Editorial for “Relationship Between Dp140 Genotype and Cortical Similarity Network Phenotype in Duchenne Muscular Dystrophy: Preliminary T1 Weighted Study”

Duchenne muscular dystrophy (DMD) is a severe X-linked disorder affecting predominantly boys and caused by mutations in the dystrophin gene, leading to progressive muscle degeneration and reduced life expectancy. However, dystrophin is not confined to skeletal and cardiac muscle. Several isoforms, including the full-length Dp427 and shorter variants such as Dp140 and Dp71, are also expressed in the central nervous system, with distinct spatial and developmental expression patterns [1, 2]. The location of the underlying mutation determines which isoforms are affected. Increasing evidence indicates that mutations predicted to disrupt Dp140 are associated with more pronounced cognitive and behavioral difficulties, highlighting the heterogeneity of the neurodevelopmental phenotype in boys with DMD [2, 3]. The neurocognitive profile of boys with DMD extends well beyond reduced full-scale IQ [1]. On average, affected boys score approximately one standard deviation below the population mean on standardized intelligence measures, although substantial interindividual variability exists. Vulnerabilities in working memory, executive functioning, processing speed, and attentional regulation are frequently observed, accompanied by increased neurobehavioral problems such as attention-deficit/hyperactivity disorder and autism spectrum traits. These difficulties may substantially affect academic achievement, social participation, and adaptive functioning, often contributing to long-term challenges in independence and quality of life [4]. Working memory impairments appear particularly pronounced in boys lacking Dp140, further supporting the concept of isoform-specific cognitive vulnerability within the broader DMD phenotype. Neuroimaging studies in DMD have provided valuable but largely exploratory insights into brain involvement, often based on modest sample sizes and heterogeneous methodologies, including volumetric analyses, diffusion imaging, and functional MRI [5]. While alterations in frontal and parietal regions have been reported, a coherent framework linking dystrophin isoform deficiency to network-level cortical organization remains lacking. In particular, the mechanisms by which Dp140 deficiency influences brain development and large-scale network maturation are still poorly understood. This knowledge gap has become increasingly relevant in the era of emerging genetic and molecular therapies [1]. Many novel interventions primarily target skeletal muscle, yet their potential impact on brain development, whether direct, indirect, or negligible, remains uncertain. As therapeutic strategies evolve, there is a growing need for robust, developmentally informed neuroimaging biomarkers capable of capturing genotype-specific brain vulnerability and tracking neurocognitive outcomes over time. In this context, the current study [6] represents an important step forward. By stratifying boys with DMD according to predicted Dp140 expression and applying morphometric similarity network (MSN) analysis to T1-weighted MRI data, the authors move beyond regional volumetric descriptions toward an integrative perspective on cortical architecture [6]. Morphometric similarity networks quantify the degree to which cortical regions resemble one another across multiple structural features within individuals, providing an integrated measure of large-scale cortical organization [7]. The findings demonstrate reduced cortical similarity and altered network topology in boys lacking Dp140, particularly within the frontoparietal network, a system centrally implicated in working memory and executive control [8]. The authors further report that frontoparietal morphometric similarity may partially mediate the relationship between Dp140 status and working memory performance, thereby suggesting a potential framework that links genotype to cognition at the network level [6]. Notably, this association was attenuated after adjustment for broader intellectual functioning. This hypothesis is biologically plausible, as Dp140 is expressed during early cortical development, including periods critical for neuronal migration and circuit formation. Disruption of this isoform may therefore influence the maturation of distributed cortical systems. By integrating imaging findings with transcriptomic data, the study additionally implicates molecular pathways related to neuronal projection development and cytoskeleton-dependent transport as potential biological substrates of these alterations [9]. While these findings are compelling, several considerations underscore the need for continued investigation. The cross-sectional design limits insight into developmental trajectories, which are central to understanding how early dystrophin deficiency translates into later cognitive outcomes. A clearer delineation of the natural history of behavioral and brain development in DMD will be essential to determine whether morphometric similarity alterations precede, parallel, or follow cognitive divergence over time. In addition, treatment context warrants careful consideration. Corticosteroids remain standard of care in DMD, typically initiated in early childhood, often around 4 years of age, and continued into adolescence and adulthood. While their positive impact on motor outcomes and survival is well established, corticosteroid exposure was also considered in the present analyses. Nevertheless, corticosteroids are also known to influence brain structure and function, and their long-term interaction with genotype, cortical maturation, and neurodevelopmental effects remains incompletely understood [10]. The interaction between genotype, chronic treatment exposure, and cortical maturation therefore represents an important area for future research. Finally, longitudinal, multicenter, and cross-cultural studies will be necessary to assess the robustness, reproducibility, and clinical relevance of these network-based metrics across scanners, populations, and neuropsychological phenotypes. As the therapeutic landscape of DMD continues to evolve, understanding the brain consequences of isoform-specific dystrophin deficiency becomes increasingly important. The present study situates Dp140 within a biologically informed framework linking genotype to distributed cortical organization and working memory performance. Notably, the authors report findings in an exceptionally large DMD cohort for neuroimaging research, strengthening the robustness of their observations. At the same time, the marked phenotypic heterogeneity of DMD, together with developmental variability and treatment-related influences, underscores the need for even larger collaborative efforts across centers. Advancing the field will require coordinated longitudinal investigations that delineate developmental trajectories, integrate treatment exposure, and harmonize imaging and neuropsychological protocols across sites. Morphometric similarity networks may represent a promising step in that direction; their clinical value, however, will ultimately depend on reproducibility, scalability, and their ability to inform patient-centered outcomes within internationally diverse and representative populations.