Myotonic dystrophy (DM) is a multisystem disorder and the most common form of muscular dystrophy in adults. Individuals with DM2 have muscle pain and stiffness, progressive muscle weakness, myotonia, male hypogonadism, cardiac arrhythmias, diabetes, and early cataracts. Other ... Myotonic dystrophy (DM) is a multisystem disorder and the most common form of muscular dystrophy in adults. Individuals with DM2 have muscle pain and stiffness, progressive muscle weakness, myotonia, male hypogonadism, cardiac arrhythmias, diabetes, and early cataracts. Other features may include cognitive dysfunction, hypersomnia, tremor, and hearing loss (summary by Heatwole et al., 2011). See also myotonic dystrophy-1 (DM1; 160900), caused by an expanded CTG repeat in the dystrophia myotonica protein kinase gene (DMPK; 605377) on 19q13. Although originally reported as 2 disorders, myotonic dystrophy-2 and proximal myotonic myopathy are now referred to collectively as DM2 (Udd et al., 2003).
Moxley et al. (1998) reviewed the diagnostic criteria of PROMM that had been delineated at the 54th European Neuromuscular Center International Workshop in 1997, before the causative ZNF9 mutation had been identified. Mandatory inclusion criteria included autosomal dominant ... Moxley et al. (1998) reviewed the diagnostic criteria of PROMM that had been delineated at the 54th European Neuromuscular Center International Workshop in 1997, before the causative ZNF9 mutation had been identified. Mandatory inclusion criteria included autosomal dominant inheritance, proximal weakness, primarily in the thighs, myotonia demonstrable by EMG, cataracts identical to those seen in DM1, and a normal size of the CTG repeat in the DM1 gene. Noting that the extremely large size and somatic instability of the DM2 expansion make molecular testing and interpretation difficult, Day et al. (2003) developed a repeat assay that increased the molecular detection rate of DM2 to 99%.
Thornton et al. (1994) reported patients with clinical characteristics consistent with classic myotonic dystrophy, but without the CTG repeat in the DMPK gene (see also Rowland, 1994).
Ricker et al. (1994) described 15 affected individuals in ... Thornton et al. (1994) reported patients with clinical characteristics consistent with classic myotonic dystrophy, but without the CTG repeat in the DMPK gene (see also Rowland, 1994). Ricker et al. (1994) described 15 affected individuals in 3 pedigrees showing segregation of a novel autosomal dominant disorder, termed proximal myotonic myopathy (PROMM). Affected individuals showed features of myotonia, typically appearing between the third and fourth decade of life, and mild proximal weakness, which did not appear until the fifth to seventh decade. The severity of this disease was quite variable. None of the patients had hypersomnia, gonadal atrophy, hearing deficits, gastrointestinal hypermotility, ptosis, cardiac arrhythmia, or respiratory weakness, features often present in cases of classic myotonic dystrophy-1. Muscle biopsy demonstrated a nonspecific mild myopathy with hypertrophy of type 2 fibers with variation in diameter, but no ringbinden or subsarcolemmal masses. Physiologic studies of muscle fiber bundles taken from 2 patients demonstrated long-lasting runs of repetitive action potentials which were abolished by tetrodotoxin and/or consistently diminished by increasing the potassium concentration, a finding distinct from that present in myotonic dystrophy. Chloride conductance was normal. The number of CTG repeats in the DMPK gene was normal in the proband from each of the families. Linkage analysis performed on each of the 3 kindreds gave a significant negative lod score for DM1, chloride channel-1 (CLCN1; 118425) on chromosome 7q, and muscle sodium channel (SCN4A; 603967) on 17q, excluding allelism with DM1, myotonia congenita, and paramyotonia. Ricker et al. (1995) reported 27 patients with proximal myotonic myopathy from 14 families. Of the 27, 21 had proximal without distal weakness of the legs. Although only 17 of them had clinical myotonia, 23 had myotonia demonstrated electromyographically. Twenty-four had cataracts, several of which were similar to those seen in DM1. Fourteen patients complained of a burning, tearing muscle pain. Muscle atrophy was not a major feature. Ricker et al. (1995) concluded that PROMM is a multisystem disorder similar to DM1 with involvement of skeletal muscle, lens, and heart. However, it appeared to have a more favorable long-term prognosis inasmuch as none of these patients demonstrated late deterioration in mental status, hypersomnia, dysphagia, or other respiratory complications. Clinically, PROMM could be distinguished from myotonic dystrophy by the proximal, rather than distal, weakness and sparing of the facial muscles. Ricker (1999) concluded that PROMM is a more benign disorder than DM1, and suggested that, in Germany, the frequency of PROMM may be almost equal to that of DM. Abbruzzese