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Neuromuscular Disorders 21 (2011) 443–450

Workshop report

Myotonic dystrophy type 2 (DM2) and related disordersReport of the 180th ENMC Workshop

including guidelines on diagnostics and management3–5 December 2010, Naarden, The Netherlands

B. Udd ⇑, G. Meola, R. Krahe, D.G. Wansink, G. Bassez, W. Kress, B. Schoser, R. Moxley

Neurology Department, Tampere University and University Hospital, Folkhalsan Institute of Genetics, Dept. of Medical Genetics and

Haartman Institute, University of Helsinki and Vasa Central Hospital, Finland

1. Introduction

Myotonic dystrophy is characterized by autosomaldominant progressive myopathy, myotonia and multiorganinvolvement. Two distinct entities are currently known:Myotonic dystrophy type 1 (DM1, Steinert’s disease) [1],and Myotonic dystrophy type 2 (DM2) [2–4]. The firstENMC workshop on PROMM/DM2 in 1997 establishedclinical diagnostic criteria [5]. Before the second ENMCWorkshop in 2000, Ranum et al. published mapping ofthe new genetic DM2 locus on chromosome 3q21 [6]. Sub-sequently the current nomenclature was adopted renamingthe locus for myotonic dystrophy/Steinert’s disease asDM1 and the PROMM locus as DM2 [7]. Most of the pre-viously reported families mapped to the DM2 locus [8], andthe workshop adopted the term Myotonic dystrophy type 2(DM2) for all the progressive myotonic multiorgan disor-ders linked to the DM2 locus.

Prior to the 3rd workshop in 2003, the mutation underly-ing DM2 was discovered [9]. The mutation is a large(CCTG)n microsatellite repeat expansion in the first intronof ZNF9 gene on chromosome 3q21 and is thus similar tothe untranslated (CTG)n repeat causing DM1. The 4thworkshop reviewed epidemiology, evaluated moleculardiagnostic DNA-tests, the range of clinical presentationsand new findings on muscle biopsy, imaging and brainexaminations in DM2 patients. The workshop discussedthe molecular pathomechanisms based on the uncoveredtoxic RNA-gain-of-function with secondary effects on targetgenes and learned about the first DM2 mouse models [10].

0960-8966/$ - see front matter � 2011 Elsevier B.V. All rights reserved.

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⇑ Corresponding author. Fax: +358 6 3232888.E-mail address: Bjarne.Udd@pshp.fi (B. Udd).

The clinical course of DM2 was considered to be usuallymore favourable compared to DM1. Families with DM2do not have the severe congenital form of illness thatoccurs in DM1. Abnormalities in the social and cognitiveabilities of adults with DM2 are typically mild or absent,and there is no prominent late weakness of the respiratory,facial and bulbar muscles [10]. In DM2 the manual skillslargely remain intact and complications during generalanesthesia have not been reported. However, DM2 hasbeen reported with very severe variants of the disease:severe fatal cardiac complications have occurred as wellas severe muscle weakness and disability [11].

The aims of this 5th ENMC Workshop on DM2 andrelated disorders were:

(a) To evaluate the current DM2 diagnostic tests, theiravailability and their indications.

(b) To learn more about the phenotype and itsvariations.

(c) To review and update the Management guidelinesfrom 2006.

(d) To thoroughly review and discuss the current under-standing of the molecular pathomechanisms.

(e) To issue a statement on the position of DM2 related toongoing preparations for therapy readiness in DM1.

2. DM2-mutation: Nature, molecular diagnosis andepidemiology

Wolfram Kress from Wurzburg, one of the major diag-nostic centers for myotonic dystrophy in Germany, showedstatistics indicating similar numbers of positive diagnostic

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tests for DM2 and DM1. Both disorders are diagnosed inabout 100 patients each year in the lab, with a positivehit rate of around 25% for samples referred for DM2testing.

