review open access consensus-based care recommendations

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REVIEW OPEN ACCESS Consensus-based care recommendations for congenital and childhood-onset myotonic dystrophy type 1 Nicholas E. Johnson, MD, MSCI, Eugenio Zapata Aldana, MD, Nathalie Angeard, PhD, Tetsuo Ashizawa, MD, Kiera N. Berggren, MA/CCC-SLP, MS, Chiara Marini-Bettolo, MD, PhD, Tina Duong, MPT, PhD, Anne-Berit Ekstr¨ om, MD, PhD, Valeria Sansone, MD, Cuixia Tian, MD, Leah Hellerstein, LCSW, MPH, and Craig Campbell, MD, on behalf of the Myotonic Dystrophy Foundation Neurology: Clinical Practice October 2019 vol. 9 no. 5 443-454 doi:10.1212/CPJ.0000000000000646 Correspondence Leah Hellerstein, LCSW, MPH [email protected] Abstract Purpose of review Myotonic dystrophy type 1 is a multisystemic disorder caused by a noncoding triplet repeat. The age of onset is variable across the lifespan, but in its most severe form, the symptoms appear at birth (congenital myotonic dystrophy) or in the pediatric age range (childhood-onset myotonic dystrophy). These children have a range of disabilities that reduce the lifespan and cause signicant morbidity. Currently, there are no agreed upon recommendations for caring for these children. Recent findings The Myotonic Dystrophy Foundation recruited 11 international clinicians who are experienced with congenital and childhood-onset myotonic dystrophy to create consensus-based care recommendations. The experts used a 2-step methodology using elements of the single text procedure and nominal group technique. Completion of this process has led to the de- velopment of clinical care recommendations for this population. Summary Children with myotonic dystrophy often require monitoring and interventions to improve the lifespan and quality of life. The resulting recommendations are intended to standardize and improve the care of children with myotonic dystrophy. Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder caused by a toxic CTG repeat expansion in the 39UTR of the DMPK gene. 13 In adults with DM1, symptoms are characterized by progressive distal muscle weakness, myotonia, early onset cataracts, cardiac and gastrointestinal problems, and dysfunction in the CNS. 4,5 The multiorgan involvement is often more pronounced and with earlier onset in individuals with symptom onset in childhood. The age of onset of DM1 is variable, and intergenerational repeat expansion (known as anticipation) may result in symptom onset during childhood. When symptom onset occurs at birth, this is known as congenital onset myotonic dystrophy (CDM). Symptom onset after the newborn period and up to Virginia Commonwealth University (NEJ, KNB), Richmond, VA; University of Western Ontario (EZA, CC), Ontario, Canada; Inserm & University of Paris Descartes (NA), France; Houston Methodist Neurological Institute (TA), TX; Institute of Genetic Medicine (CM-B), Newcastle University and Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Stanford University (TD), CA; Queen Silvia Childrens Hospital (A-BE), Gothenburg, Sweden; NEMO Clinic (VS), Milan, Italy; Cincinnati Childrens Hospital Medical Center (CT), OH; and Myotonic Dystrophy Foundation (LH), San Francisco, CA. Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp. The Article Processing Charge was funded by the Myotonic Dystrophy Foundation. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 443

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REVIEW OPEN ACCESS

Consensus-based care recommendations forcongenital and childhood-onset myotonicdystrophy type 1Nicholas E Johnson MD MSCI Eugenio Zapata Aldana MD Nathalie Angeard PhD Tetsuo Ashizawa MD

Kiera N Berggren MACCC-SLP MS Chiara Marini-Bettolo MD PhD Tina Duong MPT PhD

Anne-Berit Ekstrom MD PhD Valeria Sansone MD Cuixia Tian MD Leah Hellerstein LCSW MPH

and Craig Campbell MD on behalf of the Myotonic Dystrophy Foundation

Neurology Clinical Practice October 2019 vol 9 no 5 443-454 doi101212CPJ0000000000000646

Correspondence

Leah Hellerstein LCSW MPH

LeahHellersteinmyotonicorg

AbstractPurpose of reviewMyotonic dystrophy type 1 is a multisystemic disorder caused bya noncoding triplet repeat The age of onset is variable across thelifespan but in its most severe form the symptoms appear at birth(congenital myotonic dystrophy) or in the pediatric age range(childhood-onset myotonic dystrophy) These children havea range of disabilities that reduce the lifespan and cause significantmorbidity Currently there are no agreed upon recommendationsfor caring for these children

Recent findingsTheMyotonic Dystrophy Foundation recruited 11 international clinicians who are experiencedwith congenital and childhood-onset myotonic dystrophy to create consensus-based carerecommendations The experts used a 2-step methodology using elements of the single textprocedure and nominal group technique Completion of this process has led to the de-velopment of clinical care recommendations for this population

SummaryChildren with myotonic dystrophy often require monitoring and interventions to improve thelifespan and quality of life The resulting recommendations are intended to standardize andimprove the care of children with myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder caused by a toxic CTGrepeat expansion in the 39UTR of the DMPK gene1ndash3 In adults with DM1 symptoms arecharacterized by progressive distal muscle weakness myotonia early onset cataracts cardiac andgastrointestinal problems and dysfunction in the CNS45 The multiorgan involvement is oftenmore pronounced and with earlier onset in individuals with symptom onset in childhood The ageof onset of DM1 is variable and intergenerational repeat expansion (known as anticipation) mayresult in symptom onset during childhood When symptom onset occurs at birth this is known ascongenital onset myotonic dystrophy (CDM) Symptom onset after the newborn period and up to

Virginia Commonwealth University (NEJ KNB) Richmond VA University of Western Ontario (EZA CC) Ontario Canada Inserm ampUniversity of Paris Descartes (NA) France HoustonMethodist Neurological Institute (TA) TX Institute of Genetic Medicine (CM-B) Newcastle University and Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon TyneUK Stanford University (TD) CAQueen Silvia Childrenrsquos Hospital (A-BE) Gothenburg Sweden NEMOClinic (VS) Milan Italy Cincinnati Childrenrsquos HospitalMedical Center (CT) OH andMyotonic Dystrophy Foundation (LH) San Francisco CA

Funding information and disclosures are provided at the end of the article Full disclosure form information provided by the authors is available with the full text of this article atNeurologyorgcp

The Article Processing Charge was funded by the Myotonic Dystrophy Foundation

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 443

18 years of age is typically referred to as childhood-onset myo-tonic dystrophy (ChDM) However alternate definitions des-ignate further cut points depending on age of onset67 Althoughthe exact global prevalence is unknown children with CDMlikely represent 10ndash30 of the overall DM1 population48

These disorders cause significant morbidity and mortalityChildren with CDM often require intensive intervention atbirth because of hypotonia respiratory failure and feedingdifficulties49 For children with CDM ventilated longer than3 months there is a 30 mortality in the first year of life10

Both children with CDM and ChDM may have symptomsassociated with attention deficit hyperactivity disorder or autismspectrum disorder (sometimes referred to as social communi-cation disorder) during childhood1112 They also have signifi-cant motor delays13 and may have intractable irritable bowelsymptoms including incontinence Previous research suggeststhat 88 of individuals with congenital or childhood-onsetmyotonic dystrophy are unemployed over the age of 18 years14

Themultisystemicnaturemorbidity andmortality associatedwithcongenital and childhood-onset myotonic dystrophy necessitatethe development of care recommendations to standardize careThese consensus-based recommendations will also set the foun-dation for innovative clinical initiatives where gaps exist and alsofurther research to improve aspects of management These carerecommendations may also better prepare the pediatric DM1community for future clinical trials because variation in clinical caremay have significant effects on the outcome of children partici-pating in geographically dispersed clinical research sites

MethodsParticipant recruitmentThe Myotonic Dystrophy Foundation recruited cliniciansfrom the United States Canada and Europe who have ex-perience in the treatment of children with DM1 to developconsensus-based recommendations

Consensus approachAs previously described the Myotonic Dystrophy Founda-tion developed a two-phase consensus buildingmethodologyusing components of the single text procedure and nominalgroup technique15 This approach was chosen given both thesparsity of literature surrounding many of the clinical aspectsand the extensive experience of the clinicians in this area

Three of the authors (NEJ CC and EZ) created theinitial draft document drawing from the existing literatureand clinical practice that served as an initial text for the rec-ommendation developments

After creation of the single text stakeholders were engagedto refine the recommendations through a consensus-basedapproach The experts were initially assigned to specific areas ofrecommendations where they refined the recommendations Afacilitator (LH) then lead a series of meetings to review reviseand finalize the recommendations with the entire author panel

These efforts led to the final consensus-based care recom-mendations along with a quick reference guide The care rec-ommendations are divided into 2 main sections the GeneralCare Considerations and Systems-based Approach to Manage-ment Because there are differences between childhood-onsetand congenital-onset DM1 recommendations specific to CDMare separated throughout the document The Quick ReferenceGuide is provided as an appendix and the full document isavailable online (appendix e-1 linkslwwcomCPJA89) Bothfeature flowcharts and other infographics for ease of use

ResultsSee full recommendations at Neurologyorgcp

General care considerationsDiagnosis and classification

c The diagnosis of DM1 should be suspected in any childwith a family history of DM1 andor presenting withone or more of the following features Eyelid ptosis andor oral motor weakness Distal weakness primarily of the finger and wrist flexorswithout contractures or weakness of the neck flexors

Myotonia or ldquostiffnessrdquo of muscles Autistic features or social communication difficulties Attention deficit disorder anxiety and other behav-ioral problems

Developmental delay andor Intellectual disability

The age of onset of DM1 is variable

and intergenerational repeat

expansion (known as anticipation)

may result in symptom onset during

childhood

The multisystemic nature morbidity

and mortality associated with

congenital and childhood-onset

myotonic dystrophy necessitate the

development of care

recommendations to standardize and

improve the care of this population

444 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

Learning disabilities (eg dyslexia dyscalculia) Excessive daytime sleepiness (EDS) Gastrointestinal issues constipation or diarrhea Scoliosis Arrhythmia Prolonged recovery or respiratory arrest after anesthesia Neonatal features of hypotonia weakness club footrespiratory distress or feeding problems

c The classification of congenital and childhood-onsetDM1 is provided in table 1 in Quick Reference GuideNote that diagnosis may be made retrospectively afterreviewing symptom onset Fetal tissue with long CTGrepeats should not be called CDMbecause this diagnosisis reserved for newborns In these cases we wouldsuggest use of fetal DM1 as more appropriate

c Genetic counseling is recommended for patientsexhibiting clinical signs indicative of DM1 or have at-risk family members to enable them to make aninformed decision about whether to proceed to genetictesting Individuals with 37ndash49 CTG repeats aredeemed very unlikely to develop detectable DM1symptoms However such ldquopremutationsrdquo can expandinto the disease range in subsequent generationsparticularly when transmitted by women Individualsthus identified should be offered genetic counseling(see Genetic counseling) to discuss their risk fortransmitting DM1

Genetic counselingc Referral to genetic counseling (see nsgcorg) is recom-

mended for all patients with congenital and childhood-onset DM1 and their parents and to assess the parents forthe diagnosis of DM1

c Genetic counseling in affected families should conveyinformation about The inheritance pattern of disease (autosomal

dominant inheritance) The wide variability in the scope and severity of DM1

symptoms even within the same family The possibility of changes in symptom scope and

severity over time The likelihood that the mutation will expand and the

disease will become more severe as it is passed fromgeneration to generation (anticipation)

Particular attention to the possibility of a minimallyaffected mother giving birth to a severely affected child

Options for family planningc Do not use CTG repeat numbers if available for genetic

advice or prognostication these need to be discussedwith a genetic counselor Specifically repeat size may bean indicator of severity but it does not provide anyinformation about the prognosis

Focus on CDMc Once a family has had a child with CDM there is an

increased risk that the next affected child with DM1 islikely to have congenital form as well

Neonatal care A high-risk obstetrician should provide prenatal obstetric

care for mothers known or suspected to carry a child withDM1

Pediatric or neonatal specialist should be present atdelivery if a mother is known to have DM1 or if the childis known or suspected to have DM1

Focus on CDM Children with CDM will often need management in

a neonatal intensive care unit with the capability to dealwith breathing and feeding support This team requiresa range of neonatal and consulting specialists who canmanage the genetic respiratory gastrointestinal or-thopedic neuromuscular neurosurgical and cardiacissues See figure 1 in Quick Reference Guide forneonatal care

End of life counseling and management Recommend the introduction of palliative care at the

time of diagnosis and at regular intervals thereafter Whena formal pediatric palliative care team is available theyshould be consulted

Recognize and address caregiver burden whether thecaregiver has DM1 offering respite care or equivalentmeasures to patient to improve family support Addressnormal grief on the part of the patient and family andoffer counseling as appropriate

Establish an emergency health care plan and advancedirectives with the family

Focus on CDM Introduce the concept that the natural history of the

disease includes progressive improvement of strength forthe first decade of life however the complications ofCDM can be critical and have a high risk of mortalityparticularly in the first year of life

Advise families or caregivers that invasive and non-invasive ventilation (NIV) and nutrition through gastro-stomy tube are acceptable parts of care for patients withCDM

Surgery and anesthesia Inform all caregivers that anyone administering an

anesthetic should be aware of the DM1 diagnosis When possible combine procedures under a single

sedation Arrange for a preanesthetic visit for all children planning

to have deep sedation for a diagnostic test procedureor surgery If possible include a pulmonologist withexpertise in neuromuscular diseases during this visit

Even if the patient has mild DM1 monitoring for a longerperiod of time than is typical following anesthesia orsurgery will allow for identifying serious adverse events inthe hospital setting

Providers are encouraged to review the MyotonicDystrophy Foundation Practical Suggestions for the

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 445

Anesthetic Management of a Myotonic Dystrophy Patient(myotonicorgsitesdefaultfilesMDF_LongForm_AnesGuidelines_01Cpdf) for anesthesia risks andrecommendations before any surgeries or proceduresrequiring anesthesia and the Anesthesia Quick ReferenceGuide (myotonicorgsitesdefaultfilesMDF Anes-thesia Guidelines FNL 2016 2 2 pdf) These docu-ments should be reviewed before treatment decisions

Focus on CDM It is worth noting that children with CDM are at a higher

risk of anesthetic complications given the underlyingrespiratory involvement as opposed to those withchildhood-onset myotonic dystrophy

Systems-based approachto managementRespiratory Signs of respiratory problems in children with myotonic

dystrophy include ineffective cough recurrent pulmo-nary infections orthopnea dyspnea poor sleep morningheadaches apnea fatigue and snoring

See figure 2 in Quick Reference Guide for a flowchart oftesting and treatment options in congenital andchildhood-onset myotonic dystrophy

Focus on CDM For CDM children who remain on longer term trach

ventilation there is often improvement in respiratorystrength over time and consideration to decannulatea tracheostomy should be made after careful considerationwith the multidisciplinary team including neurologyrespirology ear nose and throat and the familyConsideration of airway control respiratory infectionfrequency ability to tolerate a facial or nasal mask for NIVand compliance and cooperation with maintenancepulmonary therapy such as cough assist breathe stakingetc Testing for hypoventilation in sleep should be donebefore decannulation

Cardiovascularc Inform families of the risks of arrhythmias and cardiac

dysfunction and the importance of prompt medicalattention if symptoms are observed (ie palpitationspresyncope syncope dyspnea chest pain unexplainedfatigue) A 12-lead ECG should be performed at DM1 diagnosisand if normal and the patient remains asymptomatic ECGshould be performed annually and warrants moreinvestigation if the patient is symptomatic

If the ECG is normal and clinical suspicion is high a24-hour Holter monitor may be considered asa second-line investigation

Because specific medications such as mexiletine andpsychostimulants are antiarrhythmic an ECG before

use again within 3 months of starting therapy andthen at serial intervals is recommended

Consider in-hospital cardiac monitoring to detectarrhythmias if admitted for longer duration thantypical after surgical procedures or if admitted due tosevere illness or infection

c For young DM1 patients serial exercise stress testingand signal-averaged ECGs may be considered

c Evaluate and treat using American Heart Association(AHA) Management of Cardiac Involvement AssociatedWith Neuromuscular Diseases A Scientific Statement Fromthe American Heart Association 2017 circahajournalsorgcontent13613e200long and ACC ([AmericanCollege of Cardiology]AHA)ESC (European Societyof Cardiology) Guidelines for Management of Patientswith Ventricular Arrhythmias and the Prevention of SuddenCardiac Death (see ncbinlmnihgovpubmed16949478)- section on pediatric issues 134

Skeletal muscle weakness orthopediccomplications and rehabilitation

c Children should be evaluated early and often forphysical occupational and speech therapy needs withspecific attention to Feeding concerns and dysphagia Gross motor delay Gross and fine motor weakness Dysarthria and potential augmentative and alternativecommunication needs

Language acquisition delaysc The spine should be assessed for scoliosis and if

necessary consider bracing or referral to orthopedicsurgeon

c Children should be encouraged to participate in speechtherapy targeting speech language and communicationfrom a very early age

Focus on CDM Newborns with CDM often having difficulty feeding and

alternative nutrition should be considered After abouta year of actively working with a speech therapist oroccupational therapist most children can generally starton oral feeding

Children with CDM experience progressive improve-ment in their proximal strength until adolescence ata minimum Therefore children should be encouraged toparticipate in physical activities

Prevention of joint contractures are key to managementand should be closely monitored with early initiation ofstretching Treatment of talipes equinovarus and otherjoint contractures should include initial stretchingregimen and appropriate ankle bracing (for talipesequinovarus) Serial casting may be considered

Skeletal muscle myotoniac Delayed relaxation after grip or percussion difficulty

related to activities of daily life progressive speech

446 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

impairment or profound irritable bowel symptoms aresigns often related to myotonia

c Mexiletine (Mexitil) is an option for myotonia if it isdemonstrated and is distressing to the patient Mexiletinemay not be approved for use in every country In these casesother sodium channel antagonists may be considered Because mexiletine is an antiarrhythmic an ECG

before use again within 3 months of starting therapyand then at serial intervals is recommended

Instruct the patient to avoid dyspepsia and transientldquodizzy feelingsrdquo associated with mexiletine treatmentby taking it with food to extend absorption and lowerpeak level in blood

Ocular and hearing management Baseline audiometry should be performed especially at

school age Ophthalmologic assessment should be performed at

diagnosis and at least yearly to evaluate for hyperopiastigmatism strabismus and visual acuity to preventevolution of visual impairment

Eyelid ptosis if ptosis becomes severe and interferes withvision intervention such as eyelid ldquocrutchesrdquo that can beinserted into glasses may be warranted Try crutches asa remedy for ptosis before eyelid surgery is consideredbecause of anesthesia risks Ophthalmic lubricants for dryeye may be considered

Gastrointestinal andgenitourinary management

c Presence of gastrointestinal symptoms such as abdom-inal pain constipation fecal incontinence or diarrheamay be a frequent problem The symptoms may mimicirritable bowel syndrome (IBS)15 Fiber supplementa-tion (more than 8 g daily) is the first-line treatment

c Gentle laxatives (see below) for constipation Oilsshould be avoided as they will lead to diarrhea Ifa patient does not respond to the first- or second-linerecommendations below a referral to a gastrointestinalspecialist for anal manometry should be considered First-line therapy recommendations polyethylene

glycol (Miralax) senna (Ex-Lax Senokot) docusate(Colace) or lactulose (Cholac)

Second-line therapy recommendations bisacodyl(Dulcolax Correctol) lubiprostone (Amitiza) orlinaclotide (Linzess)

Metoclopramide (Reglan) may be used to reduce thesymptoms of gastroparesis pseudo-obstruction andgastric reflux Providers should be aware of the risk ofacute dystonic reactions with this medication Long-term use is not recommended because this drug cancause tardive dyskinesia

Cholestyramine and loperamide are other options inthe presence of mainly diarrhea and anticholinergicdrug such as hyoscyamine sulfate in the presence ofIBS Because anticholinergic drugs may be antiar-rhythmic see Cardiac section on management

Mexiletine may be considered for refractory diarrheaor constipation because the drug may be antiarrhyth-mic see Cardiac section on management

c If bacterial overgrowth is found on breath testingtreating with antibiotics may reduce diarrhea

Focus on CDM As mentioned in the neonatal care section children with

CDMmay require a temporary feeding tube If dysphagiapersists consider enteral nutrition Refer to speech therapyChildren should be periodically re-assessed for improvingdysphagia

Children with CDMoften benefit from dysphagia therapyWith aggressive dysphagia therapy children with CDMoften are able to feed orally within the first year of life

Neurodevelopmental managementRecommendations

c Neuropsychological testing should be performed inevery child with DM1 to delineate cognitive strengthsand weaknesses This may include the following Psychometric assessment of global intellectual abilityand adaptive functioning

Assessment of executive functions Assessment of social cognition Assessment of visuomotor integration and visuospatialability

Assessment of receptive and expressive language abilities Assessment of EDS Assessment of learning disabilities (specific tests fordyscalculia dyslexia and dyspraxia)

c The assessments should be performed in the congenitalform in preschool age and should be repeated depend-ing on the level of functioning 2ndash3 times beforeadulthood In childhood DM1 neuropsychologicaltesting is recommended at diagnosis and repeated inpreschool or school age and college period

c Patients with psychiatric or behavioral issues should bereferred to a mental health care professional forassessment of Autism Spectrum Disorders AttentionDeficit disorders with or without Hyperactivity alex-iythmia and other behavioral problems

c Psychostimulants may be beneficial if attention deficitsare associated with an impairing level of fatigue or EDS(see excessive daytime sleepiness) As psychostimulantsmay be proarrhythmic see Cardiac section on stimulantmanagementSerotonin-enhancing antidepressants if excessive anxietyor other treatable psychiatric symptoms are present

Specific cognitive remediation programs to enhance socialemotional abilities (visual contact joint attention emotionalregulation) or executive functions efficiency (inhibitorycontrol attention working memory and cognitive flexibil-ity) using dedicated software (eg Cogmedreg)

c Language remediation and reading therapy should beconsidered because of the presence of cognitive deficitseven in children with normal intelligence Attention deficit

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 447

fatigability and visualndashspatial construction dysfunctioncan result in specific learning disorders with impair-ment in reading and spelling as well as in mathematics

Psychosocial management Healthcare professionals have a responsibility to co-

ordinate specialist care and support services for childrenwith DM1 There is a need to be alert to the psychologicaland social dysfunctions and monitor home and educa-tional circumstances Liaison between agencies is essentialto ensure a consistent approach between health educationand social care agencies

Children with DM1 should have access to appropriatepsychological and therapy services at an early age to ensurethey are fulfilling their maximum potential and learningcoping strategies for later life The modification of activitiesincluding social engagement strategies would providea foundation for each child to grow in confidence and esteem

Family care and support is essential throughout child-hood with support and social care assistance whererequired Schools should be provided with specialistinformation about the care and management of a childwith DM1 A social work consult or a referral to nursingcase management can also be beneficial for patients Aholistic approach is critical because the affected parentmay also need additional assistance

Families should have access to disability benefitsadequate housing and adaptations during the progressionof the condition

Excessive daytime sleepiness Family members and educators should be educated about

the EDS that comes with DM1 Children should be screened for signs of EDS including

prolonged naps or falling asleep in school Possible sleep apnea should be evaluated with overnight

oximetry or polysomnogram Positive-pressure ventilation can be considered if a DM1

patientrsquos sleepiness is thought to be related to nocturnalor daytime hypoventilation or sleep apnea Patientsshould be referred to pulmonologists who have experi-ence in neuromuscular diseases for consideration ofassisted ventilation

Stimulant therapy with a psychostimulant such asmodafinil (Provigil) methylphenidate or other stimulantcan be considered if central hypersomnia is suspectedOften difficulty staying awake in school is a triggeringfactor Special care should be taken in children withpreviously detected cardiac arrhythmia (See Cardiacsection on stimulant management)

Endocrine and metabolismc DM1 male patients should undergo a detailed physical

examination in search of gonadal atrophy or cryptorchidismc Patients should have a HbA1c and thyroid-stimulating

hormone and Free T4 level measured at baseline andevery 3 years or if there is a clinical suspicion

c Adolescent patients should be screened as adult patients Gonadal insufficiency and complications of the

reproductive system Inquiring about amenorrheaor dysmenorrhea for the female patients and erectiledysfunction for male patients

Fasting blood lipids plasma glucose liver enzymesbilirubin levels and gamma-glutamyl transpeptidaseshould be measured at baseline

ConclusionsThe recommendations for care of congenital and childhood-onset myotonic dystrophy have been created by consensus ofclinicians experienced in their care management Given theabsence of rigorous studies in many of these areas theseguidelines were created by consensus They are designed tostandardize the care of children with a multisystemic disorderthat leads to significant morbidity and mortality

Study fundingMyotonic Dystrophy Foundation

DisclosureN Johnson serves on the scientific advisory boards ofCytokinetics AveXis AMO Pharma and Biogen Idec hasreceived funding for travel andor speaker honoraria fromStrongbridge serves as a consultant for AMO PharmaAveXis and Vertex Pharma and receives research supportfrom Ionis Pharmaceuticals Biogen Idec Valerion Thera-peutics Cytokinetics Acceleron AveXis AMO PharmaNIHNINDS FDA Muscular Dystrophy Association andMyotonic Dystrophy Foundation EZ Aldana and NAngeard report no disclosures T Ashizawa serves on sci-entific advisory boards for the Myotonic Dystrophy Foun-dation NIH and National Ataxia Foundation has receivedfunding for travel from Biohaven PacBio and NIHreceives research support from Myotonic DystrophyFoundation National Ataxia Foundation Biohaven Phar-maceuticals Biogen andNIHNINDS and is a professor atWeill Cornell Medical College adjunct professor at BaylorCollege of Medicine guest faculty at Central South Uni-versity China KN Berggren serves on the scientific advi-sory board of Biogen and receives funding for travel andorspeaker honoraria from HDSA and FSH Society C Marini-Bettolo has served on the scientific advisory boards ofAvexis and Biogen T Duong A-B Ekstrom V Sansone CTian and L Hellerstein report no disclosures C Campbellserves on the scientific advisory boards of Catabasis andPTC Therapeutics and receives research support fromValerion Pharmaceuticals PTC Therapeutics Pfizer IonisEli Lilly Prosensa Child Health Foundation and JessersquosJourney Foundation Full disclosure form informationprovided by the authors is available with the full text of thisarticle at Neurologyorgcp

Publication historyReceived byNeurology Clinical PracticeDecember 21 2018 Accepted infinal form March 4 2019

448 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

Appendix Authors

Name Location Role Contribution

Nicholas EJohnson MDMCSI

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscriptpublication of thedraft and revision

EugenioZapataAldana MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NathalieAngeard PhD

Inserm ampUniversity of ParisDescartes ParisFrance

Author Data acquisitiondrafting andrevision of themanuscript

TetsuoAshizawa MD

HoustonMethodistNeurologicalInstitute Texas

Author Data acquisitiondrafting andrevision of themanuscript

Kiera NBerggren MACCC-SLP MS

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscript

Chiara Marini-Bettolo MDPhD

Institute of GeneticMedicineNewcastleUniversity andNewcastle uponTyne HospitalsNHS FoundationTrust Newcastleupon Tyne UK

Author Data acquisitiondrafting andrevision of themanuscript

Appendix (continued)

Name Location Role Contribution

Tina DuongMPT PhD

StanfordUniversity CA

Author Data acquisitiondrafting andrevision of themanuscript

Anne-BeritEkstrom MDPhD

Queen SilviaChildrenrsquo sHospitalGothenburgSweden

Author Data acquisitiondrafting andrevision of themanuscript

ValeriaSansone MD

NEMO ClinicMilan Italy

Author Data acquisitiondrafting andrevision of themanuscript

Cuixia TianMD

CincinnatiChildrenrsquos HospitalMedical CenterCincinnati OH

Author Data acquisitiondrafting andrevision of themanuscript

LeahHellersteinLCSW MPH

MyotonicDystrophyFoundation SanFrancisco CA

CorrespondingAuthor

Obtaining fundingdrafting andreviewing themanuscript studyconcept anddesign

CraigCampbell MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 449

450 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 451

452 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 453

References1 Fu YH Pizzuti A Fenwick RG Jr et al An unstable triplet repeat in a gene related to

myotonic muscular dystrophy Science 19922551256ndash12582 Brook JD McCurrach ME Harley HG et al Molecular basis of myotonic dystrophy

expansion of a trinucleotide (CTG) repeat at the 3rsquo end of a transcript encodinga protein kinase family member Cell 199268799ndash808

3 Mahadevan M Tsilfidis C Sabourin L et al Myotonic dystrophy mutation an unstableCTG repeat in the 3rsquo untranslated region of the gene Science 19922551253ndash1255

4 Harper PS Myotonic Dystrophy 3rd ed London WB Saunders 20015 Bugiardini E Meola G DM-CNS Group Consensus on cerebral involvement in

myotonic dystrophy Neuromuscul Disord 201424445ndash4526 Koch MC Grimm T Harley HG Harper PS Genetic risks for children of women

with myotonic dystrophy Am J Hum Genet 1991481084ndash10917 Gagnon C Heatwole C Hebert LJ et al Report of the third outcome measures in

myotonic dystrophy type 1 (OMMYD-3) international workshop Paris France June8 2015 J Neuromuscul Dis 20185523ndash537

8 Johnson NE Hung M Nasser E et al The impact of pregnancy on myotonic dys-trophy a registry-based study J Neuromuscul Dis 20152447ndash452

9 Campbell C Levin S Siu VM et al Congenital myotonic dystrophy Canadianpopulation-based surveillance study J Pediatr 2013163120ndash123

10 Campbell C Sherlock R Jacob P Blayney M Congenital myotonic dystrophyassisted ventilation duration and outcome Pediatrics 2004113811ndash816

11 Angeard N Gargiulo M Jacquette A et al Cognitive profile in childhood myotonicdystrophy type 1 is there a global impairment Neuromuscul Disord 200717451ndash458

12 Ekstrom AB Hakenas-Plate L Tulinius M Wentz E Cognition and adaptive skills inmyotonic dystrophy type 1 a study of 55 individuals with congenital and childhoodforms Dev Med Child Neurol 200951982ndash990

13 Kroksmark AK Ekstrom AB Bjorck E Tulinius M Myotonic dystrophy muscleinvolvement in relation to disease type and size of expanded CTG-repeat sequenceDev Med Child Neurol 200547478ndash485

14 Johnson NE Ekstrom AB Campbell C et al Parent-reported multi-national study ofthe impact of congenital and childhood onset myotonic dystrophy Dev Med ChildNeurol 201658698ndash705

15 Yao X Yang YS Cui LH et al Subtypes of irritable bowel syndrome on Rome IIIcriteria a multicenter study J Gastroenterol Hepatol 201227760ndash765

Share Your Insights Expertise and Experiencesbull How are you employing drugs and devices in your field

bull What ethical challenges do you face

bull Do you have a case report that is illustrative of a clinical challenge

bull What challenges have you faced or successes have you enjoyed in bringing greater efficiency to your practice

Deliver a high-quality peer-reviewed message to your colleagues in practice submit your paper at NPuborgNCPsubmit

454 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

DOI 101212CPJ000000000000064620199443-454 Published Online before print April 24 2019Neurol Clin Pract

Nicholas E Johnson Eugenio Zapata Aldana Nathalie Angeard et al dystrophy type 1

Consensus-based care recommendations for congenital and childhood-onset myotonic

This information is current as of April 24 2019

ServicesUpdated Information amp

httpcpneurologyorgcontent95443fullhtmlincluding high resolution figures can be found at

References httpcpneurologyorgcontent95443fullhtmlref-list-1

This article cites 14 articles 3 of which you can access for free at

Citations httpcpneurologyorgcontent95443fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpcpneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpcpneurologyorgcgicollectionall_pediatricAll Pediatric

httpcpneurologyorgcgicollectionall_neuromuscular_diseaseAll Neuromuscular Diseasefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

18 years of age is typically referred to as childhood-onset myo-tonic dystrophy (ChDM) However alternate definitions des-ignate further cut points depending on age of onset67 Althoughthe exact global prevalence is unknown children with CDMlikely represent 10ndash30 of the overall DM1 population48

These disorders cause significant morbidity and mortalityChildren with CDM often require intensive intervention atbirth because of hypotonia respiratory failure and feedingdifficulties49 For children with CDM ventilated longer than3 months there is a 30 mortality in the first year of life10

Both children with CDM and ChDM may have symptomsassociated with attention deficit hyperactivity disorder or autismspectrum disorder (sometimes referred to as social communi-cation disorder) during childhood1112 They also have signifi-cant motor delays13 and may have intractable irritable bowelsymptoms including incontinence Previous research suggeststhat 88 of individuals with congenital or childhood-onsetmyotonic dystrophy are unemployed over the age of 18 years14

Themultisystemicnaturemorbidity andmortality associatedwithcongenital and childhood-onset myotonic dystrophy necessitatethe development of care recommendations to standardize careThese consensus-based recommendations will also set the foun-dation for innovative clinical initiatives where gaps exist and alsofurther research to improve aspects of management These carerecommendations may also better prepare the pediatric DM1community for future clinical trials because variation in clinical caremay have significant effects on the outcome of children partici-pating in geographically dispersed clinical research sites

MethodsParticipant recruitmentThe Myotonic Dystrophy Foundation recruited cliniciansfrom the United States Canada and Europe who have ex-perience in the treatment of children with DM1 to developconsensus-based recommendations

Consensus approachAs previously described the Myotonic Dystrophy Founda-tion developed a two-phase consensus buildingmethodologyusing components of the single text procedure and nominalgroup technique15 This approach was chosen given both thesparsity of literature surrounding many of the clinical aspectsand the extensive experience of the clinicians in this area

Three of the authors (NEJ CC and EZ) created theinitial draft document drawing from the existing literatureand clinical practice that served as an initial text for the rec-ommendation developments

After creation of the single text stakeholders were engagedto refine the recommendations through a consensus-basedapproach The experts were initially assigned to specific areas ofrecommendations where they refined the recommendations Afacilitator (LH) then lead a series of meetings to review reviseand finalize the recommendations with the entire author panel

These efforts led to the final consensus-based care recom-mendations along with a quick reference guide The care rec-ommendations are divided into 2 main sections the GeneralCare Considerations and Systems-based Approach to Manage-ment Because there are differences between childhood-onsetand congenital-onset DM1 recommendations specific to CDMare separated throughout the document The Quick ReferenceGuide is provided as an appendix and the full document isavailable online (appendix e-1 linkslwwcomCPJA89) Bothfeature flowcharts and other infographics for ease of use

ResultsSee full recommendations at Neurologyorgcp

General care considerationsDiagnosis and classification

c The diagnosis of DM1 should be suspected in any childwith a family history of DM1 andor presenting withone or more of the following features Eyelid ptosis andor oral motor weakness Distal weakness primarily of the finger and wrist flexorswithout contractures or weakness of the neck flexors

Myotonia or ldquostiffnessrdquo of muscles Autistic features or social communication difficulties Attention deficit disorder anxiety and other behav-ioral problems

Developmental delay andor Intellectual disability

The age of onset of DM1 is variable

and intergenerational repeat

expansion (known as anticipation)

may result in symptom onset during

childhood

The multisystemic nature morbidity

and mortality associated with

congenital and childhood-onset

myotonic dystrophy necessitate the

development of care

recommendations to standardize and

improve the care of this population

444 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

Learning disabilities (eg dyslexia dyscalculia) Excessive daytime sleepiness (EDS) Gastrointestinal issues constipation or diarrhea Scoliosis Arrhythmia Prolonged recovery or respiratory arrest after anesthesia Neonatal features of hypotonia weakness club footrespiratory distress or feeding problems

c The classification of congenital and childhood-onsetDM1 is provided in table 1 in Quick Reference GuideNote that diagnosis may be made retrospectively afterreviewing symptom onset Fetal tissue with long CTGrepeats should not be called CDMbecause this diagnosisis reserved for newborns In these cases we wouldsuggest use of fetal DM1 as more appropriate

c Genetic counseling is recommended for patientsexhibiting clinical signs indicative of DM1 or have at-risk family members to enable them to make aninformed decision about whether to proceed to genetictesting Individuals with 37ndash49 CTG repeats aredeemed very unlikely to develop detectable DM1symptoms However such ldquopremutationsrdquo can expandinto the disease range in subsequent generationsparticularly when transmitted by women Individualsthus identified should be offered genetic counseling(see Genetic counseling) to discuss their risk fortransmitting DM1

Genetic counselingc Referral to genetic counseling (see nsgcorg) is recom-

mended for all patients with congenital and childhood-onset DM1 and their parents and to assess the parents forthe diagnosis of DM1

c Genetic counseling in affected families should conveyinformation about The inheritance pattern of disease (autosomal

dominant inheritance) The wide variability in the scope and severity of DM1

symptoms even within the same family The possibility of changes in symptom scope and

severity over time The likelihood that the mutation will expand and the

disease will become more severe as it is passed fromgeneration to generation (anticipation)

