Myotonic syndromes

Myotonic syndromes are a heterogenous group of inherited disorders with similar pathological mechanisms. Myotonic syndromes are subdivided into the rare non-dystrophic myotonic syndromes and more common myotonic dystrophies. Non-dystrophic myotonic syndromes include Thomsen's, Becker's and Eulenberg's disease. 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 (Curschmann-Steinert disease) and myotonic dystrophy type II (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.

• Non-dystrophic myotonic syndromes
  • Rare disorders
  • Often occur in the first decade of life (Becker's disease may present later)
• Myotonic dystrophies
  • One of the most common forms of adult-onset muscular dystrophy
  • Myotonic dystrophy type I: congenital, juvenile, or adult onset
  • Myotonic dystrophy type II: usually adult onset

References:^[1][2]

Epidemiological data refers to the US, unless otherwise specified.

• Non-dystrophic myotonic syndromes
  • Autosomal recessive or dominant
  • Expanded CTG trinucleotide repeat on the DMPK gene
• Myotonic dystrophies
  • Autosomal dominant condition
  • Type 1: CTG trinucleotide repeat expansion of the DMPK gene
  • Type 2: CCTG tetranucleotide repeat expansion of the ZNF9 gene (CNBP gene)

Non-dystrophic myotonic syndromes

The predominant symptom in all non-dystrophic myotonic syndromes is painful tension in the muscles caused by prolonged muscle contractions. In general, it is accompanied by a loss of strength (esp. Becker muscular dystrophy); however, this may go unnoticed by the affected person.

• Thomsen's disease
  • Muscles primarily affected: leg, eyes, tongue, and jaw
  • No atrophy, but hypertrophy (athletic physique, Hercules-like appearance)
  • Initial difficulties in muscle relaxation (e.g., delayed release from a handshake), improvement through repeated contractions (warming up)
• Becker's disease
  • Myotonia of the legs more pronounced
  • Possibly weakness in the arms
• Eulenburg's disease
  • Clinical features: Myotonia and flaccid paralysis occur especially in the cold. The weakness of the muscle increases with muscle activity (myotonia paradoxa).
  • Clinical manifestation: from birth

Myotonic dystrophies

Myotonic dystrophy type I (DM1, Curschmann-Steinert disease)	Myotonic dystrophy type II (DM2, proximal myotonic myopathy)
Skeletal muscle weakness and myotonia Muscle pain Arrhythmias Cataracts Testicular atrophy or features of ovarian insufficiency (i.e., infertility) Hypogammaglobulinemia Features of insulin resistance Frontal balding Cognitive impairment
Most common in the distal sections of extremities: face, neck, forearm, foot dorsiflexor, intrinsic muscles of the hand. Myopathic facies Long, narrow face Hollowed cheeks, and high arched palate Ptosis Sternocleidomastoid muscle wasting Clinical myotonia: Classically manifests as difficulty releasing a handshake. Respiratory involvement, dysphagia, dysarthria, irritable bowel-like symptoms (e.g., abdominal pain, bloating), impaired sleep, daytime somnolence are common	Most common in the proximal muscles: neck flexors, hip flexors, elbow flexors, finger flexors Mild clinical myotonia Uncommon symptoms: respiratory muscle involvement, dysphagia, dysarthria, irritable bowel-like symptoms (e.g., abdominal pain, bloating), impaired sleep, daytime somnolence are uncommon

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.

References:^[1]

Non-dystrophic myotonic syndromes

• Percussion myotonia: myotonia can be triggered by tapping with a reflex hammer
• EMG: repetitive discharges that wax and wane in both frequency and amplitude (crescendo-decrescendo sound), synonym: "dive bomber" sound

Myotonic dystrophies

• Electromyography (EMG): identifies 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 ↓/↔︎ testosterone
  • ECG: to exclude cardiac arrhythmias and other abnormalities
  • MRI: signs of global atrophy

References:^[3][1]

	Non-dystrophic myotonic syndromes			Myotonic dystrophies		Duchenne muscular dystrophy	Becker muscular dystrophy
	Myotonia congenita Thomsen (Thomsen's disease)	Myotonia congenita Becker (Becker's disease)	Paramyotonia congenita Eulenburg (Eulenburg's disease)	Type 1 (DM1; Curschmann-Steinert disease)	Type 2 (DM2; Proximal Myotonic Myopathy, PROMM)
Onset	From childhood	5–35 years	From infancy	Congenital, juvenile, or adult-onset	Adulthood	2–3 years of age	Usually > 15 years of age
Genetics	Autosomal dominant	Autosomal recessive	Autosomal dominant	Autosomal dominant Type 1: CTG trinucleotide repeat in the region of the DMPK gene	Autosomal dominant Expanded CCTG tetranucleotide repeat expansion on the ZNF9 gene (CNBP gene)	X-linked recessive Chromosomal defect affects the dystrophin gene on the short arm of the X chromosome (Xp21)→ Frameshift mutation in DMD	X-linked recessive Chromosomal defect affects the dystrophin gene on the short arm of the X chromosome (Xp21) → point mutation in BMD
Defect	Chloride channel	Chloride channel	Sodium channel	Myotonin-protein kinase in skeletal and heart muscle, gonads, and brain		Complete impairment (DMD) of the dystrophin protein	Partial impairment (DMD) of the dystrophin protein
Clinical features	No atrophy, but hypertrophy Initial difficulties in muscle relaxation Primarily affected muscles: legs, eyes, tongue, jaw	No atrophy, but hypertrophy Initial difficulties in muscle relaxation Primarily affected muscles: legs, eyes, tongue, jaw Possibly upper extremities affected	Muscle weakness in the cold	Muscle pain Arrhythmias Cataracts Testicular atrophy or features of ovarian insufficiency (i.e., infertility) Frontal balding		Paresis and atrophy starting in the proximal lower limbs, later spreading to the upper body and distal areas Weak reflexes Bilateral Trendelenburg's sign Gower maneuver Calf pseudohypertrophy	Symptoms identical to those of Duchenne muscular dystrophy Slower progression and milder symptoms Heart involvement is more common compared to DMD.
				Severe disease Skeletal muscle weakness and myotonia is more common in the distal muscles of all extremities: face, neck, forearm, foot dorsiflexor, intrinsic muscles of the hand Myopathic facies	Mild disease Skeletal muscle weakness and myotonia is more common in the proximal muscles: neck flexors, hip flexors, elbow flexors, finger flexors

References:^[4][1]

The differential diagnoses listed here are not exhaustive.