CTNNB1 Neurodevelopmental Syndrome - Natural History Study

Официальное название

Dragonfly Study: An International, Prospective, Longitudinal, Observational Natural History Study of Children and Adults Living With CTNNB1 Neurodevelopmental Syndrome

Обзор

The aim of the Dragonfly study is to characterise and monitor the neurodevelopment of children and adults diagnosed with CTNNB1 syndrome through an international collaborative effort. Gaining comprehensive understanding of the mental, physical and social development of people with CTNNB1 neurodevelopmental syndrome and how their symptoms and abilities change over time will help improve and standardize care for these patients, as well as facilitate future research and clinical trials design.

Подробное описание

CTNNB1 syndrome is a rare debilitating neurodevelopmental disorder caused by mutations in the CTNNB1 gene, which is characterised by developmental delay and intellectual disability. Due to its relatively recent discovery, very little is known about the natural history of the condition. The aim of the Dragonfly study is to characterise and monitor the neurodevelopment of children and adults diagnosed with CTNNB1 syndrome through an international collaborative effort. This study is being conducted across several countries, including Slovenia, Spain, Brazil, the USA, and Australia.

In this natural history study, tinvestigators aim to recruit 150 children or adults of any age and phenotype with a confirmed genetic diagnosis of CTNNB1 syndrome, and their primary carers. Investigators will invite the participant and their carers to attend an annual study visit over a period of 5 years, during which investigators will collect retrospective and prospective clinical data. This will include a clinical neurological examination and assessments of motor and cognitive function, communication, behaviour, vision, sleep, assessment of gait using actimetry, and recordings of brain activity using electroencephalography (EEG). Investigators will also assess results of retinal assessment using Optical Coherence Tomography, and structural brain assessments using magnetic resonance imaging (MRI) - these diagnostic procedures will be performed in the participant's home county and not on site. Blood tests will be performed to reconfirm the underlying mutations in the CTNNB1 gene and investigate biomarkers of the condition. Carers will also be invited to complete questionnaires exploring their child's/dependent's abilities and the impact of the condition on their family's quality of life.

There is currently no curative treatment available for CTNNB1 syndrome. However, pre-clinical studies have been successfully completed with promising results and genetic therapies are currently in development. A comprehensive understanding of the natural progression of the condition is essential prior to commencing clinical trials of potential treatments. By improving our understanding of CTNNB1 syndrome, this study aims to lay the foundation for future clinical trials and the development of targeted treatments.

