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

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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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ARTICLE OPEN
Factors inuencing the attainment of major motor milestones
in CDKL5 deciency disorder
Kingsley Wong
1
, Mohammed Junaid
1
, Scott Demarest
2
, Jacinta Saldaris
1
, Tim A. Benke
2
, Eric D. Marsh
3
, Jenny Downs
1
and
Helen Leonard
1
© The Author(s) 2022
This study investigated the inuence of factors at birth and in infancy on the likelihood of achieving major motor milestones in
CDKL5 Deciency Disorder (CDD). Data on 350 individuals with a pathogenic CDKL5 variant was sourced from the International
CDKL5 Disorder Database. A rst 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 specic ages was estimated by evaluating the time-to-event function at specic 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.
European Journal of Human Genetics; https://doi.org/10.1038/s41431-022-01163-1
INTRODUCTION
CDKL5 Deciency Disorder (CDD) is a relatively newly recognised
Developmental Epileptic Encephalopathy, originally thought to be
an atypical form of Rett syndrome with which it shares many
characteristics [13]. However, it is the early onset seizures, later
becoming refractory, and the severe motor, cognitive [2] and
cortical visual [4,5] impairment that are the main differentiating
clinical features. CDD is caused by a pathogenic variant in the
CDKL5 gene which encodes for CDKL5, a serine threonine kinase,
with a role in the regulation of axon outgrowth, dendritic
morphogenesis and synapse formation early in life [6]. Recent
data has indicated that over 200 different CDKL5 variants are
harboured by as few as 285 affected individuals making it
challenging to assess genotype phenotype relationships [7]. Thus,
many studies have categorised variants into four groups according
to their position on the gene and functional consequences [8].
The extreme rarity of this disorder [9,10] prompted the need for
an international database, the International CDKL5 Disorder
Database (ICDD), with capacity to accrue a large enough number
of cases to understand the clinical prole of this disorder and the
variability therein [11,12]. The rst published study using these
data (n=127) found that by the age of ve years less than three
quarters of females and less than half of males had achieved
independent sitting [12]. The ability to walk was even further
compromised with only a quarter of females able to walk by the
age of four and a half years and only one of 18 males achieving
this ability. Depending on their familys socioeconomic status and
the resources available in their country of residence it would be
expected that many children with CDD may be provided with
early intervention therapies at a young age. However, there is no
published data to conrm this and thus no evaluation of the
benets or otherwise.
Onset of seizures early in life is generally the main presentation
in CDD with six weeks the median age of onset and the majority
commencing in the rst year of life [13]. These seizures tend to be
difcult to control and can require polypharmacy, with its own
inherent adverse effects, from an early age. However just under
half of affected children do experience a honeymoon period, i.e. a
brief period of seizure control [14,15], when seizures appear to
remit for a median duration of six months but with a range of
2 months to 11 years [4,13].
There is variability in the attainment of milestones in CDD. For
example, some females may achieve independent sitting by age
6 months whilst one quarter would still not have achieved
this milestone by ve years of age [12]. Similar variability has been
described with the development of walking in females. Males, on
Received: 31 January 2022 Revised: 22 April 2022 Accepted: 21 July 2022
1
Telethon Kids Institute, The University of Western Australia, Northern Entrance, 15 Hospital Avenue, Nedlands, WA, Australia.
2
Childrens Hospital Colorado, Pediatric Neurology,
University of Colorado, School of Medicine, Aurora, USA.
3
Division of Neurology, Childrens Hospital of Philadelphia, School of Medicine, University of Pennsylvania, Philadelphia,
USA. email: helen.leonard@uwa.edu.au
www.nature.com/ejhg
1234567890();,:
the other hand, tend to be more delayed except if they are
mosaic [7].
Increasingly infants are being diagnosed with CDD due to
expanding use of epilepsy gene panels [16], but at present, there
is no way to predict their developmental outcomes. With higher
seizure burden at an earlier time point potentially associated with
subsequent poorer development [17], the question emerges as to
whether developmental trajectories are predetermined at birth or
if factors occurring in the rst year of life including effectiveness of
seizure treatment or access to early intervention may alter the
trajectory.
The aims of this study were to use available data from the ICDD
to estimate the likelihood of children with CDD achieving the
major milestones of sitting and walking by certain time points,
and to investigate the impact of inuencing factors for which data
were available including childs sex, variant group, age at seizure
onset, occurrence of a honeymoon period, number of anti-seizure
medications used and receipt of formal therapy in the rst year
of life.
METHODS
Data source and study population
The International CDKL5 Disorder Database (ICDD) served as the data
source for this study [12]. We included children who had a pathogenic or
likely pathogenic CDKL5 variant and whose families completed a baseline
questionnaire between 2012 and 2021. Data was supplemented when
available by information from a follow-up questionnaire completed
between 2018 and 2019.
Outcome variables
The outcomes variables for this study were age at independent sitting and
independent walking. Independent sitting and walking related to the times
at rst reported episode of sitting and walking without support,
respectively. Outcome data were mostly drawn from the baseline
questionnaire. However, we also updated these details from the follow-
up questionnaire if information related to independent sitting and/or
walking had previously been missing or the child had not reached these
milestones at the time of submission of the baseline questionnaire.
Explanatory variables
Variant group and mosaicism. As previously done [7,8], variants were
grouped into the following categories: 1. no functional protein, comprising
any variant that prevents function in the catalytic domain; 2. missense/in-
frame variants within the catalytic domain, including any missense variant
within the protein kinase active region or in-frame variant that results in
loss of some kinase region (with consequent protein intact) due to a
deletion; 3. truncating variants occurring between amino acid (aa) 172 and
aa781, including any truncating variant such as a nonsense or frameshift
variant that causes loss of C- terminal region whilst maintaining kinase
activity; and 4. late truncating variants occurring after aa781 including
those that maintain the kinase activity and a large portion of the
C-terminal region. Those individuals whose variants could not be grouped
in either of the above-mentioned categories were classied as other
variants. Mosaicism was considered to be present when indicated on the
genetic report.
Age at seizure onset. Age at seizure onset was dened as the age of the
child (in months) when the rst seizure episode was observed or reported
by parents/caregivers. For analysis the variable was grouped into two
categories 1.5 monthsand >1.5 months.
Number of anti-seizure medications prescribed in the rst year of life.We
dichotomised the number of anti-seizure medications (ASMs) used in the
rst year of life as either up to three medications or four or more per day.
Ever honeymoon period. In our study a honeymoon period was
considered to be a seizure-free episode of >2 months after seizure onset.
Data on ever experiencing a honeymoon period was dichotomised into
two groups Yesand No.
Formal therapy during the rst year of life. Formal therapy referred to
those children who had undergone either physiotherapy or occupational
therapy during their rst year of life. This variable was categorised as either
Yesor No.
Statistical analyses
Descriptive statistics were used to summarise the characteristics of the
study population. For time-to-event analysis, all individuals were followed
from birth until censoring (i.e. time of independent sitting/walking or date
of last questionnaire returned, whichever occurred rst). Total observation
time was the sum of follow-up time for each individual. Cox proportional
hazard regression was used to estimate the likelihood of achieving the
milestones using the explanatory variables, and the corresponding beta
coefcients, hazard ratios and their 95% condence intervals were
reported. The proportional hazard assumption was tested and conrmed
using the Schoenfeld residuals and graphical assessment.
The probability of achieving the milestones at specic age (sitting: 1, 1.5,
2, 3 and 5 years; walking: 1.5, 2, 4, and 6 years) was estimated by evaluating
the time-to-event function at specic covariate values of four selected
proles (Supplementary Table 1). For sitting, individuals selected for prole
A had truncating variants after aa781, with no mosaicism, experienced a
honeymoon period, took three or less anti-seizure medications during the
rst year of life, had a later seizure onset (>1.5 months), and received
formal therapy during their rst year of life. Prole B was similar to Prole A
except for the presence of mosaicism. Prole C was also similar to prole A
except for variant group (missense/in-frame variants) and number of ASMs
(4). Prole D was selected as having the least favourable outcome and
included those individuals with truncating variants occurring between
amino acid (aa) 172 and aa781, with no mosaicism, who had never
experienced a honeymoon period, took four or more anti-seizure
medication in the rst year of life, had an earlier seizure onset
(1.5 months), and did not receive formal therapy during their rst year
of life. Proles selected for estimating the probability of independent
walking were similar to those selected for sitting except for exclusion of
formal therapy in the rst year of life for which we felt the time frame was
inappropriate. The log-log based condence interval for the likelihood
estimates was derived from the asymptomatic variance of the covariate-
adjusted time-to-event function as described by Marubini and Valsecchi
[18]. Two models were developed to accommodate explanatory variables.
In the rst model we included only those covariates that were available at
birth (e.g., sex, variant group and mosaicism) and in the second model we
additionally included those that became available during rst year of life
(e.g., age at seizure onset, number of ASMs used in rst year of life,
experience of a honeymoon period and formal therapy). The starting age
of observation was at birth in the rst model and at one year of age (1 and
1.5 years for walking) in the second model. In the second model,
individuals who were censored prior to the start of observation period
were excluded. All analyses were carried out using Stata 16.0 (Stata Corp,
College Station, TX, USA).
RESULTS
Clinical, genetic, and demographic characteristics of the 350
individuals with CDD are presented in Supplementary Table 2. The
majority (83.4%) of individuals were female and just under half
(46.3%) were born in North America. The median age at most
recent questionnaire was 5.7 years (interquartile range [IQR]
2.4,10.9). A quarter (24.9%) had variants classied as no functional
protein, 31.7% as missense/in-frame variants within the kinase
domain and 27.4% as truncating variants from aa172 to aa781. A
smaller proportion (10.6%) had truncating variants after aa781,
and mosaicism was reported in the genetic reports of 10 (2.9%)
individuals (seven (12%) males and three (1%) females). In just
over a half (56.6%) of individuals seizure onset was at or before
one and a half months. During their rst year of life almost a half
(47.7%) were on four or more ASMs, just over a third (34.8%) on
two or three ASMs and a small proportion (10.6%) took none or
only one ASM. More than half experienced a honeymoon period
(56.3%) and nearly two thirds (63.4%) received formal therapy
during their rst year of life.
K. Wong et al.
2
European Journal of Human Genetics
Independent sitting
Independent sitting was achieved by 177 children over a total
observation period of 1262.2 years. Close to a quarter (22.3%, 95%
condence interval [CI] 18.2, 27.2) of those who ever learned to sit
were able to do so by one year of age. Among females, the
median time to sitting was 26 months (95% CI 24, 36) and over
two thirds (67.1%, 95% CI 60.6, 73.5) achieved this milestone by
seven years. On the other hand, slightly less than a quarter (23.0%,
95% CI 13.7, 37.1) of males were sitting by two years and only
37.5% (95% CI 23.5, 56.0) by seven years. Among the explanatory
variables, when observed from birth, being female had the largest
impact on the likelihood of independent sitting (hazard ratio [HR]
3.0, 95% CI 1.7, 5.1), followed by presence of mosaicism (HR 2.5,
95% CI 1.1, 5.4) and having a truncating variant after aa781 (HR
1.7, 95% CI 1.0, 3.0) (Table 1). When observed from one year of age
(n=242, number of events =102, total observation time =935.1
years), being female (HR 3.5, 95% CI 1.6, 7.9), having a truncating
variant after aa781 (HR 2.1, 95% CI 1.0, 4.6) and ever experiencing
a honeymoon period (HR 1.8, 95% CI 1.1, 2.8) had the largest
inuence on the chance of achieving the milestone (Table 1).
Formal therapy during rst year of life (HR 1.36, 95% CI 0.82, 2.25)
and taking three or fewer ASMs in the rst year of life (HR 1.19,
95% CI 0.76, 1.84) had less inuence.
Independent walking
Among the 325 individuals with data on independent walking, 57
achieved the milestone over a total observation time of 2,037.6
years. Time-to-event analysis revealed that a quarter each of
females and males achieved independent walking by 8 (95% CI
4.5, ) and 6 (95% CI 3.5, ) years, respectively. When observed
from birth, truncating variants after aa781had the largest impact
on the probability of independent walking (HR 2.7, 95% CI 1.2, 6.4),
followed by presence of mosaicism (HR 2.5, 95% CI 0.9, 7.1) and
other variants(HR 2.3, 95% CI 0.8, 6.6) (Table 2). These factors, in
addition to ever experiencing a honeymoon period (HR 1.9, 95% CI
1.0, 3.5), were highly ranked when observation started from one
year of age (n=290, number of events =53, total observation
time =1713.6 years). Shifting the starting age of observation to
1.5 years (n=266, number of events =45, total observation
time =1573.6 years) increased the importance of the honeymoon
period (HR 2.5, 95% CI 1.3, 5.2), whilst other factors such as
truncating variants after aa781,other variantsand presence of
mosaicism remained inuential (Table 2). In contrast to the
ndings for independent sitting, gender played a lesser role in
affecting the likelihood of independent walking. However, as with
sitting, having three or fewer ASMs in the rst year of life had
minimal inuence.
Likelihood of independent sitting and walking over time
The estimated probability of independent sitting and walking at
specic age (by sex, prole of explanatory variables and starting
age of observation) is shown in Tables 3,4and Figs. 14.In
general, females were more likely to achieve either milestone than
males. Furthermore, the time-to-event curves of a favourable and
much less favourable proles (female: Prole A and Prole D; male:
Prole B and Prole D) changed as more pertinent information
Table 1. Multivariable regression analysis of time to independent sitting in individuals with CDKL5 deciency disorder, by starting age of
observation.
Starting age of observation (year) 0 1 0 1
n350 197 350 197
HR (95% CI) β(95% CI)
Sex
Female 2.97 (1.75, 5.11) 3.52 (1.57, 7.90) 1.09 (0.56, 1.63) 1.26 (0.45, 2.07)
Male Ref Ref Ref Ref
Variant group
Truncating variants between aa178 and aa781 Ref Ref Ref Ref
Truncating variants after aa781 1.72 (1.00, 2.95) 2.11 (0.96, 4.62) 0.54 (0.003,1.08) 0.74 (0.04, 1.53)
No functional protein 1.57 (1.02, 2.39) 1.50 (0.80, 2.79) 0.45 (0.03, 0.87) 0.40 (0.22, 1.03)
Missense/in-frame 1.37 (0.92, 2.04) 1.57 (0.87, 2.84) 0.31 (0.09, 0.71) 0.45 (0.14, 1.04)
Other variants 1.19 (0.58, 2.46) 1.67 (0.56, 4.95) 0.18 (0.55, 0.90) 0.51 (0.58, 1.60)
Mosaicism
Absent Ref Ref Ref Ref
Present 2.47 (1.14, 5.35) 1.57 (0.50, 4.96) 0.91 (0.13, 1.68) 0.45 (0.69, 1.60)
Ever honeymoon period
No Ref Ref
Yes 1.78 (1.12, 2.81) 0.57 (0.12, 1.03)
Number of ASM used in rst year of life
031.19 (0.76, 1.84) 0.17 (0.27, 0.61)
4Ref Ref
Age at onset of seizures (month)
1.5 Ref Ref
>1.5 1.41 (0.90, 2.22) 0.35 (0.10, 0.80)
Formal therapy during rst year of life
No Ref Ref
Yes 1.36 (0.82, 2.25) 0.31 (0.19, 0.81)
Ref reference category, aa amino acid, ASM anti-seizure medication, HR hazard ratio.
K. Wong et al.
3
European Journal of Human Genetics
became available later in life (Figs. 14). For instance, as seen in
Table 3, when the observation period started at birth, for females
with truncating variants after aa781 and without mosaicism (i.e.,
Prole A most favourable) the likelihood of independent sitting
at 5 years of age was 73.8% (95% CI 57.7, 87.6), compared with
54.1% (95% CI 43.7, 65.3) for those with truncating variants
between aa172 and aa781 and without mosaicism (i.e., Prole D
least favourable). When medical history during the rst year of life
was taken into account and observation started at one year, the
likelihood of sitting unaided at 5 years of age in females with
Prole A who had experienced a honeymoon period, used less
than 4 ASMs, had later seizure onset and received formal therapy
was 89.6% (95% CI 65.8, 99.2) (Table 3). In contrast the likelihood
of achieving the same was only 23.3% (95% CI 12.8, 40.3) when
observed from one year of age for those with Prole D who had
truncating variants between aa172 and aa781 and no mosaicism
and for whom no honeymoon period had been reported, had
used > =4 ASMs), had a history of early seizure onset and received
no formal therapy during their rst year of life (Table 3).
Regarding independent walking, the estimated probability of
achieving this milestone at 6 years of age when observed from
birth was 39.7% (95% CI 23.9, 60.8) and 16.9% (95% CI 9.7, 28.6) for
females with the most and least favourable prole, respectively
(Table 4). The probability changed to 60.9% (95% CI 35.2, 86.8) and
8.2% (95% CI 3.5, 18.5) when additional explanatory variables were
included in the modelling when observed from one year of age
(Table 4). Presence of mosaicism appeared to expedite achieve-
ment of either milestone in females as well as males with the most
favourable prole, as the likelihood of independent sitting and
walking increased in individuals with Prole B, which was the
same as Prole A except for the presence of mosaicism (Tables 3
and 4).
DISCUSSION
Despite being a severe DEE [11], considerable variability has been
demonstrated in CDD with motor ability ranging from inability to
maintain independent sitting to the ability to walk and run. Similar
variation in hand function and communication has also been
shown [11]. In this study we aimed to investigate how the age at
acquisition of major milestones might be inuenced by a range of
factors early in life. We found the likelihood of children achieving
Table 2. Multivariable regression analysis of time to independent walking in individuals with CDKL5 Deciency Disorder, by starting age of
observation.
Starting age of
observation (year)
0 1 1.5 0 1 1.5
n325 262 240 325 262 240
HR (95% CI) β(95% CI)
Sex
Female 1.32
(0.63, 2.77)
1.30
(0.56, 3.04)
1.24
(0.49, 3.15)
0.28
(0.47, 1.02)
0.26
(0.59, 1.11)
0.22
(0.72, 1.15)
Male Ref Ref Ref Ref Ref Ref
Variant group
Truncating variants
between aa178 and aa781
Ref Ref Ref Ref Ref Ref
Truncating variants
after aa781
2.73
(1.17, 6.35)
2.24
(0.92, 5.47)
2.64
(0.96, 7.28)
1.00 (0.16,1.85) 0.80
(0.09, 1.70)
0.97
(0.04, 1.98)
No functional protein 1.54
(0.71, 3.32)
1.24
(0.55, 2.81)
1.28
(0.49, 3.32)
0.43
(0.34, 1.20)
0.21
(0.60, 1.03)
0.24
(0.71, 1.20)
Missense/in-frame 0.97
(0.43, 2.18)
0.95
(0.39, 2.34)
1.37
(0.51, 3.69)
0.03
(0.84, 0.78)
0.05
(0.94, 0.85)
0.31
(0.04, 1.98)
Other variants 2.29
(0.79, 6.61)
2.11
(0.62, 7.16)
2.17
(0.53, 8.84)
0.83
(0.23, 1.89)
0.75
(0.47, 1.97)
0.77
(0.63, 2.18)
Mosaicism
Absent Ref Ref Ref Ref Ref Ref
Present 2.51
(0.89, 7.08)
1.87
(0.54, 6.49)
2.21
(0.61, 8.01)
0.92
(0.12, 1.96)
0.62
(0.62, 1.87)
0.79
(0.49,2.08)
Ever honeymoon period
No Ref Ref Ref Ref
Yes 1.88
(1.00, 3.51)
2.54
(1.25, 5.18)
0.63 (0.003, 1.25) 0.93 (0.22,1.65)
Number of ASM used in rst year of life
031.55
(0.83, 2.90)
1.47
(0.74, 2.94)
0.44
(0.19, 1.06)
0.39
(0.30,1.08)
4Ref Ref Ref Ref
Age at seizure onset (month)
1.5 Ref Ref Ref Ref
>1.5 1.68
(0.93, 3.04)
1.68
(0.88, 3.21)
0.52
(0.07, 1.11)
0.52
(0.13, 1.17)
Ref reference category, aa amino acid, ASM anti-seizure medication, HR hazard ratio.