Particular attention to the possibility of a minimallyaffected mother giving birth to a severely affected child

Options for family planningc Do not use CTG repeat numbers if available for genetic

advice or prognostication these need to be discussedwith a genetic counselor Specifically repeat size may bean indicator of severity but it does not provide anyinformation about the prognosis

Focus on CDMc Once a family has had a child with CDM there is an

increased risk that the next affected child with DM1 islikely to have congenital form as well

Neonatal care A high-risk obstetrician should provide prenatal obstetric

care for mothers known or suspected to carry a child withDM1

Pediatric or neonatal specialist should be present atdelivery if a mother is known to have DM1 or if the childis known or suspected to have DM1

Focus on CDM Children with CDM will often need management in

a neonatal intensive care unit with the capability to dealwith breathing and feeding support This team requiresa range of neonatal and consulting specialists who canmanage the genetic respiratory gastrointestinal or-thopedic neuromuscular neurosurgical and cardiacissues See figure 1 in Quick Reference Guide forneonatal care

End of life counseling and management Recommend the introduction of palliative care at the

time of diagnosis and at regular intervals thereafter Whena formal pediatric palliative care team is available theyshould be consulted

Recognize and address caregiver burden whether thecaregiver has DM1 offering respite care or equivalentmeasures to patient to improve family support Addressnormal grief on the part of the patient and family andoffer counseling as appropriate

Establish an emergency health care plan and advancedirectives with the family

Focus on CDM Introduce the concept that the natural history of the

disease includes progressive improvement of strength forthe first decade of life however the complications ofCDM can be critical and have a high risk of mortalityparticularly in the first year of life

Advise families or caregivers that invasive and non-invasive ventilation (NIV) and nutrition through gastro-stomy tube are acceptable parts of care for patients withCDM

Surgery and anesthesia Inform all caregivers that anyone administering an

anesthetic should be aware of the DM1 diagnosis When possible combine procedures under a single

sedation Arrange for a preanesthetic visit for all children planning

to have deep sedation for a diagnostic test procedureor surgery If possible include a pulmonologist withexpertise in neuromuscular diseases during this visit

Even if the patient has mild DM1 monitoring for a longerperiod of time than is typical following anesthesia orsurgery will allow for identifying serious adverse events inthe hospital setting

Providers are encouraged to review the MyotonicDystrophy Foundation Practical Suggestions for the

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 445

Anesthetic Management of a Myotonic Dystrophy Patient(myotonicorgsitesdefaultfilesMDF_LongForm_AnesGuidelines_01Cpdf) for anesthesia risks andrecommendations before any surgeries or proceduresrequiring anesthesia and the Anesthesia Quick ReferenceGuide (myotonicorgsitesdefaultfilesMDF Anes-thesia Guidelines FNL 2016 2 2 pdf) These docu-ments should be reviewed before treatment decisions

Focus on CDM It is worth noting that children with CDM are at a higher

risk of anesthetic complications given the underlyingrespiratory involvement as opposed to those withchildhood-onset myotonic dystrophy

Systems-based approachto managementRespiratory Signs of respiratory problems in children with myotonic

dystrophy include ineffective cough recurrent pulmo-nary infections orthopnea dyspnea poor sleep morningheadaches apnea fatigue and snoring

See figure 2 in Quick Reference Guide for a flowchart oftesting and treatment options in congenital andchildhood-onset myotonic dystrophy

Focus on CDM For CDM children who remain on longer term trach

ventilation there is often improvement in respiratorystrength over time and consideration to decannulatea tracheostomy should be made after careful considerationwith the multidisciplinary team including neurologyrespirology ear nose and throat and the familyConsideration of airway control respiratory infectionfrequency ability to tolerate a facial or nasal mask for NIVand compliance and cooperation with maintenancepulmonary therapy such as cough assist breathe stakingetc Testing for hypoventilation in sleep should be donebefore decannulation

Cardiovascularc Inform families of the risks of arrhythmias and cardiac

dysfunction and the importance of prompt medicalattention if symptoms are observed (ie palpitationspresyncope syncope dyspnea chest pain unexplainedfatigue) A 12-lead ECG should be performed at DM1 diagnosisand if normal and the patient remains asymptomatic ECGshould be performed annually and warrants moreinvestigation if the patient is symptomatic

If the ECG is normal and clinical suspicion is high a24-hour Holter monitor may be considered asa second-line investigation

Because specific medications such as mexiletine andpsychostimulants are antiarrhythmic an ECG before

use again within 3 months of starting therapy andthen at serial intervals is recommended

Consider in-hospital cardiac monitoring to detectarrhythmias if admitted for longer duration thantypical after surgical procedures or if admitted due tosevere illness or infection

c For young DM1 patients serial exercise stress testingand signal-averaged ECGs may be considered

c Evaluate and treat using American Heart Association(AHA) Management of Cardiac Involvement AssociatedWith Neuromuscular Diseases A Scientific Statement Fromthe American Heart Association 2017 circahajournalsorgcontent13613e200long and ACC ([AmericanCollege of Cardiology]AHA)ESC (European Societyof Cardiology) Guidelines for Management of Patientswith Ventricular Arrhythmias and the Prevention of SuddenCardiac Death (see ncbinlmnihgovpubmed16949478)- section on pediatric issues 134

Skeletal muscle weakness orthopediccomplications and rehabilitation

c Children should be evaluated early and often forphysical occupational and speech therapy needs withspecific attention to Feeding concerns and dysphagia Gross motor delay Gross and fine motor weakness Dysarthria and potential augmentative and alternativecommunication needs

Language acquisition delaysc The spine should be assessed for scoliosis and if

necessary consider bracing or referral to orthopedicsurgeon

c Children should be encouraged to participate in speechtherapy targeting speech language and communicationfrom a very early age

Focus on CDM Newborns with CDM often having difficulty feeding and

alternative nutrition should be considered After abouta year of actively working with a speech therapist oroccupational therapist most children can generally starton oral feeding

Children with CDM experience progressive improve-ment in their proximal strength until adolescence ata minimum Therefore children should be encouraged toparticipate in physical activities

Prevention of joint contractures are key to managementand should be closely monitored with early initiation ofstretching Treatment of talipes equinovarus and otherjoint contractures should include initial stretchingregimen and appropriate ankle bracing (for talipesequinovarus) Serial casting may be considered

Skeletal muscle myotoniac Delayed relaxation after grip or percussion difficulty

related to activities of daily life progressive speech

446 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

impairment or profound irritable bowel symptoms aresigns often related to myotonia

c Mexiletine (Mexitil) is an option for myotonia if it isdemonstrated and is distressing to the patient Mexiletinemay not be approved for use in every country In these casesother sodium channel antagonists may be considered Because mexiletine is an antiarrhythmic an ECG

before use again within 3 months of starting therapyand then at serial intervals is recommended

Instruct the patient to avoid dyspepsia and transientldquodizzy feelingsrdquo associated with mexiletine treatmentby taking it with food to extend absorption and lowerpeak level in blood

Ocular and hearing management Baseline audiometry should be performed especially at

school age Ophthalmologic assessment should be performed at

diagnosis and at least yearly to evaluate for hyperopiastigmatism strabismus and visual acuity to preventevolution of visual impairment

Eyelid ptosis if ptosis becomes severe and interferes withvision intervention such as eyelid ldquocrutchesrdquo that can beinserted into glasses may be warranted Try crutches asa remedy for ptosis before eyelid surgery is consideredbecause of anesthesia risks Ophthalmic lubricants for dryeye may be considered

Gastrointestinal andgenitourinary management

c Presence of gastrointestinal symptoms such as abdom-inal pain constipation fecal incontinence or diarrheamay be a frequent problem The symptoms may mimicirritable bowel syndrome (IBS)15 Fiber supplementa-tion (more than 8 g daily) is the first-line treatment

c Gentle laxatives (see below) for constipation Oilsshould be avoided as they will lead to diarrhea Ifa patient does not respond to the first- or second-linerecommendations below a referral to a gastrointestinalspecialist for anal manometry should be considered First-line therapy recommendations polyethylene

glycol (Miralax) senna (Ex-Lax Senokot) docusate(Colace) or lactulose (Cholac)

Second-line therapy recommendations bisacodyl(Dulcolax Correctol) lubiprostone (Amitiza) orlinaclotide (Linzess)

Metoclopramide (Reglan) may be used to reduce thesymptoms of gastroparesis pseudo-obstruction andgastric reflux Providers should be aware of the risk ofacute dystonic reactions with this medication Long-term use is not recommended because this drug cancause tardive dyskinesia

Cholestyramine and loperamide are other options inthe presence of mainly diarrhea and anticholinergicdrug such as hyoscyamine sulfate in the presence ofIBS Because anticholinergic drugs may be antiar-rhythmic see Cardiac section on management

Mexiletine may be considered for refractory diarrheaor constipation because the drug may be antiarrhyth-mic see Cardiac section on management

c If bacterial overgrowth is found on breath testingtreating with antibiotics may reduce diarrhea

Focus on CDM As mentioned in the neonatal care section children with

CDMmay require a temporary feeding tube If dysphagiapersists consider enteral nutrition Refer to speech therapyChildren should be periodically re-assessed for improvingdysphagia

Children with CDMoften benefit from dysphagia therapyWith aggressive dysphagia therapy children with CDMoften are able to feed orally within the first year of life

Neurodevelopmental managementRecommendations

c Neuropsychological testing should be performed inevery child with DM1 to delineate cognitive strengthsand weaknesses This may include the following Psychometric assessment of global intellectual abilityand adaptive functioning

Assessment of executive functions Assessment of social cognition Assessment of visuomotor integration and visuospatialability

Assessment of receptive and expressive language abilities Assessment of EDS Assessment of learning disabilities (specific tests fordyscalculia dyslexia and dyspraxia)

c The assessments should be performed in the congenitalform in preschool age and should be repeated depend-ing on the level of functioning 2ndash3 times beforeadulthood In childhood DM1 neuropsychologicaltesting is recommended at diagnosis and repeated inpreschool or school age and college period

c Patients with psychiatric or behavioral issues should bereferred to a mental health care professional forassessment of Autism Spectrum Disorders AttentionDeficit disorders with or without Hyperactivity alex-iythmia and other behavioral problems

c Psychostimulants may be beneficial if attention deficitsare associated with an impairing level of fatigue or EDS(see excessive daytime sleepiness) As psychostimulantsmay be proarrhythmic see Cardiac section on stimulantmanagementSerotonin-enhancing antidepressants if excessive anxietyor other treatable psychiatric symptoms are present

Specific cognitive remediation programs to enhance socialemotional abilities (visual contact joint attention emotionalregulation) or executive functions efficiency (inhibitorycontrol attention working memory and cognitive flexibil-ity) using dedicated software (eg Cogmedreg)

c Language remediation and reading therapy should beconsidered because of the presence of cognitive deficitseven in children with normal intelligence Attention deficit

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 447

fatigability and visualndashspatial construction dysfunctioncan result in specific learning disorders with impair-ment in reading and spelling as well as in mathematics

Psychosocial management Healthcare professionals have a responsibility to co-

ordinate specialist care and support services for childrenwith DM1 There is a need to be alert to the psychologicaland social dysfunctions and monitor home and educa-tional circumstances Liaison between agencies is essentialto ensure a consistent approach between health educationand social care agencies

Children with DM1 should have access to appropriatepsychological and therapy services at an early age to ensurethey are fulfilling their maximum potential and learningcoping strategies for later life The modification of activitiesincluding social engagement strategies would providea foundation for each child to grow in confidence and esteem

Family care and support is essential throughout child-hood with support and social care assistance whererequired Schools should be provided with specialistinformation about the care and management of a childwith DM1 A social work consult or a referral to nursingcase management can also be beneficial for patients Aholistic approach is critical because the affected parentmay also need additional assistance

Families should have access to disability benefitsadequate housing and adaptations during the progressionof the condition

Excessive daytime sleepiness Family members and educators should be educated about

the EDS that comes with DM1 Children should be screened for signs of EDS including

prolonged naps or falling asleep in school Possible sleep apnea should be evaluated with overnight

oximetry or polysomnogram Positive-pressure ventilation can be considered if a DM1

patientrsquos sleepiness is thought to be related to nocturnalor daytime hypoventilation or sleep apnea Patientsshould be referred to pulmonologists who have experi-ence in neuromuscular diseases for consideration ofassisted ventilation

Stimulant therapy with a psychostimulant such asmodafinil (Provigil) methylphenidate or other stimulantcan be considered if central hypersomnia is suspectedOften difficulty staying awake in school is a triggeringfactor Special care should be taken in children withpreviously detected cardiac arrhythmia (See Cardiacsection on stimulant management)

Endocrine and metabolismc DM1 male patients should undergo a detailed physical

examination in search of gonadal atrophy or cryptorchidismc Patients should have a HbA1c and thyroid-stimulating

hormone and Free T4 level measured at baseline andevery 3 years or if there is a clinical suspicion

c Adolescent patients should be screened as adult patients Gonadal insufficiency and complications of the

reproductive system Inquiring about amenorrheaor dysmenorrhea for the female patients and erectiledysfunction for male patients

Fasting blood lipids plasma glucose liver enzymesbilirubin levels and gamma-glutamyl transpeptidaseshould be measured at baseline

ConclusionsThe recommendations for care of congenital and childhood-onset myotonic dystrophy have been created by consensus ofclinicians experienced in their care management Given theabsence of rigorous studies in many of these areas theseguidelines were created by consensus They are designed tostandardize the care of children with a multisystemic disorderthat leads to significant morbidity and mortality

Study fundingMyotonic Dystrophy Foundation

DisclosureN Johnson serves on the scientific advisory boards ofCytokinetics AveXis AMO Pharma and Biogen Idec hasreceived funding for travel andor speaker honoraria fromStrongbridge serves as a consultant for AMO PharmaAveXis and Vertex Pharma and receives research supportfrom Ionis Pharmaceuticals Biogen Idec Valerion Thera-peutics Cytokinetics Acceleron AveXis AMO PharmaNIHNINDS FDA Muscular Dystrophy Association andMyotonic Dystrophy Foundation EZ Aldana and NAngeard report no disclosures T Ashizawa serves on sci-entific advisory boards for the Myotonic Dystrophy Foun-dation NIH and National Ataxia Foundation has receivedfunding for travel from Biohaven PacBio and NIHreceives research support from Myotonic DystrophyFoundation National Ataxia Foundation Biohaven Phar-maceuticals Biogen andNIHNINDS and is a professor atWeill Cornell Medical College adjunct professor at BaylorCollege of Medicine guest faculty at Central South Uni-versity China KN Berggren serves on the scientific advi-sory board of Biogen and receives funding for travel andorspeaker honoraria from HDSA and FSH Society C Marini-Bettolo has served on the scientific advisory boards ofAvexis and Biogen T Duong A-B Ekstrom V Sansone CTian and L Hellerstein report no disclosures C Campbellserves on the scientific advisory boards of Catabasis andPTC Therapeutics and receives research support fromValerion Pharmaceuticals PTC Therapeutics Pfizer IonisEli Lilly Prosensa Child Health Foundation and JessersquosJourney Foundation Full disclosure form informationprovided by the authors is available with the full text of thisarticle at Neurologyorgcp

Publication historyReceived byNeurology Clinical PracticeDecember 21 2018 Accepted infinal form March 4 2019

448 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

Appendix Authors

Name Location Role Contribution

Nicholas EJohnson MDMCSI

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscriptpublication of thedraft and revision

EugenioZapataAldana MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NathalieAngeard PhD

Inserm ampUniversity of ParisDescartes ParisFrance

Author Data acquisitiondrafting andrevision of themanuscript

TetsuoAshizawa MD

HoustonMethodistNeurologicalInstitute Texas

Author Data acquisitiondrafting andrevision of themanuscript

Kiera NBerggren MACCC-SLP MS

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscript

Chiara Marini-Bettolo MDPhD

Institute of GeneticMedicineNewcastleUniversity andNewcastle uponTyne HospitalsNHS FoundationTrust Newcastleupon Tyne UK

Author Data acquisitiondrafting andrevision of themanuscript

Appendix (continued)

Name Location Role Contribution

Tina DuongMPT PhD

StanfordUniversity CA

Author Data acquisitiondrafting andrevision of themanuscript

Anne-BeritEkstrom MDPhD

Queen SilviaChildrenrsquo sHospitalGothenburgSweden

Author Data acquisitiondrafting andrevision of themanuscript

ValeriaSansone MD

NEMO ClinicMilan Italy

Author Data acquisitiondrafting andrevision of themanuscript

Cuixia TianMD

CincinnatiChildrenrsquos HospitalMedical CenterCincinnati OH

Author Data acquisitiondrafting andrevision of themanuscript

LeahHellersteinLCSW MPH

MyotonicDystrophyFoundation SanFrancisco CA

CorrespondingAuthor

Obtaining fundingdrafting andreviewing themanuscript studyconcept anddesign

CraigCampbell MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 449

450 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 451

452 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 453

References1 Fu YH Pizzuti A Fenwick RG Jr et al An unstable triplet repeat in a gene related to

myotonic muscular dystrophy Science 19922551256ndash12582 Brook JD McCurrach ME Harley HG et al Molecular basis of myotonic dystrophy

expansion of a trinucleotide (CTG) repeat at the 3rsquo end of a transcript encodinga protein kinase family member Cell 199268799ndash808

3 Mahadevan M Tsilfidis C Sabourin L et al Myotonic dystrophy mutation an unstableCTG repeat in the 3rsquo untranslated region of the gene Science 19922551253ndash1255

4 Harper PS Myotonic Dystrophy 3rd ed London WB Saunders 20015 Bugiardini E Meola G DM-CNS Group Consensus on cerebral involvement in

myotonic dystrophy Neuromuscul Disord 201424445ndash4526 Koch MC Grimm T Harley HG Harper PS Genetic risks for children of women

with myotonic dystrophy Am J Hum Genet 1991481084ndash10917 Gagnon C Heatwole C Hebert LJ et al Report of the third outcome measures in

myotonic dystrophy type 1 (OMMYD-3) international workshop Paris France June8 2015 J Neuromuscul Dis 20185523ndash537

8 Johnson NE Hung M Nasser E et al The impact of pregnancy on myotonic dys-trophy a registry-based study J Neuromuscul Dis 20152447ndash452

