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1.
Am J Med Genet A ; 194(7): e63570, 2024 07.
Article in English | MEDLINE | ID: mdl-38425131

ABSTRACT

CDKL5 deficiency disorder (CDD) is a genetically caused developmental epileptic encephalopathy that causes severe communication impairments. Communication of individuals with CDD is not well understood in the literature and currently available measures are not well validated in this population. Accurate and sensitive measurement of the communication of individuals with CDD is important for understanding this condition, clinical practice, and upcoming interventional trials. The aim of this descriptive qualitative study was to understand how individuals with CDD communicate, as observed by caregivers. Participants were identified through the International CDKL5 Disorder Database and invited to take part if their child had a pathogenic variant of the CDKL5 gene and they had previously completed the Communication and Symbolic Behavior Checklist (CSBS-DP ITC). The sample comprised caregivers of 23 individuals with CDD, whose ages ranged from 2 to 30 years (median 13 years), 15 were female, and most did not use words. Semistructured interviews were conducted via videoconference and analyzed using a conventional content analysis. Three overarching categories were identified: mode, purpose and meaning, and reciprocal exchanges. These categories described the purposes and mechanism of how some individuals with CDD communicate, including underpinning influential factors. Novel categories included expressing a range of emotions, and reciprocal exchanges (two-way interactions that varied in complexity). Caregivers observed many communication modes for multiple purposes. Understanding how individuals with CDD communicate improves understanding of the condition and will guide research to develop accurate measurement for clinical practice and upcoming medication trials.


Subject(s)
Caregivers , Communication , Epileptic Syndromes , Protein Serine-Threonine Kinases , Spasms, Infantile , Humans , Caregivers/psychology , Female , Male , Child , Epileptic Syndromes/genetics , Adolescent , Adult , Child, Preschool , Spasms, Infantile/genetics , Spasms, Infantile/physiopathology , Spasms, Infantile/diagnosis , Protein Serine-Threonine Kinases/genetics , Young Adult , Qualitative Research
2.
Am J Med Genet A ; : e63843, 2024 Aug 28.
Article in English | MEDLINE | ID: mdl-39205479

ABSTRACT

Pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene are associated with CDKL5 deficiency disorder (CDD), a severe X-linked developmental and epileptic encephalopathy. Deletions affecting the 5' untranslated region (UTR) of CDKL5, which involve the noncoding exon 1 and/or alternatively spliced first exons (exons 1a-e), are uncommonly reported. We describe genetic and phenotypic characteristics for 15 individuals with CDKL5 partial gene deletions affecting the 5' UTR. All individuals presented characteristic features of CDD, including medically refractory infantile-onset epilepsy, global developmental delay, and visual impairment. We performed RNA sequencing on fibroblast samples from three individuals with small deletions involving exons 1 and/or 1a/1b only. Results demonstrated reduced CDKL5 mRNA expression with no evidence of expression from alternatively spliced first exons. Our study broadens the genotypic spectrum for CDD by adding to existing evidence that deletions affecting the 5' UTR of the CDKL5 gene are associated with the disorder. We propose that smaller 5' UTR deletions may require additional molecular testing approaches such as RNA sequencing to determine pathogenicity.

3.
Epilepsia ; 2024 Aug 27.
Article in English | MEDLINE | ID: mdl-39190322

ABSTRACT

OBJECTIVE: The CDKL5 Clinical Severity Assessment (CCSA) is a comprehensive, content-validated measurement tool capturing the diverse challenges of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD), a genetically caused developmental epileptic encephalopathy (DEE). The CCSA is divided into clinician-reported (CCSA-Clinician) and caregiver-reported (CCSA-Caregiver) assessments. The aim of this study was to evaluate the factor structure of these measures through confirmatory factor analysis (CFA) and evaluate their validity and reliability. METHODS: Participants were recruited from the International CDKL5 Clinical Research Network to take part in an in-clinic CCSA-Clinician evaluation (n = 148) and/or complete the CCSA-Caregiver questionnaire (n = 198). CFA was used to determine domains, and factor loadings and validity were assessed. For the CCSA-Clinician, inter-rater reliability was assessed by nine CDD experienced clinicians via 14 pre-recorded evaluations. Eight clinicians re-viewed and re-scored the videos after 4 weeks to evaluate intra-rater reliability. The CCSA-Caregiver was completed on a second occasion by 34 caregivers after 2-4 weeks to assess test-retest reliability. RESULTS: CFA resulted in three domains for the CCSA-Clinician (motor and movement, communication, vision) and four domains for the CCSA-Caregiver (seizures, behavior, alertness, feeding), with good item loadings across both measures. Structural statistics, internal consistency, discriminant validity, and reliability were satisfactory for both measures, and scores were consistent between known groups. SIGNIFICANCE: This study provides strong evidence that the CCSA measures are suitable to assess the clinical severity of individuals with CDD, supporting their use in clinical trials. Further evaluation of responsiveness to change in a longitudinal assessment is planned. Use may also be appropriate in similar DEEs but would require validation in those populations.