et al. (1996) reported 6 patients from 2 families with myotonic dystrophy characterized by multisystem manifestations that were indistinguishable from those seen in DM1 and PROMM, but who did not have expansions of the chromosome 19 repeat. Among 50 patients with PROMM from 10 unrelated families in Italy, Meola et al. (1998) found that 38 showed autosomal dominant inheritance and the remainder were sporadic cases. Symptoms at onset included myotonia in 30 to 60% of patients, muscle pain in 30 to 50% of patients, and lower leg weakness. Cataracts identical to those found in myotonic dystrophy-1 were identified in 15 to 30% of patients. Cardiac symptoms were present in only 5 to 10% of patients and consisted mainly of cardiac arrhythmias. Linkage analysis in the families of Meola et al. (1998) excluded linkage to chromosomes 19, 17, 7, and 3. Ranum et al. (1998) identified a 5-generation family with a form of myotonic dystrophy with clinical features remarkably similar to those found in classic DM1, without the chromosome 19 CTG expansion. The authors named the locus for the disorder myotonic dystrophy-2 (DM2). Clinical features included myotonia, proximal and distal limb weakness, frontal balding, polychromatic cataracts, infertility, and cardiac arrhythmias. Day et al. (1999) noted that the genetically distinct form of myotonic dystrophy in this 5-generation kindred shared some of the clinical features of previously reported families with proximal myotonic myopathy. Newman et al. (1999) reported a family in which proximal myopathy, cataracts, intermittent myotonia, and myalgia occurred in several members in an autosomal dominant pattern. The presentation was unusual in the proband and her 2 sisters, all of whom presented with myotonia during pregnancy which resolved after each delivery. Two of the sisters experienced myalgia between each pregnancy. Vihola et al. (2003) reported the pathologic findings in DM2. Muscle biopsies from affected patients showed myopathic changes, including increased fiber size variation and internalized nuclei. There were scattered thin, angular, atrophic fibers, with preferential type 2 fiber atrophy. Bonsch et al. (2003) discussed PROMM and DM2 as one entity characterized by myotonia, muscular dystrophy with proximal weakness, cardiac conduction defects, endocrine disorders, and cataracts. They noted that hearing loss had been described as one feature of PROMM. Day et al. (2003) provided a detailed review of DM2. Schoser et al. (2004) reported 4 DM2 patients from 3 families who died of sudden cardiac death between ages 31 and 44 years. None of the 4 had high blood pressure, diabetes, or arteriosclerosis, and all had only mild symptoms of DM2. Only 1 patient had increasing cardiac insufficiency 6 months before death. Cardiopathologic findings in 3 patients showed dilated cardiomyopathy, with conduction system fibrosis in 2 patients. Two patients had accumulation of CCUG ribonuclear inclusions in cardiomyocytes. Maurage et al. (2005) identified tau (MAPT; 157140)-positive neurofibrillary tangles (NFTs) in multiple brain regions of a patient with DM2 originally reported by Udd et al. (2003). The findings were similar to the NFTs identified in patients with DM1 who also had cognitive impairment or mental retardation. However, the patient with DM2 studied by Maurage et al. (2005) was mentally normal, demonstrated no cognitive decline, and died at age 71 years from a bilateral renal thrombosis. Maurage et al. (2005) suggested that the findings may be related to abnormal processing of tau protein isoforms similar to the mechanism observed in DM1. Rudnik-Schoneborn et al. (2006) reported the clinical details of pregnancy in 42 women with DM2 from 37 families. Nine women (21%) had the first symptoms of DM2 during pregnancy and worsening of symptoms in subsequent pregnancies. There was often a marked improvement in symptoms after delivery. Of 96 pregnancies, 13% ended as early miscarriage and 4% as late miscarriage. Women with overt DM2 symptoms in pregnancy had a high risk of preterm labor (50%) and preterm births (27%). There was no evidence of congenital DM2 in the offspring and the overall neonatal outcome was favorable. Heatwole et al. (2011) analyzed the laboratory abnormalities of 83 patients with genetically confirmed or clinically probable DM2. Among 1,442 laboratory studies performed, 10 tests showed abnormal values in more than 40% of patients. These included increased serum creatine kinase, decreased IgG, increased total cholesterol, decreased lymphocyte count, increased lactate dehydrogenase, increased ALT, decreased creatinine, increased basophils, variable glucose levels, and decreased total protein. Only 33% of patients had increased GGT. Although endocrine laboratory studies were limited, the trend suggested low testosterone and increased FSH. The findings reinforced the idea that DM2 is a multisystem disorder and provided a means for disease screening and monitoring.
Sun et al. (2011) reported a large 3-generation Norwegian family in which 13 individuals had DM2 confirmed by genetic analysis. Six of the 13 patients also carried a heterozygous F413C substitution in the CLCN1 gene (118425.0001); the F413C ... Sun et al. (2011) reported a large 3-generation Norwegian family in which 13 individuals had DM2 confirmed by genetic analysis. Six of the 13 patients also carried a heterozygous F413C substitution in the CLCN1 gene (118425.0001); the F413C mutation is usually associated with autosomal recessive myotonia congenita (255700) when present in the homozygous or compound heterozygous state. All family members, regardless of genotype, had myotonic discharges on EMG, but the discharges were more prominent in those with both mutations. Similarly, most patients reported muscle stiffness and myalgia, and but those with both mutations tended to report more stiffness than those with only the ZNF9 expansion. These findings suggested that the CLCN1 mutation may have exaggerated the myotonia phenotype in those with the ZNF9 expansion. A 64-year-old man with only the ZNF9 expansion had generalized myalgia during his entire adult life, bilateral cataracts, and cardiomyopathy with evidence of abnormal relaxation of the myocardium. He had mild action myotonia. EMG showed myopathic changes and myotonia runs consistent with DM2. His brother, who had both mutations, had myalgia and complained of stiffness and mild muscle weakness, but strength was normal. EMG and physical examination showed myotonia. All of his 5 daughters, 3 of whom carried both mutations, developed myotonia during pregnancy that persisted after delivery. The most severely affected daughter also had cold-induced stiffness in the perioral muscles. All patients had normal cognitive function. The genetic findings helped to explain the clinical variability in this family.
Liquori et al. (2001) reported that DM2 is caused by a CCTG expansion located in intron 1 of the ZNF9 gene (116955.0001). Expanded allele sizes ranged from 75 to approximately 11,000 CCTG repeats, with a mean of approximately ... Liquori et al. (2001) reported that DM2 is caused by a CCTG expansion located in intron 1 of the ZNF9 gene (116955.0001). Expanded allele sizes ranged from 75 to approximately 11,000 CCTG repeats, with a mean of approximately 5,000 repeats. Expansion sizes in the blood of affected children were usually shorter than in their parents (reverse anticipation), but the authors noted that the time-dependent somatic variation of repeat size may complicate interpretation of this difference. No significant correlation between the age of onset and expansion size was observed. Liquori et al. (2003) and Bachinski et al. (2003) provided evidence for a founder effect of the CCTG(n) expansion in European populations. Saito et al. (2008) reported a Japanese woman with DM2 who had a heterozygous expanded ZNF2 CCTG allele of 3,400 repeats. Haplotype analysis showed a background distinct from that observed in European patients, indicating a different ancestral origin of the mutation in this patient. Bachinski et al. (2009) identified 3 classes of large non-DM2 repeat alleles: short interrupted alleles of up to CCTG(24) with 2 interruptions, long interrupted alleles of up to CCTG(32) with up to 4 interruptions, and uninterrupted alleles of CCTG(22-33) with lengths of 92 to 132 bp. Large non-DM2 alleles above 40 repeats were more common among African Americans (8.5%) than European Caucasians (less than 2%). Uninterrupted alleles were significantly more unstable than interrupted alleles (p = 10(-4) to 10(-7)). SNP analysis was consistent with the hypothesis that all large alleles occurred on the same haplotype as the DM2 expansion. Bachinski et al. (2009) concluded that unstable uninterrupted CCTG(22-33) alleles may represent a premutation allele pool for DM2 full mutations.
Suominen et al. (2011) found 2 DM2 mutations among 4,508 Finnish control individuals. One of 988 Finnish patients with a neuromuscular disorder also carried a DM2 mutation, but this patient also had genetically verified tibial muscular dystrophy (TMD; ... Suominen et al. (2011) found 2 DM2 mutations among 4,508 Finnish control individuals. One of 988 Finnish patients with a neuromuscular disorder also carried a DM2 mutation, but this patient also had genetically verified tibial muscular dystrophy (TMD; 600334), but no myotonia. The exact sizes of the expanded repeats could not be determined. Overall, the DM2 mutation frequency was estimated to be 1 in 1,830 in the general population. In addition, 1 of 93 Italian patients with proximal myopathy or increased serum creatine kinase also carried a DM2 mutation. This 49-year-old patient had waddling gait, proximal weakness, and Gowers sign, but normal serum creatine kinase. EMG showed a myopathic pattern without myotonic discharges, possibly expanding the phenotypic spectrum of DM2 or suggesting that patients with variant symptoms may not be properly diagnosed. In the same study, the frequency of DM1 mutations was estimated to be 1 in 2,760. Suominen et al. (2011) stated that the estimates of DM1 and DM2 in their study were significantly higher than previously reported estimates, which they cited as 1 in 8,000 for both DM1 and DM2. They concluded that DM1 and DM2 are more frequent than previously thought.
Myotonic dystrophy type 2 (DM2) should be suspected in individuals with the following:...
DiagnosisClinical DiagnosisMyotonic 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 TestingMuscle 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. 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]. Molecular Genetic TestingGene. 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)FigureFigure 1. Complex repeat at the DM2 locus. TG, TCTG, and CCTG tracts, each of which is polymorphic in length, comprise the overall 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 in Mutable normal alleles; see following); 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. 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 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. Summary of Molecular Genetic Testing Used in Myotonic Dystrophy Type 2View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityCNBPMutation analysis CCTG tetranucleotide repeat expansion in intron 1 99% 2Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene 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 StrategyTo confirm/establish the diagnosis in a proband. 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]. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotype is known to be associated with mutations in CNBP.
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%)....
Natural HistoryMyotonic 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 et al 2004b].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-Schöneborn et al 2006]. Polyhydramnios, a recognized feature of DM1, has not been reported in individuals with DM2.
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 one of CNBP (DM2). Definitive diagnosis of these two forms of myotonic dystrophy relies on molecular genetic testing. ...
Differential DiagnosisMultisystem 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 one 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 mutation [Udd et al 2006, Weihl et al 2006], a disorder pathophysiologically distinct from DM.Hereditary distal myopathy. The differential diagnosis for hereditary distal myopathies includes hereditary inclusion body myositis (IBM), hereditary myofibrillar myopathy (MFM), distal muscular dystrophy (e.g., Miyoshi (see Dysferlinopathy), Nonaka, Welander, Markesbery-Griggs, Udd), and some limb-girdle muscular dystrophies. Additionally, IBM and MFM may occur sporadically (see Table 2). Table 2. Distal MyopathiesView in own windowDistal MyopathyMean Age at OnsetInitial Muscle Group InvolvedSerum Creatine Kinase ConcentrationMuscle BiopsyInheritanceChromosomal LocusGene SymbolWelander distal myopathy>40 yearsDistal upper limbs (finger and wrist extensors)Normal or slightly increasedRimmed vacuolesAutosomal dominant2p13UnknownUdd distal myopathy >35Anterior compartment in legsRimmed vacuoles +/-2q24.3TTN Markesbery- Griggs late-onset distal myopathy>40Vacuolar myopathy2q31UnknownLaing childhood- onset distal myopathy (MPD1)Anterior compartment in legs and neck flexorsModerately increasedFiber atrophy and disproportion14q12MYH7 Nonaka early-adult- onset distal myopathy15-20Anterior compartment in legsRimmed vacuolesAutosomal recessive9p12-p11GNE Miyoshi early-adult- onset myopathy Posterior compartment in legs>10 timesMyopathic changes2p13.3-p13.1DYSF Distal myopathy with vocal cord and pharyngeal signs (MPD2)35-60Asymmetric lower leg and hands plus dysphonia1-8 timesRimmed vacuolesAutosomal dominant5qUnknownDistal myopathy with pes cavus and areflexia15-50Anterior and posterior lower leg, dysphonia plus dysphagia2-6 timesDystrophic, rimmed vacuoles19p13New Finnish distal myopathy (MPD3)>30Hands or anterior lower leg1-4 timesDystrophic, rimmed vacuoles, and eosinophilic inclusions8p22-q11 and 12q13-q22Udd & Griggs [2001]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 mutations in 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.
To establish the extent of disease in an individual diagnosed with myotonic dystrophy type 2 (DM2), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 abnormalies on routine ECG Baseline serologic 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 ManifestationsA 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 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 patients respond to prokinetic agents such as metochlopromide (Reglan™) and tegaserod (Zelnorm™).Prevention of Primary ManifestationsNo specific treatment exists for the progressive weakness in individuals with DM2.Prevention of Secondary ComplicationsIncreased 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.SurveillanceAnnual ECG is indicated to detect asymptomatic and progressive cardiac conduction defects.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.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCNBP3q21.3Cellular nucleic acid-binding proteinCNBP homepage - Mendelian genesCNBPData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Myotonic Dystrophy Type 2 (View All in OMIM) View in own window 116955ZINC FINGER PROTEIN 9; ZNF9 602668MYOTONIC DYSTROPHY 2; DM2Molecular Genetic PathogenesisThe 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 the repeat expansion 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 subsequently alters gene splicing of various downstream genes. Increased CUG-BP RNA results in missplicing of cardiac troponin T (cTNT), the insulin receptor (IR), 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].Normal allelic variants. The CNBP (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 interruptions similar to those seen in normal-length SCA1 and FMR1 alleles [Chung et al 1993, Kunst & Warren 1994]. 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]. Pathologic allelic variants. DM2 is caused by a single mutational mechanism: 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 heterogeneity; the affected individual with the smallest repeat expansion also has very large expansions, all of which may or may not be 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 cellular nucleic acid-binding protein [Pellizzoni et al 1997, Pellizzoni et al 1998]. The gene is widely expressed. CNBP 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 mutations result in pathogenic RNA expansions rather than alteration of gene expression or gene products. 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].