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- Primary inherited myopathies caused by dysfunctional proteins of muscle fibers and extracellular matrix
- Distribution of weakness, other associated symptoms, and disease prognosis depend on the specific gene affected and severity of the mutation.
- Duchenne muscular dystrophy (DMD)
- Highest incidence muscular dystrophy, X-linked inheritance, early onset, progressive
- Patients are wheelchair-dependent by age 13 years.
- Becker muscular dystrophy (BMD)
- Less severe phenotype compared to DMD; also caused by mutation in DMD gene; later onset and milder clinical course
- Distinction from DMD is clinical: Patients are usually wheelchair-dependent at age 16 years.
- Collectively referred to as dystrophinopathies
- Myotonic muscular dystrophy (MMD)
- Myotonia (slow relaxation after muscle contraction), distal and facial weakness
- Second most common inherited muscle disease
- Facioscapulohumeral muscular dystrophy (FSHMD)
- Facial and shoulder muscles most affected
- Third most common inherited muscle disease
- Limb-girdle muscular dystrophy (LGMD)
- Proximal weakness and atrophy, variable prognosis with many different identified mutations
- Oculopharyngeal muscular dystrophy (OPMD)
- Usually adult-onset, affects extraocular and pharyngeal muscles; presents with ptosis and dysphagia
- Emery-Dreifuss muscular dystrophy (EDMD)
- Triad of early development of joint contractures, slowly progressive muscle wasting, and cardiomyopathy; can present as sudden death in apparently healthy, young adults
- Congenital muscular dystrophies (CMD)
- Heterogeneous group of autosomal recessive myopathic diseases presenting in infancy, with generally poor prognosis
- Include Fukuyama CMD, Ullrich CMD, Walker-Warburg syndrome, muscle-eye-brain disease
- Duchenne: 1/3,600 male births (1)
- Myotonic dystrophy: 1/10,000 births
- CMD: 0.99 per 100,000
- Other muscular dystrophies vary widely by population but are generally rare.
Etiology and Pathophysiology
Mutations affect proteins connecting cytoskeleton to cell membrane and extracellular matrix, causing muscle fibers to become fragile and easily damaged; muscle weakness and atrophy result.
- Defective protein is dystrophin, product of the largest human gene, DMD; Duchenne phenotype results from mutations that cause profound loss of dystrophin, the protein involved in calcium transport in muscle cells and stabilizing fibers during contraction.
- Becker phenotype results from less severe mutations in DMD gene; patients have low but detectable levels of functional dystrophin.
- MMD: Trinucleotide repeat expansion in the untranslated region of the gene DMPK on chromosome 19; encodes myotonin–protein kinase
- LGMD: mutations in genes encoding proteins associated with dystrophin: Calpain-, dysferlin-, and fukutin-related proteins are affected most commonly.
- EDMD: Dysfunctional proteins are associated with the nuclear membrane in muscle fibers; emerin in X-linked form, lamin A/C in autosomal forms
- OPMD: Trinucleotide repeat expansion in PABPN1 results in nuclear inclusions in muscle cells by hampering normal transport of mRNA from the nucleus.
- FSHMD: deletion in untranslated region of chromosome 4; function of deleted genes is unclear, although the most accepted concept is that they likely affect the expression of multiple genes by epigenetic effects.
- Duchenne and Becker muscular dystrophies
- Gene located at Xp21
- 30% of affected males have a de novo mutation (mother is not a carrier).
- 20% of female carriers have some manifestation of the mutation (usually mild muscle weakness or cardiomyopathy).
- Autosomal dominant
- Generally later onset and less severe than diseases with recessive or X-linked inheritance
- FSHMD, OPMD, some forms of LGMD and EDMD
- Myotonic dystrophy
- Trinucleotide repeat expansion with more severe phenotype in subsequent generations due to accumulation of repeats
- Autosomal recessive
- Most types of CMD
Genetic counseling for carriers and prenatal diagnosis
Commonly Associated Conditions
- Decreased IQ: on average, 1 SD below the mean in DMD; speech and language delay
- Dilated cardiomyopathy and conduction abnormalities
- Can be severe in EDMD
- Can affect otherwise asymptomatic female carriers of DMD
- Progressive scoliosis