PracticeUpdate

Low Dystrophin Protein Levels Linked to Attenuation of Duchenne Muscular Dystrophy Progression

The findingmay halt clinical evaluations of therapies designed to restore normal dystrophin levels in patients with DMD S pontaneous exon skipping and production of low dystrophin levels may impact the clinical course of

over 2 years than those with mutations amenable to exon 53 or 51 skipping. A separate study showed that individu- als with mutations amenable to exon 44 skipping exhibited higher baseline results in the 6-minute walk test and had more modest declines at 12 months than those with mutations amenable to skipping exons 45 or 53 (difference not significant). Evidence suggests that individuals with DMD and deletions of exons 3 to 7 also experience a milder phenotype and express low levels of dystrophin. A recent case study described an indi- vidual aged 10 years with a nonsense mutation in exon 42 and a mild phenotype presumed as the result of spontaneous exon 42 skipping and subsequent dys- trophin production. Dr. Charleston concluded that these find- ings demonstrate that spontaneous exon skipping and production of low dystrophin levels may impact the clinical course of DMD. Insights are offered in this study regard- ing the interpretation of results of clinical trials evaluating therapeutic interventions designed to restore dystrophin in individ- uals with DMD. www.practiceupdate.com/c/70788

Dr. Charleston and colleagues explored potential associations between low dys- trophin levels in individuals with DMD and the attenuation of disease progression. They conducted a literature search to identify recent, relevant evaluations of the natural occurrence of exon skipping and clinical disease progression in individuals with DMD. A body of evidence indicated that individ- uals with DMD with mutations amenable to exon 44 skipping, experience a milder disease course than other DMD sub- groups. In one natural history study, individuals with mutations amenable to exon 44 skipping, experienced a slower rate of disease progression, with loss of ambulation 2 years later than those with other mutations. However, traces of dystrophin were detected in only three out of six individu- als by immunohistochemistry, and in zero out of four individuals by Western blot analysis using clinical diagnostic methods. Notably, in a sub-analysis of individuals treated with corticosteroids, those with mutations amenable to exon 44 skipping did not achieve a median age of loss of ambulation during follow-up. Those with mutations amenable to exon 51 skipping were a median of 13.0 years of age at loss of ambulation. In a separate analysis of individuals with DMD treated with corticosteroids, median age at loss of ambulation was 15.2 years in those amenable to exon 44 skipping and 10.5 years in those amenable to exon 51 skipping. Spontaneous low-level exon 44 skipping in these individuals is thought to facilitate restoration of the mRNA reading frame. Such restoration facilitates dystrophin expression and/or the presence of dys- trophin-positive muscle fibers. An analysis utilizing the NorthStar Ambulatory Assessment demonstrated that individuals with mutations amenable to exon 44 skipping declined more slowly

Duchenne muscular dystrophy (DMD) and the progression of this disease may be attenuated, suggests a systematic literature review reported at ICNMD 2018. J.S. Charleston,MD, of SareptaTherapeutics, Inc, Cambridge, Massachusetts, explained that DMD is a degenerative, fatal, X-linked recessive disorder that affects one in 3500 to 5000 male newborns worldwide. DMD gene mutations cause the absence of dystrophin in muscle fibers. The absence of dystrophin leads to progressive loss of muscle function. Dystrophin is a protein located between each muscle fiber’s plasma membrane (sarcolemma) and the outermost layer of myofilaments in themuscle fiber (myofiber). It is a cohesiveprotein, linkingactin filaments to another support protein that resides on the inside surface of each muscle’s sarco- lemma. In turn, this support protein on the inside surface of the sarcolemma links to two other consecutive proteins for a total of three linking proteins. The final linking pro- tein is attached to the fibrous endomysium of the entire muscle fiber. Dystrophin supports muscle fiber strength. The absence of dystrophin reduces muscle stiffness, increases sarcolemmal deform- ability, and compromises the mechanical stability of costameres and their connec- tions to nearby myofibrils. Biomechanical properties of the sarcolemma and its links through costameres to the con- tractile apparatus have been measured. Dystrophin helps prevent muscle fiber injury. Movement of thin filaments (actin) creates a pulling force on the extracellular connective tissue that eventually becomes the tendon of the muscle. The precise amount of dystrophin associ- ated with clinically meaningful benefit in DMD is unclear, though numerous findings indicate that small amounts of dystrophin, associated with natural mechanisms such as spontaneous exon skipping, may lead to slower disease progression.

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