Myotonic dystrophy type 1

Other Names: Dystrophia myotonica type 1; DM1; Steinert disease; Steinert myotonic dystrophy; Steinert's disease

Myotonic dystrophy type 1 (MD1), one of the two types of myotonic dystrophy, is an inherited type of muscular dystrophy that affects the muscles and other body systems (e.g., heart, eyes, endocrine system, and central nervous system). File:Myotonic-dystrophy-type-1-patient-derived-iPSCs-for-the-investigation-of-CTG-repeat-instability-srep42522-s2.ogv

Forms

Myotonic dystrophy type 1 (MD1), one of the two types of myotonic dystrophy, is an inherited type of muscular dystrophy that affects the muscles and other body systems (e.g., heart, eyes, endocrine system, and central nervous system). MD1 has three forms that somewhat overlap: the mild form, classic form, and congenital form (present at birth).

The mild form has the least severe symptoms of the different forms of MD1 and is associated with a normal life span.

The classic form is characterized by muscle weakness and wasting, prolonged muscle tensing (myotonia), cataract, and often, abnormal heart function. Adults with the classic form may become physically disabled and may have a shortened life span.

The congenital form is characterized by severe generalized weakness at birth (hypotonia), often causing complications with breathing and early death.

Epidemiology

Myotonic dystrophy affects at least 1 in 8,000 people worldwide. The prevalence of the two types of myotonic dystrophy varies among different geographic and ethnic populations. In most populations, type 1 appears to be more common than type 2. However, recent studies suggest that type 2 may be as common as type 1 among people in Germany and Finland.

Cause

MD1 is caused by a mutation called a CTG trinucleotide repeat in the DMPK gene. It is made up of three DNA building blocks (CTG stands for cytosine, thymine, and guanine) that appear multiple times in a row. If the number of CTG repeats is more than 34, it creates an unstable region in the gene. Repeats between 35 and 49 are considered premutations. Individuals with CTG repeats in this range do not have symptoms themselves, but their children are at increased risk of inheriting a larger repeat size and thus having symptoms.

The protein made by the DMPK gene is believed to play a role in communication and impulse transmission within and between cells. It appears to be important for the correct functioning of cells in the heart, brain, and skeletal muscles. The more than normal number of CTG repeats leads to the creation of longer and toxic RNA. This causes problems for cells mainly because it traps and disables important proteins. This prevents cells in muscles and other tissues from functioning normally, leading to the signs and symptoms of MD1.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

MD1 is inherited in an autosomal dominant pattern, which means one copy of the mutated gene in each cell is sufficient to cause the disorder. In most cases, the person with MD1 has a parent who also has the disorder. The children of a person with MD1 have a 50% chance of inheriting the disorder.

As myotonic dystrophy is passed from one generation to the next, the disorder generally begins earlier in life and signs and symptoms become more severe. This phenomenon is called anticipation. It is caused by an increase in the length of the number of CTG repeats (unstable region) in the DMPK gene. The expansion of the unstable region causes the features of the disorder to become more severe with each successive generation.

Some people diagnosed with MD1 have a parent who has the signs and symptoms of the disorder; others do not. A parent may appear to be unaffected because symptoms may be mild or absent. Genetic testing is available to confirm the presence of the condition.

Signs and symptoms

People with MD1 have progressive muscle wasting and weakness beginning in their 20's or 30's. The muscle wasting and weakness develop in their lower legs, hands, neck and face. They also have stiffness and tightness of their muscles (called myotonia), so they are slow to relax certain muscles after using them. This condition is characterized by difficulty releasing the hand from a handshake or a doorknob. In addition to muscle weakness and wasting, people who have MD1 may have fatigue, muscle pain, difficulty swallowing, clouding of the lens in their eyes (cataracts), and irregularities in the electrical control of their heartbeat (cardiac conduction defects). People with advanced disease may develop respiratory complications. Men with MD1 have changes in their hormones that can cause balding and sometimes the inability to father a child (infertility).The severity of symptoms varies among people with MD1.

Compared to myotonic dystrophy type 2, MD1 is more severe and may affect lifespan. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Cardiac conduction abnormality
• Distal muscle weakness(Weakness of outermost muscles)
• EMG: myotonic discharges
• Excessive daytime somnolence(Excessive daytime sleepiness)
• Myotonia with warm-up phenomenon
• Posterior subcapsular cataract

30%-79% of people have these symptoms

• Abnormal rapid eye movement sleep
• Abnormality of masticatory muscle
• Atrial fibrillation(Quivering upper heart chambers resulting in irregular heartbeat)
• Fatigable weakness of bulbar muscles
• Fatigue(Tired)
• Foot dorsiflexor weakness(Foot drop)
• Hypersomnia(Excessive sleepiness)
• Myalgia(Muscle ache)
• Obstructive sleep apnea
• Poor fine motor coordination
• Prolonged PR interval
• Prolonged QRS complex

Diagnosis

Suggestive Findings Myotonic dystrophy type 1 (DM1) should be suspected in adults with the following:

• Muscle weakness, especially of the distal leg, hand, neck, and face
• Myotonia (sustained muscle contraction), which often manifests as the inability to quickly release a hand grip (grip myotonia) and which can be demonstrated by tapping a muscle (e.g., the thenar muscles) with a reflex hammer (percussion myotonia)
• Posterior subcapsular cataracts detectable as red and green iridescent opacities on slit lamp examination

DM1 should be suspected in neonates with some combination of the following:

• Hypotonia
• Facial muscle weakness
• Generalized weakness
• Positional malformations including clubfoot
• Respiratory insufficiency

Establishing the Diagnosis The diagnosis of DM1 is established in a proband with identification of a heterozygous pathogenic variant in DMPK by molecular genetic testing.

Treatment

Treatment of manifestations: Use of ankle-foot orthoses, wheelchairs, or other assistive devices; special education support for affected children; treatment of hypothyroidism; management of pain; consultation with a cardiologist for symptoms or ECG evidence of arrhythmia; removal of cataracts if vision is impaired; hormone replacement therapy for males with hypogonadism; surgical excision of pilomatrixoma and basal cell carcinomas.

Prevention of secondary complications: Choice of induction agents, airway care, local anesthesia, and neuromuscular blockade to minimize complications during surgery; cardiac pacemakers or implantable cardioverter-defibrillators may prevent life-threatening arrhythmias; continue physical activity and maintain appropriate weight.

NIH genetic and rare disease info

• NIH info on Myotonic dystrophy type 1

Myotonic dystrophy type 1 is a rare disease.

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