Neurology Department of Yale School of Medicine

Yale University
School of Medicine
Department of Neurology
P.O. Box 208018
New Haven, CT
06520-8018

Myotonic Dystrophy

History

Myotonic dystrophy is an inherited disorder of muscle weakness and wasting characterized by sustained involuntary muscle contractions. These involuntary contractions arise in response to voluntary muscle use or percussion of the muscle. The disease was described by Steinert in 1909; it is also called myotonia atrophica. Clinically myotonic dystrophy is classified as a muscular dystrophy although the disease mechanism is distinct from that of the other muscular dystrophies. The familial pattern of inheritance is similar to that of myotonia congenita (Thomsen, 1876) and paramyotonia congenita (Eulenburg, 1886). Myotonic dystrophy is distinct in having widespread effects throughout the systems of the body. That this disease primarily affects muscle and not nerve was shown by Denny-Brown and Nevin in 1941. The tendency of the disease to become more severe with successive generations, called anticipation, was recognized by Fleischer in 1918. The genetic basis for the disease was elicited in 1992.

Clinical Presentation

Epidemiology
Myotonic dystrophy occurs in one per 8,000 live births. It is among the more common inherited neurological disorders and occurs equally in men and women. The disease most often affects members of the same family, often becoming more severe with successive generations - this is most true when the disorder is passed on from the mother, when passed on from the father the disease may become less severe. There are rare sporadic cases of myotonic dystrophy.

Clinical Features
Myotonic dystrophy has effects throughout most of the body. Although chiefly characterized by muscle weakness and wasting there are associated cardiac, hormonal, respiratory, digestive and mental effects.

Typically the disease first develops in the early teen years with hand weakness and a tendency towards foot drop. The patient may notice difficulty releasing a firm grasp especially in the cold. Handling objects such as keys, a hammer or the vacuum cleaner can be problematic. The characteristic appearance of a "haggard" or "mournful" face is caused by facial muscle wasting, frontal hair loss, drooping eyelids and an open mouth. In middle age the patient may develop frequent falls, minor difficulty swallowing, voice changes and recurrent jaw dislocations. The tendency towards falling results because a sudden movement may produce a sustained muscle contraction leading to the loss of balance. Muscle atrophy sometimes becomes pronounced and there may be early infertility. Often the disease is mild, progressing slowly and producing weakness only later in life. When severe the disease causes progressive disability over ten to twenty years and may lead to death in the sixth decade from respiratory failure or cardiac disease. Many live a normal life span.

There are many systemic features. Subcapsular cataracts, which may be asymptomatic, are detectable in 90% of those with the gene. Potentially life threatening arrythmias can result from defects in cardiac conduction. The precise cause of premature death is not always known but has been speculated to be due to arrythmia or weakness in the walls of the heart. There are many hormonal effects. These include reproductive abnormalities: atrophy of the testicles, loss of sex drive, early menopause in women and habitual abortion. Thyroid function may be disordered and insulin resistance without frank diabetes is not uncommon. Abnormalities in the respiratory system leads to excessive sleepiness and sensitivity to sedation. The patient with myotonic dystrophy is at increased risk from anesthesia and has abnormal sensitivity to drugs which decrease respiratory drive (barbiturates and morphine). Effects on the digestive system produce chronic constipation, pancreatic enzyme dysfunction and increased gall bladder inflammation.

Congenital myotonic dystrophy has typical features present at birth. These include extremely decreased tone, shark mouth appearance due to facial weakness, a feeble cry, feeding difficulties, failure to thrive and club feet. The usual course is one of disability and severe mental retardation. Almost all children with congenital myotonic dystrophy are born to mothers with myotonic dystrophy and display a substantial increase in the size of the gene defect.

Pathophysiology
The structure of the affected gene suggests that it is a serine threonine protein kinase. The messenger RNA of the gene is not properly transported to the cytoplasm when the defect is present. This protein kinase may have a role in the normal function of skeletal muscle sodium channels.

Microscopic observation reveals changes in skeletal and heart muscle. Skeletal muscle shows type I (slow twitch) muscle fiber atrophy, internalized nuclei, ring fibers and fibrosis. Heart muscle shows fibrosis of the conducting system, myocyte hypertrophy and fatty infiltration.

Diagnosis

Standard evaluation
Evaluation of a patient for myotonic dystrophy includes neurological examination, EMG assessment and obtaining serum for genetic testing. These are described in detail below. The differential diagnosis of myotonic dystrophy includes causes of myotonia: paramyotonia, congenital myotonia, mild tetanus and the rare stiff man syndrome. At later stages the myotonic dystrophy may resemble limb-girdle atrophy, polymyositis or dermatomyositis.

Neurological examination
Examination is often diagnostic because the findings of myotonic dystrophy are uniquely characteristic. The key diagnostic feature is a marked transient increase in muscle tone elicited by percussion or use of a muscle. Other disease features are a "haggard" facies, muscle weakness, muscle atrophy and in males testicular atrophy. Distal muscle involvement precedes proximal muscle involvement. Late in the disease course increased tone becomes a less prominent feature and diagnosis may not be as easily made on the basis of exam alone.

Electromyography (EMG)
Before genetic testing was available EMG was more important for confirming the diagnosis of myotonic dystrophy. The EMG shows a typical myotonic discharge which has a waxing and waning quality giving rise to the descriptive term, the "divebomber" sound. The predictable variability in amplitude and frequency of the myotonic muscle action potential distinguishes it from that of complex repetitive discharge (CRD), which displays a continuous frequency and amplitude.

Genetic testing
DNA testing is definitive. Compared with the normal population, there is a part of chromosome 19 which is expanded in those with myotonic dystrophy. This expansion is readily detectable using standardized tests of the genetic material. (see below)

Genetics

Myotonic dystrophy is an autosomal dominant disorder. The gene for myotonic dystrophy is located on the short arm of chromosome 19 (19q). The genetic defect producing myotonic dystrophy was characterized in 1992. Several papers were published that year demonstrating that a small part of the genetic sequence (a CTG trinucleotide) was repeated many times over. In the unaffected population there are typically from five to 30 repeats of this "CTG" sequence. In individuals with myotonic dystrophy the repeat region expands until there are dozens or hundreds of these "CTG" repeats. This defect is present in a part of the genome which controls to production of a protein identified as "myotonic dystrophy protein kinase" or DMPK. The defect decreases the amount of protein made. The messenger RNA instructing the cell how to make the protein is trapped inside the cell nucleus. The repetitive nature of the CTG expansion region initially presented a barrier to sequencing the gene. By combining the restriction fragment length polymorphism (RFLP) method with the polymerase chain reaction (PCR) method the gene defect was characterized. Prior to sequencing linkage analysis was used demonstrate the heritable nature of the disease.

Anticipation describes the tendency of myotonic dystrophy to become symptomatic at a younger age with each generation. This occurs because at the time of fertilization the genetic defect frequently grows larger during recombination. As a result of the enlarged defect, the disease becomes more pronounced and begins earlier in life.

Treatment

Efforts to find a cure for myotonic dystrophy are ongoing. At present treatment is symptom oriented. The increased muscle tone for which the disease is named is often not debilitating however the excess tone may respond to medication. Genetic counseling is important especially since prenatal diagnosis is possible. Ankle-foot-orthotics (AFOS) are used for foot drop, wrist braces can be recommended for wrist weakness. Cataracts are removed when symptomatic. Special attention to cardiac complications is warranted; recommendations have included yearly electrocardiograms. Because cardiac arrythmias have been detected in as many as 50% of those with myotonic dystrophy, holtor monitoring is an important diagnostic modality. Pulmonary hygiene includes breathing exercises and postural drainage. Genetic counseling is important especially since prenatal diagnosis is possible. Patients with myotonic dystrophy should be aware of a special vulnerability when undergoing anesthesia.

Support Groups

Muscular Dystrophy Association (MDA)
National Headquarters
3300 East Sunrise Drive
Tucson, Arizona 85718
Phone: 1-800-572-1717

The MDA supports research and patient care for over 40 diseases, including Myotonic Dystrophy. They can put patients and families in touch with local chapters and support groups.

Internet Links to other Myotonic Dystrophy sites

Disclaimer

This page is intended for educational purposes only, to provide an overview of Myotonic Dystrophy for patients, their families, and health care providers. It is not intended to recommend any specific treatment, nor should it be used as a guide for self-treatment. Patients with Myotonic Dystrophy should consult their physician before making any changes to their treatment regimen.