View source for Myotonic dystrophy

{{Short description|Disorder in which muscles fail to relax}}
{{Use dmy dates|date=October 2024}}
{{Infobox medical condition
| name          = Myotonic dystrophy
| image         = Myotonic dystrophy muscle distribution.jpg
| caption       = Areas of the body affected in myotonic dystrophy, types 1 and 2, colored in red
| field         = [[Neurology]], [[neuromuscular medicine]], [[physical medicine and rehabilitation]], [[medical genetics]], [[pediatrics]]
| synonyms      = Dystrophia myotonica,<ref name=NIH2016/> myotonia atrophica,<ref name=NIH2016/> myotonia dystrophica,<ref name=NIH2016/> Curschmann–Batten–Steinert syndrome
| symptoms      = [[Muscle loss]], weakness, muscles which [[myotonia]]<ref name=NIH2016/>
| complications = [[Cataracts]], [[intellectual disability]], [[arrhythmia|heart conduction problems]]<ref name=NIH2016/><ref name=Me2015/>
| onset         = 20s to 30s<ref name=NIH2016/>
| duration      = [[chronic (medical)|Long term]]<ref name=NIH2016/>
| types         = Type 1, type 2<ref name=NIH2016/>
| causes        = [[Genetic disorder]] ([[autosomal dominant]])<ref name=NIH2016/>
| risks         = 
| diagnosis     = [[Genetic testing]].<ref name=Me2015/>
| differential  = 
| prevention    = 
| treatment     = Braces, wheelchair, [[pacemakers]], [[non invasive positive pressure ventilation]]<ref name=Me2015/>
| medication    = [[Mexiletine]], [[carbamazepine]], [[tricyclic antidepressants]], [[nonsteroidal anti inflammatory drugs]]<ref name=Me2015/>
| prognosis     = 
| frequency     = >1 in 8,000 people<ref name=NIH2016/>
| deaths        = 
}}
<!-- Definition and symptoms -->
'''Myotonic dystrophy''' ('''DM''') is a type of [[muscular dystrophy]], a group of [[genetic disorder]]s that cause progressive [[muscle loss]] and [[weakness]].<ref name="NIH2016" /> In DM, muscles are often [[myotonia|unable to relax]] after contraction.<ref name="NIH2016" /> Other manifestations may include [[cataracts]], [[intellectual disability]] and [[arrhythmia|heart conduction problems]].<ref name="NIH2016" /><ref name="Me2015" /> In men, there may be early [[balding]] and [[infertility]].<ref name="NIH2016" /> While myotonic dystrophy can occur at any age, onset is typically in the 20s and 30s.<ref name="NIH2016" />

<!-- Causes and diagnosis -->
Myotonic dystrophy is caused by a genetic mutation in one of two genes. Mutation of the ''[[Myotonin-protein kinase|DMPK]]'' gene causes myotonic dystrophy type 1 (DM1). Mutation of ''[[CNBP]]'' gene causes type 2 (DM2).<ref name=NIH2016/> DM is typically [[heredity|inherited]], following an [[autosomal dominant]] inheritance pattern,<ref name=NIH2016/> and it generally [[anticipation (genetics)|worsens with each generation]].<ref name=NIH2016/> A type of DM1 may be apparent at birth.<ref name=NIH2016/> DM2 is generally milder.<ref name=NIH2016/> Diagnosis is confirmed by [[genetic testing]].<ref name=Me2015/>

<!-- Treatment -->
There is no cure.<ref name=Kl2015>{{cite journal|last1=Klein|first1=AF|last2=Dastidar|first2=S|last3=Furling|first3=D|last4=Chuah|first4=MK|title=Therapeutic Approaches for Dominant Muscle Diseases: Highlight on Myotonic Dystrophy.|journal=Current Gene Therapy|date=2015|volume=15|issue=4|pages=329–37|pmid=26122101|doi=10.2174/1566523215666150630120537}}</ref> Treatments may include braces or wheelchairs, [[pacemakers]] and [[non-invasive positive pressure ventilation]].<ref name="Me2015" /> The medications [[mexiletine]] or [[carbamazepine]] can help relax muscles.<ref name="Me2015" /> Pain, if it occurs, may be treated with [[tricyclic antidepressants]] and [[nonsteroidal anti-inflammatory drugs]] (NSAIDs).<ref name=Me2015/>

<!-- Epidemiology and history -->
Myotonic dystrophy affects about 1 in 2,100 people,<ref>{{Cite journal |last=Johnson |first=N. |year=2021 |title=Population-Based Prevalence of Myotonic Dystrophy Type 1 Using Genetic Analysis of Statewide Blood Screening Program |journal=Neurology|volume=96 |issue=7 |pages=e1045–e1053 |doi=10.1212/WNL.0000000000011425 |pmid=33472919 |pmc=8055332 }}</ref> a number that was long estimated to be much lower (often cited as 1 in 8,000), reflecting that not all patients have immediate symptoms and, once they do have symptoms, the long time it typically takes to get to the right diagnosis.<ref name=NIH2016/> It is the most common form of muscular dystrophy that begins in adulthood.<ref name=NIH2016>{{cite web|title=myotonic dystrophy|url=https://ghr.nlm.nih.gov/condition/myotonic-dystrophy|website=GHR|access-date=16 October 2016|date=11 October 2016|url-status=live|archive-url=https://web.archive.org/web/20161018224630/https://ghr.nlm.nih.gov/condition/myotonic-dystrophy|archive-date=18 October 2016}}</ref> It was first described in 1909, with the underlying cause of type 1 determined in 1992.<ref name=Me2015>{{cite journal|last1=Meola|first1=G|last2=Cardani|first2=R|title=Myotonic dystrophies: An update on clinical aspects, genetic, pathology, and molecular pathomechanisms.|journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease|date=April 2015|volume=1852|issue=4|pages=594–606|pmid=24882752|doi=10.1016/j.bbadis.2014.05.019|doi-access=free}}</ref>