9 Campbell C Levin S Siu VM et al Congenital myotonic dystrophy Canadianpopulation-based surveillance study J Pediatr 2013163120ndash123

10 Campbell C Sherlock R Jacob P Blayney M Congenital myotonic dystrophyassisted ventilation duration and outcome Pediatrics 2004113811ndash816

11 Angeard N Gargiulo M Jacquette A et al Cognitive profile in childhood myotonicdystrophy type 1 is there a global impairment Neuromuscul Disord 200717451ndash458

12 Ekstrom AB Hakenas-Plate L Tulinius M Wentz E Cognition and adaptive skills inmyotonic dystrophy type 1 a study of 55 individuals with congenital and childhoodforms Dev Med Child Neurol 200951982ndash990

13 Kroksmark AK Ekstrom AB Bjorck E Tulinius M Myotonic dystrophy muscleinvolvement in relation to disease type and size of expanded CTG-repeat sequenceDev Med Child Neurol 200547478ndash485

14 Johnson NE Ekstrom AB Campbell C et al Parent-reported multi-national study ofthe impact of congenital and childhood onset myotonic dystrophy Dev Med ChildNeurol 201658698ndash705

15 Yao X Yang YS Cui LH et al Subtypes of irritable bowel syndrome on Rome IIIcriteria a multicenter study J Gastroenterol Hepatol 201227760ndash765

Share Your Insights Expertise and Experiencesbull How are you employing drugs and devices in your field

bull What ethical challenges do you face

bull Do you have a case report that is illustrative of a clinical challenge

bull What challenges have you faced or successes have you enjoyed in bringing greater efficiency to your practice

Deliver a high-quality peer-reviewed message to your colleagues in practice submit your paper at NPuborgNCPsubmit

454 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

DOI 101212CPJ000000000000064620199443-454 Published Online before print April 24 2019Neurol Clin Pract

Nicholas E Johnson Eugenio Zapata Aldana Nathalie Angeard et al dystrophy type 1

Consensus-based care recommendations for congenital and childhood-onset myotonic

This information is current as of April 24 2019

ServicesUpdated Information amp

httpcpneurologyorgcontent95443fullhtmlincluding high resolution figures can be found at

References httpcpneurologyorgcontent95443fullhtmlref-list-1

This article cites 14 articles 3 of which you can access for free at

Citations httpcpneurologyorgcontent95443fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpcpneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpcpneurologyorgcgicollectionall_pediatricAll Pediatric

httpcpneurologyorgcgicollectionall_neuromuscular_diseaseAll Neuromuscular Diseasefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

Learning disabilities (eg dyslexia dyscalculia) Excessive daytime sleepiness (EDS) Gastrointestinal issues constipation or diarrhea Scoliosis Arrhythmia Prolonged recovery or respiratory arrest after anesthesia Neonatal features of hypotonia weakness club footrespiratory distress or feeding problems

c The classification of congenital and childhood-onsetDM1 is provided in table 1 in Quick Reference GuideNote that diagnosis may be made retrospectively afterreviewing symptom onset Fetal tissue with long CTGrepeats should not be called CDMbecause this diagnosisis reserved for newborns In these cases we wouldsuggest use of fetal DM1 as more appropriate

c Genetic counseling is recommended for patientsexhibiting clinical signs indicative of DM1 or have at-risk family members to enable them to make aninformed decision about whether to proceed to genetictesting Individuals with 37ndash49 CTG repeats aredeemed very unlikely to develop detectable DM1symptoms However such ldquopremutationsrdquo can expandinto the disease range in subsequent generationsparticularly when transmitted by women Individualsthus identified should be offered genetic counseling(see Genetic counseling) to discuss their risk fortransmitting DM1

Genetic counselingc Referral to genetic counseling (see nsgcorg) is recom-

mended for all patients with congenital and childhood-onset DM1 and their parents and to assess the parents forthe diagnosis of DM1

c Genetic counseling in affected families should conveyinformation about The inheritance pattern of disease (autosomal

dominant inheritance) The wide variability in the scope and severity of DM1

symptoms even within the same family The possibility of changes in symptom scope and

severity over time The likelihood that the mutation will expand and the

disease will become more severe as it is passed fromgeneration to generation (anticipation)

Particular attention to the possibility of a minimallyaffected mother giving birth to a severely affected child

Options for family planningc Do not use CTG repeat numbers if available for genetic

advice or prognostication these need to be discussedwith a genetic counselor Specifically repeat size may bean indicator of severity but it does not provide anyinformation about the prognosis

Focus on CDMc Once a family has had a child with CDM there is an

increased risk that the next affected child with DM1 islikely to have congenital form as well

Neonatal care A high-risk obstetrician should provide prenatal obstetric

care for mothers known or suspected to carry a child withDM1

Pediatric or neonatal specialist should be present atdelivery if a mother is known to have DM1 or if the childis known or suspected to have DM1

Focus on CDM Children with CDM will often need management in

a neonatal intensive care unit with the capability to dealwith breathing and feeding support This team requiresa range of neonatal and consulting specialists who canmanage the genetic respiratory gastrointestinal or-thopedic neuromuscular neurosurgical and cardiacissues See figure 1 in Quick Reference Guide forneonatal care

End of life counseling and management Recommend the introduction of palliative care at the

time of diagnosis and at regular intervals thereafter Whena formal pediatric palliative care team is available theyshould be consulted

Recognize and address caregiver burden whether thecaregiver has DM1 offering respite care or equivalentmeasures to patient to improve family support Addressnormal grief on the part of the patient and family andoffer counseling as appropriate

Establish an emergency health care plan and advancedirectives with the family

Focus on CDM Introduce the concept that the natural history of the

disease includes progressive improvement of strength forthe first decade of life however the complications ofCDM can be critical and have a high risk of mortalityparticularly in the first year of life

Advise families or caregivers that invasive and non-invasive ventilation (NIV) and nutrition through gastro-stomy tube are acceptable parts of care for patients withCDM

Surgery and anesthesia Inform all caregivers that anyone administering an

anesthetic should be aware of the DM1 diagnosis When possible combine procedures under a single

sedation Arrange for a preanesthetic visit for all children planning

to have deep sedation for a diagnostic test procedureor surgery If possible include a pulmonologist withexpertise in neuromuscular diseases during this visit

Even if the patient has mild DM1 monitoring for a longerperiod of time than is typical following anesthesia orsurgery will allow for identifying serious adverse events inthe hospital setting

Providers are encouraged to review the MyotonicDystrophy Foundation Practical Suggestions for the

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 445

Anesthetic Management of a Myotonic Dystrophy Patient(myotonicorgsitesdefaultfilesMDF_LongForm_AnesGuidelines_01Cpdf) for anesthesia risks andrecommendations before any surgeries or proceduresrequiring anesthesia and the Anesthesia Quick ReferenceGuide (myotonicorgsitesdefaultfilesMDF Anes-thesia Guidelines FNL 2016 2 2 pdf) These docu-ments should be reviewed before treatment decisions

Focus on CDM It is worth noting that children with CDM are at a higher

risk of anesthetic complications given the underlyingrespiratory involvement as opposed to those withchildhood-onset myotonic dystrophy

Systems-based approachto managementRespiratory Signs of respiratory problems in children with myotonic

dystrophy include ineffective cough recurrent pulmo-nary infections orthopnea dyspnea poor sleep morningheadaches apnea fatigue and snoring

See figure 2 in Quick Reference Guide for a flowchart oftesting and treatment options in congenital andchildhood-onset myotonic dystrophy

Focus on CDM For CDM children who remain on longer term trach

ventilation there is often improvement in respiratorystrength over time and consideration to decannulatea tracheostomy should be made after careful considerationwith the multidisciplinary team including neurologyrespirology ear nose and throat and the familyConsideration of airway control respiratory infectionfrequency ability to tolerate a facial or nasal mask for NIVand compliance and cooperation with maintenancepulmonary therapy such as cough assist breathe stakingetc Testing for hypoventilation in sleep should be donebefore decannulation

Cardiovascularc Inform families of the risks of arrhythmias and cardiac

dysfunction and the importance of prompt medicalattention if symptoms are observed (ie palpitationspresyncope syncope dyspnea chest pain unexplainedfatigue) A 12-lead ECG should be performed at DM1 diagnosisand if normal and the patient remains asymptomatic ECGshould be performed annually and warrants moreinvestigation if the patient is symptomatic

If the ECG is normal and clinical suspicion is high a24-hour Holter monitor may be considered asa second-line investigation

Because specific medications such as mexiletine andpsychostimulants are antiarrhythmic an ECG before

use again within 3 months of starting therapy andthen at serial intervals is recommended

Consider in-hospital cardiac monitoring to detectarrhythmias if admitted for longer duration thantypical after surgical procedures or if admitted due tosevere illness or infection

c For young DM1 patients serial exercise stress testingand signal-averaged ECGs may be considered

c Evaluate and treat using American Heart Association(AHA) Management of Cardiac Involvement AssociatedWith Neuromuscular Diseases A Scientific Statement Fromthe American Heart Association 2017 circahajournalsorgcontent13613e200long and ACC ([AmericanCollege of Cardiology]AHA)ESC (European Societyof Cardiology) Guidelines for Management of Patientswith Ventricular Arrhythmias and the Prevention of SuddenCardiac Death (see ncbinlmnihgovpubmed16949478)- section on pediatric issues 134

Skeletal muscle weakness orthopediccomplications and rehabilitation

c Children should be evaluated early and often forphysical occupational and speech therapy needs withspecific attention to Feeding concerns and dysphagia Gross motor delay Gross and fine motor weakness Dysarthria and potential augmentative and alternativecommunication needs

Language acquisition delaysc The spine should be assessed for scoliosis and if

necessary consider bracing or referral to orthopedicsurgeon

c Children should be encouraged to participate in speechtherapy targeting speech language and communicationfrom a very early age

Focus on CDM Newborns with CDM often having difficulty feeding and

alternative nutrition should be considered After abouta year of actively working with a speech therapist oroccupational therapist most children can generally starton oral feeding

Children with CDM experience progressive improve-ment in their proximal strength until adolescence ata minimum Therefore children should be encouraged toparticipate in physical activities

Prevention of joint contractures are key to managementand should be closely monitored with early initiation ofstretching Treatment of talipes equinovarus and otherjoint contractures should include initial stretchingregimen and appropriate ankle bracing (for talipesequinovarus) Serial casting may be considered

Skeletal muscle myotoniac Delayed relaxation after grip or percussion difficulty

related to activities of daily life progressive speech

446 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

impairment or profound irritable bowel symptoms aresigns often related to myotonia

c Mexiletine (Mexitil) is an option for myotonia if it isdemonstrated and is distressing to the patient Mexiletinemay not be approved for use in every country In these casesother sodium channel antagonists may be considered Because mexiletine is an antiarrhythmic an ECG

before use again within 3 months of starting therapyand then at serial intervals is recommended

Instruct the patient to avoid dyspepsia and transientldquodizzy feelingsrdquo associated with mexiletine treatmentby taking it with food to extend absorption and lowerpeak level in blood

Ocular and hearing management Baseline audiometry should be performed especially at

school age Ophthalmologic assessment should be performed at

diagnosis and at least yearly to evaluate for hyperopiastigmatism strabismus and visual acuity to preventevolution of visual impairment

Eyelid ptosis if ptosis becomes severe and interferes withvision intervention such as eyelid ldquocrutchesrdquo that can beinserted into glasses may be warranted Try crutches asa remedy for ptosis before eyelid surgery is consideredbecause of anesthesia risks Ophthalmic lubricants for dryeye may be considered

Gastrointestinal andgenitourinary management

c Presence of gastrointestinal symptoms such as abdom-inal pain constipation fecal incontinence or diarrheamay be a frequent problem The symptoms may mimicirritable bowel syndrome (IBS)15 Fiber supplementa-tion (more than 8 g daily) is the first-line treatment

c Gentle laxatives (see below) for constipation Oilsshould be avoided as they will lead to diarrhea Ifa patient does not respond to the first- or second-linerecommendations below a referral to a gastrointestinalspecialist for anal manometry should be considered First-line therapy recommendations polyethylene

glycol (Miralax) senna (Ex-Lax Senokot) docusate(Colace) or lactulose (Cholac)

Second-line therapy recommendations bisacodyl(Dulcolax Correctol) lubiprostone (Amitiza) orlinaclotide (Linzess)

Metoclopramide (Reglan) may be used to reduce thesymptoms of gastroparesis pseudo-obstruction andgastric reflux Providers should be aware of the risk ofacute dystonic reactions with this medication Long-term use is not recommended because this drug cancause tardive dyskinesia

Cholestyramine and loperamide are other options inthe presence of mainly diarrhea and anticholinergicdrug such as hyoscyamine sulfate in the presence ofIBS Because anticholinergic drugs may be antiar-rhythmic see Cardiac section on management

Mexiletine may be considered for refractory diarrheaor constipation because the drug may be antiarrhyth-mic see Cardiac section on management

c If bacterial overgrowth is found on breath testingtreating with antibiotics may reduce diarrhea

Focus on CDM As mentioned in the neonatal care section children with

CDMmay require a temporary feeding tube If dysphagiapersists consider enteral nutrition Refer to speech therapyChildren should be periodically re-assessed for improvingdysphagia

Children with CDMoften benefit from dysphagia therapyWith aggressive dysphagia therapy children with CDMoften are able to feed orally within the first year of life

Neurodevelopmental managementRecommendations

c Neuropsychological testing should be performed inevery child with DM1 to delineate cognitive strengthsand weaknesses This may include the following Psychometric assessment of global intellectual abilityand adaptive functioning

Assessment of executive functions Assessment of social cognition Assessment of visuomotor integration and visuospatialability

Assessment of receptive and expressive language abilities Assessment of EDS Assessment of learning disabilities (specific tests fordyscalculia dyslexia and dyspraxia)

c The assessments should be performed in the congenitalform in preschool age and should be repeated depend-ing on the level of functioning 2ndash3 times beforeadulthood In childhood DM1 neuropsychologicaltesting is recommended at diagnosis and repeated inpreschool or school age and college period

c Patients with psychiatric or behavioral issues should bereferred to a mental health care professional forassessment of Autism Spectrum Disorders AttentionDeficit disorders with or without Hyperactivity alex-iythmia and other behavioral problems

c Psychostimulants may be beneficial if attention deficitsare associated with an impairing level of fatigue or EDS(see excessive daytime sleepiness) As psychostimulantsmay be proarrhythmic see Cardiac section on stimulantmanagementSerotonin-enhancing antidepressants if excessive anxietyor other treatable psychiatric symptoms are present

Specific cognitive remediation programs to enhance socialemotional abilities (visual contact joint attention emotionalregulation) or executive functions efficiency (inhibitorycontrol attention working memory and cognitive flexibil-ity) using dedicated software (eg Cogmedreg)

c Language remediation and reading therapy should beconsidered because of the presence of cognitive deficitseven in children with normal intelligence Attention deficit

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 447

fatigability and visualndashspatial construction dysfunctioncan result in specific learning disorders with impair-ment in reading and spelling as well as in mathematics

Psychosocial management Healthcare professionals have a responsibility to co-

ordinate specialist care and support services for childrenwith DM1 There is a need to be alert to the psychologicaland social dysfunctions and monitor home and educa-tional circumstances Liaison between agencies is essentialto ensure a consistent approach between health educationand social care agencies

Children with DM1 should have access to appropriatepsychological and therapy services at an early age to ensurethey are fulfilling their maximum potential and learningcoping strategies for later life The modification of activitiesincluding social engagement strategies would providea foundation for each child to grow in confidence and esteem

Family care and support is essential throughout child-hood with support and social care assistance whererequired Schools should be provided with specialistinformation about the care and management of a childwith DM1 A social work consult or a referral to nursingcase management can also be beneficial for patients Aholistic approach is critical because the affected parentmay also need additional assistance

Families should have access to disability benefitsadequate housing and adaptations during the progressionof the condition

Excessive daytime sleepiness Family members and educators should be educated about

the EDS that comes with DM1 Children should be screened for signs of EDS including

prolonged naps or falling asleep in school Possible sleep apnea should be evaluated with overnight

oximetry or polysomnogram Positive-pressure ventilation can be considered if a DM1

patientrsquos sleepiness is thought to be related to nocturnalor daytime hypoventilation or sleep apnea Patientsshould be referred to pulmonologists who have experi-ence in neuromuscular diseases for consideration ofassisted ventilation

Stimulant therapy with a psychostimulant such asmodafinil (Provigil) methylphenidate or other stimulantcan be considered if central hypersomnia is suspectedOften difficulty staying awake in school is a triggeringfactor Special care should be taken in children withpreviously detected cardiac arrhythmia (See Cardiacsection on stimulant management)

Endocrine and metabolismc DM1 male patients should undergo a detailed physical

examination in search of gonadal atrophy or cryptorchidismc Patients should have a HbA1c and thyroid-stimulating

hormone and Free T4 level measured at baseline andevery 3 years or if there is a clinical suspicion

c Adolescent patients should be screened as adult patients Gonadal insufficiency and complications of the

reproductive system Inquiring about amenorrheaor dysmenorrhea for the female patients and erectiledysfunction for male patients

Fasting blood lipids plasma glucose liver enzymesbilirubin levels and gamma-glutamyl transpeptidaseshould be measured at baseline

ConclusionsThe recommendations for care of congenital and childhood-onset myotonic dystrophy have been created by consensus ofclinicians experienced in their care management Given theabsence of rigorous studies in many of these areas theseguidelines were created by consensus They are designed tostandardize the care of children with a multisystemic disorderthat leads to significant morbidity and mortality

Study fundingMyotonic Dystrophy Foundation

DisclosureN Johnson serves on the scientific advisory boards ofCytokinetics AveXis AMO Pharma and Biogen Idec hasreceived funding for travel andor speaker honoraria fromStrongbridge serves as a consultant for AMO PharmaAveXis and Vertex Pharma and receives research supportfrom Ionis Pharmaceuticals Biogen Idec Valerion Thera-peutics Cytokinetics Acceleron AveXis AMO PharmaNIHNINDS FDA Muscular Dystrophy Association andMyotonic Dystrophy Foundation EZ Aldana and NAngeard report no disclosures T Ashizawa serves on sci-entific advisory boards for the Myotonic Dystrophy Foun-dation NIH and National Ataxia Foundation has receivedfunding for travel from Biohaven PacBio and NIHreceives research support from Myotonic DystrophyFoundation National Ataxia Foundation Biohaven Phar-maceuticals Biogen andNIHNINDS and is a professor atWeill Cornell Medical College adjunct professor at BaylorCollege of Medicine guest faculty at Central South Uni-versity China KN Berggren serves on the scientific advi-sory board of Biogen and receives funding for travel andorspeaker honoraria from HDSA and FSH Society C Marini-Bettolo has served on the scientific advisory boards ofAvexis and Biogen T Duong A-B Ekstrom V Sansone CTian and L Hellerstein report no disclosures C Campbellserves on the scientific advisory boards of Catabasis andPTC Therapeutics and receives research support fromValerion Pharmaceuticals PTC Therapeutics Pfizer IonisEli Lilly Prosensa Child Health Foundation and JessersquosJourney Foundation Full disclosure form informationprovided by the authors is available with the full text of thisarticle at Neurologyorgcp

