Laboratory Abnormalities in Patients with Myotonic Dystrophy Type 2

Home , Muscular dystrophy, Myotonic dystrophy

ORIGINAL CONTRIBUTION Laboratory Abnormalities in Patients With Myotonic Dystrophy Type 2

Chad Heatwole, MD, MS-CI; Nicholas Johnson, MD; Bradley Goldberg, BS; William Martens, BA; Richard Moxley III, MD

Background: Myotonic dystrophy type 2 (DM2) is a re- Main Outcome Measures: The individual frequen- cently discovered adult muscular dystrophy. Similar to cies of abnormal laboratory values in the population with DM1, this disease causes progressive debilitating weak- DM2 studied. ness, clinical myotonia, and early cataracts and is thought Results: Of the 1442 studies, results for 359 (24.9%) were to cause widespread physiologic dysfunction of mul- outside of their standard reference ranges. Of the 68 types tiple organ systems. of laboratory tests studied, 43 had values from 15 or more different patients with DM2. The relative frequency of an Objective: To analyze and compile the laboratory ab- abnormally elevated laboratory value was greater than 50% normalities of patients with DM2. in several tests, including the levels of creatine kinase, total cholesterol, lactate dehydrogenase, and alanine amino- Design: Baseline DM2 laboratory data were compiled transferase. In addition, serum levels of IgG were low in representing 68 different types of laboratory tests and 1442 75% of all patients with DM2 tested, and absolute lympho- total studies. cyte counts were low in 54% of all patients with DM2 tested. Conclusions: There is a high frequency of laboratory ab- Setting: University medical center. normalities in patients with DM2. These abnormalities provide insight into the widespread pathologic manifes- Patients: Eighty-three adults with genetically con- tations of DM2 and may form a basis for clinical moni- firmed or clinically probable DM2 were identified. Of toring and disease screening. these patients, 49 had documented baseline laboratory screening. Arch Neurol. 2011;68(9):1180-1184

YOTONIC DYSTROPHY In the past, a large-scale study5 identi- type 2 (DM2) is an au- fied a high frequency of abnormal clini- tosomal dominant cal laboratory values in the DM1 popula- muscular dystrophy tion. Ambulatory patients with DM1 were discovered in 1994.1 found to have a wide range and a high MAlthough DM2 shares many of the mul- prevalence of abnormal laboratory val- tisystemic clinical features of DM1, it does ues reflecting dysfunction of the endocri- not carry DM1’s characteristic CTG re- nologic, hematologic, hepatic, and renal peat on the 3Ј region of the DMPK gene systems.5 This study was similarly de- on chromosome arm 19q. Instead, DM2 signed to analyze and compile the base- is genetically linked to a unique CCTG re- line laboratory values of a symptomatic peat located on intron 1 of the zinc finger group of patients with DM2. This analy- protein 9 (ZNF9) gene.2 Both DM1 and sis has the potential to (1) further define Author Affiliations: DM2 have widespread clinical implica- the clinical manifestations of DM2, (2) dis- Neuromuscular Division, tions. Similar to patients with DM1, pa- cover previously unrecognized areas of Department of Neurology, tients with DM2 experience muscle pain, DM2 systemic dysfunction, (3) provide a University of Rochester Medical progressive extremity and truncal weak- baseline laboratory profile for physicians Center, Rochester, NY ness, stiffness, muscle myotonia, male hy- caring for patients with DM2, and (4) iden- (Drs Heatwole, Johnson, and pogonadism, cardiac arrhythmias, diabe- tify dysfunction amenable to early thera- Moxley and Mr Martens); and 3 Sackler School of tes mellitus, and early cataracts. More peutic intervention. Herein, we compile the Medicine/New York State recently, cognitive dysfunction, hearing laboratory abnormalities of 1442 sepa- Program, Tel Aviv University, loss, hypersomnia, and tremor have been rate baseline studies from patients with Tel Aviv, Israel (Mr Goldberg). reported in patients with DM2.4 DM2.

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 METHODS each laboratory test listed, the reference range is included in addition to the mean (SD) DM2 value, total number of patients with DM2 studied, and number (and This study was approved by the University of Rochester (Roch- percentage) of abnormal values from tested patients with ester, New York) institutional review board. Adult patients with DM2. Tests with responses from fewer than 15 patients DM2 previously evaluated in the University of Rochester Health- care System were identified for participation in this study. All are listed in the eTable (http:www.archneurol.com). the patients were older than 18 years and had (1) genetically Altogether, 10 laboratory tests in the Table had ab- confirmed DM2; (2) weakness and myotonia, with a sympto- normal values in more than 40% of patients with DM2 matic first-degree relative with genetically confirmed DM2; or tested. These tests included the following: creatine ki- (3) clinical features consistent with and suggestive of the diag- nase (CK), IgG, total cholesterol, absolute lymphocyte nosis of DM2. count, lactate dehydrogenase (LD), alanine aminotrans- Participants who had not been genetically tested for DM2 ferase (ALT), creatinine, absolute basophil count, se- were included if they met the following criteria: (1) clinically rum glucose, and total protein. For some studies, the DM2 suspected DM2, (2) medical council weakness of 4 or fewer at values were consistently high (ie, CK, total cholesterol, an upper or lower extremity, (3) electrodiagnotic or clinical and ALT levels), whereas other studies demonstrated fre- myotonia (as demonstrated through grip contraction, percussion of the wrist extensors, or percussion of the thenar emi- quent low values (ie, IgG, creatinine, and total protein nence region), and (4) negative genetic testing for DM1 or nega- levels). Still other studies had both abnormally high and tive genetic testing for DM1 in a similarly affected first-degree low values (ie, serum glucose level). Certain laboratory relative. tests showed no abnormalities, including the levels of po- All selected participants with DM2 had previously re- tassium, sodium, total bilirubin, and IgA. ceived care at the University of Rochester in the Muscular Dys- The tabulated data add to previous clinical reports of trophy Association clinic, outpatient setting, or electrodiag- abnormal laboratory values in DM2. Before this study, notic laboratory or through their participation in a University the 2 most commonly reported DM2 laboratory values of Rochester DM2 clinical trial. Of 83 patients with DM2 iden- were CK and ␥-glutamyltransferase (GGT) levels. In one tified, 49 (29 men and 20 women) had recorded baseline labo- of the initial clinical descriptions of DM2 (then called ratory data. Each participant underwent multiple laboratory studies, al- proximal myotonic myopathy), 18 of 26 patients (69%) had though none underwent all 68 separate tests. Patients were di- elevated CK levels and 14 of 18 patients (78%) had higher 6 vided into male and female study groups. Laboratory refer- GGT levels than their stated reference range. Similarly, ence ranges were defined based on standardized test reference Day et al3 observed that 90% of patients with DM2 had ranges from the University of Rochester Medical Center Clini- elevated CK levels and 64% had elevated GGT levels. In cal Laboratories on April 5, 2010. These ranges are set through a population of Italian and American families with DM2, various methods, including local volunteer testing and out- Meola and Moxley7 reported that 60% of their patients side data accumulation. Wherever applicable, sex-specific ranges had elevations in CK levels and 58% had increased GGT were defined. In instances in which standard laboratory ranges levels. Although the present study demonstrated a simi- were based on menstrual staging (ie, levels of follicle-stimu- lar elevation in CK levels (31 of 40 patients tested [78%]), lating hormone and luteinizing hormone), the reference range was broadened to include all possible premenstrual and post- only 33% of the patients had elevations in their GGT lev- menopausal values. Sex-specific reference ranges were used to els. Compared with a similarly studied DM1 popula- 5 determine whether a laboratory value was high, low, or normal. tion, on average, the present patients with DM2 had For each selected participant, past laboratory data were re- higher CK levels (DM2: 537 U/L; DM1: 183 U/L [to con- corded in a spreadsheet format. In several instances, patients vert to microkatals per liter, multiply by 0.0167]) and were found to have multiple studies (over time) for 1 type of lower GGT levels (DM2: 61.1 U/L; DM1: 110.4 U/L [to test. In these cases, the patient’s laboratory result obtained un- convert to microkatals per liter, multiply by 0.0167]). der direct clinical trial supervision was selected. Otherwise, ini- In 2003, Day et al3 observed that 29% of patients with tial baseline laboratory studies were used for patients who did DM2 had low testosterone levels, 65% had high follicle- not participate in a previous DM2 clinical trial. Only labora- stimulating hormone levels, and 75% had insulin insen- tory tests with input from 5 or more patients with DM2 were reported. Once collected, abnormal laboratory results were tabu- sitivity (elevated basal insulin levels or prolonged insu- lated and processed using a commercially available statistical lin elevation). Decreased levels of luteinizing hormone 8 software program (SAS; SAS Institute Inc, Cary, North Caro- have also been reported. Although endocrinologic labo- lina) for review, analysis, and display. ratory sampling was limited in this study, we found similar trends in this population. Five of 12 patients had elevated follicle-stimulating hormone levels and 1 of 11 had RESULTS a low level of luteinizing hormone. In 7 patients who had their testosterone tested, 1 had a low level and 3 had val- Of the 1442 laboratory studies performed, patients with ues higher than the standard reference range. It is un- DM2 had 359 (24.9%) abnormal laboratory values. Forty- known, however, whether any of these patients were tak- three of the 68 types of laboratory studies had values from ing testosterone supplementation at the time of testing. 15 or more different patients with DM2 (representing 1271 Although none of the present patients had basal insulin total studies). For these 43 different types of laboratory level testing, 9 of 30 (30%) had baseline serum glucose test, 312 of the 1271 studies (24.5%) were outside of their elevations. standard reference range. Tests with responses from 15 An association between autoimmune laboratory dys- or more patients are listed in the Table in order from function and DM2 has been previously hypothesized.9 highest to lowest percentage of total abnormal values. For Dayetal3 reported that although patients with DM2 have

