Myotonic dystrophy: Etiology, clinical features, and diagnosis

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 — Links 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 5^th to 6^th 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 10^th to 12^th 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.