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Myotonic Dystrophy Type 2

Synonym: Proximal Myotonic Myopathy (PROMM)

, MS, , PhD, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: July 3, 2013.


Clinical characteristics.

Myotonic dystrophy type 2 (DM2) is characterized by myotonia (90% of affected individuals) and muscle dysfunction (weakness, pain, and stiffness) (82%), and less commonly by cardiac conduction defects, iridescent posterior subcapsular cataracts, insulin-insensitive type 2 diabetes mellitus, and testicular failure. Although myotonia (involuntary muscle contraction with delayed relaxation) has been reported during the first decade, onset is typically in the third decade, most commonly with fluctuating or episodic muscle pain that can be debilitating and weakness of the neck flexors and finger flexors. Subsequently, weakness occurs in the elbow extensors and the hip flexors and extensors. Facial weakness and weakness of the ankle dorsiflexors are less common. Myotonia rarely causes severe symptoms.


CNBP (ZNF9) is the only gene in which pathogenic variants are known to cause myotonic dystrophy type 2. CNBP intron 1 contains a complex repeat motif, (TG)n(TCTG)n(CCTG)n. Expansion of the CCTG repeat causes DM2. The number of CCTG repeats in expanded alleles ranges from approximately 75 to more than 11,000, with a mean of approximately 5000 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.


Treatment of manifestations: Ankle-foot orthoses, wheelchairs, or other assistive devices as needed for weakness; defibrillator placement for those with arrhythmias; removal of cataracts that impair vision; and testosterone replacement therapy for hypogonadism in males. Myotonia rarely requires treatment. Routine physical activity appears to help maintain muscle strength and endurance and to control musculoskeletal pain. Medications used with some success in pain management include mexilitene, gabapentin, nonsteroidal anti-inflammatory drugs (NSAIDS), low-dose thyroid replacement, low-dose steroids (e.g., 5 mg prednisone on alternate days), and tricyclic antidepressants.

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 to reduce secondary weakness.

Surveillance: Annual ECG and echocardiogram or possible cardiac MRI to detect/monitor cardiac conduction defects and cardiomyopathy; annual measurement of fasting serum glucose concentration and glycosylated hemoglobin level; and testing of males every few years for evidence of hypogonadism.

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

Genetic counseling.

Myotonic dystrophy type 2 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 CNBP expansion; de novo pathogenic variants have not been reported. Each child of an individual with a CNBP expansion has a 50% chance of inheriting the expansion. Neither the size of a predominant allele nor the total number of different detectable expansions in a single sample can predict disease severity, age of onset, or clinical symptoms. Prenatal testing for pregnancies at increased risk is possible if the presence of a CNBP expansion has been identified in the affected parent.


Clinical Diagnosis

Myotonic dystrophy type 2 (DM2) should be suspected in individuals with the following:

  • 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 arising 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), or electrical myotonia (repetitive spontaneous discharges observed on EMG). The myotonia in individuals with DM2 is not always detectable by EMG [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
  • 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 myotonic dystrophy types 1 and 2 but has not been associated with any clinical abnormalities
  • 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
  • Primary gonadal failure in males, as evidenced by low serum testosterone concentration, elevated serum FSH concentration, oligospermia, and infertility


Muscle biopsy. 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, Schoser et al 2004c], all of which occur in both myotonic dystrophy type 1 (DM1) and DM2 and thus cannot be used to distinguish between them:

Molecular Genetic Testing


CNBP (formerly ZNF9), the gene encoding cellular nucleic acid-binding protein (zinc finger protein 9), is the only gene in which pathogenic variants are known to cause DM2. CNBP intron 1 contains a complex repeat motif, (TG)n(TCTG)n(CCTG)n. Expansion of the CCTG repeat causes DM2 [Liquori et al 2001].

Allele Sizes

Normal alleles. All three repeat tracts (TG, TCTG, and CCTG) are present as a complex motif on all normal and pathogenic alleles; additionally, the CCTG repeat tract in normal alleles typically contains one or more tetranucleotide interruptions (TCTG or GCTG) [Liquori et al 2003] (see Figure 1). The overall length of the (TG)n(TCTG)n(CCTG)n complex repeat in normal alleles ranges from 104 to 176 base pairs. Because TG and TCTG repeat tracts are highly polymorphic, allele sizes determined by methods other than sequencing are reported in overall base-pair length rather than as a definable number of CCTG repeats.

Figure 1. . Complex repeat at the DM2 locus.

Figure 1.

Complex repeat at the DM2 locus. The DM2 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...)

Sequence analysis of 24 normal alleles [Liquori et al 2001, Liquori et al 2003] showed that:

  • The largest number of uninterrupted CCTG repeats was nine (except for a single case discussed below; see Mutable normal alleles).
  • The overall normal CCTG repeat tract, including any GCTC and TCTG interruptions, ranged from 11 to 26 tetranucleotide repeats.
  • In 85% of unaffected individuals, the overall lengths of the complex repeat tract clearly differ on the two alleles and are thus distinct on analysis of PCR amplicons.