Stan Vohanka from Brno reported on the first results ofDM2 genetic testing in the Czech population. The totalnumber of inhabitants in the Republic is about 10 millionand currently two different laboratories carry out DNAtesting for DM2. Since the start of DM2 genetic testing87 patients have been diagnosed with DM1 and 152patients with DM2 disease. Because clinical ascertainmentfor DM2 is still highly variable the numbers obtained sug-gest DM2 might be more frequent than DM1 in the Czechpopulation. The overall clinical presentation of the DM2confirmed patients was within the range of previouslyreported phenotypes with proximal lower limb weaknessin all patients, muscle pains in 42%, and myotonia in80%. They had also identified one family with a homozy-gote DM2 patient presenting with pronounced myotoniaat age 20. A registry is established in the country providingmore detailed information in the future.

Bjarne Udd (Tampere, Finland) described recent popu-lation studies on the frequency of DM1 and DM2 muta-tions performed by Tiina Suominen in Finland. The basiccohort consisted of 4532 samples from healthy blooddonors and was supplemented by additional cohorts of827 patients diagnosed with other non-myotonic neuro-muscular diseases and their 127 healthy relatives. Theresults show a surprisingly high frequency 1/1830 of theDM2 mutation in the Finnish population, which is >4-foldhigher than any previous estimates of the prevalence of thedisease prevalence for DM1 and DM2 combined [12]. Thestudy raised many questions, such as how well the Finnishpopulation may reflect the mutation frequency in otherEuropean populations and whether the mutation in factis 100% penetrant in all circumstances. The results suggesta prevalence of more than 1000 patients in Finland,whereas to date only some 300 have been identified.

1.1. Genetic testing – Diagnostic methods

Claudio Catalli from Rome, Italy gave a detaileddescription of the tetranucleotide repeat primed PCR(TP-PCR) method used in their laboratory for DM2 diag-nostic purposes and the minor changes to the protocol theyhave adopted. The technique has been very reliable in thestudied patients and individuals and is able to detect bothshort and very large expansions with no false negativeresults obtained so far.

Charles Thornton (Rochester, NY) showed a new min-imal Southern blotting technique for identification ofDM1 and DM2 mutations which was developed in his lab-oratory to avoid radioactive steps and to make use of smal-ler sample sizes in the order of 100–500 ng of DNA. Thehigher sensitivity was obtained by applying multiple diges-tions closer to the repeat and use of an LNA-modifiedprobe. The expansions usually appear as a smear and the

lower limit for detection of DM1 or DM2 repeat copieshas not been established; DM1 in muscle has been detecteddown to 600 repeats. Whether other (CCTG)n repeats inthe genome might be included in the assay has not beenclarified. The sensitivity for small expansions might beenhanced by modifications of the protocol.

Wolfram Kress reviewed the molecular genetic testsavailable and currently used for DM2 diagnostic and con-cluded that all different methods have their innate advanta-ges and disadvantages. Any diagnostic laboratory shouldnot rely on just one methodological approach since a mar-ginal number of samples will be difficult to conclusivelydetermine with any single method. Different versions ofrepeat primed PCRs are most widely used in combinationwith the first step PCR across the region containing themutation to determine the sizes of alleles in the normalor premutation range.The laboratory should have accessto complementary techniques such as modified Southerns,FISH or CISH, and even genotyping the haplotype ofthe mutant allele to clarify uncertain results. Muscle tissueDNA may provide a more reliable results if leukocyteDNA results remain uncertain.

Richard Moxley (Rochester, NY) heads the initiative fora North-American registry of myotonic dystrophy aimingto provide a more detailed natural history of both DM1and DM2. Currently 700 DM1 patients and 117 DM2patients are registered. How well these numbers reflectthe proportions of diagnosed DM1 and DM2 patients isnot known. One of the already available findings basedon the registry data is the wide range of previous diagnosesand the very long delay until final diagnosis in the DM2patient group. This fact provides direct evidence that thediagnostic accuracy and awareness of DM2 among neurol-ogists is still far too limited to the harm of the DM2patients.

3. DM2 – The spectrum of clinical expression

Giovanni Meola (Milan, Italy) updated the clinical andmolecular information in a peculiar DM2 family with juve-nile onset myotonia in the daughter of the proband mother.Both carry a verified DM2 mutation with larger expansionin muscle than leukocyte DNA. The mother has a commonphenotype whereas the daughter shows clinical and EMGmyotonia only. Histopathology in the muscle biopsy ofthe daughter is also within normal range despite the occur-rence of ribonuclear foci in similar numbers and sizes aswith the findings in the mother’s biopsy. Extensive studiesof other genes causing myotonia such as CLCN1 andSCN4A have so far not identified a second gene defectaccounting for the myotonia.

Benedikt Schoser (Germany) reported on the experiencein Munich based on a new cohort of 134 DM2 patients col-lected in a registry during the last years. The average age ofonset was 40 years (±14 years) and the age of diagnosis47 years (±14 years). The first symptoms consisted of prox-imal lower limb weakness in 40% of the patients, myalgia

B. Udd et al. / Neuromuscular Disorders 21 (2011) 443–450 445

stiffness and cramps in 20%, and others were referred fordiagnostics because of elevated CK values or a positivefamily history. At diagnosis the range of symptoms wassimilar, however with the addition of findings in clinicalexaminations showing arrhythmia, cataracts, dysphagia,obesity, COPD, thyroid abnormalities, associated autoim-mune diseases like psoriasis or rheumatoid arthritis, andGI cancers or constipation in 20–25% of the patients.Around 10% were eventually wheel-chair-bound and aminority needed respiratory devices or pacemakers (4%and 3%). The educational level of the diagnosed DM2patients was in keeping with the normal distribution. Asreported there is no increased risk of severe anesthetic com-plications (0.6% equals normal distribution) associatedwith DM2 disease. In the previous cohort of 480 patientscollected by late Ken Ricker, there were four cases of sud-den cardiac deaths, six males having heart transplantationbecause of cardiomyopathy before DM2 diagnosis, threecases of dilatied cardiomyopathy in the follow-up, and fourstrokes. The overall life expectancy was normal despite car-diac arrhythmia in 35%, coronary heart disease in 11%,myocardiac infarcts in 6% and pacemakers in 3%.

Guillaume Bassez (Paris, France) complemented withdata from the French registry showing that heart conduc-tion defects were more prevalent in DM1 than DM2, evenif the arrhythmia incidence was equal and strokes in DM2patients frequently were associated with atrial fibrillation.

Alide Tieleman from the Netherlands detailed the recentstudies performed on the Dutch DM2 patient cohortregarding GI-abnormalities, dysphagia symptoms, sleepand other management problems usually less well recog-nized and addressed. Dysphagia was mild but occurred inmore or less all patients. 24% used continuous pain medi-cation. Despite experienced fatigue there was no day timesleepiness in DM2 patients. Sleep disturbances were usuallyassociated with myalgic pains and caused increased sleeplatency.

A new subtype of DM2 related myopathy has been iden-tified in a Finnish family showing late onset dominantmyalgia cramps and mild proximal lower limb weaknessbut without myotonia even on EMG. The family was iden-tified based on similar muscle biopsy pathology with fre-quent highly atrophic type 2 and nuclear clump fibers.Further molecular diagnostics showed just one normalsized allele over the mutation but no ribonuclear inclusionsas antisense oligo FISH/CISH proved negative on musclesections. Further investigation by Southern, repeat primedPCR and sequencing revealed a very short expansion of 55uninterrupted repeats on a different microsatellite haplo-type than all other Finnish DM2 patients, and apparentlycausing a mild myopathy without the abnormal splicingdefect characteristic of DM2.

4. Molecular pathomechanism of DM2

Linda Bachinski (Houston, TX) started off the sessionby describing recent results on alternative splicing events

occurring also in other muscle diseases than the myotonicdystrophies. The group had investigated and comparedBecker, Duchenne and Tibial muscular dystrophy sampleswith DM1 and DM2 samples, and observed alternativeexon 5 splicing of MEF2A and MEF2C in all dystrophies[13]. Despite considerable methodological difficulties, theapproach based on microarray screening and RT-PCR ver-ification was able to identify a number of new genes show-ing splicing abnormality in DM1 and DM2 such asinclusion of exon 2 in MBNL2. The conclusion was thatDM1 and DM2 are rather similar regarding splicing abnor-mality and that qualitative splicing differences seem not toaccount for phenotype differences of the two diseases.

