Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

Abstract

Myotonic dystrophy is an autosomal dominant muscular dystrophy not only associated with muscle weakness, atrophy, and myotonia but also prominent multisystem involvement. There are 2 similar, but distinct, forms of myotonic dystrophy; type 1 is caused by a CTG repeat expansion in the DMPK gene, and type 2 is caused by a CCTG repeat expansion in the CNBP gene. Type 1 is associated with distal limb, neck flexor, and bulbar weakness and results in different phenotypic subtypes with variable onset from congenital to very late-onset as well as variable signs and symptoms. The classically described adult-onset form is the most common. In contrast, myotonic dystrophy type 2 is adult-onset or late-onset, has proximal predominant muscle weakness, and generally has less severe multisystem involvement. In both forms of myotonic dystrophy, the best characterized disease mechanism is a RNA toxic gain-of-function during which RNA repeats form nuclear foci resulting in sequestration of RNA-binding proteins and, therefore, dysregulated splicing of premessenger RNA. There are currently no disease-modifying therapies, but clinical surveillance, preventative measures, and supportive treatments are used to reduce the impact of muscular impairment and other systemic involvement including cataracts, cardiac conduction abnormalities, fatigue, central nervous system dysfunction, respiratory weakness, dysphagia, and endocrine dysfunction. Exciting preclinical progress has been made in identifying a number of potential strategies including genome editing, small molecule therapeutics, and antisense oligonucleotide-based therapies to target the pathogenesis of type 1 and type 2 myotonic dystrophies at the DNA, RNA, or downstream target level.

Assessment of small sensory fiber function in myotonic dystrophy type 1

“…Our findings support the need for further studies in DM1 using other testing modalities such as IENF density determination to better characterize this complex disease, particularly as disease modifying therapies are developed …”

Association of Sjögren’s syndrome with myotonic dystrophy type 1

“…The muscular symptoms of DM1 include myalgias, myotonia and weakness affecting craniobulbar and distal limb muscles. Manifestations in other systems include cardiac arrhythmias, cognitive impairment, endocrine disturbances, gastrointestinal dysmotility, sleep disorders, cataracts, polyneuropathy, hypogammaglobulinemia and increased susceptibility to malignancy 7. The non-muscular symptoms contribute greatly to morbidity and mortality in DM1 patients.…”

Clinical implication of maximal voluntary ventilation in myotonic muscular dystrophy

“…Myotonic muscular dystrophy type 1 (DM1), caused by an abnormal cytosine–thymine–guanine (CTG) repeat expansion in the region of the dystrophia myotonica protein kinase ( DMPK ) gene, [1–4] is one of the most common neuromuscular diseases. The expanded repeat is transcribed in RNA and forms discrete inclusions in the nucleus, leading to muscle fiber hyperexcitability and impaired transmembrane conductance of either chloride or sodium ions.…”

“…Cardiac muscles predominantly exhibit rhythmic problems such as conduction abnormalities, and cardiomyopathies are usually secondary to arrhythmia and ventilatory failure. [4,7–9] Most likely, the diaphragm and intercostal muscles, which enable rhythmic breathing by contraction and passive relaxation, can also be affected by myotonia. [9,10]…”