Mutable normal alleles (also called intermediate or premutation alleles). No CNBP alleles have been reported in the size range of 177-372 bp (equivalent to ~27-74 CCTG repeats); furthermore, whether normal alleles within any particular size range or with any particular sequence characteristics are prone to expand into the pathogenic range remains unclear at this time. The sequence interruptions that are routinely found within the CCTG tracts of normal alleles are not found in sequenced pathogenic CCTG expansions of CNBP alleles. Loss of these interruptions from normal alleles may increase instability and predispose these repeat tracts to expansion in subsequent generations; although this type of instability has been confirmed for other diseases, it has not yet been observed in individuals with DM2. Consistent with this hypothesis, however, is the report of an allele in an unaffected individual in whom 20 uninterrupted CCTG repeats were present on a haplotype identical to that found in all affected individuals [Liquori et al 2003]. Although this individual's repeat tract did not expand when transmitted to the next generation, it is possible that the loss of the sequence interruptions may predispose uninterrupted CCTG repeat tracts to expansion in future generations. Because it has not been confirmed that large normal CNBP repeat alleles can expand into the pathogenic range, alleles with 177-372 bp are referred to more accurately as borderline expansions rather than premutations.

Full penetrance (or abnormal) alleles. In smaller pathogenic alleles that have been sequenced, only the CCTG portion of the complex repeat has been shown to expand. In large expansions, which cannot be sequenced accurately, alleles greater than 372 bp (equivalent to 75 CCTG repeats) appear to be fully penetrant in causing DM2. Pathogenic alleles range in size from 372 bp to more than 44,000 bp (equivalent to ~75-11,000 CCTG repeats), with a mean of approximately 20,000 bp (equivalent to ~5000 repeats).

The CCTG repeat tract displays:

  • Somatic instability. CCTG repeat size increases with age. More than 25% of affected individuals have two or more CCTG expansion sizes detectable in peripheral blood. This somatic heterogeneity of CCTG repeat size makes it difficult to establish a pathogenic threshold; for example, the affected individual with the shortest identified CCTG repeat expansion on one allele (~75 CCTG repeats or ~300 bp) also has an allele with a very large CCTG expansion containing more than 11,000 CCTG repeats or 44,000 bp; either or both of the expanded alleles could be pathogenic [Liquori et al 2001, Day et al 2003].
  • Intergenerational instability. On transmission to the next generation, CNBP repeat length sometimes diminishes dramatically, without significant differences determined by the gender of the transmitting parent; however, the marked somatic mosaicism and age dependence of the repeat length complicate interpretation of this observation [Day et al 2003].
Clinical Testing

Targeted analysis for pathogenic variants. The detection of abnormal CNBP alleles is complicated by the large size of the CCTG expansion and the presence of somatic mosaicism (varying lengths of allele due to somatic instability of the CCTG expansion). The detection rate of a CNBP CCTG expansion increases to more than 99% with use of a set of diagnostic tests that combines routine PCR, Southern blot analysis, and the "PCR repeat-primed assay" [Day et al 2003]. In 2012, best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2 were published. See Kamsteeg et al [2012] (full text).

Table 1.

Molecular Genetic Testing Used in Myotonic Dystrophy Type 2

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Gene and Test Method 3
CNBPTargeted analysis for pathogenic variants 4CCTG tetranucleotide repeat expansion in intron 199% 5
Sequence analysis 6Sequence variantsNo reported cases 7

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene.


May involve:
a. Routine PCR, which detects normal-sized alleles but not abnormal-sized alleles because it cannot amplify across the expansion;
b. Southern blot analysis, which detects approximately 80% of expansions;
c. PCR repeat-primed assay, which aids in the detection of the CCTG repeat expansion. This assay, in which the primers are adjacent to and within the elongated CCTG repeat, differentially detects expanded alleles as a smear with varying repeat sizes but shows control alleles as a discrete band. The PCR repeat-primed assay products are probed with an internal probe to assure the necessary specificity.


Detection frequency varies by method used. When routine PCR analysis, Southern blot analysis, and PCR repeat-primed assay are all used, the variant detection frequency is greater than 99%.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Because of variation in the number of flanking TG and TCTG repeats and variation in the number of interruptions within the CCTG repeat tract, the precise number of CCTGs can only be determined by sequence analysis. Although sequencing of some expanded alleles was necessary to demonstrate that only the CCTG portion of the complex repeat expands in affected individuals, sequencing to determine the specific CCTG repeat length is not useful for diagnostic purposes because most expansions are too long for efficient sequence analysis.

Interpretation of Test Results

PCR analysis alone can exclude a diagnosis of DM2 if two normal-sized alleles are clearly resolvable.