Nicolas Charlet-Berguerand (Illkirch, France) describedtheir extensive studies on Amphiphysin (BIN1) missplicingand tubular defects in DM1 and DM2. Missplicing wasnot identical in unaffected vs. affected muscles in DM1and apparently less in DM2 compared to DM1, neverthelessleading to secondary effects on tubulation in the muscle pos-sibly over abnormal phosphoinositide signalling. Theresults were confirmed in mouse model studies and mightbe related to both the central nucleation and weakness-hypotonia of congenital DM1 and to the increase of internalnuclei in the adult myopathology of both DM2 and DM1.

Charles Thornton summarized the current understand-ing of the splicing abnormality caused by mutant tran-scripts in myotonic dystrophies. The effects of manysplicing events on the clinical phenotype may be moderateor difficult to show. In different models exon skippingevents are easier to monitor correctly, whereas overexpres-sion is always more difficult, as shown by the conflictingdata on exon 11 inclusion in insulin receptor. The seques-tered splicing factors in DM are involved in many othermolecular processes and the phenotype of the MBNL1KO-mouse is caused also by other dysregulations thansplicing. The splicing events, however, serve as good bio-markers of the pathology and can be easily monitored.

Lubov Timchenko (Houston, TX) discussed the obser-vations of increased CUGBP1 in DM and any differencesbetween DM1 and DM2. The increase in DM1 consistsof both active and inactive forms particularly in congenitalDM1 whereas in DM2 only the active form is increased.The regulation of CUGB1 activity involves phosphoryla-tion at S302 and the active form binds eIF2 on polysomesaffecting translation. If phosphorylated, eIF2 binds inac-tive CUGBP1 resulting in arrest of translation. Increaseof inactive CUGBP1 may also be involved in delayed myo-genesis in congenital DM1.

Chantal Sellier (Illkirch, France) reported on new obser-vations on FOX1 and 2, which bind (CCUG)n but not(CUG)n and compete with MBNL in binding to CCUGrepeats. This may in the end affect the amount of freeMBNL1 in DM2 vs. DM1.

In the absence of Olayinka Raheem, Bjarne Udd relatedher recent results indicating an altered expression of ZNF9in human DM2 muscle tissue. Previous studies, mostly onmyoblast or lymphocyte culture and not on patient muscle

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tissue, indicated that the mRNA and protein expression ofthe ZNF9 resident gene were not affected in DM2. How-ever, new results using three different ZNF9 antibodiesand a larger sample collection including DM1 muscle tissuefor comparison show that there is a significant decrease ofZNF9 protein in DM2, based on inappropriate processingof mutant pre-mRNA transcript [14].

Andrew Link (Nashville, TN) introduced new resultsregarding ZNF9’s function in internal ribosome entry site(IRES)-mediated cap-independent translation and its rolein DM2. ZNF9 binds directly to the IRES of the humanornithine decarboxlyase (ODC) mRNA and promotescap-independent translation initiation. ZNF9 associateswith actively translating human ribosomes as shown withpolysome profiling analysis. Overexpression of ZNF9increases IRES-mediated translation initiation in humancells. DM2 myoblasts have significantly reduced cap-inde-pendent translation, which was partially restored by over-expressing ZNF9 [15]. Finally, the S. cerevisiae gene Gis2is a yeast ortholog of ZNF9, which will provide an oppor-tunity to use genetic and molecular approaches to dissectthe functional role of ZNF9.

Ralf Krahe (Houston, Texas) summarized their exten-sive experience with expression profiling and pathway anal-ysis of DM biopsies, indicating that the net effect of theDM2 mutation is more or less globally affecting transcrip-tional levels of many genes (�2000) with �80% showingincreased expression. Significantly dysregulated pathwaysincluded among others, the large field of Ca2+-handlinggenes, actin dynamics, upregulation of TGFB genes. Sev-enty-one of 386 genes specifically involved in RNA metab-olism were dysregulated, with �80% showing increasedexpression. Exon specific array profiling for the assessmentof splicing events showed dysregulation of 225 genes inDM1, 530 genes in DM2, and in a comparison betweenDM1 and DM2 181 dysregulated genes were identicalbetween both diseases [16]. However, dysregulation alsooccurred in 256 genes shared with other non-DM neuro-muscular diseases studied, apparently many of which aredue to secondary compensatory mechanisms in disease.

