Duchenne’s muscular dystrophy

Duchenne muscular dystrophy: associated with mutations in the dystrophin gene, and characterized by rapid progression of muscle degeneration, eventually leading to loss of skeletal muscle control, respiratory failure, and death.

Severe debilitating childhood neuromuscular disease with progressive weakness in skeletal muscles, cardiomyopathy, respiratory failure and can affect the brain as well.

Signs of Duchenne muscular dystrophy usually occur in early childhood.

Characterized by the absence of the dystrophin protein, and is considered a disease caused by muscle fiber fragility.

Impaired muscle stem cells have an important role in muscle degeneration.

x-linked muscle wasting disease.

Affects 1 in 5000-6000 newborn boys.

Most common muscular dystrophy in children, and predominantly affects males.

Results in loss of ambulation between ages seven and 13 years, and this in the teens or 20s.

Symptoms include muscle weakness, clumsiness, and difficulty, going up and downstairs

Untreated children,p progress to a loss of ambulation by 10 years of age.

Fatal respiratory, or cardiac complications commonly develop in the second and third decades of life.

Average age at diagnosis is five years.

Most all require wheelchair for mobility by age 12 years.

Most die in early adulthood.

Duchenne muscular dystrophy in particular is associated with shortened life expectancy.

Prevalence estimated one in 3500 male births.

Caused by deletions and duplications of one or more exons or point mutations in the 2.4-Mb DMD gene.

The 2.4-Mb DMD gene encodes for dystrophin, a protein that is essential for sarcolemma integrity.

Mutations in the dystrophin gene, leading to disruption of the open reading frame, dystrophin deficiency at the myofiber membrane, and fiber degeneration.

Frameshift mutations in any of the 79 exons that produce an unstable or non-functional protein will cause Duchenne’s muscular dystrophy.

Dystrophin deficiency produces severe to asymptomatic phenotypes.

Failure to produce dystrophin results in disconnection of the cytoskeletal elements from the sarcolemma.

In patients with the disease, contractions of the muscle causes microtears in the sarcolemma, cell injury, cell death, and ultimately loss of muscle function.

Most DMD patients become wheelchair-dependent early in life, and the gradual development of cardiac hypertrophy, a result of severe myocardial fibrosis, typically results in premature death in the first two or three decades of life. 

In Becker’s muscular dystrophy mutations in the dystrophin gene is also present, but the open reading frame is maintained and has a milder phenotype and longer life span.

The deletions of one or several exons of the dystrophin DMD gene can result in the disease known as Becker’s muscular dystrophy which has a milder phenotype and longer survival.

Affects striated muscles of the extremities, diaphragm, and heart.

Associated with progressive loss of muscle mass eventually leading to impaired ambulation and paralysis.

Muscles accumulate calcium deposits as they undergo myofiber degeneration and necrosis with replacement of fat and connective tissue.

Survival improved with modern respiratory techniques and glucocorticoid treatment.

With treatments that include steroids, assistive ventilation, spinal surgery and measures to manage cardiomyopathy related to heart failure, some patients are now living into the 30s or 40s.

Intramuscular administration of the antisense oligonucleotide PRO051 which can induce the skipping of exon 51 during pre-messenger RNA splicing of the dystrophin gene and to facilitate new dystrophin expression in muscle fiber membranes was associated with a modest improvement in a 6 minute walk after 12 weeks of treatment (Goemans NM et al).

Deflazacort(Emflaza) a corticosteroid approved for treatment.

Corticosteroids increases muscle strength and function in DMD, and it is considered for all patients.

Daily prednisone or deflazacort results in better outcomes compared with intermittent prednisone.

Eteplirsen, an oligonucleotide agent that induces the skipping of exon 51.

Eteplirsen functions by hybridizing to a site within exon 51, blocking the splicing machinery from binding and forcing it to skip the exon to correct the frameshift mutation.

A weekly intravenous infusion Eteplirsen yielded slight increase in the shortened mRNA encoding DMD and in the expression of dystrophin, and some preservation of the six minute walk distance.

Exon 52 is spliced to exon 50, generating a shortened but still functional version of dystrophin.

No cure exists.