Muscle Disorders
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
Others: Utrophin is a protein that is expressed at neuromuscular and musculotendinous junctions. It shows homology to dystrophin. Upregulation of utrophin may be able to compensate for some of the effects of dystrophin loss.Inducing muscle hypertrophy by upregulating genes involved in muscle growth, such as insulin-like growth factor 1 (IGF-1) or L-arginine, may help to fight muscle wasting.Blocking the effect of myostatin as a negative regulator of muscle mass could have a similar beneficial effect.
The locomotor system
C. Simon Herrington in Muir's Textbook of Pathology, 2020
Mutations in the dystrophin gene on the short arm of chromosome X cause both disorders and its protein product, dystrophin, has been characterized. Normal dystrophin is a large molecular component of the sarcolemmal plasma membrane. When the gene is mutated, dystrophin is either absent or undetectable as in Duchenne dystrophy, or of abnormal constitution as in Becker dystrophy. The clinical phenotypes correlate well with the quantity and quality of dystrophin (Figure 13.49). In Duchenne dystrophy two-thirds of mutations are inherited from the mother. The remaining third of mutations are new mutations, reflecting the large size of the gene, which contains several hot spots. Most patients with Duchenne dystrophy have a deletion or duplication resulting in the truncation of translation and a small unstable molecule. The muscle biopsy shows a characteristic appearance with variation in muscle fibre size, some showing necrosis. In the later stages muscle is replaced by fat and fibrous tissue (Figure 13.50). Diagnosis can now be made by sequencing of DNA to identify mutation of the dystrophin gene. This is done on a blood sample.
Part 1: ‘Where’s my sitcom?’ The young adult’s voice
Rita Pfund, Susan Fowler-Kerry, Sister Frances Dominica in Perspectives on Palliative Care for Children and Young People, 2017
For those of you who aren’t familiar with the condition, Duchenne Muscular Dystrophy is essentially a mutation in the dystrophin gene – a gene responsible for the creation of protein that creates a kind of membrane around the muscle. With no dystrophin, the muscle degenerates and is replaced with a combination of fat and fibrotic tissue – in layman’s terms, this gives the muscles no substance. The effect of this really is the progressive weakening of every single muscle in the body; first causing difficulty in walking, which eventually leads to a dependence on a wheelchair; then curvatures of the spine that if not treated accordingly will lead to skeletal deformities, and to wrap things off the cardiac and respiratory muscles experience a ‘wasting’ effect, leading to respective difficulties in later life. Phew. I do worry myself sometimes with how easy it is for me to rattle the above description off without so much as a shudder, but hey that was the gist of what I was told and I think that upbringing is what made me so content with my situation. The approach for my parents, then, despite all that – and for me to this day – runs along the lines of ‘well, let’s see what happens’. To give you an example; I think one of the first things they did aft er I was diagnosed was sign me up for judo practice: can you believe?
Next steps for the optimization of exon therapy for Duchenne muscular dystrophy
Published in Expert Opinion on Biological Therapy, 2023
Galina Filonova, Annemieke Aartsma-Rus
Duchenne muscular dystrophy (DMD) is an X-linked inherited muscle disorder, caused by an absence of a functional dystrophin protein. Dystrophin is a crucial protein for the maintenance of muscle fiber stability. It links the intracellular actin cytoskeleton and extracellular matrix through N-terminal and C-terminal domains, respectively, thus forming the dystrophin protein complex (DPC). The DPC functions as a structural complex to mechanically stabilize the muscle membrane, and as a signaling complex. Due to the absence of dystrophin, the DPC cannot properly form. Consequently, muscle fibers of DMD patients are susceptible to damage during contraction, leading to chronic inflammation, impaired regeneration, and fibrosis formation [1]. DMD is primarily diagnosed in early childhood when clinical signs and symptoms such as muscle weakness, clumsiness, and difficulties with climbing and walking occur. Further testing for serum creatine kinase level, which is increased in DMD patients, and testing for DMD gene mutations confirm a suspected diagnosis of DMD. The disease progresses over the lifespan gradually leading at first to skeletal muscle dysfunction and loss of ambulation, next to the loss of arm function, dysfunction of respiratory and cardiac muscles, and death usually in the 3rd to 4th decade [2].
Trunk Control and Upper Limb Function of Walking and Non-walking Duchenne Muscular Dystrophy Individuals
Published in Developmental Neurorehabilitation, 2021
Ana Lucia Yaeko da Silva Santos, Flaviana Kelly de Lima Maciel, Francis Meire Fávero, Luis Fernando Grossklauss, Cristina dos Santos Cardoso de Sá
The absence of dystrophin causes weakness in the muscles1 responsible for functional independence in individuals with Duchenne Muscular Dystrophy (DMD). As proximal to distal2 muscle weakness progresses, individuals are increasingly dependent on help for self-care activities, and this functional dependence impacts their quality of life,3 as well as that of their caregivers.4 These routine activities require both trunk control and upper limb (UL) functional ability.5 The trunk interacts with UL and head by being part of a kinematic chain and by providing a stable basis. When trunk control becomes impaired, it may have consequences for the execution of UL tasks.6,7 The progression of the disease shows that individuals with DMD find it difficult to maintain both seating and orthostatism without support, as well as to reach these postures in the anterior and lateral direction, which may indicate impairment in anticipatory8 postural adjustments.
Developments in reading frame restoring therapy approaches for Duchenne muscular dystrophy
Published in Expert Opinion on Biological Therapy, 2021
Anne-Fleur E. Schneider, Annemieke Aartsma-Rus
However, though there will be variation between patients, we believe that restoring even low amounts of dystrophin will slowdown the disease progression to some extent. The challenge lies in measuring this slower progression in a clinical trial setting [25]. The rate of functional decline as measured with a certain outcome measure is generally not linear, but is stable in some patients, while it cannot be measured in others, who have already lost that function. One thus has to identify the patients able to perform the functional tests for the duration of the clinical trial but who without intervention would show a measurable decline. Only then can a slower decline be picked up reliably. Two collaborative initiatives (the collaborative trajectory analysis project (cTAP) and the Duchenne muscular dystrophy regulatory science consortium (D-RSC)) are generating models to facilitate optimize patient selection for clinical trials [119–122].
Related Knowledge Centers
- Costamere
- Cytoplasm
- Cytoskeleton
- Protein
- Cell Membrane
- Extracellular Matrix
- Muscle Cell
- Protein Complex
- Dystrophin-Associated Protein Complex
- Sarcoglycan