The application of population data linkage to capture sibling health outcomes among children and young adults with neurodevelopmental conditions. A scoping review.International journal of population data science • March 21, 2025
Caitlin Gray, Helen Leonard, Matthew Cooper, Dheeraj Rai, Emma Glasson
Siblings of children with neurodevelopmental conditions have unique experiences and challenges related to their sibling role. Some develop mental health concerns as measured by self-reported surveys or parent report. Few data are available at the population level, owing to difficulties capturing wide-scale health data for siblings. Data linkage is a technique that can facilitate such research. To explore the application of population data linkage as a research method to capture health outcomes of siblings of children with neurodevelopmental conditions. Peer reviewed papers that captured health outcomes for siblings of children and young adults with neurodevelopmental conditions using population data linkage. JBI Scoping review methods were followed. Papers were searched within CINAHL, Ovid, Scopus, and Web of Science from 2000 to 2024 using search terms relating to 'data linkage' 'neurodevelopmental conditions' 'siblings' and 'health outcomes'. The final data extraction included 31 papers. The neurodevelopmental conditions of index children were autism, attention deficit hyperactivity disorder, intellectual disability, cerebral palsy and developmental delay. The mean follow-up time was 31 years, and the majority of studies originated from Scandinavia. Sibling health outcomes observed were psychiatric diagnoses, self-harm and suicide, other neurodevelopmental conditions, and medical conditions such as atopic disease, cancer and obesity. Data linkage can help capture sibling health outcomes quickly across large cohorts with a range of neurodevelopmental conditions. Future research could be enhanced by focusing on siblings as the primary group of interest, increased integration of genealogical data, and comparisons between diagnostic groups and severity levels. Adoption of established rigorous reporting methods will increase the replicability of this type of research, and provide a stronger evidence-base from which to inform sibling supports.
Caregivers' Perceptions of Clinical Symptoms, Disease Management, and Quality of Life Impact in Cases of Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Cross-Sectional Online Survey.JMIR Formative Research • February 12, 2025
Sam Amin, Carol-anne Partridge, Helen Leonard, Jenny Downs, Helen Allvin, Valentine Ficara, Emilie Pain, Minna Korolainen
Background: Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is an ultrarare genetic condition causing developmental epileptic encephalopathy characterized by seizures and motor and intellectual disabilities. No disease-modifying therapies are available, and treatments focus mainly on symptom management to improve quality of life.
Objective: The aim of this study was to better understand the burden of CDD based on family caregivers' perceptions.
Methods: The study was a cross-sectional, web-based survey comprising 40 questions for caregivers of patients with CDD and focusing on sociodemographic and medical characteristics, disease burden, unmet needs, treatments, and support. An adapted version of the EQ-5D-5L instrument was included to measure patients' health-related quality of life as perceived by their caregivers.
Results: A total of 132 caregivers, mostly from western parts of Europe, responded. The median patient age was 7.6 (IQR 2.9-12.2) years. Seizure onset occurred early, with the median onset at 2.0 (IQR 1.0-3.0) months of age. The median age at diagnosis was 1.2 (IQR 0.6-4.0) years. Epilepsy (123/132, 93.2%) and limited communication skills (111/132, 84.1%) were the most commonly reported symptoms. The highest number of different types of symptoms was reported for patients aged 5-9 years, with a median of 9.0 (IQR 7.5-10.0) symptoms. Most patients with epilepsy experienced daily seizures (81/123, 65.9%), and nearly all (119/123, 96.7%) were on antiseizure medications. A minority was on a ketogenic diet (21/123, 17.1%) or underwent vagus nerve stimulation (14/123, 11.4%). The care received was multidisciplinary. Compared to younger patients, adults had fewer medical appointments and a smaller variety of health care professionals in their care team. The EQ-5D-5L, adapted for caregivers, indicated low health-related quality of life for patients, with a median global index value of 0.18 (IQR 0.11-0.32). The most severe consequences of CDD on patients' daily lives were reported for mobility (88/132, 66.7%), self-care (120/132, 90.9%), and everyday activities (103/132, 78.0%). Caregiver burden was also substantial, with all life aspects reportedly impacted by CDD, including professional life and financial resources (median impact ratings of 9.0/10 and 7.0/10, respectively). Access to support and care varied depending on location. Caregivers outside Europe reported a longer time between the first seizure and diagnosis (26.5, IQR 3.2-47.0 months) compared to European caregivers (11.0, IQR 5.0-45.0 months). They also reported a higher impact of CDD on their financial resources (rating of 10/10) compared to European caregivers (rating of 6/10) and greater challenges in covering costs.