Publication historyReceived byNeurology Clinical PracticeDecember 21 2018 Accepted infinal form March 4 2019

448 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

Appendix Authors

Name Location Role Contribution

Nicholas EJohnson MDMCSI

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscriptpublication of thedraft and revision

EugenioZapataAldana MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NathalieAngeard PhD

Inserm ampUniversity of ParisDescartes ParisFrance

Author Data acquisitiondrafting andrevision of themanuscript

TetsuoAshizawa MD

HoustonMethodistNeurologicalInstitute Texas

Author Data acquisitiondrafting andrevision of themanuscript

Kiera NBerggren MACCC-SLP MS

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscript

Chiara Marini-Bettolo MDPhD

Institute of GeneticMedicineNewcastleUniversity andNewcastle uponTyne HospitalsNHS FoundationTrust Newcastleupon Tyne UK

Author Data acquisitiondrafting andrevision of themanuscript

Appendix (continued)

Name Location Role Contribution

Tina DuongMPT PhD

StanfordUniversity CA

Author Data acquisitiondrafting andrevision of themanuscript

Anne-BeritEkstrom MDPhD

Queen SilviaChildrenrsquo sHospitalGothenburgSweden

Author Data acquisitiondrafting andrevision of themanuscript

ValeriaSansone MD

NEMO ClinicMilan Italy

Author Data acquisitiondrafting andrevision of themanuscript

Cuixia TianMD

CincinnatiChildrenrsquos HospitalMedical CenterCincinnati OH

Author Data acquisitiondrafting andrevision of themanuscript

LeahHellersteinLCSW MPH

MyotonicDystrophyFoundation SanFrancisco CA

CorrespondingAuthor

Obtaining fundingdrafting andreviewing themanuscript studyconcept anddesign

CraigCampbell MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 449

450 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 451

452 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 453

References1 Fu YH Pizzuti A Fenwick RG Jr et al An unstable triplet repeat in a gene related to

myotonic muscular dystrophy Science 19922551256ndash12582 Brook JD McCurrach ME Harley HG et al Molecular basis of myotonic dystrophy

expansion of a trinucleotide (CTG) repeat at the 3rsquo end of a transcript encodinga protein kinase family member Cell 199268799ndash808

3 Mahadevan M Tsilfidis C Sabourin L et al Myotonic dystrophy mutation an unstableCTG repeat in the 3rsquo untranslated region of the gene Science 19922551253ndash1255

4 Harper PS Myotonic Dystrophy 3rd ed London WB Saunders 20015 Bugiardini E Meola G DM-CNS Group Consensus on cerebral involvement in

myotonic dystrophy Neuromuscul Disord 201424445ndash4526 Koch MC Grimm T Harley HG Harper PS Genetic risks for children of women

with myotonic dystrophy Am J Hum Genet 1991481084ndash10917 Gagnon C Heatwole C Hebert LJ et al Report of the third outcome measures in

myotonic dystrophy type 1 (OMMYD-3) international workshop Paris France June8 2015 J Neuromuscul Dis 20185523ndash537

8 Johnson NE Hung M Nasser E et al The impact of pregnancy on myotonic dys-trophy a registry-based study J Neuromuscul Dis 20152447ndash452

9 Campbell C Levin S Siu VM et al Congenital myotonic dystrophy Canadianpopulation-based surveillance study J Pediatr 2013163120ndash123

10 Campbell C Sherlock R Jacob P Blayney M Congenital myotonic dystrophyassisted ventilation duration and outcome Pediatrics 2004113811ndash816

11 Angeard N Gargiulo M Jacquette A et al Cognitive profile in childhood myotonicdystrophy type 1 is there a global impairment Neuromuscul Disord 200717451ndash458

12 Ekstrom AB Hakenas-Plate L Tulinius M Wentz E Cognition and adaptive skills inmyotonic dystrophy type 1 a study of 55 individuals with congenital and childhoodforms Dev Med Child Neurol 200951982ndash990

13 Kroksmark AK Ekstrom AB Bjorck E Tulinius M Myotonic dystrophy muscleinvolvement in relation to disease type and size of expanded CTG-repeat sequenceDev Med Child Neurol 200547478ndash485

14 Johnson NE Ekstrom AB Campbell C et al Parent-reported multi-national study ofthe impact of congenital and childhood onset myotonic dystrophy Dev Med ChildNeurol 201658698ndash705

15 Yao X Yang YS Cui LH et al Subtypes of irritable bowel syndrome on Rome IIIcriteria a multicenter study J Gastroenterol Hepatol 201227760ndash765

Share Your Insights Expertise and Experiencesbull How are you employing drugs and devices in your field

bull What ethical challenges do you face

bull Do you have a case report that is illustrative of a clinical challenge

bull What challenges have you faced or successes have you enjoyed in bringing greater efficiency to your practice

Deliver a high-quality peer-reviewed message to your colleagues in practice submit your paper at NPuborgNCPsubmit

454 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

DOI 101212CPJ000000000000064620199443-454 Published Online before print April 24 2019Neurol Clin Pract

Nicholas E Johnson Eugenio Zapata Aldana Nathalie Angeard et al dystrophy type 1

Consensus-based care recommendations for congenital and childhood-onset myotonic

This information is current as of April 24 2019

ServicesUpdated Information amp

httpcpneurologyorgcontent95443fullhtmlincluding high resolution figures can be found at

References httpcpneurologyorgcontent95443fullhtmlref-list-1

This article cites 14 articles 3 of which you can access for free at

Citations httpcpneurologyorgcontent95443fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpcpneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpcpneurologyorgcgicollectionall_pediatricAll Pediatric

httpcpneurologyorgcgicollectionall_neuromuscular_diseaseAll Neuromuscular Diseasefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

Anesthetic Management of a Myotonic Dystrophy Patient(myotonicorgsitesdefaultfilesMDF_LongForm_AnesGuidelines_01Cpdf) for anesthesia risks andrecommendations before any surgeries or proceduresrequiring anesthesia and the Anesthesia Quick ReferenceGuide (myotonicorgsitesdefaultfilesMDF Anes-thesia Guidelines FNL 2016 2 2 pdf) These docu-ments should be reviewed before treatment decisions

Focus on CDM It is worth noting that children with CDM are at a higher

risk of anesthetic complications given the underlyingrespiratory involvement as opposed to those withchildhood-onset myotonic dystrophy

Systems-based approachto managementRespiratory Signs of respiratory problems in children with myotonic

dystrophy include ineffective cough recurrent pulmo-nary infections orthopnea dyspnea poor sleep morningheadaches apnea fatigue and snoring

See figure 2 in Quick Reference Guide for a flowchart oftesting and treatment options in congenital andchildhood-onset myotonic dystrophy

Focus on CDM For CDM children who remain on longer term trach

ventilation there is often improvement in respiratorystrength over time and consideration to decannulatea tracheostomy should be made after careful considerationwith the multidisciplinary team including neurologyrespirology ear nose and throat and the familyConsideration of airway control respiratory infectionfrequency ability to tolerate a facial or nasal mask for NIVand compliance and cooperation with maintenancepulmonary therapy such as cough assist breathe stakingetc Testing for hypoventilation in sleep should be donebefore decannulation

Cardiovascularc Inform families of the risks of arrhythmias and cardiac

dysfunction and the importance of prompt medicalattention if symptoms are observed (ie palpitationspresyncope syncope dyspnea chest pain unexplainedfatigue) A 12-lead ECG should be performed at DM1 diagnosisand if normal and the patient remains asymptomatic ECGshould be performed annually and warrants moreinvestigation if the patient is symptomatic

If the ECG is normal and clinical suspicion is high a24-hour Holter monitor may be considered asa second-line investigation

Because specific medications such as mexiletine andpsychostimulants are antiarrhythmic an ECG before

use again within 3 months of starting therapy andthen at serial intervals is recommended

Consider in-hospital cardiac monitoring to detectarrhythmias if admitted for longer duration thantypical after surgical procedures or if admitted due tosevere illness or infection

c For young DM1 patients serial exercise stress testingand signal-averaged ECGs may be considered

c Evaluate and treat using American Heart Association(AHA) Management of Cardiac Involvement AssociatedWith Neuromuscular Diseases A Scientific Statement Fromthe American Heart Association 2017 circahajournalsorgcontent13613e200long and ACC ([AmericanCollege of Cardiology]AHA)ESC (European Societyof Cardiology) Guidelines for Management of Patientswith Ventricular Arrhythmias and the Prevention of SuddenCardiac Death (see ncbinlmnihgovpubmed16949478)- section on pediatric issues 134

Skeletal muscle weakness orthopediccomplications and rehabilitation

c Children should be evaluated early and often forphysical occupational and speech therapy needs withspecific attention to Feeding concerns and dysphagia Gross motor delay Gross and fine motor weakness Dysarthria and potential augmentative and alternativecommunication needs

Language acquisition delaysc The spine should be assessed for scoliosis and if

necessary consider bracing or referral to orthopedicsurgeon

c Children should be encouraged to participate in speechtherapy targeting speech language and communicationfrom a very early age

Focus on CDM Newborns with CDM often having difficulty feeding and

alternative nutrition should be considered After abouta year of actively working with a speech therapist oroccupational therapist most children can generally starton oral feeding

Children with CDM experience progressive improve-ment in their proximal strength until adolescence ata minimum Therefore children should be encouraged toparticipate in physical activities

Prevention of joint contractures are key to managementand should be closely monitored with early initiation ofstretching Treatment of talipes equinovarus and otherjoint contractures should include initial stretchingregimen and appropriate ankle bracing (for talipesequinovarus) Serial casting may be considered

Skeletal muscle myotoniac Delayed relaxation after grip or percussion difficulty

related to activities of daily life progressive speech

446 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

impairment or profound irritable bowel symptoms aresigns often related to myotonia

c Mexiletine (Mexitil) is an option for myotonia if it isdemonstrated and is distressing to the patient Mexiletinemay not be approved for use in every country In these casesother sodium channel antagonists may be considered Because mexiletine is an antiarrhythmic an ECG

before use again within 3 months of starting therapyand then at serial intervals is recommended

Instruct the patient to avoid dyspepsia and transientldquodizzy feelingsrdquo associated with mexiletine treatmentby taking it with food to extend absorption and lowerpeak level in blood

Ocular and hearing management Baseline audiometry should be performed especially at

school age Ophthalmologic assessment should be performed at

diagnosis and at least yearly to evaluate for hyperopiastigmatism strabismus and visual acuity to preventevolution of visual impairment

Eyelid ptosis if ptosis becomes severe and interferes withvision intervention such as eyelid ldquocrutchesrdquo that can beinserted into glasses may be warranted Try crutches asa remedy for ptosis before eyelid surgery is consideredbecause of anesthesia risks Ophthalmic lubricants for dryeye may be considered

Gastrointestinal andgenitourinary management

c Presence of gastrointestinal symptoms such as abdom-inal pain constipation fecal incontinence or diarrheamay be a frequent problem The symptoms may mimicirritable bowel syndrome (IBS)15 Fiber supplementa-tion (more than 8 g daily) is the first-line treatment

c Gentle laxatives (see below) for constipation Oilsshould be avoided as they will lead to diarrhea Ifa patient does not respond to the first- or second-linerecommendations below a referral to a gastrointestinalspecialist for anal manometry should be considered First-line therapy recommendations polyethylene

glycol (Miralax) senna (Ex-Lax Senokot) docusate(Colace) or lactulose (Cholac)

Second-line therapy recommendations bisacodyl(Dulcolax Correctol) lubiprostone (Amitiza) orlinaclotide (Linzess)

Metoclopramide (Reglan) may be used to reduce thesymptoms of gastroparesis pseudo-obstruction andgastric reflux Providers should be aware of the risk ofacute dystonic reactions with this medication Long-term use is not recommended because this drug cancause tardive dyskinesia

Cholestyramine and loperamide are other options inthe presence of mainly diarrhea and anticholinergicdrug such as hyoscyamine sulfate in the presence ofIBS Because anticholinergic drugs may be antiar-rhythmic see Cardiac section on management

Mexiletine may be considered for refractory diarrheaor constipation because the drug may be antiarrhyth-mic see Cardiac section on management

c If bacterial overgrowth is found on breath testingtreating with antibiotics may reduce diarrhea

Focus on CDM As mentioned in the neonatal care section children with

CDMmay require a temporary feeding tube If dysphagiapersists consider enteral nutrition Refer to speech therapyChildren should be periodically re-assessed for improvingdysphagia

Children with CDMoften benefit from dysphagia therapyWith aggressive dysphagia therapy children with CDMoften are able to feed orally within the first year of life

Neurodevelopmental managementRecommendations

c Neuropsychological testing should be performed inevery child with DM1 to delineate cognitive strengthsand weaknesses This may include the following Psychometric assessment of global intellectual abilityand adaptive functioning

Assessment of executive functions Assessment of social cognition Assessment of visuomotor integration and visuospatialability

Assessment of receptive and expressive language abilities Assessment of EDS Assessment of learning disabilities (specific tests fordyscalculia dyslexia and dyspraxia)

c The assessments should be performed in the congenitalform in preschool age and should be repeated depend-ing on the level of functioning 2ndash3 times beforeadulthood In childhood DM1 neuropsychologicaltesting is recommended at diagnosis and repeated inpreschool or school age and college period

c Patients with psychiatric or behavioral issues should bereferred to a mental health care professional forassessment of Autism Spectrum Disorders AttentionDeficit disorders with or without Hyperactivity alex-iythmia and other behavioral problems

c Psychostimulants may be beneficial if attention deficitsare associated with an impairing level of fatigue or EDS(see excessive daytime sleepiness) As psychostimulantsmay be proarrhythmic see Cardiac section on stimulantmanagementSerotonin-enhancing antidepressants if excessive anxietyor other treatable psychiatric symptoms are present

Specific cognitive remediation programs to enhance socialemotional abilities (visual contact joint attention emotionalregulation) or executive functions efficiency (inhibitorycontrol attention working memory and cognitive flexibil-ity) using dedicated software (eg Cogmedreg)

c Language remediation and reading therapy should beconsidered because of the presence of cognitive deficitseven in children with normal intelligence Attention deficit

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 447

fatigability and visualndashspatial construction dysfunctioncan result in specific learning disorders with impair-ment in reading and spelling as well as in mathematics

Psychosocial management Healthcare professionals have a responsibility to co-

ordinate specialist care and support services for childrenwith DM1 There is a need to be alert to the psychologicaland social dysfunctions and monitor home and educa-tional circumstances Liaison between agencies is essentialto ensure a consistent approach between health educationand social care agencies

Children with DM1 should have access to appropriatepsychological and therapy services at an early age to ensurethey are fulfilling their maximum potential and learningcoping strategies for later life The modification of activitiesincluding social engagement strategies would providea foundation for each child to grow in confidence and esteem

Family care and support is essential throughout child-hood with support and social care assistance whererequired Schools should be provided with specialistinformation about the care and management of a childwith DM1 A social work consult or a referral to nursingcase management can also be beneficial for patients Aholistic approach is critical because the affected parentmay also need additional assistance

Families should have access to disability benefitsadequate housing and adaptations during the progressionof the condition

Excessive daytime sleepiness Family members and educators should be educated about

the EDS that comes with DM1 Children should be screened for signs of EDS including

prolonged naps or falling asleep in school Possible sleep apnea should be evaluated with overnight

oximetry or polysomnogram Positive-pressure ventilation can be considered if a DM1

patientrsquos sleepiness is thought to be related to nocturnalor daytime hypoventilation or sleep apnea Patientsshould be referred to pulmonologists who have experi-ence in neuromuscular diseases for consideration ofassisted ventilation

Stimulant therapy with a psychostimulant such asmodafinil (Provigil) methylphenidate or other stimulantcan be considered if central hypersomnia is suspectedOften difficulty staying awake in school is a triggeringfactor Special care should be taken in children withpreviously detected cardiac arrhythmia (See Cardiacsection on stimulant management)

Endocrine and metabolismc DM1 male patients should undergo a detailed physical

examination in search of gonadal atrophy or cryptorchidismc Patients should have a HbA1c and thyroid-stimulating

hormone and Free T4 level measured at baseline andevery 3 years or if there is a clinical suspicion

c Adolescent patients should be screened as adult patients Gonadal insufficiency and complications of the

reproductive system Inquiring about amenorrheaor dysmenorrhea for the female patients and erectiledysfunction for male patients

Fasting blood lipids plasma glucose liver enzymesbilirubin levels and gamma-glutamyl transpeptidaseshould be measured at baseline

ConclusionsThe recommendations for care of congenital and childhood-onset myotonic dystrophy have been created by consensus ofclinicians experienced in their care management Given theabsence of rigorous studies in many of these areas theseguidelines were created by consensus They are designed tostandardize the care of children with a multisystemic disorderthat leads to significant morbidity and mortality

Study fundingMyotonic Dystrophy Foundation

DisclosureN Johnson serves on the scientific advisory boards ofCytokinetics AveXis AMO Pharma and Biogen Idec hasreceived funding for travel andor speaker honoraria fromStrongbridge serves as a consultant for AMO PharmaAveXis and Vertex Pharma and receives research supportfrom Ionis Pharmaceuticals Biogen Idec Valerion Thera-peutics Cytokinetics Acceleron AveXis AMO PharmaNIHNINDS FDA Muscular Dystrophy Association andMyotonic Dystrophy Foundation EZ Aldana and NAngeard report no disclosures T Ashizawa serves on sci-entific advisory boards for the Myotonic Dystrophy Foun-dation NIH and National Ataxia Foundation has receivedfunding for travel from Biohaven PacBio and NIHreceives research support from Myotonic DystrophyFoundation National Ataxia Foundation Biohaven Phar-maceuticals Biogen andNIHNINDS and is a professor atWeill Cornell Medical College adjunct professor at BaylorCollege of Medicine guest faculty at Central South Uni-versity China KN Berggren serves on the scientific advi-sory board of Biogen and receives funding for travel andorspeaker honoraria from HDSA and FSH Society C Marini-Bettolo has served on the scientific advisory boards ofAvexis and Biogen T Duong A-B Ekstrom V Sansone CTian and L Hellerstein report no disclosures C Campbellserves on the scientific advisory boards of Catabasis andPTC Therapeutics and receives research support fromValerion Pharmaceuticals PTC Therapeutics Pfizer IonisEli Lilly Prosensa Child Health Foundation and JessersquosJourney Foundation Full disclosure form informationprovided by the authors is available with the full text of thisarticle at Neurologyorgcp