4.
Dev Med Child Neurol ; 66(4): 469-482, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37804112

ABSTRACT

AIM: To compare growth in individuals with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder with population norms and to investigate the effect of gastrostomy on growth. METHOD: The longitudinal study included 353 individuals from the International CDKL5 Disorder Database with any anthropometric measurement in baseline and/or follow-up questionnaires. The British 1990 growth reference was used to determine the age- and sex-standardized z-score. Repeated cross-sectional data were fitted using a Gaussian linear regression model with generalized estimating equations. RESULTS: All growth parameters were below the general population norm (mean z-scores: weight -0.97, height -0.65, body mass index [BMI] -0.81, head circumference -2.12). The disparity was particularly pronounced for all anthropometric measurements after 4 years of age except for BMI. Moreover, individuals with gastrostomy placement were shown to have a larger decrease than those without. INTERPRETATION: In addition to weight, height, and BMI, head circumference was also compromised in this disorder. Microcephaly could be considered a helpful diagnostic feature, especially in adults. Any benefit of gastrostomy on weight and BMI was mainly seen in the early years.


Subject(s)
Body Height , Epileptic Syndromes , Protein Serine-Threonine Kinases , Spasms, Infantile , Adult , Humans , Body Weight , Longitudinal Studies , Cross-Sectional Studies , Body Mass Index , Protein Serine-Threonine Kinases/genetics
5.
J Med Genet ; 60(10): 951-959, 2023 10.
Article in English | MEDLINE | ID: mdl-37055168

ABSTRACT

BACKGROUND: Rett syndrome is a genetically caused neurodevelopmental disorder associated with severe impairments and complex comorbidities. This study examined predictors of anxiety and depression in Rett syndrome, including genotype. METHODS: The International Rett Syndrome Database, InterRett, was the data source for this observational study. Associations between genotype, functional abilities, comorbidities, anxiety and depression were estimated with univariate and multivariate regression models. An additional regression model for anxiety included use of an anxiety medication as a predictor variable. RESULTS: The sample included 210 individuals aged 6-51 years of whom 54 (25.7%) were on psychotropic medication for anxiety or depression. Individuals with the p.Arg294* variant had the highest anxiety scores, as did those with insomnia or excessive daytime sleepiness, irrespective of anxiety medication use. Individuals with the p.Arg306Cys variant had the lowest depression scores, as did those with insomnia or excessive daytime sleepiness. CONCLUSION: Findings indicated that genotype and sleep have implications for mental health in Rett syndrome, suggesting that anticipatory guidance and proactive management of poor sleep could improve mental health. More research is needed to understand the effects of psychometric medications, which cannot be inferred from this cross-sectional study.


Subject(s)
Disorders of Excessive Somnolence , Rett Syndrome , Sleep Initiation and Maintenance Disorders , Humans , Rett Syndrome/complications , Rett Syndrome/epidemiology , Rett Syndrome/genetics , Mental Health , Cross-Sectional Studies , Sleep , Disorders of Excessive Somnolence/psychology , Genotype
6.
Article in English | MEDLINE | ID: mdl-39141588