5. Animals models to understand DM2

Ralf Krahe updated the findings in the transgenic mousemodel of DM2 disease called DM2-HSAtg-121: ribonucle-ar foci of (CCUG)n transcripts are present in musclemainly nuclear but some also in the cytoplasm. Expressionwas found also in brain and smooth muscle despite theskeletal muscle actin promotor used. The mouse shows amild muscle pathology and also myotonia features onEMG despite normal CLC-1 and no abnormal splicing ofthe gene. MBNL1 co-localizes with the ribonuclear foci,with total protein levels unchanged, while CUGBP1 wasincreased. Abnormal splicing was neither observed forSERCA1, RYR1, ANKRD2 or TNNT3.

Andreas Bergmann (Houston, TX) reported on a trans-genic DM2-Drosophila fly model that he has developed in

collaboration with Ralf Krahe (Houston, TX). Expressionof (CCTG)106 under control of the eye-specific GMR pro-moter causes ribonuclear and cytoplasmic foci, increasedapoptosis, as well as irregular numbers and positions ofphotoreceptor neurons and cone cells. Inhibition of apop-tosis using the Caspase3-inhibitor P35 reduces apoptosisand ameliorates the phenotype. Reduction of MBNL wors-ens and overexpression rescues the phenotype, whereasincreasing or decreasing CUGBP1 does not make any dif-ference. A screen for compounds having a beneficial effecton the phenotype has provided very promising results.

6. Therapy and practical management

Rick Wansink (Nijmegen, NL) gave an overview ofongoing approaches towards molecular interventions inDM1 and their possible practicability in DM2. The Nijme-gen lab focusses on complete elimination of toxic repeattranscripts in DM1 models. Powerful and stable AONshave been identified – most of them complementary tothe (CUG)n expansion – that reduce products from theexpanded DMPK allele and diminish ribonuclear foci inmodel systems without reducing much of the total DMPKprotein. Apparently by binding to the repeat expansion,degradation of harmful expanded RNA is induced. Detailsof the underlying cellular pathway still need to be eluci-dated, however. Local AON delivery to muscle in DM1mouse models has been completed with good results, butsystemic treatment requires further optimization. The pro-ject is in good progress towards clinical Phase 1 trials in afew years time if all preclinical studies will develop fine.For DM2, related specific AONs directed at the CCUGexpansion are easy to design and only few other genes witha long CCTG stretch exist in the human genome. Whetherrepeat-complementary AONs will be effective remains tobe established, as the DM2 repeat segment is containedwithin an intron, which normally has a nuclear fateentirely different from that of mRNA. Small compoundsthat specifically bind C/CUG structures to counteractMBNL1 sequestration have been developed by other labs[17], but there remains some concern about their cellulartoxicity.

Charles Thornton continued on the same theme. Twentyyears of experience with using AONs has provided a singlelicensed molecule for therapeutic usage and the combinedexperience sofar indicates overall little toxicity. However,by systemic i.v. delivery most of the molecules end up inthe liver or kidney with much less in muscle tissue. Conju-gates to increase uptake in muscle are searched for but evenwithout such components the experience with tail veinmorpholino injections in a mice model makes an effect onreduced myotonia in 4–5 weeks.

Guillaume Bassez (Paris, France) presented a compre-hensive overview of which components could be includedas clinically meaningful, sensitive and robust outcome mea-sures in any future therapeutic intervention trial for DM2.A favorable clinical outcome would need assessment of

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pain and QoL by reliable questionnaire method, assess-ment of weakness probably with a DM2 specific scaledespite new reliable devices used in DM1, and a longenough pretreatment natural history study along the estab-lished parameters used for sporadic IBM (six MWT, climb-ing four steps, rising from supine). MRI could possibly beused depending on the rate of change over time; correlationbetween weakness and T1 fatty degenerative changes inTibialis Anterior muscle have been shown in DM1. Heartassessment could be similar to DM1 and conductionabnormality can be used as outcome measure.

7. Outcome of the initiatives from the previous workshop

1. Retrospective study of the outcome of general anesthe-sia in DM2 patients to overcome the lack of reliableand confirmed data.� The German group of scientists have performed and

published the study showing no increase of severecomplications of general anesthesia in DM2 [18].

2. A web site for general information and Guidelines wassupported.� This is still under consideration and will probably be

set up as a link on the ENMC homepage with directaccess to the published reports of the workshops.

3. Development of reliable clinical measures of myotonia.� Assessment methods of myotonia have been pub-

lished by the Rochester, NY group [19].

4. Questionnaire instrument to describe and quantify painin its specific locations.� Chronic pain questionnaire tools have been applied

in a Finnish study and will be reported.

5. Documentation of frequency of EKG and cardiac ultra-sound abnormalities and heart attacks in DM2.� This is part of the registry parameters in Germany,

France and the USA.

6. Documentation of changes in CK and any toxicity dur-ing statin treatment.� Studies on the increased statin adverse reaction sus-

ceptibility are initiated in Germany and in Finland.

7. Therapeutic trial readiness in DM2?� Since DM2 usually does not end up with severe dis-

ability, dysphagia or respiratory insufficiency, thecurrent baseline for trial readiness is to improve nat-ural history and outcome measures, but any collec-tion of patients will await positive outcome fromtrials in DM1 with shown efficacy in model systemsof DM2.

8. Guidelines and recommendations

8.1. Guidelines #1: indications for genetic DM2 testing

It is important to note that the overall clinical appear-ance of DM2 is different from DM1. DM2 needs to be con-

sidered in many other patients than those who havemyotonia. In the single patient, none of the commonclinical features: proximal weakness, myotonia, cataracts,elevated CK-values or established family history is abso-lutely mandatory for DM2 disease.

– Based on clinical findings, the threshold for genetic test-ing should generally be lower in DM2 than the findingsrequired for DM1 genetic testing because myotonia andcataracts are frequently absent.

– One common clinical presentation is late or very lateonset of mild proximal weakness and stiffness with orwithout myotonic findings on EMG.

– Other presentations may involve prominent myalgia inthe 30–50’s as the most disabling symptom associatedwith one or more other feature of muscle disease.

– Findings typical for DM2 on muscle biopsy may beanother indication for genetic testing [20,21].

– A considerable number of patients with a verified DM2mutation have had very unusual phenotypes such ascramps, radiculopathic or chest pains, fluctuating weak-ness etc., which requests a high degree of awareness bythe clinician regarding DM2 disease.

– Presymptomatic genetic testing, as with other geneticdisorders, requires appropriate genetic counselling.

– The ENMC consortium provides a platform forexchanging expertise and quality control for labdiagnostics.

8.2. Guidelines #2: indications for genetic DM2 testing in

fibromyalgia

Screening everyone with fibromyalgia symptoms maynot be practical despite the many overlapping symptomsfatigue, myofascial pain, stiffness, GI problems, etc. Fibro-myalgia cannot explain many of the other symptoms thatmay occur in DM patients and these findings should alerttowards testing:

� Check CK first!

More and less important findings:

� Some family history demonstrating a dominant patternof inheritance.� Proximal muscle weakness.� Myotonia, or even just increased insertional activity on

EMG.� Muscle atrophy or calf hypertrophy.� Cardiac issues: sudden death, syncope and presyncope,

cardiac conduction defects, cardiac arrhythmias.� Endocrine disturbances including insulin resistance, dia-

betes, male hypogonadism.� Elevated CK or liver enzymes, hypogamma-

globulinemia.� Cataracts: posterior subcapsular iridiscent.

448 B. Udd et al. / Neuromuscular Disorders 21 (2011) 443–450

� Slight ptosis or facial weakness.� Tremors.

8.3. Guidelines #3: Recommendations for management

� Clinical myotonia is rarely severe or disabling but sincemyotonic stiffness is mixing with myalgic pain a trial ofmexiletine, and alternatively flecainide (2 � 50 –2 � 100 mg) or propafenone (2 � 150–2 � 300 mg), canbe considered.� Baseline and serial monitoring of blood count, electro-

lytes, and liver gamma glutamyl transferase level andEKG are recommended.� The consortium recommends serial monitoring of mus-

cle weakness and suggests use of supervised aquatictherapy and land based resistive training to amelioratefatigue and to maintain strength.� No specific medication for muscle pain in DM2 has

shown consistent benefit. Referral to a pain specialistmay be necessary if completely disabling pain persists.� Cataracts are treated by surgical removal as necessary.� Cardiac fatalities have occurred, but the frequency is

