Curr Neurol Neurosci Rep (2014) 14:429 DOI 10.1007/s11910-013-0429-1

NERVE AND MUSCLE (L WEIMER, SECTION EDITOR)

Recent Advances in Myotonic Dystrophy Type 2 Christina M. Ulane & Sarah Teed & Jacinda Sampson

# Springer Science+Business Media New York 2014

Abstract Myotonic dystrophy is the commonest adult muscular dystrophy. Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are often discussed jointly, and although they share many clinical and molecular features, differences do exist. Historically, more is known about DM1 than about DM2. The literature in the field of myotonic dystrophy is broad, with advances in our understanding of DM2. This article reviews recent developments in DM2 with respect to diagnosis, systemic features, and molecular mechanisms of the disease. Keywords Myotonic dystrophy type 2 . Proximal myotonic myopathy . Zinc finger 9 . Cellular retroviral nucleic acid binding protein 1 . CCTG

Introduction Myotonic dystrophy type 1 (DM1) was first described by Steinert in 1909, and the features of cataracts and anticipation were described by Fleischer in 1918. The causative gene dystrophia myotonica protein kinase (DMPK ) was identified

This article is part of the Topical Collection on Nerve and Muscle C. M. Ulane Department of Neurology, The Neurological Institute, Columbia University Medical Center, 710 West 168 St., New York, NY 10032, USA e-mail: [email protected] S. Teed Gertrude H. Sergievsky Center, Columbia University Medical Center, 710 West 168 St., New York, NY 10032, USA e-mail: [email protected] J. Sampson (*) Gertrude H. Sergievsky Center, Department of Neurology, The Neurological Institute, Columbia University Medical Center, 710 West 168 St., New York, NY 10032, USA e-mail: [email protected]

in 1992 [1]. Myotonic dystrophy type 2 (DM2), a relative newcomer, was first described in 1994 by two groups [2, 3]. Although some clinical features of this newly described syndrome were similar to those of DM1, others were atypical, and these patients lacked a trinucleotide repeat expansion in DMPK. A lively discussion regarding nomenclature ensued, with proposals for this new disease to be named as an eponym (“Thornton–Griggs–Moxley disease”), on the basis of the pattern of weakness (proximal myotonic myopathy), or simply “myotonic muscular dystrophy, type 2 (no trinucleotide expansion)” [4]. Our understanding of the clinical characteristics and genetic basis of DM2 has advanced appreciably since its first description; in 1999 linkage analysis of German families identified the chromosome arm 3q locus [5], and in 2001 an intronic CCTG repeat expansion was found in the cellular retroviral nucleic acid binding protein 1/zinc finger 9 (CNBP) gene [1]. Although the prevalence of DM2 likely varies by population, it may be as high as 1:8,000 in the Finnish population [6], similar to that reported for DM1. Nonetheless, in the literature, case series, and clinical descriptions, DM2 patients are routinely outnumbered by DM1 patients. The name “proximal myotonic myopathy” underscores prominent proximal weakness as distinct from the distal weakness of DM1, yet with wider recognition, the range of the DM2 phenotype broadened. DM1 and DM2 are progressive muscular dystrophies with multisystemic involvement including muscle, heart, eye, brain, and the endocrine system. There is no congenital form of DM2. DM2 is caused by a complex, large, tetranucleotide repeat (CCTG) within an intron in the CNBP gene. DM2 repeat sizes range from 75 to 11,000 repeats [1] and do not correlate with the age of onset or symptom severity [7]. Unlike DM1, the DM2 repeat number may contract, rather than increase, over the generations [8]. The CCTG repeats are much larger than the DM1-associated CTG repeats (50–2,000) found in the DMPK gene. Descriptions of messenger RNA (mRNA) splicing dysregulation from sequestration of muscleblind 1 (MBNL1), a regulatory splicosome component, by the

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polynucleotide repeat expansions are revolutionizing understanding of the myotonic dystrophies. Patients with DM2 and their physicians are eager to know what discoveries are specific to DM2, including explanations for the differences in clinical manifestations and pathophysiology. This review summarizes the latest findings specific to DM2 from 2012 to the publication date.

Review Diagnosis DM2 masquerades as other commoner disorders, and diagnosis can be delayed or missed. Hilbert et al. [9] highlighted this problem in their review of the Myotonic Dystrophy National Registry. Comparing adult-onset DM1 and DM2, they showed the “diagnostic odyssey” (the time between the onset of symptoms and diagnosis) was twice as long for DM2 as for DM1 (average 14.4 years vs 7.3 years), involved more testing, and was not shortened by a known family history. The initial symptoms most often reported by DM2 patients were leg weakness (32.6 %), arm weakness (8.1 %), general weakness (12.6 %), grip myotonia (17.8 %), and pain (11.1 %). Other misdiagnoses (26 %) included fibromyalgia, chronic fatigue, arthritis, limb-girdle muscular dystrophy, and inclusion body myositis—often misdiagnosed by neurologists (76 % of these cases). Because DM2 is likely underdiagnosed, the true prevalence of DM2 is uncertain. The report of a genetic prevalence of 1:1,830 in Finland [1] led others to examine their own populations. In a series of 34 non-DM1 myotonic patients and 119 limb-girdle muscular dystrophy patients without genetic diagnosis, Matsuura et al. [10] did not uncover any DM2 cases; they concluded that DM2 is rare in the Japanese population. Genetic diagnosis of DM2 is generally by tetranucleotideprimed PCR amplification followed by Southern blot (necessitated by the large CCTG repeat size). Kamsteeg et al. [11] emphasized that although tetranucleotide-primed PCR (using three primers) distinguishes normal from expanded CCTG repeats, it cannot accurately determine the size of repeat expansions. They recommend reporting repeat expansions as a range or confidence intervals in their practice guidelines. In addition, the normal CCTG repeat motif is interspersed by dinucleotide and other tetranucleotide repeat motifs (TG, GCTG, TCTG, ACTG), and expansions are typically reported as base pair length, rather than repeat number as is typical in DM1. Electrodiagnostic studies play a critical role in the diagnosis of DM2. Myotonic discharges by needle electromyography in resting muscles of DM2 patients are often evoked by percussion or contraction and are enhanced by cold temperature. Although myotonic discharges significantly narrow the

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differential diagnosis, they are not an entirely specific finding; DM1, various neuromuscular channelopathies, acid maltase deficiency, and (rarely) inflammatory muscle disease also produce myotonic discharges. Further complicating matters is that in DM2 patients, myotonic discharges may be minimal, absent, unrecognized, or misinterpreted. Myotonic discharges alone cannot distinguish DM2 from DM1. Short and long exercise tests and cooling are useful tools in differentiating neuromuscular channelopathies [12]. Gawel et al. [13] studied the short exercise test with and without cooling to distinguish between DM1 and DM2. In DM2 patients (n =28), there was a small mean increment in compound muscle action potential amplitude of 0.58 % compared with a mean decrement of 25.62 % in DM1 patients (n = 32). The findings were similar with cooling. Perhaps this distinction is due to the predilection for distal muscles in DM1 (tested here) versus proximal muscles in DM2. Cardiac Involvement Clinically significant cardiac features in DM2 include arrhythmias, atrioventricular (AV) conduction defects, and even overt dilated cardiomyopathy [14]. Sansone et al. [15] conducted a prospective observational study of 104 patients with DM2 following electrocardiogram, echocardiogram, electrophysiologic study, and muscle strength testing. The average patient age was 58.7 years (range 24–92 years); half the patients had at least one cardiovascular risk factor (smoking, hypertension, hypercholesterolemia, and diabetes mellitus), yet only 10 % had coronary artery disease. Over an average of 7.4 years, 6 % of patients required pacemaker or pacer/defibrillator placement. Common conduction abnormalities included firstdegree block (10 %) and QRS widening (17 %), which progressed over time, but no echocardiogram structural abnormalities were found. Three of the four deaths occurring during the study were cardiac deaths; a pacemaker had been placed in two of these patients. AV conduction disease occurs in 20 % of myotonic dystrophy patients on resting electrocardiogram, whereas 50 % myotonic dystrophy patients with a normal electrocardiogram display conduction delay below the AV node on invasive electrophysiologic cardiac study. AV conduction disease and infra-Hisian conduction delay are associated with a threefold increase in the risk of sudden cardiac death, underscoring the need to identify patients with these abnormalities. Ha et al. [16] assessed clinical predictors of cardiac conduction disease in a 57-month (median) cohort study of DM1 (n =211) and DM2 (n =25) patients. At the baseline, severe electrocardiogram abnormality (PR interval 240 ms or greater, QRS duration 120 ms or greater, second- or third-degree AV block, or rhythm other than sinus rhythm) was found in 23.8 % of DM1 patients and 16.7 % of DM2 patients. Although both DM1 and DM2 patients with severe electrocardiogram abnormality