ABSTRACT

BACKGROUND: Communication impairments are a leading concern for parent caregivers of individuals with rare neurodevelopmental disorders (RNDDs). Clinical trials of disease modifying therapies require valid and responsive outcome measures that are relevant to individuals with RNDDs. Identifying and evaluating current psychometric properties for communication measures is a critical step towards the selection and use of appropriate instruments. AIMS: This systematic review offers (1) a description of parent-reported communication measures and (2) evidence for their psychometric properties, in RNDDs. METHODS: The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022334649). MEDLINE (Ovid), Embase, PsychINFO, Web of Science, CINAHL Plus, Cochrane Library, ClinicalTrials.gov, the Australian New Zealand Clinical Trials Registry were searched from inception to August 2023. Methodological assessment of quality was completed using the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) checklist. Parent-reported measures used in observational studies and clinical trials were identified. Data on utility, reliability and validity for RNDDs were extracted. MAIN CONTRIBUTION: Sixteen parent-reported communication measures were used in RNDD research, the Vineland Adaptive Behavior Scales being most commonly used. Validation data in RNDDs were identified for six of these measures. Limitations related to sample size or the scope of psychometric testing. CONCLUSIONS: Many communication measures have been used for RNDDs but there are few data validating their use. Valid and reliable methods of measuring communication in persons with RNDDs is a priority for future high-quality clinical trials. WHAT THIS PAPER ADDS: What is already known on the subject Communication is a critical domain for families with a child with a rare neurodevelopmental disorder (RNDD). Validated outcome measures are essential for accurate evaluation and interpretation of responses to treatments in clinical trials. What this paper adds to existing knowledge We identified 16 parent-reported communication measures that have been used with RNDDs, but only six measures had validation data for at least one RNDD. High quality evidence is accumulating, with all validation studies in this review published between 2020 to 2023. Modifications of existing measures may be required to assess communication for RNDDs. What are the clinical implications of this work? This systematic review catalogues the available psychometric data for communication measures and indicates an ongoing need for new validation studies to ensure they are fit-for-purpose for upcoming clinical trials in RNDDs. This review will inform the selection of communication measures for clinical trials and research studies.

7.
J Pediatr ; 259: 113418, 2023 08.
Article in English | MEDLINE | ID: mdl-37030611

ABSTRACT

OBJECTIVE: To describe trends, age-specific patterns, and factors influencing hospitalizations for 5 rare craniofacial anomalies (CFAs). METHODS: Data on livebirths (1983-2010; n = 721 019) including rare CFA (craniofacial microsomia, mandibulofacial dysostosis, Pierre Robin sequence, Van der Woude syndrome, and frontonasal dysplasia), episodes of death, and demographic and perinatal factors were identified from the Western Australian Register of Developmental Anomalies, Death Registrations and Midwives Notification System. Information on incident craniofacial and noncraniofacial related admissions, length of hospital stay, and intensive care and emergency-related admissions were identified using principal diagnosis and procedural codes were extracted from the Hospital Morbidity Data Collection and linked to other data sources. Associations of hospitalizations by age groups as well as demographic and perinatal factors were expressed as incidence rate ratio (IRR). RESULTS: The incident hospitalizations were 3 times as high for rare CFA (IRR 3.22-3.72) throughout childhood into adolescence than those without. Children with rare CFA had 3-4 times as many potentially preventable hospitalizations until 18 years of age than those without. Specifically, respiratory infections (IRR 2.13-2.35), ear infections (IRR 7.92-26.28), and oral health-related conditions contributed for most noncraniofacial admissions until the adolescence period. A greater incidence of noncraniofacial related hospitalizations was observed among Indigenous children, births with intrauterine growth restrictions, and families with high socioeconomic disadvantage. CONCLUSIONS: Throughout childhood, individuals with rare CFA had greater hospital service use, specifically for potentially preventable conditions, than those without. These population-level findings can inform new preventive strategies and early disease management targeted toward reducing preventable hospitalizations.


Subject(s)
Cleft Palate , Hospitalization , Child , Pregnancy , Female , Adolescent , Humans , Western Australia/epidemiology , Australia/epidemiology , Length of Stay
8.
Epilepsy Behav ; 139: 109069, 2023 02.
Article in English | MEDLINE | ID: mdl-36634535

ABSTRACT

CDKL5 Deficiency Disorder (CDD) is a rare genetic disorder with symptoms of epilepsy, developmental impairments, and other comorbidities. Currently, there are no outcome measures for CDD with comprehensive evidence of validation. This study aimed to evaluate the psychometric properties of the Quality of Life Inventory-Disability (QI-Disability) in CDD. Quality of Life Inventory-Disability was administered to 152 parent caregivers registered with the International CDKL5 Disorder Database (ICDD). Confirmatory factor analysis was conducted and the goodness of fit of the factor structure was assessed. Fixed-effects linear regression models examined the responsiveness of QI-Disability to reported changes in child health. A subset of parent caregivers (n = 56) completed QI-Disability, as well as additional health-related questions, on two occasions separated by four weeks to evaluate test-retest reliability. Test-retest reliability was assessed using intra-class correlations (ICCs) calculated from QI-Disability scores. Based upon adjustments for changes in child health, ICCs were recalculated to estimate responsiveness to change. Confirmatory factor analysis, internal consistency, and divergent validity were mostly satisfactory, except divergent validity was not satisfactory for the Social Interactions and Independence domains. The Physical Health, Social Interactions, Leisure, and Total scores responded to changes in the child's Physical health, and the Negative Emotions and Leisure domains responded to changes in the child's behavior. Unadjusted and adjusted ICC values were above 0.8 for the Positive Emotions, Negative Emotions, Social Interactions, Leisure, Independence domains and Total score, and above 0.6 for the Physical Health domain. Findings suggest that QI-Disability is suitable to assess the quality of life of children and adults with CDD and could be of value for upcoming clinical trials.