==Signs and symptoms==
[[File:Myotonic dystrophy patient.JPG|thumb|left|A 40-year-old with myotonic dystrophy who presented with muscle wasting, bilateral cataracts, and complete [[heart block]]]]

{{multiple image
 | width = 100
 | image1 = Myotonic Dystrophy 2.jpg
 | alt1 = Girl
 | image2 = Myotonic Dystrophy 3.jpg
 | alt2 = Boy
 | footer = Myotonic dystrophy in a girl (left) and a boy (right)
}}
DM causes muscle weakness, early onset of cataracts, and [[myotonia]], which is delayed relaxation of muscles after contraction.<ref name="Johnson2019Continuum" /> Cataracts can be either cortical cataracts with a blue dot appearance or posterior subcapsular cataracts.<ref>{{cite book|last=Yanoff|first=Myron|author2=Jay S. Duker|title=Ophthalmology|year=2008|publisher=Mosby|location=Edinburgh|isbn=978-0323057516|pages=411|edition=3rd}}</ref> Other organs affected include the heart, lungs, gastrointestinal tract, skin, and brain.<ref name="Johnson2019Continuum" /> [[Insulin resistance]] can also occur.<ref name="Johnson2019Continuum" /> Signs and symptoms vary considerably by severity, unusual phenotype, and form (DM1/DM2).{{Citation needed|date=October 2021}} DM1 and DM2 differ in regards to the muscles they affect, age of onset, severity of disease, and extramuscular manifestations.<ref name="Johnson2019Continuum" />

===DM1===
DM1 usually begins in the muscles of the hands, feet, neck, or face.<ref name="Johnson2019Continuum" /> One manifestation of facial weakness is drooping of the eyelid ([[ptosis (eyelid)|ptosis]]).{{citation needed|date=April 2022}} It slowly progresses to involve other muscle groups, including the heart. Myotonia tends to be more prominent in DM1 compared to DM2.<ref name="Johnson2019Continuum" /> Other DM1 manifestations include problems with executive function (e.g., organization, concentration, word-finding) and [[hypersomnia]].<ref name="Johnson2019Continuum">{{cite journal |last1=Johnson |first1=NE |title=Myotonic Muscular Dystrophies. |journal=Continuum (Minneapolis, Minn.) |date=December 2019 |volume=25 |issue=6 |pages=1682–1695 |doi=10.1212/CON.0000000000000793 |pmid=31794466|s2cid=208531759 }}</ref> Abnormalities in the electrical activity of the heart are common in DM1, manifesting as [[arrhythmia]]s or [[heart block|conduction blocks]].<ref name=Me2015 /> Sometimes, [[dilated cardiomyopathy]] occurs.<ref name=Me2015 /> Symptoms onset any time from birth to adulthood.<ref name="Johnson2019Continuum" /> The earlier the disease onset, the greater the variety of possible signs and symptoms. {{citation needed|date=April 2022}} Thus, various diagnostic classifications based on the age of onset/severity of the disease have been proposed, although DM1 manifestations likely lie on a continuum.<ref name="Ho2019DM1Childhood">{{cite journal |last1=Ho |first1=G |last2=Carey |first2=KA |last3=Cardamone |first3=M |last4=Farrar |first4=MA |title=Myotonic dystrophy type 1: clinical manifestations in children and adolescents. |journal=Archives of Disease in Childhood |date=January 2019 |volume=104 |issue=1 |pages=48–52 |doi=10.1136/archdischild-2018-314837 |pmid=29871899|s2cid=46949763 |url=https://unsworks.unsw.edu.au/bitstreams/b488a59d-8dee-4357-97a6-b001f7aec6a7/download |hdl=1959.4/unsworks_61891 |hdl-access=free }}</ref>

====Congenital DM1====
When DM1 onsets at birth, it is called congenital DM1.<ref name="Johnson2019Continuum" /> Manifestations that can be present at birth include [[hypotonia]], respiratory failure, feeding difficulty, and club foot ([[talipes equinovarus]]), any of which tend to resolve over several years.<ref name="Johnson2019Continuum" /> During childhood, intellectual impairment, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorders (ASD) can result.<ref name="Johnson2019Continuum" /> Gastrointestinal issues can result, which can be severe, manifestations including diarrhea, constipation, and fecal incontinence.<ref name="Johnson2019Continuum" /> The symptoms of adult DM often manifest during adolescence.<ref name="Johnson2019Continuum" /> Infantile DM1 can be distinguished as another disease category, or it can be grouped with congenital DM1 or childhood-onset DM1.<ref name="Ho2019DM1Childhood"/>{{citation needed|date=April 2022}}

====Childhood-onset DM1====
Childhood-onset DM1 is defined as the onset of symptoms between ages 1 and 10 years.<ref name="Johnson2019Continuum" /> Manifestations include the same intellectual and gastrointestinal symptoms seen in congenital DM1.<ref name="Johnson2019Continuum" />

===DM2===
DM2 is generally milder than DM1, with generally fewer DM2 people requiring assistive devices than DM1 people.<ref name="Myotonic Dystrophies">{{cite web |url= https://www.lecturio.com/concepts/myotonic-dystrophies/| title= Myotonic Dystrophies
|website=The Lecturio Medical Concept Library |access-date= 11 August 2021}}</ref>
DM2 preferentially affects muscles closer to or on the torso, including the neck flexors, hip flexors, and hip extensors.<ref name="Johnson2019Continuum" /> Muscle pain is prominent in DM2.<ref name="Johnson2019Continuum" /> Heart issues, while still potentially fatal, are less common and severe in DM2 than DM1.<ref name=Me2015 /> Symptoms onset in early to late adulthood.<ref name="Johnson2019Continuum" /> Severe [[congenital]] onset, which can occur in DM1, has not been observed in DM2.<ref name="Myotonic Dystrophies"/>

==Genetics==
[[File:Autosomal dominant - en.svg|thumb|right|Myotonic dystrophy is inherited in an autosomal dominant pattern.]]
Myotonic dystrophy (DM) is a [[Genetics|genetic]] condition that is inherited in an [[autosomal dominant]] pattern, meaning each child of an affected individual has a 50% chance of inheriting the disease. The mutation involves [[satellite DNA]], which is tandemly repeated sequences of DNA that do not code for a protein. The repeats implicated in myotonic dystrophy are either 3 or 4 nucleotides in length, classified as [[microsatellites]]. Disease results from an abnormally increased number of these microsatellites, termed microsatellite expansion.