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Reference Range DM2 Values

Patients High Low Abnormal Tested, Values, Values, Values, Test Men Women Mean (SD) No. (F) No. No. % Creatine kinase, U/L 46-171 34-145 537.6 (671.8) 40 (16) 31 2 82 IgG, mg/dL 751-1560 751-1560 667.2 (290.4) 16 (7) 0 12 75 Total cholesterol, mg/dL Ͻ200 Ͻ200 212.2 (38.8) 24 (11) 15 0 62 Lymphocytes, /µL 1300-3600 1200-3700 1400 (600) 24 (10) 0 13 54 Lactate dehydrogenase, U/L 118-225 118-225 322.6 (208.4) 18 (10) 9 0 50 Alanine aminotransferase, U/L 0-50 0-35 44.2 (26.0) 16 (6) 8 0 50 Creatinine, mg/dL 0.67-1.17 0.51-0.95 0.7 (0.2) 27 (9) 1 12 48 Basophils/µL 0-100 0-100 500 (600) 16 (8) 7 0 44 Glucose, mg/dL 74-106 74-106 102.3 (43.3) 30 (13) 9 4 43 Total protein, g/dL 6.3-7.7 6.3-7.7 6.3 (0.6) 23 (9) 0 10 43 Red blood cells, ϫ106/µL 4.6-6.1 3.9-5.2 4.6 (0.8) 43 (19) 2 12 33 Hematocrit, % 40-51 39-45 41.9 (5.4) 43 (17) 3 11 33 ␥-Glutamyltransferase, U/L 8-61 8-61 61.1 (92.8) 15 (6) 5 0 33 White blood cells, /µL 4200-9100 4000-10 000 5600 (2200) 42 (18) 4 9 31 Calcium, mg/dL 9.0-10.5 9.0-10.4 9.2 (0.6) 29 (13) 0 9 31 Albumin, g/dL 3.5-5.2 3.5-5.2 3.7 (0.4) 30 (13) 0 8 27 Neutrophils, /µL 1800-5400 1600-6100 4600 (5900) 26 (10) 4 3 27 Triglycerides, mg/dL 0-200 0-200 149.2 (67.5) 19 (10) 5 0 26 Lymphocytes, % 21.8-53.1 19.3-51.7 27.3 (10.6) 32 (15) 0 8 25 Eosinophils, % 0.8-70 0.7-5.8 4.0 (2.7) 31 (16) 6 1 23 Partial thromboplastin time, s 22.5-35.3 22.5-35.3 25.2 (3.7) 30 (14) 0 7 23 Mean corpuscular volume/fL 79-92 79-95 89.4 (4.9) 46 (19) 9 1 22 Monocytes, % 5.3-12.2 4.7-12.5 9.4 (3.2) 32 (15) 6 1 22 Red blood cell distribution width, % 11.6-14.4 11.7-14.4 12.8 (1.2) 43 (19) 5 4 21 Prothrombin time, s 11.9-14.7 11.9-14.7 12.4 (0.8) 29 (14) 1 5 21 Carbon dioxide, mEq/L 20-28 20-28 25.3 (2.9) 29 (13) 5 1 21 Basophils, % 0.2-1.2 0.1-1.2 0.9 (0.7) 27 (11) 3 2 19 Platelets, /µL 150 000-330 000 160 000-370 000 212 200 (65 600) 42 (18) 1 6 17 Aspartate aminotransferase, U/L 0-50 0-50 36.3 (18.1) 30 (14) 5 0 17 Neutrophils, % 34.0-67.9 34.0-71.1 53.7 (15.4) 28 (13) 2 2 14 Hemoglobin, g/dL 13.7-17.5 11.2-15.7 14.3 (1.9) 41 (17) 1 4 12 IgM, mg/dL 46-304 46-304 105.6 (62.4) 17 (7) 0 2 12 Mean corpuscular hemoglobin, pg/cell 27-33 27-33 30.8 (2.1) 46 (19) 3 2 11 Thyrotropin, µIU/mL 0.4-5.5 0.4-5.5 2.9 (3.9) 32 (13) 3 0 9 Chloride, mEq/L 96-108 96-108 104.8 (2.7) 29 (13) 2 0 7 Urea nitrogen, mg/dL 6-20 6-20 12.9 (8.8) 29 (12) 2 0 7 Alkaline phosphatase, U/L 40-130 35-105 88.3 (55.7) 27 (12) 2 0 7 Monocytes, /µL 300-800 200-900 500 (200) 24 (10) 0 1 4 Mean corpuscular hemoglobin concentration, g/dL 31-36 31-36 34.3 (1.1) 46 (19) 1 0 2 Potassium, mEq/L 3.3-5.1 3.3-5.1 4.2 (0.4) 30 (14) 0 0 0 Sodium, mEq/L 133-145 133-145 139.8 (2.3) 29 (13) 0 0 0 Total bilirubin, mg/dL 0-1.2 0-1.2 0.6 (0.2) 24 (9) 0 0 0 IgA, mg/dL 82-453 82-453 158.2 (52.7) 17 (7) 0 0 0 Total 1271 (551) 160 152 24.5

