Inherited Muscular Dystrophies
From Iusmgenetics
Contents
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[edit] Inherited Muscular Dystrophies: Duchenne Muscular Dystrophy
[edit] General background information
- Progressive muscle weakness
- Characteristic muscle pathology
- Pleomorphic: shows up in other organ systems, too.
- Duchenne Muscular Dystrophy is the classic example and our focus
[edit] Mode of inheritance
- X-linked recessive
- Mostly boys
- "Genetic lethal"
[edit] Single important gene
- DMD: dystrophin gene
- A large gene: 2.3 million base pairs, 79 exons
- Positional cloning identified the location of the gene defect in Duchenne muscular dystrophy
- Partially knew it was on the X because we could see the size of the X ch reduced
- Dystrophin protein:
- 427 kDa proteins--one of the larges proteins coded by the human genome
- 3685 amino acids
- 5% of the protein on muscle membrane
- Dystrophin binds actin (the subsarcolemmal cytoskelton) to the sarcolemma membrane.
- Dystrophin binds to actin and to a subunit of the dystrophin glycoprotein complex (DGC)
- Laminins and merosins bind the DGC (dystrophin glycoprotein complex) to the extracellular matrix
- Sarcoglycans bind the DGC (dystrophin glycoprotein complex) to the sarcolemma membrane
[edit] Etiology
- Many defects are deletions
[edit] Pathogenesis
- When dystrophin is mutated, actin fibers are no longer connected to the DGC.
- In carrier females, because Duchennes muscular dystrophy is X-linked, there is mosaicism that results in some muscle fibers (cells) having proper dystrophin-DRG connection and some with improper connection.
- This can be demonstrated with immunofluoresence.
[edit] Phenotypic information
- (Sometimes) hypotonic at birth
- Onset at 4-6 yo
- Inability to run, walks on toes
- Progressive muscle weakness
- Muscle wasting
- Gower sign: inability to rise without pressing thighs
- Pseudohypertrophy of calf muscles
- Looks like a good muscle but there is actually wasting with fibrosis
- Elevated serum creatine kinase
- Can be used to look for carrier females
- Early death (14-20 yo)
- Usually from respiratory failure or cardiomyopathy
[edit] Diagnosis
- We can use creatinine kinase levels to detect carrier females.
[edit] Treatment
[edit] Recent research
[edit] 5 important facts
[edit] Not to be confused with
- X-linked Dilated Cardiomyopathy (XLDC)
- Mutations occur in the promoter (5' end) of dystrophin (DMD)
- Reduced expression in cardiac muscle results
- Results in no expression in cardiac muscle
- A failure of dystrophin regulation
- Mutations occur in the promoter (5' end) of dystrophin (DMD)
- Limb-girdle Muscular Dystrophy
- Variable severity
- Overlaps with DMD and BMD
- Can be autosomal dominant or autosomal recessive
- Defect in sarcoglycans, calpain, caveolin, or other unknown proteins
- Congenital Muscular Dystrophy
- Autosomal recessive
- CNS involvement
- Defects in merosin / laminin (both parts of the DGC that connect the DGC to the ECM)
- Oculopharyngeal Muscular Dystrophy
- Autosomal dominant or autosomal recessive
- Ptosis
- Dysphagia
- Onset after 50
- Defects in polyadenylation binding protein 2
[edit] Becker Muscular Dystrophy
- Falls in the same allele as Duchenne Muscular Dystrophy (DMD gene on the X chromosome)
- Less severe than DMD
- Onset is later (16 yo versus 4-6 yo)
- Becker mutations can be big or small or can be frameshifts or not.
- Changing the reading frame (frameshift deletions) cause the rest of the protein to be screwed up.
- Becker individuals commonly have DMD that is simply reduced in function
- Carrier (heterozygous) females:
- May have skeletal symptoms
- Often have cardiac abnormalities
- Elevated levels of creatine kinase
