Duchenne muscular dystrophy is a devastating inherited neuromuscular disorder that affects one in 3300 live male births. Although the responsible gene and its product, dystrophin, have been ...characterized for more than 15 years, and a mouse model ( mdx ) has been developed, comprehensive understanding of the mechanism leading from the absence of dystrophin to the muscular degeneration is still debated. First, dystrophin is considered a key structural element in the muscle fiber, and the primary function of the dystrophin-associated protein complex is to stabilize plasma membrane, although a role of signaling is still possible. Mechanically induced damage through eccentric contractions puts a high stress on fragile membranes and provokes micro-lesions that could eventually lead to loss of calcium homeostasis, and cell death. Altered regeneration, inflammation, impaired vascular adaptation, and fibrosis are probably downstream events that take part in the muscular dystrophy and that probably vary a lot along species (i.e., mdx mice), probands within families, stressing the importance of epigenic factors. Because no etiologic therapy is available for Duchenne muscular dystrophy, a better understanding of the primary and downstream mechanisms could prove useful for producing new adjuvant treatments. All pathophysiologic mechanisms are reviewed together with perspectives on management.
This text is a one-stop resource on best practice in the management of the most frequent neuromuscular disorders and the key body functions affected by them.
Summary Background Duchenne muscular dystrophy is caused by dystrophin deficiency and muscle deterioration and preferentially affects boys. Antisense-oligonucleotide-induced exon skipping allows ...synthesis of partially functional dystrophin. We investigated the efficacy and safety of drisapersen, a 2′-O-methyl-phosphorothioate antisense oligonucleotide, given for 48 weeks. Methods In this exploratory, double-blind, placebo-controlled study we recruited male patients (≥5 years of age; time to rise from floor ≤7 s) with Duchenne muscular dystrophy from 13 specialist centres in nine countries between Sept 1, 2010, and Sept 12, 2012. By use of a computer-generated randomisation sequence, we randomly allocated patients (2:2:1:1; block size of six; no stratification) to drisapersen 6 mg/kg or placebo, each given subcutaneously and either continuously (once weekly) or intermittently (nine doses over 10 weeks). The primary endpoint was change in 6-min walk distance (6MWD) at week 25 in patients in the intention-to-treat population for whom data were available. Safety assessments included renal, hepatic, and haematological monitoring and recording of adverse events. This trial is registered with ClinicalTrials.gov , number NCT01153932. Findings We recruited 53 patients: 18 were given continuous drisapersen, 17 were given intermittent drisapersen, and 18 were given placebo (continuous and intermittent groups combined). At week 25, mean 6MWD had increased by 31·5 m (SE 9·8) from baseline for continuous drisapersen, with a mean difference in change from baseline of 35·09 m (95% CI 7·59 to 62·60; p=0·014) versus placebo. We recorded no difference in 6MWD changes from baseline between intermittent drisapersen (mean change −0·1 SE 10·3) and placebo (mean difference 3·51 m −24·34 to 31·35) at week 25. The most common adverse events in drisapersen-treated patients were injection-site reactions (14 patients given continuous drisapersen, 15 patients given intermittent drisapersen, and six given placebo) and renal events (13 for continuous drisapersen, 12 for intermittent drisapersen, and seven for placebo), most of which were subclinical proteinuria. None of the serious adverse events reported (one for continuous, two for intermittent, and two for placebo) resulted in withdrawal from the study. Interpretation Continuous drisapersen resulted in some benefit in 6MWD versus placebo at week 25. The safety findings are similar to those from previous studies. Ambulation improvements in this young population with early-stage Duchenne muscular dystrophy are encouraging but need to be confirmed in larger studies. Funding GlaxoSmithKline, Prosensa Therapeutics BV (a subsidiary of Prosensa Holding NV).
Abstract Congenital muscular dystrophies (CMDs) are early onset disorders of muscle with histological features suggesting a dystrophic process. The congenital muscular dystrophies as a group ...encompass great clinical and genetic heterogeneity so that achieving an accurate genetic diagnosis has become increasingly challenging, even in the age of next generation sequencing. In this document we review the diagnostic features, differential diagnostic considerations and available diagnostic tools for the various CMD subtypes and provide a systematic guide to the use of these resources for achieving an accurate molecular diagnosis. An International Committee on the Standard of Care for Congenital Muscular Dystrophies composed of experts on various aspects relevant to the CMDs performed a review of the available literature as well as of the unpublished expertise represented by the members of the committee and their contacts. This process was refined by two rounds of online surveys and followed by a three-day meeting at which the conclusions were presented and further refined. The combined consensus summarized in this document allows the physician to recognize the presence of a CMD in a child with weakness based on history, clinical examination, muscle biopsy results, and imaging. It will be helpful in suspecting a specific CMD subtype in order to prioritize testing to arrive at a final genetic diagnosis.
This magnetoencephalography (MEG) study investigates how procedural sequence learning performance is related to prior brain resting-state functional connectivity (rsFC), and to what extent sequence ...learning induces rapid changes in brain rsFC in school-aged children.
Procedural learning was assessed in 30 typically developing children (mean age ± SD: 9.99 years ± 1.35) using a serial reaction time task (SRTT). During SRTT, participants touched as quickly and accurately as possible a stimulus sequentially or randomly appearing in one of the quadrants of a touchscreen. Band-limited power envelope correlation (brain rsFC) was applied to MEG data acquired at rest pre- and post-learning. Correlation analyses were performed between brain rsFC and sequence-specific learning or response time indices.
Stronger pre-learning interhemispheric rsFC between inferior parietal and primary somatosensory/motor areas correlated with better subsequent sequence learning performance and faster visuomotor response time. Faster response time was associated with post-learning decreased rsFC within the dorsal extra-striate visual stream and increased rsFC between temporo-cerebellar regions.
In school-aged children, variations in functional brain architecture at rest within the sensorimotor network account for interindividual differences in sequence learning and visuomotor performance. After learning, rapid adjustments in functional brain architecture are associated with visuomotor performance but not sequence learning skills.
Developmental coordination disorder (DCD) is a heterogeneous condition. Besides motor impairments, children with DCD often exhibit poor visual perceptual skills and executive functions. This study ...aimed to characterize the motor, perceptual, and cognitive profiles of children with DCD at the group level and in terms of subtypes. A total of 50 children with DCD and 31 typically developing (TD) peers (7–11 years old) underwent a comprehensive neuropsychological (15 tests) and motor (three subscales of the Movement Assessment Battery for Children-2) assessment. The percentage of children with DCD showing impairments in each measurement was first described. Hierarchical agglomerative and K-means iterative partitioning clustering analyses were then performed to distinguish the subtypes present among the complete sample of children (DCD and TD) in a data-driven way. Moderate to large percentages of children with DCD showed impaired executive functions (92%) and praxis (meaningless gestures and postures, 68%), as well as attentional (52%), visual perceptual (46%), and visuomotor (36%) skills. Clustering analyses identified five subtypes, four of them mainly consisting of children with DCD and one of TD children. These subtypes were characterized by: (i) generalized impairments (8 children with DCD), (ii) impaired manual dexterity, poor balance (static/dynamic), planning, and alertness (15 DCD and 1 TD child), (iii) impaired manual dexterity, cognitive inhibition, and poor visual perception (11 children with DCD), (iv) impaired manual dexterity and cognitive inhibition (15 DCD and 5 TD children), and (v) no impairment (25 TD and 1 child with DCD). Besides subtle differences, the motor and praxis measures did not enable to discriminate between the four subtypes of children with DCD. The subtypes were, however, characterized by distinct perceptual or cognitive impairments. These results highlight the importance of assessing exhaustively the perceptual and cognitive skills of children with DCD.
Three new therapies for spinal muscular atrophy (SMA) have been approved by the United States Food and Drug Administration and the European Medicines Agency since 2016. Although these new therapies ...improve the quality of life of patients who are symptomatic at first treatment, administration before the onset of symptoms is significantly more effective. As a consequence, newborn screening programs have been initiated in several countries. In 2018, we launched a 3-year pilot program to screen newborns for SMA in the Belgian region of Liège. This program was rapidly expanding to all of Southern Belgium, a region of approximately 55,000 births annually. During the pilot program, 136,339 neonates were tested for deletion of exon 7 of SMN1, the most common cause of SMA. Nine SMA cases with homozygous deletion were identified through this screen. Another patient was identified after presenting with symptoms and was shown to be heterozygous for the SMN1 exon 7 deletion and a point mutation on the opposite allele. These ten patients were treated. The pilot program has now successfully transitioned into the official neonatal screening program in Southern Belgium. The lessons learned during implementation of this pilot program are reported.
