Myotonic syndromes

Last updated: March 4, 2024

Summary

Myotonic syndromes are a heterogeneous group of inherited disorders with similar pathological mechanisms. Myotonic syndromes are subdivided into dystrophic myotonic syndromes and nondystrophic myotonic syndromes. Nondystrophic myotonic syndromes are channelopathies and include Thomsen disease, Becker disease, and Eulenberg disease. The channelopathies are autosomal dominant or autosomal recessive conditions caused by defective ion channels in the skeletal muscle sarcolemma. All three diseases manifest with myotonia, muscle stiffness, and weakness. Thomsen disease and Becker disease are furthermore characterized by muscular hypertrophy. Myotonic dystrophies, the most prevalent myotonic syndromes, are one of the most common forms of adult-onset muscular dystrophy. Both types, myotonic dystrophy type I (DM1, Curschmann-Steinert disease) and myotonic dystrophy type II (DM2, proximal myotonic myopathy), are autosomal dominant conditions with CTG trinucleotide repeat and CCTG tetranucleotide repeat expansions respectively. Type I is a severe (often life-threatening) form of disease, while type II is usually mild. Both present with skeletal muscle weakness and myotonia, muscle pain, heart conduction defects, cataracts, testicular atrophy, and frontal balding. Electromyography may confirm myotonia that is not identified during clinical examination; however, genetic tests usually confirm the diagnosis. As no curative therapy exists, treatment is symptomatic. Except for DM1, patients with myotonic syndromes have a normal lifespan.

Dystrophic myotonic syndromes

Epidemiology ^[1]^[2]

One of the most common forms of adult-onset muscular dystrophy
DM1 prevalence in US: ∼ 5 per 10,000 births ^[3]
Congenital DM1: most commonly inherited through the mother ^[4]

Etiology

Autosomal dominant inheritence
Type 1: CTG trinucleotide repeat expansion in the DMPK gene → changes in myotonin protein kinase expression
Type 2: CCTG tetranucleotide repeat expansion of the ZNF9 gene (CNBP gene)

Clinical features ^[1]

Clinical features of myotonic dystrophies
	Myotonic dystrophy type I (DM1, Curschmann-Steinert disease)	Myotonic dystrophy type II (DM2, proximal myotonic myopathy)
Clinical features	Myotonia: delayed muscle relaxation following normal muscle contraction Skeletal muscle weakness (due to muscle atrophy) Myalgia Arrhythmia Cataracts Testicular atrophy or features of ovarian insufficiency (i.e., infertility) Frontal balding Cognitive and behavioral impairment: more severe in infant or juvenile onset disease; usually not progressive Hypogammaglobulinemia Features of insulin resistance
Clinical features	Myopathic facies Long, narrow face Hollowed cheeks, and high arched palate Ptosis Sternocleidomastoid muscle atrophy Clinical myotonia: classically manifests as difficulty releasing a handshake Daytime somnolence, impaired sleep Dysphagia, dysarthria Respiratory involvement Irritable bowel-like symptoms (e.g., abdominal pain, bloating)	Mild clinical myotonia Uncommon symptoms: respiratory muscle involvement, dysphagia, dysarthria, irritable bowel-like symptoms (e.g., abdominal pain, bloating), impaired sleep, daytime somnolence
Typical location	The distal sections of extremities: face, neck, forearm, foot dorsiflexor, intrinsic muscles of the hand.	The proximal muscles: neck flexors, hip flexors, elbow flexors, finger flexors
Symptom onset	Congenital, juvenile, or adult onset	Usually adult onset

Myotonic dystrophy type I is caused by a CTG nucleotide repeat expansion and results in Cataracts, Toupee (premature hair loss in men), and Gonadal atrophy.

Diagnostics ^[1]^[5]

Electromyography (EMG): allows for the identification of myotonia
Genetic diagnostics: (confirmatory test) detection of trinucleotide repeat expansion mutation in leukocytes
Biopsy: to distinguish between an inflammatory and a metabolic cause of the myopathy
Other supportive tests
- ↑ CK, IgG and IgM hypogammaglobulinemia, ↑ FSH, and ↓/normal testosterone
- ECG: to exclude cardiac arrhythmias and other abnormalities
- MRI: signs of global atrophy

Treatment ^[1]^[2]

Incurable
Symptomatic treatment (e.g., analgesia, physiotherapy, walking aids, pacemaker, medical therapy for myotonia )
Regular monitoring (i.e., of respiratory compromise, dysphagia)
Genetic counseling and testing

Prognosis

The course of DM1 is chronic progressive. Cardiac complications reduce life expectancy.
DM2 has a milder disease course.

