Introduction

Myotonic dystrophy is the most common adult muscular dystrophy. Multiple organ systems are affected, although to varying degrees in different individuals. The most commonly affected systems are the skeletal muscle, heart, central nervous system, gastrointestinal tract, and endocrine system. The disorder is further subdivided into two distinct entities, myotonic dystrophy type 1 and type 2 (DM1 and DM2, respectively).

DM2 was first described in 1994 after the discovery that some patients thought to have DM1 did not harbor the genetic mutation that causes DM1, a CTG repeat expansion in the DMPK gene (Ricker et al., Neurology, 1994). Instead, they were shown to have a unique CCTG repeat expansion on a different chromosome, in the CNBP gene (Ranum et al., Nature, 1998Liquori et al., Science, 2001). This group of patients was noted to have a slightly different clinical phenotype in which muscle weakness and myotonia (difficulty relaxing the muscles) were present, but the most affected muscles were closer to the center of the body, such as the shoulders and hips. They also tended to have much milder symptoms (Ricker et al., Neurology, 1994Udd et al., Neuromuscul Disord, 1997). For these reasons, DM2 is now recognized as a distinct entity and further supports the idea that DM pathology is caused by gain-of-function mechanisms from the expanded repeats.

The true prevalence of DM2 has been difficult to ascertain. Population studies in Europe have yielded conflicting results, with prevalence estimates ranging from 1 in 1,830 to 1 in 8,000 (Suominen, Eur J Human Genet, 2011). No formal investigations have been completed within the U.S. population, but anecdotal evidence suggests that DM2 presents far less frequently than DM1 (Thornton, Neurol Clin, 2014). Nonetheless, the disease prevalence in the U.S. is likely underappreciated due to the heterogeneity of disease and subsequent misdiagnosis. One analysis demonstrated that up to a third of all DM2 patients had been previously misdiagnosed with other conditions, such as degenerative joint disease, fibromyalgia, and multiple sclerosis (Hilbert et al., J Neurol, 2013), which resulted in an average delay in diagnosis of 14 years.

Disease Course

Unlike DM1, patients with DM2 usually achieve a full lifespan. This is likely due to a milder disease course and differences in major symptoms. For example, the muscle weakness of DM2 is significantly less severe and typically does not occur until the fourth or fifth decade of life. Fewer patients require ambulatory support, and, as of 2013, there were no reported cases of respiratory failure (Day et al, Neurology, 2013). Heart disease also occurs less frequently in DM2, although it is still present in up to 37% of patients (Wahbi, Neuromusc Dis, 2009). Furthermore, intellectual impairment and excessive daytime sleepiness are less common, in spite of similar rates of poor sleep quality and severe fatigue (Tieleman, J Neurol Neurosurg Psych, 2010).

Despite a disease course that is in general milder than DM1, DM2 is not without its disabling features. In fact, research has shown that overall self-rated quality of life does not substantially differ between DM1 and DM2 patients (Heatwole et al, Neurology 2015, Rakocevic, J Neurol Sci, 2016). In other words, both DM1 and DM2 patients reported significant impairments in their physical, psychological, and social functioning as compared to the general population. DM2 patients actually reported their pain to be worse than in DM1. This is not surprising given that severe musculoskeletal and abdominal pain is one of the most common symptoms, occurring in ~80% of patients (Heatwole et al, Neurology 2015).

Pathogenesis

DM2 results from a CCTG repeat expansion in the CNBP gene, which is inherited in an autosomal dominant fashion. This means parents have a 50% chance of passing on the trait to their children. While the function of CNBP in humans has not been fully elucidated, it is thought to play a role in translational regulation, by binding to RNAs containing G-rich sequences (Benhalevy et al, Cell Rep 2017, Xue et al, Mol Cell 2016). The specific causative mutation in the CNBP gene results from too many repeats of four DNA building blocks (nucleotides): cytosine-cytosine-thymine-guanine (CCTG). The mutation is therefore called a CCTG tetranucleotide repeat. Healthy individuals possess 11 to 26 tetranucleotide repeats in the CNBP gene, while affected individuals harbor between 75 and 11,000 repeats (Liquori et al., Science, 2001).

Given the high degree of clinical overlap between DM2 and DM1, and the fact that DM1 is caused by expanded CTG repeats in the DMPK gene, it is now established that the expanded CTG and CCTG repeats drive much of the disease symptomatology, despite the mutation occurring on two different genes. The repeats in both diseases are transcribed into an abnormal messenger RNA (mRNA) molecule, which binds and sequesters other proteins, such as the muscleblind-like protein (MB). MB normally regulates the splicing of mRNAs that encode proteins critical for skeletal, cardiac, and nervous system function (Pascual et al, Differentiation, 2006). The functional loss of MB results in many of the abnormalities observed in both DM1 and DM2. Nonetheless, some key differences do exist between the inheritance patterns of DM1 and DM2. For example, in DM2, there is no strong correlation between repeat length and severity of disease, which is a key feature of DM1. Moreover, transmission of DM2 to the next generation typically does not show anticipation. Taken together, this means the disease severity does not increase from generation to generation and overall phenotype among DM2 patients is difficult to predict.

Standard of Care

Absolute diagnosis of DM2 is based on genetic testing for CCTG nucleotide repeats in the CNBP gene. Typically, this is only ordered after DM1 is ruled out. Much like DM1, management of the condition is purely symptomatic. Interventions are aimed at increasing function and maintaining independence, while also preventing adverse outcomes. Particular emphasis is placed on management of muscle pain, which may be achieved with a number of pharmacologic agents. Stimulants may also be prescribed to address sleep issues. The potential for fatal cardiac complications also warrant close monitoring and/or intervention by cardiac devices.

Opportunity

No intervention currently exists to slow the progression of DM2. Affected individuals are considerably impaired with a substantial burden placed on their quality of life. Furthermore, the number of individuals with DM2 is likely significantly underestimated. This means tens of thousands of individuals suffering from both DM1 and DM2 in the U.S. are receiving suboptimal and costly care that does nothing to prevent worsening of their symptoms. There is a clear unmet need for disease-modifying therapies for both conditions.