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were more likely to be older, only DM1 patients had higher prevalence of cardiovascular disorders, a family history of sudden death, and higher polynucleotide repeat numbers. At follow-up, two DM2 patients had died (1.59 % per year), and in 12 % a pacemaker had been placed or a cardiac defibrillator had been implanted. For all myotonic dystrophy patients, 65 % of those with severe electrocardiogram abnormality had a pacemaker or an implanted cardiac defibrillator, compared with 0 % of those without. Severe electrocardiogram abnormality was associated with higher prevalence of allcause death (12 % vs 3 %) despite aggressive prophylactic pacing [16]. Altered muscle metabolism is an early change in various myopathies, and magnetic resonance spectroscopy (MRS) is a noninvasive method for analyzing muscle metabolism. In 2004, Schneider-Gold et al. [17] studied MRI/MRS in cardiac and skeletal muscle of 11 patients with DM2 without overt heart disease. Patients aged 53 years or older and with more advanced disease showed increased left ventricular volume (35 %) and mass (26 %) compared with controls. Patients with DM2 showed reduced cardiac phosphocreatine (25 %) and adenosine triphosphate (20 %) levels regardless of age compared with controls. Skeletal muscle MRS showed reduced phosphocreatine and adenosine triphosphate levels only in patients aged 53 years or older who had overt hip flexor weakness. This study provided a basis for future studies regarding subclinical cardiac involvement in DM2 patients. Functional cardiac MRI (CMRI) with gadolinium detects postinfarction subclinical cardiomyopathy, in hypertrophic states and in other cardiomyopathies, most often in the interventricular septum, and correlates histopathologically with fibrosis. Spengos et al. [18] reported on CMRI in a woman with DM2 who had a normal electrocardiogram, 24-h Holter monitoring, and transthoracic echocardiogram. CMRI revealed anterior interventricular septum signal hyperintensity and delayed gadolinium contrast enhancement. Turkbey et al. [19] used CMRI to assess DM1 (n =24) and DM2 (n =9) patients. Significant differences were found between DM1 patients and controls with reduced left ventricular volume, but not in DM2 patients. This may be due to the older age of the DM2 patients (mean 57±9 years); the differences found by Schneider-Gold et al. [17] were seen in DM2 patients only after the age of 53 years. The delayed contrastenhanced myocardial T1 time was significantly shorter in all myotonic dystrophy patients compared with controls, but this was not analyzed by myotonic dystrophy subset.

study comparing DM1 patients (n =18), DM2 patients (n = 12), and controls (n =12) using questionnaires found that DM2 patients have poorer sleep quality than DM1 patients [20]. Furthermore, from the questionnaires it was found that sleep apnea is the most prevalent sleep-related symptom in DM2 patients. Polysomnography (PSG) of DM2 patients confirmed decreased total sleep time, sleep efficiency, and REM sleep time compared with controls. These data suggest that sleep apnea and poor sleep quality may be one of the major contributing factors in DM2 fatigue. In a retrospective review of eight DM2 patients, Shepard et al. [21] found EDS to be the most commonly reported symptom (75 %). DM2 patients also reported insomnia (62.5 %) and excessive fatigue (50 %). Mild obstructive sleep apnea (OSA) was diagnosed by PSG in 60 % of patients, and 50 % of patients had RLS. All patients tested for pulmonary function had respiratory muscle weakness. Likewise, in a case–control study, Lam et al. [22] reported RLS, EDS, sleep quality, and fatigue in DM2 patients were all significantly increased compared with controls. Conversely, OSA was similar in DM2 patients and controls; however, these results were based on symptom surveys rather than PSG, which might explain the discrepancy between these results and the sleep apnea results reported by Romigi et al. [20]. Bhat et al. [23] described clinical and PSG data from a series of five DM2 patients. Increased arousals, reduced sleep efficiency, OSA, and REM behavior disorder were common in their small sample. This information may help clinicians consider DM2 in patients with muscle fatigue and sleep complaints, or to investigate DM2 patients for possible sleep disorders.