Nondystrophic myotonic syndromes

Epidemiology ^[6]

Rare disorders (prevalence < 1:100,000)

Etiology and clinical features ^[7] ^[6]

	Myotonia congenita (Thomsen disease)	Myotonia congenita (Becker disease)	Paramyotonia congenita (Eulenburg disease)
Inheritance	Autosomal dominant	Autosomal recessive	Autosomal dominant
Pathophysiology	Loss of function mutation in the CLCN gene → defective chloride channel in skeletal muscle		SCN4A gene mutation → defective sodium channel in skeletal muscle sarcolemma
Symptom onset	Childhood (first decade of life)	5–35 years	Congenital
Typical location	Legs, eyes, tongue, and jaw	Lower extremities more than upper extremities	Face, eyes, tongue, and hands are most commonly affected
Clinical features	Myotonia (e.g., delayed release from a handshake) Transient muscle weakness Muscle stiffness Warming-up effect: Symptoms improve through repeated contractions. Muscular hypertrophy (athletic physique)	Same as Thomsen disease but symptoms are more severe	Painful myotonia and episodic muscle weakness Precipitating factors Cold temperatures Strenuous exercise (paradoxical myotonia)

Physeo - Myotonic Dystrophy

Diagnostics

Percussion myotonia: percussion of a muscle results in myotonia with delayed muscle relaxation (e.g., tapping the thenar eminence with a reflex hammer causes the thumb to abduct)
EMG: repetitive discharges with oscillating frequency and amplitude (crescendo-decrescendo sound )
Genetic testing: confirms the diagnosis

Treatment ^[7]

Mild cases
- Usually no treatment necessary
- Avoid precipitating factors, e.g., strenuous exercise.
Severe cases
- Sodium channel blocker (e.g., mexiletine, carbamazepine, tocainide)
- Acetazolamide

Prognosis

Incurable
Varying degree of life-long disability but no effect on life expectancy
No symptom progression throughout the course of the disease

Differential diagnoses

Overview of myotonic syndromes

Comparison of myotonic syndromes and muscular dystrophies ^[1]
Types		Onset	Pathophysiology	Clinical features
Myotonic dystrophies	Type 1 (DM1)	Congenital, juvenile, or adult-onset	Autosomal dominant CTG trinucleotide repeat in the region of: DM1: DMPK gene (a gene that encodes dystrophia myotonica protein kinase) DM2: ZNF9 gene (CNBP gene) Myotonin-protein kinase in skeletal and heart muscle, gonads, and the brain	Myalgia Arrhythmias Cataracts Testicular atrophy or features of ovarian insufficiency (i.e., infertility) Frontal balding	Severe disease Skeletal muscle weakness and myotonia More common in the distal muscles of the extremities: face, neck, forearm, foot dorsiflexor, intrinsic muscles of the hand Myopathic facies
Myotonic dystrophies	Type 2 (DM2)	Adulthood			Mild disease Skeletal muscle weakness and myotonia is more common in proximal muscles: neck flexors, hip flexors, elbow flexors, finger flexors
Nondystrophic myotonic syndromes	Thomsen disease	From childhood	Autosomal dominant Defective chloride channel	No atrophy, but hypertrophy Initial difficulties in muscle relaxation Primarily affected muscles: Legs, eyes, tongue, jaw In Becker disease: possibly upper extremities
	Becker disease	5–35 years	Autosomal recessive Defective chloride channel
	Eulenburg disease	From infancy	Autosomal dominant Defective sodium channel	Paradoxical myotonia (worsens with exercise) Muscle weakness exacerbated by cold temperatures
Duchenne muscular dystrophy		2–5 years of age	X-linked recessive Chromosomal defect affects the dystrophin gene on the short arm of the X chromosome (Xp21) → frameshift mutation Complete impairment (DMD) of the dystrophin protein	Paresis and atrophy starting in the proximal lower limbs, later spreading to the upper body and distal areas Weak reflexes Bilateral Trendelenburg sign Gowers maneuver Calf pseudohypertrophy
Becker muscular dystrophy		Usually > 15 years of age	X-linked recessive Chromosomal defect affects the dystrophin gene on the short arm of the X chromosome (Xp21) → in-frame mutation Partial impairment (DMD) of the dystrophin protein	Symptoms identical to those of Duchenne muscular dystrophy, but less severe Slower progression Heart involvement is more common compared to DMD.

