Myotonic Dystrophies

Myotonic dystrophies are genetic disorders due to autosomal-dominant genetic mutations and have 2 major clinical forms: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2). Myotonic dystrophies are heterogeneous diseases primarily affecting the muscles, but, unlike other muscular dystrophies, also have multisystem effects. Both DM1 and DM2 present with myotonia, muscle weakness, and myalgias; however, DM1 is severe and carries a reduced life expectancy, whereas DM2 is mild with a normal life expectancy. Diagnosis is made clinically, with genetic testing, and by electromyography (EMG). Management is primarily supportive.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Myotonic dystrophy is an inherited, autosomal-dominant muscular disease, which causes muscle relaxation incompetence, resulting in progressive muscle wasting and weakness.

Epidemiology

  • The most common muscular dystrophy in people of European descent
  • Prevalence (based on variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables reporting): 1 per 2,100–9,000 births
  • Similar prevalence between myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2)

Classification

  • DM1 is also known as Steinert disease:
    • More severe than DM2
    • Congenital form: 
      • Presents with hypotonia and up to 40% mortality
      • Surviving children have foot deformities Foot deformities Foot deformities in children include congenital or acquired malformations of the feet. Two common examples are talipes equinovarus, commonly known as clubfoot, and metatarsus adductus, also called metatarsus varus. Foot Deformities and intellectual disabilities.
      • Children develop the classic signs of adult-onset DM1 with age.
    • Adult-onset form:
      • Milder and “classic” forms (depends on the size of the CTG repeat)
      • Age of onset: adolescence to 40 years of age
  • DM2 is also known as proximal myotonic myopathy (PROMM):
    • Much milder than DM1
    • Adult-onset form only
    • Age of onset: adolescence to 60 years of age

Pathophysiology

  • DM1:
    • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of the DMPK gene on chromosome 19
    • Trinucleotide repeat of CTG
    • Results in: 
      • Abnormal splicing and function of several other genes → affecting muscle, brain, and cardiac cells
      • Causes skeletal muscle chloride channel dysfunction → inability of muscles fibers to relax
    • Longer repeat expansion of the gene causes:
      • Earlier symptom onset 
      • Increased severity of symptoms with each generation
  • DM2:
    • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of the CNBP (also known as ZNF9) gene on chromosome 3 
    • Tetranucleotide repeat expansion of CCTG
    • Results in similar abnormal splicing and function of other genes

Clinical Presentation

Both types of myotonic dystrophy cause myotonia (sustained muscle contraction) with difficulty in relaxation after use.

DM1

Symptoms:

  • Muscle weakness: 
    • Affects facial muscles:
      • Hollow cheeks 
      • Drooping eyelids
      • Sagging jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint
    • Weakness of the distal hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand and foot muscles progress after years
    • Gait and stability slowly deteriorate
    • Significant fall risk
    • Difficulty holding head up due to weak neck muscles
  • Muscle pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Myotonia: 
    • Inability to relax after a sustained contraction
    • Common findings: 
      • Sustained handgrip
      • Percussion of thenar eminence → thumb will flex, then slowly relax
    • Aggravated by cold and stress
    • Affects:
      • Jaw
      • Tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue
      • Small muscles of the hands

Associated manifestations:

  • Cardiac: 
    • Conduction defects and arrhythmia
    • Cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies and heart failure
  • Respiratory:
    • Hypoventilation
    • Respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure
  • Cataracts
  • Primary hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism
    • Testicular atrophy 
    • Ovarian insufficiency
    • Infertility
  • Frontal balding
  • Gastrointestinal:
    • Irritable bowel-like symptoms
    • Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia
  • Possible cognitive impairment
  • Hypersomnia

DM2

  • Milder symptoms and associated manifestations, but similar to DM1
  • Affects the proximal muscles of the hips and thighs:
    • Difficulty climbing stairs
    • Difficulty getting up from a chair
  • Affects the muscles of the shoulders and elbows, causing difficulty holding or lifting objects
  • Tremor (not seen in DM1)
Clinical presentation of two adults with myotonic dystrophy

Clinical presentation of two adults with myotonic dystrophy
A: Atrophy of the forearm Forearm The forearm is the region of the upper limb between the elbow and the wrist. The term "forearm" is used in anatomy to distinguish this area from the arm, a term that is commonly used to describe the entire upper limb. The forearm consists of 2 long bones (the radius and the ulna), the interosseous membrane, and multiple arteries, nerves, and muscles. Forearm and lower leg Leg The lower leg, or just "leg" in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg in a patient with DM1
B: Atrophy is not seen in this patient with DM2, in which symptoms tend to be milder and more proximal.

Image: “Differences in clinical presentation of adult DM1 and DM2” by Schoser B, Timchenko L. License: 2.5

Diagnosis and Management

Diagnosis

  • Diagnosed clinically and confirmed by genetic testing 
  • Genetic testing: 
    • Gold standard 
    • DM1: expanded CTG repeats in the DMPK gene
    • DM2: expanded CCTG repeats in the CNBP gene
  • Electromyography (EMG) measures electrical activity in a muscle:
    • Confirms the diagnosis in patients with abnormal genetic testing
    • The severity of myotonia correlates with muscle weakness in DM1, but not in DM2.
  • Lab tests:
    • ↑ CK in both types
    • ↓ IgG and IgM (hypogammaglobulinemia) 
    • May have insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance
  • Other tests: 
    • Muscle biopsy: distinguishes muscle from nerve disease
    • Slit-lamp examination: may show posterior subcapsular cataracts 
    • ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG): may have cardiac conduction defects

Management

  • No curative treatment
  • Supportive management: 
    • Analgesics for myalgias 
    • Physical therapy
    • Assistive devices for weakness:
      • Braces
      • Wheelchair
    • Sodium channel blockers for myotonia:
      • Mexiletine
      • Phenytoin
      • Procainamide
    • Speech therapy for dysphagia
    • Cardiology consultation for arrhythmia 
    • Ophthalmology evaluation (and potential corrective surgery) for cataracts
    • Neurostimulants (e.g., modafinil) for excessive daytime sleepiness 
    • Ventilatory and feeding support if needed
  • Genetic counseling to discuss the risk for future family members
  • Note: Patients have a high risk of pulmonary complications with general anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts.
  • Prognosis:
    • Reduced life expectancy for patients with DM1
    • Normal to near-normal life expectancy for patients with DM2 

Differential Diagnosis

  • Myotonia congenita: a nondystrophic myopathy with both autosomal-recessive and autosomal-dominant forms, caused by mutations in the CLCN1 gene. Clinical presentation is variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables but starts in childhood with muscle stiffness and weakness. A potential complication of harmful side effects from anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts may exist. Exercise may temporarily help the myotonia. Management may include medications such as mexiletine, carbamazepine, or phenytoin.
  • Paramyotonia congenital (Eulenburg disease): an autosomal-dominant genetic mutation, caused by mutations in the SCN4A gene. Symptoms of myotonia worsen with exercise and repeated movements. The condition presents with myotonia in muscles of the face Muscles of the Face The facial muscles (also called mimetic muscles) control facial expression and are supplied by the facial nerve. Most of them originate from the skull and attach to the skin around the facial openings, which serve as a method to group or classify them. Muscles of the Face, neck, back, upper extremities, and respiratory muscles. Diagnosis is by EMG and genetic testing. Symptom severity does not worsen, nor does the disease condition progress with time. Management is supportive.
  • Adult-onset acid maltase deficiency (type IIb) (Pompe disease): previously thought to be a disorder of infancy only, manifesting with tongue enlargement, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver impairment, and cardiac involvement. The adult form has a spectrum of clinical and pathological expression, which includes progressive muscle weakness and sometimes involves the respiratory muscles. Diagnosis is made by EMG. Two enzyme-replacement products are commercially available and greatly improve the quality and quantity of life for patients.

References

  1. Darras, B.T. (2021). Myotonic dystrophy: Etiology, clinical features, and diagnosis. UpToDate. Retrieved June 15, 2021, from https://www.uptodate.com/contents/myotonic-dystrophy-etiology-clinical-features-and-diagnosis
  2. Darras, B.T. (2021). Myotonic dystrophy: Treatment and prognosis. In Dashe, J.F. (Ed.), UpToDate. Retrieved June 20, 2021, from https://www.uptodate.com/contents/myotonic-dystrophy-treatment-and-prognosis
  3. Bird, T.D. (2021). Myotonic dystrophy type I. GeneReviews. Retrieved June 15, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK1165/
  4. Vydra, D.G., Rayi, A. (2021). Myotonic dystrophy. StatPearls. Retrieved June 20, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK557446/
  5. Rubin, M. (2020). Myotonic dystrophy (Steinert disease). MSD Manual Professional Version. Retrieved June 20, 2021, from https://www.msdmanuals.com/professional/pediatrics/inherited-muscular-disorders/myotonic-dystrophy

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