myotonic dystrophy

Myotonic Dystrophy

Definition

Myotonic dystrophy is a progressive disease in which the muscles are weak and are slow to relax after contraction.

Description

Myotonic dystrophy (DM), also called dystrophia myotonica, myotonia atrophica, or Steinert's disease, is a common form of muscular dystrophy. DM is an inherited disease, affecting males and females approximately equally. About 30,000 people in the United States are affected. Symptoms may appear at any time from infancy to adulthood. DM causes general weakness, usually beginning in the muscles of the hands, feet, neck, or face. It slowly progresses to involve other muscle groups, including the heart. DM affects a wide variety of other organ systems as well.A severe form of DM, congenital myotonic dystrophy or Thomsen's disease, may appear in newborns of mothers who have DM. Congenital means that the condition is present from birth. The incidence of congenital myotonic dystrophy is thought to be about 1:20,000.DM occurs in about 1 per 7,000-8,000 people and has been described in people from all over the world.

Causes and symptoms

The most common type of DM is called DM1 and is caused by a mutation in a gene called myotonic dystrophy protein kinase (DMPK). The DMPK gene is located on chromosome 19q. When there is a mutation in this gene, a person develops DM1. The specific mutation that causes DM1 is called a trinucleotide repeat expansion.Some families with symptoms of DM do not have a mutation in the DMPK gene. As of early 2001, scientists have found that the DM in many of these families is caused by a mutation in a gene on chromosome 3. These families are said to have DM2.Congenital myotonic dystrophy has been linked to a region on chromosome 7 that contains a muscle chloride channel gene.

Trinucleotide repeats

In the DMPK gene, there is a section of the genetic code called a CTG repeat. The letters stand for three nucleotides (complex organic molecules) known as cytosine, thymine, and guanine, and are repeated a certain number of times. In people who have DM1, this sequence of nucleotides is repeated too many times—more than the normal number of 37 times—and thus this section of the gene is too big. This enlarged section of the gene is called a trinucleotide repeat expansion.People who have repeat numbers in the normal range will not develop DM1 and cannot pass it to their children. Having more than 50 repeats causes DM1. People who have 38-49 repeats have a premutation and will not develop DM1, but can pass DM1 onto their children. Having repeats numbers greater than 1000 causes congenital myotonic dystrophy.In general, the more repeats in the affected range that someone has, the earlier the age of onset of symptoms and the more severe the symptoms. However, this is a general rule. It is not possible to look at a person's repeat number and predict at what age they will begin to have symptoms or how their condition will progress.Exactly how the trinucleotide repeat expansion causes myotonia, the inability to relax muscles, is not yet understood. The disease somehow blocks the flow of electrical impulses across the muscle cell membrane. Without proper flow of charged particles, the muscle cannot return to its relaxed state after it has contracted.Since 2001 it has been discovered that DM2 is caused by a CCTG (cytosine-cytosine-thymine-guanine) expansion on chromosome 3 at locus 3q21, but as of 2004 it is not known how this repeat affects muscle cell function.

Anticipation

Sometimes when a person who has repeat numbers in the affected or premutation range has children, the expansion grows larger. This is called anticipation. A larger expansion can result in an earlier age of onset in children than in their affected parent. Anticipation happens more often when a mother passes DM1 onto her children then when it is passed from the father. Occasionally repeat sizes stay the same or even get smaller when they are passed to a person's children.

Inheritance

DM is inherited through autosomal dominant inheritance. This means that equal numbers of males and females are affected. It also means that only one gene in the pair needs to have the mutation in order for a person to be affected. Since a person only passes one copy of each gene onto their children, there is a 50% or one in two chance that a person who has DM will pass it onto each of their children. This percentage is not changed by results of other pregnancies. A person with a premutation also has a 50%, or one in two, chance of passing the altered gene on to each of their children. However, whether or not their children will develop DM1 depends on whether the trinucleotide repeat becomes further expanded. A person who has repeat numbers in the normal range cannot pass DM1 onto their children.There is a range in the severity of symptoms in DM and not everyone will have all of the symptoms listed here.Myotonic dystrophy causes weakness and delayed muscle relaxation called myotonia. Symptoms of DM include facial weakness and a slack jaw, drooping eyelids called ptosis, and muscle wasting in the forearms and calves. A person with DM has difficulty relaxing his or her grasp, especially in the cold. DM affects the heart muscle, causing irregularities in the heartbeat. It also affects the muscles of the digestive system, causing constipation and other digestive problems. DM may cause cataracts, retinal degeneration, low IQ, frontal balding, skin disorders, atrophy of the testicles, and diabetes. It can also cause sleep apnea—a condition in which normal breathing is interrupted during sleep. DM increases the need for sleep and decreases motivation. Severe disabilities do not set in until about 20 years after symptoms begin. Most people with myotonic dystrophy maintain the ability to walk, even late in life.A severe form of DM, congenital myotonic dystrophy, may appear in newborns of mothers who have DM1. Congenital myotonic dystrophy is marked by severe weakness, poor sucking and swallowing responses, respiratory difficulty, delayed motor development, and mental retardation. Death in infancy is common in this type.Some people who have a trinucleotide repeat expansion in their DMPK gene do not have symptoms or have very mild symptoms that go unnoticed. It is not unusual for a woman to be diagnosed with DM after she has an infant with congenital myotonic dystrophy.