very low. However, prompt referral for cardiology con-sultation if EKG abnormalities or clinical signs sugges-tive of cardiac dysfunction occur.� While manifest cardiomyopathy is rare, coronary heart

disease in DM2 patients is not. Management of cardiacproblems needs to be co-ordinated with the primary carephysician and the cardiologist.� Atherosclerosis and related hyperlipidemia are frequent

in DM2 and seem to correlate closely with the insulinresistance that develops in patients. Serial monitoringof the lipid profile and intermittent assessment of oralglucose tolerance testing (including measurement ofserum insulin values at 0, 30, 60, 120, 150, and180 min time points after glucose ingestion).� Statin treatment in patients with DM2 can pose a most

challenging problem, because it is difficult in DM2patients with myalgia to determine if they are developinga statin-related myopathy. Serial measurements of crea-tine kinase before and after treatment are helpful indeciding if statin toxicity has developed. Not all DM2patients have pronounced or severe adverse reactionsto statins, but if they develop, discontinuing treatmentindefinitely is recommended. Moderate elevations ofcholesterol (<8) in older patients are less harmful thanthe toxic myopathy.� Hypothyroidism and gonadal failure (impotence) treat-

ment with thyroid and testosterone replacement whenneeded. It is helpful to maintain normal levels of testos-terone before considering additional medications forerectile dysfunction.� DM2 patients have no increased risk of general anesthe-

sia, but fairly aggressive pain management is desirableduring the post-operative period.

� Fatigue is not as severe in DM2 as with DM1, but it iscommon. Daytime sleepiness does not occur but sleepquality is decreased and is directly related to myalgicpains.� Some patients develop cognitive and neuropsychological

problems related to DM2. Screening for other causes ofthese problems is the first step.� Mildly elevated GGT do not require specific liver inves-

tigations unless progressively elevated.� Decreased IgG and IgM levels are frequently encoun-

tered but do not need monitoring.

9. Further literature related to the workshop

� Mankodi A, Teng-Umnuay P, Krym P, et al. Ribonucle-ar inclusions in skeletal muscle in myotonic dystrophytypes 1 and 2. Ann Neurol 2003; 54; 760–768� Mankodi A, Logigian E, Callahan L, McClain C, White

R, Henderson D, Krym M, Thornton CA. Myotonicdystrophy in transgenic mice expressing an expandedCUG repeat. Science. 2000; 289:1769–73.� Pyronnet, S., Pradayrol, L., and Sonenberg, N. (2000).

A cell cycle-dependent internal ribosome entry site.Mol Cell 5, 607–616.� George A, Schneider-Gold C, Zier S, Reiners K, Som-

mer C. Musculoskeletal pain in patients with myotonicdystrophy type 2. Arch Neurol. 2004;61(12):1938–42.� Merlini L, Sabatelli P, Columbaro M, et al. Hyper-CK-

emia as the sole manifestation of myotonic dystrophytype 2. Muscle Nerve. 2005;31(6):764–7.� Milone M, Batish SD, Daube JR. Myotonic dystrophy

type 2 with focal asymmetric muscle weakness and noelectrical myotonia. Muscle Nerve. 2009;39:383–5� Auvinen S, Suominen T, Hannonen P, Bachinski L,

Krahe R and Udd B. Myotonic dystrophy type 2 foundin 2 of 63 persons diagnosed with fibromyalgia. Arthritis& Rheumatism 2008; 58:3627–3631.� Suominen T, Schoser B, Raheem O, Auvinen S, Walter

M, Krahe R, Lochmuller H, Kress W, Udd B. High fre-quency of co-segregating CLCN1 mutations amongmyotonic dystrophy type 2 patients from Finland andGermany. J Neurol 2008; 255:1731–6.� Bachinski L, Czernuszewicz T, Ramagli L, Suominen T,

Shriver M, Thornton C, Udd B, Siciliano M, Krahe R.Pre-mutation allele pool in myotonic dystrophy type 2(DM2). Neurology 2008; 72:490–497.� Pisani V, Panico MB, Terracciano C, et al. Preferential

central nucleation of type 2 myofibers is an invariablefeature of myotonic dystrophy type 2. Muscle Nerve.2008;38(5):1405–11.� Bassez G, Chapoy E, Bastuji-Garin S, et al. Type 2 myo-

tonic dystrophy can be predicted by the combination oftype 2 muscle fiber central nucleation and scattered atro-phy. J Neuropathol Exp Neurol. 2008;67:319–25.

B. Udd et al. / Neuromuscular Disorders 21 (2011) 443–450 449

� Mahadevan, M.S. et al. Nat. Genet. 2006; 38: 1066–1070.� Chen W, Wang Y, Abe Y, Cheney L, Udd B, Li Y-P.

Haploinsuffciency for Znf9 in Znf9+/- mice is associatedwith multiorgan abnormalities resembling myotonicdystrophy. J Mol Biol 2007; 368(1): 8–17.� Gerbasi, V. R., and Link, A. J. (2007). The Myotonic

Dystrophy Type 2 Protein ZNF9 Is Part of an ITAFComplex That Promotes Cap-independent Translation.Mol Cell Proteomics 6, 1049–1058.� Huichalaf C, Schoser B, Schneider-Gold C, Jin B, Sar-

kar P, Timchenko L. Reduction of the rate of proteintranslation in patients with myotonic dystrophy 2. JNeurosci. 2009;29:9042–9.� Salisbury E, Schoser B, Schneider-Gold C, Wang GL,

Huichalaf C, Jin B, et al. Expression of RNA CCUGrepeats dysregulates translation and degradation of pro-teins in myotonic dystrophy 2 patients. Am J Pathol.2009 Aug;175(2):748–62.� Pelletier R, Hamel F, Beaulieu D, Patry L, Haineault C,

Tarnopolsky M, Schoser B, Puymirat J. Absence of adifferentiation defect in muscle satellite cells fromDM2 patients. Neurobiol Dis. 2009;36:181–90.� Raheem O, Huovinen S, Haapasalo H, Udd B. Novel

myosin heavy chain immunohistochemical double stain-ing developed for the routine diagnostic separation of I,IIA and IIX fibers. Acta Neuropathol 2010; 119: 495–500.� Wheeler TM, Sobczak K, Lueck JD, et al. Reversal of

RNA dominance by displacement of protein sequesteredon triplet repeat RNA. Science. 2009;325(5938):336–9.� Sammons, M. A., Samir, P., and Link, A. J. (2011). S.

cerevisiae Gis2 interacts with the translation machineryand is orthogonal to myotonic dystrophy type 2 proteinZNF9. Biochem Biophys Res Commun (in press).

10. Workshop Participants

Linda Bachinski (Houston, TX, USA).Guillaume Bassez (Paris, France).Andreas Bergmann (Houston, TX, USA).Nicolas Charlet-Berguerand (Illkirch, France).Claudio Catalli (Rome, Italy).Ralf Krahe (Houston, USA).Wolfram Kress (Wurzburg, Germany).Andrew J. Link (Nashville, TN, USA).Giovanni Meola (Milano, Italy).Richard Moxley (Rochester, NY, USA).Benedikt Schoser (Munich, Germany).Chantal Sellier (Illkirch, France).Lubov Timchenko (Houston, TX, USA).Charles Thornton (Rochester, NY, USA).Bjarne Udd (Tampere, Finland).Baziel van Engelen (Nijmegen, the Netherlands).Rick Wansink (Nijmegen, the Netherlands).Stan Vohanka (Brno, Czech Republic).

Acknowledgements

This Workshop was made possible thanks to the finan-cial support of the European Neuromuscular Centre(ENMC) and ENMC main sponsors:

- Association Franc�aise contre les Myopathies (France)

- Deutsche Gesellschaft fur Muskelkranke (Germany)- Telethon Foundation (Italy)- Muscular Dystrophy Campaign (UK)- Muskelsvindfonden (Denmark)- Prinses Beatrix Fonds (The Netherlands)- Schweizerische Stiftung fur die Erforschung der Musk-

elkrankheiten (Switzerland)- Osterreichische Muskelforschung (Austria)- Vereniging Spierziekten Nederland (The Netherlands)

and Associated member:- Asociacion Espanola contra las Enfermedades Muscul-

ares (ASEM).

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