Southern blot analysis of genomic DNA shows an expanded allele in at least 80% of affected individuals, but the size of the expansion is necessarily an estimate because of the marked somatic mosaicism of the CCTG expansion and because the adjacent non-pathogenic repeats are polymorphic. Approximately 20% of expansions cannot be detected by Southern blot analysis because of a high degree of somatic mosaicism; alleles of varying lengths do not co-migrate during electrophoresis and become difficult to detect.

The PCR repeat-primed assay can verify the presence of an allele that has expanded into the pathogenic range but does not allow determination of the total length of the expansion.

Testing Strategy

To confirm/establish the diagnosis in a proband. If routine PCR analysis detects only one allele, which occurs in 15% of normal 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].

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variant in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Characteristics

Clinical Description

Myotonic dystrophy type 2 (DM2) is a multisystem disorder characterized by myotonia (90%) and muscle dysfunction (weakness, pain, and stiffness) (82%), as well as a consistent constellation of seemingly unrelated clinical features, including: cardiac conduction defects (19%), iridescent posterior subcapsular cataracts (36%-78%, increasing with age), and a specific set of endocrine changes including insulin insensitivity (25%-75%, increasing with age) and testicular failure (29%-65%).

The onset of symptoms in individuals with DM2 is typically in the third decade, with the most common symptoms being muscle weakness and pain, although myotonia during the first decade has been reported [Day et al 1999, Day et al 2003, Udd et al 2011]. 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]. 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.

Muscle dysfunction. Individuals with DM2 often come to medical attention because of muscle weakness, pain, and myotonia [Ricker et al 1994, Moxley 1996, Day et al 1999, Ricker 1999, Ricker et al 1999, Thornton 1999, Harper 2001, Day et al 2003]. 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. Thirty percent of individuals have hip-muscle weakness that develops after age 50 years.

Facial weakness and weakness of the ankle dorsiflexors can also be present but are less common.

Myotonia, i.e., involuntary muscle contraction and delayed relaxation caused by muscle hyperexcitablity, is present in almost all individuals with DM2 but only rarely causes severe symptoms.

Fluctuating or episodic muscle pain is reported by a majority of affected individuals and can be debilitating [George et al 2004, Auvinen et al 2008, Tieleman et al 2011, Suokas et al 2012]

Multisystem features. 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].

Although cardiac involvement in individuals with DM2 appears more mild than in DM1 [Meola et al 2002; Sansone et al 2013], DM2 can be associated with atrioventricular and intraventricular conduction defects, arrhythmias, cardiomyopthy, and sudden death [Nguyen et al 1988, Colleran et al 1997, Merino et al 1998, Philips et al 1998, Day et al 2003, Schoser et al 2004b]. One study showed that DM2 is more commonly associated with left ventricular dysfunction than originally estimated [Wahbi et al 2009].

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 and testicular failure resulting in male infertility [Day et al 2003, Savkur et al 2004].

Individuals with DM2, like those with DM1, have a high incidence of hypogammaglobulinemia, with lower than normal levels of both IgG and IgM, although no associated clinical problems have been observed.

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 [Hund et al 1997, Meola et al 1999, Franc et al 2012]. 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].

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].

Gastrointestinal complications are common in DM2 and can include constipation, dysphagia, and abdominal pain [Tieleman et al 2008]

In women with DM2, symptoms may worsen during pregnancy [Day et al 1999, Newman et al 1999, Rudnik-Schöneborn et al 2006]. Polyhydramnios, a recognized feature of DM1, has not been reported in individuals with DM2.

Cancer risk. Several case reports have suggested an increased incidence for cancer in individuals with myotonic dystrophy. Recent retrospective studies have shown that individuals affected with myotonic dystrophy type 2 appear to be at a higher risk overall of developing cancer. Cancer in individuals with DM2 may involve the colon, brain, thyroid, pancreas, ovary, and endometrium [Gadalla et al 2011, Win et al 2012].

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 [Schneider et al 2000, Liquori et al 2001, Day et al 2003].


Disease penetrance reflects both an individual's sensitivity for his/her symptoms and a physician's ability to correctly identify and interpret signs of the disease. As affected families and their physicians become increasingly aware of the clinical features of DM2, penetrance approaches 100%.

Examination by experienced investigators. In a study of 234 adults age 18 years or older examined by experienced investigators, all but one individual with a DM2 expansion were correctly classified as affected. (A 50-year-old male was misclassified as unaffected, possibly the result of an incomplete examination.)

Family histories revealed the following:

  • Unexamined obligate heterozygotes were undiagnosed in the fifth and sixth decade of life or frequently were misdiagnosed as having "rheumatism," fibromyalgia, rheumatoid arthritis, inflammatory myopathy, atypical motor neuron disease, or metabolic myopathy.
  • Disease elements other than musculoskeletal features, such as early-onset cataracts, testicular failure, and cardiac arrhythmias, were often identified, but not recognized as manifestations of DM2 [Day et al 2003].


