Inherited Muscular Dystrophies

From Iusmgenetics

Contents 1 Inherited Muscular Dystrophies: Duchenne Muscular Dystrophy 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.5 Pathogenesis 1.6 Phenotypic information 1.7 Diagnosis 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.11.1 Becker Muscular Dystrophy 1.12 Questions and answers

Inherited Muscular Dystrophies: Duchenne Muscular Dystrophy

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

Mode of inheritance

• X-linked recessive
  • Mostly boys
• "Genetic lethal"

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

Etiology

• Many defects are deletions

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.
  • 

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

Diagnosis

• We can use creatinine kinase levels to detect carrier females.

Treatment

Recent research

5 important facts

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

• 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

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

Questions and answers