Myotonic Dystrophies

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 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 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 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 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
  • Weakness of the distal 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
• 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
    • Small muscles of the hands

Associated manifestations:

• Cardiac: 
  • Conduction defects and arrhythmia
  • Cardiomyopathy and heart failure
• Respiratory:
  • Hypoventilation
  • Respiratory failure
• Cataracts
• Primary hypogonadism: 
  • Testicular atrophy 
  • Ovarian insufficiency
  • Infertility
• Frontal balding
• Gastrointestinal:
  • Irritable bowel-like symptoms
  • 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)

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 resistance
• Other tests: 
  • Muscle biopsy: distinguishes muscle from nerve disease
  • Slit-lamp examination: may show posterior subcapsular cataracts 
  • 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.
• 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 but starts in childhood with muscle stiffness and weakness. A potential complication of harmful side effects from anesthesia 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, 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 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.