Вмешательства

• Диагностический тест A General Medical and Neurological Assessment
  Clinical assessments will consist of gathering demographic data, detailed relevant medical history, and parents' perspectives on treatment priorities, clinical trial interest, and acceptability of risk in future clinical trials. A general medical and neurological examination will be performed by a trained and skilled physician with a valid Good Clinical Practice Certification.
• Диагностический тест World Health Organisation (WHO) Motor Milestones
  Ages of six WHO Motor milestones achievements - sitting without support, hands and knees crawling, standing with support, walking with support, standing independently, and walking independently - will be assessed. The age of milestone achievement will be compared to normative variations in age as recommended by the WHO (WHO, 2006).
• Диагностический тест Burke-Fahn-Marsden Dystonia Rating Scale
  The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS; Burke, Fahn, Marsden et. al, 1985) is a universally applied biomarker for the severity of dystonia in children and adults. The scale consists of a movement and disability subscale (Burke-Fahn-Marsden Movement Scale \[BFMMS\] and Burke-Fahn-Marsden Disability Scale \[BFMDS\], respectively. Only the BFMMS will be assessed. The BFMMS measures dystonia in nine body regions (including the eyes, mouth, speech and swallowing, neck, trunk, arms, and
• Диагностический тест Spastic Paraplegia Rating Scale
  The Spastic Paraplegia Rating Scale (SPRS; Schüle et al., 2006) is a 13-item scale used to measure disease severity in spastic paraplegia. The items include walking distance without pause, gait quality, maximum gait speed, climbing stars, arising from chair, spasticity of hip adductor and knee flexion muscles, weakness of hip abduction and foot dorsiflexion, contracture of lower limbs, pain related to spasticity, and bladder and bowel function. Each item has a score ranging from 0 to 4, where 0
• Диагностический тест 5. CTNNB1-Related Neurodevelopmental Disorder (NEDSDV) Cardiac Health Questionnaire
  In a recent study (Sinibaldi et al., 2023), several patients with NEDSDV showed heart abnormalities. To expand on that, investigators developed a parent report questionnaire on the presence of potential heart defects.
• Диагностический тест 10m Walk-Run Test
  The 10m Walk-Run Test is is a performance measure used to assess walking or gait speed in meters per second over a short distance. It involves measuring the time it takes for a person to walk the distance, with results reported in meters/second (m/s). The patient's ability to walk at both comfortable and fast speeds can be measured, and assistive devices can be used. The test will be performed in ambulant children by an experienced physiotherapist.
• Диагностический тест The Nine Hole Peg Test
  The Nine-Hole Peg Test (9-HPT; Kellor et al., 1971) is a standardized, quantitative assessment used to measure finger dexterity. It is administered by asking the client to take the pegs from a container, one by one, and place them into holes on the board as quickly as possible. The 9-HPT has been validated for children above the age of 4 years (Poole et al., 2006). The test will be performed in children over 4 years old by a trained investigator.
• Диагностический тест The Gross Motor Function Classification System
  The Gross Motor Function Classification System (GMFCS; Palisano, Rosenbaum, Bartlett, Livingston, 2007) is a 5-level classification system that describes the gross motor function of children and youth with cerebral palsy on the basis of their self-initiated movement with particular emphasis on sitting, walking, and wheeled mobility. Distinctions between levels are based on functional abilities, the need for assistive technology, including hand-held mobility devices (walkers, crutches, or canes)
• Диагностический тест Bayley Scales of Infant and Toddler Development-4: Fine Motor, Gross Motor, Language, and Cognitive Scales
  Bayley Scales of Infant and Toddler Development-4 (BSID-4; Bayley et al., 2019) is an extensive formal developmental assessment tool for diagnosing developmental delays in early childhood. It consists of 419 items across 5 scales, each of which can be administered separately - Cognitive Scale (81 items), Language Scale (79 items), Motor Scale (104 items), Social-Emotional Scale (35 items), and Adaptive Behavior Scale (120 items). In our study, Motor, Language and Cognitive scales will be perform
• Диагностический тест Wechsler Non-Verbal Scale of Ability
  Wechsler Nonverbal Scale of Ability (WNV, Wechsler et al., 2006) is a standardized, individually administered test designed to assess general cognitive ability in individuals aged 4 to 21 years, particularly those who may have language, cultural, or communication challenges that make traditional verbal IQ tests less appropriate. It consists of six different subtests that are utilized based on the participant's age. In our study, the test will be performed in children above the age of 4 years by

Первичные конечные точки

• Collection of relevant retrospective and prospective clinical data in patients with CTNNB1 syndrome via physical assessments, scales, and questionnaires. [Срок оценки: 5 years]

Критерии участия

Критерии включения

• Clinically and genetically confirmed diagnosis of CTNNB1 syndrome.
• Age 0-99 years.
• Written informed consent/online consent to participate in study from a primary carer (parent or legal guardian).

Критерии исключения

• Child/adult with CTNNB1 syndrome participating in a clinical trial of a potential treatment for the syndrome.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Австралия · 1 центр

• Sydney Children's Hospital — Sydney

Словения · 1 центр

• University Medical Centre Ljubljana — Ljubljana

Публикации

• Zakelj N, Gosar D, Mirosevic S, Sanders SJ, Ljungdahl A, Kohani S, Huang S, Leong LI, An Y, Teo MJ, Moultrie F, Jerala R, Lainscek D, Forstneric V, Susjan P, Lisowski L, Perez-Iturralde A, Mrak JO, Chan HYE, Osredkar D. Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome. HGG Adv. 2025 Oct 9;6(4):100483. doi: 10.1016/j.xhgg.2025.100483. Epub 2025 Jul 18. PMID 40684264
• Mirosevic S, Khandelwal S, Susjan P, Zakelj N, Gosar D, Forstneric V, Lainscek D, Jerala R, Osredkar D. Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature. Int J Mol Sci. 2022 Oct 19;23(20):12564. doi: 10.3390/ijms232012564. PMID 36293418

Идентификаторы

NCT: NCT07167732 · 0120-174/2024-2711-8 · J7-4537

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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