K. Wong et al.
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European Journal of Human Genetics
Table 3. Estimated probability of independent sitting at 1, 1.5, 2, 3, and 5 years of age in individuals with CDKL5 deciency disorder, by sex, prole of explanatory variables and starting age of
observation.
Prole Start
age (yr)
Female (age in year) Male (age in year)
Probability % (95% CI) Probability % (95% CI)
n1 1.5 2 3 5 n1 1.5 2 3 5
A 0 292 30.3 (20.3, 43.6) 47.3
(33.6, 63.2)
58.1 (42.9, 74.0) 65.7
(49.8, 81.0)
73.8 (57.7, 87.6) 58 11.4
(6.1, 20.6)
19.3
(10.8, 33.1)
25.3
(14.5, 41.8)
30.1
(17.5, 48.7)
36.2
(21.4, 56.7)
1 159 47.7
(26.2, 74.9)
65.0 (39.7, 88.7) 79.6
(53.2, 96.4)
89.6 (65.8, 99.2) 38 16.8
(6.6, 39.2)
25.8
(10.7, 54.3)
36.3
(15.7, 69.7)
47.5
(21.5, 81.9)
B 0 292 59.0 (31.2, 88.1) 79.4
(49.0, 97.6)
88.3 (60.2, 99.3) 92.9
(67.8, 99.8)
96.4 (75.7, 100.0) 58 25.8
(11.8, 51.0)
41.1
(20.2, 71.2)
51.3
(26.6, 81.3)
58.8
(31.6, 87.4)
67.0
(37.8, 92.5)
1 159 63.9
(24.5, 97.5)
80.8 (37.4, 99.7) 91.8
(50.4, 100.0)
97.2 (62.9, 100.0) 38 25.1
(7.4, 66.3)
37.5
(12.1, 82.0)
50.9
(17.6, 92.7)
63.7
(24.0, 97.6)
C 0 292 24.9 (19.0, 32.3) 39.9
(32.1, 48.8)
49.9 (41.2, 59.3) 57.3
(48.1, 66.9)
65.5 (56.0, 74.9) 58 9.2
(5.2, 15.7)
15.7
(9.3, 25.7)
20.7
(12.5, 33.0)
24.8
(15.2, 38.9)
30.0
(18.7, 45.9)
1 159 33.4
(19.7, 53.0)
48.3 (30.7, 69.5) 63.2
(42.5, 83.5)
75.9 (54.5, 92.4) 38 10.9
(4.3, 26.2)
17.1
(7.1, 38.1)
24.7
(10.5, 51.7)
33.3
(14.6, 64.6)
D 0 292 18.9 (13.7, 25.8) 31.1
(23.6, 40.1)
39.7 (31.0, 49.7) 46.3
(36.8, 57.0)
54.1 (43.7, 65.3) 58 6.8
(3.7, 12.2)
11.7
(6.6, 20.2)
15.6
(9.0, 26.2)
18.8
(11.0, 31.1)
23.0
(13.6, 37.3)
1 159 7.3
(3.6, 14.5)
11.6 (6.0, 21.7) 17.0
(9.1, 30.5)
23.3 (12.8, 40.3) 38 2.1
(0.8, 5.8)
3.4
(1.3, 8.9)
5.2
(2.0, 13.1)
7.3
(2.8, 18.0)
Factors in bold represent variation from Prole A.
nnumber of individuals, CI condence interval, yr year.
Prole A: Variant group (truncating variants after aa781), mosaicism (absent), ever honeymoon period (yes), number of anti-seizure medication used in rst year of life (03), age at seizure onset (>1.5 months),
formal therapy during rst year of life (yes).
Prole B: Variant group (truncating variants after aa781), mosaicism (present), ever honeymoon period (yes), number of anti-seizure medication used in rst year of life (03), age at seizure onset (>1.5 months),
formal therapy during rst year of life (yes).
Prole C: Variant group (missense/in-frame variants within catalytic domain), mosaicism (absent), ever honeymoon period (yes), number of anti-seizure medication used in rst year of life (4), age at
seizure onset (>1.5 months), formal therapy during rst year of life (yes).
Prole D: Variant group (truncating variants between aa172 and aa781), mosaicism (absent), ever honeymoon period (no),number of anti-seizure medication used in rst year of life (4),age at seizure
onset (1.5 months),formal therapy during rst year of life (no).
K. Wong et al.
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European Journal of Human Genetics
Table 4. Estimated probability of independent walking at 1.5, 2, 4, and 6 years of age in individuals with CDKL5 Deciency Disorder, by sex, prole of explanatory variables and starting age of
observation.
