Myotonic Dystrophy Type 2

Clinical characteristics.

Myotonic dystrophy type 2 (DM2) is characterized by myotonia and muscle dysfunction (proximal and axial weakness, myalgia, and stiffness), and less commonly by posterior subcapsular cataracts, cardiac conduction defects, insulin-insensitive type 2 diabetes mellitus, and other endocrine abnormalities. While myotonia (involuntary muscle contraction with delayed relaxation) has been reported during the first decade, onset is typically in the third to fourth decade, most commonly with fluctuating or episodic muscle pain that can be debilitating and proximal and axial weakness of the neck flexors and the hip flexors. Subsequently, weakness occurs in the elbow extensors and finger flexors. Facial weakness and weakness of the ankle dorsiflexors are less common. Myotonia rarely causes severe symptoms. In a subset of individuals, calf hypertrophy in combination with brisk reflexes is notable.

Diagnosis/testing.

The diagnosis of DM2 is established in a proband by identification of a heterozygous pathogenic expansion of a CCTG repeat within a complex repeat motif, (TG)_n(TCTG)_n(CCTG)_n in CNBP. The number of CCTG repeats in a pathogenic expansion ranges from approximately 75 to more than 11,000, with a mean of approximately 5,000 repeats. The detection rate of a CNBP CCTG expansion is more than 99% with the combination of routine PCR, Southern blot analysis, and the PCR repeat-primed assay.

Management.

Treatment of manifestations: Ankle-foot orthoses, wheelchairs, or other assistive devices as needed for weakness; routine physical activity appears to help maintain muscle strength and endurance and to control musculoskeletal pain; medications used with some success in myalgia management include mexilitene, gabapentin, pregabalin, nonsteroidal anti-inflammatory drugs, low-dose thyroid replacement, and tricyclic antidepressants; myotonia rarely requires treatment but mexilitene or lamotrigine may be beneficial in some individuals; removal of cataracts or epiretinal membrane that impair vision; defibrillator placement for those with arrhythmias; hormone substitution therapy for endocrine dysfunction; prokinetic agents may be helpful for gastrointestinal manifestations; cognitive behavioral therapy and modafinil may be helpful for fatigue and daytime sleepiness; vitamin D supplementation for those with deficiency; hearing aids for sensorineural hearing loss.

Prevention of secondary complications: Anesthetic risk may be increased and therefore assessment of cardiac and respiratory function before and after surgery are recommended. Prompt treatment of hypothyroidism and vitamin D deficiency to reduce secondary weakness and myotonia.

Surveillance: Annual evaluation with neurologist, occupational therapist, and physical therapist; annual ophthalmology evaluation for posterior subcapsular cataracts and epiretinal membranes; annual ECG, echocardiogram, and 24-hour Holter monitoring to detect/monitor cardiac conduction defects and cardiomyopathy; cardiac MRI per cardiologist; annual measurement of fasting serum glucose concentration, glycosylated hemoglobin level, thyroid hormone levels, and vitamin D; serum testosterone and FSH per endocrinologist.

Agents/circumstances to avoid: Cholesterol-lowering medications when associated with increased weakness.

Genetic counseling.

DM2 is inherited in an autosomal dominant manner. To date, all individuals whose biological parents have been evaluated with molecular genetic testing have had one parent with a CCTG repeat expansion; de novo pathogenic variants have not been reported. Each child of an individual with a CCTG repeat expansion has a 50% chance of inheriting the expansion. There is no correlation between disease severity and CCTG repeat length. Prenatal testing for pregnancies at increased risk and preimplantation genetic testing are possible once the CCTG repeat expansion has been identified in an affected family member.

Suggestive Findings

DM2 should be suspected in individuals with the following findings:

• Muscle weakness with early, clinically detectable weakness on manual motor testing of neck flexors and finger flexors, and later, symptomatic weakness often involving hip-girdle muscles in climbing stairs and rising from chairs
• Myotonia (sustained muscle contraction) that can manifest as grip myotonia (the inability to release a tightened fist quickly) occurring as early as the first decade of life, percussion myotonia (sustained contraction after tapping a muscle with a reflex hammer), leg myotonia, especially while climbing a staircase or trying to run fast, or electrical myotonia (repetitive spontaneous discharges observed on EMG). The myotonia in individuals with DM2 is not always detectable by EMG and may require an extensive EMG examination of several muscle groups including proximal and paraspinal muscles [Dabby et al 2011].
• Posterior subcapsular cataracts detectable as nonspecific vacuoles and opacities on direct ophthalmoscopy or as pathognomonic posterior subcapsular red and green iridescent opacities on slit lamp examination
• Cardiac conduction defects or progressive cardiomyopathy, the former diagnosable as atrioventricular or various intraventricular conduction defects on routine ECG and the latter identifiable as a dilated cardiomyopathy on echocardiography
• Insulin insensitivity that can appear clinically as impaired normalization of glucose on a glucose tolerance test despite normal or elevated serum insulin concentrations, and which predisposes to hyperglycemia and diabetes mellitus
• Hypogammaglobulinemia, defined as low gamma protein fraction on serum protein electrophoresis or low immunoglobulin G or immunoglobulin M content on immunoprotein electrophoresis, which occurs in 75% of adults with DM2 but has not been associated with any clinical abnormalities. The frequency of concomitant autoimmune disorders is increased in individuals with DM2.

Establishing the Diagnosis

The diagnosis of DM2 is established in a proband with a heterozygous pathogenic expansion of a complex repeat in CNBP identified by molecular genetic testing (see Table 1).

Allele sizes. CNBP intron 1 contains a complex repeat motif: (TG)_n(TCTG)_n(CCTG)_n. All three repeat tracts (TG, TCTG, and CCTG) are present in all normal and pathogenic alleles (see Figure 1):

Figure 1.

Complex repeat at the CNBP locus. The CNBP repeat tract is a complex repeat comprising TG, TCTG, and CCTG tracts, in this order. Each repeat can vary in length. On normal alleles, the overall length of the CCTG portion ranges from 11 to 26 tetranucleotide (more...)

• Normal
  • ≤30 uninterrupted CCTG repeats
  • 11-26 CCTG repeats with any GCTC or TCTG interruptions
• Unknown significance (normal vs. mutable). 27-29 CCTG repeats
• Mutable normal (premutation) alleles. ~30-~54 CCTG repeats
• Unknown significance (premutation vs pathogenic). ~55-74 CCTG repeats
• Pathogenic. ~75-11,000 CCTG repeats

Note: (1) The boundary between stable and unstable alleles is estimated to be 30 CCTG repeats, with alleles <30 CCTG being stable. Large interrupted alleles have also been observed to be stable with stability decreasing with increasing uninterrupted repeat length [Liquori et al 2001, Liquori et al 2003, Radvanszky et al 2013, Mahyera et al 2018]. (2) Due to variability in the TG and TCTG portions of the repeat tract, a total repeat size in base pairs is frequently reported and CCTG repeat length is often estimated [Liquori et al 2001, Liquori et al 2003, Radvanszky et al 2013, Mahyera et al 2018]. When close to a normal / mutable normal / premutation / pathogenic boundary, sequence analysis is necessary to better estimate the size of the CCTG repeat.

Molecular Genetic Testing

Testing approaches can include targeted analysis for an increased number (i.e., an expansion) of the CCTG nucleotide repeat. If routine PCR analysis detects only one allele, which occurs in 15% of unaffected individuals who are homozygous and in all affected individuals, it is necessary to perform both Southern blot analysis and the PCR repeat-primed assay to determine if the individual is homozygous for the normal-sized allele or has both a normal-sized allele and an expanded allele that fails to amplify by PCR because of its large size [Liquori et al 2001].

Other Testing

Muscle biopsy. Although molecular genetic testing is the diagnostic test of choice, muscle biopsy remains a useful diagnostic tool. Muscle pathology includes atrophic fibers, scattered severely atrophic fibers with pyknotic myonuclei, and marked proliferation of fibers with central nuclei [Day et al 1999, Day et al 2003, Vihola et al 2003, Schoser et al 2004c], all of which occur in both DM2 and myotonic dystrophy type 1 (DM1) and thus cannot be used to distinguish between them.

• Type 1 fiber atrophy is a common feature in individuals with congenital DM1, distinguishing it from DM2.
• Preferential type 2 fiber atrophy has been observed in individuals with DM2 [Vihola et al 2003, Schoser et al 2004c, Pisani et al 2008, Giagnacovo et al 2012].

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.

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, Wahabi 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].

Genotype-Phenotype Correlations

No significant correlation exists between CCTG repeat size and age of onset of weakness or other measures of disease severity (e.g., age of cataract extraction). The observation that phenotypic features in individuals with CCTG repeat expansions in both CNBP alleles are as severe as those seen in their heterozygous sibs and parents further demonstrates that CCTG repeat number does not alter the clinical course [Schoser et al 2004a].

