The Duchenne brain

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD gene mutations leading to absence of the full-length dystrophin protein in muscle. Multiple dystrophin isoforms are expressed in brain, but little is known about their function. DMD is associated with specific learning and behavioral disabilities which are more prominent in patients with mutations in the distal part of the DMD gene, predicted to affect expression of shorter protein isoforms. The aim of this thesis was to provide a detailed description of the structural, perfusion and metabolic differences in the brain between patients with DMD and healthy age-matched controls and to assess the role of dystrophin isoforms.  Duchenne Parent Project, The Netherlands Gratama Foundation, The Netherlands Philips Healthcare, The NetherlandsLUMC / Geneeskund

Longitudinal follow-up of verbal span and processing speed in Duchenne muscular dystrophy

Neurocognitive deficits are frequently described in Duchenne muscular dystrophy (DMD), but it is unknown how these progress over time. Our aim was to longitudinally assess verbal span capacity and information processing speed in DMD and to explore a genotype-phenotype relation. Verbal span and processing speed scores were available of 28 males with DMD on two time-points, with a mean time interval of 28.34 months (SD = 16.09). The cohort contained of six patients missing only dystrophin isoform Dp427, sixteen missing Dp427 and Dp140, and six were undeterminable. A lower verbal span capacity was found at the first and second assessment, whereas processing speed was normal at both time-points. Post-hoc analyses suggested lower scores on verbal span and processing speed for patients missing Dp427 and Dp140. In DMD, a developmental stagnation in verbal span capacity, irrespective of normal processing speed, is detected through longitudinal follow-up. This appears more pronounced in patients missing Dp427 and Dp140. (C) 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.Neuro Imaging Researc

Resting-state functional MRI shows altered default-mode network functional connectivity in Duchenne muscular dystrophy patients

Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder caused by absence of dystrophin protein. Dystrophin is expressed in muscle, but also in the brain. Difficulties with attention/inhibition, working memory and information processing are well described in DMD patients but their origin is poorly understood. The default mode network (DMN) is one of the networks involved in these processes. Therefore we aimed to assess DMN connectivity in DMD patients compared to matched controls, to better understand the cognitive profile in DMD. T1-weighted and resting state functional MRI scans were acquired from 33 DMD and 24 male age-matched controls at two clinical sites. Scans were analysed using FMRIB Software Library (FSL). Differences in the DMN were assessed using FSL RANDOMISE, with age as covariate and threshold-free cluster enhancement including multiple comparison correction. Post-hoc analyses were performed on the visual network, executive control network and fronto-parietal network with the same methods. In DMD patients, the level of connectivity was higher in areas within the control DMN (hyperconnectivity) and significant connectivity was found in areas outside the control DMN. No hypoconnectivity was found and no differences in the visual network, executive control network and fronto-parietal network. We showed differences both within and in areas outside the DMN in DMD. The specificity of our findings to the DMN can help provide a better understanding of the attention/inhibition, working memory and information processing difficulties in DMD.Neuro Imaging Researc

EMQN best practice guidelines for genetic testing in dystrophinopathies.

Dystrophinopathies are X-linked diseases, including Duchenne muscular dystrophy and Becker muscular dystrophy, due to DMD gene variants. In recent years, the application of new genetic technologies and the availability of new personalised drugs have influenced diagnostic genetic testing for dystrophinopathies. Therefore, these European best practice guidelines for genetic testing in dystrophinopathies have been produced to update previous guidelines published in 2010.These guidelines summarise current recommended technologies and methodologies for analysis of the DMD gene, including testing for deletions and duplications of one or more exons, small variant detection and RNA analysis. Genetic testing strategies for diagnosis, carrier testing and prenatal diagnosis (including non-invasive prenatal diagnosis) are then outlined. Guidelines for sequence variant annotation and interpretation are provided, followed by recommendations for reporting results of all categories of testing. Finally, atypical findings (such as non-contiguous deletions and dual DMD variants), implications for personalised medicine and clinical trials and incidental findings (identification of DMD gene variants in patients where a clinical diagnosis of dystrophinopathy has not been considered or suspected) are discussed

The Duchenne brain

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD gene mutations leading to absence of the full-length dystrophin protein in muscle. Multiple dystrophin isoforms are expressed in brain, but little is known about their function. DMD is associated with specific learning and behavioral disabilities which are more prominent in patients with mutations in the distal part of the DMD gene, predicted to affect expression of shorter protein isoforms. The aim of this thesis was to provide a detailed description of the structural, perfusion and metabolic differences in the brain between patients with DMD and healthy age-matched controls and to assess the role of dystrophin isoforms.  </div

Combining genetics, neuropsychology and neuroimaging to improve understanding of brain involvement in Duchenne muscular dystrophy - a narrative review

Duchenne muscular dystrophy is a multifactorial disease including a cognitive phenotype. It is caused by mutations in the X-chromosomal DMD gene from which dystrophin is synthesized. Multiple isoforms of dystrophin have been identified. The full length dystrophin isoform Dp427 m is expressed predominantly in muscle. Other isoforms include: Dp427(c), Dp427(p), Dp260, Dp140, Dp116, Dp71 and Dp40. The majority of these isoforms are expressed in brain and several hypotheses exist on their role in subtypes of neurons and astrocytes. However, their function in relation to cognition remains unclear. Unlike progressive muscle wasting, cognitive involvement is not seen in all DMD patients and the severity varies greatly. To achieve a better understanding of brain involvement in DMD, a multidisciplinary approach is required. Here, we review the latest findings on dystrophin isoform expression in the brain; specific DMD-associated learning and behavioural difficulties; and imaging and spectroscopy findings relating to brain structure, networks, perfusion and metabolism. The main challenge lies in determining links between these different findings. If we can determine which factors play a role in the differentiation between severe and minor cognitive problems in DMD in the near future, we can both provide better advise for the patients and also develop targeted therapeutic interventions. (C) 2020 The Author(s). Published by Elsevier B.V.Neuro Imaging Researc

The Duchenne brain

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD gene mutations leading to absence of the full-length dystrophin protein in muscle. Multiple dystrophin isoforms are expressed in brain, but little is known about their function. DMD is associated with specific learning and behavioral disabilities which are more prominent in patients with mutations in the distal part of the DMD gene, predicted to affect expression of shorter protein isoforms. The aim of this thesis was to provide a detailed description of the structural, perfusion and metabolic differences in the brain between patients with DMD and healthy age-matched controls and to assess the role of dystrophin isoforms.  </div

Brain imaging indicates genotype-phenotype association in Duchenne muscular dystrophy

Neuro Imaging Researc

Continuous infusion of manganese improves contrast and reduces side effects in manganese-enhanced magnetic resonance imaging studies

Functional Genomics of Muscle, Nerve and Brain Disorder