Prole Start
age (yr)
Female (age in year) Male (age in year)
Probability % (95% CI) Probability % (95% CI)
n1.5 2 4 6 n1.5 2 4 6
A 0 268 6.8 (3.0, 14.8) 10.3 (5.0, 20.4) 30.4 (17.6, 49.3) 39.7 (23.9, 60.8) 57 5.2 (1.9, 13.6) 7.9 (3.1, 19.1) 24.0 (11.0, 47.7) 31.9 (15.2, 59.2)
1 216 15.5 (6.5, 34.5) 49.7 (27.0, 77.6) 60.9 (35.2, 86.8) 46 12.1 (4.0, 33.9) 41.0 (16.9, 77.9) 51.4 (22.6, 87.0)
1.5 198 5.1 (1.4, 18.6) 46.3 (23.4, 76.5) 59.3 (32.4, 87.3) 42 4.2 (0.9, 18.3) 39.4 (14.9, 78.9) 51.6 (21.1, 89.1)
B 0 268 16.1 (4.7, 47.6) 23.8 (7.5, 61.2) 50.7 (24.4, 94.7) 71.9 (32.5, 98.3) 57 12.5 (3.8, 36.8) 18.6 (6.1, 48.9) 49.8 (20.4, 87.5) 61.8 (27.4, 94.4)
1 216 27.0 (6.8, 75.6) 72.2 (26.8, 99.5) 82.6(34.8, 99.9) 46 21.5 (5.6, 63.9) 62.7 (22.7, 97.7) 74.0 (29.8, 99.4)
1.5 198 11.0 (1.9, 51.7) 74.7 (26.9, 99.8) 86.3 (36.6, 100.0) 42 9.0 (1.6, 41.7) 67.0 (24.4, 98.7) 79.9 (33.6, 99.8)
C 0 268 2.5 (1.1, 5.3) 3.8 (1.9, 7.5) 12.1 (6.9, 20.5) 16.4 (9.7, 27.6) 57 1.9 (0.7, 5.1) 2.9 (1.1, 7.3) 9.3 (4.0, 20.7) 12.7 (5.6, 27.3)
1 216 4.5 (1.7, 12.0) 17.2 (7.5, 36.8) 22.8 (10.2, 46.4) 46 3.5 (1.0, 11.6) 13.5 (4.6, 36.3) 18.0 (6.3, 45.7)
1.5 198 1.8 (0.5, 7.2) 19.6 (8.4, 41.8) 27.1 (12.1, 53.9) 42 1.5 (0.3, 7.1) 16.1 (5.3, 43.5) 22.4 (7.6, 55.7)
D 0 268 2.5 (1.1, 5.6) 3.9 (1.9, 7.9) 12.4 (6.9, 21.7) 16.9 (9.7, 28.6) 57 1.9 (0.7, 5.5) 3.0 (1.1, 7.9) 9.6 (3.9, 22.3) 13.1 (5.5, 29.4)
1 216 1.5 (0.6, 4.2) 6.1 (2.6, 14.1) 8.2 (3.5, 18.5) 46 1.2 (0.3, 4.0) 4.7 (1.6, 13.8) 6.4 (2.1, 18.2)
1.5 198 0.3 (0.1, 1.4) 3.7 (1.3, 10.1) 5.3 (1.9, 14.0) 42 0.3 (0.0, 1.4) 3.0 (0.8, 10.4) 4.3 (1.2, 14.5)
Factors in bold represent variation from Prole A.
nnumber of individuals, CI condence interval, yr year.
Prole A: Variant group (truncating variants after aa781), mosaicism (absent), ever honeymoon period (yes), number of anti-seizure medication used in rst year of life (03), age at seizure onset (>1.5 months).
Prole B: Variant group (truncating variants after aa781), mosaicism (present), ever honeymoon period (yes), number of anti-seizure medication used in rst year of life (03), age at seizure onset (>1.5 months).
Prole C: Variant group (missense/in-frame variants within catalytic domain), mosaicism (absent), ever honeymoon period (yes), number of anti-seizure medication used in rst year of life (4), age at
seizure onset (>1.5 months).
Prole D: Variant group (truncating variants between aa172 and aa781), mosaicism (absent), ever honeymoon period (no), number of anti-seizure medication used in rst year of life (4), age at seizure
onset (1.5 months).
K. Wong et al.
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European Journal of Human Genetics
independent sitting by the age of one year was 22% (median age
three years), and in general children with late (after aa781)
truncating variants or variants resulting in no functional protein
were more likely to sit than those with truncating variants
between aa172 and aa781. If a child had not achieved
independent sitting by the age of one year, factors that increased
their likelihood of subsequently achieving this skill were having a
favourable genotype (in this case a truncating variant after aa781),
having a later onset of seizures (after six weeks), having been on
three or less ASMs in the rst year of life, having experienced a
honeymoon period and having received therapy in the rst year of
life. Females had a much greater likelihood than males of
achieving independent sitting as had males where a mosaic
genotype had been reported. With respect to walking the
likelihood was also increased for those with a truncating variant
after aa781 and according to similar factors as for sitting.
0 20 40 8060 100
Likelihood of independent sitting (%)
0 1 2 3 4 5
Age (year)
Observed from birth
0 20 40 60 80 100
0 1 2 3 4 5
Age (year)
Observed from age 1
Fig. 1 Estimated time to independent sitting curves in females with CDD, by starting age of observation. Prole A: Variant group
(truncating variants after aa781), mosaicism (absent), ever honeymoon period (yes), number of anti-seizure medications used in rst year of
life (03), age at seizure onset (>1.5 months), formal therapy during rst year of life (yes). Prole D: Variant group (truncating variants between
aa172 and aa781), mosaicism (absent), ever honeymoon period (no), number of anti-seizure medications used in rst year of life (4), age at
seizure onset (1.5 months), formal therapy during rst year of life (no).
0 20 40 60 80 100
Likelihood of independent sitting (%)
0 1 2 3 4 5
Age (year)
Observed from birth
0 20 40 60 80 100
0 1 2 3 4 5
Age (year)
Observed from age 1
Fig. 2 Estimated time to independent sitting curves in males with CDD, by starting age of observation. Prole B: Variant group (truncating
variants after aa781), mosaicism (present), ever honeymoon period (yes), number of anti-seizure medications used in rst year of life (03), age
at seizure onset (>1.5 months), formal therapy during rst year of life (yes). Prole D: Variant group (truncating variants between aa172 and
aa781), mosaicism (absent), ever honeymoon period (no), number of anti-seizure medications used in rst year of life (4), age at seizure onset
(1.5 months), formal therapy during rst year of life (no).
K. Wong et al.
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European Journal of Human Genetics
Prediction models have previously been used to assess the
likelihood of an infant born preterm surviving to various ages
without a major disability [19] and to estimate the likelihood of
seizure onset in Rett syndrome [20]. They allow the clinician to
relate these factors to their own particular patient in order to
provide some degree of prognostic guidance. In the case of CDD
we have shown that it is possible to make use of information both
available at birth (i.e., gender, genotype and presence of
mosaicism) and subsequently (i.e., age at seizure onset, use of
ASMs, occurrence of a honeymoon period and engagement in
therapy programs) to predict likely later development. In the
future, our models could be further rened and extended to
increase their utility as we collect more data on an even larger
number of cases.
This study has both strengths and weaknesses. An obvious
strength is the international data collection of 350 genetically
020 40 60 80 100
Likelihood of independent walking (%)
0 2 4 6
Age (year)
Observed from birth
020 40 60 80 100
0 2 4 6
Age (year)
Observed from age 1
020 40 60 80 100
0 2 4 6
Age (year)
Observed from age 1.5
Fig. 4 Estimated time to independent walking curves in males with CDD, by starting age of observation. Prole B: Variant group
(truncating variants after aa781), mosaicism (present), ever honeymoon period (yes), number of anti-seizure medications used in rst year of
life (03), age at seizure onset (>1.5 months), formal therapy during rst year of life (yes). Prole D: Variant group (truncating variants between
aa172 and aa781), mosaicism (absent), ever honeymoon period (no), number of anti-seizure medications used in rst year of life (4), age at
seizure onset (1.5 months), formal therapy during rst year of life (no).