Clinical features have been reported to worsen from generation to generation in families that participated in the original characterization of DM2 [Schneider et al 2000, Day et al 2003]. Data suggested that this was caused by anticipation (the tendency for individuals in successive generations to present at an earlier age and/or with more severe manifestations) rather than bias of ascertainment (inadvertent inclusion of more severely affected younger-generation family members in the study).

  • However, CNBP molecular genetic testing revealed no overt congenital form of DM2 comparable to the congenital form of myotonic dystrophy type 1 (DM1), which established the role of anticipation in that disease.
  • Furthermore, the lack of correlation between disease severity and CCTG repeat length underscores the conclusion that intergenerational changes in repeat length would not be expected to worsen disease severity reliably.
  • The lack of correlation between repeat length and disease severity is furthermore substantiated by the observation that individuals homozygous for repeat expansions have clinical disease indistinguishable from that of their heterozygous sibs [Schoser et al 2004a].


The International Myotonic Dystrophy Consortium (IDMC) and Online Mendelian Inheritance in Man (OMIM) both recognize that DM2 and proximal myotonic myopathy (PROMM) refer to the same condition. Individuals with PROMM were originally described as having some features of DM1 but without the characteristic DMPK trinucleotide repeat expansion. DM2 was originally thought to be clinically distinct from PROMM because of apparent differences in the clinical descriptions of families with PROMM and DM2. However, most families with PROMM have now been shown to have the characteristic CNBP expansion observed in individuals with DM2.

Note: The term 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 of 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 an unusual presentation of Paget's disease with familial inclusion body myositis [Udd et al 2006], also known as inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFTD) and caused by mutation of VCP. (See Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia.)


Myotonic dystrophy is the most common adult form of muscular dystrophy, estimated to affect approximately one in 8000 in the general population. The proportions of myotonic dystrophy caused by DM1 and DM2 are unknown. The incidence of DM2 remains unknown due to the range of clinical severity.

Prevalence appears to differ in various populations; however, few definitive demographic studies have been performed. A higher prevalence of DM2 is observed in Germany and Poland and in individuals of German or Polish descent [Udd et al 2003]. In Finland, the incidence of DM2 (1:1830) is higher than DM1 [Suominen et al 2011]. DM2 has been reported in Afghanistan and Sri Lanka but not in China, Japan, or Sub-Saharan Africa.

Differential Diagnosis

Multisystem myotonic myopathies. The only definite causes of the myotonic dystrophy phenotype to date are either an untranslated CTG expansion at the 3' untranslated region in DMPK (myotonic dystrophy type 1, DM1) or a CCTG expansion in intron 1 of CNBP (DM2). Definitive diagnosis of these two forms of myotonic dystrophy relies on molecular genetic testing.

Although routine clinical evaluation can reliably identify myotonic dystrophy, the true adult-onset forms of DM1 and DM2 cannot be reliably distinguished from each other using clinical criteria alone. The cataracts in individuals with DM1 and DM2 are indistinguishable. The most robust difference between DM1 and DM2 is that club feet, neonatal weakness and respiratory insufficiency, mental retardation, craniofacial abnormalities, and childhood hypotonia and weakness have been reported in individuals with DM1 but not those with DM2. In addition, or possibly because of the presence of these congenital effects, adults with DM1 often have more weakness and myotonia than adults with DM2; individuals with DM1 tend to have more pronounced facial and bulbar weakness, 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].

Previous reports of a multisystemic myotonic disorder that is not linked to the DM1 locus or the DM2 locus (i.e., "non-DM1, non-DM2 cases of PROMM") have been retracted after some family members were found to have a CNBP CCTG expansion, confirming the diagnosis of DM2 in those families [Day et al 2003]. Nonetheless, additional genetic causes of DM may exist.

The family described as having a novel multisystemic myotonic disorder ("DM3") [Le Ber et al 2004] has some features in common with DM1 and DM2 (cataracts and myotonia) but also has distinctly different neurologic abnormalities (motor neuron disease and spongiform encephalopathy); although the phenotype in this family was initially thought to mirror myotonic dystrophy, the family has now been classified as having Paget's disease and familial inclusion body myositis caused by a VCP pathogenic variant [Udd et al 2006, Weihl et al 2006], a disorder pathophysiologically distinct from DM. (See Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia.)

Distal myopathies. The other major group in the differential diagnosis is distal myopathy (see Table 2).