Subject(s)
Quality of Life , Spasms, Infantile , Adult , Child , Humans , Quality of Life/psychology , Psychometrics , Reproducibility of Results , Spasms, Infantile/genetics , Surveys and Questionnaires , Protein Serine-Threonine Kinases/genetics
9.
Dev Med Child Neurol ; 65(4): 489-497, 2023 04.
Article in English | MEDLINE | ID: mdl-36284370

ABSTRACT

AIM: To evaluate the effects of a physical activity programme on sedentary behaviour and physical activity in ambulant individuals with Rett syndrome (RTT). METHOD: In this multicentre randomized waitlist-controlled trial, we recruited 43 ambulatory individuals with RTT in Australia and Denmark. Adequate baseline data were obtained from 38 participants (mean age 20 years, range 6-41, SD 10 years 6 months, one male). All completed the trial. Participants received 12 weeks of usual care (n = 19) or a goal-based, telehealth-supported programme in which activities occurred in their familiar environments (n = 19). Sedentary time and daily steps were assessed at baseline, post-test, and 12-week follow-up. The data analyst was blinded to group allocation. RESULTS: Sedentary time decreased in the intervention group by 2.7% (95% confidence interval [CI] -6.0 to 0.6) and increased in the control group by 1.3% (95% CI -4.8 to 7.4). Intervention and control groups increased the number of their steps per day by 264.7 (95% CI -72.2 to 601.5) and 104.8 (95% CI -178.1 to 387.7) respectively. No significant differences were found on any outcomes at post-test. There were three minor adverse events. INTERPRETATION: A goal-based telehealth intervention seemed to produce small improvements in physical activity for individuals with RTT. Families require more support to increase these individuals' extremely low physical activity levels. WHAT THIS PAPER ADDS: A telehealth-supported intervention may produce small changes in physical activity in Rett syndrome (RTT). Increasing physical activity in individuals with RTT is challenging for caregivers. Families require substantial out-of-home support to increase their children's activity levels.


Subject(s)
Rett Syndrome , Telemedicine , Child , Humans , Male , Infant , Child, Preschool , Exercise , Sedentary Behavior , Health Promotion , Quality of Life
10.
Eur J Pediatr ; 182(5): 2379-2392, 2023 May.
Article in English | MEDLINE | ID: mdl-36899143

ABSTRACT

Understanding hospital service use among children with a diagnosis of craniosynostosis (CS) is important to improve services and outcomes. This study aimed to describe population-level trends, patterns, and factors influencing hospitalizations for craniosynostosis in Western Australia. Data on live births (1990-2010; n = 554,624) including craniosynostosis, episodes of death, demographic, and perinatal factors were identified from the midwives, birth defects, hospitalizations, and death datasets. Information on craniosynostosis and non-craniosynostosis-related admissions, cumulative length of hospital stay (cLoS), intensive care unit, and emergency department-related admissions were extracted from the hospitalization dataset and linked to other data sources. These associations were examined using negative binomial regression presented as annual percent change and associations of hospitalizations by age groups, demographic, and perinatal factors were expressed as incidence rate ratio (IRR). We found an increasing trend in incident hospitalizations but a marginal decline in cLoS for craniosynostosis over the observed study period. Perinatal conditions, feeding difficulties, nervous system anomalies, respiratory, and other infections contributed to majority of infant non-CS-related admissions.Respiratory infections accounted for about twice the number of admissions for individuals with CS (IRRs 1.94-2.34) across all observed age groups. Higher incidence of non-CS hospitalizations was observed among females, with associated anomalies, to families with highest socioeconomic disadvantage and living in remote areas of the state.   Conclusion: Marginal reduction in the cLoS for CS-related admissions observed over the 21-year period are potentially indicative of improved peri-operative care. However, higher incidence of respiratory infection-related admissions for syndromic synostosis is concerning and requires investigation.