A correlation does exist between the repeat size and the age of the individual with DM2 at the time that the repeat size is measured, indicating that the repeat length increases with age [Day et al 2003].

Penetrance

Penetrance is age dependent and approaches 100%.

Anticipation

Anticipation is not observed in DM2. There is no correlation between disease severity and CCTG repeat length; therefore, intergenerational changes in repeat length would not be expected to worsen disease severity.

Nomenclature

The International Myotonic Dystrophy Consortium (IDMC) and Online Mendelian Inheritance in Man (OMIM) both recognize that DM2 and the historical term proximal myotonic myopathy (PROMM) refer to the same condition. PROMM is still sometimes used to refer to the clinical phenotype if the causative variant is unknown; however, when the diagnosis is established through molecular genetic testing of CNBP, the more precise term "DM2" is preferable.

No other genetic causes of multisystem myotonic dystrophies have been confirmed, although their existence has been suggested. The International Myotonic Dystrophy Consortium has agreed that any newly identified multisystem myotonic dystrophies will be sequentially named as forms of myotonic dystrophy.

One family posited to have a myotonic dystrophy type 3 (DM3) [Le Ber et al 2004] has subsequently been shown to have Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia caused by a pathogenic variant in VCP.

Prevalence

Prevalence appears to differ in various populations; however, few definitive demographic studies have been performed. A higher prevalence of DM2 is observed in Germany, Czech Republic, Serbia, and Poland and in individuals of German or Polish descent [Udd et al 2003, Montagnese et al 2017]. In Finland, the incidence of DM2 (1:1,830) is higher than DM1 [Suominen et al 2011]. In Germany, cumulative empiric evidence suggests an estimated prevalence of DM2 of roughly 9:100,000; therefore, DM2 is as prevalent as DM1 [Mahyera et al 2018]. DM2 has been reported worldwide.

Multisystem Myotonic Myopathies

Routine clinical evaluation can reliably identify myotonic dystrophy. Molecular genetic testing is required for definitive diagnosis of myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2); however, suggestive findings can be used to clinically distinguish between DM2 and DM1.

• The most robust clinical difference between DM1 and DM2 is that clubfeet, neonatal weakness and early respiratory insufficiency, developmental delay / intellectual disability, craniofacial abnormalities, and childhood hypotonia and weakness have been reported in individuals with DM1 only. DM2 has not been associated with developmental abnormalities and thus does not cause severe childhood manifestations [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 the two forms of DM.
• Adults with DM1 often have more weakness and myotonia than adults with DM2.
• Individuals with DM1 tend to have more pronounced facial, bulbar, and distal weakness; as well as muscle atrophy, cardiac involvement, and central nervous system abnormalities including central hypersomnia [Meola et al 2002, Ranum & Day 2002, Ranum & Day 2004, Day & Ranum 2005, Montagnese et al 2017, De Antonio et al 2019].

Note: The cataracts in individuals with DM1 and DM2 are indistinguishable.

Other Myopathies to Consider

The other major group in the differential diagnosis of DM2 is distal myopathy (see Table 3).

Nondystrophic Myotonias

Electrical myotonia occurs in several conditions (e.g., hypothyreosis) but the presence of myotonia in multiple family members restricts diagnostic possibilities to either DM1 or DM2, or to the nondystrophic myotonias, which are caused by mutation of chloride, sodium, or calcium channel genes, resulting in myotonia congenita, paramyotonia congenita (OMIM 168300), and periodic paralyses (see Hypokalemic Periodic Paralysis and Hyperkalemic Periodic Paralysis). Those conditions are not associated with the muscular dystrophy or multisystem features typical of DM1 and DM2 and can thus be distinguished on clinical grounds.

Other

Occasionally, individuals with DM2 have been misdiagnosed as having atypical motor neuron disease [Rotondo et al 2005], inflammatory myopathy, fibromyalgia, rheumatoid arthritis, or metabolic myopathy.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with myotonic dystrophy type 2 (DM2), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. Detailed international guidelines and recommendations for evaluation of individuals with DM2 have been published [Rastelli et al 2018, Schoser et al 2019].

Treatment of Manifestations

Detailed guidelines for treatment are provided in the new international care recommendations for DM2 [Schoser et al 2019].