  • Udd distal myopathy is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after the age of 35 years. Disease progression is slow and muscle weakness remains confined to the anterior tibial muscles. The long-toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. Udd distal myopathy is caused by mutation of TTN, the gene encoding titin [Hackman et al 2002].
  • Nonaka early-adult-onset distal myopathy with rimmed vacuoles usually begins in the second or third decade in the anterior compartment of the legs and in the toe extensors. Foot drop and a steppage gait are present with progression to loss of ambulation after 12 to 15 years. This is the same condition as quadriceps-sparing myopathy and is caused by mutation of GNE [Nishino et al 2002]. See GNE-Related Myopathy.
  • Zaspopathy (Markesbery-Griggs late-onset distal myopathy) is characterized by weakness of ankle dorsiflexion usually beginning in the late 40s, followed later by slow progression to the finger and wrist extensor muscles and to the intrinsic muscles of the hand. Eventually the proximal leg muscles become involved. This disease is caused by mutation of LDB3 (also known as ZASP) [Griggs et al 2007]. See Myofibrillar Myopathy.
  • MPD3, a dominant distal myopathy, was described in Finland in a single family in which some affected individuals had onset in the upper limbs and others in the lower limbs; later, both upper and lower limbs are involved [Haravuori et al 2004].
  • Miyoshi early-adult-onset myopathy begins in the posterior compartment of the legs, manifests as difficulty climbing stairs and walking on toes and progresses to other distal and proximal muscles as with LGMD2B (see Dysferlinopathy). The serum CK concentration is usually more than 50 times normal.
  • Welander distal myopathy may sometimes have onset in the anterior compartment muscles of the lower legs, instead of the usual onset in the hand and finger extensors [von Tell et al 2002]. Typically, affected individuals experience weakness of the extensor of the index finger after age 40 years, followed by slow progression to the other finger extensors and to the anterior and posterior leg muscles.

Table 2.

Distal Myopathies

DisorderMean Age at Onset (Years)Initial Muscle Group InvolvedSerum Creatine Kinase ConcentrationMuscle BiopsyGene (Locus) 1
Autosomal dominant
Welander distal myopathy>40Distal upper limbs (finger & wrist extensors)Normal or slightly increasedRimmed vacuoles(2p13)
Udd distal myopathy>35Anterior compartment in legs± Rimmed vacuolesTTN
Zaspopathy (Markesbery-Griggs late-onset distal myopathy)>40Vacuolar & myofibrillar myopathyLDB3 (also known as ZASP)
Distal myotilinopathy>40Posterior > anterior in legsSlightly increasedVacuolar & myofibrillarMYOT
Laing early-onset distal myopathy (MPD1)<20Anterior compartment in legs and neck flexorsNormal to (rarely) moderately increasedType 1 fiber atrophy in tibial anterior muscles; disproportion in proximal musclesMYH7
Distal myopathy with vocal cord and pharyngeal signs (MPD2)35-60Asymmetric lower leg & hands; dysphonia1-8 timesRimmed vacuolesMATR3
Distal myopathy with pes cavus and areflexia15-50Anterior & posterior lower leg; dysphonia & dysphagia2-6 timesDystrophic, rimmed vacuoles(19p13)
New Finnish distal myopathy (MPD3)>30Hands or anterior lower leg1-4 timesDystrophic; rimmed vacuoles; eosinophilic inclusions(8p22-q11 and 12q13-q22)
Autosomal recessive
Nonaka early-adult-onset distal myopathy15-20Anterior compartment in legs<10 timesRimmed vacuolesGNE
Miyoshi early-adult-onset myopathyPosterior compartment in legs>10 timesMyopathic changesDYSF

Locus is given only if the gene is not known

Myotonia. Electrical myotonia occurs in several conditions, but the presence of myotonia in multiple family members restricts diagnostic possibilities to either DM or to the nondystrophic myotonias, which are caused by mutation of chloride and sodium channel genes, resulting in myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis. Those conditions are not associated with the muscular dystrophy or multisystem features that typify 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 in an individual diagnosed with myotonic dystrophy type 2 (DM2), the following evaluations are recommended:

  • Routine clinical evaluation of muscle strength and functional status
  • Examination by an ophthalmologist familiar with DM iridescent posterior subcapsular cataracts in order to establish a baseline
  • Initial cardiac evaluation including at minimum:
    • ECG to establish a baseline record for future comparison
    • Holter monitoring or invasive electrophysiologic testing if the person is either symptomatic or shows significant rhythm or conduction abnormalities on routine ECG
    • Because of the risk of cardiomyopathy, consideration of echocardiogram and possible cardiac MRI [Spengos et al 2012]
  • Baseline serologic testing including fasting lipid profiles, glucose, and glycosylated hemoglobin concentrations to assess for evidence of insulin insensitivity and diabetes mellitus
  • Measurement of serum concentrations of testosterone and FSH in post-pubertal males to assess gonadal function
  • Thyroid studies. While thyroid dysfunction has not been conclusively and causatively related to the DM2-causing pathogenic variants, hypothyroidism from any cause has been associated with increased muscle weakness and symptoms in individuals with DM2 [Sansone et al 2000, Day & Ranum 2005].
  • Measurement of the serum activities of CK, transaminases (AST and ALT), and γ-glutamyltransferase (GGT). Serum activities of AST, ALT, and GGT are frequently elevated in individuals with DM2, although it is unclear whether the abnormal levels are hepatocellular or myogenic in origin. Determination of baseline abnormal transaminase and GGT activities resulting from DM2 can help prevent needless investigations of the liver.
  • Serum protein electrophoresis and immunoprotein electrophoresis to establish a baseline, since the gamma fraction is frequently reduced in individuals with DM2 as a result of low levels of both IgG and IgM. Although these changes have not been associated with clinical problems, determination of abnormal immunoglobulin levels in persons with DM2 can establish individual baseline values and prevent misinterpretation of future studies demonstrating the hypogammaglobulinemia.