The overlap/distinctiveness between Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) has been increasingly investigated in recent years, particularly since the DSM-5 ...allows the dual diagnosis of ASD and ADHD, but the underlying brain mechanisms remain unclear. Although both disorders are associated with brain volumetric abnormalities, it is necessary to unfold the shared and specific volume abnormalities that could contribute to explain the similarities and differences in the clinical and neurocognitive profiles between ADHD and ASD. In this voxel-based morphometry (VBM) study, regional grey matter volumes (GMV) were compared between 22 children with ADHD, 18 children with ASD and 17 typically developing (TD) children aged 8 to 12 years old, controlling for age and total intracranial volume. When compared to TD children or children with ASD, children with ADHD had a larger left precuneus, and a smaller right thalamus, suggesting that these brain abnormalities are specific to ADHD relative to ASD. Overall, this study contributes to the delineation of disorder-specific structural abnormalities in ADHD and ASD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Synthesizes evidence from 12 studies on cognitive and communicative impacts in SMA, focusing on nuanced functional outcomes.•Highlights cognitive variability in SMA1, revealing subtle challenges in ...SMA2 and 3, and stresses tailored assessment methodologies.•Identifies communication barriers in SMA, emphasizing the urgency of investigating their potential interplay with cognitive functions.•Stresses integrating cognitive and communicative assessments into SMA management, to enhanceunderstanding of treatment impacts.•Calls for standardized, sensitive tools to evaluate cognition and communication, ensuring consistent assessments across SMA phenotypes.
The spectrum of clinical phenotypes associated with a deficiency or dysfunction of collagen VI in the extracellular matrix of muscle are collectively termed 'collagen VI-related myopathies' and ...include Ullrich congenital muscular dystrophy, Bethlem myopathy and intermediate phenotypes. To further define the clinical course of these variants, we studied the natural history of pulmonary function in correlation to motor abilities in the collagen VI-related myopathies by analysing longitudinal forced vital capacity data in a large international cohort. Retrospective chart reviews of genetically and/or pathologically confirmed collagen VI-related myopathy patients were performed at 10 neuromuscular centres: USA (n = 2), UK (n = 2), Australia (n = 2), Italy (n = 2), France (n = 1) and Belgium (n = 1). A total of 486 forced vital capacity measurements obtained in 145 patients were available for analysis. Patients at the severe end of the clinical spectrum, conforming to the original description of Ullrich congenital muscular dystrophy were easily identified by severe muscle weakness either preventing ambulation or resulting in an early loss of ambulation, and demonstrated a cumulative decline in forced vital capacity of 2.6% per year (P < 0.0001). Patients with better functional abilities, in whom walking with/without assistance was achieved, were initially combined, containing both intermediate and Bethlem myopathy phenotypes in one group. However, one subset of patients demonstrated a continuous decline in pulmonary function whereas the other had stable pulmonary function. None of the patients with declining pulmonary function attained the ability to hop or run; these patients were categorized as intermediate collagen VI-related myopathy and the remaining patients as Bethlem myopathy. Intermediate patients had a cumulative decline in forced vital capacity of 2.3% per year (P < 0.0001) whereas the relationship between age and forced vital capacity in patients with Bethlem myopathy was not significant (P = 0.1432). Nocturnal non-invasive ventilation was initiated in patients with Ullrich congenital muscular dystrophy by 11.3 years (±4.0) and in patients with intermediate collagen VI-related myopathy by 20.7 years (±1.5). The relationship between maximal motor ability and forced vital capacity was highly significant (P < 0.0001). This study demonstrates that pulmonary function profiles can be used in combination with motor function profiles to stratify collagen VI-related myopathy patients phenotypically. These findings improve our knowledge of the natural history of the collagen VI-related myopathies, enabling proactive optimization of care and preparing this patient population for clinical trials.
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