Muscle hypertrophy and muscle weakness are well known in Duchenne muscular dystrophy. Decreased muscle force can have secondary effects on skeletal growth and development such as facial and dental morphology changes. In this study, we quantified temporal muscle thickness, circumference, and eccentricity of the skull and the head on T1-weighted magnetic resonance imaging (MRI) scans of the head of 15 Duchenne muscular dystrophy patients and 15 controls. Average temporal muscle thickness was significantly increased in patients (12.9 ± 5.2 mm) compared to controls (6.8 ± 1.4 mm) ( P < .0001), whereas the shape of the skull was significantly rounder compared to controls. Temporal muscle thickness and skull eccentricity were significantly negatively correlated in patients, and positively in controls. Hypertrophy of the temporal muscles and changes in skull eccentricity appear to occur early in the course of Duchenne muscular dystrophy. Further studies in younger patients are needed to confirm a causal relationship.
Abstract BACKGROUND The rise in neuroimaging has resulted in an increase of incidentally discovered brain lesions suspect for a neoplasm (‘incidentaloma’) in children. With the experience in our national hospital, we aim to diversify and broaden the knowledge on the management and natural history of pediatric incidentaloma. METHODS A retrospective analysis of all incidentaloma patients in the Princess Maxima Center for Pediatric Oncology from June 2018 until March 2023. RESULTS Our research population consists of 23 patients (10M/13F) with an incidentaloma. The lesions were mostly located in the cerebellum (21.7%), thalamus and ventricle (both 17%) and cerebral hemisphere (13%) The average age at diagnosis was 7.9 years (range 0-15 years) and the mean duration of follow-up was 4.6 years (range 0-11 years). The initial management was clinical and radiological follow-up in seventeen (74%), resection in five (22%) and biopsy in one patient (4%). Pathological examination performed in the six neurosurgical patients revealed low grade gliomas (LGGs) in three patients, medulloblastoma in one and plexus papilloma in one patient respectively. The pathological analysis of the patient with biopsy only was indecisive. One patient became symptomatic with clear tumor growth on imaging after 6.8 years of follow-up. Biopsy showed a H3K27M mutant diffuse midline glioma. She died 8.1 years after initial diagnosis. In 11 other patients radiographic changes (mostly tumor progression) were observed with a median of 23 months after diagnosis (range 3-70 months). Two of these underwent complete resection of an LGG. CONCLUSIONS For most incidentalomas, clinical and radiological follow-up is sufficient. As late disease progression can occur as seen in our patient who became symptomatic after 7 years, this follow-up should be long-term. Future studies should focus on identifying (radiological) prognostic factors for tumor progression, so follow-up of incidentaloma can be more personalized.
Duchenne and Becker muscular dystrophies are caused by out-of-frame and in-frame mutations, respectively, in the dystrophin encoding DMD gene. Molecular therapies targeting the precursormRNA are in clinical trials and show promising results. These approaches will depend on the stability and expression levels of dystrophin mRNA in skeletal muscles and heart. We report that the DMD gene is more highly expressed in heart than in skeletal muscles, in mice and humans. The transcript mutated in the mdx mouse model shows a 5′ to 3′ imbalance compared with that of its wild-type counterpart and reading frame restoration via antisense-mediated exon skipping does not correct this event. We also report significant transcript instability in 22 patients with Becker dystrophy, clarifying the fact that transcript imbalance is not caused by premature nonsense mutations. Finally, we demonstrate that transcript stability, rather than transcriptional rate, is an important determinant of dystrophin protein levels in patients with Becker dystrophy. We suggest that the availability of the complete transcript is a key factor to determine protein abundance and thus will influence the outcome of mRNA-targeting therapies.—Spitali, P., van den Bergen, J. D., Verhaart, I. E. C., Wokke, B., Janson, A.A.M., van den Eijnde, R., den Dunnen, J. T., Laros, J. F. J., Verschuuren, J. G. M., 't Hoen, P. A. C., Aartsma-Rus, A., DMD transcript imbalance determines dystrophin levels. FASEB J. 27, 4909–4916 (2013). www.fasebj.org
Abstract Becker muscular dystrophy (BMD) is the milder allelic variant of Duchenne muscular dystrophy, with higher dystrophin levels. To anticipate on results of interventions targeting dystrophin expression it is important to know the natural variation of dystrophin expression between different muscles and over time. Dystrophin was quantified using capillary Western immunoassay (Wes) in the anterior tibial (TA) muscle of 37 BMD patients. Variability was studied using two samples from the same TA biopsy site in nine patients, assessing nine longitudinal TA biopsies, and eight simultaneously obtained vastus lateralis (VL) muscle biopsies. Measurements were performed in duplicate with two primary antibodies. Baseline dystrophin levels were correlated to longitudinal muscle strength and functional outcomes. Results showed low technical variability and high precision for both antibodies. Dystrophin TA levels ranged from 4.8 to 97.7%, remained stable over a 3–5 year period, and did not correlate with changes in longitudinal muscle function. Dystrophin levels were comparable between TA and VL muscles. Intra-muscle biopsy variability was low (5.2% and 11.4% of the total variability of the two antibodies). These observations are relevant for the design of clinical trials targeting dystrophin production, and may urge the need for other biomarkers or surrogate endpoints.
Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).
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