Treatment of Manifestations

Treatment guidelines for DM2 have been published [Udd et al 2011].

A physiatrist, occupational therapist, or physical therapist can help determine the need for ankle-foot orthoses, wheelchairs, or other assistive devices as the disease progresses [Johnson et al 1995].

Routine physical activity appears to be beneficial for maintaining muscle strength and endurance in persons with DM2, and as an aid to control musculoskeletal pain.

Myotonia is typically mild and rarely requires treatment [Ricker 1999], though use of mexilitene, which is very effective in controlling some forms of myotonia, has helped control muscle pain in some individuals with DM2.

The effectiveness of medications and combination of medications in pain management varies. No one medication has been consistently effective; medications that have been used with some success include mexilitene, gabapentin, nonsteroidal anti-inflammatory drugs (NSAIDS), low-dose thyroid replacement, low-dose steroids (e.g., 5 mg prednisone on alternate days), and tricyclic antidepressants. Low-dose narcotic analgesics, when used as part of a comprehensive pain management program, may help but may also lead to development of tolerance and escalating doses.

Consultation with a cardiologist is strongly recommended for individuals with cardiac symptoms or ECG evidence of arrhythmia because fatal arrhythmias can occur prior to the onset of other symptoms. ECG, Holter monitoring, and an echocardiogram should be performed to evaluate syncope, palpitations, and other symptoms of potential cardiac origin. More advanced, invasive electrophysiologic testing of the heart may be required [Florek et al 1990, Hawley et al 1991]. Due to the increased risk for cardiomyopathy, echocardiography and possibly cardiac MRI should be considered.

The value of defibrillator placement is increasingly evident in individuals with DM2 who have overt arrhythmias, but the role of pacemaker/defibrillators in asymptomatic patients is yet to be determined [Schoser et al 2004b].

Cataracts can be removed if they impair vision. As compared to the more typical senile nuclear cataracts, direct ophthalmoscopy and even slit lamp examination can underestimate the functional significance of cataracts in individuals with DM2 because the alteration of vision depends on location, not just the number of subcapsular opacities.

Testosterone replacement therapy can be beneficial in males with symptomatic hypogonadism.

Direct gastrointestinal manifestations of DM2 are yet to be characterized, but some patients complain of postprandial abdominal pain, bloating, constipation, and diarrhea. As in myotonic dystrophy type 1 (DM1), some individuals respond to prokinetic agents such as metochlopromide (Reglan™) and tegaserod (Zelnorm™).

Prevention of Secondary Complications

Anesthetic risk may be increased in those with DM2; therefore, careful assessment of cardiac and respiratory function before and after surgery are recommended [Veyckemans & Scholtes 2013].

Increased weakness in individuals with DM2 has been associated with hypothyroidism; thus, some strength may return if hypothyroidism is treated.


Annual ECG and echocardiogram or possible cardiac MRI is indicated to detect asymptomatic and progressive cardiac conduction defects and cardiomyopathy.

Some centers perform annual 24-hour Holter monitoring even in the absence of cardiac symptoms.

Fasting serum glucose concentration and glycosylated hemoglobin level should be measured annually.

Males should be tested for hypogonadism if they become increasingly fatigued or have reduced sexual energy, and should be tested every few years even without symptoms to see if they would benefit from replacement therapy.

Agents/Circumstances to Avoid

Increased weakness has been associated with the use of certain cholesterol-lowering medications. In these cases, some strength can return if statin-type cholesterol-lowering medications are eliminated.

Note: Not all individuals with DM2 have an adverse response to statin medications, and thus diagnosis of DM2 is not an absolute contraindication to use of these drugs.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Myotonic dystrophy type 2 is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • To date, all probands whose biological parents have been evaluated with molecular genetic testing have had one parent with a CNBP expansion.
  • Probands with de novo pathogenic variants have not been reported.
  • The CNBP expansion shows size differences between generations in the same family. In general, the repeat size appears to contract when passed on to the subsequent generation and then to increase in size as the affected individual ages (see Related Genetic Counseling Issues, Somatic mosaicism). There is no maternal or paternal preference for contraction or expansion.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents.
  • Sibs of an affected individual have a 50% chance of inheriting the CNBP expansion if one parent has the expansion.

Offspring of a proband

  • Each child of an individual with a CNBP expansion has a 50% chance of inheriting the expansion.
  • The CNBP CCTG repeat tract tends to contract when passed from one generation to the next and then to increase in size as the affected individual ages.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents: if a parent is affected, his or her family members are at-risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

There is no correlation between the measured repeat size and disease severity; thus, age of onset or clinical course cannot be predicted from molecular genetic test results.

Somatic mosaicism. The CNBP CCTG repeat expansion is highly unstable and tends to increase in size with age of the affected individual. The results of multiple tests performed on distinct peripheral blood samples drawn from affected individual at the same time or at different ages may differ in expansion size. In addition, an individual may have more than one expanded allele size detectable by Southern blot analysis in a single sample of peripheral blood. Neither the size of a predominant allele nor the total number of different detectable expansions in a single sample can predict disease severity, age of onset, or clinical symptoms of the condition.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults is possible using the techniques described in Molecular Genetic Testing. Predictive testing can determine whether an individual has a CNBP expansion, and thus whether or not that individual is at risk of developing the disease. The repeat size cannot predict age of onset, severity, or clinical symptoms. An affected family member should be tested prior to offering testing to at-risk family members to confirm the presence of a CNBP expansion in the family. Predictive testing should be accompanied by genetic counseling to assure that individuals are aware of the limitations of the molecular genetic test and the possible risks associated with predictive testing.

Testing of at-risk individuals younger than age 18 years. Testing of at-risk asymptomatic individuals younger than age 18 years is not recommended for adult-onset conditions in which there is no known effective treatment that prevents the disease or improves the outcome. Individuals younger than age 18 years who are symptomatic usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the CNBP pathogenic expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Myotonic Dystrophy Type 2: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CNBP3q21​.3Cellular nucleic acid-binding proteinCNBP databaseCNBPCNBP

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Myotonic Dystrophy Type 2 (View All in OMIM)


Molecular Genetic Pathogenesis

The clinical and molecular parallels of myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) strongly suggest that the untranslated RNAs that contain the repeat expansion are responsible for the pathologic features common to both disorders.

The pathogenesis of both DM1 and DM2 can be explained by a gain-of-function RNA mechanism in which the CUG and CCUG repeats, respectively, alter cellular function, including alternative splicing of various genes [Tapscott & Thornton 2001, Ranum & Day 2002, Ranum & Day 2004, Day & Ranum 2005]. Both DM1 and DM2 have RNA foci containing RNA of the abnormally expanded allele that colocalize with several forms of the RNA-binding protein muscleblind (MBNL, MBLL, and MBXL) [Mankodi et al 2001, Fardaei et al 2002].

Dysregulation of muscleblind and of the RNA-binding protein CUG-BP (encoded by CNBP) subsequently alters gene splicing of various downstream genes. Increased CUG-BP RNA results in missplicing of cardiac troponin T, the insulin receptor, and the chloride channel, possibly contributing to the cardiac involvement, insulin insensitivity, and myotonia, respectively [Philips et al 1998, Mankodi et al 2001, Savkur et al 2001]. Downstream effects of abnormal insulin receptor splicing in both DM1 and DM2 correlate with the insulin insensitivity in both disorders [Savkur et al 2004]. Knockout of muscleblind in mice leads to the myotonia, cataracts, and myopathy characteristic of DM1 and DM2 [Kanadia et al 2003].

Gene structure. The CNBP (formerly ZNF9) CCTG repeat is part of a complex repeat motif with the overall configuration (TG)n(TCTG)n(CCTG)n. In normal CNBP alleles, the CCTG repeat contains nucleotide interruptions. The longest known normal CNBP allele, in which the overall repeat motif is 176 bp in length, includes 26 CCTG repeats with two interruptions [Liquori et al 2001]. Such nucleotide interruptions are similar to those seen in normal-length alleles of genes that cause other nucleotide repeat disorders (spinocerebellar ataxia type 1 and FMR1-related disorders) [Chung et al 1993, Kunst & Warren 1994].

CNBP is widely expressed. It shares no functional similarity to any genes at the DM1 locus, including the dystrophica myotonica-protein kinase gene (DMPK), within the 3'-untranslated region of which the DM1 CTG expansion exists. Likewise, none of the genes in the DM2 region share similarity to genes in the DM1 region. The lack of similar genes at the two loci further indicates that the causative variants result in pathogenic RNA expansions rather than alteration of gene expression or gene products. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. DM2 is caused by a single mutational mechanism of a CCTG tetranucleotide repeat expansion of more than 75 (overall repeat lengths greater than 372 bp). The expanded repeat length ranges from 372 bp to more than 44,000 bp (equivalent to a range of 75 to >11,000 repeats), although the actual pathogenic threshold has not been determined because the repeat tract is highly unstable and displays marked somatic mosaicism. The affected individual with the smallest repeat expansion also a second large expansions, it remains unknown if both or just one is pathogenic. The CCTG repeat that is expanded in DM2 lies in intron 1 of CNBP and is transcribed into RNA but not translated into protein.

Normal gene product. CNBP encodes a 19,463-dalton cellular nucleic acid-binding protein with 177 amino acids (NP_003409.1) [Pellizzoni et al 1997, Pellizzoni et al 1998].

Abnormal gene product. The CCTG repeat that is expanded in DM2 is transcribed into RNA but is not translated into protein. There is no evidence of CNBP haploinsufficiency in DM2 [Margolis et al 2006].


Published Guidelines / Consensus Statements

  • Kamsteeg EJ, Kress W, Catalli C, Hertz JM, Witsch-Baumgartner M, Buckley MF, van Engelen BGM, Schwartz M, Scheffer H. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2. Available online. 2012. Accessed 3-14-18. [PMC free article: PMC3499739] [PubMed: 22643181]
  • Udd B, Meola G, Krahe R, Wansink DG, Bassez G, Kress W, Schoser B, Moxley R. Myotonic dystrophy type 2 (DM2) and related disorders report of the 180th ENMC workshop including guidelines on diagnostics and management 3–5 December 2010, Naarden, The Netherlands. Neuromuscul Disord. 2011;21:443–50. [PubMed: 21543227]

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  • Udd B, Griggs R. Distal myopathies. Curr Opin Neurol. 2001;14:561–6. [PubMed: 11562566]
  • Udd B, Meola G, Krahe R, Wansink DG, Bassez G, Kress W, Schoser B, Moxley R. Myotonic dystrophy type 2 (DM2) and related disorders report of the 180th ENMC workshop including guidelines on diagnostics and management 3-5 December 2010, Naarden, The Netherlands. Neuromuscul Disord. 2011;21:443–50. [PubMed: 21543227]
  • Udd B, Meola G, Krahe R, Thornton C, Ranum L, Day J, Bassez G, Ricker K. Report of the 115th ENMC workshop: DM2/PROMM and other myotonic dystrophies. 3rd Workshop, 14-16 February 2003, Naarden, The Netherlands. Neuromuscul Disord. 2003;13:589–96. [PubMed: 12921797]
  • Udd B, Meola G, Krahe R, Thornton C, Ranum LP, Bassez G, Kress W, Schoser B, Moxley R. 140th ENMC International Workshop: Myotonic Dystrophy DM2/PROMM and other myotonic dystrophies with guidelines on management. Neuromuscul Disord. 2006;16:403–13. [PubMed: 16684600]
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  • von Tell D, Somer H, Udd B, Edström L, Borg K, Ahlberg G. Welander distal myopathy outside the Swedish population: phenotype and genotype. Neuromuscul Disord. 2002;12:544–7. [PubMed: 12117477]
  • Wahbi K, Meune C, Bécane HM, Laforêt P, Bassez G, Lazarus A, Radvanyi-Hoffman H, Eymard B, Duboc D. Left ventricular dysfunction and cardiac arrhythmias are frequent in type 2 myotonic dystrophy: a case control study. Neuromuscul Disord. 2009;19:468–72. [PubMed: 19481939]
  • Weihl CC, Dalal S, Pestronk A, Hanson PI. Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation. Hum Mol Genet. 2006;15:189–99. [PubMed: 16321991]
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  • Win AK, Perattur PG, Pulido JS, Pulido CM, Lindor NM. Increased cancer risks in myotonic dystrophy. Mayo Clin Proc. 2012;87:130–5. [PMC free article: PMC3498332] [PubMed: 22237010]

Suggested Reading

  • Chaudhry SP, Frishman WH. Myotonic dystrophies and the heart. Cardiol Rev. 2012;20:1–3. [PubMed: 22143278]
  • Johnson NE, Heatwole CR. Myotonic dystrophy: from bench to bedside. Semin Neurol. 2012;32:246–54. [PubMed: 23117949]
  • Udd B, Krahe R. The myotonic dystrophies: molecular, clinical, and therapeutic challenges. Lancet Neurol. 2012;11:891–905. [PubMed: 22995693]

Chapter Notes

Patient Information

Muscular Dystrophy Association

Myotonic Dystrophy Foundation

Revision History

  • 3 July 2013 (me) Comprehensive update posted live
  • 23 April 2007 (jwd) Revision: Allele sizes; to provide information to aid clinicians in interpreting test reports
  • 21 September 2006 (me) Review posted to live Web site
  • 14 June 2004 (jwd) Original submission
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