Periodic paralysis

Overview of periodic paralysis (PP) ^[8]^[9]
Types		Hypokalemic PP	Hyperkalemic PP	Thyrotoxic PP	Andersen-Tawil syndrome
Definition		A group of rare muscular conditions characterized by recurrent episodes of muscle weakness that typically develop after strenuous exercise, changes in diet, or medication use
Epidemiology ^[10]		Most common type ♂ > ♀ 1:100,000 Peak age of onset: late childhood and adolescence	♂ = ♀ 1:200,000 Peak age of onset: early childhood	♂ = ♀ Peak age of onset: > 20 years of age	1:1,000,000 Peak age of onset: childhood and adolescence
Etiology		Genetic: familial hypokalemic PP Autosomal dominant Mutations of the sodium and calcium channel genes
Etiology			Autosomal dominant Mutations of the sodium channel genes	Hyperthyroidism Unclear genetic predisposition	Mutations of the genes encoding the inward rectifier potassium channel in skeletal muscle and cardiac muscle cells
Triggers		Carbohydrate-rich meals Exercise Alcohol Medications (e.g., laxatives, corticosteroids, anesthesia) Stress	Potassium-rich meals Rest after exercise Exposure to cold temperatures Fasting Pregnancy Anesthesia	Carbohydrate-rich meals Exercise Stress	Stress Exercise Prolonged periods of rest
Clinical features	Common	Attacks of focal or generalized flaccid muscle weakness (periodic paralysis) Proximal muscles are more prominently affected; respiratory and facial muscles are generally spared Variable duration (hours to days) Concomitant fatigue, muscle pain, and/or altered state of consciousness during the attacks Neurological examination is usually normal between attacks.
Clinical features	Specific	Infrequent attacks of muscle weakness (e.g., transient paraparesis or quadriparesis) Hyporeflexia or areflexia Variable myopathy can develop over time	Myotonia on physical exam or EMG Frequent attacks of muscle weakness (several per day) Myopathy can develop later in life	Attacks of muscle weakness coincide with acute thyroid hyperactivity Symptoms of hyperthyroidism	Period attacks of muscle weakness Ventricular arrhythmias Dysmorphic features: broad forehead, ocular hypertelorism, low ear implantation, small mandible, syndactyly, clinodactyly of the 5^th digit, short stature, scoliosis
Diagnostics	Laboratory analysis	↓ K⁺	↔︎/↑ K⁺	↓ K⁺ ↓ TSH, ↑ T₃, T₄ hormones	↔︎/↑/↓ K⁺
	EMG	Reduced amplitude of compound muscle action potentials Electrical silence depending on the degree of muscle weakness	Positive sharp waves Repetitive discharges that wax and wane in both frequency and amplitude ^[11]	Reduced amplitude of compound muscle action potentials	Reduced amplitude of compound muscle action potentials during an attack
	Long exercise test	Procedure: stimulation of a nerve (e.g., ulnar nerve) and recording of compound muscle action potentials (e.g., of the adductor digiti minimi muscle) Positive test: ≥ 40% reduction in muscle action potential amplitude or > 50% area reduction during or post exercise During an attack, the test is positive in all types of PP.
	Muscle biopsy	May show normal findings or signs of myopathy (e.g., muscle fiber atrophy, variable muscle fiber sizes, split fibers) ^[12]
Differential diagnoses		Muscle weakness (e.g., due to type IV renal tubular acidosis, Gitelman syndrome, Bartter syndrome) Myasthenia gravis Paramyotonia congenita Seizures Guillain-Barré syndrome Spinal cord injury Stroke Neuromuscular junction disorders
Acute treatment	Mild attacks	May subside spontaneously or resolve with low-intensity exercise (e.g., walking around a room)
Acute treatment	Severe attacks	Oral potassium chloride until serum potassium levels normalize	Thiazide diuretics, inhaled beta-agonists (e.g., salbutamol)	N/A
Prevention		Carbonic anhydrase inhibitors Avoidance of triggers (e.g., low sodium and carbohydrate diet for patients with hypokalemic PP)
Prevention		Potassium-sparing diuretics (e.g., triamterene, spironolactone, eplerenone)	Thiazide diuretics (e.g., hydrochlorothiazide)	Hyperthyroidism treatment (e.g., methimazole, propylthiouracil) Propranolol	N/A

The differential diagnoses listed here are not exhaustive.

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Myotonic syndromes

Summary

Dystrophic myotonic syndromes

Epidemiology [1][2]

Etiology

Clinical features [1]

Diagnostics [1][5]

Treatment [1][2]

Prognosis

Nondystrophic myotonic syndromes

Epidemiology [6]

Etiology and clinical features [7] [6]

Diagnostics

Treatment [7]

Prognosis

Differential diagnoses

Overview of myotonic syndromes

Periodic paralysis

Epidemiology ^[1]^[2]

Clinical features ^[1]

Diagnostics ^[1]^[5]

Treatment ^[1]^[2]

Epidemiology ^[6]

Etiology and clinical features ^[7] ^[6]

Treatment ^[7]