Subject(s)
Hospitalization , Respiratory Tract Infections , Infant , Child , Pregnancy , Female , Humans , Western Australia/epidemiology , Length of Stay
11.
Oral Dis ; 29(1): 220-231, 2023 Jan.
Article in English | MEDLINE | ID: mdl-34033206

ABSTRACT

OBJECTIVES: To explore patterns of parafunction, and bruxism, and its relationships with genotype and snoring in individuals with Rett syndrome (RTT). METHODS: Retrospective observational data of those with confirmed MECP2 mutations in the InterRett database (n = 216) were used to investigate experience of parafunctional habits, and bruxism and their relationships with genotype and snoring using multivariable linear regression. RESULTS: The prevalence of parafunction was 98.2%. Bruxism was reported (66.2%) with the patterns mostly both diurnal and nocturnal (44.1%) and exclusively diurnal (42.7%). Compared to individuals with C-terminal deletion, individuals with p.Arg106Trp mutations were less likely to have bruxism reported (aOR = 0.15; 95% CI 0.02-0.98, p = 0.05) and those with p.Arg168* mutation were more likely to have frequent bruxism than none or occasional bruxism reported (aROR 3.4; 95% CI 1.1-10.7 p = 0.04). The relative odds of having nocturnal bruxism constantly, compared to none/occasionally, were higher among those 'always' snoring (aROR 6.24; 95% CI 2.1-18.2, p = 0.001) than those with no snoring. CONCLUSIONS: There appeared to be genotypic association with bruxism in p.Arg168* and p.Arg106Trp mutations and association between nocturnal bruxism and frequent snoring in an international sample of individuals with RTT. Clinical significance of the high prevalence of bruxism should be highlighted in relation to difficulty communicating pain and increased dental treatment need in RTT.


Subject(s)
Rett Syndrome , Sleep Bruxism , Humans , Rett Syndrome/complications , Rett Syndrome/genetics , Sleep Bruxism/complications , Sleep Bruxism/genetics , Retrospective Studies , Genotype , Mutation
12.
BMC Pediatr ; 23(1): 106, 2023 03 04.
Article in English | MEDLINE | ID: mdl-36870968

ABSTRACT

BACKGROUND: Children with congenital heart defects (CHDs) are at higher risk of developing an intellectual disability. However, severity of intellectual disabilities among this group of children are largely unknown. Our objective was to determine the risk of intellectual disability (ID), ID severity, and autism among children with CHDs. METHODS: We conducted a retrospective cohort study of singleton live births in Western Australia (n = 20,592) between 1983 and 2010. Children with CHDs were identified from the Western Australian Register for Developmental Anomalies (n = 6563) and infants without CHDs were randomly selected from state birth records (n = 14,029). Children diagnosed with ID before 18 years were identified by linkage to statewide Intellectual Disability Exploring Answers database. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from logistic regression models for all CHDs combined and by CHD severity adjusting for potential confounders. RESULTS: Of 20,592 children, 466 (7.1%) with CHDs and 187 (1.3%) without CHDs had an ID. Compared to children without CHDs, children with any CHD had 5.26 times (95% CI 4.42, 6.26) the odds of having an ID and 4.76 times (95% CI 3.98, 5.70) the odds of having mild/moderate ID. Children with any CHD had 1.76 times the odds of having autism (95% CI 1.07, 2.88), and 3.27 times the odds of having an unknown cause of ID (95% CI 2.65, 4.05) compared to children without CHD. The risk of having autism (aOR 3.23, 95% CI 1.11, 9.38), and unknown cause of ID (aOR 3.45, 95% CI 2.09, 5.70) was greatest for children with mild CHD. CONCLUSIONS: Children with CHDs were more likely to have an ID or autism. Future research should elucidate underlying etiology of ID in children with CHDs.


