Myotonic Dystrophy - Etiology, Clinical Features, and Diagnosis - Uptodate Free

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Myotonic dystrophy: Etiology,

clinical features, and diagnosis
Myotonic dystrophy: Etiology, clinical features, and diagnosis
Author:
Basil T Darras, MD
Section Editors:
Jeremy M Shefner, MD, PhD
Douglas R Nordli, Jr, MD
Deputy Editor:
John F Dashe, MD, PhD
Literature review current through: Dec 2022. | This topic last

updated: Jun 22, 2022.
INTRODUCTION — Myotonic dystrophy (DM) is

a clinically and genetically heterogeneous disorder. There are two
major forms:
●DM1, for a century known as Steinert disease
●DM2, recognized in 1994 as a milder version of DM1
These autosomal dominant conditions are among the most

common forms of adult-onset muscular dystrophy. However, DM
is more than simply a muscular dystrophy per se, since affected
individuals may show cataracts, cardiac conduction
abnormalities, infertility, and insulin resistance. Furthermore,
there is a severe congenital form of DM1 with marked
developmental disability.
One consequence of the multisystemic nature of this disorder is

that individuals affected by DM1 or DM2 may first present to
internists, cardiologists, ophthalmologists, endocrinologists, and
pediatricians (in the case of DM1), before they see a neurologist.
The genetics, pathophysiology, clinical features, and diagnosis of

DM will be reviewed here. The prognosis and management of DM
are discussed separately. (See "Myotonic dystrophy: Treatment
and prognosis".)
Other muscular dystrophies are also discussed separately. (See

"Duchenne and Becker muscular dystrophy: Clinical features and
diagnosis" and "Emery-Dreifuss muscular dystrophy" and "Limb-
girdle muscular dystrophy" and "Oculopharyngeal, distal, and
congenital muscular dystrophies".)
GENETICS — Myotonic dystrophy type 1 (DM1) results

from an expansion of a cytosine-thymine-guanine (CTG)
trinucleotide repeat in the 3'-untranslated region of the
dystrophia myotonica protein kinase (DMPK) gene on
chromosome 19q 13.3 [1-5]. Wild-type individuals have 5 to 34
CTG repeats at this locus, whereas individuals with classic DM1
have repeats in the hundreds to thousands. In DM1, the
expansion of a normal allele (<35 repeats) into the abnormal
range is rare.
Myotonic dystrophy type 2 (DM2) is caused by an expanded

cytosine-cytosine-thymine-guanine (CCTG) tetranucleotide repeat
expansion located in intron 1 of the ZNF9 gene, also known as
the CNBP gene, on chromosome 3q 21.3 [6]. On normal alleles,
there are 11 to 26 tetranucleotide repeats; on pathogenic alleles,
the number of repeats ranges from 75 to more than 11,000, with
a mean of 5000 repeats [7].
In both DM1 and DM2, the repeat expansion is transcribed into

ribonucleic acid (RNA) but remains untranslated. The marked
intergenerational instability of the size of the repeat expansion
may explain the phenomenon of anticipation, at least in DM1, in
which increased size of the expansion is associated with an
earlier age of onset and more severe clinical phenotype [8,9].
Intergenerational contraction of the CTG repeat has also been
observed [10].
In DM1, the length of the CTG repeat expansion is moderately

correlated with disease severity and age of onset (see
'Phenotypes' below). Another factor that contributes to the
variable clinical expression of DM1 is somatic mosaicism, which is
due to instability of the CTG repeat expansion in somatic cells
during life. The somatic instability is thought to be due to
abnormal deoxyribonucleic acid (DNA) repair [11]. The CTG
expansion is particularly unstable in nondividing cells of the
brain, skeletal muscle, and cardiac muscle, whereas the
expansion is relatively stable in leukocytes [12-14]; this probably
explains why CTG repeat lengths are 5- to 10-fold longer in the
brain, skeletal muscle, and heart compared with CTG repeat
lengths in blood leukocytes [9]. Thus, variations in organ-specific
progression of severity for an individual with DM1 are related, at
least in part, to the burden of somatic mosaicism within each
organ [14,15].
In DM2, there is no definite correlation between repeat length

and disease severity [7,16]. In addition, there is no maternal or
paternal predilection in DM2 for repeat size contraction or
expansion. While the CCTG repeat tract displays
intergenerational instability, transmission to the next generation
more often results in smaller rather than larger repeat lengths,
such that anticipation is rare. However, the CCTG repeat tract also
displays somatic instability, whereby the CCTG repeat length
increases with age. These factors complicate the analysis of
repeat length as related to disease onset and severity.
PATHOPHYSIOLOGY — DM provides an
example of a novel mechanism of disease, that of RNA toxicity,
which results from the expanded repeat in the transcripts from
the mutant DM alleles [17]:
●In myotonic dystrophy type 1 (DM1), the expanded trinucleotide

repeat is located in the 3'-untranslated region of the dystrophia
myotonica protein kinase (DMPK) gene, and also happens to be
located within the promoter region of the adjacent SIX5 gene.
●In myotonic dystrophy type 2 (DM2), the expanded

tetranucleotide repeat is located within the first intron of the
ZNF9 (CNBP) gene.
In each instance, the gene is transcribed into RNA but is not

translated. It is notable that DMPK, a serine-threonine kinase,
shows no functional similarity to ZNF9 (CNBP), an RNA-binding
protein. The fact that both genes were associated by repeat
expansions in transcribed but untranslated regions suggests that
the mutant RNA might have a significant role in the disease
process [18].
Current understanding of the pathophysiology of this disease

posits what is known as a "trans" effect, in which the repeat
expansions exert a dominant toxic effect on other genes not
localized to either the DM1 or DM2 loci. This effect is mediated by
two RNA-binding protein families [19,20]:
●Muscleblind-like (MBNL)
●CUG-BP- and ETR-3-like-factors (CELF)
According to this theory, for which there is some experimental

support, the cytosine-uracil-guanine (CUG) and cytosine-cytosine-
uracil-guanine (CCUG) RNA expansions fold into a hairpin
structure, and these mutant RNAs accumulate in the nucleus
[21]. In DM1, the mutant CUG repeat containing RNA sequesters
MBNL1 and leads to loss of its function [19].
The mutant RNAs alter RNA-binding protein activity, which in turn

results in aberrant splicing and abnormal function of several
genes, including the bridging integrator 1 gene (BIN1) [22], the
skeletal muscle chloride channel [23], the insulin receptor [24],
and cardiac troponin T [25]. Muscle weakness may result from
sequestration of MBNL1 by expanded CUG or CCUG repeats,
leading to alternative splicing of the BIN1 gene and skipping of
muscle-specific exon 11 of BIN1 messenger RNA, which in turn
causes disorganized T tubules and impairs excitation-contraction
coupling (figure 1) [22]. Skeletal muscle chloride channel
dysfunction is responsible for the myotonia [20,26,27] and is
related to increased inclusion of exon 7A during misregulated
alternative splicing of the CLCN1 gene [20]. Mutant RNA appears
to induce expression of the cardiac transcription factor NKX2-5,
which may account for the cardiac conduction disturbances
associated with DM1 [28]. Dysregulation of alpha-dystrobrevin
splicing may also play a role in the muscle weakness and wasting
found with DM1 [29].
EPIDEMIOLOGY — DM is the most common

muscular dystrophy among adults of European ancestry. The
prevalence of DM ranges from 1 in 7400 to 1 in 10,700 in Europe
[30-32]. These prevalence rates are likely to be underestimates; a
2021 study analyzing dried blood spots from the newborn
screening program in the state of New York found cytosine-
thymine-guanine repeat expansions ≥50, and therefore
consistent with a diagnosis of DM1 in 4.76 per 10,000 births, or 1
in 2100 births [33], which is up to five times higher than
previously reported estimates. The prevalence is much higher in
certain regions, including Quebec in Canada and the Basque
region of Spain, suggesting a founder effect [9,34,35]. Among
Asian populations in Taiwan and Black populations in South
Africa, myotonic dystrophy type 1 (DM1) is uncommon or rare
[36-39].
Though less well studied, reports from Europe suggest the

prevalence of myotonic dystrophy type 2 (DM2) is similar to that
of DM1 [40,41]. However, anecdotal evidence suggests that DM2
is less frequent than DM1 in the United States [17]. In a single
center in the US, DM2 was the fifth most common type of
muscular dystrophy but five-fold less common than DM1 [42].
Estimates of the incidence of congenital DM vary widely, ranging

from 2.1 to 28.6 per 100,000 live births in different studies, few of
which were population based [43-46].
PHENOTYPES — Myotonic dystrophy type 1 (DM1)

and type 2 (DM2) are similar in that both are multisystem
disorders characterized by skeletal muscle weakness and
myotonia (ie, abnormally slow or delayed muscle relaxation
following normal muscle contraction with a characteristic
neurophysiologic signature on electromyographic [EMG] testing),
cardiac conduction abnormalities, cataracts, and other
abnormalities (table 1 and table 2) [15,17,47]. DM1 is further
divided into congenital, childhood, classic, and mild phenotypes.
In general, the severity of the DM1 phenotype correlates loosely

with the cytosine-thymine-guanine (CTG) repeat size, but there is
considerable variability and overlap between phenotypes (table
3).
●Individuals with a CTG repeat size between 35 and 49,

designated premutation status or mutable normal, are
asymptomatic.
●A mutation of 50 to approximately 150 CTG repeats can

manifest as a phenotype characterized by mild myotonia,
weakness, or cataracts. (See 'Mild DM1' below.)
●Repeats in the range of 50 to 1000 are seen in individuals with

the classic DM1 phenotype (onset between 10 and 30 years of
age) characterized by muscle wasting and weakness, myotonia,
cataracts, frontal balding, and cardiac conduction defects.
Average lifespan is reduced. (See 'Classic DM1' below.)
●CTG repeat lengths >500 may manifest as childhood DM1,

which typically presents with cognitive and behavioral problems.
Muscle weakness develops later similar to severe adult-onset
classic DM1. Some cases of childhood DM1 occur in children with
repeat lengths ≤500. (See 'Childhood DM1' below.)
●With CTG repeat lengths >1000, DM1 may manifest at birth with
infantile hypotonia, respiratory dysfunction, and the emergence
of intellectual disability; congenital DM1 has also been observed
with CTG repeat lengths between 730 and 1000. (See 'Congenital
DM1' below.)
DM2 is generally a less severe disease than classic DM1. (See

