title: Myotonic disorders.
abstract: Myotonia reflects a state of muscle fiber hyperexcitability. Impaired transmembrane conductance of either chloride or sodium ions results in myotonia. Myotonic disorders include the myotonic dystrophies and nondystrophic myotonias. Mutations in the genes encoding chloride (ClC-1) or sodium (SCN4A) channels expressed exclusively in skeletal muscle cause nondystrophic myotonias. Genetic defects in the myotonic dystrophies do not involve ion channel or its regulator proteins. Recent research supports a novel RNA-mediated disease mechanism of myotonia in the myotonic dystrophies. Myotonic dystrophy Type 1 is caused by CTG repeat expansion in the 3' untranslated region in the Dystrophia Myotonica Protein Kinase (DMPK) gene. Myotonic dystrophy Type 2 is caused by CCTG repeat expansion in the first intron in Zinc Finger Protein 9 (ZNF9) gene. The expanded repeat is transcribed in RNA and forms discrete inclusions in nucleus in both types of myotonic dystrophies. Mutant RNA sequesters MBNL1, a splice regulator protein and depletes MBNL1 from the nucleoplasm. Loss of MBNL1 results in altered splicing of ClC-1 mRNA. Altered splice products do not encode functional ClC-1 protein. Subsequent loss of chloride conductance in muscle membrane causes myotonia in the myotonic dystrophies. The purpose of this review is to discuss the clinical presentation, recent advances in understanding the disease mechanism with particular emphasis on myotonic dystrophies and potential therapy options in myotonic disorders.
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA. amankod1@jhmi.edu
authors.forename: Ami
authors.initials: A
authors.lastname: Mankodi
mesh_terms: D018118:Chloride Channels / Q000235:genetics; D004576:Electromyography; D006801:Humans; D009154:Mutation / Q000235:genetics; D020967:Myotonic Disorders / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D062553:NAV1.4 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels; D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels