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Page 339 Gonzalez Castillo et al. J Transl Genet Genom. 2025;9:338-51 https://dx.doi.org/10.20517/jtgg.2025.57

last 15-20 years, the mean age at diagnosis in the United States has been 4.9 years. While there is no cure for
DMD, advances in standard of care, including systemic corticosteroid use, cardioprotective interventions,
non-invasive ventilatory support and a multidisciplinary management model, have been shown to slow
[1]
disease progression and delay the onset of comorbidities . These improvements have led to a median life
expectancy of 30 years, with reported variability ranging from 21 to 40 years . The time of diagnosis, access
[3]
to available treatments, and other socio-economic factors can also affect survival.

Despite recent advancements, significant unmet needs remain in DMD treatment. Early diagnosis is
[4]
essential, as it allows timely intervention, improves clinical outcomes, and enhances quality of life .
MOLECULAR BASIS OF DISEASE
The DMD gene is located on the X chromosome and is the largest known human gene, comprising 79
exons (2.3 Mb) and encoding the protein dystrophin . Most mutations in the DMD gene are large deletions
[1]
(68%) or duplications (11%), and the remaining 21% are small pathogenic variants. Half of that 21% are
nonsense mutations, and small deletions, small insertions and splice site mutations represent 5%, 2% and
3%, respectively . Reports of variations in mutation-type frequency across different cohorts and countries
[5]
suggest that ethnic background may contribute to mutation diversity . Deletions and duplications are
[6-9]
concentrated with increased frequency in two hot spots in the DMD gene: exons 45-55 and exons 2-10 .
[10]
These regions have structural characteristics that increase susceptibility to instability and breakage, leading
to a higher rate of rearrangements and an increased mutation frequency [11-13] .

Dystrophin is a cytoskeletal protein localized to the sarcolemma, connecting the dystrophin-associated
protein complex (DAPC) and the intracellular cytoskeleton c-actin. This interaction protects the
sarcolemma against damage that can occur due to the forces involved in muscle contraction. Dystrophin
contains four functional domains: the actin-binding amino-terminal domain (ABD), a central rod domain,
a cysteine-rich domain, and a carboxy-terminal domain. Pathogenic variants in the DMD gene also abolish
dystrophin expression in stem cells, which affects cell polarity and mitosis. Stem cells lacking functional
dystrophin undergo aberrant asymmetric division and impaired myogenic differentiation [1,10] .

The pathophysiological mechanisms involved in DMD secondary to the lack of dystrophin lead to (1)
membrane instability, (2) calcium dysregulation within the muscle, (3) inflammation, (4) mitochondrial
dysfunction, and (5) increased oxidative stress. With repeated injury and regeneration over time, chronic
inflammation leads to muscle fiber fibrosis, reducing contractile function .
[14]

HISTORICAL BACKGROUND AND NATURAL HISTORY OF THE DISEASE
DMD was the first genetic muscle disorder to be systematically described. Early reports in the first part of
the 19th century were made by Meryon and Conte, followed by monographic works by Duchenne and
Gowers . The first unequivocal clinical and pathological reports of DMD were by Edward Meryon in his
[15]
paper, “On granular and fatty degeneration of the voluntary muscles” on November 28th, 1851. He also
[16]
recognized the X-linked recessive inheritance of the disease .

Duchenne examined a larger cohort of patients, refined the clinical observations and also introduced the
[17]
needle muscle biopsy technique to aid in diagnosis .

Over time, several natural history studies have described the clinical milestones of the disease including loss
of ambulation, need for ventilatory support, scoliosis, cardiomyopathy and mortality. Factors that can
impact the timing of key clinical milestones include the individual genotype and corticosteroid regimen .
[18]