Publication historyReceived byNeurology Clinical PracticeDecember 21 2018 Accepted infinal form March 4 2019

448 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

Appendix Authors

Name Location Role Contribution

Nicholas EJohnson MDMCSI

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscriptpublication of thedraft and revision

EugenioZapataAldana MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NathalieAngeard PhD

Inserm ampUniversity of ParisDescartes ParisFrance

Author Data acquisitiondrafting andrevision of themanuscript

TetsuoAshizawa MD

HoustonMethodistNeurologicalInstitute Texas

Author Data acquisitiondrafting andrevision of themanuscript

Kiera NBerggren MACCC-SLP MS

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscript

Chiara Marini-Bettolo MDPhD

Institute of GeneticMedicineNewcastleUniversity andNewcastle uponTyne HospitalsNHS FoundationTrust Newcastleupon Tyne UK

Author Data acquisitiondrafting andrevision of themanuscript

Appendix (continued)

Name Location Role Contribution

Tina DuongMPT PhD

StanfordUniversity CA

Author Data acquisitiondrafting andrevision of themanuscript

Anne-BeritEkstrom MDPhD

Queen SilviaChildrenrsquo sHospitalGothenburgSweden

Author Data acquisitiondrafting andrevision of themanuscript

ValeriaSansone MD

NEMO ClinicMilan Italy

Author Data acquisitiondrafting andrevision of themanuscript

Cuixia TianMD

CincinnatiChildrenrsquos HospitalMedical CenterCincinnati OH

Author Data acquisitiondrafting andrevision of themanuscript

LeahHellersteinLCSW MPH

MyotonicDystrophyFoundation SanFrancisco CA

CorrespondingAuthor

Obtaining fundingdrafting andreviewing themanuscript studyconcept anddesign

CraigCampbell MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 449

450 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 451

452 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 453

References1 Fu YH Pizzuti A Fenwick RG Jr et al An unstable triplet repeat in a gene related to

myotonic muscular dystrophy Science 19922551256ndash12582 Brook JD McCurrach ME Harley HG et al Molecular basis of myotonic dystrophy

expansion of a trinucleotide (CTG) repeat at the 3rsquo end of a transcript encodinga protein kinase family member Cell 199268799ndash808

3 Mahadevan M Tsilfidis C Sabourin L et al Myotonic dystrophy mutation an unstableCTG repeat in the 3rsquo untranslated region of the gene Science 19922551253ndash1255

4 Harper PS Myotonic Dystrophy 3rd ed London WB Saunders 20015 Bugiardini E Meola G DM-CNS Group Consensus on cerebral involvement in

myotonic dystrophy Neuromuscul Disord 201424445ndash4526 Koch MC Grimm T Harley HG Harper PS Genetic risks for children of women

with myotonic dystrophy Am J Hum Genet 1991481084ndash10917 Gagnon C Heatwole C Hebert LJ et al Report of the third outcome measures in

myotonic dystrophy type 1 (OMMYD-3) international workshop Paris France June8 2015 J Neuromuscul Dis 20185523ndash537

8 Johnson NE Hung M Nasser E et al The impact of pregnancy on myotonic dys-trophy a registry-based study J Neuromuscul Dis 20152447ndash452

9 Campbell C Levin S Siu VM et al Congenital myotonic dystrophy Canadianpopulation-based surveillance study J Pediatr 2013163120ndash123

10 Campbell C Sherlock R Jacob P Blayney M Congenital myotonic dystrophyassisted ventilation duration and outcome Pediatrics 2004113811ndash816

11 Angeard N Gargiulo M Jacquette A et al Cognitive profile in childhood myotonicdystrophy type 1 is there a global impairment Neuromuscul Disord 200717451ndash458

12 Ekstrom AB Hakenas-Plate L Tulinius M Wentz E Cognition and adaptive skills inmyotonic dystrophy type 1 a study of 55 individuals with congenital and childhoodforms Dev Med Child Neurol 200951982ndash990

13 Kroksmark AK Ekstrom AB Bjorck E Tulinius M Myotonic dystrophy muscleinvolvement in relation to disease type and size of expanded CTG-repeat sequenceDev Med Child Neurol 200547478ndash485

14 Johnson NE Ekstrom AB Campbell C et al Parent-reported multi-national study ofthe impact of congenital and childhood onset myotonic dystrophy Dev Med ChildNeurol 201658698ndash705

15 Yao X Yang YS Cui LH et al Subtypes of irritable bowel syndrome on Rome IIIcriteria a multicenter study J Gastroenterol Hepatol 201227760ndash765

Share Your Insights Expertise and Experiencesbull How are you employing drugs and devices in your field

bull What ethical challenges do you face

bull Do you have a case report that is illustrative of a clinical challenge

bull What challenges have you faced or successes have you enjoyed in bringing greater efficiency to your practice

Deliver a high-quality peer-reviewed message to your colleagues in practice submit your paper at NPuborgNCPsubmit

454 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

DOI 101212CPJ000000000000064620199443-454 Published Online before print April 24 2019Neurol Clin Pract

Nicholas E Johnson Eugenio Zapata Aldana Nathalie Angeard et al dystrophy type 1

Consensus-based care recommendations for congenital and childhood-onset myotonic

This information is current as of April 24 2019

ServicesUpdated Information amp

httpcpneurologyorgcontent95443fullhtmlincluding high resolution figures can be found at

References httpcpneurologyorgcontent95443fullhtmlref-list-1

This article cites 14 articles 3 of which you can access for free at

Citations httpcpneurologyorgcontent95443fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpcpneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpcpneurologyorgcgicollectionall_pediatricAll Pediatric

httpcpneurologyorgcgicollectionall_neuromuscular_diseaseAll Neuromuscular Diseasefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

impairment or profound irritable bowel symptoms aresigns often related to myotonia

c Mexiletine (Mexitil) is an option for myotonia if it isdemonstrated and is distressing to the patient Mexiletinemay not be approved for use in every country In these casesother sodium channel antagonists may be considered Because mexiletine is an antiarrhythmic an ECG

before use again within 3 months of starting therapyand then at serial intervals is recommended

Instruct the patient to avoid dyspepsia and transientldquodizzy feelingsrdquo associated with mexiletine treatmentby taking it with food to extend absorption and lowerpeak level in blood

Ocular and hearing management Baseline audiometry should be performed especially at

school age Ophthalmologic assessment should be performed at

diagnosis and at least yearly to evaluate for hyperopiastigmatism strabismus and visual acuity to preventevolution of visual impairment

Eyelid ptosis if ptosis becomes severe and interferes withvision intervention such as eyelid ldquocrutchesrdquo that can beinserted into glasses may be warranted Try crutches asa remedy for ptosis before eyelid surgery is consideredbecause of anesthesia risks Ophthalmic lubricants for dryeye may be considered

Gastrointestinal andgenitourinary management

c Presence of gastrointestinal symptoms such as abdom-inal pain constipation fecal incontinence or diarrheamay be a frequent problem The symptoms may mimicirritable bowel syndrome (IBS)15 Fiber supplementa-tion (more than 8 g daily) is the first-line treatment

c Gentle laxatives (see below) for constipation Oilsshould be avoided as they will lead to diarrhea Ifa patient does not respond to the first- or second-linerecommendations below a referral to a gastrointestinalspecialist for anal manometry should be considered First-line therapy recommendations polyethylene

glycol (Miralax) senna (Ex-Lax Senokot) docusate(Colace) or lactulose (Cholac)

Second-line therapy recommendations bisacodyl(Dulcolax Correctol) lubiprostone (Amitiza) orlinaclotide (Linzess)

Metoclopramide (Reglan) may be used to reduce thesymptoms of gastroparesis pseudo-obstruction andgastric reflux Providers should be aware of the risk ofacute dystonic reactions with this medication Long-term use is not recommended because this drug cancause tardive dyskinesia

Cholestyramine and loperamide are other options inthe presence of mainly diarrhea and anticholinergicdrug such as hyoscyamine sulfate in the presence ofIBS Because anticholinergic drugs may be antiar-rhythmic see Cardiac section on management

Mexiletine may be considered for refractory diarrheaor constipation because the drug may be antiarrhyth-mic see Cardiac section on management

c If bacterial overgrowth is found on breath testingtreating with antibiotics may reduce diarrhea

Focus on CDM As mentioned in the neonatal care section children with

CDMmay require a temporary feeding tube If dysphagiapersists consider enteral nutrition Refer to speech therapyChildren should be periodically re-assessed for improvingdysphagia

Children with CDMoften benefit from dysphagia therapyWith aggressive dysphagia therapy children with CDMoften are able to feed orally within the first year of life

Neurodevelopmental managementRecommendations

c Neuropsychological testing should be performed inevery child with DM1 to delineate cognitive strengthsand weaknesses This may include the following Psychometric assessment of global intellectual abilityand adaptive functioning

Assessment of executive functions Assessment of social cognition Assessment of visuomotor integration and visuospatialability

Assessment of receptive and expressive language abilities Assessment of EDS Assessment of learning disabilities (specific tests fordyscalculia dyslexia and dyspraxia)

c The assessments should be performed in the congenitalform in preschool age and should be repeated depend-ing on the level of functioning 2ndash3 times beforeadulthood In childhood DM1 neuropsychologicaltesting is recommended at diagnosis and repeated inpreschool or school age and college period

c Patients with psychiatric or behavioral issues should bereferred to a mental health care professional forassessment of Autism Spectrum Disorders AttentionDeficit disorders with or without Hyperactivity alex-iythmia and other behavioral problems

c Psychostimulants may be beneficial if attention deficitsare associated with an impairing level of fatigue or EDS(see excessive daytime sleepiness) As psychostimulantsmay be proarrhythmic see Cardiac section on stimulantmanagementSerotonin-enhancing antidepressants if excessive anxietyor other treatable psychiatric symptoms are present

Specific cognitive remediation programs to enhance socialemotional abilities (visual contact joint attention emotionalregulation) or executive functions efficiency (inhibitorycontrol attention working memory and cognitive flexibil-ity) using dedicated software (eg Cogmedreg)

c Language remediation and reading therapy should beconsidered because of the presence of cognitive deficitseven in children with normal intelligence Attention deficit

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 447

fatigability and visualndashspatial construction dysfunctioncan result in specific learning disorders with impair-ment in reading and spelling as well as in mathematics

Psychosocial management Healthcare professionals have a responsibility to co-

ordinate specialist care and support services for childrenwith DM1 There is a need to be alert to the psychologicaland social dysfunctions and monitor home and educa-tional circumstances Liaison between agencies is essentialto ensure a consistent approach between health educationand social care agencies

Children with DM1 should have access to appropriatepsychological and therapy services at an early age to ensurethey are fulfilling their maximum potential and learningcoping strategies for later life The modification of activitiesincluding social engagement strategies would providea foundation for each child to grow in confidence and esteem

Family care and support is essential throughout child-hood with support and social care assistance whererequired Schools should be provided with specialistinformation about the care and management of a childwith DM1 A social work consult or a referral to nursingcase management can also be beneficial for patients Aholistic approach is critical because the affected parentmay also need additional assistance

Families should have access to disability benefitsadequate housing and adaptations during the progressionof the condition

Excessive daytime sleepiness Family members and educators should be educated about

the EDS that comes with DM1 Children should be screened for signs of EDS including

prolonged naps or falling asleep in school Possible sleep apnea should be evaluated with overnight

oximetry or polysomnogram Positive-pressure ventilation can be considered if a DM1

patientrsquos sleepiness is thought to be related to nocturnalor daytime hypoventilation or sleep apnea Patientsshould be referred to pulmonologists who have experi-ence in neuromuscular diseases for consideration ofassisted ventilation

Stimulant therapy with a psychostimulant such asmodafinil (Provigil) methylphenidate or other stimulantcan be considered if central hypersomnia is suspectedOften difficulty staying awake in school is a triggeringfactor Special care should be taken in children withpreviously detected cardiac arrhythmia (See Cardiacsection on stimulant management)

Endocrine and metabolismc DM1 male patients should undergo a detailed physical

examination in search of gonadal atrophy or cryptorchidismc Patients should have a HbA1c and thyroid-stimulating

hormone and Free T4 level measured at baseline andevery 3 years or if there is a clinical suspicion

c Adolescent patients should be screened as adult patients Gonadal insufficiency and complications of the

reproductive system Inquiring about amenorrheaor dysmenorrhea for the female patients and erectiledysfunction for male patients

Fasting blood lipids plasma glucose liver enzymesbilirubin levels and gamma-glutamyl transpeptidaseshould be measured at baseline

ConclusionsThe recommendations for care of congenital and childhood-onset myotonic dystrophy have been created by consensus ofclinicians experienced in their care management Given theabsence of rigorous studies in many of these areas theseguidelines were created by consensus They are designed tostandardize the care of children with a multisystemic disorderthat leads to significant morbidity and mortality

Study fundingMyotonic Dystrophy Foundation

DisclosureN Johnson serves on the scientific advisory boards ofCytokinetics AveXis AMO Pharma and Biogen Idec hasreceived funding for travel andor speaker honoraria fromStrongbridge serves as a consultant for AMO PharmaAveXis and Vertex Pharma and receives research supportfrom Ionis Pharmaceuticals Biogen Idec Valerion Thera-peutics Cytokinetics Acceleron AveXis AMO PharmaNIHNINDS FDA Muscular Dystrophy Association andMyotonic Dystrophy Foundation EZ Aldana and NAngeard report no disclosures T Ashizawa serves on sci-entific advisory boards for the Myotonic Dystrophy Foun-dation NIH and National Ataxia Foundation has receivedfunding for travel from Biohaven PacBio and NIHreceives research support from Myotonic DystrophyFoundation National Ataxia Foundation Biohaven Phar-maceuticals Biogen andNIHNINDS and is a professor atWeill Cornell Medical College adjunct professor at BaylorCollege of Medicine guest faculty at Central South Uni-versity China KN Berggren serves on the scientific advi-sory board of Biogen and receives funding for travel andorspeaker honoraria from HDSA and FSH Society C Marini-Bettolo has served on the scientific advisory boards ofAvexis and Biogen T Duong A-B Ekstrom V Sansone CTian and L Hellerstein report no disclosures C Campbellserves on the scientific advisory boards of Catabasis andPTC Therapeutics and receives research support fromValerion Pharmaceuticals PTC Therapeutics Pfizer IonisEli Lilly Prosensa Child Health Foundation and JessersquosJourney Foundation Full disclosure form informationprovided by the authors is available with the full text of thisarticle at Neurologyorgcp

Publication historyReceived byNeurology Clinical PracticeDecember 21 2018 Accepted infinal form March 4 2019

448 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

Appendix Authors

Name Location Role Contribution

Nicholas EJohnson MDMCSI

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscriptpublication of thedraft and revision

EugenioZapataAldana MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NathalieAngeard PhD

Inserm ampUniversity of ParisDescartes ParisFrance

Author Data acquisitiondrafting andrevision of themanuscript

TetsuoAshizawa MD

HoustonMethodistNeurologicalInstitute Texas

Author Data acquisitiondrafting andrevision of themanuscript

Kiera NBerggren MACCC-SLP MS

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscript

Chiara Marini-Bettolo MDPhD

Institute of GeneticMedicineNewcastleUniversity andNewcastle uponTyne HospitalsNHS FoundationTrust Newcastleupon Tyne UK

Author Data acquisitiondrafting andrevision of themanuscript

Appendix (continued)

Name Location Role Contribution

Tina DuongMPT PhD

StanfordUniversity CA

Author Data acquisitiondrafting andrevision of themanuscript

Anne-BeritEkstrom MDPhD

Queen SilviaChildrenrsquo sHospitalGothenburgSweden

Author Data acquisitiondrafting andrevision of themanuscript

ValeriaSansone MD

NEMO ClinicMilan Italy

Author Data acquisitiondrafting andrevision of themanuscript

Cuixia TianMD

CincinnatiChildrenrsquos HospitalMedical CenterCincinnati OH

Author Data acquisitiondrafting andrevision of themanuscript

LeahHellersteinLCSW MPH

MyotonicDystrophyFoundation SanFrancisco CA

CorrespondingAuthor

Obtaining fundingdrafting andreviewing themanuscript studyconcept anddesign

CraigCampbell MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 449

450 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 451

452 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 453

References1 Fu YH Pizzuti A Fenwick RG Jr et al An unstable triplet repeat in a gene related to

myotonic muscular dystrophy Science 19922551256ndash12582 Brook JD McCurrach ME Harley HG et al Molecular basis of myotonic dystrophy

expansion of a trinucleotide (CTG) repeat at the 3rsquo end of a transcript encodinga protein kinase family member Cell 199268799ndash808

3 Mahadevan M Tsilfidis C Sabourin L et al Myotonic dystrophy mutation an unstableCTG repeat in the 3rsquo untranslated region of the gene Science 19922551253ndash1255

4 Harper PS Myotonic Dystrophy 3rd ed London WB Saunders 20015 Bugiardini E Meola G DM-CNS Group Consensus on cerebral involvement in

myotonic dystrophy Neuromuscul Disord 201424445ndash4526 Koch MC Grimm T Harley HG Harper PS Genetic risks for children of women

with myotonic dystrophy Am J Hum Genet 1991481084ndash10917 Gagnon C Heatwole C Hebert LJ et al Report of the third outcome measures in

myotonic dystrophy type 1 (OMMYD-3) international workshop Paris France June8 2015 J Neuromuscul Dis 20185523ndash537

8 Johnson NE Hung M Nasser E et al The impact of pregnancy on myotonic dys-trophy a registry-based study J Neuromuscul Dis 20152447ndash452

9 Campbell C Levin S Siu VM et al Congenital myotonic dystrophy Canadianpopulation-based surveillance study J Pediatr 2013163120ndash123

10 Campbell C Sherlock R Jacob P Blayney M Congenital myotonic dystrophyassisted ventilation duration and outcome Pediatrics 2004113811ndash816

