Myotonic Dystrophy Type 2

[Proximal Myotonic Myopathy (PROMM)]

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)

• 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 echocardicography

• 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

Testing

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, Schneider-Gold et al 2004], all of which occur in both myotonic dystrophy type 1 (DM1) and DM2 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, Schneider-Gold et al 2004].

Molecular Genetic Testing

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Gene.   CNBP(ZNF9), the gene encoding cellular nucleic acid-binding protein (zinc finger protein 9), is the only gene known to be associated with 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

•  

  

  Figure 1. Complex repeat at the DM2 locus.
  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 complex repeat length in normal alleles ranges from 104 to 176 base pairs. Because TG and TCTG repeat tracts are highly polymorphic, allele sizes determined by routine molecular genetic testing without sequencing are reported in overall base-pair length rather than as a definable number of CCTG repeats.

  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 track clearly differ on the two alleles and are thus distinct on PCR analysis.

Clinical uses

• Diagnostic testing

• Predictive testing

• Prenatal diagnosis

• Preimplantation genetic diagnosis

Clinical testing

Mutation analysis.  The large size of the CCTG expansion and the presence of somatic heterogeneity complicate the detection of abnormal CNBP alleles. 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 assay" [Day et al 2003].

• Routine PCR analysis can detect normal-sized alleles but not abnormal-sized alleles because it cannot amplify across the expansion.

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

  If PCR analysis shows a single normal-sized allele, which occurs in 15% of normal individuals and in all affected individuals, it is necessary to perform both Southern blot analysis and the PCR repeat 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].

• Southern blot analysis detects approximately 80% of expansions, but interpretation of results is complicated both by the large size of the expansion and the presence of somatic heterogeneity. Approximately 20% of expansions cannot be detected by Southern blot analysis because of somatic repeat instability.

• PCR repeat assay was developed to aid 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 assay products are probed with an internal probe to assure the necessary specificity.

Sequence analysis.  Because of variability in size of the flanking TG and TCTG repeats and because of variability in the number of interruptions within the CCTG repeat tract, the number of CCTGs must 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 the sequencing reactions.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Myotonic Dystrophy Type 2

Test Method	Mutations Detected	Mutation Detection Frequency  1	Test Availability
Mutation analysis	CCTG tetranucleotide repeat expansion in intron 1 of the CNBP gene	99%  2	Clinical

1.  Proportion of affected individuals with a mutation(s) as classified by gene/locus, phenotype, population group, genetic mechanism, and/or test method
2. Detection rate varies by method used. When routine PCR analysis, Southern blot analysis, and PCR repeat assay are used together, the mutation detection rate is greater than 99%.

Interpretation of test results

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

• Southern 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.

• The PCR repeat 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

If PCR analysis shows a single band, indicating presence of only a single normal allele size, which occurs in 15% of normal individuals and in all affected individuals, it is necessary to perform both Southern blot analysis and the PCR repeat 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].

Genetically Related (Allelic) Disorders

No other phenotype is known to be associated with mutations in CNBP.

Natural History

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]. Note that unlike myotonic dystrophy type 1 (DM1), which can present in adulthood as a degenerative disorder or during infancy or childhood with variably severe congenital features, DM2 has not been associated with developmental abnormalities and thus does not cause severe childhood symptoms. 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.

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], DM2 can be associated with atrioventricular and intraventricular conduction defects, arrhythmias, cardiomyopthy, and sudden death [Colleran et al 1997; Merino et al 1998; Nguyen et al 1988; Philips et al 1998; Day et al 2003; Schoser, Ricker et al 2004].

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 causes of significant morbidity and mortality.

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 hypogammablobulinemia, 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]. These anatomical changes appear to have some effect on cognition, behavior, and personality, although unlike DM1, DM2 has not been associated with mental retardation [Meola et al 2002, Meola et al 2003]. Increased sleepiness has been reported in some individuals with DM2 [Day et al 1999], but no reports have rigorously compared or contrasted sleep issues in DM1 and DM2.

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

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, Kress et al 2004].

A correlation exists 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].

Penetrance

Disease penetrance reflects both a subject'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 without recognition that they were manifestations of DM2 [Day et al 2003].

Anticipation

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 (worsening of the disease on transmission) 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 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 reliably worsen disease severity, distinguishing DM2 inheritance from polyglutamine diseases in which increases of the CAG trinucleotide repeat expansion correlate with worsening disease manifestations. 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 siblings [Schoser, Kress et al 2004].

Nomenclature

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 mutation 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 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 mutations in VCP.

Prevalence

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.

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 decent [Udd et al 2003]. DM2 has been reported in Afghanistan and Sri Lanka but not in China, Japan or Sub-Saharan Africa.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with myotonic dystrophy type 2 (DM2):

• 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 abnormalies on routine ECG

• Baseline serological testing including fasting lipid profiles, glucose, and glycosylated hemoglobin concentrations to assess for evidence of insulin insensitivity and diabetes mellitus

• Testosterone and FSH testing in post-pubertal males to assess gonadal function

• Thyroid studies. While thyroid dysfunction has not been conclusively and causatively related to the DM2-causing mutations, 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). AST, ALT, and GGT levels 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 levels 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

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].

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, Ricker et al 2004].

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 patients respond to prokinetic agents such as metochlopromide (Reglan^TM) and tegaserod (Zelnorm^TM).

Prevention of Primary Manifestations

No specific treatment exists for the progressive weakness in individuals with DM2.

Prevention of Secondary Complications

Increased weakness in individuals with DM2 has been associated with both hypothyroidism and certain cholesterol-lowering medications, so that some strength can return if hypothyroidism is treated and 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.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.