===DM1===
The microsatellite expansion responsible for DM1 is of [[cytosine]]-[[thymine]]-[[guanine]] (CTG) triplet repeats, termed [[trinucleotide repeat expansion]] and classifying DM1 as one of several [[trinucleotide repeat disorder]]s. This expansion occurs at the end of the ''[[Myotonin-protein kinase|DMPK]]'' gene, in the [[3' untranslated region]]. ''DMPK'' is located on the long arm of [[chromosome 19 (human)|chromosome 19]].<ref name="pmid2037285">{{cite journal | vauthors = Harley HG, Walsh KV, Rundle S, Brook JD, Sarfarazi M, Koch MC, Floyd JL, Harper PS, Shaw DJ | title = Localisation of the myotonic dystrophy locus to 19q13.2-19q13.3 and its relationship to twelve polymorphic loci on 19q | journal = Hum. Genet. | volume = 87 | issue = 1 | pages = 73–80 | date = May 1991 | pmid = 2037285 | doi = 10.1007/BF01213096 | s2cid = 31229908 }}</ref><ref>{{cite journal|last1=Bird|first1=Thomas D.|title=Myotonic Dystrophy Type 1|journal=GeneReviews|date=1 January 1993|url=https://www.ncbi.nlm.nih.gov/books/NBK1165/|access-date=9 May 2016|url-status=live|archive-url=https://web.archive.org/web/20170118123627/https://www.ncbi.nlm.nih.gov/books/NBK1165/|archive-date=18 January 2017|pmid=20301344}}update 2015</ref> ''DMPK'' codes for [[myotonic dystrophy protein kinase]],<ref name="pmid1546325">{{cite journal | vauthors = Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G, Neville C, Narang M, Barceló J, O'Hoy K | title = Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene | journal = Science | volume = 255 | issue = 5049 | pages = 1253–5 | date = March 1992 | pmid = 1546325 | doi = 10.1126/science.1546325 | bibcode = 1992Sci...255.1253M }}</ref> a protein expressed predominantly in skeletal muscle.<ref name="pmid8281152">{{cite journal | vauthors = van der Ven PF, Jansen G, van Kuppevelt TH, Perryman MB, Lupa M, Dunne PW, ter Laak HJ, Jap PH, Veerkamp JH, Epstein HF | title = Myotonic dystrophy kinase is a component of neuromuscular junctions | journal = Hum. Mol. Genet. | volume = 2 | issue = 11 | pages = 1889–94 | date = November 1993 | pmid = 8281152 | doi = 10.1093/hmg/2.11.1889 }}</ref>

Between 5 and 37 repeats are considered normal; between 38 and 49 repeats are considered pre-mutation, and although not producing symptoms, children can have further repeat expansion and symptomatic disease;<ref name=Turner>{{cite journal | vauthors = Turner C, Hilton-Jones D | title = The myotonic dystrophies: diagnosis and management | journal = J. Neurol. Neurosurg. Psychiatry | volume = 81 | issue = 4 | pages = 358–67 | date = April 2010 | pmid = 20176601 | doi = 10.1136/jnnp.2008.158261 | doi-access = free }}</ref> greater than 50 repeats almost invariably is symptomatic, with some noted exceptions. Longer repeats are usually associated with earlier onset and more severe disease.<ref>{{Cite journal |last1=Yum |first1=Kevin |last2=Wang |first2=Eric T |last3=Kalsotra |first3=Auinash |date=2017 |title=Myotonic dystrophy: disease repeat range, penetrance, age of onset, and relationship between repeat size and phenotypes |url=|journal=Current Opinion in Genetics & Development |volume=44 |pages=30–37 |doi=10.1016/j.gde.2017.01.007 |pmid=28213156 |issn=0959-437X|pmc=5447468 }}</ref>

DMPK [[alleles]] with greater than 37 repeats are unstable and additional trinucleotide repeats may be inserted during cell division in [[mitosis]] and [[meiosis]]. Consequently, the children of individuals with premutations or mutations inherit DMPK alleles that are longer than their parents and therefore are more likely to be affected or display an earlier onset and greater severity of the condition, a [[phenomenon]] known as [[anticipation (genetics)|anticipation]]. [[Trinucleotide repeat expansion|Repeat expansion]] is generally considered to be a consequence of the incorporation of additional bases as a result of [[slipped strand mispairing|strand slippage]] during either [[DNA replication]] or [[DNA repair]] synthesis.<ref name="pmid25608779">{{cite journal | vauthors = Usdin K, House NC, Freudenreich CH | title = Repeat instability during DNA repair: Insights from model systems | journal = Crit. Rev. Biochem. Mol. Biol. | volume = 50 | issue = 2 | pages = 142–67 | date = 2015 | pmid = 25608779 | pmc = 4454471 | doi = 10.3109/10409238.2014.999192 }}</ref>  Misalignments occurring during [[homologous recombination]]al repair, double-strand break repair or during other DNA repair processes likely contribute to trinucleotide repeat expansions in DM1.<ref name="pmid25608779" /> Paternal transmission of the congenital form is uncommon (13%), possibly due to selection pressures against sperm with expanded repeats, but juvenile or adult-onset is equally transmitted from either parent. Anticipation tends to be less severe than in cases of maternal inheritance.{{citation needed|date=July 2021}}

The RNA from the expanded trinucleotide repeat region forms intranucleoplasmic hairpin loops due to the extensive hydrogen bonding between C-G base pairs, and it has been demonstrated that these sequester the splicing regulator MBNL1 to form distinctive foci.<ref name="pmid15961406">{{cite journal | vauthors = Ho TH, Savkur RS, Poulos MG, Mancini MA, Swanson MS, Cooper TA | title = Colocalization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophy | journal = J. Cell Sci. | volume = 118 | issue = Pt 13 | pages = 2923–33 | date = July 2005 | pmid = 15961406 | doi = 10.1242/jcs.02404  | doi-access = free }}</ref>

A severe form of DM1, congenital myotonic dystrophy, may appear in newborns of mothers who have DM. Congenital myotonic dystrophy can also be inherited via the paternal gene, although it is said to be relatively rare. Congenital means that the condition is present from birth.<ref name="Myotonic Dystrophies"/>

===DM2===
The microsatellite expansion responsible for DM2 is of cytosine-cytosine-thymine-guanine (CCTG) repeats, classifying it as a tetranucleotide repeat disorder. This expansion occurs in the first intron ''[[CNBP]]'' gene on [[chromosome 3 (human)|chromosome 3]].<ref name="day">{{cite journal | vauthors = Day JW, Ricker K, Jacobsen JF, Rasmussen LJ, Dick KA, Kress W, Schneider C, Koch MC, Beilman GJ, Harrison AR, Dalton JC, Ranum LP | title = Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum | journal =   Neurology| volume =  60| issue =  4| pages =  657–64| date = February 2003 | pmid = 12601109 | doi = 10.1212/01.wnl.0000054481.84978.f9 | s2cid = 35860531 }}</ref><ref name="gen">{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK1466/|title=Myotonic Dystrophy Type 2|last1=Dalton|first1=Joline C.|last2=Ranum|first2=Laura P.W.|last3=Day|first3=John W.|date=1993-01-01|publisher=University of Washington, Seattle|editor-last=Pagon|editor-first=Roberta A.|location=Seattle (WA)|pmid=20301639|editor-last2=Adam|editor-first2=Margaret P.|editor-last3=Ardinger|editor-first3=Holly H.|editor-last4=Wallace|editor-first4=Stephanie E.|editor-last5=Amemiya|editor-first5=Anne|editor-last6=Bean|editor-first6=Lora J.H.|editor-last7=Bird|editor-first7=Thomas D.|editor-last8=Fong|editor-first8=Chin-To|editor-last9=Mefford|editor-first9=Heather C.|url-status=live|archive-url=https://web.archive.org/web/20170128161943/https://www.ncbi.nlm.nih.gov/books/NBK1466/|archive-date=2017-01-28}}updated 2013</ref><ref name="pmid11486088">{{cite journal | vauthors = Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, Day JW, Ranum LP | title = Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9 | journal = Science | volume = 293 | issue = 5531 | pages = 864–7 | date = August 2001 | pmid = 11486088 | doi = 10.1126/science.1062125  | s2cid = 30903810 }}</ref>

The repeat expansion for DM2 is much larger than for DM1, ranging from 75 to over 11,000 repeats.<ref name="day"/> Like DM1, the size of the microsatellite repeat array lengthens from generation to generation.<ref name="Johnson2019Continuum" /> Unlike DM1, anticipation does not result, as the degree of repeat expansion beyond 75 repeats does not affect the age of onset or disease severity.<ref name="Johnson2019Continuum" /><ref name=Turner/>

The repeat expansion produces an RNA transcript that binds to RNA-binding proteins such as MBNL1, as in DM1.<ref name="Johnson2019Continuum" /> Also, repeat expansion likely reduces expression of ''CNBP'', loss of which causes muscle toxicity.<ref name="Johnson2019Continuum" />

==Pathophysiology==
[[File:DM2 Histopathology.jpg|thumb|right|Histopathology of DM2. Muscle biopsy showing mild myopathic changes and grouping of atrophic fast fibers (type 2, highlighted). Immunohistochemical staining for type-1 ("slow") myosin.]]

===Molecular===
Mutations of DM1 and DM2 cause the production of RNA that sequesters RNA-binding proteins, causing dysregulated [[RNA splicing]].<ref name="Johnson2019Continuum" /> This dysregulated RNA splicing is particularly toxic to [[skeletal muscle|skeletal]], [[cardiac muscle|cardiac]], and [[smooth muscle]].<ref>{{Cite journal |last1=Peterson |first1=Janel A. M. |last2=Cooper |first2=Thomas A. |date=2022-11-26 |title=Clinical and Molecular Insights into Gastrointestinal Dysfunction in Myotonic Dystrophy Types 1 & 2 |journal=International Journal of Molecular Sciences |volume=23 |issue=23 |pages=14779 |doi=10.3390/ijms232314779 |pmid=36499107 |pmc=9737721 |issn=1422-0067|doi-access=free }}</ref> One example in DM1 involves the [[chloride channel]] ClC-1.<ref name="Johnson2019Continuum" /> Mutated DMPK RNA binds to [[MBNL1]], causing ClC-1 pre-mRNA to be spliced into the fetal form instead of the adult form.<ref name="Johnson2019Continuum" /> Functional loss of the chloride channel causes myotonia.<ref name="Johnson2019Continuum" />

===Histology===
In DM1, there can be increased central nuclei, angular fibers, fiber atrophy, and pyknotic clumps.<ref name="Johnson2019Continuum" /> There can be selective atrophy of type 1 muscle fibers.<ref name="Gherardi2019Neuropathology_textbook">{{cite book |last1=Gherardi |first1=Romain |last2=Amato |first2=Anthony A. |last3=Lidov |first3=Hart G. |last4=Girolami |first4=Umberto De |editor1-last=Gray |editor1-first=Francoise |editor2-last=Duyckaerts |editor2-first=Charles |editor3-last=Girolami |editor3-first=Umberto de |title=Escourolle and Poirier's manual of basic neuropathology |date=Nov 2018 |publisher=Oxford University Press |location=New York, NY |isbn=9780190675011 |edition=Sixth |chapter=Pathology of Skeletal Muscle | doi = 10.1093/med/9780190675011.001.0001}}</ref> Muscle fibers show signs of degeneration and regeneration.<ref name="Gherardi2019Neuropathology_textbook" /> There is modest fibrosis of the [[endomysium]].<ref name="Gherardi2019Neuropathology_textbook" />

In DM2, there can be variation in the sizes of muscle fibers, although often there are no abnormalities.<ref name="Johnson2019Continuum" /> There is selective atrophy of type 2 muscle fibers. Again, there are central nuclei and nuclear clumps.<ref name="Gherardi2019Neuropathology_textbook" />

==Diagnosis==
{{More medical citations needed|section|date=April 2016}}
The diagnosis of DM1 and DM2 can be difficult due to the large number of neuromuscular disorders, most of which are very rare. One study found that diagnosis is made an average of seven years after symptom onset for DM1, and fourteen years for DM2.<ref name="Hilbert2013DiagnosticDelay">{{cite journal |last1=Hilbert |first1=JE |last2=Ashizawa |first2=T |last3=Day |first3=JW |last4=Luebbe |first4=EA |last5=Martens |first5=WB |last6=McDermott |first6=MP |last7=Tawil |first7=R |last8=Thornton |first8=CA |last9=Moxley RT |first9=3rd |title=Diagnostic odyssey of patients with myotonic dystrophy. |journal=Journal of Neurology |date=October 2013 |volume=260 |issue=10 |pages=2497–504 |doi=10.1007/s00415-013-6993-0 |pmid=23807151|pmc=4162528 }}</ref><ref name="Johnson2019Continuum" />

As a result, people with multiple symptoms that may be explained by a complex disorder such as DM1 or DM2 will generally be referred by their [[primary care physician]] to a [[neurologist]] for diagnosis. Depending on the presentation of symptoms, people may be referred to a number of medical specialists including [[cardiologist]]s, [[ophthalmologist]]s, [[endocrinologist]]s, and [[rheumatologist]]s. In addition, the clinical presentation is obscured by the degree of severity or the presence of unusual [[phenotype]]s.

Though there is presently no cure for DM and management is currently symptom-based, a precise diagnosis is still necessary to anticipate multiple other problems that may develop over time (e.g. cataracts). An accurate diagnosis is important to assist with appropriate medical monitoring and management of symptoms. In addition, genetic counseling should be made available to all people because of the high risk of transmission. Potentially serious [[anesthetic]] risks are important to note, so the presence of this disorder should be brought to the attention of all medical providers.

===Classification===
{|class="wikitable floatright"
|+ Myotonic dystrophy subtypes
|-
! Type
! Gene
! Repeat
! Anticipation
! Severity
|-
| DM1
| ''[[Myotonin-protein kinase|DMPK]]''
| CTG
| Yes
| Moderate-severe
|-
| DM2
| ''[[ZNF9]]''
| CCTG
| Minimal/none
| Mild-moderate
|}

There are two main types of myotonic dystrophy. Type 1 (DM1), also known as Steinert disease, has a severe congenital form and a milder childhood-onset form as well as an adult-onset form.<ref>{{cite web|title=Juvenile-Onset MMD1|url=http://mda.org/disease/myotonic-muscular-dystrophy/signs-and-symptoms/juvenile-onset-mmd1|website=Muscular Dystrophy Association|publisher=MDA|access-date=17 March 2015|url-status=live|archive-url=https://web.archive.org/web/20150308160001/http://mda.org/disease/myotonic-muscular-dystrophy/signs-and-symptoms/juvenile-onset-mmd1|archive-date=8 March 2015}}</ref> This disease is most often in the facial muscles, levator palpebrae superioris, temporalis, sternocleidomastoids, distal muscles of the forearm, hand intrinsic muscles, and ankle dorsiflexors.<ref>{{cite web |url=http://www.uptodate.com/contents/myotonic-dystrophy-etiology-clinical-features-and-diagnosis |title=Myotonic dystrophy: Etiology, clinical features, and diagnosis |access-date=2014-02-15 |url-status=live |archive-url=https://web.archive.org/web/20140222055038/http://www.uptodate.com/contents/myotonic-dystrophy-etiology-clinical-features-and-diagnosis |archive-date=2014-02-22 }}</ref> Type 2 (DM2), also known as proximal myotonic myopathy (PROMM), is rarer and generally manifests with milder signs and symptoms than DM1.<ref name="Myotonic Dystrophies"/>

Other forms of myotonic dystrophy not associated with DM1 or DM2 genetic mutations have been described.<ref name=Turner/> One case which was proposed as a candidate for the "DM3" label,<ref name="pmid15215218">{{cite journal | vauthors = Le Ber I, Martinez M, Campion D, Laquerrière A, Bétard C, Bassez G, Girard C, Saugier-Veber P, Raux G, Sergeant N, Magnier P, Maisonobe T, Eymard B, Duyckaerts C, Delacourte A, Frebourg T, Hannequin D | title = A non-DM1, non-DM2 multisystem myotonic disorder with frontotemporal dementia: phenotype and suggestive mapping of the DM3 locus to chromosome 15q21-24 | journal = Brain | volume = 127 | issue = Pt 9 | pages = 1979–92 | date = September 2004 | pmid = 15215218 | doi = 10.1093/brain/awh216  | doi-access = free }}</ref> was later characterized as an unusual form of inclusion body myopathy associated with [[Paget's disease of bone|Paget's disease]] and [[frontotemporal dementia]].<ref name=Turner/><ref name=gen/><ref name="pmid16684600">{{cite journal | vauthors = Udd B, Meola G, Krahe R, Thornton C, Ranum LP, Bassez G, Kress W, Schoser B, Moxley R | title = 140th ENMC International Workshop: Myotonic Dystrophy DM2/PROMM and other myotonic dystrophies with guidelines on management | journal = Neuromuscul. Disord. | volume = 16 | issue = 6 | pages = 403–13 | date = June 2006 | pmid = 16684600 | doi = 10.1016/j.nmd.2006.03.010  | s2cid = 37453148 }}</ref>

===Genetic testing===
Genetic tests, including [[prenatal testing]], are available for both confirmed forms. Molecular testing is considered the [[Gold standard (test)|gold standard]] of diagnosis.

====Prenatal testing====
Testing at pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a DMPK mutation. This can be done at 10–12 weeks gestation by a procedure called chorionic villus sampling (CVS) that involves removing a tiny piece of the placenta and analyzing DNA from its cells. It can also be done by amniocentesis after 14 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it and those who are interested in learning more should check with their doctor or genetic counselor.
There is also another procedure called preimplantation diagnosis that allows a couple to have a child that is unaffected by the genetic condition in their family. This procedure is experimental and not widely available. Those interested in learning more about this procedure should check with their doctor or genetic counselor.

====Predictive testing====
It is possible to test someone who is at risk for developing DM1 before they show symptoms to see whether they inherited an expanded trinucleotide repeat. This is called predictive testing. Predictive testing cannot determine the age of onset at which someone will begin to have symptoms or the course of the disease. If the child is not having symptoms, the testing is not possible except for emancipated minors as a policy.

===Auxiliary testing===
Electrodiagnostic testing (EMG and NCS) can detect the electrical signs of myotonia before myotonia becomes noticeable to the affected individual.<ref name="Johnson2019Continuum" />

[[Muscle biopsy]] can reveal damage to the muscle, but findings are generally nonspecific and do not greatly aid in diagnosis.<ref name="Johnson2019Continuum" />

==Management==
There is currently no cure for or treatment specific to myotonic dystrophy. Management is focused on the complications of the disease, particularly those related to the lungs and heart, which are life-threatening.<ref name="Ashizawa2018Guidelines" /> Complications relating to the cardiopulmonary system account for 70% of deaths due to DM1.<ref name=Turner/> Compromised lung function can, in turn, contribute to life-threatening complications during anesthesia and pregnancy.<ref name="Ashizawa2018Guidelines" />

Lung complications are the leading cause of death in DM1, warranting lung function monitoring with [[pulmonary function test]]s every 6 months.<ref name="Ashizawa2018Guidelines" /> [[Central sleep apnea]] or [[obstructive sleep apnea]] may cause excessive daytime sleepiness, and these individuals should undergo a sleep study. [[Continuous positive airway pressure|Non-invasive ventilation]] may be offered if there is an abnormality. Otherwise, there is evidence for the use of [[modafinil]] as a central nervous system stimulant, although a [[Cochrane Collaboration|Cochrane]] review has described the evidence thus far as inconclusive.{{citation needed|date=May 2017}}

Cardiac complications are the second leading cause of death in DM1, and commonly no symptoms are present before adverse events.<ref name="Ashizawa2018Guidelines" /> All affected individuals are advised to have an annual or biennial [[ECG]].<ref name="Ashizawa2018Guidelines" /> Pacemaker insertion may be required for individuals with cardiac conduction abnormalities. Improving the quality of life which can be measured using specific questionnaires<ref name="Dany2015"/> is also a main objective of medical care.

===Physical activity===
There is a lack of high-quality evidence to determine the effectiveness and the safety of physical activities for people who have myotonic dystrophy.<ref name=":0">{{Cite journal|last1=Voet|first1=Nicoline Bm|last2=van der Kooi|first2=Elly L.|last3=van Engelen|first3=Baziel Gm|last4=Geurts|first4=Alexander Ch|date=2019|title=Strength training and aerobic exercise training for muscle disease|journal=The Cochrane Database of Systematic Reviews|volume=2019|issue=12|pages=CD003907|doi=10.1002/14651858.CD003907.pub5|issn=1469-493X|pmc=6953420|pmid=31808555}}</ref> Further research is required to determine if combined strength and aerobic training at moderate intensity is safe for people who have neuromuscular diseases, however the combination of aerobic and strength exercises may increase muscle strength.<ref name="pmid17964887">{{cite journal | vauthors = Cup EH, Pieterse AJ, Ten Broek-Pastoor JM, Munneke M, van Engelen BG, Hendricks HT, van der Wilt GJ, Oostendorp RA | title = Exercise therapy and other types of physical therapy for patients with neuromuscular diseases: a systematic review | journal = Arch Phys Med Rehabil | volume = 88 | issue = 11 | pages = 1452–64 | date = November 2007 | pmid = 17964887 | doi = 10.1016/j.apmr.2007.07.024  }}</ref><ref name=":0" /> Aerobic exercise via [[stationary bicycle]] with an ergometer may be safe and effective in improving fitness in people with DM1.<ref name=Orngreen>{{cite journal | vauthors = Orngreen MC, Olsen DB, Vissing J | title = Aerobic training in patients with myotonic dystrophy type 1 | journal = Ann. Neurol. | volume = 57 | issue = 5 | pages = 754–7 | date = May 2005 | pmid = 15852373 | doi = 10.1002/ana.20460 | s2cid = 26547411 }}</ref> Cardiovascular impairments and myotonic sensitivities to exercise and temperature necessitate close monitoring of people and educating people in self-monitoring during exercise via the [[Borg scale]], [[heart rate monitor]]s, and other physical exertion measurements.<ref name=Pandya>{{cite web|author1=Pandya, S|author2=Eichinger, K|title=Role of physical therapy in the assessment and management of individuals with myotonic dystrophy|url=http://www.myotonic.org/?LinkServID=840CCB58-13CE-4E3A-9F5A9130FFD62B7E&amp;showMeta=0|publisher=Myotonic Dystrophy Foundation|access-date=5 May 2012|url-status=live|archive-url=https://web.archive.org/web/20150926111744/http://www.myotonic.org/?LinkServID=840CCB58-13CE-4E3A-9F5A9130FFD62B7E&showMeta=0|archive-date=26 September 2015}}</ref>