Conclusions: The study findings provide valuable insights on symptoms and disease burden related to CDD. This burden was quantitatively characterized with the EQ-5D-5L for the first time and was perceived as substantial by family caregivers. Discrepancies between geographic regions and age groups were highlighted, especially regarding available support and access to resources and care.
The natural history of CDKL5 deficiency disorder into adulthood.MedRxiv : The Preprint Server For Health Sciences • January 27, 2025
Angel Aledo Serrano, David Lewis Smith, Helen Leonard, Allan Bayat, Mohamed Junaid, Eveline Hagebeuk, Christina Fenger, Juliana Laze, Alessandra Rossi, Marina Trivisano, Beatriz Gonzalez Giraldez, Julio Lama, Ilona Krey, Konrad Platzer, Elise Brischoux Boucher, Catherine Sarret, Lysa Lomax, Caterina Zanus, Luciana Musante, Paola Costa, Patrick Moloney, Norman Delanty, Angelo Russo, Bitten Schönewolf Greulich, Anne-marie Bisgaard, Colette Berger, Elena Freri, Satoru Takahashi, Pia Zacher, Julien Jung, Scott Demarest, Eric Marsh, Alan Percy, Jeff Neul, Heather Olson, Lindsay Swanson, Stefano Meletti, Maria Cioclu, Quratulain Ali, Ana Suller, Alvaro Beltran Corbellini, Antonio Gil Nagel, Xiaoming Zhang, Roberto Previtali, Anne Højte, Nicola Specchio, Jenny Downs, Gaetan Lesca, Guido Rubboli, Danielle Andrade, Elena Gardella, Elia Pestana, Orrin Devinsky, Timothy Benke, Ingo Helbig, Rhys Thomas, Rikke Møller
Knowledge of the natural history of CDKL5 deficiency disorder (CDD) is limited to the results of cross-sectional analysis of largely pediatric cohorts. Assessment of outcomes in adulthood is critical for clinical decision-making and future precision medicine approaches but is challenging because of the diagnostic gap and duration of follow-up that would be required for prospective studies. We aimed to delineate the natural history retrospectively from adulthood. We analyzed clinical data about an international cohort of 67 adults with CDD. We analyzed demographic, phenotypic, CDKL5 Developmental Score (CDS), and treatment data, and tested associations with genetic factors, sex, and a positive or negative history of neonatal seizures, as an early predictor of prognosis. All but one of 67 adults (55 females, median age of 24 years at last follow-up) had epilepsy, typically beginning with epileptic spasms or tonic seizures before 4 months of age. Focal-onset and non-motor seizures emerged later. Fewer than a third had been documented as having bilateral tonic-clonic seizures or status epilepticus. Seizures often improved with age, but 73% had never experienced more than 6 months of seizure-freedom. Clobazam, sodium valproate, and lamotrigine were the most frequently prescribed antiseizure medications, but no specific treatment demonstrated superiority. Common comorbidities included movement disorders, visual impairment, sleep disorders, constipation, and scoliosis. All participants had intellectual disability, 75% had not acquired speech and 45% had regressed developmentally. 16% never achieved any CDS skill, but most attained at least three, and 28% attained six or all seven. By adulthood, half of those who had achieved any CDS skill retained all their CDS skills. The skills most frequently lost were independent walking and standing. Those with a history of neonatal seizures tended to attain fewer CDS skills and were more likely to have abnormal muscle tone in adulthood, atrioventricular conduction delay, and potential complications of their illness and treatment. Individuals carrying missense variants attained more CDS skills than those with other variants and were more likely to lose skills in adulthood and develop anxiety, possibly reflecting the limited neurodevelopment of those with non-missense variants, who manifested a more multisystemic disorder. In summary, retrospective data from adulthood elucidates the evolution of symptoms, variation in developmental outcomes, and the treatment landscape in CDKL5 deficiency disorder. Presence a non-missense variants or a history of neonatal seizures indicates a more complex disorder and lower developmental trajectory. Our findings will inform management decisions, prognostication, and the design of clinical trials in CDKL5 Deficiency Disorder.
