Clinical Description
Core phenotype characteristics of myotonic dystrophy type 2 (DM2) are myotonia, proximal and axial muscle weakness, and late muscle atrophy in combination with myalgia. DM2 is a multisystem disease and additional features include cardiac conduction defects, posterior subcapsular cataracts, insulin-insensitive type 2 diabetes mellitus, and other endocrine dysfunctions.
To date, more than 1500 individuals in more than 700 families have been identified with a pathogenic variant in CNBP [Heatwole et al 2015, Montagnese et al 2017, Bozovic et al 2018, Wood et al 2018, De Antonio et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Select Features of Myotonic Dystrophy Type 2
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Feature | % of Persons with Feature | Comment |
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Muscle dysfunction (proximal & axial weakness, myalgia, late atrophy) | 100% | |
Myotonia | 70%-90% | |
Iridescent posterior subcapsular cataracts | 50%-80% | Incidence ↑ w/age |
Cardiac conduction defects & cardiomyopathy | 10%-20% | |
Insulin insensitivity & type 2 diabetes | 25%-75% | Incidence ↑ w/age |
Other endocrine dysfunction | 20% | Incls thyroid dysfunction |
Gastrointestinal complications | 10%-20% | |
Hearing impairment | 10%-20% | |
Onset. The onset of symptoms in individuals with DM2 is typically in the third to fourth decade, with the most common symptoms being muscle weakness and pain, although myotonia during the first two decades has been reported [Udd et al 2011, Montagnese et al 2017]. Note that unlike myotonic dystrophy type 1 (DM1), which can present in adulthood as a degenerative disorder or with variably severe congenital features, DM2 has not been associated with developmental abnormalities and thus does not cause severe childhood symptoms [Udd et al 2011, Montagnese et al 2017, De Antonio et al 2019]. The absence of developmental defects in any affected family members with DM2 is a reliable and clinically significant difference between DM1 and DM2.
Muscle dysfunction. Individuals with DM2 often come to medical attention because of proximal and axial muscle weakness, myalgia, and myotonia. The muscles affected in the earliest stages of the disease are the neck flexors and finger flexors. Subsequently, weakness is seen in the elbow extensors and the hip flexors and extensors. Fifty percent of individuals have hip-muscle weakness that develops after age 40 years. Facial weakness and weakness of the ankle dorsiflexors can also be present but are less common. Calf hypertrophy is seen in a subset of individuals, and is frequently associated with brisk reflexes and restless leg symptoms.
Myotonia (i.e., involuntary muscle contraction and delayed relaxation caused by muscle hyperexcitability) is present in almost all individuals with DM2 but only rarely causes severe symptoms. Proximal leg myotonia is a prominent finding.
Fluctuating or episodic muscle pain is reported by a majority of affected individuals and can be debilitating [Tieleman et al 2011, Suokas et al 2012, Moshourab et al 2016, Montagnese et al 2017, van Vliet et al 2018b].
In women with DM2, symptoms may worsen during pregnancy [Rudnik-Schöneborn et al 2006]. Polyhydramnios, a recognized feature of DM1, has not been reported in individuals with DM2.
Cataracts and epiretinal membranes. Posterior subcapsular iridescent cataracts can be seen on slit lamp examination as early as the second decade of life. The reported age of cataract extraction ranges from 28 to 74 years [Day et al 2003]. With aging, an increase in macular thickness based on epiretinal membranes can lead to visual impairment. Epiretinal membranes can be treated surgically [Kersten et al 2016].
Cardiac conduction defects and cardiomyopathy. Although cardiac involvement in individuals with DM2 appears more mild than in DM1 [Sansone et al 2013], DM2 can be associated with atrioventricular and intraventricular conduction defects, arrhythmias, left ventricular dysfunction, cardiomyopathy, and sudden death [Day et al 2003, Schoser et al 2004b, Wahbi et al 2009, Sansone et al 2013, Peric et al 2019]. Rarely, a Brugada-like syndrome can occur in individuals with DM2 [Rudnik-Schöneborn et al 2011].
Anesthetic complications have not been reported in individuals with DM2, and probably occur less frequently than in DM1, where intraoperative and postoperative cardiac arrhythmias, ventilatory suppression, and poor airway protection are recognized possible causes of significant morbidity and mortality [Kirzinger et al 2010, Weingarten et al 2010].
Endocrine abnormalities described in individuals with DM2 include insulin-insensitive type 2 diabetes mellitus, thyroid dysfunction, and hypogonadism in adult males [Day et al 2003, Savkur et al 2004, Montagnese et al 2017, Bozovic et al 2018].
Gastrointestinal complications are common in DM2 and can include constipation, dysphagia, and abdominal pain [Tieleman et al 2008, Hilbert et al 2017].
Hypogammaglobulinemia. Individuals with DM2, like those with DM1, have a high incidence of hypogammaglobulinemia, with lower-than-normal levels of both IgG and IgM. A higher incidence of concomitant autoimmune disorders is recognized in individuals with DM2 [Montagnese et al 2017].
Daytime sleepiness, fatigue, and sleep disturbance. A range of sleep disturbances including daytime sleepiness, insomnia, REM behavior disorders, and restless leg syndrome have been observed in case reports and case series of individuals with DM2 [Day et al 1999, Bhat et al 2012, Chokroverty et al 2012, Shepard et al 2012, Silvestri et al 2014, Montagnese et al 2017, Romigi et al 2019]. Daytime sleepiness can be associated with restless leg syndrome [Silvestri et al 2014].
Hearing impairment. Cochlear sensorineural hearing impairment is reported in about 60% of individuals with DM2, suggesting an early presbycusis [van Vliet et al 2018a].
Cancer risk. Retrospective studies have shown that individuals with DM2 appear to be at a higher risk of developing cancer. A cross-sectional analysis of a large DM study showed that tumor risk is higher in DM1 than DM2. Cancer in individuals with DM2 may involve the colon, brain, thyroid, pancreas, ovary, prostate, and endometrium [Gadalla et al 2011, Das et al 2012, Win et al 2012].
Brain MRI findings. Central nervous system abnormalities reported in individuals with DM2 include white matter changes apparent on MRI and reduced cerebral blood flow in the frontal and temporal region apparent on PET scan [Franc et al 2012]. A longitudinal observational study over a period of five years found unchanged pattern of white matter alterations in DM2. Gray matter appears unaffected in DM2 [Gliem et al 2019]. FDG-PET and detailed neuropsychological testing showed executive and naming dysfunction in DM2. FDG-PET showed the most prominent glucose hypometabolism in prefrontal, temporal, and pericentral regions with additional affect on insula and subcortical grey matter in DM2. Executive dysfunction in DM2 was more common in individuals with prefrontal and insular hypometabolism, right parietotemporal and frontotemporal hypometabolism, as well as left striatal hypometabolism. Individuals with parietotemporal defect on FDG-PET were more likely to have naming dysfunction (p<0.01) [Peric et al 2017]. These anatomic changes appear to have some effect on cognition, behavior, and personality, although unlike DM1, DM2 has not been associated with intellectual disability [Meola et al 2002, Meola et al 2003].