Myotonic Dystrophy

Home , Myotonic dystrophy

CME 51 51–55 DMPK 36: 2006; C Longman, October 2005 [email protected] +44 (0)20 7188 7188 e-mail J R Coll Physicians Edinb Coll Physicians J R tel. Hospital, London SE1 9RT 7th Floor, New Guy’s House, Guy’s Department of Clinical Genetics, Correspondence to Published online © 2006 Royal College of Physicians of Edinburgh of Physicians College of Royal © 2006 GENETICS of 1 is one of a group type dystrophy Myotonic ‘triplet repeat termed conditions neurogenetic disorders’. an expansion in the size of a It is caused by sequence in the base-pair (triplet) repeat three gene. The repeat, comprising CTG, individuals.times in unaffected occurs up to 35 dystrophy,myotonic is greater of repeats the number In patients with than 50. increase, of repeats As the number signs and prominent,symptoms become more with earlier age of onset. In general, are repeats patients with 50–100 affected;mildly are with 200–500 repeats those affected;classically than 1,000 and those with more congenital or childhood-onset disease. have repeats However, in an individual patient, size is a the repeat of clinical prognosis. poor predictor Central nervous system (CNS), s Hospital, London, England ’ No conflict of interests declared. No conflict of interests gene located on chromosome 19.gene located on chromosome is an The gene mutation DMPK Myotonic dystrophy is the most common form of muscular dystrophy of muscular common form is the most dystrophy Myotonic APER APER P C Longman Department of Clinical Genetics, Guy P INTRODUCTION type 1 is a progressive, dystrophy Myotonic inherited of with an estimated prevalence dystrophy muscular 1 in 8,000. dystrophies other muscular It is unlike in that presents disorder because it is a multi-system 1).Table (see a large variety of ways The age of birth to old before onset of symptoms ranges from age, main under three but can be considered categories. patients dystrophy Classical myotonic weakness, muscle have myotonia, and a range of other symptoms, adult life; to mid in early congenital symptoms severe have patients dystrophy myotonic at birth; weakness, have adults may affected mildly myotonia, cataract, or diabetes in mid to late adulthood. genetic other rare are Although there dystrophy,types of myotonic this article deals with DM1. specifically ABSTRACT in adults, of 1 in 8,000. with a prevalence progressive, It is a slowly multi-system muscles, skeletal that affects disorder the heart, smooth muscle, gastrointestinal uterine smooth muscle, the eyes, and the endocrine and central nervous systems. dominant gene an autosomal caused by is almost always dystrophy Myotonic in the mutation Myotonic dystrophy Myotonic expansion in the length of a three base-pair (triplet) repeat sequence repeat base-pair (triplet) length of a three expansion in the (cytosine–thymine–guanine, the normal upper limit of 35 repeats. CTG) above or because the number mutation ‘dynamic’ classed as a is The expanded CTG repeat generations in myotonic successive in size over tends to increase of repeats families.dystrophy In general, associated with earlier are larger CTG expansions dystrophy. signs and symptoms of myotonic severe age-of-onset and more cataract, develop may Patients with 50–100 CTG repeats diabetes, grip myotonia, in mid to late adulthood. weakness or mild muscle Patients with 200–500 CTG and distal limb muscle facial by severely earlier and more affected are repeats and myotonia.weakness 1,000 is associated with size above A CTG repeat dystrophy, onset of disease and congenital myotonic be fatal prenatal which may due to respiratory failure.deformity, difficulties, Feeding in surviving present infants. impairments are and cognitive weakness, muscle Although dystrophy, to inherit myotonic the very large likely equally are males and females club foot of myotonic congenital form in the which result repeats) (>1,000 mutations mother. affected an by transmitted virtually always are dystrophy DNA tests are prenatal, size and permit accurate used to estimate repeat presymptomatic, and diagnostic genetic testing. ABBREVIATIONS LIST OF cytosine–thymine–guanine (CTG),cytosine–thymine–guanine (ECG), electrocardiogram (mRNA), messenger RNA kinase (DMPK), protein dystrophy type 1 myotonic dystrophy myotonic (DM1), type 2 (DM2), dystrophy myotonic zinc finger transcription factor 9 (ZNF9) OF INTERESTS DECLARATION C Longman

TABLE 1 Presentations of myotonic dystrophy. Specialty Presenting scenario Obstetrician Polyhydramnios, premature delivery. Neonatologist Neonatal respiratory distress, hypotonia, weakness, feeding difficulties, club foot deformity. Paediatrician Muscle weakness, hypotonia, drooling, ‘clumsiness’, mild learning difficulties, speech problems, dysphagia, abdominal pain, diarrhoea, constipation, soiling. Adult Physician Muscle weakness, myotonia, diabetes, cardiac conduction defect/arrhythymia, dysphagia, diarrhoea, constipation, abdominal pain, respiratory infections. Neurologist Muscle weakness, myotonia. Gynaecologist/ Subfertility, impotence. Urologist Orthodontist/ Temporomandibular joint pain, jaw Craniofacial surgeon malocclusion. Intensive Care Post-operative respiratory failure. Specialist FIGURE 1 Moderately affected myotonic dystrophy patient. Ophthalmologist Early onset bilateral, posterior Note ptosis and facial muscle weakness. subcapsular cataract. of skeletal and cardiac muscle. The repeat expansion Clinical Geneticist Diagnosis of congenital myotonic dystrophy affects the amount of protein made from adjacent leads to examination of relatives. genes, and reduced levels of one of these, SIX5, is General Practitioner Any of the above, note that symptoms can implicated in the pathogenesis of cataract in overlap with ‘myalgic encephalomyelitis’. myotonic dystrophy.

CME CLINICAL FEATURES OF MYOTONIC DYSTROPHY Myotonic dystrophy is an autosomal dominant condition. When one parent carries the mutation, there is a 50% Classically affected adults chance that it will be transmitted to his or her child. Males and females are equally likely to be affected. These patients have facial weakness, ptosis, hollowing of However, the clinical severity tends to increase in the temples due to temporalis muscle wasting, atrophy successive generations in a family, a phenomenon termed of the jaw muscles (see Figure 1), and, particularly in ‘anticipation’. This is due to the dynamic nature of the males, early frontal balding. Dysarthric, hypernasal repeat expansion, which tends to increase in size as it is speech is prominent. Grip myotonia is often the first passed from parent to child. The largest expansions are symptom. Percussion myotonia is elicited in the thenar only transmitted in the egg cell, so the most severe and tongue muscles but the latter is painful for patients. manifestation, congenital myotonic dystrophy, is virtually Muscle weakness and wasting affect the always transmitted by an affected mother. sternocleidomastoids and distal limb muscles first, whilst proximal limb musculature is affected later. PATHOGENESIS Weakness is slowly progressive, but the rate of progression and each individual’s prognosis is difficult to The CTG repeat mutation is located towards the end predict. Even in the late stages of the disease, most of the DMPK gene and its corresponding mRNA, but patients retain at least limited mobility. is outwith the part of the mRNA that is translated into protein. Many of the effects of the mutation Non-neuromuscular symptoms of myotonic dystrophy can result from effects of the abnormal, expanded be disabling and challenging to manage (see Table 2). mRNA, which binds to different nuclear proteins Daytime hypersomnolence is common and does not that, in turn, affect the processing of other genes. correlate with the severity of muscle involvement. Changes affecting insulin receptor mRNA and muscle Central nervous system mechanisms are thought to chloride channel mRNA cause insulin resistance and underlie most cases and modafinil is helpful in some. myotonia, respectively. The repeat expansion also Hypersomnolence can also be a symptom of nocturnal leads to reduction in the level of DMPK protein itself, hypoventilation, and in these patients nocturnal non- and this affects ion channels, altering the excitability invasive ventilation improves symptoms.

TABLE 2 Common clinical features of myotonic dystrophy and their management. Symptom/Sign Management Muscle weakness Occupational therapy; physiotherapy; orthotics. Myotonia Heated gloves; anti-myotonic medication rarely required. Temporomandibular joint dysfunction Physiotherapy. Cardiac conduction abnormalities, Consider 24-hour ECG at diagnosis; annual ECG; 24-hour ECG if increasing PR arrhythmias interval or other risk arrhythmia.* Dysphagia Speech therapy; behavioural modifications (neck flexed when swallowing).

Gastrointestinal symptoms Various treatments according to cause, specialist gastroenterology assessment recommended. Ptosis Consider surgery if affects vision, but rarely required. Cataract (posterior subcapsular) Annual eye assessment. Blepharitis Lubricant eye drops. Diabetes Annual glucose measurement. Testicular atrophy Testosterone unhelpful. Male subfertility Assisted conception (intracytoplasmic sperm injection).

Impotence Daytime hypersomnolence Modafinil helps some cases; exclude respiratory involvement.

Respiratory failure Respiratory assessment; nocturnal non-invasive ventilation; offer influenza and Pneumococcus vaccination.

Raised liver enzymes Awareness can avoid unnecessary investigation. CME Gallstones

*Recommendation of the European Neuromuscular Centre workshop on cardiac management of myotonic dystrophy.

Gastrointestinal symptoms arise from delayed gastric Cardiac involvement is frequent and sudden cardiac death emptying, smooth muscle and sphincter dysfunction, bile occurs in 10–30% of patients. The severity of cardiac acid malabsorption, and small bowel bacterial overgrowth. complications does not correlate with the degree of Cholestyramine improves diarrhoea, incontinence, and muscle weakness or the size of the repeat expansion. pain in some patients, and metoclopramide is helpful for Approximately 65% of adults have an abnormal symptoms related to delayed gastric emptying. In difficult electrocardiograph. Conduction abnormalities cases, referral to a gastroenterologist is recommended. (atrioventricular more commonly than intraventricular) and arrhythmias (atrial more commonly than ventricular) Endocrine complications of myotonic dystrophy include predominate, whereas cardiomyopathy is rare. Pacemakers diabetes mellitus, which is increased approximately are required in 5% of patients but their insertion does fourfold. Testicular atrophy, with degeneration of the not prevent sudden death due to ventricular seminiferous tubules, results in reduced spermatogenesis arrhythmia. The optimal intensity of cardiac surveillance and subfertility in some males. and the role of 24-hour ECG monitoring is disputed, but a European Neuromuscular Centre workshop has Respiratory complications account for 30–40% of deaths in considered cardiac management of myotonic dystrophy myotonic dystrophy. Reduced central drive and and published evidence-based guidelines. respiratory muscle weakness contribute to nocturnal hypoventilation. This results in difficulty wakening, feeling Myotonic dystrophy patients are at increased risk of unrefreshed after sleep, morning nausea and headaches, complications of general anaesthesia, such as hypotension, reduced energy levels, and daytime somnolence. Non- pulmonary aspiration, and respiratory depression. Risks invasive nocturnal ventilation improves symptoms and are maximal in undiagnosed patients for whom post- may prolong survival,but the myotonic dystrophy patient’s operative respiratory failure is a serious hazard. Elective compliance with this treatment is often poor; this may surgery requires detailed pre-operative cardio- reflect reduced drive and reduced ability to sustain respiratory assessment and careful intra- and post- interest in activities, which are common CNS operative monitoring. Drugs that are arrhythmogenic, complications of myotonic dystrophy. that precipitate myotonia, or depress respiration (such as

FIGURE 2 Congenitally affected child with mother. Note open-mouthed appearance of child and subtly reduced facial FIGURE 3 Patient with childhood-onset myotonic dystrophy. expression in mildly affected mother. Note ptosis and facial weakness.

depolarising neuromuscular blocking agents) should be CONGENITAL AND CHILDHOOD-ONSET avoided. Local or regional anaesthetic alternatives should MYOTONIC DYSTROPHY be considered. CME Pregnancies that result in the birth of a congenitally Pregnancy and delivery risks in females with myotonic affected child are frequently complicated by dystrophy result from involvement of uterine smooth polyhydramnios and premature birth. At birth, infants are muscle. When the fetus is severely affected, impaired fetal hypotonic and weak, and often require mechanical swallowing and movement also contribute. There is an ventilation and nasogastric tube feeding owing to increased risk of placenta praevia, polyhydramnios, preterm respiratory failure and reduced ability to suck or swallow. birth, and postpartum haemorrhage. Specialist obstetric Club foot deformity also occurs in most infants. care is required but, not infrequently,the affected mother is only diagnosed after the birth of her affected infant. In older studies, high mortality rates, ranging from 17–41%, were due to respiratory muscle weakness and Usually, the management of myotonic dystrophy patients complications of prematurity. However, with improved and their extended families is coordinated by the general neonatal intensive care, survival has improved. Feeding practitioner, neurologist, or clinical geneticist. An ‘Alert’ and respiratory problems also improve with age. In older card, or patient-held care card, is useful to inform health infants, facial weakness results in a characteristic open- care professionals about complications of myotonic mouthed appearance (see Figure 2), and drooling can be dystrophy. The Myotonic Dystrophy Support Group and problematic. Cardiomyopathy has occurred in a small the Muscular Dystrophy Campaign are sources of support number of infants and an echocardiogram at diagnosis is and information for patients, and the latter group fund recommended. Interestingly, myotonia is not present in care advisors to provide family support. the first decade.

Mildly affected adults Most children have mild learning difficulties. Virtually all children learn to walk, although this may be delayed, partly These patients may be diagnosed only after genetic related to the surgery and/or orthotic intervention that is studies in their family, or may present with isolated required for foot deformity. As in adults, gastrointestinal cataract or diabetes. Mild weakness of grip or myotonia symptoms can be prominent. in late adulthood is often overlooked by the patient. Cardiac complications still occur in this group and cardiac Childhood-onset myotonic dystrophy is defined by onset surveillance is required. of symptoms after one year and is intermediate in severity

between congenital and adult myotonic dystrophy (see For couples who wish to avoid the birth of an affected Figure 3). In congenital and childhood-onset cases, infant but who are unable to contemplate medical myotonia and distal limb muscle weakness develop during termination of an affected pregnancy, in vitro fertilisation the teenage years. Although ECG abnormalities are techniques and pre-implantation genetic diagnosis is one common, sudden cardiac death is rare before the mid- option that has recently become available in a few teenage years. Unlike congenital myotonic dystrophy, specialist centres. childhood-onset disease is found in the offspring of affected males as well as females. OTHER FORMS OF MYOTONIC DYSTROPHY: PROXIMAL MYOTONIC MYOPATHY (DM2) GENETIC COUNSELLING IN MYOTONIC DYSTROPHY Fewer than 5% of patients with myotonic dystrophy have a different condition that shows considerable clinical The smallest expansions of 50 to 60 repeats are found in overlap with DM1. Myotonic dystrophy type 2 (previously older, unaffected, or mildly affected individuals, who are in called proximal myotonic myopathy, PROMM) is due to a topmost generations of the family tree. Such small repeat tetranucleotide (CCTG) repeat expansion in the ZNF9 expansions are unstable during gamete production and gene located on chromosome 3. A congenital form has the repeat size rises when the mutation is transmitted to not been described in DM2, and perhaps very large the next generation. expansions in the DM2 gene have a lethal effect on the fetus. Family studies also indicate the existence of at least Usually, several relatives of each affected patient are one other myotonic dystrophy gene. themselves at risk of having inherited the disorder. Relatives who have symptoms can be offered a DNA- KEYPOINTS based diagnostic test, but asymptomatic individuals should • Myotonic dystrophy is a multisystem disorder that be offered referral to the genetic clinic to discuss the displays marked variability in signs and symptoms: the genetic implications of their family history, and options non-neuromuscular complications of myotonic such as DNA-based presymptomatic or prenatal testing. dystrophy may be severely disabling or fatal. •

For females with myotonic dystrophy, the chance that an Myotonic dystrophy is caused by an autosomal CME infant who inherits the mutation has congenital disease dominant gene mutation. Each affected person, male (as opposed to childhood or later onset disease) is much or female, has a 50% chance of transmitting the higher if the mother is symptomatic than if she is disease gene to their child. asymptomatic. Interestingly, when females already have a • Cardiac arrhythmias and conduction defects are congenitally affected child, subsequent children inheriting common and their severity does not correlate with the mutation are always congenitally affected. the severity of muscle involvement or the size of the gene mutation. Regular cardiac monitoring is required. Genetic testing of children requires special consideration. • In myotonic dystrophy families, there tends to be Symptomatic children are assessed by a paediatrician or progressively younger age of onset of disease with neurologist and diagnostic testing may follow. Genetic increasing clinical severity in successive generations. testing of the asymptomatic child is not recommended: Congenital myotonic dystrophy is nearly always there are no obvious treatment benefits, medical transmitted by an affected mother. complications are unlikely, and routine testing in • Patients are at increased risk of anaesthetic childhood removes the right of the informed adult to complications, and should carry a ‘MedicAlert’ or choose not to be tested. Anxious parents sometimes similar card. request testing of their healthy children but after detailed discussion at the genetic clinic, it is usually possible for this to be postponed until the child is mature and can make an informed decision.

FURTHER READING aspects of the myotonic dystrophies:A review. Muscle Nerve 2005; 32(1):1–18. • • Harper PS, van-Engelen B, Eymard B,Wilcox DE (editors). Myotonic Day JW, Ranum LP. RNA pathogenesis of the myotonic dystrophy. Present management and future therapy. (1st ed.) dystrophies. Neuromuscul Disord 2005; 15(1):5–16. • Oxford: Oxford University Press; 2004. Bushby K, Muntoni F, Bourke JP. 107th ENMC international • Harper PS. Myotonic dystrophy. (3rd ed.) London: WB Saunders; workshop: the management of cardiac involvement in muscular 2001. dystrophy and myotonic dystrophy. 7th–9th June 2002, Naarden, • Machuca-Tzili L, Brook D, Hilton-Jones D. Clinical and molecular the Netherlands. Neuromuscul Disord 2003; 13(2):166–72.