'DM2' below.)
Congenital DM1 — The congenital form of DM1 is

characterized by profound hypotonia, facial diplegia, poor
feeding, arthrogryposis (congenital joint contractures), especially
of the legs, and respiratory failure [9]. The majority of affected
infants (at least 80 percent) have a characteristic "V" shape of the
upper lip that results from facial diplegia [48]. In addition to the
profound hypotonia and facial weakness, physical examination
also shows truncal and appendicular weakness as well as
areflexia or marked hyporeflexia. Arthrogryposis usually involves
at least the ankles, leading to clubfoot deformity.
In some cases, DM1 may present before birth as

polyhydramnios, talipes (clubfoot), and reduced fetal movement
[49]. In the most severely affected infants, polyhydramnios is
common during pregnancy and is related to disturbance in
swallowing [50-55]; polyhydramnios in the mother usually
indicates serious involvement of the fetus [50]. Labor also tends
to be either prolonged or abbreviated, presumably on the basis
of maternal uterine muscle involvement [52,56]. (See
'Complications of pregnancy' below.)
Myotonia is not usually present in the first year of life, and

electrical myotonia is rare; therefore, the hallmark of congenital
DM1 is hypotonia rather than myotonia. Respiratory involvement
is common and is the leading cause of death in the neonatal
period. It may be so severe that the newborn sustains an
asphyxial episode leading to hypoxic brain injury; the
encephalopathy is these cases may so dominate the clinical
presentation that the underlying myopathy is overlooked [50]. In
other cases, neonates with congenital DM1 may be
misdiagnosed with hypoxic-ischemic encephalopathy when white
matter abnormalities on brain magnetic resonance imaging
(MRI), which are commonly seen in DM1, are misattributed to
perinatal injury [57].
Mechanical ventilation is required for 70 to 80 percent or more of

patients [46,50]. Gastrointestinal (GI) and feeding difficulties are
also common, with many children requiring a nasogastric or
gastric feeding tube [46]. The feeding difficulties involve both
sucking and swallowing and are related to weakness of the facial,
masticatory, and pharyngeal muscles. A disturbance of gastric
motility, probably related to the smooth muscle involvement in
DM1, may play a major role in the feeding difficulties in some
infants.
With intensive support, most infants survive the neonatal period,
but the overall mortality rate is approximately 15 to 20 percent,
and approaches 40 percent in severely affected infants [50]. In
severely affected infants, cardiomyopathy may be apparent early
on and contribute to neonatal death [50,58].
In early childhood, there is often a gradual improvement of

motor function. Despite this improvement, some degree of
hypotonia and facial weakness persists; at age three to five, foot
deformities, learning, and behavioral abnormalities present as
the main clinical problems [59]. Subsequently, pronounced
delays are experienced in motor and mental development, with
intellectual disability in 50 to 60 percent of children [55,59,60].
Intelligence quotient (IQ) scores in the 50 to 65 range are
common in congenital DM1 patients who survive the neonatal
period [50], and the majority of children require assistive services
in traditional schools or attend specialized day schools [48].
There appears to be no correlation between the severity of

congenital DM at birth and the extent of complications during
teenage years [59]. As patients with congenital DM1 age, they
develop many of the symptoms and signs of classic, adult-onset
DM1, such as the distal predominance of muscle weakness,
myotonia, and electrocardiogram (ECG) abnormalities. Those
patients who survive early childhood typically experience
significant cardiorespiratory morbidity and mortality. Serious
cardiac rhythm disturbances may occur as early as the second
decade of life in children with the congenital or infantile form of
DM1 [61].
The CTG repeat size associated with congenital DM1 is usually

>1000 [15], though one report noted a few cases with CTG repeat
lengths between 730 and 1000 [62]. Inheritance of congenital
DM1 is maternal in approximately 90 percent of cases [17,63,64].
This phenomenon stems from the much greater likelihood for
anticipation (ie, expansions of CTG repeats) to occur in maternal
compared with paternal transmissions. It is not uncommon for
an adult (typically the mother) to be diagnosed with DM only
after giving birth to an affected neonate, underscoring the
potential for subclinical presentation of this disorder.
Paternally inherited cases of congenital DM are less common,
ranging from 8 to 12 percent of cases in large series [48,65-69].
Whereas mothers of infants with maternally transmitted
congenital DM have larger mean trinucleotide (CTG) repeat sizes
than mothers of patients with childhood or adult-onset disease
[70], fathers of infants with paternally transmitted congenital
DM1 have small repeat sizes and/or are asymptomatic at the
time of the affected child's birth [71].
Childhood DM1 — The childhood (infantile) form of

DM1 typically presents before the age of 10 years with the
involvement of systems and organs other than skeletal muscle.
In most cases, the initial manifestations are cognitive and
behavioral problems such as intellectual impairment with low IQ,
attentional deficits, executive dysfunction, anxiety, and mood
disorders [9,72-75]. The CTG repeat size is usually >500 in
childhood DM1, although some affected children have a repeat
size ≤500 [15,48,76]. Over time, affected children develop muscle
symptoms and physical disability that is similar to severe adult-
onset classic DM1 [9,74,75].
Serious cardiac rhythm disturbances may occur in asymptomatic

adolescents with no or only subtle signs of DM [61]. The rate of
cardiac conduction abnormalities in childhood DM1 is 15 to 20
percent, most commonly atrioventricular block or incomplete
bundle branch block [48]. Sports and physical exercise precipitate
arrhythmias in over one-half of these patients. Fewer than 10
percent of patients have clinical evidence of structural heart
disease including cardiomyopathy and heart failure [48,77].
Classic DM1 — The classic form of DM1 becomes

symptomatic during the second, third, or fourth decade of life.
Major clinical manifestations include (but are not limited to)
skeletal and respiratory muscle weakness, myotonia, cataracts,
cardiac arrhythmias, and excessive daytime somnolence [9]. In
these patients, average lifespan is reduced. The CTG repeat size
is generally in the range of 50 to 1000 [15].
Mild DM1 — The mild (minimal or oligosymptomatic) form

of DM1 is characterized by mild weakness, myotonia, and
cataracts. Age at onset is between 20 to 70 years, typically after
age 40 years, and life expectancy is normal. The CTG repeat size
is usually in the range of 50 to 150 [15].
DM2 — Onset for DM2 ranges from the second to the seventh
decades [9,16], often presenting with myotonia (median 30
years), weakness (median 41 years), or cataracts (median 45
years) [16]. In general, DM2 is a less severe disease than classic
DM1. In most cases, weakness predominantly involves the
proximal muscles, particularly the hip girdle muscles. There is no
clear correlation in DM2 between cytosine-cytosine-thymine-
guanine (CCTG) repeat size and age of onset or other measures
of disease severity.
CLINICAL FEATURES — The clinical features

of DM at presentation differ according to phenotype (see
'Phenotypes' above), though most share muscle weakness and
myotonia (ie, abnormally slow or delayed muscle relaxation
following a normal muscle contraction) as characteristic
manifestations.
Skeletal muscle weakness — Skeletal muscle

weakness is a characteristic feature of myotonic dystrophy type 1
(DM1) and type 2 (DM2). Differences between DM1 and DM2 with
respect to muscle group involvement (table 4) are discussed in
the sections that follow.
Weakness in DM1 — In DM1, weakness occurs most

frequently in facial muscles (levator palpebrae superficialis,
temporalis), sternocleidomastoids, distal muscles of the forearm,
hand intrinsic muscles (leading to compromised finger dexterity),
and ankle dorsiflexors (causing bilateral foot drop) [78-81]. Less
commonly, weakness occurs in the quadriceps, respiratory
muscles, palatal and pharyngeal muscles, tongue, and
extraocular muscles. Muscles of the pelvic girdle, the hamstrings,
and ankle plantar flexors are relatively spared in most cases of
DM1.
Patients with DM1 often have a characteristic facial appearance

due to the pattern and longstanding nature of the muscle
weakness and wasting. The face is long and narrow, and the
palate is high arched. The cheeks are hollowed and the jaw sags.
Ptosis and wasting of the sternocleidomastoid muscles are
common in DM1 and typically absent in DM2.
The natural history of DM1 is that of gradual progression in

weakness.
●In a study that followed 50 patients aged 16 to 67 years with

DM1, muscle weakness at baseline was symmetrical, with neck
flexor and distal muscles weaker than proximal muscle groups
[82]. Using manual muscle testing, the average strength decline
was approximately 1 percent per year, similar for men and
women, and more rapid for distal than proximal muscles (2 to 3
percent for hand grip flexors and 1.2 to 1.6 percent per year for
hip flexors).
●In a series of 158 patients with DM1 who had assessment of

finger flexor muscle strength using a hand-held dynamometer,
strength diminished at a rate of 1.18 kgN/year for women and
1.61 kgN/year for men [79].
As the disease progresses, distal muscles become increasingly

weak, and proximal muscles, perhaps spared in the early stages,
begin to weaken so that gait and stability slowly deteriorate.
Thus, patients with DM1 develop a combination of distal and
proximal weakness (foot dorsiflexor weakness, along with knee
extensor and hip abductor and flexor weakness) that contributes
to an increased incidence of falls. This point is illustrated by the
finding that falls and stumbles in patients with DM1 are 10 times
more frequent than in a group of healthy volunteers [83].
Weakness in DM2 — In DM2, neck flexors and finger

flexors muscles are affected in the earliest stages [84]. Prior to
the identification of its genetic basis, DM2 went by various
names, including proximal myotonic myopathy (PROMM) and
proximal myotonic dystrophy (PDM) [85,86]. These terms
underscore the fact that weakness in the hip girdle region is
often the presenting feature of DM2 [16,87]. Weakness of thigh,
hip flexor, and extensor muscles frequently impairs the ability to
arise from a squat, arise from a chair, or climb stairs [84].
Weakness of elbow extensors in DM2 typically develops along
with proximal leg weakness. In patients with DM2 over 50 years
old, triceps weakness affects approximately 50 percent [16].
Although it is generally symmetrical in distribution, isolated
weakness of one triceps has been reported in DM2 [88].
Facial weakness may occur in DM2, generally in later stages of

the disease, involving approximately 13 percent of patients over
age 50 in one study [16]. However, facial weakness is not as
prominent in DM2 as it is in DM1. Neck flexor muscle
involvement is universal in DM1 and nearly so in DM2 [16].
Weakness of neck flexion and neck extension in DM2 is less
severe than in DM1, where a "dropped head posture" is
occasionally encountered.
Muscle pain — Muscle pain is a very common symptom

in DM1. It does not clearly parallel myotonia and, in fact, it is
more common in the legs, where myotonia cannot be
demonstrated [89].
Most studies have found that pain is also a major complaint and
management concern in DM2 [9,90-93]; by contrast, a single-
center study of 50 patients with DM2 reported pain symptoms
were not common [42]. Pain is one of the symptoms (along with
stiffness and fatigue) that can bring patients with DM2 to medical
attention before the onset of symptomatic weakness [16,94]. The
pain is typically proximal in location, affects the legs more than
the arms, is unrelated to myotonia, varies from day to day, and
may be problematic at rest. Pain in DM2 may be induced by
exercise, palpation, or temperature changes [84,90,91]. Chest
pain may trigger a work-up for heart disease.
The muscle pain and stiffness of DM2 have been likened to those
of fibromyalgia. In one study of 63 randomly selected patients
diagnosed with fibromyalgia, the DM2 mutation was identified in
two (3 percent) [95].
Myotonia — Myotonia is a slowed relaxation following a

normal muscle contraction. Most patients with DM do not
describe symptoms referable to the myotonia (unlike patients
with myotonia congenita), and those who do often refer to it as
muscle stiffness.
Myotonia is most prominent in the early stages of the illness, is

aggravated by cold and stress, and is seen most consistently in
facial, jaw, tongue, and hand intrinsic muscles [89]. Myotonia is
universally present in DM1, whereas myotonia is found in
approximately 75 percent of patients with DM2 [16,94]. Myotonia
is also more pronounced and relatively more constant in severity
in DM1 than DM2. Myotonia varies in DM2, with patients
reporting being free of symptoms for days or weeks [84].
As a clinical sign, myotonia is often best appreciated in the hand

and fingers.
●To elicit grip myotonia, the patient is instructed to grip the

examiner's fingers firmly and then to let go rapidly; in the
presence of myotonia, the relaxation of the fingers is delayed.
●To demonstrate percussion myotonia, the examiner firmly

percusses the thenar eminence (specifically the abductor pollicis
brevis); in the presence of myotonia, the thumb will abduct and
then relax slowly. Alternately, the examiner percusses the
extensor digitorum; in the presence of myotonia, the third digit
will extend and then relax slowly. Percussion myotonia can be
elicited in other muscles as well.
Patients with DM1 (but not DM2) tend to lose clinical myotonia
(grip or percussion) as muscle weakness progresses over time.
Cardiac abnormalities — DM1, and possibly DM2,

is associated with a significantly increased risk of
cardiomyopathy, heart failure, conduction disorders, and
arrhythmias [96], which are potential causes of early mortality.
Arrhythmias or heart block may occasionally be very early
manifestations of DM1, even when neuromuscular symptoms are
mild or even unrecognized. While there is some risk of sudden
death from cardiac arrhythmias in DM1 [97-100] and DM2 [101],
the magnitude of this risk is not easily quantified based on the
available data, which consist mainly of small observational
studies. (See "Myotonic dystrophy: Treatment and prognosis",
section on 'Life expectancy'.)
●In a prospective study of 406 patients with DM1, severe
electrocardiogram (ECG) abnormalities were present in 24
percent at baseline [102]. Severe ECG abnormalities were defined
as rhythm other than sinus, a PR interval ≥240 msec, QRS
duration of ≥120 msec, or second- or third-degree
atrioventricular block.
●In a retrospective multicenter study of 100 patients with DM1, a

PR interval >200 msec or a QRS complex duration of >120 msec
on ECG were independent predictors of infra-Hisian conduction
block [103]. In another study, however, similar ECG parameters
were found to have poor predictive value for infra-Hisian
conduction delay; thus, electrophysiology testing was
recommended for screening of all patients with DM1 to inform
the decision regarding prophylactic pacemaker implantation
[104].
●In a 2021 systematic review of 3677 patients with DM1, the

incidence of atrial fibrillation was 10.9 percent [105].
●A population-based study found that the risk of a cardiac

conduction disorder for patients with DM was 60 times greater
than that of the general population [106].
Conduction disturbances also affect patients with DM2, although

data are sparse. In several small studies, cardiac conduction
defects in patients with DM2 were present in 12 to 37 percent
[16,42,107].
Structural heart abnormalities have also been associated with

DM1 and DM2:
●In a report that evaluated 382 patients with DM1 using

transthoracic echocardiography, the following structural
abnormalities were noted [77]:
•Left ventricular hypertrophy in 20 percent
•Left ventricular dilatation in 19 percent
•Left ventricular systolic dysfunction in 14 percent
•Regional wall motion abnormality in 11 percent

•Left atrial dilatation in 6 percent
•Heart failure was found in 2 percent, based upon clinical history
●Among 100 patients with DM2 who were older than 50 years, a
history of progressive cardiomyopathy in the absence of
myocardial ischemia was found in 7 percent [16].
●In a study of 38 patients with DM2, left ventricular systolic

dysfunction was found in 16 percent [107].
●In an autopsy study of four patients with DM2 and sudden

death, all had dilated cardiomyopathy, and two had conduction
system fibrosis [101].
Respiratory function — Respiratory complications

are common in congenital and classic DM1 and stem from
pharyngoesophageal weakness, weakness and myotonia of
respiratory muscles, and possibly an alteration of central
respiratory drive [108]. Weakness of respiratory muscles leads to
a diminution in vital capacity and causes alveolar hypoventilation.
Respiratory failure may occur, sometimes precipitated by general
anesthesia because of heightened sensitivity to sedatives,
anesthetics, and neuromuscular blocking agents [109].
Respiratory muscle weakness is rare in patients with DM2 [9].
Sleep disturbance — Patients with DM1 often

exhibit hypersomnia and excessive daytime sleepiness (EDS)
[110,111]. The most likely cause is a central disorder of sleep
regulation, rather than sleep fragmentation or a sleep-related
disordered breathing [112,113]. The burden of impaired sleep
and EDS among patients with DM1 is substantial, with prevalence
rates of 33 to 88 percent [114,115]. The wide range of prevalence
rates is likely due to methodologic and population differences
among studies.
While EDS is described in some patients with DM2, it is less

severe and far less prevalent than in DM1. In one case-control
study, the prevalence of EDS among 29 patients with DM1, 29
with DM2, and 65 population controls was 45, 7, and 6 percent,
respectively [116].
A distinction should be drawn between EDS associated with DM
and the narcolepsy phenotype in which EDS, short sleep latency,
and sleep-onset REM are accompanied by sleep paralysis,
cataplexy, and hypnagogic and/or hypnopompic hallucinations.
Endocrine abnormalities — Primary

hypogonadism (low-serum testosterone, elevated serum follicle-
stimulating hormone [FSH] concentration, oligospermia, and
infertility), testicular atrophy, and associated low sperm count
with infertility are common problems in DM1 [117-119] and less
common in DM2 [84].
Insulin hypersecretion is another common finding in patients

with DM. It is thought to be a compensatory beta cell response to
tissue insulin resistance, and related to the formation of an
insulin-resistant receptor because of aberrant regulation of
mRNA [89]. In DM1, insulin resistance is present, but frank
diabetes is uncommon. The prevalence of diabetes is greater in
DM2 [89].
Gastrointestinal involvement — In DM1,

smooth muscle involvement is more common than in other
muscular dystrophies and manifests particularly with
gastrointestinal (GI) symptoms such as colicky abdominal pain,
constipation, diarrhea, and pseudo-obstruction [120]. Irritable
bowel-like symptoms (abdominal pain, bloating, and changes in
bowel habits) are common in DM1.
Upper GI tract involvement is seen in most patients with classic

DM1 and leads to dysphagia with resulting aspiration
pneumonia, an important cause of morbidity and mortality in
DM1. Gallstones also occur in DM1 because of increased tone of
the gall bladder sphincter. The presence and severity of GI
disturbances in DM1 correlate poorly with the degree of skeletal
muscle involvement, and correlate positively with the duration of
skeletal muscle disease [121].
Although GI symptoms were previously considered uncommon in

DM2 [84], a later case-control study that evaluated 29 patients
with genetically proven DM2 found that dysphagia for solid food,
abdominal pain, and constipation were reported by 41, 62, and
62 percent of patients, respectively [122]. These GI symptoms
were significantly more frequent in patients with DM2 than in
healthy controls, but were similar to rates found in patients with
DM1 [122]. A small companion study that evaluated the
subgroup of patients with DM2 and dysphagia found that the
dysphagia was relatively mild when assessed with swallowing
studies [123]. In addition, no patient with DM2 and dysphagia
had a history of aspiration pneumonia or weight loss.
Cognitive impairment — Neonates with DM1

develop cognitive dysfunction in a pattern consistent with
intellectual disability [60]. (See 'Congenital DM1' above.)
Intellectual disability is a prominent feature of the congenital and

childhood (juvenile) forms of DM1 and is often associated with
generalized atrophy on magnetic resonance imaging (MRI)
studies. Intellectual disability is rare in DM2 [84]. In general, for
patients with DM1, the IQ decreases with younger age of onset.
In addition, lower IQ has been correlated with longer CTG
expansions, mainly related to maternal inheritance [124].
There is also evidence for subtle cognitive impairment in patients

with classic DM1 and DM2, particularly involving executive and
visual-spatial dysfunction [60,125-127]. Even patients with IQ
scores in the normal range may show impairment in executive
function and abnormalities in visual perception, constructional
ability, and visual memory [124]. Furthermore, patients with DM1
have been described with personality and behavioral
disturbances [124]. However, the involvement in DM2 appears to
be considerably less than in DM1.
In both classic DM1 and DM2, frontal lobe cognitive impairment

(attention deficits) worsens over time, but does not extend to
other areas of cognition [128]. Thus, cognitive problems do not
show the same degree of deterioration over time that is typical of
muscle dysfunction in DM1.
Other features — A number of other systemic features

are associated with DM1 or DM2 [9,17]:
●Cataracts occur in almost all patients with DM1 and in a

majority of patients with DM2.
●Hearing impairment is common in patients with DM1 and DM2.
In one study, mild to moderate sensorineural hearing loss
localizing to the cochlea was present in approximately half of
adults with DM2 [129].
●Premature frontal balding can affect men and women with DM1
but is uncommon in DM2.
●Creatine kinase concentration may be mildly to moderately

elevated in both DM1 and DM2.
●Abnormal liver function tests are frequent in DM1 and DM2,

with modestly elevated levels of aminotransferases, alkaline
phosphatase, and gamma-glutamyl transpeptidase [130,131].
●Serum immunoglobulin studies will typically disclose

immunoglobulin G (IgG) and immunoglobulin M (IgM)
hypogammaglobulinemia in both DM1 and DM2 [89].
●Several reports suggest that patients with DM can develop an

axonal sensorimotor polyneuropathy [132,133], and that this
manifestation is independent of underlying glucose intolerance
[134].
Cancer susceptibility — Mounting evidence

suggests that DM is associated with an increased risk of cancer.
The largest study evaluated data from the Swedish and Danish
registries that included 1658 patients with myotonic muscular
dystrophy [135]. In 14,170 patient-years of follow-up, the number
of DM cases who developed cancer was twofold higher than
expected (104 versus 52 expected, standardized incidence ratio
2.0 [95% CI 1.6-2.4]). In particular, significantly elevated risk was
found for cancers of the endometrium, brain, ovary, and colon.
A number of earlier case reports also suggested that DM is

associated with an increased risk of neoplasms, mainly for
pilomatricoma (a benign calcifying skin tumor associated with
hair follicles), and multiple basal cell carcinomas of the skin [136].
Neuroimaging — Brain MRI studies in patients with

DM1 demonstrate abnormalities in the frontal and anterior
portion of the temporal lobes, including cortical atrophy and
subcortical white matter hyperintense lesions (image 1) [137].
Ventriculomegaly and white matter abnormalities are commonly
seen in congenital DM1 and may be detected prenatally on fetal
MRI [57]. In a longitudinal MRI study of 33 patients with DM1,
white matter lesions were noted in 49 percent; other findings
included ventriculomegaly, global cortical atrophy, and a
decrease in the volume of deep gray matter structures [138]. The
white and gray matter involvement was progressive with
associated decline in cognitive function over time, suggesting a
neurodegenerative process.
In patients with DM1, and to a limited degree in DM2, positron

emission tomography (PET) studies demonstrate hypoperfusion
of frontal and temporal lobes, a finding that might underlie the
executive dysfunction seen primarily in DM1 and to a lesser
extent in DM2 [139]. Limited MRI data suggest that patients with
DM2 develop loss of gray matter involving the brainstem,
hypothalamic and thalamic regions, and white matter mainly
involving the corpus callosum [140].
Muscle biopsy — Muscle biopsy in DM1 and DM2 is

notable for pathologic alterations, including a marked increase of
internalized nuclei (arrayed in chains in longitudinal section),
severely atrophic muscle fibers with pyknotic nuclear clumps,
muscle fiber necrosis and regeneration of isolated muscle fibers,
architectural changes such as sarcoplasmic masses and ring
fibers, and a preferential atrophy of type I fibers [16,141].
Examples of muscle biopsy specimens from patients with DM are
available online from the Washington University (St. Louis, MO)
Neuromuscular Disease Center.
Complications of
pregnancy — Complications of pregnancy may be seen in
both DM1 and DM2.
●In a study and literature review of DM1, preterm labor before 34

weeks occurred in 19 percent of gestations and was often but not
exclusively attributed to congenitally affected fetuses [142].
There were an increased number of operative deliveries because
of prolonged labor, with a cesarean delivery rate of 36 percent.
Ectopic pregnancy occurred in 4 percent, and placenta previa in 9
percent of gestations. Postpartum hemorrhage due to uterine
atonia was a rare event.
●In a study of 96 pregnancies involving 42 women with DM2,

early and late miscarriages occurred in 13 and 4 percent,
respectively [143]. Preterm labor occurred in 50 percent of
pregnancies, resulting in 27 percent preterm deliveries in women
with overt DM2 in pregnancy.
DIAGNOSIS — In the vast majority of patients with

myotonic dystrophy type 1 (DM1) or typical type 2 (DM2), the
diagnosis can be made clinically and confirmed with genetic
testing.
The diagnostic process begins with the clinical impression that

DM might account for the presenting symptoms and signs.
Typically, patients with DM1 come to medical attention because
of intellectual disability or severe muscle weakness and
myotonia, whereas patients with DM2 usually present with
muscle pain, stiffness, fatigue, or proximal muscle weakness [16].
The clinical diagnosis of one of the DMs can be readily

established when there is muscle weakness and clinical myotonia
in the setting of a positive family history. A family history of
affected neonates (congenital DM) points to the diagnosis of
DM1, as does a distribution of weakness that includes the neck,
face, and distal muscles with relative sparing of the proximal
muscles. Prominent early involvement of neck flexors, finger
flexors, and, later, hip girdle muscles and sparing facial and hand
intrinsic muscles, should suggest the diagnosis of DM2.
Because genetic testing is the gold standard for confirming the

diagnosis of DM1 and DM2, the diagnostic role of
electromyography (EMG) is limited. However, it is still important
in atypical cases where the detection of myotonia provides
support for the diagnosis of DM. EMG is also used when
molecular testing for DM1 or DM2 is normal. In such cases, the
demonstration of electrical myotonia supports the alternative
diagnosis of a channelopathy, such as myotonia congenita,
paramyotonia, and hyperkalemic periodic paralysis.
In some instances, the diagnosis may be challenging for both
DM1 and DM2. As an example, patients may present with muscle
pain and/or mild to moderate elevations in serum creatine
kinase, or with an extramuscular manifestation of DM in the
absence of significant muscle weakness or a family history
[88,144]. In such circumstances, a high index of suspicion for a
DM is required so that appropriate testing can be carried out and
the diagnosis established.
Genetic testing — Specific genetic testing to

demonstrate the presence of an expanded cytosine-thymine-
guanine (CTG) repeat in the dystrophia myotonica protein kinase
(DMPK) gene is the gold standard for the diagnosis of DM1.
Normal DMPK gene alleles contain 5 to 34 CTG repeats. Mutable
normal alleles (premutation alleles) contain 35 to 49 repeats.
Children of individuals with the premutation are at increased risk
of inheriting a larger repeat size and having symptoms. Full
penetrance alleles of ≥50 CTG repeats are associated with disease
manifestations. (See 'Genetics' above.)
Specific genetic testing for the cytosine-cytosine-thymine-

guanine (CCTG) repeat in the ZNF9 (CNBP) gene is appropriate if
DM1 testing is negative and the clinical suspicion of DM is high.
DM2 is caused by a single mutational mechanism, a CCTG
tetranucleotide expansion of ≥75 repeats (up to 11,000 repeats).
(See 'Genetics' above.)
A high-throughput screening technique based on melt curve

analysis seems to detect expanded CTG repeats readily and is
adaptable to large-scale testing programs like newborn
screening [33,145]. Traditional methods used to detect the
expanded CTG repeats include Southern blot or triplet-primed
PCR, but they are technically challenging and not suited for
newborn screening or population studies [145].
Electromyography — It is appropriate to begin the

confirmatory testing for DM1 and DM2 with genetic analysis and
omit electrodiagnostic studies when there is a strong clinical
suspicion for the diagnosis of DM. However, EMG is still an
important test in the evaluation of select patients suspected of
having a myopathic disorder, such as one of the DMs. It is useful
for demonstrating the presence of myotonia if this has not been
found clinically or if uncertainty persists regarding its presence or
absence on examination.
Electrical myotonia typically consists of repetitive discharges of

muscle fiber action potentials at 20 to 80 Hz that wax and wane
in amplitude and frequency, producing a sound often
reminiscent of a dive bomber or a motorcycle engine when
audio-amplified. (See "Overview of electromyography", section
on 'Myotonic discharges'.)
Not every muscle will show evidence for myotonia, so a thorough

EMG examination should include evaluation of multiple distal
arm and facial muscles. Myotonia is generally easier to elicit in
DM1 than DM2 [146]. In DM1, it tends to be waxing-waning (ie,
classic discharges that increase and decrease in both amplitude
and frequency), whereas in DM2 it tends to be waning (ie,
discharges that gradually decrease in frequency or amplitude).
The most distal muscles (the tibialis anterior and first dorsal
interosseous) are most likely to have myotonic discharge in both
disorders. The severity of myotonia correlates with muscle
weakness in DM1, but not in DM2 [146]. In occasional instances
of DM2, neither clinical nor electrical myotonia can be
demonstrated [88,144,147].
Electrical myotonia may also be encountered in nondystrophic

myopathies [148]. These include:
●Myotonia congenita
●Hyperkalemic periodic paralysis
●Paramyotonia congenita
●Adult-onset acid maltase deficiency
Myotonia is present uncommonly in a number of other

conditions, including chronic denervating disorders,
polymyositis, inclusion body myositis, and toxic myopathies (eg,
associated with statins, clofibrate, chloroquine, and colchicine).
Other investigations — Slit lamp examination may

reveal the characteristic posterior subcapsular cataracts, which
are detectable as red and green iridescent opacities.
Electrocardiography (ECG) is critically important for the
recognition and characterization of asymptomatic cardiac
conduction defects that are often encountered in DM1 and DM2
and require vigilant monitoring. (See 'Cardiac abnormalities'
above and "Myotonic dystrophy: Treatment and prognosis",
section on 'Cardiac disturbances'.)
The diagnostic role for muscle biopsy is limited, given the

availability of genetic testing for DM1 or DM2. However, muscle
biopsy may be useful to help distinguish DM2 from an
inflammatory or metabolic myopathy when they cannot be
differentiated by clinical presentation alone. Muscle biopsy may
suggest the diagnosis of DM in atypical cases with minimal
weakness, unexplained elevations in creatine kinase, and
nonspecific EMG findings [88,144].
Differential diagnosis — DM1 and DM2 are the

only known hereditary causes of multisystem DMs. Additional
evaluation with EMG, serum creatine kinase level, and/or muscle
biopsy may be needed to look for other causes of muscle disease
if molecular genetic testing excludes DM1 and DM2 [81].
The differential diagnosis for hereditary distal myopathies

(without myotonia) includes a number of distal muscular
dystrophies/myopathies (table 5), such as [81]:
●Hereditary inclusion body myopathy
●Welander distal myopathy
●Limb-girdle muscular dystrophy (LGMD) types R2

(dysferlinopathy) and R12 (anoctamin 5-related) (see "Limb-girdle
muscular dystrophy")
Besides lacking myotonia, these disorders can be distinguished

from DM1 and DM2 based upon clinical features, muscle biopsy
findings, and molecular genetic testing (table 5).
Although rarely confused with DM, electrical myotonia may be

encountered in a number of nondystrophic myopathies. (See
'Electromyography' above.)
SOCIETY GUIDELINE LINKS — LinksYour activity: 4 p.v.
to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately.
(See "Society guideline links: Muscular dystrophy".)
INFORMATION FOR
PATIENTS — UpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at
the 5th to 6th grade reading level, and they answer the four or five
key questions a patient might have about a given condition.
These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade
reading level and are best for patients who want in-depth
information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this
topic. We encourage you to print or e-mail these topics to your
patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the
keyword(s) of interest.)
●Basics topics (see "Patient education: Muscular dystrophy (The

Basics)")
●Beyond the Basics topics (see "Patient education: Overview of

muscular dystrophies (Beyond the Basics)")
SUMMARY AND
RECOMMENDATIONS
●Description – Myotonic dystrophy type 1 (DM1) and type 2
(DM2) are multisystem disorders characterized by skeletal muscle
weakness and myotonia (table 1), cardiac conduction
abnormalities, cataracts, and other abnormalities (table 2). (See
'Phenotypes' above and 'Clinical features' above.)
●Genetics – DM1 results from an expansion of a cytosine-
thymine-guanine (CTG) trinucleotide repeat in the 3'-untranslated
region of the dystrophia myotonica protein kinase (DMPK) gene.
DM2 is caused by an expansion of a cytosine-cytosine-thymine-
guanine (CCTG) tetranucleotide repeat located in intron 1 of the
ZNF9 (CNBP) gene. (See 'Genetics' above.)
●Pathophysiology – Although the pathophysiology of DM is

incompletely understood, the mechanism appears to involve RNA
toxicity that results from the expanded repeat in the transcripts
from the mutant DM alleles (figure 1). (See 'Pathophysiology'
above.)
●Epidemiology – DM is the most common muscular dystrophy

among adults of European ancestry. (See 'Epidemiology' above.)
●Clinical features and phenotypes – The clinical features of DM

at presentation differ according to phenotype, though most
phenotypes share muscle weakness and myotonia. In general,
the severity of the DM1 phenotype correlates loosely with the
cytosine-thymine-guanine (CTG) repeat size (table 3), but there is
considerable variability and overlap between phenotypes (see
'Phenotypes' above and 'Clinical features' above):
•Congenital DM1 – The congenital form of DM1 is characterized

by hypotonia, poor feeding, and respiratory failure, which is the
leading cause of death in the neonatal period. (See 'Congenital
DM1' above.)
•Childhood DM1 – The childhood form of DM1 typically presents

before the age of 10 years. In most cases, the initial
manifestations are cognitive and behavioral problems. Over time,
affected children develop muscle symptoms and disability that is
similar to severe adult-onset classic DM1. (See 'Childhood DM1'
above.)
•Classic DM1 – The classic form of DM1 becomes symptomatic

during the second, third, or fourth decade of life. Major clinical
manifestations include (but are not limited to) skeletal and
respiratory muscle weakness, myotonia, cataracts, cardiac
arrhythmias, and excessive daytime sleepiness (EDS). Average
lifespan is reduced. (See 'Classic DM1' above.)
•Mild DM1 – The mild form of DM1 is characterized by mild
weakness, myotonia, or cataracts. The age at onset is between 20
to 70 years, though onset is usually after age 40 years. Life
expectancy is normal. (See 'Mild DM1' above.)
•DM2 – The onset of DM2 ranges from the second to the seventh
decades, and the condition often presents with myotonia,
weakness, or cataracts. In most cases, proximal muscle weakness
predominates, particularly involving the hip girdle muscles. In
general, DM2 is a less severe disease than classic DM1 (table 4).
(See 'DM2' above.)
●Evaluation and diagnosis – The diagnosis of DM can usually be

made clinically in a patient with the characteristic presentation
and a positive family history. Genetic testing for an expanded
CTG repeat in the DMPK gene is the gold standard for confirming
the diagnosis of DM1. Testing for the CCTG repeat in the ZNF9
gene is appropriate if DM1 testing is negative. Electromyography
(EMG) will usually demonstrate the presence of myotonia if this
has not been found clinically or if uncertainty persists regarding
its presence or absence on examination. (See 'Diagnosis' above.)
●Differential diagnosis – The differential diagnosis for

hereditary distal myopathies (without myotonia) includes a
number of distal muscular dystrophies/myopathies (table 5),
such as hereditary inclusion body myopathy, Welander distal
myopathy, and limb-girdle muscular dystrophy (LGMD) types R2
and R12. (See 'Differential diagnosis' above.)
●Treatment – There is no disease-modifying therapy available

for the treatment of DM. Management is symptomatic, as
discussed separately. (See "Myotonic dystrophy: Treatment and
prognosis".)
ACKNOWLEDGMENT — The UpToDate

editorial staff acknowledges David A Chad, MD, who contributed
to an earlier version of this topic review.
1. Brook JD, McCurrach ME, Harley HG, et al. Molecular basis of
myotonic dystrophy: expansion of a trinucleotide (CTG)
repeat at the 3' end of a transcript encoding a protein kinase
family member. Cell 1992; 68:799.
2. Buxton J, Shelbourne P, Davies J, et al. Detection of an
unstable fragment of DNA specific to individuals with
myotonic dystrophy. Nature 1992; 355:547.
3. Fu YH, Pizzuti A, Fenwick RG Jr, et al. An unstable triplet
repeat in a gene related to myotonic muscular dystrophy.
Science 1992; 255:1256.
4. Harley HG, Brook JD, Rundle SA, et al. Expansion of an
unstable DNA region and phenotypic variation in myotonic
dystrophy. Nature 1992; 355:545.
5. Mahadevan M, Tsilfidis C, Sabourin L, et al. Myotonic
dystrophy mutation: an unstable CTG repeat in the 3'
untranslated region of the gene. Science 1992; 255:1253.
6. Liquori CL, Ricker K, Moseley ML, et al. Myotonic dystrophy
type 2 caused by a CCTG expansion in intron 1 of ZNF9.
Science 2001; 293:864.
7. Dalton JC, Ranum LPW, Day JW. Myotonic dystrophy type 2.
GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1466/
(Accessed on October 17, 2016).
8. Hamshere MG, Harley H, Harper P, et al. Myotonic dystrophy:
the correlation of (CTG) repeat length in leucocytes with age
at onset is significant only for patients with small expansions.
J Med Genet 1999; 36:59.
9. Udd B, Krahe R. The myotonic dystrophies: molecular,
clinical, and therapeutic challenges. Lancet Neurol 2012;
11:891.
10. Puymirat J, Giguère Y, Mathieu J, Bouchard JP.
Intergenerational contraction of the CTG repeats in 2 families
with myotonic dystrophy type 1. Neurology 2009; 73:2126.
11. Pearson CE, Nichol Edamura K, Cleary JD. Repeat instability:
mechanisms of dynamic mutations. Nat Rev Genet 2005;
6:729.
12. Ashizawa T, Dubel JR, Harati Y. Somatic instability of CTG
repeat in myotonic dystrophy. Neurology 1993; 43:2674.
13. Thornton CA, Johnson K, Moxley RT 3rd. Myotonic dystrophy
patients have larger CTG expansions in skeletal muscle than
in leukocytes. Ann Neurol 1994; 35:104.
14. Morales F, Couto JM, Higham CF, et al. Somatic instability of
the expanded CTG triplet repeat in myotonic dystrophy type
1 is a heritable quantitative trait and modifier of disease
severity. Hum Mol Genet 2012; 21:3558.
15. Turner C, Hilton-Jones D. Myotonic dystrophy: diagnosis,
management and new therapies. Curr Opin Neurol 2014;
27:599.
16. Day JW, Ricker K, Jacobsen JF, et al. Myotonic dystrophy type
2: molecular, diagnostic and clinical spectrum. Neurology
2003; 60:657.
17. Thornton CA. Myotonic dystrophy. Neurol Clin 2014; 32:705.
18. Cho DH, Tapscott SJ. Myotonic dystrophy: emerging
mechanisms for DM1 and DM2. Biochim Biophys Acta 2007;
1772:195.
19. Lee JE, Cooper TA. Pathogenic mechanisms of myotonic
dystrophy. Biochem Soc Trans 2009; 37:1281.
20. Kino Y, Washizu C, Oma Y, et al. MBNL and CELF proteins
regulate alternative splicing of the skeletal muscle chloride
channel CLCN1. Nucleic Acids Res 2009; 37:6477.
21. Cooper TA. A reversal of misfortune for myotonic dystrophy?
N Engl J Med 2006; 355:1825.
22. Fugier C, Klein AF, Hammer C, et al. Misregulated alternative
splicing of BIN1 is associated with T tubule alterations and
muscle weakness in myotonic dystrophy. Nat Med 2011;
17:720.
23. Charlet-B N, Savkur RS, Singh G, et al. Loss of the muscle-
specific chloride channel in type 1 myotonic dystrophy due to
misregulated alternative splicing. Mol Cell 2002; 10:45.
24. Savkur RS, Philips AV, Cooper TA. Aberrant regulation of
insulin receptor alternative splicing is associated with insulin
resistance in myotonic dystrophy. Nat Genet 2001; 29:40.
25. Philips AV, Timchenko LT, Cooper TA. Disruption of splicing
regulated by a CUG-binding protein in myotonic dystrophy.
Science 1998; 280:737.
26. Berg J, Jiang H, Thornton CA, Cannon SC. Truncated ClC-1
mRNA in myotonic dystrophy exerts a dominant-negative
effect on the Cl current. Neurology 2004; 63:2371.
27. Wheeler TM, Lueck JD, Swanson MS, et al. Correction of ClC-1
splicing eliminates chloride channelopathy and myotonia in
mouse models of myotonic dystrophy. J Clin Invest 2007;
117:3952.
28. Yadava RS, Frenzel-McCardell CD, Yu Q, et al. RNA toxicity in
myotonic muscular dystrophy induces NKX2-5 expression.
Nat Genet 2008; 40:61.
29. Nakamori M, Kimura T, Kubota T, et al. Aberrantly spliced
alpha-dystrobrevin alters alpha-syntrophin binding in
myotonic dystrophy type 1. Neurology 2008; 70:677.
30. Magee A, Nevin NC. The epidemiology of myotonic dystrophy
in Northern Ireland. Community Genet 1999; 2:179.
31. Siciliano G, Manca M, Gennarelli M, et al. Epidemiology of
myotonic dystrophy in Italy: re-apprisal after genetic
diagnosis. Clin Genet 2001; 59:344.
32. Norwood FL, Harling C, Chinnery PF, et al. Prevalence of
genetic muscle disease in Northern England: in-depth
analysis of a muscle clinic population. Brain 2009; 132:3175.
33. Johnson NE, Butterfield RJ, Mayne K, et al. Population-Based
Prevalence of Myotonic Dystrophy Type 1 Using Genetic
Analysis of Statewide Blood Screening Program. Neurology
2021; 96:e1045.
34. Yotova V, Labuda D, Zietkiewicz E, et al. Anatomy of a founder
effect: myotonic dystrophy in Northeastern Quebec. Hum
Genet 2005; 117:177.
35. López de Munain A, Blanco A, Emparanza JI, et al. Prevalence
of myotonic dystrophy in Guipúzcoa (Basque Country, Spain).
Neurology 1993; 43:1573.
36. Lotz BP, van der Meyden CH. Myotonic dystrophy. Part I. A
genealogical study in the northern Transvaal. S Afr Med J
1985; 67:812.
37. Ashizawa T, Epstein HF. Ethnic distribution of myotonic
dystrophy gene. Lancet 1991; 338:642.
38. Hsiao KM, Chen SS, Li SY, et al. Epidemiological and genetic
studies of myotonic dystrophy type 1 in Taiwan.
Neuroepidemiology 2003; 22:283.
39. Goldman A, Ramsay M, Jenkins T. Ethnicity and myotonic
dystrophy: a possible explanation for its absence in sub-
Saharan Africa. Ann Hum Genet 1996; 60:57.
40. Suominen T, Bachinski LL, Auvinen S, et al. Population
frequency of myotonic dystrophy: higher than expected
frequency of myotonic dystrophy type 2 (DM2) mutation in
Finland. Eur J Hum Genet 2011; 19:776.
41. Udd B, Meola G, Krahe R, et al. 140th ENMC International
Workshop: Myotonic Dystrophy DM2/PROMM and other
myotonic dystrophies with guidelines on management.
Neuromuscul Disord 2006; 16:403.
42. Roy B, Wu Q, Whitaker CH, Felice KJ. Myotonic Muscular
Dystrophy Type 2 in CT, USA: A Single-Center Experience With
50 Patients. J Clin Neuromuscul Dis 2021; 22:135.
43. Wesström G, Bensch J, Schollin J. Congenital myotonic
dystrophy. Incidence, clinical aspects and early prognosis.
Acta Paediatr Scand 1986; 75:849.
44. González de Dios J, Martínez Frías ML, Egües Jimeno J, et al.
[Epidemiological study of Steinert's congenital myotonic
dystrophy: dysmorphological characteristics]. An Esp Pediatr
1999; 51:389.
45. Darin N, Tulinius M. Neuromuscular disorders in childhood: a
descriptive epidemiological study from western Sweden.
46. Campbell C, Levin S, Siu VM, et al. Congenital myotonic
dystrophy: Canadian population-based surveillance study. J
Pediatr 2013; 163:120.
47. Arsenault ME, Prévost C, Lescault A, et al. Clinical
characteristics of myotonic dystrophy type 1 patients with
small CTG expansions. Neurology 2006; 66:1248.
48. Lagrue E, Dogan C, De Antonio M, et al. A large multicenter
study of pediatric myotonic dystrophy type 1 for evidence-
based management. Neurology 2019; 92:e852.
49. Zaki M, Boyd PA, Impey L, et al. Congenital myotonic
dystrophy: prenatal ultrasound findings and pregnancy
outcome. Ultrasound Obstet Gynecol 2007; 29:284.
50. Darras BT, Volpe JJ. Muscle involvement and restricted
disorders. In: Volpe's Neurology of the Newborn, 6th ed,
Volpe JJ, Inder TE, Darras BT, et al (Eds), Elsevier, Philadephia
2017. p.922.
51. Pearse RG, Höweler CJ. Neonatal form of dystrophia
myotonica. Five cases in preterm babies and a review of
earlier reports. Arch Dis Child 1979; 54:331.
52. Shore RN, MacLachlan TB. Pregnancy with myotonic
dystrophy: course, complications and management. Obstet
Gynecol 1971; 38:448.
53. Dunn LJ, Dierker LI. Recurrent hydramnios in association with
myotonia dystrophica. Obstet Gynecol 1973; 42:104.
54. Moosa A. The feeding difficulty in infantile myotonic
dystrophy. Dev Med Child Neurol 1974; 16:824.
55. Hageman AT, Gabreëls FJ, Liem KD, et al. Congenital
myotonic dystrophy; a report on thirteen cases and a review
of the literature. J Neurol Sci 1993; 115:95.
56. Sarnat HB, O'Connor T, Byrne PA. Clinical effects of myotonic
dystrophy on pregnancy and the neonate. Arch Neurol 1976;
33:459.
57. Peglar LM, Nagaraj UD, Tian C, Venkatesan C. White Matter
Lesions Detected by Magnetic Resonance Imaging in
Neonates and Children With Congenital Myotonic Dystrophy.
Pediatr Neurol 2019; 96:64.
58. Igarashi H, Momoi MY, Yamagata T, et al. Hypertrophic
cardiomyopathy in congenital myotonic dystrophy. Pediatr
Neurol 1998; 18:366.
59. Roig M, Balliu PR, Navarro C, et al. Presentation, clinical
course, and outcome of the congenital form of myotonic
dystrophy. Pediatr Neurol 1994; 11:208.
60. Modoni A, Silvestri G, Pomponi MG, et al. Characterization of
the pattern of cognitive impairment in myotonic dystrophy
type 1. Arch Neurol 2004; 61:1943.
61. Bassez G, Lazarus A, Desguerre I, et al. Severe cardiac
arrhythmias in young patients with myotonic dystrophy type
1. Neurology 2004; 63:1939.
62. Redman JB, Fenwick RG Jr, Fu YH, et al. Relationship between
parental trinucleotide GCT repeat length and severity of
myotonic dystrophy in offspring. JAMA 1993; 269:1960.
63. Tsilfidis C, MacKenzie AE, Mettler G, et al. Correlation
between CTG trinucleotide repeat length and frequency of
severe congenital myotonic dystrophy. Nat Genet 1992;
1:192.
64. De Temmerman N, Sermon K, Seneca S, et al.
Intergenerational instability of the expanded CTG repeat in
the DMPK gene: studies in human gametes and
preimplantation embryos. Am J Hum Genet 2004; 75:325.
65. Nakagawa M, Yamada H, Higuchi I, et al. A case of paternally
inherited congenital myotonic dystrophy. J Med Genet 1994;
31:397.
66. Ohya K, Tachi N, Chiba S, et al. Congenital myotonic
dystrophy transmitted from an asymptomatic father with a
DM-specific gene. Neurology 1994; 44:1958.
67. Tachi N, Ohya K, Yamagata H, et al. Haplotype analysis of
congenital myotonic dystrophy patients from asymptomatic
DM father. Pediatr Neurol 1997; 16:315.
68. de Die-Smulders CE, Smeets HJ, Loots W, et al. Paternal
transmission of congenital myotonic dystrophy. J Med Genet
1997; 34:930.
69. Tanaka Y, Suzuki Y, Shimozawa N, et al. Congenital myotonic
dystrophy: report of paternal transmission. Brain Dev 2000;
22:132.
70. Harley HG, Rundle SA, MacMillan JC, et al. Size of the
unstable CTG repeat sequence in relation to phenotype and
parental transmission in myotonic dystrophy. Am J Hum
Genet 1993; 52:1164.
71. Zeesman S, Carson N, Whelan DT. Paternal transmission of
the congenital form of myotonic dystrophy type 1: a new
case and review of the literature. Am J Med Genet 2002;
107:222.
72. Ekström AB, Hakenäs-Plate L, Tulinius M, Wentz E. Cognition
and adaptive skills in myotonic dystrophy type 1: a study of
55 individuals with congenital and childhood forms. Dev Med
Child Neurol 2009; 51:982.
73. Douniol M, Jacquette A, Cohen D, et al. Psychiatric and
cognitive phenotype of childhood myotonic dystrophy type 1.
Dev Med Child Neurol 2012; 54:905.
74. Angeard N, Jacquette A, Gargiulo M, et al. A new window on
neurocognitive dysfunction in the childhood form of
myotonic dystrophy type 1 (DM1). Neuromuscul Disord 2011;
21:468.
75. Echenne B, Rideau A, Roubertie A, et al. Myotonic dystrophy
type I in childhood Long-term evolution in patients surviving
the neonatal period. Eur J Paediatr Neurol 2008; 12:210.
76. Ho G, Cardamone M, Farrar M. Congenital and childhood
myotonic dystrophy: Current aspects of disease and future
directions. World J Clin Pediatr 2015; 4:66.
77. Bhakta D, Lowe MR, Groh WJ. Prevalence of structural cardiac
abnormalities in patients with myotonic dystrophy type I. Am
Heart J 2004; 147:224.
78. Avaria M, Patterson V. Myotonic dystrophy: relative
sensitivity of symptoms signs and abnormal investigations.
Ulster Med J 1994; 63:151.
79. Whittaker RG, Ferenczi E, Hilton-Jones D. Myotonic dystrophy:
practical issues relating to assessment of strength. J Neurol
Neurosurg Psychiatry 2006; 77:1282.
80. Bouchard JP, Cossette L, Bassez G, Puymirat J. Natural history
of skeletal muscle involvement in myotonic dystrophy type 1:
a retrospective study in 204 cases. J Neurol 2015; 262:285.
81. Bird TD. Myotonic dystrophy type 1. In: GeneReviews
[Internet], Adam MP, Ardinger HH, Pagon RA, et al. (Eds),
University of Washington, Seattle. Available at:
https://www.ncbi.nlm.nih.gov/books/NBK1165/ (Accessed on
January 26, 2021).
82. Mathieu J, Boivin H, Richards CL. Quantitative motor
assessment in myotonic dystrophy. Can J Neurol Sci 2003;
30:129.
83. Wiles CM, Busse ME, Sampson CM, et al. Falls and stumbles
in myotonic dystrophy. J Neurol Neurosurg Psychiatry 2006;
77:393.
84. Meola G, Moxley RT 3rd. Myotonic dystrophy type 2 and
related myotonic disorders. J Neurol 2004; 251:1173.
85. Ricker K, Koch MC, Lehmann-Horn F, et al. Proximal myotonic
myopathy: a new dominant disorder with myotonia, muscle
weakness, and cataracts. Neurology 1994; 44:1448.
86. Udd B, Krahe R, Wallgren-Pettersson C, et al. Proximal
myotonic dystrophy--a family with autosomal dominant
muscular dystrophy, cataracts, hearing loss and
hypogonadism: heterogeneity of proximal myotonic
syndromes? Neuromuscul Disord 1997; 7:217.
87. Papadimas GK, Kekou K, Papadopoulos C, et al. Phenotypic
variability and molecular genetics in proximal myotonic
myopathy. Muscle Nerve 2015; 51:686.
88. Milone M, Batish SD, Daube JR. Myotonic dystrophy type 2
with focal asymmetric muscle weakness and no electrical
myotonia. Muscle Nerve 2009; 39:383.
89. Machuca-Tzili L, Brook D, Hilton-Jones D. Clinical and
molecular aspects of the myotonic dystrophies: a review.
Muscle Nerve 2005; 32:1.
90. Suokas KI, Haanpää M, Kautiainen H, et al. Pain in patients
with myotonic dystrophy type 2: a postal survey in Finland.
91. George A, Schneider-Gold C, Zier S, et al. Musculoskeletal
pain in patients with myotonic dystrophy type 2. Arch Neurol
2004; 61:1938.
92. Meola G. Myotonic dystrophy type 2: the 2020 update. Acta
Myol 2020; 39:222.
93. van Vliet J, Tieleman AA, Verrips A, et al. Qualitative and
Quantitative Aspects of Pain in Patients With Myotonic
Dystrophy Type 2. J Pain 2018; 19:920.
94. Heatwole C, Johnson N, Bode R, et al. Patient-Reported
Impact of Symptoms in Myotonic Dystrophy Type 2 (PRISM-
2). Neurology 2015; 85:2136.
95. Auvinen S, Suominen T, Hannonen P, et al. Myotonic
dystrophy type 2 found in two of sixty-three persons
diagnosed as having fibromyalgia. Arthritis Rheum 2008;
58:3627.
96. Lund M, Diaz LJ, Ranthe MF, et al. Cardiac involvement in
myotonic dystrophy: a nationwide cohort study. Eur Heart J
2014; 35:2158.
97. Fragola PV, Luzi M, Calò L, et al. Cardiac involvement in
myotonic dystrophy. Am J Cardiol 1994; 74:1070.
98. Florek RC, Triffon DW, Mann DE, et al. Electrocardiographic
abnormalities in patients with myotonic dystrophy. West J
Med 1990; 153:24.
99. Hawley RJ, Milner MR, Gottdiener JS, Cohen A. Myotonic heart
disease: a clinical follow-up. Neurology 1991; 41:259.
100. Melacini P, Buja G, Fasoli G, et al. The natural history of
cardiac involvement in myotonic dystrophy: an eight-year
follow-up in 17 patients. Clin Cardiol 1988; 11:231.
101. Schoser BG, Ricker K, Schneider-Gold C, et al. Sudden cardiac
death in myotonic dystrophy type 2. Neurology 2004;
63:2402.
102. Groh WJ, Groh MR, Saha C, et al. Electrocardiographic
abnormalities and sudden death in myotonic dystrophy type
1. N Engl J Med 2008; 358:2688.
103. Joosten IBT, van Lohuizen R, den Uijl DW, et al.
Electrocardiographic predictors of infrahissian conduction
disturbances in myotonic dystrophy type 1. Europace 2021;
23:298.
104. Creta A, Providência R, Gossios T, et al. A Normal
Electrocardiogram Does Not Exclude Infra-Hisian Conduction
Disease in Patients With Myotonic Dystrophy Type 1. JACC
Clin Electrophysiol 2021; 7:1038.
105. Russo V, Papa AA, Lioncino M, et al. Prevalence of atrial
fibrillation in myotonic dystrophy type 1: A systematic review.
106. Johnson NE, Abbott D, Cannon-Albright LA. Relative risks for
comorbidities associated with myotonic dystrophy: A
population-based analysis. Muscle Nerve 2015; 52:659.
107. Wahbi K, Meune C, Bécane HM, et al. Left ventricular
dysfunction and cardiac arrhythmias are frequent in type 2
myotonic dystrophy: a case control study. Neuromuscul
Disord 2009; 19:468.
108. Bogaard JM, van der Meché FG, Hendriks I, Ververs C.
Pulmonary function and resting breathing pattern in
myotonic dystrophy. Lung 1992; 170:143.
109. Klompe L, Lancé M, van der Woerd D, et al.
Anaesthesiological and ventilatory precautions during
cardiac surgery in Steinert's disease. J Card Surg 2007; 22:74.
110. Culebras A. Sleep and neuromuscular disorders. Neurol Clin
2005; 23:1209.
111. Ho G, Widger J, Cardamone M, Farrar MA. Quality of life and
excessive daytime sleepiness in children and adolescents
with myotonic dystrophy type 1. Sleep Med 2017; 32:92.
112. Laberge L, Gagnon C, Dauvilliers Y. Daytime sleepiness and
myotonic dystrophy. Curr Neurol Neurosci Rep 2013; 13:340.
113. Ono S, Takahashi K, Jinnai K, et al. Loss of serotonin-
containing neurons in the raphe of patients with myotonic
dystrophy: a quantitative immunohistochemical study and
relation to hypersomnia. Neurology 1998; 50:535.
114. Laberge L, Bégin P, Montplaisir J, Mathieu J. Sleep complaints
in patients with myotonic dystrophy. J Sleep Res 2004; 13:95.
115. Heatwole C, Bode R, Johnson N, et al. Patient-reported
impact of symptoms in myotonic dystrophy type 1 (PRISM-1).
Neurology 2012; 79:348.
116. Tieleman AA, Knoop H, van de Logt AE, et al. Poor sleep
quality and fatigue but no excessive daytime sleepiness in
myotonic dystrophy type 2. J Neurol Neurosurg Psychiatry
2010; 81:963.
117. Vazquez JA, Pinies JA, Martul P, et al. Hypothalamic-pituitary-
testicular function in 70 patients with myotonic dystrophy. J
Endocrinol Invest 1990; 13:375.
118. Ørngreen MC, Arlien-Søborg P, Duno M, et al. Endocrine
function in 97 patients with myotonic dystrophy type 1. J
Neurol 2012; 259:912.
119. Peric S, Nisic T, Milicev M, et al. Hypogonadism and erectile
dysfunction in myotonic dystrophy type 1. Acta Myol 2013;
32:106.
120. Rönnblom A, Forsberg H, Danielsson A. Gastrointestinal
symptoms in myotonic dystrophy. Scand J Gastroenterol
1996; 31:654.
121. Bellini M, Biagi S, Stasi C, et al. Gastrointestinal
manifestations in myotonic muscular dystrophy. World J
Gastroenterol 2006; 12:1821.
122. Tieleman AA, van Vliet J, Jansen JB, et al. Gastrointestinal
involvement is frequent in Myotonic Dystrophy type 2.
123. Tieleman AA, Knuijt S, van Vliet J, et al. Dysphagia is present
but mild in myotonic dystrophy type 2. Neuromuscul Disord
2009; 19:196.
124. D'Angelo MG, Bresolin N. Cognitive impairment in
neuromuscular disorders. Muscle Nerve 2006; 34:16.
125. Meola G, Sansone V, Perani D, et al. Reduced cerebral blood
flow and impaired visual-spatial function in proximal
myotonic myopathy. Neurology 1999; 53:1042.
126. Meola G, Sansone V, Perani D, et al. Executive dysfunction
and avoidant personality trait in myotonic dystrophy type 1
(DM-1) and in proximal myotonic myopathy (PROMM/DM-2).
127. Gaul C, Schmidt T, Windisch G, et al. Subtle cognitive
dysfunction in adult onset myotonic dystrophy type 1 (DM1)
and type 2 (DM2). Neurology 2006; 67:350.
128. Sansone V, Gandossini S, Cotelli M, et al. Cognitive
impairment in adult myotonic dystrophies: a longitudinal
study. Neurol Sci 2007; 28:9.
129. van Vliet J, Tieleman AA, van Engelen BGM, et al. Hearing
impairment in patients with myotonic dystrophy type 2.
Neurology 2018; 90:e615.
130. Heatwole CR, Miller J, Martens B, Moxley RT 3rd. Laboratory
abnormalities in ambulatory patients with myotonic
dystrophy type 1. Arch Neurol 2006; 63:1149.
131. Achiron A, Barak Y, Magal N, et al. Abnormal liver test results
in myotonic dystrophy. J Clin Gastroenterol 1998; 26:292.
132. Panayiotopoulos CP, Scarpalezos S. Dystrophia myotonica.
Peripheral nerve involvement and pathogenetic implications.
J Neurol Sci 1976; 27:1.
133. Logullo F, Censori B, Danni M, et al. Peripheral neuropathy in
myotonic dystrophy: electrophysiological and clinical
features. Electromyogr Clin Neurophysiol 1992; 32:515.
134. Olson ND, Jou MF, Quast JE, Nuttall FQ. Peripheral
neuropathy in myotonic dystrophy. Relation to glucose
intolerance. Arch Neurol 1978; 35:741.
135. Gadalla SM, Lund M, Pfeiffer RM, et al. Cancer risk among
patients with myotonic muscular dystrophy. JAMA 2011;
306:2480.
136. Mueller CM, Hilbert JE, Martens W, et al. Hypothesis:
neoplasms in myotonic dystrophy. Cancer Causes Control
2009; 20:2009.
137. Donahue LA, Mangla R, Westesson PL. Neuroimaging in
myotonic dystrophy type 1. Neurology 2009; 73:1931.
138. Cabada T, Díaz J, Iridoy M, et al. Longitudinal study in
patients with myotonic dystrophy type 1: correlation of brain
MRI abnormalities with cognitive performances.
Neuroradiology 2021; 63:1019.
139. Meola G, Sansone V. Cerebral involvement in myotonic
dystrophies. Muscle Nerve 2007; 36:294.
140. Minnerop M, Luders E, Specht K, et al. Grey and white matter
loss along cerebral midline structures in myotonic dystrophy
type 2. J Neurol 2008; 255:1904.
141. Lieberman AP, Fischbeck KH. Triplet repeat expansion in
neuromuscular disease. Muscle Nerve 2000; 23:843.
142. Rudnik-Schöneborn S, Zerres K. Outcome in pregnancies
complicated by myotonic dystrophy: a study of 31 patients
and review of the literature. Eur J Obstet Gynecol Reprod Biol
2004; 114:44.
143. Rudnik-Schöneborn S, Schneider-Gold C, Raabe U, et al.
Outcome and effect of pregnancy in myotonic dystrophy
type 2. Neurology 2006; 66:579.
144. Merlini L, Sabatelli P, Columbaro M, et al. Hyper-CK-emia as
the sole manifestation of myotonic dystrophy type 2. Muscle
Nerve 2005; 31:764.
145. Butterfield RJ, Imburgia C, Mayne K, et al. High throughput
screening for expanded CTG repeats in myotonic dystrophy
type 1 using melt curve analysis. Mol Genet Genomic Med
2021; 9:e1619.
146. Logigian EL, Ciafaloni E, Quinn LC, et al. Severity, type, and
distribution of myotonic discharges are different in type 1
and type 2 myotonic dystrophy. Muscle Nerve 2007; 35:479.
147. Young NP, Daube JR, Sorenson EJ, Milone M. Absent,
unrecognized, and minimal myotonic discharges in myotonic
dystrophy type 2. Muscle Nerve 2010; 41:758.
148. Miller TM. Differential diagnosis of myotonic disorders.
Topic 5147 Version 34.0
References
1 : Molecular basis of myotonic dystrophy: expansion of a

trinucleotide (CTG) repeat at the 3' end of a transcript encoding a
protein kinase family member.
2 : Detection of an unstable fragment of DNA specific to individuals

with myotonic dystrophy.
3 : An unstable triplet repeat in a gene related to myotonic

muscular dystrophy.
4 : Expansion of an unstable DNA region and phenotypic variation

in myotonic dystrophy.
5 : Myotonic dystrophy mutation: an unstable CTG repeat in the 3'

untranslated region of the gene.
6 : Myotonic dystrophy type 2 caused by a CCTG expansion in

intron 1 of ZNF9.
7 : Myotonic dystrophy type 2 caused by a CCTG expansion in

intron 1 of ZNF9.
8 : Myotonic dystrophy: the correlation of (CTG) repeat length in

leucocytes with age at onset is significant only for patients with
small expansions.
9 : The myotonic dystrophies: molecular, clinical, and therapeutic

challenges.
10 : Intergenerational contraction of the CTG repeats in 2 families

with myotonic dystrophy type 1.
11 : Repeat instability: mechanisms of dynamic mutations.
12 : Somatic instability of CTG repeat in myotonic dystrophy.
13 : Myotonic dystrophy patients have larger CTG expansions in

skeletal muscle than in leukocytes.
14 : Somatic instability of the expanded CTG triplet repeat in

myotonic dystrophy type 1 is a heritable quantitative trait and
modifier of disease severity.
15 : Myotonic dystrophy: diagnosis, management and new

therapies.
16 : Myotonic dystrophy type 2: molecular, diagnostic and clinical

spectrum.
17 : Myotonic dystrophy.
18 : Myotonic dystrophy: emerging mechanisms for DM1 and DM2.
19 : Pathogenic mechanisms of myotonic dystrophy.
20 : MBNL and CELF proteins regulate alternative splicing of the

skeletal muscle chloride channel CLCN1.
21 : A reversal of misfortune for myotonic dystrophy?
22 : Misregulated alternative splicing of BIN1 is associated with T

tubule alterations and muscle weakness in myotonic dystrophy.
23 : Loss of the muscle-specific chloride channel in type 1 Your activity: 4 p.v.
myotonic dystrophy due to misregulated alternative splicing.
24 : Aberrant regulation of insulin receptor alternative splicing is

associated with insulin resistance in myotonic dystrophy.
25 : Disruption of splicing regulated by a CUG-binding protein in

myotonic dystrophy.
26 : Truncated ClC-1 mRNA in myotonic dystrophy exerts a

dominant-negative effect on the Cl current.
27 : Correction of ClC-1 splicing eliminates chloride channelopathy

and myotonia in mouse models of myotonic dystrophy.
28 : RNA toxicity in myotonic muscular dystrophy induces NKX2-5

expression.
29 : Aberrantly spliced alpha-dystrobrevin alters alpha-syntrophin

binding in myotonic dystrophy type 1.
30 : The epidemiology of myotonic dystrophy in Northern Ireland.
31 : Epidemiology of myotonic dystrophy in Italy: re-apprisal after

genetic diagnosis.
32 : Prevalence of genetic muscle disease in Northern England: in-

depth analysis of a muscle clinic population.
33 : Population-Based Prevalence of Myotonic Dystrophy Type 1

Using Genetic Analysis of Statewide Blood Screening Program.
34 : Anatomy of a founder effect: myotonic dystrophy in

Northeastern Quebec.
35 : Prevalence of myotonic dystrophy in Guipúzcoa (Basque

Country, Spain).
36 : Myotonic dystrophy. Part I. A genealogical study in the Your activity: 4 p.v.
northern Transvaal.
37 : Ethnic distribution of myotonic dystrophy gene.
38 : Epidemiological and genetic studies of myotonic dystrophy

type 1 in Taiwan.
39 : Ethnicity and myotonic dystrophy: a possible explanation for its

absence in sub-Saharan Africa.
40 : Population frequency of myotonic dystrophy: higher than

expected frequency of myotonic dystrophy type 2 (DM2) mutation
in Finland.
41 : 140th ENMC International Workshop: Myotonic Dystrophy

DM2/PROMM and other myotonic dystrophies with guidelines on
management.
42 : Myotonic Muscular Dystrophy Type 2 in CT, USA: A Single-

Center Experience With 50 Patients.
43 : Congenital myotonic dystrophy. Incidence, clinical aspects and

early prognosis.
44 : [Epidemiological study of Steinert's congenital myotonic

dystrophy: dysmorphological characteristics].
45 : Neuromuscular disorders in childhood: a descriptive

epidemiological study from western Sweden.
46 : Congenital myotonic dystrophy: Canadian population-based

surveillance study.
47 : Clinical characteristics of myotonic dystrophy type 1 patients

with small CTG expansions.
48 : A large multicenter study of pediatric myotonic dystrophy type

1 for evidence-based management.
49 : Congenital myotonic dystrophy: prenatal ultrasound findings Your activity: 4 p.v.
and pregnancy outcome.
50 : Congenital myotonic dystrophy: prenatal ultrasound findings

and pregnancy outcome.
51 : Neonatal form of dystrophia myotonica. Five cases in preterm

babies and a review of earlier reports.
52 : Pregnancy with myotonic dystrophy: course, complications

and management.
53 : Recurrent hydramnios in association with myotonia

dystrophica.
54 : The feeding difficulty in infantile myotonic dystrophy.
55 : Congenital myotonic dystrophy; a report on thirteen cases and

a review of the literature.
56 : Clinical effects of myotonic dystrophy on pregnancy and the

neonate.
57 : White Matter Lesions Detected by Magnetic Resonance

Imaging in Neonates and Children With Congenital Myotonic
Dystrophy.
58 : Hypertrophic cardiomyopathy in congenital myotonic

dystrophy.
59 : Presentation, clinical course, and outcome of the congenital

form of myotonic dystrophy.
60 : Characterization of the pattern of cognitive impairment in

myotonic dystrophy type 1.
61 : Severe cardiac arrhythmias in young patients with myotonic

dystrophy type 1.
62 : Relationship between parental trinucleotide GCT repeat length
and severity of myotonic dystrophy in offspring.
63 : Correlation between CTG trinucleotide repeat length and

frequency of severe congenital myotonic dystrophy.
64 : Intergenerational instability of the expanded CTG repeat in the

DMPK gene: studies in human gametes and preimplantation
embryos.
65 : A case of paternally inherited congenital myotonic dystrophy.
66 : Congenital myotonic dystrophy transmitted from an

asymptomatic father with a DM-specific gene.
67 : Haplotype analysis of congenital myotonic dystrophy patients

from asymptomatic DM father.
68 : Paternal transmission of congenital myotonic dystrophy.
69 : Congenital myotonic dystrophy: report of paternal

transmission.
70 : Size of the unstable CTG repeat sequence in relation to

phenotype and parental transmission in myotonic dystrophy.
71 : Paternal transmission of the congenital form of myotonic

dystrophy type 1: a new case and review of the literature.
72 : Cognition and adaptive skills in myotonic dystrophy type 1: a

study of 55 individuals with congenital and childhood forms.
73 : Psychiatric and cognitive phenotype of childhood myotonic

dystrophy type 1.
74 : A new window on neurocognitive dysfunction in the childhood

form of myotonic dystrophy type 1 (DM1).
75 : Myotonic dystrophy type I in childhood Long-term evolution in
patients surviving the neonatal period.
76 : Congenital and childhood myotonic dystrophy: Current aspects

of disease and future directions.
77 : Prevalence of structural cardiac abnormalities in patients with

myotonic dystrophy type I.
78 : Myotonic dystrophy: relative sensitivity of symptoms signs and

abnormal investigations.
79 : Myotonic dystrophy: practical issues relating to assessment of

strength.
80 : Natural history of skeletal muscle involvement in myotonic

dystrophy type 1: a retrospective study in 204 cases.
81 : Natural history of skeletal muscle involvement in myotonic

dystrophy type 1: a retrospective study in 204 cases.
82 : Quantitative motor assessment in myotonic dystrophy.
83 : Falls and stumbles in myotonic dystrophy.
84 : Myotonic dystrophy type 2 and related myotonic disorders.
85 : Proximal myotonic myopathy: a new dominant disorder with

myotonia, muscle weakness, and cataracts.
86 : Proximal myotonic dystrophy--a family with autosomal

dominant muscular dystrophy, cataracts, hearing loss and
hypogonadism: heterogeneity of proximal myotonic syndromes?
87 : Phenotypic variability and molecular genetics in proximal

myotonic myopathy.
88 : Myotonic dystrophy type 2 with focal asymmetric muscle

weakness and no electrical myotonia.
89 : Clinical and molecular aspects of the myotonic dystrophies: aYour activity: 4 p.v.
review.
90 : Pain in patients with myotonic dystrophy type 2: a postal

survey in Finland.
91 : Musculoskeletal pain in patients with myotonic dystrophy type

2.
92 : Myotonic dystrophy type 2: the 2020 update.
93 : Qualitative and Quantitative Aspects of Pain in Patients With

Myotonic Dystrophy Type 2.
94 : Patient-Reported Impact of Symptoms in Myotonic Dystrophy

Type 2 (PRISM-2).
95 : Myotonic dystrophy type 2 found in two of sixty-three persons

diagnosed as having fibromyalgia.
96 : Cardiac involvement in myotonic dystrophy: a nationwide

cohort study.
97 : Cardiac involvement in myotonic dystrophy.
98 : Electrocardiographic abnormalities in patients with myotonic

dystrophy.
99 : Myotonic heart disease: a clinical follow-up.
100 : The natural history of cardiac involvement in myotonic

dystrophy: an eight-year follow-up in 17 patients.
101 : Sudden cardiac death in myotonic dystrophy type 2.
102 : Electrocardiographic abnormalities and sudden death in

103 : Electrocardiographic predictors of infrahissian conduction Your activity: 4 p.v.
disturbances in myotonic dystrophy type 1.
104 : A Normal Electrocardiogram Does Not Exclude Infra-Hisian

Conduction Disease in Patients With Myotonic Dystrophy Type 1.
105 : Prevalence of atrial fibrillation in myotonic dystrophy type 1: A

systematic review.
106 : Relative risks for comorbidities associated with myotonic

dystrophy: A population-based analysis.
107 : Left ventricular dysfunction and cardiac arrhythmias are

frequent in type 2 myotonic dystrophy: a case control study.
108 : Pulmonary function and resting breathing pattern in myotonic

dystrophy.
109 : Anaesthesiological and ventilatory precautions during cardiac

surgery in Steinert's disease.
110 : Sleep and neuromuscular disorders.
111 : Quality of life and excessive daytime sleepiness in children

and adolescents with myotonic dystrophy type 1.
112 : Daytime sleepiness and myotonic dystrophy.
113 : Loss of serotonin-containing neurons in the raphe of patients

with myotonic dystrophy: a quantitative immunohistochemical
study and relation to hypersomnia.
114 : Sleep complaints in patients with myotonic dystrophy.
115 : Patient-reported impact of symptoms in myotonic dystrophy

type 1 (PRISM-1).
116 : Poor sleep quality and fatigue but no excessive daytime

sleepiness in myotonic dystrophy type 2.
117 : Hypothalamic-pituitary-testicular function in 70 patients with
myotonic dystrophy.
118 : Endocrine function in 97 patients with myotonic dystrophy

type 1.
119 : Hypogonadism and erectile dysfunction in myotonic

dystrophy type 1.
120 : Gastrointestinal symptoms in myotonic dystrophy.
121 : Gastrointestinal manifestations in myotonic muscular

dystrophy.
122 : Gastrointestinal involvement is frequent in Myotonic

Dystrophy type 2.
123 : Dysphagia is present but mild in myotonic dystrophy type 2.
124 : Cognitive impairment in neuromuscular disorders.
125 : Reduced cerebral blood flow and impaired visual-spatial

function in proximal myotonic myopathy.
126 : Executive dysfunction and avoidant personality trait in

myotonic dystrophy type 1 (DM-1) and in proximal myotonic
myopathy (PROMM/DM-2).
127 : Subtle cognitive dysfunction in adult onset myotonic

dystrophy type 1 (DM1) and type 2 (DM2).
128 : Cognitive impairment in adult myotonic dystrophies: a

longitudinal study.
129 : Hearing impairment in patients with myotonic dystrophy type

2.
130 : Laboratory abnormalities in ambulatory patients with

131 : Abnormal liver test results in myotonic dystrophy. Your activity: 4 p.v.
132 : Dystrophia myotonica. Peripheral nerve involvement and

pathogenetic implications.
133 : Peripheral neuropathy in myotonic dystrophy:

electrophysiological and clinical features.
134 : Peripheral neuropathy in myotonic dystrophy. Relation to

glucose intolerance.
135 : Cancer risk among patients with myotonic muscular

dystrophy.
136 : Hypothesis: neoplasms in myotonic dystrophy.
137 : Neuroimaging in myotonic dystrophy type 1.
138 : Longitudinal study in patients with myotonic dystrophy type 1:

correlation of brain MRI abnormalities with cognitive
performances.
139 : Cerebral involvement in myotonic dystrophies.
140 : Grey and white matter loss along cerebral midline structures
in myotonic dystrophy type 2.
141 : Triplet repeat expansion in neuromuscular disease.
142 : Outcome in pregnancies complicated by myotonic dystrophy:

a study of 31 patients and review of the literature.
143 : Outcome and effect of pregnancy in myotonic dystrophy type

2.
144 : Hyper-CK-emia as the sole manifestation of myotonic

dystrophy type 2.
145 : High throughput screening for expanded CTG repeats in Your activity: 4 p.v.
myotonic dystrophy type 1 using melt curve analysis.
146 : Severity, type, and distribution of myotonic discharges are

different in type 1 and type 2 myotonic dystrophy.
147 : Absent, unrecognized, and minimal myotonic discharges in

148 : Differential diagnosis of myotonic disorders.

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Myotonic dystrophy: Etiology,

Douglas R Nordli, Jr, MD

Literature review current through: Dec 2022. | This topic last

INTRODUCTION — Myotonic dystrophy (DM) is

●DM1, for a century known as Steinert disease

●DM2, recognized in 1994 as a milder version of DM1

These autosomal dominant conditions are among the most

One consequence of the multisystemic nature of this disorder is

The genetics, pathophysiology, clinical features, and diagnosis of

Other muscular dystrophies are also discussed separately. (See

GENETICS — Myotonic dystrophy type 1 (DM1) results

Myotonic dystrophy type 2 (DM2) is caused by an expanded

In both DM1 and DM2, the repeat expansion is transcribed into

In DM1, the length of the CTG repeat expansion is moderately

In DM2, there is no definite correlation between repeat length

●In myotonic dystrophy type 1 (DM1), the expanded trinucleotide

●In myotonic dystrophy type 2 (DM2), the expanded

In each instance, the gene is transcribed into RNA but is not

Current understanding of the pathophysiology of this disease

●CUG-BP- and ETR-3-like-factors (CELF)

According to this theory, for which there is some experimental

The mutant RNAs alter RNA-binding protein activity, which in turn

EPIDEMIOLOGY — DM is the most common

Though less well studied, reports from Europe suggest the

Estimates of the incidence of congenital DM vary widely, ranging

PHENOTYPES — Myotonic dystrophy type 1 (DM1)

In general, the severity of the DM1 phenotype correlates loosely

●Individuals with a CTG repeat size between 35 and 49,

●A mutation of 50 to approximately 150 CTG repeats can

●Repeats in the range of 50 to 1000 are seen in individuals with

●CTG repeat lengths >500 may manifest as childhood DM1,

DM2 is generally a less severe disease than classic DM1. (See

Congenital DM1 — The congenital form of DM1 is

In some cases, DM1 may present before birth as

Myotonia is not usually present in the first year of life, and

Mechanical ventilation is required for 70 to 80 percent or more of

In early childhood, there is often a gradual improvement of

There appears to be no correlation between the severity of

The CTG repeat size associated with congenital DM1 is usually

Childhood DM1 — The childhood (infantile) form of

Serious cardiac rhythm disturbances may occur in asymptomatic

Classic DM1 — The classic form of DM1 becomes

Mild DM1 — The mild (minimal or oligosymptomatic) form

CLINICAL FEATURES — The clinical features

Skeletal muscle weakness — Skeletal muscle

Weakness in DM1 — In DM1, weakness occurs most

Patients with DM1 often have a characteristic facial appearance

The natural history of DM1 is that of gradual progression in

●In a study that followed 50 patients aged 16 to 67 years with

●In a series of 158 patients with DM1 who had assessment of

As the disease progresses, distal muscles become increasingly

Weakness in DM2 — In DM2, neck flexors and finger

Facial weakness may occur in DM2, generally in later stages of

Muscle pain — Muscle pain is a very common symptom

Myotonia — Myotonia is a slowed relaxation following a

Myotonia is most prominent in the early stages of the illness, is

As a clinical sign, myotonia is often best appreciated in the hand

●To elicit grip myotonia, the patient is instructed to grip the

●To demonstrate percussion myotonia, the examiner firmly

Cardiac abnormalities — DM1, and possibly DM2,

●In a retrospective multicenter study of 100 patients with DM1, a

●In a 2021 systematic review of 3677 patients with DM1, the