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David Hilton-Jones



Additional comments on clinical correlation with CTG repeat expansion size in myotonic dystrophy type 1.

Revised comments concerning pregnancy and reproductive options in myotonic dystrophy.

Updated on 28 November 2012. The previous version of this content can be found here.
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Myotonia is defined at an electrical level as repetitive discharge of the muscle fibre membrane after initial activation, which occurs due to dysfunction of the membrane’s ion channels, most commonly the chloride channel, less commonly the sodium channel. This manifests clinically as stiffness of the muscle and delayed relaxation after voluntary contraction, e.g. difficulty relaxing the grip after clenching the fingers, and stiffness in the thigh muscles and difficulty walking on first moving after rest. Disabling myotonia may respond to mexiletine.

Particular myotonic disorders

Useful clinical distinction can be made between (1) myotonic dystrophies—multisystem disorders in which weakness is a significant feature, and (2) nondystrophic myotonias.

Myotonic dystrophy type 1 (Steinert’s disease)—caused by expansion of an unstable trinucleotide repeat in the myotonic dystrophy protein kinase (DMPK) gene, leading to myotonia through altered splicing of the chloride channel gene. There are four main patterns of disease: (1) congenital; (2) childhood onset; (3) classic or early adult onset; (4) late onset, asymptomatic or oligosymptomatic. The classic form of the disease is the most frequent cause of myotonia and the most prevalent muscular dystrophy in adults (c.1 in 8000). In addition to myotonia and a characteristic pattern of weakness affecting the facial muscles and (unusually for a myopathic disorder) distal limbs, other features include premature male pattern balding, cataracts, central nervous system involvement (cognitive change, excessive daytime sleepiness), cardiac conduction abnormalities (which may lead to sudden death), gastroenterological involvement (dysphagia and irritable bowel syndrome), and respiratory problems. Recurrent chest infections are common due to the combination of muscular weakness and the tendency to aspirate, and death is often secondary to pneumonia. The underlying trinucleotide repeat is unstable and increases in size during meiosis, giving rise to anticipation in which the disease has an earlier onset in the offspring of affected individuals.

Myotonic dystrophy type 2 (proximal myotonic myopathy)—caused by a quadruplet repeat expansion in the zinc finger 9 protein (ZNF9) gene that leads to disruption of normal RNA processing and altered splicing patterns of numerous genes. Clinical features are similar to type 1, but with proximal (rather than distal) weakness and less evident anticipation.

Nondystrophic myotonias—mutations affecting the skeletal muscle chloride channel (CLCN-1) gene give rise to the rare condition myotonia congenita, which can be inherited as either an autosomal dominant or recessive trait. Myotonia is striking; leg stiffness causing difficulty walking is the major feature, but persistent weakness is uncommon.


Myotonia can be considered as a symptom, a physical sign, or a neurophysiological phenomenon, but understanding is perhaps best served by discussing these in the reverse order.

The basic neurophysiological finding is of repetitive muscle-fibre action potentials following a stimulus, which may be voluntary contraction or muscle percussion. The repetitive electrical activity causes muscle contraction, and thus myotonia is characterized by delayed muscle fibre relaxation after such a stimulus. Electromyography demonstrates the repetitive firing. Characteristically, the discharge gradually declines in amplitude and frequency, producing the so-called ‘dive-bomber’ sound in the monitoring loudspeaker. The term ‘myotonia’, and apparently related terms such as ‘paramyotonia’ and ‘neuromyotonia’, cause much confusion. Various diseases accompanied by myotonia have different molecular origins and many associated symptoms and signs

As a physical sign, myotonia is demonstrated either as delayed muscle relaxation following voluntary contraction (e.g. grip myotonia—Fig., or as persistent muscle dimpling following percussion (percussion myotonia—Fig.

Fig. Grip myotonia: the patient was asked to grip the examiner’s fingers tightly for 3 s, and then to release the grip as rapidly as possible. The two photographs were taken at 3-s intervals.

Grip myotonia: the patient was asked to grip the examiner’s fingers tightly for 3 s, and then to release the grip as rapidly as possible. The two photographs were taken at 3-s intervals.

Fig. Percussion myotonia: following a sharp tap, the thenar eminence muscles contract and then relax slowly (photographs taken at 3-s intervals).

Percussion myotonia: following a sharp tap, the thenar eminence muscles contract and then relax slowly (photographs taken at 3-s intervals).

As a symptom, complaints relating to myotonia differ between patients with myotonic dystrophy, which is by far the most common cause of myotonia, and those with myotonia congenita. In myotonic dystrophy, even when grip myotonia is readily evident on examination, the patient may offer no symptoms. They are more likely to complain of hand weakness than of myotonia. When the myotonia is symptomatic, the patient complains of difficulty releasing objects after a tight grip. This is sometimes striking. One patient first noted grip myotonia in early adult life, when he was appointed as a teacher at a school—as his future headmaster shook his hand to congratulate him, he was embarrassingly unable to release his grip. In myotonic dystrophy, bulbar symptoms relating to myotonia are quite common—patients complain of their tongue or jaw ‘locking’ when speaking or swallowing, and tongue myotonia on percussion may be demonstrated.

By contrast, in myotonia congenita weakness is absent and the myotonia, which is generalized, is problematic, particularly in the lower limbs. Patients complain of stiffness that is most evident on trying to initiate movement after rest. Thus, the patient who has been sitting in the waiting room rises and walks with profound leg stiffness, somewhat reminiscent of spasticity, into the consulting room. A classic presentation is the soldier on the parade ground—after a prolonged period ‘standing to attention’, the order to march results in his falling due to leg muscle stiffness. One such patient also demonstrated marked grip myotonia—on an unfortunate occasion he alighted from a bus but, unable to release his grip from the handrail before the bus departed, was dragged along the road.

In most disorders, myotonia lessens with repeated activity of the muscle. Thus, the sign becomes less striking with repeated percussion of the thenar eminence or attempts to demonstrate grip myotonia. As a symptom, for example, the leg stiffness in myotonia congenita lessens as the patient continues to walk. In paramyotonia the reverse is seen, with myotonia increasing with activity—so-called paradoxical myotonia. Some, but by no means all, patients complain that their myotonia is worse in the cold. This is again a particular characteristic of paramyotonia.

As the anecdotes described above indicate, severe myotonia—which is more common in myotonia congenita than the myotonic dystrophies—can be very disabling. It may respond to phenytoin, but side-effects can be problematic. Recent evidence favours the use of mexiletine, which is effective and generally well-tolerated, with no adverse cardiac effects even in the myotonic dystrophies in which cardiac conduction defects are common.

Classification of myotonic disorders

As with many other inherited neuromuscular disorders, nomenclature and classification are currently in a state of flux as molecular mechanisms are being unravelled. For clinical purposes a useful distinction is between those multisystem disorders in which weakness is a significant feature, and which are therefore referred to as dystrophies, and the nondystrophic myotonias (Table

Table Classification of myotonic disorders

Myotonic dystrophies (multisystem myotonic myopathies)

Nondystrophic myotonias

DM1: myotonic dystrophy type 1 (chromosome 19q)

Chloride channelopathies: myotonia congenita (chromosome 7q)

DM2: myotonic dystrophy type 2 (chromosome 3q)

Sodium channelopathies: paramyotonia congenita (chromosome 17q)

Schwartz–Jampel syndrome: chondrodystrophic myotonia (chromosome 1p)

Classic myotonic dystrophy was previously called dystrophia myotonica, which gave rise to the abbreviation DM. It shows no genetic heterogeneity, all cases being associated with a trinucleotide repeat expansion in the 3′‎-untranslated region of a novel protein kinase gene (DMPK) on chromosome 19q. This locus and clinical disorder are referred to as DM1. A closely related condition, previously called proximal myotonic myopathy (PROMM), is caused by a quadruplet repeat expansion in intron 1 of the zinc finger 9 protein gene (ZNF9) on chromosome 3q and is referred to as DM2.

The most common nondystrophic myotonias are the autosomal dominant and recessive forms of myotonia congenita, both of which are caused by mutations of the skeletal muscle chloride channel gene (CLCN1). Different mutations of the skeletal muscle sodium channel gene (SCN4A) give rise to hyperkalaemic periodic paralysis and related disorders, including paramyotonia congenita. These chloride and sodium channelopathies, together with the calcium channel disorders causing hypokalaemic periodic paralysis, are discussed further in Chapter 24.24.5.

Schwartz–Jampel syndrome is a very rare recessive disorder of infantile onset, characterized by skeletal abnormalities (chondrodysplasia), abnormal facial appearance, and abnormal muscle electrical activity. Electromyography shows periods of continuous electrical activity, which are probably neural in origin. It is caused by mutations in the HSPG2 gene, encoding the basement membrane protein perlecan.

Myotonic dystrophy type 1 (DM1)

DM1 is the most frequent cause of myotonia and indeed is also the most prevalent muscular dystrophy in adults. It is a multisystem disorder that has very important (but sometimes rather neglected) manifestations other than skeletal muscle dysfunction, involving cardiac conduction tissues, smooth muscle, eyes, and the central nervous system. Clinical severity ranges from death in utero to a condition so mild that it may be asymptomatic and with no abnormal physical signs in old age. The molecular basis is an expansion of an unstable trinucleotide repeat in a gene coding for a novel protein kinase, DMPK. There is strong evidence that the molecular mechanism in both DM1 and DM2 is disruption of normal RNA processing which causes altered splicing patterns of numerous genes, including the chloride channel gene (compare myotonia congenita)—this explains the myotonia—and the insulin receptor gene, causing insulin resistance. Myotonic dystrophy provides a dramatic example of the phenomenon of ‘anticipation’, by which succeeding generations may be much more severely affected than their predecessors, and this correlates with the size of the genetic expansion.


The disease is seen worldwide, with a particularly high frequency in French Canadians in Quebec (originating from a single immigrant couple). Incidence and prevalence figures are unreliable, and probably mostly underestimates, because of the difficulty in identifying asymptomatic individuals. A generally accepted prevalence value is 8/100 000 population.


MyotoniaThe molecular basis is the expansion of a trinucleotide (cytosine–thymine–guanine, CTG) repeat sequence in the 3′‎-untranslated region of the myotonic dystrophy protein kinase (DMPK) gene on chromosome 19q. In the normal population the size of the repeat is in the range CTG5–37, with a trimodal distribution of 5, 11 to 17, and 19 to 37 repeats. Expansions in the range CTG37–49 are believed to represent premutations. Individuals with myotonic dystrophy have repeats in the range CTG50–5000 and, as noted below, there is a correlation between the size of the repeat and clinical severity, and an inverse correlation between repeat size and age of onset. Diagnostic studies are based on measurement of the expansion size in blood lymphocyte DNA. There is only a broad correlation between lymphocyte expansion size and clinical severity, in large part because other tissues may have very different expansion sizes compared with lymphocytes. The expansion size in lymphocytes cannot therefore be used in any meaningful predictive fashion for clinical severity and because of misunderstandings relating to this, some laboratories will only report ‘positive or negative’ for an expansion, without stating the size.

A fundamental concept is that the expanded gene is unstable. It is mitotically unstable, and so the size of the gene increases with age. There is somatic mosaicism, so that the expansion is not the same size in different tissues.

More important is intergenerational CTG-repeat instability, which explains why the disease tends to increase in severity, and also show rather different clinical features, in subsequent generations. The gender of the parent of origin is important. In most transmissions the allele size increases. However, there appears to be a threshold limit for sperm, and males never transmit the very large expansions associated with congenital myotonic dystrophy (see below), which occurs only when the mother is the gene carrier. There is some evidence of meiotic drive, which leads to preferred transmission of the abnormal expanded allele.

Clinical features

From the above it is apparent that there is a continuous distribution of expanded allele size, and a relationship between allele size and disease severity and between allele size and age of onset. While accepting that some patients will fall between these categories, for practical clinical purposes myotonic dystrophy can be considered to give rise to four main patterns of disease:

  • congenital

  • childhood onset

  • classic or early adult onset

  • late onset, asymptomatic, or oligosymptomatic

As it is the best known, and illustrates the multifarious manifestations of myotonic dystrophy, the classic form is discussed first.

Classic form

Onset is in adolescence or early adult life. The principal manifestations are summarized in Table A number of rarer or clinically less important associations are also recognized, including reduced fertility, testicular atrophy, insulin resistance (but rarely overt diabetes), retinopathy, eye movement disorder, peripheral neuropathy, disturbed tests of endocrine function, hypotension, pilomatrixomas, and reduced levels of immunoglobulins and complement.

Table Main clinical features of myotonic dystrophy








Central nervous system

Excessive daytime sleepiness

Low IQ

Sensorineural deafness


Heart block


Sudden death


Recurrent infections

Sleep apnoea


Premature balding



Irritable bowel syndrome


Skeletal and smooth muscle

The features of myotonia have already been discussed. The distribution of muscle weakness is highly characteristic. Wasting and weakness of the facial muscles, combined with premature male-pattern balding (in males much more apparent than females), give rise to the typical facial appearance of the condition (Fig. The temporalis muscle is atrophic, giving a sunken appearance over the temples. There is ptosis. Eye closure is weak and in severe cases the sclera may remain visible. The jaw tends to hang down. Neck flexion is weak and in some, but not all, patients there is evident atrophy of the sternomastoid muscles. In the limbs, and in marked contrast to most other myopathic disorders, the weakness is predominantly distal. In the upper limbs there is weakness and wasting of the small hand muscles and of the long wrist, and finger flexor and extensor muscles in the forearm. There is often profound weakness of grip and the patient complains of difficulty with tasks such as wringing out a cloth and removing the lid from a bottle. A simple hand-held dynamometer reveals the extent of the weakness—whereas a normal woman would easily exceed 35 kg, patients of either sex may manage only 1 or 2 kg. In the lower limbs there is weakness of ankle dorsiflexion, presenting as tripping easily and foot-drop. As the disease advances, weakness becomes evident more proximally, but the marked distal predilection remains throughout.

Fig. Adult-onset myotonic dystrophy: typical facial features (see text).

Adult-onset myotonic dystrophy: typical facial features (see text).

Bulbar muscle weakness presents with dysarthria and dysphagia. Smooth muscle involvement contributes towards the dysphagia. Symptoms akin to those of irritable bowel syndrome are frequent. Constipation is also common and pseudo-obstruction rare. There may be evidence of incoordinate uterine contraction in labour but there is little evidence that this is of any clinical significance and most women can deliver a pregnancy normally.


Cataracts develop at an early age. The initial manifestation is multicoloured opacities in the subcapsular regions, readily seen on slit-lamp examination. Identification of cataracts used to be important in screening asymptomatic family members for the disease, but that has now been replaced by DNA testing. In practice, the cataracts are managed as any other cataracts, being operated on when vision is significantly impaired. Early-onset cataracts, even in the absence of any other suggestive features, should always raise the suspicion of myotonic dystrophy.

Central nervous system

Central nervous system (CNS) disease is expressed in two main ways. As a group, patients with myotonic dystrophy have a lower intelligence than average, but many mildly affected patients have intelligence within the normal range. They are often perceived as apathetic or lacking self-motivation. There is neuropsychological evidence of specific defects of frontal lobe functioning. The second principal feature is excessive daytime sleepiness, which affects over three-quarters of patients, some profoundly. This appears to be a central phenomenon and is only rarely attributable to obstructive sleep apnoea/nocturnal sleep disturbance.


Cardiovascular dysfunction is arguably the most important extramuscular manifestation of myotonic dystrophy and is probably responsible for most of the not infrequently reported cases of sudden death. The most commonly recognized pattern is of progressive conduction disturbance. Thus, in very early cases the ECG is normal. Subsequently, the PR interval gradually lengthens until first-degree block is present. Left anterior hemiblock is particularly common. Later features include bundle-branch and complete heart block. Tachyarrhythmias also occur, most frequently atrial flutter or fibrillation, but also ventricular arrhythmias, which may be fatal. Symptoms include palpitation, dizzy spells, and fainting. Prolonged ECG monitoring and sometimes intracardiac electrophysiological studies are indicated if such symptoms are reported, or the standard ECG shows significant change. All patients should have an ECG annually, and be advised to report any cardiac symptoms immediately. Rhythm disturbances precipitated by anaesthesia or surgery are common, as are respiratory problems. For these reasons, patients should carry a medical alert bracelet/medallion and, for elective admissions for surgery, be reminded to inform the anaesthetist of their diagnosis. The latter is particularly important for asymptomatic individuals diagnosed on the basis of DNA studies following family screening, because they may not consider themselves to be at risk; they are. Although there is some correlation between cardiac involvement and overall severity of the myotonic dystrophy, it is not absolute and individuals with minimal muscle involvement may have significant ECG changes.

Heart muscle disease, as opposed to disordered cardiac conducting tissues, is not clinically significant and routine echocardiography is not required.


Recurrent chest infections are common and relate to respiratory muscle weakness and the tendency to aspirate. In advanced disease, death is often secondary to pneumonia. Respiratory insufficiency may become apparent following anaesthesia, with difficulty in weaning from the ventilator. Chronic hypoventilation and sleep fragmentation may cause excessive daytime sleepiness, but in practice are much less common than the presumed central mechanism already mentioned. However, it must be considered and excluded (e.g. by overnight oximetry) if felt to be a possibility. Particular warning features would include a history of disturbed night-time sleep, snoring, waking with headaches, and the development of secondary polycythaemia.

Congenital form

By definition, this form of myotonic dystrophy is evident at birth, but the spectrum of early onset myotonic dystrophy is much wider, as noted below. The exclusive (with only very rare exceptions) maternal transmission of congenital myotonic dystrophy has already been discussed. Many fetuses carrying large expansions are aborted spontaneously in early pregnancy and there is a high rate of fetal wastage. As a result of the unstable nature of the CTG repeat and the associated phenomenon of anticipation, it is not uncommon for the mother to be unaware of her own diagnosis at the time of birth. In that situation, the diagnosis in the infant is not always immediately apparent, because there are no entirely specific clinical features.

There is often a history of polyhydramnios and poor fetal movement in the pregnancy. The child is born hypotonic (‘floppy’) and talipes is present in about half. Respiratory and feeding difficulties may necessitate assisted ventilation or an oxygen tent, and feeding by nasogastric tube. Some die in the neonatal period from respiratory complications, but, somewhat surprisingly, there are few further deaths in the survivors until the late teens and early adult life. There is generalized weakness, including the face—the jaw hangs open and the mouth has a characteristic tented or carp-like (as in fish) appearance. Myotonia is not evident clinically and even electromyographically may not appear for several years.

In those who survive, hypotonia resolves and motor function improves over the following few years, but during adolescence the features of the classic adult form of the disease appear (Fig.

Fig. Myotonic dystrophy: the affected mother’s two children have the congenital form of the disease.

Myotonic dystrophy: the affected mother’s two children have the congenital form of the disease.

Cognitive impairment is invariable and may be severe. Most require special needs schooling. Bowel involvement is common, with faecal soiling and irregular bowel habit. Curiously, cataracts are relatively uncommon.

The overall prognosis is poor. Some 25% die in the first 18 months of life, most in the neonatal period. Half survive into the mid-30s, death most commonly resulting from respiratory involvement, but with a proportion of sudden deaths almost certainly due to cardiac conduction defects. Few achieve an independent adult life.

Childhood-onset form

It is only recently that the specific problems of childhood-onset disease have been recognized. By definition, such children do not have evidence of disease at birth. Motor milestones may be delayed. Problems are often first recognized around the start of schooling with evidence of cognitive delay and poor language development. Dysarthria is common. Fatigue and slowness of activities are often striking. Facial weakness is almost invariable, together with weakness of neck flexion.

Late-onset form

This form is associated with a small CTG-repeat expansion. It is typically asymptomatic or oligosymptomatic, and diagnosed during family studies or by an alert ophthalmologist when the patient presents with cataracts. Skeletal muscle disease may be absent, or confined to mild myotonia and weakness restricted to the hands. Balding may be a feature. It is not uncommon to see the parents of a patient with the classic adult form of the disease and not be able to identify the transmitting parent on clinical examination.

Importantly, even patients with such minimal symptoms may occasionally develop significant cardiac conduction problems and they should have annual electrocardiograms.


The essential management issues in myotonic dystrophy are:

  • genetic counselling

  • annual ECG

  • anaesthetic risks

  • physical therapies

  • cataract surgery

A particular concern relates to the genetic phenomenon of anticipation and the potential for an asymptomatic mother, ignorant of the diagnosis, to give birth to a congenitally affected child. When the diagnosis of myotonic dystrophy is established in a family member it is imperative that at-risk relatives are offered screening. Reproductive options include prenatal diagnosis, by chorionic villus sampling, with termination of an affected fetus and, gradually becoming more widely available, preimplantation genetic diagnosis. Annual ECG should be performed in all patients. They and their medical attendants must be aware of the cardiorespiratory complications associated with anaesthesia. They should be encouraged to wear an appropriate medical alert bracelet or medallion. A few patients require nocturnal positive-pressure ventilation by facemask, but most excessive daytime sleepiness is not related to respiratory insufficiency. Recurrent chest infections are common. Annual influenza immunization should be advised. Pneumococcal immunization is also given but is of uncertain value.

Physiotherapy, and occupational and speech and language therapy all have a role, as does the use of orthotic devices (e.g. for foot drop). Bowel problems in the congenital form require specific advice and counselling.

Excessive daytime sleepiness may respond, sometimes dramatically, to modafinil (but sleep-related breathing abnormalities should be excluded).

Cataract surgery is required when vision is significantly impaired.

Myotonic dystrophy type 2 (DM2)

Despite the similarity in name, and overlapping clinical features, there should generally be little difficulty distinguishing this condition from DM1. There appears to be remarkable variability in the incidence of this disorder between countries, only partly explained by missed or failed diagnosis of the condition. Thus, in Germany DM2 appears to be about as prevalent as DM1; it is common in North America, but only a handful of families have been identified in the United Kingdom.

Similar to DM1, the underlying molecular basis is an unstable nucleotide repeat expansion in an untranslated part of a gene, the consequences of which seem to be mediated through disruption of RNA metabolism.

Despite the superficial similarities to myotonic dystrophy, there are also differences. Onset, or at least presentation, is usually in mid-adult life. Muscle pain and stiffness, particularly affecting the thighs, are common, and are sometimes the presenting symptoms. The pattern and distribution of myotonia are similar to DM1, but, in contrast to DM1, early proximal weakness is usually evident, but hand weakness may also be prominent. Cataracts may be indistinguishable from those seen in myotonic dystrophy. Cardiac conduction problems appear to be less common. Male hypogonadism and deafness occur. A congenital form of DM2 has not been described. Cognitive involvement appears to be rare and excessive daytime sleepiness does not appear to be a major feature.

Further reading

Myotonic dystrophy type 1

Brook JD, et al. (1992). Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat in the 3′‎ end of a transcript encoding a protein kinase family member. Cell, 68, 799–808.Find this resource:

Gagnon C, et al. (2010). Health supervision and anticipatory guidance in adult myotonic dystrophy type 1. Neuromuscular Disorders, 20, 847–51.Find this resource:

Harper P (2001). Myotonic dystrophy, 3rd edition. W B Saunders, London.Find this resource:

    Harper P, et al. (2004). Myotonic dystrophy: present management, future therapy. Oxford University Press, Oxford.Find this resource:

      Reardon W, et al. (1993). The natural history of congenital myotonic dystrophy: mortality and long term clinical aspects. Arch Dis Childh, 68, 177–81.Find this resource:

      Myotonic dystrophy type 2

      Day JW, et al. (2003). Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology, 60, 657–64.Find this resource:

      Ranum LPW, et al. (1998). Genetic mapping of a second myotonic dystrophy locus. Nat Genet, 19, 196–8.Find this resource:

      Molecular basis of myotonic dystrophy

      Machuca-Tzili L et al. (2005). Clinical and molecular aspects of the myotonic dystrophies: A review. Muscle Nerve, 32, 1–18.Find this resource:


      Logigian E, et al. (2010). Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1. Neurology, 74, 1441–8.Find this resource: