D-Brain
Research type
Research Study
Full title
D-BRAIN: Defining outcome measures for behavioural and emotional problems in dystrophinopathies
IRAS ID
302390
Contact name
Francesco Muntoni
Contact email
Sponsor organisation
University College London
Duration of Study in the UK
2 years, 11 months, 31 days
Research summary
Research Summary
Duchenne Muscular Dystrophy is characterised by out-of-frame gene deletions that abolish the ability to produce dystrophin in muscles and in the brain. Studies have shown that brain dystrophin deficiency results in a neuropsychiatric syndrome in more than 50% of patients and have indicated higher incidence of neurobehavioural comorbidities such as Autism Spectrum Disorders (ASD), Attention Deficit Hyperactivity Disorders (ADHD), Obsessive Compulsive Disorders (OCD), Anxiety Disorders and Depressive disorders [1,2] These central nervous system (CNS) manifestations of DMD have major implications for the quality of life of the individuals affected. The milder allelic variant Becker Muscular Dystrophy (BMD), is associated with less severe progression of muscle weakness; individuals also experience brain comorbidities but their prevalence and severity in BMD has never been systematically assessed.It is possible to restore brain-expressed dystrophin through intrathecal administration of antisense oligonucleotides (AONs) in mice, leading to reversal of the neurobehavioural phenotype [3]. This implies aspects of the human neurobehavioural phenotype could be improved in DMD patients following dystrophin restoration in the brain. Clinical trials in boys with DMD are currently being conducted to improve skeletal muscle functioning in DMD, using exon skipping to restore the mRNA reading frame. AONs introduced into the CNS could potentially improve cognitive, behavioural and emotional symptoms associated with DMD and BMD, many of which are believed to result from brain dysfunction secondary to the genetic anomaly. Evaluating the effectiveness of treatment in a clinical trial demands robust clinical outcome measures, including biomarkers of the neurobehavioural phenotype.
The aim of this study is to develop a set of biometric outcome measures that are appropriately sensitive to change, for use in future clinical trials designed to improve neurobehavioural and neurocognitive functioning in DMD/BMD.
Summary of Results
The D-Brain study explored how Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD) affect brain function, emotional well-being, and behaviour in children and young people. These conditions are caused by changes in the dystrophin gene, known mainly for causing muscle weakness. However, research suggests that dystrophin also plays a role in brain development and mental health. This study aimed to understand these effects better and find reliable ways to measure them.Who took part?
The study included 71 boys and young men:35 with DMD,
11 with BMD, and
24 healthy peers for comparison.
Participants were grouped based on specific genetic changes that affect different versions of the dystrophin protein in the brain. They completed two visits, involving cognitive tests, parent questionnaires, brain scans (MRI), and a task to measure emotional responses.What were the key findings?
Cognitive Function:
Children with DMD and BMD showed slower thinking speeds and difficulties with memory compared to healthy peers. These challenges were more noticeable in those lacking a specific version of dystrophin called DP140.Emotional and Behavioural Well-being:
Parents reported higher levels of emotional difficulties, such as anxiety and mood problems, especially in children with DMD. These children also found it harder to manage their emotions and behaviour in everyday life.Social Communication:
Many children with DMD showed social difficulties similar to autism spectrum conditions, even if they did not have a formal diagnosis. This was most common in those with DP140-related genetic changes.Emotional Response Testing:
The fear conditioning task showed that children with DMD had stronger and longer-lasting fear responses compared to their peers. This suggests they may find it harder to "calm down" after stressful situations.Brain Imaging:
MRI scans revealed changes in the white matter of the brain, which helps different parts of the brain communicate. These changes were linked to the cognitive and emotional challenges seen in the study.Why does this matter?
These findings show that DMD and BMD affect not just muscles but also brain function, emotional health, and behaviour. Importantly, the study identified potential "biomarkers" – measurable changes in brain structure and function – that could help track how these conditions progress or respond to treatment.By understanding the brain-related challenges of dystrophinopathies, healthcare providers can offer better support to families and tailor treatments to each child's needs. The study also highlights the importance of considering emotional and cognitive well-being alongside physical health in managing these conditions.
REC name
West Midlands - Black Country Research Ethics Committee
REC reference
21/WM/0267
Date of REC Opinion
24 Feb 2022
REC opinion
Further Information Favourable Opinion