Abbreviation: DM2, myotonic dystrophy type 2. SI conversion factors: To convert basophils, lymphocytes, monocytes, neutrophils, and white blood cells to ϫ109 per liter, multiply by 0.001; alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, creatine kinase, ␥-glutamyltransferase, and lactate dehydrogenase to microkatals per liter, multiply by 0.0167; albumin, hemoglobin, mean corpuscular hemoglobin concentration, and total protein to grams per liter, multiply by 10.0; calcium to millimoles per liter, multiply by 0.25; carbon dioxide, chloride, potassium, and sodium to millimoles per liter, multiply by 1.0; creatinine to micromoles per liter, multiply by 88.4; glucose to millimoles per liter, multiply by 0.0555; IgA and IgM to milligrams per liter, multiply by 10.0; IgG to grams per liter, multiply by 0.01; platelets to ϫ109 per liter, multiply by 1.0; red blood cells to ϫ1012 per liter, multiply by 1.0; total bilirubin to micromoles per liter, multiply by 17.104; total cholesterol to millimoles per liter, multiply by 0.0259; triglycerides to millimoles per liter, multiply by 0.0113; and urea nitrogen to millimoles per liter, multiply by 0.357.

normal IgA levels, 65% have low IgG levels and 11% have netic differences between DM1 and DM2, many simi- low IgM levels. Similarly, 17 of the present patients with larities were noted between the laboratory profiles of these DM2 (100%) had normal IgA levels, 12 of 16 (75%) had conditions. Both populations were found to have el- low IgG levels, and 2 of 17 (12%) had low IgM levels. evated serum cholesterol levels, increased liver and muscle We also found that 5 of 14 patients (36%) had eleva- markers, decreases in select hematologic counts, reductions in their IgE values. tions in nutritional markers, and relatively preserved elec- In a 2006 Archives of Neurology article,5 we detailed trolyte studies. Despite these similarities, the mean val- the laboratory abnormalities of DM1. Despite the ge- ues and percentage of abnormal values for each study