020 40 60 80 100
Likelihood of independent walking (%)
0 2 4 6
Age (year)
Observed from birth
020 40 60 80 100
0 2 4 6
Age (year)
Observed from age 1
020 40 60 80 100
0 2 4 6
Age (year)
Observed from age 1.5
Fig. 3 Estimated time to independent walking curves in females with CDD, by starting age of observation. Prole A: Variant group
(truncating variants after aa781), mosaicism (absent), ever honeymoon period (yes), number of anti-seizure medications used in rst year of
life (03), age at seizure onset (>1.5 months), formal therapy during rst year of life (yes). Prole D: Variant group (truncating variants between
aa172 and aa781), mosaicism (absent), ever honeymoon period (no), number of anti-seizure medications used in rst year of life (4), age at
seizure onset (1.5 months), formal therapy during rst year of life (no).
K. Wong et al.
8
European Journal of Human Genetics
conrmed cases accumulated over a period of nine years. This has
been made possible because of ongoing support from advocacy
associations and is currently the largest available dataset on this
disorder. A further strength is that the questions we ask are
important both to families and to the clinicians who provide
counselling to them. One important limitation is that we had to
use a broad classication of genotype because with over two
hundred unique pathogenic variants represented in the ICDD the
number that were recurrent was too small (with only 13/207
variants affecting three or more individuals) [7] to allow us to
analyse according to individual variants. The latter much more
preferable option would likely provide even better estimates
given our previous ndings of some statistical differences in
development and in severity between some individual variants
which did not necessary correspond to our nding here
according to variant group. For instance, in our previous study
those with a p.Arg134* had the lowest severity score and a
relatively high developmental score but would not be categorised
as a late truncating variant rather as one with no functional
protein.Similarly, p.Arg559*, the variant with the highest
developmental score and the next lowest severity score after
p.Arg134*, was classied as a truncating variant occurring
between amino acid (aa) 172 and aa781 and would not be
categorised as a late truncating variant which one might have
expected given the relationship we have found here with the late
truncating group and earlier milestone achievement. However,
including more recurrent variants which could be analysed
individually would be dependent on a considerable increase in
recruitment, which is challenging for an ultra-rare disorder such
as CDD [9,10]. With respect to mosaicism its presence may not
have been reported uniformly by laboratories and it is possible
that for some children this information may have been missed. A
further limitation is the availability and choice of variables
including the absence of detail on therapy interventions,
accessibility to which may depend on geographical location
and socioeconomic circumstances [21]. Furthermore, not all
families were able to provide the specic information ideally
required in relation to the honeymoon period. We improved the
power and strength of the estimates of the model we presented
in relation to walking by not restricting to children who were able
to sit. However, in a supplementary analysis which included this
restriction we were able to show, as might be expected, that the
earlier the child achieved sitting the more likely they were to
achieve walking (Supplementary Table 3). Regarding ASMs we
cannot account for clinician variability in prescribing practices.
Finally, while CDD is a rare disorder with considerable genetic
heterogeneity, and, although our sample size is one of the largest
available, the accuracy and precision of estimates involving
specic combinations of factors could still be compromised.
The factors that we investigated were (1) those determined at
birth i.e., gender, genotype group and presence of mosaicism,
(2) those that occurred subsequently relating to epilepsy i.e., age
of onset, number of ASMs and presence of a honeymoon period
and (3) nally the presence of therapy intervention in the rst
year of life. It had previously been reported that males were
considerably more impaired than females [11,12]. We have now
shown for the rst time, but as might be expected, [22]thatthe
presence of mosaicism, affecting seven (12%) of the 58 males,
benecially altered their developmental trajectory such that the
overall likelihood of walking by age six years was not dissimilar
in males and females. We could postulate that gene replacement
therapy might also alter the phenotype by improving motor
skills through a similar mechanism to mosaicism [23]. With
respect to genotype our ndings in relation to late truncating
variants after aa781 mirrored those found previously using a
much smaller sample [12]. However, in this study we also
included the impact of early factors relating to epilepsy. For
instance, if a female child aged 12 months with a late truncating
varianthadnotlearnedtositbytheageof12monthsthe
likelihood that she would achieve sitting would increase from
47.7% at 1.5 years to 89.6% by the age of ve years if their
seizures started later, they had used fewer ASMs, and they had
experienced a honeymoon period. We acknowledge that most
of these factors are not modiable and we do not know whether
the honeymoon period is an inherent component of the natural
history of this disorder or whether it relates to a specic
management regime. We also know that the ASM regime may
be a consequence of the epilepsy severity and may or may not
be related to clinician prescribing habit.
In terms of physical therapies, the majority of children did
receive therapy in the rst year of life making it more difcult to
use this as a discriminating factor. We can certainly postulate that
in general early therapy has the potential to achieve more
because of greater neuroplasticity [24]. However, in CDD therapy
sessions may often be interrupted by episodes of epilepsy which if
protracted can also result in regression of skills [17]. Moreover, we
had limited detail on the quality and intensity of the intervention
which could have considerable relevance. The data has been
collected over a period of nine years with the oldest individuals
being born two to three decades ago. Availability of intervention
may have improved over time, but we do not know what the
impact of an early conrmed CDD diagnosis is on the likelihood of
institution of therapy.
In conclusion this paper is but a rst attempt to understand
the factors underlying the variability of motor development in
CDD and to assist clinicians in providing prognostic guidance
to their patientsfamilies. In the future aggregation of unique
data from multiple settings could potentially further increase
sample size and the range of variables that could be
investigated. Most importantly it could provide the opportu-
nity to increase the numbers of those with individual recurrent
variants and thereby further clarify the role of genetic and
environmental factors in attainment of motor milestones in this
ultra-rare disorder.
DATA AVAILABILITY
The dataset analysed during the current study is not publicly available but may be
available from the corresponding author on reasonable request following an
application to and with approval from the local ethics committee.
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ACKNOWLEDGEMENTS
We would like to express our thanks and appreciation to all the families who have
participated in the International CDKL5 disorder Database and to the International
Foundation for CDKL5 Research for ongoing support.
AUTHOR CONTRIBUTIONS
HL, MJ and KW generated the outline of the manuscript and HL, KW and MJ wrote the
rst draft. KW and MJ prepared the tables. HL, MJ, KW, JD, SD, TB, EM and JS revised
the manuscript and approved the nal version.
