Myotonic dystrophy (DM) is the most common muscular dystrophy in adults, and is the second most common muscular dystrophy after Duchenne muscular dystrophy. It is an autosomal dominant genetic disorder affecting one in 8,000 individuals. Onset is usually in the second or third decade and the life span of affected individuals is typically six decades. A congenital form of DM can occur in second or third generations, however, and can be fatal for affected infants. Characteristics of DM include myotonia, as well as progressive weakening and wasting of the voluntary muscles of the eyes, face, neck, arms and legs. Muscles related to involuntary activities such as swallowing and breathing, as well as those surrounding the internal organs such as the upper and lower digestive tracts, the gall bladder, and the uterus may also be affected as the disease progresses in an individual. Other characteristics include cataracts, cardiac conduction abnormalities, cognitive deficits, and frontal balding.

	Muscle groups affected in myotonic dystrophy

The genetic causes of three forms of DM have been identified:

• DM1, also known as Steinert's disease
• DM2, also known as proximal myotonic myopathy (PROMM)
• Congenital myotonic dystrophy (CMyD)

DM1 and DM2 have similar clinical presentations, however, DM2 may present with milder symptoms. Both DM1 and DM2 are equally prevalent. CMyD is the most serious form of DM. Affected infants typically have severe muscle weakness, hypotonia and difficulties with breathing, sucking and swallowing. Intensive clinical intervention is necessary to improve the chance of survival of such children. CMyD and early onset DM1 are attributable to the phenomenon of anticipation. The abnormal repeat expansion that has been identified as the cause of DM1 can lengthen in successive generations, which lowers the age of onset and increases symptom severity.¹

All three forms of DM are caused by an abnormal nucleotide repeat expansion. In DM1 and CMyD, the expansion is in a non-coding region of the DMPK (Dystrophia-myotonica protein kinase) gene on chromosome 19. In DM2, the expansion is in a non-coding region of the ZNF9 (zinc finger protein 9) gene on chromosome 3.² The fact that both repeat expansions occur in non-coding regions of these genes, yet result in very similar multi-systemic symptoms, has led researchers to hypothesize that mutant RNA is a contributing factor to DM.

Individuals affected with DM1 and DM2 can present with a range of symptoms, including myotonia, muscle weakness and wasting, cataracts, foot drop, hyperinsulinism, and smooth muscle problems. Weakness of the voluntary muscles in the arms and legs tends to be the first symptom noticed by affected individuals.³

Figure 1: Electromyogram reveals spontaneous myotonic discharge following needle insertion. Source: Netter, F.H. The CIBA collection of Medical Illustrations. 1986. New Jersey: CIBA Pharmaceutical Co.

The prolonged muscle spasms and stiffening that characterize myotonia are caused by irregularities in the ion channels of the muscle membrane. Electromyogram reveals a spontaneous myotonic discharge in affected individuals (see Figure 1).

Figure 2: On percussion of thenar muscles, the thumb moves sharply into opposition and adduction and slowly returns to initial position in individuals exhibiting a myotonic response. Source: Netter, F.H. The CIBA collection of Medical Illustrations. 1986. New Jersey: CIBA Pharmaceutical Co.

Mechanical stimulation (percussion) evokes a sharp response with a slow return to initial position (see Figure 2). Myotonia is not a clinical finding of CMyD at birth, but if the infant survives, he/she may develop myotonia later in life.

The clinical findings of DM1 can be categorized into three overlapping phenotypes - mild, classical and congenital (CMyD).

Mild DM. Individuals affected with the mild DM phenotype may lead active lives and be unaware that they have the disorder. If they note muscle weakness or mild myotonia, they may attribute it to "stiffness" or arthritis.² Clinical findings of cataracts or diabetes mellitus, in the absence of marked muscle weakness, pronounced myotonia, or family history of DM, are unlikely to lead a clinician to a DM diagnosis. Individuals with mild DM are often diagnosed only after testing precipitated by a positive result in a more severely affected relative.

Figure 3: Some of the clinical signs of classical myotonic dystrophy. Source: Netter, F.H. The CIBA collection of Medical Illustrations. 1986. New Jersey: CIBA Pharmaceutical Co.

Classical DM. Affected individuals typically present with muscle weakness and wasting, myotonia and foot drop (resulting in gait disturbance). Other clinical findings may include cataracts, myotonic facies (usually caused by weakness of the facial and levator palpebrae muscles), ophthalmoplegia, dysarthria, and smooth muscle involvement resulting in dysphagia, constipation or diarrhea. While age of onset is typically in the second or third decade, mild myotonic facies and myotonia may be observed in childhood.³

Cardiac conduction abnormalities are common in classical DM and are a major cause of early mortality. DM poses additional risks for women during pregnancy. Complications can include increased spontaneous abortion rate, prolonged labor, polyhydramnios, reduced fetal movement, retained placenta and post-partum hemorrhage.⁴ A mother affected with DM1 is more likely to have a child with CMyD than a father affected with DM1.

Figure 4: Infant with the congenital form of myotonic dystrophy. Note the "tented" or inverted "V" shape of the upper lip, which is characteristic of the congenital form of the disorder. Source: Nelson W.E. et al. Myotonic muscular dystrophy in Textbook of pediatrics, 15th edition, 1749-1750. 1996. Philadelphia: WB Saunders Co.

Congenital Myotonic Dystrophy: Infants with CMyD exhibit muscle weakness, hypotonia, inverted "V" shaped upper lip (see Figure 4) and compromised respiratory function - the latter of which results in a high infant mortality rate. Motor function gradually improves in surviving children and they are usually able to walk. However they will develop the same clinical signs of classical DM later in life. Mental retardation is present in 50-60% of these individuals.³

Correlation between expansion length and clinical signs in DM1 and CMyD: There is a general (though not absolute) correlation between the severity and age of onset of symptoms with the length of the nucleotide repeat expansion in DM1 and CMyD. Table 1 illustrates how clinical signs correlate with the length of the CTG trinucleotide repeat expansion in the DM1 and CMyD form of the disorder. Note the overlap in repeat length between the phenotypes, and use caution when attempting to predict symptom severity based on repeat length.³

Table 1. Reported Correlation between Phenotype and CTG Repeats in DM1 and CMyD

Adapted from Mathieu et al⁵ and de Die-Smulders et al.⁶
† CTG repeat sizes overlap between phenotypes.
§ Redman et al⁷ reported a few congenital cases with repeats between 730 and 1000.
‡ Does not include neonatal deaths.

DM2 is phenotypically similar to DM1. Affected individuals may present with proximal and distal limb weakness, myotonia, cardiac arrhythmias, frontal balding and cataracts.

Unlike DM1, there is no reported correlation between repeat expansion size and age of onset and severity of symptoms for DM2.¹ In addition, there is no reported congenital form of the disorder.

Figure 5: Top - An example of a normal CTG repeat expansion in the DMPK gene (5-150 repeats). Bottom - An example of an altered CTG expansion in the DMPK gene (50-2000 repeats).

DM1 and CMyD are caused by an abnormal trinucleotide (CTG) repeat expansion in the DM1 locus on chromosome 19q13.3.

Figure 6: Top - A CTG repeat expansion in the DMPK gene at the DM1 locus on chromosome 19 causes DM1. Bottom - A CCTG repeat expansion at the DM2 locus on chromosome 3 causes DM2. In both instances, mutant RNAs containing the repeat expansions accumulate in nucleus foci. RNA from the normal allele is spliced to form mRNA, which is exported to the cytoplasm and then translated into protein. Source: Science (2001) 293:816-817.

DM2 is caused by an abnormal tetranucleotide (CCTG) repeat expansion in the DM2 locus on chromosome 3q21.

Exactly how the expansions in the DMPK and ZNF9 genes result in DM are unknown. Researchers hypothesize that after the repeat expansion is transcribed in RNA, the RNA has a pathogenic effect that disrupts cellular function. For example, in the case of DM1, the CTG repeat expansion (transcribed as CUG in the RNA) results in altered splicing of the DMPK transcript.⁸ RNA with the CUG expansion repeat accumulates in discrete foci within the cell nucleus instead of translocating to the cytoplasm, where the mRNA is translated into DMPK (see Figure 6). The accumulated RNA in the cell nucleus disrupts the activity of nuclear RNA binding proteins and disrupts cellular metabolism.

While there is no cure for myotonic dystrophy, managing the clinical manifestations of the disorder can greatly improve the quality of life of individuals affected with this disorder.

Myotonia: Because myotonia precedes weakness in adult onset DM, electromyograms can aid in the assessment of disease progression. Myotonia can be controlled with phenytoin, carbamazepine, or quinine sulfate.¹⁰

Muscle weakness and wasting: Wrist supports, ankle-foot orthoses, canes and walkers will assist individuals affected by muscle weakness and wasting. Wheelchairs are rarely required.

Cardiac conduction abnormalities: The possibility of cardiac conduction abnormalities in myotonic dystrophy gene carriers dictates periodic electrocardiogram follow-up. P-R intervals >0.20 msec are a warning of impending heart block. If P-R intervals are >0.22 msec, invasive electrophysiological testing should be considered. Individuals with His-ventricular conduction times >65 msec should be monitored and are candidates for elective pacemaker placement.⁹

Respiratory Complications: In some adults, weakness of the muscles of the respiratory system may be managed using portable ventilators. In infants, ventilators are usually required to prevent death.¹¹

Pregnancy: When a mother is affected with DM1, CMyD should be suspected in the fetus. The size of the CTG expansion repeat in the fetus can be determined through chorionic villus sampling (CVS). The occurrence of polyhydramnios is an additional clinical sign of CMyD and can usually be confirmed by ultrasound examination.

CMyD: Infants with CMyD have a high risk of mortality caused by respiratory failure. These children require intensive clinical intervention to improve their chance of survival. The symptoms of hypotonia may improve through their childhood years. Talipes equinovarus may necessitate surgical correction. Children with learning disabilities or mental retardation may require educational and social support services. They should be tested for hearing impairments and may benefit from speech therapy to assist with speech difficulties. While myotonia is not a clinical finding at birth, affected children may develop myotonia later in life.⁹

Complications from anesthesia: A higher rate of complications is associated with the use of anesthesia in the DM population. Cardiac arrhythmias may be exacerbated or induced by anesthetic agents. While not well documented, individuals with DM may be more likely to develop malignant hyperthermia. Post-operative pulmonary complications are common. Careful monitoring of cardiac and respiratory functions during surgery and post operatively is indicated.⁹

Although DM is inherited as a classic autosomal dominant disease, incomplete penetrance, possible anticipation, and extreme variation in clinical expression make genetic counseling a critical component of DM diagnosis and case management.

Genetic counseling encompasses the clinical, technical and psychosocial components of genetic testing and disease. The genetic counseling process is an opportunity for patients to explore their questions and concerns about genetic disease and testing, as well as a means for medical professionals to develop comprehensive clinical histories.

The following components may be part of a genetic counseling session:

• Development of detailed personal and familial medical histories
• Discussion of testing options and capabilities
• Assessment of genetic risk to patient and family members
• Psychosocial discussion and support
• Decision making/prenatal diagnostic options
• Discussion of test results

Understanding the role of anticipation in DM is especially important when affected individuals contemplate reproduction. A mother with a 50 to 150 CTG repeat expansion in the DMPK gene (mild phenotype) can have a child with a 1000 to 2000 CTG repeat expansion (CMyD phenotype) as a result of anticipation.

In the event of pregnancy in a DM affected woman, a genetic counselor discusses the options for prenatal diagnostic genetic tests. DM1 and DM2 are both autosomal dominant disorders that have variable penetrance and extreme variation in clinical expression between multiple members of each pedigree.⁹ A dramatic example of variation in clinical expression is a mother with the mild form of DM1 transmitting the severest form of DM, CMyD, to her child.

The cause of variability in clinical expression between generations is anticipation. In DM1, the CTG trinucleotide repeat expansions can amplify in successive generations, resulting in a decrease in the age of onset and increase in the severity of symptoms in successive generations. CMyD can be inherited by either sex, but typically is through a mother affected with DM1, not an affected father. Anticipation has not been identified as a characteristic of DM2.

DNA diagnostic tests that measure the length of the CTG repeat expansion responsible for DM1 can now establish the diagnosis of DM1 with molecular certainty. These tests have supplanted the extensive clinical workup formerly required to document the multi-systemic clinical features of the disorder. The recent identification of the CCTG repeat expansion in the ZNF9 gene has made it possible to quantify the length of the expansion implicated in DM2, as well.

Individuals testing positive for DM1 and DM2 should receive annual cardiac and eye evaluations. Genetic counseling should be offered to individuals testing positive for DM1 or DM2, because the implications can be vastly different. Negative DM1 and DM2 test results indicate that the physician must continue his/her quest for the cause of the myopathy.

The multi-systemic presentation, incomplete penetrance, anticipation and variation in clinical expression of myotonic dystrophy have perplexed researchers and clinicians for many years. The identification of the repeat expansions in non-coding regions of the DMPK and ZNF9 genes, however, has led to intriguing investigations into the pathogenic effects of mutant RNA on cellular function.

The identification of the DMPK and ZNF9 loci has also led to the development of DNA diagnostic tests that aid clinicians in making a definitive DM diagnosis and in managing the clinical manifestations of the disorder.

1 2 3 4 5 Your understanding of the disease or condition How you will diagnose patients with this disorder How you will explain the disease or condition to patients and their families None of the above Breaking news in genetics Dementias Epilepsy Mitochondrial disorders Movement disorders Multiple sclerosis Neuromuscular disorders Pediatric disorders

Current NeuroCAST | NeuroCAST Library | Contact Us | Athena Diagnostics | LabCAST™ | Sign Up | Home

©, Athena Diagnostics, Inc. All Rights Reserved. Internet Site Notice / Disclaimer Form Use of this site is subject to the Internet Site Notice/Disclaimer Form, which you are urged to read prior to proceeding.

Designed and Developed by embarc.