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Published on: May 24, 2016
Disrupted structural connectome and neurocognitive functions in Duchenne muscular dystrophy: classifying and
Veeramani Preethish-Kumar1, Apurva Shah2, Kiran Polavarapu1
1Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.
Insights
Duchenne muscular dystrophy (DMD) children with Dp140 gene deletions show significant neurocognitive impairments and brain connectivity alterations. The Dp140- subgroup exhibits more severe motor and cognitive deficits, highlighting genotype-phenotype correlations in DMD.
Area of Science:
- Neuroscience
- Genetics
- Pediatrics
Background:
- Duchenne muscular dystrophy (DMD) is associated with neurocognitive disabilities.
- Distal DMD gene deletions, particularly those affecting the Dp140 isoform, are linked to more severe cognitive impairments.
- Brain-network metrics from MRI offer insights into microstructural integrity and pathophysiology in DMD.
Purpose of the Study:
- To investigate structural brain network abnormalities in children with DMD using diffusion MRI and network-based statistics.
- To correlate brain connectivity patterns with clinical markers and genotypic classifications, specifically the Dp140 isoform status.
- To characterize the impact of Dp140 gene deletions on neurocognitive function and brain structure in DMD.
Main Methods:
- A prospective study included 57 DMD patients and 38 healthy controls (HC).
- Clinical assessments involved the Muscular Dystrophy Functional Rating Scale (MDFRS) and neuropsychology batteries.
- Genotypic classification used multiplex ligand-dependent probe amplification (MLPA) testing; diffusion MRI analyzed structural connectomes.
Main Results:
- DMD patients showed significantly lower IQ scores compared to HC, with the Dp140- subgroup exhibiting the lowest scores.
- Significant differences in global efficiency, transitivity, and characteristic path length were observed between HC and DMD groups.
- The Dp140- subgroup displayed more pronounced motor disabilities and widespread connectivity alterations than the Dp140+ subgroup.
Conclusions:
- Structural network abnormalities are evident in DMD, particularly in the Dp140- subgroup, characterized by widespread connectivity alterations.
- Participants with the Dp140+ isoform showed relatively intact brain connectivity compared to the Dp140- subgroup.
- Findings support a genotype-phenotype correlation, linking Dp140 gene status to brain-behavior involvement in DMD children.
Objective:
Neurocognitive disabilities in Duchenne muscular dystrophy (DMD) children beginning in early childhood and distal DMD gene deletions involving disruption of Dp140 isoform are more likely to manifest significant neurocognitive impairments. MRI data analysis techniques like brain-network metrics can provide information on microstructural integrity and underlying pathophysiology.
Methods:
A prospective study on 95 participants [DMD = 57, and healthy controls (HC) = 38]. The muscular dystrophy functional rating scale (MDFRS) scores, neuropsychology batteries, and multiplex ligand-dependent probe amplification (MLPA) testing were used for clinical assessment, IQ estimation, and genotypic classification. Diffusion MRI and network-based statistics were used to analyze structural connectomes at various levels and correlate with clinical markers.
Results:
Motor and executive sub-networks were extracted and analyzed. Out of 57 DMD children, 23 belong to Dp140 + and 34 to Dp140- subgroup. Motor disabilities are pronounced in Dp140- subgroup as reflected by lower MDFRS scores. IQ parameters are significantly low in all-DMD cases; however, the Dp140- has specifically lowest scores. Significant differences were observed in global efficiency, transitivity, and characteristic path length between HC and DMD. Subgroup analysis demonstrates that the significance is mainly driven by participants with Dp140- than Dp140 + isoform. Finally, a random forest classifier model illustrated an accuracy of 79% between HC and DMD and 90% between DMD- subgroups.
Conclusions:
Current findings demonstrate structural network-based characterization of abnormalities in DMD, especially prominent in Dp140-. Our observations suggest that participants with Dp140 + have relatively intact connectivity while Dp140- show widespread connectivity alterations at global, nodal, and edge levels. This study provides valuable insights supporting the genotype-phenotype correlation of brain-behavior involvement in DMD children.