Bipolar Disorder in a female with CDKL5 Deficiency Disorder: A Case Report.Research Square • September 24, 2024
Jenna Lucash, William Hong, Lindsay Swanson, Kiran Maski, David Urion, Jung Kim, Helen Leonard, Heather Olson
CDKL5 deficiency disorder (CDD) is an early-onset developmental and epileptic encephalopathy. While a subset of individuals is believed to experience comorbid behavioral disorders, none have reported well-defined affective disorders. Though there is a documented association between epilepsy and mood disorders, they may go undetected in the CDD population due to difficulty assessing mood in the presence of severe/profound intellectual disability and disease-related sleep dysregulation. We aimed to identify the clinical characteristics of an individual with CDD who presented with a mood disorder falling outside this expected behavioral phenotype. We identified one 22-year-old female with CDD diagnosed with unspecified bipolar disorder at 18 years of age. Family history was noncontributory. At diagnosis, she had fluctuations in mood, characterized by periods of elated affect, increased energy and vocalizations, hypertonia, and insomnia lasting 3-4 days alternating with periods of depressed affect, irritability, hypotonia, and excessive sleep lasting for up to one month. She had experienced frequent mood swings and sleep dysregulation from early childhood, and by early adulthood the duration of "up" and "down" periods fell in the range specified in the DSM-5 bipolar disorder criteria. Trazodone and suvorexant did not alleviate sleep related symptoms. Her epilepsy was well controlled on lamotrigine monotherapy since early childhood. Though lamotrigine treatment has had no psychiatric benefit despite its known mood stabilizing properties, aripiprazole has been effective in reducing severity and frequency of fluctuations between hypomania and depression. While sleep and behavioral disorders fall within the expected phenotype for CDD, this is the first report of bipolar disorder. Careful attention to patterns of sleep and behavior that may indicate mood cycling in this population is required, particularly in the setting of limited communication and functional abilities.
Modification of a parent-report sleep scale for individuals with CDKL5 deficiency disorder: a psychometric study.Journal Of Clinical Sleep Medicine : JCSM : Official Publication Of The American Academy Of Sleep Medicine • July 04, 2024
Jacinta Saldaris, Scott Demarest, Peter Jacoby, Heather Olson, Kiran Maski, Elia Pestana Knight, Dana Price, Rajsekar Rajaraman, Bernhard Suter, Judith Weisenberg, Helen Leonard, Eric Marsh, Tim Benke, Jenny Downs
Objective: Sleep difficulties are common in CDKL5 deficiency disorder, a developmental and epileptic encephalopathy. This study evaluated the factor structure of the Disorders of Initiating and Maintaining Sleep (DIMS), Disorders of Excessive Somnolence (DOES), and Sleep Breathing Disorders domains of the Sleep Disturbance Scale for Children for CDKL5 deficiency disorder. Methods: A cross-sectional psychometric study design was used. Data were collected for 125 individuals aged 3 years or older who attended a United States Centers of Excellence clinic or registered with the International CDKL5 Disorder Database. Results: The median age was 10.3 years (range 3.2-40.7 years) and 105 (84%) were female. Two of the 3 Sleep Breathing Disorders items were not observed by most respondents and analysis was restricted to the DIMS and DOES domains. Using all items in the initial confirmatory factor analysis, 2 items in the DIMS domain and 1 item in the DOES domain loaded poorly. After deleting these items and repeating the analysis, item loading (.524-.814) and internal consistency (DIMS: .78, DOES: .76) statistics were good. The square of the interdomain correlation coefficient was .17, less than average variance extracted values for both domains and indicating good discriminant validity. The Tucker-Lewis and Comparative Fit indices were slightly lower than the threshold of > .9 for establishing goodness of fit. Conclusions: The modified DIMS and DOES domains from the Sleep Disturbance Scale for Children could be suitable clinical outcome assessments of insomnia and related impairments in CDKL5 deficiency disorder and potentially other developmental and epileptic encephalopathy conditions.
Background: Saldaris JM, Demarest S, Jacoby P, et al. Modification of a parent-report sleep scale for individuals with CDKL5 deficiency disorder: a psychometric study. J Clin Sleep Med. 2024;20 (12):1887-1893.