Predictive testing

It is possible to test someone who is at risk for developing DM1 before they are showing symptoms to see whether they inherited an expanded trinucleotide repeat. This is called predictive testing. Predictive testing cannot determine the age of onset that someone will begin to have symptoms, or the course of the disease.

Diagnosis

Diagnosis of DM is not difficult once the disease is considered. However, the true problem may be masked because symptoms can begin at any age, can be mild or severe, and can occur with a wide variety of associated complaints. Diagnosis of DM begins with a careful medical history and a thorough physical exam to determine the distribution of symptoms and to rule out other causes. A family history of DM or unexplained weakness helps to establish the diagnosis.A definitive diagnosis of DM1 is done by genetic testing, usually by taking a small amount of blood. The DNA in the blood cells is examined and the number of repeats in the DMPK gene is determined. Various other tests may be done to help establish the diagnosis, but only rarely would other testing be needed. An electromyogram (EMG) is a test is used to examine the response of the muscles to stimulation. Characteristic changes are seen in DM that helps distinguish it from other muscle diseases. Removing a small piece of muscle tissue for microscopic examination is called a muscle biopsy. DM is marked by characteristic changes in the structure of muscle cells that can be seen on a muscle biopsy. An electrocardiogram could be performed to detect characteristic abnormalities in heart rhythm associated with DM. These symptoms often appear later in the course of the disease.

Prenatal testing

Testing a pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a DMPK mutation. This can be done at 10-12 weeks gestation by a procedure called chorionic villus sampling (CVS) that involves removing a tiny piece of the placenta and analyzing DNA from its cells. It can also be done by amniocentesis after 14 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it and those who are interested in learning more should check with their doctor or genetic counselor.There is also another procedure called preimplantation diagnosis that allows a couple to have a child that is unaffected with the genetic condition in their family. This procedure is experimental and not widely available. Those interested in learning more about this procedure should check with their doctor or genetic counselor.A group of researchers in Houston, Texas, reported in 2004 that they have successfully developed a technique for detecting the CCTG expansion that causes DM2 and estimating the size of the repeat expansion.

Treatment

Myotonic dystrophy cannot be cured, and no treatment can delay its progression. As of the early 2000s there is no standardized treatment for these disorders because the precise reasons for muscle weakness are not yet fully understood. However, many of the symptoms can be treated. Physical therapy can help preserve or increase strength and flexibility in muscles. Ankle and wrist braces can be used to support weakened limbs. Occupational therapy is used to develop tools and techniques to compensate for loss of strength and dexterity. A speech-language pathologist can provide retraining for weakness in the muscles controlling speech and swallowing.Irregularities in the heartbeat may be treated with medication or a pacemaker. A yearly electrocardiogram is usually recommended to monitor the heartbeat. Diabetes mellitus in DM is treated in the same way that it is in the general population. A high-fiber diet can help prevent constipation. Sleep apnea may be treated with surgical procedures to open the airways or with nighttime ventilation. Treatment of sleep apnea may reduce drowsiness. Lens replacement surgery is available when cataracts develop. Pregnant woman should be followed by an obstetrician familiar with the particular problems of DM because complications can occur during pregnancy, labor and delivery.Wearing a medical bracelet is advisable. Some emergency medications may have dangerous effects on the heart rhythm in a person with DM. Adverse reactions to general anesthesia may also occur.

Prognosis

The course of myotonic dystrophy varies. When symptoms appear earlier in life, disability tends to become more severe. Occasionally people with DM may require a wheelchair later in life. Children with congenital DM usually require special educational programs and physical and occupational therapy. For both types of DM, respiratory infections pose a danger when weakness becomes severe.

