, variant group and mosaicism) and the second additionally included factors available during infancy (e.g., age at seizure onset, number of anti-seizure medications used, experience of a honeymoon period and formal therapy). Cox regression was used to model the time to achieve the milestones. The probability of attaining the outcomes at specific ages was estimated by evaluating the time-to-event function at specific covariate values. Independent sitting and walking were achieved by 177/350 and 57/325 children respectively. By seven years of age, 67.1% of females but only 37.3% of males could sit independently. About a quarter each of females and males achieved independent walking by eight and six years, respectively. When observed from birth, female gender, a late truncating variant and mosaicism impacted most positively on the likelihood of independent sitting. When observed from one year, later seizure onset and experiencing a honeymoon period also improved the likelihood of independent sitting. Factors that favoured sitting (except gender) also improved walking. Having a truncating variant between aa178 and aa781 reduced the likelihood of achieving independent sitting and walking. It is possible to utilise factors occurring early in life to inform the likelihood of future motor development in CDD.

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Conflict of interest statement

H.L. and J.D. have consulted for Avexis, Anavex, GW, Newron and Neurogene on unrelated subject matter. Both H.L. and J.D. have funding from the NIH related to this subject matter. H.L. and J.D. have consulted for Ovid Therapeutics and Marinus on related subject matter. T.B. has received funding from the NIH and the Children’s Hospital Foundation on related subject matter. He has consulted for Neuren/Acadia, Ovid/Takeda, AveXis, Marinus Taysha, Alcyone, and Marinus. All compensation has been made to his department. S.D. has funding from the NIH and International foundation for CDKL5 research related to this subject matter. He has consulted for Marinus and Ovid Therapeutics on related subject matter. He is a Scientific Advisory Board Member for Families SCN2A and SLC6A1 Connect. E.D.M has funding from the NIH, Orphan Disease Center at the University of Pennsylvania, International foundation for CDKL5 research, and LouLou Foundation related to this subject matter. He has funding from the NIH, Orphan Disease Center, Eagles Autism Foundation, for work not related. He is a site PI for industry sponsored trials for Marinus Pharmaceuticals, Zogenix Pharmaceuticals, Stoke Therapeutics, Epygenix Pharmaceuticals, and Takeda Pharmaceuticals on related subject matter. He is a Scientific Advisory Board Member for International Rett Syndrome Foundation and Lennox Gastaut Foundation. The remaining authors have no competing interests.

Figures

Fig. 1
Fig. 1. Estimated time to independent sitting curves in females with CDD, by starting age of observation.
Profile A: Variant group (truncating variants after aa781), mosaicism (absent), ever honeymoon period (yes), number of anti-seizure medications used in first year of life (0–3), age at seizure onset (>1.5 months), formal therapy during first year of life (yes). Profile D: Variant group (truncating variants between aa172 and aa781), mosaicism (absent), ever honeymoon period (no), number of anti-seizure medications used in first year of life (≥4), age at seizure onset (≤1.5 months), formal therapy during first year of life (no).
Fig. 2
Fig. 2. Estimated time to independent sitting curves in males with CDD, by starting age of observation.
Profile B: Variant group (truncating variants after aa781), mosaicism (present), ever honeymoon period (yes), number of anti-seizure medications used in first year of life (0–3), age at seizure onset (>1.5 months), formal therapy during first year of life (yes). Profile D: Variant group (truncating variants between aa172 and aa781), mosaicism (absent), ever honeymoon period (no), number of anti-seizure medications used in first year of life (≥4), age at seizure onset (≤1.5 months), formal therapy during first year of life (no).
Fig. 3
Fig. 3. Estimated time to independent walking curves in females with CDD, by starting age of observation.
Profile A: Variant group (truncating variants after aa781), mosaicism (absent), ever honeymoon period (yes), number of anti-seizure medications used in first year of life (0–3), age at seizure onset (>1.5 months), formal therapy during first year of life (yes). Profile D: Variant group (truncating variants between aa172 and aa781), mosaicism (absent), ever honeymoon period (no), number of anti-seizure medications used in first year of life (≥4), age at seizure onset (≤1.5 months), formal therapy during first year of life (no).
Fig. 4
Fig. 4. Estimated time to independent walking curves in males with CDD, by starting age of observation.
Profile B: Variant group (truncating variants after aa781), mosaicism (present), ever honeymoon period (yes), number of anti-seizure medications used in first year of life (0–3), age at seizure onset (>1.5 months), formal therapy during first year of life (yes). Profile D: Variant group (truncating variants between aa172 and aa781), mosaicism (absent), ever honeymoon period (no), number of anti-seizure medications used in first year of life (≥4), age at seizure onset (≤1.5 months), formal therapy during first year of life (no).
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