FUNDING
We would like to acknowledge funding from the Orphan Disease Centre, University of
Pennsylvania (CDKL519-D-101-3), the International Foundation for CDKL5 Research
and the Australian National Health & Medical Research Council (NHMRC Senior
Research Fellowship (#1117105) to HL). Open Access funding enabled and organized
by CAUL and its Member Institutions.
COMPETING INTERESTS
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 Childrens
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 Scientic 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
Scientic Advisory Board Member for International Rett Syndrome Foundation and
Lennox Gastaut Foundation. The remaining authors have no competing interests.
ETHICS APPROVAL
The Human Research Ethics Committee, University of Western Australia provided
approval for this study.
ADDITIONAL INFORMATION
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41431-022-01163-1.
Correspondence and requests for materials should be addressed to Helen Leonard.
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European Journal of Human Genetics
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Article
Full-text available
Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children's hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9-57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26-14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93-12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24-9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07-7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.
Article
Objective The study investigated the effect of seizure and medication burden at initial contact with the International CDKL5 Disorder Database on subsequent development and clinical severity and compared quality of life among those whose development progressed, remained stable, or regressed between baseline and follow-up. Methods The effects of seizure and medication burden at baseline (high or low) on the CDKL5 Disorder Severity Scores and CDKL5 Developmental Score (CDS) at follow-up were assessed using linear and negative binomial regressions, respectively, with adjustment for age at baseline, gender, and follow-up duration with and without genotype. Seizure and medication burden were defined by average daily seizure count (high, ≥5/day; low, <5/day) and number of antiseizure medications (high, ≥3/day; low, <3/day), respectively. The effects of change in CDS over time (improved, stable, or deteriorated) on Quality of Life Inventory–Disability (QI-Disability) total and domain scores at follow-up were assessed in those aged at least 3 years at follow-up using linear regression models with adjustment for baseline CDS, gender, and follow-up duration. Results The expected follow-up CDS was lower for individuals with high compared to low seizure burden at baseline (β = −.49, 95% confidence interval [CI] = −.84 to −.13). The average total QI-Disability score was 5.6 (95% CI = −.2 to 11.5) points higher among those with improved compared with stable or deteriorating CDS and 8.5 (95% CI = 3.1–13.8) points lower for those with deteriorating compared to stable or improved CDS. Significance Our finding that later development showed slight improvement in those with better earlier seizure control even after adjustment for genotype suggests that the trajectory for an individual child is not necessarily predetermined and could possibly be influenced by optimal seizure management. This has implications for children's quality of life.
Article
Aim To characterize the neuro-ophthalmological phenotype of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) and assess visual acuity as a reproducible, quantitative outcome measure. Method We retrospectively analyzed clinical data from patients with CDD. Complete neuro-ophthalmological assessments, including visual acuity, were evaluated. Results Of 26 patients (22 females, four males; median age 4y, interquartile range 2y 1mo–7y 10mo), cerebral visual impairment (CVI), defined as visual dysfunction in the absence of ocular or anterior visual pathway abnormalities, was diagnosed in all those over 2 years of age. Ophthalmological examinations revealed nystagmus in 10 patients and strabismus in 24 patients. Visual acuity was measured in 24 patients, by preferential looking in all and by sweep visual evoked potential in 13. Visual acuities were lower than age expectations and demonstrated improvement in the first 3 years. Adjusting for age and sex, average preferential looking visual acuity after 2 years of age was higher in patients with intact mobility than in those who were non-mobile. Interpretation CVI was observed in patients with CDD. Visual acuity improved over time and correlated with mobility. Visual acuity, as a quantifiable measure of visual function, should be considered as an outcome measure in pre-clinical and clinical studies for CDD.
Article
Background CDKL5 Deficiency Disorder (CDD) is a rare genetic disorder caused by a mutation in the cyclin-dependent kinase-like 5 (CDKL5) gene. It is now considered to be a developmental and epileptic encephalopathy because of the early onset of seizures in association with severe global delay. Other features include cortical visual impairment, sleep and gastro-intestinal problems. Progress in clinical understanding, especially regarding the spectrum of functional ability, seizure patterns, and other comorbidities was initially slow but accelerated in 2012 with the establishment of the International CDKL5 Database (ICDD). Our aim was to use this data source to investigate quality of life (QOL) and associated factors in this disorder. Method A follow-up questionnaire was administered in 2018 to parents of children registered with the ICDD who had a pathogenic CDKL5 variant. QOL was assessed using QI Disability, an instrument, specifically developed to measure total and specific domains of QOL (physical health, positive emotions, negative emotions, social interaction, leisure and the outdoors (leisure) and independence) in children with intellectual disability. Associations with functional abilities, physical health, mental health and family factors were investigated, initially using univariate analyses followed by multivariate analyses for each of these groups with a final composite model which included the important variables identified from previous models. Results Questionnaires were returned by 129/160 families with a child aged >3 years. Functional impairment, including lack of ability to sit, use hands and communicate had the greatest adverse impact on QOL. There were also some relationships with major genotype groupings. Individuals using three or more anti-epileptic medications had poorer QOL than those on one or no medication, particularly in the physical health domain. There was also variation by geographical region with those living in North America typically having the best QOL and those living in middle or lower income countries poorer QOL. Conclusion Although lower functional abilities were associated with poorer quality of life further research is needed to understand how environmental supports might mitigate this deficit. Comprehensive care and support for both the child and family have important roles to play in helping families to thrive despite the severity of CDD.
Article
Characterized by early-onset seizures, global developmental delay and severe motor deficits, CDKL5 deficiency disorder is caused by pathogenic variants in the cyclin-dependent kinase-like 5 gene. Previous efforts to investigate genotype-phenotype relationships have been limited due to small numbers of recurrent mutations and small cohort sizes. Using data from the International CDKL5 Disorder Database we examined genotype-phenotype relationships for 13 recurrent CDKL5 variants and the previously analyzed historic variant groupings. We have applied the CDKL5 Developmental Score (CDS) and an adapted version of the CDKL5 Clinical Severity Assessment (CCSA), to grade the severity of phenotype and developmental outcomes for 285 individuals with CDKL5 variants. Comparisons of adapted CCSA and CDS between recurrent variants and variant groups were performed using multiple linear regression adjusting for age and sex. Individuals with the mis- sense variant, p.Arg178Trp, had the highest mean adapted CCSA and lowest mean developmental scores. Other variants producing severe phenotypes included p.Arg559* and p.Arg178Gln. Variants producing milder phenotypes included p.Arg134*, p.Arg550*, and p.Glu55Argfs*20. There are observed differences in phenotype severity and developmental outcomes for individuals with different CDKL5 variants. However, the historic variant groupings did not seem to reflect differences in phenotype severity or developmental outcomes as clearly as analyzed by individual variants.