11 Angeard N Gargiulo M Jacquette A et al Cognitive profile in childhood myotonicdystrophy type 1 is there a global impairment Neuromuscul Disord 200717451ndash458

12 Ekstrom AB Hakenas-Plate L Tulinius M Wentz E Cognition and adaptive skills inmyotonic dystrophy type 1 a study of 55 individuals with congenital and childhoodforms Dev Med Child Neurol 200951982ndash990

13 Kroksmark AK Ekstrom AB Bjorck E Tulinius M Myotonic dystrophy muscleinvolvement in relation to disease type and size of expanded CTG-repeat sequenceDev Med Child Neurol 200547478ndash485

14 Johnson NE Ekstrom AB Campbell C et al Parent-reported multi-national study ofthe impact of congenital and childhood onset myotonic dystrophy Dev Med ChildNeurol 201658698ndash705

15 Yao X Yang YS Cui LH et al Subtypes of irritable bowel syndrome on Rome IIIcriteria a multicenter study J Gastroenterol Hepatol 201227760ndash765

Share Your Insights Expertise and Experiencesbull How are you employing drugs and devices in your field

bull What ethical challenges do you face

bull Do you have a case report that is illustrative of a clinical challenge

bull What challenges have you faced or successes have you enjoyed in bringing greater efficiency to your practice

Deliver a high-quality peer-reviewed message to your colleagues in practice submit your paper at NPuborgNCPsubmit

454 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

DOI 101212CPJ000000000000064620199443-454 Published Online before print April 24 2019Neurol Clin Pract

Nicholas E Johnson Eugenio Zapata Aldana Nathalie Angeard et al dystrophy type 1

Consensus-based care recommendations for congenital and childhood-onset myotonic

This information is current as of April 24 2019

ServicesUpdated Information amp

httpcpneurologyorgcontent95443fullhtmlincluding high resolution figures can be found at

References httpcpneurologyorgcontent95443fullhtmlref-list-1

This article cites 14 articles 3 of which you can access for free at

Citations httpcpneurologyorgcontent95443fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpcpneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpcpneurologyorgcgicollectionall_pediatricAll Pediatric

httpcpneurologyorgcgicollectionall_neuromuscular_diseaseAll Neuromuscular Diseasefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

fatigability and visualndashspatial construction dysfunctioncan result in specific learning disorders with impair-ment in reading and spelling as well as in mathematics

Psychosocial management Healthcare professionals have a responsibility to co-

ordinate specialist care and support services for childrenwith DM1 There is a need to be alert to the psychologicaland social dysfunctions and monitor home and educa-tional circumstances Liaison between agencies is essentialto ensure a consistent approach between health educationand social care agencies

Children with DM1 should have access to appropriatepsychological and therapy services at an early age to ensurethey are fulfilling their maximum potential and learningcoping strategies for later life The modification of activitiesincluding social engagement strategies would providea foundation for each child to grow in confidence and esteem

Family care and support is essential throughout child-hood with support and social care assistance whererequired Schools should be provided with specialistinformation about the care and management of a childwith DM1 A social work consult or a referral to nursingcase management can also be beneficial for patients Aholistic approach is critical because the affected parentmay also need additional assistance

Families should have access to disability benefitsadequate housing and adaptations during the progressionof the condition

Excessive daytime sleepiness Family members and educators should be educated about

the EDS that comes with DM1 Children should be screened for signs of EDS including

prolonged naps or falling asleep in school Possible sleep apnea should be evaluated with overnight

oximetry or polysomnogram Positive-pressure ventilation can be considered if a DM1

patientrsquos sleepiness is thought to be related to nocturnalor daytime hypoventilation or sleep apnea Patientsshould be referred to pulmonologists who have experi-ence in neuromuscular diseases for consideration ofassisted ventilation

Stimulant therapy with a psychostimulant such asmodafinil (Provigil) methylphenidate or other stimulantcan be considered if central hypersomnia is suspectedOften difficulty staying awake in school is a triggeringfactor Special care should be taken in children withpreviously detected cardiac arrhythmia (See Cardiacsection on stimulant management)

Endocrine and metabolismc DM1 male patients should undergo a detailed physical

examination in search of gonadal atrophy or cryptorchidismc Patients should have a HbA1c and thyroid-stimulating

hormone and Free T4 level measured at baseline andevery 3 years or if there is a clinical suspicion

c Adolescent patients should be screened as adult patients Gonadal insufficiency and complications of the

reproductive system Inquiring about amenorrheaor dysmenorrhea for the female patients and erectiledysfunction for male patients

Fasting blood lipids plasma glucose liver enzymesbilirubin levels and gamma-glutamyl transpeptidaseshould be measured at baseline

ConclusionsThe recommendations for care of congenital and childhood-onset myotonic dystrophy have been created by consensus ofclinicians experienced in their care management Given theabsence of rigorous studies in many of these areas theseguidelines were created by consensus They are designed tostandardize the care of children with a multisystemic disorderthat leads to significant morbidity and mortality

Study fundingMyotonic Dystrophy Foundation

DisclosureN Johnson serves on the scientific advisory boards ofCytokinetics AveXis AMO Pharma and Biogen Idec hasreceived funding for travel andor speaker honoraria fromStrongbridge serves as a consultant for AMO PharmaAveXis and Vertex Pharma and receives research supportfrom Ionis Pharmaceuticals Biogen Idec Valerion Thera-peutics Cytokinetics Acceleron AveXis AMO PharmaNIHNINDS FDA Muscular Dystrophy Association andMyotonic Dystrophy Foundation EZ Aldana and NAngeard report no disclosures T Ashizawa serves on sci-entific advisory boards for the Myotonic Dystrophy Foun-dation NIH and National Ataxia Foundation has receivedfunding for travel from Biohaven PacBio and NIHreceives research support from Myotonic DystrophyFoundation National Ataxia Foundation Biohaven Phar-maceuticals Biogen andNIHNINDS and is a professor atWeill Cornell Medical College adjunct professor at BaylorCollege of Medicine guest faculty at Central South Uni-versity China KN Berggren serves on the scientific advi-sory board of Biogen and receives funding for travel andorspeaker honoraria from HDSA and FSH Society C Marini-Bettolo has served on the scientific advisory boards ofAvexis and Biogen T Duong A-B Ekstrom V Sansone CTian and L Hellerstein report no disclosures C Campbellserves on the scientific advisory boards of Catabasis andPTC Therapeutics and receives research support fromValerion Pharmaceuticals PTC Therapeutics Pfizer IonisEli Lilly Prosensa Child Health Foundation and JessersquosJourney Foundation Full disclosure form informationprovided by the authors is available with the full text of thisarticle at Neurologyorgcp

Publication historyReceived byNeurology Clinical PracticeDecember 21 2018 Accepted infinal form March 4 2019

448 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

Appendix Authors

Name Location Role Contribution

Nicholas EJohnson MDMCSI

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscriptpublication of thedraft and revision

EugenioZapataAldana MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NathalieAngeard PhD

Inserm ampUniversity of ParisDescartes ParisFrance

Author Data acquisitiondrafting andrevision of themanuscript

TetsuoAshizawa MD

HoustonMethodistNeurologicalInstitute Texas

Author Data acquisitiondrafting andrevision of themanuscript

Kiera NBerggren MACCC-SLP MS

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscript

Chiara Marini-Bettolo MDPhD

Institute of GeneticMedicineNewcastleUniversity andNewcastle uponTyne HospitalsNHS FoundationTrust Newcastleupon Tyne UK

Author Data acquisitiondrafting andrevision of themanuscript

Appendix (continued)

Name Location Role Contribution

Tina DuongMPT PhD

StanfordUniversity CA

Author Data acquisitiondrafting andrevision of themanuscript

Anne-BeritEkstrom MDPhD

Queen SilviaChildrenrsquo sHospitalGothenburgSweden

Author Data acquisitiondrafting andrevision of themanuscript

ValeriaSansone MD

NEMO ClinicMilan Italy

Author Data acquisitiondrafting andrevision of themanuscript

Cuixia TianMD

CincinnatiChildrenrsquos HospitalMedical CenterCincinnati OH

Author Data acquisitiondrafting andrevision of themanuscript

LeahHellersteinLCSW MPH

MyotonicDystrophyFoundation SanFrancisco CA

CorrespondingAuthor

Obtaining fundingdrafting andreviewing themanuscript studyconcept anddesign

CraigCampbell MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 449

450 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 451

452 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 453

References1 Fu YH Pizzuti A Fenwick RG Jr et al An unstable triplet repeat in a gene related to

myotonic muscular dystrophy Science 19922551256ndash12582 Brook JD McCurrach ME Harley HG et al Molecular basis of myotonic dystrophy

expansion of a trinucleotide (CTG) repeat at the 3rsquo end of a transcript encodinga protein kinase family member Cell 199268799ndash808

3 Mahadevan M Tsilfidis C Sabourin L et al Myotonic dystrophy mutation an unstableCTG repeat in the 3rsquo untranslated region of the gene Science 19922551253ndash1255

4 Harper PS Myotonic Dystrophy 3rd ed London WB Saunders 20015 Bugiardini E Meola G DM-CNS Group Consensus on cerebral involvement in

myotonic dystrophy Neuromuscul Disord 201424445ndash4526 Koch MC Grimm T Harley HG Harper PS Genetic risks for children of women

with myotonic dystrophy Am J Hum Genet 1991481084ndash10917 Gagnon C Heatwole C Hebert LJ et al Report of the third outcome measures in

myotonic dystrophy type 1 (OMMYD-3) international workshop Paris France June8 2015 J Neuromuscul Dis 20185523ndash537

8 Johnson NE Hung M Nasser E et al The impact of pregnancy on myotonic dys-trophy a registry-based study J Neuromuscul Dis 20152447ndash452

9 Campbell C Levin S Siu VM et al Congenital myotonic dystrophy Canadianpopulation-based surveillance study J Pediatr 2013163120ndash123

10 Campbell C Sherlock R Jacob P Blayney M Congenital myotonic dystrophyassisted ventilation duration and outcome Pediatrics 2004113811ndash816

11 Angeard N Gargiulo M Jacquette A et al Cognitive profile in childhood myotonicdystrophy type 1 is there a global impairment Neuromuscul Disord 200717451ndash458

12 Ekstrom AB Hakenas-Plate L Tulinius M Wentz E Cognition and adaptive skills inmyotonic dystrophy type 1 a study of 55 individuals with congenital and childhoodforms Dev Med Child Neurol 200951982ndash990

13 Kroksmark AK Ekstrom AB Bjorck E Tulinius M Myotonic dystrophy muscleinvolvement in relation to disease type and size of expanded CTG-repeat sequenceDev Med Child Neurol 200547478ndash485

14 Johnson NE Ekstrom AB Campbell C et al Parent-reported multi-national study ofthe impact of congenital and childhood onset myotonic dystrophy Dev Med ChildNeurol 201658698ndash705

15 Yao X Yang YS Cui LH et al Subtypes of irritable bowel syndrome on Rome IIIcriteria a multicenter study J Gastroenterol Hepatol 201227760ndash765

Share Your Insights Expertise and Experiencesbull How are you employing drugs and devices in your field

bull What ethical challenges do you face

bull Do you have a case report that is illustrative of a clinical challenge

bull What challenges have you faced or successes have you enjoyed in bringing greater efficiency to your practice

Deliver a high-quality peer-reviewed message to your colleagues in practice submit your paper at NPuborgNCPsubmit

454 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

DOI 101212CPJ000000000000064620199443-454 Published Online before print April 24 2019Neurol Clin Pract

Nicholas E Johnson Eugenio Zapata Aldana Nathalie Angeard et al dystrophy type 1

Consensus-based care recommendations for congenital and childhood-onset myotonic

This information is current as of April 24 2019

ServicesUpdated Information amp

httpcpneurologyorgcontent95443fullhtmlincluding high resolution figures can be found at

References httpcpneurologyorgcontent95443fullhtmlref-list-1

This article cites 14 articles 3 of which you can access for free at

Citations httpcpneurologyorgcontent95443fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpcpneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpcpneurologyorgcgicollectionall_pediatricAll Pediatric

httpcpneurologyorgcgicollectionall_neuromuscular_diseaseAll Neuromuscular Diseasefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

Appendix Authors

Name Location Role Contribution

Nicholas EJohnson MDMCSI

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscriptpublication of thedraft and revision

EugenioZapataAldana MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NathalieAngeard PhD

Inserm ampUniversity of ParisDescartes ParisFrance

Author Data acquisitiondrafting andrevision of themanuscript

TetsuoAshizawa MD

HoustonMethodistNeurologicalInstitute Texas

Author Data acquisitiondrafting andrevision of themanuscript

Kiera NBerggren MACCC-SLP MS

VirginiaCommonwealthUniversity Virginia

Author Data acquisitiondrafting andrevision of themanuscript

Chiara Marini-Bettolo MDPhD

Institute of GeneticMedicineNewcastleUniversity andNewcastle uponTyne HospitalsNHS FoundationTrust Newcastleupon Tyne UK

Author Data acquisitiondrafting andrevision of themanuscript

Appendix (continued)

Name Location Role Contribution

Tina DuongMPT PhD

StanfordUniversity CA

Author Data acquisitiondrafting andrevision of themanuscript

Anne-BeritEkstrom MDPhD

Queen SilviaChildrenrsquo sHospitalGothenburgSweden

Author Data acquisitiondrafting andrevision of themanuscript

ValeriaSansone MD

NEMO ClinicMilan Italy

Author Data acquisitiondrafting andrevision of themanuscript

Cuixia TianMD

CincinnatiChildrenrsquos HospitalMedical CenterCincinnati OH

Author Data acquisitiondrafting andrevision of themanuscript

LeahHellersteinLCSW MPH

MyotonicDystrophyFoundation SanFrancisco CA

CorrespondingAuthor

Obtaining fundingdrafting andreviewing themanuscript studyconcept anddesign

CraigCampbell MD

University ofWestern OntarioOntario Canada

Author Data acquisitiondrafting andrevision of themanuscript

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 449

450 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 451

452 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 453

References1 Fu YH Pizzuti A Fenwick RG Jr et al An unstable triplet repeat in a gene related to

myotonic muscular dystrophy Science 19922551256ndash12582 Brook JD McCurrach ME Harley HG et al Molecular basis of myotonic dystrophy

expansion of a trinucleotide (CTG) repeat at the 3rsquo end of a transcript encodinga protein kinase family member Cell 199268799ndash808

3 Mahadevan M Tsilfidis C Sabourin L et al Myotonic dystrophy mutation an unstableCTG repeat in the 3rsquo untranslated region of the gene Science 19922551253ndash1255

4 Harper PS Myotonic Dystrophy 3rd ed London WB Saunders 20015 Bugiardini E Meola G DM-CNS Group Consensus on cerebral involvement in

myotonic dystrophy Neuromuscul Disord 201424445ndash4526 Koch MC Grimm T Harley HG Harper PS Genetic risks for children of women

with myotonic dystrophy Am J Hum Genet 1991481084ndash10917 Gagnon C Heatwole C Hebert LJ et al Report of the third outcome measures in

myotonic dystrophy type 1 (OMMYD-3) international workshop Paris France June8 2015 J Neuromuscul Dis 20185523ndash537

8 Johnson NE Hung M Nasser E et al The impact of pregnancy on myotonic dys-trophy a registry-based study J Neuromuscul Dis 20152447ndash452

9 Campbell C Levin S Siu VM et al Congenital myotonic dystrophy Canadianpopulation-based surveillance study J Pediatr 2013163120ndash123

10 Campbell C Sherlock R Jacob P Blayney M Congenital myotonic dystrophyassisted ventilation duration and outcome Pediatrics 2004113811ndash816

11 Angeard N Gargiulo M Jacquette A et al Cognitive profile in childhood myotonicdystrophy type 1 is there a global impairment Neuromuscul Disord 200717451ndash458

12 Ekstrom AB Hakenas-Plate L Tulinius M Wentz E Cognition and adaptive skills inmyotonic dystrophy type 1 a study of 55 individuals with congenital and childhoodforms Dev Med Child Neurol 200951982ndash990

13 Kroksmark AK Ekstrom AB Bjorck E Tulinius M Myotonic dystrophy muscleinvolvement in relation to disease type and size of expanded CTG-repeat sequenceDev Med Child Neurol 200547478ndash485

14 Johnson NE Ekstrom AB Campbell C et al Parent-reported multi-national study ofthe impact of congenital and childhood onset myotonic dystrophy Dev Med ChildNeurol 201658698ndash705

15 Yao X Yang YS Cui LH et al Subtypes of irritable bowel syndrome on Rome IIIcriteria a multicenter study J Gastroenterol Hepatol 201227760ndash765

Share Your Insights Expertise and Experiencesbull How are you employing drugs and devices in your field

bull What ethical challenges do you face

bull Do you have a case report that is illustrative of a clinical challenge

bull What challenges have you faced or successes have you enjoyed in bringing greater efficiency to your practice

Deliver a high-quality peer-reviewed message to your colleagues in practice submit your paper at NPuborgNCPsubmit

454 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

DOI 101212CPJ000000000000064620199443-454 Published Online before print April 24 2019Neurol Clin Pract

Nicholas E Johnson Eugenio Zapata Aldana Nathalie Angeard et al dystrophy type 1

Consensus-based care recommendations for congenital and childhood-onset myotonic

This information is current as of April 24 2019

ServicesUpdated Information amp

httpcpneurologyorgcontent95443fullhtmlincluding high resolution figures can be found at

References httpcpneurologyorgcontent95443fullhtmlref-list-1

This article cites 14 articles 3 of which you can access for free at

Citations httpcpneurologyorgcontent95443fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpcpneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpcpneurologyorgcgicollectionall_pediatricAll Pediatric

httpcpneurologyorgcgicollectionall_neuromuscular_diseaseAll Neuromuscular Diseasefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

450 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 451

452 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 453

References1 Fu YH Pizzuti A Fenwick RG Jr et al An unstable triplet repeat in a gene related to

myotonic muscular dystrophy Science 19922551256ndash12582 Brook JD McCurrach ME Harley HG et al Molecular basis of myotonic dystrophy

expansion of a trinucleotide (CTG) repeat at the 3rsquo end of a transcript encodinga protein kinase family member Cell 199268799ndash808

3 Mahadevan M Tsilfidis C Sabourin L et al Myotonic dystrophy mutation an unstableCTG repeat in the 3rsquo untranslated region of the gene Science 19922551253ndash1255