===Orthotics===
Muscular weakness of dorsiflexors ([[dorsiflexion]]) hinders the ability to clear the floor during the swing phase of [[gait]] and people may adopt a [[steppage gait]] pattern<ref name=Pandya/> or ankle-foot-[[orthotics]] may be indicated.<ref name=Turner/> Factors such as hand function, skin integrity, and comfort must be assessed before prescription. Neck braces can also be prescribed for neck muscle weakness.<ref name=Turner/>

===Mobility aids and adaptive equipment===
Upper and lower limb weakness, visual impairments, and myotonia may lead to the need for [[mobility aids]] and functional adaptive equipment such as [[buttonhook]]s and handled sponges for optimal hand function. If assistive devices and home adaptations are needed, physical therapists may refer to [[occupational therapist]](s) for further assessment.<ref name=Turner/>

==Prognosis==
[[Life expectancy]] in non-congenital late-onset or adult onset DM1 is in the early 50s,<ref name="Johnson2019Continuum" /> with pulmonary complications being the leading cause of death, followed by cardiac complications.<ref name="Ashizawa2018Guidelines">{{cite journal |last1=Ashizawa |first1=T |last2=Gagnon |first2=C |last3=Groh |first3=WJ |last4=Gutmann |first4=L |last5=Johnson |first5=NE |last6=Meola |first6=G |last7=Moxley R |first7=3rd |last8=Pandya |first8=S |last9=Rogers |first9=MT |last10=Simpson |first10=E |last11=Angeard |first11=N |last12=Bassez |first12=G |last13=Berggren |first13=KN |last14=Bhakta |first14=D |last15=Bozzali |first15=M |last16=Broderick |first16=A |last17=Byrne |first17=JLB |last18=Campbell |first18=C |last19=Cup |first19=E |last20=Day |first20=JW |last21=De Mattia |first21=E |last22=Duboc |first22=D |last23=Duong |first23=T |last24=Eichinger |first24=K |last25=Ekstrom |first25=AB |last26=van Engelen |first26=B |last27=Esparis |first27=B |last28=Eymard |first28=B |last29=Ferschl |first29=M |last30=Gadalla |first30=SM |last31=Gallais |first31=B |last32=Goodglick |first32=T |last33=Heatwole |first33=C |last34=Hilbert |first34=J |last35=Holland |first35=V |last36=Kierkegaard |first36=M |last37=Koopman |first37=WJ |last38=Lane |first38=K |last39=Maas |first39=D |last40=Mankodi |first40=A |last41=Mathews |first41=KD |last42=Monckton |first42=DG |last43=Moser |first43=D |last44=Nazarian |first44=S |last45=Nguyen |first45=L |last46=Nopoulos |first46=P |last47=Petty |first47=R |last48=Phetteplace |first48=J |last49=Puymirat |first49=J |last50=Raman |first50=S |last51=Richer |first51=L |last52=Roma |first52=E |last53=Sampson |first53=J |last54=Sansone |first54=V |last55=Schoser |first55=B |last56=Sterling |first56=L |last57=Statland |first57=J |last58=Subramony |first58=SH |last59=Tian |first59=C |last60=Trujillo |first60=C |last61=Tomaselli |first61=G |last62=Turner |first62=C |last63=Venance |first63=S |last64=Verma |first64=A |last65=White |first65=M |last66=Winblad |first66=S |title=Consensus-based care recommendations for adults with myotonic dystrophy type 1. |journal=Neurology. Clinical Practice |date=December 2018 |volume=8 |issue=6 |pages=507–520 |doi=10.1212/CPJ.0000000000000531 |pmid=30588381|pmc=6294540 }}</ref> DM2 life expectancy has yet to be studied.<ref name="Johnson2019Continuum" />

==Epidemiology==
The [[prevalence]] of DM1 ranges from 5 to 20 per 100,000 (1:20,000–1:5000).<ref name="Johnson2019Continuum" /> Up to 48 per 100,000 (1:2100) individuals tested positive for the mutation of DM1 in New York, although not all of these individuals would have become symptomatic.<ref name="Johnson2021NY_genetic_prevalence">{{cite journal |last1=Johnson |first1=NE |last2=Butterfield |first2=RJ |last3=Mayne |first3=K |last4=Newcomb |first4=T |last5=Imburgia |first5=C |last6=Dunn |first6=D |last7=Duval |first7=B |last8=Feldkamp |first8=ML |last9=Weiss |first9=RB |title=Population-Based Prevalence of Myotonic Dystrophy Type 1 Using Genetic Analysis of Statewide Blood Screening Program. |journal=Neurology |date=16 February 2021 |volume=96 |issue=7 |pages=e1045–e1053 |doi=10.1212/WNL.0000000000011425 |pmid=33472919|pmc=8055332 }}</ref> Again in New York, premutations for DM1 were found in 191 per 100,000 (1:525).<ref name="Johnson2021NY_genetic_prevalence" /> DM2 prevalence is unknown, but genetic studies estimate it to be as high as 1:1830.<ref name="Johnson2019Continuum" /> DM affects males and females approximately equally.{{Citation needed|date=August 2021}} About 30,000 people in the United States are affected.{{Citation needed|date=August 2021}} In most populations, DM1 appears to be more common than DM2. However, recent studies suggest that type 2 may be as common as type 1 among people in Germany and Finland.<ref name=NIH2016/>

DM1 is the most common form of myotonic [[muscular dystrophy]] diagnosed in children, with a prevalence ranging from 1 per 100,000 in Japan to 3–15 per 100,000 in Europe.<ref name=Turner/> The prevalence may be as high as 1 in 500 in regions such as Quebec, possibly due to the [[founder effect]]. The incidence of congenital myotonic dystrophy is thought to be about 1:20,000.

== History ==
Myotonic dystrophy was first described by a German physician, [[Hans Gustav Wilhelm Steinert]], who first published a series of six cases of the condition in 1909.<ref name="pmid30122835">{{cite journal | vauthors = Mishra SK, Singh S, Lee B, Khosa S, Moheb N, Tandon VA | title = "Dystrophia Myotonica" and the Legacy of Hans Gustav Wilhelm Steinert | journal = Ann Indian Acad Neurol | volume = 21 | issue = 2 | pages = 116–118 | date = 2018 | pmid = 30122835 | pmc = 6073962 | doi = 10.4103/aian.AIAN_182_17 | doi-access = free }}</ref>  Isolated case reports of myotonia had been published previously, including reports by Frederick Eustace Batten and Hans Curschmann, and type 1 myotonic dystrophy is therefore sometimes known as Curschmann-Batten-Steinert syndrome.<ref name="pmid7331343">{{cite journal | vauthors = Olbrych-Karpińska B, Tutaj A | title = [Case of Curschmann-Batten-Steinert syndrome] | language = pl | journal = Wiad. Lek. | volume = 34 | issue = 17 | pages = 1467–9 | date = September 1981 | pmid = 7331343 | issn = 0043-5147 }}</ref> The underlying cause of type 1 myotonic dystrophy was determined in 1992.<ref name="Me2015" />

== Research directions ==
Altered splicing of the muscle-specific chloride channel 1 (ClC-1) has been shown to cause the myotonic [[phenotype]] of DM1 and is reversible in mouse models using [[Morpholino]] antisense to modify [[Splicing (genetics)|splicing]] of ClC-1 [[mRNA]].<ref name="Wheeler">{{cite journal | vauthors = Wheeler TM, Lueck JD, Swanson MS, Dirksen RT, Thornton CA | title = Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy | journal = J. Clin. Invest. | volume = 117 | issue = 12 | pages = 3952–7 | date = December 2007 | pmid = 18008009 | pmc = 2075481 | doi = 10.1172/JCI33355  }}</ref>

Some small studies have suggested that [[imipramine]], [[clomipramine]], and [[taurine]] may be useful in the treatment of myotonia.<ref name=Turner/> However, due to the weak evidence and potential side effects such as cardiac arrhythmias, these treatments are rarely used. A recent study in December 2015 showed that a common FDA-approved antibiotic, [[erythromycin]], reduced myotonia in mice.<ref name="Nakamori">{{cite journal | vauthors = Nakamori M, Taylor K, Mochizuki H, Sobczak K, Takahashi MP | title = Oral administration of erythromycin decreases RNA toxicity in myotonic dystrophy | journal = Annals of Clinical and Translational Neurology | volume = 3 | issue = 1 | pages = 42–54 | date = January 2016 | pmid = 26783549 | pmc = 4704483 | doi = 10.1002/acn3.271 }}</ref> Human studies are planned for erythromycin. Erythromycin has been used successfully in patients with gastric issues.<ref name="Rönnblom">{{cite journal | vauthors = Rönnblom A, Andersson S, Hellström PM, Danielsson A | title = Gastric emptying in myotonic dystrophy | journal = Eur. J. Clin. Invest. | volume = 32 | issue = 8 | pages = 570–4 | date = August 2002 | pmid = 12190956 | doi = 10.1046/j.1365-2362.2002.01028.x | s2cid = 12510078 }}</ref>

==References==
{{Reflist|2|refs=
<ref name="Dany2015">{{cite journal | vauthors = Dany A, Barbe C, Rapin A, Réveillère C, Hardouin JB, Morrone I, Wolak-Thierry A, Dramé M, Calmus A, Sacconi S, Bassez G, Tiffreau V, Richard I, Gallais B, Prigent H, Taiar R, Jolly D, Novella JL, Boyer FC | title = Construction of a Quality of Life Questionnaire for slowly progressive neuromuscular disease | journal = Qual Life Res | volume = 24 | issue = 11 | pages = 2615–23 | date = November 2015 | pmid = 26141500 | doi = 10.1007/s11136-015-1013-8 | s2cid = 25834947 }}</ref>
}}

== External links ==
{{Medical resources
| DiseasesDB       = 8739
| ICD10            = {{ICD10|G|71|1|g|70}}
| ICD9             =
| ICDO             =
| OMIM             = 160900
| MedlinePlus      =
| eMedicineSubj    =
| eMedicineTopic   =
| MeshID           = D009223
| GeneReviewsNBK   = NBK1165
| GeneReviewsName  = Myotonic Dystrophy Type 1
| Orphanet         = 206647
| oMIM_mult        = {{OMIM2|602668}}
| geneReviewsNBK2  = NBK1466
| geneReviewsName2 = Myotonic Dystrophy Type 2
}}

{{Muscular dystrophy}}
{{Diseases of myoneural junction and muscle}}
{{Trinucleotide repeat disorders}}
{{Deficiencies of intracellular signaling peptides and proteins}}
{{Transcription factor and coregulator deficiencies}}

[[Category:Autosomal dominant disorders]]
[[Category:Muscular dystrophy|*]]
[[Category:Myoneural junction and neuromuscular diseases]]
[[Category:Trinucleotide repeat disorders]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Wikipedia neurology articles ready to translate]]