Sleep Disorders

Brain Imaging

Sleep disturbances occurring in DM2 include excessive daytime sleepiness (EDS), restless leg syndrome (RLS), rapid eye movement (REM) sleep abnormalities, and sleep apnea. One

Unlike DM1, DM2 is not associated with developmental delay. However, cognitive and behavioral symptoms have been described in DM2 [27]. To understand the structural changes

Myotonic Muscle Imaging MRI of DM2 patients’ muscle exhibits fibrofatty changes on T1 imaging and increased signal on fluid-attenuated inversion recovery imaging [24]. However, MRI may not be sufficiently sensitive for mild/moderate muscle involvement in DM2 [25]. Using ultrasound to study echogenic properties of muscles, Tielemann et al. [26] found increased muscle echogenicity correlates with histologic atrophy and fibrous and fatty changes, and applied this technique to study muscles of DM2/DM1 patients and healthy controls. They found increased echogenicity in all muscles tested in all DM2 study subjects; unfortunately, there was no muscle MRI comparison. However, ultrasound imaging is a noninvasive technique that may be a useful outcome measure in clinical trials.

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underlying these functional changes, Franc et al. [28] performed brain MRI scans on DM2 patients, adult-onset and congenital DM1 patients, and healthy controls. They found significantly decreased gray matter volumes (both total and supracallosal) in DM1 patients but not in DM2 patients. Fractional anisotropy, an imaging correlate to axonal connectivity, was not different in DM2 patients compared with controls. However, the inferior frontal, supracallosal, and occipital regions in both congenital and adult-onset DM1 patients showed decreased anisotropy, and thus decreased connectivity. Pain and Depression Extensive pain is frequently reported in DM2 and includes abdominal, musculoskeletal, and exercise-related pain. A survey study of Finnish DM2 patients (n =93) highlights the lifestyle, psychological, and economic impact of pain in DM2 [29]. Via a postal survey, Suokas et al. [29] reported that 76 % of participants experienced pain currently or had previously experienced pain. Moreover, many of the patients were taking pain medications (n =60), anti-inflammatory drugs (n =38), and other analgesics for symptom control. Depression (13 % of the total, 76 % of those reporting pain), decreased quality-of-life scores, and inability to maintain employment (34 %) were also common among the DM2 participants, underscoring the importance of better pain management therapies for mental well-being.

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activate innate antiviral pathways and the interferon response. They observed that other upregulated pathways included cell adhesion, cell cycle arrest, transcriptional repression, and immune response—known downstream consequences of interferon signaling. Endocrine Changes Hyperparathyroidism occurs in up to 20 % of myotonic dystrophy patients. Passeri et al. [31] studied vitamin D, parathyroid function, calcium, and phosphate in male DM1 (n =31) and DM2 (n =13) patients and found that parathyroid hormone levels were elevated in myotonic dystrophy patients compared with controls; 18 % were diagnosed with hyperparathyroidism (no difference between DM1 and DM2), with normal calcium levels. Phosphate levels were normal in DM2 patients, but low in DM1 patients. The level of vitamin D (25hydroxyvitamin D) was significantly lower in all myotonic dystrophy patients (correlated with increased adiposity); 88 % had hypovitaminosis D (25-hydroxyvitamin D, 30 ng/ml) and 40 % had severe deficiency (25-hydroxyvitamin D, below10ng/ml), with no difference between DM1 and DM2. Abnormal parathyroid function and decreased muscle strength correlated for DM1 patients but not for DM2 patients. The negative correlation between 25-hydroxyvitamin D and parathyroid hormone levels indicates that the hyperparathyroidism is secondary in patients with myotonic dystrophy (although one patient was found to have primary hyperparathyroidism) [31].

Cataracts Anesthesia The unusual, early-onset, posterior subcapsular cataracts shared by DM1 and DM2 patients strongly suggest a common pathophysiologic pathway; requiring removal, they provided tissue for an illuminating exploration of gene expression by Rhodes et al. [30]. This group established that both DM1 and DM2 cataracts expressed their respective repeat expansion genes (DMPK and CNBP). They compared gene expression changes in DM1 and DM2 cataracts with those in nonmyotonic cataracts, and validated the findings with realtime PCR. A remarkable overlap (75 %) in the genes dysregulated in DM1 and DM2 was found. Rhodes et al. also discovered, by gene set enrichment analysis, a strong upregulation (15.3 % of the total for DM2) of interferon-regulated genes, including the STAT1 pathway. This finding is particularly striking, because the lens is an immunologically privileged tissue and circulating interferons should not access and activate the epithelial and fiber cells of the lens. Rhodes et al. suggest the lens itself may be an autocrine/paracrine source of interferon activating the interferon-regulated gene response. They note that the DM2 CCUG repeat expansions form double-stranded RNA hairpin secondary structures, which if degraded by the DICER pathway (as demonstrated in vitro for DM1 CUG repeats) could

Potential complications of and recommendations for anesthesia administration in myotonic individuals have been reviewed by Mathieu et al. [32]. Risk factors include upper abdominal surgery and preoperative severe muscle disability [33]. Major complications were atelectasis, pneumonia, and acute ventilatory failure [32]. DM2 patients had fewer anesthesia complications than DM1 patients; however, DM2 patients (14.9 %) reported reduced muscle strength and increased muscle cramping after anesthesia [33]. On the basis of this evidence, clinicians should approach anesthesia with caution and inform DM2 patients of possible symptom exacerbation. It may also be beneficial for myotonic dystrophy patients to carry a wallet care card (available from http://www.myotonicdystrophysupportgroup.org/assets/files/ DMCARECARDSCOTV11_2%5B1%5D(2).pdf) to alert emergency care providers. Cancer There is little information about the relationships between DM2 and neoplasms. In a cohort study including 86 DM2 patients, myotonic dystrophies correlated with a significantly increased risk of thyroid cancer, choroidal melanoma, and

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possibly prostate cancer [34]. Another study suggests that being a woman, having DM1, or being woman and having DM1 (but not DM2) is associated with increased risk of skin tumor growth [35]. Das et al. [35] reported the most frequent neoplasms in DM2 patients were endocrine neoplasms (pancreas, pituitary, thyroid, parathyroid). Furthermore, they did not find increased tumor risk with increased expansion length in DM1/DM2. This suggests that it may be beneficial for those with DM1/DM2 to schedule regular cancer screenings with their physician. Pregnancy Limited data are available regarding pregnancy and childbirth in women with hereditary neuromuscular disorders. Awater et al. [36] conducted a retrospective review of women with various neuromuscular diseases which included 42 women with DM2 and 32 women with DM1. The average age of DM2 onset was 34.1 years, and the average age at the first pregnancy was 23.1 years. Overall, early pregnancy loss rates were not increased in any group. There was a trend toward increased placenta previa in patients with DM2, but it was not statistically significant, unlike in DM1. DM2 patients had an increased number of urinary tract infections (7.6 %), half of which progressed to acute pyelonephritis. Otherwise, patients with DM2 had normal incidence of miscarriage, hypertensive disease, polyhydramnios, preterm delivery, cesarean delivery, instrumental delivery, and nonvertex presentation, as in the general population. Likewise, there was no increased incidence of prolonged labor. The incidence of premature labor (prior to 36 gestational weeks) was increased significantly at 17.7 % of DM2 patients. Neonatal outcome (vitals, measurements) was normal in patients with DM2. Although no significant changes in disease condition were observed in patients with DM2, the first symptoms of the disease were noted during pregnancy in 14 % of DM2 patients. Evolution of CCTG Repeat Expansion Kurosaki et al. [37] investigated the evolutionary origin of the polynucleotide repeat expansion that preceded the DM2 disease expansion. They found that just as in Friedreich ataxia and spinocerebellar ataxia type 10, the motif originated from the insertion of an Alu element. Alu elements are retrotransposons, or short interspersed elements. This insertion sequence of the polyA tail end of an AluSx element in primates occurred approximately 48 million years ago, then diverged into dinucleotide repeats in Old World and New World monkeys, and into dinucleotide and tetranucleotide repeats in apes and humans approximately ten million years ago. Previously, Bachinski et al. [38] showed that the DM2associated expansion mutation in Europeans occurred

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between 4,000 and 11,000 years ago. In humans, the normal polynucleotide repeat is composed of (TG)n (TCTG)n motifs interspersed in the CCTG repeats. These non-CCTG motifs are lost in the homogeneous CCTG DM2-associated expansion. CCTG Repeat Effects In both DM2 CCTG polynucleotide repeats and DM1 CTG trinucleotide repeats the RNA splicing regulator MBNL1 is sequestered into nuclear foci. This diversion of MBNL1 from its normal function results in expression of inappropriate isoforms of many proteins, leading to the concept of a spliceopathy, or “toxic RNA.” The missplicing of RNAs in both DM2 and DM1 and the downstream biological consequences are topics of intensive research. RNA splicing isoforms were studied using microarray analysis by Nakamori et al. [39] in muscle biopsy specimens from patients with DM2, DM1, or fascioscapulohumeral muscular dystrophy and controls. They found that a similar pattern of altered gene expression in DM2 as in DM1; 4,949 gene expressions were either upregulated or downregulated in the same direction, whereas only 35 gene products were regulated in opposite directions. The insulin receptor gene (INSR) is aberrantly spliced in DM1 and DM2; a relative increase of the level of insulin receptor A compared with insulin receptor B (generated by alternative splicing) in muscle tissue underlies the insulin resistance in these patients. Santoro et al. [40] used laser capture microdissection and reverse transcriptase PCR to compare the alternative splicing in both type I and type II fibers in DM1 and DM2 muscle and found similar increases in the level of immature insulin receptor A relative to insulin receptor B in myotonic dystrophy patients (three with DM1 and three with DM2) compared with controls. Since the myotonic dystrophies are multisystemic disorders, Lukáš et al. [41] sought to look at MBNL1 sequestration in different cell types in DM2. They found MBNL1-positive nuclear foci in more than 50 % of nuclei of adipocytes, vascular smooth muscle cells, endothelial cells, Schwann cells, and skeletal muscle cells. They found fewer MBNL1positive nuclear foci (31-48 %) in keratinocytes. The dynamic nature of MBNL1/CCTG repeat foci through the cell was studied by Giagnacovo et al. [42] in both actively dividing and senescent DM2 fibroblasts. They hypothesized that the foci move to the cytosol as the nuclear envelope dissolves, are degraded in G1 phase, and are formed anew in interphase, increasing in size and number over time. In postmitotic cells, such as neurons and myofibers, the lack of MBNL1 foci degradation during mitosis may result in progressive sequestration of MBNL1 and splice defects. In DM2 patients undergoing repeat muscle biopsy, MBNL1 foci area increased from the first to the second biopsy. However,

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Giagnacovo et al. did not test for possible changes in repeat expansion size between the first and the second biopsy. In addition to splicing defects, dysregulation of microRNA control of mRNA translation may be an important marker or mechanism of pathophysiology in myotonic dystrophies. MicroRNA pathways and their target mRNAs are dysregulated in muscular dystrophies [43]. In a study of 13 DM2 patients, age- and sex-matched DM1 patients, and normal controls, Greco et al. [44] found dysregulation of microRNAs and pathways previously described in other muscular dystrophies. Although these findings did not identify pathways unique to DM2, they show myotube maturation and differentiation, myofibril organization, transforming growth factor b signaling, phosphatidylinositol 3-kinase/AKT signaling pathways, and calcium regulation are important in pathophysiology and are potential targets for drug development. Another possible molecular mechanism for myotonic dystrophy is a block in myoblast differentiation. Faenza et al. [45] used an in vitro system whereby insulin activates myoblast differentiation through expression of phosphoinositidephospholipase Cβ1 (PLCβ1). which in turn activates differentiation pathways via myogenic factors. They used human myoblast cultures derived from muscle biopsy specimens from DM1/DM2 patients. They found PLCβ1 expression decreases (rather than the normal increase) in response to insulin in DM1/DM2 cultures. Overexpression of PLCβ1 rescued the defect, correlating with increased cell fusion into myotubes, indicating differentiation. These data suggest that a block in myogenesis may contribute to the cellular disease in both DM1 and DM2, and increasing PLCβ1 expression may rescue the early steps of differentiation. Channels in Myotonic Muscle Unlike DM1, DM2 has a known disease-modifier gene: mutation of the chloride channel CLCN1 associated with myotonia congenita. CLCN1 mutations (most commonly R894X) are found in 5 % of Finnish and German DM2 patients. Ursu et al. [46] studied the contribution to chloride conductance (and by extension, myotonia) of co-occurring DM2 and CLCN1 R894X mutations. Patients with both DM2 and CLCN1 R894X reported myotonia (83 % vs 34 %) and muscle pain (39 % vs 14 %), and had myotonia on electromyography (94 % vs 68 %). There were no differences in the age of onset, the age of onset of myotonia, the prevalence of muscle weakness, cardiac arrhythmia, or creatine kinase level. Ursu et al. [46] found five isoforms of CLCN1 due to alternative splicing, in both DM2 and control muscle. Of these, the isoform excluding exons 6 and 7 results in a truncated protein; the level of this isoform is increased fourfold in DM2 muscle biopsy compared with controls. In comparison with the observation of Berg et al. [47] of a dominant negative effect of chloride channel isoforms, Ursu

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et al. [46] found no effect on ClCN1 function caused by the R894X myotonia congenita mutation. However, the R894X CLCN1 localized poorly (10 % of cells) to the plasma membrane, suggesting a mislocalization defect. Another alternatively spliced channel, the L-type voltage gated calcium channel CaV1.1, has been implicated in the dystrophic, degenerative changes in myotonic dystrophies, and also correlated with ankle dorsiflexion weakness in DM1. The level of the isoform CaV1.1-E29 is also increased in DM2 [48]. Tang et al. [48] were successful in causing E29 skipping in 97-99 % of the CaV1.1 RNA in wild-type mouse muscle using electroporated morpholinos and tested the calcium channel properties of the CaV1.1-E29 isoform. They found shifts in hyperpolarization of the calcium channel in both activation and inactivation.

Conclusion Important publications in the last year will guide physicians in the diagnosis and clinical care of DM2 patients. Recognizing that pain and weakness are common symptoms, questioning the diagnosis of masquerading disorders, and testing promptly in the setting of a known family history can shorten the diagnostic odyssey. The impact of pain and sleep disorders raises clinical attention to these problems. Longitudinal studies of cardiac involvement confirm the importance of arrhythmia monitoring. Parathyroid and vitamin D abnormalities in DM2 as well as the well-known insulin resistance are relevant clinical measures. The lower incidence of pregnancy complications and possibly lower incidence of cancer in DM2 are encouraging findings, but anesthesia should still be approached with caution and routine cancer screening with vigilance. The pathophysiology of DM2 continues to show overlap with that of DM1, particularly MBNL1-mediated splice isoform dysregulation. The common final pathways in DM1 and DM2 in cataracts and muscle are encouraging because drug targets may be found, or translation of therapeutic strategies from DM1 to DM2 may emerge. Acknowledgments We thank Lewis P. Rowland for inspiration, wisdom, and guidance. Compliance with Ethics Guidelines Conflict of Interest Christina M. Ulane and Sarah Teed declare that they have no conflict of interest. Jacinda Sampson has received a grant from the Marigold Foundation for myotonic dystrophy support group development. She also has received honorarium and paid travel expenses from the Myotonic Dystrophy Foundation for her role as a guest speaker. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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Recent advances in myotonic dystrophy type 2.

Myotonic dystrophy is the commonest adult muscular dystrophy. Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are often discussed ...
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