Subject(s)
Autistic Disorder , Heart Defects, Congenital , Intellectual Disability , Infant , Humans , Child , Western Australia , Australia , Retrospective Studies
13.
Cleft Palate Craniofac J ; 60(5): 569-576, 2023 05.
Article in English | MEDLINE | ID: mdl-35130078

ABSTRACT

To describe trends, age, and sex-specific patterns of population hospital admissions with a diagnosis of craniosynostosis (CS) in Australia.Population data for hospital separations (in-patient) from public and private hospitals (July 1996-June 2018) were obtained from the publicly available Australian Institute of Health and Welfare (AIHW) National Hospital Morbidity Database.The outcome variables were hospital separation rates (HSR) (number of hospital separations divided by the estimated resident population [ERP] per year) and average length of stay (aLOS) (patient days divided by the number of hospital separations) with a diagnosis of CS. Trends in HSR and aLOS adjusted for age, sex, and type of CS were investigated by negative binomial regression presented as annual percent change (APC).In 8057 admissions identified, we observed no significant change in the annual trend for HSR for the 22-year period. However, a marginal annual decrease of 1.6% (95% CI: -0.7, -2.4) in the aLOS was identified for the same time period. HSR were higher for males, infants, and single suture synostosis. aLOS was 3.8 days (95% CI: 3.8, 3.9) per visit, longer for syndromic conditions.There was a minor reduction in the average length of hospital stay for CS over the 22-year period potentially indicative of improved care. Population-level information on hospitalisations for rare craniofacial conditions can inform research, clinical, and surgical practice.


Subject(s)
Craniosynostoses , Hospitalization , Infant , Male , Female , Humans , Australia/epidemiology , Length of Stay , Hospitals , Craniosynostoses/epidemiology
14.
J Pediatr ; 241: 162-172.e9, 2022 02.
Article in English | MEDLINE | ID: mdl-34626670

ABSTRACT

OBJECTIVE: To describe birth prevalence of rare craniofacial anomalies and associations with antenatal and perinatal factors. STUDY DESIGN: All live and stillbirths in Western Australia between 1980 and 2010 were identified from the Western Australian Birth Registrations and the Midwives Notification System (also provides information on antenatal and perinatal factors). Rare craniofacial anomalies (craniosynostosis, craniofacial microsomia, and others [Pierre Robin, Van der Woude, and Treacher Collins syndrome]) were ascertained from the Western Australian Register of Developmental Anomalies and linked to other data sources. Trends in prevalence, adjusted for sex and Indigenous status, were investigated by Poisson regression and presented as annual percent change (APC). Strengths of association of related factors were assessed using multivariable log-binomial regression adjusted for sex, Indigenous status, birth year, socioeconomic disadvantage, and remoteness and reported as risk ratios with 95% CIs. RESULTS: There was a temporal increase in prevalence of metopic synostosis (APC 5.59 [2.32-8.96]) and craniofacial microsomia (Goldenhar syndrome) (APC 4.43 [1.94-6.98]). Rare craniofacial anomalies were more likely among infants born preterm, as twins or greater-order multiples, with growth restriction, to older parents, to mothers undertaking fertility treatments, and with pre-existing medical conditions, specifically epilepsy, diabetes, or hypothyroidism. Prenatal identification of rare craniofacial anomalies was uncommon (0.6%). CONCLUSIONS: Our findings indicate a steady increase over time in prevalence of metopic synostosis and craniofacial microsomia (Goldenhar syndrome). Possible associations of fertility treatments and pre-existing maternal medical conditions with rare craniofacial anomalies require further investigation.


Subject(s)
Craniofacial Abnormalities/epidemiology , Craniofacial Abnormalities/etiology , Female , Humans , Infant, Newborn , Information Storage and Retrieval , Male , Prevalence , Regression Analysis , Retrospective Studies , Risk Factors , Western Australia/epidemiology
15.
Epilepsia ; 63(2): 352-363, 2022 02.
Article in English | MEDLINE | ID: mdl-34837650

ABSTRACT

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 (ß = -.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.


Subject(s)
Epileptic Syndromes , Quality of Life , Child , Epileptic Syndromes/genetics , Humans , Protein Serine-Threonine Kinases/genetics , Seizures/drug therapy , Seizures/genetics , Spasms, Infantile
16.
Pediatr Res ; 92(6): 1795-1804, 2022 12.
Article in English | MEDLINE | ID: mdl-35352007

ABSTRACT

BACKGROUND: Accurate knowledge of the relationship between craniofacial anomalies (CFA), intellectual disability (ID) and autism spectrum disorder (ASD) is essential to improve services and outcomes. The aim is to describe the association between CFA, ID and ASD using linked population data. METHODS: All births (1983-2005; n = 566,225) including CFA births (comprising orofacial clefts, craniosynostosis, craniofacial microsomia and mandibulofacial dysostosis) surviving to 5 years were identified from the birth, death, birth defects and midwives population data sets. Linked data from these data sets were followed for a minimum of 5 years from birth until 2010 in the intellectual disability database to identify ID and ASD. These associations were examined using a modified Poisson regression. RESULTS: Prevalence of ID and ASD was higher among CFA (especially with additional anomalies) than those without [prevalence ratio 5.27, 95% CI 4.44, 6.25]. It was higher among CFA than those with other gastrointestinal and urogenital anomalies but lower than nervous system and chromosomal anomalies. Children with CFA and severe ID had a higher proportion of nervous system anomalies. CONCLUSIONS: Findings indicate increased ID and ASD among CFA but lower than nervous system and chromosomal anomalies. This population evidence can improve early identification of ID/ASD among CFA and support service planning. IMPACT: Our study found about one in ten children born with craniofacial anomalies (CFA) are later identified with intellectual disability (ID). Prevalence of ID among CFA was higher than those with other gastrointestinal, urogenital, and musculoskeletal birth defects but lower than those with the nervous system and chromosomal abnormalities. Most children with craniofacial anomalies have a mild-to-moderate intellectual disability with an unknown aetiology. On average, intellectual disability is identified 2 years later for children born with non-syndromic craniofacial anomalies than those with syndromic conditions. Our findings can improve the early identification of ID/ASD among CFA and support service planning.


Subject(s)
Autism Spectrum Disorder , Cleft Lip , Cleft Palate , Intellectual Disability , Child , Pregnancy , Female , Humans , Autism Spectrum Disorder/diagnosis , Autism Spectrum Disorder/epidemiology , Intellectual Disability/epidemiology , Australia , Cleft Palate/epidemiology
17.
J Sleep Res ; 31(5): e13600, 2022 10.
Article in English | MEDLINE | ID: mdl-35415902

ABSTRACT

Cyclin-dependent kinase-like 5 (CDKL5) gene pathogenic variants result in CDKL5 deficiency disorder (CDD). Early onset intractable epilepsy and severe developmental delays are prominent symptoms of CDD. Comorbid sleep disturbances are a major concerning symptom for families. We aimed to explore the relationship between insomnia, daytime sleepiness, sleep medications and quality of life in children with CDD. Caregivers of 129 children with CDD in the International CDKL5 Disorder Database completed the Quality-of-Life Inventory-Disability (QI-Disability) questionnaire and "Disorders of Maintaining Sleep" (DIMS) and the "Disorders of Excessive Somnolence" (DOES) items of the Sleep Disturbance Scale for Children. Adjusting for covariates, a unit increase in DOES score was associated with reduced quality of life total (coefficient -3.06, 95% confidence interval [CI] 1.35-7.80), physical health (coefficient -7.20, 95% CI -10.64, -3.76) and negative emotions (coefficient -3.90, 95% CI -7.38, -0.42) scores. Adjusting for covariates, a unit increase in DIMS score was associated with reduced negative emotions (coefficient -6.02, 95% CI -10.18, -2.86). Use of sleep medications had small influences on the effect sizes. This study highlights the importance of sleep problems as a determinant of quality of life in children with CDD, consistent with effects observed for other groups of children with intellectual disability. Excessive daytime sleepiness was particularly associated with detrimental effects on quality of life. Further research in optimal behavioural and pharmaceutical management of sleep problems for this population is required.


Subject(s)
Disorders of Excessive Somnolence , Sleep Initiation and Maintenance Disorders , Sleep Wake Disorders , Child , Disorders of Excessive Somnolence/diagnosis , Epileptic Syndromes , Humans , Quality of Life , Sleep Initiation and Maintenance Disorders/complications , Sleep Wake Disorders/epidemiology , Surveys and Questionnaires
18.
Dev Med Child Neurol ; 64(9): 1145-1155, 2022 09.
Article in English | MEDLINE | ID: mdl-35322406

ABSTRACT

AIM: To identify factors associated with quality of life (QoL) in children with intellectual disability. We aimed to identify patterns of association not observable in previous hypothesis-driven regression modelling using the same data set from a cross-sectional observational study. METHOD: A questionnaire was completed by 442 caregivers of children with confirmed intellectual disability and a diagnosis of autism spectrum disorder, cerebral palsy, Down syndrome, or Rett syndrome. The Quality of Life Inventory-Disability (QI-Disability) questionnaire was used to assess child QoL. Independent variables described the child's health, functional abilities, community participation, and sociodemographics. The R package rpart was used to build the regression trees. RESULTS: The mean total QI-Disability score was 69.2 out of a maximum 100. The subgroup with the lowest QoL scores comprised children with a high degree of daytime sleepiness (n=74, mean 57.5) while the subgroup with the highest QoL scores (n=91, mean 80.3) comprised children with little daytime sleepiness who participated more frequently in community activities and displayed good eye contact while listening. INTERPRETATION: Regression tree analysis provides insights into the relative importance of associated factors. Sleep problems and community participation were more important than functional abilities in accounting for differences in QoL. WHAT THIS PAPER ADDS: A hypothesis-free regression tree analysis enables examination of multiple factors potentially influencing quality of life (QoL) in children with intellectual disability. Functional abilities were less strongly associated with QoL than sleep problems and community participation.


Subject(s)
Autism Spectrum Disorder , Disorders of Excessive Somnolence , Intellectual Disability , Sleep Wake Disorders , Child , Cross-Sectional Studies , Humans , Quality of Life , Surveys and Questionnaires
19.
Eur J Pediatr ; 181(6): 2491-2500, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35316366

ABSTRACT

Individuals with Prader-Willi syndrome (PWS) often have excessive daytime sleepiness and emotional/behavioral disturbances. The objective of this study was to examine whether daytime sleepiness was associated with these emotional/behavioral problems, independent of nighttime sleep-disordered breathing, or the duration of sleep. Caregivers of individuals with PWS (aged 3 to 25 years) completed the Pediatric Sleep Questionnaire (PSQ), Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), and the parent version of the Developmental Behavior Checklist (DBC-P). Sleep adequacy was adjusted for age by computing sleep duration against age-specific recommendations. The associations between ESS-CHAD and the total DBC and its subscale scores were evaluated by linear regression, adjusted for sleep-related breathing difficulties, sleep adequacy, and body mass index (BMI). There were 54 responses for individuals with PWS (including 22 males) aged 4.4-24.0 (mean 12.5) years. Daytime sleepiness predicted a substantial proportion of the variance in total DBC-P scores in the unadjusted model (28%; ß = 0.028; p < 0.001) and when adjusted for sleep adequacy, BMI, and sleep-related breathing difficulties (29%; ß = 0.023; p = 0.007). This relationship was not moderated by BMI Z-scores, but the relationship was more prominent for children younger than 12 years than for children older than 12 years.Conclusions: These findings provide preliminary novel evidence that daytime sleepiness may drive the expression of emotional/behavioral disturbances, and should be explored as a potential modifiable risk factor for these disturbances in PWS, particularly pre-adolescent children.


Subject(s)
Disorders of Excessive Somnolence , Prader-Willi Syndrome , Problem Behavior , Adolescent , Child , Disorders of Excessive Somnolence/complications , Emotions , Humans , Male , Prader-Willi Syndrome/complications , Sleep
20.
J Med Genet ; 58(9): 637-644, 2021 09.
Article in English | MEDLINE | ID: mdl-32843489

ABSTRACT

BACKGROUND: Rett syndrome is a genetically caused neurodevelopmental disorder associated with functional deficits and comorbidities. This study investigated relationships between genotype, functional abilities and comorbidities and quality of life in Rett syndrome. METHODS: The International Rett Syndrome Database, InterRett, was used as a sampling frame for this observational study. Information was collected to describe functional abilities (walking and feeding), health (Sleep Disorder Scale for Children, the Rett Syndrome Behavioural Questionnaire), parental health (12-item Short Form Health Survey) sociodemographic factors (parental employment and education) and quality of life (Quality of Life Inventory-Disability) for 210 individuals with Rett syndrome. Univariate and multivariate regressions were used to analyse the relationships between the independent variables and quality of life. RESULTS: Compared with individuals with the p.Arg270* mutation, those with the p.Arg294* mutation type had the poorest quality of life (coeff -12.81, 95% CI -23.49 to 2.12), despite this being recognised as a clinically milder genotype. Overall better walking and feeding skills and seizure parameters were more associated with better quality of life and poor sleep and behavioural difficulties with poorer quality of life. CONCLUSIONS: These findings suggest that genotype, functioning and health each have implications for quality of life and should be considered when counselling families and planning clinical and support management strategies.


Subject(s)
Quality of Life , Rett Syndrome/epidemiology , Alleles , Amino Acid Substitution , Comorbidity , Databases, Factual , Genetic Predisposition to Disease , Genotype , Humans , Mutation , Phenotype , Public Health Surveillance , Rett Syndrome/diagnosis
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