Myotonic Dystrophy

From Iusmgenetics

Contents 1 Myotonic 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 1.12 Questions and answers

Myotonic Dystrophy

General background information

• Most common inherited neuromuscular disorder of adult life

Mode of inheritance

• Autosomal dominant
• Demonstrates anticipation
• Because of anticipation and instability, and because there is more expansion in female gametogenesis the most severe forms (congenital myotonic dystrophy) are transmitted by the mother.

Single important gene

• dmpk: dystrophia myotonica protein kinase

Etiology

• CTG repeats accumulate in the 3' UTR region.
  • There are usually 5-35 repeats in the 3' UTR of the dmpk gene.
• Myotonic dystrophy manifests in pts with > 50 repeats.
• NB: the protein sequence is normal!
• Myotonic dystrophy demonstrates instability and anticipation.

Pathogenesis

• There is probably less DMPK protein but myotonic dystrophy is a disease of RNA accumulation, primarily.
• As repeats expand, the RNA transcript becomes less apt to be translated and less apt to degraded so it accumulates.
• Accumulated DMPK RNA has been shown to cause aberrant splicing of CIC-1 pre-mRNA which leads to hyperexcitability of skeletal muscle.
  • CIC-1 is the main chloride channel in skeletal muscle.
• This "toxic RNA" is called a trans-dominant effect: one in which excess of a product (in this case RNA) gives it a gain-of-negative-function.
• This is the first well-documented example of this pathogenic mechanism in humans.
• Note that mouse models of myotonic dystrophy are best produced through repeat expansion and are not representative of human disease with simple knockouts.

• There is a second gene that can have a similar "trans-dominant effect": ZNF9
  • Expansions in ZNF9 cause myotonic dystrophy type 2 (DM2).
  • The repeat expansion in ZNF9 (DM2) is "CCUG" (a quartet repeat) in the first intron.
  • ZNF9 expansions generate only a small percentage of myotonic distrophy cases.
  • ZNF9 mRNA accumulation interrupts proper RNA processing of other genes.

Phenotypic information

• Progressive muscle weakness and wasting
  • Begins in the face then generalized
• Myotonia: cannot relax after contraction
  • From defects in CIC-1 (chloride channel) splicing
• Early cataracts
• Cardiac involvement: conduction defects
  • Perhaps from cardiac troponin T splicing defects?
• Endocrine issues: insulin resistance
  • Insulin receptor splicing issues
• Reproductive defects: gonadal failure

Diagnosis

Treatment

Recent research

5 important facts

Not to be confused with

Questions and answers