4 Harper PS Myotonic Dystrophy 3rd ed London WB Saunders 20015 Bugiardini E Meola G DM-CNS Group Consensus on cerebral involvement in

myotonic dystrophy Neuromuscul Disord 201424445ndash4526 Koch MC Grimm T Harley HG Harper PS Genetic risks for children of women

with myotonic dystrophy Am J Hum Genet 1991481084ndash10917 Gagnon C Heatwole C Hebert LJ et al Report of the third outcome measures in

myotonic dystrophy type 1 (OMMYD-3) international workshop Paris France June8 2015 J Neuromuscul Dis 20185523ndash537

8 Johnson NE Hung M Nasser E et al The impact of pregnancy on myotonic dys-trophy a registry-based study J Neuromuscul Dis 20152447ndash452

9 Campbell C Levin S Siu VM et al Congenital myotonic dystrophy Canadianpopulation-based surveillance study J Pediatr 2013163120ndash123

10 Campbell C Sherlock R Jacob P Blayney M Congenital myotonic dystrophyassisted ventilation duration and outcome Pediatrics 2004113811ndash816

11 Angeard N Gargiulo M Jacquette A et al Cognitive profile in childhood myotonicdystrophy type 1 is there a global impairment Neuromuscul Disord 200717451ndash458

12 Ekstrom AB Hakenas-Plate L Tulinius M Wentz E Cognition and adaptive skills inmyotonic dystrophy type 1 a study of 55 individuals with congenital and childhoodforms Dev Med Child Neurol 200951982ndash990

13 Kroksmark AK Ekstrom AB Bjorck E Tulinius M Myotonic dystrophy muscleinvolvement in relation to disease type and size of expanded CTG-repeat sequenceDev Med Child Neurol 200547478ndash485

14 Johnson NE Ekstrom AB Campbell C et al Parent-reported multi-national study ofthe impact of congenital and childhood onset myotonic dystrophy Dev Med ChildNeurol 201658698ndash705

15 Yao X Yang YS Cui LH et al Subtypes of irritable bowel syndrome on Rome IIIcriteria a multicenter study J Gastroenterol Hepatol 201227760ndash765

Share Your Insights Expertise and Experiencesbull How are you employing drugs and devices in your field

bull What ethical challenges do you face

bull Do you have a case report that is illustrative of a clinical challenge

bull What challenges have you faced or successes have you enjoyed in bringing greater efficiency to your practice

Deliver a high-quality peer-reviewed message to your colleagues in practice submit your paper at NPuborgNCPsubmit

454 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

DOI 101212CPJ000000000000064620199443-454 Published Online before print April 24 2019Neurol Clin Pract

Nicholas E Johnson Eugenio Zapata Aldana Nathalie Angeard et al dystrophy type 1

Consensus-based care recommendations for congenital and childhood-onset myotonic

This information is current as of April 24 2019

ServicesUpdated Information amp

httpcpneurologyorgcontent95443fullhtmlincluding high resolution figures can be found at

References httpcpneurologyorgcontent95443fullhtmlref-list-1

This article cites 14 articles 3 of which you can access for free at

Citations httpcpneurologyorgcontent95443fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpcpneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpcpneurologyorgcgicollectionall_pediatricAll Pediatric

httpcpneurologyorgcgicollectionall_neuromuscular_diseaseAll Neuromuscular Diseasefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 451

452 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 453

References1 Fu YH Pizzuti A Fenwick RG Jr et al An unstable triplet repeat in a gene related to

myotonic muscular dystrophy Science 19922551256ndash12582 Brook JD McCurrach ME Harley HG et al Molecular basis of myotonic dystrophy

expansion of a trinucleotide (CTG) repeat at the 3rsquo end of a transcript encodinga protein kinase family member Cell 199268799ndash808

3 Mahadevan M Tsilfidis C Sabourin L et al Myotonic dystrophy mutation an unstableCTG repeat in the 3rsquo untranslated region of the gene Science 19922551253ndash1255

4 Harper PS Myotonic Dystrophy 3rd ed London WB Saunders 20015 Bugiardini E Meola G DM-CNS Group Consensus on cerebral involvement in

myotonic dystrophy Neuromuscul Disord 201424445ndash4526 Koch MC Grimm T Harley HG Harper PS Genetic risks for children of women

with myotonic dystrophy Am J Hum Genet 1991481084ndash10917 Gagnon C Heatwole C Hebert LJ et al Report of the third outcome measures in

myotonic dystrophy type 1 (OMMYD-3) international workshop Paris France June8 2015 J Neuromuscul Dis 20185523ndash537

8 Johnson NE Hung M Nasser E et al The impact of pregnancy on myotonic dys-trophy a registry-based study J Neuromuscul Dis 20152447ndash452

9 Campbell C Levin S Siu VM et al Congenital myotonic dystrophy Canadianpopulation-based surveillance study J Pediatr 2013163120ndash123

10 Campbell C Sherlock R Jacob P Blayney M Congenital myotonic dystrophyassisted ventilation duration and outcome Pediatrics 2004113811ndash816

11 Angeard N Gargiulo M Jacquette A et al Cognitive profile in childhood myotonicdystrophy type 1 is there a global impairment Neuromuscul Disord 200717451ndash458

12 Ekstrom AB Hakenas-Plate L Tulinius M Wentz E Cognition and adaptive skills inmyotonic dystrophy type 1 a study of 55 individuals with congenital and childhoodforms Dev Med Child Neurol 200951982ndash990

13 Kroksmark AK Ekstrom AB Bjorck E Tulinius M Myotonic dystrophy muscleinvolvement in relation to disease type and size of expanded CTG-repeat sequenceDev Med Child Neurol 200547478ndash485

14 Johnson NE Ekstrom AB Campbell C et al Parent-reported multi-national study ofthe impact of congenital and childhood onset myotonic dystrophy Dev Med ChildNeurol 201658698ndash705

15 Yao X Yang YS Cui LH et al Subtypes of irritable bowel syndrome on Rome IIIcriteria a multicenter study J Gastroenterol Hepatol 201227760ndash765

Share Your Insights Expertise and Experiencesbull How are you employing drugs and devices in your field

bull What ethical challenges do you face

bull Do you have a case report that is illustrative of a clinical challenge

bull What challenges have you faced or successes have you enjoyed in bringing greater efficiency to your practice

Deliver a high-quality peer-reviewed message to your colleagues in practice submit your paper at NPuborgNCPsubmit

454 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

DOI 101212CPJ000000000000064620199443-454 Published Online before print April 24 2019Neurol Clin Pract

Nicholas E Johnson Eugenio Zapata Aldana Nathalie Angeard et al dystrophy type 1

Consensus-based care recommendations for congenital and childhood-onset myotonic

This information is current as of April 24 2019

ServicesUpdated Information amp

httpcpneurologyorgcontent95443fullhtmlincluding high resolution figures can be found at

References httpcpneurologyorgcontent95443fullhtmlref-list-1

This article cites 14 articles 3 of which you can access for free at

Citations httpcpneurologyorgcontent95443fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpcpneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpcpneurologyorgcgicollectionall_pediatricAll Pediatric

httpcpneurologyorgcgicollectionall_neuromuscular_diseaseAll Neuromuscular Diseasefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

452 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 453

References1 Fu YH Pizzuti A Fenwick RG Jr et al An unstable triplet repeat in a gene related to

myotonic muscular dystrophy Science 19922551256ndash12582 Brook JD McCurrach ME Harley HG et al Molecular basis of myotonic dystrophy

expansion of a trinucleotide (CTG) repeat at the 3rsquo end of a transcript encodinga protein kinase family member Cell 199268799ndash808

3 Mahadevan M Tsilfidis C Sabourin L et al Myotonic dystrophy mutation an unstableCTG repeat in the 3rsquo untranslated region of the gene Science 19922551253ndash1255

4 Harper PS Myotonic Dystrophy 3rd ed London WB Saunders 20015 Bugiardini E Meola G DM-CNS Group Consensus on cerebral involvement in

myotonic dystrophy Neuromuscul Disord 201424445ndash4526 Koch MC Grimm T Harley HG Harper PS Genetic risks for children of women

with myotonic dystrophy Am J Hum Genet 1991481084ndash10917 Gagnon C Heatwole C Hebert LJ et al Report of the third outcome measures in

myotonic dystrophy type 1 (OMMYD-3) international workshop Paris France June8 2015 J Neuromuscul Dis 20185523ndash537

8 Johnson NE Hung M Nasser E et al The impact of pregnancy on myotonic dys-trophy a registry-based study J Neuromuscul Dis 20152447ndash452

9 Campbell C Levin S Siu VM et al Congenital myotonic dystrophy Canadianpopulation-based surveillance study J Pediatr 2013163120ndash123

10 Campbell C Sherlock R Jacob P Blayney M Congenital myotonic dystrophyassisted ventilation duration and outcome Pediatrics 2004113811ndash816

11 Angeard N Gargiulo M Jacquette A et al Cognitive profile in childhood myotonicdystrophy type 1 is there a global impairment Neuromuscul Disord 200717451ndash458

12 Ekstrom AB Hakenas-Plate L Tulinius M Wentz E Cognition and adaptive skills inmyotonic dystrophy type 1 a study of 55 individuals with congenital and childhoodforms Dev Med Child Neurol 200951982ndash990

13 Kroksmark AK Ekstrom AB Bjorck E Tulinius M Myotonic dystrophy muscleinvolvement in relation to disease type and size of expanded CTG-repeat sequenceDev Med Child Neurol 200547478ndash485

14 Johnson NE Ekstrom AB Campbell C et al Parent-reported multi-national study ofthe impact of congenital and childhood onset myotonic dystrophy Dev Med ChildNeurol 201658698ndash705

15 Yao X Yang YS Cui LH et al Subtypes of irritable bowel syndrome on Rome IIIcriteria a multicenter study J Gastroenterol Hepatol 201227760ndash765

Share Your Insights Expertise and Experiencesbull How are you employing drugs and devices in your field

bull What ethical challenges do you face

bull Do you have a case report that is illustrative of a clinical challenge

bull What challenges have you faced or successes have you enjoyed in bringing greater efficiency to your practice

Deliver a high-quality peer-reviewed message to your colleagues in practice submit your paper at NPuborgNCPsubmit

454 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

DOI 101212CPJ000000000000064620199443-454 Published Online before print April 24 2019Neurol Clin Pract

Nicholas E Johnson Eugenio Zapata Aldana Nathalie Angeard et al dystrophy type 1

Consensus-based care recommendations for congenital and childhood-onset myotonic

This information is current as of April 24 2019

ServicesUpdated Information amp

httpcpneurologyorgcontent95443fullhtmlincluding high resolution figures can be found at

References httpcpneurologyorgcontent95443fullhtmlref-list-1

This article cites 14 articles 3 of which you can access for free at

Citations httpcpneurologyorgcontent95443fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpcpneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpcpneurologyorgcgicollectionall_pediatricAll Pediatric

httpcpneurologyorgcgicollectionall_neuromuscular_diseaseAll Neuromuscular Diseasefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 5 | October 2019 453

References1 Fu YH Pizzuti A Fenwick RG Jr et al An unstable triplet repeat in a gene related to

myotonic muscular dystrophy Science 19922551256ndash12582 Brook JD McCurrach ME Harley HG et al Molecular basis of myotonic dystrophy

expansion of a trinucleotide (CTG) repeat at the 3rsquo end of a transcript encodinga protein kinase family member Cell 199268799ndash808

3 Mahadevan M Tsilfidis C Sabourin L et al Myotonic dystrophy mutation an unstableCTG repeat in the 3rsquo untranslated region of the gene Science 19922551253ndash1255

4 Harper PS Myotonic Dystrophy 3rd ed London WB Saunders 20015 Bugiardini E Meola G DM-CNS Group Consensus on cerebral involvement in

myotonic dystrophy Neuromuscul Disord 201424445ndash4526 Koch MC Grimm T Harley HG Harper PS Genetic risks for children of women

with myotonic dystrophy Am J Hum Genet 1991481084ndash10917 Gagnon C Heatwole C Hebert LJ et al Report of the third outcome measures in

myotonic dystrophy type 1 (OMMYD-3) international workshop Paris France June8 2015 J Neuromuscul Dis 20185523ndash537

8 Johnson NE Hung M Nasser E et al The impact of pregnancy on myotonic dys-trophy a registry-based study J Neuromuscul Dis 20152447ndash452

9 Campbell C Levin S Siu VM et al Congenital myotonic dystrophy Canadianpopulation-based surveillance study J Pediatr 2013163120ndash123

10 Campbell C Sherlock R Jacob P Blayney M Congenital myotonic dystrophyassisted ventilation duration and outcome Pediatrics 2004113811ndash816

11 Angeard N Gargiulo M Jacquette A et al Cognitive profile in childhood myotonicdystrophy type 1 is there a global impairment Neuromuscul Disord 200717451ndash458

12 Ekstrom AB Hakenas-Plate L Tulinius M Wentz E Cognition and adaptive skills inmyotonic dystrophy type 1 a study of 55 individuals with congenital and childhoodforms Dev Med Child Neurol 200951982ndash990

13 Kroksmark AK Ekstrom AB Bjorck E Tulinius M Myotonic dystrophy muscleinvolvement in relation to disease type and size of expanded CTG-repeat sequenceDev Med Child Neurol 200547478ndash485

14 Johnson NE Ekstrom AB Campbell C et al Parent-reported multi-national study ofthe impact of congenital and childhood onset myotonic dystrophy Dev Med ChildNeurol 201658698ndash705

15 Yao X Yang YS Cui LH et al Subtypes of irritable bowel syndrome on Rome IIIcriteria a multicenter study J Gastroenterol Hepatol 201227760ndash765

Share Your Insights Expertise and Experiencesbull How are you employing drugs and devices in your field

bull What ethical challenges do you face

bull Do you have a case report that is illustrative of a clinical challenge

bull What challenges have you faced or successes have you enjoyed in bringing greater efficiency to your practice

Deliver a high-quality peer-reviewed message to your colleagues in practice submit your paper at NPuborgNCPsubmit

454 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

DOI 101212CPJ000000000000064620199443-454 Published Online before print April 24 2019Neurol Clin Pract

Nicholas E Johnson Eugenio Zapata Aldana Nathalie Angeard et al dystrophy type 1

Consensus-based care recommendations for congenital and childhood-onset myotonic

This information is current as of April 24 2019

ServicesUpdated Information amp

httpcpneurologyorgcontent95443fullhtmlincluding high resolution figures can be found at

References httpcpneurologyorgcontent95443fullhtmlref-list-1

This article cites 14 articles 3 of which you can access for free at

Citations httpcpneurologyorgcontent95443fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpcpneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpcpneurologyorgcgicollectionall_pediatricAll Pediatric

httpcpneurologyorgcgicollectionall_neuromuscular_diseaseAll Neuromuscular Diseasefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

References1 Fu YH Pizzuti A Fenwick RG Jr et al An unstable triplet repeat in a gene related to

myotonic muscular dystrophy Science 19922551256ndash12582 Brook JD McCurrach ME Harley HG et al Molecular basis of myotonic dystrophy

expansion of a trinucleotide (CTG) repeat at the 3rsquo end of a transcript encodinga protein kinase family member Cell 199268799ndash808

3 Mahadevan M Tsilfidis C Sabourin L et al Myotonic dystrophy mutation an unstableCTG repeat in the 3rsquo untranslated region of the gene Science 19922551253ndash1255

4 Harper PS Myotonic Dystrophy 3rd ed London WB Saunders 20015 Bugiardini E Meola G DM-CNS Group Consensus on cerebral involvement in

myotonic dystrophy Neuromuscul Disord 201424445ndash4526 Koch MC Grimm T Harley HG Harper PS Genetic risks for children of women

with myotonic dystrophy Am J Hum Genet 1991481084ndash10917 Gagnon C Heatwole C Hebert LJ et al Report of the third outcome measures in

myotonic dystrophy type 1 (OMMYD-3) international workshop Paris France June8 2015 J Neuromuscul Dis 20185523ndash537

8 Johnson NE Hung M Nasser E et al The impact of pregnancy on myotonic dys-trophy a registry-based study J Neuromuscul Dis 20152447ndash452

9 Campbell C Levin S Siu VM et al Congenital myotonic dystrophy Canadianpopulation-based surveillance study J Pediatr 2013163120ndash123

10 Campbell C Sherlock R Jacob P Blayney M Congenital myotonic dystrophyassisted ventilation duration and outcome Pediatrics 2004113811ndash816

11 Angeard N Gargiulo M Jacquette A et al Cognitive profile in childhood myotonicdystrophy type 1 is there a global impairment Neuromuscul Disord 200717451ndash458

12 Ekstrom AB Hakenas-Plate L Tulinius M Wentz E Cognition and adaptive skills inmyotonic dystrophy type 1 a study of 55 individuals with congenital and childhoodforms Dev Med Child Neurol 200951982ndash990

13 Kroksmark AK Ekstrom AB Bjorck E Tulinius M Myotonic dystrophy muscleinvolvement in relation to disease type and size of expanded CTG-repeat sequenceDev Med Child Neurol 200547478ndash485

14 Johnson NE Ekstrom AB Campbell C et al Parent-reported multi-national study ofthe impact of congenital and childhood onset myotonic dystrophy Dev Med ChildNeurol 201658698ndash705

15 Yao X Yang YS Cui LH et al Subtypes of irritable bowel syndrome on Rome IIIcriteria a multicenter study J Gastroenterol Hepatol 201227760ndash765

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454 Neurology Clinical Practice | Volume 9 Number 5 | October 2019 NeurologyorgCP

DOI 101212CPJ000000000000064620199443-454 Published Online before print April 24 2019Neurol Clin Pract

Nicholas E Johnson Eugenio Zapata Aldana Nathalie Angeard et al dystrophy type 1

Consensus-based care recommendations for congenital and childhood-onset myotonic

This information is current as of April 24 2019

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is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

DOI 101212CPJ000000000000064620199443-454 Published Online before print April 24 2019Neurol Clin Pract

Nicholas E Johnson Eugenio Zapata Aldana Nathalie Angeard et al dystrophy type 1

Consensus-based care recommendations for congenital and childhood-onset myotonic

This information is current as of April 24 2019

ServicesUpdated Information amp

httpcpneurologyorgcontent95443fullhtmlincluding high resolution figures can be found at

References httpcpneurologyorgcontent95443fullhtmlref-list-1

This article cites 14 articles 3 of which you can access for free at

Citations httpcpneurologyorgcontent95443fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpcpneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpcpneurologyorgcgicollectionall_pediatricAll Pediatric

httpcpneurologyorgcgicollectionall_neuromuscular_diseaseAll Neuromuscular Diseasefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract