Muscular Dystrophy
Muscular dystrophy (MD) refers to a heterogeneous group of inherited disorders characterized by progressive muscle weakness and degeneration. The pathogenesis of MD involves genetic mutations that disrupt the production or function of proteins essential for muscle fiber integrity, most notably dystrophin and related proteins in the muscle cell membrane. This deficiency leads to increased susceptibility of muscle fibers to mechanical stress, resulting in cycles of muscle fiber necrosis and regeneration, ultimately culminating in fibrosis and fatty replacement of muscle tissue. The clinical impact of MD is profound, with affected individuals experiencing progressive loss of muscle strength, impaired mobility, respiratory and cardiac complications, and, in severe forms, premature mortality. The disease spectrum ranges from early-onset, rapidly progressive forms to milder, late-onset variants, each with distinct genetic and clinical profiles.
Duchenne muscular dystrophy is the most common and severe form of MD, caused by mutations in the DMD gene leading to the absence of functional dystrophin protein. Symptoms typically manifest between ages 2 and 5, with progressive proximal muscle weakness, calf pseudohypertrophy, Gowers' sign, and delayed motor milestones. Affected individuals often lose ambulation by their early teens and may develop cardiomyopathy and respiratory insufficiency, with life expectancy historically limited to the third decade.
Becker muscular dystrophy results from mutations in the same DMD gene as Duchenne, but allows for the production of partially functional dystrophin. BMD has a later onset and a slower progression than DMD, with variable clinical severity. Patients may retain ambulation into adulthood and have a more favorable prognosis, though they remain at risk for cardiac complications.
Emery-Dreifuss muscular dystrophy is characterized by early contractures of the elbows, Achilles tendons, and neck, followed by slowly progressive muscle weakness and wasting, most prominent in the humeroperoneal muscles. Cardiac conduction defects are a hallmark and can be life-threatening. EDMD can be inherited in X-linked, autosomal dominant, or autosomal recessive patterns, depending on the mutated gene.
Limb-girdle muscular dystrophy encompasses a diverse group of disorders affecting the pelvic and shoulder girdle muscles. Onset varies from childhood to adulthood, with progressive weakness and wasting of proximal limb muscles. The genetic basis is highly heterogeneous, involving mutations in sarcoglycans, dysferlin, calpain-3, and other proteins. Severity and progression are variable.
Facioscapulohumeral muscular dystrophy primarily affects the facial, shoulder, and upper arm muscles, with onset typically in adolescence or early adulthood. It is caused by genetic changes leading to inappropriate expression of the DUX4 gene. The disease progresses slowly, and severity is variable, but some patients may develop significant disability.
Myotonic dystrophy is a multisystemic disorder characterized by myotonia (delayed muscle relaxation), progressive muscle weakness, cataracts, cardiac conduction defects, and endocrine abnormalities. It is caused by expanded nucleotide repeats in the DMPK (type 1) or CNBP (type 2) genes and exhibits autosomal dominant inheritance. Severity and age of onset are highly variable.
Congenital muscular dystrophy refers to a group of MDs with onset at birth or in early infancy, presenting with hypotonia, muscle weakness, joint contractures, and delayed motor development. CMDs are genetically diverse, with mutations affecting proteins such as laminin, collagen VI, and integrins, and may be associated with brain and eye abnormalities.
Oculopharyngeal muscular dystrophy is characterized by progressive ptosis, dysphagia, and proximal limb weakness, typically manifesting in mid-adulthood. It results from expansions in the PABPN1 gene and follows an autosomal dominant inheritance pattern. The disease progresses slowly but can significantly impact quality of life.
Muscular dystrophies collectively have an estimated global prevalence of approximately 19.8 per 100,000 individuals, though prevalence varies significantly by subtype and population. Duchenne muscular dystrophy is the most common childhood-onset form, affecting about 1 in 3,500 to 5,000 live male births worldwide, while Becker muscular dystrophy is less common, with a prevalence of 1 in 18,000 male births. Facioscapulohumeral muscular dystrophy is one of the most prevalent adult-onset forms, with an estimated prevalence of 1 in 8,000 to 20,000 individuals. Myotonic dystrophy has a prevalence of 1 in 8,000 to 20,000, varying by geographic region. The other forms, such as limb-girdle, Emery-Dreifuss, congenital, and oculopharyngeal muscular dystrophies, are rarer and display considerable genetic and phenotypic heterogeneity. The disease burden is higher in males for X-linked forms, while autosomal forms affect both sexes. Advances in genetic diagnosis and improved clinical recognition have contributed to increased detection rates, though underdiagnosis remains a challenge in many regions.