Article
Objective Rett Syndrome, CDKL5 ‐Deficiency Disorder, FOXG1 Disorder, and MECP2 Duplication Disorder are Developmental Encephalopathies with shared and distinct features. Though historically linked, no direct comparison has been performed. The first head‐to‐head comparison of clinical features in these conditions is presented. Methods Comprehensive clinical information was collected from 793 individuals enrolled in the Rett Syndrome and Related Disorders Natural History Study. Clinical features including clinical severity, regression, and seizures were cross‐sectionally compared between diagnoses to test the hypothesis that these are 4 distinct disorders. Results Distinct patterns of clinical severity, seizure onset age, and regression were present. Individuals with CDKL5 ‐Deficency Disorder were the most severely affected and had the youngest age of seizure onset (2 months) whereas children with MECP2 ‐duplication syndrome had the oldest median age of seizure onset (64 months) and lowest severity scores. Rett syndrome and FOGX1 were intermediate in both features. Smaller head circumference correlates with increased severity in all disorders and earlier age of seizure onset in MECP2‐duplication syndrome. Developmental regression occurred in all Rett syndrome participants (median 18 months) but only 23–34% of the other disorders. Seizure incidence prior to the baseline visit was highest for CDKL5 ‐Deficency Disorder (96.2%) and lowest for Rett syndrome (47.5%). Other clinical features including seizure types and frequency differed amongst groups. Interpretation While these Developmental Encephalopathies share many clinical features, clear differences in severity, regression, and seizures warrant considering them as unique disorders. These results will aid in the development of disease specific severity scales, precise therapeutics, and future clinical trials. This article is protected by copyright. All rights reserved.
Article
This scientific commentary refers to ‘Gene replacement ameliorates deficits in mouse and human models of cyclin-dependent kinase-like 5 disorder’, by Gao etal. (doi:10.1093/brain/awaa028).
Article
Background: The advent of Next Generation Sequencing (NGS) has led to a redefining of the genetic landscape of the epilepsies. Hundreds of single gene epilepsies have been described. Genes associated with epilepsy involve diverse processes. Now a substantial proportion of individuals with epilepsy can receive a high definition molecular genetic diagnosis. Methods: In this review we update the current genetic landscape of the epilepsies and categorise the major functional groupings of epilepsy-associated genes. We describe currently available genetic testing approaches. We perform a literature review of NGS studies and review the factors which determine yield in cohorts undergoing testing. We identify factors associated with positive genetic diagnosis and consider the utility of genetic testing in terms of treatment selection as well as more qualitative aspects of care. Findings: Epilepsy-associated genes can be grouped into five broad functional categories: ion transport; cell growth and differentiation; regulation of synaptic processes; transport and metabolism of small molecules within and between cells; and regulation of gene transcription and translation. Early onset of seizures, drug-resistance, and developmental comorbidity are associated with higher diagnostic yield. The most commonly implicated genes in NGS studies to date, in order, are SCN1A, KCNQ2, CDKL5, SCN2A, and STXBP1. In unselected infantile cohorts PRRT2, a gene associated with self-limited epilepsy, is frequently implicated. Genetic diagnosis provides utility in terms of treatment choice closing the diagnostic odyssey, avoiding unnecessary further testing, and informing future reproductive decisions. Conclusions: Genetic testing has become a first line test in epilepsy. As techniques improve and understanding advances, its utility is set to increase. Genetic diagnosis, particularly in early onset developmental and epileptic encephalopathies, influences treatment choice in a significant proportion of patients. The realistic prospect of gene therapy is a cause for optimism.
Article
Objective: To describe the long-term neurodevelopmental and cognitive outcomes for children born preterm. Study design: In this retrospective cohort study, information on children born in Western Australia between 1983 and 2010 was obtained through linkage to population databases on births, deaths, and disabilities. For the purpose of this study, disability was defined as a diagnosis of intellectual disability, autism, or cerebral palsy. The Kaplan-Meier method was used to estimate the probability of disability-free survival up to age 25 years by gestational age. The effect of covariates and predicted survival was examined using parametric survival models. Results: Of the 720 901 recorded live births, 12 083 children were diagnosed with disability, and 5662 died without any disability diagnosis. The estimated probability of disability-free survival to 25 years was 4.1% for those born at gestational age 22 weeks, 19.7% for those born at 23 weeks, 42.4% for those born at 24 weeks, 53.0% for those born at 25 weeks, 78.3% for those born at 28 weeks, and 97.2% for those born full term (39-41 weeks). There was substantial disparity in the predicted probability of disability-free survival for children born at all gestational ages by birth profile, with 5-year estimates of 4.9% and 10.4% among Aboriginal and Caucasian populations, respectively, born at 24-27 weeks and considered at high risk (based on low Apgar score, male sex, low sociodemographic status, and remote region of residence) and 91.2% and 93.3%, respectively, for those at low risk (ie, high Apgar score, female sex, high sociodemographic status, residence in a major city). Conclusions: Apgar score, birth weight, sex, socioeconomic status, and maternal ethnicity, in addition to gestational age, have pronounced impacts on disability-free survival.
Article
Objective: The cyclin-dependent kinase like 5 (CDKL5) gene is a known cause of early onset developmental and epileptic encephalopathy, also known as CDKL5 deficiency disorder (CDD). We sought to (1) provide a description of seizure types in patients with CDD, (2) provide an assessment of the frequency of seizure-free periods and cortical visual impairment (CVI), (3) correlate these features with genotype and gender, and (4) correlate these features with developmental milestones. Methods: This is a cohort study of patients with CDD. Phenotypic features were explored and correlated with gene variant grouping and gender. A developmental score was created based on achieving seven primary milestones. Phenotypic variables were correlated with the developmental score to explore markers of better developmental outcomes. Multivariate linear regression was used to account for age at last visit. Results: Ninety-two patients with CDD were seen during the enrollment period. Eighteen were male (19%); median age at last visit was 5 years (interquartile range = 2.0-11.0). Eighty-one percent of patients developed epileptic spasms, but only 47% of those also had hypsarrhythmia. Previously described hypermotor-tonic-spasms sequence was seen in only 24% of patients, but 56% of patients had seizures with multiple phases (often tonic and spasms). Forty-three percent of patients experienced a seizure-free period ranging from 1 to >12 months, but only 6% were still seizure-free at the last visit. CVI was present in 75% of all CDD patients. None of these features was associated with genotype group or gender. CVI was correlated with reduced milestone achievement after adjusting for age at last visit and a history of hypsarrhythmia. Significance: The most common seizure types in CDD are epileptic spasms (often without hypsarrhythmia) and tonic seizures that may cluster together. CVI is a common feature in CDD and is correlated with achieving fewer milestones.