Resources

Books

Beers, Mark H., MD, and Robert Berkow, MD, editors. "Myotonic Disorders." Section 14, Chapter 184. In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Periodicals

International Myotonic Dystrophy Consortium (IMDC). "New Nomenclature and DNA Testing Guidelines for Myotonic Dystrophy Type 1 (DM1)." Neurology 54 (2000): 1218-1221.Meola, G., and V. Sansone. "Treatment in Myotonia and Periodic Paralysis." Revue neurologique (Paris) 160, no. 5, Part 2 (May 2004: S55-S69.Meola, Giovanni. "Myotonic Dystrophies." Current Opinion in Neurology 13 (2000): 519-525.Ranum, L. P., and J. W. Day. "Myotonic dystrophy: RNA Pathogenesis Comes into Focus." American Journal of Human Genetics 74 (May 2004): 793-804.Sallinen, R., A. Vihola, L. L. Bachinski, et al. "New Methods for Molecular Diagnosis and Demonstration of the (CCTG)n Mutation in Myotonic Dystrophy Type 2 (DM2)." Neuromuscular Disorders 14 (April 2004): 274-283.

Organizations

Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717. http://www.mdausa.org.

Other

Gene Clinics. http://www.geneclinics.org.Myotonic Dystrophy Website. 〈http://www.umd.necker.fr/myotonic_dystrophy.html〉.NCBI Genes and Disease Web Page. http://www.ncbi.nlm.nih.gov/disease/Myotonic.html.

Key terms

Electrocardiogram (ECG, EKG) — A test that uses electrodes attached to the chest with an adhesive gel to transmit the electrical impulses of the heart muscle to a recording device.Electromyography (EMG) — A test that uses electrodes to record the electrical activity of muscle. The information gathered is used to diagnose neuromuscular disorders.Muscular dystrophy — A group of inherited diseases characterized by progressive wasting of the muscles.Nucleotide — Any of a group of organic molecules that link together to form the building blocks of DNA or RNA.Sleep apnea — Temporary cessation of breathing while sleeping.Trinucleotide repeat expansion — A sequence of three nucleotides that is repeated too many times in a section of a gene.

dystrophy

[dis´trah-fe] any disorder due to defective or faulty nutrition, especially muscular dystrophy. adj., adj dystroph´ic.adiposogenital dystrophy adiposity of the feminine type, genital hypoplasia, changes in secondary sex characters, and metabolic disturbances; seen with lesions of the hypothalamus; see also adiposogenital dystrophy.Becker's muscular dystrophy (Becker type muscular dystrophy) a form closely resembling Duchenne's muscular dystrophy, but having a later onset and milder course; transmitted as an X-linked recessive trait.distal muscular dystrophy distal myopathy.Duchenne's muscular dystrophy (Duchenne type muscular dystrophy) The childhood type of muscular dystrophy.facioscapulohumeral muscular dystrophy muscular dystrophy affecting the face, shoulder, and upper arm muscles; called also Landouzy-Dejerine muscular dystrophy.Landouzy-Dejerine dystrophy (Landouzy-Dejerine muscular dystrophy) facioscapulohumeral muscular dystrophy.muscular dystrophy see muscular dystrophy.myotonic dystrophy a rare, slowly progressive, hereditary disease, marked by myotonia followed by muscular atrophy (especially of the face and neck), cataracts, hypogonadism, frontal balding, and cardiac disorders. Called also dystrophia myotonica, myotonia atrophica, and myotonia dystrophica.progressive muscular dystrophy muscular dystrophy.pseudohypertrophic muscular dystrophy muscular dystrophy affecting the shoulder and pelvic girdles, beginning in childhood and marked by increasing weakness, pseudohypertrophy of the muscles, followed by atrophy, and a peculiar swaying gait with the legs kept wide apart. Called also pseudohypertrophic muscular paralysis.reflex sympathetic dystrophy a syndrome of chronic pain that usually develops after a trauma or noxious stimulus, although the nerve injury cannot be immediately identified. The pain is not limited to the distribution of a single nerve and is often out of proportion to the precipitating event. It is most often described as a burning pain, and is accompanied by swelling, sweating, sensitivity to touch, and sometimes changes in tissue growth. Called also chronic or complex regional pain syndrome. Clinical practice guidelines have been published by the Reflex Sympathetic Dystrophy Syndrome Association of America and are available on their web site at http://www.rsds.org or by writing to Reflex Sympathetic Dystrophy Syndrome Association of America, P.O. Box 502, Milford CT 06460.

my·o·ton·ic dys·tro·phy

[MIM*160900] the most common adult muscular dystrophy, characterized by progressive muscle weakness and wasting of some of the cranial innervated muscles, as well as the distal limb muscles; other clinical features include myotonia, cataracts, hypogonadism, cardiac abnormalities, and frontal balding; onset usually in the the third decade; autosomal dominant inheritance caused by abnormal trinucleotide repeat expansion in the dystrophia myotonica protein kinase gene (DMPK) on chromosome 19q. This disorder demonstrates anticipation (increase in severity in successive generations because of successive amplification of the trinucleotide repeats); the severe congenital form is almost always confined to the children of affected women. Synonym(s): dystrophia myotonica, myotonia atrophica, myotonia dystrophica, Steinert disease

myotonic dystrophy

A relatively common (affects 1:8,000) autosomal-dominant condition of early adult onset that causes distal myopathy, primarily affecting certain muscles—e.g., levator palpebrae, facial, masseter, sternocleidomastoid, forearm, hand and pretibial muscles—resulting in diffuse muscular weakness and atrophy.
Clinical findings
“Hatchet face”, lenticular opacities, endocrinopathies (testicular atrophy and androgen insufficiency), ovarian dysfunction which rarely interferes with fertility, diabetes, hypothyroidism, mild cortical atrophy, frontoparietal baldness, cardiac and smooth muscle (GI, especially oesophageal motility) defects, respiratory dysfunction and hyperostosis frontalis interna.
Prognosis
Death commonly occurs by age 50.

myotonic dystrophy

Molecular medicine An AD condition affecting ± 1:8000, age of onset, age 20-25, ↓ IQ, which causes distal myopathy, preferentially affecting certain muscles–eg, levator palpebrae, facial, masseter, sternocleidomastoid, forearm, hand and pretibial muscles, resulting in diffuse muscular weakness and atrophy beginning in early adulthood causing the characteristic 'hatchet face'; other changes include lenticular opacities, endocrinopathies–testicular atrophy with androgen insufficiency, ovarian dysfunction which rarely interferes with fertility, DM, hypothyroidism, mild cerebral cortical atrophy, frontoparietal baldness, cardiac and smooth muscle–GI, especially esophageal motility defects, respiratory dysfunction and hyperostosis frontalis interna; death usually by age 50. See Myotonia, Trinucleotide repeat disease.

my·o·ton·ic dys·tro·phy

(mīō-tonik distrŏ-fē) Most common adult muscular dystrophy, characterized by progressive muscle weakness and wasting of some of the cranial innervated muscles, as well as the distal limb muscles; other clinical features include myotonia, cataracts, hypogonadism, cardiac abnormalities, and frontal balding; onset usually in the third decade.

myotonic dystrophy

See DYSTROPHIA MYOTONICA.

Steinert,

(Steinhert), Hans, German physician, 1875–. Curschmann-Batten-Steinert syndrome - see under CurschmannSteinert disease - a chronic, slowly progressing disease marked by atrophy of the muscles, failing vision, lenticular opacities, ptosis, slurred speech, and general muscular weakness. Synonym(s): myotonic dystrophySteinert myotonic dystrophySteinert syndrome

pupil

Aperture within the iris, normally circular, through which light penetrates into the eye. It is located slightly nasally to the centre of the iris. Its diameter can vary from about 2 to 8 mm. It is often slightly smaller in old age. The function of the pupil is to regulate the amount of light admitted into the eye, to optimize the depth of focus and to mitigate ocular aberrations. See acorea; anisocoria; corectopia; dicoria; dyscoria; hippus; iridectomy; microcoria; miosis; dilator pupillae muscle; sphincter pupillae muscle; mydriasis; Edinger-Westphal nucleus; polycoria; polyopia; pupil light reflex.
Adie's pupil A pupil in which the reactions to light, direct or consensual, are almost abolished, with a reaction occurring only after prolonged exposure to light or dark. The reaction of the pupil to a near target is also delayed and slow. The condition is usually unilateral, with the affected pupil being the larger of the two (anisocoria). It may be due to a disease of, or injury to, the ciliary ganglion or to the short ciliary nerves. Other causes include temporal arteritis in elderly patients, syphilis or diabetes. Syn. myotonic pupil; pupillotonia; tonic pupil (some authors use this last term when the cause is known and Adie's pupil when the cause is unidentified). See efferent pupillary defect; Adie's syndrome; pupil light reflex.
amaurotic pupil Miotic pupil that does not react to direct and consensual ipsilateral light stimulation, but does react consensually to contralateral stimulation. It is most often noted in cases of severe optic nerve dysfunction or retinal disease.
apparent pupil See entrance pupil of the eye.
Argyll Robertson pupil Pupil that reacts when the eye accommodates and converges but fails to react directly and consensually to light. The condition is bilateral, the pupils are small and usually unequal. It is usually a sign of neurosyphilis. See iridoplegia; tabes dorsalis.
artificial pupil 1. Pupil made by iridectomy. 2. A circular aperture made in a diaphragm which can be mounted in front of the eye to provide a constant and smaller pupil size. It is used in research but also as a clinical test. See pinhole disc.
pupil block See pupillary block.
pupil constriction See miosis; pupil light reflex.
pupil dilatation See mydriatic; pupil light reflex.
ectopic pupil See corectopia.
entrance pupil of the eye This is the image of the iris aperture formed by the cornea. It is what one sees when one looks at an eye. It is some 13% larger than the real pupil and located slightly in front of it. Syn. apparent pupil (Fig. P23).
exit pupil of the eye This is the image of the iris aperture formed by the crystalline lens. It is slightly larger (,3%) than the real pupil and situated slightly behind it (Fig. P23).
Horner's pupil See syndrome, Horner's.
Hutchinson's pupil A pupil that is dilated and completely inactive to all stimuli. It is associated with lesions of the central nervous system, as may occur in head injury.
keyhole pupil A pupil shaped like a keyhole due to iridectomy in which a section of the iris extending from the pupillary margin to the periphery has been excised, or due to coloboma or trauma to the iris.
pupil light reflex See pupil light reflex.
Marcus Gunn pupil A defect of the pupillary reflex characterized by a smaller constriction of both pupils when the affected eye is stimulated by light as compared to that occurring when the normal eye is stimulated. It is easier, however, to observe this phenomenon when swinging a light from one eye to the other in a darkened room while the subject is fixating a distant object (this is called the swinging flashlight test) (Fig. P24). Stimulation of the normal eye will cause constriction of both pupils whereas rapid stimulation of the affected eye will lead to a small dilatation (a paradoxical reaction, sometimes referred to as pupillary escape). This condition is due to a lesion in one retina or in one of the optic nerves, optic chiasma, optic tract, or the pretectal olivary nucleus that affects the afferent pupillary pathway. It is often the result of central or branch retinal or vein occlusion, extensive retinal detachment, retrobulbar optic neuritis, compressive optic neuropathy, or optic tract lesion, etc. Syn. relative afferent pupillary defect (RAPD), if the magnitude of the effect is partial; afferent pupillary defect (APD), if it is complete.
myotonic pupil See Adie's pupil.
pupil reflex See pupil reflex.
tonic pupil See Adie's pupil.
white pupil See leukocoria.

" >

Fig. P23 The entrance and exit pupils of the eye. E and E′ are the centres of the entrance and exit pupils, respectively (diagram not to scale)

" >

Fig. P24 Swinging flashlight test performed in a darkened room. A, stimulation of the normal eye results in bilateral pupil constriction

Table P11 Examples of pupil abnormality
defect	appearance	light response*	consensual light response*	near response
Adie's pupil	large	impaired	impaired	slow
Argyll Robertson	both pupils small, unequal + irregular	almost abolished	almost abolished	normal
blindness in one eye	normal	abolished	abolished	normal
Horner's syndrome	small + ptosis	normal	normal	normal
Hutchinson's pupil	large	abolished	abolished	abolished
optic neuritis	normal/large	impaired	impaired	normal
3rd nerve paralysis^†	large + ptosis	abolished	abolished	abolished
*To stimulation of the affected eye.^†When caused by an aneurysm of the posterior communicating artery.

my·o·ton·ic dys·tro·phy

(mīō-tonik distrŏ-fē) [MIM*160900] Most common adult muscular dystrophy, characterized by progressive muscle weakness and wasting of some of cranial innervated muscles, as well as the distal limb muscles.

myotonic dystrophy

myotonic dystrophy

myotonic dystrophy

myotonic dystrophy

Myotonic Dystrophy

Definition

Description

Causes and symptoms

Trinucleotide repeats

Anticipation

Inheritance

Predictive testing

Diagnosis

Prenatal testing

Treatment

Prognosis

Resources

Books

Periodicals

Organizations

Other

Key terms

dystrophy

my·o·ton·ic dys·tro·phy

myotonic dystrophy

myotonic dystrophy

my·o·ton·ic dys·tro·phy

myotonic dystrophy

Steinert,

pupil

my·o·ton·ic dys·tro·phy

myotonic dystrophy

Synonyms for myotonic dystrophy

noun a severe form of muscular dystrophy marked by generalized weakness and muscular wasting that affects the face and feet and hands and neck

Synonyms

Related Words