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 varied per population for each individual test. Several fac- it is possible that the ALT, LD, and aspartate amino- tors may have played a role in this, including but not lim- transferase abnormalities are, at least in part, due to ited to (1) the inclusion criteria for the DM1 and DM2 underlying muscle abnormalities caused by DM2. In the study patients (our previous DM1 population was se- present study, no patient with an elevated aspartate ami- lected only from ambulatory mild to moderately af- notransferase or ALT level had a simultaneously normal fected individuals), (2) the mild variation in laboratory CK level. In the past, patients have reported being sent techniques and reference values over time, and (3) the for liver biopsies before being diagnosed as having DM2. underlying varying pathomechanisms of these 2 diseases. Such hepatic biopsies generate extra risk, cost, and dis- comfort to patients with DM2 without providing clear benefit. Through additional education regarding the DM2 COMMENT phenotype and associated laboratory abnormalities, it may be possible to limit future unnecessary referrals for he- Myotonic dystrophy type 2 is associated with numerous patic biopsies. Knowledge of liver enzyme abnormali- abnormal clinical laboratory results. Although previous ar- ties may also assist physicians and researchers who se- ticles3,6,7,9 have described select laboratory abnormalities in rially follow up patients with DM2. Baseline and periodic DM2, to our knowledge, this is the first large-scale system- monitoring of liver enzyme levels should be considered atic summary of the abnormal DM2 laboratory values in before implementing any DM2 therapy. Without such test- more than 68 different types of laboratory evaluations. De- ing, potentially helpful treatments could be discontin- spite phenotypical overlap between DM1 and DM2, this ued secondary to the misperception of drug-induced he- study demonstrates that these disorders have both over- patic toxicity. lapping and distinct effects on specific laboratory mark- The results of this study may underestimate the de- ers. Overall, these data emphasize that DM2, similar to DM1, gree and number of laboratory abnormalities in the DM2 is a multisystem disease. Multiple laboratory biomarkers community. A substantial portion of the patients in- representing renal, hepatic, muscular, endocrine, hema- cluded in this research were selected given their previ- tologic, and immunologic function were found to be af- ous participation in controlled DM2 clinical trials. Be- fected in this population of patients with DM2. cause these clinical trials excluded patients with significant This research provides a deeper glimpse into the wide- comorbidities, it is possible that this data set represents spread clinical manifestations of a relatively rare, re- a healthier subset of patients with DM2. In addition, for cently discovered, and understudied dystrophy. These data participants with DM2 who did not participate in a clini- may provide an identifiable disease/laboratory profile to cal trial, their earliest known laboratory studies were used assist in the initial identification of undiagnosed cases. when multiple values were available. By selecting these Indeed, there are clinical reports of patients with DM2 earlier test results, it is possible that these data under- being diagnosed presymptomatically secondary to the represented the progressive systemic dysfunction thought identification of elevated CK levels during routine blood to occur as patients with DM2 age.3 Also note that co- work.10 Similarly, the identification of other clinical mark- existing medication use was not known during each in- ers, such as elevated total cholesterol, LD, and ALT lev- dividual laboratory sampling. It is possible that abnor- els and reductions in IgG levels, lymphocyte counts, and mal thyroid, testosterone, or lipid levels were masked by creatinine levels, may improve a physician’s ability to rec- simultaneous drug use in a portion of patients studied. ognize an undiagnosed case of DM2. Ultimately, these laboratory results may provide in- These data also emphasize the increased frequency of sight into future potential avenues of DM2 research. Of several potentially treatable conditions in the DM2 popu- note, 75% of patients with DM2 were found to have low lation. Patients with DM2 were found to have laboratory levels of IgG. Although at first glance this may suggest an markers suggestive of hypercholesterolemia, hypertriglyc- impaired immune response mechanism in DM2, it is in- eridemia, insulin insensitivity, and, possibly, malnutri- teresting that IgA, IgE, and IgM levels did not show simi- tion. The presence of such conditions, as manifested by high lar levels of decrement. Compared with patients with DM1, cholesterol levels, high triglyceride levels, high serum glu- age- and sex-matched patients with DM2 may have a higher cose levels, and low albumin and globulin levels, may be frequency of autoimmune disorders.9 It is also possible that amendable to early screening, pharmacologic therapeu- IgG has an accelerated turnover rate in DM2 and that IgG tics, or alterations in diet. The early identification of co- is selectively impaired (or sequestered) via an RNA- morbid states in an at-risk DM2 population has the poten- mediated process.12 If this is the case, IgG may have a role tial to lead to early treatment and improved clinical as a serum biomarker during clinical trials of agents (such outcomes for this population. Patients with DM2 had nearly as morpholino antisense oligonucleotides), which may al- identical mean albumin levels as their DM1 counter- ter the toxic burden of RNA13 while simultaneously modi- parts.5 These albumin reductions may correspond to dys- fying IgG counts. At the very least, the etiology of selec- phagia, dietary habits, or impaired intestinal absorption in tive IgG reduction in DM2 deserves more investigation. these 2 populations.11 All 3 of these mechanisms may rep- More studies are needed to determine the true signifi- resent potential avenues for early clinical intervention for cance, etiology, and therapeutic implications of the nu- these 2 populations. merous laboratory abnormalities of DM2. Similar to DM1, there was a high proportion of elevated liver enzyme levels (ALT, GGT, LD, and aspar- Accepted for Publication: January 31, 2011. tate aminotransferase) in DM2. Although GGT eleva- Correspondence: Chad Heatwole, MD, MS-CI, Neuro- tions may suggest underlying hepatocyte involvement, muscular Division, Department of Neurology, Univer-

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 sity of Rochester Medical Center, 601 Elmwood Ave, PO REFERENCES Box 673, Rochester, NY 14642 (Chad_Heatwole@URMC .Rochester.edu). 1. Thornton CA, Griggs RC, Moxley RT III. Myotonic dystrophy with no trinucleo- Author Contributions: All authors had full access to all tide repeat expansion. Ann Neurol. 1994;35(3):269-272. 2. Liquori CL, Ricker K, Moseley ML, et al. Myotonic dystrophy type 2 caused by a the data in the study and take responsibility for the in- CCTG expansion in intron 1 of ZNF9. Science. 2001;293(5531):864-867. tegrity of the data and the accuracy of the data analysis. 3. Day JW, Ricker K, Jacobsen JF, et al. Myotonic dystrophy type 2: molecular, di- Study concept and design: Heatwole, Goldberg, and Mox- agnostic and clinical spectrum. Neurology. 2003;60(4):657-664. 4. Udd B, Meola G, Krahe R, et al. 140th ENMC International Workshop: Myotonic ley. Acquisition of data: Heatwole, Goldberg, Martens, and dystrophy DM2/PROMM and other myotonic dystrophies with guidelines on Moxley. Analysis and interpretation of data: Heatwole, management. Neuromuscul Disord. 2006;16(6):403-413. Johnson, Martens, and Moxley. Drafting of the manu- 5. Heatwole CR, Miller J, Martens B, Moxley RT III. Laboratory abnormalities in ambulatory patients with myotonic dystrophy type 1. Arch Neurol. 2006;63(8): script: Heatwole, Johnson, Martens, and Moxley. Criti- 1149-1153. cal revision of the manuscript for important intellectual con- 6. Ricker K, Koch MC, Lehmann-Horn F, et al. Proximal myotonic myopathy: clini- tent: Heatwole, Johnson, Goldberg, and Moxley. Statistical cal features of a multisystem disorder similar to myotonic dystrophy. Arch Neurol. 1995;52(1):25-31. analysis: Heatwole and Martens. Obtained funding: Heat- 7. Meola G, Moxley RT III. Myotonic dystrophy type 2 and related myotonic disorders. wole and Moxley. Administrative, technical, and material J Neurol. 2004;251(10):1173-1182. 8. Ricker K. Myotonic dystrophy and proximal myotonic myopathy. J Neurol. 1999; support: Heatwole, Johnson, Goldberg, Martens, and Mox- 246(5):334-338. ley. Study supervision: Heatwole and Moxley. 9. Tieleman AA, den Broeder AA, van de Logt AE, van Engelen BG. Strong associa- Financial Disclosure: None reported. tion between myotonic dystrophy type 2 and autoimmune diseases. J Neurol Neu- rosurg Psychiatry. 2009;80(11):1293-1295. Funding/Support: This research received support from 10. Merlini L, Sabatelli P, Columbaro M, et al. Hyper-CK-emia as the sole manifes- grant 1K23AR055947 from the National Institute of Ar- tation of myotonic dystrophy type 2. Muscle Nerve. 2005;31(6):764-767. thritis and Musculoskeletal and Skin Disorders (Dr Heat- 11. Tieleman AA, Knuijt S, van Vliet J, de Swart BJ, Ensink R, van Engelen BG. Dysphagia is present but mild in myotonic dystrophy type 2. Neuromuscul Disord. wole), the Muscular Dystrophy Association (Dr Heat- 2009;19(3):196-198. wole), and the University of Rochester Clinical 12. Wheeler TM, Thornton CA. Myotonic dystrophy: RNA-mediated muscle disease. Translational Science Institute (Dr Heatwole). Curr Opin Neurol. 2007;20(5):572-576. 13. Wheeler TM, Sobczak K, Lueck JD, et al. Reversal of RNA dominance by dis- Online-Only Material: The eTable is available at http: placement of protein sequestered on triplet repeat RNA. Science. 2009;325 //www.archneurol.com. (5938):336-339.

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