The diagnostic approach to muscular dystrophy is multifaceted, integrating clinical evaluation, laboratory testing, electrophysiological studies, imaging, and genetic analysis. The initial assessment includes a thorough history and physical examination, focusing on the pattern of muscle weakness, age at onset, family history, and associated systemic features such as cardiac or respiratory involvement. Laboratory investigations typically reveal elevated serum creatine kinase (CK) levels, indicative of muscle damage. Electromyography (EMG) can demonstrate myopathic changes, while nerve conduction studies help exclude neuropathic processes. Muscle imaging, particularly magnetic resonance imaging (MRI), aids in characterizing the distribution and severity of muscle involvement. Muscle biopsy may be performed to assess histopathological features such as fiber necrosis, regeneration, fibrosis, and specific protein deficiencies by immunohistochemistry or Western blot analysis. However, the definitive diagnosis relies increasingly on genetic testing, which can identify pathogenic variants in genes associated with specific MD subtypes. Molecular techniques such as multiplex ligation-dependent probe amplification (MLPA), next-generation sequencing (NGS) panels, and whole-exome sequencing are commonly employed. Diagnostic criteria are tailored to the suspected subtype, incorporating clinical, biochemical, histological, and genetic data to establish a precise diagnosis, inform prognosis, and guide management.
Several pharmacological agents are available for the management of muscular dystrophy, each with distinct mechanisms and indications. Vamorolone is a corticosteroid analog developed to reduce inflammation and muscle degeneration, offering a favorable safety profile compared to traditional steroids. Givinostat hydrochloride acts as a histone deacetylase inhibitor, targeting epigenetic pathways to modulate muscle repair and reduce fibrosis. Delandistrogene moxeparvovec is a gene therapy designed to deliver a functional micro-dystrophin gene to muscle cells, aiming to restore dystrophin expression in affected individuals. Casimersen is an antisense oligonucleotide indicated for patients with specific genetic mutations, promoting exon skipping to facilitate production of a truncated but functional dystrophin protein. Viltolarsen and golodirsen are also antisense oligonucleotides that induce exon skipping for certain DMD mutations, thereby enhancing dystrophin synthesis. Eteplirsen is another exon-skipping agent, used to treat patients amenable to exon 51 skipping, with the goal of increasing dystrophin production. Ataluren is a small molecule that enables ribosomal read-through of premature stop codons in the dystrophin gene, potentially restoring functional protein in patients with nonsense mutations. Deflazacort is a glucocorticoid with anti-inflammatory and immunosuppressive effects, widely used to slow disease progression and preserve muscle strength. Prednisolone, another glucocorticoid, is similarly employed to reduce inflammation and delay loss of ambulation in affected individuals. These therapies represent a range of pharmacological strategies targeting the underlying molecular defects, inflammatory pathways, and symptomatic progression of muscular dystrophy.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
 | vamorolone (Rec INN) | 13209-41-1 | C22 H28 O4 | 356.455 |
 | givinostat hydrochloride (Prop INNM; USAN) | 732302-99-7 | C24 H27 N3 O4 . Cl H . H2 O | 475.965 |
| delandistrogene moxeparvovec (Rec INN; USAN); delandistrogene moxeparvovec-rokl | 2305040-16-6 | |||
| casimersen (Rec INN; USAN) | 1422958-19-7 | |||
| viltolarsen (Rec INN; USAN) | 2055732-84-6 | |||
| golodirsen (Rec INN; USAN) | 1422959-91-8 | |||
| eteplirsen (USAN) | 1173755-55-9 | |||
 | ataluren (Prop INN; USAN) | 775304-57-9 | C15 H9 F N2 O3 | 284.242 |
 | azacort; deflazacort (Rec INN; USAN; BAN); oxazacort | 14484-47-0 | C25 H31 N O6 | 441.517 |
 | 1-dehydrocortisol; prednisolone | 50-24-8 | C21 H28 O5 | 360.444 |
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